CS227689B2 - Manufacture of closed complexes of n-/1-phenylethyl/-3,3diphenylpropylamine or its hydrochloride with cyclodextrine - Google Patents

Description

The present invention relates to a process for the preparation of closed complexes of N- (1-phenylethyl) -3,3-diphenylpropylamine or its cyclodextrin hydrochloride.

N- (1-phenylethyl) -3,3-diphenylpropylamine (hereinafter called fendilin) is an active substance that enlarges the coronary arteries and acts opposite to calcium. Its preparation is described in Hungarian patent specification 150 334. The substance is an oily liquid whose salt, hydrochloride, is known as a medicament under the commercial name Sensit. The solid medicament form can only be made from the hydrochloride. Fendil hydrochloride is poorly wetted with water. The substance is highly hydrophobic. The rate of resorption of fendilin and the rate of resorption are not sufficient.

SUMMARY OF THE INVENTION It was an object of the present invention to provide a process by which fendiline and its hydrochloride can be converted into a form that dissolves faster and better, thereby improving the rate and rate of absorption.

It has been found that when fendiline or its hydrochloride is converted into a closed complex with cyclodextrin, the complex thus obtained dissolves at a pH corresponding to the pH of the stomach acid and at its temperature much faster and at a higher concentration than the parent molecule. '

As is known, cyclodextrin molecules have the shape of a cylindrical molecule with an internal apolar surface and can therefore bind hydrophobic molecules in the form of a closed complex. Such a hydrophobic molecule may be a molecule of fendilin or its hydrochloride, which is very sparingly soluble in water.

It has been found that if fendiline is reacted with a cyclodextrin, it will form two

cyclodextrin molecules with one fendilin molecule closed complex, which surprisingly loses in aqueous solution of hydrochloric acid, corresponding to the pH value of gastric acid, one of the cyclodextrin molecules and turns into a rapid dispersion at a high rate. Thus, better solubility and thus better bioavailability can be observed.

When the cyclodextrins and fendiline are mixed vigorously in an aqueous and / or ethanolic environment, the fendilin molecule displaces the water molecules located in the inner cavity of the cyclodextrin, causing apolar-apolar interaction to form a closed complex.

This intensive method of dissolving the closed complex that can be formed with a cyclodextrin, combined with salt formation and partial elimination _; cyclodextrin is new.

The process according to the invention is characterized in that the base of N- (1-phenylethyl) -3,3-diphenylpropylamine or its hydrochloride is reacted in an aqueous and / or ethanolic medium with stirring at 4 to 60 ° C with 1 ° C. 3 mmol of cyclodextrin, calculated on 1 mmol of base or hydrochloride, and, for the production of hydrochloride, the complex obtained is optionally treated with hydrochloric acid.

The foreign molecule is ionized in a closed complex formed from a cyclodextrin and a non-ionic foreign molecule, resulting in a high charge intensity and hydrated state due to the ionic bond, whereupon the cyclodextrin coating is reflected off the foreign-molecule. water and having a crystalline lattice structure, converts to an ionic state, explosively disintegrates the granules of the crystal and becomes a molecular dispersed state and thus the total amount is dissolved.

The molecular structure thus formed is relatively well soluble, since one end of the molecule is hydrated due to ionization and the other end 'which is also strongly apolar and induces a heavy solubility of the molecule - is externally coated with a hydrophilic cyclodextrin ring.

Fendiline is insoluble in water, but its hydrochloride is extremely difficult to dissolve. When the free base is treated with hydrochloric acid, the strongly hydrophobic hydrochloride formed on the surface of the oil droplets of the base prevents dissolution and even further salt formation. When the fendilin molecule forms a closed complex with the two cyclodextrin molecules, a crystalline base, relatively slightly soluble in water, is obtained.

However, if this closed complex enters an acidic environment (for example, stomach acid), then the nitrogen atom of fendilin is ionized by receiving a proton and bounces off the cyclodextrin ring located near the nitrogen atom. As a result, a structure is formed in which the ionic phenylethylamine portion of fendilin is found to be free and for the most part hydrated and the apolar diphenylpropyl group forms a complex with the cyclodextrin molecule. Thus, the 2: 1 complex forms a 1: 1 complex in an acidic environment, i.e. the complex of fendilin with cyclodoxtrin becomes very rapidly in the acidic state into a molecular dispersed state, i.e. the complex dissolves.

