CN103301068A - Cefixime dry suspension and preparation method thereof - Google Patents

Abstract

The invention discloses a cefixime dry suspension and a preparation method thereof. The preparation comprises the following components in parts by weight: 1 part of cefixime, 0.8-4 parts of polyoxyethylene castor oil, 3-6 parts of medium-chain fatty glyceride, 2-6 parts of a suspending agent and 8-15 parts of a filling agent; the preparation method comprises the following steps: dissolving cefixime in medium-chain fatty glyceride containing polyoxyethylene castor oil, and adsorbing with mixture of suspending agent and filler. The preparation of the invention has good stability, rapid dissolution and simple process, and is suitable for industrial mass production.

Description

A kind of cefixime dry suspension and preparation method thereof

technical field

The invention belongs to the technical field of medicine, and in particular relates to a cefixime dry suspension and a preparation method thereof.

Background technique

Cefixime (Cefixime) is an oral third-generation cephalosporin antibiotic, chemical name: (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2- (Carboxymethoxyimino)acetamido]-8-oxo-3-ethylene-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid trihydrate, Chem The structural formula is as follows:

Cefixime is white to light yellow crystalline powder, odorless, with slight specific odor, easily soluble in methanol, dimethyl sulfoxide, slightly soluble in acetone, hardly soluble in ethanol, almost insoluble in water, ethyl acetate, ether, in hexane. As the third-generation oral cephalosporin antibiotic, cefixime has a broad antibacterial spectrum and strong antibacterial activity. , Proteus mirabilis, and Neisseria gonorrhoeae (including enzyme-producing strains) all have good antibacterial activity, are stable to most β-lactamases, and have the advantages of small side effects. Streptococcus (except Enterococcus), pneumococcus, Neisseria gonorrhoeae, Branhamella catarrhalis, Escherichia coli, Klebsiella, Serratia, Proteus and influenza, which are susceptible to cefixime The following bacterial infectious diseases caused by bacillus: bronchitis, bronchiectasis, secondary infection of chronic respiratory infection, pneumonia; pyelonephritis, cystitis, gonococcal urethritis; cholecystitis, cholangitis; scarlet fever; otitis media , Sinusitis, etc.

Currently, cefixime preparations on the market include capsules, tablets, dispersible tablets, chewable tablets, granules and dry suspensions, all of which are traditional oral administration forms. Due to the poor stability and relatively low bioavailability of cefixime, the absorption and distribution of the drug in the body are slow, which affects the speed of onset and final curative effect of the drug. Instability problems with cefixime during treatment.

Chinese patent CN101889987A discloses a new method for preparing cefixime tablets and capsules. The method includes micronizing cefixime, a solubilizer and water-soluble excipients, and then mixing them with other excipients before dry granulation. Chinese patent CN101721363A discloses a cefixime oral suspension and its preparation method. The oral suspension consists of the following components per 100ml: cefixime 0.5-4.0g, thickening suspending agent greater than 0-20.0g, Cosolvents, flavoring agents, preservatives, and the rest are non-aqueous liquid media. Chinese patent CN101606913A discloses a cefixime dispersible tablet and its preparation method, each tablet contains cefixime 40-420mg, starch 0-100mg, pregelatinized starch 0-250mg, mannitol 10-80mg, microcrystalline cellulose 0-150mg, sodium starch glycolate 10-60mg, povidone K302-20mg, magnesium stearate 0.4-10mg, stevia 0-10mg, sweet orange essence 0-10mg. Chinese patent CN101496791A discloses a cefixime sustained-release tablet and a preparation method thereof. The sustained-release tablet is composed of the following raw and auxiliary materials in the weight ratio: 200 parts of cefixime (calculated as anhydrous), 20 to 200 parts At least one pharmaceutically acceptable sustained-release material that can be adjusted for sustained, slow and complete release of the drug, 20-400 parts of at least one pharmaceutically acceptable excipient, and 5-100 parts of at least one that can effectively improve the drug release rate solubilizer. Chinese patent CN1803138A discloses a cefixime orally disintegrating tablet and its preparation method. The weight ratio components are: cefixime 10.0%-35.0%, microcrystalline cellulose 0%-10.0%, lactose starch 0% ~35.0%, mannitol 35.0%~59.0%, croscarmellose sodium 4.0%~15.0%, copovidone 1.0%~5.0%, sodium lauryl sulfate 0.01%~1.0%, micronized silica gel 0.01% %~0.5%. The cefixime preparations involved in the above-mentioned patented technologies all have the problems of poor stability and relatively low bioavailability.

