MX2007008833A - Pharmaceutical formulations and methods of use. - Google Patents

Abstract

This invention relates to new pharmaceutical formulations, and to new medical uses, of gabapentin and pregabalin. The formulations may comprise up to three components including an immediate release component, a sustained release component and a delayed release component. The proportion of each component in the formulation may be adjusted to achieve the desired AUC and therapeutic effect following oral administration in a human subject.

Description

PHARMACEUTICAL FORMULATIONS AND METHODS OF USE FIELD OF THE INVENTION The present invention relates to new pharmaceutical formulations and new medical uses of gabapentin and pregabalin. BACKGROUND OF THE INVENTION Gabapentin (US Patent Nos. 4,024,175 and 4,087,544), are a known GABA analogue (amino-butyl gamma-acid), which has been used clinically to treat epilepsy, neuropathic pain and a number of other conditions. Gabapentin also has potentially useful therapeutic effects in other conditions of chronic pain, eg, muscular and skeletal pain; in psychiatric disorders, for example, panic, anxiety, depression, manic behavior and alcoholism; in movement disorders, for example, multiple sclerosis, tremors of action, tardive dyskinesia, etc .; in migraine, in bipolar illness; in muscle spasm and as an analgesic.

More recently, the US Patent No. 6,310,098, demonstrates that gabapentin can be used to treat hot flashes. For its current clinical uses, the REF 184482 gabapentin is formulated as a tablet or capsule formulation of immediate release unit dose, containing 100, 300, 400, 600 or 800 mg of the active agent. These unit doses are usually administered three times a day (TVD), with a maximum dosage of 3,600 mg, or more usually, 2,700 mg. The TVD administration is inconvenient and compliance of the patient with TVD dosages is often erratic. Depending on the condition to be treated, the consequences of losing or miscalculating a dose can be serious. U.S. Patent No. 6,723,340, describes a gabapentin tablet formulation that is designed to be retained in the stomach and release gabapentin in the stomach. This formulation provides sustained supply of gabapentin, but only in the stomach and upper small intestine. This formulation provides prolonged controlled release time in the stomach and upper gastrointestinal tract (Gl), and improved opportunity for absorption in the stomach and upper Gl tract, preferably in the lower portions of the Gl tract. Such formulation must be continuously to maintain blood concentrations therapeutic Intermittent administration may require a delay in time to reach therapeutic blood concentrations, since this formulation is not appropriate for a medication to be taken only as required. All absorption of gabapentin in this formulation may be expected to occur in the stomach and / or upper small intestine, particularly the duodenum. U.S. Patent No. 6,818,787, describes certain prodrugs of gabapentin and U.S. Patent No. 6,465,012, discloses certain improved immediate release gabapentin formulations. The above describes an attempt to provide sustained release of gabapentin by linking a ratio to the amino and / or carboxyl gamma group of gabapentin (and other GABA analogs) to improve bioavailability and transport to the brain. This patient describes new chemical entities that derive the mechanism of active transport known for gabapentin and related compounds that delay absorption to further down the intestinal tract. Patent '012, describes a tablet formulation with improved compressibility characteristics, but does not provide some sustained release of Gabapentin U.S. Patent No. 5,906,832, describes a variety of formulations of continuous administration of a large number of anti-epileptic drugs that focus on osmotic formulations of phenytoin. It also briefly refers to gabapentin, but does not describe the specific parts of the gastrointestinal tract where the drug is released, and in particular, does not describe the rapid release of gabapentin in the lower small intestine. This formulation does not include any immediate release component and must be taken continuously to maintain therapeutic blood concentrations. Intermittent administration may require a delay in time to reach therapeutic blood levels, since this formulation is not appropriate for a medication to be taken only as required. The drug, pregabalin, has properties similar to gabapentin. Pregabalin is available only in immediate release form without currently available sustained release formulation. This drug, therefore, is taken TVD to maintain therapeutic blood levels. As with gabapentin, DVT administration is inconvenient and compliance with the patient with dosing TVD is often erratic. Depending on the condition to be treated, the consequences of losing or miscalculating a dose can be serious. There is a need for a more convenient and improved dosing regimen not only for established clinical uses, but also, for use in other treatments, for example, for the treatment of hot flashes. There is also a need for gabapentin formulations which have more appropriate release patterns and / or which provide improved bioavailability of gabapentin and / or do not lead to saturation of the body's absorption mechanisms, thereby giving the possibility of reducing the dosage for a given effect and thus, reduce the likelihood of adverse effects. Through the following parts of this specification (unless it is clear from the context, that this is not the case), it is understood that where it refers to gabapentin, pregabalin can be replaced by gabapentin. Now, we have found a way to meet some or all of these needs. SUMMARY OF THE INVENTION The present invention is directed to a composition comprising an active ingredient coated by an insoluble polymer carrier independent of pH, a active ingredient coated by an insoluble polymer carrier independent of pH, and an active ingredient coated by a pH-dependent soluble polymer excipient. The active ingredient may be gabapentin and pregabalin. The pH-independent soluble polymer excipient is hydroxypropylmethylcellulose. The insoluble polymer carrier independent of pH may be Eudragit RL30D, Eudragit RS30D, or a combination thereof. The pH-dependent soluble polymer can be Eudragit L30D-55, Eudragit FS30D, or a combination thereof. The present invention is also directed to the composition wherein the insoluble polymer independent of pH, has a thickness of 25 to 150 microns. The pH-dependent soluble polymer has a thickness of 25 to 150 microns. The present invention is also directed to the active ingredient in the form of coated mini-tablets by either the insoluble polymer independent of the PH, the pH-independent soluble polymer, or the pH-independent soluble polymer. The present invention, moreover, is directed to the composition which further comprises a disintegrant, a flavor component, a colorant, a sweetener, a binder, a lubricant, a plasticizer, or a combination of the same . The present invention is also directed to a controlled oral release formulation of gabapentin, adapted for a rapid release in part and a sustained release in part, of gabapentin in the stomach and upper small intestine (thereby, providing the drug to the stomach and the upper small intestine), and partly release in the lower or middle part of the lower small intestine. The formulation is adapted to release gabapentin or other active ingredients in three phases. In the first phase, gabapentin or other active ingredients are released quickly into the stomach; in the second phase, gabapentin or other active ingredients are released over a period of sustained release, mainly in the lower stomach, duodenum and jejunum sections of the small intestine; and in the third phase, the release of gabapentin or other active ingredients are retarded to the jejunum and ileum sections of the small intestine, where gabapentin or other active ingredients are rapidly released. The present invention is also directed to the composition, wherein 20 to 60%, or from 25 to 50%, or from 35 to 45% of gabapentin or other active ingredients, are released in the first phase, for example, within a period of up to 2 or within 3 hours after dosing. These amounts of gabapentin or other active ingredients will be for the most part, released in the stomach. The present invention is also directed to the composition, wherein 20 to 60%, or from 25 to 50%, or from 35 to 45% of gabapentin or other active ingredients, are released in the second phase, for example, within a period of up to 12 or within 6 hours or within 1 to 5 hours after dosing. These amounts of the active ingredient will, for the most part, be released into the lower stomach and upper / middle small intestine that includes the duodenum and jejunum. The present invention is also directed to the composition, wherein 15 to 50%, or from 30 to 45%, or from 30 to 40% of gabapentin or other active ingredients, are released rapidly after a delay of from 3 to 10 or 4 to 8 hours after dosing. These amounts of the active ingredient will be for the most part, released in the middle to lower small intestine that includes the jejunum and ileus. One goal of drug release in the third phase is to make the drug readily available at a time, when blood levels of the drug released in the early stages are likely to be reduced. Another aspect of the present invention is directed to the composition comprising an active ingredient encapsulated by a pH-independent soluble polymer excipient, an active ingredient encapsulated by an insoluble polymer carrier independent of pH, and an active ingredient encapsulated by a pH-dependent soluble polymer excipient, wherein -60% of the active ingredient is released by the soluble polymer excipient independent of pH, within a period of up to 3 hours after dosing, wherein 20-60% of the active ingredient is released by the insoluble polymer excipient independent of pH, within a period of up to 12 hours after dosing, and wherein 15-50% of the active ingredient is released by the pH-dependent soluble polymer excipient, after a delay of 3 to 10 hours after dosing . The present invention is also directed to the composition wherein 25-50% of the active ingredient encapsulated by a soluble polymer independent of pH is released within a period of up to 2 or 3 hours. The present invention is also directed to the composition wherein 35-45% of the active ingredient encapsulated by a soluble polymer independent of pH is released within a period of up to 2 or 3 hours. These proportions of the active ingredient released by the soluble polymer independent of pH, will occur in the stomach. Another aspect of the present invention is directed to the composition wherein 25 to 50% of the active ingredient encapsulated by an insoluble polymer independent of pH is released for a sustained period up to 12 hours or up to 6 hours, or up to or between 1 to 5 hours. The present invention is also directed to the composition wherein 25-35% of the active ingredient is released for a sustained period up to 12 hours or up to 6 hours, or between 1 to 5 hours. These proportions of the active ingredient released by the insoluble polymer independent of pH, will be released into the stomach and lower and upper sections of the small intestine, which includes the duodenum and jejunum. The present invention is also directed to the composition wherein 30 to 45% of the active ingredient is released from the pH-dependent soluble polymer after a delay of 3 to 10, or 4 to 8 hours. The present invention is also directed to the composition wherein 30 to 40% of the active ingredient is released from the pH-dependent soluble polymer after a delay of 3 to 12, or 4 to 8 hours. These proportions of the active ingredient released by the soluble pH-dependent polymer will be released in the middle to lower sections of the small intestine, which include the jejunum and ileum of the small intestine. The sum of the release of the active ingredient on the three phases or of the insoluble, soluble pH independent polymers and the pH-dependent polymer is close to 100%.

