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WO2008110080A1 - Composition pharmaceutique contenant un complexe d'inclusion de cyclodextrine constitué de cefixime, et son procédé de préparation - Google Patents

Composition pharmaceutique contenant un complexe d'inclusion de cyclodextrine constitué de cefixime, et son procédé de préparation Download PDF

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Publication number
WO2008110080A1
WO2008110080A1 PCT/CN2008/000515 CN2008000515W WO2008110080A1 WO 2008110080 A1 WO2008110080 A1 WO 2008110080A1 CN 2008000515 W CN2008000515 W CN 2008000515W WO 2008110080 A1 WO2008110080 A1 WO 2008110080A1
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Prior art keywords
cyclodextrin
cefixime
pharmaceutical composition
parts
inclusion compound
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Ceased
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PCT/CN2008/000515
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English (en)
Chinese (zh)
Inventor
Yong Ren
Xiaojie Wang
Xueqin Ma
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NANJING J ONE MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Nanjing Normal University
Original Assignee
NANJING J ONE MEDICAL TECHNOLOGY DEVELOPMENT Co Ltd
Nanjing Normal University
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Publication of WO2008110080A1 publication Critical patent/WO2008110080A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
    • A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes

Definitions

  • the present invention relates to a pharmaceutical composition comprising a cefixime cyclodextrin inclusion complex and a process for the preparation thereof. Background technique
  • Cefixime is a third-generation oral cephalosporin, an important antibiotic, chemical name: (6 R , 7 R)-7- ⁇ ⁇ (Z)-2-(2-aminothiazole-4 -yl)-2-((carboxymethoxy)imine) acetyl)amino 3-vinyl-8-oxo-5-thiathiazepine (4,2,0)-2-octene -2-carboxylic acid, molecular formula: C16H15N507S2, molecular weight: 453.44.
  • the drug was developed and marketed by Fujisawa Pharmaceutical Industry Co., Ltd. under the trade name Cefspan.
  • Cefixime has become the first oral cephalosporin in the market. The United States, Britain, Japan and the European Pharmacopoeia have both contained this product. Widely used in more than 80 countries.
  • Cefixime has a broad antibacterial spectrum and strong action, long lasting effective concentration, stable lactamase and wide distribution in the body. It is used in urinary system inflammation, biliary system inflammation, gonorrhea, scarlet fever, otitis media, sinusitis and other diseases.
  • Treatment Li Jiatai, Hou Fang, Zhao Caiyun et al., Double-blind double-simulated randomized controlled bacterial infection in a multi-center clinical trial of ceftriaxone and cefixime. Chinese Journal of Clinical Pharmacology, 1998, 15 ( 1 ) : 1-8 ), is the ⁇ -lactam antibacterial drug that is second only to amoxicillin in the world, and is the preferred treatment for gonorrhea in the World Health Organization.
  • cefixime The usual oral dose of cefixime is 50 to 100 mg for adults and children weighing more than 30 kg, twice a day.
  • Cefixime has a variety of oral drug release characteristics.
  • six dosage forms have been developed and approved in China, namely capsules, tablets, dispersible tablets, granules, dry suspensions and chewable tablets.
  • the drug is not only used in adult patients, but its low-dose drugs are also designed for children.
  • This product has poor antibacterial effect on grapevine, and has no antibacterial effect on Pseudomonas aeruginosa, Enterobacter, Bacteroides fragilis and Clostridium.
  • the original drug is excreted from the urine, and those with renal dysfunction should be reduced.
  • Cyclodextrin (CD) is a cyclic oligosaccharide natural product obtained by linking 6 ⁇ 15 glucose molecules obtained by enzymatic cyclization of cyclodextrin glucan transposase, usually ⁇ . -, en Y -CD, containing 6, 7, 8 glucose molecules, respectively.
  • --cyclodextrin is a truncated cone formed by the linkage of seven glucose molecules with glycoside bonds, and has a special molecular structure of "internal hydrophobicity, external hydrophilicity".
  • Cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin Cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin and sulfobutyl- ⁇ -cyclodextrin.