Chinese patents CN101972231A, CN101966166A, CN101966160A, CN101966159A and CN101966154A disclose dry suspensions, capsules, dispersible tablets, tablets and granules containing cefixime liposomes respectively, and the liposome preparations of these cefixime are stable It needs to be further improved. Chinese patent CN101711741A discloses a submicron emulsion solid preparation of cefixime. Since there is no oil phase, the surfactant dissolves rapidly in the water phase during the dissolution test, resulting in the crystallization of the drug, so the drug is not dissolved quickly. CN102327235B discloses a cefixime lipid nanoparticle solid preparation and a preparation method thereof. The provided solid lipid nanoparticle preparation has high drug loading, uniform particle size, long retention time of medicine in blood circulation, and better Sustained-release and controlled-release effects, however, liposome technology is complicated to prepare and not utilized in production applications.

Contents of the invention

In view of the deficiencies in the prior art, the object of the present invention is to provide a cefixime dry suspension with good stability, rapid dissolution and simple process and a preparation method thereof.

Specifically, the purpose of the present invention is achieved through the following technical solutions:

A cefixime dry suspension, comprising the following components by weight:

Preferably, the above-mentioned cefixime dry suspension is prepared from the following components by weight:

Further preferably, the above-mentioned cefixime dry suspension, wherein said medium-chain fatty acid glyceride is selected from the following: saturated caprylic acid triglyceride, saturated capric acid triglyceride, saturated caprylic acid-capric acid mixed triglyceride .

Cefixime dry suspension of the present invention, wherein said suspending agent is selected from following one or more: sodium carboxymethylcellulose, povidone, hydroxypropyl cellulose, hypromellose and xanthan gum. Preferably said suspending agent is hydroxypropyl cellulose.

Cefixime dry suspension of the present invention, wherein said filler is selected from following one or more: pregelatinized starch, cyclodextrin, lactose, starch, sucrose, mannitol, calcium hydrogen phosphate and sulfuric acid calcium. Preferably the filler is pregelatinized starch.

Another object of the present invention provides the preparation method of above-mentioned cefixime dry suspension, comprises the steps:

(1) Take cefixime, add it into caprylic triglyceride under stirring condition, make it dissolve, then add polyoxyethylene castor oil, stir to get a solution;

(2) Mix the suspending agent and the filler uniformly to obtain a mixture, use the mixture to absorb the solution in step (1), stir evenly, and subpackage on a granule packing machine to obtain the cefixime dry suspension.

The preparation method of cefixime dry suspension of the present invention, wherein said suspending agent is selected from following one or more: sodium carboxymethylcellulose, povidone, hydroxypropyl cellulose, hypromellose Cellulose and xanthan gum; the filler is selected from one or more of the following: pregelatinized starch, cyclodextrin, lactose, starch, sucrose, mannitol, calcium hydrogen phosphate and calcium sulfate.

The preparation method of cefixime dry suspension of the present invention, wherein said suspending agent is preferably hydroxypropyl cellulose; said filler is preferably pregelatinized starch.

In the present invention, raw materials are dissolved in the oil phase containing surfactant, and the hydrophobic property of the oil phase is used to avoid the influence of external moisture on the medicine; the oil phase itself has an antioxidant effect, which further improves the stability of the medicine; at the same time, due to The surfactant polyoxyethylene castor oil is added, and the prepared oil phase is an emulsion concentrate, which quickly disperses into an emulsion when the dissolution test is carried out, and the dissolution is rapid. Compared with the prior art, the cefixime dry suspension and the preparation method thereof involved in the present invention have the following advantages and significant progress: (1) the process is simple and suitable for large-scale industrial production; (2) the formulation has good stability, Rapid dissolution improves bioavailability.

specific embodiment

In the process of completing the present invention, the inventors considered that, in order to improve drug stability, the drug should be protected from moisture. In the prior art, the powder coating operation is difficult; adding water-insoluble lipids, such as stearic acid, can protect the drug, but the unfavorable factor is that the dissolution of the drug is slow; preparation of liposomes, microspheres, etc. The process is complicated and the industrialization is difficult. In order to overcome the above problems, the inventors creatively proposed the following idea: if the drug is dissolved in low-viscosity oil containing surfactants, and then the oil phase solution is adsorbed with auxiliary materials, the following effects will be achieved: to protect the drug and avoid the influence of water ;During the dissolution measurement process, the oil phase can be dispersed in the dissolution medium in an instant to form a microemulsion solution, and the drug is dissolved rapidly; when the sedimentation volume ratio is measured, the oil phase can be fully dispersed in water because it is similar to an emulsion concentrate. Layered, good suspension effect. Based on this, the inventor selected from a large number of oil phases, and finally selected medium-chain fatty acid glycerides as the oil phase, which is a colorless, odorless, low-viscosity lipophilic emollient with high oxidation resistance; The active agent is polyoxyethylene castor oil, because it is miscible with medium-chain fatty acid glycerides. The inventor dissolves cefixime raw materials in medium-chain fatty acid glycerides containing polyoxyethylene castor oil to obtain a clear solution, and then absorbs the solution with commonly used pharmaceutical auxiliary materials to obtain cefixime dry suspension.

