LU87411A1 - AQUEOUS COMPOSITIONS CONTAINING A PIPERIDINYLCYCLOPENTYLHEPTENOIC ACID DERIVATIVE - Google Patents

Description

ί I

Aqueous compositions containing a derivative of piperidinylcyclopentylheptenoic acid

The present invention relates to aqueous compositions containing, as active ingredient, the acid β & -βa (Z), 2β, 3β, 5α7 ^ - (+) - 7 - /, 5-Z ~ Z ^ (1, 1 '-biphenyl) -4-yl7methoxy / -3-hydroxy-2- (1 -5 piperidinyl) -cyclopentyl7 * -4-heptenoic (which will be called hereinafter "compound A"), processes for the preparation of these compositions, as well as their use in the medical field.

Compound A is described in our British Patent No. 2097397 as being one of the substances belonging to a group of aminocydopentane derivatives having endo-peroxidic activity and thromboxane antagonist and it is reported therein that the compounds of these kinds are of interest for the treatment of asthma and of cardiovascular disorders · More recently, we discovered that the hydrochloride salt of compound A presented advantages compared to compound A 20 and other salts and solvates of the latter, both in terms of its preparation and its use in medicine. The hydrochloride salt is described in our British patent No. 2127406.

Unfortunately, Compound A is only only very poorly soluble in water and aqueous compositions which contain the chlor- *, 2 hydrate salt of Compound A together with conventional vehicles and / or excipients have been found to be unacceptable for intravenous administration, since the chlor-5 hydrate salt of compound A converts to virtually insoluble compound A near physiological pH.

We have now discovered that the water solubility of compound A or its hydrochloride salt can be improved considerably, near physiological pH, in the presence of a substituted α-, ß- or γ-cyclodextrin. unsubstituted (or a hydrate of this substance). We have also discovered that the aqueous compositions comprising compound A or the hydrochloride salt thereof and a substituted or unsubstituted α-, ß- or γ-cyclodextrin „(or a hydrate thereof) are suitable for use in medicine, more particularly for the treatment or prophylaxis of conditions caused by thromboxane A2 "when administered orally, by inhalation or parenterally, more particularly by injection (for example intravenous) .

Consequently, according to one of the characteristics of the present invention, we provide an aqueous composition comprising compound A or the hydrochloride salt thereof in combination with a substituted or unsubstituted α-, ß- or γ-cyclodextrin. substituted (or a hydrate thereof).

According to another characteristic of the present invention, we provide an aqueous composition as defined in the present memoirè for use in medicine, more particularly for the treatment or prophylaxis of conditions caused by thromboxane a2.

According to another of the features of the present invention, we provide a method of treating conditions caused by thromboxane 5 A2, according to which an effective amount of compound A is administered to a human or animal in the form of a composition. aqueous as defined in this specification.

Suitable conditions which can be treated with the aqueous compositions according to the present invention include those described in British Patents Nos. 2097397 and 2127406, treated using other (e.g. oral) compositions of compound A and the hydrochloride salt of compound A respectively. More particularly, the aqueous compositions according to the present invention can be used for the treatment or prophylaxis of occlusive vascular disorders, including myocardial infarction, sudden or acute heart failure, unstable angina pectoris , cerebral infarction and temporary or momentary ischemic attacks, atherosclerosis and disorders of the walls of the vessels, peripheral vascular disorders, retinopathies, postoperative thrombosis and pulmonary embolism. The aqueous compositions also find use for the prophylaxis of peri-and post-operative complications following organ transplants (in particular cardiac and renal), bypass of the coronary artery, bypass of a peripheral artery and thrombolysis.

The aqueous compositions are also of potential interest in relation to the disease represented by peptic ulcers, more particularly for the prevention of relapse of healed or healed peptic ulcers.

Preferably, compound A is used in the form of its hydrochloride salt in the aqueous compositions according to the present invention.

