WO2017107768A1 - 阿普斯特缓释制剂 - Google Patents

阿普斯特缓释制剂 Download PDF

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Publication number
WO2017107768A1
WO2017107768A1 PCT/CN2016/108709 CN2016108709W WO2017107768A1 WO 2017107768 A1 WO2017107768 A1 WO 2017107768A1 CN 2016108709 W CN2016108709 W CN 2016108709W WO 2017107768 A1 WO2017107768 A1 WO 2017107768A1
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Prior art keywords
release
weight
pharmaceutical preparation
sustained
component
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PCT/CN2016/108709
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English (en)
French (fr)
Inventor
潘凯
刘凯
郭辰宁
刘通
Original Assignee
江苏恒瑞医药股份有限公司
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Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Priority to US16/063,779 priority Critical patent/US20200170999A1/en
Priority to MX2018007682A priority patent/MX2018007682A/es
Priority to EP16877579.9A priority patent/EP3395334A4/en
Priority to CN201680013031.8A priority patent/CN107405311B/zh
Priority to JP2018529290A priority patent/JP6904955B2/ja
Priority to BR112018012218-1A priority patent/BR112018012218A2/pt
Priority to AU2016377524A priority patent/AU2016377524A1/en
Priority to KR1020187019547A priority patent/KR20180097623A/ko
Priority to CA3008471A priority patent/CA3008471A1/en
Publication of WO2017107768A1 publication Critical patent/WO2017107768A1/zh
Priority to HK18104377.5A priority patent/HK1244714A1/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
    • A61K9/205—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention provides a sustained release preparation of a poorly soluble drug, Apster, in particular, a sustained release pharmaceutical preparation containing a sustained release component and a sustained release component, wherein the pharmaceutical preparation is tested in an in vitro release test.
  • the release is gentle, and the blood concentration can be ensured to be gentle and lasting.
  • Apster is a small molecule phosphodiesterase inhibitor with specific inhibition against cyclic adenosine monophosphate (cAMP). Inhibition of PDE4 leads to an increase in intracellular cAMP levels, which is associated with a down-regulation of inflammatory responses by modulation of TNF- ⁇ , IL-23 and other inflammatory cytokines.
  • cAMP cyclic adenosine monophosphate
  • Apster is a poorly soluble compound that is a BCSIV drug that is almost insoluble in water and can be used for the treatment of psoriasis.
  • Psoriasis is a common skin disease characterized by chronic inflammatory lesions that have long plagued patients and are difficult to treat.
  • the main biological agents include TNF- ⁇ inhibitors, interleukin-12, 23 (IL-12/IL-23) inhibitors and targets of B cells and T cells.
  • Antibodies currently used in the treatment of psoriasis, have rapid development and significant clinical effects, but biological products are generally administered by injection, requiring long-term therapeutic control in psoriasis, so biological products are often used in systemic long-term treatment of psoriasis. There are problems such as low compliance and easy tolerance. In view of the above situation, Apster has great advantages as an oral drug for the treatment of psoriasis.
  • the Apster preparations currently on the market are ordinary tablets, and the dosage form for long-term use is 30 mg twice a day, with an interval of 12 hours.
  • the Apster sustained-release tablets can change the number of medications once a day, which makes the patient's compliance higher, while the blood concentration fluctuations are smaller, which can greatly reduce the side effects during the medication. Therefore, sustained-release tablets have great advantages for patients who take long-term medication.
  • Puester sustained release preparation can reduce the number of medications per day and increase the compliance of patients taking medication, which is necessary for patients who need long-term medication.
  • the sustained release preparation of the Apster sustained release drug is stable after being taken, and can be slowly released in the body, which reduces the fluctuation of blood concentration caused by twice-daily administration, and can greatly reduce the incidence of side effects.
  • WO2013119607 discloses a sustained-release pharmaceutical composition using a high molecular polymer such as hydroxypropylcellulose as a sustained-release skeleton material. From the drug release data in the specification, the release degree of the sustained-release drug has a linear relationship and cannot be achieved. Good release release effect.
  • US20140370092 discloses an oral preparation prepared from components containing different sustained release ingredients, one of which is a sustained release component encapsulated with a single layer of coating agent and the other of which is coated with a double layer coating agent. Sustained release component.
  • the release rate of the tablet or capsule prepared according to the method is not smooth enough, and the release amount is not constant.
  • the technical solution does not solve the prior art problem well, that is, the number of times of taking the medicine is reduced, and the blood medicine of the patient is ensured. Concentration fluctuations are smaller, providing drug availability while reducing side effects during medication.
  • the present invention provides a sustained-release pharmaceutical preparation comprising a sustained-release preparation of an Apostal sustained-release component and a sustained-release component, which is combined with two components of different release behaviors to regulate Apost's oral administration.
  • the release behavior in the body so as to ensure that the Apothe blood concentration after oral administration is more constant than the ordinary tablets, reducing the fluctuation of blood concentration after taking the drug, significantly reducing the incidence of side effects and the duration of action is longer, thereby reducing the number of medications.
  • the present invention is characterized in that the site-releasing component II is composed of Apost or its pharmacologically acceptable by mixing the Apostide sustained-release component I and the localization-releasing component II in a certain weight ratio. Prepared by a salt or a solvate thereof, and a sustained release component I prepared by using Apost or its pharmacologically acceptable salt or a solvate thereof and a sustained release material
  • the composition is a matrix-type sustained-release component, and the active ingredient of Apster or a pharmacologically acceptable salt thereof or a solvate thereof accounts for a corresponding percentage by weight of the sustained-release component I or the site-releasing component II. 5 to 20%.
