KR100990223B1 - Pharmaceutical composition for improving dissolution rate of cefdinir - Google Patents

Abstract

The present invention relates to a pharmaceutical composition which improves the dissolution rate of ceftoririn, an oral cephalosporin-based antibiotic, ceftinir. More specifically, cefedi having a lower dissolution rate in an acidic medium compared to ceftinir crystalline form A The present invention relates to a pharmaceutical composition in which the dissolution rate is enhanced by using carbonate for the nir crystalline form.

Cefdinir, Form B, Dissolution Rate, Carbonate

Description

Pharmaceutical composition which improves dissolution rate of Cefdinir {PHARMACEUTICAL COMPOSITION FOR IMPROVING DISSOLUTION RATE OF CEFDINIR}

The present invention relates to a pharmaceutical composition that enhances the dissolution rate of ceftorispor, an oral cephalosporin-based antibiotic, ceftinir. More specifically, ceftinir has a slower dissolution rate in an acidic medium than cefdinir crystalline form A. The present invention relates to a pharmaceutical composition in which the dissolution rate is improved by using carbonate in a crystalline form.

Cefdinir is a Cephalosporins (Third Generation) substance with excellent antibiotic activity. Cefdinir is structurally similar to cefixime, exhibits broader antimicrobial spectra in Gram (+) and Gram (-) bacteria, and TEM-1, TEM than Cefhalexin and cefaclor. -2, a substance showing strong resistance to beta-lactamases of SHV-1.

Cefdinir describes Cefdinir crystalline Form A in U.S. Patent No. 4,935,507, and a new Cefdinir crystalline Form B having higher stability than crystalline Form A is disclosed in U.S. Patent No. 2003/0204082. However, the U.S. Patent Publication discloses Cefdinir crystalline Form B is slower in dissolution rate in acidic media than Cefdinir crystalline Form A.

The stability of the main raw material is very important in formulating the formulation and processing into suitable properties and forms so as to be convenient while maintaining the physical and chemical properties of the drug. Therefore, when Cefdinir is used as the main raw material, it is more advantageous to use Form B having higher stability than Form A. However, Form B has a low dissolution rate in the acidic medium because it may cause problems in bioavailability and medication compliance due to the low dissolution rate in the acidic medium, that is, the pH similar to the stomach in which the active drug is eluted. It is important to solve the problem.

The present invention is to solve the above-mentioned problems, it has a higher stability than Cefdinir crystalline form A, but the dissolution rate in acidic medium is a new cepdinir showing a rapid dissolution rate using a crystalline cefdinir The purpose is to develop a containing pharmaceutical composition.

In order to achieve the above object, the present invention provides a pharmaceutical composition using carbonate as a substance for improving the dissolution rate of ceftinir.

Specifically, the present invention provides a pharmaceutical composition comprising cepdinir crystalline form and carbonate as a dissolution aid with a slow dissolution rate in acidic medium compared to cepdinir crystalline Form A.

Cefdinir-containing pharmaceutical compositions according to the present invention not only have high stability but also show a rapid dissolution rate in an acidic medium to provide excellent bioavailability and medication compliance of the drug.

Hereinafter, the configuration and operation of the present invention will be described in detail.

The ceftinir-containing pharmaceutical composition of the present invention comprises ceftinir crystalline forms and carbonates which have a slow dissolution rate in an acidic medium as compared to ceftinir crystalline Form A.

Cefdinir crystalline form (hereinafter, referred to as "low dissolution Cefdinir crystalline form") having a slow dissolution rate in an acidic medium compared to Cefdinir crystalline Form A used in the present invention, for example, US Patent No. 4,935,507 Compared to Cefdinir crystalline form A disclosed in the present invention has a slower elution rate in acidic medium. At this time, the acid medium means a condition of less than pH 7, preferably about 1 to 4 pH.

The low-elevating Cefdinir crystalline form is not particularly limited in kind, but it is preferable to use Cefdinir crystalline Form B having higher stability than Cefdinir crystalline Form A.

