WO2014154029A1 - 复合骨架材料及其药物组合物 - Google Patents

复合骨架材料及其药物组合物 Download PDF

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Publication number
WO2014154029A1
WO2014154029A1 PCT/CN2014/000354 CN2014000354W WO2014154029A1 WO 2014154029 A1 WO2014154029 A1 WO 2014154029A1 CN 2014000354 W CN2014000354 W CN 2014000354W WO 2014154029 A1 WO2014154029 A1 WO 2014154029A1
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Prior art keywords
hydrophilic
framework material
composite
skeleton
ratio
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PCT/CN2014/000354
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English (en)
French (fr)
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魏世峰
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北京罗诺强施医药技术研发中心有限公司
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Priority to EP14774405.6A priority Critical patent/EP2979707B1/en
Publication of WO2014154029A1 publication Critical patent/WO2014154029A1/zh
Priority to US14/865,624 priority patent/US10507185B2/en

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K9/2022—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
    • 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
    • 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
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and more particularly to a composite framework material and a pharmaceutical composition comprising the same, which is used for the preparation of a pharmaceutical sustained release preparation.
  • Sustained-release preparations are very useful preparations which can reduce the number of administrations and control the concentration of the drug in the blood to maintain the efficacy.
  • a sustained-release preparation may be used to replace ibuprofen, phenylpropanol hydrochloride, fluvastatin, lovastatin, etc., which are usually required to be taken several times a day, for one day, Jll, 1-2 times.
  • a plurality of hydrophilic polymeric materials can be used as a sustained release matrix.
  • the fluvastatin sodium sustained-release tablet described in Chinese Patent ZL 200780014499.X and Chinese Patent ZL 99812081.2 is a tablet made of a pharmaceutically active ingredient, a hydrophilic skeleton material which swells after being exposed to water, and other excipients; The water permeates into the tablet to dissolve the active ingredient of the drug, and causes the hydrophilic matrix material to swell to form a gel of high viscosity; the dissolved drug is slowly released through the gel of high viscosity.
  • the preparation for sustained release generally has a high content of hydrophilic polymer material, which is prone to cause problems in drug production and storage after being swollen with water, such as more waste generated, and the film is swollen with water to cause a film package. Difficulty in clothing, or slow release tablets will cause water to be absorbed, which will affect the stability of some drugs during storage.
  • the prior art discloses the use of osmotic pump technology to prepare sustained release formulations, such as the lovastatin sustained release tablets described in U.S. Patent 5,916,595.
  • the pharmaceutically active ingredient, the osmotic pressure adjusting agent and other auxiliary materials are made into a core; since lovastatin is hardly soluble in water, the material in the core of the tablet needs to be a hydrophilic material, resulting in more waste, Film coating is difficult, or it is easily absorbed, which causes the stability of the drug to be affected.
  • a sustained release preparation containing a pharmaceutically active ingredient having a small or insoluble water solubility the auxiliary material, particularly the sustained release skeleton material, is hydrophilic.
  • water solubility is greater
  • the pH of the dissolution medium has a great influence on the solubility and dissolution of the drug, and therefore preparation of a sustained release preparation containing a large amount of the active ingredient of the drug is also a major problem.
  • the present invention provides a composite framework material comprising a hydrophobic framework material and a hydrophilic framework material, wherein the ratio of the hydrophobic framework material to the hydrophilic framework material ranges from 1:0.01 to 1:5, preferably 1:0.05 to 1:4, more preferably 1:0.1 to 1:3, most preferably 1:0.4 to 1:2, for example 1:0.4 to 1:1.3.
  • the invention provides a preparation method of a composite skeleton material, which comprises:
  • the hydrophobic framework material and the hydrophilic framework material are from 1:0.01 to 1:5, preferably from 1:0.05 to 1:4, more preferably from 1:0.1 to 1:3, most preferably from 1:0.4 to 1:2. , for example, mixing in a ratio range of 1:0.4 to 1:1.3;
  • the hydrophilic framework material comprises a hydrophilic framework material of various viscosities; more preferably, the hydrophilic framework material is composed of a high viscosity and low viscosity hydrophilic framework material;
  • the high viscosity and low viscosity hydrophilic framework material ratio ranges from 1:0.01 to 1:10, preferably, the ratio ranges from 1:0.05 to 1:8, and more preferably, the ratio ranges from 1:0.3 to 1. : 4, most preferably, the ratio ranges from 1:1 to 1:3.
  • the present invention also provides the use of the composite framework material of the present invention for preparing a drug sustained release preparation, preferably, the prepared sustained release preparation is administered in water or intestinal pH (for example, pH 4-8) after administration.
  • the release time is up to 4 to 24 hours, preferably 6 to 20 hours, more preferably 8 to 18 hours; preferably, the prepared sustained release preparation (for example, the fluvastatin sodium sustained release tablet prepared by the present invention) is
  • the release rate of the 0.5 hour in the dissolution medium of the test method specified in Appendix XD and Appendix XC of the Chinese Pharmacopoeia of the Chinese Pharmacopoeia of 2010 is less than 15%, for example less than 10%;
  • the release rate of the second hour is 1-40%, preferably 5-35 %; release at 10 hours is 10-70%, preferably 15-60%; release at 6 hours is 20-90%, preferably 30-88%; release at eighth hour is not less than 80% .
  • the present invention also provides a composite hydrophilic skeleton material comprising a hydrophilic skeleton material of various viscosities; preferably, the composite hydrophilic skeleton material is composed of a high viscosity and low viscosity hydrophilic skeleton material;
  • the ratio of the high viscosity and low viscosity hydrophilic framework material in the composite hydrophilic framework material ranges from 1:0.01 to 1:10, preferably, the ratio ranges from 1:0.05 to 1:8, more preferably, the ratio range From 1:0.3 to 1:4, most preferably, the ratio ranges from 1:1 to 1:3.
  • the invention also provides a composite hydrophilic framework material for use in combination with a hydrophobic framework material for preparing a pharmaceutical composition, wherein the ratio of the hydrophobic framework material to the composite hydrophilic framework material ranges from 1:0.01 to 1:5 Preferably, it is 1:0.05 to 1:4, more preferably 1:0.1 to 1:3, and most preferably 1:0.4 to 1:2.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the composite framework material of the present invention and one or more pharmaceutically active ingredients, preferably, the ratio of the composite framework material to the pharmaceutically active ingredient ranges from 1:0.01 to 1 : 8, more preferably from 1:0.02 to 1:5, most preferably from 1:0.03 to 1:1, for example from 1:0.3 to 1:0.7.
  • the invention also provides a preparation method of the pharmaceutical composition of the invention, which comprises:
  • a hydrophobic skeleton material with a hydrophilic skeleton material to obtain a composite framework material, wherein a mixing ratio of the hydrophobic skeleton material to the hydrophilic skeleton material is 1:0.01 to 1:5, preferably 1:0.05 to 1:4, more preferably 1:0.1 to 1:3, most preferably 1:0.4 to 1:2, for example 1:0.4 to 1:1.3;
  • the mixing ratio with the pharmaceutically active ingredient is preferably from 1:0.01 to 1:8, more preferably from 1:0.02 to 1:5, most preferably from 1:0.03 to 1:1, such as 1:0.3 to 1:0.7;
  • the pharmaceutical composition is prepared into a suitable dosage form, for example, granulated or tableted.
  • the present invention provides a composite framework material comprising a hydrophobic framework material and a hydrophilic framework material, wherein the ratio of the hydrophobic framework material to the hydrophilic framework material ranges from 1:0.01 to 1:5, preferably 1:0.05 to 1:4, more preferably 1:0.1 to 1:3, most preferably 1:0.4 to 1:2, for example 1:0.4 to 1:1.3.
  • the hydrophobic framework material may comprise two or more different hydrophobic framework materials having different melting points, different acid numbers, or different solubility in ethanol mixed in any ratio.
  • the hydrophilic skeleton material may include two or more different hydrophilic skeleton materials mixed in an arbitrary ratio.
  • the present invention provides a composite framework material composed of a hydrophobic framework material and a hydrophilic framework material, wherein the ratio of the hydrophobic framework material to the hydrophilic framework material ranges from 1 From 0.01 to 1:5, preferably from 1:0.05 to 1:4, more preferably from 1:0.1 to 1:3, most preferably from 1:0.4 to 1:2, for example from 1:0.4 to 1:1.3.
  • hydrophobic framework material as used herein includes insoluble framework materials and biodegradable framework materials, wherein the insoluble framework material and the biodegradable framework material are as defined below.
  • the hydrophobic backbone material has a hydrophilic-lipophilic balance (HLB) value of less than 11, preferably less than 9, more preferably less than 7.
  • HLB hydrophilic-lipophilic balance
  • the hydrophobic framework material has a number average molecular weight in the range of from about 100 Daltons to about 7,000,000 Daltons, more preferably in the range of from about 200 Daltons to about 5,000,000 Daltons, still more preferably about 250 Daltons. Up to approximately 3,000,000 Daltons.