  • HP-SBE- ⁇ -cyclodextrin hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin
  • the research on the administration technology of cefixime mainly focuses on the techniques of oral tablets and capsules, but there are problems such as low oral bioavailability and large daily dose, especially for clinical kidney disease (low renal function). Or incomplete) medication for patients with inflammation.
  • the research of the invention shows that: the cyclodextrin inclusion technique is applied to the cefixime preparation, which not only helps to improve the water solubility of the drug (the maximum solubilization ratio reaches 33 times, and the solubility of cefixime in water increases from 1.08 mg/mL to about 41 mg). /mL), increase the stability of the drug, and the increase in acid hydrolysis stability is particularly beneficial to improve the bioavailability of oral drugs.
  • cefixime inclusion complex can significantly increase the activity of cefixime, which lays the foundation for the development of low-dose new formulations and the development of parenteral dosage forms such as injection formulations.
  • studies on the preparation of cyclodextrin formulations for cyclodextrin have not been reported. Summary of the invention
  • One of the objects of the present invention is to provide a pharmaceutical composition of a cefixime cyclodextrin inclusion compound, which comprises encapsulating cefixime with a cyclodextrin to obtain a clathrate having good stability of the main drug, and the inclusion compound
  • the obtained pharmaceutical composition can improve the solubility of cefixime, increase stability, reduce side effects, and obtain a new formulation of cefacoxime having clinical application value.
  • Another object of the present invention is to provide a process for the preparation of the above pharmaceutical composition.
  • the pharmaceutical composition of the present invention achieves further improvement in the medicinal properties of cefixime and facilitates clinical application by the addition of cyclodextrin and optionally other pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical composition
  • a cefixime cyclodextrin inclusion compound the basic composition of which comprises:
  • the pharmaceutically acceptable cyclodextrin is selected from one or more of ⁇ -cyclodextrin, cyclodextrin, quinone-cyclodextrin and derivatives thereof; preferably selected from ⁇ -cyclodextrin, hydroxypropyl One or more of benzyl- ⁇ -cyclodextrin, sulfobutyl ether cyclodextrin and hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin; further preferably hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin fine.
  • the molecular weight of ⁇ -cyclodextrin is 1135; hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl- ⁇ -cyclodextrin and hydroxypropyl-sulfobutyl group -
  • the average molecular weight of ⁇ -cyclodextrin is: 1297 ⁇ 1744, 2089 2264 and 1353 2625, the mass ratio of the 1:1 molecular inclusion ratio of cefixime to cyclodextrin according to the molecular weight of different cyclodextrin, the ratio range is: 1:2.503 1:5.789.
  • the mass ratio of cefixime to cyclodextrin is 1:2.5 1 :100, preferably 1:1:50:50, more preferably 1:5-1:30.
  • the molecular inclusion ratio of the head sputum and the cyclodextrin may be 1:1 to 1:5, that is, in the clathrate system,
  • the cefacazole of the guest molecule and the cyclodextrin as the host molecule have a molecular ratio of 1:1 to 1:5; preferably 1:1 to 1:3.
  • the clathrate of the present invention is a clathrate prepared by a inclusion process using a cefixime as a guest molecule and a cyclodextrin as a host molecule.
  • a cyclodextrin containing a plurality of host molecules may contain one guest molecule of Cefixime, or a host molecule of cyclodextrin may contain one guest molecule of Cefixime.
  • a pharmaceutical composition consisting of a clathrate will use an excess of cyclodextrin, and an excess of cyclodextrin may be added as an excipient (or excipient), such as a stabilizer, Flavoring agents, fillers or solubilizers to further improve the medicinal properties of cefixime and the technical requirements for various dosage forms; in some cases it is also possible to use cyclodextrins with a molecular ratio of less than 1:1.
  • the drug is mainly present in the form of a clathrate.
  • the present invention uses a cyclodextrin ( ⁇ -cyclodextrin) having a minimum mass ratio of 1:2.5, and the ratio of the drug to the cyclodextrin molecule is 1:1, although the cyclodextrin and the drug are only The molecular ratio is equal, but because the ⁇ -cyclodextrin inclusion cefixime has a large inclusion constant, the drug still has the inclusion form as the main form.