The present invention is also directed to a composition wherein the plasma level of the AUC drug of gabapentin is greater than 100 to 20% of that which is obtained for an equivalent dose of conventional immediate release gabapentin, for example, which is sells under the trade name Nuerontin®. The present invention can determine the AUC either as by the integration of the data points from time zero to infinity time, when those data points are concentrations (levels) of gabapentin in the plasma after single doses of gabapentin either as Neurontin® or as a formulation according to this invention (Xenolev-CR ™), in healthy volunteers, and / or in the target population, or by the integration of the equivalent data points during a dosing interval in the ready state of pharmacokinetics in which, the prolonged daily dosages, balance the daily elimination. The present invention determines its Tmax of the formulation kinetics as well as the same as, or up to 3.0 times greater than the Tma? corresponding to an equivalent dose of conventional immediate release formulation. The time to Cmax is from 2 to 6 hours of dosing. The peak plasma concentration of gabapentin (Cma?) Is lower than for an equivalent dose of conventional immediate release formulation, for example, as low as 0.5 of that of Cmax. The plasma concentration of gabapentin is up to 3 times, or 1.5 to 2.5 times that provided by a conventional release formulation from 8 to 24 hours after dosing. A formulation where the time of Cmax up to 50% of Cma? It is from 2 to 24 hours, 3 to 12 hours or 4 to 8 hours. A formulation where the time from Cmax to 50 percent Cma? / Is greater than the corresponding time for an immediate release gabapentin by a factor of 1.1 to 3, or 1.5 to 2.5. Formulations of gabapentin or other active ingredient, which are essentially 100% immediate release (ie, not in accordance with this invention), demonstrate non-linearity in absorption, such that the AUC is not duplicated by doubling the doses. The present invention is also directed to the composition wherein the active ingredient or gabapentin is released at a Cmax and AUC (absolute bioavailability of active ingredient), which is 25-200%, 30-100%, 40-100%, 45- 100%, 50-100%, 55-100%, 60-100%, 65-100%, 70-100%, 75-100%, 80-100%, 85-100%, 90-100%, 95- 100%, proportional to the dosage strength of gabapentin or an active ingredient. Thus, the bioavailability of gabapentin immediate-release formulations ranges from 70% at the lowest doses to less than 30% at higher doses. Thus, when the present invention comprises the use of appropriate percentages of three components and the dose is doubled or tripled, the AUC can correspondingly, increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, lx (times), l.lx, 1.2x, 1.3x, 1.4x, 1.5 x, 1.6x, 1.7x, 1.8x, 1.9x, or 2.0x. Thus, the bioavailability of gabapentin from the invention is from about 1.0 to about 1.5 that of gabapentin immediate release at lower doses, and from about 1.0 to about 3.0 that of gabapentin immediate release at higher doses. As yet another aspect of the invention, it is directed to the composition wherein the gabapentin or other active ingredient is in a single dose of a formulation that totals 900 mg or 800 mg or 700 mg or 600 mg or 500 mg, or 400 mg or 375 mg or 325 mg or 300 mg or 275 mg or 250 mg of gabapentin, where 180 mg to 540 mg, 160 to 480 mg, 140 to 420 mg, 120 to 360 mg, 100 to 300 mg, 80 to 240 mg , 75 to 225 mg, 70 to 210 mg, 65 to 195 mg, 60 to 180 mg, 55 to 165 mg, and 50 to 150 mg of gabapentin or another active ingredient, is released in the first phase from the independent soluble polymer of pH. The present invention is also directed to 180 mg to 540 mg, 160 to 480 mg, 140 to 420 mg, 120 to 360 mg, 100 to 300 mg, 80 to 240 mg, 75 to 225 mg, 70 to 210 mg, 65 up to 195 mg, 60 to 180 mg, 55 to 165 mg, and 50 to 150 mg of gabapentin or another active ingredient that is released during a sustained period during the second phase from the insoluble polymer independent of pH. The present invention is also directed to 270 to 405 mg, 240 to 360 mg, 210 to 315 mg, 180 to 270 mg, 150 to 225 mg, 120 to 180 mg, 110 to 170 mg, 105 to 160 mg, 100 to 150 mg. mg, 80 to 125 mg, and 75 to 115 mg of gabapentin or another active ingredient that is released during the third phase from the soluble polymer dependent on pH. Correspondingly, lower ranges of mg will be required, and can be simply calculated from the above data for smaller dosages of the drug. The present invention is also directed to using the composition in dosing regimens of 500 mg of gabapentin or an active ingredient administered twice daily as a single unit dose or as two unit doses of 250 mg each, or 900 mg of gabapentin or ingredient active administered twice daily as three unit doses of 300 mg each, or as two unit doses of 450 mg each or 750 mg of gabapentin or active ingredient administered twice daily as a single unit dose or as two unit doses of 375 mg of each one.

