JPH0118882B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel suppository containing a cephalosporin compound. For more details, see the general formula () (In the formula, R ₁ is 2-(2-thienyl)acetyl group, 2-(1H-tetrazol-1-yl)acetyl group, (R)-2-amino-2-(phenyl)
Acetyl group, 2-(cyanomethylthio)acetyl group, R ₂ is hydrogen atom or methoxy group, R ₃ is lower alkyl group, carbamoyloxymethyl group,
The main component is a compound represented by an acetoxymethyl group, a thiomethyl group substituted with a nitrogen-containing heterocyclic group, or a water-soluble salt thereof, and a water-soluble organic acid or a water-soluble salt thereof is blended with the main component. This invention relates to a new suppository with excellent absorption from the body. In recent years, cephalosporin antibiotics represented by the general formula () have a broad antibacterial spectrum,
It is also known to exhibit excellent effects against many bacterial infections. However, although these antibiotics are easily soluble in water, when administered orally, satisfactory blood circulation cannot be expected, and they are usually administered as injections. Injections are an effective means of administration for the purpose of suppressing acute symptoms in the early stages of infection, but when trying to maintain a constant blood concentration over several days afterwards, repeated administration by injection is cumbersome and It causes pain and inconvenience to people and is not desirable. For this reason, the development of formulations other than injections has been strongly desired, but no satisfactory results have been obtained. For example, JP-A-52-83922 reports a rectally administered pharmaceutical composition containing a cephalosporin compound and a surfactant for the purpose of promoting rectal absorption. However, these preparations tend to cause damage to the rectal mucosal tissue due to the surfactants they contain, and therefore cannot be administered continuously. Furthermore, Japanese Patent Application Laid-Open No. 107408/1983, which aims to improve the above-mentioned drawbacks, discloses a method of administering various poorly absorbed drugs such as cefazolin as a micellar rectal preparation composition. However, such micellar solutions are not always satisfactory because they require a separate rectal injector and are unstable over time. In addition, a method to improve the above-mentioned disadvantages, that is, after adding an excipient to the micelle solution, a powder composition is obtained by freeze-drying, etc., and the powder composition is filled with a soft capsule or a regular suppository. Also disclosed is a method in which the powder composition is mixed with a drug and administered rectally as a suppository, or a method in which the above-mentioned pre-powder composition is simply dissolved before use and then rectally administered again as a micelle solution. However, the formulation process for these preparations is complicated, and the reproducibility of micelle formation during administration is not good when the micelle solution is prepared again after dissolution before use. It is difficult to say that it is satisfactory due to the lack of convenience. Therefore, the present inventors conducted intensive studies on cephalosporin-based preparations that do not have the above-mentioned drawbacks, have the same biological utility as injections, and are highly safe. When a pharmaceutical composition containing a water-soluble organic acid or its salt, more preferably a nonionic surfactant, is administered rectally, the same amount of the compound represented by the general formula () (main drug ingredient) is added as an aqueous solution. It has been shown that a blood concentration comparable to or higher than that obtained by intravenous injection can be obtained, that is, good rectal absorption can be obtained, and furthermore, damage to the rectal mucosal tissue seen with conventional techniques can be suppressed. This discovery led to the completion of the present invention. A feature of the present invention is that by maintaining the rectal pH in the acidic range of 3.5 to 5.5 during rectal administration of cephalosporin compounds using a specific water-soluble organic acid or its salt, drug absorption efficiency is extremely high. Furthermore, no attempt has been made to date to promote the absorption of cephalosporin compounds by maintaining the rectal pH at an acidic level. More specifically, there are examples of formulations for rectal administration containing acids and their salts, but they are all different from the present application both in terms of the intent and effect of using acids. For example, the above-mentioned Japanese Patent Application Publication No. 53-
In Publication No. 107408, a phosphate buffer (PH6.0-6.5) is used to promote micelle formation.