  • ⁇ -cyclodextrin cyclodextrin having a minimum mass ratio of 1:2.5, and the ratio of the drug to the cyclodextrin molecule is 1:1, although the cyclodextrin and the drug are only The molecular ratio is equal, but because the ⁇ -cyclodextrin inclusion cefixime has a large inclusion constant, the drug still has the inclusion form as the main form.
  • a portion of the excess cyclodextrin which is usually added is present in admixture with the clathrate in free form.
  • the partially free form of the cyclodextrin may be removed by a known method, for example, using a solvent having different solubility properties, in the case of pharmacy application, in most cases,
  • the unconjugated free cyclodextrin is present in admixture of the clathrate and is used directly to prepare a pharmaceutical composition without removal to prepare a pharmaceutical composition for oral or parenteral administration.
  • the present invention also provides a process for the preparation of a pharmaceutical composition of the present invention, which comprises the preparation of a cefixime cyclodextrin inclusion compound, the preparation of the cefacoxime cyclodextrin inclusion compound comprising the steps of:
  • the resulting clathrates can be used in the preparation of pharmaceutical compositions or formulation products for oral administration or for injection.
  • the adjusted pH may be adjusted to slightly acidic or alkali to slightly alkaline by addition of acid.
  • the resulting clathrate can be used in the preparation of a pharmaceutical or preparation product for oral administration or for injection.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a cefixime cyclodextrin inclusion compound, wherein the mass ratio of cefixime to cyclodextrin is 1:2.5 to 1:100, inclusion complexes and other drugs
  • the excipients are formulated in a conventional formulation ratio to prepare a composition suitable for clinical use.
  • the solid inclusion compound prepared by the invention has high water solubility and is easy to dissolve without adding other cosolvents, and the prepared aqueous solution has small side effects of hemolysis and strong activity, and is suitable for clinical use.
  • the pharmaceutical composition of the present invention may be in various dosage forms such as an oral dosage form, a parenteral administration dosage form and the like.
  • oral dosage forms include, but are not limited to, tablets, capsules, granules, sustained release tablets or dispersible tablets and the like.
  • parenteral dosage forms include, but are not limited to, freeze-dried powder injections, sterile powder injections, small-volume injections, and large-volume infusion solutions.
  • the pharmaceutical composition of the present invention may optionally further comprise one or more pharmaceutically acceptable excipients or excipients for oral administration, such as diluents, disintegrants, lubricants, One or more of a wetting agent and a binder.
  • pharmaceutically acceptable excipients or excipients for oral administration such as diluents, disintegrants, lubricants, One or more of a wetting agent and a binder.
  • the content of cefixime in the pharmaceutical composition can be determined according to factors such as the dosage form, suitable population, and the like, and it is usually 0.5 to 28.6 wt%.
  • the amount of the above excipient or excipient used is not particularly limited, and those skilled in the art can select as needed in the preparation of a specific dosage form.
  • the content of the diluent in the pharmaceutical composition is 0 to 80% by weight, preferably 10 to 50% by weight ; the content of the disintegrant is 0 to 30% by weight, preferably less than 0.5% by weight; the content of the lubricant is 0 to 10% by weight, preferably It is 0.3 ⁇ 1wt%; the content of wetting agent or binder is 0 ⁇ 5%.
  • the pharmaceutically acceptable excipient or excipient used in the preparation of the pharmaceutical composition of the present invention in an oral dosage form is not particularly limited, and may be a commonly used excipient or excipient for oral use in the art, for example, the diluent may be selected from starch, pre- a plurality of one or any combination of gelatinized starch, dextrin, powdered sugar, lactose, citric acid, glucose, mannitol, ⁇ -cyclodextrin or microcrystalline cellulose; the disintegrant may be selected from starch, carboxy Sodium methyl starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl fiber A combination of one or any combination of sodium sulphate or cross-linked polyvinylpyrrolidone; the lubricant may be selected from magnesium stearate, sodium lauryl sulfate, stearic acid, talc, PEG 4000, PEG 6000 or micronized silica gel.
