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WO2005082330A2 - Cefditoren pivoxil amorphe coprecipite et formes posologiques comprenant celui-ci - Google Patents

Cefditoren pivoxil amorphe coprecipite et formes posologiques comprenant celui-ci Download PDF

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Publication number
WO2005082330A2
WO2005082330A2 PCT/IB2005/000419 IB2005000419W WO2005082330A2 WO 2005082330 A2 WO2005082330 A2 WO 2005082330A2 IB 2005000419 W IB2005000419 W IB 2005000419W WO 2005082330 A2 WO2005082330 A2 WO 2005082330A2
Authority
WO
WIPO (PCT)
Prior art keywords
cefditoren pivoxil
water insoluble
pharmaceutical composition
amoφhous
sodium
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.)
Ceased
Application number
PCT/IB2005/000419
Other languages
English (en)
Other versions
WO2005082330A3 (fr
Inventor
Khalid Rafi
Sudhir Verma
Rajesh Bhaskar
Vinod Kumar Arora
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2005082330A2 publication Critical patent/WO2005082330A2/fr
Publication of WO2005082330A3 publication Critical patent/WO2005082330A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/14—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
    • A61K9/146—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 macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—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
    • A61K9/143—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 inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • cefditoren pivoxil which is a pivaloxymethyl ester of cefditoren
  • cephalosporin derivative belonging to the class of 3-(2-substituted vinyl) cephalosporin, which was first developed by Meiji Seika of Japan with the aim of producing active cephalosporins with potent and broad-spectrum activity (U.S. Patent No. 4,839,350).
  • Cefditoren pivoxil is highly active, not only against a variety of gram-positive and gram-negative bacteria, but also against some resistant strains of bacteria. Chemically, cefditoren pivoxil is chemically known as [6R-[3(Z),6a,7b(Z)]]-7-[[(2-amino-4- thiazolyl)(methoxyimino)acetyl]amino]-3-[2-(4-methyl-5-thiazolyl)ethenyl]-8-oxo-5-thia- l-azabicyclo[4.2.0]oct-2-ene-carboxylic acid, pivaloyloxy-methyl ester.
  • Crystals of cefditoren pivoxil are known to have high purity, high heat stability and in addition satisfactory stability even when stored under high humidity conditions (U.S. Patent No. 6,294,669). Crystals of cefditoren pivoxil, however, have low solubility in water and thus have not been very suitable for oral administration. In general, for medicinal compounds which are sparingly soluble in water, the solubility or dissolution rate thereof is known to greatly affect the absorption of these compounds in vivo. Thus, many reports were presented on how to improve the water- solubility of such medicinal compounds, which are sparingly soluble in water.
  • 6,342,493 describes a process for preparing orally administrable compositions that include particles composed of a homogeneous mixture of a crystallographically stable, amo ⁇ hous, water soluble substance of cefditoren pivoxil and a water soluble high molecular weight polymer.
  • the process involves mixing crystalline cefditoren pivoxil and a water soluble, high molecular weight polymer in an acidic solution followed by basification of the acidic solution to precipitate a yellow-colored powdery composition that contains amo ⁇ hous cefditoren pivoxil and high molecular weight polymer.
  • Many technical problems are believed to exist in this process, such as the need for strict production controls and requirements to carry out the operation.
  • WO 02/87588 discloses another method of conversion of crystalline cefditoren pivoxil to amo ⁇ hous form by grinding crystalline cefditoren pivoxil in the presence of a pharmaceutically acceptable organic polymeric compound.
  • amo ⁇ hous cefditoren pivoxil can be obtained by preparing a solution of crystalline cefditoren pivoxil in a solvent, optionally adding a wetting agent, dispersing a water insoluble carrier in this solution and removing the solvent.
  • Summary of the Invention In one general aspect there is provided a process for preparing an amo ⁇ hous form of cefditoren pivoxil having a higher water-solubility.
  • the process includes preparing a solution of crystalline cefditoren pivoxil in one or more solvents; dispersing one or more water insoluble carriers in the solution; and removing the solvent.
  • the amo ⁇ hous cefditoren pivoxil and one or more water insoluble carriers are co-precipitated from the solution.
  • Embodiments of the process may include one or more of the following features.
  • the solution may be prepared in an organic solvent and may include one or more of ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol; and chlorinated hydrocarbons, such as methylene chloride.
  • the water insoluble carrier may be one or more of crospovidone, colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate, dibasic calcium phosphate, and combinations thereof and, in particular, the water insoluble carrier may be crospovidone or colloidal silicon dioxide, or combinations thereof.