The low-elevating Cefdinir crystalline form may be, for example, those disclosed in US 2003/0204082 A1 or US 2004/0242556 A1, and the like, and preferably Cefdinir crystalline Form B obtained in US 2003/0204082 A1 may be used. Cefdinir crystalline Form B is commercially available, for example, from Dofar.

The low elution Cefdinir crystalline form can be adjusted by those skilled in the art according to the desired efficacy, but is preferably included in an amount of 40% to 90% by weight in the composition of the present invention. When the low eluting ceftinir crystalline form is included within the above range, it is preferable in that a pharmaceutical composition having a size that is easy to take can be prepared.

The carbonate acts as a dissolution aid to enable the low-elevation ceftinir crystalline ceftinir to be rapidly eluted in an acidic medium, such as ceftinir crystalline Form B. When the carbonate is used together with the disintegrant in the composition of the present invention it can be seen that the dissolution rate is greatly improved.

As the carbonate, any carbonate known in the art may be used without particular limitation. Specifically, the carbonate includes alkali metal carbonates such as sodium carbonate and potassium carbonate; Alkali metal carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; Alkaline earth metal salts such as calcium carbonate and magnesium carbonate may be used, and these may be used alone or in combination of two or more thereof. Preferably, alkaline earth metal carbonate salts such as calcium carbonate and magnesium carbonate are used, and most preferably calcium carbonate, for example, precipitated calcium carbonate.

The content of the carbonate can be controlled according to the content of the low-elevating Cefdinir crystalline form and the desired effect, but preferably 1% (w / w) to 30% (w / w) based on the low-eluting Cefdinir crystalline form ), More preferably from 1% (w / w) to 25% (w / w) relative to the weight of the low-eluting cefdinir crystalline form, and most preferably from 2% (w / w) to the weight of the low-eluting cefdinir crystalline form It is used in an amount of 20% (w / w). When the carbonate is included in the above range it can effectively increase the dissolution rate of the low elution Cefdinir crystalline form in acidic medium.

The composition of the present invention may also further comprise a disintegrant and a lubricant.

In the present invention, the disintegrant interacts with the carbonate and serves to further improve the dissolution properties of the low-elevating ceftinir crystalline form. Such disintegrants can be used without limitation, those commonly used in the art, for example, carboxymethyl cellulose calcium, polyvinylpyrrolidone such as crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, Carmellose calcium, sodium carboxymethyl starch, sodium carboxymethyl cellulose, dried corn starch and the like. These can be used individually or in mixture of 2 or more types, respectively, It is most preferable to use carboxymethylcellulose calcium among them.

The disintegrant may be controlled in accordance with the content of the low-eluting ceftinir crystal form, the nature of the desired composition, etc., preferably in the composition of the present invention in terms of interaction with the carbonate 2 to 40% by weight More preferably, it is included in the content of 3% by weight to 25% by weight.

In the present invention, the lubricant serves to facilitate the tableting or filling of the mixed powder or granules of the raw material. Such lubricants may be used without limitation, those conventionally used in the art, for example, magnesium stearate, talc, calcium stearate, zinc stearate, magnesium oxide, stearic acid, corn starch, hydrogenated vegetable oil, light silicon dioxide, light anhydrous silicic acid , Colloidal silicon dioxide, magnesium trisilicate and the like. These can be used individually or in mixture of 2 or more types, respectively, It is most preferable to use magnesium stearate among them.

The glidant may be controlled in accordance with the content of the low-eluting ceftinir crystalline form, the nature of the desired composition, etc., preferably in the composition of the present invention 0.01% to 7% by weight, more preferably 0.05% It is included in the content of% -5% by weight. If the lubricant is included in the above range it is preferred in that it does not affect the dissolution of the composition and tableting or filling is easy.

The pharmaceutical composition of the present invention is prepared in a conventional pharmaceutical method by adding a pharmaceutically acceptable conventional excipient or auxiliary agent in addition to the above components to prepare a solid dosage form for oral administration such as tablets, capsules, granules, granules, etc. Can be. That is, granules are prepared, and glidants and other pharmaceutically acceptable additives are added thereto to fill the hard capsules directly in the form of powders, granules, or granules, or pharmaceutical additives necessary for tableting are added and known methods. By compression molding according to the invention.

