FIELD OF THE INVENTION:

The present invention generally relates to reproductive health. More particularly, it relates to a method and formulation of sublingual oxytocin film or tablet for treatment of sexual dysfunction, male factor infertility and postpartum haemorrhage.

BACKGROUND OF THE INVENTION:

Sexual dysfunction is defined by the World Health Organisation (WHO) as "the various ways in which an individual is unable to participate in a sexual relationship as he or she would wish". Sexual dysfunction affects both men and women. Male sexual dysfunction can be categorized as disorders of desire, disorders of orgasm, erectile dysfunction, disorders of ejaculation and failure of detumescence.

According to the revised definition from the American Foundation of Urological Disease (AFUD) International Consensus Committee, female sexual disorders can be categorized as sexual desire disorder, sexual arousal disorder, orgasmic disorder and sexual pain disorder.

Male factor infertility is defined as the presence of abnormalities in the semen analysis or the presence of sexual or ejaculatory dysfunction. This alteration may be associated with low sperm production (oligozoospermia), poor sperm motility (asthenozoospermia) or abnormal sperm morphology (teratozoospermia); however, generally, a combination of these, oligoasthenoteratozoospermia (OAT).

Oxytocin (OT) is considered as 'female' neurohypophysis hormone due to its role in parturition and milk ejection. However, OT is recognized as having endocrine and paracrine roles in male reproduction. At ejaculation, a burst of OT is released from the neurohypophysis into the systemic circulation and stimulates contractions of the reproductive tract aiding sperm release. There is conclusive evidence that OT is synthesized within the mammalian testis, epididymis and prostate and the presence of OT receptors (OTRs) through the reproductive tract supports a local action for this peptide. OT has a paracrine role in stimulating contractility of the seminiferous tubules, epididymis and the prostate gland. The elucidation of OT's role in male reproduction has suggested a number of potential therapeutic uses for this hormone. (Hemlata et ah 2006)

At the level of endocrine sexual physiology, oxytocin has been identified as a marker of orgasm in humans, with circulating levels of oxytocin significantly increasing in males and females around the time of orgasm, though less consistently so than those of prolactin (Carmichael et ah, 1987; Murphy et ah, 1987 and Murphy et ah, 1990; Krueger et ah, 1998 and Krueger et ah, 2003a; and Blaicher et ah, 1999). It has been postulated that OT may play a facilitating role in sperm and egg transport by increasing smooth muscle contractility in the reproductive tracts (Wildt et ah, 1998).

Moreover, several studies have well documented that levels of circulating oxytocin increase during sexual stimulation and arousal with a peak during orgasm in both women and men (Argiolas and Melis, 2003; Carmichael et ah, 1987; Carter, 1992; Gimpl and Fahrenholz, 2001; and Murphy et ah, 1990). Uckert et ah, 2003 studies indicate that the oxytocin plays an important role in male sexual arousal and penile erection.

Research study suggests that oxytocin is used in sexual dysfunction, both male (Lidberg et ah, 1977) and female (Anderson-Hunt, et ah, 1994). Thus, the oxytocin may be used in the treatment of male and female sexual dysfunction.

Oxytocin has shown to promote sperm progression through the reproductive tract by improving epididymal contractility (Filippi et ah, 2002). It can thus be used to increase sperm retrieval in men with oligozoospermia. Oxytocin is only available as injectable for inducing labor, controlling bleeding after childbirth, and for the treatment of incomplete or inevitable abortion and nasal solution for lactation stimulant.

The above research study suggests, oxytocin may also be used for treating male and female sexual dysfunction patients and male factor infertility patients.

United States Patent Number 3,943,246 to Egon Sturmer entitled "Organic Compounds" addresses to buccal and peroral administration of daily doses of 300—1500 international units (I.U.) of oxytocin or daily divided doses of 150—250 I.U. of desamino-oxytocin to treatment of impotence in men.

United States Patent Application Number 20060034920 to Finn Larsen entitled "Effervescent formulations of oxytocin" discloses effervescent formulations of oxytocin and their use in the induction or augmentation of labour during parturition.
Publication Number EP2161030 entitled "oxytocin formulation and uses thereof" relates to the aqueous oxytocin formulations and their use in therapeutic and /or prophylactic treatment of haemorrhage. The medicament is in the form of solution, suspension, emulsion, spray or gel-United States Patent Number 8790704 and PCT Publication Number 2006010939 relate to bioactive particles such as peptides that can be delivered in the form of film. The film strip is placed under the tongue for drug delivery in the treatment of diabetes mellitus.

