WO2008110079A1 - Medical composition containing cyclodextrin inclusion compound of cefdinir and its preparation method - Google Patents

Abstract

A medical composition containing the cyclodextrin inclusion complex of cefdinir and the preparing method thereof. Its basic components comprise a) cefdinir, 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 cefdinir cyclodextrin inclusion compound and preparation method thereof

 The present invention relates to a pharmaceutical composition comprising a cephalosporin antibiotic cyclodextrin inclusion compound and a process for the preparation thereof. Background technique

 Cefdinir; cefuroxime axetil, trade name: cefdinil or Cefzon, chemical name: [6ϋ-[6 α ,7 β (ζ)]]-7-[[(2-amino- 4-thiazolyl)-(indolyl)acetyl]amino]-3-vinyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid , Molecular formula: C14H13N505S2, Molecular weight: 395.42. The dosage of this product for routine use is about 100mg each time, 3 times a day; the routine dose for children is 9~18mg kg per day, divided into 3 times. Cefdinir is the third generation of new oral cephalosporin antibacterial drugs. The characteristic structure of the aminothio thiol side chain not only enhances the antibacterial activity against Gram-negative bacteria and the stability to β-lactamase, but also has strong Gram-positive cocci activity, especially S. aureus has stronger antibacterial activity than many cephalosporins. Another feature of this drug is oral administration. Cefdinir has a faster absorption in the gastrointestinal tract and a wide distribution of tissues. For the treatment of pneumonia, acute exacerbation of chronic bronchitis, acute maxillary sinusitis, pharyngitis, tonsillitis, acute bacterial otitis media, simple skin and tissue infections. Clinically, it has good effects on upper and lower respiratory tract infections and skin and soft tissue infections. The adverse reactions are similar to those of other cephalosporins, and diarrhea is common.

 Children take up quickly after oral cefdinir and the time to peak plasma concentration (Tmax) is about 2 hours. In children, cefdinir was given an effective oral dose of 3~6mg/kg. After 2.5h, the plasma mass concentration could reach 0.92~ 1.31mg/L, and the cefdinir half-life was 1.8~1.9h. Food has no significant effect on the bioavailability of cefdinir, but overall bioavailability is low, oral bioavailability of fast-food is 16-21%, and post-prandial bioavailability is 25% (suspension). At present, six cefdinir dosage forms have been developed and approved for domestic market, namely capsules, tablets, dispersible tablets, granules, dry suspensions and chewable tablets.

 Cyclodextrin (CD) is a cyclic oligosaccharide natural product obtained by cyclization of cyclodextrin glucan translocating enzyme and is composed of 6 to 15 glucose molecules, usually α. -, β- and cyclodextrin, consisting of 6, 7 or 8 glucose units, respectively. --cyclodextrin is a truncated cone composed of 7 glucose units linked by glycosidic bonds, and has a special molecular structure of "internal hydrophobicity, external hydrophilicity". Its special structure enables the cyclodextrin to form a supramolecular (inclusion complex) with weak organic and molecular molecules in a variety of spatially suitable organic small molecules, thereby improving the physical and chemical properties of organic small molecules. In the pharmaceutical industry, cyclodextrin has been widely used to improve the physical and chemical properties of drugs and reduce side effects.

There are currently three types of cyclodextrins and their derivatives that have been proven to be injected, namely: α-cyclodextrin, hydroxy Propyl-β-cyclodextrin and sulfobutyl-β-cyclodext (Expert Opin Drug Deliv, 2005 Mar; 2(2): 35-51). Oral cyclodextrin and its derivatives include β-cyclodextrin, hydroxypropyl cyclodextrin and sulfobutylcyclodextrin. Recently, we have developed a new cyclodextrin derivative: hydroxypropyl-sulfobutyl-cyclodextrin (CN 1800221A), which has excellent properties and high safety, ie it can be used orally or injection.

 At present, research on cefdinir administration technology mainly focuses on techniques such as oral tablets and capsules, but there are widespread problems such as low oral bioavailability. The cyclodextrin inclusion technique is used for the preparation of cefdinir, which will improve the water solubility of the drug, increase the stability of the drug, and improve the bioavailability of the oral drug in the human body. The poor water solubility of cefdinir raw materials limits the development and development of cefdinir injection formulations. The present study shows that cyclodextrin has a significant solubilization effect on cefdinir, of which cefdinir/sulfobutyl- The cyclodextrin inclusion complex (the mass ratio of cefdinir to sulfobutyl-β-cyclodextrin is 1: 5) The maximum solubilization ratio is more than 170 times, and the solubility in water is increased from 0.27 mg/mL to about 46 mg/ mL, greatly improved the solubility and stability of cefdinir in water. After the inclusion, the antibacterial activity of Cefdinir's Staphylococcus aureus (ATCC25923) increased by 7.8 times to 15.6 times, which highlighted the activity characteristics of the drug. The inclusion technology laid the foundation for the development and development of various formulations of cefdinir. The current research on the preparation of cefdinir by cyclodextrin has not been reported. Summary of the invention

 One of the objects of the present invention is to provide a pharmaceutical composition of cefdinir cyclodextrin inclusion complex, which comprises inclusion of cefdinir with a cyclodextrin to obtain a clathrate having good stability of the main drug. The pharmaceutical composition obtained by the composition can improve the solubility of cefdinir, increase the stability, reduce the side effects, and obtain a new formulation of the crustacean which has 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 the further improvement of the pharmaceutical properties of cefdinir and the convenience of clinical application by the addition of cyclodextrin and optionally other pharmaceutical excipients.

