JP2528652B2 - Long-acting cefradine formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a sustained-release cefradine preparation.

[Conventional technology and its problems]

Cefradine is an oral synthetic cephalosporin antibiotic and is commonly used for various infectious diseases. But,
The current cefradine preparations need to be taken 4 times a day, that is, every 6 hours, and they will be taken at night or during the daytime (at lunch), so it is difficult to take them, and many people forget to take them. There was a drawback that could not be exhibited to the maximum. Under these circumstances, there has been a demand for a sustained-release cefradine preparation that can be taken at 12-hour intervals twice a day according to the patient's daily rhythm.

In addition, many oral antibiotic preparations for the purpose of long-term release are conventionally a mixture of a fast-dissolving drug and an enteric-dissolving drug. The blood concentration was below the MIC (minimum inhibitory concentration) between the peak of the blood concentration obtained from the preparation and the peak of the enteric coated preparation, making it difficult to prepare a sustained-release preparation.

Furthermore, if the absorption site is limited to the upper small intestine, such as this drug, if a slow-release formulation using an insoluble sustained-release agent alone is used as a sustained-release formulation, it will remain constant for a long time. However, it has a drawback that it cannot maintain its blood concentration, or that it takes a long time to reach an effective blood concentration, and bioavailability is reduced.

[Means for solving problems]

Under the present circumstances, as a result of intensive studies conducted by the present inventors, a slow-dissolving cefradine preparation containing a specific sustained-release agent and an enteric-coated cefradine preparation coated with a specific film are mixed and blended. As a result, it was found that the blood concentration-time transition of cefradine can be adjusted without lowering the bioavailability, and the present invention was completed.

That is, the present invention provides a slow-dissolving cefradine preparation containing one or more sustained-release agents selected from water-insoluble polymers, paraffin wax, higher alcohols, fatty acid esters, higher fatty acids or metal salts thereof, and pH 5. An enteric-coated cefradine preparation coated with a film that dissolves in the range of 0 to 7.0 is mixed and blended so that their cephrazine titer-equivalent weight ratio is 3: 7 to 5: 5. It is intended to provide a sustained-release cefradine preparation.

The slow-dissolving cefradine preparation used in the present invention is a powder for preparation containing cefradine in advance, and a sustained-release agent is added in the form of solid, solution or suspension, and fine granules, granules and beads are prepared by a conventional method. Or, by a conventional method, a powder containing cefradine, fine granules, granules, beads obtained by microencapsulation using a sustained-release agent, wet or dry coating, Appropriate binders, lubricants, disintegrants, excipients and the like can be used if necessary.

Examples of the sustained-release agent used in the production of the slow-soluble cefradine preparation include water-insoluble polymers, paraffin wax, higher alcohols, fatty acid esters, higher fatty acids and metal salts thereof, and are not particularly limited, but preferred specific examples are: , Water-insoluble polymer such as ethyl cellulose, aminoalkyl methacrylate copolymer, polyvinyl acetate,
Paraffin wax is paraffin, microcrystalline wax, higher alcohol is stearyl alcohol, cetanol, fatty acid ester is glycerin fatty acid ester, hydrogenated oil, gallow, beeswax, mokuro, higher fatty acids or their salts are stearic acid, palmitic acid, myristin. Examples thereof include acids and their metal salts such as sodium, calcium and magnesium. These sustained-release agents are used as matrix forming agents or film-forming agents, and may be used alone or in combination of two or more kinds.

The amount of the sustained-release agent mixed varies depending on the production method and dosage form of the slow-soluble cefradine preparation, but when used as a matrix forming agent, it is 5 to 70% by weight (hereinafter simply indicated as%), preferably 10 to 50%. Is 2 to 2 when used as a film-forming agent.
It is preferably 40%, especially 2 to 30%.

Further, in order to prepare the enteric-coated cefradine preparation used in the present invention, it can be produced by coating the cephrazine-containing fine granules, granules, and beads obtained by a conventional method with the enteric-coated substance described below. Further, if necessary, suitable plasticizers, dissolution rate regulators, lubricants and the like can be added.

Since this enteric-coated cefradine preparation has a limited absorption site for cefradine in the upper small intestine, it is necessary to completely release cefradine within the range of pH 5.0 to 7.0, and more preferably pH 5.5 to 6.5. Examples of enteric coatings that can be used for this purpose include phthalic acid cellulose acetate, maleic acid cellulose acetate, hydroxypropylmethyl cellulose phthalate, carboxymethyl ethyl cellulose, styrene-maleic acid copolymer, and methacrylic acid copolymer.

The amount of enteric coating varies depending on the dosage form and is usually 10-75.
%, But the amount is not particularly limited for the purpose of forming an enteric coating.

The sustained-release cefradine preparation of the present invention can be obtained by preparing a mixed preparation in which the slow-dissolving cefradine preparation obtained by the above method and the enteric-coated cefradine preparation are mixed.