In the composition of the present invention, one or more pharmaceutically acceptable additives for formulation may be used, and examples thereof include a binder, a surfactant, a colorant, a buffer, a diluent, a flavoring agent, a preservative, a filler, and the like. These additives can be used without limitation, those commonly used in the art.

The method for preparing the pharmaceutical composition according to the present invention is not particularly limited, but a wet granulation method or an apple mixing method may be used. Preferably, a wet granulation method can be used, for example, a low-elevating cefdinir crystalline form (e.g., cefdinir crystalline form B) is mixed with a carbonate and a disintegrant, and other additives are mixed as necessary. In addition to the usual organic solvent (for example, a single solvent such as ethanol, isopropanol, or a mixed solvent thereof), it is combined and dried, and then lubricated by adding a lubricant and other additives as necessary. The pharmaceutical composition of the present invention can be prepared by filling in.

The dosage of the pharmaceutical composition of the present invention varies depending on the weight, age, sex, health condition, diet, time of administration, method of administration, excreta, and severity of the disease. Preferably the daily dose is 100mg to 300mg, it is preferable to administer it once or several times a day.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples. However, this is only provided to more easily understand the present invention, the scope of the present invention is not limited by the following examples and the like.

Example  One: Cefdinir  Weight Precipitated Calcium Carbonate  Manufactured using 10% (w / w)

50 g of Cefdinir crystalline Form B (purchased from Dopasa), 14.675 g of carboxymethyl cellulose calcium, and 5 g of precipitated calcium carbonate were added and mixed, and 15 g of ethanol was added to the mixture and combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and the lubricant was lubricated. 140 mg each of the lubricant was filled into capsule 3 to prepare a ceftinir-containing composition.

Example  2: Cefdinir  Weight Precipitated Calcium Carbonate  Manufactured using 20% (w / w)

50 g of cefdinir crystalline form B, 14.675 g of carboxymethyl cellulose calcium, and 10 g of precipitated calcium carbonate were added and mixed, and 15 g of ethanol was added to the mixture and combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and the lubricant was filled into capsule No. 3 by 150 mg to prepare a ceftinir-containing composition.

Example  3: Cefdinir  Weight Precipitated Calcium Carbonate  Manufactured using 2% (w / w)

50 g of Cefdinir crystalline form B, 14.675 g of carboxymethyl cellulose calcium, and 1.0 g of precipitated calcium carbonate were added and mixed, 15 g of ethanol was added to the mixture, and the mixture was combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and the lubricant was lubricated. The lubricant was filled in No. 3 capsules of 132 mg to prepare a ceftinir-containing composition.

Example  4 : Cefdinir  Weight Precipitated Calcium Carbonate  Manufactured using 4% (w / w)

50 g of cefdinir crystalline form B, 14.675 g of carboxymethyl cellulose calcium, and 2.0 g of precipitated calcium carbonate were added and mixed, and 15 g of ethanol was added to the mixture and combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and the lubricating agent was filled in capsule No. 3 by 134 mg to prepare a ceftinir-containing composition.

Example  5: Cefdinir  Weight Precipitated Calcium Carbonate  Manufactured using 8% (w / w)

50 g of cefdinir crystalline form B, 14.675 g of carboxymethyl cellulose calcium, and 4.0 g of precipitated calcium carbonate were added and mixed, and 15 g of ethanol was added to the mixture and combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and 138 mg of the lubricant was filled into capsule 3 to prepare ceftinir-containing composition.

Example  6: Cefdinir  Weight Precipitated Calcium Carbonate  Manufactured using 15% (w / w)

50 g of cefdinir crystalline form B, 14.675 g of carboxymethyl cellulose calcium, and 7.5 g of precipitated calcium carbonate were added and mixed, 15 g of ethanol was added to the mixture, and the mixture was combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and 145 mg of the lubricant was filled into capsule 3, thereby preparing ceftinir-containing composition.

Example  7: Cefdinir  Weight Precipitated Magnesium Carbonate  Using 4% (w / w) My article

50 g of cefdinir crystalline form B, 14.675 g of carboxymethyl cellulose calcium, and 2.0 g of precipitated magnesium carbonate were added and mixed, and 15 g of ethanol was added to the mixture and combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and the lubricating agent was filled in capsule No. 3 by 134 mg to prepare a ceftinir-containing composition.

