JPS6050166B2 - Drugs for gastrointestinal absorption - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition that is well absorbed in the gastrointestinal tract, and particularly for pharmaceutical compositions that are difficult to absorb from the gastrointestinal tract.
The present invention relates to a composition that can significantly increase blood concentration.

Several compounds have been provided as absorption aids to promote absorption from the gastrointestinal tract. It is difficult to increase the concentration, and many problems remain. The present inventor has been conducting research paying attention to these circumstances for some time, and in particular has been searching for an auxiliary agent that promotes rectal absorption when applied as a suppository. As a result, if the composition contains the absorption aid as shown below,
It has been found that high blood concentrations can be maintained for a significantly longer period of time regardless of the form of the drug, ie, suppositories, tablets, capsules, sublingual tablets, etc. That is, the pharmaceutical composition according to the present invention is a compound of the general formula (wherein 8'Ikko-8' is a residue obtained by removing one hydrogen atom from the amino group of an organic aminocarboxylic acid or an organic aminosulfonic acid; The carboxyl group or sulfo group in the residue may be an alkali metal salt or ester, respectively, a portion of R1 and R2 may jointly form a cyclic group, and R3 is a hydrogen lower alkyl group. or a lower alkyloxy group, R4 represents hydrogen, a lower alkyl group or a lower alkyloxycarbonyl group, and R5 represents a lower alkyl group or a lower alkyloxy group.

Further, when R3 and R4 are both lower alkyl groups, they may be combined to form a carbocyclic group, and when R4 is a lower alkyl group and R5 is a lower alkyloxy group, they may be combined to form a carbocyclic group. The gist of the invention is that it contains an absorption aid consisting of one or more enamine derivatives of organic aminocarboxylic acids or organic aminosulfonic acids represented by (which may form an oxygen alicyclic group) together with a therapeutically active ingredient. exists.

Among the compounds represented by the general formula (1), for example, N-
[1-methyl-2-ethoxycarbonylvinyl]-α-
Potassium aminophenylacetate is a well-known compound, and it is a well-known compound. The manufacturing method is described on page 789 (Misaki 196), and most of the other compounds (1) included in the present invention are manufactured according to the methods described in the above literature, regardless of whether they are new or known. can do.

That is, the age. Typically, it is obtained by reacting an alkali metal salt of an aminocarboxylic acid or an aminosulfonic acid with an acylacetate or a β-diketone at room temperature or with heating. The compound (1) used in the present invention includes the novel compound 4, and is defined as described above, but a more specific explanation thereof is as follows.

That is, the group shown in general formula (1) means a residue obtained by removing one hydrogen atom from the amino group of an organic aminocarboxylic acid or an organic aminosulfonic acid.

The organic aminocarboxylic acid is a carboxylic acid having a primary or secondary amino group, and includes not only amino acids but also non-amino acids such as valamine benzoic acid. The amino acids include all acidic, basic, and θ-neutral amino acids, and in some cases also include di- or tripeptides, and more specifically, glycine, alanine, valine, leucine, Aliphatic monoamino monocarboxylic acids such as isoleucine; aliphatic oxyamino acids such as serine and threonine; aliphatic sulfur-containing lateral amino acids such as cysteine, cystine, and methionine; aliphatic monoaminodicarboxylic acids such as aspartic acid and glutamic acid ( or asparagine or glutamine in which one of the carboxyl groups in these amino acids is amidated) Aliphatic diamine monocarboxylic acids such as lysine and arginine; Aromatic carboxylic acids such as phenylalanine and tyrosine; Histidine, tryptophan, proline, and oxy Examples include polycyclic amino acids such as proline, and examples of the non-amino acids include β-aminopropionic acid, γ-aminobutyric acid, anthranilic acid,
Examples include m-aminobenzoic acid, and the carboxy group in these organic aminocarboxylic acids may be an alkali metal salt or an aliphatic, aromatic, or heterocyclic ester. In addition, the organic aminosulfonic acid refers to an aliphatic, aromatic, or heterocyclic sulfonic acid such as the above-mentioned aminocarboxylic acid in which the carboxy group is substituted with a sulfonic group.
A well-known example is taurine aminobenzenesulfonic acid, and the sulfone group in these may be converted into an alkali metal salt or ester in the same manner as the carboxy group. Next, the meanings of R3 to R5 in the general formula (1) will be described. First, the lower alkyl group represented by R3 includes methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, Examples include pentyl, hexyl, cyclopentyl, cyclohexyl, etc., and lower alkyloxy groups also represented by R3 include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy,
Examples include cyclopentyloxy and cyclohexyloxy.