  • composition according to the present invention in parts by mass, comprises:
  • cefixime 50 parts of cefixime, 125-2000 parts of ⁇ -cyclodextrin or its derivatives, 30-300 parts of pregelatinized starch, 10-100 parts of microcrystalline cellulose, 2 ⁇ 50 parts of croscarmellose sodium , talc powder 0.5 ⁇ 10 parts, magnesium stearate 0.2-5 parts;
  • cefixime is present in the form of a cyclodextrin inclusion compound.
  • the clopidogrel and the cyclodextrin or a derivative thereof are prepared into a clathrate according to the method described above, and the resulting clathrate is further prepared into a desired oral dosage form in a conventional manner.
  • cefixime as a clathrate can achieve beneficial technical effects of enhancing drug stability, improving drug solubility, improving dissolution and enhancing activity.
  • the prepared oral preparation is significantly more stable under acidic conditions than the conventional preparation containing no cefepoxime cyclodextrin inclusion compound, which is advantageous for improving the oral bioavailability of cefixime.
  • the parenteral administration dosage form may be prepared by using the solid inclusion compound after sterilization treatment as a raw material, or may be prepared by using a liquid clathrate after sterilization treatment; or the above solid inclusion compound or liquid inclusion compound. It may also be sterilized by a suitable method, such as filter sterilization, or sterilized by a suitable method after the preparation is dispensed in a glass bottle, such as hot pressing, without sterilizing. bacteria.
  • the prepared parenteral dosage form may be a solution type aqueous injection, for example, may be prepared by a common aqueous injection production process; or may be a solid powder injection, for example, can be made into a sterile manner by a common aseptic dispensing process. The powder injection can be divided into powder injections, or the freeze-drying powder injection can be prepared by a common freeze-drying process.
  • the pharmaceutical composition of the present invention when the pharmaceutical composition of the present invention is in a parenteral dosage form, the pharmaceutical composition may optionally further comprise a pharmaceutically acceptable excipient or adjuvant for parenteral administration, such as an isotonicity adjusting agent, pH adjustment One or more of a dose and a topical analgesic.
  • a pharmaceutically acceptable excipient or adjuvant for parenteral administration such as an isotonicity adjusting agent, pH adjustment One or more of a dose and a topical analgesic.
  • the present invention is not particularly limited as to a pharmaceutically acceptable excipient or adjuvant for parenteral administration, and it may be an excipient or carrier for injection which is generally used in the art.
  • isotonicity adjusting agents include, but are not limited to, glucose, chlorination Sodium, mannitol, lactose, dextran, fructose or glycerol
  • pH adjusting agents include, but are not limited to, hydrochloric acid, sulfuric acid, citric acid, sodium hydroxide, disodium hydrogen phosphate or sodium dihydrogen phosphate
  • local analgesics include but not It is limited to benzyl alcohol, chlorobutanol, procaine hydrochloride or lidocaine hydrochloride.
  • the glucose, mannitol or dextran and the like also have an osmotic pressure regulating effect.
  • the content of cefixime in a pharmaceutical composition for parenteral administration can be determined according to factors such as a specific dosage form, a suitable population, and the like, and is usually 0.2 to 28.6 wt%.
  • the amount of the above isotonicity adjusting agent, pH adjusting agent and topical analgesic agent is not particularly limited, and those skilled in the art can select them as needed in preparing a specific dosage form.
  • the content of the isotonicity adjusting agent in the pharmaceutical composition is 0-20 wt%, preferably 0-5 wt%; the content of the pH adjuster can be determined according to the pH of the final product, preferably the pH is adjusted to the physiological pH range; the content of the local analgesic agent It is 0 to 3 wt%; the amount of water for injection as a solvent is well known in the art.