  • the release-release component II also contains a sustained-release material, so as to ensure that the release-release component reaches a specific region of the body, the drug can be slowly released, the administration time is prolonged, and the body is beneficial to the body. Drug absorption, reducing drug side effects.
  • the researcher conducted a detailed study on the combination ratio of the sustained release component I and the localization release component II in the pharmaceutical preparation, and found that the weight ratio of the sustained release component I to the localized release component II was 1 : 8 ⁇ 8:1, the sustained release of the drug preparation is good, and when the weight ratio is 1:6 ⁇ 6:1, the sustained release release is better, more preferably 1:5 ⁇ 4:1, specifically 2/5, 3/5, 4/5, 1/4, 1/3, 2/3, 3/4, 1/2, 1/1, 2/1, 3/2, 3/1.
  • the pharmaceutical preparation of the present invention comprises at least one localization release coating which is a gastric-soluble coating and an enteric coating (enteric coating).
  • Any enteric coating can be used in the present invention, including, but not limited to, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose titanate (HMPCP).
  • PVAP polyvinyl alcohol acetate phthalate
  • CAP cellulose acetate phthalate
  • shellac methyl methacrylate, methacrylic acid and butyl acrylate terpolymer
  • a Solution or dispersion of acrylic acid and methacrylate copolymer cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate Phthalate, acrylic resin (trade name: Eudragit), specific trade name USNF A type (Eudragit L TM ), type B (Eudragit S TM ), type C (Eudragit L 100-55 TM ), Eudragit NE 30D, Eudragit E, Eudragit RL, Eudragit RS, cellulose acetate trimellitate, one or more combinations of shellac.
  • PVAP polyvinyl alcohol acetate phthalate
  • CAP cellulose acetate phthalate
  • shellac methyl me
  • the enteric coating used in the preparation of the present invention may be formed into a single layer or a plurality of layers.
  • the thickness of the coating can be readily determined by one skilled in the art, but must be sufficient to protect the formulation in a gastric acidic environment.
  • the enteric coating weight is from 1 to 40%, more preferably from 2 to 30%, most preferably from 2 to 20%, specifically 6%, 7%, 8%, based on the total weight of the site-releasing component II. 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%.
  • sustained-release material used in the sustained-release component I and the localization-releasing component II of the present invention is polyoxyethylene, hypromellose, polyvinyl acetate and polyvinylpyrrolidone.
  • a copolymer (Kollidon SR), hydroxypropyl cellulose, polyalkyl sucrose or a copolymer of polyalkyl pentaerythritol and acrylic acid cross-linking polymer (carbomer), sodium alginate
  • the oxyethylene is a water-soluble resin
  • the water-soluble resin preferably used has a molecular weight of from 900,000 Daltons to 10,000,000 Daltons, and specific trade names are polyoxyethylene N80, polyoxyethylene N750, polyoxyethylene 1105, polyoxyethylene N60K, and the like. If a plurality of sustained-release materials are used in combination, the mixing ratio thereof is not particularly limited.
  • the sustained release material of the present invention is used in an amount of 6 to 60%, preferably 10 to 50%, more preferably 15 to 45% by weight based on the corresponding sustained release component I or the localization release component II in the pharmaceutical preparation. Specifically, it may be 20%, 25%, 30%, 35%, 40%, 45%.
  • sustained-release component I and the localization-releasing component II further comprise a pharmaceutically acceptable excipient
  • the medicinal excipients are well known to those skilled in the art as a filler, a surfactant, and a flow aid.
  • a filler a surfactant, and a flow aid.
  • the filler used in the present invention is a water-soluble or water-swellable filler, and the water-swellable filler refers to a pharmaceutical excipient which swells after being added to water.
  • the water-soluble filler contains dextrin, lactose, sucrose, mannitol, and calcium hydrogen phosphate.
  • Water-swellable fillers include pregelatinized starch, gelatinized starch, microcrystalline (crystalline) cellulose, corn starch, hydroxypropyl methylcellulose (HPMC-K100LV), calcium sulfate, sodium carboxymethyl starch, carboxymethyl Cellulose (carboxymethylcellulose), carboxymethylcellulose calcium, croscarmellose sodium (croscarmellose sodium), soy lecithin, low-substituted hydroxypropylcellulose, tragacanth Powder and bentonite.
  • HPMC-K100LV hydroxypropyl methylcellulose
  • water-soluble or water-swellable additives may be used singly or in combination of two or more types, preferably microcrystalline cellulose, pregelatinized starch, corn starch, dextrin, lactose, sucrose, mannitol, calcium sulfate.
  • the filler is used in an amount of 10 to 40% by weight of the corresponding sustained-release component I or the site-releasing component II in the pharmaceutical preparation, and may be 15%, 20%, 25%, 30%, 35%. 40%.
  • the meaning of "the amount of the corresponding sustained-release component I or the site-releasing component II in the pharmaceutical preparation” as described in the present invention is expressed as a pharmaceutical excipient in the respective components (slow-release component I or localization-releasing component).
  • Weight content for example, "the amount of the filler is 10-40% by weight of the corresponding sustained-release component I or the site-releasing component II in the pharmaceutical preparation", which means that the filler is suspended in the sustained-release component I.
  • the dosage of the agent is 10-40% by weight of the sustained-release component I in the pharmaceutical preparation, and the amount of the sustained-release component II filler is 10-40% by weight of the positioning component II in the pharmaceutical preparation.
  • the phrase "10-40% by weight of filler" as described in the present invention is described, and the expression means that the amount of the filler accounts for the weight of the corresponding sustained-release component I or the localization-releasing component II in the pharmaceutical preparation. The percentage is 10 to 40%.
  • the skilled person habitually considers the active ingredient, the sustained-release material and the medicinal auxiliary as a whole, and uses the coating agent as an additional amount, but calculates the active ingredient and releases the active ingredient.