Next, examples of the lower alkyl group represented by R4 include the same groups as those exemplified as the lower alkyl group represented by R3. Similarly, lower alkyloxy in the lower alkyloxycarbonyl group represented by R4 is,
The same groups as those exemplified as the lower alkyloxy group represented by R3 are exemplified. Further, as the lower alkyl group and lower alkyloxy group represented by R5, each of the specific examples of the lower alkyl group and lower alkyloxy group exemplified in R3 can be re-exemplified as they are.

When both of the groups represented by R3 and R4 are lower alkyl groups, the compound (1) has the general formula (where Rl, R2,
R5, etc. have the same meanings as above, and R6 represents a lower alkylene group).
The lower alkylene group represented by R6 includes methylene,
Examples include propylene and butylene.

Further, in general formula (1), R4 is a lower alkyl group, and R5
When is a lower alkyloxy group, the compound (1) may be a compound represented by the general formula (in the formula, Rl, R2, R3, etc. have the same meanings as above, and R7 represents a lower alkylene group). Examples of the lower alkylene group represented by R7 include ethylene, propylene, and butylene.

Compound (1) of the present invention is generally produced as described above, but more specifically, it is produced according to the following reaction formula.

Compound (1) (In the formula, R1 to R have the same meaning as before, R8 is a group that reacts with an amine and leaves it), i.e., a primary or secondary compound in an organic aminocarboxylic acid or an organic aminosulfonic acid (■) Since the amino group is changed into an enamine derivative by reaction with an acylacetate or β-diketone (■) or its derivative (■), compounds (■) and (■) can be further modified by using specific example compounds. To explain, for example, acetylacetone, propionylacetone, butyroylacetone, methyl acetoacetate, ethyl acetoacetate, n-propylacetoacetate, isopropylacetoacetate, n-butylacetoacetate, isobutylacetoacetate, tertiary
Butylacetoacetate, n-pentylacetoacetate, methoxyethylacetoacetate, ethoxyethylacetoacetate, isopropoxyethylacetoacetate, n-propoxyethylacetoacetate, α-
Acetyl butyrolactone, methyl cyclopentanone carboxylate, ethyl cyclonopentanone carboxylate, isopropyl cyclopentanone carboxylate, n-butyl cyclopentanone carboxylate, methyl cyclohexanone carboxylate, ethyl cyclohexanone carboxylate, propyl cyclohexanone carboxylate, ethoxymethy7 Examples include diethyl lemmalonate and dipropyl ethoxymethylenemalonate.

This reaction is generally carried out in a solvent, and examples of solvents that can be used include isopropyl alcohol, ether, chloroform, dioxane, benzophane, toluene, and other solvents that do not adversely affect the reaction.

The reaction temperature may be a mild condition ranging from room temperature to elevated temperature. Compound (1) produced in this way is used as an absorption aid to promote absorption from the gastrointestinal tract as described above, but the form of a drug for gastrointestinal absorption containing this compound (1) is oral. Examples include tablets, suppositories, sublingual tablets, etc., but the form in which the composition of the present invention is administered to the human body is not particularly limited as long as it is intended for absorption from the gastrointestinal tract.

The raw material for producing compound (1) is an organic aminocarboxylic acid (or organic aminosulfonic acid) as described above.
and acylacetate esters (or diketones), all of which have relatively good hydrophilicity, but the enamine derivatives formed as a result of the reaction are easily soluble in water, but at the same time generally have good lipophilicity. are doing.

Therefore, the reaction carried out in the presence of a lipophilic solvent often starts in a suspended state, but as the reaction progresses, as the lipophilic enamine derivative (1) is produced, these are sequentially dissolved and gradually It becomes clear. Although the present inventors have not completely elucidated the reason why the compound (1) has the effect of promoting drug absorption as described below, it is possible that such good fat solubility is due to some reason. It is presumed that this contributes. As can be understood from this, the therapeutic main drug incorporated in the composition of the present invention is generally more likely to have a significant effect when it is a compound with low fat solubility. The main drugs are nervous system drugs, antibacterial agents,
A wide range of drugs are used regardless of whether they are gastrointestinal drugs, metabolic promoters, cardiovascular drugs, respiratory drugs, etc., and excipients, fillers, and base materials are used depending on the therapeutic purpose and form of the drug. Needless to say, auxiliary agents such as the following may be used in combination. There are no restrictions on the method of preparing these preparations, and methods known per se or. is prepared according to the improved method. As a typical example, the method for preparing rectal suppositories is as follows: Compound (1) is first added to the base material and dispersed uniformly, then the therapeutically active ingredient is added and dispersed uniformly, and this is placed in a suppository container. Fill it and mold it! It is prepared by