  • composition in parts by mass includes:
  • cefixime 50 parts of cefixime, 125-2000 parts of ⁇ -cyclodextrin or its derivatives, 0 200 parts of sodium chloride, 0-500 parts of glucose, 0-2000 parts of lactose, 0-2000 parts of mannitol, water for injection 5,000 to 20,000 parts; wherein the water for injection may be present in the final pharmaceutical composition or removed from the final pharmaceutical composition; the cefixime is present in the form of a cyclodextrin inclusion compound.
  • the above-mentioned water for injection is present in the final pharmaceutical composition; as a lyophilized powder injection, the above-mentioned water for injection is from the final pharmaceutical composition. Remove.
  • cefixime cyclodextrin inclusion compound of the invention obviously increases the solubility of cefixime, the stability of cefixime is significantly enhanced, and the activity is also significantly improved.
  • the cefixime inclusion complex enhances the activity of cefixime and reduces hemolysis, and is suitable for development into various parenteral dosage forms.
  • the method of the invention can prepare the inclusion compound under pure water condition, thereby avoiding the residue of the organic solvent and ensuring the safety of administration.
  • the preparation method of the inclusion compound is simple, simple in operation, easy to control, and free from pollution.
  • the inclusion complex is stable in nature and has good compatibility with pharmaceutical excipients, and the inclusion compound is easy to process.
  • Figure 1 is a UV scan of the inclusion constant.
  • Figure 2 is a raw material of cefixime, hydroxypropyl- ⁇ -cyclodextrin, cefixime hydroxypropyl- ⁇ -cyclodextrin inclusion complex, cefixime and hydroxypropyl- ⁇ -cyclodextrin Differential thermal analysis comparison chart.
  • Figure 3 is a HPLC diagram of the cefixime ⁇ -cyclodextrin inclusion complex in 0 days, 5 days of light, and 5 days of high temperature in the influencing factors.
  • Example 1 The invention is further illustrated by the following examples, but the invention is not limited by the examples.
  • Example 1 The invention is further illustrated by the following examples, but the invention is not limited by the examples.
  • Example 2 Basically the same as in Example 2, but 16 g of sulfobutyl- ⁇ -cyclodextrin was used.
  • Example 2 Basically the same as in Example 2, but 15 g of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin.
  • cyclodextrin mixture ( ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, sulfobutyl- ⁇ -cyclodextrin, hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin 60 g of water and 180 ml of water in a mixture of equal mass ratios.
  • the resulting clathrate can be used to prepare a pharmaceutical composition.
  • cefixime 10g hydroxypropyl- ⁇ -cyclodextrin 1000g and water 1000mL.
  • dilute hydrochloric acid was added dropwise to pH 6.5, and then cooled, and kept at 5 ° C for 24 hours; cold filtered, washed twice with cold water, and dried under reduced pressure at room temperature to obtain a solid clathrate.
  • the resulting clathrate can be used to prepare a pharmaceutical composition.
  • An inclusion complex was prepared by 150 g of hydroxypropyl- ⁇ -cyclodextrin, 300 ml of purified water and 50 g of cefixime. 100 g of the clathrate, 800 g of microcrystalline cellulose, 70 g of talc and 30 g of magnesium stearate were mixed and uniformly placed in a medicinal aluminum foil pouch, sealed, and each bag was equivalent to 50 mg of cefixime.
  • An inclusion complex was prepared by 150 g of hydroxypropyl- ⁇ -cyclodextrin, 300 ml of pure water and 50 g of cefixime. 100 g of the clathrate, 358 g of microcrystalline cellulose and 214 g of sodium carboxymethyl starch were uniformly mixed, wet-granulated with 36 g of 5% starch slurry, dried, and 7 g of magnesium stearate was added, uniformly mixed, and tableted, each piece Contains 50mg of cefixime.
  • An inclusion complex was prepared by 150 g of hydroxypropyl- ⁇ -cyclodextrin, 300 ml of purified water and 50 g of cefixime. 178.4 g of the clathrate, 20 g of microcrystalline cellulose, lg of sodium carboxymethyl starch and 0.6 g of magnesium stearate were mixed, and granulated by wet method with 36 g of 5% starch slurry, dried, added, and mixed. Tablets, each containing 50 mg of cefixime.
