WO2008001389A2

WO2008001389A2 - Female contraceptive for transcervical delivery and its' preparation

Info

Publication number: WO2008001389A2
Application number: PCT/IN2007/000237
Authority: WO
Inventors: Sujoy Kumar Guha
Original assignee: Marksans Pharma Ltd.
Priority date: 2006-06-27
Filing date: 2007-06-14
Publication date: 2008-01-03
Also published as: WO2008001389A3

Abstract

A female contraceptive for transcervical approach consisting of a chemical complex of iodine, itaconic acid and methyl methacrylate in a solvent is provided. Further, a process for preparation of female contraceptive for transcervical approach comprising complexing solution of itaconic acid-methyl methacrylate copolymer comprising itaconic acid and methyl methacrylate in a ratio varying from about 1:3 to about 1:8 respectively with solution of iodine to produce chemical complex of iodine, itaconic acid and methyl methacrylate is also provided.

Description

Title of the Invention:

A Female Contraceptive for Transcervical Delivery and a Process for Preparation Thereof.

Field of the invention:

The present invention relates to a female contraceptive for transcervical delivery, particularly it relates to a female contraceptive for transcervical delivery and capable of deactivating the sperm as well as ovum in the fallopian tube, more particularly it relates to a female contraceptive for transcervical delivery and capable of deactivating the sperm and ovum passing in the lumen of the fallopian tube and acting as blocking device in the fallopian tube. Even more particularly it relates to a female contraceptive for transcervical delivery and capable of deactivating the sperm and ovum passing in the lumen of the fallopian tube and acting as blocking device in the fallopian tube, and being reversible in nature to restore the fertility.

Background of the Invention:

Rapid increase of population is a matter of great national concern. Science, technology and socioeconomics have all to be directed to manage this issue. Medical methods of fertility control are an important component of the practical techniques in use towards the goals of regulation of population growth. A number of techniques have been developed and female sterilization is an important approach.

The two most widely practiced approaches to female sterilization are minilaprotomy and laproscopic tubal occlusion. In both these procedures the fallopian tube in the female is blocked so that the female ovum (egg) does not travel down the tube and the male spermatozoa is not able to travel up the tube for an ovum - spermatozoa union. The fallopian tube is accessed in minilaprotomy through an incision in the abdominal wall and in the laproscopic sterilization the fallopian tube is viewed by inserting a laproscope into the abdominal cavity through the abdominal wall and manipulating the tube with the help of special pincer like device incorporated with the laproscope. Entry into the peritoneal cavity is necessary in both cases. Therefore, these procedures of female sterilization are invasive in nature and generally not preferred. Further, the peritoneal cavity being susceptible to infections these procedures must be conducted as sterile surgery under special care.

During the past fifteen years research has been going on internationally to arrive at a simpler and safer alternative. Transcervical sterilization has been investigated. The investigators have attempted to effect the sterilization by blocking the utero-tubal junction from the uterine side instead of blocking the fallopian tube from the abdominal side to avoid entry into the peritoneal cavity for achieving improved safety and opening up the possibility of out patient level handling. In this approach, the utero-tubal junction is viewed by inserting a hysteroscope through the vagina and the uterine cervix and the occluding agent, for example methyl cyanoacrylate, is also delivered via the transcervical route. Thus the entry into the peritoneal cavity is obviated thereby giving improved safety and opening up the possibility of out patient level handling. However, the major problem of insertion of such occluding agent is that the occluding agent employed adheres to the mucosal and muscular tissues of the fallopian tube wall and hence, the removal of the occluding agent for restoration of fertility becomes impossible.

The alternative approach is to deliver the quinacrine pellets into the uterus via the cervix using a modified intrauterine device or a catheter. The major problem of this approach is that on dissolution of the pellets the drug flows into the fallopian tube, which becomes inflamed leading to scarification, that is, formation of fibrous scar tissue. Further, the tissue scars block the fallopian tube giving contraception but complete destroying the normal morphology of the fallopian tube and, therefore, producing an undesirable effects. The major problem of blocking the fallopian tube to achieve contraception via this approach is that the patency of the fallopian tube cannot be restored to restore fertility also the extensive damage to tissue architecture tend to lead to ectopic pregnancy which is hazardous. Various biologically inert polymeric materials such as silicone rubber and polyurethane have also been tried by inserting into the fallopian tube through the transcervical route to block the fallopian tube and achieve contraception. In this approach the biologically inert polymeric material acts as blocking device or implant. However, the results of blocking the fallopian tube with the blocking device or implant of biologically inert polymeric material are not favourable. The major problem of this approach is that even with the initial blockage with such blocking device or implant it spreads over the entire length of the fallopian tube after a period of time when the fallopian tube dilates sperms and ovum leak past leading to contraceptive failure. Further, the removal of such blocking device or implant to restore fertility is not practicable due to its long length, that is, its spread over the entire length of the fallopian tube.

