Claims:WE CLAIM:
1. An oral sustained release pharmaceutical composition for once daily administration, comprising:
a) therapeutically effective amount of progesterone;
b) at least one rate controlling polymer;
c) at least one surfactant; and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 74 pg/ml.mg to about 450 pg/ml.mg,
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release progesterone reference formulation administered twice a day, with the Cmax T/R ratio falling within 80% -125% range.
2. The composition as claimed in Claim 1, wherein the mean maximum plasma concentration (Cmax) of Progesterone in the range of about 85 pg/ml.mg to about 300 pg/ml.mg.
3. The composition as claimed in Claim 1, wherein the mean maximum plasma concentration (Cmax) of Progesterone in the range of about 90 pg/ml.mg to about 150 pg/ml.mg.
4. The composition as claimed in Claim 1, wherein the rate controlling polymer is selected from a hydrophilic polymer, a hydrophobic polymer or combinations thereof.
5. The composition as claimed in Claim 1, wherein the concentration of the rate controlling polymer ranges from about 4 % to 17 % w/w of the composition.
6. The composition as claimed in Claim 4, wherein the hydrophilic polymer is hydroxypropylmethyl cellulose
7. The composition as claimed in claim 1, wherein the surfactant is a combination of anionic surfactant and non-ionic surfactant.
8. The composition as claimed in Claim 7, wherein the concentration of the anionic surfactant ranges from about 5 % w/w to about 30 % w/w of the composition.
9. The composition as claimed in Claim 7 wherein concentration of the non-ionic surfactant ranges from about 2.5 % w/w to about 15 % w/w of the composition
10. The composition as claimed in claim 7, wherein the surfactant is a combination of sodium lauryl sulfate and poloxamer.
11. The composition as claimed in claim 10, wherein the concentration of sodium lauryl sulfate ranges from 15% to 25% w/w of the composition.
12. The composition as claimed in claim 10, wherein the concentration of poloxamer ranges from 5% to 15% w/w of the composition.
13. The composition as claimed in Claim 1, wherein the composition is in the form of a tablet.
14. The composition as claimed in Claim 1, wherein the progesterone is present in the composition in an amount of about 200 mg to about 600 mg
15. An oral sustained release pharmaceutical composition comprising:
400mg of progesterone;
about 4% w/w hydroxypropylmethyl cellulose
about 20% w/w Sodium lauryl sulfate;
about 10% w/w Poloxamer 188, and
wherein upon oral administration to a subject, the composition exhibits a maximum plasma concentration (Cmax) of Progesterone in the range of about 87.5 pg/ml.mg to about 200 pg/ml.mg and,
wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range. , Description:FORM 2

THE PATENTS ACT, 1970
(39 OF 1970)

COMPLETE SPECIFICATION
(See section 10 and rule 13)

SUSTAINED RELEASE COMPOSITION OF PROGESTERONE

SUN PHARMACEUTICAL INDUSTRIES LTD.

A company incorporated under the laws of India having their office at SUN HOUSE, 201 B/1, WESTERN EXPRESS HIGHWAY, GOREGAON (E), MUMBAI-400063 MAHARASHTRA, INDIA.

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a sustained-release oral composition of Progesterone or its pharmaceutically acceptable salts thereof for once daily administration.

BACKGROUND OF THE INVENTION
Progesterone (pregn-4-ene-3,20-dione) is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation), and embryogenesis of humans and other species. Progesterone belongs to a class of hormones called progestogens, and is the major naturally occurring human progestogen. It has a molecular weight of 314.47 and a molecular formula of C21H30O2. The structural formula is:

Progesterone can be used alone, or in combination with estrogenic agents, to provide a hormonal state in women through hypothalamic, pituitarian, and some endometrial effects to enable contraception and some non-contraception indications, such as endometriosis, regular menstrual cycles, improvement in acne, dysmenorrhea and premenstrual symptoms such as dysphoric disorder, also known as PMDD, polycystic ovarian syndrome (PCOS), perimenopause, hirsutism (undesired body or facial hair growth). Although quite effective, oral hormonal contraceptive use is generally characterized by poor adherence and relatively high discontinuation
Progesterone is currently marketed under the name Prometrium® (Progesterone, USP) in US.
Prometrium® is available as soft gelatine capsules containing Progesterone 200 mg is administered twice daily for use in the prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving conjugated estrogens tablets. It is also indicated for use in secondary amenorrhea.
Progesterone undergoes extensive intestinal as well as hepatic first pass metabolism owing to which the metabolites so formed cause drowsiness and sedation. Commercially available preparations of Progesterone pose risk of such adverse effects like extreme dizziness and/or drowsiness, blurred vision, slurred speech, difficulty walking, loss of consciousness, vertigo, confusion, disorientation, feeling drunk, and shortness of breath. So they are required to be administered at bed times. Sustained release dosage forms are expected to demonstrate reduced side effects related to first pass intestinal and hepatic metabolism as observed with the immediate release formulations
Thus there is a need for a sustained release composition that could be given once daily and would be consistent with good therapeutic efficacy while not causing an unacceptable incidence or severity of side effects.

OBJECT OF THE INVENTION
An object of the present invention to provide a once-daily composition of progesterone suitable for oral administration.
Another object of the present invention to provide a composition of progesterone with in vivo pharmacokinetic (PK) profile that would be consistent with good therapeutic efficacy while not causing an unacceptable incidence or severity of side effects.
Yet another object of the present invention to provide a composition of progesterone with an in vitro release profile that would be characteristic of a well-tolerated once-daily composition of progesterone.
A further object to provide exemplary compositions exhibiting such an in vitro release and/or in vivo PK profile. The composition offers round the clock efficiency and efficacy with single daily dose administration thereby improving patient convenience and compliance.

