CN1211917A - 以大黄酸或二乙酰大黄酸为基础具有更高生物利用度的药物组合物 - Google Patents
以大黄酸或二乙酰大黄酸为基础具有更高生物利用度的药物组合物 Download PDFInfo
- Publication number
- CN1211917A CN1211917A CN97192531A CN97192531A CN1211917A CN 1211917 A CN1211917 A CN 1211917A CN 97192531 A CN97192531 A CN 97192531A CN 97192531 A CN97192531 A CN 97192531A CN 1211917 A CN1211917 A CN 1211917A
- Authority
- CN
- China
- Prior art keywords
- chrysophanic acid
- diacetyl rhein
- rhein
- sodium lauryl
- lauryl sulphate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960004590 diacerein Drugs 0.000 title claims abstract description 36
- TYNLGDBUJLVSMA-UHFFFAOYSA-N 4,5-diacetyloxy-9,10-dioxo-2-anthracenecarboxylic acid Chemical compound O=C1C2=CC(C(O)=O)=CC(OC(C)=O)=C2C(=O)C2=C1C=CC=C2OC(=O)C TYNLGDBUJLVSMA-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 239000004141 Sodium laurylsulphate Substances 0.000 claims abstract description 19
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims abstract description 19
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 18
- 150000002148 esters Chemical class 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- LQGUBLBATBMXHT-UHFFFAOYSA-N chrysophanol Chemical group C1=CC=C2C(=O)C3=CC(C)=CC(O)=C3C(=O)C2=C1O LQGUBLBATBMXHT-UHFFFAOYSA-N 0.000 claims description 50
- 238000002360 preparation method Methods 0.000 claims description 5
- 210000000664 rectum Anatomy 0.000 claims description 5
- 239000002398 materia medica Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 239000007921 spray Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 239000004094 surface-active agent Substances 0.000 description 15
- 239000002552 dosage form Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- -1 stearic acid sucrose ester Chemical class 0.000 description 7
- 239000007903 gelatin capsule Substances 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 3
- 229960003964 deoxycholic acid Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 229960003387 progesterone Drugs 0.000 description 2
- 239000000186 progesterone Substances 0.000 description 2
- 230000003019 stabilising effect Effects 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000003082 abrasive agent Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000004401 flow injection analysis Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940071117 starch glycolate Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000006211 transdermal dosage form Substances 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Physical Education & Sports Medicine (AREA)