On the other hand if a limited block is produced reversal is feasible, but the longevity of the block is insufficient for the technique to be deemed as an acceptable sterilization contraceptive.

The research so far has, therefore, brought forth procedures, which come close to being a practical contraceptive but an additional step ahead is clearly necessary. Since total blockage leads to above-defined problems and also cannot be maintained over an extended period of time it has been proposed to have only a partial blockage. The partial blockage suffers from the problem of passing of spermatozoa and ovum through the fallopian tube. Therefore, it is essential that the plugging material implanted in the fallopian tube for partial blockage is an active compound.

The methyl methacrylate is a known chemical compound widely used in industry including the furnishing industry. Its use in biomedicine is also known. The biomedical applications include making somewhat strong structures as for example chest wall filler [M Akan, et al Scand. J Plast. Reconstr. Surg. Hand Surg., 40(2)(2006) 93-100], skeletal fixation [S. Inoue, et al Clin Orthop Relat Res., 124 (1977), 92-96\, and as eye implant [D F Yin, Zhonghua Yan Ke Za ZU, 41(3) (2005) 252-6\ and encapsulating drugs [QHLi, et al, Guang Pu Xue Yu Guang Pu Fen Xi, 24(8) (2004), 960-2]. A contraceptive comprising methyl methacrylate and itaconic acid has been developed [V.Koul, et al, J of Materials Science; Materials in Medicine, 6 (1995) 192-196\. During in-vitro studies, this contraceptive has been found to be suitable for destroying sperms. However, the detailed studies have revealed that this contraceptive is not adequately suitable even for destroying sperms.

The itaconic acid-co~methyl methacrylate polymer [supra V.Koul, et al] comprising itaconic acid and methyl methacrylate in 3: 1 ratio, that is itaconic acid is taken in very high amount as compared to methyl methacrylate, and synthesized by solution porymerization using the benzoyl peroxide radical initiator, has shown complete loss of spermatozoa motility within 5 minutes exposure of sperms to the polymer. It may be noted that the immotile spermatozoa may be live and may recover motility at a later stage during transit in the male and female reproductive system. Therefore, a parameter termed vitality, which is the ratio of the number of live spermatozoa to dead spermatozoa, is studied. It was observed that the itaconic acid-co-methyl methacrylate polymer clearly shows 8 to 25% spermatozoa vitality at different treatment intervals confirming thereby that this polymer was not adequately effective even for deactivating the sperms.

During further studies, the itaconic acid-co-methyl methacrylate polymer contraceptive comprising itaconic acid and methyl methacrylate in a ratio of 3: 1 respectively, that is, comprising very high amount of itaconic acid compared to methyl methacrylate has been found to be short-lived contraceptive in the vas deferens and it washes-off in very short duration of about few weeks. If a contraceptive has been found to be short-lived in vas deferens, the same contraceptive cannot be long-lived in the fallopian tube which has a very large lumen diameter as compared to lumen diameter of vas deferens. Therefore, it is understood that the itaconic acid-co-methyl methacrylate polymer contraceptive comprising itaconic acid and methyl methacrylate in a ratio of 3: 1 respectively cannot be adopted as female contraceptive.

Further, V.Koul studied this polymer only in vas deferens, therefore, there is no teaching whether this polymer could be effective for deactivating sperms in the fallopian tube or not. Further, there is no teaching whether this polymer could also be effective for deactivating ovum, in the fallopian tube or not. Further, this study also concluded that for use as vaginal (female) contraceptive, a water-soluble polymer should be preferred and not water in-soluble polymer.

Need of the Invention:

Therefore, there is a need for a female contraceptive formulation for transcervical approach thereby giving improved safety and out patient level handling which not only has anti-spermatozoa activity, but also has anti- ovum activity thereby making it suitable for deactivating fertilizing ability of spermatozoa as well as ovum in the fallopian tube and which is also suitable for acting as blocking deλάce in the fallopian tube for partial blockage thereby obviating problems of total blockage and the sperms as well as ovum lose their fertilizing ability on their way through the partial blockage in the fallopian tube, and still being reversal in nature thereby being suitable for restoring fertility as and when desired.

Objects of the Invention:

The main object of the present invention is to provide a female contraceptive for transcervical approach thereby having improved safety and out patient level handling which not only has anti- spermatozoa activity, but also has anti-ovum activity in lumen the fallopian tube thereby being suitable for deactivating fertilizing ability of spermatozoa as well as ovum in the lumen of the fallopian tube and also being suitable for acting as blocking device in the fallopian tube for partial blockage thereby obviating problems of total blockage and still being capable of destroying fertilizing ability of sperms as well as ovum on their way through the partial blockage in the fallopian tube, and at the same time being reversal in nature thereby being suitable for restoring fertility as and when desired.

