KR100759607B1 - Cefuroxime axetil granule and process for the preparation thereof - Google Patents

Abstract

The present invention relates to cefuroxime acetil granules having a high bioavailability and excellent stability and shielding bitumen, and a preparation method thereof, wherein the amorphous cefuroxime acetil solid dispersion or amorphous cefuroxime acetil, sucrose fatty acid ester, and methacrylic acid The cefuroxime axetyl granules produced by mixing and melting the ethyl acrylate copolymer and the disintegrant are provided. The cefuroxime axetyl granules according to the present invention are excellent in the stability of the drug, the bitter taste is effectively shielded to improve the medication compliance, reproducible production, it can be useful for oral administration of cefuroxime axetyl.

Description

Cefuroxime AXETIL GRANULES AND MANUFACTURING METHOD THEREOF {CEFUROXIME AXETIL GRANULE AND PROCESS FOR THE PREPARATION THEREOF}             

1A to 1C show the results of observing changes in endothermic peaks on DSC of sucrose fatty acid esters, methacrylic acid-ethylacrylate copolymers, and their melt mixtures, respectively,

Figure 2 is a result of comparing the amount of drug released over time when dispersing in water of the cefuroxime axetil preparation according to the present invention and the comparative preparation (Ginnet ^R dry syrup, GSK),

3 is a dissolution test result of the cefuroxime axetyl preparation and the comparative preparation (jinnet ^R dry syrup) according to the present invention,

Figure 4 is a result of comparing the blood concentration of the drug over time when the administration of the cefuroxime axetyl preparation and the comparative preparation (jinnet ^R dry syrup) according to the present invention.

The present invention relates to cefuroxime axetyl granules having high bioavailability, excellent stability, and high drug compliance, and a preparation method thereof.

Cefuroxime axetil is a cephalosporin-based oral antibiotic that exhibits high activity against a wide range of Gram-positive and negative microorganisms. Sepuroxime axetyl usually has three types of polymorphisms: crystalline with a melting point of about 180 ° C., high melting point like amorphous with a melting point of about 135 ° C., and low melting point like amorphous with a melting point of about 70 to 95 ° C. There is this. Although cefuroxime axetyl has good antimicrobial activity, there are two considerations in the preparation of dry syrup.

First, due to the crystalline form of the drug substance itself is poorly soluble and due to the nature of the drug itself forms a gel phase by contact with a water-soluble medium there is a problem that the rate of dissolution and absorption in the gastrointestinal tract is inhibited.

In order to improve this problem, the present inventors have already prepared an amorphous cefuroxime axetyl solid dispersion with improved dissolution rate and bioavailability as described in Korean Patent No. 342943, which can be formulated or used as a raw material itself.

Second, despite the excellent antimicrobial activity, due to the very bitter taste of the drug itself, which can not be masked by the sweetening and flavoring agents commonly applied to granules, there is a problem that not only children but also general adult patients are reluctant to take orally.

In Korean Patent Application Publication No. 1999-0009097 of GlaxoSmithKline (GSK), in order to shield the bitter taste of cefuroxime axetyl, the drug is dispersed in a molten stearic acid and spray-dried, and the product is dried using a low temperature air stream. A method of producing granules by cooling is disclosed. However, the granules prepared by the above method are to be dispersed in water but are suspended in water due to the physical properties of stearic acid itself, so there is a problem that it is difficult to take a certain amount when taking the homogeneity. In addition, the first taste after taking a certain degree of masking the sweet taste by the sweetener and flavor, but has a disadvantage in that the aftertaste is very low, especially in compliance with the medication.

Therefore, the present inventors have studied a new method to overcome the disadvantages of the existing method, the oral administration granules containing amorphous cefuroxime axetyl, sucrose fatty acid ester, methacrylic acid-ethyl acrylate copolymer and disintegrant The present invention has been completed by confirming that the granules are easy to take and reproducibly mask the bitter taste and exhibit excellent stability and good release properties.

