FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rutel3)
1. TITLE OF THE INVENTION:
"SUBLINGUAL PHARMACEUTICAL COMPOSITION"
2. APPLICANT (S):
(a) NAME: WANBURY LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: B- Wing, 10th 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 sublingual pharmaceutical composition comprising Progesterone tablets 100 mg, along with pharmaceutically acceptable excipients 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 progesterone production is triggered by Luteinising Hormone (LH) which 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 a developing embryo in progesterone deficient women.
US4927816 discloses a pharmaceutical formula for the administration of Progesterone USP said formula comprising; Progesterone USP milled such that at least seventy-five percent of the total amount is composed of particle sizes of less than five microns diameter; said Progesterone USP being blended with a salivic stimulator in an amount adapted to stimulate sufficient saliva to dissolve said milled Progesterone USP but not enough to result in significant oral ingestion of Progesterone USP; said mixture of Progesterone USP and salivic stimulator encapsulated within a soluble capsule. Though the 75% of API is milled upto less than 5 microns, this formulation still poses bioavailability problem.
US4927816 discusses the capsule formulation and mouth spray for sublingual ingestion however, fails to discuss the tablet dosage form.
Progesterone is available as Micronized progesterone capsule which can be administered either by oral or vaginal route. Oral progesterone has disadvantage of high hepatic inactivation. It is reported that 95% of oral micronized progesterone get converted to

inactive metabolites in liver. Therefore, oral route of administration suffers from low bioavailability and low efficacy. Whereas vaginal progesterone has limitation of poor patient compliance due to vaginal irritation, discharge, leakage caused and requirement of lying down for administration.
Therefore, there is a need in the art to overcome the limitations of the available marketed dosage forms. Thus the present inventors have developed sublingual progesterone dosage forms to provide better patient convenience and better efficacy over the existing formulations.
Sublingual administration of the medicine, while resembling oral ingestion in comfort and convenience, has the added advantage of providing a direct path into the bloodstream.
Thus the present invention provides unique dosage form in which absorption through the sublingual route is actually achieved by merely placing the tablet below the tongue. The tablet formulation is designed to have good acceptable taste.
Description of drawings:
Figure 01: Mean Serum Baseline Adjusted Progesterone Concentration (ng/ml) - Time profile for various time points for two treatment groups.
Summary of the invention:
Accordingly, the present invention discloses pharmaceutical composition comprising a Progesterone sublingual Tablets 100 mg along with pharmaceutically acceptable excipients to support developing embryo in the progesterone deficient women and process for preparation thereof.

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.
As used herein the phrase "tablet" means and includes tablets, which are coated or uncoated, chewable tablets, tablet in tablet, pellets, granules, beads, extruders and Spheronizer and the like, that can be used to fill in the Capsule which employ excipients to deliver active agent(s) or quick release tablets or sublingual or mouth dissolving tablets or coated powders.
As used herein the phrase "Coated tablet" means and includes, film coated tablet, implant, sugar coated tablet and modified-release tablet.
Accordingly, the present invention describes pharmaceutical composition comprising Progesterone sublingual Tablets 100 mg along with pharmaceutically acceptable excipients and the process for preparation thereof.
The pharmaceutical composition of the present invention comprising Progesterone sublingual Tablets 100 mg that can be provided in a oral sub lingual solid dosage form, preferably tablet useful to support the developing embryo in the progesterone deficient woman and process for preparation thereof.
Sublingual progesterone according to the present invention does not undergo hepatic first pass metabolism, therefore, provides higher bioavailability and efficacy than oral micronized progesterone. Also, it will overcome limitations of oral and vaginal micron ized progesterone.
The pharmaceutical composition of the present invention can be formulated as film coated tablets, coated tablets/pellets/granules filled in capsule or small minute tablet in capsules or sub lingual tablets or mouth dissolving tablets, coated powder; most preferably, the composition is in form of tablet such as or sugar coated or uncoated

tablets. The tablet may optionally be coated within the layer of film forming polymer or pharmaceutical excipients or uncoated colored & flavoured Tablets
According to the preferred embodiment, the pharmaceutical composition of the present invention comprises 100 mg of Progesterone along with pharmaceutically acceptable excipients.
According to the present invention, the formulation is composed in such a way that the selection of API & Excipients is adapted to sublingual absorption of progesterone. The API used in the preparation of sublingual dosage form comprises, of 90% particles of <5µ & 10% particles are of <10µ, 50% particles are of <3.0µ and 25% particles are of <1.5µ. The use of specific particle size of micronized progesterone according to the invention leads to 96% dissolution in 10 minutes when evaluated in 0.1N HC1. This rate of dissolution is ideal for sublingual absorption phenomenon. The sublingual tablet according to the present invention remains only 3 minutes in oral cavity.
A medication would first need to be absorbed through the sublingual mucosa into the sublingual veins. To achieve this, optimum concentration of saliva is required to assist drug dissolution. Thus, the present invention utilizes salivic stimulators such as citric acid
Citric acid is one of the more efficient salivic stimulators. An effective & optimum concentration of citric acid is used, preferably in an amount of 0.1 to 3.0 % for the sublingual Tablets of the present invention, Formulation studied have been conducted in ' water (pH 6.5-7.5) since Saliva is reported to have pH of 6.0- 7.4.
Sodium Lauryl Sulphate is used in an amount of 0.1 to 2.5 %, as effective solubilizer according to the invention. It is an anionic surfactant; it is detergent and wetting agent effective in both alkaline and acidic conditions.
The 80% of sublingual tablet according to the present invention dissolves within 3 minutes and 90% within 5 minutes.