- Emergency Medicine (AREA)
- Rheumatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及基于大黄酸或二乙酰大黄酸的药物组合物。该组合物可经口服、直肠或皮肤(经皮或透皮)途径给药,并包括共同微粉化的大黄酸或大黄酸,或其一种药物学上可接受的盐或酯,和十二烷基硫酸钠,它们的重量比在3∶1—30∶1之间。而且该组合物的生物利用度高。
Description
本发明本发明涉及一种可用于人和动物治疗的新型稳定药物组合物，更具体而言，涉及一种适合于大黄酸和二乙酰大黄酸的格林制剂，其大大地提高了活性成分的生物利用度。
大黄酸，或者9,10-二氢-4,5-二羟基-9,10-二氧-2-蒽甲酸，及其二乙酰衍生物--二乙酰大黄酸，即4,5-二(乙酰氧基)-9,10-二氢-4,5-二羟基-9,10-二氧-2-蒽甲酸，都已在众多的科学文献和法国专利FR-A-2,508,798中被描述过。众所周知，二乙酰大黄酸具有抗关节炎活性，具体来说是用于治疗骨关节炎。但是，大黄酸和二乙酰大黄酸的缺陷是不溶解在水和醇中。而且，虽然二乙酰大黄酸可通过口服给药，但并不能完全被胃肠道所吸收，且该不完全性的吸收会产生非所希望的副作用，如缓泻。再者，人们认为给药大黄酸会产生比给药二乙酰大黄酸更多的问题。
为克服这些困难，在文献中己提出各种的衍生物及药物组合物和特殊的格林制剂。例如，EP-A-243,968描述了一种水溶性的二乙酰大黄酸钾盐，该二乙酰大黄酸钾盐可用于制备非胃肠道给药的组合物。
而且，已知可用表面活性剂处理来提高物质的溶解性和/或润湿性，这通常对提高活性成分的生物利用度有作用。还已知的是，在某种水溶性聚合物存在下研磨非水溶性的活性成分也可提高产物的溶解度和生物利用度(Yamamoto等人，J.Pharm.Sci.(1976)，第65卷，1484-88页)。
治疗物质的研磨可在常规类型的球磨机或锤式粉碎机中进行。该过程也可通过在气流喷射超微粉粉碎机中微粉化来进行，其优点是不必加热待微粉化的物质。微粉化技术已用于研制基于可生物利用且可口服给药的黄体酮的药物组合物，其生物利用度是已知晶体剂型的两倍。
EP-A-330,532描述了在十二烷基硫酸钠存在下共同微粉化降脂异丙酯。另一方面，M.Otsuda等人(J.P.S.84(1995)，第1434-37页)已研究了在表面活性剂存在下共同微粉化phenitoin，而且已表明在与如十二烷基硫酸钠和硬脂酸蔗糖酯的表面活性剂共同微粉化的情况下，phenitoin的溶解度并没有得到提高，但是在与去氧胆酸钠共同研磨的情况下，与粉末的混合物相比溶解度增加30倍。
而且，即使在表面活性剂或糖存在下微粉化或研磨物质可增加其溶解度，但这些参数仍不充分。例如，微粉化黄体酮的生物利用度仍不足，还需要例如通过分散在巴西棕榈蜡中来提高。该方法已描述在WO 89/02742中。
因此，通过微粉化或研磨处理过的物质的性质，特别是溶解度和生物利用度，仍是不可预测的，甚至可得到相矛盾的结果。而且，相同的格林制剂对一种物质可提供良好的结果，但是对另外一种物质则给出相反的结果。
本发明的目的是提供一种基于二乙酰大黄酸的新型稳定药物组合物，该组合物可经口服、直肠或皮肤(经皮或透皮)途径给药，而且其生物利用度高，并更具体而言是用于治疗炎性疾病。
根据本发明的药物组合物的特征在于，其包括共同微粉化的大黄酸或二乙酰大黄酸，或一种其药物学上可接受的盐或酯，以及十二烷基硫酸钠，它们的重量比在3∶1-30∶1之间。
可用于本发明中的药物剂型是适合于涉及通过上皮的任何给药途径的剂型，更具体而言是经口服、直肠或皮肤(经皮或透皮)给药的剂型。
大黄酸之药物学上可接受的盐或酯可选自于大黄酸钠或钾盐酯。二乙酰大黄酸本身即可被视为一个特殊的例子，也就是说大黄酸(二乙酸酯)的盐和酸。在以下部分的说明书中，术语“大黄酸”指两种酸本身，即大黄酸和二乙酰大黄酸，及其盐或酯。
根据本发明的优选实施方案，大黄酸和十二烷基硫酸钠的重量比在6∶1-15∶1之间。
本发明的目的还在于制备基于大黄酸的药物组合物，该组合物可经口服、直肠或皮肤(经皮或透皮)途径给药，而且其生物利用度高，并由共同微粉化的大黄酸和十二烷基硫酸钠组成，它们的重量比在3∶1-30∶1之间，优选在6∶1-15∶1之间。
微粉化优选在气流喷射超微粉粉碎机中进行，更优选在空气喷射或氮气喷射超微粉粉碎机中进行，以得到平均粒径小于50μm、优选小于20μm且粒径分布均匀的粉末。
如上所述的共同微粉化粉末的混合物可制成胶囊、硬明胶胶囊、乳膏、软膏、栓剂或片剂剂型并另外包含常规赋形剂的药物制剂。对于可口服给药的剂型，可使用例如稀释剂如乳糖、纤维素和糖，润滑剂如硬脂酸镁和硬脂酸，崩解剂如羟乙酸淀粉和羧甲基纤维素，抗结块剂如二氧化硅，粘合剂如polyvidone，薄膜形成化合物如羟丙基甲基纤维素和丙烯酸漆，增塑剂如癸二酸二丁基酯和聚乙二醇，增甜剂如天冬糖精和糖精钠，遮光剂如滑石粉和二氧化钛，着色剂如氧化铁，调味剂，防腐剂如对羟基苯甲酸甲酯。对于经皮剂型，可使用带脂肪和含水相(凡士林和水)的赋形剂，表面活性剂和乳化剂如脱水山梨醇酯和甘油单硬脂酸酯，增粘剂如酮基十八烷醇，凝胶剂如carbomers和羧甲基纤维素钠，以及防腐剂如对羟基苯甲酸酯。对于透皮剂型的具体情况，可使用增塑剂如甘油三乙酸酯和聚合物如甲基丙烯酸酯。可直肠给药的剂型包括亲脂和亲水性赋形剂如甘油酯、聚氧乙二醇和suppocires。组合物中的赋形剂的总量通常根据所用的药物剂型而变化，并可为组合物总重量的约50-99％。
