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WO2021129635A1 - 一种缓释递药系统 - Google Patents

一种缓释递药系统 Download PDF

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Publication number
WO2021129635A1
WO2021129635A1 PCT/CN2020/138466 CN2020138466W WO2021129635A1 WO 2021129635 A1 WO2021129635 A1 WO 2021129635A1 CN 2020138466 W CN2020138466 W CN 2020138466W WO 2021129635 A1 WO2021129635 A1 WO 2021129635A1
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composition
oil
release
solvent
drugs
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PCT/CN2020/138466
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English (en)
French (fr)
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王青松
武曲
邹丽敏
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南京清普生物科技有限公司
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Publication of WO2021129635A1 publication Critical patent/WO2021129635A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the invention belongs to the field of sustained-release pharmaceutical preparations, and specifically relates to a sustained-release drug delivery system composition and a preparation method thereof.
  • Injectable sustained-release preparations are one of the current research hotspots of pharmaceutical preparations, which aim to provide a drug reservoir that can be used for subcutaneous injection, intramuscular injection, intramuscular injection, local injection and other administration methods.
  • local injection refers to local administration, such as injection into the spinal cavity, joint cavity, wound, intraocular and other places, and the drug can be locally released after the slow release of the drug.
  • Injectable sustained-release preparations have many advantages.
  • the preparation can be directly injected into the desired administration site to release the drug slowly, reduce systemic toxicity, and increase the therapeutic effect; secondly, the preparation can also reduce the number of administrations and improve patient compliance; In addition, the preparation can significantly reduce the cost of treatment.
  • such preparations also have some disadvantages. For example, since the drug is released in a long time and usually cannot be withdrawn after administration, it needs to have good preparation stability. In addition, it is necessary to pay attention to whether the sustained-release preparation will cause a sudden release effect, or produce other adverse effects such as dispersion and toxicity at the injection site.
  • sustained-release technology for injectables is mainly based on sustained-release carriers based on polymers and lipids.
  • the polymers are mainly polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA) and polyprotocol. Acid ester (POE) and so on.
  • Lipids are mainly lipid complexes and liposomes, and a variety of long-acting preparations based on polymers and lipids have been approved for the market.
  • the patent document US200303156A1 provides a sustained-release microsphere composition and a preparation method thereof, the composition comprising polymer PLGA, active material risperidone or 9-hydroxyrisperidone and other excipients.
  • the sustained-release microspheres can provide sustained release for 14 days.
  • Heron Therapeutics Inc discloses a composition containing polyorthoesters as a sustained-release carrier, amide local anesthetics, enol non-steroidal anti-inflammatory drugs, and polyorthoesters, and a preparation method thereof.
  • PACIRA has developed a long-acting bupivacaine multivesicular liposome suspension injection with the trade name It is used to treat postoperative pain and nerve block. The analgesic effect can last for 24 hours.
  • the liposome mainly contains two synthetic phospholipids, dierucyl lecithin (DEPC) and dipalmitoyl phosphatidylglycerol (DPPG), and bupivacaine encapsulated in multivesicular liposomes can achieve a sustained release effect.
  • DEPC dierucyl lecithin
  • DPPG dipalmitoyl phosphatidylglycerol
  • bupivacaine encapsulated in multivesicular liposomes can achieve a sustained release effect.
  • the preparation process of multivesicular liposomes is complicated and requires high storage conditions.
  • Camurus has developed a long-acting liquid crystal drug delivery system.
  • Patent document CN104661648A discloses a reservoir precursor formulation, which includes a controlled release matrix, at least one oxygen-containing organic solvent, and at least 12wt% selected from buprenorphine And at least one active agent of its salt.
  • the European Union has approved a long-acting bupre
  • oil sustained-release systems in sustained-release preparations for injectables.
  • oil sustained-release systems may have a sudden release phenomenon and have potential safety hazards.
  • their release is relatively fast and cannot meet the release requirements of some drugs.
  • Oil gel is a thermoreversible viscoelastic semi-solid substance, which is composed of lipophilic liquid (mainly liquid oil) and a small amount of gel factor.
  • the gel factor mainly includes saturated hydrocarbons, biological waxes, high molecular weight ethyl cellulose, fatty acids and fatty alcohols, sterols, fatty acid glycerides, sorbitol fatty acid esters, and alanine derivatives. These gel factors are temperature-sensitive. The gel factors are usually in a sol state at high temperatures. As the ambient temperature decreases, the gel factors can trap liquid oil through self-assembly or crystallization to form a three-dimensional network structure to prevent affinity The flow of the fatty liquid makes the whole system gel solid.
  • oil gels Compared with hydrogels, oil gels have unique advantages, such as simple preparation and strong maneuverability; they can contain different types of drugs; as the oil gels degrade in the body, they can release drugs slowly and prolong the drug release cycle. . Therefore, oil gel, as a new type of drug carrier, has been gradually applied in the field of sustained-release drug delivery in recent years.
  • Vinay K et al. prepared an oleogel system containing metronidazole using sesame oil and sorbitol monostearate as drug carriers for topical administration.
  • oil gels also have the following problems. First, oil gels are semi-solid preparations with high viscosity and difficult to inject, which is not conducive to clinical administration. Secondly, most of the gel factors may have safety problems and have not been seen for injection. Route of the oil gel formulation.
  • the present invention provides a pharmaceutical composition comprising:
  • R 1 , R 2 , R 3 , R 4 , R 5 are the same or different, and are independently selected from alkyl groups;
  • L is selected from alkylene
  • At least one pharmaceutically active ingredient At least one pharmaceutically active ingredient
  • R 1 , R 2 , R 3 , R 4 , R 5 are the same or different, and are independently selected from C 1-40 alkyl groups.
  • R 1 and R 2 are the same or different, and are independently selected from C 10-30 alkyl groups, such as C 13-21 alkyl groups.
  • R 3 , R 4 , R 5 are the same or different, and are independently selected from C 1-10 alkyl groups, such as C 1-6 alkyl groups.
  • L is selected from C 1-10 alkylene, such as C 1-6 alkylene.
  • the pharmaceutical composition further comprises d. at least one pharmaceutically acceptable solvent.
  • the composition may further include a pharmaceutically acceptable release modifier and/or gel factor.
  • the liquid oil is selected from castor oil, sesame oil, corn oil, soybean oil, olive oil, safflower oil, cottonseed oil, peanut oil, fish oil, tea oil, almond oil, babassu oil, black vinegar
  • castor oil sesame oil, corn oil, soybean oil, olive oil, safflower oil, cottonseed oil, peanut oil, fish oil, tea oil, almond oil, babassu oil, black vinegar
  • borage oil canola oil, palm oil, palm kernel oil, sunflower oil, medium chain triglycerides, glyceryl dioleate, and glyceryl monooleate.
  • the compound represented by formula I is selected from phosphatidylcholine compounds, for example selected from HSPC (hydrogenated soybean phospholipid), DMPC (dimyristoyl phosphatidylcholine), DPPC (dipalmitoyl phosphatidylcholine) Acylcholine), DSPC (distearoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), or a combination of more than one.
  • HSPC hydrogenated soybean phospholipid
  • DMPC diimyristoyl phosphatidylcholine
  • DPPC dipalmitoyl phosphatidylcholine
  • Acylcholine Acylcholine
  • DSPC disearoylphosphatidylcholine
  • DLPC diilauroylphosphatidylcholine
  • the at least one pharmaceutically active ingredient is not limited to the type of treatment, and may be an anti-inflammatory drug, a local anesthetic, an analgesic, an antipsychotic, an anxiolytic, a sedative hypnotic, an antidepressant , Antihypertensive drugs, steroid hormones, antiepileptic drugs, antiseptics, anticonvulsants, antiparkinsonian drugs, central nervous system stimulants, antipsychotics, antiarrhythmic drugs, antiangina drugs, antithyroid drugs, antidote , Antiemetics, hypoglycemic drugs, anti-tuberculosis drugs, anti-AIDS drugs, anti-hepatitis B drugs, anti-tumor drugs, anti-rejection drugs and mixtures thereof.
  • an anti-inflammatory drug a local anesthetic, an analgesic, an antipsychotic, an anxiolytic, a sedative hypnotic, an antidepressant , Antihypertensive drugs,
  • a suitable pharmaceutically active ingredient may be selected from one or a combination of more of the following compounds: aspirin, acetaminophen, benoxate, indomethacin, sulindac, diclofenac, Diclofenac potassium, diclofenac sodium, ibuprofen, naproxen, flurbiprofen, flurbiprofen axetil, loxoprofen, nabumetone, ketorolac, butyl benzene, bufenac, fenox Profen, Celecoxib, Rofecoxib, Polmacoxib, Nimesulide, Meloxicam, Lornoxicam, Piroxicam, Etodolac, Valdecoxib, Parecoxib, Irecoxib, Lu Micoxib.
  • Chlorpromazine triflupromazine, mesoridazine, pipetazine, thioridazine, chloroprothixol.
  • Procainamide isoamyl nitrite, nitroglycerin, propranolol, metoprolol, prazosin, phentolamine, mithiophene, captopril, enalapril.
  • Clonidine dexmedetomidine, epinephrine, norepinephrine, tizanidine, ⁇ -methyldopa, glycopyrrolate.
  • Benzalkonium chloride benzethonium chloride, sulfamethonium acetate, benzethonium chloride, nitrocresol, nitrocresol.
  • Phenobarbital pentobarbital, pentobarbital, secobarbital. Carbidopa, Levodopa, Aniracetam, Oxiracetam, Piracetam, Doxapram, Aripiprazole, Olanzapine, Haloperidol, Quetiapine, Risperidone , Clozapine, paliperidone, atenolol, bisoprolol, metoprolol.
  • Atenolol Amlodipine, Nimodipine, Isosorbide Mononitrate, Epoprostol, Treprostinil, Iloprost, Beraprost. Methimazole, propylthiouracil, propranolol, naloxone, lofexidine, flumazenil, amphetamine.
  • the pharmaceutically active ingredient is selected from one of ropivacaine, bupivacaine, levobupivacaine, meloxicam, celecoxib, ketoprofen, and triamcinolone acetonide Or a combination of several.
  • the pharmaceutically active ingredient is selected from a combination of a local anesthetic and a non-steroidal anti-inflammatory drug, such as a combination of ropivacaine and meloxicam, a combination of levobupivacaine and meloxicam, Bupivacaine and meloxicam composition, ropivacaine and celecoxib composition, levobupivacaine and celecoxib composition, bupivacaine and celecoxib composition, etc.
  • a non-steroidal anti-inflammatory drug such as a combination of ropivacaine and meloxicam, a combination of levobupivacaine and meloxicam, Bupivacaine and meloxicam composition, ropivacaine and celecoxib composition, levobupivacaine and celecoxib composition, bupivacaine and celecoxib composition, etc.
  • the pharmaceutically acceptable release modifier is selected from one or more combinations of unsaturated phospholipids and other surfactants.
  • the unsaturated phospholipids are soybean phospholipids, egg yolk phospholipids, dierucyl lecithin, dioleyl lecithin, and the like.
  • the surfactants are polyoxyl 40 stearate, polyglycerol caprylate caprate, lauroyl polyoxyethylene glyceride, stearoyl polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, Vitamin E polyethylene glycol succinate, poloxamer 407, poloxamer 188, polysorbate 80, polyethylene glycol-12-hydroxystearate, propylene glycol monocaprylate.
  • the pharmaceutically acceptable gel factor is selected from one or more combinations of sterols, fatty acid glycerides, fatty acids and fatty alcohols.
  • the sterol is cholesterol
  • the fatty acid glycerides are monoglycerides, diglycerides or triglycerides containing fatty acid chains of 8 to 22 carbon atoms.
  • the fatty acids are fatty acids containing 12 to 22 carbon atoms and their salts.
  • the fatty alcohol is a fatty alcohol containing 14 to 22 carbon atoms.
  • the composition may further include a surfactant, which is used to adjust the hydrophilicity of the sustained-release drug delivery system so as to achieve a desired drug release rate.
  • the surfactant is a nonionic surfactant.
  • the surfactant includes polyoxyl 40 stearate, polyglycerol caprylate caprate, polyoxyethylene lauroyl glyceride, polyoxyethylene stearoyl glyceride, and oleyl polyoxyethylene glyceride.
  • Polyoxyethylene glyceride vitamin E polyethylene glycol succinate, egg yolk lecithin, soybean phospholipid, hydrogenated soybean phospholipid, poloxamer 407, poloxamer 188, polysorbate 80, polyethylene glycol-12 -Hydroxystearate, propylene glycol monocaprylate, etc.
  • the composition may further include one or more antioxidants.
  • Antioxidants can be used to prevent or reduce the oxidation of phospholipids or liquid oils in the sustained-release drug delivery system of the present invention.
  • the antioxidants provided by the present invention include but are not limited to vitamin C (ascorbic acid), cysteine or its hydrochloride, vitamin E (tocopherol), ascorbyl palmitate, glutathione, alpha lipoic acid, thioglycerol .
  • the composition may further include other conventional excipients in the field of pharmacy.
  • suitable pharmaceutical excipients are in Excipients and their use in injectable products. PDA J Pharm Sci Technol. Volume 51 , July-August 1997, pages 166-171 and Excipient Selection In Parenteral Formulation Development, Pharma Times, Volume 45, Issue 3, March 2013, pages 65-77. They are combined by reference. Into the present invention.
  • the liquid oil accounts for about 20% to about 99.5% (w/w) of the total composition, such as about 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43% , 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60 %, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93% , 94%, 95%, 95%, 95%, 9
  • the compound represented by formula I accounts for 0.5% to 40% (w/w) of the total composition, such as 0.5%, 1%, 2%, 3%, 4%, 5% , 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22 %, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%.
  • the compound represented by formula I accounts for 0.5% to 30% (w/w) of the total composition.
  • the pharmaceutically active ingredient accounts for 0.1% to 50.0% (w/w) of the total composition.
  • the pharmaceutically active ingredient accounts for 0.1% to 15% (w/w) of the total composition, such as 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0% , 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%.
  • the pharmaceutically active ingredient is present in an amount of 3% (w/w) to 10% (w/w).
  • the total amount of solvents accounts for 0% to 50% (w/w) of the total amount of the composition.
  • the pharmaceutical composition does not contain solvents (the total amount of solvents accounts for the combined 0% of the total amount of the composition).
  • the total amount of the solvent may account for 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23% , 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40 %, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%.
  • the total amount of solvents accounts for 10%-50% (w/w) of the total composition.
  • the total amount of solvents accounts for 20%-50% of the total composition. (w/w). In some embodiments, the total amount of solvents accounts for 0%, 10%, 25%, 30%, 35%, 40%, 45%, 50% of the total composition.
