FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"VAGINAL PROGESTERONE TABLETS"
2. APPLICANT (S):
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: B- Wing, 10lh Floor, BSEL Tech Park, Sector 30 A,
Plot no.39/5 & 39/5A, Opp. Vashi Railway Station, Navi-Mumbai- 400 705, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

Technical field:
The present invention relates to. sustained release effervescent vaginal progesterone pharmaceutical composition to support developing embryo in progesterone deficient women and to process for preparation thereof.
Background and prior art:
Hormonal Balance is an important factor when it comes to healthy fertility and getting pregnant. During the course of a menstrual cycle various hormones are working together in a complex symphony to trigger the various components of ovulation and menstruation. Progesterone is one of these key hormones. After ovulation, Luteinizing Hormone (LH) stimulates the corpus luteum (the remnant egg sac) in the ovary to produce progesterone. One of the main actions of progesterone with fertility is to help support developing embryo in progesterone deficient women. Natural progesterone is devoid of teratogenicity as well as it is devoid of any androgenic activity that might compromise lipoprotein metabolism. Moreover, it probably has a direct beneficial effect on blood vessels (Jiang et al), Eur. J. Pharmacol. 211(1992), 163-167). However, the major difficulty in utilizing natural progesterone is its highly limited bioavailability through oral route.
Various methods for administering progesterone are known such as creams, foams, gels, in solid oral dosage forms etc.
US6866865 relates to the oil based and polymer based oral progesterone drug delivery systems in the form of solid dosage forms such as tablets, capsules, caplets, powders. encapsulated pellets, encapsulated granules, or encapsulated powders along with polymer coating. Further, the said patent uses oils as vehicles for absorption & solubilising agent like polyethylene glycol of different molecular weights and grades for oral route of progesterone administration.
Indian patent Application 3 18/K.OLNP/2007 relates to the polymer based vaginal ring composition comprising of a synthetic polymer having contained therein a contraceptive!}' effective amount of a progesterone receptor modulator (PRM)

U.S. Pat. Nos. 5,084.277 and 5,116,619, both to Greco et al., disclose a process for the preparation of a progesterone-containing tablet. The Greco et al. process involves wet granulation of progesterone into the tablets.
However the prior art methods of delivering progesterone are met with certain limitations such as low bioavailability and often require multiple daily doses to ensure the desired therapeutic effect.
The vagina provides a promising site for local effect as well as systemic drug delivery because of its large surface area, rich blood supply, avoidance of the first-pass effect, relatively high permeability to many drugs and self-insertion; [Valenta C. The use of mucoadhesive polymers in vaginal delivery.Adv Drug Deliv Rev 2005; 57: 1692-1712.(2) Knuth K, Amiji M, Robinson JR;. Hydrogel delivery systems for vaginal and oral applications. Formulation and biological considerations. Adv Drug Deliv Rev 1993; 1 1: 137-167]
Many vaginal formulations have been assayed, mostly as suppositories (Price et al., Fertil. Steril. 39 (1983), 490-493; Norman et al., Fertil. Steril. 56 (1991), 1034-1039; Archer et al., Am. J. Obstet. Gynecol., 173 (1995), 471-478), gelatin capsules (Devroey et al., Int. J. Fertil. 34 (1989), 188-193: Smitz et al; Hum. Reprod. 2 (1992), 309-314; Miles et al., Fertil. Steril, 62 (1994), 485-490), and recently as bio-adhesive gels (Fanchin et al., Obstet. Gynecol. 90 (1997), 396-401; Ross et al., Am. J. Obstet. Gynecol. 177 (1997), 937-941).
Although the suppositories are easily inserted, they melt at body temperature and lead to disturbing vaginal discharge. Oral gelatin capsule containing micronized progesterone have also been used vaginally (Devroey et al., Int. J. Fertil. 34 (1989), 188-193; Smitz et al. Hum. Reprod. 2 (1992), 309-314; Miles et al, Fertil. Steril. 62 (1994), 485-490), but insertion of a small capsule deep within the vagina is difficult and large doses are needed to achieve adequate plasma concentration (Smitz et al. Hum. Reprod. 2 (1992), 309-314; Miles et al, Fertil. Steril. 62 (1994), 485-490; Bourgain et al. Hum. Reprod. 5 (1990), 537-543).