  • the range or content range of the materials or medicinal excipients is calculated based on the weight of the entire component, and the present invention is also the same. For details, see Example 2.
  • the surfactant of the present invention includes an ionic surfactant and a nonionic surfactant.
  • the ionic surfactant is stearic acid, sodium lauryl sulfate, lecithin, amino acid, etc.;
  • the nonionic surfactant is glyceryl monostearate, polysorbate, fatty acid sorbitan, polyoxyethylene-poly The oxypropylene copolymer (poloxamer), sodium lauryl sulfonate, etc., preferably used in an amount of 0.5 to 10% by weight of the corresponding sustained-release component I or the sustained-release component II, which may be 1%. 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%.
  • the glidant of the present invention may be hydrated silica (colloidal silica), light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, Magnesium stearate, tricalcium phosphate, talc, corn starch or aluminum metasilicate, preferably in colloidal silica, preferably the amount of the glidant is in the pharmaceutical formulation, corresponding to the sustained release component I) or
  • the weight percent of the site-releasing component II) is from 0.1 to 5%, which may be 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%.
  • the lubricant of the present invention may be cocoa fat, carnauba wax, hydrated silica (colloidal silica), aluminum hydroxide xerogel, glycerin fatty acid ester, magnesium silicate, light anhydrous silicic acid.
  • the weight percentage of the corresponding sustained-release component I or the localization-releasing component II is 0.1 to 5%, which may be 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%. .
  • the coating agent (non-localized release coating) of the present invention may be hypromellose, methyl cellulose, ethyl cellulose, methyl cellulose or hydroxypropyl cellulose, polyvinyl alcohol, polydimensional Ketone, polyvinyl acetate resin or polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS and acrylic acid B
  • An ester-methyl methacrylate copolymer dispersion comprising a sugar alcohol sucrose, a mannitol paste, or a commercial product of Opadry.
  • the sustained-release component I contains (A) 5 to 20% by weight of Apost or a pharmacologically acceptable salt thereof or a solvate thereof, and (B) a sustained-release material
  • the sustained-release material is selected from one or two of polyoxyethylene, hypromellose or hydroxypropylcellulose, and preferably the sustained-release material is used in the sustained release component I or the localization release group in the pharmaceutical preparation.
  • the weight percentage of the fraction II is 6 to 60%, preferably 10 to 50%, more preferably 15 to 45%, (C) 10 to 40% by weight of the filler, and (D) 0.5 to 10% by weight of the surfactant, E) 0.1 to 5% by weight of a glidant, (F) 0.1 to 5% by weight of a lubricant; and a release-releasing component II containing A) 5 to 20% by weight of Apost or a pharmacologically acceptable thereof a salt or a solvate thereof, (B) 10 to 40% by weight of a filler, (C) 0.5 to 10% by weight of a surfactant, (D) 0.1 to 5% by weight of a flow aid, (E) 0.1 to 5% by weight of the lubricant, (F) the positioning coating material is an enteric coating, which is preferably ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, acrylic resin At least one, preferred Location targeting release coating for releasing an amount by
  • the pharmaceutical preparation of the present invention has a weight ratio of the sustained release component I to the localization release component II of 1:8 to 8:1, preferably 1:6 to 6:1, more preferably 1:5 to 4:1. It can be 2/5, 3/5, 4/5, 1/4, 1/3, 2/3, 3/4, 1/2, 1/1, 2/1, 3/2, 3/1.
  • the localization release component II further contains a sustained-release material, and the sustained-release material is polyoxyethylene, hypromellose or hydroxypropylcellulose, and the amount of the sustained-release material is preferably occupied.
  • the weight percentage of the corresponding sustained-release component I or the site-releasing component II in the pharmaceutical preparation is 6 to 60%, preferably 10 to 50%, more preferably 15 to 45%.
  • the sustained release component I in the pharmaceutical preparation of the present invention is a matrix type sustained release component. Specifically, the active ingredient, Apster, is distributed in a sustained-release matrix and is mainly sustained by a sustained-release material distributed in the matrix.
  • the sustained release component I may or may not contain a coating agent.
  • the active ingredient is also distributed in the sustained release matrix to be a matrix type sustained release component.
  • the positioning release component II of the present invention may further contain other types of coatings (non-enteric coatings), which mainly play a role of identification and differentiation in the production process of the pharmaceutical preparations.
  • the pharmaceutical preparation dosage form according to the present invention is a solid preparation, and is a tablet, a granule, a powder (including a fine granule), a pellet, or a capsule, preferably a capsule or a tablet.
  • Solid preparations can be prepared by widely known methods of preparation, including wet granulation, dry granulation, or powder direct compression processes.
  • the pharmaceutical preparation of the present invention is in a capsule form, granules, pellets or powders prepared by a widely known preparation method may be encapsulated.
  • the apster of the present invention is a solvate (including a hydrate) or a pharmaceutically acceptable salt or a solvate (including a hydrate) of a salt.
  • a solvate including a hydrate
  • a pharmaceutically acceptable salt including a hydrate
  • a solvate including a hydrate
  • a salt including hydrochloride, sulfate, hydrobromide, citrate, hydroiodide, phosphate, nitrate, benzoate, methanesulfonate, besylate, 2-hydroxyethanesulfonate , p-toluenesulfonate, acetate, propionate, oxalate, malonate, succinate, glutarate, adipate, tartrate, maleate, fumarate , malate and mandelic acid.
  • apster of the present invention or a pharmaceutically acceptable salt or solvate thereof can be used according to US6962940 or Synthesized by the method disclosed in J. Med. Chem. 2009, 52, 155-1524, also commercially available.
  • the content value and the release degree value described in the present invention have inevitable experimental errors, and the error value is ⁇ 1%.
