JPS591417A - Long-acting cephalexin tablet and its preparation - Google Patents

Abstract

PURPOSE:To obtain a cephalexin tablet exhibiting excellent long-activity even by reducing the content of oil and fat, by dissolving an oil or fat in an organic solvent, mixing the solution with cephalexin, removing the solvent from the mixture, and if necessary adding a vehicle thereto and compression molding the mixture. CONSTITUTION:An oil or fat such as higher fatty acid (preferably >=10C saturated straight-chain fatty acid), a higher alcohol (preferably >=6C saturated aliphatic alcohol) and an alcohol ester, is dissolved in a proper organic solvent (e.g. dichloromethane, acetone, etc.), and the solution is mixed with cephalexin. After removing the organic solvent, the mixture of cephalexin and the oil or fat is optionally mixed with a vehicle and compression molded. The molded product is crushed, granulated to a definite particle size (20-150 mesh, especially 50-80 mesh) by dry granulator, and tabletted to obtain a tablet containing 4-10wt% of the oil and fat based on the cephalexin.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a long-acting cephalexin tablet and a method for making the same.

Conventionally, the antibiotic cephalexin has been used as an oral or drug preparation, and as for the oral preparation, a long-acting preparation has been formulated for rapid absorption and excretion of cephalexin.

This long-acting cephalexin preparation includes a preparation comprising fast-dissolving cephalexin granules and enteric-coated cephalexin granules coated with an enteric polymer having an elution pH of 5.5-6.5 (Japanese Patent Publication No. 55-47611); A core tablet of cephalexin containing a surfactant of 8 mm is coated with an enteric polymer that dissolves at around pH 5, and the core tablet is coated with cephalexin as a fast-dissolving portion (Japanese Patent Laid-Open Publication No. 1989-1999). No. 126722), granules containing sustained release granules containing cephalexin and hydrogenated oil coated with ethyl cellulose, and fast-dissolving cephalexin granules (Japanese Patent Application Laid-open No. 55
-45601) is known.

However, from the viewpoint of ease of administration, granules and granules generally have the disadvantage of being bulky, and are not necessarily suitable as a dosage form, and for this reason, a tablet form is desired. However, with regard to cephalexin tablets, due to the good solubility of cephalexin under acidic conditions, individual differences such as the acidity of gastric acid and the length of empty time have a large influence. By using a surfactant and limiting the diameter of the core tablet, good tablets that are less affected by individual differences have been obtained. However, these dry-coated tablets have a low cephalexin content per tablet, and for example, in the case of administering a 500 mg potency, three tablets are administered, which increases the number of tablets to be administered, and the tablet press used to manufacture the dry-coated tablets is expensive. Furthermore, there were disadvantages in that the technical tolerance range was extremely small, such as off-center, binding between the fast-dissolving part and the core tablet, and damage to the core tablet due to overload. Furthermore, in general, delayed dissolution tablets include matrix type and spantab type, but in these tablets, body fluids permeate through capillaries leading from the surface of the tablet to the inside, and the liquid gradually absorbs the active drug. The main drug is dissolved and elutes over a long period of time, but in this case, the tablet often does not disintegrate and remains as it is, and is excreted without being dissolved in its entirety within the time required for it to pass through the absorption site of the gastrointestinal tract. There was a drawback that it could be done. This can be inferred from the example of Merrell R tablets, which reached a parallel state with a dissolution rate of 60 to 80% after 5 hours in an in vitro dissolution test.
p. 135). Also, in matrix type,
There was a drawback that a larger amount of matrix material was required than the main drug.

