JPH0463047B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to compositions for rectal administration of compounds having a β-lactam ring. Compounds having a β-lactam ring, such as cephalosporins and cefamycin antibiotics, have a broad antibacterial spectrum and low toxicity, and are therefore widely used or tested as prophylactic and therapeutic agents for bacterial infections. However, among these antibiotics, there are many examples of compounds that cannot be expected to have inherent antibacterial activity because they are difficult to absorb and have low bioavailability when administered orally. Conventionally, these compounds have been injected intravenously or intramuscularly, but injection administration has disadvantages such as pain, muscle disorders, convenience, and long-lasting action. Under these circumstances, rectal dosage forms that utilize the absorption promoting effects of various additives have recently attracted attention and been proposed in place of injections (for example, Japanese Patent Application Laid-open No. 149209/1983, Japanese Patent Application Publication No. 56-100712, and Japanese Patent Application Publication No. 56-1999).
104812, 56-104813). However, there are practical problems with conventional rectally administered drugs, such as stability and
It has drawbacks such as irritation and tissue damage. The present inventors solved the above problems by blending a certain type of vegetable oil, a nonionic surfactant, and a condensed phosphate into a compound having a β-lactam ring, and achieved very good rectal absorption. The present invention was completed based on the discovery that the present invention exhibits the same properties. The present invention provides a compound having a β-lactam ring,
This invention relates to a rectal administration composition containing one or more vegetable oils selected from olive oil, sesame oil, coconut oil, linseed oil, and rapeseed oil, a nonionic surfactant, and a condensed phosphate. The composition for rectal administration of the present invention can be produced, for example, by the following method. That is, the base is a mixture of one or more of the vegetable oils mentioned above, a nonionic surfactant and, if necessary, one or more of the absorption promoting aids described below. It is obtained by heating to 60° C. or higher, cooling to room temperature while stirring, and then adding condensed phosphate to make it homogeneous. A composition for rectal administration can be obtained by mixing a compound having a β-lactam ring with the base thus obtained and finely dispersing or dissolving the mixture using a homogenizer. The dispersion or solution can be used in the form of a solid, ointment, or solution by sealing an appropriate amount of 0.5 to 3 g into a general suppository, a soft capsule for rectal administration, or a suitable container for rectal administration. Examples of the compound having a β-lactam ring of the present invention include the following compounds and their various salts (alkali metal salts, alkaline earth metal salts, nitrogen-containing organic salts, organic acid salts, etc.). The amount of the compound having a β-lactam ring is usually 1 to 50%, preferably 3 to 30% W/W, based on the base.