  • the weight ratio of cefditoren pivoxil to water insoluble carrier may be from about 1:0.1 to about 1 :2.
  • Removing the solvent may include, for example, one or more of distillation, distillation under vacuum, evaporation, and spray drying.
  • the process may further include processing the mixture with one or more pharmaceutically inert excipients.
  • the pharmaceutically inert excipients may be one or more of fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers, and preservatives.
  • the process may further include forming one or more of a tablet, a capsule, and a powder.
  • a process for preparing an amo ⁇ hous form of cefditoren pivoxil having a higher water-solubility includes preparing a solution of crystalline cefditoren pivoxil in one or more solvents; adding one or more wetting agents; dispersing one or more water insoluble carriers in the solution; and removing the solvent.
  • the amo ⁇ hous cefditoren pivoxil, one or more wetting agents, and one or more water insoluble carriers are co-precipitated from the solution.
  • the wetting agent may be one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens.
  • a pharmaceutical composition for oral administration that includes a co-precipitated mixture of amo ⁇ hous cefditoren pivoxil and one or more water insoluble carriers.
  • Embodiments of the pharmaceutical composition may include one or more of the following features.
  • the water insoluble carrier may be one or more of crospovidone, colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate, dibasic calcium phosphate, and combinations thereof and, in particular, the water insoluble carrier may be crospovidone or colloidal silicon dioxide, or combinations thereof.
  • a pharmaceutical composition for oral administration that includes a co-precipitated mixture of amo ⁇ hous cefditoren pivoxil, one or more wetting agents, and one or more water insoluble carriers.
  • the wetting agent may be one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens.
  • the pharmaceutical composition may further include one or more pharmaceutically inert excipients.
  • the one or more pharmaceutically inert excipients may be one or more of fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers, and preservatives.
  • the pharmaceutical composition may be a solid dosage form and the solid dosage form comprises one or more of tablets, capsules, and powders, and, in particular, may be a tablet.
  • the weight ratio of cefditoren pivoxil to water insoluble carrier may be from about 1:0.1 to about 1:2.
  • a method for the treatment of bacterial infections in a mammal includes administering a pharmaceutical composition that includes a co-precipitate of amo ⁇ hous cefditoren pivoxil and one or more water insoluble carriers, and one or more of pharmaceutically acceptable excipients.
  • a co-precipitate of amo ⁇ hous cefditoren pivoxil and one or more water insoluble carriers may include any one or more of the following features or the features described above.
  • the weight ratio of cefditoren pivoxil to water insoluble carrier may be from about 1 :0.1 to about 1 :2.
  • a co-precipitate of amo ⁇ hous cefditoren pivoxil, one or more wetting agents, and one or more water insoluble carriers is provided.
  • 'amo ⁇ hous' as used herein means a solid state in which cefditoren pivoxil molecules gather together with a pharmaceutically acceptable organic polymeric compound without forming crystals having a regular special configuration, more specifically, a solid state in which the amo ⁇ hous form can be confirmed by conventional powder X-ray diffractometry.
  • the crystalline cefditoren pivoxil exhibits sha ⁇ diffraction peaks
  • the co-precipitate of amo ⁇ hous cefditoren pivoxil and one or more water insoluble carriers according to the present invention does not substantially exhibit any X-ray diffraction peaks.
  • amo ⁇ hous cefditoren pivoxil may be prepared by a process that includes forming a solution of cefditoren pivoxil in one or more solvents, dispersing a water insoluble carrier into the solution, and removing the solvent by spray drying, thereby co-precipitating the amo ⁇ hous cefditoren pivoxil and water insoluble carriers.
  • the spray dryer used for drying the solution may be any of the conventional spray driers known in the art including nozzle type, disc type or jet type. Based on the selection of spray dryer, the various process parameters may be varied.
  • the solvent may be, for example, one or more of ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol; and chlorinated hydrocarbons, such as methylene chloride.
  • water insoluble carrier may include one or more of crospovidone, colloidal silicon dioxide, microcrystalline cellulose, cross-linked sodium carboxymethylcellulose, starch, carboxymethylcellulose calcium, calcium carbonate and dibasic calcium phosphate, and combinations thereof. More particularly, the water insoluble carrier is crospovidone, or colloidal silicon dioxide, or combinations thereof.
  • the weight ratio of cefditoren pivoxil to water insoluble carrier may vary from about 1 :0.1 to about 1:2.
