WO2019238068A1 - 一种普瑞巴林缓释组合物及其制备方法 - Google Patents

一种普瑞巴林缓释组合物及其制备方法 Download PDF

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WO2019238068A1
WO2019238068A1 PCT/CN2019/090933 CN2019090933W WO2019238068A1 WO 2019238068 A1 WO2019238068 A1 WO 2019238068A1 CN 2019090933 W CN2019090933 W CN 2019090933W WO 2019238068 A1 WO2019238068 A1 WO 2019238068A1
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pregabalin
sustained
release composition
release
composition according
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PCT/CN2019/090933
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English (en)
French (fr)
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朱朝露
吴昀
卢迪
赵焰平
周丽莹
刘亚男
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北京泰德制药股份有限公司
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Priority claimed from CN201810608326.0A external-priority patent/CN110585153A/zh
Priority claimed from CN201811202248.0A external-priority patent/CN111053749B/zh
Application filed by 北京泰德制药股份有限公司 filed Critical 北京泰德制药股份有限公司
Priority to US16/618,756 priority Critical patent/US11938222B2/en
Priority to CN201980014023.9A priority patent/CN111741748B/zh
Publication of WO2019238068A1 publication Critical patent/WO2019238068A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present application belongs to the technical field of pregabalin preparations, and particularly relates to a pregabalin sustained-release composition and a preparation method thereof.
  • Pregabalin is used to treat neuropathic pain and postherpetic neuralgia (PHN) associated with diabetic peripheral neuropathy (DPN).
  • PPN postherpetic neuralgia
  • DPN diabetic peripheral neuropathy
  • the drug acts as a calcium channel regulator and inhibits the ⁇ 2- ⁇ subunits of the voltage-dependent calcium channels of the central nervous system. Reducing the influx of calcium ions, and consequently reducing the release of excitatory neurotransmitters such as glutamate, norepinephrine, and substance P, thereby effectively controlling neuropathic pain and having anxiolytic and anticonvulsant effects.
  • pregabalin is not uniformly absorbed in the gastrointestinal tract. It is well absorbed in the human small intestine and ascending colon, but is rarely absorbed in the intestinal segments outside the colonic hepatic curvature. This means that the average absorption window of pregabalin is about 6 hours or less. Therefore, if pregabalin is made into a conventional sustained-release dosage form, after more than 6 hours, the preparation passes through the colonic hepatic flexure, and the released drug will not be effectively absorbed. Cause waste of drugs. Therefore, how to improve the absorption of pregabalin in the small intestine and the ascending colon has become a technical problem to be solved urgently by those skilled in the art.
  • the purpose of the embodiments of the present application is to provide a pregabalin sustained-release composition to improve the absorption of pregabalin in the small intestine and the ascending colon.
  • the present application also provides a method for preparing the pregabalin sustained-release composition.
  • the specific technical solutions are as follows:
  • This application first provides a pregabalin sustained-release composition, which comprises:
  • the swelling agent comprises one or at least two of croscarmellose sodium, carboxymethylcellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and polyoxyethylene.
  • pregabalin can be prepared as a drug substance by known methods, or it can be obtained through commercial means. No matter what method is used, it is easy for those skilled in the art to implement. Therefore, this application I will not repeat them here. In some specific embodiments of the present application, pregabalin is commercially obtained as a drug substance.
  • pregabalin pharmaceutically acceptable salts refer to the addition salts of pharmaceutically acceptable acids and bases; such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, Sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acids (such as acetic acid, HOOC- (CH 2 ) n-COOH ( Where n 0 to 4)) and so on.
  • Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, ammonium, and the like.
  • a hydrate means a molecular complex of a drug (such as pregabalin) and a stoichiometric or non-stoichiometric amount of water.
  • the swelling agent may include sodium carboxymethyl starch and include at least one of low-substituted hydroxypropyl cellulose and polyoxyethylene; preferably, the swelling agent includes carboxyl starch. Sodium methyl starch and polyoxyethylene.
  • the swelling agent may include at least one of carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, and polyoxyethylene; preferably, the swelling agent includes poly Oxyethylene.
  • the particle size range of the pregabalin or a pharmaceutically acceptable salt or hydrate thereof is preferably D 90 250-600 ⁇ m, preferably 300-600 ⁇ m, and more preferably 350-500 ⁇ m.
  • the weight percentage of the active ingredient may be 5% -55%, 5% -50%, 10% -40%. , 10% -35%, 20% -30%, or 25% -30%, etc.
  • the active ingredient in addition to pregabalin or a pharmaceutically acceptable salt or hydrate thereof, may optionally include at least one other compound having a synergistic therapeutic effect with pregabalin.
  • the active ingredient may optionally include at least one other compound having a synergistic therapeutic effect with pregabalin.
  • matrix-forming agents are used to provide structural integrity to the composition and help control or prolong the rate of drug release and other functions.
  • Those skilled in the art can select a suitable matrix-forming agent based on the description of the role of the matrix-forming agent herein.
  • the weight percentage of the matrix-forming agent is 5% -45%, 5% -40%, 15% -35%. Or 15% -30% and so on.
  • the matrix-forming agent may be selected from a mixture of polyvinyl acetate and polyvinylpyrrolidone.
  • Polyvinylpyrrolidone (PVP) is a homopolymer of 1-vinyl-pyrrolidin-2-one, and the molecular weight Mw is usually about 1 ⁇ 10 3 to about 1 ⁇ 10 7 , about 2.5 ⁇ 10 3 to about 3 ⁇ 10 6 or about 1 ⁇ 10 4 to about 1 ⁇ 10 5 .
  • Polyvinylpyrrolidone is available from BASF under the trade name Available from ISP under the trade name Polyvinyl acetate (PVAc) is a homopolymer of vinyl acetate, and the molecular weight Mw is usually about 1 ⁇ 10 5 to about 1 ⁇ 10 6 .
  • the matrix-forming agent may include PVAc in a weight percentage of 0% -90%, 20% -90%, 60% -90%, 70% -85%.
  • the matrix-forming agent is obtained from BASF, and its trade name is SR, labeled 80/19 (w / w) mixture of PVAc and PVP.
  • the swelling agent can absorb water from the gastric fluid, thereby causing the size of the pregabalin sustained-release composition to swell, and, possibly, the drug release rate can be affected by, for example, creating channels or by forming a hydrocolloid.
  • Swelling agents are soluble in water or insoluble in water.
  • the weight percentage of the swelling agent may be 5% -70%, 6.5% -70%, 20% -60% , 9% -50%, 20% -30%, 9% -29%, etc.
  • Patent document CN101330907A states that the swelling agent must contain cross-linked polyvinyl pyrrolidone (also known as cross-linked povidone); through a large number of experiments, the inventor unexpectedly found that instead of using cross-linked polyvinyl pyrrolidone, cross-linked carboxyl
  • cross-linked polyvinyl pyrrolidone also known as cross-linked povidone
  • the inventors also found that the oxides contained in crospovidone have a certain effect on the stability of the composition, and that the formulations containing crospovidone are more hygroscopic and are not conducive to the storage of the formulations.
  • the swelling agents croscarmellose sodium, calcium carboxymethylcellulose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and polyoxyethylene used in the present application are commonly used medicines.
  • the auxiliary materials are familiar to those skilled in the art for their structure, properties, and access methods, and are finally used to implement the technical solution of the present application.
  • a gelling agent may alter (eg, prolong) the drug release characteristics of the composition.
  • Gels include synthetic polymers and / or natural polymers that generally have low water solubility (eg, slightly to poorly soluble). When exposed to water, the gel forms a viscous mixture (viscosity greater than water), extending the release of the drug, such as the time for which pregabalin is released from the composition.
  • the weight percentage of the gelling agent may be 1% -30%, 1% -20%, 3% -20 %, 4% -14% or 3% -10%, etc.
  • the gelling agent is selected from one of carbomer, polysaccharide, or a combination thereof.
  • the gelling agent is carbomer.
  • Carbomer is an acrylic polymer bonded to allyl sucrose or pentaerythritol allyl ether. Based on the dry product, the carboxylic acid group (-COOH) is generally 56.0% -68.0%. The average molecular weight of the Carbomer number is about 1 ⁇ 10 5 to about 1 ⁇ 10 10 or about 7 ⁇ 10 5 to about 4 ⁇ 10 9 .