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

 a) Cefdinir, and .

 b) pharmaceutically acceptable cyclodextrin.

The pharmaceutically acceptable cyclodextrin is selected from one of 0-cyclodextrin (01 0), 3-cyclodextrin (30), Y-cyclodextrin (Y-CD) and derivatives thereof. Or more; preferably selected from the group consisting of Ρ-cyclodextrin, sulfobutyl-cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin and hydroxypropyl-sulfobutyl-β One or more of cyclodextrin; more preferably Hydroxypropyl-sulfobutyl-β-cyclodextrin.

 Preferably, in the cyclodextrin seed used in the present invention, the molecular weight of β-cyclodextrin is 1135; hydroxypropyl-3-cyclodextrin, sulfobutyl-P-cyclodextrin and hydroxypropyl-sulfobutyl group - The average molecular weight of β-cyclodextrin is: 1297~1744, 2089~2264 and 1353~2625, the mass ratio of cefdinir to cyclodextrin 1:1 molecular inclusion ratio according to the molecular weight of different cyclodextrin, The scale range is: 1:2.87~ 1 :6.65ο

 In the clathrate of the present invention, the mass ratio of cefdinir to cyclodextrin is 1:2.8 to 1:100, preferably 1:3 to 1:50, more preferably 1:5 to 1:30. .

 The clathrate of the present invention is a clathrate prepared by the inclusion process using cefdinir as a guest molecule and cyclodextrin as a host molecule. Among them, cefdinir in which a cyclodextrin of a plurality of host molecules is contained in one guest molecule, or cefdinir in which a cyclodextrin of one host molecule contains one guest molecule may be used. 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 pharmaceutical properties of cefdinir and for the technical requirements of various dosage forms; in some cases it may also be possible to use cyclodextrin 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 1:2.8, and the ratio of the drug to the cyclodextrin molecule is 1: 1.026, although the cyclodextrin is only slightly excessive. However, since the cyclodextrin inclusion cefdinir has a large inclusion constant, the drug is still mainly in the form of inclusion complex.

 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 addition to the unsuited free cyclodextrin; of course, in most cases of pharmaceutical applications, The encapsulated free cyclodextrin is present in admixture with the clathrate and is used directly to prepare a pharmaceutical composition without removal to prepare a pharmaceutical composition for oral or parenteral administration.

 The invention also provides a preparation method of the pharmaceutical composition of the invention, which comprises the preparation of the cefdinir cyclodextrin inclusion compound, the preparation of the budesonide cyclodextrin inclusion compound comprises the following steps - a Taking 1 part by mass of budesonide and 2.8 100 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 cefdinir bulk drug;

 d) completely or evenly dissolve the system by one or more of the following processes:

 i) Mix and grind at room temperature,

 Ii) heating and stirring,

Iii) adjust the pH value, then stir and stir. 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 cefdinir cyclodextrin inclusion compound, wherein the mass ratio of budesonide to cyclodextrin is 1:2.8 to 1:100, inclusion complexes and others The pharmaceutical excipients are formulated in a conventional formulation ratio to prepare a composition suitable for clinical use. The pharmaceutical composition containing the cefdinir cyclodextrin inclusion compound has sufficient stability, the inclusion stability constant of different cyclodextrins is Ka = 2226M-l ~ 11620M-l, and other pharmaceutical excipients added to cefdinir The stability and solubility of the cyclodextrin inclusion compound have no effect.

 The formation of a stable inclusion complex of cyclodextrin and cefdinir is the technical basis of the present invention. Cefdinir has poor water solubility and strong molecular lipophilicity. After mixing with cyclodextrin in aqueous solution, the hydrophobic cavity of the cyclodextrin (inner diameter 7.84A~9.07A) has enough space to accommodate the lipophilic crustacean molecule ( 4.17~6.35A), after cefdinir enters the cyclodextrin cavity, the inclusion water in the cavity is removed (up to 10~12 molecules of water), thereby forming a stable inclusion complex, which reaches a stable state after molecular inclusion, and reduces The possibility of external interference, so that the stability of cefdinir molecules is enhanced; since cyclodextrin has higher water solubility than cefdinir, the solubility of cefdinir in the inclusion state is also improved. The addition of water-soluble organic solvents during the inclusion process can increase the solubility of cefdinir and accelerate the formation of inclusion. However, organic solvents are more likely to participate in the competition between cefdinir and cyclodextrin inclusion. Therefore, the general situation The organic solvent is not added or added as little as possible during the preparation of the cefdinir clathrate. The mass ratio of cefdinir (molecular weight 395.42) to β-cyclodextrin equimolar inclusion (1:1 molecular inclusion) is 1:2.8, and the molecular weight of sulfobutyl-β-cyclodextrin (average molecular weight) The mass ratio of equimolar inclusions in the range of 2200 was 1:5.6. The actually prepared pharmaceutical composition is often added with an excess of cyclodextrin, and the excess cyclodextrin can act as an excipient or co-solvent to exert a pharmaceutical effect other than inclusion.

 The solid inclusion compound prepared by the invention has high water solubility and is easy to dissolve without adding other auxiliary solvents, and the prepared aqueous solution has small side effects of hemolysis and is suitable for clinical use. The solid inclusion compound containing 50 mg of cefdinir is diluted with water for 10 to 500 times and can be kept stable for several days. The solid inclusion compound is diluted 10 to 500 times to reach a suitable concentration for clinical injection.

