RU2599017C2 - Extended-release formulation for reducing the frequency of urination and method of use thereof - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions relates to methods and compositions for inhibiting the contraction of muscles and, in particular, to methods and compositions for inhibiting the contraction of smooth muscles of the urinary bladder. Method comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising acetaminophen and one or more additional active ingredients selected from a group, comprising of α-blockers and 5α-reductase inhibitors. Group of inventions also relates to pharmaceutical compositions containing acetaminophen and one or more αblocker or acetaminophen and one or more 5α-reductase inhibitor, in which acetaminophen is made for prolonged release, and one or more αblockers and one or more 5α-reductase inhibitors - for immediate release.

EFFECT: this allows to reduce a rate of urination due to inhibition of smooth muscle contraction of the urinary bladder.

36 cl, 9 tbl, 8 ex, 2 dwg

Description

[0001] This application claims priority based on US Patent Application Serial No. 13/487348, registered June 4, 2012, and US Patent Application Serial No. 13/424000, registered March 19, 2012.

FIELD OF THE INVENTION

[0002] The present invention relates to methods and compositions for inhibiting muscle contraction and, in particular, to methods and compositions for inhibiting smooth muscle contraction of the bladder.

BACKGROUND OF THE INVENTION

[0003] The detrusor muscle is a layer of the wall of the bladder, consisting of smooth muscle fibers twisted into a spiral, elongated and circular cords. When the bladder is stretched, it serves as a signal to the parasympathetic nervous system to contract the detrusor muscle. This stimulates urinary expulsion of the urinary bladder through the urethra.

[0004] In order for urine to flow out of the bladder, it is necessary that the autonomously controlled internal sphincter and the arbitrarily controlled external sphincter are open. Problems with these muscles can lead to incontinence. If the amount of urine reaches 100% of the maximum capacity of the bladder, an arbitrary sphincter becomes involuntary, and an immediate discharge of urine will occur.

[0005] An adult bladder typically contains about 300-350 ml of urine (working volume), but an adult full bladder can hold up to about 1000 ml (absolute volume) with differences among subjects. With the accumulation of urine, the folds formed as a result of bending of the wall of the bladder (folds) are smoothed, and the wall of the bladder becomes thinner as it stretches, making it possible for the bladder to hold more urine without a significant increase in internal pressure.

[0006] In most subjects, a desire to urinate typically occurs when the volume of urine in the bladder reaches approximately 200 ml. At this stage, the subject is willing to tolerate urination if desired. As the bladder continues to fill up, the urge to urinate becomes stronger and more difficult to ignore. As a result, the bladder is filled to the point at which the urge to urinate becomes impossible to endure, and the subject is no longer able to ignore it. In some subjects, this urge to urinate occurs when the bladder is less than 100% full relative to the working volume. Such an increased urge to urinate may interfere with normal activities, including the ability to sleep for sufficient continuous periods of time during rest. In some cases, such an increased urge to urinate may be associated with medical conditions such as benign prostatic hyperplasia or prostate cancer in men or pregnancy in women. However, an increased urge to urinate also occurs in subjects, both men and women, who do not suffer from another medical condition.

[0007] Thus, there is a need for compositions and methods for treating male and female subjects who suffer from urination when the bladder is filled with urine of less than 100% of its working volume. These compositions and methods are necessary to inhibit muscle contraction in order to ensure the urge to urinate when the volume of urine in the bladder exceeds approximately 100% of its working volume.

SUMMARY OF THE INVENTION

[0008] One aspect of the present invention relates to a method for reducing urination in a subject. The method comprises administering to a subject in need of an effective amount of one or more analgesic agents and an effective amount of one or more additional active ingredients selected from the groups consisting of α-blockers and 5α-reductase inhibitors. The method can be used to treat nocturia or overactive bladder.

[0009] Another aspect of the present invention relates to a pharmaceutical composition comprising an active ingredient comprising one or more analgesic agents, an α-blocker and a pharmaceutically acceptable carrier.

[0010] Another aspect of the present invention relates to a pharmaceutical composition comprising an active ingredient comprising one or more analgesic agents, a 5α-reductase inhibitor and a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] Figure 1A and 1B are diagrams showing that analgesics regulate the expression of co-stimulatory molecules by Raw 264 macrophage cells in the absence (Figure 1A) or in the presence (Figure 1B) of LPS. Cells were cultured for 24 hours in the presence of a single analgesic or together with LPS Salmonella typhimurium (0.05 μg / ml). The results are the average of% CD40 + CD80 + cells.

DETAILED DESCRIPTION

[0012] The following detailed description is provided in order to enable any person skilled in the art to make and use the invention. For clarification, specific terminology is provided to provide a thorough understanding of the present invention. However, it will be apparent to those skilled in the art that such specific details are not necessary for the practice of the invention. Descriptions of specific applications are provided as representative examples only. It is not intended that the present invention be limited by the demonstrated embodiments, but corresponds to the broadest possible scope in accordance with the principles and features described herein.

[0013] As used in the present description, the term "effective amount" means the amount required to obtain the selected results.

[0014] As used herein, the term “analgesic” refers to an agent, compounds, or drugs used to relieve pain, and includes anti-inflammatory compounds. Illustrative analgesic and / or anti-inflammatory drugs, compounds or drugs include, but are not limited to the following substances: non-steroidal anti-inflammatory drugs (NSAIDs), salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazino, , acetanilide, acetaminophen, phenacetin, phenamates, mefenamic acid, meclofenamate, sodium meclofenamate, heteroaryl acetic acid derivatives, tolmetin, ketorolac, diclofenac, industrial derivatives of propionic acid, ibuprofen, naproxen sodium, naproxen, phenoprofen, ketoprofen, flurbiprofen, oxaprozin, enolic acids, derivatives of oksikama, piroxicam, meloxicam, tenoxicam, ampiroxicam, droxicam, pivoxicamone, phenylpyrinone pyrozipinone, pyroperiphenone pirazinone coxib, celecoxib, rofecoxib, nabumetone, apazone, indomethacin, sulindac, etodolac, isobutylphenylpropionic acid, lumiraxoxib, etoricoxib, parecoxib, valdecoxib, thyracoxib, etodolac, darbufelon, dexcetoprofen lofenac, lycofelon, bromfenac, loxoprofen, pranoprofen, piroxicam, nimesulide, cisolirin, 3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one, meloxicam, lornoxicam, am-indolefen, d-indolefen, pranoprofen, tolfenamic acid, flurbiprofen, suprofen, oxaprozin, zaltoprofen, alminoprofen, thiaprofenic acid, their pharmacological salts, their hydrates and their solvates.

[0015] As used herein, the terms “coxib” and “COX inhibitor” refer to compositions of compounds that are capable of inhibiting the activity or expression of COX2 enzymes, or are capable of inhibiting or reducing the severity, including pain and swelling, of a severe inflammatory response.

[0016] As used in the present description, the term "derivative" refers to a chemically modifiable compound, where a chemist in the art considers the modification to be common, such as an ester or acid amide, protecting groups such as a benzyl group for an alcohol or thiol, and tert-butoxycarbonyl group for amine.

[0017] As used in the present description, the term "analogue" refers to a compound that contains a chemically modified form of a particular compound or its class, and which retains pharmaceutical and / or pharmacological activity characteristic of the specified compound or class.

[0018] As used herein, a “subject” or “patient” includes mammals. In one aspect, the mammal is a human. In another aspect, the mammal is a non-human primate, such as chimpanzees and other monkeys and monkey species. In one aspect, the mammal is a pet, such as a rabbit, dog, or cat. In another aspect, the mammal is an agricultural animal, such as cattle, horse, sheep, goat or pig. In another aspect, the mammal is a laboratory animal, including rodents such as rats, mice and guinea pigs, and the like.

[0019] As used in the present description, "pharmaceutically acceptable salts" refer to derivatives of the described compounds, where the starting compound is modified to obtain its acidic or basic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues, such as amines, alkaline or organic salts of acid residues, such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, and salts derived from organic acids such as acetic, propionic, succinic, glycolic , stearic, dairy, apple, wine, lemon, ascorbic, pamic, maleic, hydroxymaleic, phenylacetic, glutamine, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane vaya, oxalic, isethionic, etc.

[0020] As used herein, the phrase "pharmaceutically acceptable" is used in relation to compounds, substances, compositions and / or dosage forms that are medically suitable for use in contact with human and animal tissues without excessive toxicity, irritation, an allergic reaction or other problems or complications in accordance with a reasonable benefit / risk ratio.

[0021] The bladder has two important functions: storing urine and emptying. Storage of urine occurs at low pressure, which implies that the detrusor muscle is relaxed during the filling phase. To empty the bladder, a coordinated contraction of the detrusor muscle and relaxation of the muscles of the urethral sphincter are necessary. Impaired storage function can lead to lower urinary tract symptoms, such as urge, frequency and urgent urinary incontinence, components of the bladder hyperactivity syndrome. Bladder hyperactivity syndrome, which may be due to involuntary contractions of the smooth muscle of the bladder (detrusor) during the storage phase, is a common and poorly illuminated problem for which the frequency of spread has only recently been evaluated.

[0022] One aspect of the present invention relates to a method for reducing frequent urination. The method comprises administering to a subject in need thereof an effective amount of one or more analgesic agents and an effective amount of an α-blocker. In some embodiments, one or more analgesic agents and an α-blocker are administered separately in different dosage forms. In other embodiments, one or more analgesic agents and an α-blocker are administered simultaneously in the same dosage form (eg, in one pill or tablet). In some embodiments, one or more analgesic agents and an α-blocker are formulated for immediate release after administration. In other embodiments, one or more analgesic agents and an α-blocker are formulated for delayed release after administration. In other embodiments, one or more analgesic agents and an α-blocker are formulated for sustained release after administration. In other embodiments, one or more analgesic agents and an α-blocker are formulated for delayed-sustained release after administration. In other embodiments, one or more analgesic agents are formulated for delayed release, sustained release, or delayed-prolonged release, and an α-blocker is formulated for immediate release. In other embodiments, one or more analgesic agents are formulated for immediate release and an α-blocker is formulated for delayed release, sustained release, or delayed-prolonged release. The method can be used to treat nocturia or overactive bladder. Another aspect of the present invention relates to a pharmaceutical composition comprising an active ingredient comprising one or more analgesic agents, an α-blocker and a pharmaceutically acceptable carrier.

[0023] Alpha blockers, also called α-adrenergic antagonists or α-blockers, are pharmacological agents that act as receptor antagonists of α-adrenergic receptors, which are further divided into α1-adrenergic receptors and α2-adrenergic receptors. Alpha blockers can be classified as selective blockers that selectively act on α1-adrenergic receptors or α2-adrenergic receptors, and non-selective alpha-blockers that act on both types of α-adrenergic receptors.

[0024] Examples of selective α1-adrenergic blockers include, but are not limited to, alfuzosin, prazosin, doxazosin, tamsulosin, terazosin, carvedilol, labetalol, and silodosin. Examples of selective α2-adrenergic blockers include, but are not limited to, atipamezole, idazoxane, and yohimbine. Examples of non-selective α-adrenergic blockers include phenoxybenzamine, phentolamine, tolazoline, trazodone, typical and atypical antipsychotics.

[0025] In some embodiments, one or more analgesic agents is administered orally in an individual or in a combined daily dose of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg , 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg , 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg , 200-800 mg, 200-600 mg, 200-400 mg, 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg , 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg , 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500- 2000 mg and one or more α-blockers are administered orally in an individual or combined daily dose of 0.01-100 mg, 0.01-30 mg, 0.01-10 mg, 0.01-3 mg, 0.01-1 mg, 0.01-0.3 mg, 0.01-0.1 mg, 0.01-0.03 mg, 0.03-100 mg, 0.03-30 mg, 0.03-10 mg, 0.03-3 mg, 0.03-1 mg, 0.03-0.3 mg, 0.03-0.1 mg, 0.1-100 mg, 0.1-30 mg, 0.1- 10 mg, 0.1-3 mg, 0.1-1 mg, 0.1-0.3 mg, 0.3-100 mg, 0.3-30 mg, 0.3-10 mg, 0.3 -3 mg, 0.3-1 mg and 0.2-1 mg.

[0026] In some embodiments, the α-blocker is a non-selective α-blocker. In other embodiments, the α-blocker is a selective α1-adrenergic blocker. In other embodiments, the α-blocker is a selective α2-adrenergic blocker. In other embodiments, the α-blocker is tamsulosin.

[0027] Another aspect of the present invention relates to a pharmaceutical composition comprising one or more analgesic agents, one or more α-blockers, and a pharmaceutically acceptable carrier. In some embodiments, one or more analgesic agents is selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen.

[0028] In some embodiments, the pharmaceutical composition comprises one or more analgesic agents alone or in combination in an amount of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg , 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg , 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg , 200-800 mg, 200-600 mg, 200-400 mg, 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg , 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg , 1000-1200 mg, 1200-2000 mg, 1200-1500 mg and whether 1500-2000 mg and one or more α-blockers in an amount of 0.01-100 mg, 0.01-30 mg, 0.01-10 mg, 0.01-3 mg, 0.01-1 mg, 0 , 01-0.3 mg, 0.01-0.1 mg, 0.01-0.03 mg, 0.03-100 mg, 0.03-30 mg, 0.03-10 mg, 0.03 -3 mg, 0.03-1 mg, 0.03-0.3 mg, 0.03-0.1 mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, 0.1-1 mg, 0.1-0.3 mg, 0.3-100 mg, 0.3-30 mg, 0.3-10 mg, 0.3-3 mg 0.3-1 mg and 0.2-1 mg.

[0029] In some embodiments, the α-blocker is a non-selective α-blocker. In other embodiments, the α-blocker is a selective α1-adrenergic blocker. In other embodiments, the α-blocker is a selective α2-adrenergic blocker. In other embodiments, the α-blocker is tamsulosin.

[0030] In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 100-200 mg, 200-400 mg, 400-600 mg, 600-800 mg, 800-1000 mg or 1000-1200 mg and tamsulosin in an amount of 0.1- 0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg, 0.9-1.2 mg or 1.2-1.5 mg.

[0031] In other embodiments, one or more analgesic agents and one or more α-blockers are formulated for immediate release. In other embodiments, one or more analgesic agents are formulated for immediate release and one or more α-blockers are formulated for sustained release.

[0032] In other embodiments, one or more analgesic agents are formulated for sustained release and one or more α-blockers are formulated for immediate release. In some embodiments, one or more analgesic agents are released continuously or at a constant rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours. In some embodiments, at least 90% of the one or more analgesic agents are released continuously or at a constant speed over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

[0033] In some other embodiments, one or more analgesic agents are excreted within 2 hours after administration, and the remainder is excreted continuously or at a constant speed for a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16- 24 hours.

[0034] In other embodiments, one or more analgesic agents and one or more α-blockers are formulated for sustained release. In some embodiments, one or more analgesic agents and one or more α-blockers are formulated for sustained release, such that one or more analgesic agents and one or more α-blockers are released continuously or at a constant speed over a period of 5-24 hours , 5-8 hours, 8-16 hours or 16-24 hours. In some other embodiments, one or more analgesic agents and one or more α-blockers are formulated for sustained release with a biphasic release profile, wherein 20-60% of such one or more analgesic agents and one or more α-blockers are released within 2 hours after administration, and the remainder is allocated continuously or at a constant speed for a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

[0035] In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 50-1000 mg, 50-250 mg, 250-400 mg, 400-600 mg, 600-800 mg, or 800-1000 mg in combination with tamsulosin in an amount of 0, 1-1.2 mg, 0.1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg or 0.9-1.2 mg, where the composition is formulated for prolonged release of acetaminophen and tamsulosin with a drug release profile in which at least 90% of acetaminophen and tamsulosin is released continuously or at a constant speed over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

[0036] In other embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 500-1000 mg, 50-200 mg, 50-400 mg, 100-400 mg, 100-300 mg, 200-400 mg, 400-600 mg, 600- 800 mg, 800-1000 mg or 1000-1200 mg and tamsulosin in an amount of 0.1-1.2 mg, 0.1-0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg or 0.9-1.2 mg, where the composition is formulated for sustained release with a biphasic release profile, in which 20-60% of acetaminophen and tamsulosin is released within 2 hours of administration, and the remainder is released continuously or at a constant speed for a period 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

[0037] "Sustained Release", also known as Slow Release (SR), Slow Release (SA), Time Release (TR), Controlled Release (CR), Modified Release (MR), or Continuous Release (CR), represents is a mechanism used in medicinal tablets or capsules to slowly dissolve and release the active ingredient over a period of time. The benefits of sustained-release tablets or capsules are that they can be taken, as a rule, less often than formulations with immediate release of the same drug, and that they maintain constant levels of the drug in the bloodstream, thereby increasing the duration of the drug and reducing the peak amount of the drug in the bloodstream. For example, a sustained release analgesic may provide the subject with the ability to sleep all night without waking up to go to the toilet.

[0038] In one embodiment, the pharmaceutical composition is formulated for sustained release by immersing the active ingredient in a matrix of insoluble substance (s), such as acrylics or chitin. A sustained release form is designed to isolate the analgesic compound at a predetermined rate, maintaining a constant level of the drug for a specific period of time. This can be obtained through various formulations, including, but not limited to, liposomes and drug-polymer conjugates, such as hydrogels.

[0039] A sustained release formulation can be designed to release the active agents at a predetermined rate, so as to maintain a constant level of drug over a specific long period of time, such as up to about 24 hours, up to about 20 hours, up to about 16 hours, up to approximately 12 hours, approximately 10 hours, approximately 9 hours, approximately 8 hours, approximately 7 hours, approximately 6 hours, approximately 5 hours, approximately up to about 4 hours, up to about 3 hours, up to about 2 hours, or up to about 1 hour after administration or after a delay period associated with a delayed release of the drug.

[0040] In certain preferred embodiments, the active agents are released over a period of time from about 2 to about 10 hours. Alternatively, active agents may be released within about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9, about 10 hours, about 12 hours, about 16 hours, about 20 hours or approximately 24 hours. In other embodiments, active agents are released over a period of about three to about eight hours after administration.

[0041] In some embodiments, a sustained release formulation comprises an active core consisting of one or more inert particles, each of which is in the form of a granule, pill, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule or nanosphere, the surface of which coated with drugs in the form of, for example, a drug-containing coating or film-forming composition, using, for example, a fluidized bed technique or other methods known and specialists in this field. An inert particle can be of various sizes, provided that it is large enough to remain slightly soluble. Alternatively, the active core can be obtained by granulating and grinding and / or extruding and spheronizing a polymer composition containing a drug substance.

[0042] The active agents can be introduced into an inert carrier by methods known to one skilled in the art, such as drug layering, powder coating, extrusion / spheronization, rolling or granulation. The amount of drug in the core depends on the dose that is necessary, and usually varies from about 5 to 90% by weight. Typically, the polymer coating on the active core is from about 1 to 50% by weight of the coated particle, depending on the required delay time and / or the selected polymers and solvents of the coating. Those skilled in the art are able to select the appropriate amount of drug for coating the core or for introducing into the core to obtain the desired dose. In one embodiment, the inactive core may be a sphere of sugars or a crystal of a buffer solution or an encapsulated crystal of a buffer solution, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alter the microenvironment of the drug, facilitating it release.

[0043] Another aspect of the present invention relates to a method for decreasing the frequency of urination. The method comprises administering to a subject in need thereof an effective amount of one or more analgesics and an effective amount of a 5α-reductase inhibitor. Examples of 5α-reductase inhibitors include, but are not limited to, finasteride, bexlosteride, episteride, isonsteride, lapisteride, and tourosteride. In some embodiments, the 5α-reductase inhibitor is finasteride.

