DESC:Field of Invention
The present invention relates to a pharmaceutical composition comprising a combination of Aspirin and Progesterone, wherein the active ingredients are either in immediate release or Modified release form.
Background of the Invention
Aspirin is widely used in clinical practice to inhibit platelet aggregation and prevent thrombosis. Clinically low dose aspirin is frequently used to prevent miscarriage. Low-dose aspirin is often considered useful to treat pregnancy-related complications, such as pregnancy complicated by antiphospholipid syndrome (APS), preeclampsia, and unexplained recurrent spontaneous miscarriage. However, a larger observational study on the use of aspirin in recurrent miscarriage showed that it did not improve pregnancy outcomes.
Progesterone is one of the most important hormones to maintain early pregnancy and is recommended to prevent spontaneous miscarriage. Progesterone is a natural progestogen which has an important effect on the secretion of endometrium. It can promote the change of endometrium when being normally secreted in vivo, and provides favorable conditions for implantation of fertilized eggs. Progesterone is widely used clinically, mainly for the treatment of luteal insufficiency, threatened abortion, menstrual disorders, etc., and in Hormone Replacement Therapy (HRT) in combination with estrogens to counteract the effects of simple estrogens on the intima.
Low dose aspirin alone or progesterone alone or dual therapy of aspirin and progesterone has been reported to inhibit the apoptosis of HTR-8/s Vneo cells, upregulate PGR expression and reduce oxidative stress-mediated reactive oxygen specific production and apoptosis in HTR-8/SVneo. It has also been reported that in dual therapy of low dose aspirin combined with progesterone (10-7mol/L) did not have any synergistic effect, and that there was no significant difference between the combined treatments group and the groups treated with aspirin or progesterone alone. (Shi et al., Reproductive and Developmental Medicine, 2021,5:1-8).
But the use of two separate medicaments adds to the cost of the treatment, assigned the correct use, and carries a risk of certain per se not therapeutic monitoring which can cause a decrease in the expected therapeutic efficacy of the treatment.
Thus, a therapy comprising the combination of Aspirin and progesterone in a single dose form that acts synergistically and targets the major pathological features which affects pregnancy related complications is desirable. The combination of these two therapeutic agents in a single dose is also a rational approach for achieving optimal therapeutic benefits while minimizing pill-burden. Greater convenience with decreased pill-burden leads to improved adherence, resulting in superior clinical outcomes and greater cost-effectiveness.
But combining progesterone with additional therapeutic agent like Aspirin has been found to be problematic. Preparing an oral composition of progesterone itself is problematic. Since progesterone oral tablets are rapidly destroyed in the gastrointestinal tract, have low bioavailability (around 10%), only a very small amount of the drug acts on the uterus, and are difficult to supplement and treat. This fact together with the fact that the first-pass liver metabolism of progesterone is very high has hitherto made oral administration of progesterone problematic. The oral preparation improves the solubility of the progesterone by increasing the concentration of the surfactant but it cannot fundamentally solve the problems of strong first pass effect and low bioavailability of the progesterone; the daily dose still needs to be very large to achieve the curative effect, and the side effect is large. Hence intramuscular injections are used clinically.
The conventional progesterone injection is an oil solution injection, and is injected daily for about 12 weeks. When the oil solution is injected, discomfort such as pain, local inflammation, allergy and other symptoms of a patient is easily caused, and the individual pathological reports even indicate that progesterone is injected intramuscularly to induce acute eosinophilic pneumonia. The long-term high-frequency injection can also cause other symptoms such as induration and the like at the injection part, which is not favorable for the health of the tissue of the injection part. Patients are pregnant women, progesterone injection is very inconvenient every day, and the progesterone injection has the problems of muscle hardening, pain and the like caused by an oil solvent.
The main target of progesterone production is the uterus, and thus topical administration of progesterone from the vagina is also a route of administration, such as pessaries and vaginal gels, common in clinical use for assisted reproduction (e.g. in test tube infants), threatened abortion and amenorrhea. Although the suppository is convenient to use, the suppository needs to be pushed into the vagina by hands, and the risk of pollution is caused; in addition, suppository drug release is slow and irregular, and requires higher doses.
There is also a mode, namely, percutaneous administration of progesterone, which can avoid the first pass action of the liver and the degradation of the gastrointestinal tract, and because of the fat-soluble property of progesterone, subcutaneous fat can play a role in slow release, maintain stable and proper blood concentration, and is safe and convenient, but at present, no related preparation is available on the market. The problem with transdermal administration of progesterone is that the penetration of progesterone drugs into the skin is too weak and special measures are needed to improve the transdermal efficacy of the drugs.