The pharmaceutically acceptable excipients are selected from diluents, disintegrates, lubricants, binder's, glidants and anti-adherent, anti-tacking agent, film forming polymer, vehicle, colorant and solvent, flavouring agents, colouring agents, taste masking agent's and, sweetening agents.
The diluents may be selected from Mannitol, sorbitol, xylitol and maltitol, present in an amount of l-75% w/w.
Disintegrants may be selected from crospovidone, carmellose sodium, sodium cmc, 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 carboxymethyicellulose sodium salt; e.g. Ac-Di-Sol®); alginic acid or alginates; insoluble polyvinylpyrrolidone (e.g. Po\yvidon® CL, Potyvidon® CL-M, Kottidon® CL, Polyplasdone® XL, Polyplasdone® XL-10); sodium starch Glycollate (e.g. Primogel® and Explotab®); present in an amount of 1-30% w/w.
The suitable lubricants may be selected from zinc stearate, magnesium oxide, magnesium aluminium silicate, calcium stearate, sodium chloride and / or magnesium stearate; present in an amount of 0.5 - 5.0% w/w.
The binders may be selected from HPMC, Hydroxypropyl Cellulose, Starch paste, Starch 1500, Gum acacia, and /OR Polyvinpyrrolidone, Gelatin preserrt in an amount. of \ - 20%
w/w.
The glidants 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 0.5 - 10% w/w.
Anti-adherents may be selected from colloidal silicon dioxide, Bentonate clay; present in an amount of 0.5 - 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.
Sweetening agents may be selected from aspartame, neotame, sucralose, sucrose, etc.
. 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-methacryiic 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.
. In another embodiment, the pharmaceutical composition of present invention comprising Progesterone, in a sub lingual or mouth dissolving tablet form is prepared using either wet granulation process or dry granulation, hot or cold granulation process, direct compression or slugging process.
Accordingly, the invention discloses a process for preparation of Progesterone sublingual Tablets 100 mg as follows:

1. Weighed quantities of
Progesterone(micronized) 10-80%
Citric Acid 0.5 - 20%
Mannitol 5 -70 %
Sodium Lauryl Sulphate 0.1-5.0%
Polyvinylpyrrolidone 1 -20%
Aspartame 0.2 - 5%
Neotame 0.1-3%.
Added to cone blender and blended for suitable time
2. Appropriately weighed, sifted
Colour 0.01 -2%
Crospovidone 0.2-10%
Colloidal Silicon Dioxide 0.2-10%
Talc 0.2-10%
Magnesium Stearate 0.1-10%
are added in cone blender and blended for suitable time; and
3. The Lubricated blend is then compressed to tablets.
Alternately, the process for preparing pharmaceutical composition by wet granulation is described as follows:
1. Screening micronized Progesterone, sucrose, citric acid, mannitol,aspartame,aerosol. sodium lauryl sulphate through suitable mesh;
2. Dissolving Polyvinylpyrrolidone in hydroalcoholic solvent or in water or in nonaqueous solvent and dispersing colour & flavour in this mixture; and granulating the mixture of step 1.
3. Drying the granulated mix in a tray dryer or in fluidized bed dryer at temperature of 40°-60°C till LOD NMT 2.00%;
4. Passing dried granules through suitable mesh or if required using Multimill;

