IE44387B1 - Delayed-action hypotensive pharmaceutical compositions - Google Patents

Abstract

1521594 Pharmaceutical compositions ROUSSEL UCLAF 21 Sept 1976 [22 Sept 1975] 39109/76 Heading A5B A delayed-action, hypotensive, pharmaceutical composition comprises (A) 1-(2, 6-dichlorobenzylidene-amino)-3-hydroxy-guanidine and/ or an acid addition salt thereof and (B) a wax comprising mixed C 18 -C 39 fatty acids esterified with a C 2 -C 6 diol.

Description

This invention relates to delayed-action, hypotensive pharmaceutical compositions.

It is known that the absorption of pharmaceuticals by the system varies in duration and degree according to the route of administration. In the most favourable cases fast absorption results in quick activity which last: a few hours.

In order to spread this activity over a period of time, various methods have been employed. Thus, for example, the size of the particles of the active ingredient can be modified and/or the latter can be coated or incorporated in an appropriate spbstance.

Moreover, in the field of hypotensive agents, it is particularly useful to obtain products which work over longer periods of time and of which the action is as constant as possible, since the complaint to be treated most frequently’ requires therapy which is uninterrupted over a long period of time.

According to one feature of the present invention delayed-action hypotensive there are provided/pharmaceutical compositions comprising I l-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine or a physiologically compatible acid addition salt thereof and a xvax comprising a mixture of fatty acids each containing - 2 4438 from 18 to 39 carbon atoms esterified with a diol containing from 2 to $ carton atoms. 1-(2,6-Dichlorobenzylidene-amino)-3-hydroxy-guanidine is a known hypotensive agent which is described, for example, in French Patent Specification No. 2,000,512.

The addition salts which may be employed in the compositions according to the invention can be formed with mineral or organic acids. Suitable salts include, for example, the hydrochloride, hydrobromide, hydriodide, nitrate, sulphate, phosphate, acetate, formate, benzoate, maleate, fumarate, succin ate, tartrate, citrate, oxalate, glyoxylate and aspartate, an alkanesulphonate e.g. methanesulphonate and arylsulphonate e.g. benzenesulphonate.

The fatty acids are preferably selected from octadecanoic, nonadecanoic, eicosanoic, heneicosanoic, docosanoic, tricosanoic, tetracosanoic, pentacosanoic, hexacosanoic, heptacosanoic, octacosanoic and nonacosanoic acid. Also preferred are compositions wherein the fatty acids each contain from 22 to 39 carbon atoms. Especially preferred are those compositions^ containing esterified nonacosanoic acid.

The fatty acids are esterified with a diol of low molecular weight such as, for example, 1,2- or 1,3-propane-diol, 1,3- or 2,3-butane'-diol or, preferably ethane-diol.

' S»- The wax sold by the company Farbwerke Hoechst under the description ester E wax (wax based on montan wax : drop point : 76 to 81°C; acid index: 15-20; saponification index 140-160) is an example of a preferred wax for use in the present invention and comprises a mixture of fatty acids each containing from 22 to 39 carbon atoms, said acids being esterified with ethanediol .

A particularly preferred composition according to the present i nventi on, contains 1-(2,6-di ch1orobenzy1i dene-amino)-3-hydroxy-guani di ne hydrochloride and a wax comprising a mixture of fatty acids each containing from 22 to 39 carbon atoms, said acids being esterified with ethane-diol.

Advantageously, the compositions will contain 1 part by weight of 1-(2,6-dich1orobenzylidene-amino)-3-hydroxy-guanidine or a salt thereof e.g. the hydrochloride to from>J to 2 parts by weight of the wax.

The compositions according to the invention are of particular use in the preparation of pharmaceutical compositions having remarkable delayedaction hypotensive properties. These properties are illustrated hereinafter. Pharmaceutical compositions according to the invention may if desired contain additional pharmaceutical carriers and excipients.

Because of their properties, these pharmaceutical compositions may be used in the treatment of, for example, essential arterial hypertension, hypertension occurring at an - 4 44387 age of about 50, at the menopause, hypertension of diabetics, obese people and plethoric people, as well as in the treatment of arterial hypertension in elderly patients, atherosclerosis and in the treatment of hypertension of renal origin.

. Study in vitro of the delayed-action activity of compositions according to the invention The study of the release over a period of time of a composition..comprising l-(2,6-dichlorobenzylidene-amino)~ 1Q 3-hydroxy-guanidine hydrochloride and ester E wax (Farbwerke Hoechst) was carried out in vitro using a batch of tablets prepared as indicated hereinafter in Example 2.