The following examples further describe the preparation process and beneficial effects of the present invention. The examples are only for the purpose of illustration and do not limit the scope of the present invention. Simultaneously, the obvious changes and modifications made by those of ordinary skill in the art according to the present invention are also included in within the scope of the present invention.

Example 1

Preparation Process:

(1) Weigh cefixime for the prescription amount, add it to saturated caprylic triglyceride under stirring condition, and dissolve it, then add polyoxyethylene castor oil to the oil solution, stir to obtain a clear solution;

(2) The prescription amount weighs povidone and pregelatinized starch, and mixes them evenly to obtain a mixture;

(3) Adsorb the solution of step (1) with the mixture of step (2), and stir evenly;

(4) Subpackage on a granule packaging machine to obtain Cefixime dry suspension.

Example 2

Preparation Process:

(1) Weigh cefixime according to the prescription amount, add it into saturated capric triglyceride under stirring condition to dissolve, then add polyoxyethylene castor oil into the oil solution, stir to obtain a clear solution;

(2) Weigh the lactose and sodium carboxymethyl cellulose for the prescription amount, mix them evenly, and obtain the mixture;

(3) Adsorb the solution of step (1) with the mixture of step (2), and stir evenly;

(4) Subpackage on a granule packaging machine to obtain Cefixime dry suspension.

Example 3

Preparation Process:

(1) The prescription quantity weighs cefixime, and under stirring conditions, add caprylic acid to capric acid molar ratio of 1:1 saturated caprylic acid-capric acid mixed triglyceride to dissolve, and then add polyoxygen to the oil solution. Ethylene castor oil, stirred to obtain a clear solution;

(2) Pre-gelatinized starch and hydroxypropyl cellulose are weighed for the prescription amount, and mixed evenly to obtain a mixture;

(3) Adsorb the solution of step (1) with the mixture of step (2), and stir evenly;

(4) Subpackage on a granule packaging machine to obtain Cefixime dry suspension.

Comparative Example 1

Preparation Process:

(1) Weigh cefixime for the prescription amount, and under stirring conditions, add it into saturated caprylic acid-capric acid mixed triglyceride with caprylic acid and capric acid molar ratio of 1:1 to dissolve to obtain a clear solution;

(2) Pre-gelatinized starch and hydroxypropyl cellulose are weighed for the prescription amount, and mixed evenly to obtain a mixture;

(3) Adsorb the solution of step (1) with the mixture of step (2), and stir evenly;

(4) Subpackage on a granule packaging machine to obtain Cefixime dry suspension.

Comparative Example 2

Preparation Process:

(1) Weigh cefixime according to the prescription amount, add it into the saturated caprylic acid-capric acid mixed triglyceride with caprylic acid and capric acid molar ratio of 1:1 under stirring condition, make it dissolve, then add Tween into the oil solution 80, stir to get a cloudy oil solution;

(2) Pre-gelatinized starch and hydroxypropyl cellulose are weighed for the prescription amount, and mixed evenly to obtain a mixture;

(3) Adsorb the solution of step (1) with the mixture of step (2), and stir evenly;

(4) Subpackage on a granule packaging machine to obtain Cefixime dry suspension.

Comparative Example 3

Cefixime 50g

Pregelatinized starch 470g

Preparation Process:

The cefixime is passed through a 100-mesh sieve, mixed evenly with the pregelatinized starch, and packed separately to obtain the cefixime dry suspension.

Example 4

1. Dissolution test

Get the samples prepared in Example 1 and Comparative Examples 1-3 respectively, test according to the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix XC first method), with phosphate buffer (pH7.2) 900ml as solvent, The rotating speed is 100 revolutions per minute, operate according to the law, and at 5 minutes, take an appropriate amount of the solution, filter, accurately measure an appropriate amount of the subsequent filtrate, and dilute it with the above-mentioned solvent to form a solution containing about 12 μg of cefixime per 1 ml, as the test sample solution; in addition, accurately weigh an appropriate amount of this product, add an appropriate amount of methanol (2ml of methanol for every 5mg of cefixime) to dissolve, dilute with the above-mentioned solvent according to the marked amount to make a solution containing about 250μg of cefixime per 1ml, filter, Precisely measure an appropriate amount of the filtrate, dilute it with the above-mentioned solvent to make a solution containing about 12 μg of cefixime per 1 ml, and use it as a control solution. Take the above two solutions, according to the spectrophotometric method (Chinese Pharmacopoeia 2010 edition two appendix IVA), respectively measure the absorbance at a wavelength of 288nm, and calculate the dissolution rate of each tablet according to the ratio of the two absorbances. The results are shown in Table 1.

