JPH0235724B2 - SEFUAROSUHORINKEIKAGOBUTSUGANJUCHOKUCHOTOYOYOSEIZAI - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel formulation for rectal administration containing a cephalosporin compound. More specifically, the present invention relates to a novel preparation for rectal administration, which has a cephalosporin compound as its main component and contains maleic acid or a salt thereof to improve the rectal absorption of the main component. In recent years, many cephalosporin antibiotics have been known that have a broad antibacterial spectrum and are highly effective against many bacterial infections. However, although these antibiotics are water-soluble, their absorption rate when administered orally is low, and they are usually administered as injections. Since injections have many limitations in use, other administration methods that are as absorbent as injections have been investigated. Among these, suppositories are the most effective administration method, but they have problems such as insufficient absorption efficiency compared to injections, easy damage to the rectal mucosal tissue, and inducing defecation. In order to solve these problems,
Many studies have been carried out in the past, but they are not always satisfactory. The present applicant found a powerful means to solve the above problems and filed a patent application (Japanese Patent Application Laid-Open No. 11917/1983). It is characterized by the use of water-soluble organic acids or their salts to improve the rectal pH during rectal administration of cephalosporin compounds.
by maintaining it in the acidic range of 3.5 to 5.5.
This improves the absorption efficiency of drugs. As a result of further studies related to the above method, the present inventors found that when maleic acid or its salt was added to a cephalosporin compound, the rectal absorption rate was significantly higher than when other organic acids were added. The present invention has been completed based on the discovery that this can be promoted. The maleic acid salts used in the present invention include:
Any compound that releases maleate ions at the absorption site and is pharmaceutically acceptable may be used, such as monosodium maleate, disodium maleate, and the like. When used, these can be used alone or in combination of two or more. The amount used may be any pharmaceutically acceptable amount. When using maleic acid or a salt thereof, it may be used as a maleate salt of a basic cephalosporin compound, or the maleic acid or salt thereof may be used in combination with maleic acids. Examples of cephalosporin compounds which are the main components of the rectal preparation of the present invention include the existing cefoxitin, cefmetazole, cefazoline, cephalothin, ceftesol, cefaladine, cefapirin, cefacetril, cefamandole,
Examples include cefuroxime and salts thereof.
In addition, as a cephalosporin compound having basicity, Japanese Patent Application No. 1983-1999 filed by the present applicant
7β-[2-(2-aminothiazol-4-yl)-2-{(imidazol-4-yl) disclosed in No. 57010
Methoxyimino)}acetamide]-3-(1-pyridinium)methyl-3-cephem-4-carboxytolate and the like. As the salts,
Examples include alkali metal salts such as sodium and potassium salts, ammonium salts, and salts with nitrogen-containing organic bases such as glucamine and triethanolamine. As bases used in the pharmaceutical composition of the present invention, all oil bases and water-soluble bases commonly used in the production of ointments, suppositories, etc. can be used. That is, examples of oily bases include cacao butter, esters of fatty acids having 6 to 30 carbon atoms and glycerin (for example, Huiteppuzol manufactured by Dynamite Nobel), rattan oil, corn oil, camellia oil, sesame oil, soybean oil, olive oil, and rapeseed oil. , fats and oils such as menjitsu oil, bran oil, linseed oil, lard, beef tallow, wool fat, and squalene, or oils and fats modified by hydrogenation, fatty acid conversion, acetylation, or fractional extraction, minerals such as petrolatum, paraffin, etc. Examples include oil, higher aliphatic alcohols such as isopropyl myristate and n-butyl myristate, and higher fatty acid esters. Examples of water-soluble bases include polyethylene glycol, propylene glycol, glycerogelatin, and the like. These bases may be used alone or in combination of two or more, and the amount used is preferably 0.4 to 4 grams, particularly 0.8 to 2.5 grams per preparation. Furthermore, stabilizers such as antioxidants and preservatives, and excipients for volume adjustment may be added to these. The rectal administration preparation of the present invention may be prepared by forming a composition comprising the above-mentioned ingredients into a conventional rectal suppository, or by filling a liquid or ointment into a rectal capsule or rectal administration tube. It is formulated by conventional methods. For example, to manufacture the suppositories of the present invention, maleic acid or its salt is uniformly mixed in a base, the main component compound is added thereto, mixed and dispersed, and then molded according to a known manufacturing method. Just prepare it. In this case, the particle size of maleic acid or its salt and the main component used is
Preferably 150 microns or less. The rectal administration preparation of the present invention thus produced exhibits extremely excellent absorption effects. That is, as shown in the following test examples, compared to the absorption enhancement achieved by the addition of conventionally known organic acids such as sodium salicylate, monosodium succinate, and disodium fumarate, the maleic acid or its salt of the present invention was added. is uniquely superior, exhibiting several times the absorption effect. The present invention will be explained below using test examples and examples. Test Example 1 Male Wistar rats (3 rats per group) weighing approximately 250 g that had been fasted for 24 hours were fixed in a dorsal position, and 0.3 ml of each aqueous solution shown in Table 1 was administered into the rectum via the anus using a syringe. The container was sealed with cyanoacrylate adhesive to prevent the contents from leaking out. After administration,
Blood was collected from the jugular vein after 0.5, 1, 2, and 3 hours.
Serum was collected using a conventional method. Urine, including bladder urine, was collected 3 hours after administration. The samples were analyzed using high performance liquid chromatography. The area under the blood concentration curve (AUC _0-3 hr) was determined using the trapezoidal method.
The results are shown in Table 1.

[Table] Test Example 2 According to Test Example 1, each aqueous solution shown in Table 2 was administered, the serum concentration and AUC _0-3 hr were determined, and the effect of addition of disodium maleate was investigated.
The results are shown in Table 2.

【table】

[Table] Test Example 3 The suppositories prepared in Examples 1 to 3 and Comparative Examples 1 to 2 (containing 10 mg of cefoxitin sodium) were added to an aqueous solution.
The effect of addition of maleic acid, monosodium maleate, and disodium maleate was investigated in the same manner as in Test Example 1, using 0.3 ml instead of 0.3 ml.
The results are shown in Table 3.

[Table] Example 1 Higher saturated fatty acid triglyceride (Uitepsol H-12 manufactured by Dynamite Nobel) 21.7 g
Melt at 40-45℃, add 2.5g of pulverized cefoxitin sodium and pulverized maleic acid.
2.5 g was added, stirred to uniformly disperse, and poured into a suppository container and molded. Example 2 A suppository was molded in the same manner as in Example 1 except that maleic acid was replaced with monosodium maleate. Example 3 A suppository was molded in the same manner as in Example 1 except that maleic acid was replaced with disodium maleate monohydrate. Reference example 1 21.7 g of higher saturated fatty acid triglyceride (Uitepsol H-12 manufactured by Dynamite Nobel)
The mixture was melted at 40 to 45°C, and 2.5 g of pulverized cefoxitin sodium was added thereto, stirred to uniformly disperse, and poured into a suppository container and molded. Reference Example 2 A suppository was molded in the same manner as in Example 1 except that maleic acid was replaced with disodium fumarate.

Claims (1)

[Scope of Claims] 1. A preparation for rectal administration containing a cephalosporin compound and maleic acid or a salt thereof. 2. The preparation for rectal administration according to claim 1, wherein the cephalosporin compound is cefoxitin sodium.