KR100464210B1 - Pharmaceutical compositions containing cefuroxime axetile and processes for preparing the same - Google Patents

Abstract

PURPOSE: Provided are a pharmaceutical composition containing cefuroxime axetil which comprises a copolymer of methacrylate-methyl methacrylate, a copolymer of methacrylate-ethylacrylate or the mixture thereof, and a method for manufacturing the same. CONSTITUTION: The method for manufacturing pharmaceutical composition containing cefuroxime comprises the steps of: mixing 100 parts by weight of cefuroxime axetil with 10-100 parts by weight of a copolymer of methacrylate-methyl methacrylate, a copolymer of methacrylate-ethylacrylate or the mixture thereof; and granulating the mixture.

Description

Pharmaceutical compositions containing cefuroxime axetile and processes for preparing the same

The present invention relates to a cefuroxime axetyl-containing pharmaceutical composition comprising a powdered methacrylic acid-methyl methacrylate copolymer, a methacrylic acid-ethyl acrylate copolymer, or a mixture thereof as an antigelling agent and a method for preparing the same.

Cefuroxime axetile is a drug used as an oral cephalosporin antibiotic. In addition, cefuroxime axetyl is preferably used in an amorphous form unlike other cephalosporin antibiotics, and its bioavailability is relatively low due to its chemical structure and low solubility in water. Furthermore, as noted in US Pat. No. 4,897,720 (Korean Patent Publication No. 1987-2832), cefuroxime axetyl can inhibit the dissolution of cefuroxime axetyl by forming gelatinous lumps upon contact with an aqueous medium. This may reduce absorption in the body.

Thus, various studies have been conducted to prevent the gelling formation of cefuroxime axetyl in aqueous media.

U.S. Patent No. 4,897,270 (Korean Patent Publication No. 1987-2832) provides a coating to mask the bitter taste of cepuroxime axetyl and discloses an oral dosage tablet designed to disintegrate after rapid rupture within 40 seconds. I've done it. It is disclosed that the film-forming agent can be used hydroxyalkyl cellulose, cellulose base polymer, alkyl cellulose, polyvinylpyrrolidone, polyvinylacetate, Eudragit E, E30D and the like.

In addition, U.S. Patent No. 4,865,851 (Korean Patent Publication No. 1995-9097) is a lipid composed of a straight chain saturated or unsaturated aliphatic carboxylic acid having 10 to 30 carbon atoms, its glyceryl ester or aliphatic alcohol having 10 to 30 carbon atoms. Or compositions comprising cefuroxime axetyl in particulate form coated with a lipid mixture.

In addition, Korean Patent Publication No. 1999-73761 discloses a solid dispersion of cefuroxime acetyl using a sugar alcohol or a sugar selected from the group consisting of lactitol, sorbitol, xylitol, glucose, fructose and maltose as an excipient. The composition has been disclosed.

In addition, WO 99/44614 (Korean Patent Publication No. 1999-76487) discloses a composition using silicon dioxide or a hydrate thereof as a pH control agent and an antigelling agent, and further includes Eudragit L or S and the like. It is described that a film can be formed as an acidic coating agent.

WO01 / 10410 (Korean Patent Publication No. 2001-16826) discloses a cefuroxime acetyl-containing solid dispersion comprising a surfactant such as a polyoxyethylene-polyoxypropylene block copolymer and a water-insoluble inorganic carrier. The sieve has been initiated.

In addition, WO 99/08683 prepared cefuroxime acetyl as a co-precipitate to suppress gelation, but it did not overcome the gelation phenomenon and added an excess disintegrant. WO 99/62559 In order to solve the problem of WO 99/08683, a formulation using carbonate or bicarbonate has been disclosed. In addition, US Pat. No. 6,323,193 discloses pharmaceutical compositions containing up to 25% of crystalline cefuroxime axetyl.

Most of the pharmaceutical compositions according to the prior art form a separate film, or quickly disintegrate using an excess disintegrant, or use sugar alcohol or sugars, silicon dioxide or a hydrate thereof, a surfactant, and the like. However, when the disintegrant is used in excess, the moisture property of the disintegrant itself absorbs moisture in the air, which may adversely affect the gelability and drug stability. In addition, materials such as silicon dioxide can absorb the dispersion solvent in aqueous solution and rather promote gelation.