As yet another aspect of the present invention, it is directed to a composition produced by a process comprising the steps of separately mixing an active ingredient of a soluble polymer independent of pH, an insoluble polymer independent of pH, and a soluble polymer dependent on pH , forming the resulting mixtures in mini-tablets, and filling the mini-tablet mixture in a capsule suitable for oral administration. The present invention is also directed to a composition produced by the process comprising the steps of mixing an active ingredient with a filler, granulating the mixture, combining the granulated mixture with a lubricant, compressing the combined mixture into mini-tablets, coating the mini -tablets with excipients of a pH-independent soluble polymer, an insoluble polymer independent of pH, and a pH-dependent soluble polymer, drying the coated mini-tablets, and formulating the mixture of coated mini-tablets in a single unit dosage form suitable for oral administration. The present invention is also directed to a composition comprising gabapentin or pregabalin or another active ingredient used for the treatment of a neurological disorder or injury, selected from the group consisting of epilepsy, in the treatment of epileptic seizures secondary to stroke, cranial / cerebral trauma or peri or post-operative neurosurgery, multiple sclerosis, or tremors of involuntary action. The present invention is also directed to a composition comprising gabapentin or pregabalin or another active ingredient used for the treatment of chronic pain associated with neuropathic pain, muscular and skeletal pain, tardive dyskinesia or migraines, sympathetic reflex dystrophy syndrome (RSD), [also known as complex regional pain syndrome (CRP)] and fibromyalgia or muscle disorders. The present invention is also directed to a composition comprising psychiatric disorders such as, but not limited to, bipolar disease, panic, anxiety, depression, manic behavior and alcoholism. The formulations or compositions may also be used to treat the conditions described in U.S. Patent No. 6,310,098 (which is incorporated herein by reference) and in particular, hormonal variation in menopause or other related syndromes of hot flushes, fevers, nausea. and vomit. The present invention is also directed to the treatment of symptoms of post-menopausal women, selected from the group consisting of urgent incontinence, vaginal dryness and dry eye syndrome. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the cumulative in vi tro dissolution profile for a formulation comprising 80% as a percentage of the mini-tablets Lot B, 10% of the mini-tablets Lot B, where the Eudragit RL30D and Eudragit RS30D, are at a ratio of 2: 8, and 10% of mini-tablets Lot D, with a content of Eudragit L30D-55 at 15%. Figure 1 shows three different flavors of the gabapentin capsules with milligrams of gabapentin released shown on the y-axis. Figure 2 shows the cumulative cumulative dissolution profile for a formulation comprising 20% as a percentage of mini-tablets Lot B, 40% of mini-tablets Lot C, where Eudragit RL30D and Eudragit RS30D, are at a ratio of 2: 8, and 40% of mini-tablets Lot D, with a content of Eudragit L30D-55 at 10%. Figure 2 shows three different flavors of gabapentin capsules with released milligrams of gabapentin shown in e and y. DETAILED DESCRIPTION OF THE INVENTION To completely cover the need for Gabapentin formulations which have more appropriate release patterns and / or which provide improved bioavailability of gabapentin and / or do not lead to saturation of the body's absorption mechanisms, thereby providing the possibility of reducing the dosage for an effect given and so, reducing the likelihood of adverse effects, the present invention is directed to a composition comprising an active ingredient coated by a soluble polymer carrier independent of pH, an active ingredient coated by a soluble polymer carrier independent of pH and a coated active ingredient. by a pH-dependent soluble polymer excipient. The present invention is directed to a composition or formulation comprising an active ingredient such as gabapentin and the drug pregabalin. Other ingredients that could be used in the composition or formulation of the present invention include, but are not limited to, the following table.

