KR19990073761A - Oral Solid Dispersion Composition of Sepuroxime Axetyl - Google Patents

Abstract

The present invention relates to oral pharmaceutical compositions containing, as active ingredients, cephatic antibiotics having low solubility, in particular cefuroxime axetyl. More specifically, the present invention relates to an oral pharmaceutical composition and a method for preparing the same, which have a dissolution rate of the active ingredient by preparing a solid dispersion of cefuroxime axetyl using sugar alcohols or sugars.

Description

Oral Solid Dispersion Composition of Sepuroxime Axetyl

The present invention relates to oral pharmaceutical compositions containing, as active ingredients, cephatic antibiotics having low solubility, in particular cefuroxime axetyl. More specifically, the present invention relates to an oral pharmaceutical composition and a method for preparing the same, which improve the dissolution rate of the active ingredient by preparing a solid dispersion of cefuroxime axetyl using sugar alcohols or sugars.

Sepuroxime is a drug with high stability against β-lactamases and a broad antimicrobial spectrum against gram positive and gram negative microorganisms, as disclosed in British Patent No. 1,453,040. However, cefuroxime has been mainly used only as an injection because of insufficient absorption from the gastrointestinal tract.

Sepuroxime Axetyl is a derivative of 1-acetoxyethyl group substituted with a 4-position carboxyl group of the cefuroxime skeleton as disclosed in British Patent No. 1,571,683. It's a prodrug. Cepuroxime axetyl is rapidly deesterified by deesterification enzymes of the intestinal wall after oral administration, and exhibits antibacterial activity as cefuroxime. In particular, cefuroxime axetyl is advantageously used in amorphous form as disclosed in British Patent No. 2,127,401.

Sepuroxime axetyl has a strong bitter taste that is not easily masked, and therefore suitable measures are needed to mask it. Several methods have been developed for this purpose. For example, Korean Patent No. 73572 describes a method of masking bitter taste by coating the tablet when formulating cefuroxime axetyl into tablets, and Korean Patent No. 92904 also discloses a particulate form completely coated with water insoluble lipids. A method of formulating cefuroxime axetyl of as a powder, granules and suspension using the same has been developed.

It is very difficult to develop an optimal pharmaceutical composition because cefuroxime axetyl has relatively poor bioavailability due to its chemical structure and low solubility in water. In particular, as disclosed in Korean Patent No. 73572, cefuroxime axetyl can form gelatinous masses when contacted with a water-soluble medium, and when formulated into tablets, water penetrates into the nucleus relatively slowly through the coating to purify the tablets. If disintegration of the nucleus is not performed immediately, there is a problem in which the cefuroxime axetyl present in the purified nucleus gels. Such gel formation results in a lower solubility of cefuroxime axetyl and thus significantly reduced absorption from the gastrointestinal tract. On the other hand, even in the case of a hard capsule agent, if the gelatin capsule film is not ruptured quickly, the absorption of water from the film is slowed, and the cefuroxime acetyl may gel inside the film. For the reasons of gelling and poor solubility, the most important objective in the development of oral pharmaceutical compositions containing cefuroxime axetyl is to improve the dissolution rate of the active ingredient and consequently to improve the absorption of the active ingredient. To manufacture.

Several methods have been developed for this purpose. That is, Korean Patent No. 73572 has developed a tablet consisting of a film which rapidly ruptures in 0.07N hydrochloric acid solution and a tablet core that disintegrates immediately upon rupture of the film. That is, the film ruptures rapidly, thereby preventing the gelation of cepuroxime axetyl, which may be caused by water penetrating slowly through the film, thereby maintaining a high bioavailability. This technique rapidly breaks down the film within 40 seconds, ultimately minimizing the time it takes for the tablet to disintegrate, increasing the dissolution rate of cefuroxime axetyl. However, the inventors have found that when the tablets according to the above technique are treated according to the dissolution test method described in US Pat. No. 23, Sepuroxime Axetyl Purification section on page 316, an undissolved mass frequently remains after 45 minutes. Found out. This results in the complete dissolution of the drug and decreases the bioavailability.