与常规的药物制剂相比，本发明的组合物提高了大黄酸的生物利用度，这可降低活性成分在药物中的用量。因此，对于口服给药的硬明胶胶囊或者直肠给药的剂型，本发明的组合物通常每单元剂量包含20-50mg的活性成分。
最后，本发明的目的是共同微粉化的大黄酸和十二烷基硫酸钠在制备用于治疗炎性疾病、特别是骨关节炎的药物中的应用。
在用本发明组合物进行的测试中观察到，共同微粉化的十二烷基硫酸钠和大黄酸并没有使后者分解，即使在二乙酰大黄酸时也是如此，也就是说，在对碱敏感的酯的情况下，与其他表面活性剂如去氧胆酸钠进行的共同微粉化使活性成分分解，而且表面活性剂的浓度越高，其分解得越多。
而且，用几种表面活性剂(表面活性剂/活性成分重量比=1∶4，用杵研磨；研磨时间4分钟)进行的溶解速度测试得到了下表所示的结果(T是活性成分100％溶解所需的时间，以分钟表示)。
| 表面活性剂 | T |
| 十二烷基硫酸钠蔗糖酯HLB15*去氧胆酸钠 | 21220 |
*HLB=亲脂-亲水平衡，由Griffin开发的表面活性剂分类系统。HLB值在0.5-20之间变化，分别相应于亲脂性和亲水性。
这些结果，特别是十二烷基硫酸钠对溶解速度的提高，即使考虑到Otsuda等人(同上)用相同表面活性剂和phenitoin共同微粉化，也是出乎意料的。
一方面，用本发明组合物和包含未微粉化之活性成分和表面活性剂(经微粉化或未经微粉化的)的组合物在体外进行溶解速度的对比测试，另一方面得到以下结果：
| 20分钟 | 30分钟 | 90分钟 | |
| 未微粉化二乙酰大黄酸+未微粉化表面活性剂 | 60％ | 80％ | |
| 未微粉化二乙酰大黄酸+微粉化表面活性剂 | 60％ | 80％ | |
| 本发明组合物 | 95％ | 100％ | 100％ |
可以看出，在根据本发明的组合物中，活性成分的溶解速度明显提高。
根据随机表中的双盲设计在10位健康的自愿者中，在包含50mg市售二乙酰大黄酸的硬明胶胶囊和包含根据本发明共同微粉化的50mg二乙酰大黄酸和5.6mg十二烷基硫酸钠的硬明胶胶囊之间进行生物等效研究。
得到的结果表明，与原始产物相比，与表面活性剂共同微粉化的二乙酰大黄酸的吸收度提高30％。
这些结果被在22位健康自愿者中进行的第二次双盲生物等效研究所证实，其中，在以Cmax(血浆浓度)、Tmax(达到Cmax所需的时间)和AUC(曲线下的面积)表现的药代动力学特征方面，50mg二乙酰大黄酸的原始制剂是可与包含共同微粉化的35mg二乙酰大黄酸和3.9mg表面活性剂的本发明制剂相比的。
而且，所进行的测试还表明本发明组合物具有优异的经时稳定性。
以下制剂的实施例是用于说明本发明，而不是用于限制本发明。实施例1
将10kg二乙酰大黄酸和1kg十二烷基硫酸钠连续地引入至一个方形混合器中，并混合至形成均匀粉末。
将如此得到的粉末混合物在气流喷射磨机中进行共同微粉化。由此得到粉末，以激光粒径测试仪测定，该粉末的粒径分布曲线是单模型的Gaussian形式，颗粒的平均粒径小于10μm。
在该混合物中加入如下所示的赋形剂，以得到硬明胶胶囊形式的组合物No.1：
二乙酰大黄酸 17.5mg
十烷基硫酸钠 1.75mg
纤维素 267.5mg
硬脂酸镁 4.5mg实施例2
如实施例1，将10kg二乙酰大黄酸和0.75kg十二烷基硫酸钠连续地引入至一个合适的方形混合器中。
如实施例1所述，将混合物在气流喷射磨机中进行共同微粉化。由此得到粉末，以激光粒径测试仪测定，该粉末的粒径分布曲线是单模型的Gaussian形式，颗粒的平均粒径小于10μm。
在该混合物中加入如下所示的赋形剂，以得到硬明胶胶囊形式的组合物No.1：
二乙酰大黄酸 40 mg
十二烷基硫酸钠 3 mg
乳糖 230 mg
淀粉 20 mg
滑石粉 2 mg
硬脂酸镁 10 mg
Claims (7)
1、基于大黄酸或二乙酰大黄酸的药物组合物，该组合物可经口服、直肠或皮肤(经皮或透皮)途径给药，而且其生物利用度高，其特征在于，其包括共同微粉化的大黄酸或二乙酰大黄酸，或其一种药物学上可接受的盐或酯，和十二烷基硫酸钠，它们的重量比在3∶1-30∶1之间。
2、如权利要求1所述的组合物，其特征在于，大黄酸或二乙酰大黄酸与十二烷基硫酸钠的重量比在6∶1-15∶1之间。
3、如任一前述权利要求所述的组合物，其特征在于，大黄酸或二乙酰大黄酸和十二烷基硫酸钠的平均粒径为小于20μm。
4、如任一前述权利要求所述的组合物，可通过口服或直肠途径给药，其特征在于，其每单元剂量包含20-50mg的大黄酸或二乙酰大黄酸。
5、通过微粉化活性成分制备基于大黄酸或二乙酰大黄酸且生物利用度高的药物组合物的方法，其特征在于，按3∶1-30∶1的重量比共同微粉化大黄酸或二乙酰大黄酸，或其一种药物学上可接受的盐或酯，和十二烷基硫酸钠。
6、如权利要求5所述的方法，其特征在于，所述的微粉化是在气流喷射微粉粉碎机中进行的。
7、共同微粉化的大黄酸或二乙酰大黄酸和十二烷基硫酸钠在制备用于治疗炎性疾病、特别是骨关节炎的药物中的应用。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9615867A FR2757397B1 (fr) | 1996-12-23 | 1996-12-23 | Composition pharmaceutique a base de rheine ou de diacerheine a biodisponibilite amelioree |
| FR96/15867 | 1996-12-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1211917A true CN1211917A (zh) | 1999-03-24 |
| CN1128612C CN1128612C (zh) | 2003-11-26 |
