JPS6133127A - Method of including drug active compound - Google Patents

Abstract

PURPOSE:To improve harmful characteristics, not preferable as a drug, which a drug active compound has potentially, by including the drug active compound in a cyclic (1 2)-beta-D-glucan. CONSTITUTION:A drug active compound, preferably a slightly water-soluble compound such as an antitumor agent, etc., a hydrophilic compound having low absorbing properties from digestive tube, such as polypeptide drug, etc., a compound having low stability in blood, such as prostaglandin compound, etc., or a compound having local irritation and injury, such as anti-inflammatory analgesic, etc. is included in a cyclic (1 2)-beta-D-glucan (CG), so that harmful characteristics of the drug active compound (water solubility, absorbing properties from digestive tubes, stability, local irritation and injury, etc.) are improved, and bioavailability is raised. CG having 17-24 polymerization is well-known, its mixture may be used, and isolated CG having each polymerization degree also may be used.

Description

DETAILED DESCRIPTION OF THE INVENTION TECHNICAL FIELD This invention relates to methods for improving the potentially harmful properties of pharmaceutically active compounds. From another point of view, the present invention provides that pharmaceutically active compounds can be synthesized into cyclic (1→2)-
The present invention relates to a novel method for inclusion of pharmaceutically active compounds by inclusion with β-D-glucan (hereinafter referred to as CG).

[Prior art]

Inclusion is when a cavity of an appropriate size exists inside a three-dimensional structural compound (hereinafter referred to as a host) formed by combining atoms or molecules, and other atoms or molecules ( (hereinafter referred to as a guest) at a certain composition ratio, and the resulting compound is called an clathrate compound.

Conventionally, compounds that can serve as hosts for pharmaceutically active compounds include urea and deoxycholic acid, which are formed by the association of several molecules, and monomers such as cyclodextrin and amylose. It is applied to stabilization, solubilization, etc.

However, conventional hosts have been found to be difficult to stabilize pharmaceutically active compounds;
Although it has some effect on solubilization, it cannot be said to be sufficient as a host for pharmaceutically active compounds due to the degree of solubilization of the host and the hemolytic properties of the host itself.

[Problems to be solved by the present invention]

It is an object of the present invention to provide a new method for inclusion of pharmaceutically active compounds.

Another object of the present invention is to improve the harmful properties of hydrophilic compounds with poor absorption from the gastrointestinal tract, compounds with local irritation/disorder effects, compounds with poor stability, poorly water-soluble compounds, etc. The objective is to provide a method for improving the unfavorable characteristics.

Another object of the present invention is to provide a novel inclusion method that provides a pharmaceutical product that does not exhibit hemolytic properties.

[Structure of the invention]

The present invention consists of a method for inclusion of a pharmaceutically active compound, which comprises including the pharmaceutically active compound with CG.

The polymerization degree of CG used as a host is 17~
24 are known (J, Chromatog
r, +265, 89 (1983)). In the present invention, mixtures of CG of various degrees of polymerization (Type I to
(2) (see Table 1) may be used in the present invention, or CG of each degree of polymerization may be isolated and used.

(Left below) Table 1 Composition (%) of CG produced by various microorganisms The pharmaceutically active compounds as guests used in the present invention include:
There is no particular restriction as long as it can be included in CG and has pharmaceutical activity. Particularly preferred pharmaceutically active compounds include, for example, hydrophilic compounds with poor absorbability from the gastrointestinal tract, compounds with poor stability, compounds with local irritation/disorder properties, and poorly water-soluble compounds.

As a poorly water-soluble compound, for example, the solubility in water is 0.
．． Examples include compounds that have pharmaceutical activity at 1 mg/ml or less. The effect of the clathration method of the present invention is significant when such a compound is a low-molecular compound with a molecular weight of 1000 or less. Specific examples of such compounds include antitumor agents such as spadicomycin, anthramycin, fluorouracil, daunomycin, and adriamycin, anti-inflammatory drugs such as flurbiprofen and acemethacin, prostaglandins, and lipoxygenases. Examples include inhibitors.

Examples of hydrophilic compounds that are poorly absorbed from the gastrointestinal tract include compounds that are highly hydrophilic and have a low oil-water distribution ratio. Such pharmaceutically active compounds are poorly absorbed from the gastrointestinal tract, and their medicinal activities are not fully exhibited. Even in such a compound, absorption from the gastrointestinal tract including the rectum is improved by clathrating it according to the present invention. Examples of hydrophilic compounds that are poorly absorbed from the gastrointestinal tract include polypeptide drugs, polysaccharide drugs, aminoglycoside drugs,
Examples include β-lactam antibiotics and nucleic acid drugs.