[0044] In some embodiments, one or more analgesic agents and a 5α-reductase inhibitor are administered separately in different dosage forms. In other embodiments, one or more analgesic agents and an α-blocker are administered simultaneously in the same dosage form (eg, in one pill or tablet). In some embodiments, one or more analgesic agents and a 5α-reductase inhibitor are formulated for immediate release after administration. In other embodiments, one or more analgesic agents and a 5α-reductase inhibitor are formulated for delayed release after administration. In other embodiments, one or more analgesic agents and a 5α-reductase inhibitor are formulated for sustained release after administration. In other embodiments, one or more analgesic agents and a 5α-reductase inhibitor are formulated for delayed-sustained release after administration. In other embodiments, one or more analgesic agents are formulated for delayed release, sustained release, or delayed-prolonged release, and a 5α-reductase inhibitor is formulated for immediate release. In other embodiments, one or more analgesic agents are formulated for immediate release, and a 5α-reductase inhibitor is formulated for delayed release, sustained release, or delayed-sustained release. The method can be used to treat nocturia or overactive bladder. Another aspect of the present invention relates to a pharmaceutical composition comprising an active ingredient comprising one or more analgesic agents, a 5α-reductase inhibitor and a pharmaceutically acceptable carrier.

[0045] In some embodiments, one or more analgesic agents is administered orally in an individual or combined daily dose of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 mg, 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg or 1500-200 0 mg and one or more 5α-reductase inhibitors are administered orally in an individual or combined daily dose of 0.1-250 mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1- 3 mg, 0.1-1 mg, 0.3-250 mg, 0.3-100 mg, 0.3-30 mg, 0.3-10 mg, 0.3-3 mg, 0.3-1 mg, 1-100 mg, 1-30 mg, 1-10 mg, 1-3 mg, 3-7 mg and 4-6 mg.

[0046] In some embodiments, the 5α-reductase inhibitor is tamsulosin.

[0047] Another aspect of the present invention relates to a pharmaceutical composition comprising one or more analgesic agents, one or more 5α-reductase inhibitors, and a pharmaceutically acceptable carrier. In some embodiments, one or more analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone, and acetaminophen.

[0048] In some embodiments, the pharmaceutical composition comprises one or more analgesic agents individually or in combination in an amount of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg , 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg , 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg , 200-800 mg, 200-600 mg, 200-400 mg, 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg , 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg , 1000-1200 mg, 1200-2000 mg, 1200-15 00 mg or 1500-2000 mg and one or more 5α-reductase inhibitors in an amount of 0.1-250 mg, 0.1-100 mg, 0.1-30 mg, 0.1-10 mg, 0.1-3 mg, 0.1-1 mg, 0.3-250 mg, 0.3-100 mg, 0.3-30 mg, 0.3-10 mg, 0.3-3 mg, 0.3-1 mg , 1-100 mg, 1-30 mg, 1-10 mg, 1-3 mg, 3-7 mg and 4-6 mg.

[0049] In some embodiments, the α-blocker is a non-selective α-blocker. In other embodiments, the α-blocker is a selective α1-adrenergic blocker. In other embodiments, the α-blocker is a selective α2-adrenergic blocker. In other embodiments, the α-blocker is tamsulosin.

[0050] In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 100-200 mg, 200-400 mg, 400-600 mg, 600-800 mg, 800-1000 mg, or 1000-1200 mg and finasteride in an amount of 0.1 -0.3 mg, 0.3-0.6 mg, 0.6-0.9 mg, 0.9-1.2 mg or 1.2-1.5 mg.

[0051] In other embodiments, one or more analgesic agents and one or more 5α-reductase inhibitors are formulated for immediate release. In other embodiments, one or more analgesic agents are formulated for immediate release and one or more α-blockers are formulated for sustained release.

[0052] In other embodiments, one or more analgesic agents are formulated for sustained release and one or more 5α-reductase inhibitors are formulated for immediate release. In some embodiments, one or more analgesic agents are released continuously or at a constant rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours. In some embodiments, at least 90% of the one or more analgesics are released continuously or at a constant rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16-24 hours.

[0053] In some other embodiments, one or more analgesic agents are released within 2 hours after administration, and the remainder is released continuously or at a constant rate over a period of 5-24 hours, 5-8 hours, 8-16 hours, or 16- 24 hours.

[0054] In other embodiments, one or more analgesic agents and one or more 5α-reductase inhibitors are formulated for sustained release. In some embodiments, one or more analgesic agents and one or more 5α-reductase inhibitors are formulated for sustained release, such that one or more analgesic agents and one or more 5α-reductase inhibitors are released continuously or at a constant rate over a period of 5- 24 hours, 5-8 hours, 8-16 hours or 16-24 hours. In some other embodiments, one or more analgesic agents and one or more 5α-reductase inhibitors are formulated for sustained release with a biphasic release profile, wherein 20-60% of such one or more analgesic agents and one or more 5α-reductase inhibitors are released into within 2 hours after administration, and the remainder is released continuously or at a constant speed for a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

[0055] In some embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 50-1000 mg, 50-250 mg, 250-400 mg, 400-600 mg, 600-800 mg, or 800-1000 mg in combination with finasteride in an amount of 1- 20 mg, 1-3 mg, 3-7 mg, 7-10 mg, 10-15 mg or 15-20 mg, where the composition is formulated for prolonged release of acetaminophen and finasteride with a drug release profile in which at least 90% acetaminophen and finasteride are released continuously or at a constant speed for a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours at.

[0056] In other embodiments, the pharmaceutical composition comprises acetaminophen in an amount of 50-1000 mg, 50-100 mg, 50-200 mg, 50-300 mg, 50-400 mg, 50-600 mg, 50-800 mg, 100- 200 mg, 100-300 mg, 100-400 mg, 100-600 mg, 100-800 mg, 100-1000 mg, 200-400 mg, 200-600 mg, 200-800 mg, 200-1000 mg, 400- 600 mg, 400-800 mg, 400-1000 mg, 600-800 mg, 600-1000 mg, 800-1000 mg or 1000-1200 mg and finasteride in an amount of 1-20 mg, 1-3 mg, 1-7 mg , 1-10 mg, 1-15 mg, 3-7 mg, 3-10 mg, 3-15 mg, 3-20 mg, 7-10 mg, 7-15 mg, 7-20 mg, 10-15 mg , 10-20 mg or 15-20 mg, where the composition is formulated for sustained release with a biphasic release profile in which 20-60% acetaminophen and finista Ride is released within 2 hours after administration, and the remainder is released continuously or at a constant rate over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

[0057] "Sustained Release", also known as Slow Release (SR), Slow Release (SA), Time Release (TR), Controlled Release (CR), Modified Release (MR) or Continuous Release (CR), represents is a mechanism used in medicinal tablets or capsules to slowly dissolve and release the active ingredient over a period of time. The benefits of sustained-release tablets or capsules are that they can be taken, as a rule, less often than formulations with immediate release of the same drug, and that they maintain constant levels of the drug in the bloodstream, thereby increasing the duration of the drug and reducing the peak amount of the drug in the bloodstream. For example, a sustained release analgesic may provide the subject with the ability to sleep all night without waking up to go to the toilet.

[0058] In one embodiment, the pharmaceutical composition is formulated for sustained release by immersing the active ingredient in a matrix of an insoluble substance (c), such as acrylic or chitin. A sustained release form is designed to isolate the analgesic compound at a predetermined rate, maintaining a constant level of the drug for a specific period of time. This can be obtained through various formulations, including, but not limited to, liposomes and drug-polymer conjugates, such as hydrogels.

[0059] A sustained release formulation can be designed to release the active agents at a predetermined rate, so as to maintain a constant level of drug over a specific long period of time, such as up to about 24 hours, up to about 20 hours, up to about 16 hours, up to approximately 12 hours, approximately 10 hours, approximately 9 hours, approximately 8 hours, approximately 7 hours, approximately 6 hours, approximately 5 hours, approximately up to about 4 hours, up to about 3 hours, up to about 2 hours, or up to about 1 hour after administration or after a delay period associated with a delayed release of the drug.

[0060] In certain preferred embodiments, the active agents are released over a period of time from about 2 to about 10 hours. Alternatively, active agents may be released within about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9, about 10 hours, about 12 hours, about 16 hours, about 20 hours or approximately 24 hours. In other embodiments, active agents are released over a period of about three to about eight hours after administration.

[0061] In some embodiments, a sustained release formulation comprises an active core consisting of one or more inert particles, each of which is in the form of a granule, microsphere, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule or nanosphere, the surface of which coated with drugs in the form of, for example, a drug-containing coating or film-forming composition, using, for example, a fluidized bed technique or other methods known Specialists in this field. An inert particle can be of various sizes, provided that it is large enough to remain slightly soluble. Alternatively, the active core can be obtained by granulating and grinding and / or extruding and spheronizing a polymer composition containing a drug substance.

[0001] The active agents can be introduced into an inert carrier by methods known to one of skill in the art, such as drug layering, powder coating, extrusion / spheronization, rolling or granulation. The amount of drug in the core depends on the dose that is necessary, and usually varies from about 5 to 90% by weight. Typically, the polymer coating on the active core is from about 1 to 50% by weight of the coated particle, depending on the required delay time and / or the selected polymers and solvents of the coating. Those skilled in the art can select the appropriate amount of drug for coating the core or for introducing into the core to obtain the desired dose. In one embodiment, the inactive core may be a sphere of sugars or a crystal of a buffer solution or an encapsulated crystal of a buffer solution, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alter the microenvironment of the drug, facilitating it release.

[0062] In a sustained release formulation, various sustained release coatings or mechanisms can be used to facilitate the gradual release of active agents over a period of time. In some embodiments, the sustained release agent comprises a polymer that controls release by controlled release dissolution. In a specific embodiment, the active agent (a) is introduced into a matrix containing an insoluble polymer and particles or granules of a drug coated with polymeric substances of various thicknesses. The polymer substance may contain a lipid barrier containing a waxy substance such as carnauba wax, beeswax, spermaceti wax, candelilla wax, shellac wax, cocoa butter, cetostearyl alcohol, partially hydrogenated vegetable oils, refined wax, paraffin wax, ceresin, myristyl alcohol, stearyl alcohol, cetyl alcohol and stearic acid, along with surfactants such as polyoxyethylene sorbitan monooleate. Upon contact with an aqueous medium, such as biological fluids, the polymer coating emulsifies or breaks down after a predetermined delay time depending on the thickness of the polymer coating. The delay time does not depend on the motor activity of the gastrointestinal tract, pH or retention in the stomach.

[0063] In other embodiments, the sustained release agent comprises a polymer matrix that provides controlled release diffusion. The matrix may contain one or more hydrophilic and / or water-swellable matrix-forming polymers, pH-dependent polymers and / or pH-independent polymers.

[0064] In one embodiment, the sustained release formulation comprises a water soluble or water swellable matrix forming polymer, optionally containing one or more solubility enhancing excipients and / or release agents. After solubilization of the water-soluble polymer, the active agent (s) dissolves (if soluble) and gradually diffuses through the hydrated portion of the matrix. Over time, the gel layer increases as water penetrates the core of the matrix, increasing the thickness of the gel layer and providing a diffusion barrier with the release of the drug. As the outer layer becomes fully hydrated, the polymer chains become completely weakened and can no longer maintain the integrity of the gel layer, leading to disruption of the weave and erosion of the external hydrated polymer on the surface of the matrix. Water continues to penetrate the core through the gel layer until it is completely washed out. While soluble drugs are released as a result of this combination of diffusion and erosion mechanisms, erosion is the predominant mechanism for insoluble drugs regardless of dose.

[0065] Likewise, water-swellable polymers typically hydrate and swell in body fluids, forming a homogeneous matrix structure that retains its shape during drug release and serves as a drug carrier, solubility enhancers and / or release accelerators. The initial phase of hydration of the polymer matrix leads to a delayed release of the drug (lag phase). After the polymer swelling in water undergoes complete hydration and swells, the water in the matrix can similarly dissolve the drug substance and ensure its diffusion through the coating of the matrix.

[0066] Furthermore, matrix porosity may increase due to leaching of pH dependent release accelerators, thereby leading to drug release at a higher rate. Then, the drug release rate becomes constant and depends on the diffusion of the drug through the hydrated polymer gel. The rate of release from the matrix depends on various factors, including the type and level of polymer, the solubility and dose of the drug, the polymer: drug ratio, the type and level of filler, the polymer to filler ratio, the particle size of the drug and polymer, and the porosity and shape matrices.

[0067] Illustrative hydrophilic and / or water-swellable matrix-forming polymers include, but are not limited to, cellulosic polymers including hydroxyalkyl celluloses and carboxyalkyl celluloses such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ), carboxymethyl cellulose (CMC), powdered cellulose, such as microcrystalline cellulose, cellulose acetate, ethyl cellulose, their salts and combinations thereof; alginates, gums, including heteropolysaccharide gums and homopolysaccharide gums, such as xanthan gum, tragacanth, pectin, gum arabic, karaya, alginates, agar, guar, hydroxypropyl guar, wigum, carrageenan, locust bean gum, gellan gum, acrylic resin, gellan gum polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate and methyl methacrylate and cross-linked polyacrylic acid derivatives such as carbomers (e.g. Carbopol®, including, such as Carbopol® 71G NF, available with various types molecular weight from Noveon, Inc., Cincinnati, OH), carrageenan, polyvinyl acetate (e.g. KolliDON® SR), polyvinylpyrrolidone and its derivatives, such as crospovidone, polyethylene oxides and polyvinyl alcohol. Preferred hydrophilic and water-swellable polymers include cellulosic polymers, in particular HPMC.

[0068] A sustained release formulation may further comprise at least one binding agent that is capable of crosslinking the hydrophilic compound to form a hydrophilic polymer matrix (eg, a gel matrix) in an aqueous medium, including biological fluids.

[0069] Illustrative binders include homopolysaccharides, such as galactomannan gums, guar gum, hydroxypropyl guar gum, hydroxypropyl cellulose (HPC, for example EXF clusel) and locust bean gum. In other embodiments, the binder is an alginic acid derivative, HPC, or microcrystalline cellulose (MCC). Other binders include, but are not limited to, starches, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose and polyvinylpyrrolidone.

[0070] In one embodiment, the administration method is layering a drug by spraying a suspension of the active agent (c) and a binding agent onto an inert carrier.

[0071] The binder may be contained in the composition of the granules in an amount of from about 0.1% to about 15% by weight and preferably from about 0.2% to about 10% by weight.

[0072] In some embodiments, the hydrophilic polymer matrix may further comprise an ionic polymer, a nonionic polymer, or a water-insoluble hydrophobic polymer to provide a denser gel layer and / or to reduce the number and size of pores in the matrix, so as to slow diffusion rates and erosion and concomitant release of the active agent (c). This can further suppress the initial “explosive effect” and provide a more stable, “zero order release” of the active agent (c).

[0073] Illustrative ionic polymers to slow the rate of dissolution include both anionic and cationic polymers. Illustrative anionic polymers include, for example, sodium carboxymethyl cellulose (Na CMC), sodium alginate, acrylic acid polymers or carbomers (e.g. Carbopol® 934, 940, 974P NF), intestinal soluble polymers such as polyvinyl acetate phthalate (PVAP), methacrylic copolymers acids (e.g. EUDRAGIT® L100, L30D 55, A and FS 30D), hypromellose acetate succinate (AQUAT HPMCAS) and xanthan gum. Illustrative cationic polymers include, for example, dimethylaminoethyl methacrylate copolymer (e.g. EUDRAGIT® E 100). The introduction of anionic polymers, in particular intestinally soluble polymers, is suitable for developing a pH independent release profile for weakly basic drugs compared to a single hydrophilic polymer.

[0074] Illustrative non-ionic polymers for slowing the dissolution rate include, for example, hydroxypropyl cellulose (HPC) and polyethylene oxide (PEO) (eg POLYOX ™).

[0075] Illustrative hydrophobic polymers include ethyl cellulose (eg, ETHOCEL ™, SURELEASE®), cellulose acetate, methacrylic acid copolymers (eg EUDRAGIT® NE 30D), ammonium methacrylate copolymers (eg EUDRAGIT® RL100 or PO RS100), polyvinyl acetate glyceryl monostearate; fatty acids such as acetyl tributyl citrate; and combinations and derivatives thereof.

[0076] The swellable polymer can be incorporated into the composition in a proportion of from 1% to 50% by weight, preferably from 5% to 40% by weight, most preferably from 5% to 20% by weight. Swellable polymers and binders can be formulated before or after granulation. The polymers can also be dispersed in organic solvents or aqueous-alcoholic solutions and sprayed during granulation.

[0077] Illustrative release agents are considered suitable as release agents for the present invention, which include pH-dependent intestinal soluble polymers that remain intact when the pH is less than about 4.0 and dissolve when the pH is above 4, 0, preferably above 5.0, most preferably about 6.0. Illustrative pH-dependent polymers include, but are not limited to, methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (e.g. EUDRAGIT® L100 (type A), EUDRAGIT® S100 (type B), Rohm GmbH, Germany, methacrylic acid-ethyl acrylate copolymers (e.g. EUDRAGIT® L100-55 (type C) and a dispersion of EUDRAGIT® L30D-55 copolymers, Rohm GmbH, Germany), methacrylic acid-methyl methacrylate and methyl methacrylate (EUDRAGIT® FS) copolymers, methacrylic acid terpolymers, methacrylate and ethyl acrylate, cellulose acetate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP) (on example, HP-55, HP-50, HP-55S, Shinetsu Chemical, Japan), polyvinyl acetate phthalates (PVAP) (e.g. Coateric®, Opadry® intestinal soluble white OY-P-7171), polyvinyl butyrate acetate, cellulose acetate succinates (CAS ), hydroxypropyl methylcellulose acetate succinate (HPMCAS), e.g. HPMCAS grade LF, grade MF, grade HF, including AQOAT® LF and AQOAT® MF (Shin-Etsu Chemical, Japan), Shinetsu Chemical, Japan), shellac (e.g. MARCOAT ™ 125 and MARCOAT ™ 125N), a copolymer of vinyl acetate-maleic anhydride, a copolymer of styrene-monoester of maleic acid, carboxymethyl ethyl cellulose (CMEC, Freund Corporation, Japan), cellulose acetate phthalates (CAP) (for example , Aquateric®), cellulose acetate trimellitates (CAT) and mixtures of two or more of these compounds in mass ratios of from about 2: 1 to about 5: 1, such as, for example, a mixture of EUDRAGIT® L 100-55 and EUDRAGIT® S 100 in mass a ratio of about 3: 1 to about 2: 1 or a mixture of EUDRAGIT® L 30 D-55 and EUDRAGIT® FS in a mass ratio of about 3: 1 to about 5: 1.

[0078] These polymers can be used alone or in combination or in conjunction with polymers other than the above polymers. Preferred intestinal soluble pH dependent polymers are pharmaceutically acceptable methacrylic acid copolymers. Such copolymers are anionic polymers based on methacrylic acid and methyl methacrylate and preferably have an average molecular weight of approximately 135,000. The ratio of free carboxyl groups to methyl esterified carboxyl groups in such copolymers can range from, for example, from 1: 1 to 1: 3. for example, approximately 1: 1 or 1: 2. Such polymers are sold under the trade name EUDRAGIT®, such as the Eudragit L series, for example, Eudragit L 12.5®, Eudragit L 12.5P®, Eudragit L100®, Eudragit L 100-55®, Eudragit L-30D®, Eudragit L -30 D-55®, Eudragit S® series, e.g. Eudragit S 12.5®, Eudragit S 12.5P®, Eudragit S100®. Release accelerators are not limited to pH dependent polymers. For similar purposes, you can also use other hydrophilic molecules that quickly dissolve and quickly wash out of the dosage form, leaving a porous structure.

[0079] The release promoting agent may be administered in an amount of from 10% to 90%, preferably from 20% to 80%, and most preferably from 30% to 70% by weight of a dosage unit. The tool can be introduced into the composition before granulation or after it. The release promoting agent can be added to the composition either as a dry substance, or it can be dispersed or dissolved in a suitable solvent and dispersed during granulation.