The active ingredients of the composition including gabapentin can be applied for uses by any convenient means, including orally, using a formulation according to the invention, for the treatment of neurological disorders or injuries, treatment of chronic pain, treatment of psychiatric disorders or mental illness, treatment of symptoms related to menstruation and symptoms related to post-menopause. The dosage for these uses will generally be lower than that used for epilepsy and will generally be in the range of 100 to 3,000 mg per day, which can be given in divided doses up to 2 or 3 times per day. When using an immediate release formulation, or a formulation according to the invention, the dosages are as provided below in relation to the formulation according to the invention. When drugs (ie, active ingredients in particular pharmaceutical formulations) are administered orally, they necessarily pass through the gastrointestinal tract. The active ingredients in a formulation or composition of the present invention first enter the highly acidic environment of the stomach, where the pH ranges from pH 1-3. The small intestine, which comprises the duodenum, jejunum and ileum, is predominantly where absorption of the nutrient / drug occurs. The small intestine progresses from a highly acidic environment (~ pH 6-7 in the jejunum and ileus). Based on the highly acidic environment, the formulation which prevents the dissolutions of drugs or active ingredient in the stomach, can provide a sustained and delayed release of the drug, while in the small intestine. As used in the application in this document, a excipient is defined as an inert substance used as a diluent or vehicle for a drug. The excipient may be in a solid form coating form, or a liquid coating, or a semi-solid capsule coating an active drug ingredient such as gabapentin. The excipients in the present invention are defined in three different coating forms by being a soluble polymer independent of pH, an insoluble polymer independent of pH, and a soluble polymer dependent on pH. The pH-dependent soluble polymer is soluble in a particular pH environment. Accordingly, the soluble polymer becomes soluble at a particular pH, preferably soluble at any pH. A soluble polymer independent of pH, is defined as a pharmaceutical grade carrier or vehicle that readily dissolves in the soluble environment, including the stomach, and includes, for example, and without limitation, calcium phosphate dihydrate, calcium dihydrate sulfate, cellulose microcrystalline, cellulose derivatives, dextrose, gelatin, lactose, lactose anhydrous, spray dried lactose, lactose monohydrate, mannitol, starches, sorbitol and sucrose. Additional examples include acacia, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol, butyrate cellulose acetate, hydroxyethylcellulose, ethylcellulose, polyvinyl alcohol, polypropylene, dextrans, dextrins, hydroxypropyl-beta-cyclodextrin, chitosan, copolymers of lactic and glycolic acid, lactic acid polymers, methacrylic acid copolymers containing acidic groups, glycolic acid polymers , polyorthoesters, polyanhydrides, polyvinyl chloride, polyvinyl acetate, polyvinyl alcohol, polyethylene glycol copolymer, vinylethylene acetate, lectins, carbopoles, silicon elastomers, polyacrylic polymers, maltodextrins, fructose, inositol, trehalose, maltose, raffinose, and alpha cyclodextrins , beta and gamma, suitable mixtures of those mentioned above and the like. These polymers are susceptible to dissolution in low pH environments (pH 1-5), medium pH (5-7.5), or high pH (pH 7.5-10) of the gastrointestinal tract. These polymers are easily soluble and after contact in a liquid medium, they dissolve and release gabapentin or other active ingredients. An insoluble, pH-dependent polymer is also used in the composition to coat the active ingredient. An insoluble, pH-independent polymer is a pharmaceutical grade carrier or carrier that coats an active drug ingredient such as gabapentin. Examples of insoluble polymer independent of pH include, but are not limited to, hydroxypropylmethylcellulose acetate succinate, phthalate polyvinyl acetate, amino acrylate methacrylate copolymer E, which includes methyl cellulose, ethyl cellulose, or a combination thereof and aminoalkylmethane acrylate copolymers RS and RL, including Eudragit RL30D, and Eudragit RS30D. The insoluble polymer independent of pH, may have a low permeability and expansion such as Eudragit RS30D or an insoluble polymer independent of pH having a high permeability and expansion, such as Eudragit RL30D. Such variations in the permeability of the membrane independent of the insoluble pH affect the release kinetics of the active ingredient or gabapentin allowing a sustained release of up to 12 hours after the original dosage in the stomach and upper small intestine that includes the duodenum. A pH-dependent soluble polymer is a pharmaceutical grade carrier or vehicle that coats an active ingredient such as gabapentin. Examples of pH-dependent soluble polymer include, but are not limited to, natural polymers such as purified lacquer and white lacquer, synthetic polymers such as cellulose-derived polymers: hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylcellulose, cellulose acetate trimethylate, phthalate cellulose acetate, acrylic polymers such as those obtained from acrylic acid and / or methacrylic acid, polymers obtained from acid acrylic and / or methacrylic acid and a carboxylic ester, and polyvinyl alcohol type polymers such as polyvinyl acetate phthalate. In addition, soluble pH-dependent polymers include those with a carboxyl group obtained from acrylic acid and / or methacrylic acid or those obtained from acrylic acid and / or methacrylic acid and a carboxylic ester. Examples of the carboxylic ester used herein include acrylic esters and methacrylic esters such as methylacrylate, ethylacrylate, n-propylacrylate, isopropylacrylate, n-butylacrylate, isobutylacrylate, t-butyl acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropylacrylate, methyl methacrylate, ethyl methacrylate, n -propylmethacrylate, isopropylmethacrylate, 2-hydroxyethylmethacrylate, 2-hydroxypropylmethacrylate, n-butylmethacrylate, isobutylmethacrylate and t-butyl methacrylate. Examples of co-polymers of methacrylic acid-methyl methacrylate include Eudragit L100 or SlOO. In addition, the pH-dependent soluble polymer Eudragit L30D-55 and Eudragit FS30D can be used in the composition. Such soluble pH-dependent polymers dissolve in a certain pH environment preferably after the soluble contents. The Eudragit L30D-55, can be used for dissolution of the active ingredient above pH 5.5, while the Eudragit FS30D, can be used for dissolution of the active ingredient above pH 7.0, to provide a release in the small intestine that includes the duodenum, jejunum and ileum. Specifically, the Eudragit LD30D-55, could be susceptible to dissolution of the active ingredient such as gabapentin, when the pH changes to pH more than 5.5 at some point in the duodenum of the small intestine, while the Eudragit FS30D, could dissolve above pH 7.0 at some point in the jejunum and ileus. The pH-dependent soluble polymer can also be combined with a disintegrant, which will affect the release of the active ingredient from the formulation or composition. The composition of the present invention may further comprise a disintegrant, a flavor component, a colorant, a sweetener, a binder, a filler, a lubricant, a glidant, a plasticizer or a combination thereof. The mini-tablet cores of gabapentin or other active agents can be formed using conventional techniques, for example, they can contain disintegrants; which include but are not limited to, croscarmellose sodium or glycolate sodium starch; binders, including but not limited to, polyvinylpyrrolidone; fillers including but not limited to microcrystalline cellulose and / or lubricants including, but not limited to, magnesium stearate. Examples of glidants include, but are not limited to, talc and colloidal anhydrous silica. Gabapentin in powder form it can be directly coated or it can be granulated, using known wet or dry techniques (compaction), followed if desired, by selection and tabletting to obtain the desired particle size. The coating can, if desired, also contain a plasticizer or adjuvant. Suitable plasticizers for use in the second and third phase coating include but are not limited to, polyethylene glycol, dibutyl phthalate, diethyl phthalate, dibutyl sebacate and citric acid esters, phthalates, phosphates, citrates, adipates, tartrates, sebacates, succinates, glycolates, glycerolates , benzoates, myristates, polyethylene glycols, polypropylene glycols and halogenated phenyl, triacetin, acetylated monoglycerides, grapeseed oil, olive oil, sesame oil, acetyltributyl citrate, acetyltriethyl citrate, glycerin sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethylmalonate, dioctylphthalate , dibutylsebacate, triethyl citrate, tributyl citrate, glycerol tributyrate, mixtures thereof and the like. Adjuvants suitable for inclusion in these coatings include talcum, silicon dioxide, titanium dioxide, coloring agents, soy lecithin and magnesium stearate. Suitable barrier coatings for placing each of several coated mini-tablets or other powder forms of the active ingredient as described above include, but are not limited to, hydroxypropylmethylcellulose, methylcellulose and shellac. The various coatings used above may contain different coloring agents to enable them to be easily distinguished and also to provide a distinguished multicolored appearance to the total formulation, for example, wherein the mixture of the various components is placed in a transparent capsule. The present invention is also directed to an oral controlled release formulation of gabapentin, adapted to release part of the gabapentin in the stomach (thereby, providing the drug in the stomach and upper small intestine) and being rapidly released partly in the lower small intestine, which includes in part the duodenum and in part, the jejunum and ileum. The formulation is adapted to release gabapentin or other active ingredients in three phases. In the first phase, gabapentin or other active ingredients are released quickly into the stomach. The release of gabapentin or other active ingredients is controlled by a soluble polymer coating independent of pH. In the second phase, gabapentin or other active ingredients are released during a sustained period mainly in the lower stomach, sections of the duodenum and jejunum of the small intestine. The release of gabapentin or other ingredients active, is controlled by the insoluble polymer coating independent of the pH and is dependent on the water permeability of said coating membrane. In the third phase, the release of gabapentin or other active ingredients is delayed up to the sections of the jejunum and ileum of the small intestine, where gabapentin or other active ingredients are rapidly released, depending on the dissolving pH-dependent polymer coating. at various pHs ranging from 4 to 10. The immediate release component (first phase), which is designed to release gabapentin rapidly when ingested in the stomach, can be formed by making mini-tablets that use a soluble polymer independent of the pH as the coating. These may or may not incorporate a disintegrant. These mini-tablets, which may for convenience be the core of mini-tablets described immediately above, may be provided with a barrier coating (which may serve to protect gabapentin from interaction with any of the subsequent coatings), for example, in a tray coater or by drying in a fluid bed system. This barrier coating can be provided by use of a suitable polymer, for example, hydroxypropylmethylcellulose, dissolved or suspended in an organic solvent, or a mixture of organic solvents, or a mixture of organic solvents and water, or in solution, dispersion or aqueous emulsion. The thickness of the coating of mini-tablets in the various stages of their production, can also be varied to achieve the required release characteristics of the drug, through the coating. The coatings can have a thickness of 25 to 10 microns. The second phase component is designed to achieve a programmed release of gabapentin or another active ingredient using an insoluble polymer independent of pH as the coating. This may, for convenience, be the immediate release component or some other mini-tablets containing appropriate gabapentin, carrying an insoluble polymer coating independent of pH. This coating may for example be one or a mixture of a water insoluble polymer having high permeability and expansion, which is independent of pH, for example, Eudragit RL30D, and a water insoluble polymer having low permeability and expansion which is independent of pH, for example, Eudragit RS30D. This coating can, if desired, contain a plasticizer or adjuvant. The third phase component may be formed of mini-tablets, which may contain a disintegrant, which is coated with a pH-dependent soluble polymer, or enteric material including, but not limited to, phthalate cellulose acetate, hydroxypropylmethylcellulose phthalate, or an anionic methacrylic acid polymer such as Eudragit L30D-55 for dissolution above pH 5.5, or Eudragit FS30D for solution above pH 7.0. Specifically, the pH-dependent soluble polymer Eudragit L30D-55 dissolves and releases the active ingredient in environments with pH 5.5 or higher, and can be directed to the duodenum to the jejunum, where the ambient pH changes from 4 to 7. The polymer pH-dependent soluble Eudragit FS30D, it dissolves and releases the active ingredient in environments with pH 7.0 or higher, and can be directed to the jejunum and ileum, where the pH environment changes to more than 7. This release of gabapentin in the lower small intestine is achieved by coating with a membrane with pH-dependent solubility, and more particularly, with a membrane which is insoluble at a pH greater than 5.5, so that it remains intact in the stomach and upper part of the small intestine ( duodenum) and dissolves when a pH greater than 5.5 is reached in the lower small intestine (ie, the jejunum and ileus), thereby releasing the drug. Thus, if the formulation is coated with an EudragitS membrane (which dissolves at a pH higher than 7), there is little or no release in the solutions until pH 6. But, when the pH is increased to more than 7, rapid dissolution of the drug occurs. The present invention is also directed to a gabapentin formulation administered such that it is effective for the desired treatment. Effective amounts of gabapentin will depend on the patient (patients with renal impairment may need lower doses than those with normal renal function), the condition to be treated, the frequency of administration, and the specific composition according to the invention used to deliver gabapentin. While the individual needs to vary, the determination of optimal ranges of effective amounts of gabapentin is within the skill of the art. In this way, the formulation can be administered in doses of between 100 and 1500 mg to be taken either in the morning for the suppression of symptoms that occur mainly during the day, or at night for the suppression of symptoms that occur mainly, at night, or both, in this way, giving a total daily dose from 100 to 3000 mg of gabapentin. Doses of 250 to 750 nm in the morning and / or evening, which provide a total daily dose of 250 to 1500 mg and doses of 350 to 600 mg in the morning and / or evening, which provide a daily dose of 350 to 1200 nm, they can also be administered. There are many suitable formulations to achieve the release profiles, and other parameters, which are describe above. As will be appreciated from these release profiles, the formulation may have three components, a first immediate release component, a second sustained release component (on the lower stomach and duodenum), and a third component designed to release its content from gabapentin in the lower small intestine, such as the jejunum and ileum. The provision of these three components can be achieved in a number of different ways. One such form is forming a core of the last component that carries (for example, surrounds) a layer of the sustained release component, which instead carries (for example, it is encircled), an additional layer of the immediate release component. Alternatively, the desired release pattern can be achieved by providing a mixture, in suitable proportions, of three separate components having the desired release characteristics. The excipients to be used in the three components can be chosen from those known in the art to provide the desired properties to such a component. In accordance with the invention, there is also provided a process for the production of a formulation according to the invention, which comprises mixing the active ingredient with one or more suitable excipients, diluents or carriers and forming the resulting mixture in a controlled release formulation. Each unit dose contains from 5 to 95%, or 60% to 80% w / w of gabapentin. The formulation of the present invention is a multiple dose formulation in the form of mini-tablets for example. The multiple dose formulations comprise a plurality of small units (tablets), in which individual units that make a unit dose spread over a wide area of the gastrointestinal tract in this manner, avoid or reduce any possible problem of mucosal irritation. due to the high concentration of the formulation. The multiple dose forms of gabapentin may be in the form of crystals, granules, pellets or tablets of small dimensions (mini-tablets), some or all of which are coated as described below. The size of the small units of the multiple dose forms, that is, of the crystals, granules, pellets or mini-tablets, can vary from 0.1 to 3.5 mm, but does not exceed 5 mm. The smaller these units are, the wider the distribution in the gastrointestinal tract. In addition, while units greater than 5 mm are retained on a full stomach, units less than 5 mm pass through the stomach much very quickly and in a liquid-like manner.