Family
ID=9499012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97192531A Expired - Fee Related CN1128612C (zh) | 1996-12-23 | 1997-12-23 | 以大黄酸或二乙酰大黄酸为基础具有更高生物利用度的药物组合物 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US6124358A (zh) |
| EP (1) | EP0904061B1 (zh) |
| JP (1) | JP4166834B2 (zh) |
| CN (1) | CN1128612C (zh) |
| AT (1) | ATE225649T1 (zh) |
| BR (1) | BR9707581A (zh) |
| CA (1) | CA2247520C (zh) |
| DE (1) | DE69716261T2 (zh) |
| DK (1) | DK0904061T3 (zh) |
| ES (1) | ES2184148T3 (zh) |
| FR (1) | FR2757397B1 (zh) |
| IL (1) | IL125794A (zh) |
| PT (1) | PT904061E (zh) |
| WO (1) | WO1998027965A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102202673A (zh) * | 2008-10-28 | 2011-09-28 | Twi生物技术有限公司 | 包含双醋瑞因的药物组合物 |
| CN107921013A (zh) * | 2015-07-01 | 2018-04-17 | 安成生物科技股份有限公司 | 双醋瑞因或大黄酸局部用制剂及其用途 |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2270306C (en) * | 1999-04-27 | 2000-09-26 | Bernard Charles Sherman | Pharmaceutical compositions comprising co-micronized fenofibrate |
| AR026801A1 (es) * | 2000-01-12 | 2003-02-26 | Medidom Lab | Sustancias para uso en el tratamiento de la psoriasis |
| WO2002040053A1 (fr) * | 2000-11-17 | 2002-05-23 | Takeda Chemical Industries, Ltd. | Preparation pharmaceutique contenant du talc/ du sulfate de baryum |
| US20020128317A1 (en) * | 2001-01-23 | 2002-09-12 | Laboratories Negma | Treatment of pathological conditions characterized by an increased IL-1 level |
| FR2821555B1 (fr) * | 2001-03-01 | 2003-05-16 | Besins Int Lab | Progestatif co-micronise avec un tensioactif, composition pharmaceutique le comprenant, leurs procedes de fabrication et leurs utilisations |
| US6797727B2 (en) * | 2001-07-16 | 2004-09-28 | Transition Therapeutics Inc. | Use of rhein or diacerhein compounds for the treatment or prevention of vascular diseases |
| GB0404953D0 (en) * | 2004-03-04 | 2004-04-07 | Arakis Ltd | Pro-drugs |
| US8406858B2 (en) | 2005-04-29 | 2013-03-26 | The Regents Of The University Of Colorado, A Body Corporate | Multi-excitation diagnostic system and methods for classification of tissue |
| ES2560899T3 (es) | 2007-09-14 | 2016-02-23 | Wockhardt Limited | Composiciones de diacereína |
| FR2920991A1 (fr) * | 2007-09-14 | 2009-03-20 | Wockhardt Ltd | Composition a base de diacerheine pour le traitement de l'arthrose |
| AU2013200968B2 (en) * | 2007-09-27 | 2013-11-21 | Wockhardt Limited | Pharmaceutical compositions of rhein or diacerein |
