WO2008110080A1

WO2008110080A1 - Medical composition containing cyclodextrin inclusion compound of cefixime and its preparation method

Info

Publication number: WO2008110080A1
Application number: PCT/CN2008/000515
Authority: WO
Inventors: Yong Ren; Xiaojie Wang; Xueqin Ma
Original assignee: Nanjing Normal University; Nanjing J. One Medical Technology Development Co., Ltd.
Priority date: 2007-03-14
Filing date: 2008-03-14
Publication date: 2008-09-18
Also published as: CN101264086A

Abstract

A medical composition containing the cyclodextrin inclusion compound of cefixime and its preparing method. Its basic components comprise a) cefixime, and b) a pharmaceutically acceptable cyclodextrin; said cyclodextrin is one or more components chosen from β-cyclodextrin, sulfobutyl ether-β-cyclodextrin,hydroxypropyl-β-cyclodextrin,hydroxypropyl-sulfobutyl ether-β-cyclodextrin.

Description

Pharmaceutical composition containing cefixime cyclodextrin inclusion compound and preparation method thereof

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. Currently, 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 β-lactam antibacterial drug that is second only to amoxicillin in the world, and is the preferred treatment for gonorrhea in the World Health Organization. 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. At present, 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 α. -, 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". Its special structure enables CD to form a supramolecular body (clustered compound) with weak organic and molecular molecules in a variety of spatially suitable organic small molecules, thereby improving the partial physicochemical properties of small organic molecules, and has been widely used to improve the physical and chemical properties of drugs. Performance, reducing side effects such as drugs. Cyclodextrins and their derivatives which have been proven to be useful for injection include α-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin (Expert Opin Drug Deliv, 2005 Mar; 2(2): 335 - 51). Oral cyclodextrin and its derivatives Cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin. At present, we have developed a new type of cyclodextrin derivative in which hydroxypropyl-sulfobutyl-β-cyclodextrin (HP-SBE-β-cyclodextrin) is a mixture of hydroxypropyl and sulfobutyl groups.

(CN 1800221A), this product has excellent performance, and it has been proved to be safe for oral administration or for injection administration.

At present, 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. More importantly, the 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. At present, 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.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising a cefixime cyclodextrin inclusion compound, the basic composition of which comprises:

a) cefixime, and

b) pharmaceutically acceptable cyclodextrin.

The pharmaceutically acceptable cyclodextrin is selected from one or more of α-cyclodextrin, cyclodextrin, quinone-cyclodextrin and derivatives thereof; preferably selected from β-cyclodextrin, hydroxypropyl One or more of benzyl-β-cyclodextrin, sulfobutyl ether cyclodextrin and hydroxypropyl-sulfobutyl-β-cyclodextrin; further preferably hydroxypropyl-sulfobutyl-β-cyclodextrin fine.

Preferably, in the cyclodextrin used in the present invention, the molecular weight of β-cyclodextrin is 1135; hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin and hydroxypropyl-sulfobutyl group - The average molecular weight of β-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.

In the clathrate of the present invention, the mass ratio of cefixime to cyclodextrin is 1:2.5 1 :100, preferably 1:1:50:50, more preferably 1:5-1:30.

In the cefixime cyclodextrin inclusion compound of the present invention, 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. Among them, 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. Since cyclodextrin has many uses, in many cases, 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 (β-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 β-cyclodextrin inclusion cefixime has a large inclusion constant, the drug still has the inclusion form as the main form.

In the preparation of the clathrate, a portion of the excess cyclodextrin which is usually added is present in admixture with the clathrate in free form. In the preparation of the preparation, 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:

a) taking 1 part by mass of cefixime and 2.5 100 parts by mass of cyclodextrin;

b) mixing 1~5 times of pure water according to the mass of cyclodextrin with cyclodextrin to prepare a suspension or solution; c) adding a cefacazole bulk drug;

d) completely or evenly dissolve the system by one or more of the following processes - i) thoroughly mixing and grinding at room temperature,

Ii) heating and stirring,

Iii) adjust the pH value, then stir and stir. Iv) adding an appropriate amount of ethanol, heating and stirring;

e) stirring for several hours, allowing to stand for more than 10 hours;

f) After filtration, it is dried under reduced pressure or directly freeze-dried to obtain a clathrate.