  • insoluble framework material refers to a polymer material which is insoluble in water and the like. Examples thereof include: ethyl cellulose, polyethylene, polypropylene, polysiloxane, polyvinyl chloride, ethylene-vinyl acetate copolymer, polydecyl methacrylate, or a mixture thereof.
  • biodegradable framework material includes low melting point (eg melting point less than 200 ° C), insoluble in water but soluble in organic solvents (eg chloroform or acetone) or low hydrophilic-lipophilic balance values (eg HLB) Biodegradable framework material with a value less than 9).
  • organic solvents eg chloroform or acetone
  • HLB hydrophilic-lipophilic balance values
  • Biodegradable framework material with a value less than 9 examples thereof include waxes, fatty acids and esters thereof, such as C 16 -C 22 fatty acids, carnauba wax (abbreviation)
  • Base wax a glyceride of a C 16 -C 22 fatty acid, a C 16 -C 22 alkyl alcohol, a beeswax, a synthetic wax, a hydrogenated vegetable oil, or a mixture thereof; preferably a carnauba wax, a C 16 -C 22 fatty acid a glyceride (including a C 16 -C 22 fatty acid glyceride, a C 16 -C 22 fatty acid diglyceride and a C 16 -C 22 fatty acid monoglyceride), the glyceride of the C 16 -C 22 fatty acid being selected from at least one of the following : glyceryl behenate, behenic acid diglyceride, behenic acid monoglyceride, and mixtures thereof.
  • hydrophilic framework material refers to a framework material that swells in contact with water or an aqueous solution such as a digestive juice to form a gel barrier.
  • examples include: natural plant or animal glue, such as sodium alginate, agar, scutellaria, xanthan gum, pectin, guar gum, etc.; Biologicals such as mercapto cellulose (MC), hydroxyethyl cellulose (HEC), hydroxyethyl fluorenyl cellulose (HEMC), hydroxypropyl cellulose (HPC), hydroxypropyl fluorenyl cellulose (HPMC), Sodium carboxymethyl cellulose (SCMC); non-cellulosic polysaccharides such as chitin, galactomannan, dextran, etc.; ethylene polymers and acrylic resins such as polyethylene oxide, crosslinked polyvinylpyrrolidone , polyvinyl alcohol and carbopol.
  • the hydrophilic framework material includes, but is not limited to, hydroxypropyl ketone cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium hydroxymethyl cellulose, sodium alginate, chitin, polyepoxy A dissociative or non-dissociated polymer material that swells when exposed to water, such as ethane. More preferably, the hydrophilic framework material is hydroxypropyl ketone cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium hydroxydecyl cellulose.
  • the hydrophilic backbone material used in the present invention has a number average molecular weight in the range of from about 50 Daltons to about 9,000,000 Daltons, preferably in the range of from about 50,000 Daltons to about 8,000,000 Daltons, more preferably. Approximately 90,000 Daltons to approximately 7,000,000 Daltons.
  • the number average molecular weight of the cellulose derivative in the hydrophilic framework material used in the present invention is preferably in the range of from about 50 Daltons to about 2,500,000 Daltons, more preferably from about 70 Daltons to about Within the range of 2,000,000 Daltons, most preferably in the range of from about 80 Daltons to about 1,800,000 Daltons.
  • the number average molecular weight of the polyethylene oxide in the hydrophilic framework material used in the present invention is preferably in the range of from about 50,000 Daltons to about 8,000,000 Daltons, more preferably from about 100,000 Daltons to about 7,000,000 Daltons. Within the range.
  • the hydrophilic framework material comprises a high viscosity hydrophilic framework material and a low viscosity hydrophilic framework material; preferably, wherein the high viscosity hydrophilic framework material and the low viscosity hydrophilic framework material
  • the ratio ranges from 1:0.01 to 1:10, preferably from 1:0.05 to 1:8, more preferably from 1:0.1 to 1:6, most preferably from 1:0.3 to 1:4, for example from 1:1 to 1:3.
  • examples of the high viscosity hydrophilic matrix material are hydrophilic framework materials having a viscosity ranging from 4,000 to 100,000 mPa.s, such as hydroxypropylcellulose 75HD15000 (or K15M).
  • an example of the low viscosity hydrophilic matrix material is a hydrophilic framework material having a viscosity of not more than 1,000 mPa.s, such as hydroxypropylcellulose 75HD10 (K or K100LV).
  • viscosity refers to the viscosity (in mPa.s) of a solution obtained by dissolving 2 g of a substance in 100 ml of distilled water at 20 Torr.
  • low viscosity means that the hydrophilic skeleton material has a viscosity of from 20 to 2,000 mPa.s, preferably from 20 to 800 mPa.s, more preferably from 20 to 600 mPa.s.
  • high viscosity means that the viscosity of the hydrophilic framework material is
  • the invention provides a preparation method of a composite skeleton material, which comprises:
  • the hydrophobic framework material and the hydrophilic framework material are from 1:0.01 to 1:5, preferably from 1:0.05 to 1:4, more preferably from 1:0.1 to 1:3, most preferably from 1:0.4 to 1:2. , for example, mixing in a ratio range of 1:0.4 to 1:1.3;
  • the hydrophilic framework material comprises a hydrophilic matrix material of various viscosities; more preferably, the hydrophilic framework material is composed of a high viscosity and low viscosity hydrophilic framework material; more preferably, The high viscosity and low viscosity hydrophilic framework material ratio ranges from 1:0.01 to 1:10, preferably, the ratio ranges from 1:0.05 to 1:8, and more preferably, the ratio ranges from 1:0.3 to 1. : 4, most preferably, the ratio ranges from 1:1 to 1:3.
  • the present invention provides the use of the composite framework material of the present invention for preparing a drug sustained release preparation.
  • the sustained release preparation prepared has a release time of 4 to 24 hours, preferably 6 to 20 hours after administration. More preferably, it is 8 to 18 hours; preferably, the prepared sustained-release preparation (for example, the fluvastatin sodium sustained-release tablet prepared by the present invention) is tested in the 2010 edition of the Chinese Pharmacopoeia Part II Appendix XD and Appendix XC.
  • the release time in the dissolution medium of the method is less than 15% by weight, for example less than 10%; the release in the second hour is from 1% to 40%, preferably from 5 to 35%; the release in the fourth hour is 10- 70%, preferably 15-60%; release at 20 hours is 20-90%, preferably 30-88%; release at 8 hours is not less than 80%.
  • the composite framework material of the present invention can be used in sustained release preparations to avoid premature release of the pharmaceutically active ingredient.
  • the present invention also provides a composite hydrophilic skeleton material comprising a hydrophilic skeleton material of various viscosities; preferably, the composite hydrophilic skeleton material is composed of a high viscosity and low viscosity hydrophilic skeleton material;
  • the ratio of the high viscosity and low viscosity hydrophilic framework material in the composite hydrophilic framework material ranges from 1:0.01 to 1:10, preferably, the ratio ranges from 1:0.05 to 1:8, more preferably, the ratio range From 1:0.3 to 1:4, most preferably, the ratio ranges from 1:1 to 1:3.
  • the invention also provides a composite hydrophilic framework material for use in combination with a hydrophobic framework material for preparing a pharmaceutical composition, wherein the hydrophobic skeleton material and the composite hydrophilic framework material
  • the ratio of the material ranges from 1:0.01 to 1:5, preferably from 1:0.05 to 1:4, more preferably from 1:0.1 to 1:3, most preferably from 1:0.4 to 1:2, for example from 1:0.4 to 1:1.3.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the composite framework material of the present invention and one or more pharmaceutically active ingredients, preferably, the ratio of the composite framework material to the pharmaceutically active ingredient ranges from 1:0.01 to 1:8, more preferably 1:0.02 to 1:5, most preferably 1:0.03 to 1:1, such as 1:0.3 to 1:0.7.
  • the pharmaceutically active ingredient may comprise one or more substances in a total amount (in unit dosage form) of from 0.02 mg to 1 g and having the following properties:
  • the oil-water partition coefficient is from 0.05 to 10, preferably from 1 to 8.
  • the pharmaceutically active ingredient is, for example, fluvastatin, atorvastatin, lovastatin, mesalazine, paroxetine, tolterodine, daprene, gabapentin, venlafaxine, sodium divalproate, tan Sorosin, alfuzosin, carbamazepine, quetiapine, chlorpheniramine, isradipine, doxazosin, piperazine, paliperidone, prazosin or pramipexole, or A pharmaceutically acceptable salt; preferably fluvastatin, atorvastatin, lovastatin, mesalazine, paroxetine, tolterodine or pramipexole, or a pharmaceutically acceptable salt thereof.
  • the hydrophobic backbone material may be from 1% to 30%, preferably from 3% to 25%, more preferably from 5% to 22%, most preferably from 16% to 20%, based on the total weight of the pharmaceutical composition.
  • the hydrophilic backbone material may be from 0.1% to 30%, preferably from 1% to 25%, more preferably from 2% to 24%, most preferably from 8 to 23%, based on the total weight of the pharmaceutical composition. .
