KR20050065536A - Clathrates of butylphthalide with cyclodextrin or its derivatives, a process for their preparations and the use there of - Google Patents

Abstract

The present invention relates to the clathrates of butylphtualide, which is D,L-mixed or levorotatory, with cyclodextrin or its derivatives, a process for their preparations and the use thereof. In the invention, the butylphthalide is included with cyclodextrin or its derivatives, prefered hydroxypropyl-beta-cyclodextin, in order to improve the water- solubility of butylphthalide, develop clinical solid or liquid formulation and so that the curing effect of butylphthalide can exhibit better. The clathrate, in which the mole ratio of butylphthalide and cyclodextin or derivatives thereof is 1:1-10, can be used in preparing transfusion, injection, injectable powder, orally liquid, syrup, tablets, granules,dispersible tablets and others.

Description

CLATHRATES OF BUTYLPHTHALIDE WITH CYCLODEXTRIN OR ITS DERIVATIVES, A PROCESS FOR THEIR PREPARATIONS AND THE USE THERE OF}

The present invention relates to pharmaceutical compositions. More specifically, the present invention relates to inclusion complexes of butylphthalide, cyclodextrins or derivatives thereof, and dextrorotary-levorotary-mixed or lecithin, methods for their preparation and use.

Butylphthalide is an insoluble oily compound having the formula

There are two optical isomers in the compound which are sitent and preferential butylphthalides due to the presence of chiral carbon. Chinese patent application No. 98125618.X discloses the use of leprosy butylphthalide in the preparation of pharmaceutical compositions for preventing thrombosis and platelet aggregation. Butylphthalide was found to control the function of the NOS-NO-cGMP system and metabolism of arachidonic acid in neurons after ischemia. Chinese patent application 93117148.2 discloses the use of racemic butylphthalide mixtures in the manufacture of a medicament for the prevention and treatment of ischemia-induced diseases in mammals or humans.

Butyl desorption profile lifting Note conventional extraction from natural celery seed oil, or realize the Chinese Patent Application No. 99109673.8, and the use of butylphthalide literature jeongsyan amount, can yarun, Chinese Pharmaceutical Bulletin, 1984, 31; Obtained by the chemical synthesis described in 671.

Pharmaceutical agents are required to rapidly release active agents and to exhibit a therapeutic effect when used to treat ischemia-induced diseases or thrombosis. Usually, agents for the treatment of acute diseases are administered by intravenous injection. However, butylphthalide has to be formulated into soft capsules for oral administration because of its oily properties. Thus, the solubility problem of butylphthalide has to be solved first to obtain an injectable dosage form.

In order to study the clinical therapeutic value of butylphthalide, the Applicant has solved the problem of solubility of butylphthalide as of June 18, 2001. The inclusion complexes of cyclodextrin derivatives and butylphthalide, their preparation methods and uses Filed a Chinese patent titled " However, leprosy butylphthalide is not mentioned in this application.

It is an object of the present invention to provide inclusion complexes of butylphthalide with cyclodextrins or derivatives thereof, methods for their preparation and uses.

 In order to improve the water solubility of butylphthalide, which is preferential, lecithin-mixed or lecithin, complexes are formed with cyclodextrins or derivatives thereof, and the inclusion complexes can be used to prepare solid and liquid formulations for use in various therapeutic fields. have.

Embodiments according to the present invention are as follows:

Inclusion complexes of cycllodextrin or derivatives thereof and butylphthalide include butylphthalide and cyclodextrin or derivatives thereof, and the molar ratio of butylphthalide to cyclodextrin or derivatives thereof is in the range of 1: 1-10.

Such butylphthalides include preferential, lecithin-mixed or lecithin butylphthalides.

Said cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin.

Derivatives of the above cyclodextrins are hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, glucose cyclodextrin, maltose cyclodextrin , Maltotriose cyclodextrin, carboxymethyl cyclodextrin and sulfonylalkyl cyclodextrin.

Among the derivatives of the cyclodextrins described above, hydroxypropyl-β-cyclodextrin is preferred.