[0080] In some embodiments, the matrix may comprise a combination of release accelerators and solubility enhancers. Solubility enhancers can be ionic and nonionic surfactants, complexing agents, hydrophilic polymers, pH modifiers, such as acidifying agents and alkalizing agents, as well as molecules that increase the solubility of a poorly soluble drug through molecular incorporation. Some solubility enhancers can be used simultaneously.

[0081] Solubility enhancers may include surfactants such as sodium docusate, sodium lauryl sulfate, sodium stearyl fumarate, Tween® and Span (PEO modified sorbitan monoesters and esters of fatty acids and sorbitan), poly (ethylene oxide) -polypropylene oxide block copolymers -poly (ethylene oxide) (also called PLURONIC ™), complexing agents such as low molecular weight polyvinyl pyrrolidone and low molecular weight hydroxypropyl methylcellulose, molecules that promote solubility through molecular li ne, such as cyclodextrins, and pH modifying agents including acidifying agents such as citric acid, fumaric acid, tartaric acid and hydrochloric acid, and alkalizing agents such as sodium hydroxide and meglumine.

[0082] Solubility enhancing agents typically comprise from 1% to 80% by weight, preferably from 1% to 60%, more preferably from 1% to 50% of the dosage form, and can be administered in various ways. They can be formulated prior to granulation in dry or wet form. They can also be added to the composition after the remaining substances are subjected to granulation or otherwise processed. During granulation, the solubilizers can be sprayed in the form of a solution with or without a binding agent.

[0083] In some embodiments, the sustained release formulation comprises a polymer matrix that can provide release of the drug after a certain period of time regardless of pH. For the purposes of the present invention, “pH independent” is defined as having characteristics (eg, dissolution) that are not substantially affected by pH. pH independent polymers are generally referred to in relation to "time-controlled" or "time-independent" release profiles.

[0084] A pH independent polymer can be used to coat an active agent and / or to produce a polymer for a hydrophilic matrix in a sustained release coating over it. The pH independent polymer may be water insoluble or water soluble. Illustrative water-insoluble pH independent polymers include, but are not limited to, neutral methacrylic acid esters with a small portion of trimethylammonium ethyl methacrylate chloride (e.g. EUDRAGIT® RS and EUDRAGIT® RL, dispersions of neutral esters without any functional groups (e.g. EUDRAGIT® NE30D and EUDRAGIT® NE30), cellulosic polymers such as ethyl cellulose, hydroxyethyl cellulose, cellulose acetate or mixtures, and other pH independent coating products. Illustrative water soluble pH independent polymers including hydroxyalkyl cellulose ethers such as hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl cellulose (HPC), polyvinyl pyrrolidone (PVP), methyl cellulose, OPADRY®amb, guar gum, xanthan gum, gum arabic, ethyl hydroxy ethyl ethyl cellulose and methylcellulose.

[0085] In one embodiment, the sustained release formulation comprises a water-insoluble water-permeable polymer coating or matrix comprising one or more water-insoluble water-permeable film-forming polymers on the active core. The coating may further comprise one or more water soluble polymers and / or one or more plasticizers. The water-insoluble polymer coating contains a barrier coating for the release of active agents in the core, where species with a lower molecular weight (viscosity) have higher release rates compared to species with a higher viscosity.

[0086] In preferred embodiments, the water-insoluble film-forming polymers comprise one or more alkyl cellulose ethers such as ethyl celluloses and mixtures thereof (for example, ethyl cellulose types PR100, PR45, PR20, PR10 and PR7, ETHOCEL®, Dow).

[0087] An exemplary water soluble polymer such as polyvinylpyrrolidone (POVIDONE®), hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and mixtures thereof.

[0088] In some embodiments, the water-insoluble polymer has suitable properties (eg, sustained release characteristics, mechanical properties, and hiding properties) without the need for a plasticizer. For example, without plasticizers, coatings containing polyvinyl acetate (PVA), neutral acrylate / methacrylate ester copolymers such as commercially available NE30D euradite from Evonik Industries, ethyl cellulose in combination with hydroxypropyl cellulose, waxes, etc. can be used.

[0089] In yet another embodiment, the water-insoluble polymer matrix may further comprise a plasticizer. The amount of plasticizer required depends on the plasticizer, the properties of the water-insoluble polymer and the final desired coating properties. Suitable plasticizer levels range from about 1% to about 20%, from about 3% to about 20%, from about 3% to about 5%, from about 7% to about 10%, from about 12% to about 15% , from about 17% to about 20%, or about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10% , approximately 15%, or approximately 20% by weight relative Tel'nykh total coating weight, including all ranges and subranges therebetween.

[0090] Illustrative plasticizers include, but are not limited to, triacetin, acetylated monoglyceride, oils (castor oil, hydrogenated castor oil, rapeseed oil, sesame oil, olive oil, etc.), citrate esters, triethyl citrate, acetyl triethyl citrate, acetyl triethyl citrate, acetyl triethyl citrate. , tributyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl phthalate, dioctyl phthalate, methyl paraben, propyl paraben, propyl paraben, butyl paraben, diethyl sebacate, dibutyl sebacate, glyceryl trihydrate, cerides, monoacetylated and diacetylated glycerides (e.g. Myvacet® 9-45), glyceryl monostearate, glycerol tributyrate, polysorbate 80, polyethylene glycol (such as PEG-4000, PEG-400), propylene glycol, 1,2-propylene glycol, glycerol, sorbitol, sorbitol, sorbitol, sorbitol diethyl malate, diethyl fumarate, diethyl malonate, dibutyl succinate, fatty acids, glycerin, sorbitol, diethyl oxalate, diethyl malate, diethyl maleate, diethyl fumarate, diethyl succinate, diethyl malonate, dioctyl phthalate, and dibutyl mixtures thereof. The plasticizer may have the properties of surfactants, so that it can act as a release modifier. For example, nonionic detergents such as Bridge 58 (polyoxyethylene cetyl ether (20)) and the like can be used.

[0091] The plasticizers can be high boiling point organic solvents used to impart elasticity to other hard or brittle polymeric substances, and can affect the release profile of the active agent (s). Plasticizers, as a rule, cause a decrease in the cohesive forces of intermolecular interaction in polymer chains, leading to various changes in the properties of polymers, including a decrease in tensile strength and an increase in stretching, and a decrease in the glass transition temperature or softening temperature of the polymer. The amount and choice of plasticizer can affect, for example, the rigidity of the tablet and can even affect its solubility or dispersibility properties, as well as its physical and chemical stability. Certain plasticizers can increase the elasticity and / or plasticity of the coating, thereby reducing the brittleness of the coating.

[0092] In another embodiment, the sustained release formulation comprises a combination of at least two gel-forming polymers, including at least one non-ionic gel-forming polymer and / or at least one anionic gel-forming polymer. The gel formed by the combination of gel-forming polymers provides controlled release, so that when the composition is taken orally and it comes into contact with gastrointestinal fluids, the polymers near the surface are hydrated to form a viscous gel layer. Due to its high viscosity, the viscous layer dissolves only gradually, exposing the lower substance to a similar process. Thus, the mass dissolves slowly, thus slowly releasing the active ingredient in the fluid of the gastrointestinal tract. The combination of at least two gel-forming polymers provides properties of the resulting gel, such as viscosity, which can be adjusted to obtain the desired release profile.

[0093] In a specific embodiment, the composition comprises at least one non-ionic gel-forming polymer and at least one anionic gel-forming polymer. In another embodiment, the composition comprises two different non-ionic gel-forming polymers. In yet another embodiment, the composition comprises a combination of nonionic gel-forming polymers of a similar chemical structure, but with different solubilities, viscosities and / or molecular weights (e.g., a combination of hydroxypropyl methylcellulose of varying degrees of viscosity, such as HPMC K100 and HPMC K15M or HPMC K100M).

[0094] Illustrative anionic gel-forming polymers include, but are not limited to, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose (CMC), anionic polysaccharides such as sodium alginate, alginic acid, pectin, polyglucuronic acid (poly-α-and-β- 1,4-glucuronic acid), polygalacturonic acid (pectic acid), chondroitin sulfate, carrageenan, furcellaran, anionic gums such as xanthan gum, acrylic acid polymers or carbomers (Carbopol® 934, 940, 974P NF), Carbopol® copolymers, polymers Pemulen®, polycarbophil and d prob.

[0095] Illustrative non-ionic gel-forming polymers include, but are not limited to, povidone (PVP: polyvinylpyrrolidone), polyvinyl alcohol, a copolymer of PVP and polyvinyl acetate, HPC (hydroxypropyl cellulose), HPMC (hydroxypropyl methyl cellulose, hydroxyethyl cellulose cellulose, polyethylene gels, hydroxyethyl cellulose cellulose, polyethylene gels, gum, hydroxyethyl cellulose cellulose, , starch, polyhydroxyethyl methacrylate (PHEMA), water-soluble non-ionic polymethacrylates and their copolymers, modified cellulose, modified polysaccharides, non-ionic gums, non-ionic polysaccharides and / and whether their mixtures.

[0096] The composition may optionally contain an intestinal soluble polymer, as described above, and / or at least one excipient, such as an excipient, a binding agent (as described above), a disintegrant and / or a flow improver or a glidant.

[0097] Illustrative excipients include, but are not limited to, lactose, glucose, fructose, sucrose, calcium diphosphate, sugar alcohols, also known as “sugar polyol,” such as sorbitol, mannitol, lactitol, xylitol, isomalt, erythritol, and hydrogenated hydrolysates starch (a mixture of several sugar alcohols), corn starch, potato starch, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, intestinal soluble polymers or a mixture thereof.

[0098] Illustrative binders include, but are not limited to, water-soluble hydrophilic polymers such as povidone (PVP: polyvinylpyrrolidone), copovidone (a copolymer of polyvinylpyrrolidone and polyvinyl acetate), low molecular weight HPC (hydroxypropyl cellulose) low molecular weight, low molecular weight, low molecular weight, low molecular weight, low molecular weight, low molecular weight, low molecular weight , gelatin, polyethylene oxide, gum arabic, dextrin, magnesium aluminosilicate, starch and polymethacrylates such as tear NE 30D, tear RL, tear RS, tear E, gender ivinyl acetate and intestinal soluble polymers or mixtures thereof.

[0099] Illustrative disintegrants include, but are not limited to, low-displacement sodium carboxymethyl cellulose, crospovidone (cross-linked polyvinyl pyrrolidone), sodium carboxymethyl starch (sodium starch glycolate) 1500 cross-linked carboxymethyl cellulose (cellulose), cellulose (pepticulose), microcrystalline cellulose, water-insoluble starch, calcium carboxymethyl cellulose, low substitution hydroxypropyl cellulose and magnesium silicate or aluminum silicate.

[0100] Illustrative glidants include, but are not limited to, magnesium, silica, talc, starch, titanium dioxide, and the like.

[0101] In yet another embodiment, a sustained release formulation is prepared by coating a particle containing a water-soluble / dispersible drug, such as a granule or a population of granules therein (as described above), a coating agent and optionally pore-forming and other excipients. The coating agent is preferably selected from the group consisting of cellulosic polymers such as ethyl cellulose (e.g. SURELEASE®), methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose acetate and cellulose acetate phthalate, acrylic polymers such as polyacrylates and other polymers Substances for coating based on water or based on a solvent. The release control coating for a given granule population can be controlled by at least one control release coating parameter, such as the nature of the coating, coating level, type and concentration of pore former, process parameters, and combinations thereof. Thus, a change in a parameter, such as the concentration of a blowing agent, or curing conditions, allows you to change the release of the active agent (C) from any given population of granules, thus providing selective regulation of the composition to a predetermined release profile.

[0102] Pore formers suitable for use in controlling release of the coating in the present description may be organic or inorganic agents and include substances that can dissolve, extract, or leach from the coating into the environment of use. Illustrative blowing agents include, but are not limited to, organic compounds such as mono-, oligo-, and polysaccharides, including sucrose, glucose, fructose, mannitol, mannose, galactose, sorbitol, pullulan, dextran, polymers soluble in use, such such as water-soluble hydrophilic polymers, hydroxyalkyl cellulose, carboxyalkyl cellulose, hydroxypropyl methyl cellulose, cellulose ethers, acrylic resins, polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, types of carboax, arbopol and the like, diols, polyols, polyhydric alcohols, polyalkylene glycols, polyethylene glycols, polypropylene glycols or their block polymers, polyglycols, poly (α-Ω) alkylenediols, inorganic compounds such as alkali metal salts, lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate, sodium citrate, suitable calcium salts, a combination thereof, and the like.

[0103] The release control coating may additionally contain other additives known in the art, such as plasticizers, slip adhesives (or flow improvers), and anti-foaming agents.

[0104] In some embodiments, the coated particles or granules may further comprise an “outer coating” to provide, for example, protection against moisture, reducing static charge, masking taste, aromatization, imparting color and / or polishing, or other aesthetic appeal to the granules. Suitable coating materials for such an external coating are known in the art and include, but are not limited to, cellulosic polymers such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose and microcrystalline cellulose, or combinations thereof (e.g., various OPADRY® coating materials).

[0105] Coated particles or granules may further comprise enhancers, examples of which may include, but are not limited to, solubility enhancers, dissolution enhancers, absorption enhancers, permeability enhancers, stabilizers, complexing agents, enzyme inhibitors, p-glycoprotein inhibitors and multidrug protein inhibitors sustainability. Alternatively, the composition may also contain enhancers that are separated from the coated particles, for example, in a separate population of granules or in powder form. In yet another embodiment, the enhancer (s) may be contained in a separate layer on the coated particles under or above the release control coating.

[0106] In other embodiments, a sustained release formulation is formulated to release the active agent (c) via an osmosis mechanism. As an example, a capsule may be formulated with an osmotic element, or it may contain 2, 3, 4, 5, or 6 ejection-extruding elements encapsulated in a hard gelatin capsule, such that each two-layer ejection-extrusion element contains an osmotic ejection layer and drug layer surrounded by a semipermeable membrane. One or more holes are drilled through the membrane after the drug layer. Such a membrane can be further coated with a pH-dependent enteric coating to prevent release prior to gastric emptying. The gelatin capsule dissolves immediately after oral administration. As soon as the extruding-extruding element (s) enter the small intestine, the coating dissolving in the intestine is destroyed, which then ensures the penetration of liquid through the semipermeable membrane, swelling of the osmotic ejection chamber with the expulsion of drugs through the hole (s) at a speed precisely controlled by the speed of transport water through a semipermeable membrane. Drug release can occur at a constant rate of up to 24 hours or more.

[0107] The osmotic ejection layer contains one or more osmotic means that create a motive force for the transport of water through a semipermeable membrane to the core of the delivery system. One class of osmotic agents includes water-swellable hydrophilic polymers, also referred to as “osmopolymers” and “hydrogels,” including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol ( PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl methacrylate), poly (acrylic) acid, poly (methacrylic) acid, polyvinyl pyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA copolymers / PVP with hydrophobic monomers, such such as methyl methacrylate and vinyl acetate, hydrophilic polyuterans containing large blocks of PEO, croscarmellose sodium, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC, gel carboxymethyl cellulose, carboxymethyl carboxylate, carboxymethyl cellulose, and carboxymethyl cellulose); xanthan gum and sodium starch glycolate.

[0108] Another class of osmotic agents includes osmogens, which are capable of absorbing water, affecting the osmotic pressure gradient across a semipermeable membrane. Illustrative osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, para-toluenesulfonic acid, succinic acid and tartaric acid; urea and mixtures thereof.

[0109] Substances suitable for the preparation of a semi-permeable membrane include various types of acrylics, vinyls, ethers, polyamides, polyesters and cellulose derivatives that are water-permeable and insoluble in water at physiologically significant pH or capable of remaining insoluble in water due to chemical changes such as crosslinking.

[0110] In some embodiments, a sustained release formulation may comprise a polysaccharide coating that is resistant to degradation in both the stomach and intestines. Such polymers can be destroyed only in the colon, which contains a large amount of microflora, containing biodegradation enzymes that destroy, for example, polysaccharide coatings with the release of drug contents in a controlled, time-dependent manner. Illustrative polysaccharide coatings may include, for example, amylose, arabinogalactan, chitosan, chondroitin sulfate, cyclodextrin, dextran, guar gum, pectin, xylan, and combinations or derivatives thereof.

[0111] In some embodiments, the pharmaceutical composition of the present invention is formulated for delayed sustained release. As used herein, the term “delayed release” refers to a medicament that does not instantly disintegrate or release the active ingredient (s) in the body. In some embodiments, the term “delayed delayed release” is used to refer to a formulation with a release profile in which there is a predetermined delay in the release of the drug after administration. In some embodiments, a sustained release formulation comprises a sustained release formulation coated with an enteric coating that is a barrier to the oral drug that prevents the drug from being released before it reaches the small intestine. Delayed release formulations, such as enteric coatings, prevent the dissolution of stomach irritant drugs, such as aspirin, in the stomach. Such coatings are also used to protect acid-unstable drugs from the effects of stomach acid, delivering them to an environment with an alkaline pH (pH in the intestines 5.5 and above), where they do not break down and exert their desired effect.

[0112] The term "pulsating release" is a type of delayed release, which is used in the present description in relation to the composition of the drug, which provides quick and temporary release of the drug for a short period of time immediately after a predetermined period of delay, thereby forming " pulsating "drug profiles in plasma after drug administration. The compositions can be designed to obtain one pulsating release or many pulsating releases at certain time intervals after administration or pulsating release (for example, 20-60% of the active ingredient), followed by a sustained release over a certain period of time (for example, continuous release of the remaining part of the active ingredient) .

[0113] A delayed release or pulsed release formulation typically contains one or more elements coated with a barrier coating that dissolves, erodes, or collapses after a certain lag phase. In some embodiments, the pharmaceutical composition of the present invention is formulated for sustained release or delayed sustained release, and it comprises 100% of the total dose of the active agent administered in a single unit dose. In other embodiments, the pharmaceutical composition comprises a sustained / delayed release component and an immediate release component. In some embodiments, the immediate release component and the sustained / delayed release component contain the same active ingredient. In other embodiments, the immediate release component and the sustained / delayed release component comprise various active ingredients (eg, an analgesic in one component and an α-blocker in another component). In some embodiments, each of the first and second components comprises an α-blocker and an analgesic selected from the group consisting of aspirin, ibuprofen, sodium naproxen, indomethacin, nabumetone and acetaminophen. In other embodiments, each of the first and second components comprises a 5α-reductase inhibitor selected from the group consisting of finasteride, bexlosteride, episteride, isonsteride, lapisteride and tourosteride, and an analgesic selected from the group consisting of aspirin, ibuprofen, sodium naproxen, indomethacin, nabumetone and acetaminophen. In other embodiments, the sustained / delayed release component is coated with an enteric coating. In other embodiments, the immediate release component and / or the sustained / delayed release component further comprises an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine. In other embodiments, the immediate release component and / or the sustained / delayed release component further comprises an antidiuretic agent, an antimuscarinic agent, or both. In other embodiments, the method of treatment comprises administering to the subject a diuretic at least 8 or 7 hours before a predetermined point in time, such as sleep time, and administering to the subject a pharmaceutical composition comprising an immediate release component and / or a sustained / delayed release component in 2 hours to a given point in time.

[0114] In other embodiments, the "immediate release" component provides about 5-50% of the total dose of the active agent (c), and the "sustained release" component provides 50-95% of the total dose of the active agent (c) delivered pharmaceutical composition. For example, the immediate release component may provide about 20-60% or about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% of the total dose of the active agent (c), delivered by pharmaceutical composition. The sustained release component provides approximately 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 80% of the total active agent dose (c) delivered by the composition. In some embodiments, the sustained release component further comprises a barrier coating to delay the release of the active agent.