As described in Korean Patent No. 73572, in order for the film to rupture rapidly, the thickness of the film is preferably smaller, and the film forming composition is described as a water-soluble film forming agent. However, in the case of tablets of drugs that can be gelled by moisture absorption in the air, such as drugs that are sensitive to the external environment, for example humidity and temperature, in particular cefuroxime axetyl, the coating thinly coated with a water-soluble coating agent may You can't completely block the effect. That is, when the cefuroxime axetyl tablet is stored in a brown glass bottle at 40 ° C. and 75% relative humidity, the moisture content is increased by 2 to 3% even after 1 month, and the tablet disintegrates more than 60 minutes. It is known to get [[area of chemotherapy, Japanese magazine], Vol. 7, No. 11, 1991]. This phenomenon can be explained as the result of the penetration of water into the tablet core during storage and the gelation of cepuroxime axetyl in the tablet core, resulting in a decrease in dissolution rate and thus a decrease in bioavailability due to such incomplete disintegration. Will be imported. Therefore, it has been found that a method of rapidly rupturing the coating and dissolving the tablet nucleus immediately by using a water-soluble coating agent is an incomplete method of obtaining a desirable bioavailability by increasing the dissolution rate of the poorly soluble drug, cefuroxime axetyl.

Accordingly, the present inventors have developed a wide range of methods to prevent the gelation of cefuroxime axetyl and ultimately improve the dissolution rate even if the tablet nucleus does not immediately disintegrate in the gastrointestinal tract, regardless of the rate of disintegration of the tablet nucleus. And intensive research was conducted. As a result, the dissolution rate and dissolution rate of cefuroxime acetyl is increased when cefuroxime axetyl, a water-soluble drug, and a sugar alcohol or sugar having a melting point below a certain temperature are mixed by melting to prepare a solid dispersion. I found the facts. In addition, the solid preparation of cefuroxime axetyl prepared using the solid dispersion as described above did not cause the gelation of the drug even if it did not disintegrate quickly, and it was found that the dissolution rate of the drug was improved. Based on these findings, the present invention has been completed.

1 is a graph showing the dissolution rate of the cefuroxime axetyl powder and the dispersion powder of cefuroxime axetyl and xylitol according to the present invention as measured according to Example 6 [-◆-Sepuroxime axetyl powder ,-■-1: 3 dispersion powder of cefuroxime axetyl and xylitol according to Example 2,-▲-1: 5 dispersion powder of cefuroxime axetyl and xylitol according to Example 1].

Figure 2 is measured according to Example 10 dissolution rate of the tablet prepared by using the 1: 3 dispersion powder of cefuroxime axetyl and xylitol according to the present invention (tablet of Example 7: Test formulation) Korea It is a graph compared with the dissolution rate of the tablet (comparative) according to Patent No. 73572 [-■-test formulation,-◆-comparative formulation].

Figure 3 is measured according to Example 11 dissolution rate of the tablet prepared using a 1: 1 dispersion powder of cefuroxime axetyl and xylitol according to the present invention (tablet of Example 8: Test formulation) Korea It is a graph compared with the dissolution rate of the tablet (comparative) according to Patent No. 73572 [-■-test formulation,-◆-comparative formulation].

FIG. 4 shows the dissolution rate of tablets prepared using a 1: 0.9 dispersion powder of cepuroxime axetyl and xylitol according to the present invention as measured according to Example 13. It is a graph compared with the dissolution rate of the tablet (comparative) according to Patent No. 73572 [-■-test formulation,-◆-comparative formulation].

Accordingly, it is an object of the present invention to provide a pharmaceutical composition capable of increasing the dissolution rate of cefuroxime axetyl while containing an effective amount of amorphous cefuroxime axetyl as an active ingredient.

More specifically, it is an object of the present invention to provide a pharmaceutical composition in the form of a solid dispersion containing cefuroxime axetyl and sugar alcohols or sugars having a melting point below a certain temperature as an excipient and a preparation method thereof.

Hereinafter, the present invention will be described in more detail.

Commonly used methods to increase the solubility of poorly soluble drugs include the addition of surfactants or dissolution aids, complex formation, prodrugation, and solid dispersion formation. Formation of the solid dispersion is a method of reducing the size of the main particle particles by dispersing the main component insoluble in water in a material that is well dissolved in water, and increases the solubility by making a eutectic mixture. The dispersion medium used should be inert and stable. In the present invention as a dispersion medium having such a purpose, in the present invention, sugar alcohols or saccharides that are well dissolved in water are selected, and the poorly soluble cefuroxime axetyl is mixed with these sugar alcohols or sugars by melting to form a solid dispersion, thereby producing cefuroxime axetyl. It is confirmed that the dissolution rate of is increased. In particular, it was found that when tablets were mixed with suitable excipients in solid dispersions, the gelation of cefuroxime axetyl did not occur and the dissolution rate in 0.07N hydrochloric acid solution was also increased.