PCT Publication Number 2011064316 to Paolo Botti et al. entitled "Mucosal delivery compositions comprising a peptide complexed with a crown compound and/or a counter ion" relates to compositions and methods for mucosal delivery of peptides. The compositions can be provided in a free form, such as a liquid, gel, foam, cream, ointment, semisolid or spray, or can comprise a device of determined physical form, such as tablets, patches, films, and troches in the treatment of diabetes, obesity and related conditions.

United States Patent Application Number 20120183580 to Michel Lazdunski entitled "Analgesic Composition for Transbuccal Administration" relates to a composition of analgesic peptide. The composition is administrated via transbuccal route for preventing or treating pain. The composition can be administered in any shape of film, lollipop, chewing-gum, mouthwash, toothpaste, buccal drop or spray.

PCT Publication Number 2011137491 to Allan Mark Evans et al. entitled "Novel drug delivery system" relates to transmuscosal drug delivery. The active agent is absorbed across buccal, tongue, sublingual means in the mouth. The active ingredient can be in the form of tablet, pellet, powder, granule, film or capsule.

United States Patent Application Number 20130085100 to Francoise Rohner-Jeanrenaud entitled "New Uses of Oxytocin-Like Molecules and Related Methods" relates to composition of oxytocin for treatment purpose. The compositions may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, ointments, emulsions, elixirs, or capsules filled with the same, films or gels which are all for oral use in the treatment of metabolic syndrome.

Patent and Publication Numbers EP0857063, WO2004041118 and US20130231279 relate to methods for delivering a paramedical / therapeutic agent such as oxytocin peptide. The composition of drugs can be delivered through oral route such as via buccal tissue.
PCT Publication Number 2000062764 to Alayne Yates entitled "Gum pad for delivery of medication to mucosal tissues" relates to a method for providing treatment to systemic diseases. It includes a layered pad (Gum Pad) which is worn intra-orally on the gums for dispensing medication contained in the pad by saliva diffusion and transporting to the oral mucosal tissues.

The above listed prior art disclose about oral dissolving drug delivery containing peptide drug oxytocin for treating disease such as diabetes, systemic diseases and metabolic syndrome.

The existing formulation for treatment of sexual dysfunction, male factor infertility and postpartum haemorrhage uses injection and nasal solutions for administering oxytocin. Currently, there is a need for a simple, convenient, non invasive dosage form which can be administered immediately before sex, to treat sexual dysfunction patients and male infertility patients and provide its action quickly.

Therefore, the present invention provides a formulation and method for administering oxytocin in the form of sublingual film or tablet for treating diseases like sexual dysfunction, male factor infertility and postpartum haemorrhage. The film or tablet disintegrates in mouth faster between about 20 sec to 3 minutes and most desirably between 20 sec to 1 minute.

SUMMARY OF THE INVENTION

An object of the present invention is to provide a method and formulation of oxytocin in the form of sublingual film or sublingual tablet for treating male and female sexual dysfunction, male factor infertility and postpartum hemorrhage.

The pharmaceutical formulation of sublingual film or tablet comprises an active ingredient oxytocin. The quantity of the active ingredient to be used in the composition depends on the disease to be treated, the desired frequency of administration and the desired effect. Preferred active ingredient quantity is between 20 and 600 I.U and more preferably between 25 and 400 I.U per film or tablet.

The sublingual oxytocin film or tablet formulation also comprises one or more diluents, one or more saliva stimulating agents, one or more polyols and one or more pharmaceutically acceptable excipient. In addition, the sublingual film formulation of oxytocin comprises a one or more film formers.
The film formers are selected from a group consisting of polyethylene oxide, pullulan, hydroxypropylm ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, maltodextrin, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch and gelatine.

The diluents are selected from a group consisting of anhydrous dibasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, mannitol, maltodextrin, pregelatinized starch, hydroxypropyl methyl cellulose, hydroxyl ethyl cellulose, maltitol, sorbitol, starch, dextrin, calcium carbonate and xylitol.