[0115] The delayed release barrier coating may consist of a number of different substances, depending on the application. In addition, the composition may contain a number of barrier coatings to temporarily facilitate release. The coating may be a sugar coating, a film coating (for example, based on hydroxypropylmethyl cellulose, methyl cellulose, methyl hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, acrylate copolymers, polyethylene glycols, and / or polyvinyl cellulose methyl acetate, methyl cellulose methyl acetate) polyvinyl acetate, shellac and / or ethyl cellulose. In addition, the composition may further comprise a time delay agent, such as, for example, glyceryl monostearate or glyceryl distearate.

[0116] In some embodiments, a sustained release formulation comprises an enteric coating containing one or more polymers that facilitate the release of active agents in the proximal or distal gastrointestinal tract. As used herein, the term “enteric-soluble polymer coating” is a coating containing one or more polymers having a pH dependent or pH independent release profile. Typically, the coating is resistant to dissolution in the acidic environment of the stomach, but dissolves or breaks down in the more distal parts of the gastrointestinal tract, such as the small intestine or colon. An enteric-soluble polymer coating generally inhibits the release of active agents for a period of time after gastric emptying, a delay period of approximately 3-4 hours after administration.

[0117] pH-dependent intestinal-soluble coatings contain one or more pH-dependent or pH-sensitive polymers that retain their structural integrity at low pH, such as in the stomach, but dissolve in higher pH environments in the more distal gastrointestinal regions intestinal tract, such as the small intestine, where the contents of the drug are released. For the purposes of the present invention, “pH dependent” is defined as having characteristics (eg, dissolution) that vary with the pH of the environment. Illustrative pH-dependent polymers include, but are not limited to, methacrylic acid copolymers, methacrylic acid-methyl methacrylate copolymers (e.g. EUDRAGIT® L100 (type A), EUDRAGIT® S100 (type B), Rohm GmbH, Germany; methacrylic acid-ethyl acrylate copolymers (e.g. EUDRAGIT® L100-55 (type C) and a dispersion of EUDRAGIT® L30D-55 copolymers, Rohm GmbH, Germany); methacrylic acid-methyl methacrylate and methyl methacrylate copolymers (EUDRAGIT® FS); methacrylic acid terpolymers, methacrylate and ethyl acrylate; cellulose acetate phthalates (CAP); hydroxypropyl methylcellulose phthalate (HPMCP) (on example, HP-55, HP-50, HP-55S, Shinetsu Chemical, Japan); polyvinyl acetate phthalates (PVAP) (e.g. Coateric®, Opadry® intestinal soluble white OY-P-7171); cellulose acetate succinates (CAS); hydroxypropyl methylcellulose acetate succinate (HPMCAS), for example, HPMCAS type LF, type MF, type HF, including AQOAT® LF and AQOAT® MF (Shin-Etsu Chemical, Japan), Shinetsu Chemical, Japan); shellac (e.g. Marcoat ™ 125 and Marcoat ™ 125N); carboxymethyl ethyl cellulose (CMEC, Freund Corporation, Japan); cellulose acetate phthalates (CAP) (e.g., Aquateric®); cellulose acetate trimellitates (CAT) and mixtures of two or more of the above agents in a weight ratio of from about 2: 1 to about 5: 1, such as, for example, a mixture of EUDRAGIT® L 100-55 and EUDRAGIT® S 100 in a mass ratio of about 3 : 1 to about 2: 1 or a mixture of EUDRAGIT® L 30 D-55 and EUDRAGIT® FS in a weight ratio of from about 3: 1 to about 5: 1.

[0118] pH-dependent polymers typically have a characteristic optimum pH level for dissolution. In some embodiments, the implementation of the pH-dependent polymer has an optimal pH from about 5.0 to 5.5, from about 5.5 to 6.0, from about 6.0 to about 6.5, or from about 6.5 to 7, 0. In other embodiments, the implementation of the pH-dependent polymer has an optimal level of pH≥5.0, ≥5.5, ≥6.0, ≥6.5 or ≥7.0.

[0119] In a particular embodiment, the coating method comprises mixing one or more pH dependent and one or more pH independent polymers. Mixing pH-dependent and pH-independent polymers can reduce the release rate of the active ingredients after the soluble polymer reaches its optimum pH for solubilization.

[0120] In some embodiments, a “time-controlled” or “time-dependent” release profile can be obtained using a water-insoluble capsule body containing one or more active agents, where the capsule body is closed at one end with an insoluble stopper, but permeable and swelling hydrogel. After contact with the fluid of the gastrointestinal tract or the dissolution medium, the plug swells, being pushed out of the capsule and releasing drugs after a predetermined delay period, which can be controlled, for example, by the position and size of the plug. The capsule body can be further coated with an external pH-dependent intestinal-dissolving coating that keeps the capsule intact before it enters the small intestine. Suitable cork materials include, for example, polymethacrylates, washable extruded polymers (e.g. HPMC, polyvinyl alcohol), a thickened molten polymer (e.g. glyceryl monooleate), and enzymatically-controlled washable polymers (e.g. polysaccharides, such as amylose, arabinogalactone chitosan, chitosan, , cyclodextrin, dextran, guar gum, pectin and xylan).

[0121] In other embodiments, capsules or bilayer tablets may be formulated to contain a core containing a drug coated with a swelling layer and an external insoluble but semi-permeable polymer coating or membrane. The delay time to failure can be controlled by the permeability and mechanical properties of the polymer coating and the nature of the swelling of the swelling layer. Typically, a swellable layer contains one or more swellable agents, such as swellable hydrophilic polymers, which swell and retain water in their structures.

[0122] Illustrative water-swellable substances used in a delayed release coating include, but are not limited to, polyethylene oxide (for example, with an average molecular weight of 1,000,000 to 7,000,000, such as POLYOX®), methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose; polyalkylene oxides with a weight average molecular weight of from 100,000 to 6,000,000, including, but not limited to, poly (methylene oxide), poly (butylene oxide); poly (hydroxyalkyl methacrylate) with a molecular weight of from 25,000 to 5,000,000; poly (vinyl) alcohol with a low content of acetal residue, which is cross-linked with glyoxal, formaldehyde or glutaraldehyde and has a polymerization degree of from 200 to 30,000; mixtures of methyl cellulose, cross-linked agar and carboxymethyl cellulose; hydrogel-forming copolymers obtained by dispersing a finely divided copolymer of maleic anhydride with styrene, ethylene, propylene, butylene or isobutylene, crosslinked from 0.001 to 0.5 mol of a saturated crosslinking agent per mole of maleic anhydride in the copolymer; Carbopol® acid carboxypolymers with a molecular weight of 450,000 to 4,000,000; Cyanamer® polyacrylamides; cross-linked water-swellable polymers of indenmaleic anhydride; Goodrite® polyacrylic acid with a molecular weight of 80,000 to 200,000; grafted starch copolymers; Aqua-Keeps® acrylate polymer polysaccharides consisting of condensed glucose units, such as diester cross-linked polyglycan; carbomers with a viscosity of 3000 to 60,000 mPz in the form of 0.5% -1% wt./about. aqueous solution; cellulose ethers such as hydroxypropyl cellulose with a viscosity of about 1000-7000 mPz as 1% w / w. aqueous solution (25 ° C); hydroxypropyl methylcellulose with a viscosity of about 1000 or higher, preferably 2500 or higher, up to a maximum of 25000 mPz in the form of 2% w / v. aqueous solution; polyvinylpyrrolidone with a viscosity of approximately 300-700 mPz in the form of 10% wt./about. aqueous solution at 20 ° C and combinations thereof.

[0123] Alternatively, the drug release time can be controlled by dividing the delay time depending on the equilibrium state between the tolerance and the thickness of the membrane of a water-insoluble polymer (such as ethyl cellulose, EC) containing predetermined micropores at the bottom of the body and the amount of swelling excipient, such as low substitution hydroxypropyl cellulose (L-HPC) and sodium glycolate. After oral administration, GI fluids penetrate through the micropores, causing swelling of the swelling excipients, which form an internal pressure that disengages the components of the capsule, including the first capsule body containing the swellable substances, the second capsule body containing the drugs and the outer cap attached to the first capsule body.

[0124] The intestinal soluble layer may further comprise anti-adhesive agents such as talc or glyceryl monostearate and / or plasticizers. The intestinal soluble layer may further comprise one or more plasticizers, including, but not limited to, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, polyethylene glycol, acetylated monoglycerides, glycerol, triacetin, propylene glycol, phthalate dibate, e.g. , iron oxides, castor oil, sorbitol and dibutylsebatsat.

[0125] In another embodiment, a delayed release formulation utilizes a water-permeable but insoluble film coating on the enclosed active ingredient and the osmotic agent. Due to the fact that water from the gut diffuses slowly through the film into the core, the core swells until the film breaks, thereby releasing the active ingredients. The film coating can be adjusted to provide different rates of water permeability or release time.

[0126] In another embodiment, a delayed release formulation utilizes a waterproof tablet coating, whereby water enters through an adjustable opening in the coating until the core is destroyed. When a tablet breaks down, the contents of the drug are released immediately or over a longer period of time. These and other techniques can be modified to initiate a predetermined delay period before drug release.

[0127] In another embodiment, the active agents are delivered in a formulation to provide delayed release and sustained release (delayed sustained). The term “delayed sustained release” is used herein to refer to a composition of a medicament providing a pulsating release of the active agents in a predetermined period of time or with a delay period after administration, followed by a prolonged release of the active agents.

[0128] In some embodiments, immediate release, sustained release, delayed release, or delayed sustained release formulations comprise an active core containing one or more inert particles, each in the form of a granule, pellet, pill, granular particle, microcapsule, microsphere, microbead, nanocapsules or nanospheres whose surfaces are coated with drugs in the form of, for example, a drug-containing film-forming composition, using, for example, ehnik fluidized bed or by other methods known to those skilled in the art. An inert particle may have a different size, provided that it is large enough to remain poorly soluble. Alternatively, the active core can be obtained by granulating and grinding and / or extruding and spheronizing a polymer composition containing a drug substance.

[0129] The amount of drug in the core depends on the dose that is necessary, and typically varies from about 5 to 90% by weight. Typically, the polymer coating on the active core is from about 1 to 50% by weight of the coated particle, depending on the required delay period and type of release profile and / or selected polymers and solvents for the coating. Those skilled in the art are able to select the appropriate amount of drug for coating the core or introducing into the core in order to obtain the desired dose. In one embodiment, the inactive core may be a sphere of sugars or a crystal of a buffer solution or an encapsulated crystal of a buffer solution, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alter the microenvironment of the drug, facilitating it release.

[0130] In some embodiments, for example, a delayed release or delayed sustained release composition can be prepared by coating a particle containing a water-soluble / dispersible drug, such as a granule, with a mixture of a water-insoluble polymer and an intestinal soluble polymer, wherein the water insoluble polymer and an intestinal soluble polymer may be present in a weight ratio of 4: 1 to 1: 1, and the total weight of the coatings is 10 to 60% by weight of the total weight of the coated granules. The multilayer drug coated granules may optionally contain an internal dissolution control ethyl cellulose membrane. The composition of the outer layer, as well as the individual masses of the inner and outer layers of the polymer membrane, are optimized to obtain the desired daily rhythms of the release profiles for this active compound, which are theoretically calculated based on in vitro / in vivo correlations.

[0131] In other embodiments, the compositions may comprise a mixture of drug-containing particles with immediate release without controlling the dissolution rate of the polymer membrane and delayed sustained-release granules having, for example, a delay period of 2-4 hours after oral administration, thereby providing a biphasic release profile.

[0132] In some embodiments, to obtain the desired release profiles with or without a delay period, the active core is coated with one or more layers of dissolution rate control polymers. The membrane of the inner layer can significantly control the rate of release of the drug after the core has been soaked in water or body fluids, while the outer membrane can provide the desired delay period (period of no release of the drug or slight release after soaked in water or body fluids). The membrane of the inner layer may contain a water-insoluble polymer or a mixture of water-insoluble and water-soluble polymers.

[0133] Polymers suitable for the outer membrane, which largely controls the delay period of up to 6 hours, may include an intestinal soluble polymer as described above and a water insoluble polymer of 10 to 50% by weight. The ratio of water-insoluble polymer to intestinally soluble polymer may vary from 4: 1 to 1: 2, preferably the polymers are contained in a ratio of about 1: 1. The water-insoluble polymer, typically used, is ethyl cellulose.

[0134] Illustrative water insoluble polymers include ethyl cellulose, polyvinyl acetate (Kollicoat SR # 0D from BASF), neutral copolymers based on ethyl acrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as EUDRAGIT® NE, RS30 and RS30 and RS30 , RL or RL30D, and the like. Illustrative water-soluble polymers include low molecular weight HPMC, HPC, methyl cellulose, polyethylene glycol (PEG molecular weight> 3000) in a narrow range from 1% to 10% by weight, depending on the solubility of the active compound in water and a solvent or latex suspension based on the coating composition used. The ratio of water-insoluble polymer to water-soluble polymer, as a rule, can vary from 95: 5 to 60:40, preferably from 80:20 to 65:35.

[0135] In some embodiments, AMBERLITE ™ IRP69 resin is used as a sustained release carrier. AMBERLITE ™ IRP69 is an insoluble, strongly acidic cation exchange resin in sodium form, which is suitable as a carrier for cationic (alkaline) substances. In other embodiments, a DUOLITE ™ AP143 / 1093 resin is used as a sustained release carrier. DUOLITE ™ AP143 / 1093 is an insoluble, highly alkaline, anion-exchange resin, which is suitable as a carrier for anionic (acidic) substances.

[0136] When used as a drug carrier, AMBERLITE IRP69 or / and DUOLITE ™ AP143 / 1093 resin is a drug binding agent on an insoluble polymer matrix. Sustained release is obtained through the formation of resin-drug complexes (drug resinates). The drug is released from the resin in vivo as soon as the drug reaches an equilibrium state with high electrolyte concentrations that are characteristic of the gastrointestinal tract. More hydrophobic drugs tend to elute from the resin at a lower rate due to hydrophobic interactions with the aromatic structure of the cation exchange system.

[0137] Most intestinal dissolving coatings act by providing a surface that is stable at the very acidic pH found in the stomach, but is rapidly degraded at a less acidic (relatively more alkaline) pH. Thus, a pill with a coating dissolving in the intestine does not dissolve in the acid juices of the stomach (pH ~ 3), but they dissolve in an alkaline (pH 7-9) medium contained in the small intestine. Examples of enteric coating materials include, but are not limited to, methyl acrylate-methacrylic acid copolymers, cellulose acetosuccinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetosuccinate (hypromellose acetosuccinate), polyvinyl acetate phthalate, methyl methoxy acid copolymers, methyl copolymers and methyl acrylate. In some embodiments, the pharmaceutical composition is formulated for oral administration. Oral dosage forms include, for example, tablets, capsules, caplets, and may also include many granules, spheres, powders or pellets that can be encapsulated or not encapsulated. Tablets and capsules are the most suitable oral dosage forms in which case solid pharmaceutical carriers are employed.

[0138] In a delayed release formulation, one or more barrier coatings can be applied to pellets, tablets, or capsules to facilitate slow dissolution and concomitant release of drugs in the intestine. Typically, the barrier coating contains one or more polymers enclosing, surrounding or forming a layer or membrane around a therapeutic composition or active nucleus.

[0139] In some embodiments, the active agents are delivered in a formulation to provide a delayed release over a predetermined period of time after administration. The delay can be up to about 10 minutes, about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours or more.

[0140] To obtain various and specific release profiles, various coating methods can be applied to granules, spheres, powders or pellets, tablets, capsules, or combinations thereof containing active agents. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule containing one coating layer. In other embodiments, the pharmaceutical composition is in the form of a tablet or capsule containing a multilayer coating.

[0141] In some embodiments, the pharmaceutical composition comprises one or more analgesics, one or more α-blockers, and one or more other active ingredients selected from the group consisting of antimuscarinic agents, antidiuretics, and antispasmodics. In some embodiments, the pharmaceutical composition comprises one or more analgesics, one or more 5α-reductase inhibitors, and one or more other active ingredients selected from the group consisting of antimuscarinic agents, antidiuretics, α-blockers, and antispasmodics. Examples of antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, and atropine. Examples of antidiuretics include, but are not limited to, antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (e.g. desmopressin, agripressin, lipressin, felipressin, ornipressin, terlipressin, antagonist vasopressin natripeptid receptor antagonists (eg, NPR1, NPR2, NPR3) of type C natriuretic peptide (CNP) (eg, HS-142-1, isatin, [Asu7.23 '] b-ANP- (7-28)], anantine, cyclic peptide from Streptomyces coerulescens and monoclonal antibody 3G12), somatostat receptor antagonists type 2 (for example, somatostatin) and their pharmaceutically acceptable derivatives, analogs, salts, hydrates and solvates.

[0142] In some embodiments, the pharmaceutical composition comprises one or more analgesics and one or more α-blockers. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more α-blockers, and (3) one or more antimuscarinic agents. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more α-blockers, and (3) one or more antidiuretics. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more α-blockers, and (3) one or more antispasmodics. In another embodiment, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or more α-blockers, (3) one or two antimuscarinic agents, and (4) one or two antidiuretics. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more α-blockers, (3) one or more antispasmodics, and (4) one or more antidiuretics.

[0143] In some embodiments, the pharmaceutical composition comprises one or more analgesics and one or more 5α-reductase inhibitors. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, and (3) one or more antimuscarinic agents. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, and (3) one or more antidiuretics. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, and (3) one or more antispasmodics. In another embodiment, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or more 5α-reductase inhibitors, (3) one or two antimuscarinic agents, and (4) one or two antidiuretics. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more antispasmodics, and (4) one or more antidiuretics.

[0144] In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, and (3) one or more α-blockers. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more α-blockers, and (4) one or more antidiuretics. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more α-blockers, and (4) one or more antispasmodics. In another embodiment, the pharmaceutical composition comprises (1) one or two analgesics, (2) one or more 5α-reductase inhibitors, (3) one or two antimuscarinic agents, (4) one or two antidiuretics, and (5) one or more α -blockers. In another embodiment, the pharmaceutical composition comprises (1) one or more analgesics, (2) one or more 5α-reductase inhibitors, (3) one or more antispasmodics, (4) one or more antidiuretics and (5) one or more α -blockers.

[0145] In one embodiment, most of the active ingredients are formulated for immediate release. In another embodiment, most of the active ingredients are formulated for sustained release. In another embodiment, most of the active ingredients are formulated for immediate release and sustained release (for example, the first part of each active ingredient is formulated for immediate release and the second part of each active ingredient is formulated for sustained release). In yet another embodiment, some of the majority of the active ingredients are formulated for immediate release and some of the majority of the active ingredients are formulated for sustained release (e.g., active ingredients A, B, C are formulated for immediate release, and active ingredients C and D are formulated for long-term release. release). In some other embodiments, the immediate release component and / or the sustained release component are further coated with a delayed release coating, such as an enteric coating.

[0146] In certain embodiments, the pharmaceutical composition comprises an immediate release component and a sustained release component. The immediate release component may contain one or more active ingredients selected from the group consisting of analgesics, α-blockers, 5α-reductase inhibitors, antimuscarinic agents, antidiuretics, and antispasmodics. The sustained release component may contain one or more active ingredients selected from the group consisting of analgesics, α-blockers, antimuscarinic agents, antidiuretics, and antispasmodics. In some embodiments, the immediate release component and the sustained release component contain the exact same active ingredients. In other embodiments, the immediate release component and the sustained release component comprise various active ingredients. In other embodiments, the immediate release component and the sustained release component comprise one or more of the same active ingredients. In some other embodiments, the immediate release component and / or the sustained release component are further coated with a delayed release coating, such as an enteric coating.