It is an object of the present invention to provide cefuroxime axetyl granules which are excellent in dissolution rate and stability and effectively mask the bitter taste.

Another object of the present invention is to provide a method for producing the granules.

In accordance with the above object, in the present invention, cefuroxime axetyl granules prepared by mixing and melting amorphous cefuroxime acetyl solid dispersion or amorphous cefuroxime acetyl, sucrose fatty acid ester, methacrylic acid-ethylacrylate copolymer and disintegrant To provide.

In addition, in the present invention, 1) mixing the sucrose fatty acid ester and methacrylic acid-ethyl acrylate copolymer and then applying heat to melt; 2) dispersing by adding an amorphous cefuroxime axetyl solid dispersion or amorphous cefuroxime axetyl and disintegrant to the melt mixture of step 1); And 3) cooling the molten mixture of step 2) and then pulverizing it to a predetermined size to produce granules.

Hereinafter, the present invention will be described in detail.

The cefuroxime axetyl granules according to the present invention can be prepared using amorphous cefuroxime axetyl solid dispersion or amorphous cefuroxime axetyl, sucrose fatty acid ester, methacrylic acid-ethylacrylate copolymer and disintegrating agent as essential components. , Coating materials and pharmaceutically acceptable additives may be included as additional components.

Referring to each component of the composition for oral administration is as follows.

(1) Sepuroxime Axetyl

Sepuroxime axetyl is used as an active ingredient of the present invention. Amorphous cefuroxime axetyl solid dispersion prepared by the method described in Korean Patent No. 342943, or amorphous cefuroxime axetyl raw material is preferable. They have the same bitter taste as crystalline cefuroxime axetyl, but are amorphous and have very good solubility and dissolution properties.

(2) sucrose fatty acid ester

Sucrose fatty acid ester used in the composition of the present invention is an essential ingredient to obtain a formulation capable of masking the bitter taste of cepuroxime axetyl. When the sucrose fatty acid ester having a low melting point of 58 to 70 ℃ can be melted at a low temperature, the manufacturing process can be facilitated and the decomposition of the drug can be suppressed to ensure stability. In particular, sucrose fatty acid ester is a waxy type with strong properties of oil and has very low affinity with water, so when dispersing agent is used together, even if it is stored for several days or more with water, it does not disintegrate easily to prevent the dissolution of the drug.

Preferred sucrose fatty acid esters are commercially available under the trade name SUCROSE FAESTER (DK ES.F-20W) (Dai-ichi Kogyo Seiyaku, Japan), with an HLB value of about 2 and a melting point of about 65. It is an oil-soluble carrier which is -68 degreeC.

The sucrose fatty acid ester of the present invention may be used in an amount of 0.2 to 40 parts by weight, preferably 0.5 to 10 parts by weight, based on 1 part by weight of cefuroxime axetyl, a pharmacologically active ingredient.

(3) methacrylic acid-ethyl acrylate copolymer

In the present invention, the methacrylic acid-ethyl acrylate copolymer is not melted when used alone, but may be dissolved when used in combination with the sucrose fatty acid ester in a constant ratio (by weight) of about 1: 0.5 to 1.5, thereby dissolving drug particles It can be coated and made into a uniform granule. 1A-1C show endothermic peaks on DSC of a melted mixture of sucrose fatty acid ester, methacrylic acid-ethylacrylate copolymer, and a sucrose fatty acid ester and methacrylic acid-ethylacrylate copolymer (weight ratio 1: 1), respectively. As a result of observing the change, as shown in FIG. 1C, when melting and mixing the sucrose fatty acid ester and the ethyl methacrylate as one peak on the DSC, the eutectic phenomenon occurs. In addition, the methacrylic acid-ethyl acrylate copolymer, which is an enteric material, readily dissolves at a pH of 5.5 or higher, thereby increasing the dissolution rate of the drug.