Those skilled in the art will appreciate that the advantages of the present invention can be achieved by using more than one cyclodextrin, although the use of a single cyclodextrin is generally preferred.

When a substituted cyclodextrin is used, any suitable substituted cyclodextrin, well known to those skilled in the art, can be used for the purposes of the present invention.

Substituted cyclodextrins suitable for use in accordance with the present invention can be readily determined by those skilled in the art and will include sulfur-containing cyclodextrins, nitrogen-containing cyclodextrins, alkylated cyclodextrins (e.g. methylated example), such as mono-, di- or trimethylated derivatives of a cyclodextrin (for example ß-cyclodextrin) and hydroxyalkyl (for example hydroxypropyl) cyclo-dextrins, such as hydroxypropyl ß-cyclodextrin and their derivatives acylated. Hydroxyalkyl (e.g. hydroxypropyl) cyclodextrins, such as hydroxypropyl β-cyclodextrin, have been found to be particularly well suited for use in accordance with the present invention.

An unsubstituted cyclodextrin according to the present invention is conveniently used. Most particularly advantageously, β-cyclodextrin is used, conveniently used in its hydrated form.

5

In order for the aqueous composition to exhibit the desired properties, it is important that the correct molar ratio of compound A or its hydrochloride salt with respect to the cyclodextrin (s) is used. We have discovered that a molar ratio of compound A or its hydrochloride salt with respect to cyclodextrin (s), varying from 11 to 1: 4 * is particularly suitable.

Those skilled in the art will understand that the aqueous compositions according to the present invention may, if desired, also contain one or more pharmaceutical excipients or carriers. Suitable excipients which can be incorporated into the aqueous composition include agents for rendering the preparation isotonic with blood plasma (e.g. sodium chloride, dextrose or, preferably, mannitol) and buffering agents (e.g. phosphate, or a mixture of sodium acid phosphate and disodium phosphate).

The aqueous compositions in accordance with the present invention are very particularly suitable for administration by the parenteral route, more particularly by injection (for example intravenous). When presented for parenteral administration, it is desirable that the composition has an approximately physiological pH. Therefore, it may prove to be appropriate to adjust the pH to around the physiological pH, using conventional means, for example using an appropriate base, such as a hydroxide (for example an alkali metal hydroxide, such as sodium hydroxide). The pH is conveniently adjusted to about 6.0.

6

For administration by the parenteral route, more particularly for administration by injection (eg intravenously), it is highly desirable to present the composition in the form of a clear solution. A clear solution does not require further processing (for example, making up a dry powder) and can be administered immediately. The use of a clear solution also ensures that the product can be easily inspected for the presence of any particles or any other visible contamination. In addition, intravenous injection of an aqueous solution of a drug can cause immediate physiological action.

We have found that at least one mole of cyclodextrin should be used for each mole of the hydrochloride of compound A, in order to obtain a clear solution near physiological pH, at normal storage temperatures and, in the case of of ß-cyclodextrin, at least about 1.2 moles of this compound should be used.

According to a preferred embodiment of the present invention, we therefore provide a clear aqueous composition comprising the hydrochloride salt of compound A and β-cyclo-dextrin (or a hydrate thereof), at about physiological pH, where the composition contains at least about 1.2 moles of β-cyclodextrin (e.g. 1.2 to 2 moles) for each mole of the salt hydrochloride of compound A. Preferably, the molar ratio is about 1: 1, 4.