In developing a good dosage form for a long-acting cephalexin preparation, the present inventors have developed a variety of tablets that do not require specific dry-coated tablets, and which yield 1 to 2 tablets when administered at a titer of 500 mg. As a result of research, cephalexin has higher fatty acids,
One or more types of fats and oils such as higher alcohols, vegetable oils, and waxes are mixed by a dry method, and if necessary, excipients with excellent disintegration and moldability such as crystalline cellulose, lactose, and hydroxypropyl cellulose, and magnesium stearate are added. Add excipients with excellent lubricity and compression mold to form granules, which are then compressed to obtain slug tablets.
The tablets were further crushed into granules and re-compressed several times to obtain cephalexin tablets containing cephalexin and oils. One to two tablets contained cephalexin with a titer of 500 mg. By adjusting the number of times of slug molding and the amount of oil and fat used, good tablets can be obtained in which the dissolution rate of cephalexin can be controlled very easily. The dissolution of cephalexin after administration is controlled and all of the cephalexin is eluted, which is why it is called a delayed-disintegration formulation, and it is a good tablet with higher bioavailability than conventional delayed-dissolution tablets. I learned something (Special Application No. 56-52117).

However, in the above-mentioned prior invention, since cephalexin and fats and oils are mixed by a dry method, when the content ratio of fats and oils is as low as 5 W/W% with respect to cephalexin, four times of slap molding is required. Even with such tablets, cephalexin was eluted in a short period of time, and it was difficult to significantly delay the dissolution time.

Therefore, the present inventors discovered that even if the content ratio of oils and fats is low,
As a result of further research into long-acting cephalexin tablets that can sufficiently delay the dissolution time of cephalexin, instead of mixing cephalexin and fats and oils using a dry method, we have developed a wet method, that is, mixing oils and fats with an appropriate organic solvent. After mixing with cephalexin as a dissolved solution, removing the organic solvent, mixing with excipients as necessary, and compression molding,
It has been found that good long-lasting cephalexin tablets can be obtained even when the content ratio of fats and oils is about 5 W/W%.

The present invention was completed based on the above findings,
Approximately 4 to 1 for cephalexin and cephalexin
A long-acting cephalexin tablet characterized by containing 0W/W% of oils and fats, the purpose of which is to:
An object of the present invention is to provide a long-lasting cephalexin tablet that has good long-lasting properties even when the content ratio of oils and fats is low. The present invention is also characterized in that after mixing a solution of a solubilizing solvent for cephalexin and fats and oils, the solubilizing solvent is removed and the resulting mixture containing at least cephalexin and fats and oils is compression molded. The purpose of this method is to provide a method for producing long-lasting cephalexin tablets that is good even when the content ratio of oils and fats is low.

Examples of the fats and oils used in the present invention include higher fatty acids, higher alcohols, and alcohol esters, but saturated compounds or hydrogenated products of these are preferred from the viewpoint of stability of the fats and oils. Higher fatty acids are generally water-insoluble fatty acids having 10 or more carbon atoms,
Preferably saturated straight chain higher fatty acids such as decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid,
Examples include arachidic acid. The higher alcohol is a water-insoluble aliphatic alcohol having 6 or more carbon atoms, preferably a saturated higher aliphatic alcohol, such as hexyl alcohol, heptyl alcohol, octyl alcohol, nonyl alcohol, dodecyl alcohol, tetradecyl alcohol, hexadecyl. Examples include alcohol, octadecyl alcohol, eicosyl alcohol, hexacosyl alcohol, and the like. Examples of alcohol esters include esters of higher monohydric alcohols with fatty acids, and esters of polyhydric alcohols with higher fatty acids such as ethylene glycol, propylene glycol, glycerin, and polyethylene glycol.

Preferred examples of the higher monohydric alcohol include the saturated higher aliphatic alcohols described above, and preferred examples of the higher fatty acids include the saturated higher fatty acids described above. Examples of alcohol esters include waxes that are esters with monohydric or dihydric alcohols and oils and fats that are esters with trihydric alcohols, such as carnauba wax, cotton wax, beeswax, wool wax, spermaceti wax, paraffin wax, Waxes such as vaseline, oils and fats such as sesame oil, soybean oil, rapeseed oil, olive oil, coconut oil, camellia oil, peanut oil, cottonseed oil, castor oil, cacao butter, lauric fat, wood wax, beef tallow, pork tallow, and whale tallow, preferably are hydrogenated products such as these waxes and oils, such as Lovelywax (manufactured by Freund Sangyo Co., Ltd.), which is a hydrogenated oil of castor oil, and TP-9 (manufactured by Freund Sangyo Co., Ltd.), which is a hydrogenated oil of rapeseed oil.
(manufactured by Nippon Oil & Fats Co., Ltd.). These oils and fats are 2
You may use a mixture of more than one species.