Sugar alcohols or sugars used for this purpose should have a melting point that does not decompose cefuroxime axetyl. That is, since the melting point of amorphous cefuroxime axetyl is 94 to 96 ° C. or 135 to 138 ° C. according to the preparation method, a sugar alcohol or a saccharide having a melting point of 94 ° C. or less may be used to prepare a low melting point of cefuroxime acetil as a solid dispersion. It is suitable to use, and when the high melting point of cefuroxime axetyl is prepared as a solid dispersion, it is suitable to use a sugar alcohol or sugar having a melting point of 135 ° C or lower. Especially in this invention, it is preferable to use sugar alcohol or saccharides of melting | fusing point 94 degrees C or less.

Pharmaceutically acceptable sugar alcohols and sugars that can be used according to the invention include, for example, maltose, fructose, glucose, lactitol, sorbitol, xylitol, and the like, of which xylitol is dissolved in water. Xylitol is preferred because it has good solubility in heat, is stable to heat, and generally does not cause a Maillard Reaction in which the color of the drug is changed when heating a drug containing a sugar and an amine group.

The increase in solubility of cefuroxime axetyl depends on the amount of sugar alcohol or sugar added, i.e., as the amount of sugar alcohol or sugar added increases, the cefuroxime axetyl can be better dissolved. In the present invention, it is preferable to use a sugar alcohol or sugar in a ratio of 0.2 to 5.0 times the weight of cefuroxime axetyl.

The present invention also relates to a process for preparing a solid dispersion of cefuroxime axetyl using sugar alcohols or sugars.

Methods of preparing a solid dispersion using sugar alcohols or sugars generally include a melting method and a solvent method. However, when the solvent method is used, cefuroximexetyl may be decomposed in the solvent or the crystal form may be changed. It is preferable to use the melting method. It is also possible to prepare a solid dispersion by simply compacting and grinding sugar alcohols or a mixture of sugars and cefuroxime axetyl.

That is, the sugar alcohol or sugar is heated to melt, and then the powder of cefuroxime axetyl is mixed and rapidly cooled to room temperature or lower, or the sugar alcohol or sugar is heated by slowly mixing the sugar alcohol or sugar and cefuroxime axetyl. The solid dispersion of cefuroxime axetyl can be prepared by rapidly cooling to room temperature or lower after melting.

The cooled solid dispersion may be pulverized by a pulverization method commonly used in pharmaceuticals to prepare a powder. At this time, the dissolution rate of cepuroxime axetyl can be adjusted according to the particle size after grinding, and the finer the particles, the higher the dissolution rate. Therefore, in the present invention, the particle size after grinding is preferably 500 µm or less.

As described above, the solid dispersion of cefuroxime axetyl prepared by melting method using sugar alcohol or sugar can be formulated into various solid preparations. That is, the solid dispersion of cefuroxime axetyl may be mixed with a suitable pharmaceutically acceptable additive such as excipients, binders, disintegrants, flow aids, sweeteners, colorants, flavoring agents, and the like to form tablets, capsules, granules, powders, and the like. It may be formulated as an oral preparation.

As such, when the solid dispersion of cefuroxime axetyl is formulated as an oral preparation, the preparation and molding of the solid dispersion of cepuroxime axetyl and excipients, binders and disintegrating agents are conveniently controlled. The elution rate of cefuroxime axetyl can be controlled.

Preparations such as tablets or capsules containing the solid dispersion of cefuroxime axetyl prepared according to the present invention as described above are eluted without gelling of cefuroxime axetyl without disintegration in 0.07N hydrochloric acid solution immediately. Dissolution rate can be more than 90%. Therefore, in the case of tablets, there is no such need in the present invention, unlike the prior art in which the coating is thinly coated with a water-soluble coating agent, despite the possibility of stability in order to accelerate disintegration. Even in the case of a capsule, even if the gelatin capsule film does not rupture quickly, the cefuroxime axetyl may be eluted in the capsule without gelation. In general, since the gelatinous coating of capsules does not rupture quickly in gastric or serous fluids, cefuroxime acetyl may cause gelation in the capsule coating. Even without rupture, cefuroxime acetyl does not gel and can increase the dissolution rate.

