WO2015114481A1

WO2015114481A1 - Contraceptive formulation and method of its preparation and use

Info

Publication number: WO2015114481A1
Application number: PCT/IB2015/050307
Authority: WO
Inventors: Sujoy Kumar Guha; Shubhadeep Banerjee
Original assignee: Sujoy Kumar Guha
Priority date: 2014-01-31
Filing date: 2015-01-15
Publication date: 2015-08-06

Abstract

The present invention relates to a contraceptive formulation comprising a styrene-(maleic acid-maleic anhydride)_n copolymer as active ingredient, and methods for preparation and use thereof.

Description

Title of the Invention: Contraceptive formulation and method of its preparation and use. Field of the Invention: The present invention relates to a contraceptive formulation and method of its preparation and use. Particularly, in one embodiment, the present invention relates to a contraceptive formulation comprising styrene maleic acid maleic anhydride copolymer. It may be noted that the 'styrene maleic acid maleic anhydride copolymer' may also be referred to as a copolymer of styrene maleic acid and styrene maleic anhydride'. It may be further noted that the styrene maleic acid herein after may be referred to as SMAc, and the styrene maleic anhydride herein after may be referred to as SMAn. In another embodiment, the present invention also relates to method for preparation of a contraceptive formulation comprising styrene maleic acid maleic anhydride copolymer. In still another embodiment, the present invention also relates to method of using a contraceptive formulation comprising styrene maleic acid maleic anhydride copolymer. Background of the Invention: The first inventor Professor Sujoy Kumar GUHA (GUHA) of the present invention has developed various contraceptive formulations comprising styrene maleic anhydride, couple of which are undergoing animal trials and/or multi-centric clinical trials. For achieving male contraception, the contraceptive formulation should comprise a compound which on reaction with a liquid vehicle and on injection into vas deferens of the male is capable of destroying (or blocking) sperms (US Patent No. 5,488,075 issued to GUHA). GUHA has found that such destroying of the sperms may be happening by virtue of lowering of pH on injection of the contraceptive into the vas deferens of the male. GUHA has now found that a desirable feature of the contraceptive formulation is that the acid number of the formulation should be high without causing increase in bulk of the active component of the contraceptive formulation (drug implant) so that the sperms may be effectively destroyed. The contraceptives known in the prior art have limitation that if the contraceptive comprises an acid group, then higher pH lowering may be realized, therefore, the contraceptive formulation may become unstable and may get washed out in a limited time, thereby, reducing a period of effectiveness of the contraceptive formulation. The contraceptives known in the prior art also have limitation that if it is capable of destroying the sperms on account of lowering of pH, for example, lowering the pH to about 4.0 to 4.5, and that the injection does function as an acidic material, and that the contraceptive does stay back in the vas deferens, i.e. does not wash-out for very long period, and thereby, have increased period of effectiveness, then to achieve these advantageous effects from the known contraceptive formulations, a fairly large amount of the known contraceptive formulation is required in the vas deferens. It has been observed that about one-third of the subjects of the multi-centric clinical trials may get temporary scrotal swelling. However, such swelling lasts for a week or so and does not cause any pain or discomfort to the subjects, or does not hinder in subject's routine working. However, it is still desired to have a contraceptive formulation, which can still avoid or at least minimize the temporary scrotal swelling. Need of the Invention: Therefore, there is a need of an improved contraceptive formulation, which can achieve above-discussed advantages of the known contraceptive formulations, and at the same time has following additional advantages:

a) the improved contraceptive formulation is required in comparatively lower dosages so that the above-discussed limitation of requirement of higher dosage of the known contraceptive formulations can also be overcome, and

b) the improved contraceptive formulation avoids or at least minimizing the temporary scrotal swelling. Therefore, there is also a need of an improved contraceptive formulation, which will comprise a compound capable of combining the features of:

(i) high acid number with

(ii) high stability and (iii) small volume,

that's too, (iv) without causing increase of bulk of the active component of the improved contraceptive formulation. Problem to be solved by the present Invention: Accordingly, the present invention aims to overcome above-discussed limitations of the contraceptive formulations of the prior art by providing an improved contraceptive formulation, which can achieve above-discussed advantages of the known contraceptive formulations, and at the same time has following additional advantages:

b) the improved contraceptive formulation avoids or at least minimizing the temporary scrotal swelling. The present invention also aims to provide an improved contraceptive formulation, which comprises an active ingredient which has been found to be capable of combining the features of:

(i) high acid number with

(ii) high stability and (iii) small volume,

that's too, (iv) without causing increase of bulk of the active component of the improved contraceptive formulation. Objects of the present Invention: Accordingly, main object of the present invention is to provide an improved contraceptive formulation, which can achieve above-discussed advantages of the known contraceptive formulations, and has following additional advantages:

a) the improved contraceptive formulation is still required in comparatively lower dosages so that the above-discussed limitation of requirement of higher dosage of the known contraceptive formulations can also be overcome, and

b) the improved contraceptive formulation is capable of avoiding or at least minimizing the temporary scrotal swelling. Another object of the present invention is to provide an improved contraceptive formulation, which comprises an active ingredient capable of combining the features of:

(i) high acid number with (ii) high stability and (iii) small volume,

that's too, (iv) without causing increase of bulk of the active component of the improved contraceptive formulation. Other objects and advantages of the present invention will become more apparent from the following description which has been described with the help of the accompanying figures which are not intended to limit scope of the present invention. Brief Description of the accompanying figures of the Invention: Figure 1 illustrates FTIR spectrum of the maleic acid-maleic anhydride copolymer produced in accordance with one of the preferred embodiments of the invention. It may be noted that presence of stretch bands of both anhydride group and acid group indicates the formation of maleic acid-maleic anhydride copolymer. Figure 2 illustrates FTIR spectrum of the styrene- (maleic acid-maleic anhydride)_n copolymer produced in accordance with one of the preferred embodiments of the invention. It may be noted that presence of stretch bands of anhydride group, acid group and styrene group indicates the formation of styrene- (maleic acid-maleic anhydride)_n copolymer. Description and Preferred Embodiments of the Invention: With aim to overcome above-discussed limitations of the known contraceptive formulations of the prior art and to achieve above-discussed advantages of the present invention, the inventors have found, by in-vitro studies, that if styrene- (maleic acid- maleic anhydride)_n copolymer (may be referred to as 'active ingredient' or the copolymer) prepared by chemical polymerization, preferably by using benzoyl peroxide is used for achieving contraceptive action, then the said copolymer, surprisingly and unexpectedly, inactivates the sperms very quickly, just within about 60 sec. Further, when supply of the sperms was maintained for longer durations, the said copolymer, surprisingly and unexpectedly, remained active for longer durations than comparative copolymers - a) styrene maleic acid copolymer and b) styrene maleic anhydride copolymer. Accordingly, in one embodiment, the present invention relates to a contraceptive formulation comprising styrene- (maleic acid-maleic anhydride)_n copolymer as active ingredient. Accordingly, in another embodiment, the present invention relates to a method for preparation of the contraceptive formulation comprising styrene- (maleic acid- maleic anhydride)_n copolymer as active ingredient. Accordingly, in still another embodiment, the present invention relates to a method of using the contraceptive formulation comprising styrene- (maleic acid-maleic anhydride)_n copolymer as active ingredient for achieving the contraception. It may be noted that in the present invention, the 'styrene- (maleic acid-maleic anhydride)_n copolymer' of the present invention may be expressed

as 'styrene- (maleic anhydride-maleic acid)_n copolymer', or

as 'styrene copolymer', or

as 'SMAA copolymer', or

as the copolymer, or

as the active ingredient, or

as the copolymer of the present invention. In accordance with one of the preferred embodiments of the present invention, the 'styrene- (maleic acid-maleic anhydride)_n copolymer' of the present invention may be prepared in two stages by a method comprising following steps of: Stage - 1 - Preparation of 'maleic anhydride and maleic acid copolymer'.

al) mixing maleic acid and maleic anhydride; bl) adding an ester to the mixture of maleic acid and maleic anhydride of step al);

cl) adding polymerization initiator to the mixture of step bl);

dl) heating the mixture of step cl) for initiating the polymerization of maleic acid and maleic anhydride to form a 'maleic anhydride- maleic acid copolymer';

el) isolating the 'maleic anhydride-maleic acid copolymer' formed in step dl). Stage - II - Preparation of 'styrene-(maleic acid-maleic anhydride),, copolymer' of the present invention.