2. Inspection of relevant substances

Get the appropriate amount of samples prepared in Example 1 and Comparative Examples 1-3 respectively, accurately weighed, dissolve and dilute with phosphate buffer to make a solution of 1mg/ml, as need testing solution; Salt was diluted to make a 0.01 mg/ml solution as a control solution. According to the chromatographic conditions under the content determination item, inject into the liquid chromatograph, and the single impurity shall not exceed 0.2 times (0.5%) of the main peak area of the control solution. The results are shown in Table 2.

3. Determination of sedimentation volume ratio

Take one bag each of the samples prepared in Example 1 and Comparative Examples 1-3, add 50ml of water, shake for 1min, let stand for 3h, and measure. The results are shown in Table 3.

Table 15min dissolution test results

Example 0 days (%) 40℃, 75%RH accelerated for 6 months (%) Example 1 99.8 97.9 Example 2 95.7 94.8 Example 3 99.4 98.2 Comparative Example 1 45.5 32.1 Comparative Example 2 50.2 30.2

Comparative Example 3 32.1 20.2

As can be seen from the test results in Table 1: Examples 1-3 of the present invention dissolve rapidly, and after accelerating for 6 months under the conditions of 40° C. and 75% RH, they can still dissolve completely in 5 minutes; although Comparative Example 1 dissolves the drug In the oil phase, but no surfactant is added, during the dissolution measurement, the oil phase is not well dispersed, so the dissolution is not good; Comparative Example 2 uses Tween 80 as the surfactant, does not form an emulsion pre-concentrate, so the solubility Not good; comparative example 3 did not use oil phase and surfactant, and the stripping was the worst; and after the samples of comparative examples 1-3 were accelerated, the stripping all decreased significantly.

Table 2 The results of the maximum single impurity determination of related substances

Example 0 days (%) 40℃, 75%RH accelerated for 6 months (%) Example 1 0.21 0.34 Example 2 0.22 0.35 Example 3 0.20 0.33 Comparative Example 1 0.23 0.37 Comparative Example 2 0.24 0.39 Comparative Example 3 0.23 3.56

As can be seen from the test result of table 2, owing to having added oily phase, so the related substances of embodiment 1-3 and comparative example 1-2 are all better, also change little after accelerated test; Comparative example 3 does not add oil Phase, related substances increased significantly after acceleration.

Table 3 Sedimentation volume ratio measurement result

Example The measurement results Example 1 0.95 Example 2 0.96 Example 3 0.97 Comparative Example 1 0.94 Comparative Example 2 0.94 Comparative Example 3 0.65

It can be seen from the test results in Table 3 that the samples prepared in Examples 1-3 and Comparative Examples 1-2 can meet the requirements of dry suspensions; the sedimentation volume ratio of Comparative Example 3 does not meet the requirements.

Claims (10)

1. Cefixime suspension is characterized in that: the component that comprises following weight portion:

2. Cefixime suspension according to claim 1, it is characterized in that: the component by following weight portion is prepared from:

3. Cefixime suspension according to claim 1, it is characterized in that: described medium chain length fatty acid triglyceride is selected from as follows: saturated Trivent OCG, saturated tricaprin, saturated sad-triglyceride that capric acid mixes.

4. each described Cefixime suspension according to claim 1-3 is characterized in that: described suspending agent is selected from following one or more: sodium carboxymethyl cellulose, polyvidone, hydroxypropyl cellulose, hypromellose and xanthan gum.

5. Cefixime suspension according to claim 4, it is characterized in that: described suspending agent is hydroxypropyl cellulose.

6. each described Cefixime suspension according to claim 1-3 is characterized in that: described filler is selected from following one or more: pregelatinized Starch, cyclodextrin, lactose, starch, sucrose, mannitol, calcium hydrogen phosphate and calcium sulfate.

7. Cefixime suspension according to claim 6, it is characterized in that: described filler is pregelatinized Starch.

8. the preparation method of each described Cefixime suspension is characterized in that comprising the steps: according to claim 1-3

(1) gets cefixime, add in the Trivent OCG under the stirring condition, make dissolving, and then add polyoxyethylene castor oil, stir, get solution;

(2) with suspending agent and filler mix homogeneously, get mixture, adopt the solution of described mixture adsorption step (1), stir, carry out packing at particles packing machine, namely get Cefixime suspension.

9. the preparation method of Cefixime suspension according to claim 8 is characterized in that: described suspending agent is selected from following one or more: sodium carboxymethyl cellulose, polyvidone, hydroxypropyl cellulose, hypromellose and xanthan gum; Described filler is selected from following one or more: pregelatinized Starch, cyclodextrin, lactose, starch, sucrose, mannitol, calcium hydrogen phosphate and calcium sulfate.

10. the preparation method of Cefixime suspension according to claim 8, it is characterized in that: described suspending agent is hydroxypropyl cellulose; Described filler is pregelatinized Starch.