The titration weight ratio of cefradine contained in the slow-dissolving cefradine formulation and the enteric-soluble cefradine formulation also varies depending on the properties of the slow-dissolving cefradine formulation used, but it is generally 3: 7.
It is preferably in the range of to 5: 5.

Further, the dosage form of the sustained-release cefradine preparation is not particularly limited, but may be a powder, fine granules, granules, beads or tablets in advance or as needed. Further, a slow-dissolving cefradine preparation may be provided in a separate layer to form a multi-layered tablet or a dry-coated tablet.

[Action and effect]

The long-acting cefradine preparation of the present invention thus obtained,
No decrease in bioavailability was observed, a constant blood concentration was obtained for a long time, and the same effect as the conventional preparation could be expected by taking twice less than the conventional preparation twice a day. As a result, the sustained-release cefradine preparation can be taken in accordance with the patient's daily rhythm, and it is possible to avoid a decrease in clinical effect due to forgetting to take it, which is often the case with conventional preparations, so that the therapeutic effect of cefradine is further enhanced. It was possible.

〔Example〕

 Next, the present invention will be described with reference to examples.

Example 1 Production of naked granules A: To a mixed powder of 1721.6 g of cefradine, 6144 g of lactose and 480 g of purified white sugar, 640 g of 10% hydroxypropylcellulose solution was added and kneaded. The kneaded product is granulated using a cylindrical granulator and then dried at 55 ° C. for 2 hours. The bare granules A that pass through 16 meshes of this dried granules and do not pass through 30 meshes
And The composition of the naked granules A is as follows.

Composition% Cefradine 59.8 Lactose 21.3 Purified sucrose 16.7 Hydroxypropylcellulose 2.2 Total 100.0 Example 2 Production of bare granules B: Kneaded by adding 440g of 10% hydroxypropylcellulose solution to a mixed powder of 1183.6g of cefradine, 594g of lactose and 268.4g of purified white sugar. Then, bare granules B are produced according to the method of Example 1 below. The composition of this naked granule B is as follows.

Composition% Cefradine 56.7 Lactose 28.4 Purified sucrose 12.8 Hydroxypropyl cellulose 2.1 Total 100.0 Example 3 Production of slow - dissolving granules S-1: 500 g of the bare granules A produced in Example 1 were put into a fluidized bed coating device, and a coating solution having the following composition was used. 1000 g was spray-coated according to a conventional method and slowly soluble granules S-
Make 1. The coating amount of this product was about 4% based on the weight of the bare granules.

Composition% Ethylcellulose 2.0 Ethanol 98.0 Total 100.0 Example 4 Production of slow- dissolving granules S-2: 500 g of the bare granules A produced in Example 1 and 2500 g of the coating liquid produced in Example 3 were used in the method of Example 3 below. Therefore, spray coating was performed and slow-dissolving granules S-2
I got The coating amount of this product was about 10% based on the weight of the bare granules.

Example 5 Production of slow-soluble cefradine granules S-3: To a mixed powder of 528 g of cefradine, 150 g of stearyl alcohol, 50 g of ethyl cellulose and 172 g of lactose, 1000 g of 10% ethyl cellulose solution was added and kneaded. This kneaded product is granulated using a cylindrical granulator and then dried at 50 ° C. for 3 hours. Those that passed through 16 mesh of the dry granules and did not pass through 30 mesh were designated as slow-dissolving cefradine granules S-3.
The composition of the slowly soluble cefradine granule S-3 is as follows.

Composition% Cefradine 52.8 Stearyl alcohol 15.0 Ethylcellulose 15.0 Lactose 17.2 Total 100.0 Example 6 Production of enteric-coated granules I-1: 500 g of the naked granules B produced in Example 2 were put into a fluidized bed coating device, and a coating solution of 2777.8 g having the following composition was used. Was spray-coated according to the usual method to produce enteric coated granules I
-1 is produced. The coating amount of this product is approx.
It was 40%.

Composition% Methacrylic acid copolymer L 6.5 Macrogol 6000 0.5 Talc 0.2 Purified water 6.8 Isopropyl alcohol 86.0 Total 100.0 Example 7 Production of sustained release cefradine granules R-1: Slowly soluble cefradine granules S-1 produced in Example 3 The enteric-coated cefradine granules I-1 produced in Example 6 were mixed so that the weight ratio in terms of titer was 4: 6 to produce sustained-release cefradine granules R-1.

Example 8 Production of sustained-release cefradine granules R-2: The slow-solubility cefradine granules S-3 produced in Example 5 and the enteric-coated cefradine granules I-1 produced in Example 6 each had a titer conversion weight ratio. The mixture was mixed at a ratio of 4: 6 to produce sustained-release cefradine granules R-2.