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.

More specifically, the present invention provides 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 pharmaceutical composition containing the cefacoxime cyclodextrin inclusion compound has sufficient stability, the inclusion stability constant of different cyclodextrin is Ka=833~1666M-l, and other medicinal excipients added to the cefacoxime cyclodextrin The stability and solubility of the fine inclusion compound have no effect.

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. Such oral dosage forms include, but are not limited to, tablets, capsules, granules, sustained release tablets or dispersible tablets and the like. The parenteral dosage forms include, but are not limited to, freeze-dried powder injections, sterile powder injections, small-volume injections, and large-volume infusion solutions.

When the pharmaceutical composition of the present invention is in an oral dosage form, the pharmaceutical composition 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.

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. Generally, 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, β-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. One or any combination of the plurality; the wetting agent or binder may be selected from one of water, ethanol, starch, sodium carboxymethylcellulose, hydroxypropylmethylcellulose or dextrin or A variety of any combination.

Still further, a specific embodiment of the pharmaceutical composition according to the present invention, in parts by mass, comprises:

50 parts of cefixime, 125-2000 parts of β-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;

Among them, 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.

The inclusion of 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.

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.

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. For example, 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. Generally, 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.

Further, a specific embodiment of the pharmaceutical composition in parts by mass includes:

50 parts of cefixime, 125-2000 parts of β-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.

It will be readily understood by those skilled in the art that, as a solution type parenteral administration form, 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.

The 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. DRAWINGS

Figure 1 is a UV scan of the inclusion constant.

Figure 2 is a raw material of cefixime, hydroxypropyl-β-cyclodextrin, cefixime hydroxypropyl-β-cyclodextrin inclusion complex, cefixime and hydroxypropyl-β-cyclodextrin Differential thermal analysis comparison chart.

Figure 3 is a HPLC diagram of the cefixime β-cyclodextrin inclusion complex in 0 days, 5 days of light, and 5 days of high temperature in the influencing factors.

detailed description

(1) Preparation Example

The invention is further illustrated by the following examples, but the invention is not limited by the examples. Example 1

10 g of β-cyclodextrin was mixed with 10 ml of pure water, heated, and 4.0 g of cefixime (equimolar) was added at 50 Torr, mixed well for 3 hours, and then cooled at 5 ° C for 24 hours; It was washed twice with water and dried under pressure at room temperature to obtain a solid clathrate.

Example 2:

14 g of hydroxypropyl-β-cyclodextrin was mixed with 20 ml of pure water, heated, and 4.0 g of cefixime was added at a temperature of 50 Torr. The mixture was stirred and dissolved by adding a dilute alkali, and then neutralized by neutral acid to neutralize. The mixture was cooled by stirring, then filtered through a 0.25 membrane, and dried under reduced pressure at 50 ° C to obtain a solid clathrate.

Example 3:

Basically the same as in Example 2, but 16 g of sulfobutyl-β-cyclodextrin was used.

Example 4:

Basically the same as in Example 2, but 15 g of hydroxypropyl-sulfobutyl-β-cyclodextrin.

Example 5'·

Take 10g cefixime and 100g sulfobutyl-β-cyclodextrin; mix and dissolve cyclodextrin 300g pure water, add cefixime, mix well, stir for 8 hours, press filter, wash the solids, dry, get solid Inclusion compound.

Example 6:

Take 10g cefixime and 50g hydroxypropyl-β-cyclodextrin; mix and dissolve cyclodextrin 100g pure water, add cefixime, mix well, stir for 6 hours, press filter, direct drying under reduced pressure, then solid Inclusion compound.

Example 7

Take cefixime 10g, cyclodextrin mixture (β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, hydroxypropyl-sulfobutyl-β-cyclodextrin 60 g of water and 180 ml of water in a mixture of equal mass ratios. Mix the cyclodextrin with water and add Cefixime, fully mixed and milled for 5 hours to make the system completely uniform, stirred for 3 hours, allowed to stand at room temperature for 12 hours, 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.

