JPS5857407B2 - Base for rectal administration - Google Patents

Description

[Detailed description of the invention] The present invention relates to a base for rectal administration.

Pharmacologically active substances that are difficult to absorb into the blood through oral administration are
It is generally administered by injection.

However, in the case of injection, it is not convenient to use due to pain (and is not necessarily satisfactory due to the risk of muscular contracture, etc.).

Furthermore, when a relatively well-absorbed pharmacologically active substance in antibiotics is orally administered, the blood concentration decreases in a very short period of time, so the dose must be increased or the frequency of administration must be increased. The resulting unabsorbed matter sterilizes or stabilizes the resident bacteria in the intestines, resulting in changes in the intestinal flora, causing clinically undesirable problems.

Furthermore, many compounds are known to be degraded by digestive enzymes in the gastrointestinal tract upon oral administration.

Under these circumstances, various attempts have been made to improve the absorption of pharmacologically active substances into the living body, and in particular, many attempts have been made by intrarectal administration.

In particular, β-
Polymer peptides such as lactam compounds and insulin are hardly absorbed from the rectum by themselves, and attempts have been made to develop formulations for rectal administration of these compounds, but none of them have been satisfactory.

In view of the above circumstances, the present inventors have conducted intensive research and found that one or more selected from fatty acids having 8 to 14 carbon atoms, salts thereof, leucinic acid, and salts thereof, in an amount of 0.5 to 2
If a base for rectal administration containing 5W/W% is used as a base, a wide range of pharmacologically active substances, especially β-lactam antibiotics such as penicillins and cephalosporins, and polymeric peptides such as insulin can be administered from the rectum. It was found that it was well absorbed into the blood.

The above-mentioned fatty acids are generally not incorporated into conventional bases for rectal administration.

However, Uitepsol (Dynamite Nobel)
In such cases, a small amount may be mixed in during the manufacturing process, but this is also ultimately removed as an impurity.

Therefore, such an acid or its salt should be used at 0.5 to 25 W/
It is completely unexpected that a base containing a large amount of W% promotes the absorption of pharmacologically active substances.

The present invention was completed based on the above findings, and includes at least one selected from fatty acids having 8 to 14 carbon atoms, leucinic acid, and non-toxic salts thereof.
/W%.

The fatty acid having 8 to 14 carbon atoms used in the present invention may be obtained naturally or synthetically, but naturally obtained fatty acids are preferably used.

The fatty acids include both linear and branched fatty acids,
Preferably, linear ones are used.

The number of carbon atoms in the fatty acid is preferably 8 to 12 (eg, capric acid, lauric acid, etc.), and more preferably 10 (eg, capric acid).

The non-toxic salts of leucinic acid, a fatty acid having 8 to 14 carbon atoms, as used in the present invention may be any pharmacologically acceptable salts. Examples of such salts include alkali metal salts (e.g., sodium salts). , potassium salts), and organic base salts (for example, basic amino acid salts such as arginine salts and lysine salts).

Specific examples of the fatty acid, leucinic acid, and non-toxic salts thereof include caprylic acid, its sodium salt, potassium salt, lysine salt, and arginine salt; pelargonic acid, its sodium salt, lysine salt, and arginine salt;
Capric acid, its sodium salt, potassium salt, lysine salt and arginine salt; undecylic acid, its arginine salt; lauric acid, its tonalium salt, potassium salt, lysine salt and arginine salt; dodecylic acid, its lysine salt; myristic acid, its Sodium, potassium, lysine and arginine salts: leucinic acid, its sodium salt,
Examples include lysine salts and arginine salts, and among these, the above-mentioned capric acid and its salts; lauric acid and its salts; and caprylic acid and its salts are preferred.

More preferred are caprylic acid, capric acid, and salts thereof.

These fatty acids having 8 to 14 carbon atoms, leucinic acid, and their non-toxic salts may be used alone or in combination of two or more.

The amount of fatty acids having 8 to 14 carbon atoms, leucinic acid, and their nontoxic salts added to the base is usually 0.5 to 25 W/
W%, preferably 1 to 20 W/W%, more preferably 2
~13W/W%.

By the way, when preparing a pharmaceutical composition for rectal administration using the base for rectal administration of the present invention, a main drug is added, and if necessary, a third component such as an antioxidant may be added.

Therefore, it is preferable to increase or decrease the amount of the acid and non-toxic salt added to the base based on the amount of the main drug and third component added (preferably, in this case, the total amount of the entire preparation (
The blending amount of the acid and/or non-toxic salt in the conventional base + main drug, 13 components, 10 nucleic acids and/or non-toxic salts is 0.5 to 20 W/W%, preferably 1 to 15 W/W. %, more preferably 2 to 10 W/W %, the amount may be increased or decreased.

Examples of rectally administered preparations include rectal suppositories, suspensions or ointments dispersed in a liquid oil base, filled into soft capsules, or dosage forms that are put into a tube and injected at the time of use. It will be done.

In the present invention, the base to which fatty acids, leucinic acid and non-toxic salts thereof are added refers to bases in such formulations, and particularly preferred are oily bases and water-soluble bases.