The concentration of compound A or its salt hydrochloride in the above-mentioned aqueous compositions, suitable for parenteral administration, more particularly for administration by injection (eg intravenously), fluctuates appropriately in the range of 0.1 to 10 mg / ml, for example 0.1 to 5 mg / ml, these values being expressed in the form of the free base * Preferably, the concentration is 1 mg / ml, expressed in form of the free base, when the aqueous composition is administered by intravenous injection. If desired, a higher concentration can be used and the solution can be diluted, prior to use, with, for example, a mannitol or dextrose solution, or an isotonic saline solution. Conveniently, solutions suitable for injection are presented in a suitable dosing volume (eg 1 - 100 ml). Dilutions suitable for continuous infusion may have a concentration of compound A or its hydrochloride.

te salt from 0.01 to 0.2 mg / ml, expressed as the free base. The solution for continuous infusion can be presented in this form, for example in packages of 50 - 100 ml, or it can be presented in more concentrated forms intended for further dilution before use with, for example , a mannitol or dextrose solution, or an isotonic saline solution. Alternatively, smaller volumes of a more concentrated solution (eg 0.1 to 5 mg / ml) can be used for continuous infusion, conveniently administered at a rate of 0.5 to 9.9 ml / hour. The aqueous compositions described in the present specification can conveniently be prepared by mixing the compound A or, more advantageously, its hydrochloride salt, with the residual constituents, in water. Preferably, the compound A 35 or its salt hydrochloride is dissolved in water and the residual constituents are then added to it. For administration by the parenteral route, more particularly by injection (for example intravenously), the bulk solution is preferably filtered, then introduced into suitable containers and finally sterilized, for example under heating.

Alternatively, the solution can also be sterilized by filtration and then introduced into aseptic containers in suitable containers.

It should be understood that water suitable for injection should be used when the parenteral composition is to be administered intravenously or by continuous infusion.

Compositions for injection may be presented as a unit dose in suitable containers, such as ampoules, vials or pre-loaded syringes, or in containers which contain multiple doses, with added preservative.

As previously mentioned, the aqueous compositions according to the present invention are also suitable for administration by the oral route (for example in the form of a capsule, syrup or solution), or for administration by inhalation. (for example in the form of an aerosol spray conveniently presented in the form of a nebulizer). British patents Nos. 2097397 and 2127406 describe suitable general methods of preparing compositions suitable for oral and inhalation administration, which can be readily adapted without undue experimentation, for the purposes of the present invention.

Aqueous compositions can also be prepared by dissolving a complex of compound A or of its hydrochloride salt with cyclodextrin, solid 9, in water, together, when this proves desirable, with one or more other constituents as defined previously.

Therefore, according to another of the features of the present invention, we provide an aqueous composition comprising a complex of compound A or its hydrochloride salt and a cyclodextrin.

According to yet another characteristic of the invention, we provide a complex of compound A or its hydrochloride salt and a cyclodextrin. The ratio of compound A or the hydrochloride salt of compound A to the cyclodextrin in the complex will obviously vary considerably depending on the cyclodextrin used and the conditions used for the preparation of the complex. However, we have found that a molar ratio of compound A or its salt hydrochloride to cyclodextrin varying from 1: 1 to 1: 3 is perfectly suitable.

The cyclodextrin used in the solid complex can be a substituted or unsubstituted α-, ß- or γ-cyclodextrin, as defined above, or it can be a mixture of cy-25 clodextrins of this kind (for example a mixture of two of these cyclodextrins). Preferably, γ-cyclodextrin is used or, more advantageously still, ß-cyclodextrin.

According to a very particular feature of the present invention, we provide a complex of compound A and ß-cyclodextrin, where the molar ratio of compound A to ß-cyclodextrin fluctuates from 1: 1 to 1: 2 and is preferably about 1: 1.

According to yet another feature of the present invention, we provide a complex of compound A and γ-cyclodextrin, where the molar ratio of compound A to γ-cyclodextrin is about 11.5.