This is also an object of the present invention to provide a female contraceptive for transcervical approach wherein ovum - spermatozoa union in fallopian tube is avoided bjr partial blockage of fallopian tube, and wherein neither fallopian tube is accessed through an incision in the abdominal wall nor it is viewed by inserting a laproscope into the abdominal cavity through the abdominal wall.

This is also an object of the present invention to provide a female contraceptive for transcervical approach wherein no entry into the peritoneal cavity is required meaning thereby the contraceptive is capable of being delivered through non-invasive technique.

This is also an object of the present invention to provide a female contraceptive for transcervical approach wherein contraceptive is capable of sterilizing sperms and ovum in fallopian tube even by partially blocking fallopian tube from abdominal side meaning thereby avoiding entry into the peritoneal cavity and blockage of utero-tubal junction from uterine side, and still contraceptive of present invention does not adhere to mucosal and muscular tissues of the fallopian tube wall, and hence, its removal for restoration of fertility becomes easily possible.

This is also an object of the present invention to provide a female contraceptive for transcervical approach which does not dissolve in fallopian tube, and hence, does not flow into the fallopian tube, accordingly, it does not cause inflammation of fallopian tube meaning thereby it is capable of avoiding scarification, that is, formation of fibrous scar tissue.

This is also an object of the present invention to provide a female contraceptive for transcervical approach which does not spread over the entire length of the fallopian tube even after a longer period of time which is expected to be about 4 years or more meaning thereby sperms and ovum does not get leak past without getting sterilized even when the fallopian tube dilates, and hence, contraception once achieved does not fail till the present contraceptive remains in the fallopian tube or till it is intentionally removed.

This is also an object of the present invention to provide a female contraceptive for transcervical approach which is capable of achieving complete loss of spermatozoa as well as ovum, that is capable of achieving complete motility within a shorter duration as short as about 5 minutes, and is also capable of achieving 0% vitality meaning thereby capable of deactivating sperms as well as ovum.

This is also an object of the present invention to provide a female contraceptive for transcervical approach which is capable of being long-lived in the fallopian tube.

The other objects and advantages of the present invention will become apparent from the following description when read in conjunction with the accompanying figures which are not intended to limit scope of the present invention.

Brief Description of Accompanying Figures:

Figure 1 illustrates FTIR of iodine-itaconic acid-co-methyl methacrylate polymer contraceptive complex in accordance with present invention.

Figure 2 illustrates FTIR of itaconic acid-co-methyl methacrylate polymer.

Figure 3 illustrates FTIR of itaconic acid.

Figure 4 illustrates FTIR of methyl methacrylate.

Figure 5a illustrates FTIR of iodine crystal.

Figure 5b illustrates FTIR of iodine in DMSO.

Figure 6 illustrates that iodine-itaconic acid-co-methyl methacrylate polymer contraceptive complex of present invention has partial blocking capability / efficacy .

Figure 7 illustrates blocking capability/ efficacy of contraceptive complex of present invention. Figure 8 illustrates reversal capability/ efficacy of contraceptive complex of present invention.

Figure 9 illustrates anti-ovum capability/efficacy of contraceptive complex of present invention, wherein Figure 9a illustrates freshly collected rat ovum and Figure 9b illustrates deactivated rat ovum.

Figure 10 illustrates anti-sperm capability/ efficacy of contraceptive complex of present invention, wherein Figure 10a illustrates freshly collected rat spermatozoa and Figure 10b illustrates deactivated rat sperms.

Summary of the Invention:

With aim to overcome problems of prior art described herein above, the inventor has found that complex of iodine, itaconic acid and methyl methacrylate prepared by complexing a solution of itaconic acid-methyl methacrylate copolymer comprising itaconic acid and methyl methacrylate in a ratio varying from about 1:3 to about 1:8 respectively, that is, comprising methyl methacrylate in very higher amount as compared to itaconic acid in a solvent with a solution of iodine in same solvent surprisingly acts as a female contraceptive which has been surprisingly found to be suitable for transcervical approach as well as capable of deactivating fertilizing ability of sperms and ovum in the fallopian tube and also being suitable for acting as blocking device in the fallopian tube for partial blockage and still being capable of long-lived in the fallopian tube and also being capable of reversal in nature for restoring fertility as and when desired, and hence, being capable of overcoming problems of prior art described herein above.

Accordingly, the present invention relates to a female contraceptive for transcervical approach consisting of a chemical complex of iodine, itaconic acid and methyl methacrylate in a solvent.

In one embodiment, the present invention relates to a process for preparation of female contraceptive for transcervical approach comprising complexing solution of itaconic acid-methyl methacrylate copolymer comprising itaconic acid and methyl methacrylate in a ratio varying from about 1:3 to about 1:8 respectively, that is, comprising methyl methacrylate in very higher amount as compared to itaconic acid in a solvent with solution of iodine in same solvent to produce chemical complex of iodine, itaconic acid and methyl methacrylate.