  • the solvent may be selected from an organic solvent or a mixed solvent composed of water and an organic solvent, and the amount of the water is less than or equal to 5% (w/w). In some embodiments, the combination of one or more of the organic solvents accounts for 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% of the total composition.
  • the amount of water is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0% , 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%, 4.1%, 4.2%, 4.3%, 4.4%, 4.5%, 4.6%, 4.7% %, 4.8%, 4.9%, 5.0%.
  • the organic solvent is selected from one or more combinations of alcohols, N-methylpyrrolidone, benzyl benzoate, and dimethyl sulfoxide.
  • the alcohols are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, glycerin, benzyl alcohol, phenethyl alcohol, polyethylene glycol.
  • the solvent is selected from a combination of ethanol, benzyl alcohol, or a combination of ethanol, benzyl alcohol, water, or a combination of ethanol, benzyl alcohol, and N-methylpyrrolidone, or a combination of ethanol, benzyl alcohol, and diethyl pyrrolidone.
  • the release modifier accounts for 0.1% to 40% (w/w) of the total composition. In some embodiments, the amount of the release modifier is 5% to 40% (w/w). w).
  • the gel factor accounts for 1% to 40% (w/w) of the total composition. In some embodiments, the gel factor accounts for 2% to 40% of the total composition. %(W/w).
  • the surfactant accounts for 0.1% to 5% (w/w) of the total composition.
  • the composition is in the form of a semi-solid or solution.
  • the composition is in a semi-solid form, and the viscosity of the composition is less than 20,000 mPa ⁇ s at 30 to 37°C. In some embodiments, the viscosity of the composition is in the range of 5000 to 10000 mPa ⁇ s at 30 to 37°C. In some embodiments, the viscosity of the composition is in the range of 3000 to 5000 mPa ⁇ s at 30 to 37°C. In some embodiments, the viscosity of the composition is in the range of 500 to 3000 mPa ⁇ s at 30 to 37°C.
  • the composition is in the form of a solution. In some embodiments, the viscosity of the composition is less than 500 mPa ⁇ s at 30 to 37°C. In some embodiments, the viscosity of the composition is in the range of 300 to 500 mPa ⁇ s at 30 to 37°C. In some embodiments, the viscosity of the composition is in the range of 150 to 300 mPa ⁇ s at 30 to 37°C. In some embodiments, the viscosity of the composition is less than 150 mPa ⁇ s at 30-37°C.
  • the present invention provides a preparation method of the sustained-release drug delivery composition, which comprises the following steps:
  • the mixing of the step (a1) further includes adding a release modifier or adding a pharmaceutically acceptable gel factor or simultaneously adding a release modifier and a pharmaceutically acceptable gel factor, for example,
  • the step (a1) can be mixing at least one compound represented by formula I, at least one pharmaceutically active ingredient, a release modifier, and at least one pharmaceutically acceptable solvent; the step (a1) can also To mix at least one compound represented by formula I, at least one pharmaceutically active ingredient, pharmaceutically acceptable gel factor, and at least one pharmaceutically acceptable solvent; the step (a1) may also be At least one compound represented by formula I, at least one pharmaceutically active ingredient, pharmaceutically acceptable gel factor, and release modifier are mixed with at least one pharmaceutically acceptable solvent.
  • the present invention also provides a method for preparing the sustained-release drug delivery composition, which includes the following steps:
  • the mixing of the step (b1) further includes adding a release modifier or adding a pharmaceutically acceptable gel factor or simultaneously adding a release modifier and a pharmaceutically acceptable gel factor.
  • the step (b1) may include mixing liquid oil, at least one compound represented by formula I, at least one pharmaceutically active ingredient, and at least one pharmaceutically acceptable solvent for release adjustment; the step ( b1) can also be liquid oil, at least one compound represented by formula I, at least one pharmaceutically active ingredient, pharmaceutically acceptable gel factor and at least one pharmaceutically acceptable solvent; said Step (b1) can also be to combine liquid oil, at least one compound represented by formula I, at least one pharmaceutically active ingredient, pharmaceutically acceptable gel factor, release modifier, and at least one pharmaceutically acceptable The solvent is mixed.
  • the present invention also provides another method for preparing the sustained-release drug delivery composition, which includes the following steps:
  • (c1) Mix at least one compound represented by formula I, at least one pharmaceutically active ingredient, and at least one pharmaceutically acceptable solvent, and stir at room temperature or under heating to a clear and uniform mixed solution.
  • the mixing of the step (c1) further includes adding a release modifier or a pharmaceutically acceptable gel factor or at the same time a release modifier and a pharmaceutically acceptable gel factor.
  • the step (c1) may be mixing at least one compound represented by formula I, at least one pharmaceutically active ingredient, a release modifier, and at least one pharmaceutically acceptable solvent;
  • the step (c1) ) Can also be mixing at least one compound represented by formula I, at least one pharmaceutically active ingredient, pharmaceutically acceptable gel factor, and at least one pharmaceutically acceptable solvent;
  • the step (c1) It may also be mixing at least one compound represented by formula I, at least one pharmaceutically active ingredient, pharmaceutically acceptable gel factor, release modifier and at least one pharmaceutically acceptable solvent.
  • the sustained-release drug delivery composition of the present invention is prepared by directly heating and mixing the liquid oil, the compound of formula I, the pharmaceutically active molecule and the solvent. In some embodiments, the sustained-release drug delivery composition of the present invention is prepared by directly heating and mixing the liquid oil, the compound of formula I, the pharmaceutically active molecule, the solvent, and the release modifier. In some embodiments, according to the properties of different pharmacologically active molecules, the more difficult to dissolve active molecules, the compound of formula I, and the release modifier can be first dissolved in the solvent, and then the liquid oil or the mixed solution formed by the liquid oil and the solvent can be added and mixed. The desired pharmaceutical composition is prepared uniformly.
  • pharmaceutically active molecules, compounds of formula I, and release modifiers can be dissolved in a solvent as part of the sustained-release drug delivery composition of the present invention, and liquid oil or a mixed solution formed by liquid oil and solvent can be used as the present invention.
  • liquid oil or a mixed solution formed by liquid oil and solvent can be used as the present invention.
  • the two parts can be mixed uniformly before use.
  • the normal temperature or heating condition is 20 to 90°C, for example, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C;
  • the formed homogeneous mixture can be sterilized by a filter membrane and then cooled to room temperature.
  • the filter membrane preferably adopts a filter membrane with a pore size of 0.22 ⁇ m.
  • the present invention provides a formulation comprising the sustained-release drug delivery composition.
  • the formulation is administered as a depot formulation. In some embodiments, it can be administered locally; in some embodiments, it can be administered parenterally; in some embodiments, it can be administered parenterally. In an embodiment, it can be administered by injection.
  • the injection administration includes subcutaneous injection, peripheral nerve injection, intramuscular injection or direct application to the wound; the preparation is suitable for administration to the skin or mucous membrane.
  • the formulation can sustain effective treatment for at least 24 hours after administration. In some embodiments, the formulation can sustain effective treatment for at least 24 to 48 hours after administration. In some embodiments, the formulation can sustain effective treatment for at least 48 to 72 hours after administration. In some embodiments, the formulation can sustain effective treatment for at least 72 hours after administration.
  • the formulation further includes a packaging material filled with the formulation, and the packaging material is selected from one or more of the following: a vial, a prefilled syringe, and a cartridge.
  • the composition may be a single-bottled preparation and a two-bottled preparation.
  • one bottle is a clear solution formed by at least one ingredient in the composition
  • the other bottle is the remaining Components, mix the two bottles evenly before administration and use.
  • the numerical range is defined as a “number” or can include “integer” or “non-integer”, it should be understood to record the two end points of the range, each integer in the range, and each decimal in the range .
  • “a number from 0 to 10” should be understood as not only recording each integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also recording at least each of the integers. Sum with 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9.
  • alkyl should be understood as a linear or branched saturated monovalent hydrocarbon group.
  • C 1-40 alkyl should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1-40 carbon atoms, such as C 1-10 alkyl, C 10-30 alkyl, C 13-21 alkyl, examples of which are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 carbon atoms linear or branched alkyl .
  • C 1-10 alkyl should be understood to preferably mean a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-di
  • the alkyl group has 1, 2, 3, 4, 5, or 6 carbon atoms ("C 1-6 alkyl”), such as methyl, ethyl, propyl, butyl, isopropyl, isopropyl Butyl, sec-butyl, tert-butyl.
  • C 1-6 alkyl such as methyl, ethyl, propyl, butyl, isopropyl, isopropyl Butyl, sec-butyl, tert-butyl.
  • alkyl can also be applied to the definition of alkyl in "alkylene".
  • biocompatibility refers to the interaction between the components of the composition and the body.
  • active ingredient refers to drugs used to treat diseases. Therefore, the active ingredients and drugs can be used interchangeably.
  • active ingredient or drug as used herein includes, but is not limited to, locally or systemically acting pharmaceutical active substances, which can be administered locally or by injection, such as subcutaneous, intradermal, intramuscular and intraarticular injection . At least one active ingredient is present in the sustained-release drug delivery system of the present invention.
  • phospholipid refers to "phosphatidylcholine", a molecule that includes a choline head group, a glycerophosphate and at least one non-polar tail group, including “saturated phospholipids” and “unsaturated phospholipids", where " “Saturated phospholipids” (or hydrogenated phosphatidylcholines) refer to “phospholipids” or “phosphatidylcholines” in which carbon-carbon double bonds are reduced to single bonds, including saturated phospholipids corresponding to compounds of formula I, such as HSPC (hydrogenated soybean phospholipids) , DLPC (Dilauroylphosphatidylcholine), DMPC (Dimyristoylphosphatidylcholine), DPPC (Dipalmitoylphosphatidylcholine), DSPC (Distearoylphosphatidylcholine); Unsaturated phospholipids Including soybean lecithin, egg yolk lecithin, etc.;
  • gel factor refers to a class of substances that have a lipophilic structure and interactable sites in the molecule, and have a certain surface activity and thermal reversibility.
  • semi-solid refers to a form that can flow under a certain pressure. More specifically, the semi-solid usually has a viscosity of 500 to 20000 mPa ⁇ s at 30 to 37°C, and particularly a viscosity of 500 to 3000 mPa ⁇ s at 30 to 37°C.
  • solution usually has a viscosity of less than 500 mPa ⁇ s at 30 to 37°C, especially a viscosity of less than 150 mPa ⁇ s at 30 to 37°C. More specifically, it refers to a syringe that can be used in the range of 18-30 Gauge, especially 20-25 Gauge needle for injection or application to the site. Each possibility is a separate embodiment of the invention.
  • viscosity refers to the resistance of the composition to gradual deformation caused by shear stress or tension.
  • SPC soybean phosphatidylcholine (soy phospholipid)
  • EPC egg yolk phosphatidylcholine (egg phospholipid)
  • HSPC hydrogenated soybean phosphatidylcholine
  • DLPC dilauroyl phosphatidyl Choline
  • DMPC dimyristoylphosphatidylcholine
  • DPPC dipalmitoylphosphatidylcholine
  • DSPC distearoylphosphatidylcholine
  • DEPC dierucylphosphatidylcholine
  • DOPC dioleoylphosphatidylcholine Acylcholine (dioleic acid acyl lecithin)
  • DPPG-Na is 1,2-palmitoylphosphatidylglycerol sodium salt
  • DPPA dipalmitoylphosphatidic acid
  • DPPE dipalmitoylphosphatidylethanolamine
  • the present invention provides a sustained-release drug delivery formulation form, which can make the drug appear in a semi-solid or solution form at room temperature.
  • the semi-solid formulation can be directly used as a drug reservoir at the administration site, and the liquid formulation is at the administration site. After contact with body fluids, a phase change occurs to form a drug reservoir; the inventor surprisingly found that the addition of the compound of formula I in the composition of the present application promotes the gelation of the sustained-release drug delivery formulation.
  • the preparation of the present invention adopts liquid oil, formula I compound, gel factor, release regulator, etc., and has good biocompatibility; the gel factor and release regulator can further improve the properties of the preparation, especially in the preparation Release of active ingredients.
  • the sustained-release drug delivery liquid composition of the present invention has a viscosity of less than 1000 mPa ⁇ s at 30 to 37°C, and has a significantly lower viscosity than other liquid compositions containing phospholipids. Due to the lower viscosity, the The sustained-release drug delivery formulation provided by the present invention is easy to administer; the sustained-release drug delivery composition of the present invention can be directly applied to the administration site, which is convenient for clinical administration.
  • composition of the present invention presents improved irritation to local tissues, and has good medication safety and tolerance.
  • the sustained-release preparation system provided by the present invention can enable the active pharmaceutical ingredient to achieve good release performance and reduce the possibility of burst release.
  • Figure 1-1 is a comparison of the morphology of a composition containing saturated phospholipids, a composition containing unsaturated phospholipids (soy phospholipid composition), and a composition containing no phospholipids (pure castor oil composition) in water.
  • Figure 2-1 and Figure 2-2 show the phase change morphology of compositions containing different phospholipids (HSPC, SPC, EPC) added to water at 0 minutes and 30 minutes.
  • Figure 2-3 shows the state after the phase transition is studied by two different methods containing high concentration of unsaturated phospholipids (SPC composition).
  • Figure 3-1 shows the composition using two different methods to study the state after phase change.
  • Figures 4-1 and 4-2 show the structure of composition 33 and composition 34
  • Figure 4-3 and Figure 4-4 show the morphological structure of the composition in water.
  • Figures 5-1 to 5-6 show the administration site of mice after subcutaneous administration of the composition of the present invention and pure castor oil composition for 2 hours, 6 hours, 12 hours, 24 hours, 48 hours and 72 hours respectively ( Figure (Circle marked) the preparation form.
  • Figure 6-1 and Figure 6-2 show the composition of ropivacaine and meloxicam (composition 8, composition 42, pure castor oil group and ropivacaine hydrochloride group, see Table 25-1 for details) Pharmacokinetic differences in dogs.
  • Figure 6-1 is the blood concentration-time curve of ropivacaine
  • Figure 6-2 is the blood concentration-time curve of meloxicam.
  • Figure 7-1 shows the efficacy results of composition 48, composition 48 (blank), and ropivacaine hydrochloride solution in a rat incision model after administration by perfusion.
  • Figure 8-1 shows the efficacy results of composition 49, composition 49 (blank), and ropivacaine hydrochloride solution in a rat incision model after being administered by multi-point subcutaneous injection.
  • EtOH stands for absolute ethanol
  • BB stands for benzyl benzoate
  • BA stands for benzyl alcohol
  • NMP stands for N-methylpyrrolidone
  • DMSO dimethyl sulfoxide.