Example 9 Production of slow-soluble microcapsules S-4: 5.4 g of cefradine was dispersed in 100 ml of 9% ethylcellulose dichloromethane solution, and 300 ml of n-hexane was added to the suspension.
Is added to cause phase separation, and the supernatant is removed. Next, the capsules are washed with 300 ml of n-hexane and the wall film is hardened, and the slowly soluble microcapsules S-4 are obtained by drying under reduced pressure.
I got

Example 10 Production of Naked Bead C: 538.3 g of cefradine, 61.8 g of corn starch and 400 g of nonpareil were granulated using a centrifugal fluidized coating granulator, and then dried at 55 ° C. for 2 hours. Bare beads C are those that pass 16 meshes of the dried beads and do not pass 30 meshes. The composition of the bare beads C is as follows.

Composition% Cefradine 53.82 Corn starch 6.18 Nonpareil 40.0 Total 100.0 Example 11 Production of enteric-coated beads I-2: 500 g of the bare beads C produced in Example 10 were put in a fluidized bed coating apparatus, and 1000 g of a coating solution having the following composition was added in a conventional manner. Therefore, spray coating is performed to produce enteric coated beads I-2. However, the coating amount was about 4% based on the weight of the bare beads.

Composition% Carboxymethylcellulose 2.0 Ethanol 98.0 Total 100.0 Example 12 Production of sustained release cefradine beads R-3: 500 g of enteric coated beads I-2 produced in Example 11 and a mixture of 179.4 g of cefradine and 20.6 g of corn starch were centrifuged. Granulate using a fluid coating granulator, then
It was dried at 55 ° C. for 2 hours. Further, 500 g of the obtained dry beads was put into a fluidized bed coating device, and 500 g of a coating solution having the following composition was spray coated according to a conventional method to produce sustained-release cefradine beads R-3.

Composition% Salamis wax 3.0 Talc 3.0 Isopropyl alcohol 19.0 Methylene chloride 75.0 Total 100.0 Example 13 Test 1: Granules A made in Examples 1, 3, 4 and 6 250 mg cefradine titers, S-1, S-2 and I. -1 was administered to healthy adults each having a titer of 500 mg after meal, and the blood concentration of cefradine was measured. The results are shown in Fig. 1.

Example 14 Test 2: Based on the results of Test 1, enteric-coated cefradine granules I-1 and
The optimum mixing ratio when the naked granules A or the slow-dissolving granules S-1 or S-2 were combined was estimated. FIG. 2 shows the simulation curve of the blood concentration-time transition curve at the optimum mixing ratio obtained. As is clear from FIG. 2, enteric-coated cefradine granules and slow-soluble cefradine granules S-
It was found that by combining 1 or S-2, the valley of blood concentration as seen when the naked granule A was used disappeared and a good sustained effect was exhibited.

Example 15 Test 3: The sustained-release cefradine granules R-1 prepared in Example 7 were administered to healthy adults in an amount equivalent to 500 mg of cefradine in titer, and the blood concentration of cefradine was measured. As shown in FIG. 3, the sustained release cefradine granules of the present invention showed excellent blood concentration-time transition curves as a sustained release preparation.

[Brief description of drawings]

FIG. 1 is a diagram showing blood concentration-time transition curves when naked granules A of cefradine, slow-soluble cefradine granules S-1 and S-2, and enteric-coated cefradine granules I-1 were each administered alone. FIG. 2 shows the blood concentration-time transition curve (simulation) at the optimal mixing ratio when the enteric-coated granules I-1 of cefradine and the naked granules A or the slow-soluble granules S-1 or S-2 were administered in combination. It is a drawing shown. FIG. 3 is a drawing showing blood concentration-time transition curves of sustained-release cefurazine granule R-1 and a conventional preparation.

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area A61K 47/32 A61K 47/32 C 47/38 47/38 C 47/44 47/44 C

Claims (6)

(57) [Claims] 1. A slow-soluble cefradine preparation containing one or more sustained-release agents selected from water-insoluble polymers, paraffin wax, higher alcohols, fatty acid esters, higher fatty acids or metal salts thereof, and pH 5.0. Characterized in that an enteric-coated cefradine preparation coated with a film that dissolves in the range of ~ 7.0 is mixed and blended so that the cephrazine titer equivalent weight ratio becomes 3: 7 to 5: 5. Effective cefradine formulation. 2. The sustained-release agent for a slow-dissolving cefradine preparation is a matrix-forming agent, which is used in an amount of 5 to 70 relative to the total weight of the preparation.
The long-acting cefradine preparation according to claim 1, which is blended in a weight percentage. 3. The sustained-release agent for a slow-dissolving cefradine preparation is a film-forming agent, which is coated with 2-40% by weight of the total weight of the preparation. The sustained-release cefradine preparation according to item 2 or item 2. 4. The sustained-release cefradine preparation according to any one of claims 1 to 3, wherein the slow-dissolving preparation is fine particles, granules or beads. 5. The first to first claims, wherein the slow-dissolving preparation is a microcapsule, coated fine granules, coated granules or coated beads.
The sustained-release cefradine preparation according to any one of 4 above. 6. The sustained-release cefradine preparation according to claim 1 or 2, wherein the enteric coated preparation is coated fine granules, coated granules or coated beads.