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. The oral dosage forms include, but are not limited to, tablets, capsules, granule sustained release tablets or dispersion 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 cefdinir in the pharmaceutical composition can be determined according to factors such as dosage form, suitable population, etc., which are usually

0.5 to 26 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 to 1 wt%; the content of the wetting agent or binder is 0 to 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 adjuvant for oral use in the art, for example, the diluent may be selected from starch, a plurality of pre-gelatinized starch, dextrin, powdered sugar, lactose, citric acid, glucose, mannitol, β-cyclodextrin or microcrystalline cellulose; the disintegrant may be selected from starch, a plurality of one or any combination of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium or cross-linked polyvinylpyrrolidone; the lubricant may be selected from magnesium stearate , one or a combination of sodium dodecyl sulfate, stearic acid, talc, PEG4000, PEG6000 or micronized silica; the wetting agent or binder may be selected from the group consisting of water, ethanol, starch slurry, carboxy A plurality of one or any combination of sodium methylcellulose, hydroxypropylmethylcellulose or dextrin.

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

 Cefdinir 50 parts 'β-cyclodextrin or its derivatives 140~2000 parts, pregelatinized starch 30 300 parts, microcrystalline cellulose '10-100 parts, croscarmellose sodium 2-50 parts , talc powder 0.5-10 parts, magnesium stearate 0.2-5 parts;

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

 Cefdinir and cyclodextrin or a derivative thereof are prepared as a clathrate according to the aforementioned method, and the resulting clathrate is further prepared into a desired oral dosage form by a conventional method.

The inclusion of cefdinir 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 without cephalosporin A common formulation of the cyclodextrin inclusion complex, which is beneficial for improving the oral bioavailability of cefdinir.

 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 water injection agent, for example, may be prepared by a common water injection production process; or may be a solid powder injection agent, for example, a sterile aseptic separation process may be used to make the sterile injection. The powder injection may be filled, or the freeze-dried powder injection may 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 excipient for parenteral administration, and may be an excipient or an excipient for injection which is generally used in the art. For example, isotonicity adjusting agents include, but are not limited to, glucose, sodium chloride, mannitol, lactose, dextran, fructose or glycerol; pH adjusting agents include, but are not limited to, hydrochloric acid, sulfuric acid, citric acid, sodium hydroxide, hydrogen phosphate Disodium or sodium dihydrogen phosphate; local analgesics include, but are not limited to, benzyl alcohol, chlorobutanol, procaine hydrochloride or lidocaine hydrochloride. The glucose, mannitol or dextran and the like also have an osmotic pressure regulating action.

 The content of cefdinir 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 26 t%. '

 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 cefdinir, 140-2000 parts of β-cyclodextrin or its derivatives, 0-200 parts of sodium chloride, 0-500 parts of glucose, 0-2000 parts of lactose, 0 to 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 cefdinir is It exists 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 cefdinir cyclodextrin inclusion compound of the invention obviously increases the solubility of cefdinir, the stability of cefdinir is significantly enhanced, and the activity is also significantly improved. The cefdinir inclusion compound enhances the activity of cefdinir and reduces the hemolysis, and is suitable for various parenteral administration forms.

The method of the present invention can prepare a clathrate under pure water conditions, thereby avoiding the residue of the organic solvent and ensuring drug safety. 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 medicinal materials, and the inclusion compound is easy to process. DRAWINGS

 Figure 1 shows the UV scan. According to formula (1), a good linear relationship is obtained by plotting 1/[Delta] Α on 1/[CD]0 (wherein ΔA is the change value of the UV absorption value of cefdinir after adding cyclodextrin, [CD]0 is sulfonate. The total concentration of butyl-β-cyclodextrin, linear regression equation is y=0.0034x+27.245 (r =0.9797) (286nm), from the intercept/slope to the head of sulfonate-β-cyclodide The inclusion constant of the precision clathrate was K=8013 M-1.

 Figure 2 is a differential thermal analysis diagram. As shown in the figure, cefdinir has a peak at 250 °C, which is a melting decomposition peak; β-cyclodextrin has a peak at 85 ° C and 31 (TC also has dehydration, respectively Endothermic peak and melting decomposition peak. The physical mixture maintains the endothermic peak of e-cyclodextrin and cefdinir, which is basically the superposition of each compound, and the position (temperature) of each peak on the spectrum of the inclusion complex. Both the shape and the shape (thermal effect) have changed, indicating that the clathrate has formed.

 Figure 3 is a differential thermal analysis diagram. As shown in the figure, cefdinir has a peak at 250 °C, which is a melting decomposition peak. Hydroxypropyl-β-cyclodextrin also has a peak at 90 Ό and 350 ,, respectively. Endothermic peak and melting decomposition peak. The physical mixture maintains the endothermic peak of hydroxypropyl-β-cyclodextrin and cefdinir, which is essentially the superposition of each compound, and the position (temperature) and shape of each peak on the spectrum of the clathrate (thermal effect) ) has changed, indicating that the inclusion compound has formed.

Figure 4 is a 1H NMR chart of cefdinir and cefdinir sulfobutyl-β-cyclodextrin inclusion complex. In the formula, a-f is the proton assignment of cefdinir signal peaks, sulfobutyl-β-cyclodextrin When the spermatozoa existed, the protons of the P-lactam ring of cefdinir showed low field shift; while the protons of cyclodextrin shifted to the high field. From this, it can be judged that cefdinir and sulfobutyl-β-cyclodextrin are combined to form a clathrate. Figure 5 is an HPLC chart of the cefdinir starting material. As shown, the retention time of cefdinir is 13.075 minutes and the content is 99.16%.