The method for preparing the inclusion complex of cyclodextrin or its derivatives with butylphthalide is as follows:

5-60% concentrated solution is prepared by adding cyclodextrin or a derivative thereof to a suitable solvent excipient. By adding butylphthalide to the solution and stirring to obtain a clear and clear solution free of oil droplets, a liquid inclusion complex of cyclodextrin or its derivatives with butylphthalide was obtained, wherein the molar ratio of butylphthalide to cyclodextrin or derivative was 1 It is the range of 1: 1 to 1:10.

The method may further comprise the step of drying the liquid inclusion complex of cyclodextrin or derivative thereof and butylphthalide at a temperature of 40-80 ° C. to obtain a solid inclusion complex of cyclodextrin or derivative thereof and butylphthalide. .

The method described above is used to obtain cyclodextrins or derivatives thereof and butylphthalide until the concentration of cyclodextrins or derivatives thereof is 10-15% (W / V) to obtain solid inclusion complexes of cyclodextrins or derivatives thereof and butylphthalide. Concentrating the liquid inclusion complex of, cooling the solution for about 12 hours to obtain a white precipitate, filtration and drying at 40-80 ℃.

According to another aspect of the present invention, a method for preparing an inclusion complex of a cyclodextrin or a derivative thereof and butylphthalide comprises placing a cyclodextrin or a derivative thereof in a colloid mill or grinder, and adding an appropriate amount of an appropriate solvent excipient. And stirring the mixture to provide a paste; Adding butylphthalide to the paste as described above, milling for about 1-5 hours to provide a uniform and viscous paste, filtering the paste and a solid inclusion complex of cyclodextrin or its derivatives with butylphthalide Drying at 40-80 ° C. to obtain a compound wherein the molar ratio of butylphthalide to cyclodextrin or derivative is in the range of 1: 1-10.

According to another aspect of the present invention, there is provided a method for preparing a cyclodextrin or a derivative thereof and the inclusion complex of butylphthalide, by adding a cyclodextrin or a cyclodextrin derivative in an appropriate solvent excipient to obtain a solution at a concentration of 5-60%. Dissolving phthalide in an appropriate amount of 99% purity of ethanol, mixing and stirring the two solutions and drying to obtain a solid inclusion complex of cyclodextrin or cyclodextrin derivatives with butylphthalide, Wherein the molar ratio of butylphthalide to cyclodextrin or derivative is in the range of 1: 1-10.

The drying method described above may be any drying method such as direct drying, spray drying or freeze-drying.

Examples of such solvent excipients are water, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycerin or acetone or mixtures of any two or more of the above excipients, with water being preferred.

Liquid inclusion complexes of cyclodextrin or derivatives thereof and butylphthalide can be used directly to produce liquid preparations such as infusions, injections, injectable powders, liquids for oral administration, syrups, and the like; Solid inclusion complexes of cyclodextrin or derivatives thereof and butylphthalide may be used to produce solid preparations such as tablets, capsules, granules, dispersible tablets and the like.

Without wishing to be bound by any theory, the inventors have found that cyclodextrins or derivatives thereof can trap butylphthalide in the tubular structure to generate inclusion complexes of cyclodextrin or derivatives thereof and butylphthalide, thereby soluble in butylphthalide. Believe that it improves. Thus, the active ingredient butylphthalide in the form of inclusion complexes can be used directly in solid or liquid dosage forms. Limitations such as poor water solubility, inability to use it directly as a solid, especially injectable dosage forms, can be overcome.

Cyclodextrins or derivatives thereof are water soluble pharmaceutical excipients which are slightly toxic. The inclusion complexes of cyclodextrins or derivatives thereof and butylphthalide thus prepared are suitable for formulating in various liquid and solid dosage forms. Inclusion complexes have advantages such as good water solubility and less vascular irritation. The solubility of the inclusion complex of hydroxypropyl-β-cyclodextrin and butylphthalide in 25 ° C. water is 924 mg / 100 ml. Inclusion complexes are particularly applicable for preparing liquid dosage forms. The present invention overcomes the limitation that butylphthalide cannot be used to prepare liquid formulations. Due to the fact that the water solubility is improved, the final solid dosage forms have advantages such as fast degradation, good solubility and high bioavailability which can be further adapted for clinical use.