  • the ratio of the hydrophobic skeleton material to the hydrophilic skeleton material ranges from 1:0.01 to 1:5, preferably from 1:0.05 to 1:4, more preferably 1 From 0.1 to 1:3, most preferably from 1:0.4 to 1:2, for example from 1:0.4 to 1:1.3.
  • the hydrophilic framework material may include a low viscosity hydrophilic matrix material (for example, hydroxypropenyl cellulose having a viscosity of 100 mPa.s) and a high viscosity hydrophilic matrix material ( For example, hydroxypropionyl cellulose having a viscosity of 15,000 mPa.s.
  • the ratio of the high viscosity hydrophilic backbone material to the low viscosity hydrophilic backbone material ranges from 1:0.01 to 1:10, preferably from 1:0.05 to 1:8, more preferably It is from 1:0.1 to 1:6, most preferably from 1:0.3 to 1:4, for example from 1:1 to 1:3.
  • the pharmaceutical composition may contain a water soluble adjuvant such as lactose, sodium chloride, polyethylene glycol, and the like, from 2 to 30%, preferably from 5% to 25, based on the total weight of the pharmaceutical composition. %.
  • a water soluble adjuvant such as lactose, sodium chloride, polyethylene glycol, and the like, from 2 to 30%, preferably from 5% to 25, based on the total weight of the pharmaceutical composition. %.
  • the pharmaceutical composition may contain a water insoluble adjuvant, such as, for example, Streptoic acid 4, from 1 to 50%, preferably from 10% to 40%, based on the total weight of the pharmaceutical composition.
  • a water insoluble adjuvant such as, for example, Streptoic acid 4
  • the pharmaceutical composition may or may not contain one or more conventional pharmaceutically acceptable carriers, adjuvants or vehicles, for example: surfactants such as sodium lauryl sulfate, Tween, etc.; diluents, excipients Or fillers such as starch, calcium carbonate, calcium phosphate, lactose, microcrystalline cellulose, etc.; osmotic pressure regulators such as sucrose, sodium chloride, etc.; acid-base regulators such as citric acid, sodium bicarbonate, etc.; Calcium citrate or magnesium stearate; etc.; slip agents such as talc; film coating materials such as polyacrylic acid; and other adjuvants such as flavoring and sweetening and/or coloring agents.
  • surfactants such as sodium lauryl sulfate, Tween, etc.
  • diluents, excipients Or fillers such as starch, calcium carbonate, calcium phosphate, lactose, microcrystalline cellulose, etc.
  • the invention also provides a preparation method of the pharmaceutical composition of the invention, which comprises:
  • the hydrophilic framework material comprises a plurality of a hydrophilic backbone material having a viscosity; more preferably, the hydrophilic skeleton material is composed of a high-viscosity and low-viscosity hydrophilic skeleton material; further preferably, the high-viscosity and low-viscosity hydrophilic skeleton material
  • the ratio ranges from 1:0.01 to 1:10, preferably, the ratio ranges from 1:0.05 to 1:8, more preferably, the ratio ranges from 1:0.3 to 1:4, and most preferably, the ratio ranges from 1:1.
  • the mixing ratio with the pharmaceutically active ingredient ranges from 1:0.01 to 1:8, more preferably from 1:0.02 to 1:5, most preferably from 1:0.03 to 1:1, such as 1:0.3 to 1:0.7;
  • the pharmaceutical composition is prepared into a suitable dosage form, for example, granulated or tableted.
  • the preparation method of the pharmaceutical composition can be carried out by conventional dry granulation, wet granulation, melt granulation, or direct compression method to compress the pharmaceutically active ingredient and the auxiliary ingredient.
  • the prepared tablets can be film coated.
  • An enteric coating can also be applied to a drug having gastric irritation or a drug unstable in gastric juice.
  • Protective coatings can also be applied to drugs that are unstable to light, heat, or moisture.
  • the pharmaceutical composition can be administered in a known dosage form including, but not limited to, capsules, tablets, powders, and granules.
  • the dosage form is prepared according to techniques well known in the art of pharmaceutical formulation. For example, for tablets, it is typically prepared using direct compression techniques, multi-layer sheet techniques, and/or in-slice sheet techniques.
  • the release of the drug sustained release preparation prepared using the pharmaceutical composition of the present invention can be as long as 4 to 24 hours, preferably 6 to 20 hours, more preferably 8 to 18 hours.
  • the drug sustained release preparation prepared by using the pharmaceutical composition of the present invention (for example, the fluvastatin sodium sustained release tablet prepared by the present invention) is prescribed in Appendix XD and Appendix XC of the Chinese Pharmacopoeia, 2010.
  • the release in the dissolution medium at the 0.5th hour is less than 15% by weight, for example less than 10%; the release in the second hour is 1-40%, preferably 5-35%; the release in the 4th hour is 10-70%, Preferably, it is 15-60%; the release rate in the 6th hour is 20-90%, preferably 30-88%; and the release in the eighth hour is not less than 80%.
  • the improvement of the present invention is as follows:
  • the production process is simple, the production cost is low, and no organic solvent is used;
  • the composite framework material of the present invention can be suitably used for preparing a sustained release preparation containing a relatively large dose of a pharmaceutically active ingredient which is more soluble in water or less soluble or even insoluble; and/or
  • the composite framework material of the present invention can be suitably used to prepare a sustained release preparation containing a relatively large amount of a non-dissociated or dissociated pharmaceutically active ingredient in water.
  • the various embodiments described herein or the different preferred levels of the scheme can be arbitrarily combined unless otherwise indicated.
  • the invention is illustrated by the following examples, which are not to be construed as limiting the scope of the invention. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
  • the compounds or reagents used in the following examples are commercially available or can be prepared by conventional methods known to those skilled in the art; the experimental apparatus used is commercially available.
  • Example 1 Preparation of lovastatin sustained release tablets
  • Lovastatin was purchased from Yantai Chu Chu Pharmaceutical Co., Ltd.; glyceryl behenate was purchased from Chengdu Aikeda Chemical Reagent Co., Ltd. or Gattefosse Co., Ltd. (France); hydroxypropyl thiol cellulose was purchased from Shandong Heda Co., Ltd. Calcium phosphate was purchased from Huzhou Prospect Pharmaceutical Co., Ltd.
  • lovastatin and excipients #2 to #6 were weighed separately and placed in a high shear mixing granulator. Mix for 1 minute. A corn starch paste made of #7 was added to the mixture for granulation. The granulated granules are dried and then granulated. The whole granules are placed in a mixer. Add magnesium stearate and talc to the granules for 1 minute. The resulting mixture was tableted to a tablet having a weight of 200 mg. Tablets can also be coated with polyacrylic acid resin. Comparative Example 1: Preparation of lovastatin sustained-release tablets
  • lovastatin sustained-release tablets were prepared by the method of Example 1 without adding glyceryl behenate and increasing the amount of calcium onion to compensate for the reduction of glyceryl behenate.
  • Comparative Example 2 Preparation of lovastatin sustained-release tablets
  • lovastatin cellulose #3 and #4 were not added, and the amount of calcium inscription was increased to compensate for the reduction of hydroxypropyl ketone cellulose.
  • the sustained release of lovastatin was prepared by the method of Example 1. sheet. Lovastatin sustained release tablets release assay
  • the method is determined by reference to the Chinese Pharmacopoeia 2010 edition two appendix XD and appendix XC.
  • the dissolution medium was prepared, i.e., a solution containing 2% sodium dodecyl sulfate, pH 7.0.
  • the lovastatin sustained-release tablet was placed at 37 ° C in 900 mL of dissolution medium using a paddle method at a revolution of 50 rpm. A suitable amount of the solution was taken for a predetermined period of time, filtered, and the content was determined. The corresponding releases were determined for the products of Example 1, Comparative Examples 1 and 2, and the commercially available products (ALTOPREV®, ANDRX, USA). Table 2 summarizes the release of lovastatin sustained-release tablets (each data is the average of 6 measurements). As can be seen from Table 2, the sustained release sheet of the present invention has a more uniform and stable release over a longer period of time than the other sustained release sheet products used in the test.
  • Table 2 also shows that the sustained release tablets prepared by using the composite skeleton material of the present invention are superior to the sustained release tablets in which any single sustained release material is applied.
  • Table 2 also shows that the sustained release tablets of the present invention have similar release properties as the marketed products ALTOPREV®, although they use different framework materials and techniques.
  • fluvastatin sodium was purchased from Aurobindo Pharma Ltd, India; glyceryl behenate was purchased from Chengdu Aikeda Chemical Reagent Co., Ltd. or Gattefosse (France); hydroxypropionyl cellulose was purchased from Shandong Hada Co., Ltd.; Calcium phosphate was purchased from Huzhou Prospect Pharmaceutical Co., Ltd.
  • fluvastatin sodium and excipients #2 to #6 were weighed separately and placed in a high shear mixing granulator. Mix for 1 minute. A corn starch paste made of #7 was added to the mixture for granulation. The granulated granules are dried and then granulated. The whole granules are placed in a mixer.