The 'tablets were placed into a solution of which the pH Was subsequently varied over a period of time so as to simulate the dissolution process occuring in the digestive tract.

At the twentieth minute, at the second hour and at the sixth hour, the percentage product released (expressed in percentage of the total dose) was determined.

The results obtained appear in Table 1 below: - 5 44387 TABLE 1 Period pH of the solution Percentage product released 20 minutes 2r.9 2nd hour 1 52 .’7 6th hour .4.5 ~ 86.'9 The results obtained show that the 1-(2,6-dichlorobenzylidene- amino)-3-hydroxy-guanidine'hydrochloride was released very gradually.and continuously over a period of time. Clinical study Tablets containing 12.5 mg, 25 mg or 50 mg (expressed as base) of 1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine hydrochloride in a conventional excipient were administered to human subjects.

It was established that the product was active mainly on the tension symptoms and only secondarily on the cardiac rhythm and on diuresis.

However, these effects have the disadvantage of being I short-lived and hence effective treatment requires several daily administrations.

The pharmaceutical compositions of the present invention were studied by administering to human subjects tablets containing -6-. 1-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine hydrochloride (such as those prepared in Example 2 described hereinafter) in doses of 25 and 50 mg of active ingredient per day (dose expressed as 1-(2,6-dichlorobenzylidene-amino)c t 5 ! 3-hydroxy-guanidine base), hydroxy-guanidine base).

The study was based upon 9 hypertensive patients (8 essential arterial hypertensions and one arterial hypertension of renal origin : chronic unilaterial interstitial Ιθ nephritis (patient no. 4) divided up as follows: a) According to age: The age of the patients ranged between 35 years and 79 years; b) According to sex: The study related to 5 men and 4 women; c) According to visceral echo: (International classification based upon the study of the arterial tension at the bottom of the eye and the biological renal study).

During this stpdy, attention was paid to observing the action on arterial tension, as well as the improvement in the general condition resulting therefrom, and the minimum number of daily doses necessary for the action to be as regular as possible and the tolerance. - 7 The results obtained appear in Table 2 below: TABLE 2 No. Age Sex Stage Result Secondary effects Tolerance 1 46 M II Good 0 Excellent 2 35 M I Good 0 Excellent 3 40 M I Good 0 Excellent 4 40 F .11 Good Orthostatic hypotension A.T. Bad 5 62 F III Average 0 Excellent 6 79 K III Good Orthostatic hypotension A.T. - diarrhoea Bad 7 76 F III Good 0 Excellent 8 49 M I Good 0 Excellent 9 53 M I Good Orthostatic hypotension A.T. Excellent The clinical study leads to the following observations: ι The hypotensive effect observed was general; this effect was immediate in the majority of cases.

In all the observations, a clear drop in the tension symptoms was noted.

All the cases in which the tension symptoms were standardised after administration of half a tablet twice a day or one tablet at night on retiring of l-(2,6-dichlorobenzylidene amino)-3-hydroxy-guanidine hydrochloride (tablets prepared as in Example 2) were considered to be good results.

In conclusion, it can be noted that pharmaceutical compositions incorporating compositions according to the present invention exhibit, very clear delayed-action hypotensive activity.

These compositions have, in addition, the advantage of being generally well tolerated, especially by elderly patients and of not causing secondary complications, such as disorders of the glucidic metabolism.

For pharmaceutical administration the compositions according to the invention may be incorporated into the conventional pharmaceutical preparations, optionally in combination with other active ingredients. Such pharmaceutical compositions may, for example, be presented in a form suitable for oral or rectal administration. Preferred forms include, for example, tablets, coated tablets, gelatin capsules, ι granules and suppositories.

The compositions may be incorporated in excipients customarily employed in these pharmaceutical compositions such as, for example, talc, an infusorial earth, e.g.

(Registered Trade Mark) kieselguhr, Celite or Supw-eel/ gum arabic, aluminium hydroxide, colloidal silica, lactose, starch, stearic acid, magnesium stearate, polyvinylpyrrolidone, cocoa butter, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Advantageously the pharmaceutical compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain from 10 to 50 mg of active ingredient (expressed as weight of base).

The oral daily dosage, which may be varied according to the subject treated and the complaint concerned may, for example, be one dose of 10 to 50 mg of active ingredient (expressed as weight of base) per day in adults.