5 Complexes of compound A can be prepared

or the hydrochloride salt thereof and cyclo-dextrin by mixing the compound A or its hydrochloride salt with the cyclodextrin (s) or a hydrate thereof, in an appropriate solvent and under conditions according to which the desired complex is formed. Thus, for example, the complexes can be prepared by dissolving compound A or its hydrochloride salt in water or an organic solvent which is miscible with water (eg an alcohol, such as methanol) and adding , to the solution, a solution of the appropriate cyclodextrin (s) or a hydrate of these in water and / or an organic solvent which is miscible with water. The reaction can take place at a temperature which fluctuates from 0eC to 80 ° C; however, the mixture is preferably maintained at about room temperature and the desired complex is collected by concentrating the mixture under reduced pressure, or allowing the mixture to cool. The mixing ratio of organic solvent and water can vary considerably depending on the solubilities of the products and starting materials. Preferably, 1 to 4 moles of cyclodextrin are used for each 30 moles of compound A or of its hydrochloride salt.

The resulting complexes can be obtained as white solids with high thermal stability and good solubility in water. Such physical characteristics make them very particularly suitable for producing pharmaceutical preparations intended for medical use. In addition to the above-mentioned aqueous compositions of complexes of compound A or its hydrochloride salt and of 5-cyclo dextrin, which are particularly suitable for administration by the parenteral route, the complexes can also be put into compositions suitable for administration by orally or parenterally or by administration by inhalation, in accordance with the general methods described in British Patent Nos. 2097397 and 2127406.

A suitable daily dose regimen for compound A or its hydrochloride salt, when used in one of the compositions according to the present invention, will, of course, depend on the specific disorder to be treated, the age and condition of the patient and method of administration. However, overall, the doses indicated in British patents Nos. 2097397 and 20 2127406 are perfectly suitable.

The following examples are included to illustrate the present invention and should not be taken as limiting the latter. In the examples below, the molar ratios were determined by nuclear magnetic resonance analysis H and all temperatures therein are indicated in eC.

Example 1 a) Complex 1: 1 / ÎR- / Tg (z), 2ß, 3ß, 5 <^ _ 7 - (+) - 7- / 5-30 / “" / Cl, 1 '-biphenyl) -4- yl / methoxy7-3-hydroxy-2- (1 - piperidinyl) cyclopentyl / -4-heptenoate; ß-cyclo-dextrin

Hydrated β-cyclodextrin (0.954 g) was almost completely dissolved in water (35 ml). The suspension was filtered and the filtrate was added to a solution of compound A (0.2 g, example 10 in GB-B-2097397) in methanol (10 ml). The reaction solution was stirred at 21 ° for 26 hours to obtain a clear solution which was evaporated to a volume of 12 ml at which slight crystallization began to appear. The suspension was cooled to 5 ° for 1 hour to produce a thick precipitate which was filtered off and dried to collect the title compound (0.275 g), having a point greater than 310 °, sinking above 230 °.

b) The filtrate of the above-mentioned experiment began to allow more crystalline material to precipitate upon standing and was therefore evaporated so as to leave a white solid which was dissolved in hot water (3 ml), solution which was cooled (5th) and left to crystallize to collect a white crystalline solid (121 mg)

AT

20 including analysis by R.M.N. H (dimethyl sulfoxide) revealed that it contains the complex (1: 1.5) -ZÎR- / Ta (Z), 2β, 3β, 5α7_7 - (+) - 7-Ζ5-Ζ “ΖΓΐ, 1 ' -biphenyl) - 4-yl / methoxy / -3-hydroxy-2- (1-piperidinyl) -cyclo-pentyl / -4-heptenoate: ß-cyclodextrin.

25

Example 2

Complex (1: 1 »5) / TR- ^ Tg (Z), 2β, 3β, 5α717 -» (+) - 7- / 5 - / “ZT1,1 * -biphenyl) -4-yl / m thoxjJ- 3-hy droxy-2- (1 -piperidinyl) cyclopentyl7-4-heptenoate: γ-cyclo-30 dextrine

A solution of γ-cyclodextrin (1.09 g) in water (25 ml) was added to a solution of compound A (0.20 g) in methanol (10 ml). The reaction solution was stirred at 21 · for 26.35 hours to form a thick white suspension 13. The precipitate was separated by filtration and dried in vacuo so as to leave the title compound, in the form of a white solid (0.612 g), having a melting point above 310 ° C, sinking beyond 250 ° C.