MEANS TO SOLVE THE PROBLEM The present inventors have studied to develop a cefuroxime axetyl-containing composition which can effectively prevent the gelation of cefuroxime axetyl without using an excessive disintegrant, and as a result, the conventional methacrylic acid- When the methyl methacrylate copolymer and the methacrylic acid-ethyl acrylate copolymer are formulated by mixing together with cefuroxime axetyl, the gelation of cefuroxime axetyl is achieved by dispersing the cefuroxime axetyl particles evenly in an aqueous solution or in vivo. The present invention has been completed by discovering that not only can be effectively prevented, but also dissolution rate can be improved in the gastrointestinal tract without including an excessive disintegrant.

Accordingly, the present invention provides a pharmaceutical composition containing cefuroxime axetyl containing a powdered methacrylic acid-methyl methacrylate copolymer, a methacrylic acid-ethyl acrylate copolymer, or a mixture thereof as an antigelling agent. The purpose.

It is also an object of the present invention to provide a method for preparing the pharmaceutical composition.

Figure 1 shows the disintegration test results of the composition (tablet) according to the invention and the tablet according to the prior art.

Figure 2 shows the dissolution test results of the composition (tablet) according to the invention and the tablet according to the prior art.

According to one aspect of the invention, powdered methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer (methacrylic) acid-ethyl acrylate copolymer), or a mixture thereof is provided.

The cefuroxime axetyl contained in the pharmaceutical composition of the present invention is preferably amorphous cepuroxime axetyl.

In addition, the powdery methacrylic acid-methyl methacrylate copolymer is preferably Eudragit L 100 ^® (Eudragit L100 ^® , Degussa), the powdery methacrylic acid-ethyl acrylate copolymer is Eudragit L Preference is given to 100-55 ^® (Eudragit L100-55 ^® , manufactured by Degussa).

Methacrylic acid copolymers, known as polymethacrylates, are known in various copolymers, depending on their substituents and forms (eg, liquid, suspension, or powder), and in the pharmaceutical art, Eudragit E 12.5 is commonly used. ^® (organic solution form), E 100 ^® (granular form), L 12.5P ^® (organic solution form), L 12.5 ^® (organic solution form), L 100 ^® (powder form), L 100-55 ^® (powder form ), L 30 D-55 ^® (in aqueous dispersion form), S 12.5P ^® (in organic solution form), S 12.5 ^® (in organic solution form), S 100 ^® (powder form), RL 12.5P ^® (in organic solution form) , RL 100 ^® (granular form), RL PO ^® (powder form), RL 30D ^® (aqueous dispersion form), RS 12.5P ^® (organic solution form), RS 100 ^® (granular form), RS PO ^® (powder form) ), RS 30D ^® (aqueous dispersion form), NE 30D ^® (aqueous dispersion form) are known.

Among the various polymethacrylates, powdery methacrylic acid-methyl methacrylate copolymers (eg Eudragit L 100 ^® ) or powdery methacrylic acid-ethyl acrylate copolymers (e.g., When Eudragit L 100-55 ^® ) is formulated with cefuroxime axetyl in a pharmaceutical composition, it is surprisingly different from the prior art that a large amount of disintegrant is used to prevent gelation of cefuroxime axetyl. Gelling of the teal can be effectively prevented. That is, the powdery methacrylic acid copolymer minimizes the aggregation between the cefuroxime axetyl particles so that the cefuroxime axetyl particles are evenly dispersed in the dispersion solvent, thereby effectively preventing the gelation of cefuroxime axetyl. It has been used mainly by enteric coatings such as Eudragit L 100 ^® or Eudragit L 100-55 ^® , and also in other solid form methacrylic acid copolymers such as Eudragit E 100 ^® , S 100 ^® , RL Given that 100 ^® , RL PO ^® , RS 100 ^® , and RS PO ^® do not exhibit these properties, powdery methacrylic acid-methyl, such as Eudragit L 100 ^® or Eudragit L 100-55 ^® It is surprising that methacrylate copolymers or powdery methacrylic acid-ethyl acrylate copolymers exhibit the antigelling effect of cefuroxime axetyl.

