KR20090005485A - Cefuroxime axetil containing granules and process for the preparation thereof - Google Patents

Abstract

A granule containing matrix type cefuroxime axetil, and a method for preparing the granule containing matrix type cefuroxime axetil are provided to block the bitter taste and foreign body feeling of cefuroxime axetil. A granule containing matrix type cefuroxime axetil comprises 100 parts by weight of cefuroxime axetil; 5-10 parts by weight of a nonionic surfactant; 20-50 parts by weight of an enteric polymer; and 1-5 parts by weight of ethyl cellulose. Preferably the nonionic surfactant is at least one selected from polysorbate, polyoxyethylene castor oil, and polyoxyethylene hydrogenated castor oil.

Description

Cefuroxime axetil containing granules and process for the preparation

The present invention relates to cefuroxime axetyl containing granules and a method for producing the same.

Cepuroxime axetyl is a very useful wide range of cephalosporin-based antibiotics that have high activity against both gram-negative and gram-positive bacteria and have stable properties, particularly for β-lactamases. Cefuroxime was originally developed as a sodium salt injection because it forms a gel phase in contact with an aqueous medium due to the nature of the drug, but was later developed as cefuroxime axetyl with 1-acetoxyethyl ester as a prodrug with improved oral absorption. There is a bar. Thus, cefuroxime axetyl enables the formulation of oral tablets and dry syrups.

On the other hand, cefuroxime axetyl is so used that its taste cannot be masked by the use of conventional sweeteners, and in particular, it is formulated as a dry syrup for pediatrics due to its properties such as gel formation when contacted with an aqueous medium. It has very difficult physical properties.

Korean Patent Publication No. 10-1988-0013560 discloses a composition in the form of fine particles coated with cefuroxime acetyl with lipids or lipid mixtures such as stearic acid and palmitic acid. In addition, Korean Patent Publication No. 10-2005-0044590 discloses that the composition in the form of the particulates hides the bitter taste of cefuroxime axetyl to some extent, but the suspension and the composition still have a bitter taste because cefuroxime axetyl is too used. In order to ameliorate the problem of "gritty" texture, it has been disclosed to further use sweetener systems such as acesulfame potassium, aspartame and texture modifiers such as xanthan gum.

Korean Patent Registration No. 10-0579898 (Patent Publication No. 10-2005-0038251) contains cepuroxime axetyl inside, and the outer wall covering the inside is made of biodegradable polymers such as alginate, chitosan or Eudragit. Microcapsules have been disclosed.

In addition, the Republic of Korea Patent Registration No. 10-0529757 discloses a method for producing amorphous cefuroxime axetyl solid dispersion using a supercritical fluid process and the cepuroxime axetyl solid dispersion prepared by this method, Korean Patent Publication Nos. 10-2005-0073513 and 10-2007-0038583 combine and melt amorphous cepuroxime axetyl solid dispersions or amorphous cefuroxime axetyls, sucrose fatty acid esters, methacrylic acid-ethylacrylate copolymers and disintegrants, respectively. Cefuroxime Axetyl granules and amorphous Cepuroxime Axetyl solid dispersions or amorphous cefuroxime Axetyl, prepared by mixing and melting a nonionic surfactant having a HLB in the range of 1 to 8 and a melting point of 35 to 80 ° C., and a disintegrant Cefuroxime Axetyl Granules have been disclosed.

However, the above-mentioned conventional cefuroxime axetyl-containing formulations are formulated using molten lipids or using additional sweetener systems and texture modifiers such as xanthan gum, which makes the preparation complex and difficult to obtain homogeneous formulations. . In addition, the formulation using the microcapsules may be difficult to obtain a microcapsule of a certain size, and the formulation using a solid dispersion, etc. also requires a special treatment (for example, high temperature melting), there is a disadvantage that the manufacturing cost increases. . In addition, there is a function of the bitterness shielding to some extent after contact with an aqueous medium, but the syrup liquid formulation is difficult to resuspend due to phase separation and gelation or curing during storage.