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[Table] The vegetable oils used in the present invention are preferably used alone or in combination as a base. In addition, as the nonionic surfactant used in the present invention, polyoxyethylene sorbitan fatty acid ester, such as polyoxyethylene (hereinafter referred to as
(abbreviated as POE) sorbitan monolaurate, POE
Sorbitan monopalmitate, POE sorbitan monostearate, POE sorbitan tristearate, POE sorbitan monooleate, POE sorbitan triolate, etc.; Sorbitan fatty acid esters, such as sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan mono Olate, sorbitan triolate, sorbitan sesquiolate, etc.; polyoxyethylene fatty acid esters, e.g. POE
Laurate, POE stearate, POE oleate,
POE palmitate, etc.; polyoxyethylene alkyl ethers, such as POE lauryl ether,
POE cetyl ether, POE oleyl ether, etc.; polyoxyethylene/polyoxypropylene copolymer; polyoxyethylene castor oil derivative;
Sugar ester; alkyl (polyoxyethylene) phosphate ester, such as di-POE alkyl ether phosphate, tri-POE alkyl ether phosphate, etc.; polyoxyethylene alkylaryl ether, such as POE nonyl phenyl ether, POE octyl phenyl ether etc.; polyoxyethylene cholesterol derivatives are used. Among these, POE sorbitan fatty acid ester, POE alkyl ether, POE fatty acid ester, and polyoxyethylene/polyoxypropylene copolymer are good, and among these, POE sorbitan intermediate fatty acid ester,
POE intermediate alkyl ether and POE intermediate fatty acid ester are most suitable. These nonionic surfactants can be used alone or in combination of two or more. The amount used is usually the total amount of base material.
0.05-70W/W%, preferably 0.5-20W/W%
It is. Examples of condensed phosphates used in the present invention include alkali metal salts such as sodium salts, potassium salts, and lithium salts of pyrophosphoric acid, tripolyphosphoric acid, trimetaphosphoric acid, and hexametaphosphoric acid;
Ammonium salts are preferred. These condensed phosphates can be used alone or in combination. The amount used is usually 0.05 of the total amount of base material.
~50W/W%, preferably 0.5~10W/W%. In the present invention, fatty acid glyceride can also be used as an absorption promoting agent if necessary. The fatty acid glycerides used include mono-, di- and triglycerides of fatty acids without limitation. Fatty acid monoglycerides include monoacetate, monopropionate, monocaproate, monocaprylate, monocaprate, monolaurate, monomyristate, monopalmitate, monostearate, monooleate, etc.; fatty acid diglycerides include dicaprylate, dicaprate, etc. , dicaproate, dilaurate, dimyristate, diolate, octyldecylglyceride, etc.; fatty acid triglycerides include tricaprylate, tricaprate,
Tricaproate, trilaurate, trimyristate, dioctyldecylglyceride, etc. are used, and intermediate fatty acid triglycerides are preferred. These fatty acid glycerides have the effect of further promoting absorption when used together with nonionic surfactants. Fatty acid glycerides can be used alone or in combination of two or more. The amount used is usually 0.01 to 0.01 of the total amount of base material.
It is 30W/W%. In the present invention, oil and fat stabilizers (e.g., antioxidants, preservatives), main ingredient stabilizers (e.g., chelating agents, complexing agents), formulation stabilizers (antisettling agents, gelling agents, Molecular substances) etc. can also be added. Next, examples will be shown. Note that all parts indicate parts by weight. Example 1 5 parts of polyoxyethylene lauryl ether (trade name Brij35) was added to 93 parts of olive oil, heated to dissolve, and then cooled to room temperature. Then, 2 parts of sodium hexametaphosphate was added to form a homogeneous base. 25 g of the sodium salt of Compound 1 was added to 175 g of this base and uniformly dispersed. 2 g each of this was filled into soft capsules for rectal administration. Example 2 3 parts of polyoxyethylene oleyl ether (trade name: Nikkor BO-10TX) was added to 95 parts of coconut oil, heated to dissolve, and then cooled to room temperature. Then, 2 parts of sodium hexametaphosphate was added to form a homogeneous base. Using this base material, a product was prepared in the same manner as in Example 1. Example 3 3 parts of polyoxyethylene oleyl ether (trade name: Nikkor BO-10TX) was added to 96.5 parts of sesame oil, heated to dissolve, and then cooled to room temperature. Next, 0.5 part of sodium hexametaphosphate was added to form a uniform base. Using this base, preparations were made in the same manner as in Example 1. Example 4 3 parts of polyoxyethylene oleyl ether (trade name: Nikkor BO-10TX) was added to 94 parts of rapeseed oil, heated to dissolve, and then cooled to room temperature. Then, 3 parts of sodium hexametaphosphate was added to form a homogeneous base. Using this base, preparations were made in the same manner as in Example 1. Example 5 5 parts of polyoxyethylene lauryl ether (trade name Brij30) was added to 90 parts of olive oil, heated to dissolve, and then cooled to room temperature. Then, 5 parts of sodium pyrophosphate was added to form a homogeneous base. Using this base, preparations were made in the same manner as in Example 1. Example 6 5 parts of polyoxyethylene lauryl ether (trade name Brij30) was added to 93 parts of olive oil, heated to dissolve, and then cooled to room temperature. Then 2 parts of sodium tripolyphosphate was added to form a homogeneous base. Using this base material, a product was prepared in the same manner as in Example 1. Example 7 The same procedure as in Example 1 was carried out except that Compound 1 was used instead of the sodium salt of Compound 1. Example 8 3 parts of polyoxyethylene lauryl ether (trade name: Brij35) and 2 parts of polyoxyethylene/polyoxypropylene copolymer (trade name: Pluronik F-68) were added to 93 parts of olive oil, heated to dissolve, and then cooled to room temperature. It was cooled to Then, 2 parts of sodium hexametaphosphate was added to form a homogeneous base. 25 g of the sodium salt of compound 6 was added to 175 g of this base and uniformly dispersed. This was prepared in the same manner as in Example 1 below. Example 9 3 parts of polyoxyethylene oleyl ether (trade name: Nikkor BO-10TX) was added to 95 parts of olive oil, heated to dissolve, and then cooled to room temperature. Then, 2 parts of sodium hexametaphosphate was added to form a homogeneous base. 25 g of the sodium salt of Compound 7 was added to 175 g of this base and uniformly dispersed. This was prepared in the same manner as in Example 1 below. Example 10 The same procedure as in Example 9 was carried out except that the sodium salt of Compound 9 was used instead of the sodium salt of Compound 7. Example 11 The same procedure as in Example 9 was carried out except that the sodium salt of Compound 19 was used instead of the sodium salt of Compound 7. Example 12 The same procedure as in Example 9 was carried out except that the sodium salt of Compound 30 was used instead of the sodium salt of Compound 7. Example 13 3 parts of polyoxyethylene lauryl ether (trade name: Brij30) was added to 95 parts of linseed oil, heated to dissolve, and then cooled to room temperature. Then, 2 parts of sodium hexametaphosphate was added to form a homogeneous base. Using this base material, a product was prepared in the same manner as in Example 1. Control example 1 Sodium salt of compound 1 in 175 g of distilled water for injection
25g was added and uniformly dispersed. 2 g each of this was filled into soft capsules for rectal administration. Control example 2 25 g of sodium salt of compound 1 in 175 g of olive oil
g was added and uniformly dispersed. 2 g each of this was filled into soft capsules for rectal administration. Control example 3 Polyoxyethylene lauryl ether aqueous solution
25 g of the sodium salt of Compound 1 was added to 175 g and uniformly dispersed. 2 g each of this was filled into soft capsules for rectal administration. Control Example 4 3 parts of polyoxyethylene lauryl ether (trade name: Brij35) was added to 97 parts of castor oil, heated to dissolve, and then cooled to obtain a uniform base. 175g of this base
25 g of sodium salt of Compound 1 was added to the solution and uniformly dispersed. 2 g each of this was filled into soft capsules for rectal administration. Control Example 5 The same procedure as in Control Example 4 was made except that peanut oil was used instead of castor oil. Control Example 6 The same procedure as in Control Example 4 was made except that safflower oil was used instead of castor oil. Control Example 7 A sample was prepared in the same manner as in Control Example 4 except that corn oil was used instead of castor oil. Control example 8 Semi-synthetic glyceride (trade name Uitebuzol)
H15) Add 5 parts of polyoxyethylene lauryl ether (trade name Brij35) to 95 parts, heat and dissolve, then
A uniform base was obtained. 25 g of the sodium salt of Compound 1 was added to 185 g of this base and uniformly dispersed. 2g of this in a suppository container (plastic)
was filled and cooled. Control example 9 Semi-synthetic glyceride (trade name Uitebuzol)
H15) Add 5 parts of polyoxyethylene lauryl ether (trade name Brij35) to 88 parts, heat and dissolve,
7 parts of sodium hexametaphosphate was added to form a uniform base. Using this base, a sample was prepared in the same manner as in Control Example 8. Control Example 10 5 parts of polyoxyethylene lauryl ether (trade name Brij35) was added to 95 parts of olive oil, heated to dissolve, and then cooled to obtain a uniform base. This base 175
25g of Compound 1 was added to the mixture and uniformly dispersed. 2 g each of this was filled into soft capsules for rectal administration. Next, an example of a rectal administration test is shown. Test Example 1 Beagle dogs (weight 10~
The preparations prepared according to each example and control example were administered into the rectum of a patient (13 kg). The concentration of the compound having a β-lactam ring in the whole urine collected 24 hours after administration was determined by bioassay method or liquid chromatography method, and the urinary recovery rate (%) was calculated. The results are shown in Table 1.