The following description refers to gabapentin in the form of mini-tablets, but is also valid for other multiple dose forms, for example, crystals, pellets and granules. The coated mini-tablets can be dried with hot air, for example, at about 30 ° C., for a suitable time, for example, about 30 minutes. More specifically, the mini-tablets of gabapentin can be formed by a first step involving mixing the drug with a suitable filler, granulating the mixture using a binder solution, drying the granules and, if desired, selecting them, combining them with a lubricant and where desired, a disintegrant and compress the mixture, for example, using a single punch or rotary punching machine, with punches having a 3 mm bucket diameter. This is followed by a second step in which, some of these mini-tablets are coated, for example, by spraying in a coating tray, with a solution / suspension, for example, an alcoholic or aqueous solution of a suitable polymer mixture. , optionally together with a plasticizer and / or adjuvant and dried to form an internal coating on the tablets. The coating applied in this step provides a sweeping to protect the active ingredient from interacting with subsequent coatings. After drying, some of these tablets may be subjected to a third stage in which, a Additional coating designed to achieve a programmed release of the drug is applied. Some of the product of the mini-tablets of the second stage can be provided, in a fourth step, with an enteric coating, for example, by atomizing the mini-tablets with a solution or suspension of the enteric coating material. The final composition can then be made by mixing the products of the second and / or third and fourth stages in such proportions to give the desired total release profile, and then formulating the mixture in a single unit dosage form, for example, filling in single-dose capsules or pouches, or in other pharmaceutical forms suitable for oral administration. The amount of drug released in vivo at each of these times can be predicted by the use of the in vi dissolution rate method described in the US Pharmacopoeia, for example, a suitable combination of the tests set forth in Example 5. Accordingly, formulations are provided that have dissolution rates in Example 5 and corresponding with the percentages to be released as discussed above. The amount of drug released in vivo can be evaluated in healthy volunteers, who are first selected by acute or recurrent disease, by prescription, during the use of the illegal drug or counter (OTC), and / or for any other reasons that make them unsuitable for participation in pharmacokinetic studies. Having fasted, volunteers are assigned to the treatment to be received and equipped with a fixed venous catheter for blood collection. Doses are given at time zero, and blood samples are collected through the catheter at pre-determined intervals for the next 48 hours. The plasma is separated from the blood by centrifugation, and then tested to determine the content of gabapentin using a validated analytical method. Data are displayed, and evaluated using pharmacokinetics software for Cma? (maximum concentration), ax (time at maximum concentration), AUC (area under the curve) and other pharmacokinetic parameters. The present invention is also directed to a composition wherein the plasma level of the AUC drug of gabapentin is greater than 100 to 200%, that which is obtained for an equivalent dose of conventional immediate release gabapentin, for example, which is sells under the trademark Neurontin®. The AUC is evaluated either by the integration of the data points from time zero to an indefinite time, when those data points are concentrations (levels) of gabapentin in the plasma, after single doses of gabapentin either as Neurontin® or as a formulation according to this invention (Xenolev-CR ™) in healthy volunteers, and / or in the target population, or by integration of the equivalent data points during a dosing interval in the pharmacokinetic study status in the which, the prolonged daily dosages balance the daily elimination. The Tma? it is the same as, or up to 3.0 times greater than the corresponding Tmax for an equivalent dose of conventional immediate release formulation. Time to Cma? it is desirably from 2 to 6 hours after dosing. The maximum value plasma concentration of gabapentin (Cmax) is lower than for an equivalent dose of conventional immediate release formulation, for example, as low as 0.5 of such Cmax. The plasma concentration of gabapentin is 1.5 to 2.0 to 3.0 times that provided by a conventional release formulation from 8 to 24 hours after dosing. A formulation in which the time from Cmax to 50% of the Cma is from 2 to 24 hours, or 3 to 12 hours, or 4 to 8 hours, is contemplated. A formulation where the time of Cmax up to 50 percent of Cma? is greater than the corresponding time for an immediate release of gabapentin by a factor of 1.1 to 3,? 1.5 to 2.5, is also contemplated. Gabapentin formulations that are essentially 100% immediate release (ie, not in accordance with this invention), of non-linearity in absorption, such that the AUC is not duplicated by doubling the dose. The active ingredients of the present invention or gabapentin are released at Cma? And AUC (absolute bioavailability of the active ingredient) which is 25-100%, 30-100%, 35-100%, 40-100%, 45% -100%, 50% -100%, 55-100%, 60- 100%, 65% -100%, 70% - 100% ,, 75% -100%, 80% -100%, 85-100%, 90-100%, 95% -100%, proportional to the dosage intensity of gabapentin or an active ingredient. Thus, the bioavailability of gabapentin immediate release formulations ranges from more than 70% at lower dosages to less than 30% at higher dosages. Thus, when the present invention comprises using appropriate percentages of the three components and the dose is doubled or tripled, the AUC can correspondingly increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, lx (times) , l.lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, or 2.0x. By the same standard, when the doses are doubled or tripled, the Cma? can correspondingly, increase by 0.5x, 0.6x, 0.7x, 0.8x, 0.9x, lx (times), l.lx, 1.2x, 1.3x, 1.4x, 1.5x, 1.6x, 1.7x, 1.8x, 1.9x, or 2.0x. Thus, the bioavailability of gabapentin from the invention is from about 1.0 to about 1.5 that of the immediate release gabapentin at lower doses, and from about 1.0 to about 3.0 of that of immediate release gabapentin at higher doses. On the contrary, the Tmax must be unchanged with increases or reductions in the dose. Equivalence in other pharmacological and physiological situations is also evaluated using plasma concentrations. For example, it is well known from the reviewed medical literature that there is no effect of food on gabapentin concentrations in the plasma after oral administration. Thus, a dose of a formulation according to the invention, which provides 900 mg of gabapentin (which can be administered as for example, 2 unit doses of 450 mg or 3 unit doses of 300 mg each) and provided two times daily, plasma peaks and depressions may occur, after dosing at the ready state of approximately 4.4 and 2.3 micrograms per ml, respectively, with peaks approximately 5 hours after each dosage and depressions only before each subsequent dose. In contrast, an immediate release dosage of 900 mg given twice daily, will provide a peak at 3 to 4 hours after each dosage, the peak is approximately 6.3 micrograms per ml, and the depressions are approximately 2 micrograms per ml, the depressions again are only before the dose subsequent The peaks and depressions with 600 mg of immediate release formulation, provided three times per day have values of approximately 4.7 and 1.95 micrograms per ml, respectively. Thus, a formulation according to the invention, administered as 900 mg twice daily dose (bd), can closely match the peaks and depressions of 600 mg of doses administered TVA. The values given in this paragraph are for an average adult human. When the final formulation is made up of separate components, the desired proportion of these components can be determined by administering each component separately to healthy volunteers and performing the pharmacokinetic analyzes as described above. Direct mathematical calculations can then be used to define the exact proportion of each component to achieve the desired total release profile of the active ingredient. The unit doses of the formulation according to the invention may contain 500 mg or less of gabapentin. One or more unit doses can be used to elaborate the dose to be administered at any time. Unit doses containing more than 500 mg of gabapentin may be difficult for some patients to swallow and may lead to erratic noncompliance with the desired dosage regimen. Unit doses are in solid form. Hot melt extrusion is known as a method for producing sustained-release pharmaceutical formulations based on polymers. Suitable polymers include derivatized cellulose, poly (methacrylate) derivatives, poly (ethylene-co-vinylacetate), poly (ethylene), poly (vinylacetate-co-methacrylic acid), epoxy resins and caprolactones. In the hot melt extrusion process, an effective amount of gabapentin powder is mixed with a polymer, and optionally, with a plasticizer such as polyethylene glycol. Other components can be added as required. The ratio of gabapentin to the excipients is generally from about 0.01 to about 99.99%, or from about 20 to about 80% w / w, depending on the desired release profile. The mixture is then placed in the nozzle of an extruder and passed through the heated area of the extruder at a temperature that will fuse or soften the mixture to form a matrix through which gabapentin is dispersed. The melted or softened mixture is then subjected to extrusion through a die, or other such element, at such a time, the mixture (now called the extrudate), begins to harden. Since the extrudate is still hot or is heated after of leaving the die, it can be easily formed, molded, cut, milled, formed into spheres in pearls, cut into strands, tabletted or otherwise, processed to the desired physical form. A further formulation technique that can be used to provide the desired release profile which is what is known as hot melt extrusion. Such formulations have the advantage that they allow the incorporation of high percentages of gabapentin. The equipment used to produce the hot melt formulation can be any commercially available model equipped to handle dry feed and having a solids transport zone, one or more heating zones and an extrusion die. A single two-stage extruder screw, such as that manufactured by C.W. Bravender Instruments Incorporated (NJ), is one such apparatus. It is particularly advantageous for the extruder to have multiple heating zones controllable by separate temperature. Many conditions can be varied during the extrusion process to arrive at a particularly desired release pattern. Such conditions include, by way of example, formulation composition, feed rate, operating temperature, extruder screw RPM, residence time, die centrifugation, length of heating zone and torsion and / or pressure of the extruder. Methods for optimizing such conditions are known to those skilled in the art. When high molecular weight excipients are employed, hot melt extrusion may require high processing temperatures, pressure and / or torsion when using an excipient having a lower molecular weight. Including a plasticizer, and, optionally, an antioxidant, in a formulation comprising excipients of very high molecular weight, processing temperatures, pressure and / or torsion, can be reduced. The heat-fused formulations can optionally be coated with various coatings as described above. The administration of gabapentin can be carried out in combination with other suitable therapeutic treatments which are used to treat the conditions to be treated. The treatments can be curative, but more usually, they will be prophylactic. The patient to be treated may be, for example, a human. The patient can be either male or female. In female patients, hot flushes may be a primary symptom that results from menopause or post-menopausal hormonal variation. However, hot flushes can also be induced by drugs by an anti-estrogen compound (for example, tamoxifen, leuprolide, acetate, etc.), or surgically induced by tissue removal that produces estrogen (for example, total abdominal hysterectomy, bilateral salpingo-oophorectomy, etc.). In male patients, hot flushes typically occur as a side effect of androgen-dependent therapy for metastatic prostate cancer. They can be surgically induced (for example, bilateral orchiectomy) or drug-induced (for example, treatment with a gonadotropin-releasing hormone agonist, leuprolide acetate, etc.). In the treatments described herein, which include the treatment of the symptoms of hormonal variation, eg, hot flashes, the present invention encompasses either reducing the number of symptomatic events, reducing the severity of symptomatic events, or both. Gabapentin can also act as an antipyretic agent, thereby moderating the thermoregulation of a patient. Thus, the present invention also provides a method for treating fever in a patient by administering a composition according to the invention to a patient who experiences fever under conditions effective to treat fever. Treating fever, the present invention encompasses reducing or eliminating fever, either completely or for a limited duration of time after each dose (for example, up to approximately 24 hours). Gabapentin can also act as an anti-emetic agent for the treatment of nausea and vomiting. Nausea and vomiting are often induced by stimulation of either the chemoreceptor activation zone or the vomiting (or vomiting) center in the central nervous system (CNS). Such stimulation can be caused by afferent stimulation (for example, pharyngeal tactile impulses, maze alterations, movement, increased intracranial pressure, pain, distention of viscera or psychological factors) or emetic substances that originate in the blood (for example, observes during pregnancy, cancer chemotherapy, uremia, radiation therapy, endocrine and electrolyte alterations, or the presence of chemical emetics). Nausea and vomiting are also common post-operative side effects that result from the use of anesthetics. Thus, a further aspect of the present invention relates to a method of treating nausea and vomiting by administering a composition according to the invention to a patient experiencing nausea and / or vomiting under conditions effective to treat nausea and vomiting. . Treating nausea and vomiting, the present invention encompasses reducing or eliminating the sensation of nausea, as well as reducing or eliminating the frequency of vomiting, either completely or for a limited time after each dose (for example, up to approximately 24 hours). Administration of the formulation can occur while a patient is experiencing nausea or vomiting or in anticipation of the patient experiencing nausea or vomiting. The U.S. Patent No. 6,310,098, mentions the use of gabapentin in the treatment of hormonal variations, but much emphasizes the use in menopausal and post-menopausal women. It has now been found that gabapentin can be used to treat dysmenorrhea and / or reduce or eliminate unpleasant effects, for example, pre-menopausal tension, sudden mood swings and pain, for example, in the lower abdomen, which are caused by menstruation. Thus, in accordance with a further feature of the invention, the use of gabapentin is provided to prevent or alleviate the side effects of menstruation. For this use, gabapentin can be given before or at the first signs of menstruation, or it can be used to treat adverse effects once menstruation has started. The treatment can be continued as soon as the menstruation ends. In accordance with yet another additional feature of the invention, the treatment of the side effects of Hodgkin's disease, pheochromocytoma, sleep apnea, allergic conditions, especially food allergies, diabetes and hyperthyroidism. In accordance with still a further feature of the invention, the use of gabapentin is provided for the treatment of women, for example, post-menopausal women, who suffer from incontinence, for example, urge incontinence; vaginal drying; or dry eye syndrome. The following examples illustrate the compositions and characteristics of the compositions of this invention considering the dispersion of gabapentin or other active ingredients. Numerous improvements and additional aspects of the invention are apparent to those skilled in the art upon consideration of the following examples. Examples Example 1 - Preparation of Lot Gabapentin? No Awakening Gabapentin powder was mixed with microcrystalline cellulose (Avicel pH 101) in a high shear mixer-granulator. The powder mixture containing the desired amount of gabapentin was then granulated using a polyvinylpyrrolidone bi solution (Kollidon K30 BASF). The The solution was added to the powder mix in the granulator, in aliquots for a period of time (usually about 5 minutes, but depending on the size of the batch) until a granulated mass was formed. The wet granules were then discharged from the granulator and dried in a hot air oven (Gallenkamp Hotbox) to produce dry granules. The dry granules were selected through a sieve (1000 μm, Erweka), and were mixed with super disintegrant sodium starch glycolate (Explotab) and then further mixed with magnesium stearate (BP Thew Arnott) as a lubricant and analyzed for drug content, before being fed to the hopper of a single punch (concentric cam) or rotating tablet press (F3 Manesty) fixed with concave punches of depth 3. Omm to form tablets of thickness approx. 2.3 mm (mini-tablets from Lot A). These tablets have the following composition: Table 2: Composition of mini-tablets of Lot A The cumulative in vi tro dissolution profile for these minitabletas of Lot A is shown in Example 5.