[0147] In one embodiment, the pharmaceutical composition comprises two or more active ingredients (eg, a mixture of one or more analgesics and one or more α-blockers, one or more 5α-reductase inhibitors, one or more antimuscarinic agents, or antidiuretics or antispasmodics) formulated for immediate release at approximately the same point in time. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated for sustained release at approximately the same point in time. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated as two sustained release components, wherein each component has a different sustained release profile. For example, the first sustained release component releases the first active ingredient with a first release rate, and the second sustained release component releases the second active ingredient with a second release rate. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated for delayed release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated for delayed release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients formulated as two delayed release components, where each component has a different delayed release profile. For example, the first delayed release component releases the first active ingredient at the first point in time, and the second delayed release component releases the second active ingredient at the second point in time. In another embodiment, the pharmaceutical composition comprises two or more active ingredients, one or more of which is formulated for immediate release, and the other is formulated for sustained release. In another embodiment, the pharmaceutical composition comprises two or more active ingredients, a fraction of which is formulated for immediate release, and the remainder is formulated for sustained release.

[0148] In some embodiments, the pharmaceutical composition comprises one or more analgesic agents and one or more α-blockers, a 5α-reductase inhibitor, an antidiuretic, where one or more analgesic agents and one or more α-blockers are formulated for delayed release and where the antidiuretic formulated for immediate release. In other embodiments, the pharmaceutical composition further comprises an additional agent selected from the group consisting of an analgesic agent, α-blocker, 5α-reductase inhibitor, antimuscarinic agent, antidiuretic agent and antispasmodic, where the additional agent is formulated for delayed release. In some embodiments, a delayed release formulation slows the release of the active ingredient over a period of 1, 2, 3, 4, or 5 hours.

[0149] The term "immediate release" is used in the present description in relation to the composition of the drug, which does not contain a substance that controls the dissolution. Essentially, there is no delay in the release of active agents after administration of an immediate release formulation. The immediate release coating may contain suitable substances that dissolve immediately after administration, so as to release drug contents therein. Illustrative immediate release coating materials include gelatin, polyvinyl alcohol and polyethylene glycol copolymers (PVA-PEG) (e.g., Kollicoat®), and various other materials known to those skilled in the art.

[0150] The immediate-release composition may be 100% of the total dose of the active agent administered in a single unit dose. Alternatively, the immediate-release component can be formulated as a component in a composition with a combined release profile, which can comprise from about 1% to about 60% of the total dose of active agent (c) delivered by the pharmaceutical formulations. For example, the immediate release component may be from about 5% -60%, from about 10% to about 60%, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30% from about 10% to about 20%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 30%, from about 30% to about 60%, from about 30% up to about 50%, from about 40% to about about 60%, from about 40% to about 50%, from about 45% to about 60%, or from about 45% to about 50% of the total dose of active agent (c) delivered to the formulations. In alternative embodiments, the immediate release component comprises about 2, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60% of the total dose of active agent (c) delivered by the formulation.

[0151] In some embodiments, the immediate release or delayed release formulation comprises an active core consisting of one or more inert particles, each in the form of a granule, pellet, pill, granular particle, microcapsule, microsphere, microgranule, nanocapsule or nanosphere, the surface of which coated with drugs in the form of, for example, a drug-containing film-forming composition, using, for example, a fluidized bed technique or other methods known Professionals widely in this area. An inert particle can be of various sizes, provided that it is large enough to remain poorly soluble. Alternatively, the active core can be obtained by granulating and grinding and / or extruding and spheronizing a polymer composition containing a drug substance.

[0152] The amount of drug in the core depends on the dose that is necessary, and typically varies from about 5 to 90% by weight. Typically, the polymer coating on the active core is about 1 to 50% by weight of the coated particle, depending on the required delay period and type of release profile and / or coating polymers and solvents chosen. Those skilled in the art are able to select the appropriate amount of drug for coating the core or introducing into the core in order to obtain the desired dose. In one embodiment, the inactive core may be a sphere of sugars or a crystal of a buffer solution or an encapsulated crystal of a buffer solution, such as calcium carbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc., which alter the microenvironment of the drug, facilitating it release.

[0153] In some embodiments, the delayed release formulation is formulated by coating a particle containing a water-soluble / dispersible drug, such as a granule, a mixture of a water-insoluble polymer and an intestinal soluble polymer, wherein the water insoluble polymer and the intestinal insoluble polymer may be contained in a mass ratio of from 4: 1 to 1: 1, and the total weight of the coatings is from 10 to 60% by weight of the total weight of the coated granules. The multilayer drug coated granules may optionally contain an internal dissolution control ethyl cellulose membrane. The composition of the outer layer, as well as the individual masses of the inner and outer layers of the polymer membrane, are optimized to obtain the desired daily rhythms of the release profiles for this active compound, which are theoretically calculated based on in vitro / in vivo correlations.

[0154] In other embodiments, the compositions comprise a mixture of drug-containing particles with immediate release, without a polymer membrane controlling the rate of dissolution, and particles with a delayed release having, for example, a delay period of 2-4 hours after oral administration, thereby providing biphasic release profile. In other embodiments, the compositions comprise a mixture of two types of delayed release granules: the first type, which has a delay period of 1-3 hours, and the second type, which has a delay period of 4-6 hours.

[0155] Preferably, the formulations are designed with release profiles to limit impaired proper sleep, where the composition releases the drug when the subject typically wakes up from urge to urinate. For example, consider a subject who goes to bed at 11 pm and, as a rule, wakes up at 12:30, 3:00 in the morning and 6:00 in the morning to go to the toilet. A delayed-release vehicle can be taken at 10 p.m., and it begins delivery of the drug at 12 a.m. and gradually releases the drug over a period of 5-8 hours, thereby delaying or eliminating the urination. In other embodiments, the compositions are designed with a release profile such that a fraction of a drug (e.g., 20-60%) is released immediately or 2 hours after administration, and the remainder is released over an extended period of time. The pharmaceutical composition can be administered daily or administered as needed. In certain embodiments, the pharmaceutical composition is administered to a subject before bedtime. In some embodiments, the pharmaceutical composition is administered immediately before bedtime. In some embodiments, the pharmaceutical composition is administered about two hours before bedtime, preferably about one hour before bedtime. In another embodiment, the pharmaceutical composition is administered approximately two hours before bedtime. In a further embodiment, the pharmaceutical composition is administered at least two hours before bedtime. In another embodiment, the pharmaceutical composition is administered about one hour before bedtime. In a further embodiment, the pharmaceutical composition is administered at least one hour before bedtime. In yet a further embodiment, the pharmaceutical composition is administered less than one hour before bedtime. In yet another embodiment, the pharmaceutical composition is administered immediately before bedtime. Preferably, the pharmaceutical composition is administered orally. Suitable compositions for oral administration include, but are not limited to: tablets, coated tablets, dragees, capsules, powders, granules and soluble tablets, and liquid, for example, suspensions, dispersions or solutions.

[0156] A suitable dose ("therapeutically effective amount") of the active agent (c) in the immediate release component or the sustained release component depends, for example, on the severity and course of the condition, route of administration, bioavailability of the particular agent (c), age and weight the patient, the patient’s medical history and reactions to the active agent (a), doctor’s decisions, etc.

[0157] As a general suggestion, a therapeutically effective amount of the active agent (c) in an immediate release component, a sustained release component or a delayed long release component is administered in the range of about 100 μg / kg body weight / day to about 100 mg / kg body weight / day for one or more administrations. In some embodiments, the range of each active agent administered daily in a single dose or a multiple dose is from about 100 μg / kg body weight / day to about 50 mg / kg body weight / day, from 100 μg / kg body weight / day up to 10 mg / kg body weight / day, from 100 μg / kg body weight / day to about 1 mg / kg body weight / day, from 100 μg / kg body weight / day to about 10 mg / kg body weight / day, from 500 μg / kg body weight / day to about 100 mg / kg body weight / day, from 500 μg / kg body weight / day to about 50 mg / kg body weight / day, from 500 μg / kg body weight / day to about 5 mg / kg body weight / day, from 1 mg / kg body weight / day to about 100 mg / kg body weight / day, from 1 mg / kg body weight / day to about 50 mg / kg body weight / day, from 1 mg / kg body weight / day to about 10 mg / kg body weight / day, from 5 mg / kg body weight / dose up to about 100 mg / kg body weight / day, from 5 mg / kg body weight / dose up to about 50 mg / kg body weight / day, from 10 mg / kg body weight / day to about 100 mg / kg body weight / day and from 10 mg / k body weight / day to about 50 mg / kg body weight / day.

[0158] The active agent (a) described herein may be contained in an immediate release component or a sustained release component, a delayed sustained release component, or combinations thereof for daily oral administration in a single dose or in a combined dose range of 1 mg up to 2000 mg, from 5 mg to 2000 mg, from 10 mg to 2000 mg, from 50 mg to 2000 mg, from 100 mg to 2000 mg, from 200 mg to 2000 mg, from 500 mg to 2000 mg, from 5 mg to 1800 mg, 10 mg to 1600 mg, 50 mg to 1600 mg, 100 mg to 1500 mg, 150 mg to 1200 mg, 200 mg to 1000 mg, 300 g to 800 mg, 325 mg to 500 mg, 1 mg to 1000 mg, 1 mg to 500 mg, 1 mg to 200 mg, 5 mg to 1000 mg, 5 mg to 500 mg, 5 mg up to 200 mg, from 10 mg to 1000 mg, from 10 mg to 500 mg, from 10 mg to 200 mg, from 50 mg to 1000 mg, from 50 mg to 500 mg, from 50 mg to 200 mg, from 250 mg to 1000 mg, 250 mg to 500 mg, 500 mg to 1000 mg, 500 mg to 2000 mg. As expected, dosing depends on the condition, size, age and condition of the patient.

[0159] In some embodiments, the pharmaceutical composition comprises one analgesic and one or more α-blockers or one or more 5α-reductase inhibitors. In one embodiment, one analgesic agent is aspirin. In another embodiment, one analgesic agent is ibuprofen. In another embodiment, one analgesic is naproxen or naproxen sodium. In another embodiment, one analgesic agent is indomethacin. In another embodiment, one analgesic agent is nabumetone. In another embodiment, one analgesic agent is acetaminophen. In another embodiment, one analgesic is acetaminophen, and one or more α-blockers includes tamsulosin. In another embodiment, one analgesic agent is acetaminophen, and one or more 5α-reductase inhibitors include finasteride.

[0160] In some embodiments, a single analgesic is administered in a daily dose of from 1 mg to 2000 mg, from 5 mg to 2000 mg, from 20 mg to 2000 mg, from 5 mg to 1000 mg, from 20 mg to 1000 mg, 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg, or 500 mg to 1000 mg. In certain embodiments, the pharmaceutical composition comprises acetylsalicylic acid, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone or acetaminophen as one analgesic agent and the analgesic agent is administered orally in a daily dose in the range from 5 mg to 2000 mg, from 20 mg to 2000 mg , from 5 mg to 1000 mg, from 20 mg to 1000 mg, from 50 mg to 500 mg, from 100 mg to 500 mg, from 250 mg to 500 mg, from 250 mg to 1000 mg or from 500 mg to 1000 mg. In some embodiments, the second analgesic is administered in a daily dose of from 1 mg to 2000 mg, from 5 mg to 2000 mg, from 20 mg to 2000 mg, from 5 mg to 1000 mg, from 20 mg to 1000 mg, from 50 mg to 500 mg, 100 mg to 500 mg, 250 mg to 500 mg, 250 mg to 1000 mg, or 500 mg to 1000 mg.

[0161] In other embodiments, the pharmaceutical composition comprises a pair of analgesic agents and one or more α-blockers. Examples of such paired analgesic agents include, but are not limited to, acetylsalicylic acid, ibuprofen, acetylsalicylic acid and sodium naproxen, acetylsalicylic acid, nabumetone, aspirin and acetaminophen, acetylsalicylic acid, indomethacin, ibuprofen and naproxen sodium, ibuprofen, nabumetone, ibuprofen and acetaminophen , ibuprofen and indomethacin, naproxen, naproxen sodium and nabumetone, naproxen sodium and acetaminophen, naproxen sodium and indomethacin, nabumetone and acetaminophen, nabumetone and ind omethacin and acetaminophen and indomethacin. Paired analgesics are mixed in a mass ratio in the range from 0.1: 1 to 10: 1, from 0.2: 1 to 5: 1, or from 0.3: 1 to 3: 1 in a combined dose in the range from 5 mg to 2000 mg, from 20 mg to 2000 mg, from 100 mg to 2000 mg, from 200 mg to 2000 mg, from 500 mg to 2000 mg, from 5 mg to 1500 mg, from 20 mg to 1500 mg, from 100 mg to 1500 mg, 200 mg to 1500 mg, 500 mg to 1500 mg, 5 mg to 1000 mg, 20 mg to 1000 mg, 100 mg to 1000 mg, 250 mg to 500 mg, 250 mg to 1000 mg , from 250 mg to 1500 mg, from 500 mg to 1000 mg, from 500 mg to 1500 mg, from 1000 mg to 1500 mg and from 1000 mg to 2000 mg. In one embodiment, paired analgesic agents are mixed in a weight ratio of 1: 1.

[0162] In some other embodiments, the pharmaceutical composition of the present invention further comprises one or more antimuscarinic agents. Examples of antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium and atropine. The daily dose of an antimuscarinic agent is in the range from 0.01 mg to 100 mg, from 0.1 mg to 100 mg, from 1 mg to 100 mg, from 10 mg to 100 mg, from 0.01 mg to 25 mg, from 0 , 1 mg to 25 mg, from 1 mg to 25 mg, from 10 mg to 25 mg, from 0.01 mg to 10 mg, from 0.1 mg to 10 mg, from 1 mg to 10 mg, from 10 mg to 100 mg and 10 mg to 25 mg.

[0163] In certain embodiments, the pharmaceutical composition comprises one or more α-blockers, an analgesic agent selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen, naproxen sodium, nabumeton, acetaminophen and indomethacin, and an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.

[0164] Another aspect of the present invention relates to a method for decreasing the frequency of urination by administering to a subject in need thereof a pharmaceutical composition formulated as an immediate release composition. The pharmaceutical composition contains one or more analgesic agents and one or more additional active ingredients selected from the group consisting of 5α-reductase inhibitors, α-blockers, antimuscarinic agents, antidiuretic agents and antispasmodics. The pharmaceutical composition may be formulated in the form of a tablet, capsule, dragee, powder, granulate, liquid, gel or emulsion. The subject may take the indicated liquid, gel or emulsion in a “naked” form or contained in a capsule.

[0165] In certain embodiments, the analgesic agent is selected from the group consisting of salicylates, aspirin, salicylic acid, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine, derivatives of para-aminophenol, acetanilide, acetaminophen, phenacethenamefenamate, phenamate, phenamate, meclofenamate sodium, derivatives of heteroaryl acetic acid, tolmetin, ketorolac, diclofenac, derivatives of propionic acid, ibuprofen, naproxen sodium, naproxen, phenoprofen, ketoprofen, flurbip ofena, oxaprozin; enolic acids, derivatives of oxicam, piroxicam, meloxicam, tenoxicam, ampiroxicam, droxicam, pivoxicam, derivatives of pyrazolone, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone, coxibib, celecoxib, rofecoxinodibulone, indofecacolindazole, nabolecinodibole, indobenone, nabolecinodibodazole, nabolecinodibole, nabolecinodibole, indobecodibasole, nabolecinodibole, nabecodibonodinum, indolefin, apinodimene, nabove and isobutylphenylpropionic acid. The antimuscarinic agent is selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine.

[0166] In some embodiments, the pharmaceutical composition comprises one analgesic, one α-blocker, and one antimuscarinic. In some embodiments, the pharmaceutical composition comprises one analgesic, one 5α-reductase inhibitor, and one antimuscarinic. In one embodiment, one analgesic agent is aspirin. In another embodiment, one analgesic agent is ibuprofen. In another embodiment, one analgesic is naproxen or naproxen sodium. In another embodiment, one analgesic agent is indomethacin. In another embodiment, one analgesic agent is nabumetone. In another embodiment, one analgesic agent is acetaminophen. In another embodiment, one α-blocker is tamsulosin. An analgesic, an α-blocker, an 5α-reductase inhibitor and an antimuscarinic agent can be administered in doses in the ranges described above. In some embodiments, the pharmaceutical composition further comprises an antidiuretic or antispasmodic.

[0167] In some embodiments, the pharmaceutical composition comprises one or more analgesic agents alone or in combination in an amount of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg , 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-100 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg , 100-1000 mg, 100-800 mg, 100-600 mg, 100-400 mg, 100-250 mg, 250-2000 mg, 250-1500 mg, 250-1200 mg, 250-1000 mg, 250-800 mg , 250-600 mg, 250-400 mg, 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg , 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg , 1200-2000 mg, 1200-1500 mg or 1500-2000 mg, wherein the composition is formulated for sustained release with a release profile in which one or more analgesic agents are released continuously over a period of 5-24 hours, 5-8, 8-16 hours, or 16-24 hours.

[0168] In some embodiments, the composition is formulated for sustained release with a release profile in which at least 90% of the active ingredients are released continuously over a period of 5-24 hours, 5-8, 8-16 hours, or 16-24 hours.

[0169] In some embodiments, the composition is formulated for sustained release with a release profile in which the active ingredients are released continuously over a period of 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours.

[0170] In other embodiments, the composition is formulated for sustained release with a release profile in which the active ingredients are released at a constant rate over a period of 5-24 hours, 5-8, 8-16 hours, or 16-24 hours. In other embodiments, the composition is formulated for sustained release with a release profile in which the active ingredients are released at a constant rate over a period of 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours. As used herein, a “constant rate over a period of time” is defined as a release profile in which the release rate at any given time in a given time period is in the range of 30% -300% of the average release rate during this given time period. For example, if 80 mg of aspirin is released at a constant rate over a period of 8 hours, the average release rate during this time period is 10 mg / hour, and the actual release rate at any point in time during this time period is in the range of 3 mg / hour to 30 mg / hour (i.e. in the range of 30% -300% of the average release of 10 mg / hour for a period of 8 hours).

[0171] In some embodiments, the analgesic is selected from the group consisting of aspirin, ibuprofen, sodium naproxen, naproxen, indomethacin, nabumetone, and acetaminophen. The pharmaceutical composition is formulated to provide continuous release of a small amount of an analgesic to maintain an effective concentration of the drug in the blood, so that the total amount of the drug in a single dose is reduced compared to the immediate-release formulation. Other active ingredients may be released immediately after administration or released with an analgesic.

