JPS58216126A - Auxiliary for dissolution - Google Patents

Abstract

PURPOSE:An auxiliary for dissolution handleable by simple operations, making a water-insoluble or water slightly soluble drug dissolve in water easily, comprising human serum albumin. CONSTITUTION:A water-insoluble or water slightly soluble drug is added to a diluted aqueous solution of human serum albumin, so that the drug is solubilized. A long-chain type carboxylic acid having an aromatic functional group with large steric hindrance, such as (5Z,15xsi)-9,11-methano-10,10-dimethyl-13-aza-15- hydroxy-16-phenyl-17,18,19,20-tetranor-11a-carbathrombo-5-enoic acid, a thromboxane A2 antagonist, not long-chain type carboxylic acid, such as (E)-3-[4- (pyridine-3-ylmethyl)]phenylmethacrylic acid, a thromboxane A2 biosynthesis inhibitor, an unfatty acid (e.g., steroid, barbiturate), etc. may be cited as the drug, and the auxiliary is effective for a drug having <=0.1mg/ml watersolubility.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides water-insoluble or sparingly soluble pharmaceutically effective
Or it relates to a solubilizing agent for biologically active organic compounds.

More specifically, the present invention relates to an adjuvant that facilitates the dissolution of water-insoluble or sparingly soluble drugs in water so that the drugs can be used as pharmaceutical preparations for injection.

Traditionally, drugs that are insoluble or sparingly soluble in water are mainly prepared for oral administration such as tablets, troches, buccal tablets, pills, suspensions, and emulsions, as well as lotions, ointments, suppositories, etc. It was formulated as a non-injectable preparation, such as, but there were many problems when it was used as an injection preparation.

Injections are classified into aqueous injections, non-aqueous injections, suspension injections, solid or powder injections, and emulsion injections, depending on the physical, chemical, and biological properties of the drug. In terms of application method, it can be classified into subcutaneous injection, subcutaneous injection, intravenous injection, arterial injection, intraperitoneal injection, intrathecal injection, etc., depending on the site of administration. In any case, if the drug itself is dissolved in water or other solvent, it can be easily formulated into an injection.

In order to solubilize a drug that is insoluble or poorly soluble in water, there are three methods: 1) changing part of the drug structure to make it a soluble derivative; 2) adding a third substance, i.e., a solubilizing agent; 3) water. A method using an organic solvent mixed with is generally used. For example, as for 1), acidic substances include sodium salt, potassium salt, sodium sulfonate salt, etc., and basic substances include hydrochloride.

2) A method of forming soluble derivatives such as hydrobromide, sulfate, methanesulfonate, etc. 2) A method of solubilizing by forming complexes or micelles by adding surfactants, 3) There is a method of solubilizing using glycol etc.

Solubilized preparations listed in the pharmacopoeia include amitodrizoic acid meglumine injection and phenobarbital 20-tipropylene glycol injection.

Amitodorizo@0 meglumine injection corresponds to the solubilization method 1), but forming a salt changes part of the drug structure and increases the solubility of the drug substance itself. That's not the point. Therefore, if a problem arises in which the drug precipitates due to pH fluctuations, the problem arises. On the other hand, 20-propylene glycol injection of funiparbital corresponds to the solubilization method 1iD3). However, there are very few biologically inactive non-hemolytic surfactants and non-aqueous solvents that can be used as solubilizing agents in the solubilization methods 2) and 3) above.
The current situation is that it has not been put into practical use.

The present invention provides a solubilizing agent for solubilization by adding a third substance. That is, it relates to the use of human serum albumin as a solubilizing agent to solubilize drugs that are insoluble or poorly soluble in water.

Human serum albumin is originally a human blood component, and has the effect of providing protein nutrition for the whole body and maintaining the colloidal osmotic pressure of blood, and is used as a special blood product. In addition, human serum albumin, like other similar protein albumins, forms a complex and is used for stabilizing active ingredients and in quantitative methods.