Pharmaceutical examples of parenteral infusions / inections 10 (i) Hydrochloride salt of compound A equivalent to 50 mg of base ß-cyclodextrin hydrate 143 mg 166 mg 238 mg 15

Hydroxide solution juice- juice-juice- 2 * 7 Th 7 2h7

Water suitable for infusion- juice- juice- 20 jection 50 mi 50 ml 50 ml

The hydrochloride salt of compound A was dissolved in 35 ml of water suitable for injection and β-cyclodextrin was added. This solution was titrated to pH 7 with 0.02 M sodium hydroxide solution and then adjusted to volume with water suitable for injection.

The solution can then be sterilized by filtration and introduced into vials or vials.

(14) hydrochloride salt of compound A equivalent to 50 mg of base 5 ß-cyclodextrin hydrate 166 mg

Sodium chloride 450 mg

Phosphate buffer pH 7.0 2.5 ml

Sodium hydroxide solution up to pH 7

Water suitable for 1 * injection up to 50 ml

The hydrochloride salt of compound 15 A was dissolved in approximately 25 ml of water suitable for injection. The β-cyclodextrin was dissolved in the above solution and the resulting solution was titrated to pH 6 with 0.02 M sodium hydroxide solution and the tam-pon was added to the phosphate. Sodium chloride was added to the solution and the pH was adjusted to 7 with sodium hydroxide. The solution was brought to volume with water suitable for injection. A sample of this solution was introduced into a glass vial which was sealed with a rubber stopper and a metal cap. This vial was then autoclaved.

(Iii) Hydrochloride salt of compound A equivalent to 50 mg of base

Hydroxypropyl-ß-cyclo dextrin 170 mg 35 Mannitol 2.5 g

* I

15

Phosphate buffer pH 6.0 5.0 ml

Sodium hydroxide solution up to pH 6 5 Water suitable for injection up to 50 ml

The hydrochloride salt of Compound A was dissolved in approximately 25 ml of water suitable for injection and hydroxypropyl-β-cyclodextrin was added thereto. The mannitol was then added and the solution was titrated to pH 6 with 0.02 M sodium hydroxide solution. The tanqpon solution was added to the phosphate and the volume of the solution was adjusted. solution with water suitable for injection. The solution was then filtered and placed in glass vials which were sealed with rubber stoppers and metal capsules. These vials were then autoclaved.

(iv) hydrochloride salt of compound A equivalent to 50 mg of base 25 ß-cyclodextrin hydrate 166 mg

Mannitol 2.5 g

Sodium acid phosphate 46 mg

Disodium phosphate, anhydrous 5 mg 30 Sodium hydroxide solution up to pH 6

Water suitable for injection up to 50 ml The hydrochloride salt of compound 16 A was dissolved in approximately 25 ml of water suitable for injection, ß-cyclodextrin and mannitol were dissolved in the above solution and the solution was titrated to a pH of 6 with a 0.02 M sodium hydroxide solution. The sodium acid phosphate and anhydrous disodium phosphate were dissolved in water suitable for injection. This solution was added to the previous solution and made up to volume with water suitable for injection. The solution was filtered and placed in glass ampoules which were sealed and then autoclaved.

17

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The salt hydrochloride of compound A was dissolved in approximately 25 ml of water suitable for injection and the cyclodextriene (s) was added thereto. The mannitol was then added and the solution was titrated to pH 6 with 0.02 M sodium hydroxide solution. The solution was added to the phosphate buffer and the volume of the solution was adjusted. solution with water suitable for injection. The solution was then filtered and placed in glass vials which were sealed with rubber stoppers and metal capsules.