Vascular stimulation assays using inclusion complexes of hydroxypropyl-β-cyclodextrin and butylphthalide are performed as follows:

Eight rabbits were divided into two groups, the test group and the control group. For the test group, 2.45 g / kg inclusion complex and 40 ml of 5% glucose were administered through the marginal ear vein of the rabbit at a rate of 1.5 ml / min.

Administration was once daily and lasted for 3 days. For the control group, 10% acetic acid was administered to one ear vein and 5% glucose was administered to the opposite rabbit ear acting as a negative control. Administration continued for 3 days. The results showed no local abnormalities in the test group, similar to the negative control group administered 5% glucose after 3 days. However, local hyperemia, concentration and exudation were observed after administration of 10% acetic acid.

Assays have shown that administration of the inclusion complexes exhibits some vascular irritation and the inclusion complexes can be used to produce injectable dosage forms.

In embodiments according to the invention, hydroxypropyl-β-cyclodextrin is preferably used as a trapping agent.

In embodiments according to the invention, a solvent excipient suitable for dissolving the cyclodextrin or derivative thereof is water.

To illustrate the invention, the following examples are preferred but the invention is not limited thereto.

Example 1: Preparation of solid inclusion complexes of hydroxypropyl-β-cyclodextrin and butylphthalide

The inclusion complexes are prepared as follows:

(1) 32.38 g (0.0210 mol) of hydroxypropyl-β-cyclodextrin was measured, added to 400 ml distilled water, and stirred to dissolve;

(2) Separately weigh 1 g (0.0052 mol) of butylphthalide into the hydroxypropyl-β-cyclodextrin solution described above;

(3) stir the mixed solution for 20 minutes by magnetic stirring until the solution becomes clear and transparent at a rate where the solution is not splashed to obtain a liquid inclusion complex of hydroxypropyl-β-cyclodextrin and butylphthalide;

(4) The liquid inclusion complexes of hydroxypropyl-β-cyclodextrin and butylphthalide are filtered through the film, divided into vials, and freeze-dried.

IR (KBr): 3393.46, 2931.26, 1158.24, 1081.60, 1032.07, 946.55, 580.68. ¹³ C-NMR: δ 131.47, 105.07, 84.03, 76.29, 75.04, 74.93, 62.89 ppm.

Example 2: Preparation of solid inclusion complexes of hydroxypropyl-β-cyclodextrin with lecithin butylphthalide

Solid inclusion complexes are prepared as follows:

(1) 32.38 g (0.0210 mol) of hydroxypropyl-β-cyclodextrin was weighed and added to 400 ml distilled water and 20 ml anhydrous ethanol, and stirred to dissolve;

(2) Separately weigh 1 g (0.0052 mol) of lecithin butylphthalide into the hydroxypropyl-β-cyclodextrin solution described above;

(3) In order to obtain a liquid inclusion complex of hydroxypropyl-β-cyclodextrin and lecithin butylphthalide, the mixed solution was stirred for 20 minutes by a magnetic stirring method until the solution became clear and transparent at a rate where the solution was not splashed. do;

(4) To obtain a solid inclusion complex of hydroxypropyl-β-cyclodextrin and lecithin butylphthalide, the liquid inclusion complex of hydroxypropyl-β-cyclodextrin and lecithin butylphthalide was concentrated and dried under reduced pressure. Let's do it.

Example 3: Preparation of Solid Inclusion Complex of Hydroxypropyl-β-cyclodextrin and Butylphthalide

Solid inclusion complexes are prepared as follows:

(1) 8.2 g (0.0053 mol) of hydroxypropyl-β-cyclodextrin were weighed and placed in a grinder, about 4 ml water was added and the mixture was milled into a paste; 1 g (0.0052 mol) butalphthalide was weighed and added to the grinder;

(2) To obtain a uniform and viscous paste, the mixture is milled for 2 hours, dried and ground at 60 ° C. for 4 hours to obtain the target inclusion complex.