Further combining two active agents into a single does often have problems, including (i) pharmacodynamics mismatch between the individual drugs where one drug has an additive/antagonistic effect to another drug in the combination, leading to reduced efficacy or enhanced toxicity for the combination; (ii) pharmacokinetic mismatch between two drugs leading to peak efficiency of the drugs at different times; (iii) chemical incompatibility between the two drugs leading to decreased shelf-life of the pharmaceutical; (iv) chemical interactions during common metabolizing pathways leading to the ineffectiveness of one or more of the drugs in the combination; and (v) dosing titration limitations of the individual drugs.
Thus to prepare a composition comprising aspirin and progesterone one has to first solve the problems associated with the preparation of oral formulation of progesterone and then solve the problems associated in formulating composition wherein Progesterone and Aspirin are present in a single dose which matches the bioavailability, stability and efficacy of the either progesterone or aspirin individually.
Thus, there is an unmet need for providing a single dosage form comprising a combination of Aspirin and Progesterone, in which all active pharmaceutical substances remain stable and wherein the active substances are provided in a formulation providing the required bioavailability and/or required therapeutic or pharmacological response.
The inventors of the present invention have not only been able to solve the problems associated with oral composition of progesterone but also has been able to prepare a single dose combination comprising an Aspirin and progesterone with the desired bioavailability of both drugs and required stability.
The inventors have found that a combination product comprising Aspirin and progesterone can be prepared as a single solid dosage form in such a manner that the two active drug substances are present in separate entities. Thus, the active substances are effectively prevented from any drug-drug interaction; and the active substances may independently of each other can be present in different release forms, i.e. in the form of targeted release, immediate release, delayed release or controlled release compositions; and the stability of the combination drug product can be maximized due to the possibility of optimizing the formulations of each of the active substances with respect to physical and/or chemical conditions.
Objective of the invention
It is an object of the present invention to provide a pharmaceutical composition comprising a single dose combination of Aspirin and progesterone.
It is another object of the present invention to provide a single dose combination of a pharmaceutically effective amount of Aspirin in targeted release drug release form and a pharmaceutically effective amount of progesterone in sustained drug release form. In some embodiments, the compositions are in the form of a capsule, mini tablets, granules, pellets.
It is also an object of the present invention to provide a pharmaceutical composition for treatment of pregnancy related disorders.
Summary of the invention
The present invention provides compositions comprising a fixed dose combination of a pharmaceutically effective amount of Aspirin in targeted drug release form and a pharmaceutically effective amount of progesterone in sustained drug release form.
In an embodiment, the present invention provides a single dose combination of pharmaceutically effective amount of Aspirin and pharmaceutically effective amount of progesterone, wherein the composition is in solid oral form, preferably in the form of capsule.
In an embodiment, the invention provides a pharmaceutical composition for oral administration comprising a first solid pharmaceutical composition containing Aspirin as the active substance and second solid pharmaceutical composition containing progesterone as the active substance, wherein the first and the second pharmaceutical composition are present as separate entities in a single solid dosage form and wherein the preferred solid dosage form is capsule.
In a preferred embodiment, the first solid pharmaceutical composition and/or the second solid pharmaceutical composition is in the form of mini-tablets, granulate, granules, grains, beads or pellets, which are mixed and filled into capsules or sachets or are compressed to tablets by conventional methods.
In an embodiment, the first solid composition comprising Aspirin with targeted drug release profile, comprises:
i) a core comprising the active ingredient and pharmaceutical acceptable excipient;
ii) a seal coating over the core;
iii) an enteric coat over the seal coat layer.
In a most preferred embodiment, the first solid composition comprising Aspirin with targeted drug release profile comprises:
i) a core comprising Aspirin and pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipients are selected from filler, disintegrant and lubricants or combination thereof;
ii) a seal coating, over the core, wherein the seal coat comprises a mixture of film forming agent, plasticizer and one or more coating solvents;
iii) an enteric coating, over the seal coat layer, wherein the enteric coating comprises a mixture of Film forming agent and one or more coating solvents.
In an embodiment, the second oral pharmaceutical composition comprising progesterone with sustained release drug profile comprises:
i) active ingredient, wherein the active ingredient is progesterone;
ii) a mixture of two or more, preferably three sustained release agents;
iii) pharmaceutically acceptable excipients; wherein the pharmaceutically acceptable excipients are selected from filler, binder, disintegrant, glidant, lubricant or combination thereof and;
iv) Coating layer comprising a mixture of film former, plasticizer, opacifier, anti-tacking agent and two or more coating solvents.