  • the method is determined by reference to the Chinese Pharmacopoeia 2010 edition two appendix XD and appendix XC.
  • the fluvastatin sodium sustained-release tablet was placed at 37 ° C in 1000 mL of water using a basket method at a revolution of 50 rpm. A suitable amount of the solution was taken for a predetermined period of time, filtered, and the content was determined.
  • the product of Example 2 and the commercially available product of fluvastatin sodium sustained-release tablets were respectively measured for their respective degrees of release.
  • Table 4 summarizes the release of fluvastatin sodium sustained-release tablets (each data is the average of 6 measurements).
  • the sustained-release sheet of the present invention is comparable to the marketed product, and although the two are applied with different skeleton materials, they have similar release degrees.
  • the skeleton material and calcium phosphate shown in the following table were reset to a high shear mixing granulator in a 1:2 ratio. Mix for 1 minute. A corn starch paste was added to the mixture for granulation. The granulated granules are dried and sieved. Excessive particles that cannot pass through the l mm sieve are waste. Table 6 lists the reject rates after granulation of each framework material. Particles containing hydrophobic framework materials (e.g., insoluble or waxy sustained release framework materials) have lower reject rates, resulting in higher yields.
  • hydrophobic framework materials e.g., insoluble or waxy sustained release framework materials
  • Example 5 Dissolution of different fluvastatin sodium sustained-release tablets in pH 4.5 medium
  • the pH of the dissolution medium affects the solubility of the dissociated drug.
  • the sustained release technique has a great influence on the release rate of dissociated drugs in different pH dissolution media.
  • Fluvastatin is a dissociative drug with a pKa of 4.6.
  • a fluvastatin sodium sustained-release tablet was prepared by a conventional sustained-release technique (hydroxypropyl ketone cellulose as a skeleton material), and its composition is shown in Table 7.
  • a tablet having a weight of 305 mg was prepared in a manner similar to that of Example 2 using a corn starch paste made of #7 as a binder.
  • the conventional fluvastatin sodium sustained-release tablets, fluvastatin sodium sustained-release tablets (Example 2), and fluvastatin sodium were respectively measured by the release method of Example 2 in an acetate buffer solution of pH 4.5. Released commercially available products (Applicable®) Corresponding release. Table 8 summarizes the results of the release of these three fluvastatin sodium sustained release tablets.
  • fluvastatin sodium sustained-release tablets using conventional sustained-release techniques do not achieve the same release rate as commercially available products of fluvastatin sodium sustained-release tablets in lower pH media and do not meet the standard within 0.5 hours (ie, : less than 10%), and the fluvastatin sodium sustained-release tablet prepared by the present invention achieves a similar release rate to a commercially available product of fluvastatin sodium sustained-release tablets in a lower pH medium.
  • Fluvastatin sodium was purchased from Aurobindo Pharma Ltd, India; hydroxypropionyl cellulose was purchased from Shandong Heda Co., Ltd.; calcium phosphate was purchased from Huzhou Prospect Pharmaceutical Co., Ltd. Table 8. Release of different fluvastatin sodium sustained release tablets (in acetate buffer pH 4.5)
  • the sustained release tablets of the present invention have a stable release at pH 4.5. To the extent that it does not result in a sudden large release of the active ingredient, the sustained release tablets of the present invention are similarly released at the same time as compared to the marketed products. It is apparent that various other modifications, substitutions and changes can be made in the form of the above-described embodiments of the present invention. Those skilled in the art can understand that various features of the technical solutions of the present invention described in the present application can be appropriately combined as needed.