Example  8: As disintegrant Crospovidone  Manufacturing using

Cefdinir-containing compositions were prepared in the same manner as in Example 1 except that crospovidone was used instead of carboxymethylcellulose calcium as a disintegrant.

Example  9: As disintegrant Croscarmellose sodium  Manufacturing using

Cefdinir-containing compositions were prepared in the same manner as in Example 1, except that croscarmellose sodium was used instead of carboxymethylcellulose calcium as a disintegrant.

Example  10: As disintegrant Low Substituted Hydroxypropyl Cellulose  Manufacturing using

Cefdinir-containing compositions were prepared in the same manner as in Example 1 except that low-substituted hydroxypropyl cellulose was used instead of carboxymethyl cellulose calcium as a disintegrant.

Comparative example  One: Precipitated calcium carbonate  Manufactured by exclusion

The same procedure as in Example 1 was conducted except that no precipitated calcium carbonate was used. That is, 50 g of cefdinir crystalline form B and 14.675 g of carboxymethyl cellulose calcium were added and mixed in order, and 15 g of ethanol was added to the mixture and combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and lubricant was added to 130 capsules of No. 3 capsules to prepare ceftinir-containing compositions.

Comparative example  2: prepared using citric acid, an acidifying agent

Cefdinir-containing compositions were prepared in the same manner as in Example 1, except that citric acid, an acidifying agent, was used instead of precipitated calcium carbonate.

Comparative example  3: being an alkalizing agent Calcium hydrogen phosphate  Manufacturing using

Cefdinir-containing compositions were prepared in the same manner as in Example 1, except that calcium hydrogen phosphate, an alkalizing agent, was used instead of precipitated calcium carbonate.

Comparative example  4: being an alkalizing agent Sodium hydrogen phosphate  Manufacturing using

Cefdinir-containing compositions were prepared in the same manner as in Example 1, except that sodium hydrogen phosphate, an alkalizing agent, was used instead of precipitated calcium carbonate.

Comparative example  5: as a dissolution aid Polyoxyl 40 stearic acid  Manufacturing using

Cefdinir-containing compositions were prepared in the same manner as in Example 1 except that polyoxyl 40 stearic acid, a dissolution aid, was used instead of precipitated calcium carbonate. That is, 50 g of cefdinir crystalline form B and 14.675 g of carboxymethyl cellulose calcium were added and mixed in order, and 5 g of polyoxyl 40 stearic acid was dissolved in 15 g of ethanol to prepare a binding solution, and then the binding solution was added to the mixture to associate. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and the lubricant was filled with 140 mg of the lubricant in capsule No. 3 to prepare a ceftinir-containing composition.

Comparative example  6: as melting aid Poloxamer  Manufactured using 407

Cefdinir-containing compositions were prepared in the same manner as in Comparative Example 5 except that poloxamer 407 was used instead of polyoxyl40 stearic acid.

Comparative example  7: Precipitated Calcium Carbonate  exclusion, As disintegrant Carboxymethyl Cellulose Calcium  Manufactured using 49.35mg

50 g of cefdinir crystalline form B and 24.675 g of carboxymethyl cellulose calcium were added sequentially, and 15 g of ethanol was added to the mixture, and they were combined. This association was dried for 10 hours (less than 2.5% of drying loss) at the drying temperature of 40 degreeC, and the dried material was established using the 18 body. 0.325 g of magnesium stearate was added to the sieved material, and the lubricant was filled into capsule No. 3 by 150 mg to prepare a ceftinir-containing composition.

Comparative example  8: Commercially available  ( Omnisev ; Cheil Pharm)

A commercially available formulation containing cefdinir crystalline Form A (Omnicef; Cheil) was prepared.

The compositions of Examples 1 to 10 and Comparative Examples 1 to 8 prepared as described above are shown in Tables 1 and 2 below.

