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)
Chinese (zh)
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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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Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104069502B (zh) * 2013-03-29 2018-02-16 北京罗诺强施医药技术研发中心有限公司 复合骨架材料及其药物组合物
CN104055792A (zh) * 2014-07-10 2014-09-24 北京人福军威医药技术开发有限公司 西地碘治疗中耳炎的用途
CN104208035A (zh) * 2014-08-22 2014-12-17 苏州大学 一种含有伊拉地平的缓释片剂
CN104606162B (zh) * 2015-01-07 2017-03-29 海南康虹医药科技开发有限公司 一种盐酸普拉克索缓释制剂及其制备方法
CN106474084B (zh) * 2015-08-28 2020-12-11 江苏先声药业有限公司 一种盐酸普拉克索缓释制剂及其制备方法
CN106983729B (zh) * 2016-01-21 2021-02-26 北京北大维信生物科技有限公司 普拉克索缓释片及制备方法
CN106983728B (zh) * 2016-01-21 2021-03-02 北京北大维信生物科技有限公司 普拉克索缓释片及制备方法
CN110917164B (zh) * 2019-12-17 2022-03-29 南京康川济医药科技有限公司 一种苯磺酸米洛巴林缓释片及其制备方法
CN111296505A (zh) * 2020-04-01 2020-06-19 佳木斯大学 一种缓释农药制剂及其制备方法、应用
CN112106889A (zh) * 2020-08-07 2020-12-22 珠海天凯生物科技有限公司 一种包衣颗粒的制备方法和应用
CN112603906A (zh) * 2020-12-30 2021-04-06 南京都盟消防技术有限公司 一种微胶囊骨架材料及制备方法
CN112704668B (zh) * 2021-01-12 2022-09-30 石药集团中奇制药技术（石家庄）有限公司 一种盐酸普拉克索缓释组合物
CN113081996A (zh) * 2021-04-01 2021-07-09 海南锦瑞制药有限公司 一种辛伐他汀胶囊的制备方法和辛伐他汀胶囊
CN113230225B (zh) * 2021-05-17 2022-10-14 海南锦瑞制药有限公司 一种阿托伐他汀钙片及其制备方法与用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1080169A (zh) * 1992-04-10 1994-01-05 厄普舍-斯密斯实验室股份有限公司 含有水溶性药物的控释片
US5916595A (en) 1997-12-12 1999-06-29 Andrx Pharmaceutials, Inc. HMG co-reductase inhibitor

Family Cites Families (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU9203780D0 (en) * 1991-12-12 1993-03-29 Sandoz Ag Stabilized pharmaceutical products of hmg-coa reductase inhibitor and method for producing them
SI20848A (sl) * 2001-03-14 2002-10-31 Lek, Tovarna Farmacevtskih In Kemijskih Izdelkov, D.D. Farmacevtska formulacija, ki vsebuje atorvastatin kalcij
AU2002217373A1 (en) * 2002-01-03 2003-07-15 Lek Pharmaceutical And Chemical Company D.D. Controlled release pharmaceutical formulation containing venlafaxine
OA12777A (en) * 2002-02-14 2006-07-06 Ranbaxy Lab Ltd Formulations of atorvastatin stabilized with alkali metal additions.
WO2005000276A1 (en) * 2003-06-25 2005-01-06 Novartis Ag Tablet comprising fluvastatin and carmellose calcium
US20080145427A1 (en) * 2005-02-03 2008-06-19 Alfred Berchielli Dosage Forms Providing Controlled and Immediate Release of Cholesteryl Ester Transfer Protein Inhibitors and Immediate Release of Hmg-Coa Reductase Inhibitors
US20100310607A1 (en) * 2005-04-08 2010-12-09 Abbott Laboratories Pharmaceutical formulations
WO2007035816A2 (en) * 2005-09-20 2007-03-29 Dr. Reddy's Laboratories Ltd. Paroxetine compositions
KR100591142B1 (ko) * 2005-11-04 2006-06-20 지엘팜텍 주식회사 파록세틴을 활성물질로 함유하는 장용성 서방형 정제
EP2457562B1 (en) * 2006-05-09 2017-04-05 Mallinckrodt LLC Zero-order modified release solid dosage forms
IS8612A (is) * 2007-02-19 2008-08-20 Actavis Group Ptc Ehf. Stöðugar statínlyfjasamsetningar
CN101352426B (zh) * 2007-07-27 2010-07-21 鲁南制药集团股份有限公司 一种渗透泵控释制剂组合物及其制备方法
US20090226515A1 (en) * 2008-03-04 2009-09-10 Pharma Pass Ii Llc Statin compositions
CN101269048A (zh) * 2008-05-23 2008-09-24 北京正大绿洲医药科技有限公司 洛伐他丁缓释滴丸及其制备方法
CN101428007A (zh) * 2008-12-04 2009-05-13 上海天赐福生物工程有限公司 一种盐酸二甲双胍缓释片的制备方法
CN101480374A (zh) * 2009-01-20 2009-07-15 苏州中化药品工业有限公司 一种稳定的固体药物组合物
KR20110086944A (ko) * 2010-01-25 2011-08-02 환인제약 주식회사 부플로메딜인산피리독살을 포함하는 서방성 제제 및 이의 제조방법
CN101791297B (zh) * 2010-02-10 2012-03-28 中国药科大学 阿托伐他汀钙口崩片及其制备方法
CN102188421A (zh) * 2010-03-12 2011-09-21 上海天龙药业有限公司 一种不含稳定剂的氟伐他汀制剂
CN101919817B (zh) * 2010-07-23 2012-05-30 山东齐都药业有限公司 一种拉呋替丁胃内滞留控制释放组合物
CN104069502B (zh) * 2013-03-29 2018-02-16 北京罗诺强施医药技术研发中心有限公司 复合骨架材料及其药物组合物
CN103191072B (zh) * 2013-04-07 2014-10-22 广东彼迪药业有限公司 一种辛伐他汀片剂及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1080169A (zh) * 1992-04-10 1994-01-05 厄普舍-斯密斯实验室股份有限公司 含有水溶性药物的控释片
US5916595A (en) 1997-12-12 1999-06-29 Andrx Pharmaceutials, Inc. HMG co-reductase inhibitor

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
APPENDIX XD AND APPENDIX XC OF CHINESE PHARMACOPOEIA, 2010
See also references of EP2979707A4

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