Example 4 Preparation of Lyophilized Injectable Powder Using Inclusion Complex of Hydroxypropyl-β-cyclodextrin and Lefty Butylphthalide

Lyophilized injectable powders are prepared as follows:

(1) 1 g (0.0052 mol) of lecieric butylphthalate is weighed out;

(2) 82 g (0.053 mol) of hydroxypropyl-β-cyclodextrin was separately weighed and dissolved in 150 ml of distilled water;

(3) lecithin butylphthalide is added to the hydroxypropyl-β-cyclodextrin solution and the mixture is stirred;

(4) The mixture is placed in a freeze dryer, freeze dried and sealed to obtain a freeze dried injectable powder.

Example 5 Preparation of a Salt-Containing Mixture of Inclusion Complexes of Hydroxypropyl-β-cyclodextrin and Butylphthalide

Salt-containing mixtures of inclusion complexes are prepared as follows:

(1) 32.38 g (0.0210 mol) of hydroxypropyl-β-cyclodextrin was weighed and added to 400 ml distilled water and stirred to dissolve, 0.5 g of activated carbon was added, followed by heating to 80 ° C. for 14 minutes with stirring, Filtration to remove activated carbon;

(2) Separately weigh 1 g (0.0052 mol) of butylphthalide and dissolve in 10 ml ethanol, add this solution to the above-described hydroxypropyl-β-cyclodextrin solution and have no oil drop of butylphthalide in hydroxypropyl-β Stir with a magnet for 20 minutes to obtain a clear and clear solution of the inclusion complex of cyclodextrin and butylphthalide (speed is controlled to prevent splashing).

(3) Replenish water to a volume of 800 ml, add 7-8 g of injectable sodium chloride, measure pH and adjust pH to 3.5-7 with 0.05 N HCl and 0.05 N NaOH, 1000 ml Add water to volume, add 0.1 g of activated carbon and stir for 20 minutes;

(4) Carbon is separated from the solution, the solution is filled into vials (100 ml) and pressurized at 115 ° C. for 30 minutes.

Example 6: Preparation of a Glucose Mixture of Inclusion Complexes of Hydroxypropyl-β-cyclodextrin and Butylphthalide

The glucose mixture of the inclusion complex is prepared as follows:

(1) preparing a solution of the inclusion complex of hydroxypropyl-β-cyclodextrin and butylphthalide as described in steps (1) and (2) of Example 5;

(2) 50 g of injectable glucose was weighed and dissolved by adding water to a volume of 100 ml and stirring, then adding 0.1 g of activated carbon and heating until the mixture boiled and maintained for 15 minutes. After that, the carbon is removed;

(3) add glucose solution into solution of inclusion complex, add water to 800 ml volume, adjust pH to 4 with 0.05 N HCl and 0.05 N NaOH, add water to 1000 ml volume 0.1 g of activated carbon is added to the solution and stirred for 20 minutes;

(4) The solution is filtered through a coarse and fine filter or filter stick (pore size of 1.0 μm, 0.45 μm, 0.22 μm), filled into vials and pressurized at 115 ° C. for 30 minutes.

Example 7 Preparation of Sterile Injectable Powder Using Inclusion Complex of Hydroxypropyl-β-Cyclodextrin with Lefty Butylphthalide

Sterile injectable powders are prepared as follows:

(1) Weigh 32.38 g (0.0210 mol) of hydroxypropyl-β-cyclodextrin in a sterile laboratory, dissolve it in water to a volume of 90 ml, add 0.1 g of activated carbon to the solution and start the mixture to boil Heat until maintained for 15 minutes and filter to remove carbon;

(2) 1 g of lecithin butylphthalide is weighed and added to a solution of hydroxypropyl-β-cyclodextrin;

(3) Agitate for 20 minutes with a magnet to obtain a clear and clear solution of the inclusion complex of butylphthalide and the ophthalmic butylphthalide and hydroxypropyl-β-cyclodextrin without oil droplets. do).

(4) Replenish water to 100 ml, filter through 0.22 μm membrane, fill into 10 ml vials (2-3 ml per vial), freeze dry and seal.

Example 8 Complexation of Cyclone Butylphthalide with β-cyclodextrin

The complex formation process is carried out as follows.