Detailed Description, Preferred Embodiments and Advantages of the Invention:

Accordingly present invention relates to a female contraceptive for transcervical delivery thereby having improved safety and out patient level handling, which is capable of deactivating fertilizing ability of sperm as well as ovum in the lumen of the fallopian tube thereby having anti-spermatozoa and anti-ovum activities and acting as blocking device in the fallopian tube for partial blockage thereby obviating problems of total blockage and still being capable of destroying fertilizing ability of sperms as well as ovum on their way through the partial blockage in the fallopian tube and also being reversible in nature thereby having capability for restoring fertility as and when desired.

In accordance with present invention the female contraceptive for transcervical approach consists of a chemical complex of iodine, itaconic acid and metliyl methacrylate in solvent, preferably dimethyl sulfoxide (DMSO) hereinafter referred to as contraceptive complex. ,

The contraceptive complex of the present invention is in the nature of a viscous liquid which can be easily delivered into the lumen of the fallopian tube via transcervical approach, that is, through a catheter inserted into the fallopian tube through the ostium which is the opening at the junction of the uterus and the fallopian tube.

It may be noted that the catheter is passed non-surgically via the vagina, cervical canal into the uterus and via the ostium into the fallopian tube thereby the presently disclosed contraceptive complex overcomes problem of invasive techniques and has been found to have advantage of improved safety and the patient can be treated in the out-patient department [OPD] itself. In accordance with the present invention, a sufficient amount of the contraceptive complex is delivered through transcervical approach so that it can spread over two-third of the length of the fallopian tube. The contraceptive complex of the present invention has been found to have advantage of special property that in due course of time it reacts with the fallopian tube secretions containing water molecules thereby leading to a hydrolytic reaction which causes the viscous liquid contraceptive complex to acquire the form of a soft solid mass and to transform into a blocking deλdce which has been found to have advantage of partially blocking lumen of the fallopian tube thereby obviating problems of total blockage and still being capable of destroying fertilizing ability of sperms as well as ovum on their way through the partial blockage in the fallopian tube.

The contraceptive complex of the present invention has been found to be insoluble in water, but soluble in DMSO, therefore it has surprisingly shown capability to stay for longer duration in the lumen of the fallopian tube and due to solubility in DMSO it has also been found to have advantage of being capable of reversal on injection of a suitable amount of DMSO which is sufficient to dissolve the contraceptive complex thereby has been found to have capability to restore fertility as and when desired.

The contraceptive complex of the present invention shows sustained pH lowering action when implanted in the lumen of the fallopian tube which appears to contribute towards the inactivation of sperms as well as ovum in the fallopian tube.

In presently disclosed contraceptive complex, the iodine preferentially

' binds with the itaconic acid and not with methyl methacrylate as illustrated by FTIR of the contraceptive complex illustrated in accompanying Figure 1 wherein peaks at 2929.9 cm ¹ and 2612.5 cm ¹ show presence of methyl group confirming binding of iodine at itaconic acid end of the complex.

During in-vitro studies performed on a simulator which mimics the fallopian tube, the presently disclosed contraceptive complex has shown strong activities against sperms as well as ovum, and has also shown stability thereby confirming its capability for long-term retention in the fallopian tube and for resisting the expulsive effect of fallopian tube peristalsis.

Accordingly, the presently disclosed contraceptive complex has been found to have strong bioactive property against both sperm as well as ovum in the fallopian tube to deactivate fertilizing ability of sperms as well as ovum. Further, the presently disclosed contraceptive complex has been found to have stable implant forming property within the fallopian tube to act as blocking device in the fallopian tube for partial blockage of fallopian tube.

The accompanying Figure 1, as stated hereinabove confirms formation of chemical complex of iodine, itaconic acid and methyl methacrylate in DMSO. Further, presence of peaks at 2929.9 cm-¹ and 2612.5 cm-¹ shows presence of methyl group which confirms that iodine preferentially binds at itaconic acid end of the complex.

The FTIR of the contraceptive complex was also compared with FTIR of itaconic acid-co-methyl methacrylate polymer [Figure 2], itaconic acid [Figure 3], methyl methacrylate [Figure 4] and iodine [Figure 5] to know whether contraceptive complex between iodine, itaconic acid and methyl methacrylate is formed or not, and if formed whether iodine binds at itaconic acid end of the contraceptive complex or at methyl methacrylate end of the contraceptive complex.