  • An inclusion complex was prepared by 250 g of hydroxypropyl- ⁇ -cyclodextrin, 500 ml of purified water and 50 g of cefixime. Take the capsule directly into the capsule, each containing 50mg of cockroach.
  • An inclusion complex was prepared by 100 g of hydroxypropyl- ⁇ -cyclodextrin, 300 ml of purified water and 50 g of cefixime.
  • the obtained clathrate was taken, and 300 g of pregelatinized starch, 10 g of microcrystalline cellulose, 50 g of croscarmellose sodium were added, and the mixture was uniformly ground through a 100 mesh sieve, and dry granulated, and the obtained granules and 0.5 g were obtained.
  • the talc powder and 5 g of magnesium stearate were mixed and sieved through a 16 mesh sieve to form 1000 pieces of cefixime cyclodextrin inclusion tablets, each containing 50 mg of cefixime.
  • An inclusion complex was prepared by treating 2000 g of hydroxypropyl- ⁇ -cyclodextrin, 2000 ml of pure water and 50 g of cefixime.
  • the obtained clathrate is obtained, and 30 g of pregelatinized starch, 100 g of microcrystalline cellulose, 2 g of croscarmellose sodium, 10 g of talc powder, and 0.2 g of magnesium stearate are added and mixed, and directly loaded into medicinal aluminum foil.
  • each bag is equivalent to 50mg of cefixime.
  • the appropriate amount of the clathrate prepared in Example 19 was prepared by adding physiological saline to 50 ml: 100 mg, 250 ml: 100 mg, and 500 ml: 100 mg solutions of cefixime, and 50 ml, 250 ml, and 500 ml were separately dispensed in a glass bottle.
  • Sterilization that is, a pharmaceutical composition of a solution-type injection containing 100 mg of each of the heads.
  • the inclusion compound containing 50 mg of cefixime obtained in Example 19 was added to the other components shown in Table 1 according to the ratio of the formulations A to C shown in Table 1, and prepared into a solution and dispensed in a glass bottle. Then, the solution is freeze-dried according to the preparation process of the freeze-dried powder injection to prepare a pharmaceutical composition containing a lyophilized powder of 50 mg of cefixime.
  • the solutions of the above four formulations are directly encapsulated in a glass bottle, they are prepared into a solution type parenteral administration form, and at this time, the water for injection used remains in the pharmaceutical composition of the present invention.
  • Hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin 100g mixed with 500 ⁇ pure water, heated to a solution, 50g of cefixime was added at 50°C, ethanol was added dropwise until the system was completely dissolved, and 0.45 ⁇ microporous
  • the membrane was filtered and dried under reduced pressure to give a solid clath.
  • the solid inclusion compound and 200 g of NaCl and 2000 g of lactose were dissolved in water for injection, and water for injection was added to 20,000 ml, and sterile filtration was carried out with a 0.22 ⁇ m microporous membrane, and the mixture was dispensed into a 20 ml ampoule. Injectable pharmaceutical compositions.
  • Example 23 2000 g of hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin, mixed with 10000 ml of pure water, heated to a solution, 50 g of cefixime was added at 50 ° C, ethanol was added dropwise until the system was completely dissolved, and 0.45 ⁇ micropores were added. The membrane was filtered and dried under reduced pressure to give a solid clath.
  • the solid inclusion compound and 500 g of glucose and 2000 g of mannitol were dissolved in water for injection, and then water for injection was added to 15000 ml, and sterilely filtered with a 0.22 ⁇ m microporous membrane, and dispensed into a 15 ml ampoule, ie, A pharmaceutical composition for injectables.
  • Hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin 100g mixed with 500ml of pure water, heated to a solution, 50g of cefixime was added at 50 °C, ethanol was added dropwise until the system was completely dissolved, with 0.45 ⁇ microporous
  • the membrane was filtered and dried under reduced pressure to give a solid clath.