JP-A No. 48-55015 discloses that by forming a long-chain fatty acid similar to brostanic acid having a cyclopentane ring in the middle of the hydrocarbon chain into a complex with albumin,
It is disclosed that the solubility in water is increased. However, this technology recognizes that (1) solubility can only be increased by the formation of a complex between fatty acids and albumin through their own bonding forces, such as van der Waals bonds, dion bonds, hydrogen bonds, etc. This invention is based on

(21 Complex formation requires very complex and many steps. For example, fatty acids contained in albumin molecules are delipidated by pretreatment, followed by dialysis equilibration method, Sephadex method, and concentration method. Otherwise, it is necessary to perform complicated operations such as aqueous layer-organic solvent equilibration method, and finally dialyze with glucose-saline solution and freeze-dry.

(3) Intended only for freeze-dried products.

(4) Compounds that form a complex with albumin are limited to brostanic acid, which has a cyclopentane ring in the middle of the hydrocarbon chain of a long-chain fatty acid, and some analogs thereof.

This is completely different from the present invention in this respect, and is not intended to imply the present invention in any way. That is, the present invention provides good solubility regardless of whether a complex is formed, and does not require operations involving many separate steps. That is, it is sufficient to simply add an insoluble or II'i-dissolvable compound to an aqueous dilution of albumin. Surprisingly, fatty acids with substituents with large steric hindrance, such as non-long-chain carvone fermentation conductors with aromatic functional groups, were previously thought to be unsuitable for protein binding with albumin. Furthermore, it is notable for its ability to solubilize compounds that are not fatty acids.

Further, JP-A-56-115725 discloses a kallikrein preparation containing albumin. This preparation is said to be extremely stable and is a kallikrein preparation with high potency when administered as a medicine, and experimental examples supporting this are also presented. However, there is no mention of improving solubility.
There are no experimental examples to support this. Kallikrein is an acidic protein and is insoluble in water, but it is a known fact that its solubility can be greatly improved by adjusting the pH with a buffer, as shown in the examples in the above specification. Furthermore, although some mention is made of the improvement in solubility during freeze-drying, there is no mention of whether this increase in solubility is due to the addition of albumin. It is thought that freeze-drying made the powder finer and improved its condensing properties, resulting in improved solubility. Therefore, the invention of JP-A-56-115723 also does not relate to albumin as a solubility aid.

In the present invention, human serum albumin that is already commercially available as a special blood product is used.

The drug that can be solubilized with the solubilizing agent of the present invention may be any drug as long as it is insoluble or poorly soluble in water. However, PGF, , PGF', , PGF2゜PG described in the above-mentioned Japanese Patent Application Laid-open No. 48-53013
F3. PG Ml + PG M B * PG %
* Excludes PGB@, their 20-nor forms, their methyl substituted forms, and their esters.

Specifically, +1) Long-chain carboxylic acid T having an aromatic functional group with large steric hindrance, such as (5Z, 15ξ)-9,11-Nucno 10.1, which is a thromboxane A2 antagonist.
0-dimethyl-13-aza-15-hydroxy-16-
Phenyl-17,18,19゜20-tetratrue 11
a-carbatrombo-5-enoic acid and (5Z, 15ξ)
-9,11-methano-10,10-dimethyl-15-aza-15-hydroxy-16-(4-ethylphenylthio)-17,1B, 19.20-tetratrue 11&-
(2) A non-long-chain carboxylic acid having an aromatic functional group with high steric hindrance and (K)-5-C4-(pyridine), which is a trompoxamum 2 biosynthetic enzyme inhibitor. -3-
phenyl methacrylic acid, an aldose reductase inhibitor (1!j)-3-carboxine methyl-
5-[(II-2-methylcinnamylidene] rhodanine, amitodorizoic acid which is an X-ray contrast agent) and (3) drugs that do not have a carboxylic acid group, such as steroid hormones such as progesterone, testosterone, and estradiol; Barbital compounds such as amobarbital, phenobarbital, and
[3-(5-methyl-13,14-oxadiazole-
2-yl)-&3-diphenylpropyl]-azabicyclo[2,2,23 octane) and the like are effectively solubilized. Therefore, the solubilizing agent of the present invention is considered to be effective for substances that will be developed in the future, as long as they are as described in (1), +21, and (3).