  • the wetting agents are the substances, usually surface-active agents, which reduce the surface tension of a liquid and thereby increase its adhesion to a solid surface. Due to poor dispersibility in solvents, the pharmaceutical composition containing cefditoren pivoxil may optionally include a wetting agent.
  • the wetting agent wets the particles of cefditoren pivoxil such that when the solvent evaporates, the particles of cefditoren pivoxil which precipitate are tiny and do not aggregate.
  • wetting agents may include one or more of propylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, poloxamers, polyethylene glycols and tweens.
  • the amo ⁇ hous cefditoren pivoxil prepared as generally described above may be further processed with one or more pharmaceutically inert excipients to prepare pharmaceutical compositions.
  • pharmaceutical composition includes solid dosage forms such as one or more of tablets, capsules, and powders that are formulated by conventional methods of admixture such as one or more of blending, filling, and granulation. Of course, other formulation methods also may be used.
  • the dosage form may be optionally coated with one or more film forming polymers.
  • the cefditoren pivoxil tablet may be prepared by blending a spray dried, co-precipitated mixture of cefditoren pivoxil and water insoluble carriers with diluents and disintegrants, mixing the blend with lubricant and glidants, directly compressing the mixed blend in a suitable tableting machine, and coating with one or more film forming polymers.
  • dry granulation and wet granulation techniques may be used for preparing cefditoren pivoxil tablets. Coating may be performed by applying one or more film forming polymers with or without other pharmaceutically inert excipients.
  • Suitable film forming polymers include one or more of ethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, waxes, methacrylic acid polymers such as Eudragit® RL and RS, and mixtures thereof.
  • the coating can also be performed using any commercially available ready to coat preparations such as opadry-AMB, opadry-white, opadry-clear, etc.
  • Suitable solvents used for making a solution/suspension of film forming polymer include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.
  • cefditoren pivoxil capsules may be prepared by blending the spray dried, co-precipitated mixture of cefditoren pivoxil and water insoluble carrier with other pharmaceutically inert excipients and filling into suitably sized hard gelatin capsules.
  • pharmaceutically inert excipient includes one or more of fillers, buffering agents, binders, disintegrants, coloring agents, flavoring agents, lubricants, glidants, plasticizers and preservatives for pharmaceutical compositions.
  • Suitable fillers may include one or more of corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, sucrose and mixtures thereof.
  • buffering agents include one or more of sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, and other sodium and potassium salts.
  • binders include methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullutan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol or mixtures thereof.
  • disintegrants examples include starch, croscarmellose sodium, crospovidone, sodium starch glycolate or mixtures thereof.
  • lubricants and glidants include colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like.
  • the coloring agents of the present invention may be selected from any FDA approved colors for oral use.
  • the amo ⁇ hous cefditoren pivoxil composition according to the present invention may be used as antibacterial agents.
  • Bacteria referred to herein include, for example gram- positive bacteria such as staphylococcus and streptococcus, gram-negative bacteria such as Escherchia coii, BranhameUa catarrhalis, Klebsiella, Proteus, and Haemophilus influenzae, and anaerobes such as Peptostreptococcus, Propionibacterium acnes, and Bacteriocides. Further, the composition according to the present invention is useful for the prophylaxis or therapy of diseases induced by gram-positive bacteria or gram-negative bacteria.
  • the pharmaceutical composition according to the present invention may be used by any administration route so far as the high dissolvability of the amo ⁇ hous cefditoren pivoxil can be utilized, for example by oral administration, intraoral administration, parenteral administration, topical administration, or rectal administration.
  • the pharmaceutical composition according to the present invention is particularly administered orally.
  • the amo ⁇ hous Cefditoren pivoxil compositions according to the present invention may be administered in combination with other medicines, for example, other antibacterial agents.
  • the following examples illustrate various aspects of the present inventions. These examples are for illustration only and do not limit the scope of the inventions. Examples 1- 4: Amo ⁇ hous cefditoren pivoxil 1
  • Cefditoren pivoxil was dissolved in acetone and colloidal silicon dioxide was dispersed in it. The solvent was removed to obtain the amo ⁇ hous cefditoren pivoxil. Amo ⁇ hous Cefditoren pivoxil 4