The methacrylic acid-ethyl acrylate copolymer is marketed under the trade name Eudragit® L100-55 (Rohm).

The methacrylic acid-ethylacrylate copolymer of the present invention may be used in an amount of 0.1 to 30 parts by weight, preferably 0.5 to 10 parts by weight, based on 1 part by weight of cefuroxime acetyl.

(4) disintegrant

In granules coated with melt-mixed sucrose fatty acid ester and methacrylic acid-ethylacrylate copolymer, a disintegrant is used as a component necessary for the rapid disintegration of the drug to show the desired elution. The disintegrants which can be used for this purpose are as follows. Same as

1) microcrystalline cellulose

2) Crosslinked Sodium Carboxymethyl Cellulose

3) crosslinked polyvinyl pyrrolidone

4) Ion exchange resins, in particular amberlite IRP-88

5) alginic acid

6) sodium starch glycolate

Alginate is used as the most preferable component among these components.

The disintegrant of the present invention may be used in an amount of 0.05 to 20 parts by weight, preferably 0.1 to 10 parts by weight, based on 1 part by weight of cefuroxime axetyl.

(5) coating material

Granules coated with the sucrose fatty acid ester and methacrylic acid-ethylacrylate copolymer of the present invention can be coated in a conventional manner using an appropriate coating material as necessary. As a coating material which can be used for this purpose, an enteric material for protecting cefuroxime axetyl is preferable.

Representative examples of coating materials that can be used in the present invention are as follows.

Representative examples of enteric coatings include hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate phthalate, shellac, methacrylic acid-methyl methacrylate copolymer, methacrylate Acid-ethyl acrylate copolymer etc. are mentioned.

The coating material of the present invention may be used in an amount of 0.2 to 20 parts by weight, preferably 0.2 to 10 parts by weight, based on 1 part by weight of cefuroxime acetyl.

(6) pharmaceutically acceptable additives

The composition for oral administration according to the present invention may be formulated into pharmaceutical formulations such as powders, dry syrups, and granules according to conventional methods, and may further include other pharmaceutically acceptable additives to aid in formulation. Representative examples of the additives include sugars such as sugars, viscosity modifiers such as gum, powder excipients that can be used in emulsifiers, pH adjusters, and other powders, and the like, and fragrances, colorants, sweeteners and the like can be further added.

Pharmaceutically acceptable additives required for formulation may be used in amounts of 0.01 to 100 parts by weight, preferably 0.02 to 50 parts by weight, based on 1 part by weight of cefuroxime axetyl.

In addition, the present invention is a step of preparing a granule after the addition of amorphous cefuroxime acetyl solid dispersion or amorphous cefuroxime axetyl and disintegrant to the melt-mixed sucrose fatty acid ester and methacrylic acid-ethyl acrylate copolymer It includes, it provides a method for producing the cefuroxime axetyl granules.

The method for producing cefuroxime axetyl granules of the present invention

1) mixing the sucrose fatty acid ester and methacrylic acid-ethyl acrylate copolymer and then applying heat to melt;

2) adding and dispersing an amorphous cefuroxime acetyl solid dispersion or a mixture of amorphous cefuroxime axetyl and a disintegrant to the molten sucrose fatty acid ester and methacrylic acid-ethylacrylate copolymer mixture; And

3) cooling the molten mixture of step 2) and then grinding the melt mixture to a predetermined size to produce granules.

The melting temperature in step 1) is preferably from 60 to 75 ° C. In order to use the prepared granules in the form of suspension for oral administration, in step 3), it is preferable to adjust the size of the particles to 35 mesh or less.

The cefuroxime axetyl granules of the present invention prepared as described above are easy to take and reproducibly mask the bitter taste, exhibit excellent dissolution rate and stability, and exhibit good release properties.