[0172] In some embodiments, the pharmaceutical composition comprises 50-400 mg, 50-250 mg, 250-400 mg, or 400-600 mg of an analgesic formulated for sustained release with a release profile in which at least 90% of the analgesic is released continuously or at a constant speed for a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0173] In one particular embodiment, the pharmaceutical composition comprises 50-250 mg of acetaminophen formulated for sustained release with a release profile wherein at least 90% of acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16, or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0174] In another specific embodiment, the pharmaceutical composition comprises 250-400 mg of acetaminophen formulated for sustained release with a release profile in which 90% of acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0175] In another specific embodiment, the pharmaceutical composition comprises 400-600 mg of acetaminophen formulated for sustained release with a release profile in which 90% of acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0176] In another specific embodiment, the pharmaceutical composition comprises 600-800 mg of acetaminophen formulated for sustained release with a release profile in which 90% of acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0177] In yet another embodiment, the pharmaceutical composition comprises 800-1000 mg of acetaminophen formulated for sustained release with a release profile in which at least 90% of acetaminophen is released continuously or at a constant rate over a period of 5-8, 8-16, or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0178] In some other embodiments, the pharmaceutical composition comprises one or more analgesic agents alone or in combination in an amount of 50-2000 mg, 50-1500 mg, 50-1200 mg, 50-1000 mg, 50-800 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 100-2000 mg, 100-1500 mg, 100-1200 mg, 100-1000 mg, 100-800 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-200 mg, 200-2000 mg, 200-1500 mg, 200-1200 mg, 200-1000 mg, 200-800 mg, 200-600 mg, 200-400 mg, 400-2000 mg, 400-1500 mg, 400-1200 mg, 400-1000 mg, 400-800 mg, 400-600 mg, 600-2000 mg, 600-1500 mg, 600-1200 mg, 600-1000 mg, 600-800 mg, 800-2000 mg, 800-1500 mg, 800-1200 mg, 800-1000 mg, 1000-2000 mg, 1000-1500 mg, 1000-1200 mg, 1200-2000 mg, 1200-1500 mg and whether 1500-2000 mg, where the analgesic agent (a) is formulated for sustained release, which is characterized by a biphasic release profile, in which 20-50% of the analgesic agent (a) is released 2 hours after administration, and the remainder is released continuously or at a constant speed , over a period of 5-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0179] In yet another embodiment, the analgesic agent (a) is formulated for sustained release with a biphasic release profile, wherein 20, 30, 40, or 50% of the analgesic agent (c) is released within 2 hours after administration, and the remainder is released continuously or at a constant speed for a period of 5-8, 8-16 or 16-24 hours. In one embodiment, the analgesic agent (a) is selected from the group consisting of aspirin, ibuprofen, sodium naproxen, naproxen, indomethacin, nabumetone and acetaminophen. In another embodiment, the analgesic is acetaminophen. In some embodiments, the pharmaceutical composition further comprises an antimuscarinic agent, antidiuretic agent, or antispasmodic. Other active ingredients may be released immediately after administration or released with an analgesic.

[0180] In another embodiment, the pharmaceutical composition comprises 50-400 mg of acetaminophen formulated for sustained release with a biphasic release profile, wherein 20%, 30%, 40%, or 50% of acetaminophen is released within 2 hours after administration, and the remainder is released continuously or at a constant speed for a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0181] In another embodiment, the pharmaceutical composition comprises 100-300 mg of acetaminophen formulated for sustained release with a biphasic release profile in which 20%, 30%, 40%, or 50% of acetaminophen is released within 2 hours after administration, and the remainder released at a constant speed for a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0182] In another embodiment, the pharmaceutical composition comprises 400-600 mg of acetaminophen formulated for sustained release with a biphasic release profile in which 20%, 30%, 40%, or 50% of acetaminophen is released within 2 hours after administration, and the remainder is released continuously or at a constant speed for a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0183] In another embodiment, the pharmaceutical composition comprises 600-800 mg of acetaminophen formulated for sustained release with a biphasic release profile, wherein 20%, 30%, 40%, or 50% of acetaminophen is released within 2 hours after administration, and the remainder released continuously or at a constant speed for a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0184] In another embodiment, the pharmaceutical composition comprises 800-1000 mg of acetaminophen formulated for sustained release with a biphasic release profile, wherein 20%, 30%, 40%, or 50% of acetaminophen is released within 2 hours after administration, and the remainder is released continuously or at a constant speed for a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0185] In another embodiment, the pharmaceutical composition comprises 1000-1200 mg of acetaminophen formulated for sustained release with a biphasic release profile, wherein 20%, 30%, 40%, or 50% of acetaminophen is released within 2 hours after administration, and the remainder is released continuously or at a constant speed for a period of 5-8, 8-16 or 16-24 hours. Other active ingredients may be released immediately after administration or released with an analgesic.

[0186] Another aspect of the present invention relates to a method for treating nocturia by administering to a subject in need of (1) one or more analgesic agents, (2) an α-blocker or 5α-reductase inhibitor, or both, and (3) one or more antidiuretic agents. In certain embodiments, the antidiuretic agent (a) acts, (1) increasing the secretion of vasopressin, (2) increasing the activation of the vasopressin receptor, (3) decreasing the secretion of the atrial natriuretic peptide (ANP) or type C natriuretic peptide (CNP), or (4) decreasing activation of the ANP receptor and / or CNP.

[0187] Illustrative antidiuretic agents include, but are not limited to, antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogues (eg, desmopressin, agripressin, lipressin, felipressin, ornipressin, terlipressin); vasopressin receptor agonists, atrial natriuretic peptide (ANP) and receptor antagonists (eg NPR1, NPR2, NPR3) of type C natriuretic peptide (CNP) (eg, HS-142-1, isatin, [Asu7,23 '] b-ANP- (7-28)], anantine, a cyclic peptide from Streptomyces coerulescens and a monoclonal antibody 3G12); type 2 somatostatin receptor antagonists (e.g., somatostatin) and their pharmaceutically acceptable derivatives, analogs, salts, hydrates and solvates.

[0188] In certain embodiments, one or more analgesic agents, an α-blocker and / or 5α-reductase inhibitor are formulated for sustained release, and one or more antidiuretic agents are formulated for immediate release. In other embodiments, one or more analgesic agents, an α-blocker and / or 5α-reductase inhibitor are formulated for delayed release and an antidiuretic formulated for immediate release. In some embodiments, the delayed release formulation delays the release of the active ingredient (eg, analgesic, antimuscarinic, antidiuretic, and antispasmodic) for a period of 1, 2, 3, 4, or 5 hours.

[0189] Another aspect of the present invention relates to a method for reducing urination by administering to a subject in need thereof a first pharmaceutical composition containing a diuretic, followed by a second pharmaceutical composition containing (1) one or more analgesic agents and (1) one or more α -blockers, one or more 5α-reductase inhibitors, or both. The first pharmaceutical composition is dosed and formulated to have a diuretic effect within 6 hours after administration, and administered at least 8 or 7 hours before bedtime. The second pharmaceutical composition is administered 2 hours before bedtime. The first pharmaceutical composition is formulated for immediate release and the second pharmaceutical composition is formulated for sustained release or delayed sustained release.

[0190] Examples of diuretics include, but are not limited to, acidifying salts such as CaCl ₂ and NH ₄ Cl; arginine-vasopressin receptor 2 antagonists such as amphotericin B and lithium citrate; watercolors such as goldenrod and junip; Na-H exchanger antagonists such as dopamine; carbonic anhydrase inhibitors such as acetazolamide and dorzolamide; loop diuretics such as bumetanide, ethacrylic acid, furosemide and torsemide; osmotic diuretics such as glucose and mannitol; potassium-sparing diuretics such as amiloride, spironolactone, triamteren, potassium canrenoate; thiazides, such as bendroflumethiazide and hydrochlorothiazide, and xanthines, such as caffeine, theophylline and theobromine.

[0191] In some embodiments, the second pharmaceutical composition further comprises one or more antimuscarinic agents. Examples of antimuscarinic agents include, but are not limited to, oxybutynin, solifenacin, darifenacin, fesoterodine, tolterodine, trospium and atropine. The second pharmaceutical composition can be formulated in an immediate release formulation or a delayed release formulation or a sustained release formulation. In some other embodiments, the second pharmaceutical composition further comprises one or more antidiuretic agents. In some other embodiments, the second pharmaceutical composition further comprises one or more antispasmodics. Another aspect of the present invention relates to a method for decreasing the frequency of urination by administering to a subject in need of two or more analgesic agents, alternatively, to prevent the development of drug resistance. In one embodiment, the method comprises administering a first analgesic agent for a first period of time, and then administering a second analgesic agent for a second period of time. In another embodiment, the method further comprises administering a third analgesic agent during a third time period. The first, second, and third analgesic agents are different from each other, and at least one of them is formulated for sustained release or delayed sustained release. In one embodiment, the first analgesic is acetaminophen, the second analgesic is ibuprofen and the third analgesic is naproxen sodium. The duration of each period may vary depending on the reaction of the subject to each analgesic. In some embodiments, each period lasts from 3 days to three weeks. In another embodiment, the first, second, and third analgesics are all formulated for sustained release or delayed sustained release.

[0192] Another aspect of the present invention relates to a pharmaceutical composition comprising a series of active ingredients and a pharmaceutically acceptable carrier, wherein at least one of the series of active ingredients is formulated for sustained release or delayed sustained release. In some embodiments, the implementation of a number of active ingredients contains one or more analgesics and one or more antidiuretics. In other embodiments, a series of active ingredients comprises one or more analgesics, one or more α-blockers, one or more 5α-reductase inhibitors, and one or more antimuscarinic agents. In other embodiments, a number of active ingredients comprise one or more analgesics, one or more α-blockers, one or more antidiuretic agents, and one or more antimuscarinic agents. In other embodiments, the pharmaceutical composition comprises two different analgesics selected from the group consisting of cetylsalicylic acid, ibuprofen, sodium naproxen, naproxen, nabumetone, acetaminophen, and indomethacin. In other embodiments, the pharmaceutical composition comprises one analgesic selected from the group consisting of cetylsalicylic acid, ibuprofen, naproxen sodium, nabumetone, acetaminophen and indomethacin, one or more α-blockers and an antimuscarinic agent selected from the group consisting of oxybutynin, solifenacin darifenacin and atropine.

[0193] In other embodiments, the pharmaceutical composition of the present invention further comprises one or more antispasmodics and / or one or more antidiuretics. Examples of antispasmodics include, but are not limited to, carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, metocarbamol, clonidine, an analogue of clonidine and dantrolene. In some embodiments, antispasmodics are used in a daily dose of from 1 mg to 1000 mg, from 1 mg to 100 mg, from 10 mg to 1000 mg, from 10 mg to 100 mg, from 20 mg to 1000 mg, from 20 mg to 800 mg , from 20 mg to 500 mg, from 20 mg to 200 mg, from 50 mg to 1000 mg, from 50 mg to 800 mg, from 50 mg to 200 mg, from 100 mg to 800 mg, from 100 mg to 500 mg, 200 mg to 800 mg and 200 mg to 500 mg. Antispasmodics can be formulated alone or together with other active ingredient (s) in the pharmaceutical composition for immediate release, sustained release, delayed sustained release, or combinations thereof.

[0194] In some embodiments, the pharmaceutical composition comprises one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone and acetaminophen, in a total amount of 50-400 mg per agent, one or more α-blockers and one or more antimuscarinic agents selected from the group consisting of oxybutynin, solifenacin, darifenacin and atropine, in a total amount of 1-25 mg, where the pharmaceutical composition is formulated for sustained release I have a two-phase release profile in which 20-60% of the active ingredients are released within 2 hours after administration, and the remaining part of the active ingredients is released continuously or at a constant speed over a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

[0195] In some embodiments, the pharmaceutical composition comprises one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone and acetaminophen, in an amount of 50-400 mg per agent, one or more α -blockers and one or more antidiuretic agents selected from the group consisting of antidiuretic hormone (ADH), angiotensin II, aldosterone, vasopressin, vasopressin analogs (e.g. desmopressin, agripressin, lipressin, felipr ssina, ornipressina, terlipressin); vasopressin receptor agonists, atrial natriuretic peptide (ANP) and antagonist receptor (eg NPR1, NPR2, NPR3) type C natriuretic peptide (CNP) (eg, HS-142-1, isatin, [Asu7,23 '] b-ANP- (7-28)], anantine, a cyclic peptide from Streptomyces coerulescens and monoclonal antibody 3G12); type 2 somatostatin receptor antagonists (e.g., somatostatin) and their pharmaceutically acceptable derivatives, analogs, salts, hydrates and solvates, wherein the pharmaceutical composition is formulated for sustained release with a biphasic release profile in which 20-60% of the active ingredients are released within 2 hours after introduction, and the remaining part is released continuously or at a constant speed for a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

[0196] In some embodiments, the pharmaceutical composition comprises (1) one or more analgesic agents selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin, nabumetone and acetaminophen, in an amount of 50-400 mg per agent, ( 2) one or more α-blockers or one or more 5α-reductase inhibitors, or both and (3) one or more antispasmodics selected from the group consisting of carisoprodol, benzodiazepines, baclofen, cyclobenzaprine, metaxalone, methocarbamol, clonidine, ana the log of clonidine and dantrolene, in a total amount of 50-500 mg, where the pharmaceutical composition is formulated for sustained release with a biphasic release profile, in which 20-60% of the active ingredients are released within 2 hours after administration, and the remaining part is released continuously or at a constant speed for a period of 5-24 hours, 5-8 hours, 8-16 hours or 16-24 hours.

[0197] As used herein, a "pharmaceutically acceptable carrier" includes any and all solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic and delaying absorption agents, sweeteners, and the like. Pharmaceutically acceptable carriers can be prepared from a wide range of substances, but not limited to flavors, sweeteners and excipients, such as buffers and absorbents, which may be necessary to produce a particular therapeutic composition. The use of such media and agents with pharmaceutically active substances is well known in the art. Unless any conventional medium or agent is incompatible with the active ingredient, their use in therapeutic compositions is contemplated.

[0198] The present invention is further illustrated by the following example, which should not be construed as limiting. The contents of all reference materials, patents, and published patent applications cited throughout this application are hereby incorporated by reference.

EXAMPLE 1: INHIBITING A urge to urinate

[0199] The study included twenty male and female volunteer subjects, each of whom experienced a premature urination or desire that interferes with the ability to sleep for a sufficient period of time to feel sufficiently rested. Each subject was taken orally 400-800 mg of ibuprofen in a single dose at bedtime. At least 14 subjects noted that they could have a better rest, as they did not wake up so often from the urge to urinate.

[0200] Some subjects noted that after several weeks of taking ibuprofen overnight, the beneficial effect of less frequent urges no longer occurred. However, all these subjects additionally noted the appearance of a beneficial effect after a few days after refraining from dosing.

EXAMPLE 2: EFFECT OF ANALGETIC MEDICINES, BOTULINIC NEUROTOXIN AND ANTIMUSKARIN MEDICINES ON THE RESPONSES OF MACROPHAGES TO INFLAMMATORY AND NON-INFLAMMATORY INCENTIVES

Experiment design

[0201] This study was planned to determine the dose and efficacy of in vitro analgesics and antimuscarinic agents in the controlled macrophage response to inflammatory and non-inflammatory stimuli mediated by COX2 and prostaglandins (PGE, PGH, etc.). Based on this, the initial responses (dose and kinetics) of inflammatory and non-inflammatory effectors in the cells of the bladder were established. Briefly, cultured cells are exposed to analgesics and / or antimuscarinic agents in the absence or presence of various effectors.

[0202] Effectors include: lipopolysaccharide (LPS), an inflammatory agent and an inducing factor Cox2 as inflammatory stimuli; carbachol or acetylcholine, a stimulator of smooth muscle contraction as non-inflammatory stimuli; botulinum neurotoxin A, a known inhibitor of the release of acetylcholine as a positive control and arachidonic acid (AA), gamma-linolenic acid (DGLA) or eicosapentaenoic acid (EPA) as precursors of prostaglandins, which are produced after the sequential oxidation of AA, DGLA or EPA within the cyclooxides (COX1 and COX2) and as a result of the pathways of the final synthesis of prostaglandins.

[0203] Analgesic agents include: salicylates, such as aspirin, a derivative of isobutylpropionic-phenolic acid (ibuprofen), such as advil, motrin, nuprin and mediprene, naproxen sodium, such as olive, anaprox, antalgin, feminax ultra, flanax, inza, midol long-term analgesia, nalgesin, naposin, naprezan, naprogesic, naprosin, naprosin suspension, EC-naprosin, narocin, proxene, sinflex and xenobide, an acetic acid derivative such as indomethacin (indocin), 1-naphthalene acetic acid derivative, such as nabuccinic acid relief en, a derivative of N-acetyl-para-aminophenol (APAP), such as acetaminophen or paracetamol (Tylenol) and celecoxib.

[0204] Antimuscarinic agents include: oxybutynin, solifenacin, darifenacin and atropine.

[0205] Macrophages were subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation:

(1) Each analgesic separately in different doses.

(2) Each analgesic in various doses in the presence of LPS.

(3) Each analgesic in various doses in the presence of carbachol or acetylcholine.

(4) Each analgesic in various doses in the presence of AA, DGLA or EPA.

(5) Botulinum neurotoxin A alone at various doses.

(6) Botulinum neurotoxin A at various doses in the presence of LPS.

(7) Botulinum neurotoxin A in various doses in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin A in various doses in the presence of AA, DGLA or EPA.

(9) Each antimuscarinic agent separately in different doses.

(10) Each antimuscarinic agent in various doses in the presence of LPS.

(11) Each antimuscarinic agent in various doses in the presence of carbachol or acetylcholine.

(12) Each antimuscarinic agent in various doses in the presence of AA, DGLA or EPA.

[0206] Then, the cells were analyzed for the isolation of PGH ₂ , PGE, PGE ₂ , postacidin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, cAMP and cGMP production, IL-1β, IL-6 production, TNF-α and COX2 mRNA, and surface expression of CD80, CD86 and class II MHC molecules.

Materials and methods

Macrophage cells

[0207] Macrophage cells of RAW264.7 or J774 mice (obtained from ATCC) were used in the study. Cells were maintained in a culture medium containing RPMI 1640 supplemented with 10% fetal calf serum (FBS), 15 mM HEPES, 2 mM L-glutamine, 100 U / ml penicillin and 100 μg / ml streptomycin. Cells were cultured at 37 ° C in an atmosphere of 5% CO ₂ and separated (reseeded) once a week.

Treatment of macrophage cells with in vitro analgesics

[0208] RAW264.7 macrophage cells were plated on 96-well plates at a cell density of 1.5 × 10 ⁵ cells per well in 100 μl of culture medium. Cells were treated (1) with different concentrations of analgesic (acetaminophen, aspirin, ibuprofen or naproxen), (2) different concentrations of lipopolysaccharide (LPS), which is an effector of inflammatory stimuli in macrophage cells, (3) different concentrations of carbachol or acetylcholine, which are non-inflammatory effectors stimuli, (4) analgesic and LPS, or (5) analgesic and carbachol or acetylcholine. Briefly, analgesics were dissolved in an FBS-free culture medium (i.e., RPMI 1640 supplemented with 15 mM HEPES, 2 mM L-glutamine, 100 U / ml penicillin and 100 μg / ml streptomycin) and diluted to the desired concentration with serial breeding the same medium. For cells treated with an analgesic in the absence of LPS, 50 μl of analgesic solution and 50 μl of FBS-free culture medium were added to each well. For cells treated with an analgesic in the presence of LPS, 50 μl of an analgesic solution and 50 μl of LPS (from Salmonella typhimurium) in FBS-free culture medium were added to each well. All conditions were tested in duplicate.

[0209] After 24 or 48 hours of cultivation, 150 μl of culture supernatants were collected, centrifuged for 2 minutes at 8000 rpm. at 4 ° C to remove cells and detritus and stored at -70 ° C for analysis of cytokine ELISA responses. Cells were harvested and washed by centrifugation (5 minutes at 1,500 rpm at 4 ° C) in 500 μl phosphate buffer (PBS). Then half of the cells were quickly frozen in liquid nitrogen and stored at -70 ° C. The remaining cells were stained with fluorescent monoclonal antibodies and analyzed by flow cytometry.

Flow cytometry analysis of co-stimulatory molecule expression

[0210] For flow cytometry analysis, macrophages were diluted with 100 μl FACS buffer (phosphate buffered saline (PBS) with 2% bovine serum albumin (BSA) and 0.01% NaN ₃ ) and stained for 30 minutes at 4 ° C by adding conjugated to FITC anti-CD40 antibodies, PE conjugated anti-CD80 antibodies, PE conjugated anti-CD86 antibodies, anti-MHC class II (IA ^d ) PE antibodies (BD Bioscience). Cells were then washed by centrifugation (5 minutes at 1500 rpm at 4 ° C) in 300 μl of FACS buffer. After a second wash, the cells were resuspended in 200 μl FACS buffer and the percentage of cells expressing this marker (positive signal) or combination of markers (double positive) was analyzed using an Accuri C6 flow cytometer (BD Biosciences).