Weigh 3.5 g of β-cyclodextrin, add to 100 ml distilled water and heat the mixture at 40-60 ° C. to dissolve β-cyclodextrin, add 1 g of left-handed butylphthalide and mechanically for 2-3 hours It is stirred, cooled in a refrigerator for 4 hours, filtered, washed with ethanol and dried to obtain inclusion complexes of leprosy butylphthalide and β-cyclodextrin. Inclusion complexes are formulated into a variety of solid dosage forms such as tablets and capsules.

In the context of the present invention

Claims (12)

An inclusion complex of cyclodextrin or cyclodextrin derivatives with butylphthalide, wherein the molar ratio of butylbutyride to cyclodextrin or cyclodextrin derivative is 1: 1-10 and comprises butylphthalide and cyclodextrin or cyclodextrin derivatives. The method of claim 1, An inclusion complex of cyclodextrin or cyclodextrin derivatives with butylphthalide, wherein buttalphthalide is a preferential, leciposity-mixed or lecithin butylphthalide. The method of claim 1, The cyclodextrin is an inclusion complex of a cyclodextrin or cyclodextrin derivative and butylphthalide selected from the group consisting of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. The method of claim 1, The cyclodextrin derivatives are hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, maltote Inclusion complex of butylphthalide with a cyclodextrin or cyclodextrin derivative selected from the group consisting of lyose cyclodextrin, carboxymethyl cyclodextrin and sulfonylalkyl cyclodextrin. The method according to claim 1 or 4, Inclusion complex of cyclodextrin or cyclodextrin derivative with butylphthalide, wherein the preferred cyclodextrin derivative is hydroxyethyl-β-cyclodextrin. Adding cyclodextrin or cyclodextrin derivatives in an appropriate solvent excipient to obtain a solution of 5-60% concentration, adding butylphthalide in the solution, liquid inclusion complex of cyclodextrin or cyclodextrin derivatives with butylphthalide Method for producing an inclusion complex of a cyclodextrin or cyclodextrin derivative and butylphthalide comprising the step of stirring to obtain. The method of claim 6, Drying the cyclodextrin or cyclodextrin derivative and the butylphthalide, and the liquid inclusion complex of the cyclodextrin or cyclodextrin derivative and butyl phthalide in order to obtain a solid inclusion complex of the cyclodextrin or cyclodextrin derivative and butyl phthalide Methods of Making Inclusion Complexes. The method of claim 6, Concentrating the liquid inclusion complex of cyclodextrin or cyclodextrin derivatives with butylphthalide to a solution of 10-15% (W / V) concentration, cooling to obtain white precipitate, and cyclodextrin or cyclodextrin derivatives with butyl A cyclodextrin or cyclodextrin derivative comprising a step of drying to obtain a solid inclusion complex of phthalide and a butyl phthalide containing method. Placing the cyclodextrin or cyclodextrin derivative in a colloid mill or grinder, adding an appropriate solvent excipient to obtain a paste, adding butylphthalide to the paste, filtering and cyclodextrin or cyclodextrin derivatives and butylphthal A method for producing an inclusion complex of a cyclodextrin or cyclodextrin derivative with butylphthalide, which comprises drying to obtain a solid inclusion complex of lead. Adding cyclodextrin or cyclodextrin derivative in an appropriate solvent excipient to obtain a solution of 5-60% concentration, dissolving butylphthalide in ethanol of 99% purity in an appropriate amount, mixing the two solutions, stirring And drying the cyclodextrin or cyclodextrin derivative with a butylphthalide to obtain a solid inclusion complex of the cyclodextrin or cyclodextrin derivative. The method according to any one of claims 6, 9 and 10, The appropriate solvent excipient is selected from water, ethanol, methanol, propanol, isopropanol, ethylene glycol, propylene glycol, glycerin or acetone or a mixture of any two or more of the above excipients, preferably with water, cyclodextrins or cyclodextrin derivatives Process for preparing inclusion complexes of butylphthalide. Liquid inclusion complexes of cyclodextrin or its derivatives with butylphthalide can be used directly to produce liquid dosage forms such as infusions, injections, injectable powders, liquids for oral administration, syrups, and the like; The solid inclusion complexes of cyclodextrins or derivatives thereof with butylphthalide can be used to produce solid dosage forms such as tablets, capsules, granules, dispersible tablets and the like.