Example 2 - Preparation of Gabapentin from Lot B Coated with pH Iet Soluble Polymer Another lot, Lot B, of mini-tablets was prepared in a manner similar to that described for Lot A, with the exception that Lot B is coated ( Huttlin Microlab fluid bed coeter) with a layer barrier of Methocel E5 (hydroxypropylmethylcellulose-Colorcon), a soluble polymer iet of pH, which protects the active ingredient from interaction with any subsequent coating. Lot B forms the immediate release component (first phase) of the drug delivery system. These tablets have the same composition as the tablets of Lot A, except that the hydroxypropylmethylcellulose forms 5% of the total weight of the tablets, and have an average thickness of 2.5 mm. The cumulative in vitro dissolution profile for these mini-tablets of Lot B is shown in Example 5. Example 3 - Preparation of Gabapentin from Lot C Coated with Insoluble pH Iet Polymer Mini-tablets from Lot B of Example 2 were coated. with a polymer membrane Eudragit (Degussa AG) to achieve a programmed release of the drug. The mini-tablets were placed in the coating machine, (lower Wurster atomization), and a mixture of Eudragit RL30D (a water-insoluble polymer having high permeability and expansion which is insoluble polymer iet of pH, ie methacrylate copolymer with trimethylammonium methyl methacrylate functional groups) and Eudragit RS30D (a water-insoluble polymer, having low permeability and expansion, which is pH-iet methacrylate copolymer with trimethyl-ammonium-ethylmethacrylate functional groups). Additionally, talcum powder is added (slider) and triethyl citrate (plasticizer) to the polymer dispersed in water, to produce the coating suspension. The coating suspension is atomized on the surface of the tablets, as they are fluidized in the applicator machine. The drying of the resulting membrane occurs in itself with a defined weight percentage (10 or 15%) of coating material (mixtures 10:90 or 20:80 of RL30D / RS30D, respectively) around the mini-tablets . Table 3. Composition of mini-tablets of Lot 3 The products of this step form the modified or sustained release portion (second phase) of the formulation (Lot C). The resulting cumulative in vitro dissolution profile for these minitablets from Lot C are shown in Example 5. Example 4 - Preparation of Gabapentin from Lot D Coated with pH-Dependent Soluble Polymer Mini-Tablets from Example B of Example 2 were coated. with Eufragit L30D-55 (anionic polymer with metracrylic acid as a functional group) for dissolution above pH 5.5 or FS30D for dissolution above pH 7.0 (anionic polymer with metracrylic acid as a functional group of Degussa AG). Based on 15% w / w of polymer addition, these tablets have the following composition: Table 4. Composition of mini-tablets of Lot D The cumulative cumulative dissolution profile resulting for this delayed release from Lot D of mini-tablets (third phase) is shown in Example 5. Example 5 - Lot Characterization Solution A, B "C and The dissolution characterization of Lots A, B, C and D was determined using the USP II Dissolution Apparatus (palette) USP 28 2005 [711], used at 75 rpm. The solution medium is a buffered phosphate solution at pH 7.6 (BP 2004 buffered phosphate at pH 7.6) for Lot B, C and D parts of the formulation. The dissolution results for each of the individual components are shown in Tables 3 to 5 in which t50 is the time at 50% release and tgo is the time at 90% release and the ratios are w / w. Table 5. Dissolution of the Immediate Release Component (from Example 2).