In addition, in order to prevent such gelation, Korean Patent Registration No. 10-0299356 discloses the use of silicon dioxide, but in order to prevent gelation or hardening in the syrup solution, a large amount of silicon dioxide should be used. Due to the nature of silicon dioxide used as a water absorption is easy to at the same time difficult to obtain a bitter taste shielding effect.

On the other hand, Korean Patent Registration No. 10-0523082 (Patent Publication No. 10-2004-0023167) is coated with an enteric polymer particles containing amorphous cefuroxime acetyl and polysorbate, and the elution in neutral saliva In order to prevent the surface has been disclosed a method for preparing a gourmet concealed cefuroxime axetyl-containing oral pharmaceutical composition prepared by mixing an acidic material, such as citric acid, which is an acidic material and secondary coating.

The manufacturing method can be prepared by using a conventional pharmaceutical manufacturing method, there is a relatively simple advantage compared to other prior art, but a separate coating layer forming step using expensive equipment such as a fluidized bed granulator in multiple stages There is a problem that the manufacturing cost increases because it must be performed. In addition, since the obtained cefuroxime axetyl-containing granules have a coating form, an additional acid such as citric acid or ascorbic acid is added to the coating layer to prevent damage to the coating film due to the increase in pH around the particle surface when suspended by adding water. There is a problem that must be designed.

Literature Information of the Prior Art

[Document 1] Republic of Korea Patent Publication No. 10-1988-0013560 1988.12.21

[Patent 2] Republic of Korea Patent Publication No. 10-2005-0044590 2005.5.12

[Document 3] Korean Patent Registration No. 10-0579898 2006.05.08 (Patent Publication No. 10-2005-0038251 2005.4.27)

[Document 4] Republic of Korea Patent Registration No. 10-0529757 2005.11.11 (Patent Publication No. 10-2004-0072057 2004.08.18)

[Patent 5] Republic of Korea Patent Publication No. 10-2005-0073513 2005.07.14

[Document 6] Republic of Korea Patent Publication No. 10-2007-0038583 2007.04.11

[Document 7] Republic of Korea Patent Registration No. 10-0299356 2001.06.08 (Patent Publication No. 10-1999-0076487 1999.10.15)

[Reference 8] Republic of Korea Patent Registration No. 10-0523082 2005.10.13 (Patent Publication No. 10-2004-0023167 2004.03.18)

The present inventors have conducted various studies to develop cefuroxime axetyl-containing formulations that can solve the problems of the prior art described above. That is, to develop a solution that can solve the recurrence of bitter taste that occurs after the shielding of bitter gourd, curing according to the form of the preparation during storage as a suspension, increase of granule manufacturing stages, increase of foreign body feeling and economical efficiency when taken by multiple coating process. The study was conducted.

As a result, when cefuroxime axetyl is formulated with ethyl cellulose together with a nonionic surfactant and an enteric polymer, it effectively prevents bitterness and foreign substances, while effectively preventing gelation in an aqueous medium and curing in an aqueous medium. It has been found that stability can be increased by avoiding this. In addition, the formulation does not require a coating process using an acidic substance, and can be granulated by a conventional granulation process, thus performing cumbersome manufacturing processes of performing a separate coating layer forming step using expensive equipment such as a fluidized bed granulator. It has been found that granules can be produced at a low cost and simple in manufacturing, since they can be easily prepared without the need.

Accordingly, an object of the present invention is to provide a cefuroxime axetyl-containing granule which can mask bitterness and foreign body, prevent gelation and prevent curing of the formulation when stored in suspension.

It is also an object of the present invention to provide a method for producing the cefuroxime axetyl-containing granules, which is simple in production and low in manufacturing cost.

According to one aspect of the present invention, the cefuroxime acetyl in matrix form is composed of 100 parts by weight of cefuroxime axetyl, 5 to 15 parts by weight of nonionic surfactant, 20 to 50 parts by weight of enteric polymer, and 1 to 5 parts by weight of ethyl cellulose. Containing granules are provided.

According to another aspect of the present invention, (a) 100 parts by weight of cefuroximexetyl, 5 to 15 parts by weight of nonionic surfactant, 20 to 50 parts by weight of enteric polymer, and ethyl to the C _{1 to} C ₅ alcohol or aqueous alcohol solution Adding 1 to 5 parts by weight of cellulose to associate; And (b) granulating the association obtained in step (a), a method for producing cefuroxime axetyl-containing granules in matrix form.