Pharmaceutical example of oral syrup 15 Hydrochloride salt of compound A equivalent to 2.5 mg of base ß-cyclodextrin hydrate 9 mg 20 Citric acid up to pH 4.5

Sodium methyl hydroxybenzoate 5 mg

Sodium propyl hydroxybenzoate 2 mg 25 Liquid orange essence qs

Sucrose 3 »25 g

Purified water up to 5.0 ml

Sucrose must be dissolved in the minimum amount of water. Add the hydrochloride salt of compound A and then the ß-cyclodextrin, with stirring; adjust the pH to 4.5 with citric acid. With continuous stirring, a solution of the hydroxybenzoates and, finally, the gasoline must be added. It is necessary to bring practically to volume by adjustment with water and to agitate. The pH should be checked and adjusted to 4.5 with citric acid if necessary. Then make up the volume with water.

Pharmaceutical example of solution for inhalation

Per 2 ml dose

Hydrochloride salt of compound A equivalent to 2 mg of base ß-cyclodextrin hydrate 7 mg

Sodium chloride 18 mg 15 Sodium hydroxide solution up to pH 7.2

* PH 7.2 phosphate buffer 0.2 ml

Water suitable for injection up to 2 ml

Dissolve the hydrochloride salt of compound A in water suitable for injection. The β-cyclodextrin must then be dissolved therein and the solution thus obtained filtered down to a pH of 6 with a sodium hydroxide solution; add phosphate buffer solution. Add sodium chloride and adjust the pH to 7.2 with sodium hydroxide solution. The solution must be brought to volume with water suitable for injection and the solution must be sterilized by filtration. The solution in question should be aseptically introduced into containers suitable for nebulization inhalation.

Claims (13)

1 * 20 1. Aqueous composition comprising the acid ZTR-Z (<r (2), 2ß, 3ß, 5o7_7 - (+) - 7-ß-f / Jl, 1 '-biphenyl) - 4-yl / methoxy / -3 -hydroxy-2- (1-piperidinyl) cyclopentyl7-4-heptenoic (compound A) or the hydrochloride salt thereof, in combination with an unsubstituted or substituted α-, βοή y-cyclodextrin or a hydrate of the latter. 2. Composition according to claim 1, 10 characterized in that compound A is used in the form of its hydrochloride salt. 3. Composition according to any one of claims 1 and 2, characterized in that the cyclodextrin is ß-cyclodextrin. 4. Composition according to any one of the preceding claims, characterized in that it is in a form suitable for injection. 5. A clear aqueous composition according to claim 4, comprising the hydrochloride salt of compound A and β-cyclodextrin or a hydrate thereof, at about physiological pH, characterized in that the composition contains at least about 1.2 moles of ß-cyclodextrin for each mole of the hydrochloride salt of compound A. 6. Composition according to claim 5, characterized in that the molar ratio of the hydrochloride salt of compound A to ß-cyclodextrin is approximately 11.4 · 7. Composition according to any one of claims 4 to 6, characterized in that the pH is around 6.0. oh. Composition according to any one of Claims 4 to 7, characterized in that it also comprises sodium hydroxide. L * 21 9. Composition according to any one of claims 4 to 8, characterized in that it has a concentration of compound A or of hydrochloride salt thereof of 0.1 to 5 mg / ml, this concentration being expressed as form of the free pole. 10. Composition according to any one of claims 4 to 8, characterized in that it is in a form suitable for continuous infusion, having a concentration of compound A or hydrochloride salt thereof, of 0.01 at 0.2 mg / ml, this concentration being expressed in the form of the free base. 11. A method of preparing a composition according to any one of the preceding claims, characterized in that compound A or its salt hydrochloride is mixed with the residual constituents in water. 12. Complex of compound A or of its chlor-20 hydrate salt and of an unsubstituted or substituted α-, ß- or y-cyclodextrin. 13. Complex of the designed> A and of ß-cyclo-dextrin, characterized in that the molar ratio of compound A to β-cyclodextrin is approximately 1: 1.