It is observed that if the spectrum contains a strong absorption band between about 1900-1600 cm-¹, the presence of carbonyl group (>C=O) in a compound is suspected. The v C=O stretching absorption in aliphatic acids occurs at about 1725-1700 cm-¹. In vapour phase v C=O absorption occurs at about 1700 cm-¹ in acetic acid and in the liquid state absorption band appears at about 1739 cm-¹. The absorption band for maleic acid appears at about 1705 cm-¹ as compared to absorption band of fumaric acid (trans) which appears at about 1680 cm ¹ in the native compound. These observations when applied to the accompanied FTIR of itaconic acid-co- methyl methacrylate polymer confirm that FTIR peak for itaconic acid appears at about 1702.9 cm-¹ in the native compound [Figure 3]. The esters show v C=O absorption at about 1750-1735 cm-¹, the ketonic form shows C=O stretching at about 1724 cm-¹ while absorption band for hydrogen bonded C=O group [stabilized by resonance] occurs at about 1650 cm-¹. These observations when applied to the accompanied FTIR of itaconic acid- co-methyl methacrylate polymer confirm that FTIR peak for methyl methacrylate appears at about 1627.6 cm-¹ in the native compound [Figure 4]-

The FTIR of contraceptive complex, that is of iodine-itaconic acid- methyl methacrylate complex [Figure 1] shows shift in FTIR peak for itaconic acid from 1702 cm-¹ to about 1723.5 cm-¹ and shift in FTIR peak for methyl acrylate from about 1627.6 cm-¹ to about 1651.7 cm ¹. This spectra of the contraceptive complex also shows shift in FTIR peaks for iodine from about 1616.5 cm-¹, about 1454.3 cm ¹, about 1019.3 cm-¹, about 794 cm-¹ [Figure 5] to about 1659.0 cm-¹, about 1437.0 cm-¹, about 953.8 cm-¹ and about 705.0 cm-¹ respectively. The FTIR peaks for C-H structure in methyl methacrylate appears at about 2880.0 cm-¹ which also shows shift to about 2929.9 cm-¹ and a new peak at about 2612.5 cm-¹ confirming presence of methyl group which in-turn confirms binding of iodine at itaconic acid end of the contraceptive complex and not at methyl methacrylate end of the contraceptive complex. Further, significant shift in the FTIR peaks in FTIR of iodine-itaconic acid-methyl methacrylate contraceptive complex confirms that the contraceptive complex is a chemical complex formed between iodine, itaconic acid and methyl methacrylate.

In one embodiment, the present invention also relates to a process for preparation of iodine-itaconic acid-methyl methacrylate contraceptive complex.

In accordance with present invention, the contraceptive complex is prepared by complexing a solution of itaconic acid-methyl methacrylate copolymer dissolved in a solvent, preferably DMSO with a solution of iodine in same solvent, that is in DMSO.

The itaconic acid-methyl methacrylate copolymer can be prepared by any method. In accordance with preferred embodiment of the present invention it is prepared by free radical copolymerization of the weighed quantities of itaconic acid monomer and methyl methacrylate monomer in the presence of benzoyl peroxide initiator, in an inert environment, preferably in nitrogen atmosphere. It has been observed that the inert environment with nitrogen helps in achieving less cross-linking between itaconic acid and methyl methacrylate which is beneficial from the point of view of reversibility when used as a female contraceptive.

In accordance with present invention, the weighed quantities of itaconic acid monomer and methyl methacrylate monomer in benzoyl peroxide initiator are shaken under the inert environment for about 2 hours followed by keeping as such for about 3 hour and maintaining the temperature at about 55°-65°C, preferably at about 62⁰C throughout the copolymerization. On completion of copolymerization, the copolymer of itaconic acid and methyl methacrylate is dissolved in DMSO. It has been observed that DMSO leads to low toxicity and improves biocompatibility on account of sulfonation.

In accordance with present invention, before radical copolymerization of itaconic acid monomer and methyl methacrylate monomer are preferably purified individually by sublimation and vacuum distillation respectively.

In accordance with present invention itaconic acid monomer and methyl methacrylate monomer are mixed in the ratio of about 1:3 to about 1:8 respectively. In accordance with one of the preferred embodiments of this invention, ratio of itaconic acid monomer and methyl methacrylate monomer is about 1:6 respectively. Accordingly, in accordance with present invention methyl methacrylate monomer is taken in very higher amount as compared to amount of itaconic acid monomer to produce itaconic acid-methyl methacrylate copolymer. It has been surprisingly observed that itaconic acid- methyl methacrylate copolymer comprising said monomers in said ratios when complexed with solution of iodine make the iodine-itaconic acid-methyl methacrylate complex suitable as a female contraceptive for transcervical approach as well as being capable of deactivating fertilizing ability of sperms and ovum in the fallopian tube and also being suitable for acting as blocking device in the fallopian tube for partial blockage of fallopian tube and still being capable of long-lived in the fallopian tube and also being capable of reversal in nature for restoring fertility as and when desired, and hence, being capable of overcoming problems of prior art described herein above.

Further, the iodine-itaconic acid-metrryl methacrylate contraceptive complex has been found to have advantage of combining electrical charge development and stability.