The following non-limiting examples serve to illustrate the present invention.

Example 1 Sectile tablets were prepared corresponding to the formulation; 1-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine hydrochloride (corresponding to 25 mg of base)....;.. 28.7 mg; Ester E wax (Farbwerke Hoechst) ..................... 30 mg; Excipient q.s. for one tablet up to.................. 200 mg.

(Detail of the excipient : dry aluminium hydroxide gel, lactose, colloidal silica, stearic acid).

Example 2 Sectile tablets were prepared corresponding to the formulation· l-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine hydrochloride (corresponding to 50 mg of base)........ 57.4 mg; Ester E wax (Farbwerke Hoechst) ...................... 25 mg; Excipient q.s. for one tablet up to .................. 350 mg.

(Detail of the excipient : dry aluminium hydroxide gel, lactose, colloidal silica, stearic acid).

Example 3 Sectile tablets were prepared corresponding to the ι formulations 1-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine hydrochloride (corresponding to 25 mg of base)........’. 28.7 mg; Ester E wax (Farbwerke Hoechst) .................... 30 mg; Excipient q.s. for one tablet up to................ 200 mg.

(Detail of the excipient : lactose, colloidal silica, stearic acid).

Example 4 Sectile tablets were prepared corresponding to the formulations 1-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine hydrochloride (corresponding to 12.5 mg of base)...... 14.350 mg; Ester E wax (Farbwerke Hoechst) ...................... 30 mg; Excipient q.s. for one tablet up to ................. 190 mg.

(Detail of the excipient : lactose, colloidal silica, stearic acid, polyvinylpyrrolidone).

Claims (18)

1. Delayed-action hypotensive 1. / pharmaceutical compositions comprising l-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine and/or at least one physiologically compatible acid addition salt thereof and a wax 5 comprising a mixture of fatty acids each containing from 18 to 39 carbon atoms esterified with a diol containing from 2 to 6 carbon atoms,

2. Compositions as claimed in claim 1 wherein the diol comprises ethane-diol.

3. Compositions as claimed in claim 1 wherein the diol 10 comprises 1,2- or l.,3-propane-diol or 1,3- or 2,3-butane-diol.

4. Compositions as claimed in any of the preceding claims wherein the fatty acids are selected from octadecanoic, nonadecanoic, eicosanoic, heneicosanoic, docosanoic, tricosanoic, tetracosanoic, pentacosanoic, hexacosanoic, 15 heptacosanoic, octacosanoic and nonacosanoic acid.

5. Compositions as claimed in any of claims 1 to 3 wherein the fatty acids each contain from 22 to 39 carbon atoms.

6. Compositions as claimed in claim 4 or claim 5 wherein the wax comprises esterified nonacosanoic acid. 2q

7. Compositions as claimed in any of the preceding claims containing a physiologically compatible acid addition salt of 1-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine.

8. Compositions as claimed in claim 7 wherein the salt 4 43.8 7 comprises the hydrochloride, hydrobromide, hydriodide, nitrate, sulphate, phosphate, acetate, formate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate or aspartate or an alkanesulphonate or arylsulph5 onate.

9. Compositions as claimed in claim 8 wherein the salt comprises the methanesulphonate or benzenesulphonate.

10. Compositions as claimed in any of the preceding claims containing one part by weight of the 1-(2,6-dichlorobenzylidene 10 amino)-3-hydroxy-guanidine or salt thereof to from V to 2 parts by weight of the wax. . ι

11. Compositions as claimed in any of the preceding claims further containing an additional pharmaceutical carrier or excipient. 15

12. Compositions as claimed in claim ll in a form suitable for oral or rectal administration.

13. Compositions as claimed in claim 11 or claim 12 in the form of tablets, coated tablets, gelatin capsules, granules or suppositories. 20

14. Compositions as claimed in any of claims 11 to 13 in the form of dosage units.

15. Compositions as claimed in claim 14 wherein each dosage unit contains from .10'to 50 mg (expressed as weight of base) of 1-(2,6-dichlorobenzylidene-amino)-3-hydroxy-guanidine or a salt thereof.

16. Compositions as claimed in claim 15 wherein each dosage unit contains from 10 to 50 mg (expressed as weight 5 of base) of 1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine hydrochloride.

17. Compositions as claimed in claim 1 substantially as herein described.

18. Compositions substantially as herein described in 10 any one of Examples 1 to 4.