The saliva stimulating agents are selected from a group consisting of citric acid, lactic acid, malic acid, ascorbic acid and tartaric acid.

The polyols that used to prevent oxidation are selected from a group consisting of mannitol, sucralose and maltose.

The 'pharmaceutically acceptable excipient' includes any inactive ingredient which is required for the formulation of sublingual film or tablet. Particularly, the excipient includes, but not limited to, penetration enhancer, binders, lubricants, buffering agents, stabilizers, coloring agents, fillers, bulking agents, preservatives, sweetening agents, flavoring agents, plasticizers, disintegrating agents, anti-foaming agents, anti-adherents, solvents, surfactants and emulsifiers in amounts suitable for their intended purpose.

When the sublingual film or tablet formulation is placed under the tongue, that close to the base on the left or right side, it allowed to completely dissolve and provides immediate release of oxytocin by sublingual route and reaches systemic circulation by bypassing first pass metabolism.
These objectives and advantages of the invention will become more evident from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION:
Presented herein are pharmaceutical formulation and method for treating male and female sexual dysfunction, male factor infertility especially oligozoospermic and postpartum hemorrhage by sublingual administration of oxytocin in the form of film or tablet.
The pharmaceutical formulation of the sublingual oxytocin film or tablet comprises an active ingredient oxytocin, one or more diluents, one or more saliva stimulating agent, one or more polyols and one or more pharmaceutically acceptable excipient. In addition, the sublingual film formulation of oxytocin comprises a one or more film formers. The quantity of the active ingredient to be used in the composition is depends on the disease to be treated, the desired frequency of administration and the desired effect. Preferred active ingredient quantity is between 20 and 600 I.U and more preferably between 25 and 400 I.U per film or tablet.

The film formers are selected from a group consisting of polyethylene oxide, pullulan, hydroxypropylm ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, maltodextrin, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch and gelatine.

The diluents are selected from a group consisting of anhydrous dibasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, mannitol, maltodextrin, pregelatinized starch, hydroxypropyl methyl cellulose, hydroxyl ethyl cellulose, maltitol, sorbitol, starch, dextrin, calcium carbonate and xylitol.

The saliva stimulating agents are selected from a group consisting of citric acid, lactic acid, malic acid, ascorbic acid and tartaric acid.

The polyols that used to prevent oxidation are selected from a group consisting of mannitol, sucralose and maltose.

The 'pharmaceutically acceptable excipient' includes any inactive ingredient which is required for the formulation of sublingual film or tablet. Particularly the excipient includes, but not limited to, penetration enhancer, binders, lubricants, buffering agents, stabilizers, coloring agents, fillers, bulking agents, preservatives, sweetening agents, flavoring agent, plasticizers, disintegrating agents, anti-foaming agents, anti- adherents, solvents, surfactants and emulsifiers in amounts suitable for their intended purpose.
The penetration enhancer includes anionic, nonionic and cationic surfactants such as sodium lauryl sulphate, polysorbates, L-Lysine, Chelating agents such as citric acid, salicylates, EDTA and polyols such as propylene glycol, glycerol, propylene glycol, and polyvinyl pyrolidone.

The disintegrant includes croscarmellose sodium, sodium starch glycolate, crosspovidone, hydroxypropyl cellulose, amberlite, microcrystalline cellulose and pregelatinized starch.

The lubricant includes magnesium stearate, hydrogenated castor oil, stearic acid and sodium stearyl fumarate.

According to the present invention, the sublingual film is formed by solvent casting method using a wet film applicator or casting equipment. The film is dried under laminar flow and subjected to heat/vaccum. Then, the film is cut in desired shape and size of unit dosage form.

The sublingual film is alternatively prepared by extrusion method using hot melt extruder involving blending ingredients to form a film using mechanical force and moderate heat.

According to the present invention, the sublingual tablet is prepared by direct compression method or dry granulation method or wet granulation method.

When the sublingual film or tablet formulation is placed under the tongue, that close to the base on the left or right side, it allowes to completely dissolve and provides immediate release of oxytocin by sublingual route and reaches systemic circulation by bypassing first pass metabolism.

The film of the present invention has a size between about 2.5cm x 2.5 cm. Preferably, the film size is between 2 cm x 1.5 cm. The film or tablet dosage form disintegrates in mouth faster that is between 20 sec to 3 minutes and most desirably between about 20 sec and about 1 minute.