The present invention is explained in more detail by the following examples, but the present invention is not limited in any way by these.

Example 1

Sepuloxime axetyl and xylitol were mixed using a conventional mixer in a ratio of 1: 5 by weight. The resulting mixture was heated and melted for 30 minutes in a water bath at 90 to 94 캜, and then rapidly cooled to room temperature or lower. The solid mixture obtained in this way was pulverized using a grinder to have a particle size that can pass through No. 60 sieve (250 μm) to prepare a solid dispersion.

Example 2

Sepuroxime axetyl and xylitol were mixed using a conventional mixer in a ratio of 1: 3 by weight. The resulting mixture was heated and melted for 30 minutes in a water bath at 90 to 94 캜, and then rapidly cooled to room temperature or lower. The solid mixture obtained in this way was pulverized using a grinder to have a particle size that can pass through No. 60 sieve (250 μm) to prepare a solid dispersion.

Example 3

Sepuloxime axetyl and xylitol were mixed using a conventional mixer in a ratio of 1: 1 by weight. The resulting mixture was heated and melted for 30 minutes in a water bath at 90 to 94 캜, and then rapidly cooled to room temperature or lower. The solid mixture obtained in this way was pulverized using a grinder to have a particle size that can pass through No. 60 sieve (250 μm) to prepare a solid dispersion.

Example 4

Sepuloxime axetyl and xylitol were mixed using a conventional mixer in a ratio of 1: 0.9 by weight. The resulting mixture was heated and melted for 30 minutes in a water bath at 90 to 94 캜, and then rapidly cooled to room temperature or lower. The solid mixture obtained in this way was pulverized using a grinder to have a particle size that can pass through No. 60 sieve (250 μm) to prepare a solid dispersion.

Example 5

Sepuroximexetyl and xylitol were mixed using a conventional mixer in a ratio of 1: 3 by weight and then compressed by a compressor. The compressed product thus obtained was ground to have a particle size that can pass through No. 60 sieve (250 μm) to prepare a solid dispersion.

Example 6

A dissolution test was conducted to determine how much the dissolution rate of cefuroxime axetyl in the solid dispersion of the present invention was improved compared to the formulations of the prior art.

That is, according to the dissolution test method of Sepuroxime Axetyl Purification Port described in Pharmacopoeia 23, page 316, the dissolution test was carried out at a rotational speed of 100 revolutions / minute using 0.07N hydrochloric acid solution as the eluent. Sepuloxime acetil powder and the solid dispersion powder of cefuroxime axetyl and xylitol prepared according to Examples 1 and 2 were dispersed in an eluent and subjected to a dissolution test for 15 minutes, 45 minutes, 60 minutes, and 120 minutes. A certain amount of the sample was taken and the ultraviolet absorbance at 278 nm was measured to compare the dissolution rate of cefuroxime axetyl.

The measured result is shown in FIG. From the results shown in FIG. 1, the difference in the dissolution rate between the solid dispersion of cefuroxime axetyl and the cefuroxime axetyl raw material itself can be clearly seen, that is, the amount of cefuroxime axetyl eluted in 900 ml of the eluent is cepuroxime axetyl. The raw material itself was 42.9 mg at 120 minutes, whereas the solid dispersions of (1: 3) and (1: 5) of cefuroxime axetyl were 116.7 mg and 123.0 mg, respectively, at 120 minutes. It can be seen that the dissolution rate of the dispersion increased by 2.5 times or more.

Example 7

The 1: 3 dispersion powder of cefuroxime axetyl and xylitol prepared according to the method described in Example 2 was mixed with the following excipient components in a specified ratio using a conventional mixer.

Component weight ratio

1: 3 dispersion of cefuroxime axetyl and xylitol 0.801

Low Substituted Hydroxypropyl Cellulose 0.185

Sodium Lauryl Sulfate 0.007

Silicon Dioxide 0.001

Hydrogenated Vegetable Oil 0.006

The resulting mixture was compressed using a conventional purifier to contain 1: 3 dispersion of cefuroxime axetyl and xylitol, equivalent to 250 mg, as a single cefuroxime.