  • saturated phospholipids (HSPC, DPPC, DMPC, DSPC) have good solubility in alcohol solvents (ethanol, benzyl alcohol, propylene glycol, etc.), while phosphatidylglycerol (DPPG) and phosphatidylethanolamine (DPPE) , Phosphatidic acid (DPPA) can not be dissolved in the above solvents.
  • alcohol solvents ethanol, benzyl alcohol, propylene glycol, etc.
  • DPPG phosphatidylglycerol
  • DPPE phosphatidylethanolamine
  • DPPA Phosphatidic acid
  • the composition was prepared according to each ingredient and ingredient ratio shown in Table 2-1 below. Mix the solvent phospholipid, oil and solvent, stir while heating until a transparent and uniform solution is formed, cool to room temperature, and examine the physical form. At the same time, the room temperature morphology of the unsaturated phospholipid composition was used as a comparative study.
  • This example examines the formulation form of the composition containing 0.5-30% (w/w) saturated phospholipids (HSPC, DPPC, DSPC and DMPC) and 0-50% (w/w) solvent at room temperature.
  • the results are shown in Table 2.
  • the room temperature form of the composition of the present invention is related to the amount of saturated phospholipid and solvent. By changing the amount of saturated phospholipid and solvent, a semi-solid or liquid preparation can be formed, which can be used for different administration routes.
  • compositions containing unsaturated phospholipids are in solution form at room temperature, and semi-solid preparations cannot be obtained.
  • the "phospholipid" component in each group corresponds to HSPC, DPPC, DMPC, SPC, EPC, for example, the phospholipid in the HSPC group is HSPC; the "SPC" component in each group is used as a release regulator, for example In the DPPC group, the phospholipid is DPPC, and SPC is the release modifier.
  • composition 16 saturated phospholipids
  • no phospholipids pure castor oil group
  • unsaturated phospholipids were prepared respectively.
  • Meloxicam was dissolved in N-methylpyrrolidone to prepare a 50mg/g concentrated solution, and ropivacaine, soybean phospholipid or dipalmitoyl phosphatidylcholine was added to liquid oil, solvent and meloxicam at 50°C In the Kang solution, stir while heating until a transparent and uniform solution is formed, and cool to room temperature.
  • the composition was slowly injected into the water with a syringe, and the morphology of different compositions in the water was observed. The results are shown in Figure 1-1.
  • composition 16 saturated phospholipids
  • soybean phospholipid-containing compositions unsaturated phospholipid group
  • phospholipid-free compositions pure castor oil group.
  • Figure 1- 1 Compositions containing unsaturated phospholipids and compositions without phospholipids are added to water and spread on the surface in the form of droplets, while compositions containing the same proportion (10wt%) of saturated phospholipids are formed immediately after contact with water, forming a reservoir ⁇ Like substances. It is further illustrated that saturated phospholipids are the key factor for the phase transition of the composition of the present invention.
  • a composition containing different phospholipids (HSPC, SPC, EPC) in the same proportions was prepared according to Table 3-2, and the phase transition results of adding each prescription to water are shown in Figure 2-1. After standing for 30 minutes, shake slowly to observe the change of the preparation form, as shown in Figure 2-2.
  • the HSPC group can quickly change phase after adding water and become translucent to white; while the SPC group and EPC group float on the surface after adding water, and no obvious phase transition occurs.
  • Figure 2-2 shows the changes in each area after shaking for 30 minutes.
  • the HSPC group has a complete phase change and can form a better storage. After shaking, the aqueous solution is still clear, and the SPC and EPC groups are turbid after shaking. Unable to form the desired storage form.
  • the present invention conducted phase transition studies on the composition of the present invention from in vivo and in vitro.
  • the in vitro study includes the characterization of the viscosity and structure change of the in-situ oil gel composition after simulating the in vivo administration.
  • the in vivo study mainly focuses on the observation of the formulation morphology at different time points after subcutaneous administration of the composition of the present invention.
  • Examples 4-10 are all phase transition studies on the composition of the present invention, among which Examples 4-9 are simulation studies in vitro, and Example 10 is an in vivo administration study.
  • Example 4 two methods were used to study the phase change of the composition sample. The results are shown in Figure 3-1.
  • a sample of the composition is dropped into a large amount of water, a semi-solid substance can be formed in the water (right side of the figure).
  • Water was added dropwise to the composition sample, shaken and mixed, and the viscosity of the preparation increased rapidly, gradually turning into a semi-solid, and it did not flow when it was turned upside down (left in the figure).
  • the blank carrier composition of the present invention and the pure castor oil blank carrier composition were studied on the viscosity changes before and after the phase change.
  • the viscosity results are shown in Table 5-2.
  • the viscosity of the blank carrier composition of the present invention and pure castor oil blank carrier composition are both less than 100mPa ⁇ s.
  • the composition is added to a dialysis bag, placed in excess water, and shaken at 37°C.
  • the viscosity change was detected at the time point.
  • the pure castor oil group had a small viscosity change range, and the viscosity change range was within 300mPa ⁇ s, while the viscosity of the composition increased significantly during the shaking process.
  • the viscosity change range was 650 ⁇ 2000mPa. ⁇ Between s.
  • a composition containing a high concentration of unsaturated phospholipid was prepared according to Table 6-2, and the viscosity was measured in the same way.
  • the viscosity of the composition prepared by using high-concentration soybean phospholipid is significantly higher than that of the liquid composition of the present invention.
  • the composition was prepared according to Table 7-1. Dissolve meloxicam in N-methylpyrrolidone to prepare a 100mg/g concentrated solution, mix the liquid oil, phospholipids, ropivacaine, meloxicam concentrated solution and solvent at 50°C, and heat While stirring until a transparent and uniform solution is formed, cool to room temperature, add the composition to water, let stand at 37°C for 72h, and then use a viscometer equipped with a No. 14 rotor (NiRun) to measure the phase change viscosity by the shaft method. The detection temperature is 37°C. , The speed is 60 rpm, and the viscosity results are shown in Table 7-2.
  • the composition was prepared according to Table 8-1. Dissolve meloxicam in N-methylpyrrolidone to prepare a 100mg/g concentrated solution, mix the liquid oil, phospholipids, ropivacaine, meloxicam concentrated solution and solvent at 50°C, and heat While stirring until a transparent and uniform solution is formed, cool to room temperature and take 2 mL of the composition into an EP tube, add 1 mL of water, and place it in a 37°C constant temperature incubation shaker at 200 rpm. Prepare 4 samples for each sample, respectively at 1h and 4h , 6h, 24h sampling, and then use a viscometer equipped with No. 14 rotor (NiRun) to measure the phase change viscosity by the shaft method, the detection temperature is 37 °C, the rotation speed is 60 rpm, the viscosity results are shown in Table 8-2.
  • No. 14 rotor No. 14 rotor
  • the above experiment adopted a method of adding a quantitative amount of water to the composition of the present invention, and investigated the change of the viscosity of the composition at different time points.
  • the results of the viscosity change are shown in Table 8-2.
  • the viscosity of the composition 29-30 increased to varying degrees.
  • the viscosity can increase to between 500-1100 mPa ⁇ s.
  • composition Prepare the composition according to Table 9-1, mix the liquid oil, phospholipid, release modifier and solvent at 50°C, stir while heating until a transparent and uniform solution is formed, and cool to room temperature. Observe the morphology of the composition under a microscope and take pictures. The structure of the composition is shown in Figure 4-1 and Figure 4-2. Add the composition to water, take out the formed part, observe the morphology after phase change with a microscope and take a picture. The structure of the composition after phase change is shown in Figure 4-3 and Figure 4-4. Obvious change, compared with before the phase change, the phase change structure after contact with water is denser.
  • the composition was prepared according to Table 10-1 below. Dissolve meloxicam in N-methylpyrrolidone to prepare a 100mg/g concentrated solution, and mix the liquid oil, phospholipids, ropivacaine, meloxicam concentrated solution, release regulator and solvent at 50°C Mix, stir while heating until a transparent and uniform solution is formed, and cool to room temperature.
  • the preparation morphology of 2 hours, 6 hours, 12 hours, 24 hours, 48 hours and 72 hours are shown in Figure 5-1 to Figure 5-6, respectively.
  • the phase change process occurred 2 hours after the subcutaneous injection of the composition, and the formation of obvious The core-shell structure of the gel-like reservoir.
  • the reservoir After administration, the reservoir remains intact within 12 hours, and slowly degrades after 24 hours, until 72 hours, there is still obvious phase change preparation in the administration area.
  • the pure castor oil group can also form a certain reservoir after subcutaneous injection, but there is no obvious phase change process in the whole study process, and the reservoir gradually disappears with time.
  • the pure castor oil + solvent group has a certain irritation to local tissues after subcutaneous injection, which may cause safety problems.
  • the composition of the present invention has no obvious irritation to local tissues, and exhibits good safety and tolerance. Table 10-2 summarizes the results.
  • Composition 30 Composition 38 Pure castor oil group 2 hours White gel storage White gel storage Oily 6 hours White gel storage White gel storage Oily, slightly irritating 12 hours White gel storage White gel storage Oily 24 hours The storage degrades slowly The storage degrades slowly The oily state gradually disappears and is irritating 48 hours Storage morphology can still be observed Storage morphology can still be observed The oily state gradually disappears and the irritation is obvious 72 hours Storage morphology can still be observed Storage morphology can still be observed The oiliness disappears and the irritation is weakened
  • the composition is prepared according to Table 11-1 below, and the method is as described above.
  • the composition is liquid and can be gelled when added to water.
  • 100 mg of the composition was dropped directly into 200 mL of phosphate buffer to determine the release of the drug.
  • the concentration of ropivacaine and meloxicam in each sample was detected by HPLC. The results are shown in Table 11-2 below.
  • Example 12 In-situ oil gel composition containing different liquid oils
  • compositions containing organic solvents in different proportions were prepared according to each ingredient shown in Table 12-1 below.
  • the resulting composition is a liquid, which can form a gel when added to water.
  • Example 12 100 mg of the composition from Example 12 was added to a dialysis bag and placed in a tube containing 200 mL of phosphate buffer to determine the release of ropivacaine from the composition of Example 12. Shake at 37°C at 200 rpm, and take 1 mL of phosphate buffer from the tube at 24h, 48h, and 72h, respectively. The concentration of ropivacaine and meloxicam in each sample was detected by HPLC. The results are shown in Table 13-1 below.
  • Example 14 Compositions containing different types of saturated phospholipids
  • compositions containing organic solvents in different proportions were prepared according to each ingredient shown in Table 14-1 below.
  • the resulting composition is a liquid, which can form a gel when added to water.
  • Example 14 100 mg of the composition from Example 14 was added to a dialysis bag and placed in a tube containing 200 mL of phosphate buffer to determine the release of ropivacaine from the composition of Example 14. Shake at 100 rpm at 37°C, and take 1 mL of phosphate buffer from the tube at 24 h, 48 h, and 72 h, respectively. The concentration of ropivacaine and meloxicam in each sample was detected by HPLC. The results are shown in Table 15-1 below.
  • compositions containing different saturated phospholipids prepared in Example 14 all achieved better release effects.
  • Example 16 Compositions containing different release modifiers
  • compositions containing organic solvents in different proportions were prepared according to each ingredient shown in Table 16-1 below.
  • ropivacaine, hydrogenated soybean phospholipids, and different release regulators to the liquid oil at 50°C.
  • the solvent and the meloxicam solution stir while heating until a transparent and uniform solution is formed, and cool to room temperature.
  • the formed composition is a liquid and can be gelled when added to water.
  • Example 17 In vitro release of ropivacaine and meloxicam from the composition
  • Example 16 100 mg of the composition from Example 16 was added to a dialysis bag and placed in a tube containing 200 mL of phosphate buffer to determine the release of ropivacaine from the composition of Example 16. Shake at 37°C, and take 1 mL of phosphate buffer from the tube at 24h, 48h, and 72h. The concentration of ropivacaine and meloxicam in each sample was detected by HPLC. The results are shown in Table 17-1 below.
  • Example 18 Solvent pharmaceutical composition in different proportions
  • compositions containing different proportions of solvents were prepared according to each ingredient shown in Table 18-1 below. Add ropivacaine, phospholipids, and celecoxib to the liquid oil and solvent at 50°C, stir while heating until a transparent and uniform solution is formed, and cool to room temperature to form a semi-solid composition.
  • Example 20 Compositions containing amide local anesthetics
  • composition was prepared according to each ingredient shown in Table 20-1 below. Add different drugs, hydrogenated soybean phospholipids, to liquid oil and solvent at 50°C, stir while heating until a transparent and uniform solution is formed, and cool to room temperature. The resulting composition is liquid, which can be phased into glue when added to water.
  • Example 21 Composition containing non-steroidal anti-inflammatory drugs
  • the in-situ oil gel composition was prepared according to each ingredient shown in Table 21-1 below. Add different drugs, hydrogenated soybean phospholipids, cholesterol and antioxidants to the liquid oil and solvent at 50°C, stir while heating until a transparent and uniform solution is formed, and cool to room temperature. The resulting composition is liquid, and it can be phase-changed when added to water Into glue.
  • Example 22 Composition containing hormone drugs
  • the in-situ oil gel composition was prepared according to each ingredient shown in Table 22-1 below. Dissolve the drug in N-methylpyrrolidone at 50°C until a clear and transparent solution is formed. Dissolve dipalmitoylphosphatidylcholine in the remaining organic solvent and liquid oil until a clear solution is formed. Add the drug solution to the mixed solution containing the above In the composition, the formed composition is liquid and can be phased into glue when added to water.
  • Example 23 Other compositions containing local anesthetics and non-steroidal anti-inflammatory drugs
  • the composition was prepared according to each ingredient shown in Table 23-1 below. Local anesthetics, non-steroidal anti-inflammatory drugs, dipalmitoylphosphatidylcholine and antioxidants are added to the solvent, wherein the meloxicam solution is a dimethyl sulfoxide solution of meloxicam with a concentration of 50 mg/g. Stir until a clear solution is obtained, and add castor oil to the solution until it is completely mixed and uniform. The resulting composition is liquid, which can form a gel when added to water.
  • the pharmacokinetics study in dogs is as follows. Beagle dogs weighing about 10 kg were fasted for more than 12 hours before the experiment (removing the food box from which they were fed), and were allowed to drink freely, and were given food 4 hours after the administration. Each group was administered by subcutaneous injection. The sample information is shown in Table 25-1.
  • the meloxicam of composition 8 and pure castor oil group 5 is a meloxicam/N methylpyrrolidone solution with a concentration of 50 mg/g.