SUMMARY OF THE INVENTION
The present invention provides an oral sustained release pharmaceutical composition for once daily administration, comprising:
a) a therapeutically effective amount of progesterone,
b) at least one rate controlling polymer,
c) at least one surfactant, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 74 pg/ml.mg to about 450 pg/ml.mg
and, wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day, with the Cmax T/R ratio falling within 80% -125% range.
In another aspect, the present invention provides an oral sustained release pharmaceutical composition for once daily administration, comprising:
a) progesterone in the range of 200 mg to 400 mg,
b) at least one rate controlling polymer, wherein the rate controlling polymer is a hydrophilic polymer,
c) at least one surfactant; wherein the surfactant is selected from anionic surfactant, non-ionic surfactant and combinations thereof, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 74 pg/ml.mg to about 450 pg/ml.mg
and, wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day, with the Cmax T/R ratio falling within 80% -125% range.
In yet another preferred aspect, the present invention provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400 mg of progesterone,
b) hydroxypropylmethyl cellulose,
c) Sodium lauryl sulfate, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 74 pg/ml.mg to about 450 pg/ml.mg
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range.
In yet another preferred aspect, the present invention provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400 mg of progesterone,
b) hydroxypropylmethyl cellulose,
c) Poloxamer 188, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 74 pg/ml.mg to about 450 pg/ml.mg
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range.
In yet another preferred aspect, the present invention provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400 mg of progesterone;
b) hydroxypropylmethyl cellulose,
c) Sodium lauryl sulfate,
d) Poloxamer 188, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 74 pg/ml.mg to about 450 pg/ml.mg
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range.
In yet another preferred aspect, the present invention provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400 mg of progesterone;
b) about 4% w/w hydroxypropylmethyl cellulose
c) about 20% w/w Sodium lauryl sulfate;
d) about 10% w/w Poloxamer 188, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 74 pg/ml.mg to about 450 pg/ml.mg
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range.
In another aspect, the present invention is drawn to a sustained-release pharmaceutical composition comprising progesterone for use in the prevention of endometrial hyperplasia in non hysterectomized postmenopausal women who are receiving conjugated estrogens tablets. They are also indicated for use in secondary amenorrhea.