[Table] As is clear from Table 1, all the compositions of the present invention showed good results (comparison with Control Example 1). In addition, the olive oil, sesame oil, coconut oil of the present invention,
When linseed oil and rapeseed oil were used, very good results were shown compared to when other vegetable oils were used (comparison with Control Examples 4 to 7). Furthermore, when only vegetable oil was used as the base, better results were shown compared to when only nonionic surfactant was used as base (comparison with Control Examples 2 and 3). Furthermore, when using only semi-synthetic glyceride and nonionic surfactant as a base, semi-synthetic glyceride,
Compared to the case where only nonionic surfactant and condensed phosphate were used as the base, the use of the vegetable oil of the present invention showed very good results (comparison with Control Examples 8 and 9). Furthermore, when a condensed phosphate was contained in the base, very good results were shown compared to when it was not contained (comparison between Example 7 and Control Example 10). Test Example 2 A compound having a β-lactam ring was injected into the rectum of a mouse (weighing about 300 g) using the preparations prepared according to each Example and Control Example, by dividing the solid sample into portions and using a syringe for the liquid sample. A dose of 50 mg/Kg was administered.
After administration, blood was collected from the tail vein at regular intervals, and the concentration of the compound having a β-lactam ring in the blood was determined by liquid chromatography. The results are shown in Table 2.

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[Table] As is clear from Table 2, very early maximum blood concentrations and blood concentrations that could be adequately evaluated for therapeutic purposes were obtained in all cases.

Claims (1)

[Claims] 1 By blending a compound having a β-lactam ring with one or more vegetable oils selected from olive oil, sesame oil, coconut oil, linseed oil, and rapeseed oil, a nonionic surfactant, and a condensed phosphate. A composition for rectal administration.