The order of addition is not necessarily limited to the above order and can be arbitrarily selected. Furthermore, antioxidants, preservatives, fillers, etc. may be added. Examples of the base material include known materials such as oil-based base materials and water-soluble base materials; for example,
Oil bases include rattan oil, olive oil, corn oil, glycerin esters of fatty acids [for example, Uitepsol (registered trademark: manufactured by Dynamite Nobel),
SB-base material (manufactured by Kanebuchi Chemical Industry Co., Ltd.), 0. D. 0 (registered trademark: Nisshin Oil Co., Ltd.)], mineral oils such as petrolatum, and paraffin. Examples of water-soluble base materials include polyethylene glycol, propylene glycol, and glycerin. The amount of compound CI) added is usually 0.5 to 85%, preferably 1 to 20%, based on the total lumber.

More specifically, when the therapeutically active ingredient is a β-lactam antibacterial agent, it accounts for 1 to 85%, preferably 2 to 2%, of the entire preparation.
0%, in the case of insulin preparations 0.5-2 in all preparations
0%, preferably 1-15%. Examples of the present invention will be shown below.

- Production example of compound (1) Production example 1 Sodium salt or methyl ester (a) of the raw material aminocarboxylic acid or aminosulfonic acid shown in Table 1. Add 2M) to 50-100ml of isopropyl alcohol, add acylacetate or β-diketones (0.25M) listed in Table 1, and stir at room temperature or with heating until the reaction mixture becomes a clear solution. Stirred.

After the reaction, insoluble matter was removed if necessary, and the solvent was distilled off under reduced pressure. When the residue is washed with petroleum ether or diethyl ether, enamine derivatives with the molecular formula shown in Table 1 (
1) was obtained. Production Example 2 Sodium salt or methyl ester (a) of the raw material aminocarboxylic acid shown in Table 1. 2M
) and diethyl ethoxymethylenemalonate (a). 3M)
is subjected to a boiling reaction in 200 ml of benzene.

When the generated ethyl alcohol is azeotropically distilled off, a pale yellow solution with a small amount of crystals suspended is obtained in 3 to 5 hours. After the reaction is completed, benzene is distilled off, the residue is dissolved in methanol, insoluble materials are filtered off, and methanol is distilled off. When the residue was washed with petroleum ether or diethyl ether, an enamine derivative having the molecular formula shown in Table 1 was obtained. Table 2 also shows the elemental analysis results, melting points and ultraviolet absorption λMax (ethanol) of the compounds shown in Table 1.

The names of the obtained compounds are as follows. Stability in aqueous solution In order to investigate the stability of the compound (1) obtained above in an aqueous solution, a representative compound was selected and added to a phosphate buffer solution (μ: 0.15, temperature: 25°C) at pH 7.4. Half-life in °C): TO. 5 (minutes) was measured by ultraviolet absorption spectrum.

The results are shown in Table 3. In the table, 1 stable means that the enamine structure was not lost even after 6 hours had passed. Example 1 Anpine (hereinafter abbreviated as AB-PC) sodium
A capsule was prepared to give a concentration of 15m9/K9 and administered to three rabbits. Immediately after that, they were given 20ml of water, and blood oil-P was determined by a biological test method.
The C concentration was quantified.

The average of the measurement results is shown in Figure 1. The white circle in the figure is a PC
Individually, the black circles are the capsules of the present invention described above, and the compound ■
The absorption promoting effect of -a was noticeable in the eyes for 2 to 3 hours after administration, and the area under the curve (AUC: μY.min./
The comparison results for each domestic rabbit were 1.52, 1.99, and 1.73, all of which were more than 1 time. Example 2 Pigeon-P
A pellet containing C.sodium 15m9/K9 was prepared and orally administered to rabbits, followed by compound ■-
A solution prepared by dissolving A (250 m9) in water (207 TLL) was administered.

The blood AB-PC concentration (black circle) at this time is shown in FIG. The white circle indicates the case of AB-PC alone, and when the absorption enhancer was added as an aqueous solution, a remarkable absorption promotion effect was observed during the first hour. Compound (1) in rectal administration
) Absorption promoting effect Example 3 Cephalozin (hereinafter abbreviated as CET) was selected as a drug that is not absorbed at all from the rectum, and this drug was dispersed in a liquid paraffin-white vaseline base material and administered to the rectum of a rabbit.

Figure 3 shows an example of administration of a suppository containing 10% of compound ■-a added to CET2O% (dose: 50m9/Kg as CET)
Blood concentration at. It was possible to obtain a high CET blood concentration extremely quickly. Example 4 In addition to CET, AB-PC and cephalexin (hereinafter abbreviated as CEX) are also antibacterial agents that are not absorbed in the intestinal tract, but by combining these with various compounds (1), the maximum blood concentration (μ
q/Tnt) and AUG (μV-Min/TrLl), the following results were obtained.