Example 8

A 1: 1 dispersion powder of cefuroxime axetyl and xylitol prepared according to the method described in Example 3 was mixed with the following excipient components in a specified ratio using a conventional mixer.

Component weight ratio

1: 1 dispersion of xylitol of cefuroxime axetyl 0.778

Low Substituted Hydroxypropyl Cellulose 0.152

Silicon Dioxide 0.070

The resulting mixture was compressed using a conventional purifier using a conventional purifier to contain a 1: 1 dispersion of cepuroxime axetyl and xylitol in an amount equivalent to 250 mg as a single cefuroxime.

Example 9

The 1: 0.9 dispersion powder of cefuroxime axetyl and xylitol prepared according to the method described in Example 4 was mixed with the following excipient components in a specified ratio using a conventional mixer.

Component weight ratio

1: 0.9 Dispersion of Xylitol of Sepuroxime Axetyl 0.710

Low Substituted Hydroxypropyl Cellulose 0.163

Silicon Dioxide 0.085

Talc 0.014

Magnesium Carbonate 0.007

Sodium bicarbonate 0.021

The resulting mixture was compressed using a conventional purifier to contain a 1: 0.9 dispersion of cefuroxime axetyl and xylitol in an amount equivalent to 250 mg as a single cefuroxime.

Example 10

As described later, according to the dissolution test method described in Sepuroxime Axetyl Purification section of Pharmacopoeia 23, page 316, the dissolution rate of Sepuroxime Axetyl tablet (test formulation) containing a solid dispersion was disclosed in Korean Patent No. 73572. It was compared with the dissolution rate of the tablet (comparative) described. A tablet prepared in Example 7 was used as a test formulation for this experiment, and a tablet prepared as follows was used as a comparative formulation.

Comparative Preparation

Purified kernels were prepared according to the method described in Example 3 of Korean Patent No. 73572 as follows.

Ingredient mg / tablet

Equivalent to Sepuroxime Axetyl Sepuroxime 250.00 mg

Microcrystalline Cellulose 94.55

Croscarmellose Sodium 15.50

Sodium Lauryl Sulfate 4.50

Silicon Dioxide 1.25

Hydrogenated Vegetable Oil 8.50

All components except silicon dioxide were mixed together and compressed using a roller compressor. The compacted material was pulverized by a granulator and the resulting granules were mixed with silicon dioxide and compressed using a conventional tableting machine to contain 250 mg of cefuroxime axetyl as a single cefuroxime, and the tablets were prepared as a comparative agent. Used as.

As described in Korean Patent No. 73572, even if moisture slowly penetrates into the tablet core through the film of the tablet, the cefuroxime axetyl present in the tablet core gels and the tablet core is insufficiently disintegrated. Since it will be faster and the dissolution rate will increase, the above comparative formulation was prepared in uncoated form without coating the coating and used in the dissolution test.

The results of the test are shown in FIG. As can be seen from the results shown in FIG. 2, the comparative formulation showed a dissolution rate of about 34.5% after 45 minutes, and the test formulation showed a dissolution rate of about 93.3% after 45 minutes. Therefore, it can be seen that the dissolution rate of the test preparation prepared using the solid dispersion according to the present invention is superior to that of the comparative preparation according to Korean Patent No. 73572.

Example 11

A tablet prepared in Example 8 was used as a test formulation using a 1: 1 dispersion of cefuroxime axetyl and xylitol, and the tablets of Korean Patent No. 73572 prepared according to the same method as in Example 10 were compared. The dissolution test described in USP 23, Seppuroxime Axetyl Purification, 316, was used as a formulation. The measured result is shown in FIG.

As can be seen from the results shown in FIG. 3, the tablet of Example 8, a test formulation, exhibits an dissolution rate of about 83.0% at 45 minutes. Therefore, it can be seen that the tablet of the present invention shows an excellent dissolution rate compared to the comparative formulation according to Korean Patent No. 73572 shows an dissolution rate of about 34.5% at 45 minutes.

Example 12

The disintegration rate in 0.07N hydrochloric acid solution was measured according to the disintegration test described in U.S. Pharmacopoeia 23, page 1790 using the tablet prepared in Example 8 as a tablet according to the present invention. As a result, the disintegration rate of the tablet according to Example 8 was measured to be 4 minutes 30 seconds.