5. Blending screened Crospovidone, Colloidal Silicon Dioxide, Sucralose then adding screened aerosil, Magnesium Stearate into blender and blending for another 5 min; and
6. Compressing above lubricated blend into a tablet using suitable punch.
Optionally, the above prepared tablet is coated using film coating, enteric coating or sugar coating as described below:
A. Film / Enteric coating:
Polymer 0.5 -20.0%
Plasticizer 0.05-2.00%
Pigment/Opacifier 0.05-5.00%
Anti tacking agent 0 - 10%
Polymer solvent and coating medium vehicle 80-96%
Solvent can be non aqueous or hydroalcoholic or Aqueous solvent.
B. Sugar Coating can be done in four steps viz. Seal coating. Sub coating, Syruping
/Colouring and Polishing
i. Seal coating
Polyvinylpyrrolidone K-30 0-5.00%
Polyethylene Glycol 600 0-0.5%
Titanium Dioxide 0.05-5.00%
Isopropyl Alcohol Q.S
ii. Subcoating
Sugar 50-70%
Gum Acacia 0.5-10.0%
Talc 0.5-10%
Maize Starch 0.5-10%
Calcium Carbonate 0.5 - 10%
D.M.Water Q.S

iii. Syruping/colouring
Sugar 50-70%
Colour 0.5-10%
D.M.Water 20-50%
iv. Polishing
Carnauba Wax 0.01-0.5%
Carbontetra Chloride 98.0 - 98.5 %
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:-
Sub lingual Tablets

Example 1:
Tablet Core % w/w
1. Progesterone (micronized) 21.0
2. Mannitol 72
3. Citric Acid 1.60
4. Polyvinylpyrrolidone K-30 1.20
5. Colloidal Silicon Dioxide 0.60
6. Magnesium Stearate 1.30
7. sodium, lauryl sulphate 0.40
8. Isopropyl Alcohol Q.S
9. Neotame 0.1
10. Sucralose 0.30
11. Sodium Starch Glycollate 1.50
12. D.M.Water Q.S

13. Colour & Flavour

Example 2:
Ingredients % w/w
1. Progesterone (micronized) 21
2. Crospovidone 3.8
3 Citric Acid 1.8
4. Microcrystalline Cellulose PH 102 14.92
5. Polyvinylpyrrolidone K-30 2.16
6. Sorbitol powder 50
7. Sucralose 3.0
8. Colloidal Silicon Dioxide 0.6
9. Talcum 0.6
10. Magnesium Stearate 1.0
11. Colour & Flavour 1.0
Example 3:
The formulation was prepared by compressing Progesterone into small tablets and further
into another tablet. The tablet is filled into the hard gelatin capsules.
During dose administration open the capsule shell and keep the tablet under tongue.

Ingredients % w/w
I] Tablet I
1. Progesterone (micronized) 51.50
2. Sodium Starch GlycoJJate 5.0
3. PVP K-30 3.2
4. Xylitol Powder 22.7
5. Magnesium Stearate 1.3
6. Microcrystalline Cellulose pH 102 12.50
7. Aerosil 0.7

8. Talcum 1.5
II] Tablet II
1. Mannitol 40
2. Citric Acid 15
3. Microcrystalline Cellulose pH 102 30
4. PVP K-30 9.0
5. Magnesium Stearate 3.0
6. Aerosil 3.0
Dissolution Condition
Dissolution Medium: Simulated saliva with 1 % SLS in Water, 900ml
Apparatus : USP Type -II Paddle
Speed : 75 rpm
Wavelength : 240nm
TME : 10 mim
Tolerance : Not Less Than 75% in 10 min

Time in minutes % Dissolution
Tablet 1 10 84
Tablet 2 10 89
Tablet 3 10 91
Tablet 4 10 86
Tablet 5 10 88
Tablet 6 10 87
Average 10 87
Example 4:
Optionally, Progesterone beads are prepared by Spheronizer or Extruder using inactive excipients like Microcrystalline Cellulose, Ethyl Cellulose etc. by using nonaqueous or aqueous solvent along with mannitol & sorbitol Beads.

Example 5: Clinical study
Open label, balanced, randomized, single-dose, two-treatment, parallel oral bioequivalence study of Progesterone sublingual 100 rag Tablets of Wanbury Limited, India, with Susten" 200 mg capsules (containing progesterone 200 mg) manufactured by Sun Pharmaceuticals, India has been conducted in healthy, adult, human, female subjects of childbearing age under fasting conditions.
The subjects receiving sublingual progesterone (progesterone sublingual 100 mg tablets) formulations have shown higher mean percentage change in concentrations of progesterone after dosing as compared with the change seen with oral progesterone (Susten® 200 mg capsules) (Table 01 and Figure 01).
After administration of sublingual progesterone 100 mg tablets, mean serum concentrations of progesterone increased rapidly at 30 minutes post-dose and the maximum mean concentrations were seen at 01 hour post-dose and remained steady till 2 hours post-dose. Then, the mean concentrations declined gradually till 24 hours after dosing except a slight surge in mean concentrations at 12 hours and 24 hours post-dose.
After administration of Susten® 200 mg capsules (containing progesterone 200 mg). mean serum progesterone concentrations increased slowly and the maximum mean concentrations were seen at 01 hour post-dose and then declined at 03 hours post dose hours, again increased at 04 hours and 05 hours post dose and then gradually decreasing till 12 hours post dose. At 24 hours post dose the mean serum progesterone concentrations was negligible.
This comparison of mean concentration profiles suggests that progesterone is rapidly absorbed with exceptional efficiency and speed by sublingual route as compared to oral route of administration.