 Figure 6 is a HPLC diagram of the sulfobutyl-β-cyclodextrin inclusion complex. As shown in the figure, the retention time of the clathrate sample was 13.234 minutes and the content was 99.21%. ~

detailed description

 (-) Preparation Example

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

 Example 1

 Mixing 28 g of β-cyclodextrin with 30 ml of pure water, heating, adding 10 g of cefdinir at a temperature of 50 ° C, mixing well, adding a dilute NaHCO 3 (0.1 M) solution dropwise, stirring for 3 hours, dropping, etc. The mixture was neutralized with a volume of diluted hydrochloric acid (0.1 M), and then cooled at 5 Torr for 24 hours; water was removed under reduced pressure at a temperature not higher than 50 Torr, and dried to obtain a solid clathrate.

 Example 2:

 It was basically the same as in Example 1, except that 100 g of β-cyclodextrin was mixed with 100 ml of pure water.

 Example 3:

 It was basically the same as in Example 1, except that 1000 g of β-cyclodextrin was mixed with 1000 ml of pure water.

 Example 4:

 Basically the same as in Example 1, but using 38 g of hydroxypropyl-β-cyclodextrin.

 Example 5

 Basically the same as in Example 1, except that 56 g of sulfobutyl- 0-cyclodextrin was used.

 Example 6:

 Basically the same as in Example 1, but using 35 g of hydroxypropyl-sulfobutyl-β-cyclodextrin.

'Example 7:

 Take cefdinir 10g, cyclodextrin mixture (e-cyclodextrin, hydroxypropyl-cyclodextrin, sulfobutylcyclodextrin, hydroxypropyl-sulfobutyl-β-cyclodextrin in equal mass ratio mixture 60g and 180ml of water. The cyclodextrin was mixed with water, added to cefdinir, thoroughly mixed and ground 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 package. Compound. The resulting clathrate can be used to prepare a pharmaceutical composition.

 Example 8

10 g of cefdinir, 28 g of β-cyclodextrin and 140 ml of water were taken. Mix the cyclodextrin with water and heat to 60 ° C. Add cefdinir at this temperature and mix well for 3 hours, then add dilute NaHC03 (0.1M) solution dropwise to the system pH 8.8~9.0. After 1 hour, add dilute hydrochloric acid (0.1M) 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 under vacuum at room temperature to obtain a solid clathrate. The resulting clathrate can be used to prepare a pharmaceutical composition.

 Example 9

 Take cefdinir 10g, hydroxypropyl cyclodextrin lOOOOg and water 100mL. Mix the cyclodextrin with water, heat to 50 ° C, add cefdinir, stir for 1 hour, then add dropwise dilute NaHC03 solution 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; water was removed under reduced pressure at a temperature of not lower than 50 ° C, and dried to obtain a solid clathrate. The resulting clathrate can be used to prepare a pharmaceutical composition.

 Example 10

 Take the head of 10g, sulfobutyl-β-cyclodextrin 30g and water 90ml of water. Mix the cyclodextrin with water, heat, add cefdinir at 40 °C, mix well for 3 hours, then add dilute NaHC03 solution dropwise to the body pH 8.5-9.0, and add diluted hydrochloric acid to pH 6.5 after 1 hour. ~7.0, then cool, keep at 5 ° C for 24 hours; remove the water under reduced pressure at a temperature not higher than 50 ° C, and dry to obtain a solid clathrate. The resulting clathrate can be used to prepare a pharmaceutical composition.

 Example 11:

 Cefdinir 10 g, hydroxypropyl-sulfobutyl-β-cyclodextrin 500 g and water 1000 ml of water were taken. Mix the cyclodextrin with water, heat, add cefdinir 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 is 6.5 to 7.0, then cooled, and kept at 5 ° C for 24 hours; the water is removed under reduced pressure at a temperature not higher than 50 Torr, and dried to obtain a solid clathrate. The resulting clathrate can be used to prepare a pharmaceutical composition.

 Example 12:

Take 10 g of cefdinir and a mixture of cyclodextrin (mass ratio mixture of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin) _; 100 g _; mix cyclodextrin and 400 g of pure water to suspend Liquid, adding cefdinir, thoroughly mixed and ground at room temperature, determine the pH value of the suspension, add dilute NaHC03 solution dropwise, adjust to pH=7.0, mix and grind, let stand for 12 hours, adjust to pH=6.5 with dilute hydrochloric acid It is filtered and dried under reduced pressure to obtain a solid clathrate.

 Example 13:

Take cefdinir 10g and cyclodextrin mixture - cyclodextrin and hydroxypropyl-sulfobutyl-β-cyclodextrin in a mass ratio mixture) 80g; mix cyclodextrin and 240g pure water into a suspension, Add cefdinir, mix thoroughly at room temperature, determine the pH value of the suspension, add dilute NaHC03 solution dropwise, adjust to pH=7.0, mix and grind, let stand 15 In an hour, it was adjusted to pH = 6.5 with dilute hydrochloric acid, filtered, and dried under reduced pressure to give a solid clath.

 Example 14

 150 g of hydroxypropyl-β-cyclodextrin was mixed with 300 ml of pure water, heated, and 50 g of cefdinir was added at a temperature of 50 ° C, mixed well, and then diluted NaHCO 3 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 Torr for 24 hours; water was removed under reduced pressure at a temperature of not lower than 50 ° C, and dried to obtain a solid clathrate.