Table 6. Dissolution of Sustained Release Components (from Example 3).

Table 7. Potential Delayed Release Components Dissolution (of Example 4) Example 6 - Dissolution of Mixed Formulations of Lot B "C and D A formulation comprising 80 percent of mini-tablets from Lot B, 10 percent mini-tablets from Lot C (RL / RS at 10% (2: 8) ) and 10 percent mini-tablets from Lot D (L30D-55 at 15%) (the percentages are in w / w) were filled into hard gelatin capsules of size 00 (Capsugel) at a total dose of 375 mg of Gabapentin The dissolution test for this complete formulation was initially carried out at a pH of about 1.2 (0.1 M HCl) for 2 hours with a paddle speed of 75 rpm; Samples were taken through 2 hours. After sampling at 120 minutes, the solution crucible was filtered and the remaining tablets were rinsed with deionized water. The tablets the remaining were then added to 500 ml of phosphate buffer at pH 6.8 (BP 2004) (372C) with a paddle speed of 75 rpm and sampled through a run of 4 additional hours (see Figure 1). The test was repeated three times. Example 7 - Dissolution of Varied Formulations of Lot B, C and D A formulation comprising 20 percent minitabletas from Lot B, 40 percent minitabletas from Lot C (RL / RS at 10% (2: 8)) and 40 percent of minitablets from Lot D (L30D-55 to 15%) (percentages are w / w) were added to size 00 gelatin capsules at a total dose of 375 mg gabapentin. The dissolution conditions were used as for Example 6. The test was repeated three times (see Figure 2). Example 8 - N vivo Pharmacological Properties of Formulations Containing Lot B "Lot C and Lot D The capsules of Example 6 and 7 can be predicted by having the properties shown in the following table, when used in humans. The table also shows comparable properties for a single dose of 600 mg gabapentin immediate release (IR) reference in humans. Delayed solution can be used in experiments of laboratory to predict the delayed dissolution in vivo. These stimulated numbers reflect the physical properties demonstrated in the dissolution studies shown in Example 5 and Figures 1 and 2. Table 6. Pharmacokinetic properties of the Sustained Release Formulation of Phase Three * Contribution to Cma? from the IR component. The control data are current data from clinical observations; other data are predicted values (simulated), and are composed, for the designated mixtures of IR, SR and DR in each case; The simulations are for a dose of 375 mg.