Analysis of cytokine responses by ELISA

[0211] The culture supernatants were subjected to a cytokine-specific ELISA to determine the responses of IL-1β, IL-6 and TNF-α in macrophage cultures treated with analgesic, LPS alone or in combination of LPS and analgesic. Assays were performed on Nunc MaxiSorp immuno plates (Nunc), which were coated overnight with 100 ml anti-IL-6 mAb, mouse TNF-α (BD Biosciences) or anti-IL-1β mAb (R&D Systems) in 0.1 M sodium bicarbonate buffer ( pH 9.5). After two washes with PBS (200 μl per well), 200 μl PBS 3% BSA (block) was added to each well and the plates were incubated for 2 hours at room temperature. The plates were again washed twice with 200 μl per well, 100 μl of cytokine standards and serial dilutions of culture supernatants were added in duplicate, and the plates were incubated overnight at 4 ° C. Finally, the plates were washed twice and incubated with 100 μl of secondary biotinylated mAb against IL-6, mouse TNFα (BD Biosciences) or IL-1β (R&D Systems), followed by incubation with goat peroxidase labeled goat mAb to biotin (Vector Laboratories). A colorimetric study was carried out by adding a substrate of 2,2'-azino-bis (3) -ethylbenzylthiazolin-6-sulfonic acid (ABTS) and H ₂ O ₂ (Sigma) and the optical density was measured at 415 nm using a Victor® V multifunctional plate spectrophotometer ( PerkinElmer).

Determination of COX2 activity and cAMP and cGMP production

[0212] The activity of COX2 in cultured macrophages is determined by sequential competitive ELISA (R&D Systems). The production of cAMP and cGMP is determined by cAMP analysis and cGMP analysis. These analyzes are performed as is customary in the art.

results

[0213] Table 1 summarizes the experiments performed with the Raw 264 macrophage cell line and the main results regarding the effects of analgesics on the expression of CD40 and CD80 costimulatory molecules on the cell surface. The expression of these molecules is stimulated by COX2 and inflammatory signals, and thus, it was evaluated to determine the functional consequences of COX2 inhibition.

[0214] As shown in table 2, acetaminophen, aspirin, ibuprofen and naproxen inhibit the background expression of costimulatory molecules CD40 and CD80 by macrophages in all doses tested (ie 5 × 10 ⁵ nM, 5 × 10 ⁴ nM, 5 × 10 ³ nM, 5 × 10 ² nM, 50 nM and 5 nM) except for the highest dose (for example, 5 × 10 ⁶ nM), for which it was shown that it increases, but does not inhibit, the expression of co-stimulatory molecules. As shown in figures 1A and 1B, such an inhibitory effect on the expression of CD40 and CD50 was observed at doses of analgesic up to 0.05 nm (for example, 0.00005 μm). This finding confirms the notion that controlled release of small doses of an analgesic may be preferable for accurate delivery of large doses. The experiment also revealed that acetaminophen, aspirin, ibuprofen, and naproxen have a similar inhibitory effect on LPS-induced expression of CD40 and CD80.

Table 1
A brief description of the experiments The control LPS Salmonella typhimurium Acetaminophen Aspirin Ibuprofen Naproxen Tests one X 2 X Dose effects (0, 5, 50, 1000) ng / ml 3 X Dose effects (0, 5, 50, 500, 5 × 10 ³ , 5 × 10 ⁴ , 5 × 10 ⁵ , 5 × 10 ⁶ ) nM

four X X (5 ng / ml) X (50 ng / ml X (1000 ng / ml) Dose effects (0, 5, 50, 500, 5 × 10 ³ , 5 × 10 ⁴ , 5 × 10 ⁵ , 5 × 10 ⁶ ) nM Analysis a Activation / Stimulation Status Characterization: Flow Cytometry Analysis of CD40, CD80, CD86 and MHC Class II b Inflammatory response mediators: ELISA analysis of IL-1β, IL-6, TNF-α

table 2
Summary of Key Results Effectors % positive Negative control LPS 5 ng / ml Analgesic Dose (nM) 5 × 10 ⁶ 5 × 10 ⁵ 5 × 10 ⁴ 5 × 10 ³ 500 fifty 5 CD40 ⁺ CD80 ⁺ 20.6 77.8 Acetaminophen CD40 ⁺ CD80 ⁺ 63 eighteen 12 9.8 8.3 9.5 7.5 Aspirin CD40 ⁺ CD80 ⁺ 44 eleven 10.3 8.3 8 10.5 7.5 Ibuprofen CD40 ⁺ CD80 ⁺ n / a * 6.4 7.7 7.9 6.0 4.9 5.8 Naproxen CD40 ⁺ CD80 ⁺ 37 9.6 7.7 6.9 7.2 6.8 5.2 Analgesic plus LPS Acetaminophen CD40 ⁺ CD80 ⁺ 95.1 82.7 72,4 68.8 66.8 66,2 62.1 Aspirin CD40 ⁺ CD80 ⁺ 84.5 80 78.7 74.7 75.8 70.1 65.7 Ibuprofen CD40 ⁺ CD80 ⁺ n / a 67 77.9 72.9 71.1 63.7 60.3 Naproxen CD40 ⁺ CD80 ⁺ 66.0 74.1 77.1 71.0 68.8 72 73 * n / a: not performed (toxicity)

[0215] Table 3 shows the results of several studies that measured serum analgesic levels after oral therapeutic doses in adults. As shown in table 3, the maximum serum analgesic levels after an oral therapeutic dose are in the range of 10 ⁴ to 10 ⁵ nM. Thus, doses of the in vitro analgesic tested in Table 2 fall within the range of concentrations obtained in humans in vivo.

Table 3
Human serum analgesic levels after oral therapeutic doses Analgesic drug Molecular mass Maximum serum levels after oral therapeutic doses References mg / l nM Acetaminophen (Tylenol) 151.16 11-18 7.2 × 10 ⁴ -1.19 × 10 ⁵ * BMC Clinical Pharmacology, 2010, 10:10
* Anaesth Intensive Care, 2011, 39: 242 Aspirin (acetylsalicylic acid) 181.66 30-100 1.65 × 10 ⁵ -5.5 × 10 ⁵ * Disposition of Toxic Drugs and Chemicals in Man, 8th Edition, Biomedical Public, Foster City, CA, 2008, pp. 22-25
* J. Lab. Clin. Med., 1984, Jun; 103: 869 Ibuprofen (Advil, Motrin) 206.29 24-32 1.16 × 10 ⁵ -1.55 × 10 ⁵ * BMC Clinical Pharmacology, 2010, 10:10
* J. Clin. Pharmacol., 2001, 41: 330 Naproxen (olive) 230.26 up to 60 up to 2.6 × 10 ⁵ * J. Clin. Pharmacol., 2001, 41: 330

EXAMPLE 3: EFFECT OF ANALGETIC MEDICINES, BOTULINIC NEUROTOXIN AND ANTIMUSKARIN MEDICINES ON THE RESPONSE OF MUSCLE BLADDERS OF THE BLADDER ANIMAL AND INFLAMMATORY

Experiment design

[0216] This study was planned to characterize how the optimal analgesic doses determined in Example 2 affect smooth muscle cells of the bladder in cell culture or tissue cultures, and to establish whether different classes of analgesics can have a synergistic effect to more effectively inhibit responses COX2 and PGE2.

[0217] Effectors, analgesic agents and anti-muscarinic agents are described in Example 2.

[0218] The primary mouse culture of smooth muscle bladder cells was subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation:

(1) Each analgesic separately in different doses.

(2) Each analgesic in various doses in the presence of LPS.

(3) Each analgesic in various doses in the presence of carbachol or acetylcholine.

(4) Each analgesic in various doses in the presence of AA, DGLA or EPA.

(5) Botulinum neurotoxin A alone at various doses.

(6) Botulinum neurotoxin A at various doses in the presence of LPS.

(7) Botulinum neurotoxin A in various doses in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin A in various doses in the presence of AA, DGLA or EPA.

(9) Each antimuscarinic agent separately in different doses.

(10) Each antimuscarinic agent in various doses in the presence of LPS.

(11) Each antimuscarinic agent in various doses in the presence of carbachol or acetylcholine.

(12) Each antimuscarinic agent in various doses in the presence of AA, DGLA or EPA.

[0219] Then the cells were analyzed in relation to the allocation of PGH ₂ , PGE, PGE ₂ , prostacidin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, cAMP and cGMP production, IL-1β, IL-6 production, TNF-α and COX2 mRNA and surface expression of CD80, CD86 and class II MHC molecules.

Materials and methods

Isolation and purification of mouse bladder cells

[0220] Bladder cells were removed from euthanized animal C57BL / 6 mice (8-12 weeks old) and cells were isolated by enzymatic digestion, followed by purification in a Percoll gradient. Briefly, bladders from 10 mice were sheared with scissors to a fine suspension in 10 ml of cleavage buffer (RPMI 1640, 2% fetal calf serum, 0.5 mg / ml collagenase, 30 μg / ml DNase). Bladder suspensions were enzymatically digested for 30 minutes at 37 ° C. Unsplit fragments were further dispersed through a Cell-Trainer device. A cell suspension was besieged and added to a continuous Percoll gradient of 20%, 40% and 75% for purification to mononuclear cells. In each experiment, 50-60 bladders were used.

[0221] After washing in RPMI 1640, bladder cells were resuspended in RPMI 1640 supplemented with 10% fetal calf serum, 15 mM HEPES, 2 mM L-glutamine, 100 U / ml penicillin, and 100 μg / ml streptomycin and plated on 96- black well microcultural plates with a transparent bottom at a cell density of 3 × 10 ⁴ cells per well in 100 μl. Cells were cultured at 37 ° C in an atmosphere of 5% CO ₂ .

In vitro treatment of cells with analgesics

[0222] Bladder cells were treated with analgesic solutions (50 μl / well) separately or together with carbachol (10 mol, 50 μl / well) as an example of non-inflammatory stimuli, or Salmonella typhimurium lipopolysaccharide (LPS) (1 μg / ml, 50 μl / well) as an example of non-inflammatory stimuli. When no effectors were added to the cells, 50 μl of RPMI 1640 without fetal calf serum was added to the wells to bring the final volume to 200 μl.

[0223] After 24 hours of cultivation, 150 μl of culture supernatants were collected, centrifuged for 2 minutes at 8000 rpm. at 4 ° C to remove cells and detritus and stored at -70 ° C for analysis of prostaglandin E2 (PGE ₂ ) ELISA responses. To detect cyclooxygenase-2 (COX2) using a fluorogenic substrate, cells were fixed, permeabilized and blocked. In a selected experiment to analyze COX2 responses, cells were stimulated in vitro for 12 hours.

COX2 Answer Analysis

[0224] COX2 responses were analyzed by cell-based ELISA using a human / mouse total COX2 immunological assay (R&D Systems) according to the manufacturer's instructions. Briefly, after cell fixation and permeabilization, the mouse anti-total COX2 antibody and rabbit anti-total GAPDH antibody were added to the wells of 96-well clear-bottomed microcultural plates. After incubation and washing, HRP conjugated anti-mouse IgG antibody and AP conjugated anti-rabbit IgG antibody were added to the wells. After another incubation and a series of washes, HRP and AP fluorogenic substrates were added. Finally, a Victor® V multifunctional plate spectrophotometer (PerkinElmer) was used to read the fluorescence emitted at 600 nm (COX2 fluorescence) and 450 nm (GAPDH fluorescence). Results are expressed as relative total COX2 levels as determined by relative fluorescence units (RFUs) and normalized to household GAPDH protein.

PGE2 Answer Analysis

[0225] Prostaglandin E2 responses were analyzed by sequential specific ELISA (R&D Systems). More specifically, culture supernatants or PGE2 standards were added to the wells of a 96-well polystyrene microplate coated with goat anti-mouse polyclonal antibody. After one hour of incubation on the microplate shaker, HRP conjugated PGE2 was added and the plates were incubated for another two hours at room temperature. The plates were then washed and HRP substrate solution was added to each well. Leave for 30 minutes for the development of color and stop the reaction by adding sulfuric acid before taking readings from the tablet at 450 nm with the correction of the wavelength at 570 nm. The results were expressed as pg / ml PGE2.

Other analyzes

[0226] Isolation of PGH ₂ , PGE, prostacidin, thromboxane, IL-1β, IL-6 and TNF-α, production of cAMP and cGMP, production of IL-1β, IL-6, TNF-α and COX2 mRNA, and surface expression CD80, CD86 and MHC class II molecules are determined as described in example 2.

Analgesics inhibit mouse bladder COX2 response to inflammatory stimulus

[0227] To determine whether analgesics can induce COX2 responses, several analgesics (acetaminophen, aspirin, ibuprofen, and naproxen) were tested on mouse bladder cells at concentrations of 5 μM or 50 μM. An analysis of cultures at 24 hours demonstrated that none of the tested analgesics induced COX2 responses in mouse urinary bladder cells in vitro.

[0228] The effect of these analgesics on mouse COX2 cell responses to mouse stimulation with carbachol or LPS was also tested in vitro. As indicated in table 1, the dose of the tested carbachol does not have a significant effect on COX2 levels in mouse bladder cells. LPS, on the other hand, significantly increased overall COX2 levels. It should be noted that all acetaminophen, aspirin, ibuprofen, and naproxen can suppress the effect of LPS on COX2 levels. The overwhelming effect of the analgesic was observed when these drugs were tested at 5 μM or 50 μM (table 4).

Table 4
Expression of COX2 by mouse bladder cells after stimulation and treatment with an in vitro analgesic Stimulus Analgesic Common COX2 levels (normalized RFUs) no no 158 ± 18 Carbachol (mm) no 149 ± 21 LPS (1 μg / ml) no 420 ± 26 LPS (1 μg / ml) Acetaminophen (5 μM) 275 ± 12 LPS (1 μg / ml) Aspirin (5 μM) 240 ± 17 LPS (1 μg / ml) Ibuprofen (5 μM)) 253 ± 32 LPS (1 μg / ml) Naproxen (5 μM) 284 ± 11 LPS (1 μg / ml) Acetaminophen (50 μM) 243 ± 15 LPS (1 μg / ml) Aspirin (50 μM) 258 ± 21 LPS (1 μg / ml) Ibuprofen (50 μM) 266 ± 19 LPS (1 μg / ml) Naproxen (50 μM) 279 ± 23

Analgesics inhibit mouse bladder cell PGE2 responses to inflammatory stimulus

[0229] To determine the biological significance of changes in COX2 levels in mouse bladder cells, analgesics measured PGE2 secretion in the culture supernatants of mouse bladder cells. As shown in Table 5, PGE2 was not detected in the culture supernatants of unstimulated bladder cells or bladder cells cultured in the presence of carbachol. In accordance with the COX2 responses described above, stimulation of mouse LPS bladder cells induced the secretion of high levels of PGE2. The addition of acetaminophen, aspirin, ibuprofen, and naproxen analgesics suppressed the effect of LPS on PGE2 secretion, and no differences were observed in the responses of cells tested with a 5 or 50 μM analgesic dose.

Table 5
Secretion of PGE2 by mouse bladder cells after stimulation and treatment with an in vitro analgesic. Stimulus Analgesic PGE2 levels (pg / ml) no no <20.5 Carbachol (mm) no <20.5 LPS (1 μg / ml) no 925 ± 55 LPS (1 μg / ml) Acetaminophen (5 μM) 619 ± 32 LPS (1 μg / ml) Aspirin (5 μM) 588 ± 21 LPS (1 μg / ml) Ibuprofen (5 μM)) 593 ± 46 LPS (1 μg / ml) Naproxen (5 μM) 597 ± 19 LPS (1 μg / ml) Acetaminophen (50 μM) 600 ± 45 LPS (1 μg / ml) Aspirin (50 μM) 571 ± 53 LPS (1 μg / ml) Ibuprofen (50 μM) 568 ± 32 LPS (1 μg / ml) Naproxen (50 μM) 588 ± 37

[0230] In summary, these data demonstrate that analgesics alone at 5 μM or 50 μM do not induce COX2 and PGE2 responses in mouse bladder cells. However, analgesics at 5 μM or 50 μM significantly inhibit COX2 and PGE2 responses of mouse urinary bladder cells stimulated by in vitro LPS (1 μg / ml). No significant effect of analgesics on the responses of mouse urinary bladder cells stimulated by carbachol (1 mM) to COX2 and PGE2 was not observed.

EXAMPLE 4: EFFECT OF ANALGETIC MEDICINES, BOTULINIC NEUROTOXIN AND ANTIMUSCARINE MEDICINES ON THE REDUCTION OF MUSCLE BLADDERS OF THE BLADDER OF THE MOUSE

Experiment design

[0231] Cultured mouse or rat bladder smooth muscle cells and mouse or rat bladder smooth muscle tissue are exposed to inflammatory stimuli and non-inflammatory stimuli in the presence of an analgesic agent and / or antimuscarinic agent at various concentrations. In order to evaluate the inhibitory effect of the analgesic and / or antimuscarinic, stimulus-induced muscle contraction is measured.

[0232] The effectors of analgesic agents and antimuscarinic agents are described in Example 2.

[0233] The primary culture of smooth muscle cells in the mouse bladder was subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation:

(1) Each analgesic separately in different doses.

(2) Each analgesic in various doses in the presence of LPS.

(3) Each analgesic in various doses in the presence of carbachol or acetylcholine.

(4) Each analgesic in various doses in the presence of AA, DGLA or EPA.

(5) Botulinum neurotoxin A alone at various doses.

(6) Botulinum neurotoxin A at various doses in the presence of LPS.

(7) Botulinum neurotoxin A in various doses in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin A in various doses in the presence of AA, DGLA or EPA.

(9) Each antimuscarinic agent separately in different doses.

(10) Each antimuscarinic agent in various doses in the presence of LPS.

(11) Each antimuscarinic agent in various doses in the presence of carbachol or acetylcholine.

(12) Each antimuscarinic agent in various doses in the presence of AA, DGLA or EPA.

Materials and methods

[0234] The primary cells of the mouse bladder were isolated as described in Example 3. Bladder tissue cultures were used in the selected experiments. Bladder smooth muscle contractions were recorded using a Grass polygraph (Quincy Mass, USA).

EXAMPLE 5: EFFECT OF ORAL ANALGETIC AGENTS AND ANTI-MUSCARIN MEDICINES TO COX2 AND PGE2 SMOKE BLADDERS OF THE BLADDER OF THE MOUSE

Experiment design

[0235] Healthy mice and mice with overactive bladder syndrome receive oral doses of aspirin, sodium naproxen, ibuprofen, indocin, nabumetone, tylenol, celecoxib, oxybutynin, solifenacin, darifenacin, atropine, and combinations thereof. Control groups included untreated healthy mice and untreated OAB mice with overactive bladder syndrome. Thirty (30) minutes after the last doses, the bladders are collected and ex vivo stimulated with carbachol or acetylcholine. In selected experiments, the bladders are treated with botulinum neurotoxin A before stimulation with carbachol. Animals are kept in metabolic cells and the frequency (and volume) of urination is assessed. The amount of bladder excreted is determined by monitoring the water intake and the weight of the cell litter. Serum PGH ₂ , PGE, PGE ₂ , prostacidin, thromboxane, IL-1β, IL-6, TNF-α, cAMP, and cGMP levels are determined by serum ELISA. The expression of CD80, CD86, MHC class II in whole blood cells is determined by flow cytometry.

[0236] At the end of the experiment, the animals are euthanized and bladder contractions ex vivo are recorded using a Grass polygraph. Bladder patches are fixed in formalin and COX2 responses are analyzed by immunohistochemistry.

EXAMPLE 6: EFFECT OF ANALGETIC AGENTS, BOTULINIC NEUROTOXIN AND ANTIMUSKARIN MEDICINES ON THE REACTION OF HUMAN BLADDER CELLS IN RESPONSE TO INFLAMMATORY AND INFLAMMATORY

Experiment design

[0237] This study was designed to characterize how the optimal analgesic doses defined in Examples 1-5 affect smooth muscle cells of a human bladder in a cell culture or tissue culture, and to determine whether different classes of analgesics can have a synergistic effect for a more effective inhibition of COX2 and PGE2 responses.