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

L'invention concerne des formes posologiques de cefditoren pivoxil amorphe coprécipité et des procédés permettant de préparer celles-ci. Ce procédé consiste à préparer une solution de cefditoren pivoxil cristallin dans un ou plusieurs solvants, à disperser un ou plusieurs excipients insolubles à l'eau dans la solution et à éliminer le solvant. Le cefditoren pivoxil amorphe et un ou plusieurs excipients insolubles à l'eau sont séparés de la solution par coprécipitation.
PCT/IB2005/000419 2004-02-19 2005-02-18 Cefditoren pivoxil amorphe coprecipite et formes posologiques comprenant celui-ci Ceased WO2005082330A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN236/DEL/2004 2004-02-19
IN236DE2004 2004-02-19
IN207DE2005 2005-02-02
IN207/DEL/2005 2005-02-02

Publications (2)

Publication Number Publication Date
WO2005082330A2 true WO2005082330A2 (fr) 2005-09-09
WO2005082330A3 WO2005082330A3 (fr) 2006-03-16

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006100574A1 (fr) * 2005-03-23 2006-09-28 Ranbaxy Laboratories Limited Granules de cefditoren pivoxil amorphe et procedes d'elaboration correspondants
US8663684B2 (en) 2008-09-19 2014-03-04 Molkerei Meggle Wasserburg Gmbh & Co. Kg Lactose and cellulose-based tableting aid
CN104688698A (zh) * 2015-02-04 2015-06-10 山东新时代药业有限公司 一种头孢妥仑匹酯片剂
EP2744481A4 (fr) * 2011-08-16 2015-07-01 Merck Sharp & Dohme Utilisation de matrice inorganique et de combinaisons de polymères organiques pour la préparation de dispersions amorphes stables
CN110251467A (zh) * 2019-06-26 2019-09-20 北京济美堂医药研究有限公司 一种无定形态头孢妥仑匹酯组合物的制备方法
US10568839B2 (en) 2011-01-11 2020-02-25 Capsugel Belgium Nv Hard capsules
CN112190539A (zh) * 2020-11-10 2021-01-08 深圳立健药业有限公司 一种头孢妥仑匹酯组合物及其应用
CN112315930A (zh) * 2020-11-10 2021-02-05 深圳立健药业有限公司 一种头孢妥仑匹酯片及其制备方法
US11319566B2 (en) 2017-04-14 2022-05-03 Capsugel Belgium Nv Process for making pullulan
US11576870B2 (en) 2017-04-14 2023-02-14 Capsugel Belgium Nv Pullulan capsules
CN116019815A (zh) * 2023-03-24 2023-04-28 北京诚济制药股份有限公司 一种头孢托仑匹酯药物组合物及其制备方法
CN120732800A (zh) * 2025-08-19 2025-10-03 湖南恒昌医药集团股份有限公司 头孢托仑匹酯缓释片及其制备方法

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR200001903T2 (tr) * 1998-01-07 2000-11-21 Meiji Seika Kaisha, Ltd. Kristalografik açıdan kararlı, şekilsiz sefalosporin bileşimleri ve bunların üretilmesine ilişkin işlem.
PT1389462E (pt) * 2001-04-26 2012-06-19 Meiji Seika Pharma Co Ltd Composição de cefditoreno pivoxil amorfo e processo para o produzir

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006100574A1 (fr) * 2005-03-23 2006-09-28 Ranbaxy Laboratories Limited Granules de cefditoren pivoxil amorphe et procedes d'elaboration correspondants
US8663684B2 (en) 2008-09-19 2014-03-04 Molkerei Meggle Wasserburg Gmbh & Co. Kg Lactose and cellulose-based tableting aid
US10568839B2 (en) 2011-01-11 2020-02-25 Capsugel Belgium Nv Hard capsules
EP2744481A4 (fr) * 2011-08-16 2015-07-01 Merck Sharp & Dohme Utilisation de matrice inorganique et de combinaisons de polymères organiques pour la préparation de dispersions amorphes stables
CN104688698B (zh) * 2015-02-04 2018-01-19 山东新时代药业有限公司 一种头孢妥仑匹酯片剂
CN104688698A (zh) * 2015-02-04 2015-06-10 山东新时代药业有限公司 一种头孢妥仑匹酯片剂
US11319566B2 (en) 2017-04-14 2022-05-03 Capsugel Belgium Nv Process for making pullulan
US11576870B2 (en) 2017-04-14 2023-02-14 Capsugel Belgium Nv Pullulan capsules
US11878079B2 (en) 2017-04-14 2024-01-23 Capsugel Belgium Nv Pullulan capsules
CN110251467A (zh) * 2019-06-26 2019-09-20 北京济美堂医药研究有限公司 一种无定形态头孢妥仑匹酯组合物的制备方法
CN112190539A (zh) * 2020-11-10 2021-01-08 深圳立健药业有限公司 一种头孢妥仑匹酯组合物及其应用
CN112315930A (zh) * 2020-11-10 2021-02-05 深圳立健药业有限公司 一种头孢妥仑匹酯片及其制备方法
CN116019815A (zh) * 2023-03-24 2023-04-28 北京诚济制药股份有限公司 一种头孢托仑匹酯药物组合物及其制备方法
CN120732800A (zh) * 2025-08-19 2025-10-03 湖南恒昌医药集团股份有限公司 头孢托仑匹酯缓释片及其制备方法

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