The pharmaceutical composition of the present invention is 10 to 100 parts by weight, preferably 15 to 100 parts by weight of the powdered methacrylic acid-methyl methacrylate copolymer or methacrylic acid-ethyl acrylate copolymer as cepuroxime acetyl as an antigelling agent. To 50 parts by weight.

The pharmaceutical composition of the present invention may contain, in addition to cefuroxime axetyl and the anti-gelling agent, excipients, binders, disintegrants, lubricants and the like commonly used in the pharmaceutical field. That is, the composition of the present invention comprises a binder selected from the group consisting of low substituted hydroxy propyl cellulose, polyvinylpyrrolidone, and gelatinized starch; Disintegrants selected from the group consisting of croscarmellose sodium, sodium starch glycolate, and crospovidone; And a lubricant selected from the group consisting of stearic acid, talc, magnesium stearate, and silicon dioxide. The amount of the binder, the disintegrant, and the lubricant may be changed as necessary. For example, the amount of the binder, the disintegrant, and the lubricant is about 6 parts by weight and about 6 parts by weight, respectively, based on 100 parts by weight of cefuroxime axetyl. Parts by weight, and about 2 parts by weight.

The pharmaceutical compositions of the present invention may be formulated in various forms of formulations, for example in formulations for oral administration such as tablets, capsules, granules, powders and the like. In addition, if necessary, additives such as sweetening agents, coloring agents, flavoring agents, and the like may be included.

According to another aspect of the invention, (a) 10 to 100 parts by weight of powdered methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, or mixtures thereof, based on 100 parts by weight of cepuroxime axetyl Preferably mixing 15 to 50 parts by weight; And (b) granulating the mixture obtained in step (a).

The cefuroxime axetil is amorphous cefuroxime axetil and preferably, the powder form of methacrylic acid-methyl methacrylate copolymer and methacrylic acid-echil acrylate copolymers Eudragit ^® L100 or L100-55 ^® are preferred . In addition, step (a) may further mix the above-mentioned binder, disintegrant, lubricant.

In addition, the granulation process may be carried out according to a conventional granulation process, it is more preferably carried out by a dry granulation method. The obtained granules can be prepared into a capsule by filling the capsules according to a conventional method or by tableting. In addition, when formulated into a tablet, a film can be formed using, for example, a conventional film coating base such as hydroxypropylmethylcellulose, titanium oxide, and / or a plasticizer such as polyethylene glycol.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are intended to illustrate the invention, but not to limit the scope of the invention.

Examples 1-12.

Sepuloxime acetyl-containing tablets were prepared in the amounts shown in Table 1 below. Table 1 shows the weight percent. Sepuroximexetyl, an antigelling agent (eudragit L100 or L100-55) was mixed and then the binder and disintegrant, and glidant (50% of total content) were mixed. The mixture was assembled by compression with a roller compactor and passed through a # 18 sieve. A glidant (the remaining 50%) was mixed with the obtained granules, and then compressed into tablets.

Example Sepuroxime Axetyl Gelling agents Binder Disintegrant Lubricant Eudragit L100 Eudragit L100-55 Low Substituted Hydroxypropyl Cellulose Polyvinylpyrrolidone Croscarmellose sodium Sodium starch glycolate Crospovidone Stearic acid Talc Silicon dioxide One 50.4 40 - 4 - 4 - - 1.6 - - 2 60.5 25 - 6 - 6 - - 2.5 - - 3 60.5 12.5 - 12.5 - 12.5 - - 2.0 - - 4 60.5 7 - 15 - 15 - - 2.5 - - 5 60.5 25 - - 6 6 - - 2.5 - - 6 60.5 25 - 6 - - 6 - 2.5 - - 7 60.5 25 - 6 - - - 6 2.5 - - 8 60.5 25 - 6 - 6 - - - 2.5 - 9 60.5 25 - 6 - 6 - - - - 2.5 10 50.4 - 40 4 - 4 - - 1.6 - - 11 60.5 - 25 6 - 6 - - 2.5 - - 12 60.5 12.5 12.5 6 - 6 - - 2.5 - -

Comparative Examples 1 and 2.