Further progesterone has high solubility in water and is rapidly degraded by the liver which contributes to a very poor systemic availability of the active ingredient. However, if the active ingredient is to be vaginally administered, incorporation of an effervescent is found to be helpful, since the effervescent would aid in the dissolution of the tablet and absorption of the progesterone into the bloodstream.
US7393543 discloses a pharmaceutical tablet comprising of dry natural progesterone as an active ingredient, pharmaceutically acceptable excipients, and an effervescent, for the vaginal administration of progesterone for systemic use. The method comprises first mixing water with micronized progesterone, the total amount of water mixed with said micronized progesterone not exceeding the maximum wetting capacity of the micronized progesterone, drying the wetted, micronized progesterone; mixing the dry micronized progesterone with other pharmaceutically acceptable excipients or diluents; and; forming a tablet by direct compaction of the dry micronized progesterone. The tablet is having a Tmax upon disintegration of at least 3 hours but is not a sustained release tablet.
With a view that vagina could provide a potential route for systemic drug delivery with a direct entry into the blood stream through vaginal wall and with the possibility of bypassing the hepatic-gastrointestinal (Gl) metabolism, the present inventors felt a need to develop solid dosage composition comprising an effervescent for vaginal administration of progesterone for systemic use that is well tolerated, safe and which gives sustained release of API.
Object of the invention:
The object of the invention is to develop pharmaceutical composition for sustained release vaginal delivery of progesterone in solid dosage form.
Another object of the invention is to develop a formulation comprising of an effervescent along with pharmaceutical excipients having sustained release properties, without any systemic side-effects and which has a better patient compliance.

Yet another object of the invention is to provide a process for the preparation of effervescent vaginal progesterone sustained release tablets.
Summary of the invention:
In line with the objective, the present invention discloses pharmaceutical composition comprising a Sustained Release Effervescent Vaginal Progesterone in solid dosage forms along with pharmaceutically acceptable excipients to support developing embryo in progesterone deficient women and to process for preparation thereof.
In an aspect of the present invention, sustained release vaginal progesterone solid dosage form comprises of progesterone as an active ingredient, an effervescent agent along with pharmaceutically acceptable excipients.
The sustained release progesterone tablets of the current invention are delivered intravaginally without any systemic side-effects and therefore having better patient compliance.
Detailed description:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated and briefly described as follows.
As used herein the phrase "Tablet" means and includes the drug delivery system that is inserted into vagina where it dissolves or disperse or disintegrate, which are coated or uncoated, pellets and granules and the like, that can be used to fill in the capsule which employ excipients to deliver active agent(s).
The present invention discloses sustained release effervescent vaginal progesterone pharmaceutical composition and the process of preparation thereof.
Accordingly, the present invention describes pharmaceutical composition comprising Sustained Release Effervescent Vaginal Progesterone in the solid dosage form that can be