  • the present invention two different sustained-release release behaviors of the Apster component are combined in a certain ratio to prepare a final sustained-release preparation, and the release rate is constant in the in vitro release test.
  • the in vitro release and pharmacokinetics of the sustained release preparation of the present invention are compared with the pharmacokinetics of the conventional preparation, and the present invention has the following beneficial effects:
  • the blood drug concentration can be maintained for a long time to avoid the phenomenon of peaks and valleys which occur in the frequent administration of common preparations; at the same time, the drug utilization degree is provided, and the side effects of the gastrointestinal tract during the administration of the drug are reduced.
  • Figure 1 Release profile of Embodiments G, I, and H. Apost.
  • Figure 2 Release profile of Embodiments J, I, K Apost.
  • sustained-release component I and the localization-releasing component II were loaded into capsule No. 00 at different ratios to obtain sustained-release preparations of different release profiles.
  • the specific embodiment is shown in Table 3.
  • the in vitro release rate of the Apster sustained-release capsules of the embodiments G to K was measured by the second method of the Chinese Pharmacopoeia dissolution method, using 900 mL of the dissolution medium, first in the medium of pH 1.0. The measurement was carried out for 2 hours, and then placed in a phosphate buffer solution of pH 6.8, and the release degree was examined.
  • the dissolution medium temperature was 37 ⁇ 0.5 ° C, and the paddle speed was 75 rpm. Samples were taken at 2, 4, 6, 8, 12 h and measured at 230 nm by an ultraviolet spectrophotometer, as shown in Table 4.
  • the sustained release preparation of Apast prepared by the method of the present invention releases slowly in 2 hours, and can prevent the side effects caused by excessive release after oral administration while achieving therapeutic effects.
  • the release is gentle in 2-12h, which can ensure the blood concentration is gentle and lasting.

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Abstract

本发明涉及阿普斯特缓释制剂。具体而言，本发明涉及一种阿普斯特的组合物，在体内具有高的生物利用度的缓释制剂。具体而言，提供一种含有阿普斯特缓释组分和其定位释放组分的缓释药物制剂，其在体外释放试验中，释放速率平稳、恒定。

Description

阿普斯特缓释制剂 技术领域
本发明提供了一种难溶性药物阿普斯特的缓释制剂，具体而言，为含缓释组分和定位释放组分的缓释药物制剂，所述的药物制剂在体外释放试验中，释放平缓，可以保证血药浓度平缓，作用持久。
背景技术
阿普斯特，化学名N-[2-[(1S)-1(3-乙氧基-4-甲氧基苯基)-2-(甲磺酰基)乙基]-2，3-2H-1，3-二氧-1H-异吲哚-4-基]乙酰胺结构如下图所示：
Figure PCTCN2016108709-appb-000001
阿普斯特是一种小分子磷酸二酯酶抑制剂，特别针对环磷酸腺苷(cAMP)具有特异抑制性。PDE4抑制作用可导致细胞内cAMP水平增加，通过调控TNF-α、IL-23和其他炎性细胞因子的表达相应下调炎性反应。