  • the solid inclusion compound and NaCl 100g were dissolved in an appropriate amount of water for injection, and then water for injection was added to 5000 ml, and sterilely filtered with a 0.22 ⁇ microporous membrane, and dispensed into a 2 ml ampoule, which was injectable.
  • Pharmaceutical composition 100g, mixed with 500ml of pure water, heated to a solution, 50g of cefixime was added at 50 °C, ethanol was added dropwise until the system was completely dissolved, with 0.45 ⁇ microporous The membrane was filtered and dried under reduced pressure to give a solid clath.
  • Hydroxypropyl-sulfobutyl- ⁇ -cyclodextrin 150g mixed with 200ml of pure water, heated to a solution, 50g of cefixime was added at 50 °C, ethanol was added dropwise until the system was completely dissolved, 0.2 ⁇ 0.4 ⁇ The microporous membrane was filtered, and the filtrate was dehydrated to remove ethanol, and then freeze-dried to obtain a solid clathrate.
  • the inclusion constant Ka of cefixime and cyclodextrin is 833M. -1 ⁇ 1319M-1, which proves that the effect of cefixime and cyclodextrin is sufficiently stable, and the inclusion constant UV scan of the head-clamped ⁇ -cyclodextrin under acidic conditions is shown in Fig. 1.
  • the total molar concentration of fixed cefixime and ⁇ -cyclodextrin is 4.41x10-5 mol/1, so that the molar ratio of cefixime to ⁇ -cyclodextrin is 1: 3, 1: 2, 2: 3, 1 : 1, 3: 2, 2: 1, 3: 1 , Since ⁇ -cyclodextrin has no UV absorption, the mixed phosphate buffer of 6.86 can be used as a blank, and the absorbance is measured at 288 nm, and the same concentration is calculated. The difference between the absorbance values of the cefixime solution ⁇ , and the molar ratio corresponding to the maximum ⁇ is the inclusion ratio. The results of the measurements are shown in Table 4.
  • the inclusion ratio of cefixime to ⁇ -cyclodextrin is 1:1, that is, the two are mainly encapsulated in a molecular ratio of 1:1, and there are other ratios of inclusion.
  • the cefixime raw material and clathrate were separately obtained (the weight ratio of cefixime to sulfobutyl- ⁇ -cyclodextrin was 1:10).
  • a small amount was dissolved in the mobile phase, and ultrasonically obtained to obtain a sample solution.
  • the sample solution was injected under the above chromatographic conditions, and the content of the sample on the 0th day was calculated by the area normalization method at 20 ⁇ each time.
  • the appropriate amount of cefixime raw materials and inclusion complexes were divided into three parts, and the light test, high temperature test and enthalpy humidity test were respectively carried out.
  • the sample was placed in a transparent sealed container, placed in a light box equipped with a fluorescent lamp, placed under 4500 ⁇ 500 LX illuminance for 5 days, sampled and analyzed, and the result was compared with 0 days.
  • the samples were placed in a sealed clean container and placed at 6 °C for 5 days, sampled and analyzed, and the results were compared with 0 days.
  • the sample was placed in a constant humidity container and sampled at room temperature (25 ° C), relative humidity of 90 ⁇ 5% (saturated KN03 solution) for 5 days, and the results were compared with 0 days.
  • cefixime was lower than that of the inclusion compound under high temperature and light conditions.
  • the inclusion compound was placed under light and high temperature for 5 days, the appearance color did not change, the content changed little, and the impurity did not change.
  • high humidity RH90 ⁇ 5%
  • the raw materials were obviously damp, the content was reduced, the inclusion complex was slightly damp, the content was not significantly reduced, and the degradation products and impurities were not increased. The results are shown in Table 5.
  • cefixime raw material and cefixime inclusion compound weight ratio of cefixime and sulfobutyl- ⁇ -cyclodextrin 1: 10
  • cefixime inclusion compound weight ratio of cefixime and sulfobutyl- ⁇ -cyclodextrin 1: 10
  • the results are shown in Table 6.