  • Polysaccharide is a polysaccharide polymer carbohydrate composed of glycoside bond-linked sugar chains, at least more than 10 monosaccharides; in this application, the representative polysaccharides used may include raw gum, inulin, One or a combination of guar gum, chitosan, carob gum, carrageenan.
  • Xanthan gum also called corn gum
  • Xanthan gum is a polysaccharide with a molecular weight Mw of about 2 ⁇ 10 6 .
  • Inulin also known as oligofructose and polyfructose
  • oligofructose is a class of natural polysaccharides.
  • the number of D-fructose fragments in inulin ranges from 2 to about 140, and usually ranges from about 25 to about 30.
  • Guar gum is a hydrocolloid polysaccharide having a molecular weight Mw of about 2 ⁇ 10 5 .
  • Chitosan is a kind of polysaccharides that are hardly soluble in water.
  • Carob gum is a natural polysaccharide, similar to guar gum. Carob gum is a galactomannan, and its molecular weight Mw is in the range of about 5 ⁇ 10 4 to about 3 ⁇ 10 6 .
  • Carrageenan commonly known as carrageenan, has a chemical structure of calcium, potassium, sodium, and ammonium salts of polysaccharide sulfates composed of galactose and anhydrogalactose.
  • Carrageenan can be selected in various grades based on gel type, water solubility and viscosity when mixed with water. It should be noted that the above-mentioned polysaccharides are all commercial products, and those skilled in the art can easily obtain and use them to implement the present application.
  • the pregabalin sustained-release composition may further include a filler; the filler may change (eg, prolong) the drug release characteristics of the composition, and maintain the rigidity of the tablet during drug release and drug release,
  • the volume and weight of the pregabalin sustained-release composition can also be changed (eg, increased), so as to facilitate subsequent molding of the composition, such as tabletting and the like.
  • Fillers are generally water-soluble and water-insoluble. Water-soluble fillers dissolve to form pores in the framework material to accelerate dissolution; water-insoluble fillers absorb water to swell and accelerate water into the framework material to accelerate dissolution.
  • a filler commonly used in the technical field may be selected, including, but not limited to, one of microcrystalline cellulose, lactose, starch, pregelatinized starch, calcium dihydrate dihydrate, and calcium dibasic anhydrous phosphate. Or at least two.
  • the weight percentage of the filler may be 1% -40%; more specifically, in some embodiments, the filler The weight percentage may be 1% -15% or 3% -8% and the like.
  • the weight percentage of the filler is 5%- 40%, more preferably 10-35%, and most preferably 15-30%.
  • the pregabalin slow-release composition prepared based thereon has a faster volume expansion rate, especially when the filler contains microcrystalline cellulose, based on this
  • the prepared pregabalin sustained-release composition has a size that swells to more than 13 mm or even 13.5 mm or more after 2 hours of contact with the aqueous medium, and the tablet can maintain good hardness. This result is very amazing and very useful.
  • the composition "size" corresponds to the longest linear dimension of the cross-section of the dosage form having the smallest area.
  • the filler is selected from one or more of microcrystalline cellulose, lactose, and pregelatinized starch.
  • the filler is microcrystalline cellulose.
  • the pregabalin sustained-release composition may further include a lubricant, which facilitates various processing steps including component mixing, tabletting, and the like; for example, a lubricant may enable pressure distribution during tableting Uniform and make the density of the tablet uniform; the force required to push the tablet out of the die hole is reduced. Another effect that a lubricant may have is to improve the appearance of the tablet and make the surface of the tablet bright and flat.
  • a lubricant commonly used in the technical field may be selected, including but not limited to magnesium stearate, talc, micronized silica gel, sodium stearyl fumarate, glyceryl behenate, and polyethylene glycol.
  • the weight percentage of the lubricant may be 0.1% -1.5% or 0.5% -1% and the like.
  • the pregabalin sustained-release composition may further include a coating powder.
  • a coating powder commonly used in the technical field may be selected, including but not limited to polyvinyl alcohol And at least one of polyethylene glycol, at least one of silica and talc, and / or flavoring agent; in some specific embodiments of the present application, based on the pregabalin sustained-release composition
  • the total weight of the coating powder may be 2% to 6%, 3% to 4%, and the like.
  • the application also provides a method for preparing the above-mentioned pregabalin sustained-release composition, which includes:
  • the active ingredients, matrix former, swelling agent and gelling agent, and optional fillers are mixed and then shaped.
  • the forming process may include granulation, optionally granulation, and tabletting steps.
  • the particle size D 90 of the pregabalin drug substance can be controlled to 250-600 ⁇ m, more preferably 300 to 600 ⁇ m, and more preferably 350 to 500 ⁇ m, and a matrix forming agent, a swelling agent, and a coagulant with good fluidity can be selected.
  • Adhesive which realizes that the sustained-release tablets can be prepared by direct compression in the process.
  • pregabalin APIs with controlled particle size ranges can also be used, such as pregabalin APIs with D 50 of 50-200 ⁇ m, and pregabalin APIs with D 50 of 50-175 ⁇ m.
  • pregabalin APIs with D 50 of 50-200 ⁇ m can also be used, such as pregabalin APIs with D 50 of 50-200 ⁇ m, and pregabalin APIs with D 50 of 50-175 ⁇ m.
  • mixing and subsequent molding steps are conventional steps and operations in the technical field to which they belong, and are not specifically limited herein.
  • the inventors investigated the effect of the mixing time on the uniformity of the content of the mixed material; it was found that the longer the mixing time within 20 minutes, the better the content uniformity. After 20 minutes, the content uniformity has no obvious change or even worsens.
  • the specific test results are shown in Table 1. Based on this, in some specific embodiments of the present application, the mixing time in the mixing process is 10-30 minutes, preferably 10-25 minutes, more preferably 15 minutes, and most preferably 20 minutes.
  • the mixed material referred to herein includes an active ingredient, a matrix-forming agent, a swelling agent, a gelling agent, and optionally a filler.
  • the pregabalin sustained-release composition contains a lubricant
  • the active ingredient, matrix-forming agent, swelling agent, gelling agent, and optionally filler can be mixed, and then
  • the preparation method further includes: after forming, using a film coating premix to perform a coating process.
  • the film coating premix may include at least one of polyvinyl alcohol and polyethylene glycol, at least one of silica and talc, and / or a flavoring agent.
  • the content may be 10% to 25%, and the solid content of the further film coating premix may be 10% to 15%.
  • the coating process is also a conventional process and operation in the technical field, and is not specifically limited herein.
  • the pregabalin sustained-release composition provided in the present application can be made into a tablet form. Based on this, the present application also provides a pregabalin sustained-release tablet, which comprises the aforementioned pregabalin sustained-release composition.
  • the pregabalin slow-release composition provided by the present application can rapidly expand in volume when exposed to an aqueous medium, exceeding the diameter of the human gastric pylorus (13mm), and therefore can prolong gastric emptying time to increase the residence time of pregabalin in the stomach and improve The absorption of pregabalin in the small intestine and the ascending colon is achieved; meanwhile, the pregabalin sustained-release composition provided by the present application achieves a slow release for 24 hours, which can realize QD (once a day) administration, reduce the number of medications, and improve the patient Compliance.
  • FIG. 1 is a dissolution curve of Examples 1-8 and Comparative Example 1 of this application;
  • FIG. 2 shows examples 10-17 and reference preparations of the present application. Dissolution profile
  • Figure 3 shows a single oral pregabalin sustained-release tablet test preparation (330mg / tablet) and a reference preparation after a meal. (330 mg / tablet) mean drug concentration-time curve of pregabalin in plasma (Mean ⁇ SD).
  • Preparation method Weigh the prescribed amount of pregabalin, CMS-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, Pass 40 mesh sieve together with Carbomer 974P, then add PEO, mix for 10min with mixer, add half of the prescribed amount of magnesium stearate and mix for 5min, dry granulate. After granulating through 20 mesh sieve, add half of the prescribed amount of hard Magnesium stearate was mixed for 10 min and compressed.