Example 9 - Formulation Capsules Comprising Lot B, Lot C and Lot D for Human Minitabletas capsules from Lot B of Example 2, minitabletas from Lot C of Example 3, minitabletas from Lot D of Example 4, and capsules from Lot D were administered. Examples 6 and 7 to healthy human volunteers at a dose of 375 mg gabapentin and blood samples were taken at appropriate time intervals. These samples were then analyzed to provide a pharmacokinetic profile for the batch or capsule under examination. Example 10 - Gabapentin Analysis Using Reverse Phase Gradients Analysis of gabapentin solution samples is by reverse phase gradient HPLC using varying proportions of phosphate buffer and methanol at pH 7.8 as the mobile phase. Gabapentin was derivatized with ortho-talaldehyde (OPA) to improve its UV absorption and phenylalanine was used as an internal standard. The derivation reaction took place in the autosampler. Separation was performed in a Zorbax Eclipse AAA 4.6 x 150 mm, column CLAR with particle size 5 μm (Agilent part no 994400-902) and detection is by UV absorbance at 338 nm. The quantification of gabapentin in the samples is on the basis of measurements of the peak area, with calibration with known gabapentin concentration standards. Example 11 - Treatment of Hot flashes using Gabapentin Formulations To treat, for example, Hot flashes with 900 mg of gabapentin, the following formulation was used. About 360 mg of gabapentin was coated by a soluble polymer independent of suitable pH, for example, hydroxypropylmethylcellulose. Then, 270 mg of gabapentin were coated by two different water-insoluble polymers, one having high permeability and the other having low permeability, both, however, having expansion that is independent of pH. For the purpose of this experiment, Eudragit RL30D (high permeability) and Eudragit RS30D (low permeability) meet these requirements. Finally, 270 mg of gabapentin were coated with both Eudragit L30D-55 and Eudragit FS30D. The above coated gabapentin tablets were dried and then packaged in a single unit dosage form for oral administration. Ingestion results in (1) an immediate release of gabapentin coated with hydroxypropylmethylcellulose in the stomach, (2) a sustained release dose of gabapentin coated insoluble in water, in the stomach and upper small intestine, and (3) a delayed release of gabapentin in the upper and lower small intestine due to the dissolving properties of Eudragit L30D-55 (solution above) of pH 5.5) and Eudragit FS30D (solution above pH 7.0). Example 12 - In Vitro and In vivo Dissolution Relationships of Pregabalin and Formulations thereof In order to study the dissolution ratios in vi tro and in vi vo of reabalin, pregabalin can be substituted as an active ingredient by gabapentin in Lots B, D and D as described in Examples 2-4. Pregabalin in vi tro studies can be conducted similarly as in Example 5. In vi vi studies can be conducted using a 900 mg pregabalin formulation. About 360 mg of pregabalin were coated with a soluble polymer independent of the appropriate pH, for example, hydroxypropylmethylcellulose. Then, 270 mg of pregabalin were coated by two different water-insoluble polymers, one having high permeability and the other having low permeability, both, however, having expansion that is independent of pH. For the purpose of this experiment, Eudragit RL30D (high permeability) and Eudragit RS30D (low permeability) meet these requirements. Finally, 270 mg of pregabalin were coated with both Eudragit L30D-55 and Eudragit FS30D. The above coated pregabalin tablets were dried and then packaged in a single unit dosage form for oral administration. Ingestion results in (1) an immediate release of hydroxypropylmethylcellulose-coated pregabalin in the stomach, (2) a sustained-release dose of the water-insoluble coated pregabalin in the stomach and upper small intestine, and (3) delayed release of pregabalin in the upper and lower small intestine due to the dissolving properties of Eudragit L30D-55 (solution above pH 5.5) and Eudragit FS30D (solution above pH 7.0) It is noted that in relation to this date, the The best method known to the applicant for carrying out said invention is that which is clear from the present description of the invention.

Claims (27)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property.

1. Composition, characterized in that it comprises: (a) an active ingredient, selected from the group consisting of gabapentin and pregabalin coated by a soluble polymer excipient, independent of pH; (b) an active ingredient, selected from the group consisting of gabapentin and pregabalin coated by an insoluble polymer excipient, independent of pH; and (c) an active ingredient, selected from the group consisting of gabapentin and pregabalin coated by a soluble polymer excipient, dependent on pH. Composition according to claim 1, characterized in that the soluble polymer excipient, independent of pH, is hydroxypropylmethylcellulose. Composition according to claim 1, characterized in that the insoluble polymer excipient, independent of pH, is selected from the group consisting of Eudragit RL30D, Eudragit RS30D and a combination thereof. 4. Composition according to claim 3, characterized in that the insoluble polymer excipient, independent of pH has a thickness of 25 to 150 microns. Composition according to claim 1, characterized in that the pH-dependent excipient is selected from the group consisting of Eudragit L30D-55, Eudragit FS30D, and a combination thereof. 6. Composition according to claim 5, characterized in that the pH-dependent excipient has a thickness of 25 to 150 microns. Composition according to claim 1, characterized in that 20-60% of the active ingredient is released by the soluble polymer excipient, independent of the pH within a period of up to 3 hours after dosing. 8. Composition according to claim 7, characterized in that 20-60% of the active ingredient is released by the insoluble polymer excipient, independent of the pH within a period of up to 12 hours after dosing. Composition according to claim 8, characterized in that 15-50% of the active ingredient is released by the soluble polymer excipient, depending on the pH after a delay of 3 to 10 hours after dosing. 10. Composition according to claim 1, characterized in that 250 mg of gabapentin is in a solid unit dosage form. 11. Composition according to claim 1, characterized in that 375 mg of gabapentin is in a solid unit dosage form. 1

2. Composition according to claim 1, characterized in that the active ingredient is released at a Cmax and AUC (absolute bioavailability of the active ingredient) 50% proportional to the dosage strength of an active ingredient. 1

3. Composition according to claim 12, characterized in that the active ingredient is released from a Cmax up to 50% Cmax within 2 to 24 hours. 1

4. Composition according to claim 1, characterized in that the active ingredient is coated in the form of mini-tablets. 1

5. Composition according to claim 1, characterized in that it further comprises a disintegrant, a flavor component, a colorant, a sweetener, a binder, a filler, a lubricant, a plasticizer or a combination thereof. 1

6. Composition, characterized in that it comprises (a) gabapentin coated by hydroxypropylmethylcellulose; (b) gabapentin coated by an agent releasing insoluble polymer, independent of pH, selected from the group consisting of Eudragit RL30D, Eudragit RS30D and a combination thereof; (c) gabapentin coated by an agent releasing pH-dependent soluble polymer selected from the group consisting of Eudragit L30D-55, Eudragit FS30D, and a combination thereof. 1

7. Composition according to claim 16, characterized in that the insoluble polymer excipient, independent of pH, has a thickness of 25 to 150 microns. 1

8. Composition according to claim 16, characterized in that the pH-dependent excipient has a thickness of 25 to 150 microns. 1

9. Composition, characterized in that it is produced by a process comprising the steps of: (a) separately mixing an active ingredient with a soluble polymer, independent of the pH; (b) separately mixing an active ingredient with an insoluble polymer, independent of pH; (c) separately mixing an active ingredient with a soluble polymer, dependent on the pH; (d) forming the mixture resulting from steps (a) - (c) in mini-tablets; and (e) filling the mini-tablet mixture of step (d) in a single unit dosage form, suitable for oral administrations. 20. Composition, characterized in that it is produced by the process comprising the steps of: (a) mixing an active ingredient with a filler; (b) granulating the mixture of step (a); (c) combining the granulated mixture of step (b) with a lubricant; (d) compressing the combined mixture of step (c) into mini-tablets; (e) coating the mini-tablets of step (d) with excipients from the group consisting of: (i) a soluble polymer, independent of pH; (ii) an insoluble polymer, independent of pH; and (iii) a soluble polymer, dependent on pH; (f) drying the coated mini-tablets of step (e); and (g) formulating the mixture of coated mini-tablets in a single unit dosage form, suitable for oral administration. 21. Composition according to claim 16, characterized in that it is for the treatment of a neurological disease or injury, selected from the group consisting of epilepsy, crisis Secondary epilepticus due to stroke and cranial / cerebral trauma. 22. Composition according to claim 16, characterized in that it is for the treatment of chronic pain associated with the group consisting of neuropathic, muscular and skeletal pain, tardive dyskinesia or migraine, reflex sympathetic dystrophy syndrome (RDS) and fibromyalgia. 23. Composition according to claim 16, characterized in that it is for the treatment of psychiatric disorders, selected from the group consisting of bi-polar disease, panic, anxiety, depression, alcoholism and manic behavior. 24. Composition according to claim 16, characterized in that it is for the treatment of symptoms related to menstruation, selected from the group consisting of premenstrual tension, sudden mood swings, hot flashes and pain. 25. Composition according to claim 16, characterized in that it is for the treatment of symptoms related to post-menopause, selected from the group consisting of urinary incontinence, vaginal dryness, and dry eye syndrome. 26. Composition according to claim 1, characterized in that the composition is administered once or twice a day. 27. Composition according to claim 16, characterized in that the composition is administered once or twice a day.