The cyclodextrin-fendilin complex as well as its hydrochloride dissolves well in water. A complex with a 2: 1 molar ratio of the base form as well as a complex with a 1: 1 molar ratio of hydrochloride (active ingredient content of 11% or 21% on average) dissolves much better than fendiline hydrochloride and biological activity is much stronger .

To determine the biological activity, it was examined to what extent the release and resorption of fendilin and fendiline hydrochloride under in vitro conditions was affected by the enclosure of the drug with cyclodextrin.

The in vitro tests were justified by the fact that the measurements carried out in this way are easier to reproduce and the scatter is less than if the measurements were made in vivo.

Release and resorption are successive, largely and interdependent processes. Under physiological conditions, resorption is strongly influenced both by the pH ratios prevailing at the resorption site and by the residence time of the drug at the resorption site.

The mean residence time and pH of several sections of the stomach and intestine system are as follows:

in the stomach in the initial small intestine section in the other small intestine sections

0-30 minutes pH = 1.2 30-60 minutes PH = 5-6. 60-360 minutes PH = 6-7

Experiments were carried out accordingly.

The resorption tests were carried out with the Sartorius SM 16750 resorption model tool, by means of which the resorption taking place in the stomach and intestines can be modeled very well with the membranes used. The diffusion rate constant (K i) and the resorption rate constant (K i) on the test substance were calculated based on the results of the tests performed. The results are shown in the table.

Table

Substance 2 - 1 / cm min / from the stomach Χ _χ / min ¹ / from intestine fendilin 6.9x10 5.lx10 ^-3 fendilin-beta-cyclodextrin complex 1.42X1O ^-3 1.24x10 ^-2 fendilin hydrochloride 6.7x10 ^-4 4.9x10 ^-3 fendilin hydrochloride complex with beta-cyclodextrin 1.71X1O ^-3 1.52x10 ^-2

In intestinal resorption, the value as well as the value is increased by more than 100% by complexing.

Determination of dissolved (M < 4 >) and resorbed (M < 4 >) amount of drug was performed with a Sartorius SM 16751 / H dissolution modeling tool. Stricker: Pharm. Indian. 22 '157 (1971)] H. Stricker: Drugs in Germany 14, 93 (1971).

The time dependence of the release of fendilin and fendilin-cyclodextrin complex in the individual gastric-intestinal sections is shown in Diagram 1, where F shows the release of fendilin, the F-CD release of the fendilin-cyclodextrin complex.

The base amount of fendilin released from the intestine at 100 minutes is 75 mg, while the amount of fendilin-cyclodextrin complex is 150 mg.

The resorbed amount of fendilin or cyclodextrin-fendilin hydrochloride complex and fendilin hydrochloride-cyclodextrin complex from the gastrointestinal tract is shown in Figure 2, where F refers to the resorbed amount of fendilin, F-CD to the amount of fendilin-cyclodextrin complex, the amount of fendiline hydrochloride and FHCl-CD to the amount of fendiline hydrochloride-cyclodextrin complex.

In accordance with the release values, the amount of active substance resorbed from the intestinal tract in the case of the base and the salt increased to nearly twice as a result of the complex formation. Thus, about half the dose is required to achieve the same effect.

During toxicological experiments, acute toxicity of fendilin or fendilin hydrochloride cyclodextrin complex and fendilin hydrochloride or cyclodextrin complex intraperitoneally in mice was investigated.

The substances to be tested were administered with 5% Tween 80 to 10 male and 10 female mice in each group. When complexes were used, the doses were converted to the active substance fendilin. The results are summarized in the table below:

• Intraperitoneal use

observation time LD ₅₀ mg / kg fendilin 24 hours 47.54 fendilin-cyclodextrin complex 24 hours 157.47 fendilin hydrochloride 1 hour 81.14 fendilin hydrochloride complex with cyclodextrin 1 hour 160.55 Oral use fendilin ’ 72 hours 512.41 fendilin-cyclodextrin complex 72 hours 624.65 fendilin hydrochloride 24 hours 522.24 fendilin hydrochloride complex with cyclodextrin 24 hours 954.88

The fendilin-cyclodextrin complexes produced according to the invention are white, powdered microcrystalline substances which can be used as active ingredients of pharmaceutical preparations. These preparations contain, in addition to an effective amount of the fendilin-cyclodextrin complex as active ingredient, optionally pharmaceutically acceptable inorganic and organic carriers.