In accordance with preferred embodiment of present invention, the mixing of itaconic acid monomer and methyl methacrylate monomer in above ratio is preferably carried out in presence of initiator benzoyl peroxide which is taken in an amount varying from about 0.5 to about 2%, preferably about

1% of total amount of monomers.

In accordance with preferred embodiment of present invention, the copolymerization conditions include inert atmosphere preferably of nitrogen atmosphere, and temperature of about 55⁰C to about 65⁰C, continuous stirring at about 350 rpm to about 450 rpm for about 1 to 3, preferably about 1.5 hours.

The resulting itaconic acid-methyl methacrylate copolymer is preferably washed thoroughly for about 3 to 4 times preferably with warm distilled water and normal saline alternatively and repeatedly, followed by drying under vacuum of about -760 mm Hg for about 8 to 14 hrs, preferably about 12 hours.

In accordance with preferred embodiment of the present invention, the washed and dried copolymer is dissolved in the solvent [DMSO] in the ratio preferably varying from about 1:3 to about 1:7 respectively. In accordance with one of the preferred embodiments of this invention, the ratio of copolymer and solvent is preferably about 1:5 respectively. This solution is kept in an inert atmosphere for a duration preferably varying from about 24 to about 30 hours. Thereafter, normal saline or distilled water is added to the copolymer - DMSO solution to precipitate the copolymer, which has been found to have advantage of separating out unwanted products formed such as poly itaconic acid, and unbound itaconic acid monomer and methyl methacrylate monomer which will remain in the solution. The precipitate is the desired copolymer and the pH of the precipitated copolymer is then maintained in a range preferably varying from about 4.0 to about 4.5, more preferably at about 4.5.

In accordance with preferred embodiment of the present invention, the weighed amount of iodine is mixed in solvent, which is preferably DMSO in a ratio preferably varying from about 1:80 to about 1: 120 respectively. In accordance 'with one of the preferred embodiments of this invention, the ratio of iodine and solvent is preferably about 1: 100 respectively.

In accordance with present invention, the iodine-itaconic acid-methyl methacrylate contraceptive complex is prepared by complexing together the itaconic-methyl methacrylate copolymer solution in solvent with iodine solution in solvent. In accordance with preferred embodiment of this invention, the itaconic-methyl methacrylate copolymer solution and iodine solution are mixed in a ratio varying from about 1:0.1 to about 1:0.5 respectively. In accordance with one of the preferred embodiments of this invention, the itaconic-methyl methacrylate copolymer solution and iodine solution are mixed in a ratio of about 1:0.4 respectively.

In accordance with present invention, the respective amounts of solutions of itaconic-methyl methacrylate copolymer in DMSO and of iodine dissolved in DMSO may vary over a wide range so as to suit the specific need in terms of time period for onset of contraceptive action, the duration of contraceptive action and the extent of intervention required for reλfersal. However, in accordance with preferred embodiment of this invention, the itaconic-methyl methacrylate copolymer solution and iodine solution are mixed in a ratio varying from about 1:0.1 to about 1:0.5 respectively, which has been found to result in a contraceptive complex of present invention having advantages described herein.

The halogen complex of itaconic acid and methyl methacrylate when prepared in accordance with the present invention dominantly generates the electrical charge and also acts as a blocking device to partially block the fallopian tube and shows better in-υiυo stability in the fallopian tube. The contraceptive complex prepared in accordance with present invention has been found to have FTIR spectra as illustrated in Figure 1 and as discussed hereinabove, and has also been found to have advantages of being suitable for transcervical delivery thereby having improved safety and out patient level handling; capable of deactivating fertilizing ability of sperm as well as ovum in the lumen of the fallopian tube thereby having anti- spermatozoa and anti-ovum activities; capable of acting as blocking device in the fallopian tube for partial blockage thereby obviating problems of total blockage; and being reversible in nature thereby having capability for restoring fertility as and when desired and still being capable of destroying fertilizing ability of sperms as well as ovum on their way through the partial blockage in the fallopian tube.

Examples:

The present invention is now described with help of following examples, which are not intended to limit scope of present invention.

Example 1:

Partial Blocking Capability and Stability of Female Contraceptive of present Invention:-

The 2 mgs of viscous liquid form of female contraceptive complex prepared in accordance with present invention was delivered through transcervical approach into fallopian tube of female rat. After about 34 hrs it was observed that it spreads over two-third of length of fallopian tube. After about 72 hrs it was observed that it reacts with fallopian tube secretions containing water molecules and undergoes hydrolytic reaction, which converts viscous liquid form of contraceptive complex to soft solid mass having white flake like structure and not a truly cylindrical structure confirming that contraceptive complex of present invention partially blocks fallopian tube (a) as also illustrated by accompanying Figure 6, wherein white flake like structure (b) is not truly cylindrical structure. Accordingly, present contraceptive complex has been found to have advantage of obviating problems of total blockage.