a2) mixing styrene and maleic anhydride-maleic acid copolymer obtained in Stage - 1;

b2) adding an ester to the mixture of 'styrene and maleic anhydride- maleic acid copolymer' of step a2);

c2) adding polymerization initiator to the mixture of step b2);

d2) heating the mixture of step c2) for initiating the polymerization of the styrene and the maleic anhydride-maleic acid copolymer to form a styrene- (maleic acid-maleic anhydride)_n copolymer;

e2) isolating the styrene- (maleic acid-maleic anhydride)_n copolymer formed in step d2). In accordance with one of the embodiments of the present invention, the maleic acid and maleic anhydride in said step al) are preferably mixed in equivalent weights. In accordance with one of the embodiments of the present invention, the styrene and the 'maleic anhydride-maleic acid copolymer' obtained in Stage - I are preferably mixed in equivalent weights. In accordance with one of the embodiments of the present invention, the ester in said steps bl) and b2) is preferably ethyl acetate. In accordance with one of the embodiments of the present invention, the ester and 'mixture of maleic acid and maleic anhydride' in said step bl) are preferably mixed in a weight by volume ratio selected from the group comprising weight by volume ratio varying from about 1: 10 to about 1:30, about 1: 15 to about 1:25, and weight by volume ratio about 1 :20. In accordance with one of the embodiments of the present invention, the ester and the mixture of 'styrene and maleic anhydride -maleic acid copolymer' in said step b2) are preferably mixed in a weight by volume ratio selected from the group comprising weight by volume ratio varying from about 1: 10 to about 1:30, about 1: 15 to about 1:25, and weight by volume ratio about 1:20. In accordance with one of the embodiments of the present invention, the polymerization initiator in said steps cl) and c2) is preferably benzoyl peroxide. In accordance with one of the embodiments of the present invention, the polymerization initiator is added in said steps cl) and c2) in % by vol. amount selected from the group comprising % by vol. varying from about 0.15% to about 0.35%, from about 0.25% to about 0.30%, % by vol. in about 0.20%. In accordance with one of the embodiments of the present invention, the mixture of said steps dl) and d2) are heated for a period selected from the group comprising a period up to about 8 h, and up to about 6h. In accordance with one of the embodiments of the present invention, the mixture of said steps dl) and d2) are heated to a temperature selected from the group comprising up to about 100°C, and up to about 80°C. In accordance with one of the embodiments of the present invention, the isolated "maleic anhydride-maleic acid copolymer" from stage-I is dried under vacuum. In accordance with one of the embodiments of the present invention, the drying of the isolated maleic anhydride-maleic acid copolymer is carried out for a period selected from the group comprising a period varying from about 8h to about 16 h, and from about lOh to about 13 h. In accordance with one of the embodiments of the present invention, the isolated "styrene- (maleic acid-maleic anhydride)_n copolymer" from stage-II is dried under vacuum. In accordance with one of the embodiments of the present invention, the drying of the isolated styrene- (maleic acid-maleic anhydride)_n copolymer is carried out for a period selected from the group comprising a period varying from about 18h to about 27 h, and from about 20h to about 25 h. In accordance with one of the preferred embodiments of the invention, upon analysis, the isolated "maleic anhydride-maleic acid copolymer" from stage-I has been found to have following structural formula A:

Formula A In accordance with one of the preferred embodiments of the invention, upon analysis, the isolated "styrene-(maleic acid-maleic anhydride)_n copolymer" from stage-II has been found to have following structural formula B, wherein n may vary up to about 120:

Formula B In accordance with one of the preferred embodiments of the invention, upon analysis, the isolated maleic anhydride-maleic acid copolymer from stage-I has been found to have FTIR spectra as given in accompanying Figure 1. It may be noted that presence of stretch bands of both anhydride group and acid group indicates the formation of maleic acid-maleic anhydride copolymer. In accordance with one of the preferred embodiments of the invention, upon analysis, the isolated styrene- (maleic acid-maleic anhydride)_n copolymer from stage-II has been found to have FTIR spectra as given in accompanying Figure 2. It may be noted that presence of stretch bands of anhydride group, acid group and styrene group indicates the formation of styrene- (maleic acid-maleic anhydride)_n copolymer. The inventors have found that copolymer of the present invention, when prepared in accordance with one of the preferred embodiments of the present invention, has acid number of about 391.72, which is higher than the acid number of the comparative copolymer of styrene maleic anhydride which is about 274.52, and the acid number of the comparative copolymer of styrene maleic acid which is about 341.59. The inventors have found that the increased value of acid number of the present copolymer surprising and unexpectedly results in increased acidity of the copolymer, which, as discussed above, has been, surprisingly and unexpectedly, found to have increased and faster capability of inactivating the sperms for a longer durations, thereby, confirming the contraceptive action of the present copolymer. It may be noted that the inventors of the present invention have found that the active ingredient of the present contraceptive formulation can be used in small volumes, because its high acid number makes it capable of causing higher pH lowering with a smaller volume of the present contraceptive formulation. Accordingly, the above-discussed problems of the prior art have been overcome by providing a device Legend of Figures 1 and 2:

.