  • Preparation method Weigh the prescribed amount of pregabalin, CMS-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, CMS-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, CC-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, L-HPC and carbomer 974P were passed through a 40-mesh sieve, and then PEO was added, mixed by a mixer for 15 minutes, and mixed with magnesium stearate for 5 minutes, and compressed.
  • Preparation method Weigh the prescribed amount of pregabalin, L-HPC and chitosan were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, CMS-Na and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted. It was also coated with a film coating premix with a solid content of 12% (w / w), and the coating weight was increased to 3%.
  • the film coating premix contains polyvinyl alcohol, silica, talc, polyethylene glycol and flavoring agent; it is obtained by dissolving the above materials in purified water and passing through a 80 mesh sieve.
  • Preparation method Weigh the prescribed amount of pregabalin, Microcrystalline cellulose and carbomer 974P were passed through a 40-mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, CMS-Na and carbomer pass through a 18 mesh sieve together, then add PEO, mix with a mixer for 15min, add magnesium stearate and mix for 5min, and tablet.
  • Preparation method Weigh the prescribed amount of pregabalin, Carboxymethylcellulose calcium and carbomer are passed through a 18 mesh sieve together, then added with PEO, mixed with a mixer for 10 minutes, mixed with a prescribed amount of magnesium stearate and mixed for 5 min, granulated by dry method, sized through a 20 mesh sieve, and then added Half of the prescribed amount of magnesium stearate was mixed for 10 minutes and compressed into tablets.
  • Preparation method Weigh the prescribed amount of pregabalin, L-HPC and carbomer pass through a 18 mesh sieve together, then add PEO, mix with a mixer for 15min, add magnesium stearate and mix for 5min, and tablet.
  • Preparation method Weigh the prescribed amount of pregabalin, The microcrystalline cellulose and carbomer were passed through an 18 mesh sieve together, and then PEO was added, and the mixer was mixed for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, CC-Na and Carbomer were passed through an 18 mesh sieve together, and then PEO was added, mixed by a mixer for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, Pregelatinized starch and carbomer passed through an 18 mesh sieve together, then added PEO, mixed with a mixer for 20 minutes, added magnesium stearate and mixed for 5 minutes, and pressed into tablets.
  • Preparation method Weigh the prescribed amount of pregabalin, The microcrystalline cellulose and carbomer were passed through an 18 mesh sieve together, and then PEO was added, and the mixer was mixed for 15 minutes, and magnesium stearate was added for 5 minutes, and tableted.
  • Preparation method Weigh the prescribed amount of pregabalin, The microcrystalline cellulose and carbomer are passed through a 18 mesh sieve together, then PEO is added, and the mixer is mixed for 20 minutes, and magnesium stearate is added for 5 minutes, and compressed. It was also coated with a film coating premix with a solid content of 20% (w / w), and the weight of the coating was increased to 3%.
  • the film coating premix contains polyvinyl alcohol, silica, talc, polyethylene glycol and flavoring agent; it is obtained by dissolving the above materials in purified water and passing through a 80 mesh sieve.
  • Preparation method Weigh the prescribed amount of pregabalin and Pass through a 40-mesh sieve together, add PEO, mix with a mixer for 15min, add magnesium stearate and mix for 5min, and tablet.
  • Preparation method Weigh out the prescribed amounts of pregabalin and PEO, mix with a mixer for 15min, add magnesium stearate and mix for 5min, and tablet.
  • Preparation method Weigh the prescribed amount of pregabalin, Pass the 40 mesh sieve together with Carbomer 974P, mix for 10 minutes with a mixer, add half of the prescribed amount of magnesium stearate and mix for 5 minutes, dry granulate. After granulating through a 20 mesh sieve, add half of the prescribed amount of magnesium stearate and mix. 10min, compressed.
  • test solution Take 10ml of solution at each time point and filter.
  • Reference solution Take pregabalin reference solution and use 0.06mol / L HCl to prepare a reference solution solution with a concentration of about 360 ⁇ g / ml.
  • Example 1-8 The dissolution results of Example 1-8 and Comparative Example 1 in 0.06mol / L HCl medium are shown in Table 5 and Figure 1:
  • Example 1 17.3 27.1 41.3 52.4 64.8 74.3 83.5 96.5 69
  • Example 2 18.0 27.2 39.7 48.9 59.2 67.4 77.5 90.9 54
  • Example 3 17.8 27.1 40.9 51.7 64.1 73.7 83.4 95.8 67
  • Example 4 16.2 25.7 39.8 51.4 65.1 75.7 86.1 97.1 69
  • Example 5 19.8 29.8 41.1 53.4 65.2 76.4 86 99.7 74
  • Example 6 15.7 25.8 38.1 51.0 63.1 72.4 84.1 97.1
  • the swelling size of the tablets prepared in Examples 1, 3, 4, and 8 of this application after 2 hours has reached 13 mm or more (this size corresponds to the longest linear size of the cross-section of the dosage form with the smallest area), Significantly better than Comparative Example 1; after 6 hours of other examples, the swelling size also reached more than 13mm; this size can effectively delay the residence time of the sustained-release tablet in the stomach, and stay in the stomach after mechanical retardation.
  • the pharmaceutical composition can continuously release pregabalin, effectively widen the pregabalin's absorption window, and improve the absorption of pregabalin in the small intestine and ascending colon to allow QD administration.
  • Comparative Examples 2-4 it can be seen that in the absence of at least one of matrix-forming substance, swelling agent, and gelling agent, the swelling size is smaller than that of Example 1-8.
  • Test 1 For the dissolution method, refer to Test 1.
  • the sampling time is: 1h, 2h, 4h, 6h, 8h, 10h, 12h, 16h, 24h.
  • Intelligent dissolution tester is the same as test one;
  • Example 11 The sample of Example 11 was dispersed for 1 hour and the size could not be determined.
  • the swelling size of the tablets prepared in the examples of the present application has reached 13 mm and above after 2 h (this size corresponds to the longest linear size of the cross-section of the dosage form with the smallest area). Similar (the difference in the initial film size in this study was due to the difference in film type), and the increase in film thickness was greater than that in the comparative example and Tablet. This size can effectively delay the residence time of the sustained-release tablet in the stomach through mechanical block.
  • the pharmaceutical composition can continuously release pregabalin, effectively widening the pregabalin's absorption window. Increases the absorption of pregabalin in the small and ascending colons and allows QD administration.
  • Triggering force 0.5g
  • the tablets prepared in Examples 10, 11, 12 and 14 of the present application are more rigid after 2h, 6h and 24h.
  • the tablets were inferior, while the fillers of Examples 13, 15 and 16 had significantly increased rigidity, which was significantly better than Tablet.
  • the rigidity of the drug in the dissolution process can prevent the drug from being damaged by the gastrointestinal food, thereby extending the residence time of the drug in the stomach and widening the absorption window.
  • Increased pregabalin absorption in the small and ascending colons allows QD administration. It is known from the measurement result that the use of the filler of the present application effectively improves the rigidity of the preparation, maintains the shape of the drug, and ensures the continuous release of the drug.
  • Impurity C is a degradation impurity of active substance pregabalin, molecular formula C8H15NO, molecular weight 141.21, name: 4-isobutylpyrrolidin-2-one
  • the structural formula is as follows:
  • Example 17 The test results of influencing factors indicate that the samples were left for 30 days under each condition. There were no significant changes in appearance.
  • Pregabalin sustained-release tablets have a certain hygroscopicity. Under high humidity (RH 75%), the moisture absorption and weight gain of Example 17 Low, that is, the hygroscopicity of Example 17 is relatively Significant improvement. There was no significant change in dissolution under all conditions. The dissolution curves of Example 17 were the same. similar. The degradation of impurity C in pregabalin sustained-release tablets has increased under high temperature conditions. remarkable growth, The increase is more obvious, that is, the stability of Example 17 is better.
  • a single oral pregabalin extended-release reference formulation (R, Sustained-release tablets, batch number T73417, specification 330mg / tablet) and test preparation (T, Example 17, specification 330mg / tablet), the bioequivalence of the two preparations was evaluated.
  • the human plasma samples to be tested are divided into 6 batches for analysis, and the linear correlation coefficient of all analysis batches is greater than 0.9900.