As an antigelling agent, instead of Eudragit L100 and / or L100-55, microcrystalline cellulose was used to prepare tablets in the same manner as in Example 1 according to the components and contents of Table 2 below.

Comparative example Sepuroxime Axetyl Disintegrant Binder Disintegrant Lubricant Microcrystalline cellulose Lactose Low Substituted Hydroxypropyl Cellulose Croscarmellose sodium Stearic acid One 50.4 40 - 4 4 1.6 2 50.4 - 40 4 4 1.6

Test Example 1. Disintegration Test

Disintegration test of tablets prepared in Examples 1 to 12, tablets prepared in Comparative Examples 1 and 2, and commercially available tablets (Comparative Example 3, Gennet Tablet ^® 250mg) was carried out according to the Pharmacopeia 8th Amendment Disintegration Test Method. Was carried out. Disintegration test solution was used 0.07N HCl solution.

Purification of the disintegration test, Comparative Example 3 (binary net positive ^® 250mg) is a disintegration test conducted immediately refining the coating is ruptured, but, prepared in Comparative Examples 1 and 2 and Examples 1 to 12 after the start of the disintegration test product 1-2 Ruptured after minutes passed. However, as a result of the disintegration test, the tablets prepared in Examples 1 to 12 did not observe the gelation of the disintegrated products, the gels of the disintegrated products were observed in the tablets prepared in Comparative Examples 1 and 2. The disintegration test results of Examples 1 and 3 and Comparative Example 1 are representatively shown in FIG. 1.

Test Example 2 Dissolution Test

The tablets of Examples and Comparative Examples were prepared using 900 mL of purified water, pH 1.2 solution, pH 4.0 solution, and pH 6.8 solution, respectively, according to the comparative dissolution test method of KFDA 2001-61. , Dissolution test was performed at 50 rpm.

Dissolution test results, Examples 1 to 12 are purified in the (true net positive ^® 250mg), and the dissolution rate of Comparative Example 3 in all test solutions, there were no significant difference. However, in the tablets prepared in Comparative Examples 1 and 2, gelation was observed as in Test Example 1, and the dissolution rate was also 10 to 20% or lower. The results of the dissolution test in 0.07 N HCl solution of Example 1 and Comparative Example 1 are shown in Table 3 and FIG. 2.

Minutes Example 1 Comparative Example 1 Dissolution Rate Difference (%) 0 0 0 0 5 41.93 25.80 16.14 10 66.27 43.81 22.45 15 79.03 55.55 23.48 30 93.13 74.38 18.76 45 96.43 82.64 13.79 60 97.27 86.73 10.53

The pharmaceutical composition according to the present invention can effectively prevent the gelation of cefuroxime axetyl without using an excessive disintegrant and exhibits an excellent dissolution pattern in the gastrointestinal tract.

Claims (14)

delete delete delete delete delete (a) mixing 10 to 100 parts by weight of powdered methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, or a mixture thereof based on 100 parts by weight of cefuroxime acetyl; And (b) granulating the mixture obtained in step (a). 7. A process according to claim 6, wherein said cefuroxime axetyl is amorphous. The method of claim 6, wherein the methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, or a mixture thereof is 15 to 50 parts by weight based on 100 parts by weight of cefuroxime acetyl. Manufacturing method. delete delete A pharmaceutical composition prepared by the process according to any one of claims 6 to 8. A drug mixed in a single phase containing 10 to 100 parts by weight of powdery methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, or a mixture thereof as an antigelling agent based on 100 parts by weight of cefuroxime axetyl. Pharmaceutical preparations. The pharmaceutical formulation of claim 12, wherein the cefuroxime axetyl is amorphous. The method of claim 12, wherein the content of the methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, or a mixture thereof is 15 to 50 parts by weight based on 100 parts by weight of cefuroxime axetyl. Pharmaceutical formulations.