DETAILED DESCRIPTION OF THE INVENTION
It should be noted that, the singular forms “a,” “an,” and, “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” includes reference to one or more of such excipients, and reference to “the carrier” includes reference to one or more of such carriers.
As used herein, “drug,” “active agent,”, “pharmaceutically active agent,” “therapeutically active agent” and “pharmaceutical,” may be used interchangeably to refer to an agent or substance that has measurable specified or selected physiologic activity when administered to a subject in a significant or effective amount. These terms of art are well-known in the pharmaceutical and medicinal arts.
As used herein, the term “treatment” when used in conjunction with the administration of progesterone, refers to the administration of progesterone to subjects who are either asymptomatic or symptomatic. In other words, “treatment” can be to reduce, ameliorate, or eliminate symptoms associated with a condition or it can be prophylactic treatment, i.e. to prevent or reduce the occurrence or severity of the symptoms.
As used herein, the terms “formulation” and “composition” are used interchangeably and refer to a mixture of two or more compounds, elements, or molecules. When any of the above terms is modified by the term “oral” such terms refer to compositions, formulations, or dosage forms formulated and intended for oral administration to subjects.
As used herein, “carrier” or “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipients” refers to a substance with which a drug may be combined to achieve a specific dosage formulation or oral dosage form for delivery to a subject.
As used herein, “subject” refers to a mammal that may benefit from the administration of a drug composition or method of this invention. In one specific aspect, a subject is a human. In another aspect, the subject is a female. In one embodiment, the subject can be a non-pregnant female or woman.
The term “oral administration” represents any method of administration in which an active agent can be administered by swallowing, chewing, or sucking or drinking an oral dosage form.
A used herein connection with numerical values, the terms “approximately” and “about” mean ±10% of the indicated value, including the indicated value.
In one embodiment, the present disclosure provides an oral sustained-release pharmaceutical composition for once daily administration of Progesterone.
Sustained release formulations show slow sustained release pattern while demonstrating long elimination half-life with high protein binding leading to once a dosage convenience. The ‘Smooth’ Release pattern avoids sudden drug release or ‘Dose Dumping’ and therefore loss of drug due to hepatic metabolism. Thus, in turn reduces fluctuations in plasma drug concentration and better maintenance of therapeutic levels. This also minimizes dose related central side effects i.e. drowsiness.
The present invention provides an oral sustained release pharmaceutical composition for once daily administration, comprising:
a) a therapeutically effective amount of progesterone,
b) at least one rate controlling polymer,
c) at least one surfactant, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 74 pg/ml.mg to about 450 pg/ml.mg
and, wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day, with the Cmax T/R ratio falling within 80% -125% range.
It is preferred that the composition, when administered once daily, exhibit a bioavailability, as expressed conventionally by Cmax, AUC0-24 or AUC0-8, that is substantially equivalent to the same daily dose of an immediate-release Progesterone reference formulation, for example PROMETRIUM® capsules, administered twice a day. In the present context, “substantially equivalent” means that the bioavailability of such a preferred composition is about 0.8 to about 1.25 times that of the reference formulation, i.e. T/R ratio falling within 80% -125% range.
It is preferred that the composition, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 74 pg/ml.mg to about 450 pg/ml.mg. Because of high variability in the subjects, the mean Cmax is calculated from Ln-transformed data as least square geometric mean Cmax., herein referred to as mean Cmax. In another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 80 pg/ml.mg to about 400 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 85 pg/ml.mg to about 300 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 87.5 pg/ml.mg to about 200 pg/ml.mg, more preferably, in the range of 90 pg/ml.mg to about 150 pg/ml.mg. Thus, for a composition with 400 mg progesterone, the composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 35000 pg/ml to about 80000 pg/ml, more preferably in the range of 36000 pg/ml to about 60000 pg/ml, for example about 36000 pg/ml, 37000 pg/ml, about 38000 pg/ml, about 39000 pg/ml, about 40000 pg/ml, about 41000 pg/ml, about 42000 pg/ml, about 43000 pg/ml, about 44000 pg/ml, about 45000 pg/ml, about 46000 pg/ml, about 47000 pg/ml, about 48000 pg/ml, about 49000 pg/ml, about 50000 pg/ml. Most preferably, in the range of 36000 pg/ml to about 42000 pg/ml.
It is preferred that the composition, following single dose administration, exhibit a time to reach maximum plasma concentration (Tmax) of progesterone that is at least about 3 hours, preferably about 4 hours.
The Pharmacokinetic study used to generate the parameters specified above for the composition of the invention is conducted according to a protocol that is generally accepted in the art.
In another aspect, the present invention provides a sustained pharmaceutical composition comprising progesterone, wherein the concentration profile is further characterized by AUC values (AUC0-t, AUC0-24, AUC0-inf) between 25 pg/ml.mg to about 1015 pg/ml.mg. Because of high variability in the subjects, the mean AUC is calculated from Ln-transformed data as least square geometric mean AUC, herein referred to as mean AUC (AUC0-t, AUC0-24, AUC0-inf). In another aspect, following single dose administration of the present composition exhibit AUC (AUC0-t, AUC0-24, AUC0-inf) for progesterone that is in the range of about 50 pg/ml.mg to about 1000 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit AUC (AUC0-t, AUC0-24, AUC0-inf) for progesterone that is in the range of about 100 pg/ml.mg to about 800 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit AUC (AUC0-t, AUC0-24, AUC0-inf) for progesterone that is in the range of about 150 pg/ml.mg to about 650 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit AUC (AUC0-t, AUC0-24, AUC0-inf ) for progesterone that is in the range of about 200 pg/ml.mg to about 500 pg/ml.mg, preferably, in the range of 200 pg/ml.mg to about 400 pg/ml.mg, more preferably, in the range of 220 pg/ml.mg to about 360 pg/ml.mg.
According to one embodiment of the invention, progesterone may be present in the composition in an amount ranging from about of 200 mg to about 600 mg. Preferably,
progesterone may be present in the composition in an amount ranging from about 200 mg to about 500 mg. Preferably, progesterone may be present in the composition in an amount ranging from about 300 mg to about 500 mg. More preferably, progesterone may be present in the composition in an amount ranging from about 350 mg to 450 mg. In a more specific embodiment, the amount of progesterone present in the composition is 400 mg.
In certain embodiments, the rate controlling polymers as included in the present disclosure are used to control the release of progesterone from the formulation. The rate controlling polymers provided by the present disclosure include but are not limited to semi synthetic, non-biodegradable, hydrophilic, hydrophobic polymer and combinations thereof. Suitable hydrophilic polymers used according to the present invention include polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, sodium carboxymethyl cellulose, vinyl acetate copolymers, polysaccharides such as alginate, xanthum gum and the like, polyethylene oxide, acrylic acid copolymers such as carbomer; maleic anhydride/methyl vinyl ether copolymers and derivatives and mixtures thereof. Suitable hydrophobic polymers include wax materials, cellulose derivatives such as ethyl cellulose or cellulose acetate, polyvinyl chloride, copolymers of polyvinyl alcohol and high molecular weight polyvinyl alcohols.
In another aspect, the present invention provides a sustained pharmaceutical composition comprising progesterone, wherein the rate controlling polymer is selected from a hydrophilic polymer, a hydrophobic polymer and combinations thereof.
In one embodiment, the concentration of polymer is in the range of about 2 % to about 20 % w/w of the composition. Preferably, the concentration of polymer is in the range of about 4 % to about 17 % w/w of the composition. More preferably, the concentration of polymer is in the range of about 4 % to about 7 % w/w of the composition. In a preferred embodiment, the concentration of polymer is about 4 % w/w of the composition.
Preferably, the rate controlling polymer is a hydrophilic polymer. In one such embodiment, the concentration of hydrophilic polymer is not more than 7%w/w of the composition. In a preferred embodiment, the rate controlling polymer is hydroxypropyl methyl cellulose. Preferably, the concentration of hydroxylpropylmethyl cellulose is in the range of 3 % w/w to 5% w/w of the composition. More preferably, the concentration of hydroxylpropylmethyl cellulose is about 4% w/w of the composition.
The oral dosage form may also comprise one or more pharmaceutically acceptable excipients to improve performance, handling, or processing. Non-limiting examples include antioxidants, binders, buffers, diluent, film forming agents, disintegrant, adsorbents, fillers and combinations thereof. The oral dosage form can further include release retarding polymers, wetting agents, surfactants, pH modifiers, complexing agents, solubilizers, pigments, lubricants, glidants, taste masking agents and the like.
In one embodiment, the compositions comprise at least one wetting agent and/or surfactant selected from the group comprising hydrophilic, lipophilic, amphiphilic, ionic, nonionic surfactants. In one embodiment, the surfactant can be a hydrophilic surfactant. Surfactants useful for the present invention include, without limitation: anionic, nonionic, and amphoteric Surfactants. Suitable anionic Surfactants include, for example, water soluble salts of C8-20 alkyl sulfates, sulfonated monoglycerides of C8-20 fatty acids, sarcosinates and taurates; for example sodium lauryl Sulfate, Sodium tetradecyl Sulfate, Sodium Hexadecyl Sulfate, Sodium Octadecy Sulfate, Sodium coconut monoglyceride Sulfonate, Sodium lauryl sarcosinate, sodium lauryl isoethionate, Sodium laureth carboxylate and sodium dodecylbenzenesulfonate, and mixtures thereof. Suitable non-ionic Surfactants include, for example, polyoxyethylene-polyoxypropylene copolymers such as poloxamers (also known as Pluronics such as Pluronic F-68 or Pluronic L61), polyoxyethylene Sorbitan esters such as , polyoxyethylene sorbitan monooleate (also known as Tween 80 or polysorbate 80) and polyoxyethylene sorbitan monolaureate (also known as Tween 20 or polysorbate 20), Vitamin E TPGS, polyethylene glycol 8000, fatty alcohol ethoxylates, alkylphenol ethoxylates, tertiary amine oxides, tertiary phosphine oxides, dialkyl Sulfoxides, and mixtures thereof. In a preferred embodiment, the surfactant is selected from a group consisting of Sodium Lauryl Sulfate, Sodium tetradecyl Sulfate, Sodium Hexadecyl Sulfate, Sodium Octadecyl Sulfate and mixture thereof. In yet another embodiment, the surfactant is selected from a group consisting of polyethylene– propylene glycol copolymer; polyoxyethylene–polyoxypropylene glycol.