| ES2382026T3 (es) * | 2007-09-27 | 2012-06-04 | Wockhardt Limited | Composiciones farmacéuticas autoemulsionantes de reína o diacereína |
| US20100285114A1 (en) * | 2007-09-27 | 2010-11-11 | Rahul Dabre | Pharmaceutical compositions of rhein or diacerein |
| CA2926563A1 (en) * | 2007-09-27 | 2009-04-02 | Wockhardt Research Centre | Pharmaceutical compositions of rhein or diacerein |
| WO2009048940A2 (en) * | 2007-10-08 | 2009-04-16 | Dr. Reddy's Laboratories Ltd. | Diacerein pharmaceutical formulations |
| EP2060562A1 (en) * | 2007-11-16 | 2009-05-20 | Laboratoire Medidom S.A. | Dioxoanthracene sulphonate derivatives |
| US9119819B2 (en) * | 2008-04-30 | 2015-09-01 | Wockhardt Ltd. | Oral liquid compositions of rhein or diacerein |
| US20110045522A1 (en) * | 2009-08-20 | 2011-02-24 | Danchen Gao | Methods for diagnosing diabetes and determining effectiveness of treatments |
| CN101822660B (zh) * | 2010-05-13 | 2013-07-10 | 中国人民解放军肾脏病研究所 | 大黄酸类化合物或其盐在制备预防和治疗胰岛β细胞功能衰退药物中的应用 |
| WO2013095319A2 (en) | 2011-12-23 | 2013-06-27 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Formulations of flurbiprofen and diacerein |
| US9814448B2 (en) | 2012-05-21 | 2017-11-14 | Precision Biopsy, Inc. | Three-dimensional optical imaging and therapy of prostate cancer |
| EP2852324A4 (en) | 2012-05-21 | 2016-02-24 | Univ Colorado Regents | THREE-DIMENSIONAL IMAGING AND THERAPY OF PROSTATE CANCER |
| FR2997627B1 (fr) * | 2012-11-08 | 2015-01-16 | Hra Pharma Lab | Produit de co-micronisation comprenant de l'ulipristal acetate |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA761627B (en) * | 1976-03-16 | 1978-01-25 | C Friedmann | Improvements in or relating to the treatment of arthritis |
| US4344934A (en) * | 1978-11-20 | 1982-08-17 | American Home Products Corporation | Therapeutic compositions with enhanced bioavailability |
| FR2627696B1 (fr) * | 1988-02-26 | 1991-09-13 | Fournier Innovation Synergie | Nouvelle forme galenique du fenofibrate |
| IT1227626B (it) * | 1988-11-28 | 1991-04-23 | Vectorpharma Int | Farmaci supportati aventi velocita' di dissoluzione aumentata e procedimento per la loro preparazione |
| IT1241417B (it) * | 1990-03-06 | 1994-01-14 | Vectorpharma Int | Composizioni terapeutiche a rilascio controllato di farmaci supportatisu polimeri reticolati e rivestiti con film polimerici,e loro processodi preparazione |
| US5393898A (en) * | 1991-06-25 | 1995-02-28 | Madaus Ag | Method of preparing diacetyl rhein |