 200g of solid inclusion compound (containing cefdinir 50g) was mixed with 100g pregelatinized starch, 50g microcrystalline cellulose, 10g croscarmellose sodium, ground evenly through 100 mesh sieve, dry granulation, prepared 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 cefdinir clad tablets each containing 50 mg of cefdinir.

 Example 15

 An inclusion complex was prepared from 150 g of hydroxypropyl-β-cyclodextrin, 300 ml of purified water and 50 g of cefdinir. 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 cefdinir.

 Example 16:

 An inclusion complex was prepared from 150 g of hydroxypropyl-β-cyclodextrin, 300 ml of purified water and 50 g of cefdinir. 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 cefdinir 50mg.

 Example 17

 An inclusion complex was prepared from 150 g of hydroxypropyl-β-cyclodextrin, 300 ml of purified water and 50 g of cefdinir. 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 cefdinir.

 Example 18

 An inclusion complex was prepared from 250 g of hydroxypropyl-β-cyclodextrin, 500 ml of purified water and 50 g of cefdinir. The clathrate was directly encapsulated, and each capsule contained 50 mg of cefdinir.

 Example 19

An inclusion complex was prepared from 140 g of hydroxypropyl-β-cyclodextrin, 300 ml of purified water and 50 g of cefdinir. The obtained clathrate was taken, and 300 g of pregelatinized starch, 10 g of microcrystalline cellulose, 50 g of croscarmellose sodium were added, ground uniformly over 100 mesh hooves, dry granulation, and obtained granules and 0.5 g of talc. Powder, 5 g of magnesium stearate was mixed, and sieved through a 16 mesh sieve to form 1000 pieces of cefdinir cyclodextrin inclusion tablets, each containing 50 mg of cefdinir. Example 20

 An inclusion complex of 2000 g of hydroxypropyl-β-cyclodextrin, 2000 ml of purified water and 50 g of cefdinir was prepared. The obtained clathrate was added, and 30 g of pregelatinized starch, 100 g of microcrystalline cellulose, 2 g of croscarmellose sodium, 10 g of talc, 0.2 g of magnesium stearate were added and uniformly mixed, and directly loaded into a medicinal aluminum foil bag. Medium, sealed, each bag is equivalent to 50mg of cefdinir.

 Example 21:

 250 g of hydroxypropyl-sulfobutyl-β-cyclodextrin, mixed with 500 ml of pure water, heated to a solution, 50 g of cefdinir was added at 50 ° C, ethanol was added dropwise until the system was completely dissolved, to 0.22 μ πι The membrane was filtered through a micropore filter, and the filtrate was further stirred under reduced pressure for 2 hours, and then dried under reduced pressure to give a solid clath.

 Example 22

 Take the appropriate amount of the clathrate prepared in Example 21, and add 50 ml of cefdinir: 100 mg, 250 ml: 100 mg and 500 ml: 100 mg of the solution, respectively, and dispense into 50 ml, 250 ml and 500 ml respectively. Sterilization, that is, a pharmaceutical composition containing a solution injection of lOOmg of cefdinir per bottle.

 Example 23:

 The 50 mg inclusion compound containing cefdinir obtained in Example 21 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 50 mg of cefdinir lyophilized powder.

 Table 1. Cefdinib cyclodextrin inclusion complex freeze-dried powder into a distribution ratio

 *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 24: Hydroxypropyl-sulfobutyl-β-cyclodextrin 100g, mixed with 500ml of pure water, heated to a solution, 50g of cefdinir was added at 50 °C, ethanol was added dropwise until the system was completely dissolved, to 0.45 μ πι The membrane was filtered, and the ethanol was removed under reduced pressure, water was removed, and dried to obtain a solid clathrate. The solid inclusion compound and 200 g of NaCl and 2000 g of lactose were dissolved in water for injection, and then water for injection was added to 20,000 ml, and sterilely filtered with a 0.22 μm microporous membrane, and dispensed into a 20 ml ampoule. Injectable pharmaceutical compositions.

 Example 25:

 Hydroxypropyl-sulfobutyl-β-cyclodextrin 2000g, mixed with 10000ml of pure water, heated to a solution, add 50g of cefdinir at 5 °C, add ethanol to the system to completely dissolve, to 0.45 μ πι The membrane is filtered, and the ethanol is removed under reduced pressure, and the mixture is dried to obtain a solid inclusion compound. The solid inclusion compound is dissolved in 500 g of glucose and 2000 g of mannitol, and water for injection is added to 15000 ml, and 0.22 is used. The μ ηι microporous membrane was sterile-filtered and dispensed into a 15 ml ampule to obtain an injectable pharmaceutical composition.

 Example 26

 Hydroxypropyl-sulfobutyl-β-cyclodextrin 100g, mixed with 500ml of pure water, heated to a solution, 50g of cefdinir was added at 50 °C, ethanol was added dropwise until the system was completely dissolved, to 0.45 μ πι The membrane was filtered, and the ethanol was removed under reduced pressure, water was removed, and dried to obtain a solid clathrate. 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 μππ microporous membrane, and dispensed into a 2 ml ampoule, which was injectable. Pharmaceutical composition.