In the present invention, the above-mentioned fats and oils are first used in the form of a solution dissolved in a suitable solubilizing solvent, and mixed with pulverized cephalexin. The above-mentioned solubilizing solvent is preferably an organic solvent or a mixed solvent thereof that is a non-solvent for cephalexin and has a boiling point lower than the boiling point of water.

Generally, a non-toxic organic solvent is desired, but even if it is an organic solvent that is not suitable for the human body, it must have a low boiling point that can be easily and completely removed after mixing cephalexin with oils and fats. If available, organic solvents with as low flammability as possible are preferred. Examples of organic solvents that meet the above conditions include dichloromethane, acetone, ethanol, and mixed solvents thereof. The amount of fats and oils used varies depending on the type of fats and oils, the desired duration of effective blood concentration of cephalexin, etc., but if the content ratio of fats and oils to cephalexin is 3 W/W% or less, it is difficult to delay the elution of cephalexin. However, if the content ratio exceeds 10 W/W%, the dissolution of cephalexin will gradually be delayed too much, and a long-acting preparation that provides an effective blood concentration even after at least 4 to 8 hours is required. In order to obtain this, the content ratio of oils and fats to cephalexin is usually used within a range of about 4 to 10 W/W%.

When mixing a solution of cephalexin and a solvent for solubilizing fats and oils, it is okay to heat the solution to a temperature below the boiling point of the solubilizing solvent or below the softening point of the fat if the fat has a softening point. do not have.

After mixing a solution of cephalexin and a solubilizing solvent for oils and fats, the solubilizing solvent is removed, which is usually carried out by normal pressure drying or reduced pressure drying such as ventilation drying or fluidized drying.

During the above drying, drying may be performed under heating under the same temperature conditions as above.

The thus obtained mixture containing at least cephalexin and oils and fats is compression molded, and the compound is preliminarily treated with a suitable excipient such as crystalline cellulose, lactose, hydroxypropylcellulose, etc. Excipients with excellent moldability and known excipients with excellent lubricity such as magnesium stearate, calcium stearate, and talc may be added and mixed. These excipients may be added and mixed at the same time during the step of mixing the solution of cephalexin and the solvent for solubilizing oils and fats.

The above-mentioned compression molding is performed by a known dry compression method, such as a slug method, a roller press method, a briquetting machine method, or the like.

Tablets that are directly compressed without the above compression molding process disintegrate in the first liquid (pH 1.2, Japanese Pharmacopoeia 10th revision) in an extremely short time, making it impossible to delay the elution of cephalexin. , Therefore, in the present invention,
By carrying out the above compression molding step at least once, it is possible to obtain disintegrating tablets in which dissolution of cephalexin is delayed. In the present invention, the above-mentioned compression molding step is performed to delay the disintegration of the tablet, but as a result of increasing the load, the load within the tablet may become uneven. When tabletting, it is preferable to crush the preparation in advance and granulate it to a certain particle size using a dry granulator. By obtaining granules with a particle size in the range of 20 to 150 mesh, particularly 20 to 50 to 80 mesh, tablets with uniform load transmission during tableting and dense granules can be obtained.

In the present invention, the granules obtained above are compression molded again,
Although regranulation may be used, a single compression molding process usually yields good tablets with delayed cephalexin dissolution.

The granules thus obtained are compressed into tablets using a tablet machine, and the amount of granules may be determined so as to contain the desired cephalexin titer. It is usually preferable to use tablets containing 250 mg of cephalexin per tablet.

The tablets thus obtained are good long-lasting cephalexin tablets with delayed cephalexin dissolution that exhibit dissolution-type disintegration, and the dissolution rate of cephalexin can be controlled to exhibit ideal zero-order dissolution.

