JPS5855122B2 - Method for producing aminoglycoside antibiotic preparations for rectal administration - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an aminoglycoside antibiotic preparation for rectal administration.

More specifically, the present invention relates to a method for producing an aminoglycoside antibiotic preparation for rectal administration, which comprises dispersing an aminoglycoside antibiotic in a base in the presence of a surfactant.

Aminoglycoside antibiotics are basic, water-soluble antibiotics whose constituent units are amino sugars and sugars, and representative examples include streptomycin, kanamycin,
Neomycin, paromomycin (aminocidine, tigomycin), kentamicin, antibiotic XK-62-2 (Japanese Patent Publication No. 5039155), spectinomycin, neomycin, glebomycin (fluensomycin), trehalosamine, and hydroxymycin, etc. It is known as an excellent antibiotic with a broad antibacterial spectrum.

Originally, it is generally desired that antibiotic preparations have the property of having a high blood concentration after administration and maintaining this high blood concentration for a long period of time.

However, even though aminoglycoside and coside antibiotics are easily soluble in water, when administered orally, absorption from the gastrointestinal tract is extremely low, making it difficult to obtain effective therapeutic blood concentrations. There are only a few examples of streptomycin formulated with a carbowax/cocoa butter base (Boil, Soc, Ital, Biol,
5per 30.327 (1954)), but it is not yet available on the market, and all administration thereof has been by injection, either intramuscularly, subcutaneously, or intravenously.

However, in recent years, there have been reports of treatment of quadriceps femoris shortening, etc., particularly in infants and schoolchildren, and there has been a strong desire for the development of safer preparations that can be administered through the gastrointestinal tract.

Therefore, the present inventors conducted intensive research to develop a preparation that can be administered through the gastrointestinal tract, which is safer than injections, and found that an aminoglycoside antibiotic was added to an appropriate base in the presence of a surfactant. Contrary to expectations, when dispersed and administered intrarectally, the aminoglycoside antibiotic was absorbed extremely quickly from the rectum, and its blood concentration was comparable to that obtained by intramuscular injection, with less variation. It was discovered that the formulation is stable and extremely safe compared to injections, leading to the completion of the present invention.

That is, the present invention makes it possible to obtain an effective therapeutic concentration by dispersing an aminoglycoside antibiotic in an oily base or a water-soluble base in the presence of a surfactant and administering it intrarectally. , relates to a method for producing an aminoglycoside antibiotic preparation for rectal administration.

The base used in the present invention includes all oil bases and water-soluble bases that are normally used in the production of ointments, suppositories, and the like.

That is, examples of oily bases include sesame oil, olive oil, camellia oil, soybean oil, rapeseed oil, menjitsu oil, linseed oil, castor oil, bran oil, corn oil, peanut oil, coconut oil, almond oil, ahocado oil, Oils and fats such as palm oil, palm kernel oil, kaya oil, kapok oil, kuromoji oil, sasanqua oil, tea oil, eno oil, cacao butter, chive fat, lauric fat, beef tallow, pork fat, wool fat, turdle oil, squalene, etc. Modified fats and oils obtained by chemically changing these animal and vegetable oils through hydrogenation, fatty acid conversion, acetylation, fractional extraction, etc. Mineral oils such as vaseline, paraffin, and isopar silicone oils: isoprobyl myristate, n-butyl myristate, etc. State, isopropyllurylate, cetyl lysyllate, stearyl lysyllate, diethyl sepacate, diisopropyl adipate, cetyl alcohol,
Higher aliphatic alcohols such as stearyl alcohol, beeswax, greywater wax, Japanese wax, higher fatty acid esters and waxes Higher fatty acids such as nistearic acid, oleic acid, palmitic acid: All hydroxyl groups of natural saturated fatty acids with 12 to 18 carbon atoms Examples include mixtures of triglycerides esterified with .

Further, 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 1 to 30 times the amount (weight) of the aminoglycoside antibiotic used, especially 1 ~20 times the amount is preferred.

As the surfactant in the present invention, nonionic surfactants, cationic surfactants, anionic surfactants and amphoteric surfactants can be used.

Examples of nonionic surfactants include glycerin/propylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, polyoxyethylene alkyl phenyl ether, and polyoxyethylene fatty acid ester. Examples include oxyethylene castor oil, lanolin, beeswax derivatives, etc. Among these, polyoxyethylene fatty alcohol ethers (for example, manufactured by Nikko Chemicals, NITSUKOL BI, -9EX, NITSUKOL BC-10TX, NIRACOL BO-10TX,
Kao Soap Co., Ltd. Emulgen 408, Emulken 106, etc.)
is particularly preferred.

Examples of cationic surfactants include alkylamine salts, quaternary ammonium salts, alkylpyridenium halides, alkylpicolinium halides, alkyl demethylpendel ammonium chlorides, alkylamide methylpyridinium chlorides, Examples include alkyl oxymethyl pyridinium chloride and polyoxyethylene alkylamine.

Examples of anionic surfactants include alkyl sulfate ester salts, polyoxyethylene alkyl ether sulfate ester salts, alkyl sulfosuccinates, N-acyl sarcosine salts, alkyl (polyoxyethylene) phosphate esters, fatty acid esters, Examples include squalane, vitamin derivatives, and complex amino acids.