Granules prepared by the above method may be coated in a conventional pharmaceutical method as necessary, or may be formulated in various forms by mixing with a pharmaceutically acceptable carrier.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

Example 1 Preparation of Sepuroxime Axetyl Granules 1

(Step 1) Preparation of Amorphous Sepuroxime Axetyl Solid Dispersion

100 parts by weight of crystalline cefuroxime acetyl (from Hanmi Fine Chemical) and 16.63 parts by weight of Tween 80 (ICI) were dissolved in acetone, and 16.63 parts by weight of silicon dioxide were added thereto and dispersed well. The dispersion was spray dried using a spray dryer under conditions of an inlet temperature of 45 ° C. and an outlet temperature of 37 ° C. to prepare a solid dispersion. The solid dispersion was dried at 30 to 40 ° C. for about 3 hours to remove residual solvent.

(Step 2) Preparation of Cepuroxime Axetyl Granules

227 g of sucrose fatty acid ester (37318-31-3, Dai-ichi Kogyo Seiyaku), a nonionic surfactant, and 318 g of Eudragit® L100-55 (Rohm) are mixed And melted by heating to about 75 ° C. Subsequently, 31.8 g of a plasticizer triacetin was added thereto, mixed with sufficient stirring, and then, 181.8 g of the amorphous cefuroxime acetyl solid dispersion prepared in Step 1 and alginic acid as a disintegrating agent before being completely hardened while cooling. 45.4 g were added and combined and completely dispersed. It was cooled completely and granulated to a size of 35 mesh or less to finally give 804 g of cefuroxime axetyl granules.

Example 2 Preparation of Sepuroxime Axetyl Granules 2

Sepuroxime axetyl granules were prepared in the same composition and amount as in Example 1, except that amorphous cefuroxime axetyl raw material (Orchid Chemicals & Pharmaceuticals, India) was used instead of amorphous cefuroxime axetyl solid dispersion as a main component. .

Example 3 Preparation of Sepuroxime Axetyl Granules 3

Sepuroxime axetyl granules were prepared in the same composition and amount as in Example 1, except that crosslinked sodium carboxymethyl cellulose (AVEBE) was used instead of alginic acid as a disintegrant.

Example 4 Preparation of Sepuroxime Axetyl Granules 4

Sepuroxime axetyl granules were prepared in the same composition and amount as in Example 1, except that sodium starch glycolate (Penwest) was used instead of alginic acid as a disintegrant.

Example 5 Coating Preparation of Sepuroxime Axetyl Granules 1

804 g of Eudragit (registered trademark) L30D-55 (Rohm) (8.04 g as a solid powder) and 8.04 g of triacetin (Triacetin) for 804 g of cefuroxime axetyl granules prepared in Example 1 And a bottom spray in a NQ-160 fluid bed bed of DALTON, Japan, using a coating liquid composed of 536 g of distilled water. At this time, the inlet temperature was 36 to 39 ° C, the outlet temperature was 24 to 28 ° C, the liquid injection amount was 0.7 to 0.8 ml / min, spraying air pressure (40 to 50 psi) to coat the methacrylic acid- 892.4 g of a complex coated with Eudragit® L30D-55, a methyl methacrylate copolymer, was obtained.

Example 6 Coating Preparation of Cepuroxime Axetyl Granules 2

892.4 g of a coated complex was obtained in the same manner as in Example 5 except that hydroxypropyl methylcellulose phthalate (Shin-Etsu) was used as the coating material.

Example 7 Coating Preparation of Cepuroxime Axetyl Granules 3

Example 5 except that Eudragit® E-100 (Rohm), a butyl methacrylate- (2-dimethylaminoethyl) methacrylate-methylmethacrylate copolymer, was used as coating material 892.4 g of a coated complex was obtained by the same method as the above.

Example 8 Coating Preparation of Cepuroxime Axetyl Granules 4

892.4 g of a coated complex was obtained in the same manner as in Example 5 except that ethyl cellulose (IPI) was used as the coating material.