Specifically, the oily bases include peanut oil,
Olive oil, corn oil, castor oil, cacao butter,
Glycerin esters of fatty acids, such as Witepsol (manufactured by Dynamite Nobel), SB-base (manufactured by Kanegafuchi Chemical Co., Ltd.), 0. D, cf.

Examples include vegetable oils and fats such as (manufactured by Nisshin Oil Co., Ltd.), mineral oils such as petrolatum, and paraffin.

Further, examples of water-soluble bases include polyethylene glycol, propene gelicol, and glycerin.

The base for rectal administration of the present invention is generally produced by adding a fatty acid having 8 to 14 carbon atoms, leucinic acid, or a non-toxic salt thereof to the above-mentioned base and uniformly dispersing the mixture.

The base for rectal administration of the present invention may further contain known additives such as surfactants and preservatives.

The non-toxic salts of the acids are generally solid and have a particle size of 1
00 mesh or less is preferable.

Note that fatty acids having 8 to 14 carbon atoms are generally known and can be obtained by methods known per se, such as hydrolysis of natural oils and fats, and general methods for producing carboxylic acids.

Leucic acid is also a known compound. Nontoxic salts of these acids are also generally known and can be obtained, for example, by reacting nucleic acids with alkali metals or organic bases.

The base for rectal administration of the present invention obtained by the above method can be used not only for pharmacologically active substances that have conventionally been applied by rectal administration, but also for pharmacologically active substances that have not been administered rectally due to difficulty in absorption through the rectum. It is widely applicable to
It exhibits an extremely good absorption promoting effect even for such pharmacologically active substances that are difficult to absorb through the rectum.

The base of the present invention is preferably applied to, for example, β-lactam antibiotics (penicillins, cephalosporins, etc.), peptide compounds such as insulin, etc.
The amount of pharmacologically active substance added in this case varies depending on the type of pharmacologically active substance, type of base, dosage form, etc., but for example, in the case of a β-lactam antibiotic, per 1 gram of the base of the present invention. Usually 20 to 500 m9, and in the case of insulin etc., the base of the present invention is 1'? It is blended at a ratio of 1 to 80 units.

Example 1? After dissolving Witepsol H-1,5 (manufactured by Dynamite Nobel) 8.25f at 40°C or higher,
0.5 thorium caprylate passed through mesh sieve (
1 was added and stirred well to uniformly disperse the mixture to obtain a base.

Next, ampicillin sodium (abbreviated as AM-Na) having a strength of 1.25 P, which has passed through a 100 mesh sieve, is added to the base and uniformly dispersed.

This was filled into a suppository container with 12 parts and molded to form an anal suppository.

Example 2 According to the method of Example 1, a base was obtained in which the fatty acids shown in Table 1 were dispersed in the conventional base shown in Table 1.

The pharmacologically active substances listed in Table 1 were further added to this to obtain rectal suppositories.

The absorption into blood of the rectal suppositories thus obtained in Example 1.2 was measured based on the plasma concentration of the pharmacologically active substance.

The results are shown in Table 2. Measurement method: A rectal suppository was administered approximately 3 crrL deep from the anus of a dog that had been fasted for 24 hours.

To measure the blood concentration, blood was collected from the jugular vein over time, and the active concentration of plasma obtained by a conventional method was determined by a biological assay.

In other words, in accordance with the Japanese Antibiotic Standards, the test bacteria used for penicillin antibiotics are Sarcina lutea (S.
, 1utea) and Bacillus subtilis (B, 5ub) in the case of cephalosporin antibiotics.
ti lis) at 37°C using the paper disk method.
, culture assay was carried out for 15 to 20 hours.

Example 3 According to the method of Example 1, a base of the present invention consisting of the base and fatty acid listed in the sample column of Table 3 was obtained.

A rectal suppository was obtained by further adding the drug listed in the active substance column.

When the suppositories thus obtained were administered to healthy adult males, the amount of each pharmacologically active substance excreted in urine was measured.

The results are shown in Table 3.

To measure the amount excreted in urine, urine was collected periodically after administration, diluted appropriately, and quantified according to the method of Example 2.

In addition, the urinary excretion amount in Table 3 is a percentage of the administered dose.

Example 4 According to the method of Example 1, a base of the present invention consisting of the base and acid listed in the sample column of Table 4 was obtained, and insulin was further added thereto to obtain a rectal suppository.

The changes in blood sugar level over time when the rectal suppositories obtained by
The results are shown in Table 4.

Measurement method: Inject 2 suppositories into the anus of rabbits that have been fasted for 24 hours.
It was administered deep within the cm.

Blood glucose levels were measured by collecting blood from the ear vein over time and using the glucose oxidase method.

Claims (1)

[Claims] 1. One or more selected from fatty acids having 8 to 14 carbon atoms, leucinic acid, and non-toxic salts thereof at 0.5 to 25 W/
A base for rectal administration containing W%. 2. The base for rectal administration according to claim 1, wherein the non-toxic salt is one selected from alkali metal salts and organic base salts.