Examples of amphoteric surfactants include carboxylic acid type, sulfonic acid type, sulfate type, and natural lecithin,
Examples include cephalin.

In the present invention, two or more of the above various surfactants may be used in combination.

The amount of surfactant used in the present invention is 1 to 20% (by weight), particularly 3 to 10%, based on the oil base or water-soluble base.
is preferred.

In carrying out the present invention, the required amount of aminoglycoside antibiotic is uniformly dispersed in an oily base or a water-soluble base in the presence of a surfactant, and if necessary, a regular rectal suppository is used. It is prepared by molding, dispersing in a liquid oily base, dispersing it in the form of a suspension, or filling it in the form of an ointment into soft capsules, or by putting it into a tube and injecting it at the time of use. .

In the present invention, the order in which the base, surfactant, and aminoglycoside antibiotic are added is not particularly limited.

The particle size of the aminoglycoside antibiotic used is 100μ
The following are preferred.

Furthermore, antioxidants, preservatives, excipients, etc. can be added as stabilizers to the preparation, and substances that promote rectal absorption may also be added.

Next, experimental examples of the present invention will be shown.

Experimental example As an aminoglycoside antibiotic, XK62-2, G
Entam 1cin, Kanamycin.

Streptomycin, Am 1nocid
ine and dispersed in an oily base or a water-soluble base together with a surfactant (invention), the above five antibiotics in the base alone or dissolved in water (control),
The antibiotics were administered rectally, orally, or intramuscularly, and blood samples were taken over time to compare blood concentrations of each antibiotic.

For rectal administration, administer to male rabbits (body weight 2-2.5 kg) that have been fasted for 24 hours using a cylindrical single dose if the drug remains solid at room temperature, or a small syringe if the drug is in the form of an enema. It was administered intrarectally at a dose of 40η (titer)/9.

After administration, the anus was closed with instant adhesive (11 Aron Alpha 〇 manufactured by Toagosei ■) to prevent the object from leaking from the anus.

In addition, in the case of oral administration *7 [40 units (titer)/ky),
It was administered to the above rabbits using an oral administration probe, and the muscular muscle [40
m9 (titer)/kg) was injected subcutaneously into the hind limb muscle using a 1/3 needle.

Blood concentration was measured using Bacillus 5ubtili
B1oassay using sATCC6633 as the test bacterium
(Cup method).

The medium is... - Infusion agar medium °' Eiken (manufactured by Eiken Chemical Co., Ltd.) 40f dissolved in 1OO100O of purified water, 8r per 1 shear (90m/mφ)
It was made into a thin layer of ul.

The collected blood was centrifuged (3000r, p, m, 10
Take the plasma obtained by
Dilute 5 times with H7, 8) and inject into Cup, 37
The cells were cultured at ℃ for 16 hours.

The standard solution for the calibration curve was plasma from a normal rabbit to which no drug had been administered, and 0.1M IJ phosphate buffer (pH 7).
A solution diluted 5 times with 8 was used.

The results are shown in Tables 1 to 5.

As is clear from Tables 1 to 5, when the sample of the present invention is administered rectally to domestic rabbits, the absorption rate is several times higher than when the control sample (dispersed in base alone and aqueous solution) is orally administered. It can be seen that blood concentrations comparable to those obtained when the control sample was injected intramuscularly were obtained.

Next, examples of the present invention will be shown.

Example 1 45 g of peanut oil and nonionic surfactant Nitsukor BC
)-10TX (polyoxyethylene oleyl ether)
After adding and dispersing 25g, add 2.5P of XK62-2 and stir well to uniformly disperse.

Example 2 After adding and dispersing 2.5 g of nonionic surfactant Emulgen 408 (polyoxyethylene oleyl ether) to 45 g of propylene glycol, XK-62-22,5
′? Add and stir well to evenly distribute.

Example 3 Witepsol W-35,45g was mixed with non-ionic interfacial agent Ninocol BL-9EX2.5P, heated and melted, and then XK-62-22,5? Mix and disperse thoroughly, fill in a single-dose plastic container, and gradually cool to form a single-dose product.

Example 4 45 g of peanut oil and anionic surfactant Nitsukor SL
Add S (sodium lauryl sulfate) 251 and disperse, then add XK-62-22,51 (stir,
Distribute evenly.

Example 5 Sesame oil 901 and nonionic surfactant Nitsukor BL-
9EX (polyoxyethylene lauryl ether) 5fI
After adding and dispersing, Gentamicin5 Si' was added and stirred well.
Distribute evenly.

Example 6 45 g of soybean oil and nonionic surfactant Nikkor BO
-10TX (polyoxyethylene oleyl ether) 2
After adding and dispersing Kanamycin 2.5
Add the ingredients and stir well to disperse evenly.

Example 7 Nonionic surfactant Emulgen 40 in 45 g of peanut oil
After adding and dispersing 2.5P of 8 (polyoxyethylene oleyl ether), Strepto myc 1n2
Add 5g and stir well to evenly disperse.

Claims (1)

[Claims] 1. A method for producing an aminoglycoside antibiotic preparation for rectal administration, which comprises dispersing an aminoglycoside antibiotic in a base in the presence of a surfactant.