阿普斯特是一种难溶性化合物，为BCSⅣ类药物，在水中几乎不溶，可以用于银屑病的治疗。银屑病是一种常见的皮肤疾病，其特征是慢性炎症性病变，长期困扰患者且不易治疗。目前临床应用较多的是生物制剂，主要的生物制剂包括TNF-α抑制剂，白细胞介素-12、23(IL-12/IL-23)抑制剂和以B细胞和T细胞为靶点的抗体，目前用于银屑病治疗的生物制品发展迅速且临床效果显著，但生物制品一般为注射给药，在银屑病需要长期治疗控制，因此在银屑病的全身长期治疗中生物制品往往存在依从性低、易耐受等问题。针对以上情况，阿普斯特作为一种可以口服的治疗银屑病的药物有很大的优势。
目前已经上市的阿普斯特制剂为普通片，长期使用时服药方式为每日两次各30mg，间隔12h。而阿普斯特缓释片可以将服药次数改为每日一次，使患者的依从性更高，同时血药浓度波动更小，可大大减少服药期间的副作用。因此缓释片对于长期服药的患者有很大优势。
而由于阿普斯特的胃肠道副作用较严重，而副作用的发生频率与血药浓度关系密切，目前上市的速释片需要采用滴定给药方式逐日增加，具体给药方式见下表，使患者的依从性不高。
Figure PCTCN2016108709-appb-000002
基于上述原因，在临床上迫切需要一种服用后在体内血药浓度更为平缓的阿 普斯特缓释制剂。具体而言，这种阿普斯特缓释制剂可以减少每天的服药次数，增加患者服药的顺应性，这对于需要长期服药的患者而言是很有必要的。同时，这种阿普斯特缓释制剂在服用后释药速度平稳，在体内可以缓慢释放，减小了每日两次服药产生的血药浓度波动，可以大大减小副作用发生率。
WO2013119607公开了利用羟丙基纤维素等高分子聚合物作为缓释骨架材料的缓释药物组合物，从其说明书中药物释放数据来看，所述缓释药物的释放度呈现线性关系，不能达到好的缓释释放效果。
US20140370092公开了一种口服制剂，由含不同缓释成分的组分制备而成，其中一种为用单层包衣剂包裹的缓释组分，另一种为用双层包衣剂包裹的缓释组分。按所述方法制备而成的片剂或胶囊剂的释放度不够平缓，释放量不恒定，如利其技术方案并不能很好的解决现有技术问题，即减少服药次数同时，保证患者血药浓度波动更小，提供药物利用度，同时减少服药期间的副作用。
发明内容
本发明提供了一种缓释药物制剂，含有阿普斯特缓释组分和定位释放组分的缓释制剂，通过两种不同释药行为的组分相结合，调节阿普斯特口服后在体内的释放行为，从而保证口服后的阿普斯特血药浓度相对普通片更加恒定，减小服药后的血药浓度波动，显著降低副作用发生率且作用时间更持久，进而减少服药次数。
具体而言，本发明通过将阿普斯特缓释组分I和定位释放组分II按照一定重量比例混合后，所述定位释放组分II由阿普斯特或其药理学上可接受的盐或其溶剂合物和定位释放包衣制备而成，所述阿普斯特缓释组分I由阿普斯特或其药理学上可接受的盐或其溶剂合物和缓释材料制备而成，为基质型缓释组分，活性成分阿普斯特或其药理学上可接受的盐或其溶剂合物占相对应的缓释组分I或定位释放组分II的重量百分比为5～20％。
为了达到更优选缓释释放效果，定位释放组分II中还含有缓释材料，这样保证定位释放组分到达体中特定的区域内后，才能缓慢释放出药物，延长给药时间，利于身体对药物吸收，减少药物副作用。为了达到药物制剂最优缓释效果，研发人员对药物制剂中缓释组分I和定位释放组分II组合比例进行细致的研究，发现缓释组分I与定位释放组分II重量比为1:8～8:1，药物制剂缓释释放度好，而在重量比为1:6～6:1时，缓释释放度较好，更优为1:5～4:1，具体可为2/5、3/5、4/5、1/4、1/3、2/3、3/4、1/2、1/1、2/1、3/2、3/1。
本发明所述的药物制剂中至少包括一种定位释放包衣，所述定位释放包衣为胃溶性包衣和肠溶性包衣(肠溶包衣)。任何肠溶包衣都可以用于本发明中，包括，但不限于乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素钛酸酯(HMPCP)、聚乙烯醇醋酸苯二甲酸酯(PVAP)、褐藻胶、苯二甲酸醋酸纤维素(CAP)、虫胶、甲基丙烯酸甲酯、甲基丙烯酸和丙烯酸丁酯的三元共聚物、甲基丙烯酸和异丁烯酸酯共聚物的溶液或分散液、醋酞纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、聚乙酸乙烯酯邻苯二甲酸酯、丙烯酸树脂(商品名：尤特奇)，具体商品名为USNF A型(Eudragit LTM)、B型(Eudragit STM)、C型(Eudragit L 100-55TM)、Eudragit NE 30D、Eudragit E、Eudragit RL、Eudragit RS，醋酸纤维素偏苯三酸酯，紫胶中一种或多种组合。
另外，在本发明的制剂中使用的肠溶包衣可以形成单层或多层。包衣的厚度可以由本领域技术人员容易地确定，但是必须足够在胃酸性环境中保护所述制剂。基于定位释放组分II的总重量计，肠溶包衣重量为1～40％，更优选为2～30％，最优选为2～20％，具体可为6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％。
本发明所述的缓释组分I和定位释放组分II所使用的缓释材料(或称为缓释骨架材料)为聚氧乙烯、羟丙甲纤维素，聚醋酸乙烯酯和聚乙烯吡咯烷酮聚合物(Kollidon SR)、羟丙基纤维素、聚烷基蔗糖或聚烷基季戊四醇与丙烯酸交联聚合物的共聚物(卡波姆)、海藻酸钠中一种或多种，其中，环氧乙烯为水溶性树脂，优选采用的水溶性树脂分子量从900,000道尔顿至10,000,000道尔顿，具体商品名为聚氧乙烯N80、聚氧乙烯N750、聚氧乙烯1105、聚氧乙烯N60K等。如是多种缓释材料混合使用，其混合比例不需要特别限制。同时，本发明所述缓释材料的用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为6～60％，优选10～50％，更优选15～45％，具体可为20％、25％、30％、35％、40％、45％。
本发明所述的药物制剂，其中缓释组分I和定位释放组分II中还含有药用辅料，这些药用辅料种类为本技术领域人员所公知，为填充剂、表面活性剂、助流剂、润滑剂、包衣中的一种或多种。