In one aspect, the present invention provides a sustained pharmaceutical composition comprising progesterone, wherein the surfactant is selected from anionic surfactant, non-ionic surfactant and combinations thereof. In another aspect, the present invention provides a sustained pharmaceutical composition comprising progesterone, wherein the anionic surfactant is sodium lauryl sulfate. In another aspect, the present invention provides a sustained pharmaceutical composition comprising progesterone, wherein the non-ionic surfactant is poloxamer. In another aspect, the present invention provides a sustained pharmaceutical composition comprising progesterone, wherein the anionic surfactant is sodium lauryl sulfate. In another aspect, the present invention provides a sustained pharmaceutical composition comprising progesterone, wherein the non-ionic surfactant is poloxamer. In another aspect, the present invention provides a sustained pharmaceutical composition comprising progesterone, wherein the surfactant is a combination of sodium lauryl sulfate and poloxamer, specifically poloxamer 188.
In one embodiment, the surfactant can comprise about 1 % w/w to about 40 % w/w of the composition. In a preferred embodiment, the surfactant can comprise about 1 % w/w to about 30 % w/w of the composition. In another preferred embodiment, the surfactant can comprise about 5 % w/w to about 30 % w/w of the composition. In yet another preferred embodiment, the surfactant can comprise about 2.5 % w/w to about 15 % w/w of the composition. In another aspect, the concentration of sodium lauryl sulfate ranges from 15% to 25% w/w of the composition. Preferably, the concentration of sodium lauryl sulfate is about 20% w/w of the composition. In yet another aspect, the concentration of poloxamer ranges from 5% to 15% w/w of the composition. Preferably, the concentration of poloxamer 188 is about 10% w/w of the composition.
In one embodiment, the present disclosure provides an oral sustained release pharmaceutical composition for once daily administration, comprising:
a) progesterone in the range of 200 mg to 500 mg,
b) at least one rate controlling polymer, wherein the rate controlling polymer is a hydrophilic polymer,
c) at least one surfactant; wherein the surfactant is selected from anionic surfactant, non-ionic surfactant and combinations thereof, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 80 pg/ml.mg to about 400 pg/ml.mg and,
wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day, with the Cmax T/R ratio falling within 80% -125% range. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 85 pg/ml.mg to about 300 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 87.5 pg/ml.mg to about 200 pg/ml.mg, more preferably, in the range of 90 pg/ml.mg to about 150 pg/ml.mg.
In yet another embodiment, the present disclosure provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400 mg of progesterone,
b) hydroxypropylmethyl cellulose,
c) Sodium lauryl sulfate, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 80 pg/ml.mg to about 400 pg/ml.mg
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 85 pg/ml.mg to about 300 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 87.5 pg/ml.mg to about 200 pg/ml.mg, more preferably, in the range of 90 pg/ml.mg to about 150 pg/ml.mg.
In yet another embodiment, the present disclosure provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400 mg of progesterone,
b) hydroxypropylmethyl cellulose,
c) Poloxamer 188, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 80 pg/ml.mg to about 400 pg/ml.mg
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 85 pg/ml.mg to about 300 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 87.5 pg/ml.mg to about 200 pg/ml.mg, more preferably, in the range of 90 pg/ml.mg to about 150 pg/ml.mg.
In one of the preferred embodiment, the present disclosure provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400mg of progesterone;
b) hydroxypropylmethyl cellulose,
c) Sodium lauryl sulfate,
d) Poloxamer 188, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 80 pg/ml.mg to about 400 pg/ml.mg
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 85 pg/ml.mg to about 300 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 87.5 pg/ml.mg to about 200 pg/ml.mg, more preferably, in the range of 90 pg/ml.mg to about 150 pg/ml.mg.
In yet another preferred embodiment, the present disclosure provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400 mg of progesterone;
b) about 4% w/w hydroxypropylmethyl cellulose
c) about 20% w/w Sodium lauryl sulfate;
d) about 10% w/w Poloxamer 188, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of about 80 pg/ml.mg to about 400 pg/ml.mg
and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range. In another aspect of the embodiment, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 85 pg/ml.mg to about 300 pg/ml.mg. In yet another aspect, following single dose administration of the present composition exhibit a mean maximum plasma concentration (Cmax) of progesterone that is in the range of about 87.5 pg/ml.mg to about 200 pg/ml.mg, more preferably, in the range of 90 pg/ml.mg to about 150 pg/ml.mg.
In yet another preferred embodiment, the present disclosure provides an oral sustained release pharmaceutical composition for once daily administration comprising:
a) 400 mg of progesterone;
b) about 4% w/w hydroxypropylmethyl cellulose
c) about 20% w/w Sodium lauryl sulfate;
d) about 10% w/w Poloxamer 188, and
wherein upon oral administration to a subject, the composition exhibits a mean maximum plasma concentration (Cmax) of Progesterone in the range of 87.5 pg/ml.mg to about 200pg/ml.mg, more preferably, in the range of 90 pg/ml.mg to about 150 pg/ml.mg, and wherein said composition, when administered once daily, exhibits a bioavailability substantially equivalent to an equal daily dose of an immediate-release Progesterone reference formulation administered twice a day with the Cmax T/R ratio falling within 80% -125% range.
The sustained release composition of the present invention shows immediate release profile such that the pharmaceutical composition of the present invention when tested for dissolution in a USP Apparatus II at 50 rpm in 900 ml of pH 4.5 acetate buffer with 0.5% SLS, exhibits at least 50% progesterone release in 1 hour. Preferably, at least 55% in 1 hour. More preferably, at least 60% progesterone release in 1 hour. In a preferred embodiment, sustained release composition of the present invention exhibits at least 65% in 1 hour. It was observed that the composition of Example 1 releases about 69% progesterone in 1 hour when tested, as disclosed in Example 6 and was found to be bioequivalent to BID administration of Reference product (2X200mg) with respect to Cmax, AUCo-24 using the 80-125% FDA required criteria as seen in Example 3.
According to one embodiment of the invention, the present composition of the invention further comprises other pharmaceutical excipients not limited to diluents, lubricants, glidants, disintegrants, binding agents etc.
Diluents or fillers, may be added to increase the bulk to make dosage forms a practical size for compression. Examples of diluents useful in tablet dosage forms known in the art include: dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, calcium sulfate, dicalcium phosphate, tricalcium phosphate, lactose, cellulose including microcrystalline cellulose, kaolin, mannitol, sodium chloride, dry starch, pregelatinized starch, compressible sugar, and combinations of any of the foregoing.
According to one embodiment of the invention, the diluents, or fillers can comprise about
1 % w/w to about 20 % w/w of the dosage form. In a preferred embodiment, the diluents, or fillers can comprise about 1 % w/w to about 15 % w/w of the dosage form. In a more preferred embodiment, the diluents, or fillers can comprise about 1 % w/w to about 12 % w/w of the dosage form. In a preferred embodiment, the diluent or filler used is microcrystalline cellulose.
Binding agents may be included in dosage forms to facilitate adhesion of the constituents. Examples of binding agents useful in dosage forms provided by the present disclosure include polyvinyl acetate phthalate, molasses, methylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, microcrystalline cellulose (MCC), and polyvinyl pyrrolidone.
According to one embodiment of the invention, lubricants may be included in dosage forms provided by the present disclosure to reduce sticking effects during processing, film formation, and/or drying. Examples of useful lubricants include: magnesium stearate, calcium stearate, stearic acid, glycerol monostearate, and combinations of any of the foregoing.
In a preferred embodiment, the lubricant is magnesium stearate. The composition of the invention may comprise a lubricant in the range of 1% to 10%w/w of the composition. Preferably, in the range of 1% to 5%w/w of the composition.
According to one embodiment of the invention, glidants may be included in dosage forms provided by the present disclosure to improve powder flow. Examples of useful glidants include: talc, colloidal silicon dioxide, precipitated silicon dioxide, fumed silicon dioxide, and combinations of any of the foregoing. The composition of the invention may comprise less than about 2.5 % w/w of a glidant, and in certain embodiments, less than about 1 % w/w of a glidant. In a preferred embodiments, the glidant is silicon dioxide.
According to one embodiment of the invention, disintegrants may be included in dosage forms provided by the present to cause a dosage form to break apart, for example, by; expansion of a disintegrant when exposed to water. Examples of useful disintegrants include water swellable substances such as low substituted hydroxypropyl cellulose, cross-linked sodium carboxymethylcellulose (sodium croscarmellose), sodium starch glycolate, sodium carboxymethylcellulose, sodium carboxymethyl starch, ion-exchange resins, microcrystalline cellulose, crosslinked polyvinyl pyrrolidone, starches and pregelatinized starch, magnesium aluminometasilicate, formalin-casein, alginic acid, certain complex silicates, and combinations of any of the foregoing. In a preferred embodiment, the disintegrant is sodium starch glycolate. In another preferred embodiment, the disintegrant is microcrystalline cellulose. The composition of the invention may comprise a disintegrant in the range of 1% to 30%w/w of the composition. Preferably, in the range of 1% to 20% w/w of the composition, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% w/w of the composition.
The tablets can be further coated with a film forming polymer to achieve the desired drug release profile, including but not limited to Instacoat Universal Yellow. The dispersion of Instacoat Universal Yellow used for film coating comprises of hypromellose, polyethylene glycol, talc, titanium dioxide and Lake Quinoline Yellow.
The composition of the present invention may be a monolayer or a bilayer tablet. Preferably, the composition is a monolayer tablet. The composition may be prepared by standard pharmaceutical manufacturing techniques. Such techniques include, for example, wet granulation, wet milling, fluid bed drying, dry milling, dry granulation, direct compression, lubrication, tableting, and aqueous film coating. Preferably, the composition is prepared by dry granulation.
In another aspect, the present invention also relates to sustained-release pharmaceutical composition for oral administration comprising progesterone, wherein the composition is administered to a subject in need to reduce the daily dosing frequency. According to one embodiment of this aspect, the present invention relates to a once-daily sustained-release pharmaceutical composition for oral administration comprising Progesterone.
The sustained release composition progesterone of present invention is administered once daily to the subject for use in the prevention of endometrial hyperplasia in nonhysterectomized postmenopausal women who are receiving conjugated estrogens tablets. It is also indicated for use in secondary amenorrhea.
It should be clearly understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.