 Example 27

 Hydroxypropyl-sulfobutyl-6-cyclodextrin 150g, mixed with 200ml of pure water, heated to a solution, 50g of cefdinir was added at 50 °C, ethanol was added dropwise until the system was completely dissolved, 0.2~0.4 μ The mixture was filtered through a microporous membrane, and the filtrate was evaporated under reduced pressure to give 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 μηη microporous membrane, and dispensed into a 2 ml ampoule. That is, a pharmaceutical composition for injectables is obtained.

 Example 28

 150 g of hydroxypropyl-sulfobutylcyclodextrin, mixed with 200 ml of pure water, heated to a solution, 5 g of cefdinir was added at 50 Torr, ethanol was added dropwise until the system was completely dissolved, and filtered through a 0.2-0.4 μm microporous membrane. 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, use sterile filtration with 0.22 μιη microporous membrane, and dispense into 2ml ampoules. Injectable drug combination Things.

 (:2;) Experimental example

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

 1. Determination of inclusion ratio (continuous gradient test)

 Prepare a suitable concentration of cefdinir solution in pH 6.86 phosphate buffer for full wavelength scanning and select the appropriate wavelength for measurement. Prepare 1.27*10-5mol/l cefdinir solution S1 and β-cyclodextrin solution S2 with pH 6.86 phosphate buffer, and fix the total molar concentration of cefdinir and β-cyclodextrin unchanged. Mix well. The solution S1:S2 of different volume ratios makes the molar ratios of the head bulge and β-cyclodextrin 1:3, 1:2, 2:3, 1:1, 3:2, 2:1, 3: 1, the absorbance value was measured at 286 nm, and the difference ΔΑ between the absorbance values of the cefdinir solution of the same concentration was calculated, and the molar ratio corresponding to the maximum of Δ Α was the inclusion ratio.

 UV scanning showed that cefdinir had the strongest UV absorption at 286 nm. From the results of the continuous gradual test, the UV absorption values of the 1:1 molar ratio solution differed the most, indicating that the inclusion ratio of cefdinir/β-cyclodextrin was 1:1.

 Table 2. ΔΑ values for different concentration ratios.

 SI : S2 molar ratio 1:3 1:2 2:3 1:1 3:2 2:1 3:1

ΔΑ(Χ10-3) 12 5 3 29 8 7 16

 2. Determination of the inclusion constant of cefdinir and cyclodextrin

 A cefdinir dilute solution was prepared using a mixed phosphate buffer (ρ 6.5 and ρ Η 7.0), and then a cyclodextrin solution was prepared using the diluted solution. A certain volume of cefdinir solution was UV-scanned to obtain a specific 286 nm UV absorption (A0), and the cyclodextrin concentration was changed to 1.09X10-4~7.36X10-4 mol/L to obtain Al-An absorption with different cyclodextrin concentrations. Introduce the formula (1): 1 / ΔΑ = 1 / (AsKa[G]0[CD]0) + 11 As[G]0 (where Δ A is the change in the UV absorption of cefdinir after the addition of cyclodextrin [CD]0 is the total concentration of cyclodextrin, [G]0 is the total concentration of cefdinir, and Δε is the difference between the molar absorptivity of cefdinir and cyclodextrin before and after inclusion of cyclodextrin, 1/ΔΑ A straight line is plotted against 1/[CD]0, and the inclusion constant Ka of the cefdinir cyclodextrin inclusion complex is obtained from the intercept/slope of the formula. The experiment verified the inclusion constant of cefdinir β-cyclodextrin inclusion complex, cefdinir hydroxypropyl-β-cyclodextrin inclusion complex and cefdinir sulfobutyl-β-cyclodextrin inclusion complex. . The inclusion constant Ka of cefdinir and cyclodextrin is 2226 Μ-1~11620Μ-1, which proves that cefdinir and cyclodextrin are sufficiently stable, indicating that the cyclodextrin used in the present invention has strong inclusion ability. , wherein the inclusion constant UV scan of the cefdinir sulfonate-cyclodextrin inclusion complex is shown in Figure 1.

 Table 3. Inclusion constants of inclusion complexes formed with different cyclodextrins Ka (286 nm)

 Ka (M-1)

 Cyclodextrin

pH6.5 pH7.0 Β-cyclodextrin 2226 2394 Hydroxypropyl-β-cyclodextrin 4227 5713 sulfobutyl-β-cyclodextrin 8013 11620 Hydroxypropyl-sulfobutyl-β-cyclodextrin 8532 12236

 3, inclusion compound differential thermal analysis verification test

 Weigh about 5.0mg of cefdinir, β-cyclodextrin, cefdinir and cyclodextrin physical mixture, inclusion complex, and perform differential scanning thermal analysis: A1203 reference, range ±50 u V The temperature rise range is 30 ° C ~ 400 ° C, and the heating rate is 10 ° C / min, and the DTA spectrum is obtained. The results showed that: cefdinir has a peak at 250 ,, which is a melting decomposition peak; β-cyclodextrin also has one peak at 70-90 Ό and 300-330 ,, which are dehydration endothermic peak and melting decomposition peak. The physical mixture maintains the endothermic peak of cyclodextrin and cefdinir, which is basically the superposition of each compound, and the position (temperature) and shape (thermal effect) of each peak change in the spectrum of the inclusion complex. It is speculated that the inclusion compound has formed. The differential thermal analysis chart is shown in Figure 2 - Figure 3.