Example 8

Take cefixime 10g, β-cyclodextrin 25g and water 125ml. Mix the cyclodextrin with water, heat to 6 (TC, keep adding cefixime at this temperature and mix well for 3 hours, then add dilute NaHC03 solution dropwise to the system pH 8.8~9.0, add 1 hour later Diluted hydrochloric acid to pH 6.5~6.7, then cooled, allowed to stand at 5 ° C for 24 hours; cold filtered, washed twice with cold water, and dried at room temperature under vacuum to obtain a solid clathrate. The obtained clathrate can be used to prepare a pharmaceutical composition. .

Example 9

Take cefixime 10g, hydroxypropyl-β-cyclodextrin 1000g and water 1000mL. Mix the cyclodextrin with water, heat to 50 ° C, add cefixime, stir for 1 hour, then add dilute NaHC03 solution dropwise. To the system pH 8.5, after stirring for 1 hour, 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.

Example 10

10 g of cefixime, 30 _{g of} sulfobutyl-β-cyclodextrin and 90 ml of water were taken. Mix the cyclodextrin with water, heat, add cefixime at 40 ° C, mix well for 3 hours, then add dilute NaHC03 solution dropwise to the system pH 8.5~9.0, and add dilute hydrochloric acid 1 hour later. The pH was 6.5 to 7.0, 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.

Example 11:

10 g of cefixime, 500 g of hydroxypropyl-indolyl-β-cyclodextrin and 1000 ml of water were taken. Mix the cyclodextrin with water, heat, add cefixime at 40 °C, mix well for 3 hours, then add dilute NaHC03 solution dropwise to the system pH 8.5~9.0, and add dilute hydrochloric acid to pH 6.5 after 1 hour. ~7.0, then cooled, 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.

Example 12:

150 g of hydroxypropyl-β-cyclodextrin was mixed with 300 ml of pure water, heated, and 50 g of cefixime was added at a temperature of 50 ° C, mixed well, and then diluted NaHC03 solution was added dropwise to pH=8.0, and cooled to room temperature. The mixture was thoroughly mixed and ground for 3 hours, then adjusted to pH = 7.0 with dilute HC1 acid solution, and cooled at 5 ° C for 24 hours; filtered, washed once with water, and dried under reduced pressure at room temperature to obtain a solid clathrate. 200g of solid inclusion compound (containing 50g of cefixime) was mixed with 100g of pregelatinized starch, 50g of microcrystalline cellulose, 10g of croscarmellose sodium, ground evenly through 100 mesh sieve, and dry granulated. The granules were mixed with 2.0 g of talc, 1.0 g of magnesium stearate, and sieved through a 16 mesh sieve to obtain 1000 cefixime inclusion tablets, each containing cefixime. Example 13:

An inclusion complex was prepared by 150 g of hydroxypropyl-β-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.

Example 14

An inclusion complex was prepared by 150 g of hydroxypropyl-β-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.

Example 15 _:

An inclusion complex was prepared by 150 g of hydroxypropyl-β-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.

Example 16:

An inclusion complex was prepared by 250 g of hydroxypropyl-β-cyclodextrin, 500 ml of purified water and 50 g of cefixime. Take the capsule directly into the capsule, each containing 50mg of cockroach.

Example 17

An inclusion complex was prepared by 100 g of hydroxypropyl-β-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.

Example 18

An inclusion complex was prepared by treating 2000 g of hydroxypropyl-β-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. In the bag, sealed, each bag is equivalent to 50mg of cefixime.

Example 19

250g of hydroxypropyl-sulfobutyl-β-cyclodextrin, mixed with 500ml of pure water, heated to a solution, at a temperature of 50 ° C 50 g of cefixime was added thereto, ethanol was added dropwise until the system was completely dissolved, and the mixture was filtered through a 0.22 μηη microporous membrane. The filtrate was dehydrated under reduced pressure for further 2 hours, and then dried under reduced pressure to obtain a solid clathrate.

Example 20

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.

Example 21:

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.

Table 1. Distribution ratio of cefixime cyclodextrin inclusion compound freeze-dried powder injection

*Note: The above water for injection is lyophilized and finally removed from the product. In the pharmaceutical composition of the final product lyophilized powder, only a small amount of residual, pharmaceutically acceptable water is present.

Further, after 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.