Depending on this buffer solution, it is not possible to adjust the pH range of the present application. In addition, sodium dihydrogen phosphate, which is a component of this buffer solution, was tried for the purpose of the present invention, but strong aggregation of the additive occurred in the suppository base, making it impractical in terms of formulation. In JP-A No. 55-8486, dilute hydrochloric acid is used as an insulin solubilizing agent, but the addition of dilute hydrochloric acid here is not intended to make the rectum acidic, and the pH is adjusted to the pH range of the present application. When dilute hydrochloric acid was added in the required amount, the pH easily rose to 5.5 or higher over time, making it impossible to achieve the object of the present application, despite causing severe irritation to the rectum. In addition, in JP-A No. 55-24151, lactic acid is used for the purpose of preventing changes over time in analgesic suppositories, but when lactic acid is used in the amount necessary for the purpose of the present application, it may cause damage to the rectal mucosa. It was too irritating and impractical. As mentioned above, none of the above examples attempts to promote drug absorption by maintaining acidity in the rectum. Typical examples of the compound of the general formula () used as the main component of the suppository of the present invention include cefoxitin, cefmetazole, cefazolin or water-soluble salts thereof, and cephalexin. Examples of the water-soluble salts include salts with alkali metals such as sodium and potassium, ammonium salts, and salts with nitrogen-containing organic bases such as glucamine and triethanolamine. The water-soluble organic acids or salts thereof used in the present invention may be water-soluble substances that are harmless when administered rectally, such as succinic acid, citric acid, tartaric acid, malic acid, glutamic acid, carboxyvinyl polymers ( Examples include organic acids such as Carbopol (manufactured by Gutduritsu) or their salts. The amount used is preferably an amount sufficient to maintain the pH in the rectum at 3.5 to 5.5, and 50 to 1000 milligrams, particularly preferably 100 to 500 milligrams, are used per suppository. Furthermore, in order to further improve the effects of the present invention, less irritating nonionic surfactants such as polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene higher alcohol ether, polyoxyethylene Castor oil derivatives, polyoxyethylene acylglutamic acids, acylglutamic acids, bile acids, phospholipids, etc. can be added. Among these, polyoxyethylene higher alcohol ether (for example, Nikkor BL-9EX manufactured by Nikko Chemicals,
Nitsukor BO-10TX, etc.) are particularly preferred. In the present invention, two or more of the above surfactants may be used in combination. The amount of surfactant used is 0.2 to 15% (4% by weight) based on the base, and preferably 0.5 to 5%. As the base used in the pharmaceutical composition of the present invention, all oily 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, carbon atoms of 6 to
Ester of 30 fatty acids and glycerin (e.g. Uitepsol manufactured by Dynamite Nobel, ODO-1 manufactured by Nisshin Oil Co., Ltd.), rattan oil, corn oil, camellia oil, sesame oil, soybean oil, olive oil,
Oils and fats such as rapeseed oil, Menjitsu oil, bran oil, linseed oil, lard, beef tallow, wool fat, squalene, or oils and fats modified by hydrogenation, fatty acid conversion, acetylation, or fractional extraction, petrolatum, paraffin, etc. Mineral oil or isopropyl myristate, such as
Examples include higher aliphatic alcohols such as n-butyl myristate, higher fatty acid esters, and the like.
Examples of the water-soluble base 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 0.4 to 4 grams, particularly 0.8 to 2.5 grams per suppository.
Grams are preferred. Furthermore, stabilizers such as antioxidants and preservatives, and excipients for volume adjustment may be added to these. When producing the suppositories of the present invention, a predetermined amount of additives, i.e., a water-soluble organic acid or its salt, and, if necessary, a nonionic surfactant, are uniformly mixed with the base, and the main ingredients are mixed with the base. After adding a compound of a certain general formula () and mixing and dispersing it by a usual method,
It may be prepared by forming it according to a known manufacturing method for ointment suppositories. In the present invention, the order of addition of these substances is not particularly limited, but the organic acid or its salt used and the particle size of the main component are
Preferably 150 microns or less. As described below, the absorption efficiency from the intestinal tract of the representative example of the suppository of the present invention produced in this way was comparable to or even more effective than when administered intravenously. The present invention has made possible a practical administration formulation for cephalosporin antibiotics, which have been considered difficult to absorb satisfactorily. That is, cefoxitin sodium, cefmetazole sodium, cefazolin sodium, and cephalexin were selected as representative examples of the compounds represented by the general formula (), and the suppositories according to the present invention were prepared from them and administered rectally to rabbits. The results of examining the absorption rate and urinary excretion rate are shown in Table 1. Table 1 shows that in the experiment, each drug was administered at a dose of 100 mg per animal as a free form. For administration into the rectum of rabbits, the body weight after 24 hours of fasting is approximately 1.7 to 2.2
The drug was administered as a cylindrical suppository approximately 5 cm deep from the anus of a Kg female domestic rabbit. After administration, 5, 10, 15, 20,
After 30, 60, 120, and 240 minutes, blood was collected from the ear vein and the antibacterial activity of the plasma obtained by a conventional method was measured using a biological assay. Based on these measurement results, a time course curve of the plasma concentration of the drug was drawn, and the area under the curve (AUC) was quadratured using the trapezoid method, and the degree of rectal absorption was compared based on the magnitude of the AUC. In order to evaluate the overall absorption, or biological utility, it is generally said that it is better to look at the AUC than to look at the individual time values of the plasma concentration of the drug.Author: Tokuharu Suzuki (Yakugyo Jihosha, 1976, “Bioavailability of Drugs,” p. 89). At the same time, urine up to 24 hours was collected from the bladder using a cannula, and the antibiotic concentration was determined by measuring the antibacterial activity, and the urinary recovery rates were compared. The samples in Table 1 were prepared in much the same manner as shown in the Examples, and demonstrate that their biological utility is comparable to that of intravenous injection.