  • the meloxicam of substance 47 is a meloxicam/N methylpyrrolidone solution with a concentration of 100 mg/g.
  • Each beagle received two injections of 25 mg/time, in which ropivacaine hydrochloride solution was used as the positive control group, and was administered in the same manner.
  • the animals in each group were taken 0 hours before administration and 0.5 mg after administration. , 1, 2, 3, 6, 8, 12, 24, 36, 48, 60, 72, and 96 hours, respectively, collect about 0.5 mL of blood samples into EDTA-2K+ anticoagulated blood collection tubes, and collect whole blood after centrifugation at 8000 rpm for 5 minutes Plasma, and then detect the drug concentration in the plasma sample by LC-MS/MS.
  • FIG. 6-1 The blood concentration-time curves of ropivacaine and meloxicam within 96 hours after administration of the composition are shown in Figure 6-1 and Figure 6-2.
  • Figure 6-1 the blood concentration of ropivacaine for composition 8 was maintained at about 200 ng/mL for 6 hours after administration, and the blood concentration of ropivacaine for composition 42 was maintained at about 24 hours after administration.
  • the ropivacaine hydrochloride solution and castor oil group had ropivacaine blood concentrations of 1600ng/mL and 400ng/mL or more 0.5 hours after administration, with obvious burst release phenomenon.
  • Figure 6-2 is the blood concentration-time curve of meloxicam.
  • the castor oil group has obvious burst release, and the blood concentration is above 1000ng/mL between 8 hours of administration, composition 8 and composition 42 It can significantly reduce the release of meloxicam, and the blood concentration of meloxicam is maintained within 400ng/mL after administration. From the results of the plasma concentration-time curve, it can be seen that the addition of an appropriate amount of solvent to the composition of the present invention will not cause a sudden release phenomenon. In addition, compared with the ropivacaine hydrochloride solution and the pure castor oil group, the composition of the present invention can significantly reduce the individual deviation of the pharmacokinetics in dogs.
  • the temperature is set to 56 °C
  • the tolerance time in seconds
  • the left and right feet of the rat were tested 5 times at an interval of no less than 20 seconds.
  • the cut-off time was set to 12 seconds. Rats that did not lift their feet for more than 12 seconds were considered to be insensitive to thermal pain, and no more procedures thereafter. Detection.
  • Rats whose average value exceeds 5 seconds or any one measurement value exceeds 10 seconds are deemed to be unqualified for the basic threshold and cannot be administered and subsequent experiments.
  • the left and right feet of the rat were tested once at each time point, and each test was performed by a well-trained experimenter.
  • Composition 39 is a composition of Composition 39:
  • the sensory block lasted 72 hours, and the strongest block appeared 10 minutes to 8 hours after administration (12 seconds delay).
  • the exercise block lasts about 6-8 hours, and the strongest exercise block is 10 minutes to 6 hours after administration.
  • Composition 40 is a composition of Composition 40:
  • the sensory block lasted 72 hours, with the strongest block occurring 10 minutes to 6 hours after administration (12 seconds delay).
  • the exercise block lasted about 12 hours, and the strongest exercise block was 10 minutes to 4 hours after the administration.
  • one of the rats recovered their foot-lifting ability.
  • Composition 41 is a composition of Composition 41:
  • the sensory block lasted 72 hours, with the strongest block occurring 10 minutes to 6 hours after administration (12 seconds delay).
  • the exercise block lasts about 4-6 hours, and the strongest exercise block is 10 minutes to 4 hours after the administration.
  • Eight hours after the administration one rat had a normal walking gait.
  • Four hours after the administration one of the rats recovered their foot-lifting ability.
  • composition 48 (blank preparation), composition 48 (30mg/kg), positive control ropivacaine solution
  • Table 27-1 the sample information is shown in Table 27-1 , Where the meloxicam solution is prepared with N-methylpyrrolidone. Von Frey monofilaments were used to stimulate the middle of the plantar of the hind limbs of rats at different time points after administration. Each filament was tested 3 times on each plantar. The pain threshold was defined as the occurrence of at least two withdrawals in 3 consecutive trials. The lowest intensity. The detection time was 10min, 30min, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h after administration.
  • each rat was made a 1 cm long longitudinal incision with a No. 11 scalpel blade at a position 0.5 cm posterior to the plantar to separate the fascia and muscle, and make a longitudinal incision along the muscle. After light pressure to stop the bleeding, the wound was closed, and the skin was sutured with two discrete stitches at the incision site with a 5 gauge nylon thread. Multiple subcutaneous injections around the incision 0.3cm around the incision, a total of 6 points.
  • composition 49 (blank preparation), composition 49 (30 mg/kg), and the positive control ropivacaine hydrochloride solution were respectively administered.
  • the sample information is shown in Table 28-1, in which the meloxicam solution is prepared with dimethyl sulfoxide.
  • an IITC 390 thermal stimulation pain tester (Life Science, USA) was used to measure the rat thermal withdrawal latency (TWL).
  • the detection time was 10min, 30min, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, 12h, 24h, 48h, 72h after administration.

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Abstract

一种药物组合物，包含液体油，至少一种如下式I所示的化合物，至少一种药学上的活性成分。药物组合物可用于缓释制剂系统，使得药物在常温下呈现半固体或溶液形态，半固体制剂在给药部位可直接作为药物储库，而液体制剂在给药部位与体液接触后，发生相变形成药物储库。

Description

一种缓释递药系统
本申请要求2019年12月23日向中国国家知识产权局提交的，专利申请号为201911339789.2，发明名称为“一种缓释递药系统”在先申请的优先权。该申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于缓释药物制剂领域，具体涉及一种缓释递药系统组合物及其制备方法。
背景技术
可注射用缓释制剂是目前药物制剂的研究热点之一，其旨在提供一种药物贮库，可用于皮下注射、肌内注射、肌肉注射、局部注射等给药方式。其中，局部注射是指在局部给药，如在脊椎腔、关节腔、伤口、眼内等部位注射，药物缓慢释放后可在局部发挥作用的给药方式。
可注射用缓释制剂具有多种优势，例如：该制剂可以直接注入期望给药部位缓慢释药，降低系统毒性，增加治疗效果；其次，该制剂还可以减少给药次数，提高患者顺应性；此外，该制剂还可显著降低治疗费用。但是，此类制剂同样存在一些缺点，例如：由于药物在较长时间内释放，且用药后通常不能撤回，因此需要具有良好的制剂稳定性。并且，需要关注缓释制剂是否会引起突释效应，或者在注射部位产生弥散、毒性等其他不利影响。
近年来，可注射用缓释技术的研究主要以聚合物和脂质为基质的缓释载体为主，聚合物主要为聚乳酸(PLA)、聚乳酸-羟基乙酸共聚物(PLGA)和聚原酸酯(POE)等。脂质主要为脂质复合物和脂质体，目前已批准上市多种以聚合物和脂质为基质的长效制剂。例如，专利文献US200303156A1提供了一种缓释微球组合物及其制备方法，所述组合物包含聚合物PLGA、活性物质利培酮或9-羟基利培酮及其他赋形剂。2003年FDA批准了Janssen Pharmaceuticals开发的一种以PLGA为缓释载体的利培酮长效微球，商品名为RISPERDAL