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Abstract

一种复合骨架材料以及包含该符合骨架材料的药物组合物，所述复合骨架材料用于制备药物缓释制剂的用途，及所述药物组合物的制备方法。所述复合骨架材料包括疏水性骨架材料和亲水性骨架材料，其中疏水性不假材料与亲水性骨架材料的比例范围为1:0.01至1:5，优选1:0.05至1:4，更有选1：0.1至1：3，最优选1:0.4至1:2，例如1：0.4至1：1.3.所述药物组合物包含所述复合骨架材料和一种或多种药物活性成分，优选地，复合骨架材料与药物活性成分的比例范围为1:0.01至1:8，更有选为1:0.02至1:5，最优选为1:0.03至1:1，例如1:0.3至1:0.7。

Description

复合骨架材料及其药物组合物 技术领域
本发明涉及药物制剂领域，更具体而言， 涉及一种复合骨架材料及 包含该骨架材料的药物组合物， 所述复合骨架材料用于制备药物緩释 制剂。 背景技术
緩释制剂，特别是片剂和胶嚢形式等，是能够减少给药次数并能控 制血中的药物浓度使药效持续的非常有用的制剂。 例如， 緩释制剂可 使布洛芬、 盐酸苯丙醇胺、 氟伐他汀、 洛伐他汀等通常需要每天服用 多次的药物改为 1天 Jll用 1-2次。
作为制备緩释制剂的方法之一，已知可将多种亲水性高分子材料作 为緩释基质。 例如中国专利 ZL 200780014499.X 和中国专利 ZL 99812081.2 中描述的氟伐他汀钠緩释片， 是将药物活性成分、 遇水后 溶胀的亲水性骨架材料和其他辅料制成的药片； 药物服用后， 水渗入 片内溶解药物活性成分、 并使亲水性骨架材料溶胀形成高粘度的凝胶； 溶解后的药物緩慢通过高粘度的凝胶释放。 目前用于緩释的制剂一般 具有高含量的亲水性高分子材料， 其遇水溶胀后易造成药物生产和储 存方面的问题， 如产生的废料较多、 素片遇水溶胀而造成薄膜包衣困 难、 或緩释片易吸水将导致一些药物储存时稳定性受影响。
作为另一方法，现有技术公开了使用渗透泵技术制备緩释制剂，例 如美国专利 5,916,595中描述的洛伐他汀緩释片。 在该方法中， 将药物 活性成分、 渗透压调节剂和其他辅料制成片芯； 由于洛伐他汀几乎不 溶于水， 其片芯内的材料需均为亲水性材料， 造成废料较多、 薄膜包 衣困难， 或易吸水从而导致药物稳定性受影响。 另外， 将片芯进行薄 膜包衣时必须使用大量有机溶剂溶解包衣材料； 使用大量有机溶剂生 产易造成环境污染及安全风险； 薄膜包衣后需要用激光制孔， 其工艺 复杂而且废品率高。
通常，含有水溶解度较小甚至不溶的药物活性成分的緩释制剂，其 辅料材料特别是緩释骨架材料均为亲水性。 另外， 对于水溶解度较大 或较小甚至不溶的药物活性成分来说， 制备含有较大剂量的该药物活 性成分的緩释制剂仍存在较大困难。
对于 pKa值较低或较高的药物活性成分来说，溶出介质的 pH对于 药物的溶解度和溶出有很大影响， 因此制备含有较大含量的该药物活 性成分的緩释制剂也是一大难题。
因此， 仍然需要开发新型緩释制剂， 以解决现有技术中存在的一种 或多种问题。 发明内容
本发明提供了一种复合骨架材料，包括疏水性骨架材料和亲水性骨 架材料， 其中疏水性骨架材料与亲水性骨架材料的比例范围为 1:0.01 至 1:5, 优选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3。
本发明提供了一种复合骨架材料的制备方法， 其包括：
将疏水性骨架材料与亲水性骨架材料以 1:0.01至 1:5, 优选 1:0.05 至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3的比例范围进行混合；
优选地， 所述亲水性骨架材料包括多种粘度的亲水性骨架材料； 更优选地， 所述亲水性骨架材料由高粘度和低粘度的亲水性骨架材料 组成； 再优选地， 所述高粘度和低粘度的亲水性骨架材料比例范围为 1:0.01至 1:10, 优选地， 比例范围为 1:0.05 至 1:8, 更优选地， 比例范 围为 1:0.3至 1:4, 最优选地， 比例范围为 1:1至 1:3。
本发明还提供了本发明所述复合骨架材料用于制备药物緩释制剂 的用途，优选地，制得的緩释制剂给药后在水中或肠道 pH (例如 pH 4-8 ) 条件下的释放时间长达 4至 24小时， 优选 6至 20小时， 更优选 8至 18 小时； 优选地， 所述制得的緩释制剂 （例如， 本发明制得的氟伐他汀钠 緩释片）在 2010版中国药典二部附录 XD和附录 XC规定的测试方法的 溶出介质中第 0.5小时的释放度小于 15%, 例如小于 10%; 第 2小时的 释放度为 1-40%, 优选 5-35%; 第 4小时的释放度为 10-70%, 优选为 15-60%; 第 6小时的释放度为 20-90%, 优选 30-88%; 第八小时的释放 度不少于 80%。 本发明还提供了一种复合亲水性骨架材料，其包括多种粘度的亲水 性骨架材料； 优选地， 复合亲水性骨架材料由高粘度和低粘度的亲水 性骨架材料组成； 优选地， 复合亲水性骨架材料中高粘度和低粘度的 亲水性骨架材料比例范围为 1:0.01至 1:10,优选地， 比例范围为 1:0.05 至 1:8, 更优选地， 比例范围为 1:0.3至 1:4, 最优选地， 比例范围为 1:1 至 1:3。
本发明还提供一种复合亲水性骨架材料用于与疏水性骨架材料组 合制备药物组合物的用途， 其中疏水性骨架材料与复合亲水性骨架材 料的比例范围为 1:0.01至 1:5, 优选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2。
本发明还提供了一种药物组合物，其包含本发明所述的复合骨架材 料和一种或多种药物活性成分， 优选地， 复合骨架材料与药物活性成 分的比例范围为 1:0.01至 1:8,更优选为 1:0.02至 1:5,最优选为 1:0.03 至 1:1 , 例如为 1:0.3至 1:0.7。
本发明还提供了一种本发明所述药物组合物的制备方法， 其包括：
1 )将疏水性骨架材料与亲水性骨架材料混合， 得到一种复合骨架材 料，其中疏水性骨架材料与亲水性骨架材料的混合比为 1:0.01至 1:5,优 选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3;
2 )将所述复合骨架材料、 一种或多种药物活性成分和任选的一种或 多种常规的可药用载体、 助剂或介质混合， 得到一种药物组合物， 其中 复合骨架材料与药物活性成分的混合比优选为 1:0.01至 1:8, 更优选为 1:0.02至 1:5, 最优选为 1:0.03至 1:1 , 例如 1:0.3至 1:0.7; 和
3 )任选地， 将所述药物组合物制备成合适的剂型， 例如进行制粒 或压片。 具体实施方式
本发明提供了一种复合骨架材料，包括疏水性骨架材料和亲水性骨 架材料， 其中疏水性骨架材料与亲水性骨架材料的比例范围为 1:0.01 至 1:5, 优选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3。 疏水性骨架材料可以包括按任意比例混合的两种以上具有不同熔 点、 不同酸值、 或在乙醇中不同的溶解度的不同疏水性骨架材料。
亲水性骨架材料可以包括按任意比例混合的两种以上不同亲水性 骨架材料。
在本发明的一个优选实施方案中， 本发明提供了一种复合骨架材 料， 其由疏水性骨架材料和亲水性骨架材料组成， 其中疏水性骨架材 料与亲水性骨架材料的比例范围为 1:0.01至 1:5, 优选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3。
除非另有说明， 本文中所述的比例或百分比均按重量计。
本文所使用的术语 "疏水性骨架材料"包括不溶性骨架材料和生物 降解骨架材料， 其中不溶性骨架材料和生物降解骨架材料如下文所定 义。 优选地， 疏水性骨架材料的亲水亲油平衡（HLB )值小于 11 , 优 选小于 9, 更优选小于 7。 优选地， 疏水性骨架材料的数均分子量在约 100 道尔顿至约 7,000,000 道尔顿范围内， 更优选约 200 道尔顿至约 5,000,000道尔顿范围内， 再更优选约 250道尔顿至约 3,000,000道尔顿 范围内。
本文中所使用的术语 "不溶性骨架材料"指不溶于水的高分子材料 等。 其实例包括： 乙基纤维素、 聚乙烯、 聚丙烯、 聚硅氧烷、 聚氯乙 烯、 乙烯 -醋酸乙烯共聚物、 聚曱基丙烯酸曱酯， 或其混合物。
本文中所使用的术语 "生物降解骨架材料" 包括低熔点（例如熔点 小于 200°C )、 不溶于水但溶于有机溶剂 （例如氯仿或丙酮） 或低亲水 亲油平衡值 （例如， HLB值小于 9 ) 的生物降解骨架材料。 其实例包 括蜡质、 脂肪酸及其酯等物质， 如 C16-C22脂肪酸、 巴西棕榈蜡（简称
"巴蜡，，：)、 C16-C22脂肪酸的甘油酯、 C16-C22烷基醇， 蜂蜡、 合成蜡、 氢化植物油、 或其混合物； 优选巴西棕榈蜡、 C16-C22脂肪酸的甘油酯 (包括 C16-C22脂肪酸甘油酯、 C16-C22脂肪酸甘油二酯和 C16-C22脂肪 酸甘油单酯）， C16-C22脂肪酸的甘油酯选自以下至少一种： 山嵛酸甘油 酯、 山嵛酸甘油二酯、 山嵛酸甘油单酯， 及其混合物。