  • the average RE% of each concentration point on the standard curve of different batches of pregabalin sustained-release tablets was within ⁇ 15%.
  • the plasma drug concentration time curve of the test preparation and the reference preparation of a single oral pregabalin sustained-release tablet after a meal in healthy subjects is shown in FIG. 3.
  • the average elimination half-life of HPR compared to the test preparations and reference preparations was 1/2 , 6.08 ⁇ 0.718h and 6.08 ⁇ 1.05h, respectively.
  • the average peak time T max is 8.80 ⁇ 3.08h and 9.90 ⁇ 3.35h
  • the average C max is 4381 ⁇ 1107ng ⁇ mL -1 and 4370 ⁇ 870ng ⁇ mL -1
  • the average AUC 0 ⁇ t is 71361 ⁇ 12040h ⁇ ng ⁇ mL -1 and 72243 ⁇ 17132h ⁇ ng ⁇ mL -1
  • the average AUC 0 ⁇ ⁇ were 72053 ⁇ 12163h ⁇ ng ⁇ mL -1 and 73131 ⁇ 17371h ⁇ ng ⁇ mL -1, respectively .
  • AUC 0 ⁇ t , AUC 0 ⁇ ⁇ , and C max 90% confidence interval equivalent criterion 80.00% ⁇ 125.00%; T max equivalent criterion: p ⁇ 0.05

Abstract

一种普瑞巴林缓释组合物，其包含：(a)活性成分，所述活性成分包含普瑞巴林或其药学上可接受的盐、或水合物；(b)基质形成剂；(c)溶胀剂；和(d)凝胶剂；优选包含填充剂。普瑞巴林缓释组合物接触水性介质可快速体积膨胀，超过人体胃幽门直径(13mm)，因此可以延长胃排空时间以增加普瑞巴林在胃中的滞留时间，提高了普瑞巴林在小肠和升结肠中的吸收；同时，普瑞巴林缓释组合物实现了24小时缓慢释放，可以实现QD(每日一次)给药，减少服药次数，提高病人的依从性。

Description

一种普瑞巴林缓释组合物及其制备方法
本申请要求于2018年06月13日提交中国专利局、申请号为201810608326.0发明名称为“一种普瑞巴林缓释组合物及其制备方法”的中国专利申请的优先权，以及2018年10月16日提交中国专利局、申请号为201811202248.0发明名称为“一种普瑞巴林缓释组合物及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请属于普瑞巴林制剂技术领域，特别是涉及一种普瑞巴林缓释组合物及其制备方法。
背景技术
普瑞巴林用于治疗与糖尿病性周围神经病(DPN)相关的神经性疼痛和疱疹后神经痛(PHN)。该药作为钙离子通道调节剂，抑制中枢神经系统电压依赖性钙通道的α2-δ亚基。减少钙离子内流，随之减少谷氨酸盐、去甲肾上腺素、P物质等兴奋性神经递质的释放，从而有效控制神经病理性疼痛，并具有抗焦虑、抗惊厥的作用。
临床研究表明，普瑞巴林在胃肠道的吸收是不均一的，其在人类的小肠和升结肠中吸收良好，但很少在结肠肝曲外的肠段被吸收。这表示普瑞巴林的平均吸收窗约为6小时或更短，因此若将普瑞巴林制成常规的缓释剂型，超过6小时后制剂通过结肠肝曲，释放的药物将无法被有效吸收，造成药物的浪费。因此如何提高普瑞巴林在小肠和升结肠中的吸收，成为本领域技术人员亟待解决的技术问题。
发明内容
本申请实施例的目的在于提供一种普瑞巴林缓释组合物，以提高普瑞巴林在小肠和升结肠中的吸收。同时，本申请还提供了普瑞巴林缓释组合物的制备方法。具体技术方案如下：
本申请首先提供了一种普瑞巴林缓释组合物，其包含：
(a)活性成分，所述活性成分包含普瑞巴林或其药学上可接受的盐、或 水合物；
(b)基质形成剂；
(c)溶胀剂；和
(d)凝胶剂；
其中，所述溶胀剂包含交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、聚氧乙烯中的一种或至少两种。
普瑞巴林，化学名为：(S)-3-氨甲基-5-甲基己酸，化学结构式如下：
Figure PCTCN2019090933-appb-000001
在本申请中，普瑞巴林作为原料药可以采用已知的方法来制备，也可以通过商业途径获得，无论采用何种方式获得，对于所属领域技术人员来说都是容易实现的，因此本申请在此不进行赘述。在本申请的一些具体实施方式中，普瑞巴林作原料药是通过商业途径获得的。
在本申请中，普瑞巴林药学上可接受的盐是指可药用的酸和碱的加成盐；这样的可药用盐包括诸如以下的酸的盐：盐酸、磷酸、氢溴酸、硫酸、亚硫酸、甲酸、甲苯磺酸、甲磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、马来酸、氢碘酸、链烷酸(诸如乙酸、HOOC-(CH 2)n-COOH(其中n 0～4))等。这样的可药用盐还包括诸如以下的碱的盐：钠、钾、钙、铵等。本领域技术人员知晓多种无毒的可药用加成盐。
在本申请中，水合物表示药物(例如普瑞巴林)和化学计量或非化学剂量的水的分子配合物。
在本申请的一些具体实施方式中，所述溶胀剂可以包含羧甲基淀粉钠，并包含低取代羟丙基纤维素、聚氧乙烯中的至少一种；优选地，所述溶胀剂包含羧甲基淀粉钠及聚氧乙烯。
在本申请的另一些具体实施方式中，所述溶胀剂可以包含羧甲基纤维素钙、低取代羟丙基纤维素、聚氧乙烯中的至少一种；优选地，所述溶胀剂包含聚氧乙烯。
在本申请的一些具体实施方式中，所述普瑞巴林或其药学上可接受的盐、或水合物其粒径范围优选D 90250～600μm，优选300～600μm，更优选350～500μm。
在本申请的一些具体实施方式中，基于所述普瑞巴林缓释组合物的总重量，所述活性成分的重量百分数可以为5％-55％、5％-50％、10％-40％、10％-35％、20％-30％、或25％-30％等。
在本申请的一些具体实施方式中，活性成分除了包含普瑞巴林或其药学上可接受的盐、或水合物以外，还可以任选地包括至少一种与普瑞巴林具有协同治疗作用的其它化合物。
在本申请中，基质形成剂用于为组合物提供结构完整性并有助于控制或延长药物释放的速率及其它功用。本领域技术人员可以根据本申请在此对于基质形成剂的作用的描述来选择合适的基质形成剂。在本申请的一些具体实施方式中，基于所述普瑞巴林缓释组合物的总重量，所述基质形成剂的重量百分数为5％-45％、5％-40％、15％-35％或15％-30％等。
在本申请的一些具体实施方式中，基质形成剂可以选自聚醋酸乙烯酯和聚乙烯基吡咯烷酮的混合物。聚乙烯基吡咯烷酮(PVP)为1-乙烯基-吡咯烷-2-酮的均聚物，分子量Mw通常为约1×10 3至约1×10 7、约2.5×10 3至约3×10 6或约1×10 4至约1×10 5。聚乙烯基吡咯烷酮可得自BASF，其商品名为
Figure PCTCN2019090933-appb-000002
可得自ISP，其商品名为
Figure PCTCN2019090933-appb-000003
聚醋酸乙烯酯(PVAc)为乙酸乙烯酯的均聚物，分子量Mw通常为约1×10 5至约1×10 6。以PVAc和PVP的总重量为基准，基质形成剂可包含重量百分数为：0％-90％、20％-90％、60％-90％、70％-85％的PVAc。在本申请的一些具本实施方式中，基质形成剂得自BASF，其商品名为
Figure PCTCN2019090933-appb-000004
SR，标称为PVAc和PVP的80/19(w/w)混合物。
在本申请中，溶胀剂可从胃液吸水，从而导致普瑞巴林缓释组合物的尺寸膨胀，可能性地，还可以通过例如产生通道或通过形成亲水胶体而影响药物释放速率。溶胀剂可溶于水或不溶于水。在本申请的一些具体实施方式中，基于所述普瑞巴林缓释组合物的总重量，所述溶胀剂的重量百分数可以为5％-70％、6.5％-70％、20％-60％、9％-50％、20％-30％、9％-29％等。专利文献CN101330907A中记载，溶胀剂必然包含交联聚乙烯吡咯烷酮(也称为交联聚 维酮)；发明人通过大量试验，意外地发现，在不采用交联聚乙烯吡咯烷酮，而采用交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、聚氧乙烯中的一种或至少两种作为溶胀剂的情况下，同样能够使得普瑞巴林缓释组合物在接触水性介质时可快速体积膨胀，并且膨胀的尺寸可以达到、甚至好于上述专利的记载。另外，发明人还发现，交联聚维酮中含有的氧化物对组合物的稳定性造成一定的影响，且含有交联聚维酮的制剂更易吸湿，不利于制剂的储存。