Figure PCTCN2020138466-appb-000001
该缓释微球可提供14天持续释放。Heron Therapeutics Inc在专利文献CN106535886A中公开了以聚原酸酯为缓释载体，含有酰胺类局麻药，烯醇类非甾体抗炎药和聚原酸酯的组合物及其制备方法。PACIRA开发了一种长效布比卡因多囊脂质体混悬注射液，商品名为
Figure PCTCN2020138466-appb-000002
用于治疗术后疼痛及神经阻滞，镇痛效果可持续24小时。该脂质体中主要含有二芥酰基卵磷脂(DEPC)和二棕榈酰磷脂酰甘油(DPPG)两种合成磷脂，将布比卡因包裹在多囊脂质体中能起到缓释作用。但是，多囊脂质体制备工艺复杂，且对储藏条件要求高。Camurus开发了一种长效液晶递药体系，在专利文献CN104661648A中公开了一种贮库前体制剂，包括控释基质，至少一种含氧有机溶剂，至少12wt％的选自丁丙诺啡和其盐的至少一种活性剂。目前欧盟已批准了基 于液晶体系的丁丙诺啡长效制剂，商品名为
Figure PCTCN2020138466-appb-000003
已有研究将油缓释体系用于可注射用缓释制剂，但是，油缓释体系可能具有突释现象，存在安全性隐患，此外其释放较快，无法满足一些药物的释放需求。
油凝胶是一种热可逆的黏弹性半固体状物质，它由亲脂性液体(主要为液体油)与少量凝胶因子组成。凝胶因子主要包括饱和烃、生物蜡、高分子量的乙基纤维素、脂肪酸和脂肪醇、甾醇、脂肪酸甘油酯、山梨醇脂肪酸酯、丙氨酸衍生物等。这些凝胶因子具有对温度敏感的特性，高温时凝胶因子通常为溶胶状态，随着环境温度的降低，凝胶因子可以通过自组装或者结晶的方式捕集液体油形成三维网络结构，阻止亲脂性液体的流动，从而使整个体系凝胶固态化。与水凝胶相比，油凝胶具有独特的优势，如制备简单，可操作性强；可以包载不同类型的药物；随着油凝胶在体内降解可实现药物缓慢释放，延长释药周期。因此油凝胶作为一种新型的药物载体近年来逐渐被应用于缓释递药领域。
Vinay K等以芝麻油和山梨醇单硬脂酸酯为药物载体制备了含有甲硝哒唑的油凝胶(oleogel)体系，以用于局部给药。然而油凝胶也存在以下问题，首先油凝胶为半固体制剂，粘度较大，注射较为困难，不利于临床给药，其次大部分凝胶因子可能存在安全性问题，尚未看到用于注射途径的油凝胶制剂。
并且，目前使用的含有非水溶剂的制剂还容易在注射部位引发疼痛和刺激，使得此类制剂的应用受到限制。
因此，亟需开发一种适于药用，稳定性、安全性、耐受性和/或缓释性能得到改善的缓释制剂系统。
发明内容
为改善现有技术中存在的问题，本发明提供一种药物组合物，包含：
a.液体油；
b.至少一种如下式I所示的化合物：
Figure PCTCN2020138466-appb-000004
其中，R 1、R 2、R 3、R 4、R 5相同或不同，彼此独立地选自烷基；
L选自亚烷基；
c.至少一种药学上的活性成分；
根据本发明的实施方案，R 1、R 2、R 3、R 4、R 5相同或不同，彼此独立地选自C 1-40烷基。
根据本发明的实施方案，R 1、R 2相同或不同，彼此独立地选自C 10-30烷基，例如C 13-21烷基。
根据本发明的实施方案，R 3、R 4、R 5相同或不同，彼此独立地选自C 1-10烷基，例如C 1-6烷基。
根据本发明的实施方案，L选自C 1-10亚烷基，例如C 1-6亚烷基。
根据本发明的实施方案，所述药物组合物还包含d.至少一种药学上可接受的溶剂。
根据本发明的实施方案，所述组合物可以进一步包含药学上可接受的释放调节剂和/或凝胶因子。
根据本发明的实施方案，所述液体油选自蓖麻油、芝麻油、玉米油、大豆油、橄榄油、红花油、棉籽油、花生油、鱼油、茶油、杏仁油、巴巴苏油、黑醋栗种子油、琉璃苣油、卡诺拉油、棕榈油、棕榈仁油、向日葵油、中链甘油三酯、二油酸甘油酯、单油酸甘油酯中的一种或多种组合。
根据本发明的实施方案，式I所示的化合物选自磷脂酰胆碱类化合物，例如选自HSPC(氢化大豆磷脂)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)、DLPC(二月桂酰磷脂酰胆碱)中的一种或多种的组合。
根据本发明的实施方案，所述至少一种药学活性成分不限于治疗类型，并可为抗炎药、局麻药、镇痛药、抗精神失常药、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药及其混合物。
根据本发明的实施方案，合适的药学活性成分可选自下述化合物中的一种或多种的组合：阿司匹林，对乙酰氨基酚，贝诺酯，吲哚美辛，舒林酸，双氯芬酸，双氯芬酸钾，双氯芬酸钠，布洛芬，萘普生，氟比洛芬，氟比洛芬酯、洛索洛芬，萘丁美酮，酮咯酸，保泰松，丁苯羟酸，非诺洛芬，塞来昔布，罗非昔布，Polmacoxib，尼美舒利，美洛昔康，氯诺昔康，吡罗昔康，依托度酸，伐地考昔，帕瑞昔布，艾瑞昔布，卢米昔布。布比卡因，左旋布比卡因，罗哌卡因，甲哌卡因，利多卡因，普鲁卡因，苯佐卡因，丁卡因，达克罗宁。脑啡肽，强啡肽，β-内啡肽，纳曲酮，丁丙诺啡，吗啡，二甲基吗啡，可待因，双氢可待因，羟考酮、氢可酮、纳布啡，芬太尼，舒芬太尼，瑞芬太尼，曲马多，去甲曲马多，他喷他多，地佐辛，喷他佐辛，美沙酮，哌替啶，氯胺酮，地西泮，氯甲西泮，赖右苯丙胺，右丙氧芬，Difelikefalin，Oliceridine。氯丙嗪，三氟丙嗪，美索哒嗪，哌西他嗪，硫利达嗪，氯普噻吨。地西泮，阿普唑仑，氯硝西泮，奥沙西泮，丙咪嗪，阿密曲替林，多虑平，去甲替林，阿莫沙平，反苯环丙胺，苯乙肼。普鲁卡因胺，亚硝酸异戊酯，硝酸甘油，心得安，美托洛尔，哌唑嗪，酚妥拉明，咪噻吩，卡托普利，依那普利。可乐定，右美托咪定，肾上腺素，去甲肾上腺素，替扎尼定，α-甲基多巴，格隆溴铵。可的松，氢化可的松，倍他米松，曲安奈德，地塞米松，地塞米松酯，泼尼松，泼尼松龙，甲泼尼龙，倍氯米松，氯倍他索，黄体酮，睾酮，庚酸睾酮，十一烷酸睾酮，环戊丙酸睾酮，孕酮，氟维司群，别孕烯醇酮，Ganaxolone，苯妥英，乙妥英。苯扎氯铵，苄索氯铵，醋酸磺胺米隆，甲苄索氯铵，呋喃西林，硝甲酚汞。苯巴比妥、异戊巴比妥、戊巴比妥、司可巴比妥。卡比多巴，左旋多巴，阿尼西坦，奥拉西坦，吡拉西坦，多沙普仑，阿立哌唑，奥氮平，氟哌啶醇，喹硫平，利培酮，氯氮平，帕利哌酮，阿替洛尔，比索洛尔，美托洛尔。阿替洛尔，氨氯地平，尼莫地平，单硝酸异山梨酸酯，依前列醇，曲前列尼尔，伊洛前列素，贝前列素。甲巯咪唑，丙巯氧嘧啶，普萘 洛尔，纳洛酮，洛非西定，氟马西尼，苯丙胺。格拉司琼，昂丹司琼，托烷司琼，多拉司琼，帕洛诺司琼，东莨菪碱，多潘立酮，格列吡嗪，格列本脲，格列美脲，优降糖，格列齐特，甲苯磺丁脲，利拉鲁肽，艾塞拉肽，度拉鲁肽，索马鲁肽。达芦那韦，多替拉韦钠，恩曲他滨，拉替拉韦，利托那韦，司他夫定，奈韦拉平，齐多夫定，司他夫定，依曲韦林，阿德福韦酯，恩替卡韦，替比夫定，拉米夫定，替诺福韦二吡呋酯，磷丙替诺福韦，氨硫脲，吡嗪酰胺，丙硫异烟胺，环磷酰胺，5-氟尿嘧啶，卡莫司汀，洛莫司汀，马法兰，苯丁酸氮芥，甲氨蝶呤，长春新碱，博来霉素，阿霉素，他莫昔芬，环孢素，他克莫司，依维莫司，西罗莫司以及所述化合物的药学可接受的盐，立体异构体，衍生物。
在一些实施方式中，所述药学活性成分选自罗哌卡因、布比卡因、左旋布比卡因、美洛昔康、塞来昔布、酮洛芬、曲安奈德中的一种或几种的组合。
在一些实施方式中，所述药学活性成分选自局部麻醉药与非甾体抗炎药的组合，例如罗哌卡因和美洛昔康组合物、左旋布比卡因和美洛昔康组合物、布比卡因和美洛昔康组合物、罗哌卡因和塞来昔布组合物、左旋布比卡因和塞来昔布组合物、布比卡因和塞来昔布组合物等。
根据本发明的实施方案，所述药学上可接受的释放调节剂选自不饱和磷脂、其他表面活性剂中的一种或多种组合。所述不饱和磷脂为大豆磷脂、蛋黄磷脂、二芥酰基卵磷脂、二油酸酰基卵磷脂等。所述表面活性剂为硬脂酸聚烃氧40酯、辛酸癸酸聚乙二醇甘油酯、月桂酰聚氧乙烯甘油酯、硬脂酰聚氧乙烯甘油酯、油酰聚氧乙烯甘油酯、维生素E聚乙二醇琥珀酸酯、泊洛沙姆407、泊洛沙姆188、聚山梨酯80、聚乙二醇-12-羟基硬脂酸酯、丙二醇单辛酸酯。
根据本发明的实施方案，所述药学上可接受的凝胶因子选自甾醇，脂肪酸甘油酯、脂肪酸和脂肪醇中的一种或多种组合。所述甾醇为胆固醇，所述脂肪酸甘油酯为含有8至22个碳原子脂肪酸链的甘油单酯、甘油二酯或甘油三酯。所述脂肪酸为含有12至22个碳原子的脂肪酸及其盐。所述脂肪醇为含有14至22个碳原子的脂肪醇。
根据本发明的实施方案，所述组合物还可以进一步包括表面活性剂，所述表面活性剂用于调节缓释递药系统的亲水性，以便达到期望的药物释放速度。在一些实施方式中，所述表面活性剂为非离子型表面活性剂。在一些实施方式中，所述表面活性剂包括硬脂酸聚烃氧40酯、辛酸癸酸聚乙二醇甘油酯、月桂酰聚氧乙烯甘油酯、硬脂酰聚氧乙烯甘油酯、油酰聚氧乙烯甘油酯、维生素E聚乙二醇琥珀酸酯、蛋黄卵磷脂、大豆磷脂、氢化大豆磷脂、泊洛沙姆407、泊洛沙姆188、聚山梨酯80、聚乙二醇-12-羟基硬脂酸酯、丙二醇单辛酸酯等。
根据本发明的实施方案，所述组合物还可以进一步包括一种或多种抗氧化剂。抗氧化剂可用于防止或减少本发明中所述缓释递药系统中磷脂或液体油的氧化。本发明提供的抗氧化剂包括但不限于维生素C(抗坏血酸)，半胱氨酸或其盐酸盐，维生素E(生育酚)，抗坏血酸棕榈酸酯，谷胱甘肽，α硫辛酸，硫代甘油。
根据本发明的实施方案，所述组合物还可以进一步包括其他药学领域常规的赋形剂，合适的药物赋形剂的实例在Excipients and their use in injectable products.PDA J Pharm Sci Technol.第51卷，1997年7-8月，第166-171页和Excipient Selection In Parenteral Formulation Development，Pharma Times，第45卷，第3期，2013年3月，第65-77页中描述，他们通 过引用整体并入本发明中。
根据本发明的实施方案，所述液体油占组合物总量的约20％至约99.5％(w/w)，例如约21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％、60％、61％、62％、63％、64％、65％、66％、67％、68％、69％、70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％。在一些实施方案中，所述液体油比例约为30至90％(w/w)。在一些实施方案中，所述液体油比例约为40％至85％(w/w)。
根据本发明的实施方案，所述式I所示的化合物占组合物总量的0.5％至40％(w/w)，例如0.5％、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％。在一些实施方案中，所述式I所示的化合物占组合物总量0.5％至30％(w/w)。
根据本发明的实施方案，所述药学活性成分占组合物总量的0.1％至50.0％(w/w)。根据一些实施方案，药学活性成分占组合物总量的0.1％至15％(w/w)，例如0.1％、0.5％、1.0％、1.5％、2.0％、2.5％、3.0％、3.5％、4.0％、4.5％、5.0％、5.5％、6.0％、6.5％、7.0％、7.5％、8.0％、8.5％、9.0％、9.5％、10.0％、10.5％、11.0％、11.5％、12.0％、12.5％、13.0％、13.5％、14.0％、14.5％、15.0％。根据一些实施方式，药学活性成分以3％(w/w)至10％(w/w)的量存在。
根据本发明的实施方案，所述溶剂总量占组合物总量的0％至50％(w/w)，在一些实施方案中，所述药物组合物中不含有溶剂(溶剂总量占组合物总量的0％)，在一些实施方案中，所述溶剂总量可以占组合物总量的0.1％、0.5％、1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％。在一些实施方案中，所述溶剂总量占组合物总量的10％-50％(w/w)，在一些实施方案中，所述溶剂总量占组合物总量的20％-50％(w/w)，在一些实施方案中，所述溶剂总量占组合物总量的0％、10％、25％，30％，35％，40％，45％，50％。在一些实施方案中，所述溶剂可以选自有机溶剂或者为水和有机溶剂组成的混合溶剂，所述水的用量小于等于5％(w/w)。在一些实施方式中，所述有机溶剂中的一种或多种的组合占组合物总量的1％、2％、3％、4％、5％、6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％、20％、21％、22％、23％、24％、25％、26％、27％、28％、29％、30％、31％、32％、33％、34％、35％、36％、37％、38％、39％、40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％。所述水的用量占组合物总量的0.1％、0.2％、0.3％、0.4％、0.5％、0.6％、0.7％、0.8％、0.9％、1.0％、1.1％、1.2％、1.3％、1.4％、1.5％、1.6％、1.7％、1.8％、1.9％、2.0％、2.1％、2.2％、2.3％、2.4％、 2.5％、2.6％、2.7％、2.8％、2.9％、3.0％、3.1％、3.2％、3.3％、3.4％、3.5％、3.6％、3.7％、3.8％、3.9％、4.0％、4.1％、4.2％、4.3％、4.4％、4.5％、4.6％、4.7％、4.8％、4.9％、5.0％。
根据本发明的实施方案，所述有机溶剂选自醇类、N-甲基吡咯烷酮、苯甲酸苄酯、二甲亚砜中的一种或多种组合。所述醇类选自甲醇、乙醇、正丙醇，异丙醇，正丁醇，异丁醇、叔丁醇、乙二醇、丙二醇、甘油、苯甲醇、苯乙醇、聚乙二醇。根据本发明的实施方案，所述溶剂选自乙醇、苯甲醇的组合，或乙醇、苯甲醇、水的组合，或乙醇、苯甲醇和N-甲基吡咯烷酮的组合，或乙醇、苯甲醇和二甲基亚砜的组合。
根据本发明的实施方案，所述释放调节剂占组合物总量的0.1％至40％(w/w)，在一些实施方式中，所述释放调节剂用量为5％至40％(w/w)。
根据本发明的实施方案，所述凝胶因子占组合物总量的1％至40％(w/w)，在一些实施方案中，所述凝胶因子占组合物总量的2％至40％(w/w)。
根据本发明的实施方案，所述表面活性剂占组合物总量的0.1％至5％(w/w)。
根据本发明的实施方案，所述组合物为半固体或溶液形式。
在一些实施方案中，所述组合物为半固体形式，在30～37℃时所述组合物的粘度小于20000mPa·s。在一些实施方式中，在30～37℃时所述组合物的粘度在5000至10000mPa·s的范围内。在一些实施方式中，在30～37℃时所述组合物的粘度在3000至5000mPa·s的范围内。在一些实施方式中，在30～37℃时所述组合物的粘度在500至3000mPa·s的范围内。
在一些实施方案中，所述组合物为溶液形式，在一些实施方式中，在30～37℃时所述组合物的粘度小于500mPa·s。在一些实施方式中，在30～37℃时所述组合物的粘度在300至500mPa·s的范围内。在一些实施方式中，在30～37℃时所述组合物的粘度在150至300mPa·s的范围内。在一些实施方式中，在30～37℃时所述组合物的粘度小于150mPa·s。
本发明提供了一种所述缓释递药组合物的制备方法，包括如下步骤：