The cefuroxime axetyl-containing granules of the present invention contain ethyl cellulose to effectively shield the bitter taste and foreign body of cefuroxime axetyl, as well as effectively prevent gelation in an aqueous medium and at the same time prevent the hardening in an aqueous medium. Can be increased. In particular, the cefuroxime axetyl containing granules of the present invention have a matrix form containing ethyl cellulose, thereby making them acidic in conventional cefuroxime axetyl containing granules (eg, the granules of Patent No. 10-0523082) in the form of a coating. In order to provide an environment, it is not necessary to design an additional coating layer by adding an acidic substance such as citric acid and ascorbic acid, and enteric polymer (Korean Patent Publication No. 10-2005-0073513, 10-2007-0038583, Patent Registration No. 10-0523082) can significantly reduce the amount of the material used for the bitter taste shielding. In addition, the cefuroxime axetyl-containing granules of the present invention are granules in matrix form, and can be granulated by performing a series of processes such as mixing, coalescing, and granulation in a conventional granulation process. Since it can be manufactured easily without performing the cumbersome manufacturing process that has to perform a separate coating layer forming step using expensive equipment, the manufacturing is simple and can be manufactured at a low manufacturing cost (cost).

The cefuroxime axetyl used in the cefuroxime axetyl-containing granules of the present invention may be a crystalline form, a mixture of a crystalline form and an amorphous form, or an amorphous form, preferably an amorphous cepuroxime axetyl. The amount of cefuroxime axetyl may be used in a therapeutically effective amount, and the content may be easily selected by those skilled in the art from the total weight of the cepuroxy axetyl containing granules obtained according to the present invention.

The cefuroxime axetyl containing granules of the present invention comprise 5 to 15 parts by weight, preferably about 10 parts by weight, of the nonionic surfactant. The nonionic surfactants are used as dissolution / dispersion aids to facilitate the dispersion of cefuroxime axetyl, enteric polymers, and ethyl cellulose in solvents (eg, alcohols or aqueous alcohol solutions) in the preparation of granules. The nonionic surfactant that can be used in the granules of the present invention may be selected from the group consisting of polysorbate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, more preferably Preferably polyoxyl40 hydrogenated castor oil or polysorbate 80 (Tween ^TM 80) can be used, particularly preferably polyoxyl40 hydrogenated castor oil.

The cefuroxime axetyl-containing granules of the present invention comprise 20 to 50 parts by weight, preferably about 30 to 40 parts by weight, of the enteric polymer. The enteric polymer plays a role in reducing the bitter taste of cefuroxime axetyl. The enteric polymer is methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, polyvinylacetate phthalate, shellac, hydroxypropyl methylcellulose acetate succinate It may be selected from the group consisting of nate, and carboxymethyl cellulose, more preferably a copolymer of 1 part by weight of methacrylic acid and 1 part by weight of ethyl acrylate (specifically Eudragit ^TM L100-55 Eudragit ^TM L30-D55) can be used.

The cefuroxime axetyl containing granules of the present invention comprise 1 to 5 parts by weight of ethyl cellulose, preferably about 1 to 4 parts by weight. The ethyl cellulose effectively masks the bitter taste of cefuroxime axetyl and at the same time effectively prevents gelation in aqueous media. In addition, it also plays a role of increasing stability by preventing hardening during storage in an aqueous medium such as a suspension. In particular, the cefuroxime axetyl-containing granules of the present invention are prepared in a matrix form containing ethyl cellulose, thereby making it acidic in conventional cefuroxime axetyl-containing granules (eg, the granules of Patent No. 10-0523082) in the form of a coating. In order to provide an environment, it is not necessary to add an acidic substance such as citric acid and ascorbic acid to design a coating layer, and the amount of enteric polymer and the like can be significantly reduced.