EXAMPLES
EXAMPLE 1:
Progesterone composition (Table 1)-
Sr. No. Ingredients mg / tab %w/w
Dry Mixing
1 Progesterone (Micronized) 400.00 40.45
2 Sodium lauryl sulphate 200.00 20.22
3 Poloxamer 188 (Kolliphor P 188 Micro) 100.00 10.11
4 Microcrystalline cellulose (PH 102) 50.00 5.06
Granulation
5 Purified Water q.s NA
Blending
6 Silicon dioxide (Sylloid 244 FP) 25.00 2.53
7 Hypromellose 2208 (Methocel K100 LV Premium) 38.40 3.88
8 Microcrystalline cellulose (PH 102) 121.60 12.30
Lubrication
9 Magnesium Stearate 25.00 2.53
Core tablet weight (mg) 960.00 97.08
Film Coating
10 Instacoat Universal Yellow (A05D21431) 28.88 2.92
11 Purified water q.s NA
Film coated tablet weight (mg) 988.88 100.00

Manufacturing process:
Stage-A: Dry mixing: Progesterone (Micronized), Microcrystalline cellulose (PH102), Sodium lauryl sulphate and Poloxamer 188 (Kolliphor P 188 Micro) were weighed and co-sifted through ASTM 20# s.s screen and then mixed for 20 minutes at slow/off condition in a Rapid Mixer Granulator (RMG).
Stage-B: Granulation: Purified water was added to the powder blend in RMG of stage A, in slow steady stream, over a period of 5 to 10 minutes at slow/off condition. Additional purified Water was added and the granulation was completed. Wet granules were semi-dried for 20 minutes in Fluid Bed Dryer and then milled through 6.0 mm s.s. screen and dried till LOD (Loss on drying) is NMT 2.0% w/w (Target: 1.5 -1.9 % w/w).5. The dried granules were sifted through ASTM 20# s.s. screen, weighed and transferred to a suitable blender.
Stage-C: Blending: 1. Hypromellose 2208 (Methocel K100 LV Premium), Silicon dioxide (Sylloid 244 FP) and Microcrystalline cellulose (PH102) were co-sifted through ASTM 40# S.S. Screen and transferred to the blender and mixed with dried granules.
Stage-D: -Lubrication: 1. Magnesium stearate was sifted through ASTM 40# s.s screen and transferred to above blender and mixed for 5 minutes.
Stage-E: – Compression and coating: Compression was done using punch: 18 X 9 mm, caplet standard concave plain on both side at average weight of 960.00 mg. these were then Film coated using dispersion of Instacoat Universal Yellow (A05D21431).