(a1)将至少一种式I所示的化合物、至少一种药学上的活性成分与至少一种药学上可接受的溶剂混合，在常温或加热条件下搅拌至澄清均一的混合溶液；
(a2)将液体油添加到所述混合溶液中，搅拌至形成均一混合溶液；
(a3)将(a2)形成的均一混合溶液过滤并灌装。
根据本发明的实施方案，所述步骤(a1)的混合还包括加入释放调节剂或加入药学上可接受的凝胶因子或同时加入释放调节剂和药学上可接受的凝胶因子，例如，所述步骤(a1)可以为将至少一种式I所示的化合物、至少一种药学上的活性成分、释放调节剂与至少一种药学上可接受的溶剂混合；所述步骤(a1)还可以为将至少一种式I所示的化合物、至少一种药学上的活性成分、药学上可接受的凝胶因子与至少一种药学上可接受的溶剂混合；所述步骤(a1)还可以为将至少一种式I所示的化合物、至少一种药学上的活性成分、药学上可接受的凝胶因子、释放调节剂与至少一种药学上可接受的溶剂混合。
本发明还提供了一种用于制备所述缓释递药组合物的方法，包括如下步骤：
(b1)将液体油，至少一种式I所示的化合物、至少一种药学上的活性成分与至少一种药学上可接受的溶剂混合，在常温或加热条件下搅拌至澄清均一的混合溶液；
(b2)将(b1)形成的均一混合溶液过滤并灌装。
根据本发明的实施方案，所述步骤(b1)的混合还包括加入释放调节剂或加入药学上可 接受的凝胶因子或同时加入释放调节剂和药学上可接受的凝胶因子。例如，所述步骤(b1)可以为将液体油，至少一种式I所示的化合物、至少一种药学上的活性成分、释放调节至少一种药学上可接受的溶剂混合；所述步骤(b1)还可以为将液体油，至少一种式I所示的化合物、至少一种药学上的活性成分、药学上可接受的凝胶因子与至少一种药学上可接受的溶剂混合；所述步骤(b1)还可以为将液体油，至少一种式I所示的化合物、至少一种药学上的活性成分、药学上可接受的凝胶因子、释放调节剂与至少一种药学上可接受的溶剂混合。
本发明还提供了另一种用于制备所述缓释递药组合物的方法，包括如下步骤：
(c1)将至少一种式I所示的化合物、至少一种药学上的活性成分与至少一种药学上可接受的溶剂混合，在常温或加热条件下搅拌至澄清均一的混合溶液。
(c2)将(c1)得到的混合溶液过滤并灌装。
(c3)将液体油或液体油和溶剂组成的混合溶液过滤并灌装。
(c4)使用前将(c2)和(c3)混合均匀即可。
根据本发明的实施方案，所述步骤(c1)的混合还包括加入释放调节剂或加入药学上可接受的凝胶因子或同时加入释放调节剂和药学上可接受的凝胶因子。例如，所述步骤(c1)可以为将至少一种式I所示的化合物、至少一种药学上的活性成分、释放调节剂与至少一种药学上可接受的溶剂混合；所述步骤(c1)还可以为将至少一种式I所示的化合物、至少一种药学上的活性成分、药学上可接受的凝胶因子与至少一种药学上可接受的溶剂混合；所述步骤(c1)还可以为将至少一种式I所示的化合物、至少一种药学上的活性成分、药学上可接受的凝胶因子、释放调节剂与至少一种药学上可接受的溶剂混合。
在一些实施方式中，通过直接将液体油、式I化合物、药学上的活性分子和溶剂加热混合而制备本发明的缓释递药组合物。在一些实施方式，通过直接将液体油、式I化合物、药学上的活性分子、溶剂、释放调节剂加热混合而制备本发明的缓释递药组合物。在一些实施方式中，可以根据不同药学活性分子的性质，将较难溶解的活性分子、式I化合物、释放调节剂先溶于溶剂，再加入液体油或液体油和溶剂形成的混合溶液，混合均匀而制备所需的药物组合物。在一些实施方式中，可以将药学上的活性分子、式I化合物、释放调节剂溶于溶剂作为本发明的缓释递药组合物一部分，将液体油或液体油和溶剂形成的混合溶液作为本发明的缓释递药组合物的另一部分，使用前将两部分混合均匀即可。
根据本发明的实施方案，上述用于制备所述缓释递药组合物的方法中，所述常温或加热条件为20～90℃，例如可以选择20℃、30℃、40℃、50℃、60℃、70℃、80℃、90℃；所述形成的均一混合物可以先通过滤膜除菌后再冷却至室温，所述滤膜优选采用孔径为0.22μm的滤膜。
本发明提供一种包含所述缓释递药组合物的制剂，所述制剂作为储库制剂施用，在一些实施方式中，可以局部给药；在一些实施方式中，可以肠胃外施用；在一些实施方式中，可以注射给药。
所述注射给药包括皮下注射，周围神经注射，肌内注射或向伤口直接施用；所述制剂适合在皮肤或粘膜给药。
在一些实施方式中，所述制剂施用后可持续有效治疗至少24小时。在一些实施方式中，所述制剂施用后可持续有效治疗至少24至48小时。在一些实施方式中，所述制剂施用后可持续有效治疗至少48至72小时。在一些实施方式中，所述制剂施用后可持续有效治疗至少72小时。
根据本发明的实施方案，所述制剂进一步包括填充了所述制剂的包材，所述包材选自以下一种或多种：西林瓶、预灌封注射器、卡式瓶。
根据本发明的实施方案，所述组合物可为单瓶装制剂和两瓶装制剂，所述两瓶装制剂，其中一瓶为所述组合物中至少一种成分形成的澄清溶液，另一瓶为剩余组分，给药前将两瓶混合均匀后使用。
术语与缩写
除非另有说明，本申请说明书和权利要求书中记载的基团和术语定义，包括其作为实例的定义、示例性的定义、优选的定义、表格中记载的定义、实施例中具体化合物的定义等，可以彼此之间任意组合和结合。这样的组合和结合后的基团定义及化合物结构，应当属于本申请说明书记载的范围内。
本申请说明书和权利要求书记载的数值范围，当该数值范围被定义或其仅可为“整数”时，应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如，“0～10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。
当该数值范围被定义为“数”或可以包括“整数”或“非整数”时，应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如，“0～10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数，还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
术语“烷基”应理解为直链或支链饱和一价烃基。例如，术语“C 1-40烷基”应理解为表示具有1～40个碳原子的直链或支链饱和一价烃基，例如为C 1-10烷基、C 10-30烷基、C 13-21烷基，其实例为具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40个碳原子的直链或支链烷基。“C 1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直连或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。例如，所述烷基具有1、2、3、4、5或6个碳原子(“C 1-6烷基”)，例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基。
应当理解，上述术语“烷基”的定义同样可适用于“亚烷基”中烷基的定义。
术语“生物相容性”是指组合物成分与机体之间的相互作用。
术语“活性成分”是指用于治疗疾病的药物。因此，活性成分、药物可替换使用。此处使 用的术语“活性成分”或“药物”包括但不限于局部或全身作用的药物活性物质，其可以通过局部给药或通过注射，如皮下、皮内、肌内及关节内注射进行施用。至少一种活性成分存在于本发明的缓释递药系统中。
术语“磷脂”是指“磷脂酰胆碱”，包括一个胆碱头基、一个甘油磷酸和至少一个非极性尾部基团的分子，包括“饱和磷脂”和“不饱和磷脂”，其中，“饱和磷脂”(或氢化磷脂酰胆碱)是指碳碳双键被还原为单键的“磷脂”或“磷脂酰胆碱”，包括式I化合物对应的饱和磷脂，例如HSPC(氢化大豆磷脂)、DLPC(二月桂酰磷脂酰胆碱)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)；不饱和磷脂包括大豆卵磷脂，蛋黄卵磷脂等；所述“磷脂”包括天然磷脂和合成磷脂。
术语“凝胶因子”是指分子中具有亲脂结构和可相互作用位点，并且具有一定表面活性以及热可逆性的一类物质。
术语“半固体”是指在一定压力下可流动的形态。更具体地，半固体通常在30～37℃下粘度在500至20000mPa·s之间的粘度，特别是在30～37℃下500至3000mPa·s的之间粘度。
术语“溶液”通常在30～37℃下粘度小于500mPa·s，特别是在30～37℃下粘度小于150mPa·s。更具体地，指可使用范围从18-30Gauge，特别是20-25Gauge针头的注射器注射或涂抹给药至部位。每种可能性是本发明单独的实施方式。
术语“粘度”是指组合物对有剪切应力或张力引起的逐步变形的阻力。
本发明使用的缩写词具有如下定义：SPC为大豆磷脂酰胆碱(大豆磷脂)，EPC为蛋黄磷脂酰胆碱(蛋黄磷脂)，HSPC为氢化大豆磷脂酰胆碱，DLPC为二月桂酰磷脂酰胆碱，DMPC为二肉豆蔻酰基磷脂酰胆碱，DPPC为二棕榈酰基磷脂酰胆碱，DSPC为二硬脂酰基磷脂酰胆碱，DEPC为二芥酰基卵磷脂，DOPC为二油酸酰基磷脂酰胆碱(二油酸酰基卵磷脂)，DPPG-Na为1,2-棕榈酰磷脂酰甘油钠盐，DPPA为二棕榈酰磷脂酸，DPPE为二棕榈酰基磷脂酰乙醇胺，EtOH代表无水乙醇，BB代表苯甲酸苄酯，BA代表苯甲醇，NMP代表N-甲基吡咯烷酮，DMSO代表二甲基亚砜。
有益效果
1)本发明提供了一种缓释递药制剂形式，该制剂可以使药物在常温下呈现半固体或溶液形态，半固体制剂在给药部位可直接作为药物储库，液体制剂在给药部位与体液接触后，发生相变形成药物储库；发明人惊奇的发现，本申请的组合物中，式I化合物的加入，促进了缓释递药制剂的凝胶化。
2)本发明的制剂采用液体油、式I化合物、凝胶因子，释放调节剂等，具有良好的生物相容性；所述凝胶因子、释放调节剂可以进一步改善制剂性质，特别是制剂中活性成分的释放。
3)本发明的缓释递药液体组合物在30～37℃的粘度均小于1000mPa·s，与其他含有磷脂液体组合物相比，具有明显更低的粘度，由于具有更小的粘度，本发明提供的缓释递药制剂易于给药；本发明的缓释递药组合物可直接施用于给药部位，便于临床给药。
4)本发明组合物对局部组织呈现改善的刺激性，具有良好的用药安全性及耐受性。
5)本发明提供的缓释制剂系统，能够使得活性药物成分实现良好的释放性能，降低突释的可能性。
附图说明
图1-1为含有饱和磷脂的组合物、含有不饱和磷脂的组合物(大豆磷脂组合物)以及不含磷脂的组合物(纯蓖麻油组合物)在水中的形态对比。
图2-1和图2-2为含有不同磷脂(HSPC、SPC、EPC)的组合物加入水中0分钟和30分钟的相变形态。
图2-3为含有高浓度不饱和磷脂(SPC组合物)采用两种不同方法研究相变后的状态。
图3-1为组合物采用两种不同方法研究相变后的状态。
图4-1和4-2为组合物33和组合物34的结构，图4-3和图4-4为组合物在水中的形态结构。
图5-1～图5-6分别为小鼠皮下给予本发明组合物和纯蓖麻油组合物2小时、6小时、12小时、24小时、48小时和72小时后，给药部位(图中圆圈标注处)的制剂形态。
图6-1和图6-2为罗哌卡因和美洛昔康组合物(组合物8、组合物42、纯蓖麻油组和盐酸罗哌卡因组，详细信息见表25-1)在犬体内的药代动力学差异。其中图6-1为罗哌卡因血药浓度-时间曲线，图6-2是美洛昔康血药浓度-时间曲线。
图7-1为组合物48、组合物48(空白)、盐酸罗哌卡因溶液在大鼠切口模型中，通过灌注给药后的药效结果。
图8-1为组合物49、组合物49(空白)、盐酸罗哌卡因溶液在大鼠切口模型中，通过多点皮下注射给药后的药效结果。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实验动物来源：
比格犬：江苏亚东实验动物研究院有限公司
大鼠：南通大学动物实验中心
小鼠：南京市江宁区青龙山动物繁殖场
实施例1不同类型饱和磷脂在蓖麻油和各有机溶剂中的溶解情况考察
分别取1g蓖麻油、有机溶剂于EP管中，加入0.1g饱和磷脂(约100mg/g，10％w/w)，50℃超声，观察溶解情况，结果如表1-1所示。
表1-1溶解情况考察
  HSPC DPPC DMPC DSPC DPPG-Na DPPA DPPE
EtOH 溶清 溶清 溶清 溶清 浑浊 浑浊 浑浊
BB 浑浊 浑浊 浑浊 浑浊 浑浊 浑浊 浑浊
BA 溶清 溶清 溶清 溶清 浑浊 浑浊 浑浊
NMP 浑浊 浑浊 浑浊 浑浊 浑浊 浑浊 浑浊
DMSO 浑浊 浑浊 浑浊 浑浊 浑浊 浑浊 浑浊
丙二醇 溶清 溶清 —— —— —— —— ——
甘油 溶清 —— —— —— —— —— ——
其中，EtOH代表无水乙醇；BB代表苯甲酸苄酯；BA代表苯甲醇；NMP代表N-甲基吡咯烷酮；DMSO代表二甲基亚砜。
根据溶解情况考察，饱和磷脂(HSPC、DPPC、DMPC、DSPC)在醇类溶剂(乙醇、苯甲醇、丙二醇等)中有较好的溶解度，而磷脂酰甘油(DPPG)、磷脂酰乙醇胺(DPPE)、磷脂酸(DPPA)类在上述溶剂中均无法溶清。
实施例2组合物配比研究
(1)组合物室温形态试验
按照下表2-1中所示的每种成分及成分比例制备组合物。将溶剂磷脂、油和溶剂混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温，考察物理形态。同时以不饱和磷脂组合物的室温形态作为对比研究。
表2-1不同配比下组合物的室温形态
Figure PCTCN2020138466-appb-000005
Figure PCTCN2020138466-appb-000006
本实施例考察了含有0.5～30％(w/w)饱和磷脂(HSPC、DPPC、DSPC和DMPC)、0～50％(w/w)溶剂的组合物在室温的制剂形态，结果如表2-1所示，本发明的组合物室温形态与饱和磷脂和溶剂用量相关，通过改变饱和磷脂和溶剂用量，可以形成半固体或液体制剂，可用于不同给药途径。
本实施例还对比了不饱和磷脂组合物，在相同磷脂和有机溶剂用量下，含有不饱和磷脂(SPC和EPC)的组合物室温均为溶液形态，无法得到半固体制剂。
(2)不同配比液体组合物加入水后的形态研究
按照表2-2制备含有0.5～30％饱和磷脂、10～45％溶剂的液体组合物，以及加入3～5％凝胶因子或10～30％释放调节剂的液体组合物，将磷脂和溶剂混合直至溶清，再将蓖麻油加入混合溶液中至完全混合均匀，同时制备含有不饱和磷脂的液体组合物作为对比。取组合物0.5mL加入过量水中，考察加入水后2h内组合物的形态变化。
表2-2不同配比液体组合物加入水后的形态
Figure PCTCN2020138466-appb-000007
注：各组别中的“磷脂”组分分别对应于HSPC、DPPC、DMPC、SPC、EPC，例如，HSPC组的磷脂为HSPC；各组别中的“SPC”组分作为释放调节剂，例如DPPC组中，磷脂为DPPC，SPC为释放调节剂。
结果显示含有饱和磷脂(HSPC、DPPC和DMPC)的液体组合物加入水中均可快速成胶，而仅含有10％或30％的不饱和磷脂(SPC和EPC)的液体组合物在2h内均无法成胶。
实施例3
(1)不同类型磷脂对组合物相变的影响
按表3-1分别制备含有饱和磷脂(组合物16)、不含磷脂(纯蓖麻油组)和含有不饱和磷脂的药物组合物。将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的浓溶液，在50℃下将罗哌卡因、大豆磷脂或二棕榈酰磷脂胆碱加入液体油、溶剂和美洛昔康溶液中，边加热边搅拌直至形成透明均一的溶液，冷却至室温。将组合物用注射器缓慢注入水中，观察不同组合物在水中的形态变化。结果见图1-1。