 4, nuclear magnetic resonance analysis

 Samples: cefdinir, cefdinir sulfonyl 3-cyclodextrin inclusion compound, sulfobutyl-cyclodextrin, solvent D20, measuring temperature 25 °C. The nuclear magnetic map of cefdinir and the inclusion complex is shown in Figure 4. The specific data is shown in Table 4. From the nuclear magnetic resonance spectrum, it can be seen that before and after inclusion, the chemical shifts ( δ ) of the protons of cefdinir all show obvious displacement changes, in which proton e and proton d are shielded by cyclodextrin, and the amide in the inclusion complex The carbonyl oxygen forms a hydrogen bond with the hydroxyl group at the edge of the cyclodextrin cavity, suggesting that the inclusion complex is in the cyclodextrin cavity of the cefdinir side chain of cefdinir.

 Table 4. Chemical shifts of each proton

 5. Determination of solubility of inclusion complexes

 The mother liquor containing cefdinir 1.272 mg/mL was prepared with pH 6.86 mixed phosphate buffer, then diluted with purified water to 1.272 μg/mL~19.08 μg/mL series solution, and UV absorption A was measured at 286 nm, with A A standard curve was plotted against the concentration C (g/mL) and A- 58.823C+0.0054 (r =0.9999) was obtained.

Prepare a certain amount of cefdinir and clathrate solution with purified water, shake at 25 °C for 1 hour, filter, rest, remove the appropriate amount of filtrate, dilute with pure water, measure the light absorption intensity at 286nm, according to the standard Cefdinir And the inclusion compound 25 溶解 lower solubility. The solubility of each inclusion compound is shown in Table 5 below:

 Table 5. Solubilization multiples of different cyclodextrins

 Cyclodextrin solubility (mg/ml) solubilization factor

 - 0.268 - β-cyclodextrin 5.56 20.8

 Hydroxypropyl-β-cyclodextrin 35.0 130.6 sulfobutyl-β-cyclodextrin 45.89 171.3 hydroxypropyl-sulfobutyl cyclodextrin 47.46 177.1

 It can be seen from the table that the solubility of cefdinir after the cyclodextrin inclusion is greatly improved, the solubility is increased to 170 times, and it is fully developed into a parenteral dosage form.

6, the stability test of the preparation

 Cefdinoxime- 0-cyclodextrin inclusion complex (1:10 mass ratio of cefdinir and sulfobutyl-cyclodextrin) 2500 times diluted with physiological saline and isotonic glucose solution, diluted Sterilization treatment was made into different concentrations of injection solution, and continuous observation for 5 hours to 10 days. The stability observation results of the physiological saline dilution system are shown in Table 6.

 Table 6. Formulation status under different dilution factors

 Liquid state

 Dilution factor

 Oh 5h 10h 15h 20h 2 days 4 days 6 days 10 days

1 time + + + + + + + . + +

 10 times + + + + + + + + +

 20 times + + + + + + + + +

 50 times + + + + + + + + + +

 100 times + + + + + + + + +

 500 times + + + + + + + + + +

 1000 times + + + + + + + + + +

 "+" : clarification without precipitation; "-,,: precipitation or turbidity

 7. Stability test of the drug in solution

 High performance liquid chromatography using a phenyl column, water (0.015 mol/ml ammonium acetate solution): acetonitrile = 95: 5 mobile phase separates the cefdinir from the impurity baseline and avoids the effects of solvent peaks. Flow rate: l.O mL/min; column temperature: 30 ° C; injection time: 30.00 minutes; sensitivity 1.0000 AUFS; measurement wavelength 286 nm.

Preparation of cefdinir and cefdinir-butyl-β-cyclodextrin inclusion complex (ceftinib and sulfobutyl-cyclodextrin) The mass ratio was 1:10), dissolved in the mobile phase, sonicated for 30 minutes, allowed to stand, sampled at 0, 3, 6, 9, 12 hours, respectively, and injected with the above liquid phase conditions for analysis.

 Table 7. Sample content under different conditions

 Content %

 0 hours 3 hours 6 hours 9 hours 12 hours Raw materials 99.46 98.56 98.29 97.36 96.47 Inclusion compound 99.12 98.96 98.75 98.29 98.08 From the above data, it can be concluded that cefdinir has a decomposition half-life of 206.71 hours while the solution is still standing, and cefdinir The half-life of the clathrate is 526.42 hours, and the clathrate is 2.61 times that of the raw material, and the stability is enhanced.

8, with acid damage test stability

 高效Using high performance liquid chromatography, the method is the same as above.

Take cefdinir raw material and cefdinir-cyclodextrin inclusion complex (mass ratio of cefdinir and β-cyclodextrin is 1 _: 4), add 5ml of hydrochloric acid solution of pH1.O, stand still, every 2 Sampling at an hour, taking an appropriate amount of alkali to neutralize, dilute, inject, and calculate.

 The results showed that the cefdinir raw material decreased significantly under the acid destruction condition, and the half-life was 104.16 hours. The cefdinir inclusion compound was placed under the acid destruction condition for 8 hours, the content was basically no decrease, the impurity was basically unchanged, and the half-life was 290.29. hour.

 Table 8. Sample content under different conditions

Content ⁰ / ₀

 Sample

 2 hours 4 hours 6 hours 8 hours Raw materials 99.78 98.34 97.09 95.67 Inclusion compound 99.67 99.57 98.91 98.65

9, the impact factor test test stability

 Using liquid chromatography, the method is the same as above.