Example 13

A tablet prepared in Example 9 was used as a test formulation using a 1: 0.9 dispersion of cefuroxime axetyl and xylitol, and the tablets of Korean Patent No. 73572 prepared according to the same method as in Example 10 were compared. The dissolution test described in USP 23, Seppuroxime Axetyl Purification, 316, was used as a formulation. The measured result is shown in FIG.

As can be seen from the results shown in FIG. 4, the dissolution rate of the tablet of Example 9 as a test formulation at 45 minutes was about 94.0%, and the dissolution rate was about 34.5% compared to that of the comparative formulation of Korean Patent No. 73572. It can be seen that the increase significantly.

Example 14

0.07N hydrochloric acid according to the disintegration test described in U.S. Pharmacopoeia 23, page 1790, using the tablet prepared in Example 9 as a tablet according to the present invention (using a 1: 0.9 dispersion of cefuroxime axetyl and xylitol). The rate of disintegration in the solution was measured. As a result, the disintegration rate of the tablet of Example 9 was measured to be 6 minutes 51 seconds.

As can be seen from the results of Examples 12 and 14, even if the time required for disintegration of the tablet is 6 minutes or more, the dissolution rate is about 94.0%. Thus, the preparation according to the present invention using the solid dispersion of cepuroxime axetyl is It can be seen that high dissolution rate is shown even though disintegration is not carried out quickly.

In Korean Patent No. 73572, in order to prevent gelation of cefuroxime axetyl and to maintain high bioavailability, the film rapidly ruptures in less than about 15 seconds after the tablet's film is ruptured. The tablet nucleus must disintegrate immediately upon rupture of the coating. However, in order for the film to rupture rapidly, it is necessary to coat the film made of a water-soluble film forming agent and to coat the film thinly, which may cause problems in the stability of the tablet as mentioned in the above detailed description.

On the other hand, since the tablet using the solid dispersion according to the present invention exhibits an excellent dissolution rate even if disintegration is not carried out quickly, by selecting the coating composition as a dense polymer material or by increasing the thickness of the coating to block the moisture absorption during storage, the stability of the tablet There is an advantage that it can increase the dissolution rate.

Claims (13)

An oral solid dispersion composition comprising an effective amount of amorphous cefuroxime axetyl as an active ingredient and a sugar alcohol or a sugar as an excipient. The solid oral dispersion composition according to claim 1, wherein the melting point of the sugar alcohol and the sugar is 135 ° C or lower. The oral solid dispersion composition according to claim 2, wherein the melting point of the sugar alcohol and the sugar is 94 ° C or lower. 4. The oral solid dispersion composition of claim 3, wherein the sugar alcohol is selected from the group consisting of lactitol, sorbitol and xylitol. 4. The solid dispersion composition for oral use according to claim 3, wherein the sugar is selected from the group consisting of glucose, fructose and maltose. The solid oral dispersion composition according to claim 4, wherein the sugar alcohol is xylitol. The solid oral dispersion composition according to claim 1, wherein the sugar alcohol or sugar is contained in a ratio of 0.2 to 5.0 times the weight of cefuroxime axetyl. 2. The solid oral dispersion composition of claim 1, which may be further formulated in the form of a tablet, capsule or powder with a pharmaceutically acceptable carrier. Sugar alcohol or saccharides are heated and melted, followed by rapid cooling by mixing cefuroxime axetyl powder, or by heating slowly after mixing sugar alcohols or saccharides with cefuroxime axetyl, and then cooling rapidly after melting of sugar alcohols or saccharides. A method for preparing an oral solid dispersion composition according to any one of claims 1 to 8, characterized in that 10. The method according to claim 9, wherein the solid dispersion obtained by rapid cooling is continuously pulverized to obtain a powdery solid dispersion. The method according to claim 10, characterized in that the particle size of the powder produced after grinding is 500 mu m or less. A method for producing an oral solid dispersion composition according to any one of claims 1 to 8, characterized in that the solid obtained is compressed by mixing sugar alcohols or sugars with cefuroxime axetyl powder. 13. A method according to claim 12, characterized in that the particle size of the powder produced after milling is 500 탆 or less.