Examples of compounds with poor stability include compounds lacking in stability over time, compounds lacking in stability during formulation (for example, freeze-drying), and compounds lacking in blood stability.

Compounds with poor blood stability refer to, for example, compounds that are quickly degraded in the in vivo metabolic system after being administered or absorbed into the blood, and such compounds do not exhibit sufficient medicinal activity to the affected area. It has little biological utility.

Specific examples of such compounds with poor blood stability include prostaglandin compounds (E 1, E2, AI, A
2, Ft·α, F2α, etc.).

In addition, even if it has a certain degree of stability in Senchu,
Pharmaceutically active compounds that remain in the blood for a long period of time and require persistence are susceptible to in-vivo metabolism, and the method of the present invention is also effective for such pharmaceutically active compounds.

Examples of compounds lacking stability over time and/or stability in formulation include the prostaglandin compounds mentioned above, aspirin, and the like.

Compounds that are locally irritating or harmful include, for example, compounds that cause serious gastrointestinal disorders due to retention in the gastrointestinal tract when administered orally, compounds that are irritating when treating eye diseases, and compounds that are used as external preparations. These include compounds that sometimes cause skin irritation. Preferred examples of specific compounds include anti-inflammatory analgesics such as aspirin, indomethacin, flubiprofen, and phenylbutacin.

Inclusion method: Examples of methods for including various pharmaceutically active compounds in CG include the following methods. That is, a CG aqueous solution with an appropriate concentration (usually about 1 to 100% by weight, preferably about 1 to 10% by weight) is prepared, and a pharmaceutically active compound is added to this solution at an appropriate concentration (usually about 0.1 to 10% by weight). is added and stirred for 4 to 72 hours, usually at a temperature of 30 to 50°C. After standing still for 1 to 24 hours, remove only the lower aqueous layer or filter through an appropriate filter to collect the filtrate, and use an appropriate drying method such as ventilation drying, vacuum drying, or freeze drying to form a powder. You can also do that.

Administration method and dosage: The clathrate compound thus obtained is a water-soluble compound that does not exhibit hemolytic properties when administered in vivo, and is well absorbed from the gastrointestinal tract including the rectum when administered orally. Therefore, in addition to intravenous administration and subcutaneous administration, administration is possible by oral administration, rectal administration, and local administration.

The dosage can be appropriately determined by those skilled in the art depending on the type of compound to be included, since CG itself does not exhibit serious toxicity.

Formulation method: Examples of oral preparations include powders, tablets, capsules, liquids, granules, fine granules, and powders.

Examples of injection preparations include unit-dose ampoules, vials, and ampoules and vials dispensed into containers with added preservatives.

Examples of rectal administration preparations include suppositories and creams.

These formulations can be prepared according to methods known per se.

For example, suppositories are made by adding a pharmaceutically active substance and CG to an oily or aqueous base and heating it appropriately (approximately 40-6-℃).
This can be carried out by a method such as melting or dispersing the mixture, pouring it into a molding machine, and cooling it (about 10 to 23°C).

[Effects] The pharmaceutically active compounds clathrated by the clathration method of the present invention have excellent stability (because easily decomposed functional groups are protected), and in the case of poorly water-soluble pharmaceutically active compounds, their solubility liquid pharmaceutically active compounds can be powdered, volatile pharmaceutically active compounds have improved volatility, and local irritation is improved.・Provides effects such as improving disability and reducing pain during injection.

Below, the effects of the present invention will be made clearer by giving experimental examples.

Experimental Example 1 (Hemolysis) In intravenous administration, damage caused by uptake of biomembrane components is considered to be toxic, and hemolysis is an indicator thereof. Therefore, C
A hemolytic test was conducted on G and compared with other hosts. That is, 0.25 v/v% fresh human red blood cells were suspended in an isotonic phosphate buffer (pH 7.4) containing 0 to 45 mM CG, incubated at 37°C for 30 minutes, and then centrifuged (200 rpm). , for 10 minutes), and its absorbance (543 nm) was measured to determine the degree of hemolysis (Table 2).

CG, which is the host used in the present invention, has extremely low hemolytic properties compared to cyclodextrin.