表3-1不同组合物
Figure PCTCN2020138466-appb-000008
上述实验分别考察了含有饱和磷脂(组合物16)、含有大豆磷脂的组合物(不饱和磷脂组)以及不含磷脂的组合物(纯蓖麻油组)在水中的形态变化，结果见图1-1。其中含有不饱和磷脂的组合物以及不含磷脂的组合物加入水中后以液滴形式平铺在表面，而含有相同比例(10wt％)的饱和磷脂的组合物接触水后立刻成形，形成储库状物质。进一步说明饱和磷脂是本发明组合物发生相转变的关键因素。
(2)不饱和磷脂处方对比试验
按表3-2制备含有相同比例不同磷脂(HSPC、SPC、EPC)的组合物，取各处方加入水中的相转变结果见图2-1。静置30min后，缓慢振摇，观察制剂形态的变化，见图2-2。
表3-2不饱和磷脂处方组成
Figure PCTCN2020138466-appb-000009
Figure PCTCN2020138466-appb-000010
由图2-1可看到HSPC组加入水后可快速相变，变为半透明至白色；而SPC组和EPC组加入水后浮在表面，未发生明显的相转变。图2-2为静置30min振摇后各处方的变化，HSPC组相变完全，可形成较好的贮库，振摇后水溶液仍为澄清状态，SPC组和EPC组振摇后水溶液浑浊，无法形成期望的储库形态。
按表3-3制备含有高浓度不饱和磷脂(SPC)的组合物，先将组合物滴加至过量水中，观察组合物在水溶液中的变化。其次将水溶液逐滴滴加至组合物中，振摇混匀，观察组合物的变化。结果见图2-3，将水滴加至高浓度SPC组合物中，粘度增大，但倒置会缓慢流动(图中左侧)。将高浓度SPC组合物加入过量水中，可成形，但振摇溶液变浑浊(图中右侧)。
表3-3高浓度不饱和磷脂(SPC)组合物
Figure PCTCN2020138466-appb-000011
实施例4本发明组合物的相变研究
为了验证本发明的组合物可在体内发生相转变形成药物储库，从而在持续的时间内释放药物，本发明分别从体内和体外对本发明组合物进行了相变研究。体外研究包括模拟体内给药后原位油凝胶组合物的粘度和结构变化表征，体内研究主要为将本发明组合物皮下给药后，在不同时间点对制剂形态的观察。下文中，实施例4-10均是对本发明组合物的相变研究，其中实施例4-9是体外的模拟研究，实施例10为体内给药研究。
按表4-1制备不同的组合物，将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的浓溶液，在50℃下将罗哌卡因、氢化大豆磷脂或二棕榈酰磷脂胆碱加入液体油、溶剂和美洛昔康溶液中，边加热边搅拌直至形成透明均一的溶液，冷却至室温。首先将原位油凝胶逐滴滴加至水中，观察组合物在水溶液中的变化。其次将水溶液逐滴滴加至原位油凝胶中，振摇混匀，观察组合物的变化。结果见图3-1。
表4-1组合物
Figure PCTCN2020138466-appb-000012
实施例4分别采用了两种方法对组合物样品进行了相变研究。结果见图3-1，将组合物样品滴加至大量水中，可在水中形成半固体状物质(图中右侧)。而将水逐滴滴加至组合物样品中，振摇混匀，制剂粘度迅速增加，逐渐变为半固体，倒置不流动(图中左侧)。
实施例5本发明空白载体组合物和纯蓖麻油空白载体组合物的相变粘度研究
按表5-1制备本发明空白载体组合物。在50℃下将氢化大豆磷脂或二棕榈酰磷脂胆碱加入液体油、溶剂中，边加热边搅拌直至形成透明均一的溶液，冷却至室温。将组合物置于透析袋中，加入水中，于37℃振摇，分别于6h、24h、48h、72h取样，随后使用配备14号转子的粘度计(NiRun)通过轴方法测定相变粘度，检测温度为37℃，转速60rpm，粘度结果见表5-2。
表5-1本发明空白载体组合物和纯蓖麻油空白载体组合物
Figure PCTCN2020138466-appb-000013
表5-2粘度检测结果
Figure PCTCN2020138466-appb-000014
上述实验分别对本发明空白载体组合物和纯蓖麻油空白载体组合物进行了相变前后的粘度变化研究。粘度结果见表5-2，本发明空白载体组合物和纯蓖麻油空白载体组合物粘度均小于100mPa·s，将组合物加入透析袋中，置于过量水中，于37℃振摇，在不同时间点检测粘度变化，其中纯蓖麻油组粘度变化幅度较小，粘度变化范围在300mPa·s以内，而组合物的粘度在振摇过程中明显增加，根据处方不同，粘度变化范围在650～2000mPa·s之间。
实施例6组合物的粘度检测
按表6-1制备含有10％(w/w)磷脂，0％至20％(w/w)释放调节剂，5％(w/w)罗哌卡因，0.19％美洛昔康，10％至40％(w/w)溶剂的药物组合物。将美洛昔康溶于N-甲基吡咯烷 酮中，配制成50mg/g的浓溶液，在50℃下将液体油、磷脂、罗哌卡因、美洛昔康浓溶液、释放调节剂和溶剂混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温。随后使用配备64号转子的粘度计(博勒飞DVⅢ)通过轴方法测量药物组合物的粘度，检测温度为30℃转速为40rpm，粘度检测结果见下表6-1。
表6-1粘度检测结果
Figure PCTCN2020138466-appb-000015
按照表6-2制备含有高浓度的不饱和磷脂(大豆磷脂)组合物，按相同的方法检测粘度。采用高浓度大豆磷脂制备的组合物，粘度明显高于本发明的液体组合物。
表6-2高浓度大豆磷脂组合物
Figure PCTCN2020138466-appb-000016
实施例7组合物相变粘度研究
按表7-1制备组合物。将美洛昔康溶于N-甲基吡咯烷酮中，配制成100mg/g的浓溶液，在50℃下将液体油、磷脂、罗哌卡因、美洛昔康浓溶液和溶剂混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温将组合物加入水中，于37℃静置72h，随后使用配备14号转子的粘度计(NiRun)通过轴方法测定相变粘度，检测温度为37℃，转速60rpm，粘度结果见表7-2。
表7-1组合物处方
Figure PCTCN2020138466-appb-000017
表7-2 72h后的粘度结果
组合物 72h粘度(mPa·S)
组合物29 780-1200
组合物32 600-620
上述实验直接将组合物29和组合物32加入过量水中，静置72小时，考察相变情况。粘度检测结果见表7-2，可知组合物29和组合物32粘度均明显增加，72小时后粘度在600～1200mPa·s之间。
实施例8组合物相变粘度研究
按表8-1制备组合物。将美洛昔康溶于N-甲基吡咯烷酮中，配制成100mg/g的浓溶液，在50℃下将液体油、磷脂、罗哌卡因、美洛昔康浓溶液和溶剂混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温取组合物2mL于EP管中，加入1mL水，置于37℃恒温培养震荡器中200rpm振摇，每份样品配制4份，分别于1h、4h、6h、24h取样，随后使用配备14号转子的粘度计(NiRun)通过轴方法测定相变粘度，检测温度为37℃，转速60rpm，粘度结果见表8-2。
表8-1不同组合物
Figure PCTCN2020138466-appb-000018
表8-2相变粘度结果
Figure PCTCN2020138466-appb-000019
上述实验采用向本发明组合物中加入定量水的方法，在不同时间点考察组合物粘度的变化。粘度变化结果见表8-2，37℃振摇1小时后，组合物29～30粘度均有不同程度的增加，随着振摇时间的延长，粘度可增加至500～1100mPa·s之间。
实施例9组合物相变前后的结构表征
按表9-1制备组合物，在50℃下将液体油、磷脂、释放调节剂和溶剂混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温。在显微镜下观察组合物形态并拍照，组合物结构见图4-1和图4-2。将组合物加入水中，取出成形部分，用显微镜观察相变后形态并拍照，组合物相变后结构见图4-3和图4-4，可以看出，相变前后组合物的结构发生了明显变化，与相变前相比，与水接触后的相变结构更为致密。
表9-1组合物
Figure PCTCN2020138466-appb-000020
实施例10组合物在体内的相变研究
按照下表10-1制备组合物。将美洛昔康溶于N-甲基吡咯烷酮中，配制成100mg/g的浓溶液，在50℃下将液体油、磷脂、罗哌卡因、美洛昔康浓溶液、释放调节剂和溶剂混合，边加热边搅拌直至形成透明均一的溶液，冷却至室温。通过在小鼠体内皮下注射后不同时间点在给药部位的制剂形态。2小时、6小时、12小时、24小时、48小时和72小时的制剂形态分别见图5-1～图5-6，其中组合物皮下注射后2小时即发生明显的相变过程，形成明显的核壳结构凝胶状储库。给药后储库在12小时内保持完整，随时间延长至24小时后会出现缓慢降解，直至72小时在给药局部仍可见明显的相变制剂存在。纯蓖麻油组皮下注射后也可形成一定的储库，但是在整个研究过程并未出现明显相变过程，且储库随时间的延长而逐渐消失。此外，纯蓖麻油+溶剂组皮下注射后对局部组织具有一定的刺激性，可能带来安全性问题。而本发明组合物对局部组织均未见明显的刺激性，呈现出良好的安全性和耐受性。表10-2对结果进行了总结。
表10-1组合物
Figure PCTCN2020138466-appb-000021
表10-2给药部位形态
  组合物30 组合物38 纯蓖麻油组
2小时 白色凝胶状储库 白色凝胶状储库 油状
6小时 白色凝胶状储库 白色凝胶状储库 油状，轻微刺激性
12小时 白色凝胶状储库 白色凝胶状储库 油状
24小时 储库开始缓慢降解 储库开始缓慢降解 油状逐渐消失，有刺激性
48小时 仍能观察到储库形态 仍能观察到储库形态 油状逐渐消失，刺激性明显
72小时 仍能观察到储库形态 仍能观察到储库形态 油状消失，刺激性减弱
实施例11组合物与纯蓖麻油组合物的释放对比研究
按照下表11-1制备组合物，方法如前所述，所述组合物为液体，加入水中可成胶。将100mg组合物直接滴加入装有200mL的磷酸盐缓冲液中来测定药物的释放。在37℃下振摇，转速 50rpm，分别于6h、24h、48h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表11-2中。
表11-1组合物和蓖麻油组合物
Figure PCTCN2020138466-appb-000022
表11-2罗哌卡因和美洛昔康在两种组合物中的体外释放
Figure PCTCN2020138466-appb-000023
实施例12含有不同液体油的原位油凝胶组合物
按照下表12-1中所示的每种成分制备含有不同比例有机溶剂的药物组合物。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在50℃下将罗哌卡因、氢化大豆磷脂加入液体油、溶剂和美洛昔康溶液中，边加热边搅拌直至形成透明均一的溶液，冷却至室温，形成的组合物为液体，加入水中可成胶。
表12-1含有不同液体油的组合物
Figure PCTCN2020138466-appb-000024
实施例13罗哌卡因和美洛昔康从组合物中的体外释放
将100mg来自实施例12的组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例12组合物中的释放。在37℃下200rpm振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表13-1中。
表13-1罗哌卡因和美洛昔康在不同组合物中的体外释放
Figure PCTCN2020138466-appb-000025
实施例14含有不同种类饱和磷脂的组合物
按照下表14-1中所示的每种成分制备含有不同比例有机溶剂的药物组合物。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在50℃下将罗哌卡因、不同种类磷脂加入液体油、溶剂和美洛昔康溶液中，边加热边搅拌直至形成透明均一的溶液，冷却至室温，形成的组合物为液体，加入水中可成胶。
表14-1含有不同种类磷脂的原位油凝胶组合物
Figure PCTCN2020138466-appb-000026
实施例15罗哌卡因和美洛昔康从组合物中的体外释放
将100mg来自实施例14的组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例14组合物中的释放。在37℃下100rpm振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表15-1中。
表15-1罗哌卡因和美洛昔康在不同组合物中的体外释放
Figure PCTCN2020138466-appb-000027
如表15-1所示，实施例14制备的含有不同饱和磷脂的组合物均获得较好的释放效果。
实施例16含有不同释放调节剂的组合物
按照下表16-1中所示的每种成分制备含有不同比例有机溶剂的药物组合物。首先将美洛昔康溶于N-甲基吡咯烷酮中，配制成50mg/g的美洛昔康浓溶液，在50℃下将罗哌卡因、氢化大豆磷脂、不同释放调节剂加入液体油、溶剂和美洛昔康溶液中，边加热边搅拌直至形成透明均一的溶液，冷却至室温，形成的所述组合物为液体，加入水中可成胶。
表16-1含有不同释放调节剂的组合物
Figure PCTCN2020138466-appb-000028
实施例17罗哌卡因和美洛昔康从组合物中的体外释放
将100mg来自实施例16的组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例16组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表17-1中。
表17-1罗哌卡因和美洛昔康在不同组合物中的体外释放
Figure PCTCN2020138466-appb-000029
实施例18不同比例溶剂药物组合物
按照下表18-1中所示的每种成分制备含有不同比例溶剂的药物组合物。在50℃下将罗哌卡因、磷脂、塞来昔布加入液体油、溶剂中，边加热边搅拌直至形成透明均一的溶液，冷却至室温，形成的组合物为半固体。
表18-1不同组合物
Figure PCTCN2020138466-appb-000030
实施例19
罗哌卡因和塞来昔布从组合物中的体外释放
将100mg来自实施例18的油凝胶组合物加入透析袋中，置于装有200mL的磷酸盐缓冲液的管中来测定罗哌卡因从实施例18组合物中的释放。在37℃下振摇，分别于24h、48h、72h从管中取1mL磷酸盐缓冲液。通过HPLC检测每份样品中罗哌卡因和美洛昔康的浓度。结果显示于下表19-1中。
表19-1罗哌卡因和塞来昔布在不同组合物中的体外释放
Figure PCTCN2020138466-appb-000031
实施例20含有酰胺类局麻药的组合物
按照下表20-1中所示的每种成分制备组合物。在50℃下将不同药物、氢化大豆磷脂、加入液体油、溶剂中，边加热边搅拌直至形成透明均一的溶液，冷却至室温，形成的组合物为液体，加入水中可相变成胶。
表20-1含有酰胺类局麻药的组合物
Figure PCTCN2020138466-appb-000032
实施例21含有非甾体抗炎药的组合物
按照下表21-1中所示的每种成分制备原位油凝胶组合物。在50℃下将不同药物、氢化大豆磷脂、胆固醇和抗氧化剂加入液体油、溶剂中，边加热边搅拌直至形成透明均一的溶液，冷却至室温，形成的组合物为液体，加入水中可相变成胶。