The preparations may be administered in the form of tablets, dragees, capsules, or syrup, etc. The preparations contain the active ingredient mixed with diluents, lactose, dextrose, sucrose, glycine and / or glidants such as kieselguhr, talc, stearic acid and its salts with polyethylene glycol. , binders, fillers, colorants, flavor enhancers, etc. The preparations may contain / optionally other biologically active substances. The preparations can be prepared by known tableting, granulating and homogenizing methods. The active ingredient content is about 10 to 40%. The dosage depends on various factors such as the type of administration, the condition and age of the patients.

Further details of the invention can be seen from the examples below.

EXAMPLE 1 g (7.5 mmol) of beta-cyclodextrin containing 15% water are suspended at room temperature in 40 ml of water and 0.96 g (3 mmol) of phendoline in 2 ml of 96% by volume of ethanol is added dropwise with vigorous stirring. The suspension was stirred for an additional 5 hours, filtered and dried.

9.2 g of a fendilin-beta-cyclodextrin complex containing 9.7 wt. fendillnu. The product is a white powder which shows no characteristic melting point.

«

Determination of fendilin content in the complex:

0.05 g of product is dissolved in 25 ml of 50% v / v. % ethanol and the product was photometrized at 258 nm against 50% v / v. % ethanol. The fendilin content is determined by a calibration curve.

Example 2

26.8 g of beta-cyclodextrin (20 mmol) containing 15% of water are dissolved in a mixture consisting of 350 ml of water and 50 ml of 96% (v / v). % ethanol at 60 [deg.] C. and a mixture consisting of. 3.15 g (10 mmol) fendilin and 40 ml 96% v / v % ethanol. The mixture was cooled to room temperature over 6 hours and allowed to stand overnight at + 4 ° C. The precipitated crystalline product is filtered off and air-dried. 28.4 g of a fendilin-beta-cyclodextrin complex are obtained, which contains 10.7% by weight of fendilin. fendilin.

Example3

13.3 g (10 mmol) of beta-cyclodextrin containing 15% water are suspended in 10 ml of distilled water in a mortar. A solution of 1.55 g (5 mmol) of fendilin in 5 ml of 96% ethanol was added. A diluted suspension is obtained which is homogenized by continuous trituration. After about 30 minutes, the slurry has a consistency of ointment, which is spread in a desiccator and dried for 24 hours over phosphorus pentoxide. The solvent-free complex is powdered.

12.5 g of fendilin-beta-cyclodextrin complex are obtained. Fendilin content: 11.8 wt

Example 4

2.1 g (1.4 mmol) of gamma-cyclodextrine containing 15% water are dissolved in 15 ml of water at 40 ° C. While stirring, a mixture of 0.158 g (0.5 mmol) of fendilin in 1 ml of ethanol is added dropwise. Crystallization can already be observed during the addition. The suspension was cooled to room temperature over 2 hours and allowed to stand overnight at + 4 ° C. After filtration and air-drying, 0.66 g of fendilin-gamma-cyclodextrin complex is obtained, fendilin content: 11.3% by weight.

Example 5

Dissolve 1.0 g (1.0 mmol) of alpha-cyclodextrin containing 3.3% of water in 40 ml of distilled water. While stirring, a mixture consisting of 0.158 g (0.5 mmol) of fendilin in 1 ml of 96% (v / v) was added dropwise. % ethanol. Solid crystals precipitate during the addition. The suspension was cooled to room temperature over 2 hours and allowed to stand overnight at +4 ° C. The mixture was filtered and dried.

0.5 g of fendilin-alpha-cyclodextrin complex is obtained, having a fendilin content of 12.2% by weight.

Example

1.8 g of cyclodextrin mixture, containing 11% water / composition based on dry matter content determined by HPLC: 70% beta-cyclodextrin, 20% gamma-cyclodextrin, 10% alpha-cyclodextrin, average molecular weight: 1151, number of molecules: 1.4) are dissolved in 20 ml of distilled water and 3 ml of 96% v / v. % ethanol. With vigorous stirring, a mixture of 0.22 g (0.7 mmol) of fendilin in 2 ml of 98% v / v is added dropwise. % ethanol. The mixture was cooled to room temperature over 3 hours and allowed to stand overnight at + 4 ° C. The precipitated crystalline product is filtered off and air-dried.