 Take the cefdinir raw material and cefdinoxime-β-cyclodextrin inclusion compound (the mass ratio of cefdinir and sulfobutyl-β-cyclodextrin is 1:10), and divide the test into three samples. , respectively, the specific methods of light test, high temperature test and helium humidity test:

1) The light test sample is placed in a transparent sealed container, placed in a light box equipped with a fluorescent lamp, placed under the condition of 4500 ± 500 LX for 5 days, sampled and analyzed, and the result is compared with the 0 day sample. 2) The high temperature test samples were placed in a sealed clean container, placed at 60 ° C for 5 days, sampled and analyzed, and the results were compared with the 0 day sample.

 3) High-humidity test The sample was placed in a constant-humidity sealed container at room temperature for 25 ,, and placed under a relative humidity of 90±5% (saturated KN03 solution) for 5 days. The results were compared with the 0-day sample.

 The test results show that the cefdinir raw material drops significantly under high temperature and light conditions; the inclusion compound is placed under light and high temperature for 5 days, the appearance color does not change, the content is basically not reduced, and the impurities are basically unchanged. When placed under high humidity (RH90±5%), the inclusion compound was obviously wetted, the content was reduced, and the inclusion compound was slightly damp, but the content was not significantly reduced, and the degradation products and impurities were not increased.

 Table 9. Sample content under different conditions

Content ⁰ / ₀

 Sample

 0 days Light 5 days Heating 5 days High humidity 5 days Raw material 99.46 94.67 93.37 95.48 Inclusion compound 99.15 98.58 98.39 97.25

10, hemolysis experiment

 The Department of Health's Drug Standards (Part 2) Appendix 5, 1996: 109 Hemolysis Test (UV spectrophotometry) Determination of hemolysis rate, combined with cefdinir sulfonate-β-cyclodextrin synthesized in this experiment , commercially available imported ceftriaxone (Roche) and commercially available penicillin sodium for injection, shake at 37 30 for 30 min, cool, centrifuge at 2500 rps/min for about 5 min, and take the supernatant to measure UV absorption at λ = 543 nm. value.

 The results of the hemolysis experiment are shown in Table 10. It can be seen that the cefdinir inclusion compound prepared by the invention has small hemolytic effect, is superior to the commercially available penicillin sodium for injection, and is superior to the imported Roche fen, especially at high concentration, safe. Higher sex.

 Table 10, Hemolysis Test Results

 No. Drug concentration Hemolysis (%)

 (mg/ml) Commercial injection penicillin sodium inclusion complex Roche

1 0.1 I.65 1.71 0.76

 2 1 3.38 2.08 2.14

 3 3 4.47 2.08 2.67

 4 II.1 3.43 4.28

11. In vitro antibacterial experiment:

Determination of cefdinir Hydroxypropyl-sulfobutyl-β-cyclodextrin inclusion compound by agar dilution method (the quality of cefdinir and cyclodextrin) The in vitro antibacterial activity of cefdinir was 1 : 15 ), and the results are shown in Table 11.

 Table 11. In vitro antibacterial activity before and after inclusion of cefdinir

 MIC ( g/ml)

 Sample

 ATCC25922 ATCC27853 ATCC25923 Inclusion Complex 0.25 >128 0.064 Non-inclusion 0.25-0.5 >128 0.5-1.0 The results showed that cefdinir was less active against Pseudomonas aeruginosa (ATCC27853), and it was pre- and post-inclusion with Pseudomonas aeruginosa There was no difference in the activity of bacteria (ATCC27853), and the activity of Escherichia coli (ATCC25922) was not significantly enhanced, but the activity of Staphylococcus aureus (ATCC25923) was significantly different. After inclusion, the antibacterial activity of Cefdinir's Staphylococcus aureus (ATCC25923) The activity was enhanced by 7.815.6 times.

Claims

Rights request A pharmaceutical composition comprising a cefdinir cyclodextrin inclusion compound, the basic composition comprising - a) cefdinir, 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. The pharmaceutical composition according to claim 1, wherein the mass ratio of cefdinir to cyclodextrin is 1:2.8 to 1:100. The pharmaceutical composition according to claim 2, wherein the mass of cefdinir and cyclodextrin is 1:3 to 1:50. The pharmaceutical composition according to any one of claims 1 to 3, which is an oral dosage form. 5. The pharmaceutical composition according to claim 4, in parts by mass, comprising:  50 parts of cefdinir, 140~2000 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; wherein, cefdinir is in the form of cyclodextrin inclusion compound. 6. A pharmaceutical composition according to any one of claims 1 to 3 which is a parenteral dosage form. 7. The pharmaceutical composition according to claim 6, in parts by mass, comprising:  50 parts of cefdinir, 140-2000 parts of β-cyclodextrin or its derivatives, 0~200 parts of sodium chloride, 0-500 servings, 0 to 2000 parts of lactose, 0 to 2000 parts of mannitol, and 50000000 parts by injection of water; wherein the water for injection may be present in the final pharmaceutical composition or removed from the final pharmaceutical composition; The cefdinir described is in the form of a cyclodextrin clathrate. The method for producing a pharmaceutical composition according to any one of claims 1 to 7, which comprises the preparation of a cefdinir cyclodextrin inclusion compound, the preparation of the cefdinir cyclodextrin inclusion compound comprising the following steps :  a) taking 1 part by mass of cefdinir and 2.8 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 cefdinir bulk drug;  d) completely or evenly dissolve the system by one or more of the following processes:  i) Mix and grind at room temperature,  Ii) heating and stirring,  Iii) adjust the pH value, then stir and stir.  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.