表21-1含有非甾体抗炎药的原位油凝胶组合物
Figure PCTCN2020138466-appb-000033
实施例22含有激素类药物的组合物
按照下表22-1中所示的每种成分制备原位油凝胶组合物。在50℃下将药物溶于N甲基吡咯烷酮中直至形成澄清透明溶液，将二棕榈酰基磷脂酰胆碱溶于剩余有机溶剂和液体油中直至至形成澄清溶液，将药物溶液加入含有上述混合溶液中，形成的组合物为液体，加入水中可相变成胶。
表22-1含有激素类药物的组合物
Figure PCTCN2020138466-appb-000034
实施例23其他含有局部麻醉药和非甾体抗炎药的组合物
按照下表23-1中所示的每种成分制备组合物。将局部麻醉药和非甾体抗炎药、二棕榈酰基磷脂酰胆碱和抗氧化剂加入溶剂中，其中美洛昔康溶液为美洛昔康的二甲亚砜溶液，浓度为50mg/g。搅拌直至得到澄清溶液，将蓖麻油加入溶液中直至完全混合均匀，形成的组合物为液体，加入水中可成胶。
表23-1其他含有局部麻醉药和非甾体抗炎药的组合物
Figure PCTCN2020138466-appb-000035
Figure PCTCN2020138466-appb-000036
实施例24两瓶装的组合物
按照下表24-1制备两瓶装的药物组合物。将美洛昔康溶于N-甲基吡咯烷酮中，配制成100mg/g的美洛昔康浓溶液，在常温下将罗哌卡因、二棕榈酰磷脂胆碱、美洛昔康溶液加入溶剂中，搅拌至完全溶清，过0.22μm滤膜，灌装并轧盖。将液体油单独过过0.22μm滤膜，灌装并轧盖。使用前将两瓶混合均匀即可，混合后形成的组合物为液体，加入水中可成胶。
表24-1组合物
Figure PCTCN2020138466-appb-000037
实施例25组合物的体内施用
犬体内药代动力学研究如下。重量约10kg的比格犬实验前禁食12小时(取下喂食的食盒)以上，自由饮水，给药后4小时给食。各组按皮下注射进行给药，样品信息见表25-1，其中组合物8和纯蓖麻油组5的美洛昔康为浓度50mg/g的美洛昔康/N甲基吡咯烷酮溶液，组合物47的美洛昔康为浓度100mg/g的美洛昔康/N甲基吡咯烷酮溶液。每只比格犬分两次接受注射，25mg/次，其中盐酸罗哌卡因溶液作为阳性对照组，按同样的方式给药，各组动物于给药前取0小时、于给药后0.5、1、2、3、6、8、12、24、36、48、60、72和96小时各采集血样约0.5mL至EDTA-2K+抗凝的采血管中，全血经8000rpm离心5min后收集血浆，随后通过LC-MS/MS检测血浆样品中的药物浓度。
表25-1组合物处方信息
Figure PCTCN2020138466-appb-000038
组合物给药后96小时内的罗哌卡因和美洛昔康的血药浓度-时间曲线见图6-1和图6-2中。在图6-1中，组合物8在给药后至6小时罗哌卡因血药浓度维持在200ng/mL左右，组合物42在给药后至24小时罗哌卡因血药浓度维持在200ng/mL左右，盐酸罗哌卡因溶液和蓖麻油组给药后0.5小时的罗哌卡因血药浓度1600ng/mL和400ng/mL以上，具有明显的突释现象。图6-2是美洛昔康血药浓度-时间曲线，蓖麻油组有明显的突释现象，给药至8小时之间血药浓度均在1000ng/mL以上，组合物8和组合物42可明显降低美洛 昔康的释放，给药后美洛昔康血药浓度维持在400ng/mL以内。由血药浓度-时间曲线结果可知本发明组合物中添加适量的溶剂不会引起突释现象。此外，与盐酸罗哌卡因溶液和纯蓖麻油组相比，本发明的组合物可明显降低在犬体内的药代动力学个体偏差。
实施例26组合物的体内施用
所有大鼠先用3.5～4％异氟烷氧气进行麻醉，然后以1.5～2％异氟烷维持麻醉。手术后在大鼠颈部皮下注射0.5cc的40万单位青霉素溶液预防感染。在无菌条件下，剃去大鼠左腿外侧与臀部交界处的毛发，用75％酒精消毒手术部位，剪开皮肤和筋膜，用有齿弯镊钝性分离肌肉，暴露坐骨神经，将原位油凝胶组合物(见表26-1)，按30mg/kg给药剂量注入到坐骨神经旁边，闭合创口，连续缝合内部筋膜，表面皮肤创口单独缝合，每组平行试验6只。检测时间为10min、30min、1h、1.5h、2h、4h、6h、8h、10h、12h、24h、48h、72h。对大鼠进行以下测试：
感觉测试(热板实验)：
开启智能热板仪(温度设定为56℃)，待热板温度恒定后将实验大鼠放入热板上，采用秒表进行人工计时，以大鼠脚接触热板开始计时，第一次抬脚计时结束，检测大鼠在热板上的耐受时间(以秒为单位)。大鼠左、右脚分别检测5次，每次间隔时间不少于20秒，设定截止时间为12秒，超过12秒没有抬脚的大鼠视为对热痛不敏感，此后不再进行检测。去掉5次测定中的最大值和最小值，只将中间3个值的平均值作为某一特定时间点的测试结果，后取平均值。平均值超过5秒或任意一次测定值超过10秒的大鼠视为基础阈值不合格，不能进行给药和后续实验。
运动功能测试：
①恢复抬脚能力试验
将大鼠正常抓起后，使其后肢跖关节靠近桌边，缓慢地向上和向前推，使动物有自发的抬脚行为，若能正常抬脚，记为1份，不能正常抬脚记为0分。大鼠左、右脚分别检测5次。
②恢复走路运动能力试验(采用4分制)：
提起大鼠尾巴，观察足趾状态，若五跖分开，跖部曲度正常，且在地面行走步态正常，记为1分。
若跖部收缩，似无力。跖部曲度正常，在地面行走步态正常，记为2分。
若动物后肢伸展无力，曲度消失，记为3分。
3分基础上出现步态异常记为4分。
大鼠左、右脚在每个时间点均分别检测1次，每次测试都由训练有素的实验员操作。
表26-1组合物
Figure PCTCN2020138466-appb-000039
Figure PCTCN2020138466-appb-000040
组合物39：
对于所有测试大鼠，感觉阻滞持续了72小时，最强阻滞出现在给药后10分钟至8小时(延迟12秒)。运动阻滞持续了大约6-8个小时，最强运动阻滞在给药后10分钟至6小时。在给药后10小时，其中1只大鼠恢复抬脚能力。
组合物40：
对于所有测试大鼠，感觉阻滞持续了72小时，最强阻滞出现在给药后10分钟至6小时(延迟12秒)。运动阻滞持续了大约12个小时，最强运动阻滞在给药后10分钟至4小时。在给药后12小时，其中1只大鼠恢复抬脚能力。
组合物41：
对于所有测试大鼠，感觉阻滞持续了72小时，最强阻滞出现在给药后10分钟至6小时(延迟12秒)。运动阻滞持续了大约4-6个小时，最强运动阻滞在给药后10分钟至4小时。在给药后8小时，其中1只大鼠行走步态正常。在给药后4小时，其中1只大鼠恢复抬脚能力。
实施例27组合物的体内施用
所有大鼠先用3.5～4％异氟烷氧气进行诱导麻醉，然后以1.5～2％异氟烷维持麻醉。手术后在大鼠颈部皮下注射0.5cc的40万单位青霉素溶液预防感染。在无菌条件下，将每只大鼠距跖后0.5cm处向前用11号手术刀片作1cm长的纵向切口，分离筋膜和肌肉，沿肌肉纵向切口。轻压止血后闭合创口，用5号尼龙线在切口部位不连续缝合两针，缝合皮肤。围绕切口周围将药物注射进切口部位里面(灌注给药)，分别给予组合物48(空白制剂)、组合物48(30mg/kg)、阳性对照罗哌卡因溶液，样品信息见表27-1，其中美洛昔康溶液用N-甲基吡咯烷酮配制。在给药后不同时间点用Von Frey单丝刺激大鼠后肢足底中部，每根细丝在每个足底测试3次，疼痛阈值被定义为3次连续试验中发生至少两次撤足的最低强度。检测时间分别为给药后10min、30min、1h、1.5h、2h、4h、6h、8h、10h、12h、24h、48h、72h。
表27-1样品信息表
Figure PCTCN2020138466-appb-000041
结果如图7-1所示，盐酸罗哌卡因溶液在术后10min-2h增加大鼠的PWT值，显示出明显改善机械痛觉敏感即具有镇痛效应(P<0.05)，但是之后其PWT值逐渐降低至给药前水平，说明其镇痛效应起效快，但维持时间较短。。而组合物48在术后10min-72h整 个测试过程都保持明显镇痛效果，显示出非常好的长效作用特点。兼具快速镇痛效应和长效镇痛效应。
实施例28组合物的体内施用
所有大鼠先用3.5～4％异氟烷氧气进行诱导麻醉，然后以1.5～2％异氟烷维持麻醉。手术后在大鼠颈部皮下注射0.5cc的40万单位青霉素溶液预防感染。在无菌条件下，将每只大鼠距跖后0.5cm处向前用11号手术刀片作1cm长的纵向切口，分离筋膜和肌肉，沿肌肉纵向切口。轻压止血后闭合创口，用5号尼龙线在切口部位不连续缝合两针，缝合皮肤。围绕切口周围0.3cm处多点皮下注射给药，共给药6个点。分别给予组合物49(空白制剂)、组合物49(30mg/kg)、阳性对照盐酸罗哌卡因溶液。样品信息见表28-1，其中美洛昔康溶液用二甲基亚砜配制。在给药后使用IITC 390热刺激痛觉测试仪(美国Life science公司)测定大鼠热缩爪潜伏期(thermal withdrawal latency,TWL)。检测时间分别为给药后10min、30min、1h、1.5h、2h、4h、6h、8h、10h、12h、24h、48h、72h。
表28-1样品信息表
Figure PCTCN2020138466-appb-000042
结果如图8-1所示，正常大鼠TWL平均值在10s左右，而手术后大鼠TWL平均值在5-6s，盐酸罗哌卡因溶液在术后10min-2h增加大鼠的TWL值，显示出明显改善热痛觉敏感效应(P<0.05)，但是之后其TWL值逐渐降低至给药前水平，说明其镇痛效应起效快，但维持时间较短。组合物49在术后10min-48h均保持明显镇痛效果，显示出很好的长效作用特点。说明其兼具快速镇痛效应和长效镇痛效应。
以上，对本发明示例性的实施方式进行了说明。但是，本发明的保护范围不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种药物组合物，包含：
    a.液体油；
    b.至少一种如下式I所示的化合物：
    Figure PCTCN2020138466-appb-100001
    其中，R 1、R 2、R 3、R 4、R 5相同或不同，彼此独立地选自烷基；L选自亚烷基；
    c.至少一种药学上的活性成分。
  2. 根据权利要求1所述的药物组合物，其特征在于所述药物组合物还包含d.至少一种药学上可接受的溶剂。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，R 1、R 2、R 3、R 4、R 5相同或不同，彼此独立地选自C 1-40烷基。
  4. 根据权利要求1-3任一项所述的药物组合物，其特征在于，
    所述液体油选自蓖麻油、芝麻油、玉米油、大豆油、橄榄油、红花油、棉籽油、花生油、鱼油、茶油、杏仁油、巴巴苏油、黑醋栗种子油、琉璃苣油、卡诺拉油、棕榈油、棕榈仁油、向日葵油、中链甘油三酯、二油酸甘油酯、单油酸甘油酯中的一种或多种组合；
    所述式I所示的化合物选自磷脂酰胆碱类化合物，例如选自HSPC(氢化大豆磷脂)、DLPC(二月桂酰基磷脂酰胆碱)、DMPC(二肉豆蔻酰基磷脂酰胆碱)、DPPC(二棕榈酰基磷脂酰胆碱)、DSPC(二硬脂酰基磷脂酰胆碱)中的一种或多种的组合；
    所述至少一种药学活性成分可为抗炎药、局麻药、镇痛药、抗精神失常药、抗焦虑药、镇静催眠药、抗抑郁药、抗高血压药、类固醇激素、抗癫痫药、杀菌剂、抗惊厥药、抗帕金森病药、中枢神经兴奋药、抗精神病药、抗心律失常药、抗心绞痛药、抗甲状腺药、解毒药、止吐药、降糖药、抗结核病药、抗艾滋病药、抗乙肝药、抗肿瘤药、抗排斥药及其混合物，所述组合物可以进一步包含药学上可接受的释放调节剂和/或凝胶因子；优选的，所述药学上可接受的释放调节剂选自不饱和磷脂、其他表面活性剂中的一种或多种组合，所述不饱和磷脂为大豆磷脂、蛋黄磷脂、二芥酰基卵磷脂、二油酸酰基卵磷脂等，所述药学上可接受的凝胶因子选自甾醇，脂肪酸甘油酯、脂肪酸和脂肪醇中 的一种或多种组合。
  5. 根据权利要求1-4任一项所述的药物组合物，其特征在于，所述组合物还可以进一步包括表面活性剂，所述表面活性剂用于调节缓释递药系统的亲水性，以便达到期望的药物释放速度；优选的，所述表面活性剂为非离子型表面活性剂；更优选的，所述表面活性剂包括硬脂酸聚烃氧40酯、辛酸癸酸聚乙二醇甘油酯、月桂酰聚氧乙烯甘油酯、硬脂酰聚氧乙烯甘油酯、油酰聚氧乙烯甘油酯、维生素E聚乙二醇琥珀酸酯、蛋黄卵磷脂、大豆磷脂、氢化大豆磷脂、泊洛沙姆407、泊洛沙姆188、聚山梨酯80、聚乙二醇-12-羟基硬脂酸酯、丙二醇单辛酸酯；所述组合物还可以进一步包括一种或多种抗氧化剂；优选的，所述抗氧化剂选自维生素C(抗坏血酸)，半胱氨酸或其盐酸盐，维生素E(生育酚)，抗坏血酸棕榈酸酯，谷胱甘肽，α硫辛酸、硫代甘油。
  6. 根据权利要求1-5任一项所述的药物组合物，其特征在于，所述液体油占组合物总量的约20％至约99.5％(w/w)；所述式I所示的化合物占组合物总量的0.5％至40％(w/w)；所述药学活性成分占组合物总量的0.1％至50.0％(w/w)；所述溶剂总量占组合物总量的0％至50％(w/w)；所述释放调节剂占组合物总量的0.1％至40％(w/w)；所述凝胶因子占组合物总量的1％至40％(w/w)；所述表面活性剂占组合物总量的0.1％至5％(w/w)。
  7. 根据权利要求1-6任一项所述的药物组合物，其特征在于，所述溶剂选自有机溶剂或者为水和有机溶剂组成的混合溶剂；优选的，所述水的用量小于等于5％(w/w)；优选的，所述有机溶剂选自醇类、N-甲基吡咯烷酮、苯甲酸苄酯、二甲亚砜中的一种或多种组合；更优选的，所述醇类选自甲醇、乙醇、正丙醇，异丙醇，正丁醇，异丁醇、叔丁醇、乙二醇、丙二醇、甘油、苯甲醇、苯乙醇、聚乙二醇；特别优选的，所述溶剂选自乙醇、苯甲醇的组合，或乙醇、苯甲醇、水的组合，或乙醇、苯甲醇和N-甲基吡咯烷酮的组合，或乙醇、苯甲醇和二甲基亚砜的组合。
  8. 根据权利要求1-7任一项所述的药物组合物的制备方法，其特征在于，包括如下步骤：
    (a1)将至少一种式I所示的化合物、至少一种药学上的活性成分与至少一种药学上可接受的溶剂混合，在常温或加热条件下搅拌至澄清均一的混合溶液；
    (a2)将液体油添加到所述混合溶液中，搅拌至形成均一混合溶液；
    (a3)将(a2)形成的均一混合溶液过滤并灌装；
    或，包括如下步骤：
    (b1)将液体油，至少一种式I所示的化合物、至少一种药学上的活性成分与至少一种药学上可接受的溶剂混合，在常温或加热条件下搅拌至澄清均一的混合溶液；
    (b2)将(b1)形成的均一混合溶液过滤并灌装；
    或包括如下步骤；
    (c1)将至少一种式I所示的化合物、至少一种药学上的活性成分与至少一种药学上可接受的溶剂混合，在常温或加热条件下搅拌至澄清均一的混合溶液；
    (c2)将(c1)得到的混合溶液过滤并灌装；
    (c3)将液体油或液体油和溶剂形成的混合溶液过滤并灌装；
    (c4)使用前将(c2)和(c3)混合均匀即可。
  9. 一种包含权利要求1-7任一项所述药物组合物的制剂，所述制剂作为储库制剂施用，优选的，可以局部给药、肠胃外施用或注射给药。
  10. 根据权利要求9所述的制剂，其特征在于，所述制剂进一步包括填充了所述制剂的包材，所述包材选自以下一种或多种：西林瓶、预灌封注射器、卡式瓶；所述药物组合物可为单瓶装制剂和两瓶装制剂；优选的，所述两瓶装制剂，其中一瓶为所述组合物中至少一种成分形成的澄清溶液，另一瓶为剩余组分，给药前将两瓶混合均匀后使用。
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