The cefuroxime axetyl-containing granules in matrix form according to the present invention may be used in the form of granules per se, or in the form of dry syrups, which are dispersed and used in water, syrup, etc., in use. The granules or dry syrups are additives, such as sweeteners, which are commonly used in the pharmaceutical field for the cefuroxime axetyl containing granules according to the present invention; air freshener; coloring agent; pH adjusting agent; Dispersants and the like. Such additives may be used in amounts conventionally used in the pharmaceutical art.

The present invention relates to (a) 100 parts by weight of cefuroxime acetyl, 5 to 15 parts by weight of nonionic surfactant, 20 to 50 parts by weight of enteric polymer, and 1 to 5 parts by weight of ethyl cellulose in C _{1 to} C ₅ alcohol or aqueous alcohol solution. Uniting by adding wealth; And (b) granulation of the cefuroxime axetyl-containing granules in the form of a matrix comprising the step of granulating the association obtained in step (a).

Ethanol or ethanol aqueous solution may be preferably used as the alcohol or alcohol aqueous solution, and the alcohol aqueous solution (ethanol aqueous solution) may be an aqueous alcohol solution having 5 to 10 wt% of water. The amount of the alcohol or the aqueous solution of alcohol is not largely limited as long as it is used in an amount necessary to carry out the associated process of the mixture of cefuroxime axetyl, nonionic surfactant, enteric polymer, and ethyl cellulose. If too small, it may be difficult to obtain a homogeneous mixture, and too much may not be desired by the association. The amount of the alcohol or the aqueous solution of alcohol may be used, for example, 100 to 350 parts by weight, preferably about 130 to 250 parts by weight, based on 100 parts by weight of cefuroxime axetyl.

In the production method of the present invention, the cefuroxime axetyl, nonionic surfactant, enteric polymer, and ethyl cellulose may use the above-mentioned contents and types, respectively.

In the preparation method of the present invention, step (a) is performed by simultaneously adding cefuroxime acetyl, a nonionic surfactant, an enteric polymer, and ethyl cellulose to the alcohol or the aqueous solution of alcohol, or combining the nonionic to the alcohol or the aqueous solution of alcohol. The cefuroxime axetyl can be dispersed and associated in a solution obtained by dissolving the surfactant, the enteric polymer, and the ethyl cellulose. The association may be carried out by kneading uniformly according to a conventional pharmaceutical method, or may be performed using an association machine such as a high shear stress mixer.

The granulation of step (b) can be carried out using conventional extrusion granulation for the union obtained in step (a). For example, granules can be prepared by performing a series of processes of extrusion, drying, and formulation. The extrusion can preferably use a mesh having a mesh of 6 to 60 mesh, more preferably 10 to 30 mesh, the drying can be carried out at room temperature or in a drying oven, the formulation is granules of the desired size This can be carried out using a mesh having a mesh of preferably 20 to 80 mesh, more preferably 30 to 60 mesh.

In addition, the granulation of step (b) may be carried out using a conventional extrusion granulator, for example, an oscillator or a Fitz mill, for the coalescence obtained in step (a).

Hereinafter will be described in more detail through embodiments of the present invention. However, the following examples are intended to illustrate the invention and do not limit the scope of the invention.

Examples 1-9. Preparation of Granules

According to the content of Table 1 below, polyoxyl-40 hydrogenated castor oil or Tween 80; Ethyl cellulose or hydroxypropyl cellulose; And Eudragit ^™ L100-55 or Eudragit ^™ L30-D55 were dissolved in ethanol. This solution was placed in a high shear stress mixer to disperse cefuroxime axetyl and associate. After drying at room temperature, the resulting union was extruded through a 12 to 18 mesh sieve of the oscillator and again dried in a drying oven to remove ethanol. The granules were prepared by sizing them to a size of 30 to 50 mesh.

