JPS6113683B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to cephalexin sustained release formulations. Cephalexin is one of the many cephalosporin antibiotics that can be administered orally, and after taking it, most of it is quickly absorbed and is mainly excreted in the urine without being metabolized in the body. It is effective against many infectious diseases,
It is extremely useful because it is highly safe. However, because it is rapidly excreted, it requires frequent administration, such as four times a day, that is, every 6 hours, and a long-acting preparation has been desired. Traditionally, antibiotics with a bactericidal antibacterial form, such as cephalexin, generally raise the effective blood concentration of the antibiotic in the patient to a concentration much higher than the minimum inhibitory concentration (MIC) for monocytogenes. It was thought that if the drug was administered in such a manner that the therapeutic objective could be achieved by repeating this several times, even if the effective blood concentration decreased rapidly thereafter. However, in in vitro bacterial growth inhibition experiments conducted by the present inventors, as long as cephalexin reaches the MIC, it is better to let it act for a long time even at low concentrations than for a short time at high concentrations. It was found that the antibacterial effect was greater than the antibacterial effect. This fact is also common to antibacterial effects in vivo, and therefore, cephalexin preparations that enable long-term action at low concentrations are considered to have great therapeutic effects, and other types of long-acting preparations are considered to have a large therapeutic effect. proposed (for example, see Special Publication No. 55-47611). In this publication, in order to obtain a long-acting cephalexin preparation, (1) a "non-compressed preparation" is preferable in terms of the speed of transit into the gastrointestinal tract, and (2) changes in the thickness of the coating layer, etc. (3) The combination of an enteric-coated agent and a fast-dissolved agent allows the base ingredient to be absorbed more effectively than a sustained-release formulation in which the disintegration time of the formulation is adjusted by It is preferable that the ratio is in the range of about 5.5 to 6.5, and (4) the composition ratio of the rapidly dissolving component to the enteric component is in the range of 60:40 to 15:85, so that the effective blood concentration can be maintained for a long period of time as expected. It is disclosed that it can be maintained at The present inventors conducted various studies regarding enteric coatings that most effectively achieve the above object, and as a result, completed the invention as described in the claims at the beginning. That is, according to the present invention, in a long-release cephalexin preparation consisting of a combination of fast-dissolving cephalexin (hereinafter referred to as fast-dissolving component) and enteric-coated cephalexin (hereinafter referred to as enteric-coated component), the enteric-coated component is added to the granular preparation of the fast-dissolving component. , a copolymer of methacrylic acid and methyl methacrylate, shellac, talc, stearic acid and a plasticizer, and an enteric coating having an elution pH of about 6, the granules weighing 0.3
Provided is a sustained-release preparation of cephalexin, which is characterized in that the combination ratio is fast-dissolving component: enteric-coated component = approximately 3:7 in terms of titer-equivalent weight. . In the present invention, the term "granules" refers to granules, granules, fine granules (granules of about 500 μm or less), beads, etc., in which one dosage unit is divided into many pieces, and the term "granules" refers to granules, ie, granules and fine granules (granules of about 500μ or less), and beads, etc., in which one dosage unit is divided into many pieces, and is Alternatively, those manufactured by a rolling granulation method are preferable. Of both components, the enteric component must be a granular agent, but the fast-dissolving component to be combined with it should not be limited to granular agents, and in the case of a mixed granular agent, it is not particular about the particle size, and It may be in the form of fine particles, powder or pure powder. These "combination" mixed granules are conveniently packaged as single dosage units or fractions thereof (eg, strip packaging) or filled into hard gelatin capsules. It has already been disclosed that the base material for enteric coating should preferably have an elution pH of about 6;
Among these, a copolymer of methacrylic acid and methyl methacrylate is preferred. In addition, shellac is added as another enteric base. This strengthens the acid resistance of the enteric coating covering each particle, suppresses interparticle adhesion, and facilitates work. The preferred blending ratio (weight) of both is 0.05 to 0.2 parts by weight per 1 part by weight of the copolymer. In addition to the above, appropriate amounts of talc, stearic acid and a plasticizer are blended into the enteric coating layer in the present invention. Talc gives the layer an appropriate thickness and strengthens the film, and helps prevent particles from adhering to each other. Stearic acid also helps prevent adhesion, densifies and strengthens the film, and is also useful for improving fluidity. It is. Talc is preferably blended in an amount of 0.5 to 1.5 parts by weight, and stearic acid is blended in an amount of 0.1 to 0.3 parts by weight, based on 1 part by weight of the total enteric base. Further, it is preferable to mix approximately 0.15 to 0.4 parts by weight of any plasticizer commonly used for enteric coating bases with respect to 1 part by weight of the base. A suitable plasticizer is glycerin fatty acid ester (food additive), but harmless phthalate esters, PEG, PPG, triacetin, etc. may also be used. In the present invention, the thickness of the coating layer of the enteric component is important, and its weight is
It is preferred to apply the coating composition to an increase of 0.3 to 0.6. Although any coating method can be used, spray coating is the most common method. In addition to the embodiment in which the above-mentioned two granules are mixed, the present invention also provides a so-called double granule embodiment in which a fast-dissolving cephalexin component is further adhered in a layer on the outside of the enteric-coated cephalexin granules. It can also be implemented in This embodiment is advantageous in that it avoids segregation of both components, which often occurs in the case of mixture embodiments. This embodiment can be easily carried out, for example, by spray coating enteric-coated cephalexin granules with a white sugar syrup in which cephalexin (a fast-dissolving component) is suspended. The present invention will now be explained in more detail with reference to examples of granule production. Example (1) Production of naked granules Cephalexin 763g (potency), lactose 148g,
325 g of 8% starch paste was added to a mixture of 52 g of corn starch and kneaded. This kneaded product was granulated using a cylindrical granulator, and then dried at 60°C for 1 hour. The obtained dried product was pulverized using a fiber mill, and then the portions that did not pass through 16 meshes and the portions that passed through 24 meshes were removed to obtain naked granules of cephalexin. (2) Coating 1000g of the bare granules obtained in (1) above were placed in a coating pan with a diameter of 30cm, and spray coated in a conventional manner using a coating solution with the following composition until the total weight of the granules after coating was approximately 1.41Kg. Enteric-coated cephalexin granules were obtained. Eudragit L (trade name of methacrylic acid/methyl methacrylate copolymer) 57g White shellac (Japanese Bureau) 8g Talc 55g Stearic acid 10g Glycerin fatty acid ester (food additive) 15g Ethanol 387g Dichloromethane 339g Purified water 129g Total 1000g (3) Measure the titer of the naked granules produced separately in the same manner as in (1) and the enteric-coated granules obtained in (2), and the titer ratio of these is 3:7. Both granules were mixed as follows. The mixed granules were packaged using a strip packaging machine in an amount corresponding to a potency of 500 mg of total cephalexin per pocket. (4) Production of double granules 1000g of enteric-coated granules (containing 540g (potency) of cephalexin) coated with the same enteric coating as in (2) above were placed in a coating pan with a diameter of 30cm, and a coating liquid with the following composition was used. Then, spray coating was carried out in a conventional manner until the total weight of the granules after coating was about 1543 g, to obtain double granules containing an enteric component and a rapidly dissolving component in a potency ratio of 7:3. 50% sucrose syrup 622g Cephalexin 232g (potency) Colorant 0.1g Total 854.1g The preparation thus obtained was tested for potency based on the Japanese Antibiotic Pharmaceutical Standards (1981), and the total titer was is 95-108% of displayed titer
and that the titer of the gastric soluble granules in the formulation is 27
~34%. Also, Japanese Pharmacopoeia No. 10
As a result of performing the dissolution test method described in the edition, method 2 (paddle method), the presence of gastric-soluble and enteric-coated cephalexin in amounts corresponding to the above titer was observed in UV absorption (262 mm). According to the same method, when a dissolution test was conducted for only the enteric-coated granules using a test solution with a pH of 5.4, only about 3% of cephalexin was eluted after 120 minutes. On the other hand, enteric-coated granules were produced according to the example using a composition obtained by removing shellac from the composition of the example, but the coating work was difficult because the particles adhered to each other, and the coating was performed in the step of loosening the aggregated particles. The layer was broken, resulting in particles that lost their enteric properties.
After removing the broken particles, the enteric-coated granules were subjected to a dissolution test using the above-mentioned PH5.4 test method, and as a result, approximately 15 to 20% of cephalexin was eluted. In addition, the preparations of Examples and control naked granules were administered to patients with asymptomatic bacteriuria caused by various bacteria belonging to Escherichia coli, Pseudomonas, Streptomyces, Klebsiella, Retsutogerella, and Enterobacter, and urine When the number of bacteria was actually measured, the results shown in the following table were obtained.