Even after about 90 days it was observed that white flake like structure (b) in the fallopian tube (a) remains intact which confirms stability of contraceptive complex of present invention, which is expected to be about 4 years or more.

Accordingly, present contraceptive complex has been found to have advantage of having higher stability.

Example 2:

Blocking Device Capability of Female Contraceptive of present Invention:-

10 mgs of viscous liquid form of female contraceptive complex prepared in accordance with present invention was delivered through transcervical approach into both fallopian tubes of female rabbit. After about 2 days a radio opaque dye was also injected in the uterus and it was observed, on X-ray [Figure 7], that the radio opaque dye (a) remained confined to uterus confirming blockage of fallopian tubes by contraceptive complex of present invention as also illustrated by accompanying Figure 7. The blockage of fallopian tubes of female rabbit confirms that contraceptive complex of present invention also act blocking device, which as demonstrated by example 1 partially blocks the fallopian tube.

Accordingly, present contraceptive complex has been found to have advantage of being capable to act as blocking device which partially blocks the fallopian tube.

Example 3:

Reversible Capability of Female Contraceptive of present Invention:- In one of the two fallopian tubes of female rabbit of example 2, an injection [1 ml.] of sodium bicarbonate solution comprising 8.4% wt/vol of sodium bicarbonate in water was injected. It was observed, on X-ray [Figure 8], that the radio opaque dye (a) travels from uterus through fallopian tube to peritoneal cavity (b) confirming opening of blockage of fallopian tubes by reversal of contraceptive complex from that fallopian tube as also illustrated by accompanying Figure 8. The opening of blockage of fallopian tubes of female rabbit on injection of solution of sodium bicarbonate confirms that contraceptive complex of present invention is capable of reversal as and when desired, which as demonstrated by example 1 partially blocks the fallopian tube and as demonstrated by example 2 also acts as blocking device.

Accordingly, present contraceptive complex has been found to have advantage of being capable of acting as blocking device which partially blocks the fallopian tube and can be reversed as and when desired merely by an injection of solution of sodium bicarbonate.

Example 4:

Anti-Ovum Capability / Efficacy of Female Contraceptive of present Invention :-

The enhanced anti-ovum capability / efficacy of present contraceptive complex was checked on albino rat gametes. The freshly collected albino rat ovum [Figure 9a] was compared with those treated [Figure 9b] with contraceptive complex of present invention. Among several anti-ovum capabilities/ efficacy of contraceptive complex of present invention some significant effects comprise gamete swelling, discoloration followed by rupture and decrease in egg cell viability as also demonstrated by accomρan30ng Figure 9, wherein Figure 9a illustrates freshly collected ovum having intact cell membrane / boundary (a) and center (b) surrounded by immature egg cells and epithelial cells (c) and Figure 9b illustrates ovum, treated with contraceptive complex of present invention, having ruptured ovum cell boundary (a) and ovum body cell (b) and destrojred egg and epithelial cells (c) which confirms that ovum gets deactivated /destroyed and egg viability is decreased on exposure to contraceptive complex of present invention.

Accordingly, present contraceptive complex has been found to have advantage not only of being capable of acting as blocking device which partially blocks the fallopian tube and can be reversed as and when desired merely, but also having anti-ovum capability/ efficacy.

Example 5:

Anti-Spermatazoa Capability/ Efficacy of Female Contraceptive of present Invention:-

The enhanced anti-spermatazoa capability / efficacy of present contraceptive complex was checked on albino rat gametes. The freshly collected albino rat sperms [Figure 10a] were compared with those treated

(Figure 10b] with contraceptive complex of present invention. Among several anti-sperm capabilities/ efficacy of contraceptive complex of present invention some significant effects comprise decrease in sperm count and thus spermatozoa viabilit3_% discoloration and finally spermatozoa rupture when kept for longer duration with contraceptive complex of present invention as also demonstrated by accompanying Figure 10, wherein Figure

10a illustrates freshly collected spermatozoa having intact sperm head (d), middle part of sperm (e) and tail part of sperm (f) , and Figure 10b illustrates spermatozoa, treated with contraceptive complex of present invention, having ruptured sperm consisting of ruptured head of sperm (d), ruptured middle part of sperm (e) and ruptured tail part of sperm (f).

Accordingly, present contraceptive complex has been found to have advantage not only of being capable of acting as blocking device which partially blocks the fallopian tube and can be reversed as and when desired merely, anti-ovum capability/ efficacy, but also having anti-spermatazoa capability / efficacy.

It is obvious to persons skilled in the art that various modifications are possible of present invention without deviating from scope thereof. Therefore, in one embodiment, such modification are included within scope of present invention.

It may be noted that word "about" has been incorporated to include practical variations in each value to which it refers.