Preparation Example 1 Preparation of Dry Syrup 1

892.4 g of cefuroxime axetyl coating prepared in Example 5 to 3022.4 g sucrose powder, 2.1 g corn starch, 54.0 g acesulfame potassium, 72 g aspartame, 354.5 g tuti-fruit tea flavor ( tutti-frutti flavor, large product) was evenly mixed. Oral dry syrup of cepuroxime axetyl was prepared by adding and mixing 20.5 g citric acid and 21.6 g sodium citrate.

Preparation Example 2 Preparation of Dry Syrup 2

To 857.7 g of the cefuroxime acetyl coating prepared in Example 6, 2.1 g of xanthan gum, 14 g of corn starch, 1.4 g of sodium lauryl sulfate, 7 g of methylcellulose, and 3,012 g of sucrose powder were evenly mixed. The oral dry syrup of cefuroxime axetyl was then prepared by adding and mixing 284 g of tuti-fruity fragrance, 284 g of drink flavor powder, 21 g of citric acid and 21.8 g of sodium citrate.

Test Example 1 Stability Test in Aqueous Solution

The cefuroxime axetyl preparations prepared by the methods of Formulation Examples 1 and 2 above and GSK's Jinnet (Zinnat®) dry syrup, respectively, were suspended in 5 ml of purified water at 150 mg equivalent as cepuroxime axetyl, respectively. . Sepuroximexetyl was released into purified water on day 1, day 2, day 4, and day 6 while the suspension was left at room temperature, and the amount dissolved was confirmed by a UV detector. At this time, the analysis was carried out at a wavelength of 278 nm, the emission amount (%) was a total content of 100% and after a certain period of time to measure the emission amount emitted from it was recorded as a relative value.

As a result, as shown in Figure 2, the cefuroxime axetyl preparation according to the present invention was stable beyond the control in the storage conditions that patients actually take. In addition, it can be seen that it is suitable for the preparation of cefuroxime axetyl, which is unstable in an aqueous state because of no change in taste due to high stability.

Test Example 2 Dissolution Test in Phosphate Buffer

Comparative dissolution test using the preparation of cefuroxime axetyl prepared by the method of Formulation Examples 1 and 2 and GSK's Jinnet (Zinnat®) dry syrup as a cefuroxime axetyl in 150 mg equivalent amount, respectively, as a control Was performed. At this time, 900 ml of 0.05 mol / L potassium dihydrogen phosphate buffer (pH 7.0) was used as the eluent, and it was carried out as described in Method 2 of the Korean seventh tablet dissolution test method at 100 rpm at 37 ± 0.5 ° C. It was.

The eluate obtained therefrom was analyzed at 278 nm wavelength using a UV detector.

As a result, as shown in Figure 3, the cefuroxime axetyl preparation according to the present invention showed a good dissolution properties similar to the control.

<Test Example 3> Bitter taste shielding effect test

Sepuration of cefuroxime acetyl prepared by the method of Formulation Examples 1 and 2 and GSK's Jinnet (Zinnat®) dry syrup as 150 mg of cefuroxime acetil, respectively, as a control to confirm the bitter taste shielding effect The sensory test was performed.

Specifically, the formulation of Formulation Example 1, Formulation Example 2 Formulation and Jinnet dry syrup was suspended by adding 5 mL of purified water to 150 mg equivalent amount as cepuroxime axetyl. Five syrups of 20-30 year-old adult men and women were placed in the mouth for 10 seconds, and immediately after spitting, the strength of Komi was evaluated as the initial Komi strength, and after 1 minute, the Komi strength was determined as the late Komi strength. 1 is shown.

A person who expressed the bitter taste was evaluated as A when 2 or less, B when 3 to 5, C when 6 to 8, and D when 9 to 10.

Early high tail strength Late high Komi strength Formulation Example 1 A A Formulation Example 2 A A Ginnet (registered trademark) A C

From the results in Table 1, it can be seen that the formulations of the present invention exhibit lower gourd than the control formulation.