需要说明的是，本申请所采用的溶胀剂交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、聚氧乙烯均为常用的药用辅料，对于所属领域技术人员来说，熟知它们的结构、性质及获得途径，并最终用于实现本申请的技术方案。
在本申请中，凝胶剂其可改变(例如延长)组合物的药物释放特性。凝胶剂包括通常具有低水溶性(例如微溶至难溶)的合成聚合物和/或天然聚合物。当接触水时，该凝胶剂形成粘性混合物(粘度大于水)，延长药物的释放，例如普瑞巴林从组合物中释放的时间。在本申请的一些具体实施方式中，基于所述普瑞巴林缓释组合物的总重量，所述凝胶剂的重量百分数可以为1％-30％、1％-20％、3％-20％、4％-14％或3％-10％等。
在本申请的一些具体实施方式中，凝胶剂选自卡波姆、多糖中的一种或其组合，优选地，凝胶剂为卡波姆。
卡波姆为丙烯酸键合烯丙基蔗糖或季戊四醇烯丙醚的高分子聚合物。按干燥品计算，含羧酸基(-COOH)个般为56.0％-68.0％。卡波姆数的均分子量为约1×10 5至约1×10 10或约7×10 5至约4×10 9。
多糖(polysaccharide)是由糖苷键结合的糖链，至少要超过10个的单糖组成的聚合糖高分子碳水化合物；在本申请中，所采用的代表性多醣类可以包括原胶、菊粉、瓜耳树胶、壳聚糖、角豆胶、角叉菜胶中的一种或其组合。
黄原胶，也被称为玉米糖胶，为分子量Mw为约2×10 6的多醣。菊粉，也被称为寡果酸和聚果糖，为一类天然多醣，一般菊粉中的D-果糖片段的个数在2至约140，通常在约25至约30的范围内。瓜耳树胶为分子量Mw为约2×10 5的亲水胶体态多醣。壳聚糖为一类难溶于水的多醣类，由β-D-葡萄糖胺 和N-乙酰基-β-D-葡萄糖胺的共聚物组成，数均分子量通常为约1×10 4至约1×10 6。角豆胶为天然多醣类，与瓜耳胶类似，角豆胶为半乳甘露聚糖，其分子量Mw在约5×10 4至约3×10 6的范围内。角叉菜胶，俗称卡拉胶，它的化学结构是由半乳糖及脱水半乳糖所组成的多糖类硫酸酯的钙、钾、钠、铵盐。由于其中硫酸酯结合形态的不同，可分为：κ-型、ι-型、λ-型等。角叉菜胶可以以基于与水混合时的凝胶类型、水性溶度和粘度的多种等级来选择。需要说明的是，上述的多糖均为商品化的产品，对于所属领域技术人员来说，是容易获得并用于实现本申请的。
在本申请的一些具体实施方式中，普瑞巴林缓释组合物还可以包含填充剂；填充剂可以改变(例如延长)组合物的药物释放特性，保持药物释放及释药过程中药片的刚性，还可以改变(例如增加)普瑞巴林缓释组合物的体积、重量，从而便于组合物后续的成型，例如压片等。填充剂通常为水溶性和水不溶性两种，水溶性填充剂通过溶解形成骨架材料中的孔隙从而加快溶出；水不溶性填充剂通过本身吸水膨胀，加快水份进入骨架材料中，从而加速溶出。在本申请的技术方案中，可以选择所属技术领域常用的填充剂，包括但不限于微晶纤维素、乳糖、淀粉、预胶化淀粉、二水合磷酸钙、无水磷酸氢钙中的一种或至少两种。在本申请的一些具体实施方式中，基于所述普瑞巴林缓释组合物的总重量，填充剂的重量百分数可以为1％-40％；更为具体地，在一些实施方式中，填充剂的重量百分数可以为1％-15％或3％-8％等。在另一些实施方式中，为了使填充剂可以更明显地改变(例如延长)组合物的药物释放特性，保持药物释放及释药过程中药片的刚性，所述填充剂的重量百分数为5％-40％，更优选为10-35％，最优选为15％-30％。
进一步地，当溶胀剂包含聚氧乙烯，同时含有填充剂时，基于此制备的普瑞巴林缓释组合物，其体积膨胀速度更快，尤其是当填充剂包含微晶纤维素时，基于此制备的普瑞巴林缓释组合物，在接触水性介质2h后，其尺寸就膨胀到13mm以上，甚至13.5mm以上，并且片剂能保持良好的硬度，这个结果是非常惊人，同时也非常有用的；所属领域技术人员均知，尺寸越早膨胀到13mm，就更有利于普瑞巴林缓释组合物滞留在胃中，从而提高普瑞巴林的吸收；而在短短的2h，组合物尺寸就达到13mm，将更能够保证普瑞巴林缓释组合物滞留在胃中；片剂拥有良好的硬度，延长了片剂形状的维持时间， 进一步保证了组合物在胃中的滞留时间，达到缓释的效果。本申请中，组合物“尺寸”对应于剂型的具有最小面积的横截面的最长线性尺寸。
在本申请的一些具体实施例中，填充剂选自微晶纤维素、乳糖、预胶化淀粉中的一种或多种，优选地，填充剂为微晶纤维素。
在本申请的一些具体实施方式中，普瑞巴林缓释组合物还可以包含润滑剂，其有助于包括组分混合、压片等各种加工步骤；例如润滑剂可使压片时压力分布均匀，并使片剂的密度均匀；将片剂由模孔中推出所需之力减小。润滑剂可能存在的另一个作用是改善片剂的外观，使片剂表面光亮、平整。在本申请的技术方案中，可以选择所属技术领域常用的润滑剂，包括但不限于硬脂酸镁、滑石粉、微粉硅胶、硬脂富马酸钠、山嵛酸甘油酯和聚乙二醇中的一种或至少两种的组合，更优选为硬脂酸镁。在本申请的一些具体实施方式中，基于所述普瑞巴林缓释组合物的总重量，所述润滑剂的重量百分数可以为0.1％-1.5％或0.5％-1％等。
在本申请的一些具体实施方式中，普瑞巴林缓释组合物还可以包含包衣粉，在本申请的技术方案中，可以选择所属技术领域常用的包衣粉，包括但不限于聚乙烯醇及聚乙二醇中的至少一种、二氧化硅及滑石粉中的至少一种、和/或矫味剂；在本申请的一些具体实施方式中，基于所述普瑞巴林缓释组合物的总重量，所述包衣粉的重量百分数可以为2％-6％、3％-4％等。
本申请还提供了上述的普瑞巴林缓释组合物制备方法，其包括：
将活性成分、基质形成剂、溶胀剂及凝胶剂及任选的填充剂混合，然后成型处理。在具体实施过程中，成型处理可以包括制粒，任选地整粒以及压片等工序。本申请可以通过将普瑞巴林原料药粒径D 90控制为：250-600μm，进一步优选为300～600μm，更优选为350～500μm，并选择流动性较好的基质形成剂、溶胀剂及凝胶剂，实现了在工艺上可采用直接压片的方式制备缓释片。在一些实施方式中，也可以采用其它粒径范围控制的普瑞巴林原料药，例如采用D 50为50-200μm的普瑞巴林原料药，进一步D 50为50-175μm的普瑞巴林原料药。需要说明的是，混合以及其后的成型工序，均是所属技术领域的常规工序、操作，本申请在此不进行具体限定。
另外，发明人在制备普瑞巴林缓释组合物的过程中，考察了混合时间对混合物料含量均匀度的影响；外意地发现，在20分钟内，混合时间越长，含量均匀性越好，超过20分钟，含量均匀度无明显变化甚至有变差的趋势，具体试验结果详见表1。基于此，在本申请的一些具体实施方式中，混合工艺中混合时间为10-30分钟，优选10-25分钟，更优选为15分钟，最优选为20分钟。需要说明的是，此处所说的混合物料包含活性成分、基质形成剂、溶胀剂、凝胶剂及任选地填充剂。
表1
Figure PCTCN2019090933-appb-000005
在本申请的一些具体实施方式中，当普瑞巴林缓释组合物中含有润滑剂时，可以将活性成分、基质形成剂、溶胀剂、凝胶剂及任选地填充剂混合，然后
A:再与全部的润滑剂混合，然后进行成型工艺；
或者
B:先与部分的润滑剂混合，再经过制粒、任选地整粒后，再加入剩余部分的润滑剂，再进行其它的成型工序，例如压片。
在本申请的一些具体实施方式中，当普瑞巴林缓释组合物中含有包衣粉时，其制备方法，还包括：在成型后，采用薄膜包衣预混剂进行包衣工序。其中薄膜包衣预混剂可以包含聚乙烯醇及聚乙二醇中的至少一种、二氧化硅及滑石粉中的至少一种、和/或矫味剂；薄膜包衣预混剂的固含量可以为10％～25％，进一步薄膜包衣预混剂的固含量可以为10％～15％。需要说明的是，包衣工序也是所属技术领域的常规工序、操作，本申请在此不进行具体限定。
本申请提供的普瑞巴林缓释组合物可以制成片剂的形式，基于此，本申请还提供了一种普瑞巴林缓释片剂，其包含前述的普瑞巴林缓释组合物。
本申请提供的普瑞巴林缓释组合物，其接触水性介质可快速体积膨胀， 超过人体胃幽门直径(13mm)，因此可以延长胃排空时间以增加普瑞巴林在胃中的滞留时间，提高了普瑞巴林在小肠和升结肠中的吸收；同时，本申请提供的普瑞巴林缓释组合物实现了24小时缓慢释放，可以实现QD(每日一次)给药，减少服药次数，提高病人的依从性。
附图说明
为了更清楚地说明本申请实施例和现有技术的技术方案，下面对实施例和现有技术中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本申请的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本申请实施例1-8及对比例1的溶出曲线；
图2为本申请实施例10-17及参比制剂