Table 01: Mean Baseline Adjusted Serum Progesterone Concentration (ng/ml) levels for various time points for two treatment group

Example 6:
Comparison of Pharmacokinetic parameters of progesterone formulations:
Table 02: Summary of Pharmacokinetic parameters for oral and sublingual
progesterone


The evaluation of pharmacokinetic parameters as below:
1. Tmax: In case of oral progesterone (Susten' 200 mg capsules); median Tmax was 4.000
hours and in case of sublingual progesterone (progesterone sublingual 100 mg tablets).
median Tmax was 1.500 hours. The same can be concluded as the rate of absorption is
superior with sublingual route as compared to oral progesterone since there is no first pass
metabolism when it is administered with sublingual route.
2. Cmax Mean baseline adjusted Cmax for Oral progesterone (Susten® 200 mg
capsules)group was 2.3697 ng/ml as compared to 3.6805 ng/ml in sublingual
progesterone (progesterone sublingual 100 mg tablets) group. The mean Cmax is 55.3 %
higher when progesterone is administered with sublingual route as compared to that when
orally administered as capsule. In addition, the inter subject variability with Cmax is
comparatively lesser (44.0 %) with Sublingual progesterone as compared to oral
progesterone (120.6 %), which will ensure that Cmax values will be more uniform with
lesser variations with sublingual formulation as compared to oral progesterone.
3. AUCo-t On comparison of AUCo-t for test (progesterone sublingual 100 mg tablets) and reference (Susten 200 mg capsules) groups, the AUCo-t of Sublingual Progesterone is 215.4% higher in comparison to Oral Progesterone (refer table given by sublingual route as compared to oral route).
4. AUCo-o In case of oral progesterone (Susten® 200 mg capsules), mean AUCO-oo was 16.768 hours and in case of sublingual progesterone (progesterone sublingual 100 mg tablets), mean AUCO-oo was 61.9812 hours. The mean AUCO-oo of Sublingual Progesterone is 269.6 % higher in comparison to Oral Progesterone. Hence, the extent of absorption is relatively better when progesterone is given sublingual route, (table 02)
5. t ½: In case of oral progesterone (Susten® 200 mg capsules), mean t/2 was 4.3307 hours and in case of sublingual progesterone (progesterone sublingual 100 mg tablets). mean t½ was 16.7986 hours. The mean t½ of Sublingual Progesterone is 287.8 % higher in comparison to Oral Progesterone. This shows that extent of presence of drug in the body is longer in case of Sublingual Progesterone as compared to Oral Progesterone.

Thus, the more rapid rate of absorption of Sublingual progesterone (progesterone sublingual 100 rag tablets) led to a much greater Cmax (55,3 % higher), a much shorter tmax (1.5 hours),, and a much greater AUC (215.4 % higher) as compared with oral progesterone (Susten 200 mg capsules).
In conclusion, the rate and extent of absorption of Sublingual Progesterone (progesterone sublingual 100 mg tablets) was rapid and higher as compared to Oral Progesterone (Susten® 200 mg capsules). Sublingual Progesterone (progesterone sublingual 100 mg tablets) tablet formulation was superior to Oral Progesterone (Susten 200 mg capsules) in its ability to deliver progesterone to the bloodstream. The high bioavailability of Sublingual Progesterone formulation due to higher rate and extent of absorption suggest its potential for replacement of oral progesterone in the treatment of reproductive disorders.

We claim,
1. A sublingual pharmaceutical composition comprising micronized progesterone comprises 90% particles of <5µ & 10% particles are of <10µ, 50% particles are of <3.0µ and 25% particles are of <1.5µ along with pharmaceutically acceptable excipients to support developing embryo in progesterone deficient women and to process for preparation thereof.
2. The sublingual pharmaceutical composition according to claim 1, wherein said tablet comprises coated or uncoated tablets, tablet in tablet, granules, pellets, or beads.
3. The sublingual pharmaceutical composition according to claim 1, wherein said pharmaceutically acceptable excipients are selected from solubilizers, saliva stimulators, diluents, disintegrants, lubricants, binders, glidants and anti-adherent, anti-tacking agent, film forming polymer, vehicle, colorant and solvent, flavouring agents, colouring agents, taste masking agent's and sweetening agents.
4. The sublingual pharmaceutical composition according to claim 1, wherein said solubilizer is Sodium Lauryl Sulphate used in an amount of 0.1 to 2.5 %.
5. The sublingual pharmaceutical composition according to claim 1, wherein said saliva stimulator is citric acid used in an amount of 0.1 to 3.0 %.
6. The sublingual pharmaceutical composition according to claim I, wherein said composition is in the form of a tablet.