It may be noted that relative amounts of various ingredients have been defined in ratios, which is intended to include amounts by weight, by volume or molar ratios.

Claims

1. A female contraceptive for transcervical approach consisting of a chemical complex of iodine, itaconic acid and methyl methacrylate in a solvent.

2. A contraceptive as claimed in claim 1, wherein said solvent is preferably dimethyl sulfoxide (DMSO).

3. A contraceptive as claimed in claim 1 or claim 2, wherein itaconic acid and methyl methacrylate are taken in a ratio varying from about 1:3 to about 1:8 respectively.

4. A contraceptive as claimed in claim 3, wherein itaconic acid and methyl methacrylate are preferably taken in a ratio of about 1:6 respectively.

5. A contraceptive as claimed in any one of preceding claims, which is insoluble in water and soluble in DMSO.

6. A contraceptive as claimed in any one of preceding claims, wherein iodine preferentially binds with itaconic acid and not with methyl mehtacrylate and said contraceptive has FTIR illustrated in Figure 1.

7. A contraceptive as claimed in an}_^ one of preceding claims, which has sustained pH lowering action.

8. A contraceptive as claimed in any one of preceding claims, having bioactive property against both sperm as well as ovum in the fallopian tube to deactivate fertilizing ability of sperms as well as ovum.

9. A contraceptive as claimed in any one of preceding claims, having stable implant forming capability within the fallopian tube to act as blocking device in the fallopian tube for partial blockage of fallopian tube.

10. A contraceptive as claimed in any one of preceding claims, which is capable of long-lived in the fallopian tube.

11. A contraceptive as claimed in any one of preceding claims, which is capable of reversal for restoring fertility as and when desired.

12. A contraceptive as claimed in any one of preceding claims, having electrical charge development and stability.

13. A process for preparation of female contraceptive for transcervical approach comprising complexing solution of itaconic acid-methyl methacrylate copolymer comprising itaconic acid and methyl methacrylate in a ratio varying from about 1:3 to about 1:8 respectively with solution of iodine to produce chemical complex of iodine, itaconic acid and methyl methacrylate.

14. A process as claimed in claim 13, wherein said solutions are prepared in a solvent, which is preferably DMSO.

15. A process as claimed in claim 13, wherein said itaconic acid-methyl methacrylate copolymer is prepared by free radical copolymerization of weighed quantities of itaconic acid monomer and methyl methacrylate monomer.

16. A process as claimed in claim 13 or 15, wherein mixing of itaconic acid monomer and methyl methacrylate monomer is preferably carried out in presence of initiator benzoyl peroxide.

17. A process as claimed in claim 16, wherein said initiator is taken in an amount varying from about 0.5 to about 2% of the total amount of monomers.

18. A process as claimed in claim 16 or claim 17, wherein said initiator is taken in an amount of about 1% of the total amount of monomers.

19. A process as claimed in claim 13 or claim 14, wherein said copolymer is dissolved in said solvent in a ratio varying from about 1:3 to about 1:7 of copolymer and solvent respectively.

20. A process as claimed in claim 19, wherein said ratio of said copolymer and said solvent is about 1:5 respectively.

21. A process as claimed in any one of preceding claims 13 to 20, wherein said iodine is mixed in said solvent in a ratio varying from about 1:80 to about 1: 120 respectively.

22. A process as claimed in claim 21, wherein said ratio of iodine and said solvent is preferably about 1: 100 respectively.

23. A process as claimed in any one of preceding claims 13 to 22, wherein said itaconic-methyl methacrylate copolymer solution and iodine solution are mixed in a ratio varying from about 1:0.1 to about 1:0.5 respectively.

24. A process as claimed in claim 23, wherein said itaconic-methyl methacrylate copolymer solution and iodine solution are mixed in a ratio of about 1:0.4 respectively.

25. A method for delivery of female contraceptive, which is delivered into lumen of fallopian tube via transcervical approach through a catheter inserted into fallopian tube through ostium.

26. A method as claimed in Claim 25, wherein catheter is passed non- surgicaUy via the vagina, cervical canal into the uterus and via the ostium into the fallopian tube.

27. A method as claimed in Claim 25, wherein said contraceptive is delivered in sufficient amount so that it is suitable to spread over two-third of length of the fallopian tube.

28. A method for reversal of female contraceptive, which is reversed on injection of a solvent selected from DMSO and sodium bicarbonate, preferably DMSO.

29. Use of female contraceptive consisting of a chemical complex of iodine, itaconic acid and methyl methacrylate for deactivating sperms as well as ovum in the fallopian tube.

30. A female contraceptive for transcervical approach substantially as herein described with the help of foregoing examples and as illustrated with reference to accompanying figures.

31. A process for preparation of female contraceptive for transcervical approach substantially as herein described with the help of foregoing examples and as illustrated with reference to accompanying figures.