From this, it is considered that the clathrate compound of the present invention has almost no hemolytic properties and exhibits extremely high suitability for intravenous injection.

Experimental Example 2 (Solubility) Excess amounts of various pharmaceutically active compounds were added and suspended in a 4 mM aqueous solution of CG (degree of polymerization 17), and the suspension was shaken at 25° C. for 100 hours. After the shaking was completed, a filtrate was obtained through a 0.45μ Millipore filter. This filtrate was added with IN H (1-methanol (1
: After adding 9), the amount of various pharmaceutically active compounds was measured by UV, and the amount of dissolved carbon was calculated (Table 3).

(Leaving space below) Table 3 Experimental Example 3 (Inclusion rate) Equimolar (2
XIO' mol) According to Example 1, a clathrate compound was synthesized. The obtained clathrate compound is IN H(1!
- Calculate the amount of clathrated pharmaceutically active compound by dissolving it in methanol (1:9) and measuring the UV spectrum, and calculate the clathration rate (Table 4).

(Margins below) Table 4 Experimental Example 4 (Acute Toxicity) CC inclusion of various pharmaceutically active compounds (5-fluorouracil, prostaglandin E1, phenylbutacin, flurbiprofen) prepared according to Example 1 Acute toxicity of the compound was investigated during intravenous and oral administration to ddY male mice.

As a result, both clathrates were administered intravenously at 10 m
g'/kg, oral administration at 100 mg/kg was observed for 10 days, but there were no particular changes in the test animals.

Experimental Example 5 (Stability of clathrate compound) It was investigated whether the clathrate compound obtained according to the present invention is stable without releasing a pharmaceutically active compound.

When CC clathrate compounds of various pharmaceutically active compounds were dissolved in physiological saline and stored at room temperature (13-26°C) for one week (
The stability was examined from the residual rate of the pharmaceutically active compound in the clathrate compounds A) and (B) when incubated for 1 hour at 37° C. in human plasma (Table 5).

(Margin below) Table 5 All numbers represent percentages of pre-start values.

Example 1 CG with a degree of polymerization of only 17 (2!OOmg> was added to 1 part of distilled water)
After adding 4 ml of an ethanol solution containing 40 mg of phenylbutacin and shaking at 25°C for 24 hours, the solvent was distilled off under reduced pressure and dried in a desiccator. Add 1 ml of distilled water to the dried product and filter out undissolved phenylbutacin (using a 0.2μ membrane filter), and freeze-dry the filtrate to obtain 220 mg of phenylbutacin-CC clathrate compound (powder). Ta. The absorbance measurement results showed that this powder contained 1 g of phenylbutacin 20II.

Example 2 Various degrees of polymerization instead of CG with only a degree of polymerization of 17.

The procedure of Example 1 was followed except that Type n CG, which is a mixture of CGs, was used. As a result, a highly soluble clathrate compound (in powder form) could be obtained.

Example 3 The procedure of Example 1 was followed except that mefenamic acid was used instead of phenylbutacin. As a result, a highly soluble mefenamic acid-CC clathrate compound (powder) could be obtained.

Example 4 The same procedure as in Example 1 was repeated except that ketoprofen was used instead of phenylbutacin. As a result, a highly soluble ketoprofen-CG clathrate compound could be obtained.

Example 5 Prostaglandin E1 instead of phenylbutacin
All procedures were as in Example 1 except for using.

As a result, a highly soluble PCBt CG clathrate compound could be obtained.

Procedural amendment (1 button) August 28, 1985 ■

Claims (6)

[Claims] (1) A method for inclusion of a pharmaceutically active compound, which comprises including the pharmaceutically active compound with a cyclic (1→2)-β-D-glucan. (2) The method for inclusion of a pharmaceutically active compound according to claim (1), wherein the pharmaceutically active compound is a poorly water-soluble compound. (3) The method for inclusion of a pharmaceutically active compound according to claim (2), wherein the poorly water-soluble compound is an antitumor active compound. (4) The method for inclusion of a pharmaceutically active compound according to claim (1), wherein the pharmaceutically active compound is a compound that is poorly absorbed from the gastrointestinal tract. (5) The method for inclusion of a pharmaceutically active compound according to claim (1), wherein the pharmaceutically active compound is a compound with poor stability. (6) The method for inclusion of a pharmaceutically active compound according to claim (1), wherein the pharmaceutically active compound is a compound having local irritation properties.