Examples:
The present invention is illustrated in more detail with reference to the following examples, but it should be understood that the present invention is not deemed to be limited thereto.

Example 1

Preparation method for film:
The following method was used to prepare the films of Examples 1-4. The ingredients in Table 1 were combined to provide an example of an oxytocin film in accordance with the following procedure:
A. HPMC E 15 was dispersed in hot water heated at 90°C under stirring
B. Maltodextrin, mannitol, citric acid, sodium citrate, sucralose, croscarmellose sodium were mixed in separate container to provide preparation B
C. Preparation B was slowly added to Preparation A under stirring.
D. Carboxymethyl cellulose sodium and Dibasic calcium phosphate was slowly added to Preparation C under stirring.
E. Oxytocin was slowly added to Preparation D under stirring and then it was stirred for 5 minutes.
Preparation E was casted to form a film of a desired thickness at room temperature.
The casted film was dried under warm air and cut to a desired dimension and evaluated
for its physical properties such as appearance and disintegration time.

Example 2
Preparation method for tablet:
The following method was used to prepare the tablets of Example 5 and 6. The ingredients in Table 2 were combined to provide an example of an oxytocin tablet in accordance with the following procedure:
A. The ingredients were weighed and screened through a 30 mesh screen and blended in blender for 10 minutes.
B. Magnesium stearate were screened through a 60 mesh screen and then added to preparation A mix in the blender, and mixed for 5 minutes.
C. The resulting final blend of Preparation B was compressed into tablets using a rotary tablet press in a controlled environment. Tablets were compressed at a compression weight of 100 mg using round punch.

While the foregoing written description of the invention enables one of ordinary skill to make and use what is considered presently to be the best mode thereof, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The invention should therefore not be limited by the above described embodiment, method, and examples, but by all embodiments and methods within the scope and spirit of the invention as claimed.

CLAIM:

1. A pharmaceutical formulation of oxytocin for sublingual administration, comprising:
(a) an active ingredient oxytocin, wherein said oxytocin is present in an amount from about 20 - 600 I.U, preferably from about 25 - 400 I.U;
(b) at least one saliva stimulating agent;
(c) at least one polyol, wherein said polyol is to prevent oxidation;
(d) at least one diluent; and
(e) at least one pharmaceutical^ acceptable excipients.

2. The formulation according to claim 01, is in the form of sublingual film or sublingual tablet.

3. The formulation according to claim 02, wherein said sublingual film further comprises one or more film formers selected from polyethylene oxide, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, maltodextrin, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch and gelatin.

4. The formulation according to claim 01, wherein said saliva stimulating agent is selected from citric acid, lactic acid, malic acid, ascorbic acid and tartaric acid.

5. The formulation according to claim 01, wherein said polyol is selected from mannitol, sucralose and maltose.

6. The formulation according to claim 01, wherein said diluent is selected from anhydrous dibasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, mannitol, maltodextrin, pregelatinized starch, hydroxypropyl methyl cellulose, hydroxyl ethyl cellulose, maltitol, sorbitol, starch, dextrin, calcium carbonate and xylitol.

7. The formulation according to claim 01, wherein said pharmaceutically acceptable excipient is selected from a group consisting of binders, lubricants, buffering agents, stabilizers, coloring agents, fillers, bulking agents, preservatives, sweetening agents, flavoring agent, plasticizers, penetration enhancers, disintegrating agents, anti-foaming agents, anti- adherents, solvents, surfactants and emulsifiers.

8. The formulation according to claim 01, exhibits an oral disintegration time of about 20 sec to 1 minute.

9. The formulation according to claim 02, wherein said film is prepared via solvent casting or extrusion method.

10. The formulation according to claim 02, wherein said tablet is prepared via direct compression or dry granulation or wet granulation.

11. A method of treating sexual dysfunction, male factor infertility and postpartum hemorrhage in a patient in need thereof, comprising the step of: administering the pharmaceutical formulation of claim 01 to said patient sublingually, wherein said formulation is in the form of film or tablet.

12. A sublingual formulation comprising oxytocin for treating sexual dysfunction, male factor infertility and postpartum haemorrhage, as substantially described herein with reference to the examples.