In Figure 1

1.1 is asymmetric stretch, C¾, of maleic backbone, 2856 cm^"1;

1.2 is anhydride, 1810 cm^"1;

1.3 is acid, 1745 cm^'1. In Figure 2

2.1 is asymmetric stretch, CH₂, of maleic backbone, 2858cm^"1;

2.2 is anhydride, 1822cm^"1;

2.3 is acid, 1741cm^"1;

2.4 is styrene, 1495cm^"1.

Claims

Claims 1. A contraceptive formulation comprising a styrene-(maleic acid-maleic anhydride)_n copolymer as active ingredient.

2. A method for preparation of a contraceptive formulation comprising a styrene- (maleic acid-maleic anhydride)_n copolymer as active ingredient, wherein the styrene- (maleic acid-maleic anhydride)_n copolymer is prepared in two stages, wherein in Stage - I, a 'maleic anhydride and maleic acid copolymer' is prepared comprising steps of:

al) mixing maleic acid and maleic anhydride;

bl) adding an ester to the mixture of the maleic acid and the maleic anhydride of step al);

cl) adding polymerization initiator to the mixture of step bl);

dl) heating the mixture of step cl) for initiating the polymerization of the maleic acid and the maleic anhydride to form a 'maleic anhydride-maleic acid copolymer';

el) isolating the 'maleic anhydride-maleic acid copolymer' formed in step dl); and

in Stage - II, the 'styrene- (maleic acid-maleic anhydride)_n copolymer' is prepared comprising steps of:

a2) mixing styrene and the maleic anhydride-maleic acid copolymer obtained in Stage - 1;

b2) adding an ester to the mixture of the styrene and the maleic anhydride-maleic acid copolymer of step a2);

c2) adding polymerization initiator to the mixture of step b2);

e2) isolating the styrene- (maleic acid-maleic anhydride)_n copolymer formed in step d2).

3. The method as claimed in claim 1, wherein the maleic acid and the maleic anhydride in said step al) are mixed in equivalent weights; and the styrene and the 'maleic anhydride-maleic acid copolymer' in said step a2) are mixed in equivalent weights.

4. The method as claimed in claim 2 or claim 3, wherein the ester in said steps bl) and b2) is ethyl acetate.

5. The method as claimed in any one of the preceding claims 2 to 4, wherein the ester and the 'mixture of the maleic acid and the maleic anhydride' in said step bl) are mixed in a weight by volume ratio selected from the group comprising weight by volume ratio varying from about 1: 10 to about 1:30, about 1: 15 to about 1:25, and of about 1:20.

6. The method as claimed in any one of the preceding claims 2 to 5, wherein the ester and the mixture of the styrene and the maleic anhydride-maleic acid copolymer in said step b2) are mixed in a weight by volume ratio selected from the group comprising weight by volume ratio varying from about 1: 10 to about 1:30, about 1: 15 to about 1:25, and of about 1:20.

7. The method as claimed in any one of the preceding claims 2 to 6, wherein the polymerization initiator in said steps cl) and c2) is benzoyl peroxide.

8. The method as claimed in any one of the preceding claims 2 to 7, wherein the polymerization initiator is added in said steps cl) and c2) in % by vol. amount selected from the group comprising amount varying from about 0.15% to about 0.35%, from about 0.25% to about 0.30%, and about 0.20% by vol.

9. The method as claimed in any one of the preceding claims 2 to 8, wherein the mixture of said steps dl) and d2) are heated for a period selected from the group comprising a period up to about 8 h, and up to about 6h.

10. The method as claimed in any one of the preceding claims 2 to 9, wherein the mixture of said steps dl) and d2) are heated to a temperature selected from the group comprising up to about 100°C, and up to about 80°C.

11. A method of using a contraceptive formulation comprising a styrene-(maleic acid-maleic anhydride)_n copolymer as active ingredient for achieving the contraception.