Example 22

Hydroxypropyl-sulfobutyl-β-cyclodextrin 100g, mixed with 500πύ 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 0.45μιη 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 μm microporous membrane, and the mixture was dispensed into a 20 ml ampoule. Injectable pharmaceutical compositions.

Example 23 2000 g of hydroxypropyl-sulfobutyl-β-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 μιη 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 μm microporous membrane, and dispensed into a 15 ml ampoule, ie, A pharmaceutical composition for injectables.

Example 24

Hydroxypropyl-sulfobutyl-β-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 0.45μπι 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 μπν microporous membrane, and dispensed into a 2 ml ampoule, which was injectable. Pharmaceutical composition.

Example 25:

Hydroxypropyl-sulfobutyl-β-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, 0.2~0.4μηι The microporous membrane was filtered, and the filtrate was dehydrated to remove ethanol, and then freeze-dried to obtain a solid clathrate.

15 g of the obtained clathrate was added, dissolved in 100 ml of water for injection, dissolved in 1.7 g of sodium chloride to dissolve, and water for injection was added to 200 ml, and sterile-filtered with a 0.22 μηι microporous membrane, and dispensed into a 2 ml ampoule, ie, A pharmaceutical composition for injectables.

Example 26

150 g of hydroxypropyl-sulfobutyl-β-cyclodextrin, mixed with 200 ml of pure water, heated to a solution, 5 g of cefixime was added at 50 Torr, ethanol was added dropwise until the system was completely dissolved, and 0.2~0.4 μιη micropores were added. The membrane was filtered, and the filtrate was stirred under reduced pressure for 2 hours, and the mixture was sterilized to obtain a liquid clathrate.

Take 10g of the obtained clathrate, add 80ml of water for injection, add 3g of benzyl alcohol, stir to dissolve, add water to 100ml, sterilely filter with 0.22μηι microporous membrane, and dispense into 2ml ampoules. A pharmaceutical composition for injection.

(2) Experimental examples

The invention is further illustrated by the following examples in order to provide a better understanding of the invention.

1. The inclusion constant of cefixime and cyclodextrin

a. Determine the inclusion constant under neutral conditions:

Prepare a dilute solution of cefixime with pH 6.86 mixed phosphate buffer solution, and then prepare various cyclodextrins with this dilute solution. Solution. Obtain a certain volume of cefixime dilute solution UV scanning to obtain the UV absorption value (A0) at 288nm wavelength, change the concentration of cyclodextrin to 1.53xl0-4~9.6xl0-4mol/L, UV scan of each group of different cyclops The UV absorption of the concentration system (Al~An) is given by: 1 / ΔΑ = 1 / (Δε Ka [G]0[CD]0) + 1 / Δε [G]0 (where ΔΑ = An~A0, [ The total concentration of CD]0 cyclodextrin, the total concentration of [G]0 cefixime, Δε is the difference between the molar absorptivity of the mixture of cefixime and cyclodextrin, and the data is compiled according to the formula 1/[CD ]0 and 1/ΔΑ, plotted as 1/[CD]0 with 1/ΔΑ, the inclusion constant Ka of the cefixime cyclodextrin inclusion complex can be obtained from the intercept/slope of the formula. Under this condition, the inclusion constant Ka of ruthenium and cyclodextrin was 931M-1 1666M-1, which proved that the effect of cefixime and cyclodextrin was sufficiently stable.

b. Determination of inclusion constants under acidic conditions:

The dilute solution of cefixime described in a is adjusted to pH=3 with dilute hydrochloric acid, and the determination method is the same as that under neutral conditions. Under this condition, 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 β-cyclodextrin under acidic conditions is shown in Fig. 1.

Table 2. Inclusion constants of cefixime and various cyclodextrins

Ka (M-l)

Cyclodextrin

H 6.86 pH 3.0 β-cyclodextrin 931 833 Hydroxypropyl-β-cyclodextrin 1666 1148 Sulfobutyl-β-cyclodextrin 1431 1319 Hydroxypropyl-sulfobutyl-β-cyclodextrin 1411 1223

2, inclusion compound differential thermal analysis verification test

Weigh 5.0mg of each of the four samples of cefixime, cyclodextrin, cefixime and cyclodextrin, and inclusion complexes for differential scanning calorimetry: A1203 reference, range ±50μν, temperature range 40° C~400 ° C, heating rate 10 ^o C / min, DTA map. The results show that the physical mixture maintains the endothermic peak of cyclodextrin and cefixime, which is basically the superposition of each compound, and on the map of the inclusion complex, the position (temperature) and shape (thermal effect) of each peak occur. With the change, it is speculated that the inclusion compound has formed. The differential thermal analysis of each sample is shown in Figure 2.