EXAMPLE 2:
Progesterone composition (Table 2)
Sr. No. Ingredients Amount
(mg / tab) % w/w
Dried Granules of Progesterone
Dry Mixing
1 Progesterone (Micronized) 400.00 38.85
2 Sodium lauryl sulphate 200.00 19.43
3 Microcrystalline cellulose (PH 102) 100.00 9.71
Granulation
4 Poloxamer 188 (Kolliphor P 188 Micro) 100.00 9.71
5 Acetonitrile q.s NA
6 Purified Water q.s NA
Total 800.00 77.70
Layer I: Immediate Release Layer
Blending
1 Dried Granules of Progesterone 480.00 46.63
2 Sodium Starch Glycolate NF (Type-A : pH 5.5 TO 7.5) (Primojel) 60.00 5.83
3 Magnesium Aluminometasilicate NF (Neusilin US2) 12.50 1.21
Lubrication
4 Magnesium Stearate 15.00 1.46
Total (mg) 567.50 55.12
Layer II: Sustained Release Layer
Blending
1 Dried Granules of Progesterone 320.00 31.08
2 Microcrystalline cellulose IP/NF (PH 102) 12.50 1.21
3 Hypromellose 2208 USP
(Methocel K100m CR Premium) 55.00 5.34
4 Quinoline Yellow Lake 2.00 0.19
5 Magnesium Aluminometasilicate NF
(Neusilin US2) 25.00 2.43
Lubrication
6 Magnesium Stearate 17.50 1.70
Total (mg) 432.00 41.96
Weight of core Table (Layer I+ Layer II) 999.50 97.09
Film Coating
1 Instacoat Universal Yellow (A05D21431) 29.99 2.91
2 Purified water q.s NA
Film coated tablet weight (mg) 1029.49 100

Manufacturing process:
Stage-A: Dry mixing: Progesterone (Micronized), Microcrystalline cellulose (PH102), Sodium lauryl sulphate and Poloxamer 188 (Kolliphor P 188 Micro) were weighed and co-sifted through ASTM 20# s.s screen and transferred into Rapid Mixer Granulator (RMG) and mixed for 20 minutes at slow/off.
Stage-B: Granulation: Poloxamer 188 (Kolliphor P 188 Micro) was mixed in the solvent mixture of acetonitrile and purified water under continuous stirring till clear solution is obtained. This binder solution was then added to the powder blend in RMG in slow steady stream, over a period of 5 to 10 minutes at slow/off condition. Additional Purified Water was added and the granulation was completed at slow/off condition. Wet granules were milled through 10.0 mm s.s. screen and were dried LOD is NMT 2.0% w/w (Target: 1.5 -1.9 % w/w. The dried granules were sifted through ASTM 20# s.s. screen and weighed.
Layer I: Immediate Release Layer
Stage-C: Blending: Dried granules were weighed as per the 60% of weight of dried granules and transferred to the suitable blender. Sodium Starch Glycolate Type A and Magnesium Aluminometasilicate NF (Neusilin US2) were co-sifted through ASTM 40# S.S. Screen and transferred to the blender and mixed with dried granules for 20 minutes.
Stage-D: Lubrication: Magnesium stearate was sifted through ASTM 60# s.s screen and transferred to the above blender.
Layer II: Sustained Release Layer
Stage-E: Blending: Dried granules as per the 40% of weight of dried granules were weighed and transferred to the suitable blender. Microcrystalline cellulose (PH 02), Hypromellose 2208 (Methocel K100 M CR) and Magnesium Aluminometasilicate NF (Neusilin US2) were sifted through ASTM 40# s.s screen. Quinoline Yellow lake was sifted through ASTM 60# s.s screen. All the sifted materials were transferred to the blender and mixed with the dried granules for 20 minutes.
Stage-F: Lubrication: Magnesium stearate was sifted through ASTM 60# s.s screen and transferred to above blender and mixed for 5 minutes. .
Stage-G: Compression and Coating: Compression was done using punch: 18 X 9 mm, caplet standard concave plain on both side at average weight of 999.50 mg (Immediate Layer: 567.50 mg and IR Layer: 432.0 mg). Film coating of core tablets was carried out using dispersion of Instacoat Universal Yellow (A05D21431).