本发明所使用的填充剂为水溶性或水溶胀性填充剂，水溶胀性填充剂指加入水后溶胀的药用辅料。水溶性填充剂包含糊精、乳糖、蔗糖、甘露醇、磷酸氢钙。水溶胀性填充剂包括预胶凝淀粉、胶凝淀粉、微晶(结晶)纤维素、玉米淀粉、羟丙基甲基纤维素(HPMC-K100LV)、硫酸钙、羧甲基淀粉钠、羧甲纤维素(羧甲基纤维素)、羧甲纤维素钙、交联羧甲纤维素钠(交联羧甲基纤维素钠)、大豆卵磷脂、低取代的羟丙基纤维素、黄蓍胶粉和膨润土。这些水溶性或水溶胀性添加剂可以单独使用或者以两种或多种类型的组合使用，优选于微晶纤维素、预胶化淀粉、玉米淀粉、糊精、乳糖、蔗糖、甘露醇、硫酸钙、磷酸氢钙中的一种或多种， 优选所述填充剂的用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为10～40％，可为15％、20％、25％、30％、35％、40％。
本发明中所述的“用量占药物制剂中相对应的缓释组分I或定位释放组分II”的意思表示为药用辅料在各自组分中(缓释组分I或定位释放组分II)重量含量，例如，“填充剂的用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为10～40％”其表述意思为缓释组分I中填充剂的用量占药物制剂中缓释组分I重量百分比为10～40％，和缓释组分II填充剂的用量占药物制剂中定位组分II重量百分比为10～40％。
本发明中所述的如“10～40％重量的填充剂”等语句描述，其表述意思为所述填充剂用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为10～40％。同时在制备药物制剂过程中，本技术人员习惯性的将活性成分、缓释材料、药用辅料作为一个整体考虑，而将所使用包衣剂作为额外量计算，但在计算活性成分、缓释材料或药用辅料的使用量范围或含量范围时，都是以整个组分的重量为计算，本发明也是如此，具体可参见实施例2。
本发明所述的表面活性剂包括离子型表面活性剂、非离子性表面活性剂。离子型表面活性剂为硬脂酸，十二烷基硫酸钠，卵磷脂，氨基酸等；非离子型表面活性剂为单硬脂酸甘油酯，聚山梨酯，脂肪酸山梨坦，聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆)、月桂基磺酸钠等，优选用量占相对应的缓释组分I或定位缓释组分II的重量百分比为0.5～10％，可为1％、2％、3％、4％、5％、6％、7％、8％、9％。
本发明所述的助流剂可以为水合二氧化硅(胶态二氧化硅)、轻质无水硅酸、结晶纤维素、合成硅酸铝、氧化钛、硬脂酸、硬脂酸钙、硬脂酸镁、磷酸三钙、滑石粉、玉米淀粉或偏硅酸铝，优选于胶态二氧化硅，优选所述助流剂的用量占药物制剂中相对应的缓释组分I)或定位释放组分II)的重量百分比为0.1～5％，可为0.5％、1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％。
本发明所述的润滑剂可以为可可脂肪、巴西棕榈蜡、水合二氧化硅(胶态二氧化硅)、氢氧化铝干凝胶、甘油脂肪酸酯、硅酸镁、轻质无水硅酸、结晶纤维素、硬化油、合成硅酸铝、白蜂蜡、氧化镁、酒石酸钠钾、蔗糖脂肪酸酯、硬脂酸、硬脂酸钙、硬脂酸镁、聚乙二醇6000、硬脂酸富马酸钠、硬脂醇、聚乙二醇40硬脂酸酯、滑石粉、氢化蓖麻油、山嵛酸甘油酯中一种或多种，优选于硬脂酸、硬脂酸镁、硬脂酸钙、聚乙二醇6000、硬脂富马酸钠、滑石粉、氢化蓖麻油、山嵛酸甘油酯中的一种或多种，优选所述润滑剂的用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为0.1～5％，可为0.5％、1％、1.5％、2％、2.5％、3％、3.5％、4％、4.5％。
本发明所述的包衣剂(非定位释放包衣)可以为羟丙甲纤维素、甲基纤维素、乙基纤维素、甲基纤维素或羟丙基纤维素、聚乙烯醇、聚维酮、聚乙酸乙烯酯树脂或聚乙烯醇缩醛二乙氨基乙酸酯、甲基丙烯酸氨基烷基酯共聚物RS和丙烯酸乙 酯-甲基丙烯酸甲酯共聚物分散体，糖类包括糖醇蔗糖、甘露醇糊，或商品为欧巴代。
本发明所述的药物制剂，其缓释组分I含有(A)5～20％重量的阿普斯特或其药理学上可接受的盐或其溶剂合物，(B)缓释材料，所述缓释材料选自聚氧乙烯、羟丙甲纤维素或羟丙基纤维素中一种或两种，优选缓释材料用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为6～60％，优选10～50％，更优选15～45％，(C)10～40％重量的填充剂，(D)0.5～10％重量的表面活性剂，(E)0.1～5％重量的助流剂，(F)0.1～5％重量的润滑剂；定位释放组分II含A)5～20％重量的阿普斯特或其药理学上可接受的盐或其溶剂合物，(B)10～40％重量的填充剂，(C)0.5～10％重量的表面活性剂，(D)0.1～5％重量的助流剂，(E)0.1～5％重量的润滑剂，(F)定位包衣材料为肠溶性包衣，所述肠溶性包衣为优选乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、丙烯酸树脂中至少一种，优选所述定位释放包衣用量占定位释放组分II的重量百分比为1～40％，更优选为2～30％，最优选为2～20％。
本发明所述的药物制剂中缓释组分I与定位释放组分II重量比为1:8～8:1，优选1:6～6:1，更优选1:5～4:1，具体可为2/5、3/5、4/5、1/4、1/3、2/3、3/4、1/2、1/1、2/1、3/2、3/1。同时，本发明所述的药物制剂，其定位释放组分II还含有缓释材料，所述缓释材料为聚氧乙烯、羟丙甲纤维素或羟丙基纤维素，优选缓释材料用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为6～60％，优选10～50％，更优选15～45％。
本发明所述药物制剂中缓释组分I为基质型缓释组分。具体而言，活性成分阿普斯特分布在缓释基质中，由分布在基质中缓释材料起主要的缓释作用。缓释组分I可以含有或不含包衣剂。
当本发明所述定位释放组分II中含有缓释材料时，其活性成分也分布在所使用的缓释基质中，为基质型缓释组分。本发明所述的定位释放组分II中还可含有其它类型包衣(非肠溶性包衣)，在药物制剂生产过程中主要起识别、区分的作用。