本文中所使用的术语 "亲水性骨架材料"指遇水或水溶液如消化液 膨胀， 形成凝胶屏障的骨架材料。 其实例包括： 天然植物或动物胶， 如海藻酸纳、 琼脂、 西黄耆胶、 黄原胶、 果胶、 瓜耳胶等； 纤维素衍 生物， 如曱基纤维素（MC )、 羟乙基纤维素（HEC )、 羟乙基曱基纤维 素（HEMC )、 羟丙基纤维素（HPC )、 羟丙曱基纤维素（HPMC )、 羧 曱基纤维素钠（SCMC )等； 非纤维素多糖， 如壳多糖、 半乳糖甘露聚 糖、 葡聚糖等； 乙烯聚合物和丙烯酸树脂， 如聚环氧乙烷、 交联聚乙 烯吡咯烷酮、 聚乙烯醇和聚羧乙烯等。 优选地， 所述亲水性骨架材料 包括但是不限于羟丙曱基纤维素、 羟丙基纤维素、 羟乙基纤维素、 羟 曱基纤维素钠、 海藻酸钠、 壳多糖、 聚环氧乙烷等遇水后溶胀的解离 型或非解离型高分子材料。 更优选地， 所述亲水性骨架材料为羟丙曱 基纤维素、 羟丙基纤维素、 羟乙基纤维素、 羟曱基纤维素钠。 优选地， 本发明中所使用的亲水性骨架材料的数均分子量在约 50 道尔顿至约 9,000,000道尔顿范围内，优选约 50,000道尔顿至约 8,000,000道尔顿范 围内，更优选约 90,000道尔顿至约 7,000,000道尔顿范围内。具体来说， 本发明中所使用的亲水性骨架材料中的纤维素衍生物的数均分子量优 选在约 50道尔顿至约 2,500,000道尔顿范围内， 更优选约 70道尔顿至 约 2,000,000道尔顿范围内， 最优选约 80道尔顿至约 1,800,000道尔顿 范围内。 本发明中所使用的亲水性骨架材料中的聚环氧乙烷的数均分 子量优选在约 50,000道尔顿至约 8,000,000道尔顿范围内， 更优选约 100,000道尔顿至约 7,000,000道尔顿范围内。
优选地，所述亲水性骨架材料包括高粘度的亲水性骨架材料和低粘 度的亲水性骨架材料； 优选地， 其中高粘度的亲水性骨架材料与低粘 度的亲水性骨架材料的比例范围为 1:0.01至 1:10,优选为 1:0.05至 1:8, 更优选为 1:0.1至 1:6, 最优选为 1:0.3至 1:4, 例如为 1:1至 1:3。
优选地， 所述高粘度的亲水性骨架材料的实例为粘度范围为 4,000 至 100,000 mPa.s 的亲水性骨架材料， 例如羟丙曱基纤维素 75HD15000(或 K15M)。
优选地， 所述低粘度的亲水性骨架材料的实例为粘度不大于 1,000 mPa.s的亲水性骨架材料，例如羟丙曱基纤维素 75HD10(K或 K100LV )。
本文中所使用的术语"粘度"是指在 20Ό时， 2 g物质溶解于 100 ml 蒸馏水中所得的溶液的粘度（单位为 mPa.s )。
本文中所使用的术语 "低粘度" 是指亲水性骨架材料的粘度为 20-2,000 mPa.s , 优选为 20-800 mPa.s , 更优选为 20-600 mPa.s。 本文中所使用的术语 "高粘度" 是指亲水性骨架材料的粘度为
3,000-500,000 mPa.s , 优选为 3,500-300,000 mPa.s , 更优选为 4,000-200,000 mPa.s„
本发明提供了一种复合骨架材料的制备方法， 其包括：
将疏水性骨架材料与亲水性骨架材料以 1:0.01至 1:5, 优选 1:0.05 至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3的比例范围进行混合；
优选地，所述亲水性骨架材料包括多种粘度的亲水性骨架材料； 更 优选地，所述亲水性骨架材料由高粘度和低粘度的亲水性骨架材料 组成；再优选地，所述高粘度和低粘度的亲水性骨架材料比例范围 为 1:0.01至 1:10, 优选地， 比例范围为 1:0.05 至 1:8, 更优选地， 比例范围为 1:0.3至 1:4, 最优选地， 比例范围为 1:1至 1:3。
本发明提供了本发明所述复合骨架材料用于制备药物緩释制剂的 用途， 优选地， 所述制得的緩释制剂给药后的释放时间长达到 4至 24 小时， 优选 6至 20小时， 更优选 8至 18小时； 优选地， 所述制得的緩 释制剂 （例如， 本发明制得的氟伐他汀钠緩释片）在 2010版中国药典 二部附录 XD和附录 XC规定的测试方法的溶出介质中第 0.5小时的释放 度小于重量百分比 15%,例如小于 10%;第 2小时的释放度为 1%至 40%, 优选 5-35%; 第 4小时的释放度为 10-70%, 优选为 15-60%; 第 6小时 的释放度为 20-90%, 优选 30-88%; 第八小时的释放度不少于 80%。
本发明的复合骨架材料可用于緩释制剂中， 以避免药物活性成分过 早大量释放。 本发明还提供了一种复合亲水性骨架材料，其包括多种粘度的亲水 性骨架材料； 优选地， 复合亲水性骨架材料由高粘度和低粘度的亲水 性骨架材料组成； 优选地， 复合亲水性骨架材料中高粘度和低粘度的 亲水性骨架材料比例范围为 1:0.01至 1:10,优选地， 比例范围为 1:0.05 至 1:8, 更优选地， 比例范围为 1:0.3至 1:4, 最优选地， 比例范围为 1:1 至 1:3。
本发明还提供一种复合亲水性骨架材料用于与疏水性骨架材料组 合制备药物组合物的用途， 其中疏水性骨架材料与复合亲水性骨架材 料的比例范围为 1:0.01至 1:5, 优选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3。
本发明还提供了一种药物组合物，其包含本发明所述的复合骨架材 料和一种或多种药物活性成分， 优选地， 复合骨架材料与药物活性成 分的比例范围为为 1:0.01至 1:8,更优选为 1:0.02至 1:5,最优选为 1:0.03 至 1:1 , 例如 1:0.3至 1:0.7。
所述药物活性成分可包括一种或多种物质，总含量（在单位剂型中） 为 0.02 mg至 l g, 并具有以下性质：
在水（37Ό ) 中溶解度为 0 mg/mL至溶解度超过 50 mg/mL; 和 / 或在 pH 6.8 (37Ό)的緩冲溶液中溶解度为 0 mg/mL至溶解度超过 50 mg/mL; 和 /或在 pH 1.2 (37"C)的緩冲溶液中溶解度为 0 mg/mL至溶解 度超过 50 mg/mL; 和 /或
属于非解离型至解离型药物或其药学上可接受的盐；对于解离型药 物， 其在水中 pKa为 2至 14, 优选为 4至 12; 和 /或
油水分配系数为 0.05至 10, 优选 1至 8。
所述药物活性成分例如为氟伐他汀、 阿托伐他汀、 洛伐他汀、 美沙 拉嗪、 帕罗西汀、 托特罗定、 达方吡啶、 加巴喷丁、 文拉法新、 双丙 戊酸钠、 坦索罗辛、 阿夫唑嗪、 卡马西平、 喹硫平、 氯苯那敏、 伊拉 地平、 多沙唑嗪、 哌曱酯、 帕潘立酮、 哌唑嗪或普拉克索， 或其药学 上可接受的盐； 优选为氟伐他汀、 阿托伐他汀、 洛伐他汀、 美沙拉嗪、 帕罗西汀、 托特罗定或普拉克索， 或其药学上可接受的盐。
在一个具体实施方案中， 所述疏水性骨架材料可以基于药物组合物 总重量计为 1%-30%,优选 3%-25%, 更优选 5%-22%, 最优选 16-20%。
在一个具体实施方案中， 所述亲水性骨架材料可以基于药物组合物 总重量计为 0.1%-30%,优选 1%-25%,更优选 2%-24%,最优选 8-23%。
在本发明药物组合物的一个具体实施方案中， 所述疏水性骨架材料 与亲水性骨架材料的比例范围为 1:0.01至 1:5,优选 1:0.05至 1:4, 更优 选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3。
在一个具体实施方案中， 所述亲水性骨架材料可以包括低粘度的亲 水性骨架材料（例如粘度为 100 mPa.s的羟丙曱基纤维素）和高粘度的亲 水性骨架材料（例如粘度为 15000 mPa.s的羟丙曱基纤维素） 。 在一个具体实施方案中， 所述高粘度的亲水性骨架材料与低粘度的 亲水性骨架材料的比例范围为 1:0.01至 1:10, 优选为 1:0.05至 1:8, 更 优选为 1:0.1至 1:6, 最优选为 1:0.3至 1:4, 例如为 1:1至 1:3。
在一个具体实施方案中， 所述药物组合物可含有水溶性辅料， 例如 乳糖、 氯化钠、 聚乙二醇等， 基于药物组合物总重量计为 2至 30%, 优 选为 5%-25%。
在一个具体实施方案中， 所述药物组合物可含有水不溶性辅料， 例 如碑酸 4 , 基于药物组合物总重量计为 1至 50%, 优选为 10%-40%。
所述药物组合物可包含也可不含有一种或多种常规的可药用载体、 助剂或介质， 例如： 表面活性剂如十二烷基硫酸钠、 吐温等； 稀释剂、 赋形剂或填充剂如淀粉、 碳酸钙、 磷酸钙、 乳糖、 微晶纤维素等； 渗透 压调节剂如蔗糖， 氯化钠等； 酸碱调节剂如枸橼酸、 碳酸氢钠等； 润滑 剂如硬脂酸钙或硬脂酸镁等； 助滑剂如滑石粉； 薄膜包衣材料如聚丙烯 酸树酯； 以及其他辅助剂如香味剂和甜味剂和 /或着色剂。
本发明还提供一种本发明所述药物组合物的制备方法， 其包括：