EXAMPLE 3:
Comparative Composition details (Table 3)
Formulations A – without surfactant B- without rate controlling polymer C D E
Sr. No. Ingredients % w/w
Dry Mixing
1 Progesterone (Micronized) 55.5 44.7 40.5 40.5 40.5
2 Lactose Monohydrate 25.7
3 Sodium lauryl sulphate 22.3 20.2 20.2 20.2
4 Poloxamer 188 10.1 10.1 10.1
5 Microcrystalline cellulose (PH 102) 10.1 5.1 5.1 5.1
Stage –B: Granulation
1 Povidone IP/USP ( K-30 ) 3.5
2 Poloxamer 188 11.2
3 Purified Water NA NA NA NA NA
Stage – C: Blending
1 Silicon dioxide (Sylloid 244 FP) 2.2 2.5 2.5 2.5
Crospovidone (Polyplasdone XL) 4.5
2 Hypromellose 2208
(Methocel K100 LV Premium) 11.1 11.1 16.2 7.8
3 Microcrystalline cellulose (PH 102) 5.1 8.4
Stage – D: Lubrication
1 Magnesium Stearate 1.4 2.2 2.5 2.5 2.5
Core tablet weight (mg) 97.1 97.2 97.1 97.1 97.1
Stage E: Film Coating
1 Instacoat Universal Yellow (A05D21431) 3.0 2.8 2.9 2.9 2.9
2 Purified water NA NA NA NA NA
Film coated tablet weight (mg) 100 100

EXAMPLE 4:
Relative Bioavailability study: To compare the rate and extent of absorption of Progesterone from single dose of Test Product (T), Progesterone Sustained Release Tablets 400 mg of Sun Pharmaceutical Industries Limited, India (Example 1) and Reference Product (R), Prometrium (Progesterone) Capsules 200 mg (Two oral doses of one capsule was administered 12 hourly; total dose 400 mg (2×200 mg)) of Virtus Pharmaceuticals LLC, Newtown, PA 18940, USA in healthy, adult, human post-menopausal female subjects under fed conditions.
Methodology: Following an overnight fast of at least 8 hours and 2.5 hours after the start of high-fat, high-calorie breakfast, healthy, adult, human post-menopausal female subjects were orally administered either one tablet (1 × 400 mg) of progesterone composition of Example 1 (test product) once in morning or one capsule (1 × 200mg) of Prometrium (Progesterone) Capsules (reference product, R) twice (one in the morning and one in the evening) at 12 hours interval with drinking water. Blood samples were drawn before dosing (-1, -0.5 hours and 0 hour) and up to 36 hours after dosing in each period. Pharmacokinetic parameters were calculated using non-compartmental analyses. Number of observations, arithmetic mean, standard deviation (SD), coefficient of variation (CV %) and range (min. and max.) are calculated for plasma concentrations of baseline corrected progesterone, for each sampling time and treatment. Cmax (pg/mL), AUC0-24 (pg.h/mL), AUC0-t (pg.h/mL), AUC0-inf (pg.h/mL), Tmax (h) were analyzed statistically using log-transformed data. Bioequivalence was assessed by examining the T/R ratio of the test formulation mean relative to the reference formulation mean.

Results - Summary of statistical analysis of progesterone (n = 32) [with baseline correction] (Ln transformed data)
Table 4 -
Parameters Least Square geometric mean2 Point Estimate
(T/R)1 Within Subject CV% of Reference Product 95% Upper Confidence Bound
Example 1
(Test) Reference, (R)
Cmax (pg.mL-1) 37068.38 41309.49 89.73 109.85 -0.403
AUC0-t (pg.hr./mL) 99639.94 126992.02 78.46 62.27 -0.065
AUC0-24 (pg.hr/mL) 97352.37 119808.40 81.26 62.11 -0.091
AUC0-8 (pg.hr/mL) 104105.87 133574.33 77.94 62.21 -0.060
Tmax 4.0 5.0 -- -- --
N 32 32 -- -- --
1Calculated using least square means according to the formula: e(LSM Test (T) – LSM Reference (R)) X 100
2Least-square geometric means calculated from the analysis of the Ln-transformed data as e(least-square mean)

The 95% upper confidence bound of the linearized statistics for Cmax, AUC0-24 (with linear-log trapezoidal method) was less than zero and ratios of least squares geometric means (T/R) was around 81% for baseline corrected progesterone which is within the 80.00 – 125.00% bounds. The Test product Example 1 is administered once and Reference product (Prometrium (Progesterone) Capsules 200 mg)) is administered twice at 12 hour interval. Therefore, OD administration of Formulation of Example 1 is considered bioequivalent to BID administration of Reference product (2X200 mg) with respect to Cmax, AUC0-24 using the 80-125% FDA required criteria.

EXAMPLE 5:
Relative Bioavailability study: To compare the rate and extent of absorption of Progesterone from single dose of Test Product (T), Progesterone Sustained Release Tablets 400 mg of Sun Pharmaceutical Industries Limited, India and Reference Product (R), Prometrium (Progesterone) Capsules 200mg (Two oral doses of one capsule was administered 12 hourly; total dose 400 mg (2×200 mg)) of Virtus Pharmaceuticals LLC, Newtown, PA 18940, USA in healthy, adult, human post-menopausal female subjects under fed conditions.