When a higher blood concentration is required early after administration, the long-acting tablet of the present invention can be used in combination with a known fast-dissolving cephalexin preparation, or with a fast-dissolving cephalexin preparation such as a bilayer tablet. Multilayer tablets can be formed and administered in that form.

Next, the results of the disintegration test and Zartorius dissolution test of the long-acting tablet of the present invention will be described.

(1) Test tablet composition No. 1; In Example 1, Lovely Wax 10
Instead of using 50g of 1, use 30g, 20-50
Cephalexin tablets were produced in the same manner as in Example 1, except that instead of obtaining mesh granules, 20-80 mesh granules were obtained.

Composition No. 2; Long-acting cephalexin tablet obtained in Example 1.

Composition No. 3; Long-acting cephalexin tablet obtained in Example 2.

Composition No. 4; Long-acting cephalexin tablet obtained in Example 3.

Composition No. 5; Long-acting cephalexin tablet obtained in Example 4.

Composition No. 6; Long-acting cephalexin tablet obtained in Example 5.

Composition No. 7; In Example 5, Lovely Wax 10
Cephalexin tablets manufactured using 150g of 1 instead of 100g.

(2) Disintegration test One tablet to be tested was subjected to a disintegration test using the first liquid (pH 1.2, Japanese Pharmacopoeia 10th revision) as the test liquid, and the average value of the six tablets was calculated.

(3) Zatorius dissolution test Test tablet 2
The tablets were allowed to dwell in the following test solutions at 37±1° C. in sequence, and the cephalexin elution rate was calculated by measuring the UV absorbance at 26 onm after each residence time.

Residence time test solution A; pH 3.5 (Add the 2nd 0-1 hour solution to the 1st solution)
100ml Eye test solution B; pH 1.2 (
1st liquid) 10 1 to 3 hours 0ml
Eye test solution C: pH 4.5 (2nd 3rd solution added to 1st solution)
100 ml eye test solution D; pH 7.0 (water) 100 ml after 4 hours
(4) Test Results The results of the disintegration test and Sartorius dissolution test of each test tablet are shown in Table 1.

Table 1 shows that cephalexin tablets with better persistence than the long-lasting cephalexin tablets obtained by the method of Japanese Patent Application No. 56-52117 can be obtained even if the content ratio of oils and fats to cephalexin is lower. ing. Furthermore, the long-acting tablets of the present invention show that the dissolution of cephalexin is significantly delayed compared to tablets obtained by simply granulating and compressing a mixture obtained by a wet method without compression molding. This is because the granules for tabletting are made highly dense by compression molding, and the granules have a certain circular size, so when the tablets are compressed, the load is uniformly transmitted to each granule, and as a result, It is thought that a uniform tablet is obtained, and that the disintegration of the tablet is delayed because the surface inhibits wetting, indicating elution-type disintegration.

Example 1 Pulverized Cephalexin (930 mcg/mg potency) 1
000g using a Shinagawa kneading machine (AM-25 manufactured by Sanei Seisakusho Co., Ltd.)
Add 50 g of Lovely Wax 101 (manufactured by Freund Sangyo Co., Ltd.) and heated dichloromethane (300 ml) to this.
The solution was added and kneaded for 10 minutes. The kneaded product was dried with ventilation at 40° C. for 5 hours, and then crushed using a 30 mesh sieve.

150 g of crystalline cellulose (Avicel 101, manufactured by Asahi Kasei Industries, Ltd.) and 9.1 g of magnesium stearate were added to the obtained granules, mixed, compression-molded with a roller presser (Roller Press Mini, manufactured by Freund Sangyo Co., Ltd.), and then crushed. Granules of 20-50 mesh were obtained. After mixing a small amount (0.1 W/W%) of magnesium stearate with this, a rotary tablet machine (manufactured by Kikusui Seisakusho Co., Ltd., RT
-F-9-2, rotary tablet press) with a diameter of 11 mm,
Using a 12.5R punch, the thickness is 4.2mm and the weight is 326m.
g of long-acting cephalexin tablets (one tablet containing 250 mg of cephalexin) were obtained (No. 2 in Table 1).
tablets).