1 )将疏水性骨架材料与亲水性骨架材料混合， 得到一种复合骨架材 料， 其中疏水性骨架材料与亲水性骨架材料的混合比范围为 1:0.01 至 1:5, 优选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3;优选地，所述亲水性骨架材料包括多种粘度的亲 水性骨架材料； 更优选地， 所述亲水性骨架材料由高粘度和低粘度的 亲水性骨架材料组成； 再优选地， 所述高粘度和低粘度的亲水性骨架 材料比例范围为 1:0.01至 1:10, 优选地， 比例范围为 1:0.05 至 1:8, 更优选地， 比例范围为 1:0.3至 1:4, 最优选地， 比例范围为 1:1至 1:3;
2 )将所述复合骨架材料、 一种或多种药物活性成分和任选的一种或 多种常规的可药用载体、 助剂或介质混合， 得到一种药物组合物， 其中 复合骨架材料与药物活性成分的混合比范围为 1:0.01至 1:8, 更优选为 1:0.02至 1:5, 最优选为 1:0.03至 1:1 , 例如 1:0.3至 1:0.7; 和
3 )任选地， 将所述药物组合物制备成合适的剂型， 例如进行制粒 或压片。
所述药物组合物的制备方法可以应用常规的干法制粒、 湿法制粒、 熔融法制粒、 或直接压片法等方法将药物活性成分和辅料成分压制成 片。制成的药片可以进行薄膜包衣。对于具有胃刺激性的药物或在胃液 中不稳定的药物也可以进行肠溶包衣。 对于光、 热、 或水分不稳定的 药物也可以进行保护性包衣。
因此， 所述药物组合物可以制成已知剂型给药， 所述剂型包括但不 限于， 胶嚢剂、 片剂、 粉剂和颗粒剂。 所述剂型是根据药物制剂领域中 所熟知的技术而制得。 例如， 对于片剂， 通常使用直接压片技术、 多层 片技术和 /或片中片技术进行制备。
在一个具体实施方案中， 使用本发明的药物组合物制备的药物緩释 制剂在体外的释放可以长达到 4至 24小时，优选 6至 20小时， 更优选 8 至 18小时。 在一个具体实施方案中， 使用本发明的药物组合物制备的药物緩释 制剂（例如， 本发明制得的氟伐他汀钠緩释片）在2010版中国药典二部 附录 XD和附录 XC规定的溶出介质中第 0.5小时的释放度小于重量百分 比 15%, 例如小于 10%; 第 2小时的释放度为 1-40%, 优选 5-35%; 第 4小时的释放度为 10-70%,优选为 15-60%;第 6小时的释放度为 20-90%, 优选 30-88%; 第八小时的释放度不少于 80%。 本发明与现有技术相比， 其改进在于：
1 )降低了遇水溶胀的亲水性骨架材料含量， 因而降低了水分对药物 制剂质量的影响； 和 /或
2 ) 当使用本发明所述复合骨架材料制备药物緩释制剂时， 其生产工 艺简单、 生产成本低、 不使用有机溶剂； 和 /或
3 )本发明所述复合骨架材料可以适用于制备含有较大剂量的、 在 水中溶解度较大、 或较小溶解度甚至不溶的药物活性成分的緩释制剂； 和 /或
4 ) 本发明所述复合骨架材料可以适用于制备含有较大剂量的在水 中非解离型或解离型药物活性成分的緩释制剂。 本文述及的各实施方案或者不同优选级别的方案， 除非另有说明均 可任意组合。 通过以下实施例详细说明本发明， 但不应将此理解为本发明主 题的范围仅限于以下实施例。 凡基于本发明上述内容所实现的技术 均属于本发明的范围。 以下实施例中使用的化合物或试剂可通过商 业途径购得， 或者通过本领域技术人员已知的常规方法制备得到； 所使用的实验仪器可通过商业途径购得。 实施例
实施例 1: 洛伐他汀緩释片制备
表 1. 洛伐他汀緩释片组成
Figure imgf000011_0001
洛伐他汀购自烟台只楚药业有限公司；山嵛酸甘油酯购自成都艾科 达化学试剂有限公司或 Gattefosse公司 （法国）； 羟丙曱基纤维素均购 自山东赫达股份有限公司； 磷酸钙购自湖州展望药业有限公司。
按表 1中的组成， 将洛伐他汀和辅料 #2至 #6分别称重后置于高剪 切混合制粒机。 混合 1分钟。 在混合物中加入由 #7制成的玉米淀粉糊 进行制粒。 制粒后的颗粒烘干后整粒。 整粒后的颗粒置于混合机。 在 颗粒中加入硬酯酸镁和滑石粉混合 1 分钟。 将所得混合物用压片机制 成重量为 200 mg的药片。 药片也可以用聚丙烯酸树酯包衣。 对比例 1: 洛伐他汀緩释片制备
按表 1中的组成， 不加入山嵛酸甘油酯，增加碑酸钙的用量以补偿 山嵛酸甘油酯减少部分， 用实施例 1的方法制备洛伐他汀緩释片。 对比例 2: 洛伐他汀緩释片制备
按表 1 中的组成， 不加入羟丙曱基纤维素 #3和 #4, 增加碑酸钙的 用量以补偿羟丙曱基纤维素减少部分， 用实施例 1 的方法制备洛伐他 汀緩释片。 洛伐他汀緩释片释放度测定
参照中国药典 2010年版二部附录 XD和附录 XC进行所述方法测 定。
配制溶出介质， 即： 含有 2%十二烷基硫酸钠的碑酸盐溶液， pH 为 7.0。
将洛伐他汀緩释片置于 37°C , 900 mL的溶出介质， 使用桨法， 转 数为 50 rpm。 在预定时间内取适量溶液， 过滤， 测定含量。 将实施例 1、 对比例 1和 2的产品以及市售产品 （ ALTOPREV®, 美国 ANDRX 公司）分别测定其相应的释放度。 表 2 总结了洛伐他汀緩释片释放度 结果 (每个数据为 6个测量数据的平均值)。 从表 2可知， 本发明的緩释 片与该试验中所用的其他緩释片产品相比在更长时间内具有更均匀稳 定的释放度。表 2也表明应用本发明的复合骨架材料所制备的緩释片优 于应用其中任何单一緩释材料的緩释片。 表 2也表明本发明的緩释片 与上市产品 ALTOPREV®相比， 尽管二者应用不同的骨架材料和技术， 但具有类似的释放度。
表 2. 洛伐他汀緩释片释放度
实施例 1 对比例 1 对比例 2 ALTOPREV® 时间 （小时）
(%) (%) (%) (%)
0.5 0.7 10 22 0.2
2 8 20 30 5
3 15 45 50 12
4 19 60 65 22
6 34 90 90 45
8 48 98 - 62
12 63 - - 80
16 78 - - 82
20 90 - - 83
实施例 2: 氟伐他汀钠緩释片制备
表 3. 氟伐他汀钠緩释片的组成
Figure imgf000013_0001
在实施例中， 氟伐他汀钠购自印度 Aurobindo Pharma Ltd公司； 山嵛酸甘油酯购自成都艾科达化学试剂有限公司或 Gattefosse (法国）； 羟丙曱基纤维素均购自山东赫达股份有限公司； 磷酸钙购自湖州展望 药业有限公司。 按表 3中的组成， 将氟伐他汀钠和辅料 #2至 #6分别称重后置于高 剪切混合制粒机。 混合 1分钟。 在混合物中加入由 #7制成的玉米淀粉 糊进行制粒。 制粒后的颗粒烘干后整粒。 整粒后的颗粒置于混合机。 在颗粒中加入硬酯酸镁和滑石粉混合 1 分钟。 将所得混合物用压片机 制成重量为 305 mg 的药片。 药片也可以用聚丙烯酸树酯包衣。 氟伐他汀钠緩释片释放度测定
参照中国药典 2010年版二部附录 XD和附录 XC进行所述方法测 定。
将氟伐他汀钠緩释片置于 37°C , 1000 mL的水， 使用篮法， 转数 为 50 rpm。 在预定时间内取适量溶液， 过滤， 测定含量。 将实施例 2 的产品以及氟伐他汀钠緩释片市售产品（来适可⑧， 北京诺华制药有限 公司） 分别测定其相应的释放度。 表 4 总结了氟伐他汀钠緩释片释放 度结果 (每个数据为 6个测量数据的平均值)。 从表 4可知， 本发明的緩 释片与上市产品来适可相比， 尽管二者应用不同的骨架材料， 但具有类 似的释放度。
表 4. 氟伐他汀钠緩释片的释放度
Figure imgf000014_0001
实施例 3: 骨架材料溶胀度
将 1 g的如下表所示的各骨架材料分别置于 100 mL的烧杯， 加入 80 mL 纯化水。 测定骨架材料溶胀度 （溶胀高度变化除以初始高度 X100 )o 结果见表 5。
表 5. 骨架材料溶胀速度 骨架材料 山 嵛 酸 巴蜡 羟 乙基纤 羟丙 甲基 黄原胶 聚环氧乙烷 甘油酯 维素 纤维素
溶胀度 （％ ) 0 0 600 400 280 250
结果显示， 山嵛酸甘油酯和巴蜡溶胀度最低，黄原胶和聚氧化乙烯 次之。 添加有低溶胀度的材料的緩释骨架材料不易吸水造成产品溶胀 变形， 也表明含有该低溶胀度的材料的緩释骨架材料的緩释机制不同 于吸水溶胀的緩释骨架材料。 实施例 4: 骨架材料与制粒废品率的关系
将如下表所示的骨架材料和磷酸钙按 1:2 比例称重置于高剪切混 合制粒机。 混合 1 分钟。 在混合物中加入玉米淀粉糊进行制粒。 制粒 后的颗粒烘干后整粒过筛。 不能通过 l mm筛的过大颗粒为废料。 表 6 列出了各骨架材料制粒后的废品率。 含疏水骨架材料（如不溶性或蜡 质緩释骨架材料） 的颗粒废品率较低， 从而取得较高的产率。
表 6.骨架材料制粒后的废品率
Figure imgf000015_0001
实施例 5: pH 4.5介质中不同氟伐他汀钠緩释片的溶出度
溶出介质的 pH影响解离型药物的溶解度。緩释技术对解离型药物在 不同 pH溶出介质的释放度影响很大。 氟伐他汀属于解离型药物，其 pKa 为 4.6。
采用常规緩释技术（羟丙曱基纤维素为骨架材料）制备成氟伐他汀 钠緩释片， 其组成见表 7。 以由 #7制成的玉米淀粉糊为粘合剂， 以类似 实施例 2的方法制备重量为 305 mg的片剂。 以实施例 2的释放度测定方 法在 pH 4.5的醋酸盐緩冲溶液中分别测定氟伐他汀钠常规緩释片， 氟伐 他汀钠緩释片 （实施例 2 ), 以及氟伐他汀钠緩释片市售产品（来适可 ® ) 相应的释放度。 表 8总结了这三种氟伐他汀钠緩释片释放度结果。 结果 表明使用常规緩释技术的氟伐他汀钠緩释片在较低 pH 的介质中无法达 到与氟伐他汀钠緩释片市售产品一致的释放度并在 0.5 小时内达不到标 准（即： 少于 10% ), 而本发明制得的氟伐他汀钠緩释片在较低 pH的介 质中达到与氟伐他汀钠緩释片市售产品类似的释放度。