[0238] Effectors, analgesic agents and antimuscarinic agents are described in Example 2.

[0239] Smooth muscle cells of the human bladder are subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation:

(1) Each analgesic separately in different doses.

(2) Each analgesic in various doses in the presence of LPS.

(3) Each analgesic in various doses in the presence of carbachol or acetylcholine.

(4) Each analgesic in various doses in the presence of AA, DGLA or EPA.

(5) Botulinum neurotoxin A alone at various doses.

(6) Botulinum neurotoxin A at various doses in the presence of LPS.

(7) Botulinum neurotoxin A in various doses in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin A in various doses in the presence of AA, DGLA or EPA.

(9) Each antimuscarinic agent separately in different doses.

(10) Each antimuscarinic agent in various doses in the presence of LPS.

(11) Each antimuscarinic agent in various doses in the presence of carbachol or acetylcholine.

(12) Each antimuscarinic agent in various doses in the presence of AA, DGLA or EPA.

[0240] Then the cells are analyzed in relation to the release of PGH ₂ , PGE, PGE ₂ , prostacidin, thromboxane, IL-1β, IL-6, TNF-α, COX2 activity, cAMP and cGMP production, IL-1β, IL-6 production, TNF-α and COX2 mRNA and surface expression of CD80, CD86 and class II MHC molecules.

EXAMPLE 7: EFFECT OF ANALGETIC MEDICINES, BOTULINIC NEUROTOXIN AND ANTIMUSKARIN MEDICINES ON THE REDUCTION OF HUMAN BLADDERS

Experiment design

[0241] Cultured smooth muscle cells of a human bladder were exposed to inflammatory stimuli and non-inflammatory stimuli in the presence of an analgesic agent and / or an antimuscarinic agent in various concentrations. To assess the inhibitory effect of the analgesic and / or antimuscarinic, stimulus-induced muscle contraction is measured.

[0242] Effectors, analgesic agents and anti-muscarinic agents are described in Example 2.

[0243] Smooth muscle cells of the human bladder were subjected to short-term (1-2 hours) or long-term (24-48 hours) stimulation:

(1) Each analgesic separately in different doses.

(2) Each analgesic in various doses in the presence of LPS.

(3) Each analgesic in various doses in the presence of carbachol or acetylcholine.

(4) Each analgesic in various doses in the presence of AA, DGLA or EPA.

(5) Botulinum neurotoxin A alone at various doses.

(6) Botulinum neurotoxin A at various doses in the presence of LPS.

(7) Botulinum neurotoxin A in various doses in the presence of carbachol or acetylcholine.

(8) Botulinum neurotoxin A in various doses in the presence of AA, DGLA or EPA.

(9) Each antimuscarinic agent separately in different doses.

(10) Each antimuscarinic agent in various doses in the presence of LPS.

(11) Each antimuscarinic agent in various doses in the presence of carbachol or acetylcholine.

(12) Each antimuscarinic agent in various doses in the presence of AA, DGLA or EPA.

[0244] Bladder smooth muscle contractions were recorded using a Grass polygraph (Quincy Mass, USA).

EXAMPLE 8: ANALGETIC EFFECT ON THE REACTION OF HUMAN NORMAL BLADDER SMOOTH CELLS IN RESPONSE TO INFLAMMATORY AND NON-INFLAMMATORY SIGNALS

EXPERIMENTAL SCHEME

Culture of smooth muscle cells of a normal human bladder

[0245] Smooth muscle cells of a normal human bladder were isolated by enzymatic digestion from macroscopically normal pieces of a human bladder. Cells were propagated in vitro by culturing at 37 ° C in an atmosphere of 5% CO ₂ in RPMI 1640 supplemented with 10% fetal calf serum, 15 mM HEPES, 2 mM L-glutamine, 100 U / ml penicillin and 100 μg / ml streptomycin and passaged alone once a week by treatment with trypsin to detach cells, followed by reseeding in a new cultivation vial. In the first week of cultivation, 0.5 ng / ml epidermal growth factor, 2 ng / ml fibroblast growth factor, and 5 μg / ml insulin were added to the culture medium.

Treatment of normal smooth muscle cells of a normal human bladder with in vitro analgesics

[0246] Trypsinized and plated in microcultural plates at a cell density of 3 × 10 ⁴ cells per well in 100 μl, smooth muscle bladder cells were treated with analgesic solutions (50 μl / well) separately or together with carbachol (10 mol, 50 μl / well) as an example of non-inflammatory stimuli or Salmonella typhimurium lipopolysaccharide (LPS) (1 μg / ml, 50 μl / well) as an example of non-inflammatory stimuli. When no other effectors were added to the cells, 50 μl of RPMI 1640 without fetal calf serum was added to the wells to bring the final volume to 200 μl.

[0247] After 24 hours of cultivation, 150 μl of culture supernatants were collected, centrifuged for 2 minutes at 8000 rpm. at 4 ° C to remove cells and detritus and stored at -70 ° C for analysis of prostaglandin E2 responses (PGE ₂ ) by ELISA. To detect COX2 using a fluorogenic substrate, the cells were fixed, permeabilized and blocked. In a selected experiment, cells were stimulated 12 hours in vitro to analyze the responses of COX2, PGE2 and cytokines.

Analysis of COX2, PGE2, and Cytokine Responses

[0248] COX2 and PGE2 responses were analyzed as described in Example 3. Cytokine responses were analyzed as described in Example 2.

RESULTS

[0249] Analgesics inhibit COX2 responses of smooth muscle cells of a normal human bladder to inflammatory and non-inflammatory stimuli. Analysis of cells and culture supernatants after 24 hours of cultivation showed that not one of the tested analgesics separately induced COX2 responses in smooth muscle cells of a normal human bladder. However, as shown in Table 6, carbachol induced low but reliable COX2 responses in smooth muscle cells of a normal human bladder. LPS treatment, on the other hand, led to higher levels of COX2 responses in the smooth muscle cells of a normal human bladder. Acetaminophen, aspirin, ibuprofen, and naproxen can all inhibit the effects of carbachol and LPS on COX2 levels. The overwhelming effect of analgesics was observed with respect to LPS-induced responses when these drugs were tested at 5 μM or 50 μM.

Table 6
Expression of COX2 by smooth muscle cells of a normal human bladder after stimulation with inflammatory and non-inflammatory stimuli and in vitro analgesic treatment Stimulus Analgesic Common levels of COX2 ^# (normalized RFU) subject 1 General COX2 levels (normalized RFU) subject 2 no no 230 199 Carbachol 10 ^-3 M no
(50 μM) 437 462 Carbachol 10 ^-3 M Acetaminophen (50 μM) 298 310 Carbachol 10 ^-3 M Aspirin
(50 μM) 312 297

Carbachol 10 ^-3 M Ibuprofen (50 μM) 309 330 Carbachol 10 ^-3 M Naproxen (50 μM) 296 354 LPS (10 mcg / ml) no 672 633 LPS (10 mcg / ml) Acetaminophen (5 μM) 428 457 LPS (10 mcg / ml) Aspirin
(5 μM) 472 491 LPS (10 mcg / ml) Ibuprofen
(5 μM) 417 456 LPS (10 mcg / ml) Naproxen
(5 μM 458 501 LPS (10 mcg / ml) Acetaminophen (50 μM) 399 509 LPS (10 mcg / ml) Aspirin
(50 μM) 413 484 LPS (10 mcg / ml) Ibuprofen (50 μM) 427 466 LPS (10 mcg / ml) Naproxen (50 μM) 409 458 ^# Data expressed as the average of two repetitions

[0250] Analgesics inhibit the response of PGE2 smooth muscle cells of a normal human bladder to inflammatory and non-inflammatory stimuli. In accordance with the induction of the COX2 responses described above, carbachol and LPS induced PGE2 production by smooth muscle cells of a normal human bladder. It was also found that acetaminophen, aspirin, ibuprofen, and naproxen suppress PGE2-induced LPS responses at 5 μM or 50 μM (Table 7).

Table 7
Secretion of PGE2 by smooth muscle cells of a normal human bladder after stimulation with inflammatory and non-inflammatory stimuli and in vitro analgesic treatment Stimulus Analgesic PGE2 ^# levels (pg / ml) subject 1 PGE2 levels (pg / ml) subject 2 no no <20.5 <20.5 Carbachol 10 ^-3 M no 129 104 Carbachol 10 ^-3 M Acetaminophen (50 μM) 76 62 Carbachol 10 ^-3 M Aspirin
(50 μM) 89 59 Carbachol 10 ^-3 M Ibuprofen
(50 μM) 84 73 Carbachol 10 ^-3 M Naproxen
(50 μM) 77 66 Lps
(10 mg / ml) no 1125 998 Lps
(10 mcg / ml) Acetaminophen (5 μM) 817 542 Lps
(10 mcg / ml) Aspirin
(5 μM) 838 598

Lps
(10 mcg / ml) Ibuprofen
(5 μM) 824 527 Lps
(10 mcg / ml) Naproxen (5 μM 859 506 Lps
(10 mcg / ml) Acetaminophen (50 μM) 803 540 Lps
(10 mcg / ml) Aspirin (50 μM) 812 534 Lps
(10 mcg / ml) Ibuprofen (50 μM) 821 501 Lps
(10 mcg / ml) Naproxen (50 μM) 819 523 ^# Data expressed as the average of two repetitions

[0251] Analgesics inhibit the response of human normal bladder cell cytokines to inflammatory stimuli. Analysis of cells and culture supernatants after 24 hours of cultivation showed that none of the tested analgesics separately induced secretion of IL-6 or TNFα in smooth muscle cells of a normal human bladder. As shown in tables 8 and 9, doses of the tested carbachol induced low but reliable responses of TNFα and IL-6 in smooth muscle cells of a normal human bladder. LPS treatment, on the other hand, led to massive induction of these pro-inflammatory cytokines. Acetaminophen, aspirin, ibuprofen and naproxen inhibit the effect of carbachol and LPS in relation to the responses of TNFα and IL-6. The overwhelming effect of analgesics on LPS-induced responses was observed when these drugs were tested at 5 μM or 50 μM.

Table 8
Secretion of TNFα by smooth muscle cells of a normal human bladder after stimulation with inflammatory and non-inflammatory stimuli and in vitro analgesic treatment Stimulus FROM TNFα (pg / ml) ^# 1 subject TNFα (pg / ml) Subject 2 no no <5 <5 Carbachol 10 ^-3 M no 350 286 Carbachol 10 ^-3 M Acetaminophen (50 μM) 138 164 Carbachol 10 ^-3 M Aspirin
(50 μM) 110 142 Carbachol 10 ^-3 M Ibuprofen
(50 μM) 146 121 Carbachol 10 ^-3 M Naproxen
(50 μM) 129 137 LPS (10 mcg / ml) no 5725 4107 LPS (10 mg / ml) Acetaminophen (5 μM) 2338 2267 LPS (10 mcg / ml) Aspirin
(5 μM) 2479 2187 LPS (10 mcg / ml) Ibuprofen
(5 μM) 2733 2288 LPS (10 mcg / ml) Naproxen
(5 μM) 2591 2215 LPS (10 mcg / ml) Acetaminophen (50 μM) 2184 2056

LPS (10 mcg / ml) Aspirin
(50 μM) 2266 2089 LPS (10 mcg / ml) Ibuprofen
(50 μM) 2603 1997 LPS (10 mcg / ml) Naproxen
(50 μM) 2427 2192 ^# Data is expressed as the average of two repetitions.

Table 9
Secretion of IL-6 by smooth muscle cells of a normal human bladder after stimulation with inflammatory and non-inflammatory stimuli and in vitro analgesic treatment Stimulus Analgesic IL-6 (pg / ml) ^# Subject 1 IL-6 (pg / ml) Subject 2 no no <5 <5 Carbachol 10 ^-3 M no 232 278 Carbachol 10 ^-3 M Acetaminophen
(50 μM) 119 135 Carbachol 10 ^-3 M Aspirin (50 μM) 95 146 Carbachol 10 ^-3 M Ibuprofen
(50 μM) 107 118 Carbachol 10 ^-3 M Naproxen
(50 μM) 114 127 LPS (10 mcg / ml) no 4838 4383 LPS (10 mcg / ml) Acetaminophen
(5 μM) 2012 2308 LPS (10 mcg / ml) Aspirin (5 μM) 2199 2089

LPS (10 mcg / ml) Ibuprofen
(5 μM) 2063 2173 LPS (10 mcg / ml) Naproxen
(5 μM) 2077 2229 LPS (10 mcg / ml) Acetaminophen
(50 μM) 2018 1983 LPS (10 mcg / ml) Aspirin (50 μM) 1987 2010 LPS (10 mcg / ml) Ibuprofen
(50 μM) 2021 1991 LPS (10 mcg / ml) Naproxen
(50 μM) 2102 2028 ^# Data is expressed as the average of two repetitions.

[0252] Primary smooth muscle cells of a normal human bladder were isolated, their responses to analgesics were cultured and evaluated in the presence of non-inflammatory (carbachol) and inflammatory (LPS) stimuli. The purpose of this study was to assess whether it is possible or impossible to repeat the observations made previously with mouse bladder cells in relation to smooth muscle cells of the human bladder.

[0253] The experiment described above is repeated with analgesic agents and / or antimuscarinic agents in a delayed release formulation or with a sustained release or sustained release formulation.

[0254] The above description is provided to explain to a person skilled in the art how to carry out the present invention, and is not intended to describe in detail all such obvious modifications and variations that will become apparent to those skilled in the art after reading the description. However, it is intended that all such obvious modifications and variations fall within the scope of the present invention, which is defined by the following claims. The claims are intended to include the claimed components and steps in any sequence that is effective for the implementation of the tasks specified therein, unless the context specifically indicates otherwise.

Claims (36)

1. A method of reducing the frequency of urination, including:
administering to a subject in need of a pharmaceutical composition comprising an acetaminophen analgesic, and
one or more additional active ingredients selected from the group consisting of α-blockers and 5α-reductase inhibitors. 2. The method of claim 1, wherein said analgesic agent and said one or more additional active ingredients are formulated for immediate release. 3. The method of claim 1, wherein said analgesic agent and said one or more additional active ingredients are for delayed release. 4. The method of claim 1, wherein said analgesic and said one or more additional active ingredients are formulated for sustained release. 5. The method according to claim 4, where the specified analgesic agent is administered in an amount of 50-400 mg per agent, where one or more additional analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin and nabumetone, and where said pharmaceutical composition is formulated for sustained release, such that said analgesic and said one or more additional active ingredients are released continuously over a period of 5-24 hours. 6. The method of claim 5, wherein said one or more additional active ingredients comprise tamsulosin. 7. The method of claim 5, wherein said one or more additional active ingredients comprise finasteride. 8. The method of claim 5, wherein said one or more additional active ingredients comprise tamsulosin and finasteride. 9. The method of claim 4, wherein said analgesic agent is administered in an amount of 50-400 mg per agent, where one or more additional analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin and nabumetone, and where said pharmaceutical composition is formulated for sustained release, characterized by a two-phase release profile, in which 20-60% of said analgesic agents are released within two hours of administration and the remainder of said analgesic x means is released continuously over a period of 5-24 hours. 10. The method of claim 9, wherein said one or more additional active ingredients comprise tamsulosin. 11. The method according to p. 9, where the specified one or more additional active ingredients contain finasteride. 12. The method of claim 9, wherein said one or more additional active ingredients comprise tamsulosin and finasteride. 13. The method of claim 1, wherein said analgesic agent is formulated for sustained release and said one or more additional active ingredients are formulated for immediate release. 14. The method according to p. 13, where the specified analgesic agent is administered in an amount of 50-400 mg per agent, where one or more additional analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin and nabumetone, and where said analgesic agents are formulated for sustained release, so that said one or more analgesic agents are released continuously over a period of 5-24 hours. 15. The method of claim 14, wherein said one or more additional active ingredients comprise tamsulosin. 16. The method according to p. 14, where the specified one or more additional active ingredients contain finasteride. 17. The method according to p. 14, where the specified one or more additional active ingredients contain tamsulosin and finasteride. 18. The method according to p. 13, where the specified analgesic agent is administered in an amount of 50-400 mg per agent, where one or more additional analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin and nabumetone, and where said analgesic agents are for sustained release, characterized by a two-phase release profile, in which 20-60% of said analgesic agent is released within two hours of administration, and the remainder of said analgesic their funds are released continuously over a period of 5-24 hours. 19. The method of claim 18, wherein said one or more additional active ingredients comprise tamsulosin. 20. The method according to p. 18, where the specified one or more additional active ingredients contain finasteride. 21. The method of claim 18, wherein said one or more additional active ingredients comprise tamsulosin and finasteride. 22. The method of claim 1, wherein said pharmaceutical composition further comprises an antimuscarinic agent. 23. The method of claim 1, wherein said pharmaceutical composition further comprises an antidiuretic agent. 24. The method of claim 1, wherein said pharmaceutical composition further comprises an antispasmodic. 25. The method of claim 1, further comprising the step of administering an effective amount of a diuretic before administering said pharmaceutical composition, wherein said diuretic is administered 7 or 8 hours before sleep. 26. The method of claim 1, wherein said subject is a mammal. 27. A pharmaceutical composition for reducing urination, comprising
acetaminophen, one or more α-blockers, and
a pharmaceutically acceptable carrier
wherein said acetaminophen is formulated for sustained release; and wherein said one or more α-blockers are formulated for immediate release. 28. The pharmaceutical composition according to p. 27, containing acetaminophen in an amount of 50-400 mg per agent, where one or more additional analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin and nabumetone, and where the indicated analgesic the agents are formulated for sustained release, so that these analgesic agents are released continuously over a period of 5-24 hours. 29. The pharmaceutical composition of claim 28, wherein said analgesic agents contain acetaminophen and wherein said one or more α-blockers contains tamsulosin. 30. The pharmaceutical composition according to p. 27, containing acetaminophen in an amount of 50-400 mg per agent, where one or more additional analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin and nabumetone, and where the specified pharmaceutical the composition is formulated for sustained release, characterized by a biphasic release profile, in which 20-60% of said analgesic agents are released within two hours of administration, and the remainder of said analgesic funds are released continuously over a period of 5-24 hours. 31. The pharmaceutical composition of claim 30, wherein said analgesic agents contain acetaminophen, and wherein said one or more α-blockers comprise tamsulosin. 32. A pharmaceutical composition for decreasing the frequency of urination, containing acetaminophen,
one or more 5α-reductase inhibitors and
a pharmaceutically acceptable carrier
wherein said acetaminophen is formulated for sustained release; and wherein said one or more 5α-reductase inhibitors are formulated for immediate release. 33. The pharmaceutical composition according to p. 32, containing acetaminophen in an amount of 50-400 mg per agent, where one or more additional analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin and nabumetone, and where these analgesic the agents are formulated for sustained release, so that these analgesic agents are released continuously over a period of 5-24 hours. 34. The pharmaceutical composition of claim 33, wherein said analgesic agents contain acetaminophen and wherein said one or more 5α-reductase inhibitors comprise finasteride. 35. The pharmaceutical composition according to p. 32, containing acetaminophen in an amount of 50-400 mg per agent, where one or more additional analgesic agents are selected from the group consisting of aspirin, ibuprofen, naproxen, naproxen sodium, indomethacin and nabumetone, and where the specified pharmaceutical the composition is formulated for sustained release, characterized by a biphasic release profile, in which 20-60% of said analgesic agents are released within two hours of administration, and the remainder of said analgesic funds are released continuously over a period of 5-24 hours. 36. The pharmaceutical composition of claim 35, wherein said analgesic agents contain acetaminophen and wherein said one or more 5α-reductase inhibitors comprise finasteride.

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