1.3 g of product are obtained, the fendilin content of 1.1.0% by weight.

EXAMPLE 7 g (3 mmol) of .beta.-cyclodextrin containing 15% water are dissolved at 60 DEG C. in 35 ml of water. With stirring, 1.05 g (3 mmol) of phendilin hydrochloride dissolved in 8 ml of 96% (v / v) was added dropwise. The mixture was cooled to room temperature over 5 hours and allowed to stand at 4 ° C overnight. The precipitated white crystal of the substance was filtered off and dried, yielding 3.3 g of com-air-dried pendocyclodextrin p-cyclodextrin plexide with an air-dried content of fendilin hydrochloride: 22.2% by weight.

Example

13.4 g (10 mmol) of β-cyclodextrin containing 15 S of water are dissolved in a mixture consisting of 160 ml of water and 10 ml of 1N hydrochloric acid at 50 ° C. A solution of 3.15 g (10 mmol) of fendilin in 30 ml of 96% (v / v) was added. * / ethanol. The mixture was cooled to room temperature over 4 hours and allowed to stand overnight at 4 ° C. The precipitated crystalline material is filtered off and dried. 11.2 g of a complex of fendiline hydrochloride with beta-cyclodextrin are obtained with a fendiline hydrochloride content of 20.5% by weight.

Example 9

5.0 g of the fendilin-beta-cyclodextrin complex produced according to Example 2 (fendiline content 10.7% w / w) are dissolved in a mixture consisting of 35 ml of water and 2 ml of 1N hydrochloric acid at 37 ° C. The solution was allowed to stand for 24 hours and the precipitated crystalline material was filtered off. 2.0 g of fendilin-beta-cyclodextrin complex containing 21.2 wt. fendilin hydrochloride.

Example 10

Demonstration of the complex structure of the product produced according to Example 1 by X-ray diffraction i

The characteristic reflection maxima (peaks) appear at significantly different 2 G ° angles on the X-ray diffractogram and this indicates a different crystalline structure. Since the molecule enclosed in the complex is liquid, a different crystal structure confirms the formation of the complex.

Testing of the product prepared according to Example 1 by thermoanalytical methods! .

The ferroanalytical tests show substantial differences between the fendilin-beta-cyclodextrin complex and the physical mixture of fendilin-beta-cyclodextrin. Evaporation of fendilin or its decomposition begins at 150 ° C and 98% mass change can be observed up to 250 ° C. The cyclodextrin decomposes starting at 250 ° C and the beta-cyclodextrin melts at 300 ° C with decomposition.

The physical mixture loses the water contained in the cyclodextrin at 100 ° C and the fendiline contained at temperatures between 150 to 250 ° C.

The active substance is released from the complex only simultaneously with the decomposition of the cyclodextrin, that is at 270 to 300 ° C. Thermoanalytical assays indicate that fendiline forms a complex with a beta-cyclodextrin at a molar ratio of 1: 2. With an excess of fendilin, the excess of fendilin behaves as in the physical mixture, thus decomposition begins at 150 to 250 ° C.

Example 11

Solubility test of fendilin hydrochloride-beta-cyclodextrin complex prepared according to Example 7:

In 10 ml of water at 37 ° C, the fendilin hydrochloride-beta-cyclodextrin complex is dissolved in an amount corresponding to 200 mg of the active substance fendilin and stirred with a magnetic stirrer at 150 rpm.

The active substance content of the sample is determined by the spectrophotometric method.