表 7. 氟伐他汀常规緩释片的组成
Figure imgf000016_0001
氟伐他汀钠购自印度 Aurobindo Pharma Ltd公司； 羟丙曱基纤维 素均购自山东赫达股份有限公司； 磷酸钙购自湖州展望药业有限公司。 表 8. 不同氟伐他汀钠緩释片的释放度 (在 pH 4.5的醋酸盐緩冲溶液中）
Figure imgf000016_0002
从表 8可知， 在 pH 4.5时， 本发明的緩释片具有均勾稳定的释放 度， 不会导致活性成分的突然大量释放， 同时与上市产品来适可相比， 本发明的緩释片在相同时间的释放度类似。 显然， 根据本发明的上述内容， 按照本领域的普通技术知识和惯用 手段， 在不脱离本发明上述基本技术思想前提下， 还可以进行其它多种 形式的修改、 替换或变更。 本领域人员能够理解， 本申请所描述的本发 明技术方案的各个特征均可根据需要进行适当的组合。

Claims

权 利 要 求 书
1. 一种复合骨架材料， 包括疏水性骨架材料和亲水性骨架材料， 其中疏水性骨架材料与亲水性骨架材料的比例范围为 1:0.01至 1:5,优 选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1
2. 权利要求 1的复合骨架材料， 其中，
所述疏水性骨架材料包括不溶性骨架材料或生物降解骨架材料，其 中，
不溶性骨架材料包括： 乙基纤维素、 聚乙烯、 聚丙烯、 聚氯乙烯、 聚硅氧烷、 乙烯 -醋酸乙烯共聚物、 聚曱基丙烯酸曱酯， 或其混合物； 生物降解骨架材料包括： c16-c22脂肪酸、 巴西棕榈蜡、 c16-c22脂 肪酸的甘油酯、 c16-c22烷基醇、 蜂蜡、 合成蜡、 氢化植物油， 或其混 合物； 优选巴西棕榈蜡、 c16-c22脂肪酸的甘油酯， 其为选自 c16-c22 脂肪酸甘油三酯、 c16-c22脂肪酸甘油二酯和 c16-c22脂肪酸甘油单酯的 至少一种； 优选地， 所述 c16-c22脂肪酸的甘油酯选自以下至少一种： 山嵛酸甘油酯、 山嵛酸甘油二酯、 山嵛酸甘油单酯， 及其混合物； 和 / 或
亲水性骨架材料包括： 羟丙曱基纤维素、羟丙基纤维素、羟乙基纤 维素、 羟乙基曱基纤维素、 羟曱基纤维素钠、 海藻酸钠、 壳多糖、 半 乳糖甘露聚糖、 葡聚糖、 聚环氧乙烷、 交联聚乙烯吡咯烷酮、 聚乙烯 醇和聚羧乙烯、 琼脂、 西黄耆胶、 黄原胶、 果胶或瓜耳胶。
3. 权利要求 1 的复合骨架材料， 其中所述亲水性骨架材料包括多 种粘度的亲水性骨架材料； 优选地， 所述亲水性骨架材料由高粘度和 低粘度的亲水性骨架材料组成；
优选地，其中高粘度的亲水性骨架材料与低粘度的亲水性骨架材料 的比例范围为 1:0.01至 1:10, 优选为 1:0.05至 1:8, 更优选为 1:0.1至 1:6, 最优选为 1:0.3至 1:4, 例如为 1:1至 1:3;
优选地,
其中高粘度的亲水性骨架材料为粘度范围为 4,000 至 100,000 mPa.s 的亲水性骨架材料， 例如羟丙曱基纤维素 75HD15000 (或 K15M ); 其中低粘度的亲水性骨架材料为粘度不大于 1,000 mPa.s的亲水性 骨架材料， 例如羟丙曱基纤维素 75HD100 (或 K100LV )。
4. 权利要求 1-3中任一项的复合骨架材料的制备方法，， 其包括： 将疏水性骨架材料与亲水性骨架材料以 1:0.01至 1:5, 优选 1:0.05 至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3的比例范围进行混合；
优选地， 所述亲水性骨架材料包括多种粘度的亲水性骨架材料； 更优选地， 所述亲水性骨架材料由高粘度和低粘度的亲水性骨架材料 组成； 再优选地， 所述高粘度和低粘度的亲水性骨架材料比例范围为 1:0.01至 1:10, 优选地， 比例范围为 1:0.05 至 1:8, 更优选地， 比例范 围为 1:0.3至 1:4, 最优选地， 比例范围为 1:1至 1:3。
5. 一种复合亲水性骨架材料， 其包括多种粘度的亲水性骨架材料； 优选地， 复合亲水性骨架材料由高粘度和低粘度的亲水性骨架材料组 成； 优选地， 复合亲水性骨架材料中高粘度和低粘度的亲水性骨架材 料比例范围为 1:0.01至 1:10, 优选地， 比例范围为 1:0.05至 1:8, 更优 选地， 比例范围为 1:0.3至 1:4, 最优选地， 比例范围为 1:1至 1:3。
6. 权利要求 5的复合亲水性骨架材料用于与疏水性骨架材料组合 制备药物组合物的用途， 其中疏水性骨架材料与复合亲水性骨架材料 的比例范围为 1:0.01至 1:5,优选 1:0.05至 1:4, 更优选为 1:0.1至 1:3, 最优选为 1:0.4至 1:2, 例如为 1:0.4至 1:1.3。
7. 权利要求 1-3中任一项的复合骨架材料或权利要求 5的复合亲 水性骨架材料用于制备药物緩释制剂的用途， 优选地， 所述制得的緩 释制剂给药后在水中或肠道 pH (例如 pH 4-8 )条件下的释放时间长达 到 4至 24小时， 优选 6至 20小时， 更优选 8至 18小时； 优选地， 所述 制得的緩释制剂 （例如， 本发明制得的氟伐他汀钠緩释片）在 2010版 中国药典二部附录 XD和附录 XC规定的测试方法的溶出介质中第 0.5 小时的释放度小于重量百分比 15%, 例如小于 10%; 第 2小时的释放度 为 1-40%, 优选 5-35%; 第 4小时的释放度为 10-70%, 优选为 15-60%; 第 6小时的释放度为 20-90%, 优选 30-88%; 第八小时的释放度不少于 80%。
8. 一种药物组合物， 其包含权利要求 1-4 中任一项的复合骨架材 料和一种或多种药物活性成分， 优选地， 复合骨架材料与药物活性成 分的比例范围为 1:0.01至 1:8,更优选为 1:0.02至 1:5,最优选为 1:0.03 至 1:1 , 例如为 1:0.3至 1:0.7;
优选地， 药物活性成分包括一种或多种物质， 药物活性成分总含量 为 0.02 mg至 l g, 并具有以下性质：
37Ό水中溶解度为 0 mg/mL至 50 mg/mL; 和 /或在 pH 6.8 (37 °C ) 的緩冲溶液中溶解度为 0 mg/mL至溶解度至 50 mg/mL;和 /或在 pH 1.2 (37Ό )的緩冲溶液中溶解度为 0 mg/mL至溶解度至 50 mg/mL; 和 /或 属于非解离型至解离型药物或其药学上可接受的盐，解离型药物或 其药学上可接受的盐在水中 pKa为 2至 14, 优选为 4至 12; 和 /或
油水分配系数为油水分配系数为 0.05至 10, 优选为 1至 8;
优选地， 药物活性成分包括氟伐他汀、 洛伐他汀、 阿托伐他汀、 美 沙拉嗪、 帕罗西汀、 托特罗定、 达方吡啶、 加巴喷丁、 文拉法新、 双 丙戊酸钠、 坦索罗辛、 阿夫唑嗪、 卡马西平、 喹硫平、 氯苯那敏、 伊 拉地平、 多沙唑嗪、 哌曱酯、 帕潘立酮、 哌唑嗪、 或普拉克索， 或其 药学上可接受的盐； 优选为氟伐他汀、 洛伐他汀、 帕罗西汀、 托特罗 定或普拉克索， 或其药学上可接受的盐。
9.权利要求 8的药物组合物，其还包含一种或多种常规的可药用载 体、 助剂或介质， 如稀释剂或赋形剂或填充剂、 渗透压调节剂、 酸碱调 节剂、 表面活性剂、 润滑剂、 助滑剂、 薄膜包衣剂， 以及其他辅助剂如 香味剂和甜味剂和 /或着色剂；
优选地， 疏水性骨架材料的含量基于药物组合物总重量计为 1%-30% , 优选 3%-25%, 更优选 5%-22% , 最优选 16-20%; 和 /或
亲水性骨架材料的含量基于药物组合物总重量计为 0.1%-30%, 优 选 1%-25% , 更优选 2%-24%, 最优选 8-23%。
10.权利要求 8-9中任一项的药物组合物的制备方法， 其包括 1 )将 疏水性骨架材料与亲水性骨架材料混合， 得到一种复合骨架材料， 其中 疏水性骨架材料与亲水性骨架材料的混合比为 1:0.01至 1:5,优选 1:0.05 至 1:4, 更优选为 1:0.1至 1:3 , 最优选为 1:0.4至 1:2 , 例如为 1:0.4至 1:1.3; 优选地， 所述亲水性骨架材料包括多种粘度的亲水性骨架材料; 更优选地， 所述亲水性骨架材料由高粘度和低粘度的亲水性骨架材料 组成； 再优选地， 所述高粘度和低粘度的亲水性骨架材料比例范围为
1:0.01至 1:10, 优选地， 比例范围为 1:0.05 至 1:8, 更优选地， 比例范 围为 1:0.3至 1:4, 最优选地， 比例范围为 1:1至 1:3; 2 )将所述复合骨 架材料、 一种或多种药物活性成分和任选的一种或多种常规的可药用载 体、 助剂或介质混合， 得到一种药物组合物， 其中复合骨架材料与药物 活性成分的混合比优选为 1:0.01至 1:8, 更优选为 1:0.02至 1:5, 最优选 为 1:0.03至 1:1 , 例如为 1:0.3至 1:0.7; 和 3 )任选地， 将所述药物组 合物制备成合适的剂型， 例如进行制粒或压片。
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CN103800280A (zh) 2014-05-21
US20160074331A1 (en) 2016-03-17
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