3. Determination of solubility of inclusion complexes

Img/mL of cefacoxime mother liquor was prepared by mixing pH 6.86 mixed phosphate buffer solution, then diluted with purified water to a series solution of 0.002 mg/mL~0.02 mg/mL, water was used as a reference, and ultraviolet absorption A was measured at 288 nm. A A standard curve was plotted against concentration C (mg/mL) and A-46.973C+ 0.0105 (r = 0.9984) was obtained.

Prepare a certain amount of cefixime and inclusion complex solution in pure water, shake at 25 °C ± rC for 72h, filter, let stand, remove the appropriate amount of filtrate, dilute the buffer, measure the light absorption intensity at 288nm, according to the standard curve The solubility of the cefixime and the clathrate was 25, and the solubility of each clathrate was shown in Table 3.

Table 3. Solubilization of different cyclodextrins on the head

Sample solubility (mg/ml) solubilization multiple

- 1.08 ― β-cyclodextrin 11.39 10.55

Hydroxypropyl-β-cyclodextrin 20.07 18.58

Sulfobutyl-β-cyclodextrin 41.41 38.34 Hydroxypropyl-sulfobutyl-β-cyclodextrin 41.27 38.21

It can be seen from the table that the solubility of cefixime after cyclodextrin inclusion is greatly improved, and the highest is increased by more than 39 times, which will help to improve the bioavailability of cefixime.

4. Determination of inclusion ratio (continuous gradient test)

The total molar concentration of fixed cefixime and β-cyclodextrin is 4.41x10-5 mol/1, so that the molar ratio of cefixime to β-cyclodextrin is 1: 3, 1: 2, 2: 3, 1 : 1, 3: 2, 2: 1, 3: 1 , Since β-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 ΔΑ, and the molar ratio corresponding to the maximum ΔΑ is the inclusion ratio. The results of the measurements are shown in Table 4.

Table 4, inclusion ratio measurement results

Cefixime: β-cyclodextrin ΔΑ ( 10-3 )

1 : 3 1

1 : 2 2

2: 3 2

1 : 1 15

3 : 2 8

2: 1 2

3 : 1 4

As can be seen from the table, the inclusion ratio of cefixime to β-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.

5. Experiments on the influencing factors Chromatographic conditions: Column: Lichrospher C18 column (4.6mmx200nim, 5μπι), mobile phase: containing ammonium acetate 0.015mol / L acetonitrile - aqueous solution (acetonitrile: water = 5: 95), UV detection wavelength: 232nm, flow rate: lmL / min , Column temperature: 33. C.

The cefixime raw material and clathrate were separately obtained (the weight ratio of cefixime to sulfobutyl-β-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 μ each time. In addition, 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.

1) Lighting test:

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.

2) High temperature test:

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.

3) High humidity test:

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.

test results:

The content of 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. When placed under 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.

Table 5. Investigation results of influencing factors 0 days Light 5 days Heating 5 days High humidity 5 days

Cefixime raw material 95.46 93.67 92.37 91.48

Inclusion complex 95.45 95.58 94.39 94.25

6, acid stability investigation

Chromatographic conditions: Same as before.

Take cefixime raw material and cefixime inclusion compound (weight ratio of cefixime and sulfobutyl-β-cyclodextrin 1: 10), and make up to 5mL with hydrochloric acid solution of pH 10, respectively, and let stand Sampling every 2 hours, neutralizing with an appropriate amount of lye, Dilution, injection, calculation (area normalization method). The results are shown in Table 6.