| JP3459421B2 (ja) * | 1992-12-23 | 2003-10-20 | サイテック ソチエタ レスポンサビリタ リミテ | 調節された開放医薬形の調製法及びそのようにして得られた医薬形 |
| US5652265A (en) * | 1995-03-29 | 1997-07-29 | Wisconsin Alumni Research Foundation | Production of rhein and rhein derivatives |
| IT1276781B1 (it) * | 1995-06-23 | 1997-11-03 | Gentili Ist Spa | Derivati antrachinonmono- e disolfon- sostituiti e composizioni farmaceutiche che li contengono per il trattamento delle patologie |
-
1996
- 1996-12-23 FR FR9615867A patent/FR2757397B1/fr not_active Expired - Fee Related
-
1997
- 1997-12-23 IL IL12579497A patent/IL125794A/xx not_active IP Right Cessation
- 1997-12-23 JP JP52848798A patent/JP4166834B2/ja not_active Expired - Fee Related
- 1997-12-23 DE DE69716261T patent/DE69716261T2/de not_active Expired - Lifetime
- 1997-12-23 EP EP97952996A patent/EP0904061B1/fr not_active Expired - Lifetime
- 1997-12-23 ES ES97952996T patent/ES2184148T3/es not_active Expired - Lifetime
- 1997-12-23 CN CN97192531A patent/CN1128612C/zh not_active Expired - Fee Related
- 1997-12-23 BR BR9707581A patent/BR9707581A/pt active Search and Examination
- 1997-12-23 CA CA002247520A patent/CA2247520C/fr not_active Expired - Fee Related
- 1997-12-23 US US09/125,514 patent/US6124358A/en not_active Expired - Lifetime
- 1997-12-23 DK DK97952996T patent/DK0904061T3/da active
- 1997-12-23 AT AT97952996T patent/ATE225649T1/de active
- 1997-12-23 PT PT97952996T patent/PT904061E/pt unknown
- 1997-12-23 WO PCT/FR1997/002403 patent/WO1998027965A1/fr active IP Right Grant
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102202673A (zh) * | 2008-10-28 | 2011-09-28 | Twi生物技术有限公司 | 包含双醋瑞因的药物组合物 |
| CN102202673B (zh) * | 2008-10-28 | 2013-07-31 | 安成生物科技股份有限公司 | 包含双醋瑞因的药物组合物 |
| CN107921013A (zh) * | 2015-07-01 | 2018-04-17 | 安成生物科技股份有限公司 | 双醋瑞因或大黄酸局部用制剂及其用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| US6124358A (en) | 2000-09-26 |
| DK0904061T3 (da) | 2003-01-27 |
| EP0904061B1 (fr) | 2002-10-09 |
| WO1998027965A1 (fr) | 1998-07-02 |
| DE69716261T2 (de) | 2003-09-18 |
| CA2247520C (fr) | 2007-03-27 |
| IL125794A (en) | 2000-12-06 |
| JP2000505817A (ja) | 2000-05-16 |
| PT904061E (pt) | 2003-02-28 |
| FR2757397A1 (fr) | 1998-06-26 |
| FR2757397B1 (fr) | 1999-03-05 |
| IL125794A0 (en) | 1999-04-11 |
| BR9707581A (pt) | 1999-07-27 |
| JP4166834B2 (ja) | 2008-10-15 |
| EP0904061A1 (fr) | 1999-03-31 |
| CA2247520A1 (fr) | 1998-07-02 |
| ES2184148T3 (es) | 2003-04-01 |
| CN1128612C (zh) | 2003-11-26 |