Test Example 4 Animal Experiment for Evaluating Bioavailability

Sepuroxime acetyl preparation prepared by the method of Formulation Example 1 and GSK's Jinnet (Zinnat®) dry syrup, respectively, as a control was dispersed in 2 ml of water to 20 mg / kg equivalent amount as cefuroxime axetyl Oral sonde was administered orally to SD rats (Rat). After administration, a certain amount of blood was collected after 30, 60, 120, 180, 300, 420 minutes, and the method of J. Kor. Pharm. Sci., Vol. 29, No. 4, 361-365 (1999). The sample was pretreated according to the procedure. This blood sample was analyzed by liquid chromatography according to the method of the document. 1.0 ml / using Inertsil ODS-2 (4.6x250 mm) C ₁₈ as column, 0.05 M ammonium phosphate buffer (pH 3.2): acetonitrile mixture (86:14 (v / v)) as mobile phase Analyzes were made with a UV detector at 280 nm wavelength with 50 μl injection at a flow rate of minutes.

As a result, as shown in Figure 4 and Table 2, the cefuroxime axetyl dry syrup formulation according to the present invention showed a higher bioavailability than the control formulation.

AUC7h (μg.hr / ml) ^{* 1} T _max (hr) ^{* 2} C _max (μg / ml) ^{* 3} Formulation Example 1 11.3 ± 2.5 1.0 ± 0.0 3.7 ± 0.3 Ginnet (registered trademark) 7.3 ± 2.5 1.0 ± 0.0 2.9 ± 1.1  * 1: Area under the plasma concentration curve of the drug up to 7 hours after administration * 2: Time to peak plasma concentration * 3: Maximum plasma concentration

As described above, the cefuroxime axetyl granules of the present invention are excellent in the stability of the drug and effectively masked the bitter taste, showing improved medication compliance and reproducible production.

Claims (8)

Amorphous cefuroxime axetyl solid dispersion or amorphous cefuroxime axetyl; A melted mixture of a sucrose fatty acid ester and a methacrylic acid-ethyl acrylate copolymer in a weight ratio of 1: 0.5 to 1.5; And cefuroxime axetyl granules comprising a disintegrant. The method of claim 1, The disintegrant is selected from the group consisting of microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, crosslinked polyvinyl pyrrolidone, ion exchange resins, alginic acid and sodium starch glycolate. Sepuroxime Axetyl Granules. The method of claim 1, 0.5 to 10 parts by weight of sucrose fatty acid ester, 0.5 to 10 parts by weight of methacrylic acid-ethylacrylate copolymer, and 0.1 to 10 parts by weight of disintegrant, based on 1 part by weight of amorphous cefuroxime axetyl solid dispersion or amorphous cefuroxime axetyl Sepuroxime axetyl granules, characterized in that it comprises a. The method of claim 1, Sepuroxime axetyl granules further comprising a coating material and a pharmaceutically acceptable additive. The method of claim 4, wherein Sepuroxime axetyl granules, characterized in that the coating material is an enteric coating material. The method of claim 4, wherein A cefuroxime acetyl granules comprising from 0.2 to 10 parts by weight of a coating material and from 0.02 to 50 parts by weight of a pharmaceutically acceptable additive with respect to 1 part by weight of amorphous cefuroxime axetyl solid dispersion or amorphous cefuroxime axetyl. delete 1) mixing the sucrose fatty acid ester and methacrylic acid-ethyl acrylate copolymer and then melting at 60 to 75 ℃; 2) dispersing by adding an amorphous cefuroxime axetyl solid dispersion or amorphous cefuroxime axetyl and disintegrant to the melt mixture of step 1); And 3) preparing granules by cooling the melt mixture of step 2) and then pulverizing to a predetermined size Comprising, cefuroxime axetyl granules manufacturing method.

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