Methodology -
For Formulation 3A –
Following an overnight fast and 30 mins after the start of high-fat, high-calorie breakfast, healthy, adult, human post-menopausal female subjects were orally administered either one tablet (1 × 400 mg) of progesterone composition of Example 3A (test product A) once in morning or Two capsules as a single dose of Prometrium (Progesterone) 200 mg Capsule (2 x 200 mg dose) (reference product, R) was administered orally one after another with drinking water. Blood samples were drawn before dosing (-1 hour, -0.5 hour and 0 hour) and up to 36 hours after dosing in each period.
For Formulation 3B –
Following an overnight fast of at least 8 hours and 2.5 hours after the start of high-fat, high-calorie breakfast, healthy, adult, human post-menopausal female subjects were orally administered either one tablet (1 × 400mg) of progesterone composition of Example 3B (test product B) once in morning or one capsule (1 × 200 mg) of Prometrium (Progesterone) Capsules (reference product, R) twice (one in the morning and one in the evening) at 12 hours interval with drinking water. Or two capsules (2 x 200 mg) together of Prometrium (Progesterone) Capsules (reference product, R) were administered. Blood samples were drawn before dosing (-1 hour, -0.5 hour and 0 hour) and up to 36 hours after dosing in each period.
For Formulation 3C, 3D and 3E –
Following an overnight fast of at least 8 hours and 2.5 hours after the start of high-fat, high-calorie breakfast, healthy, adult, human post-menopausal female subjects were orally administered either one tablet (1 × 400 mg) of progesterone composition of Example 3C, 3D or 3E (test product) once in morning or one capsule (1 × 200mg) of Prometrium (Progesterone) Capsules (reference product, R) twice (one in the morning and one in the evening) at 12 hours interval with drinking water. Blood samples were drawn before dosing (-1 hour, -0.5 hour and 0 hour) and up to 36 hours after dosing in each period.

Pharmacokinetic parameters were calculated using non-compartmental analyses. Number of observations, arithmetic mean, standard deviation (SD), coefficient of variation (CV %) and range (min. and max.) are calculated for plasma concentrations of baseline corrected progesterone, for each sampling time and treatment. Cmax (pg/mL), AUC0-24 (pg.h/mL), AUC0-t (pg.h/mL), AUC0-inf (pg.h/mL), Tmax (h) were analyzed statistically using log-transformed data. Bioequivalence was assessed by examining the T/R ratio of the test formulation mean relative to the reference formulation mean.

Results - Summary of statistical analysis of progesterone for Formulation 3 A and 3B [with baseline correction] (Ln transformed data)
Table 5 -
Parameters Example 3A Reference (R) Example 3B Reference (R)
(1 × 200mg) twice at 12 hr interval Example 3B Reference (R)
(2 x 200 mg) once
No. of subjects 18 18 17 17 17 17
Tmax (Hrs) 4.000 4.000 4.50 14.33 4.50 3.67
Cmax (pg/mL) 7440 253210 126950 86520 126950 225340
T/R
(90% CI Value) 2.94 (2.11 - 4.10) 146.72 (90.77 - 237.18) 56.33 (33.81 - 93.87)
Intra %CV 62.12 93.41 101.58
AUC0-t (pg*hr/mL) 29570 510050 225100 164500 225100 331890
T/R
(90% CI Value) 5.80 (4.34 - 7.74) 136.84 (99.80 - 187.62) 67.82 (45.94 - 100.13)
Intra %CV 52.83 55.78 71.48
AUC0-8 (pg*hr/mL) 31910 533000 239210 173700 239210 354880
T/R
(90% CI Value) 5.99 (4.49 - 7.98) 137.71 (100.33 - 189.03) 67.41 (45.60 - 99.65)
Intra %CV 52.53 56.01 71.78

Results - Summary of statistical analysis of progesterone Formulation 3C, 3D and 3E [with baseline correction] (Ln transformed data)
Table 6 -
Parameters Example 3C
(11.45 % polymer) Reference (R) Example 3D
(16.66 % Polymer) Reference (R) Example 3E
(8.0 % Polymer)
Reference (R)
No. of subjects 21 21 21 21 50 50
Tmax (Hrs) 4.9286 8.5159 5.6190 8.5159 6.0 4.834
Cmax (pg/mL) 54446.7 86715.2 25854.3 86715.2 63210 100240
T/R
(90% CI Value) 62.87
(41.52 - 95.19) 31.14
(20.27-47.15) 63.06
(% upper Confidence Bound -0.153)
Intra %CV 93.82 93.82 122.56
AUC0-t (pg*hr/mL) 126654.8 157802.7 71134.1 157802.7 129570 193470
T/R
(90% CI Value) 80.42
(59.42-108.84) 46.05
(34.02-62.32) 66.97
(% upper Confidence Bound 0.106)
Intra %CV 63.20 63.20 56.50
AUC0-8 (pg*hr/mL) 131769.3 165970.6 75222.2 165970.6 135890 202490
T/R
(90% CI Value) 79.55
(58.77-107.67) 46.33
(34.23-62.71) 67.11
(% upper Confidence Bound 0.100)
Intra %CV 63.22 63.22 57.27

Composition 3A does not comprise any surfactant, while composition 3B does not comprise any rate controlling polymer. Composition 3D, 3E and 3F comprise a higher concentration of rate controlling polymer. The ratios of least squares geometric means (T/R) for Cmax and AUC (with linear-log trapezoidal method) for baseline corrected progesterone was outside the 80.00 – 125.00% bounds. Therefore, Compositions 3A, 3B, 3C, 3D, 3E, and 3F are not considered bioequivalent to BID administration of Reference product (2X200 mg) with respect to Cmax, AUC0-24 using the 80-125% FDA required criteria.

EXAMPLE 6:
The Dissolution profile of composition of Example 1 is compared with compositions of Example 3C and Example 3E with different concentration of rate controlling polymer, Hypromellose. The compositions when tested for dissolution in a USP Apparatus II at 50 rpm in 900 ml of pH 4.5 acetate buffer with 0.5% SLS, exhibits the following dissolution profile.
Table 7-
Compositions Example 3C Example 3E Example 1
Time (hrs.) (% Drug dissolved)
0.5 8 12 29
1.0 24 34 69
1.5 40 55 84
2.0 55 71 88
4.0 92 94 94

It was observed that the composition of Example 1 releases atleast 69% progesterone in 1 hour and was found to be bioequivalent to BID administration of Reference product (2X200 mg) with respect to Cmax, AUC0-24 using the 80-125% FDA required criteria as seen in Example 4.