The human serum albumin used in the present invention is mixed and diluted with an appropriate amount of a solution such as physiological saline, distilled water for injection, glucose injection, etc.
It can be used as a concentration of o s (w/V). Preferably it is used at a concentration of 10-25%.

By using the solubilizing agent of the present invention, injectable preparations can be manufactured. That is, the target insoluble or poorly soluble drug and appropriate adjuvants, such as excipients, are dissolved in the human serum albumin-containing solution obtained by the above method, and the solution is sterilized by a known method. It can be manufactured in various ways.

They can also be used by preparing a sterile solid composition by freeze-drying and dissolving it in distilled water for injection or a sterile solution before use.

To summarize the characteristics of human serum albumin as a solubilizing agent used in the present invention, 1. Human serum albumin is a component of human blood, and compared to other surfactants and non-aqueous solvents, it is less hemolytic and causes local irritation. It is used as a blood substitute.

2 Human serum albumin has a large solubilizing effect on highly sterically hindered fatty acids, such as carboxylic acids having aromatic functional groups.

& Human 11f albumin also has a solubilizing effect on non-fatty acids such as steroids and pulpylate.

Normally, it has a high solubilizing effect on insoluble or poorly soluble drugs whose solubility in water is 1,111 v/- or less.

The solubilizing effect of the present invention will be specifically explained below.

Experimental example As an insoluble □ or poorly soluble drug, ('5Z, 15ξ)
-9,11-methano-10,10-dimethyl-13-aza-15-hydroxy-16-phenyl-17,1B,
19.20-tetratrue 11a-carbatrombo-5
-Enoic acid (compound M), (SZ, t5ξ)-9-11-
methano-10,10-dimethyl-13-aza-15-hydroxy-16-(4-ethylphenylthio)-17,
18゜19.20-Tetratrue-11a-carbatrombo-5-enoic acid (compound B), (13-,[4-(pyridin-3-ylmethyl)]phenylmethacrylic acid (compound O), (6)-3- Carboxine methyl-5- [(6)
-2-methylcinnamyrite] rhodanine (compound D),
Amitodorizoic acid (compound i+), progesterone (compound F), testosterone (compound G), estradiol (compound ■), amobarbital (compound -13゜14-oxadiazol-2-yl)-4
3-diphenylpropyl]-asabicyclo[2,2,2
] Using octane (compound K), each compound 1
Distilled water was added to 0 wg, thoroughly stirred, and the total amount of distilled water added until complete dissolution at 25°C was measured to determine the solubility in distilled water at 25°C. Next, using 25% (w/V) human serum albumin aqueous solution instead of distilled water, 25'cK,
% (W/V) Solubility in human serum albumin aqueous solution was determined. The results are shown in the table below.

Examples of formulations using the solubilizing agent of the present invention are listed below, but the present invention is not limited thereto.

Example 1 2.5 f of human serum albumin was dissolved in 10 sd of distilled water for injection, then 40 μ of the compound was added and dissolved, and the solution was sterilely filtered using a conventional method, and 1 ml was added to a sterilized 3-volume ampoule. - By dispensing and freeze-drying, the solid preparation for injection is 10
Got the ampoule.

Example 2 2.5f of human serum albumin was dissolved in 10ml of distilled water for injection, then 100ml of Compound K was added and dissolved, the mixture was sterilely filtered in a conventional manner, and 1 g was added to each 1-volume ampoule. Note,
The mixture was sterilized by low temperature sterilization at 60°C for 60 minutes once a day for 3 days to obtain a 1° ampoule of an injection.

Claims (1)

[Claims] Relief aid similar to human serum albumin