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Abstract

L'invention concerne une composition pharmaceutique contenant un complexe d'inclusion de cyclodextrine constitué de céfixime, et son procédé de préparation. Les constituants de base de cette composition comprennent : a) du céfixime; b) une cyclodextrine pharmaceutiquement acceptable choisie parmi au moins l'un des composés suivants: β-cyclodextrine, sulfobutyl éther-β-cyclodextrine, hydroxypropyl-β-cyclodextrine,hydroxypropyl-sulfobutyl éther-β-cyclodextrine.
PCT/CN2008/000515 2007-03-14 2008-03-14 Composition pharmaceutique contenant un complexe d'inclusion de cyclodextrine constitué de cefixime, et son procédé de préparation Ceased WO2008110080A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3257505A1 (fr) 2011-07-20 2017-12-20 Hospira, Inc. Compositions contenant du diclofenac destinées au traitement des douleurs postoperatives
CN116672440A (zh) * 2023-07-07 2023-09-01 阜新蒙古族自治县蒙医医院 一种散淤解毒蒙药及其制备方法和应用
CN120501713A (zh) * 2025-07-18 2025-08-19 烟台舜康生物科技有限公司 基于头孢克肟晶型iii制备稳定化药物组合物的方法

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Publication number Priority date Publication date Assignee Title
CN102631684A (zh) * 2012-04-11 2012-08-15 迪沙药业集团有限公司 一种稳定的头孢菌素组合物
CN103908673A (zh) * 2014-01-22 2014-07-09 邓学峰 一种头孢曲松的组合药物
CN114042048B (zh) * 2021-10-29 2023-02-28 海南海灵化学制药有限公司 一种注射用盐酸头孢吡肟的制备工艺
CN120093688B (zh) * 2025-05-07 2025-08-12 康贝音生物医药科技(海南)有限公司 一种高稳定性吡拉西坦注射液的制备工艺及质量控制方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4616008A (en) * 1984-05-02 1986-10-07 Takeda Chemical Industries, Ltd. Antibacterial solid composition for oral administration
CN1037652A (zh) * 1988-04-19 1989-12-06 明治制菓株式会社 口服抗菌组合物
CN1593423A (zh) * 2004-06-18 2005-03-16 余安国 供注射用的头孢克肟药物复合物
CN1981765A (zh) * 2005-11-23 2007-06-20 兰贝克赛实验室有限公司 头孢泊肟酯和环糊精的药物组合物及其制备方法
CN100998595A (zh) * 2007-01-19 2007-07-18 南京师范大学 含有头孢特伦酯环糊精包合物的药物组合物及其制备方法
CN101002782A (zh) * 2007-01-10 2007-07-25 南京师范大学 含有头孢呋辛酯环糊精包合物的药物组合物及其制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4616008A (en) * 1984-05-02 1986-10-07 Takeda Chemical Industries, Ltd. Antibacterial solid composition for oral administration
CN1037652A (zh) * 1988-04-19 1989-12-06 明治制菓株式会社 口服抗菌组合物
CN1593423A (zh) * 2004-06-18 2005-03-16 余安国 供注射用的头孢克肟药物复合物
CN1981765A (zh) * 2005-11-23 2007-06-20 兰贝克赛实验室有限公司 头孢泊肟酯和环糊精的药物组合物及其制备方法
CN101002782A (zh) * 2007-01-10 2007-07-25 南京师范大学 含有头孢呋辛酯环糊精包合物的药物组合物及其制备方法
CN100998595A (zh) * 2007-01-19 2007-07-18 南京师范大学 含有头孢特伦酯环糊精包合物的药物组合物及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Derwent World Patents Index; AN 2005-419893 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3257505A1 (fr) 2011-07-20 2017-12-20 Hospira, Inc. Compositions contenant du diclofenac destinées au traitement des douleurs postoperatives
CN116672440A (zh) * 2023-07-07 2023-09-01 阜新蒙古族自治县蒙医医院 一种散淤解毒蒙药及其制备方法和应用
CN120501713A (zh) * 2025-07-18 2025-08-19 烟台舜康生物科技有限公司 基于头孢克肟晶型iii制备稳定化药物组合物的方法

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