[Table] was drawn and the area under the curve was calculated using the trapezoid method.
Example 1 7.69 g of higher saturated fatty acid triglycerin (Dynamite Nobel Co., Ltd. Witepsol H-15) was added to 40
Melt at ~45℃ and add 0.5% of the nonionic surfactant polyoxyethylene lauryl alcohol ether (Nitsukol BL-9EX manufactured by Nikko Chemicals) to this.
Add and dissolve succinic acid, which is further finely powdered.
1. Add 1.0 g of sodium and 1.05 g of pulverized cefazolin sodium, stir to uniformly disperse, and pour into a suppository container and mold. Example 2 0.5 g of nonionic surfactant polyoxyethylene cetyl alcohol ether (Nitsukol BC-20TX manufactured by Nikko Chemicals) to 6.5 g of rattan oil
Add and dissolve finely divided succinic acid 1.
Add 1.0 g of sodium and 1.0 g of pulverized cephalosin sodium, stir well to uniformly disperse, and make a suppository in the form of a soft gelatin capsule. Example 3 0.5 g of nonionic surfactant polyoxynonyl phenyl ether (Nitsukol NP-7.5, manufactured by Nikko Chemicals) was added and dissolved in 6.5 g of sesame oil, and 1.0 g of finely powdered sodium succinic acid and 1.0 g of pulverized sodium succinate were added and dissolved. Add 1.0 g of micronized cephalexin, stir well, and disperse uniformly to form suppositories in the form of soft gelatin capsules. Example 4 10.45 g of Witepsol H-15 was melted at 40 to 45°C, 0.5 g of Nikkol BL-9EX was dissolved therein, and 1.sodium succinate was further finely powdered.
1.0g and micronized cefoxitin sodium
Add 1.05g, stir to disperse uniformly, and pour into a suppository container to form. Example 5 7.69 g of Witepsol H-15 was melted at 40 to 45°C, 0.5 g of Nikkol BL-9EX was added and dissolved, and 1.0 g of micronized succinic acid and 1.05 g of micronized cefoxitin sodium were added. Add it, stir to disperse it evenly, pour it into a suppository container, and mold it. Example 6 6.65 g of Witepsol H-15 was melted at 40 to 45°C, 0.2 g of Nitsukol BC-20TX was added and dissolved, and further 2.0 g of finely powdered sodium succinate and finely powdered cefoxitin were added. Add 1.05g of sodium and stir to uniformly disperse it, then pour and mold the suppository container. Example 7 Macrogol 4000 1.0g and Macrogol 1000
Melt 8.0g at 40-45℃ and add 0.5g of nonionic surfactant polyoxyethylene oleyl alcohol ether (BO-10TX manufactured by Nikko Chemicals).
Add and dissolve 0.1 g of citric acid and further finely powder
g and micronized cefoxitin sodium 1.0 g
Add and stir to disperse uniformly, then pour into a suppository container and mold. Example 8 7.69 g of Witepsol H-15 was melted at 40 to 45°C, 0.1 g of Nitsukol BC-20TX was added and dissolved, and 1.0 g of micronized glutamic acid and 1.05 g of micronized cefoxitin sodium were added. Stir to disperse uniformly, then pour and mold the suppository container. Example 9 7.69 g of Witepzol H-15 was melted at 40 to 45°C, and to this was added 2.5 g of pulverized sodium succinate and pulverized cefoxitin sodium.
Add 1.05g, stir to disperse uniformly, pour into a suppository container, and mold. Example 10 7.69 g of Witepsol H-15 was melted at 40 to 45°C, and 2.5 g of micronized glutamic acid and 1.05 g of micronized cefmetazole sodium were added thereto, stirred to uniformly disperse, and prepared for suppositories. Inject into a container and mold. Example 11 Melt 7.69 g of Witepsol H-15 at 40-45°C, dissolve 0.5 g of Nikkol BL-9EX therein, and finely powder 1-sodium succinate.
2.0g and micronized cefmetazole sodium
Add 1.05g, stir to homogenize, and form into suppositories.

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is 2-(2-thienyl)acetyl group, 2-(1H-tetrazol-1-yl)acetyl group, (R)-2-amino-2-(phenyl)
acetyl group or 2-(cyanomethylthio)acetyl group, R ₂ is a hydrogen atom or methoxy group, R ₃
represents a lower alkyl group, a carbamoyloxymethyl group, an acetoxymethyl group, or a thiomethyl group substituted with a nitrogen-containing heterocyclic group) or a water-soluble salt thereof, and a water-soluble organic acid or a water-soluble salt thereof. Suppositories. 2. The suppository according to claim 1, further comprising a nonionic surfactant.