Table 6. Results of acid stability investigation

Rest time

Sample content (%)

Oh 2h 4h 6h 8h cefixime raw material 94.66 95.67 91.63 91.19 90.99 Cefixime β-cyclodextrin inclusion complex 94.84 94.69 94.79 93.78 93.53 The test results show that the content of cefixime β-cyclodextrin inclusion compound under acidic conditions The change is not big, and the stability is obviously better than the raw material of cefixime. The acidity of the inclusion complex was tl/2 = 270.90, and the acid hydrolysis of the cefixime was tl/2 = 99.25. The inclusion stability of cefixime increased the acid stability by more than 2.7 times.

7. Antibacterial activity

Determination of Cefixime sulfonate-β-cyclodextrin inclusion complex by agar dilution method (inclusion ratio 1:10 (SP, weight ratio of cefixime to sulfobutyl-β-cyclodextrin 1: 10) )) In vitro antibacterial activity with cefixime, the results are shown in Table 7.

Table 7. In vitro antibacterial activity of cefixime before and after inclusion

MIC (μ§/πι1)

Sample

ATCC25922 ATCC27853 ATCC25923 Inclusion Complex 1.0 32 2.0 Non-inclusion 0.5-1.0 >128 16-32 The results showed that there was no difference in the activity of Escherichia coli (ATCC25922) before and after inclusion. However, after inclusion, Cefixime increased the activity of Pseudomonas aeruginosa (ATCC27853) by 4.0-fold, and the activity of Staphylococcus aureus (ATCC25923) was also significantly different. The inclusion increased the activity by 8.0-16.0 times. This will be beneficial to the new low-dose cefixime preparation, especially for the clinical use of patients with kidney disease.

Claims

Rights request

A pharmaceutical composition comprising a clopidogrel cyclodextrin inclusion compound, the basic composition comprising - a) cefixime, and

b) a pharmaceutically acceptable cyclodextrin;

The cyclodextrin is selected from one of β-cyclodextrin, sulfobutyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin or hydroxypropyl-sulfobutyl-β-cyclodextrin. Kind or more.

2. The pharmaceutical composition according to claim 1, wherein the mass ratio of cefixime to cyclodextrin is 1:2.5 to 1:100.

The pharmaceutical composition according to claim 2, wherein the mass of the cefixime and the cyclodextrin is from 1:3 to 1:50.

The pharmaceutical composition according to claim 1, wherein the cefixime cyclodextrin inclusion compound has a molecular inclusion ratio of 1:1 to 1:5.

The pharmaceutical composition according to claim 2, wherein the cefixime cyclodextrin inclusion compound has a molecular inclusion ratio of 1:1 to 1:5.

6. A pharmaceutical composition according to any one of claims 1 to 5 which is in an oral dosage form.

7. The pharmaceutical composition according to claim 6, in parts by mass, comprising:

50 parts of cefixime, 125-2000 parts of β-cyclodextrin or its derivatives, 30-300 parts of pregelatinized starch, 10~100 parts of microcrystalline cellulose, and croscarmellose sodium 2~5. Serving, talcum powder 0.5-10 parts, magnesium stearate 0.2-5 parts;

Among them, cefixime is present in the form of a cyclodextrin inclusion compound.

The pharmaceutical composition according to any one of claims 1 to 5, which is a parenteral dosage form.

9. The pharmaceutical composition according to claim 8, which comprises - by mass Head holding 50 parts, β-cyclodextrin or its derivatives 125-2000 parts, sodium chloride 0-200 parts, glucose

0~2000 copies,

0-2000 parts of mannitol, and water for injection is added to 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 It exists in the form of a cyclodextrin inclusion compound.

The method for preparing a pharmaceutical composition according to any one of claims 1 to 9, which comprises the preparation of a cefixime cyclodextrin inclusion compound, the preparation of the cefacidine cyclodextrin inclusion compound comprising the following steps :

a) taking 1 part by mass of cefixime and 2.5 to 100 parts by mass of cyclodextrin;

b) mixing 1~5 times of pure water according to the mass of cyclodextrin with cyclodextrin to prepare a suspension or solution; c) adding a raw material to the head;

d) completely or evenly dissolve the system by one or more of the following steps - i) thoroughly mixing and grinding at room temperature,

Ii) heating and stirring,

Iii) adjust the pH value, then stir and stir.

Iv) adding an appropriate amount of ethanol to heat and stir;

e) stirring for several hours, allowing to stand for more than 10 hours;