inserted in vagina, useful to support the developing embryo in progesterone deficient women and to process for preparation thereof.
In an embodiment, the instant invention provides Sustained Release Effervescent Vaginal Progesterone tablets consisting of progesterone, effervescent agent along with pharmaceutically acceptable excipients.
In a preferred embodiment, the pharmaceutical composition of the present invention in a
unit dosage form comprises Progesterone in an amount of 100 mg - 400 mg. an
effervescent agent along with pharmaceuticaily acceptable excipients.
In another preferred embodiment of the invention, said effervescent agent is a mixture of a pharmaceuticaily acceptable carboxylic or dicarboxylic acid, such as citric acid, adipic acid or tartaric acid, and a pharmaceuticaily acceptable salt of carbonates or bicarbonates such as sodium bicarbonate. Preferably the acid and bicarbonate are present in an amount providing a molar excess of-COOH groups.
The pharmaceuticaily acceptable excipients are selected from diluents, disintegrants, lubricants, binders, glidants and anti-adherent, anti-tacking agent, film forming polymer. vehicle, colorant and solvent, flavouring agents .coloring agents , sweetening agents and tablet bases etc.
Diluents may be selected from sucrose, mannitol, sorbitol, xylitol, and maltitol, present in an amount of 1-75% vv/w.
Disintegrants may be selected from crospovidone, carmellose sodium, sodium cmc(carboxy methyl cellulose), carboxy methyl cellulose, cellulose and / or sodium starch glycollate, pregelatinized starch, cellulose derivatives including microcrystalline cellulose. low-substituted hydroxypropyl cellulose (e.g. LH22, LH21, LH20, LH32, LH31, LH30); starches including potato starch; croscarmellose sodium (i.e. cross-linked carboxymethylcellulose sodium salt; e.g. Ac-Di-Sol®); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Polyvidon® CL, Polyvidon® CL-M, Kollidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); sodium starch Glycollate (e.g. Primogel® and Explotab®); present in an amount of 1-25% w/w.

Lubricants may be selected from zinc stearate, magnesium oxide, magnesium aluminium silicate, calcium stearate, sodium chloride and / or magnesium stearate, oils, parrafins, sorbitol, present in an amount of 0.5 - 5.0% w/w.
Binders may be selected from HPMC, HPMCP, Hydroxypropyl Cellulose, Starch paste, Sodium CMC, Starch 1500, Gum acacia, and /or Polyvinylpyrrolidone, Gelatin present in an amount of 1 - 25% w/w.
Gildants may be selected from pregelatinised starch, talc, tribasic calcium phosphate, dibasic calcium phosphate magnesium trisilicate, and / or colloidal silicon dioxide; present in an amount of 0.25 - 10% w/w.
Anti-adherent may be selected from colloidal silicon dioxide, Bentonale clay; present in an amount of 0.25 - 5% w/w,
Anti-tacking agent may be selected from magnesium stearate, calcium stearate, talc, sodium benzoate, colloidal silicon dioxide present in an amount of 0 - 10% w/w.
Film forming polymer may be selected from cellulose acetate, phthalic acid esters, methyl cellulose, ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, polyvinyl acetate, polyvinyl alcohol, crotonic acid-methacrylic acid ester copolymer. methyl methacrylate-methacrylic acid copolymer, polyethylene glycol, polyethylene, polyethylenevinyl acetate copolymer. Polyvinylpyrrolidone, polypropylene and mixtures thereof; present in an amount of 0.1-50% w/w.
Vehicle may be selected from vegetable oil such as Flax seed oil base. Wheat germ oil
etc.
Colorant may be selected from soluble dyes and insoluble lakes; present in an amount of 0.1 to 2% w/w.
Solvent used for granulation or dissolving or suspending ingredients may be selected from corn oil, water, acetone, methanol ethanol, propylene glycol, polyethylene glycol and /or isopropyl alcohol, dichloromethane.

Tablet Base may be selected from Polyethylene glycols and its grades from 100 to 40000, Carnauba wax, witepsol, glycerol, gelatin, lanolin, bees wax etc.
The effervescent vaginal progesterone tablets according to the present invention consists of quick release part & sustained release part along with pharmaceutically acceptable excipients compacted to form tablets which can achieve a sustained release of the active ingredient.
Accordingly, in a preferred embodiment, the present invention discloses sustained release vaginal pharmaceutical composition comprising; (a) upto 30% micronized progesterone quick release granules and an effervescent agent; (b) 70% micronized progesterone sustained release granules; and a tablet base along with one or more pharmaceutical excipients.
Accordingly, the pharmaceutical composition of the present invention can be formulated in three parts as Quick release Granules, Sustained Release granules and Tablets base preparation.
In an embodiment, the process of making sustained release vaginal pharmaceutical composition comprises the steps of;
a. preparing upto 30% progesterone quick release granules;
b. preparing 70% progesterone sustained release granules;
c. preparing a tablet base;
d. dispersing granules of step fa) and step (b) to molten tablet basefc): and
e. compacting and optionally coating the tablets.
The granules may be prepared from dry granulation technique, wet granulation technique, directly compressible granules, coated granules, enteric coated granules, modified release granules, or pellets, sustained release pellets, modified release pellets, effervescent granules or polymer coated granules.
The pharmaceutically acceptable excipients are selected from polymers such as various grades of HPMC. Cellulose Acetate Phthalate, polyvinylpyrrolidone, polyethylene glycol,