Experimental Example  One: Precipitated Calcium Carbonate , pH  Evaluation of Dissolution Rate Effect by Using Modifier and Dissolution Aid

Cefdinir-containing composition prepared in Example 1, Comparative Examples 1 to 6 (containing 100 mg of cefdinir as a titer in the total content) and Cefdinir crystalline Form B 100 mg used in the preparation of the composition, and Cefdinir crystalline Form A The dissolution rate in the acidic medium was confirmed with the commercially available formulation of Comparative Example 8 containing (dissolution test method; Korean Pharmacopoeia 2 method, pH 1.2, 900 mL, 50 rpm, 37 ° C.). The results are shown in Table 3 below.

As can be seen from Table 3, the composition of Example 1 containing precipitated calcium carbonate showed a dissolution rate of about 25% higher than the dissolution rate of Cefdinir crystalline form B. This was much better than the results of using various pH adjusting agents such as citric acid, calcium hydrogen phosphate, sodium hydrogen phosphate (Comparative Examples 2-4) and dissolution aids (Comparative Examples 5-6). In addition, the composition of Example 1 showed a higher dissolution rate than the commercially available formulation of Comparative Example 8 containing Cefdinir crystalline Form A.

Experimental Example  2: Evaluation of Dissolution Rate Effect According to Carbonate Content

In order to determine the effect of the carbonate (precipitated calcium carbonate or precipitated magnesium carbonate) in accordance with the amount used, the dissolution rate in the acid medium was confirmed for the compositions of Examples 1-7. The results are shown in Table 4 below.

As can be seen from the results of Table 4, in the composition prepared using carbonate more than 2% by weight of cefdinir dissolution rate of cefdinir was increased to show a dissolution rate of more than 85% in 30 minutes.

Experimental Example  3: Disintegrant  Evaluation of Dissolution Rate Effect by Type

In order to evaluate the effect on the dissolution rate according to the type of disintegrant, the dissolution rate in the acidic medium was confirmed for the compositions of Examples 1 and 8 to 10. The results are shown in Table 5 below.

As can be seen from the results of Table 5, when carbonate is contained, the type of disintegrant did not make a big difference in the dissolution rate of ceftinir.

Experimental Example  4: Disintegrant  Evaluation of Dissolution Rate Effect by Single Use

In order to determine the effect of the use of a disintegrant alone on the dissolution rate of cefdinir, Example 1 using precipitated calcium carbonate in addition to disintegrant, Comparative Example 1 using 29.35 mg of disintegrant, and Comparative Example using 49.35 mg of disintegrant The dissolution rate in acidic medium was confirmed for the cefdinir-containing composition of 7. The results are shown in Table 6 below.

As can be seen from the results of Table 6, the use of the disintegrant and carbonate together was much more effective in improving the dissolution rate of cefdinir than in the case of using only the disintegrant alone, and the amount of the disintegrant used alone. Increasing the amount did not affect the improvement of cefdinir dissolution rate.

Claims (9)

Cefdinir crystalline form B and dissolution aids containing at least one of calcium carbonate and magnesium carbonate in a content of 1% (w / w) to 30% (w / w) relative to the weight of the cefdinir crystalline form B, A pharmaceutical composition for oral administration with improved dissolution rate of dinir in an acid medium. The method according to claim 1, A pharmaceutical composition for oral administration further comprising a disintegrant and a lubricant. delete delete delete The method according to claim 2, The disintegrant is carboxymethyl cellulose calcium, polyvinylpyrrolidone including crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose calcium, carboxymethyl starch sodium, carboxymethyl cellulose sodium and dry corn A pharmaceutical composition for oral administration, characterized in that one or two or more selected from the group consisting of starch. The method according to claim 2, The glidant is selected from the group consisting of magnesium stearate, talc, calcium stearate, zinc stearate, magnesium oxide, stearic acid, corn starch, hydrogenated vegetable oil, light silicon dioxide, light silicic anhydride, colloidal silicon dioxide and magnesium trisilicate Or oral pharmaceutical composition, characterized in that two or more species. delete The method according to claim 1, A pharmaceutical composition for oral administration further comprising one or two or more selected from the group consisting of binders, surfactants, colorants, buffers, diluents, flavoring agents, preservatives and fillers.