Example (g) One 2 3 4 5 6 7 8 9 ethanol 2250.0 2250.0 2250.0 2250.0 2250.0 1500.0 2250.0 2250.0 3750 Polyoxyl-40 Hydrogenated Castor Oil 112.5 112.5 112.5 - 112.5 112.5 112.5 97.5 112.5 Twin 80 - - - 112.5 - - - - - Ethyl cellulose 22.5 45.0 22.5 22.5 22.5 22.5 15.0 15.0 15.0 Eudragit L100-55 450.0 450.0 450.0 450.0 - 375.0 375.0 450.0 450.0 Eudragit L30-D55 - - - - ^{* 1} 1500.0 ^{* 2} 112.5 - - - Sepuroxime Axetyl 1125.0 1125.0 1125.0 1125.0 1125.0 1125.0 1125.0 1125.0 1125.0

(* 1: 450.0 g as solid content, * 2: 33.8 g as solid content)

Example 10 Preparation of Dry Syrup

To 115 g of cefuroxime acetyl granules prepared in Example 1, sucrose 2,025 g, mannitol 150 g, aspartame 50 g, acesulfam potassium 50 g, 5 g of Aerosil 200 (Aerosil ^® 200) as a dispersant Was mixed through 20 mesh, and 70 g of yoghurt flavor powder and 30 g of banana flavor powder were mixed as a fragrance to prepare a dry syrup.

Example 11 Preparation of Dry Syrup

To 110 g of cefuroxime axetyl granules prepared in Example 7, 18 mesh of sucrose powder, mannitol 300 g, aspartame 50 g, 50 g of acesulfame potassium, 35 g of Nusilin ^® UFL ₂ as a dispersant 20 mesh The mixture was passed through and mixed with 91 g of yoghurt flavor powder and 39 g of cider flavor powder as a fragrance to prepare a dry syrup.

Example 12 Preparation of Dry Syrup

With sucrose as a sweetening agent in the cefuroxime axetil granules 114g prepared in Example 8, agarose powder, 1965 g, mannitol, 150 g, aspartame, 55 g, acesulfame potassium 55 g, 6 g Aerosil 200 (Aerosil ^® 200) as a dispersant Was mixed through 20 mesh, and 100 g of yoghurt flavor powder and 50 g of roseberry flavor powder were mixed as a fragrance to prepare a dry syrup.

Comparative Example 1

Sepuloxime acetyl-containing granules were prepared in the same amount and composition as in Example 8, except that ethyl cellulose was not used. Sepuloxime acetyl dry syrup was prepared in the same manner as in Example 12 using the obtained granules.

Comparative Example 2

Sepuloxime-acetyl-containing granules were prepared in the same amount and composition as in Example 8, using 15 g of microcrystalline cellulose instead of ethyl cellulose.

Comparative Example 3

Seppuroxime axetyl-containing granules were prepared in the same amount and composition as in Example 8 using 15 g of carboxymethylcellulose sodium instead of ethyl cellulose.

Test Example 1: Stability Test (1)

5 g each of the granules of Example 1, the granules obtained in Comparative Example 1, and the granules of Comparative Examples 2 and 3 were each suspended in 10 mL of purified water, and left at room temperature for the first 6 hours, 1 day and 3 days. The characteristics of the suspension and the bitterness masking effect were tested in 10 healthy adults. The results are shown in Table 2 below.

6 hours 1 day 3 days Constellation bitter Constellation bitter Constellation bitter Example 1 Good radish Good radish Good radish Comparative Example 1 Hardening U Hardening U Hardening U Comparative Example 2 Good U Hardening U Hardening U Comparative Example 3 Good radish Good radish Hardening U

(* Bitter taste / radish; bitter taste was evaluated when there are three or more people who feel bitter taste.)

Test Example 2: Stability Test (2)

Commercially available ceftyl ^TM dry syrups (Hanmi Pharm.) As dry syrups and control agents obtained in Examples 10, 11, 12 and Comparative Example 1 were suspended in 5 mL of purified water at 150 mg of cefuroxime axetyl, respectively, and at room temperature. The suspension was observed on day 1, day 3 and day 5 while standing at. The results are shown in Table 3 below.

1 day 3 days 5 days Example 10 Good Good Good Example 11 Good Good Good Example 12 Good Good Good Comparative Example 1 Good Phase separation Phase Separation / Upper Curing Gusev butyl ^TM Good Phase separation Phase Separation / Upper Curing

As can be seen from the results of Table 3, the dry syrup according to the present invention showed a stable property over the entire period, the comparative examples and the control agent changed the properties with time and hardening occurred.