cellulose acetate, phthalic acid esters, methyl cellulose, ethyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, polyvinyl acetate, polyvinyl alcohol, crotonic acid-methacryiic acid ester copolymer, methyl methacrylate-methacryiic acid copolymer, , polyethylene, polyethylenevinyl acetate copolymer, polypropylene and mixtures thereof; present in an amount of 0.1-50% w/w.
In yet another embodiment, the pharmaceutical composition of present invention comprising Progesterone in a tablet form can be prepared using wet granulation process or dry granulation, hot or cold granulation process, direct compression or slugging process.
Accordingly, the process for preparation of Sustained Release Effervescent Vaginal Progesterone Tablet 100- 400 mg comprises the following steps:
Step-1: Preparation of Quick Release Granules

Ingredients Quantity
Progesterone(micronized) 10-50 %
Lactose 5- 50 %
Maize Starch 1-5 %
Citric Acid 0.5 - 20%
Sodium Bicarbonate 0.50-15%
Mannitol 5 -70 %
Sodium Lauryl Sulphate 0.1-5.0%
Polyvinylpyrrolidone 0.5-20%
Crospovidone 0.2 - 15 %

Process:
Micronised Progesterone and lactose is screened and mixed and then granulated with maize starch, polyvinylpyrrolidone and water with sodium laury] sulphate, granules are dried and screened through suitable mesh with citric acid and sodium bicarbonate and Ac-di-sol is added to it.
Step 2: Preparation of Sustained Release Granules

Ingredients Quantity
Progesterone (micronized) 10-80 %
Lactose 5- 50 %
Hydroxy propyl methyl cellulose 0.5 - 20%
Hydroxy methyl propyl cellulose phthalate 0.5 - 20%
Magnesium stearale 0.1 -5.0%
Talc 0.1 - 5%
Corn starch 0.50- 15%
Sodium Lauryl Sulphate 0.1-5.0%
Polyvinylpyrrolidone 0.5-20%
Crospovidone 0.2 - 15 %
The ingredients are appropriately weighed and sifted. Micronised progesterone, lactose and corn starch are mixed together with partial quantity of hydroxy propyl methyl cellulose ranging from 100 cps to 3, 00,000 cps, this blend is granulated with water, polyvinylpyrrolidone and remaining quantity of HPMC. Dry the granules and screen through appropriate mesh.
Screen and mix micronised progesterone, lactose. HPMC (Part-2 and corn starch and mix well in blender. Granulate the above blend with polyvinylpyrrolidone, dry the granules. mill the granules by using multimill and screen, add crospovidone, talc and magnesium stearate to it. Mix well in blender. .

Step3: Preparation of Tablet Base

Ingredient Quantity
Witepsol 1-20%
Microcrystalline cellulose 1-15%
Carnauba wax 1 - 30%
Polyethylene Glycol 1 - 25%
Magnesium Stearate 1-5%
Talc 1 - 5 %
Light anhydrous silicic acid I - 5%
The ingredients are appropriately weighed. Prepared molten tablet base and disperse granules of step 1) and granules of step 2). This was followed by addition of magnesium stearate to the molten Tablets base, poured the dispersed molten mass in to the Torpedo shaped Tablets mould, and then chilled the Tablet.
Preparation of molten Tablet base:
Screen witepsol, microcrystalline cellulose, and colloidal silicon dioxide through #16 mesh, granulate this blend with polyethyleneglycol and camauba wax, dry the granules and lubricate it with talc and magnesium stearate.
Alternately, the tablet preparation can be done by dry granulation process as described as follows:
1. Screening of Progesterone(micronized), sucrose, mannitol, aerosol, SLS, polyvinylpyrrolidone through suitable mesh;
2. Blending the above material in blender; and
3. Dispersing these granules in molten Tablet base followed by pouring the hot molten dispersion in Torpedo shaped Tablet mould.Chilled and solidified to obtain torpedo shaped tablet. The tablets may be coated as follows:

A. Film / pH Dependent Coating:
Polymer 0.5 -25.0%
Plasticizer 0.05-3.00%
Pigment /Opacifier 0.05-6.00%
Anti tacking agent 0.1 - 10%
Polymer solvent and coating medium vehicle 80-96%
Solvent can be non aqueous or hydro alcoholic or aqueous solvent.
Process: Dissolve polymer in suitable solvent, add plasticizer to it stir well until clear
solution is obtained, disperse opacifier and anti-caking agent to it and stir well, filter
through nylon cloth.
In an embodiment, the present invention relates to sustained release vaginal progesterone tablets by wet granulation process described as follows:

Ingredients Quantity
Progesterone (micronized) 10-80%
Lactose 5- 50 %
Hydroxy propyl methyl cellulose 0.5 - 20%
Hydroxy methyl propyl cellulose phthalate 0.5 - 20%
Magnesium stearate 0.1-5.0%
Talc 0.1 -5%
Corn starch 0.50 - 15%
Sodium Lauryl Sulphate 0.1-5.0%
Polyvinylpyrrolidone 0.5-20%
Crospovidone 0.2 - 15 %
Process:
1. Screening Progesterone, sucrose, mannitol, aerosol. SLS, HPMC (80 % of total qty.), HPMCP through suitable mesh;
2. Dissolving Polyvinylpyrrolidone and HPMC (20 % of total qty.) in hydroalcoholic solvent or in water or in Nonaqueous solvent and dispersing colour & flavour in this mixture; and granulate with step 1;

3. Drying the granulated mix in a tray dryer or in fluidized bed dryer at temperature 40°-60°C till LODNMT 2.00%;
4. Passing dried granules through suitable mesh or if required using Multimill.
5. Dispersing the dried granules in molten Tablet base, pouring the hot molten dispersion in Torpedo shaped Tablet mould, chilled to obtain the tablet.
In an embodiment of the process of present invention, step 1 comprises preparation of 30 % progesterone quick release granules; the second step consists of preparation of 70 % sustained release progesterone granules and the third step comprises preparation of Tablet base and finally incorporating step 1 and step 2 in to tablet base to obtain effervescent Vaginal tablets.
Accordingly, the first portion of 30 % quick release may release progesterone from 10 %
to 30 % in few minutes, for example from 1 minute to 10 minutes.
The second portion of progesterone (70 %) may release progesterone over a period of
several hours or up to 24 hours or more than that.
The deliver}' can be controlled to be substantially at a certain predetermined rate over the
period of delivery.
The third portion consists of preparation of tablet base in which the drug is quickly
liberated due to its rapid melting at body temperature.
The API used in the present invention is having 90% particles of size of < 5 µ & 10 % particles with the particle size < l0µ, 50% particles with the particle size of <3.0 µ and 25 % particles with the particle size of <1 .5 u thereby enhancing the bioavailability.
Further, the sustained release effervescent vaginal progesterone tablets of the present invention are formulated in water (pH 6.5-7.5) which enhances disintegration of the tablets when in contact with the vaginal water fluids at a pH of 4 to 5.
The sustained release effervescent vagina! progesterone tablets of the present invention are delivered intravaginally, wherein the API is absorbed through the wall of vagina. thereby providing direct entry into the blood stream with the possibility of bypassing the hepatic-gastrointestinal (GI) metabolism.