[Table] From the above table, the number of bacteria in the urine of the patient group administered with the preparation of the present invention decreased to 10 ³ or less within 6 hours after administration and remained at this value thereafter, whereas that of the control group administered with 250 mg of naked granules. It can be seen that after 3 hours, the number suddenly decreases to 10 ⁴ , but then continues to increase and reaches 10 ⁵ . In addition, in the control naked granule 500mg administration group, a significant difference was observed compared to the 250mg administration group only in the period from 6 hours to 12 hours, but at 22 hours, 250mg
There is no difference from the mg-administered group. This indicates that the preparation of the present invention is still effective in inhibiting the growth of bacteria in urine even after 6 hours after a single administration, whereas the control preparation of the same potency is effective for only about 3 hours. It supports the fact that this is not the case. As mentioned above, the preparation according to the present invention can exert sufficient therapeutic effects when administered every 12 hours, whereas with conventional preparations, it is necessary to take it every 6 hours, which requires administration during bedtime. It was confirmed that even administration of the drug resulted in insufficient effects. In particular, in the case of outpatients, it is difficult to force them to take the medication during bedtime, which often causes the length of treatment days to be prolonged. This situation has been improved by using the formulation of the present invention. It was proved that the effect was extremely large.

Claims (1)

[Scope of Claims] 1. A long-acting cephalexin preparation consisting of a combination of fast-dissolving cephalexin (hereinafter referred to as fast-dissolving component) and enteric-coated cephalexin (hereinafter referred to as enteric-coated component), wherein the enteric-coated component is a granular preparation of the fast-dissolving component. and an enteric coating containing a copolymer of methacrylic acid and methyl methacrylate, shellac, talc, stearic acid and a plasticizer and having an elution pH of about 6, until the weight of the granules increases by 0.3 to 0.6. , and the combination ratio is fast-dissolving component:enteric-coated component=about 3:7 in terms of titer-based weight. 2. The sustained-release cephalexin preparation according to claim 1, wherein the fast-dissolving component is a granule, and is a mixture with a granular enteric-coated component. 3. The sustained-release cephalexin preparation according to claim 1, wherein the fast-dissolving component is attached in a layered manner to the outside of the enteric coating layer of the enteric component granules. 4. The sustained-release cephalexin preparation according to claim 1, wherein both components are in the form of granules or fine granules, and are packaged as one dosage unit or a fraction thereof. 5. Both components are granules, fine particles or beads,
The sustained-release preparation of cephalexin according to claim 1, which is filled in a hard gelatin capsule as a single dosage unit or a fraction thereof.