(1yJ tool V formulation 蔀-PCNalO% Enamine derivative (1) 10% Liquid paraffin 40% White petrolatum
40% dose: 15 mg/K9 as 萀-PC-Na The results are shown in Table 24.

(CEX) Formula CEX-H2O2O% Enamine derivative (1) 10% Liquid paraffin 35% White petrolatum
5 as 35% dose CEX-H2O
The 0m9/K9 results are shown in Table 5.

CET) Prescription CET Na2O% Enamine derivative (1) 10%
Liquid paraffin 35% White petrolatum 35% Dose 50m9/K9 as CET-Na The results were as in the 6th friend.

Example 5 Although the effect of promoting absorption of β-lactam antibacterial agents was confirmed in the above example, insulin with a molecular weight of 6000 was selected in order to further examine the effect of drugs with high molecular weights.

Prescription Amorphous insulin zinc appropriate amount
Compound ■-AO. 5y base (Witepsol H-15)
4.59 0.5y of the prepared suppository was given to a rabbit (body weight: 2.0
The blood glucose concentration of ~2.5K9) when administered rectally was as shown in Figure 4.

The dashed line in the figure shows the blood sugar level in a control experiment when insulin alone or Compound (1)-a alone was added to the base material and administered separately, and there was no change at all. 7 In the figure, the white triangles are the values when 1 unit was administered per bird, and the black triangles are the values when 3 units were administered per bird, and in particular, the latter value was reduced to about 50%.

The response (R) is the value when the blood sugar level decreases.
When the so-called dose-response curve (DOseRespOnseCurve) was determined as espOns%, it was as shown in FIG.

Furthermore, DOseRe when insulin alone was injected intramuscularly
The spOnseCurve is shown in FIG. 6, and the absorption promoting effect when using the absorption enhancer of the present invention was comparable to that of intramuscular injection. Example 6 To examine the versatility of the absorption enhancer of the present invention, inulin (molecular weight 5000) was selected as another polysaccharide.

Prescription Inulin 0.1g compound -
A.O. 2y base material (Uitepsol H-15) 1.7g prepared suppositories 0.5y was given to a domestic rabbit (body weight 2.0 to 2.5 kg).
) and the blood concentration was measured.

The results are shown in Figure 7, and the enamine derivative (1)
Versatility was confirmed. The amount of inulin excreted in urine was 18% of the administered dose. Furthermore, when the following formulation was administered rectally to dogs and humans and the urinary recovery rate of inulin was measured, the same results as in the case of domestic rabbits were obtained (Table 7). Example 7 The starting amino acids or their sodium salts shown in Table 8 were added to the solvents shown in Table 8 to form a homogeneous solution or suspension.

This was stirred at room temperature or under heating, and an equimolar amount of ethyl acetoacetate was added dropwise, followed by stirring for 2 to 1 hour. When the solvent was distilled off from the reaction solution under reduced pressure and the remaining solids were purified by washing or recrystallization, each target substance was obtained in the yield shown in the table. The physical properties of the product are shown in Tables 9, 10 and 11, and the effect as an absorption aid is shown in Table 1. However, the effects in Table 12 show the results of studies conducted in accordance with the prescription of Example 5. Next, in order to examine the effect of this compound on promoting absorption of antibiotics, rectal suppositories having the formulations shown in Table 13 were prepared in a conventional manner.

The blood absorption of rectal suppositories of these formulations in dogs was measured by blood concentration, and the results are summarized in Section 1.

Measurement of blood concentration is based on the Japanese Antibiotic Drug Standards.
As test bacteria, Sarcina lutea (S. lutea) is used for penicillins, and B. subtillis is used for cephalosporins.
It was tested by the cup method using s).

[Brief explanation of drawings]

1 to 7 are graphs showing the effects of the present invention.

Claims (1)

[Claims] 1 General formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The carboxy group or sulfo group in the residue may be an alkali metal salt or ester, respectively, and R_1 and R_2 may partially form a cyclic group together. , R_3 is a hydrogen lower alkyl group or a lower alkyloxy group, R_4 is a hydrogen lower alkyl group or a lower alkyloxycarbonyl group, and R_5 is a lower alkyl group or a lower alkyloxy group. Also, R_3 and R_4 are both lower alkyl groups. When R_4 is a lower alkyl group and R_5 is a lower alkyloxy group, they may be combined to form an oxygen-containing alicyclic group. A drug for absorption in the gastrointestinal tract, characterized in that it contains an absorption aid consisting of one or more enamine derivatives of organic aminocarboxylic acids or organic aminosulfonic acids represented by the following formulas, together with a therapeutically active ingredient.