Test Example 3: Bitter taste shielding effect test

Examples 10, 12, and commercially available ceftyl ^TM dry syrup (Hanmi Pharm.) Were suspended in 5 mL of purified water at 150 mg of cefuroxime axetyl, respectively, and tested in 10 healthy adult males. Was carried out. The sensory test was carried out by comparing the high strength after taking the suspension immediately with the high strength when resuspended after storing the suspension for 4 days. The sensory test results are shown in Table 4 below.

Early high tail strength Second Half High Strength (Day 4) Initial foreign body Late Foreign Body (Day 4) Example 10 A A A B Example 12 A A A A Gusev butyl ^TM B B C C

A: 2 or fewer people sensed bitterness or foreign body

B: 3 to 5 people sensed bitterness or foreign body

C: 5 to 8 people who sense bitterness or foreign body

D: 9 or more people sensed bitterness or foreign body

As can be seen in Table 4, the dry syrup according to the present invention has a lower bite strength than the control formulation and the foreign matter in the mouth is significantly improved.

Test Example 4: Dissolution Test

A comparative dissolution test was carried out using the dry syrup of Example 12 as a test formulation and a commercially available ceftyl ^TM dry syrup (Hanmi Pharm.) As a control formulation in an amount of 150 mg of cepuroxime axetyl, respectively. At this time, the comparative dissolution test was carried out according to each item of Sepuroxime Acetyl Dissolution Test Method for syrup under "Antibiotic Drug Standard".

As shown in FIG. 1, the cefuroxime axetyl test preparation and the control preparation according to the present invention showed similar dissolution results.

1 is a dissolution test results of the test preparation and the control formulation containing the cefuroxime axetyl granules according to the present invention.

Claims (12)

A cefuroxime acetyl-containing granule in matrix form consisting of 100 parts by weight of cefuroxime axetyl, 5-15 parts by weight of a nonionic surfactant, 20-50 parts by weight of enteric polymer, and 1-5 parts by weight of ethyl cellulose. The cefuroxime accessory according to claim 1, wherein the nonionic surfactant is at least one selected from the group consisting of polysorbate, polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. Teal-containing granules. 3. The cefuroxime axetyl-containing granule according to claim 2, wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil or polysorbate. The method of claim 1, wherein the enteric polymer is methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, polyvinylacetate phthalate, shellac, hydride Sepuloxime axetyl-containing granules, characterized in that at least one selected from the group consisting of oxypropyl methylcellulose acetate succinate, and carboxymethylcellulose. The cefuroxime axetyl-containing granules according to claim 4, wherein the enteric polymer is a copolymer of 1 part by weight of methacrylic acid and 1 part by weight of ethyl acrylate. (a) 100 parts by weight of cepuroximexetyl, 5 to 15 parts by weight of nonionic surfactant, 20 to 50 parts by weight of enteric polymer, and 1 to 5 parts by weight of ethyl cellulose are added to the C _{1 to} C ₅ alcohol or aqueous alcohol solution. Doing; And (b) granulating the association obtained in step (a). 7. The method for producing cefuroxime axetyl granules according to claim 6, wherein the alcohol or aqueous alcohol solution is ethanol or an aqueous ethanol solution. The method of claim 6, wherein the amount of the alcohol or the aqueous solution of alcohol is 100 to 350 parts by weight based on 100 parts by weight of cefuroxime axetyl. The method of claim 6, wherein the nonionic surfactant is at least one selected from the group consisting of polysorbate, polyoxyethylene castor oil and polyoxyethylene hydrogenated castor oil. 10. The method for producing cefuroxime axetyl-containing granules according to claim 9, wherein the nonionic surfactant is polyoxyethylene hydrogenated castor oil or polysorbate. The method of claim 6, wherein the enteric polymer is methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, polyvinylacetate phthalate, shellac, hydride A process for producing cefuroxime axetyl-containing granules, characterized in that at least one selected from the group consisting of oxypropyl methylcellulose acetate succinate, and carboxymethylcellulose. 12. The method of claim 11, wherein the enteric polymer is a copolymer of 1 part by weight of methacrylic acid and 1 part by weight of ethyl acrylate.

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