| DE69716261D1 (de) | 2002-11-14 |
| ATE225649T1 (de) | 2002-10-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1128612C (zh) | 以大黄酸或二乙酰大黄酸为基础具有更高生物利用度的药物组合物 | |
| DE69902046T2 (de) | Neue feste dosisform enthaltend nanopartikelnaproxen | |
| Barzegar-Jalali et al. | Cogrinding as an approach to enhance dissolution rate of a poorly water-soluble drug (gliclazide) | |
| DE69811855T2 (de) | Fenofibrathaltige arzneizusammensetzung mit hoher bioverfügbarkeit und herstellungsverfahren | |
| JPS62167727A (ja) | 固形ニフエジピン製剤の製造方法及びそのようにして得られた製剤 | |
| KR20090027734A (ko) | 난용성 약물의 나노입자를 포함하는 분말의 제조방법 | |
| DE10036871A1 (de) | Dispersionen zur Formulierung wenig oder schwer löslicher Wirkstoffe | |
| Deveswaran et al. | Formulation and evaluation of albumin microspheres containing aceclofenac | |
| DE3909520C2 (de) | Feste, schnell zerfallende Darreichungsformen für Diclofenac | |
| CN1989956B (zh) | 一种阿达帕林凝胶组合物及其制备方法 | |
| Banarase et al. | Whole whey stabilized oleanolic acid nanosuspension: Formulation and evaluation study | |
| US20180028587A1 (en) | Composition comprising an onion extract and liposomes | |
| CN111419900B (zh) | 一种基于冠心宁改进的纳米混悬冻干制剂及其制备方法 | |
| US20190321430A1 (en) | Herbal Nanoformulations for Treating Psoriasis and Other Skin Conditions | |
| EP1249231A1 (de) | Pharmazeutische Formulierungen enthaltend entzündungshemmende Wirkstoffe und deren Verwendung | |
| EP0075523B1 (fr) | Nouveaux médicaments à base d'extraits d'algues, et formulations correspondantes | |
| WO2023168948A1 (zh) | 白头翁皂苷b4在制备外用治疗银屑病药物中的应用 | |
| CN102727793B (zh) | 一种益坤宁药物组合物固体脂质纳米粒制剂 | |
| Jain et al. | Formulation and characterization of liquisolid tablets of valsartan for improvement of dissolution rate | |
| WO2023052393A1 (de) | Mechanochemisch vorbehandelte, schwermetallfreie aktivkohlepartikel a, topische arzneimittel, medizinprodukte und kosmetika, herstellverfahren und verwendungen | |
| CN109996563A (zh) | 4-甲基-5-(吡嗪-2-基)-3h-1,2-二硫杂环戊烯-3-硫酮的制剂、味道改良的制剂及其制备和使用方法 | |
| Upendra et al. | Topical Nanosponge Gel For Immunosuppressive Agent | |
| Farooq et al. | Formulation and evaluation of vitamin D3 (Cholecalciferol) self-nanoemulsifying drug delivery systems for enhancing solubility | |
| JPH021403A (ja) | 医薬組成物 | |
| Ajikumar et al. | Formulation and evaluation of Ethosomal gel containing clarithromycin for the treatment of acne vulgaris |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20031126 Termination date: 20100125 |