本发明所述的药物制剂剂型为固体制剂，为片剂、粒剂、粉剂(包括精细的粒剂)、微丸，或者胶囊剂，优选胶囊、片剂。固体制剂可通过广泛已知的制备方法制备，包括湿法制粒，干法制粒，或者粉末直压工艺。
当本发明药物制剂采用胶囊剂型时，可将通过广泛已知的制备方法制备的颗粒、微丸或粉剂用胶囊包裹。
本发明的阿普斯特为溶剂合物(包括水合物)或者药学上可接受的盐或者盐的溶剂合物(包括水合物)。包括盐酸盐、硫酸盐、氢溴酸盐、柠檬酸盐、氢碘酸盐、磷酸盐、硝酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、2-羟基乙磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、戊二酸盐、己二酸盐、酒石酸盐、马来酸盐、富马酸盐、苹果酸盐和扁桃酸盐。
本发明所述的阿普斯特或其可药用盐或溶剂合物等可按照US6962940或 J.Med.Chem.2009,52,155-1524所公开的方法合成得到，也通过商业途径购得。
本发明所述的药物制剂体外释放度测定，测定方法为采用中国药典溶出度测定方法第二法桨法，使用900mL的溶出介质，先在pH＝1.0的介质中测定2h，然后放入pH6.8的磷酸盐缓冲液中，进行释放度考察，溶出介质温度37±0.5℃，桨速度为75rpm。在2，4，6，8，12h采集样品，并通过紫外分光光度计在230nm进行测定。释放特征为：
2小时后释放10～20％重量的阿普斯特，
4小时后释放30～60％重量的阿普斯特，
8小时后释放85％～96％重量的阿普斯特，
12小时后释放96％～100％重量的阿普斯特。
本发明所述的含量数值、释放度数值存在不可避免的实验误差，其误差值为±1％。
通过本发明将两种不同缓释释放行为的阿普斯特组分，按照一定比例结合后制备成最终缓释制剂，在体外释放试验中，释放速率恒定。本发明缓释制剂的体外释放度和药代动力学，并和普通的制剂的药代动力学进行对比，本发明具有以下的有益效果：
1、可以使血药浓度维持较长时间，避免普通制剂频繁给药所出现的峰谷现象；同时，提供药物利用度，减少服药期间阿普斯特对胃肠道的副作用。
2、以不同的释药机理延长作用时间，减少给药次数，提高患者的顺应性。
附图说明
图1：实施方案G、I、H阿普斯特的释放度曲线。
图2：实施方案J、I、K阿普斯特的释放度曲线。
具体实施方式
通过以下实施例进一步详细说明本发明。这些实施例仅用于说明性目的，而并不用于限制本发明的范围。
实施例1
缓释组分I制备：
将阿普斯特、填充剂、缓释材料、表面活性剂、助流剂、润滑剂按表1中的比例，采用粉末直接压片工艺，混合后直接压片。压片时，可选择任意直径的模具，包括直径从2mm到6mm的任意圆形冲模。片重从10mg到100mg。
表1(采用6mm圆形冲模，单位片重100mg)
Figure PCTCN2016108709-appb-000003
Figure PCTCN2016108709-appb-000004
实施例2
定位释放组分II制备：
将阿普斯特、填充剂、缓释材料、表面活性剂、助流剂、润滑剂按表2中的比例，采用粉末直接压片工艺，混合后直接压片。然后采用高效包衣剂对所压片剂进行包衣。压片时，可选择任意直径的模具，包括直径从2mm到6mm的任意圆形冲模。片重从10mg到100mg。
表2(采用6mm圆形冲模，单位片重100mg)
Figure PCTCN2016108709-appb-000005
实施例3
阿普斯特缓释制剂制备：
将缓释组分I和定位释放组分II以不同比例装入00号胶囊内，可得到不同释药曲线的缓释制剂，具体实施方案如表3。
表3
Figure PCTCN2016108709-appb-000006
将实施方案G到K的阿普斯特缓释胶囊进行体外释放度测定，测定方法为采用中国药典溶出度测定方法第二法桨法，使用900mL的溶出介质，先在pH1.0的介质中测定2h，然后放入pH6.8的磷酸盐缓冲液中，进行释放度考察，溶出介质温度37±0.5℃，桨速度为75rpm。在2，4，6，8，12h采集样品，并通过紫外分光光度计在230nm进行测定，具体如表4。
表4不同实施方案缓释度结果
Figure PCTCN2016108709-appb-000007
由上表中的释放度结果可以看出，采用本发明方法制备的阿普斯特缓释制剂，在2h内释放较慢，在起到治疗效果的同时可以避免口服后释放过快导致的副作用，在2-12h的时间内释放平缓，可以保证血药浓度平缓，作用持久。

Claims (21)

  1. 一种药物制剂，其特征在于包含：
    I)阿普斯特缓释组分，和
    II)阿普斯特定位释放组分。
  2. 根据权利要求1所述药物制剂，其特征在于所述缓释组分I包含：
    A)阿普斯特或其药理学上可接受的盐或其溶剂合物，优选所述其含量占缓释组分I)的重量百分比为5～20％，
    B)缓释材料。
  3. 根据权利要求1或2所述药物制剂，其特征在于所述定位释放组分II包含：
    A)阿普斯特或其药理学上可接受的盐或其溶剂合物，优选所述其含量占缓释组分II)的重量百分比为5～20％，
    B)定位释放包衣。
  4. 根据权利要求3所述药物制剂，其特征在于所述定位释放包衣为肠溶性包衣、胃溶性包衣，优选肠溶性包衣，所述肠溶性包衣为乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素钛酸酯、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基甲基纤维素乙酸琥珀酸酯、聚乙酸乙烯酯邻苯二甲酸酯、丙烯酸树脂中的一种或多种，优选乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、丙烯酸树脂，优选所述定位释放包衣用量占定位释放组分II的重量百分比为1～40％，更优选为2～30％，最优选为2～20％。
  5. 根据权利要求2所述药物制剂，其特征在于所述缓释组分I中缓释材料为羟丙甲纤维素、聚氧乙烯、羟丙基纤维素、聚烷基蔗糖或聚烷基季戊四醇与丙烯酸交联聚合物的共聚物、海藻酸钠中的一种或多种。
  6. 根据权利要求3所述药物制剂，其特征在于所述定位释放组分II中还含缓释材料，所述缓释材料为羟丙甲纤维素、聚氧乙烯、羟丙基纤维素、聚烷基蔗糖或聚烷基季戊四醇与丙烯酸交联聚合物的共聚物、海藻酸钠中的一种或多种。