Figure PCTCN2019090933-appb-000006
的溶出曲线；
图3为健康人餐后单次口服普瑞巴林缓释片受试制剂(330mg/片)和参比制剂
Figure PCTCN2019090933-appb-000007
(330mg/片)后血浆中普瑞巴林的平均药物浓度-时间曲线(Mean±SD)。
具体实施方式
为了使本申请所解决的技术问题、技术方案及有益效果更加清楚明白，以下结合具体实施例，对本申请作进一步的说明。下述实施例中，除非另有说明，所述的试验方法具体条件通常按照常规条件或制造厂商建议的条件实施；所述原料、试剂均通过市售获得或者使用公开信息制备。
普瑞巴林缓释片(椭圆形片剂)的制备实施例
以下各实施例中出现的英文缩写如下表2中所示：
表2
Figure PCTCN2019090933-appb-000008
Figure PCTCN2019090933-appb-000009
实施例1
处方：
Figure PCTCN2019090933-appb-000010
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000011
CMS-Na和卡波姆974P共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例2
处方：
Figure PCTCN2019090933-appb-000012
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000013
和卡波姆974P共同过40目筛，再加入PEO，混合机混合10min，加入处方量一半硬脂酸镁混合5min，干法制粒，过20目筛整粒后，再加入处方量一半的硬脂酸镁混合10min，压片。
实施例3
处方：
Figure PCTCN2019090933-appb-000014
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000015
CMS-Na和卡波姆974P共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例4
处方：
Figure PCTCN2019090933-appb-000016
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000017
CMS-Na和卡波姆974P共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例5
处方：
Figure PCTCN2019090933-appb-000018
Figure PCTCN2019090933-appb-000019
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000020
CC-Na和卡波姆974P共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例6
处方：
Figure PCTCN2019090933-appb-000021
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000022
L-HPC和卡波姆974P共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例7
处方：
Figure PCTCN2019090933-appb-000023
Figure PCTCN2019090933-appb-000024
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000025
L-HPC和壳聚糖共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例8
处方：
Figure PCTCN2019090933-appb-000026
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000027
CMS-Na和卡波姆974P共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。并用12％(w/w)固含量的薄膜包衣预混剂进行包衣，包衣增重至3％。薄膜包衣预混剂中含有聚乙烯醇、二氧化硅、滑石粉、聚乙二醇和矫味剂；通过将上述物料溶于纯化水中，并过80目筛而得。
实施例9
处方：
Figure PCTCN2019090933-appb-000028
Figure PCTCN2019090933-appb-000029
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000030
微晶纤维素和卡波姆974P，共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例10
处方：
Figure PCTCN2019090933-appb-000031
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000032
CMS-Na和卡波姆共同过18目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例11
处方：
Figure PCTCN2019090933-appb-000033
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000034
羧甲基纤维素钙和卡波姆共同过18目筛，再加入PEO，混合机混合10min，加入处方量一半硬脂酸镁混合 5min，干法制粒，过20目筛整粒后，再加入处方量一半的硬脂酸镁混合10min，压片。
实施例12
处方：
Figure PCTCN2019090933-appb-000035
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000036
L-HPC和卡波姆共同过18目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例13
处方：
Figure PCTCN2019090933-appb-000037
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000038
微晶纤维素和卡波姆共同过18目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例14
处方：
Figure PCTCN2019090933-appb-000039
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000040
CC-Na和卡波姆共同过18目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例15
处方：
Figure PCTCN2019090933-appb-000041
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000042
预胶化淀粉、和卡波姆共同过18目筛，再加入PEO，混合机混合20min，加入硬脂酸镁混合5min，压片。
实施例16
处方：
Figure PCTCN2019090933-appb-000043
Figure PCTCN2019090933-appb-000044
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000045
微晶纤维素和卡波姆共同过18目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
实施例17
处方：
Figure PCTCN2019090933-appb-000046
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000047
微晶纤维素和卡波姆共同过18目筛，再加入PEO，混合机混合20min，加入硬脂酸镁混合5min，压片。并用20％(w/w)固含量的薄膜包衣预混剂进行包衣，包衣增重至3％。薄膜包衣预混剂中含有聚乙烯醇、二氧化硅、滑石粉、聚乙二醇和矫味剂；通过将上述物料溶于纯化水中，并过80目筛而得。
实施例18-26
参照实施例8的制备方法，以及以下表3中的处方，完成实施例18-26。
表3
Figure PCTCN2019090933-appb-000048
Figure PCTCN2019090933-appb-000049
实施例27-34
参照实施例17的制备方法，以及以下表4中的处方，完成实施例27-34。
表4