The Progesterone tablets of the current invention when used vaginally have a high local effect on the endometrial tissue.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
EXAMPLES:-
Example 1:

Tablet Core %w/w
1. Progesterone (micronized) 28.5
2. Mannitol 7
3. Citric Acid 3.50
4. Polyvinylpyrrolidone K-30 1.5
5. HPMC 9.50
6. Magnesium Stearate 1.0
7. SLS 1.50
8. Lactose 12.5
9. Sodium Bicarbonate 3.5
10. Witepsol 30.0
11. Sodium Starch Glycollate 1.50
12. D.M. Water Q.s
13. Colour & Flavour Q.s

Example 2:
Ingredients % w/w
1. Progesterone (micronized) 40
2. Crospovidone 0.6
3 Citric Acid 5.0.
4. Sodium Bicarbonate 5.0
5. Polyvinylpyrrolidone K-30 1.50
6. Carnauba wax 33.0
.7. HPMCP 10.0
8. Crospovidone 0.6
9. Talcum 0.6
10. Magnesium Stearate 1.0
11. Colour & Flavour 1.0

Example 3:
Ingredients % w/vv
1. Progesterone (micronized) 40
2. Corn starch 0.6
3 Citric Acid 4.0
4. Sodium Bicarbonate 4.0
5. Polyvinylpyrrolidone K.-30 1.50
6. Polyethylene Glycol 36.0
7. HPMC 8.0
8. Crospovidone 0.5
9. Colloidal silicon dioxide 0.6
10. Magnesium Stearate 1.0
n. Colour & Flavour 1.0

We claim,
1. Sustained release vaginal pharmaceutical composition comprising;
a. Upto 30% micronized progesterone quick release granules and an
. effervescent agent;
b. 70% micronized progesterone sustained release granules; and
c. a tablet base along with one or more pharmaceutical excipients.
2. Sustained release vaginal pharmaceutical composition according to claim 1, wherein the progesterone is present in an amount of 100 mg - 400 mg.
3. Sustained release vaginal pharmaceutical composition according to claim1, wherein, the micronized progesterone having 90 % particles of size of < 5 µ, 10 % particles with the particle size of < l0µ, 50% particles with the particle size of <3.0 µ and 25 % particles with the particle size of <1.5 µ.
4. Sustained release vaginal pharmaceutical composition according to claim 1. wherein the pharmaceutically acceptable excipients are selected from diluents(l-75% w/w), disintegrants (1- 25% w/w), lubricants(0.5 - 5.0% w/w), binders(l - 25% w/w), glidants (0.25 - 10% w/w), anti-adherent (0.25 - 5% w/w), anti-tacking agent(0 -10% w/w), film forming polymer (0.1-50% w/w}, vehicle, colorant (0.1 to 2% w/w) and solvent, flavouring agents ,coloring agents, and sweetening agents..
5. Sustained release vaginal pharmaceutical composition according to claim 1. wherein the effervescent agent in (a) is a mixture of pharmaceutically acceptable carboxylic or dicarboxylic acid, such as citric acid, adipic acid or tartaric acid, and a pharmaceutically acceptable salt of carbonates or bicarbonates..
6. A process of making sustained release vaginal pharmaceutical composition. comprising the steps of;
a. preparing upto 30% progesterone quick release granules;
b. preparing 70% progesterone sustained release granules;
c. preparing a tablet base;
d. dispersing granules of step (a) and step (b) to molten tablet base(c); and
e. compacting and optionally coating the tablets.
7. The process of preparing sustained release vaginal progesterone tablets according
to claim 6, may be prepared by process selected from wet granulation, dry
granulation, hot or cold granulation, direct compression or slugging process.

8. A process of making sustained release vaginal pharmaceutical composition according to claim 6. wherein the tablet base is selected from Polyethylene glycols and its grades from 100 to 40000, Carnauba wax, witepsol, glycerol, gelatin, latiolin, bees wax etc.
9. Sustained release vaginal pharmaceutical composition according to claim 1, wherein, quick release granules release progesterone from 10 % to 30 % in 1-10 minutes.
10. Sustained release vaginal pharmaceutical composition according to claim 1, wherein, sustained release granules release 70% progesterone over a period of several hours or up to 24 hours or more than that.