The results of dissolution rate testing are summarized in the following table:

minute time fendilin-beta-cyclodextrin complex fendilin concentration mg / ml

1 13.3 5 12.7 15 Dec 12.9 30 12.8 60 13.3 120 14.6

Determination of the composition of the fendilin-beta-cyclodextrin complex produced according to Example 7:

Phendiline hydrochloride (0.22 g, 0.6 mmol) was stirred with magnetic stirring in 3 ml of water or in beta-cyclodextrin solutions of various concentrations for 3 hours. The concentration of dissolved fendilin hydrochloride is determined spectrophotometrically and expressed in fendilin equivalents. The test results are summarized in the following table:

concentration concentration of beta-cyclodextrin mmol beta-cyclodextrin fendilin fendilin mmol

mg / ml mmol / l mg / ml mmol / l 15 Dec 13.2 4.39 13.9 0.95 20 May 17.6 5/95 18.5 0.95 25 22.0 6.94 22.0 1.00 30 26.4 7.51 23.8 1.10

The beta-cyclodextrin mole / fendilin molar quotient value in the last column of the table clearly shows that fendiline hydrochloride forms a 1: 1 molar ratio with beta-cyclodextrin.

Example 12

Preparation of the preparation by tabletting the complex of fendilin with beta-cyclodextrin, prepared according to example 3:

fendilin complex with beta-cyclodextrin 398 g magnesium stearate 5 g colloidal silicic acid 7 g microcrystalline cellulose / Avicel PH 102/90 g

The above ingredients are mixed, homogenized and compressed into tablets having an average weight of 500 mg and a diameter of 13 mm.

The tablets contain an average of 45 mg fendilin, equivalent to 50 mg fendilin hydrochloride.

Thus, in the case of a tablet containing 50 mg of fendilin hydrochloride, this tablet contains an equivalent amount of the active ingredient.

Example 13

Production of syrup from fendilin-beta-cyclodextrin complex produced according to example 3i fendilin-beta-cyclodextrin complex 5 g methyl-p-oxybenzoate 0.1 g flavoring 0.5 g carboxymethylcellulose sodium 0.9 g microcrystalline cellulose / Avicel ŘC / 1 , 1 g sorbitol 35.0 g distilled water ad 100 ml

The sodium carboxymethylcellulose is dissolved in about half of the water, the microcrystalline cellulose is suspended in the solution, and after swelling of the suspension, the complex of fendilin with beta-cyclodextrin is mixed. Methyl p-oxybenzoate, flavor and sorbitol are dissolved in the remaining amount of water and the solution thus obtained is added to the above suspension. Make up to 100 ml with distilled water and homogenize the suspension.

Claims (12)

Process for the production of closed complexes of N- (1-phenylethyl) -3,3-diphenylpropylamine or its hydrochloride with cyclodextrin, characterized in that the base of N- (1-phenylethyl) -3,3-diphenylpropylamine or its hydrochloride is left reacted in an aqueous and / or ethanolic medium with stirring at 4 to 60 ° C with 1 to 3 mmol of cyclodextrin, calculated on 1 mmol of base or hydrochloride, and, for hydrochloride production, the complex obtained is optionally treated with hydrochloric acid. 2. A process according to claim 1, wherein N- (1-phenylethyl) -3,3-diphenylpropylamine and cyclodextrin are used in a molar ratio of 1: 3. 3. The process of claim 1, wherein N- (1-phenylethyl) -3,3-diphenylpropylamine and cyclodextrin are used in a molar ratio of 1: 1. 4. The process of claim 1, wherein N- (1-phenylethyl) -3,3-diphenylpropylamine hydrochloride and cyclodextrin are used in a molar ratio of 1: 1. Process according to one of Claims 1 to 4, characterized in that the reaction is carried out in an aqueous medium, in the presence of 1 to 20 ml of water, calculated on 1 mmol of cyclodextrin. Process according to one of Claims 1 to 4, characterized in that the reaction is carried out in an aqueous-ethanolic medium containing 5 to 32% by volume of water. 7. The process of claim 1 wherein the reactants are N- (1-phenylethyl) -3,3-diphenylpropylamine and cyclodextrin. 8. A process according to claim 1, wherein N- (1-phenylethyl) -3,3-diphenylpropylamine hydrochloride and cyclodextrin are used as reactants. 9. The process of claim 1, wherein the complex formation is carried out with in situ formed N- (1-phenylethyl) -3,3-diphenylpropylamine hydrochloride. 10. The method of claim 1 wherein the cyclodextrin is alpha-cyclodextrin. 11. The process of claim 1 wherein the cyclodextrin is beta-cyclodextrin. IN 12. The method of claim 1, wherein said method is cyclodextrin. gamma-cyclodextrin.