Example 2 Instead of obtaining 20-50 mesh granules in Example 1, 20-80 mesh granules were obtained to obtain the same long-acting cephalexin tablet as in Example 1 (No. 3 in Table 1).
tablets).

Example 3 Instead of obtaining 20-50 mesh granules in Example 1, 20-100 mesh granules were obtained to obtain long-acting cephalexin tablets similar to those in Example 1 (No. 1 in Table 1).
4 tablets).

Example 4 Instead of obtaining 20-50 mesh granules in Example 1, 20-150 mesh granules were obtained to obtain long-acting cephalexin tablets similar to those in Example 1 (No. 1 in Table 1).
5 tablets).

Example 5 Milled Cephalexin (930 mcg/mg potency) 1
A heated solution of 100 g of Lovelywax 101 (manufactured by Freund Sangyo Co., Ltd.) and 25 g of hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd., TC-5) in dichloromethane (300 ml) was added to 000 g of the mixture and kneaded for 10 minutes. The kneaded product was dried with ventilation at 40° C. for 5 hours, and then crushed using a 30 mesh sieve. 75 g of crystalline cellulose and 9.1 g of magnesium stearate were added to and mixed with the obtained granules, compression molded using a roller press, and then crushed to obtain granules of 20 to 80 mesh.

This was compressed into tablets using a rotary tablet machine, with a diameter of 11 mm and a thickness of 4 mm.
．． A 2 mm normal R-type long-acting cephalexin tablet was obtained (tablet No. 6 in Table 1). Each tablet contains 250mg of cephalexin.

Example 6 The 20-50 mesh granules (A granules) obtained in Example 1 were filled into the first stage hopper of a three-layer tablet press (manufactured by Kikusui Seisakusho Co., Ltd., RT-3L-14).

Separately, a solution of 50 g of gum arabic in water (70 ml) was added to 250 g of cephalexin, and granules were obtained by drying and sizing according to a conventional method. These granules contain crystalline cellulose (Avicel 1).
02) 1000g and magnesium stearate 5.2g
were mixed to obtain granules (B granules). This B granule is filled into the second stage hopper, and 324 g of A granule is placed in the lower layer of one tablet.
mg (225 mg titer as cephalexin) and 140 mg (25 mg titer as cephalexin) of B granules in the upper layer.
A sustained-release cephalexin double-layer tablet with a diameter of 11 mm was obtained.

patent applicant Toyo Jozo Co., Ltd. Representative Fuji Ito■

Claims (12)

[Claims] (1) A long-acting cephalexin tablet characterized by containing cephalexin and about 4 to 10 w/w% of fats and oils relative to cephalexin. (2) The long-acting cephalexin tablet according to claim 1, wherein the oil or fat is a higher fatty acid, a higher alcohol, or an alcohol ester. (3) The long-acting cephalexin tablet according to claim 1, which contains an excipient. (4) A long-lasting cephalexin characterized by mixing a solution of a solubilizing solvent of cephalexin and fats and oils, removing the solubilizing solvent, and compression molding the resulting mixture containing at least cephalexin and fats and oils. Method of manufacturing tablets. (5) Oils and fats are approximately 4W/W% relative to cephalexin.
The manufacturing method according to claim 4, which is the above. (6) The production method according to claim 4 or 5, wherein the oil or fat is a higher fatty acid, a higher alcohol, or an alcohol ester. (7), the solubilizing solvent is a non-solvent of cephalexin,
5. The production method according to claim 4, wherein the organic solvent has a boiling point lower than the boiling point of water or a mixed solvent thereof. (8) The manufacturing method according to claim 4, wherein the solubilizing solvent is removed by drying under reduced pressure or drying under normal pressure. (9) The production method according to claim 8, wherein the normal pressure drying is ventilation drying or fluidized fluid drying. (10) The manufacturing method according to claim 4, wherein compression molding is carried out at least once. (11) The manufacturing method according to claim 4, which comprises mixing excipients. (12) The manufacturing method according to claim 11, wherein the excipient is mixed when mixing the solution of cephalexin and a solvent for solubilizing oils and fats, or before compression molding.