Figure PCTCN2019090933-appb-000050
对比例1
专利CN101330907A中的实施例30
对比例2
处方：
Figure PCTCN2019090933-appb-000051
制备方法：称取处方量普瑞巴林和
Figure PCTCN2019090933-appb-000052
共同过40目筛，再加入PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
对比例3
处方：
Figure PCTCN2019090933-appb-000053
制备方法：称取处方量普瑞巴林和PEO，混合机混合15min，加入硬脂酸镁混合5min，压片。
对比例4
处方：
Figure PCTCN2019090933-appb-000054
Figure PCTCN2019090933-appb-000055
制备方法：称取处方量普瑞巴林、
Figure PCTCN2019090933-appb-000056
和卡波姆974P共同过40目筛，混合机混合10min，加入处方量一半硬脂酸镁混合5min，干法制粒，过20目筛整粒后，再加入处方量一半的硬脂酸镁混合10min，压片。
药物溶出及膨胀测试
测试一
实施例1-8及对比例1的片剂溶出测试
1、溶出方法：
1)方法：溶出度测定法(中国药典2015年版第四部通则“0931溶出度与释放度测定法”第二法(桨法)，加沉降篮)。
2)溶出介质：0.06mol/L HCl，900ml
3)转速：50转/分钟
4)取样时间：1h、2h、4h、6h、9h、12h、16h、24h
5)检测方法：高效液相色谱法，检测波长：210nm
6)供试品溶液配制：于各时间点取溶液10ml，滤过。
7)对照品溶液配制：取普瑞巴林对照品，用0.06mol/L HCl配制成浓度约为360μg/ml的对照品溶液。
2、仪器型号：
智能溶出试验仪(型号：DT820，厂家：德国艾维卡有限公司)
3、溶出结果
0.06mol/L HCl介质中实施例1-8及对比例1的溶出结果，见表5及图1：
表5
批号 1h 2h 4h 6h 9h 12h 16h 24h f 2
对比例1 18.4 28.6 44.0 55.8 69.1 79.6 90.2 100.4 NA
实施例1 17.3 27.1 41.3 52.4 64.8 74.3 83.5 96.5 69
实施例2 18.0 27.2 39.7 48.9 59.2 67.4 77.5 90.9 54
实施例3 17.8 27.1 40.9 51.7 64.1 73.7 83.4 95.8 67
实施例4 16.2 25.7 39.8 51.4 65.1 75.7 86.1 97.1 69
实施例5 19.8 29.8 41.1 53.4 65.2 76.4 86 99.7 74
实施例6 15.7 25.8 38.1 51.0 63.1 72.4 84.1 97.1 64
实施例7 15.9 25.8 36.5 48.5 61.1 73.1 81.4 94.2 58
实施例8 16.4 28.1 37.4 51.2 63.4 75.7 85.1 100.7 65
注：表中的溶出结果均以百分数计。
从表5及图1中可以看出，本申请实施例1-8制备出的普瑞巴林缓释片，24h缓慢释放，2h释放＜30％，12h释放60％～80％，24h基本释放完全；其溶出特性与专利CN101330907A中所记载的缓释片(对比例1)的溶出性能基本一致，可以实现QD给药。
测试二
实施例1-8及对比例1-4的片剂溶胀尺寸测定：
根据中国药典2015年版第四部通则“0931溶出度与释放度测定法”第二法(桨法)，对上述实施例制备的药片进行溶出实验。以900ml 0.06N HCl溶液为溶出介质，转速50rpm。在溶出实验1h、2h和6h时从溶出介质中取出药品，并用电子游标卡尺测量尺寸，同0h的片剂(实验前的片剂)比较，结果如下表6所示：
表6
Figure PCTCN2019090933-appb-000057
Figure PCTCN2019090933-appb-000058
注：对比例2样品溶胀先变大，后随溶胀时间延长，片变软，机械强度差，片厚度变低，取出后瘫在实验台上；对比例3样品溶胀6h后不成型，无法测量片长、宽和厚度。
从表6中可以看出，本申请实施例1、3、4、8制备的药片2h后溶胀尺寸已达到13mm以上(该尺寸对应于剂型的具有最小面积的横截面的最长线性尺寸)，明显优于对比例1；其它实施例在经过6小时后，溶胀尺寸也均达到13mm以上；这种尺寸通过机械阻滞，可有效延缓该缓释片在胃部的停留时间，在滞留在胃内时，该药物组合物可持续释放普瑞巴林，有效加宽了普瑞巴林的吸收窗，提高了普瑞巴林在小肠和升结肠中的吸收从而允许QD给药。而且与对比例2-4相比可以看出，在缺少基质形成质、溶胀剂、凝胶剂中的至少一种时，溶胀尺寸均小于实施例1-8。
测试三
实施例10-17及参比制剂
Figure PCTCN2019090933-appb-000059
的溶出测试
溶出方法参照测试一，取样时间为：1h、2h、4h、6h、8h、10h、12h、16h、24h。智能溶出试验仪与测试一相同；
0.06mol/L HCl介质中实施例10-17及参比制剂
Figure PCTCN2019090933-appb-000060
的溶出结果，见表7及图2：
表7
Figure PCTCN2019090933-appb-000061
注：表中的溶出结果均以百分数计。
从表7及图2中可以看出，本申请实施例10-17制备出的普瑞巴林缓释片， 24h缓慢释放，1h释放＜25％，8h释放60％以上，24h基本释放100％；其溶出特性与对比例1的缓释片及
Figure PCTCN2019090933-appb-000062
的溶出性能基本一致，可以实现QD给药。
测试四
实施例10-17与
Figure PCTCN2019090933-appb-000063
的片剂溶胀尺寸测定：
测定方法参见测试二，结果如下表8所示：
表8
Figure PCTCN2019090933-appb-000064
注：实施例11样品溶出1h后样品分散，无法测定尺寸。
从表8中可以看出，本申请实施例制备的药片2h后溶胀尺寸已达到13mm及以上(该尺寸对应于剂型的具有最小面积的横截面的最长线性尺寸)，同
Figure PCTCN2019090933-appb-000065
相似(本研究中起始片尺寸差异为片型差异所致)，片厚增长幅度大于对比例及
Figure PCTCN2019090933-appb-000066
的片剂。这种尺寸通过机械阻滞，可有效延缓该缓释片在胃部的停留时间，在滞留在胃内时，该药物组合物可持续释放普瑞巴林，有效加宽了普瑞巴林的吸收窗，提高了普瑞巴林在小肠和升结肠中的吸收从而允许QD给药。
药品刚性测定
实施例10-16及
Figure PCTCN2019090933-appb-000067
片剂的溶出测试
1.测定方法：
根据中国药典2015年版第四部通则“0931溶出度与释放度测定法”第二法(桨法)，加沉降篮，对实施例10至16制备的片剂进行溶出试验，使用900ml 0.06mol/L HCl溶液作为溶出介质，并在37±5℃下以50rpm桨速进行溶出试验。在开始试验后的第2h，6h和24h从介质中取出药品，按以下设定条件下进行样品刚性测定，测试结果如表9所示。
仪器：质构仪(EZ Test)
负载单元：5kg
探针：1/4球型探针
触发力：0.5g
测试速度：0.2m/s
获取速率：10点/秒
测试距离：8～10mm
表9
Figure PCTCN2019090933-appb-000068
从表9中可以看出，本申请实施例10、11、12及实施例14制备的药片2h、6h及24h后药品刚性均较
Figure PCTCN2019090933-appb-000069
的片剂差，而含填充剂的实施例13、15和16药品刚性明显增强，明显优于对
Figure PCTCN2019090933-appb-000070
的片剂。药品在溶出过程中的刚性可以使药品免于被胃肠道食物所破坏，从而延长药物在胃内的滞留时间，以加宽吸收窗。提高了普瑞巴林在小肠和升结肠中的吸收从而允许QD给药。由该项测定结果知，本申请填充剂的使用有效提高了制剂的刚性，保持药物形状，保证了药物的持续释放。
药品稳定性试验
实施例17及参比制剂
Figure PCTCN2019090933-appb-000071
进行影响因素考察，30天样品外观性状、增失重、溶出度、含量及有关物质考察结果如表10～表14所示：
表10 外观性状考察结果
Figure PCTCN2019090933-appb-000072
注：“—”表示未考察。
表11 增失重考察结果
Figure PCTCN2019090933-appb-000073
注：“—”表示未考察。
表12 溶出度考察结果
Figure PCTCN2019090933-appb-000074
表13 有关物质考察结果