  7. 根据权利要求5或6所述药物制剂，其特征在于所述缓释材料用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为6～60％，优选10～50％，更优选15～45％。
  8. 根据权利要求1-7任一项所述药物制剂，其特征在于所述缓释组分I与定位释放组分II重量比为1:8～8:1，优选1:6～6:1，更优选1:5～4:1。
  9. 根据权利要求2所述药物制剂，其特征在于所述缓释组分I还含有药用辅料，所述药物辅料选自填充剂、表面活性剂、助流剂、润滑剂、包衣剂中的一种或多种。
  10. 根据权利要求3所述药物制剂，其特征在于所述定位释放组分II中还含有药用辅料，所述药物辅料选自填充剂、表面活性剂、助流剂、润滑剂、包衣剂中的一种或多种。
  11. 根据权利要求9或10所述药物制剂，其特征在于所述填充剂为水溶性或水溶胀性填充剂，优选自微晶纤维素、预胶化淀粉、玉米淀粉、糊精、乳糖、蔗糖、甘露醇、硫酸钙、磷酸氢钙中的一种或多种，优选所述填充剂的用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为10～40％。
  12. 根据权利要求9或10所述药物制剂，所述表面活性剂为离子型表面活性剂或非离子型表面活性剂中的一种或多种，所述离子型表面活性剂为硬脂酸，十二烷基硫酸钠，卵磷脂，氨基酸，所述非离子型表面活性剂为单硬脂酸甘油酯，聚山梨酯，脂肪酸山梨坦，聚氧乙烯-聚氧丙烯共聚物，优选所述表面活性剂用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为0.5～10％。
  13. 根据权利要求9或10所述药物制剂，所述助流剂为二氧化硅，滑石粉，微粉硅胶中的一种或多种，优选所述助流剂的用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为0.1～5％。
  14. 根据权利要求9或10所述药物制剂，所述润滑剂选自硬脂酸、硬脂酸镁、硬脂酸钙、聚乙二醇6000、硬脂富马酸钠、滑石粉、氢化蓖麻油、山嵛酸甘油酯中的一种或多种，优选所述润滑剂的用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为0.1～5％。
  15. 根据权利要求1-14任一项所述药物制剂，其特征在于所述药物制剂为颗粒剂、散剂、片剂、胶囊剂、混悬剂、或丸剂。
  16. 根据权利要求1所述的药物制剂，其中缓释组分I包含：
    A)5～20％重量的阿普斯特或其药理学上可接受的盐或其溶剂合物，
    B)缓释材料，所述缓释材料选自聚氧乙烯、羟丙甲纤维素或羟丙基纤维素中一种或两种，优选缓释材料用量占药物制剂中相对应的缓释组分I或定位释放组分II的重量百分比为6～60％，优选10～50％，更优选15～45％，
    C)10～40％重量的填充剂，
    D)0.5～10％重量的表面活性剂，
    E)0.1～5％重量的助流剂，
    F)0.1～5％重量的润滑剂。
  17. 根据权利要求1所述药物制剂，其特征在于所述定位释放组分II包含：
    A)5～20％重量的阿普斯特或其药理学上可接受的盐或其溶剂合物，
    B)10～40％重量的填充剂，
    C)0.5～10％重量的表面活性剂，
    D)0.1～5％重量的助流剂，
    E)0.1～5％重量的润滑剂，
    F)肠溶性包衣，所述肠溶性包衣优选乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、丙烯酸树脂中的至少一种，优选所述肠溶性包衣用量占定位释放组分II的重量百分比为1～40％，更优选为2～30％，最优选为2～20％。
  18. 根据权利要求17所述药物制剂，其特征在于所述定位释放组分II还包含缓释材料，所述缓释材料为聚氧乙烯、羟丙甲纤维素或羟丙基纤维素，优选缓释材料用量占药物制剂中相对应的定位释放组分II的重量百分比为6～60％，优选10～50％，更优选15～45％。
  19. 根据权利要求16-18任一项所述药物制剂，其特征在于所述缓释组分I与定位释放组分II重量比为1:8～8:1，优选1:6～6:1，更优选1:5～4:1。
  20. 一种含有阿普斯特的缓释制剂，其特征在于，采用中国药典溶出度测定方法第二法桨法，使用900mL的溶出介质，先在pH＝1.0的介质中测定2h，然后放入pH6.8的磷酸盐缓冲液中，溶出介质温度37±0.5℃，桨速度为75rpm，并通过紫外分光光度计在230nm进行测定时，得到的释放特征为：
    2小时后释放10～20％重量的阿普斯特，
    4小时后释放30～60％重量的阿普斯特，
    8小时后释放85％～96％重量的阿普斯特，
    12小时后释放96％～100％重量的阿普斯特。
  21. 根据权利要求1至19任意一项所述的药物制剂，其具有权利要求20中所述的释放特征。
PCT/CN2016/108709 2015-12-24 2016-12-06 阿普斯特缓释制剂 WO2017107768A1 (zh)

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JP2018538289A (ja) 2018-12-27
CN107405311B (zh) 2021-10-08
JP6904955B2 (ja) 2021-07-21
CA3008471A1 (en) 2017-06-29
US20200170999A1 (en) 2020-06-04
EP3395334A1 (en) 2018-10-31
HK1244714A1 (zh) 2018-08-17
MX2018007682A (es) 2018-08-15
AU2016377524A1 (en) 2018-07-19
EP3395334A4 (en) 2019-07-31
KR20180097623A (ko) 2018-08-31

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