Figure PCTCN2019090933-appb-000075
注：杂质C是活性物质普瑞巴林的降解杂质，分子式C8H15NO，分子量141.21，名称：4-异丁基吡咯烷基-2-酮。结构式如下：
Figure PCTCN2019090933-appb-000076
表14 含量考察结果
Figure PCTCN2019090933-appb-000077
影响因素试验结果表明，在各条件下放置30天，实施例17和
Figure PCTCN2019090933-appb-000078
外观性状均无明显变化。普瑞巴林缓释片具有一定吸湿性，高湿(RH75％)条件下实施例17吸湿增重明显较
Figure PCTCN2019090933-appb-000079
低，即实施例17吸湿性较
Figure PCTCN2019090933-appb-000080
改善明显。各条件下溶出度无明显变化，实施例17溶出曲线均同
Figure PCTCN2019090933-appb-000081
相似。普瑞巴林缓释片降解杂质C在高温条件下有所增长，60℃实施例和
Figure PCTCN2019090933-appb-000082
显著增长，
Figure PCTCN2019090933-appb-000083
增长更为明显，即实施例17稳定性更好。
综上，由稳定性结果显示，自制实施例17的片剂稳定性要明显优于
Figure PCTCN2019090933-appb-000084
药品人体内生物等效性试验
1.实验目的
考察健康受试者在餐后状态下单次口服普瑞巴林缓释片参比制剂(R，
Figure PCTCN2019090933-appb-000085
缓释片，批号为T73417，规格330mg/片)与受试制剂(T，实施例17，规格330mg/片)，评估两制剂生物等效性。
2.仪器设备、药品和试剂
2.1仪器设备
名称 厂家/型号 仪器编号
天平 德国赛多利斯/MSA225S-CE Ⅱ051-021
涡旋混合器 Wiggens Vortex 300 Ⅱ050-477
多管涡旋振荡器 北京踏锦科技有限公司VX-Ⅱ Ⅱ050-490
台式高速冷冻离心机 Sigma 3K15 Ⅱ050-494
台式高速冷冻离心机 Sigma 3-18KS Ⅱ050-693
UPLC-MS/MS Waters ACQUITY UPLC H-class/XEVO TQD Ⅱ050-503
Milli Q超纯水仪 Millipore Advantage A10 Ⅱ050-325
2.2药品和试剂
Figure PCTCN2019090933-appb-000086
3.样品处理
取40μL未知血浆样品，加入40μL乙腈-水溶液(1:1，v/v)，加入内标溶液40μL(普瑞巴林-d4 1000ng·mL -1)，再加入120μL甲醇，涡旋2min，以15000rpm 4℃离心10min，取上清液50μL加入150μL 0.1％甲酸水溶液混匀，取5μL进行LC-MS/MS定量分析。
4.实验结果
4.1人血浆样品测试
所要测试的人血浆样品共分为6个批次进行分析，所有分析批线性相关系数都大于0.9900。普瑞巴林缓释片不同批次标准曲线上各浓度点的平均RE％均在±15％以内。健康受试者餐后单次口服普瑞巴林缓释片受试制剂和参比制剂的血浆药物浓度时间曲线见图3。
4.2人血浆药动学参数
健康受试者单次餐后口服HPR受试制剂和参比制剂后，受试制剂和参比制剂相比，HPR的平均消除半衰期t 1/2分别为6.08±0.718h和6.08±1.05h，平均达峰时间T max分别为8.80±3.08h和9.90±3.35h，平均C max分别为4381±1107ng·mL -1和4370±870ng·mL -1，平均AUC 0→t分别为71361±12040h·ng·mL -1和72243±17132h·ng·mL -1，平均AUC 0→∞分别为72053±12163h·ng·mL -1和73131±17371h·ng·mL -1。
4.3人血浆统计学结果
两种制剂Ln(AUC 0→t)、Ln(AUC 0→∞)和Ln(C max)比值的90％置信区间分别落在90.72％～111.45％、90.39％～111.29％和88.54％～110.80％范围内，T max经双侧t检验P值<0.05。上述结果显示两制剂生物等效。健康人单次餐后口服给予受试制剂和参比制剂后生物等效性置信区间统计结果见表15。
表15
Figure PCTCN2019090933-appb-000087
注：AUC 0→t、AUC 0→∞和C max90％置信区间等效判定标准：80.00％～125.00％；T max等 效判定标准：p≥0.05
上述实施例的作用在于说明本申请的实质性内容，但并不以此限定本申请的保护范围。本领域的普通技术人员应当理解，可以对本申请的技术方案进行修改或者等同替换，而不脱离本申请技术方案的实质和保护范围。

Claims (14)

  1. 一种普瑞巴林缓释组合物，其包含：
    (a)活性成分，所述活性成分包含普瑞巴林或其药学上可接受的盐、或水合物；
    (b)基质形成剂；
    (c)溶胀剂；和
    (d)凝胶剂；
    其中，所述溶胀剂包含交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基淀粉钠、低取代羟丙基纤维素、聚氧乙烯中的一种或至少两种。
  2. 如权利要求1所述的普瑞巴林缓释组合物，其中所述溶胀剂包含羧甲基淀粉钠，并包含低取代羟丙基纤维素、聚氧乙烯中的至少一种；优选地，所述溶胀剂包含羧甲基淀粉钠及聚氧乙烯。
  3. 如权利要求1所述的普瑞巴林缓释组合物，其中所述溶胀剂包含羧甲基纤维素钙、低取代羟丙基纤维素、聚氧乙烯中的至少一种；优选地，所述溶胀剂包含聚氧乙烯。
  4. 如权利要求1-3中任一项所述的普瑞巴林缓释组合物，其中所述普瑞巴林或其药学上可接受的盐、或水合物其粒径范围优选D 90250～600μm，优选300～600μm，更优选350～500μm。
  5. 如权利要求1-4中任一项所述的普瑞巴林缓释组合物，其中所述组合物还包含填充剂，所述填充剂优选为微晶纤维素、乳糖、淀粉、预胶化淀粉、二水合磷酸钙、无水磷酸氢钙中的一种或至少两种；更优选地，所述填充剂包含微晶纤维素、乳糖、预胶化淀粉中的一种或至少两种，最优选地，填充剂为微晶纤维素。
  6. 如权利要求5所述的普瑞巴林缓释组合物，其中基于所述普瑞巴林缓释组合物的总重量，所述填充剂的重量百分数为1％-40％；
    优选地，所述填充剂的重量百分数为1％-15％，更优选为3％-8％；
    或者优选地，所述填充剂的重量百分数为5％-40％，更优选为10-35％，最优选为15％-30％。
  7. 如权利要求1-6中任一项所述的普瑞巴林缓释组合物，其中所述基质形成剂选自聚醋酸乙烯酯和聚乙烯基吡咯烷酮的混合物。
  8. 如权利要求1-7中任一项所述的普瑞巴林缓释组合物，其中所述凝胶剂选自卡波姆、多糖中的一种或其组合，优选地，所述凝胶剂为卡波姆。
  9. 如权利要求1-8中任一项所述的普瑞巴林缓释组合物，其中基于所述普瑞巴林缓释组合物的总重量：
    所述活性成分的重量百分数为5％-55％，优选为5％-50％，更优选为10％-40％，还优选为10％-35％；
    所述基质形成剂的重量百分数为5％-45％，优选为5％-40％，更优选为15％-35％；
    所述溶胀剂的重量百分数为5％-70％，优选为6.5％-70％，还优选为20％-60％、9％-50％或9％-29％；
    所述凝胶剂的重量百分数为1％-30％，优选为3％-20％，更优选为3％-10％。
  10. 如权利要求1-9中任一项所述的普瑞巴林缓释组合物，其中所述组合物还包含润滑剂，所述润滑剂优选为硬脂酸镁、滑石粉、微粉硅胶、硬脂富马酸钠、山嵛酸甘油酯和聚乙二醇中的一种或至少两种，更优选为硬脂酸镁；还优选地，基于所述普瑞巴林缓释组合物的总重量，所述润滑剂的重量百分数为0.1％-1.5％，优选为0.5％-1％。
  11. 如权利要求1-10中任一项所述的普瑞巴林缓释组合物，其中所述组合物还包含包衣粉，优选地，所述包衣粉包含聚乙烯醇及聚乙二醇中的至少一种、二氧化硅及滑石粉中的至少一种、和/或矫味剂；更优选地，基于所述普瑞巴林缓释组合物的总重量，所述包衣粉的重量百分数为2％-6％，优选为3％-4％。
  12. 如权利要求1-11中任一项所述的普瑞巴林缓释组合物的制备方法，其包括：
    将活性成分、基质形成剂、溶胀剂、凝胶剂及任选的填充剂混合，然后进行成型处理。
  13. 如权利要求12所述的普瑞巴林缓释组合物的制备方法，其中混合时间为10-30分钟，优选为10-25分钟，更优选为15分钟，最优选为20分钟。
  14. 一种普瑞巴林缓释片剂，其包含权利要求1-11中任一项所述的普瑞巴林缓释组合物。
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