In another embodiment, the process for preparation of a single dose composition comprising:
a) Process for preparation of first solid pharmaceutical composition containing Aspirin:
I. Sieving aspirin, hydroxypropyl methylcellulose, microcrystalline cellulose, and steric acid through #20 S.S., #40 S.S., #40 S.S. and #60 S.S. sieve, respectively;
II. Mixing sieved aspirin, hydroxypropyl methylcellulose, microcrystalline cellulose, and steric acid in a blender;
III. Compressing the dry mix blend to obtain tablets;
IV. Seal coating the tablets; wherein seal coating composition comprises HPMC E-15, Diethyl Phthalate, Isopropyl alcohol and methylene chloride;
V. Enteric coating the seal coated tablets; wherein enteric coating composition comprises Instacoat EN (I-EN) 670, Isopropyl alcohol and methylene chloride;
b) Process for preparation of second solid pharmaceutical composition containing progesterone:
I. Sieving progesterone through #20 S.S. sieve, and hydroxypropyl methylcellulose, Microcrystalline cellulose, Sodium carboxymethyl cellulose and xanthan Gum through #40 S.S. sieve;
II. granulating mixer of step (I) with binder solution in rapid mixer granulator; wherein binder solution comprises Ethyl cellulose, Isopropyl alcohol and methylene chloride;
III. drying the wet granulate at temperature of 60-65 °C for 10 minutes;
IV. mixing the colloidal silicon dioxide and magnesium stearate with dry granules;
V. compressing the mixer of step (IV) to obtain tablets;
VI. coating the tablets, wherein coating composition comprises HPMC E-15, PEG 6000, Titanium Dioxide and Talcum in Isopropyl alcohol and methylene chloride;
c) Capsule filing:
Filling the first solid pharmaceutical composition containing Aspirin and second solid pharmaceutical composition containing progesterone in hard gelatin capsules.
Description of the invention
The term "single dose combination" drug refers to a formulation of two or more medications or active ingredients combined in a single unit dosage form, and available in certain fixed doses.
As used herein, the term "active substance", "active pharmaceutical substance", "active ingredient" or "active pharmaceutical ingredient" means any component that is intended to provide pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term also includes those components that may undergo chemical change in the manufacture of the drug product and are present in the drug product in a modified form intended to furnish the specified activity or effect.
As used herein, the term "vehicle" means any solvent or carrier in a pharmaceutical product that has no pharmacological role.
As used herein the term "drug" means a compound intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals.
As used herein the term "dosage form" means the form in which the drug is delivered to the patient. This could be parenteral, topical, tablet, oral (liquid or dissolved powder), suppository, inhalation, transdermal, etc.
As used herein, the term "bioavailability" denotes the degree means to which a drug or other substance becomes available to the target tissue after administration. The term "suitable bioavailability" is intended to mean that administration of a composition according to the invention will result in a bioavailability that is improved compared to the bioavailability obtained after administration of the active substance(s) in a plain tablet; or the bioavailability is at least the same or improved compared to the bioavailability obtained after administration of a commercially available product containing the same active substance(s) in the same amounts. In particular, it is desired to obtain quicker and larger and/or more complete uptake of the active compound, and thereby provide for a reduction of the administered dosages or for a reduction in the number of daily administrations.
As used herein the terms "controlled release" and "modified release" are intended to be equivalent terms covering any type of release of the active ingredient from the composition of the invention that is appropriate to obtain a specific therapeutic or prophylactic response after administration to a subject. A person skilled in the art knows how controlled release/modified release differs from the release of plain tablets or capsules. The terms "release in a controlled manner" or "releases in a modified manner” have the same meaning as stated above. The terms include slow release, extended release, delayed release as well as pulsatile release, burst release, sustained release, prolonged release, chrono-optimized release, fast release etc.
The term “Targeted release” or “targeted drug release form/profile” as used herein refers to a dosage form that releases drug at or near the intended physiologic site of action targeted-release dosage forms may have either immediate- or extended-release characteristics.
The present invention provides compositions comprising a fixed dose combination of a pharmaceutically effective amount of Aspirin in targeted drug release form and a pharmaceutically effective amount of progesterone in sustained drug release form. In some embodiments, the compositions are in the form of a capsule, mini tablets, granules, pellets. In a preferred embodiment, the compositions are solid and in the form of a capsule.
In an embodiment the present invention provides a single dose combination of pharmaceutically effective amount of Aspirin and pharmaceutically effective amount of progesterone, wherein the composition is in solid oral form, preferably in the form of capsule. In another embodiment the combination of Aspirin and progesterone are formulated as separate granules or mini-tablets or pellets.
In an embodiment, the invention provides a pharmaceutical composition for oral administration comprising a first solid pharmaceutical composition containing Aspirin as the active substance and second solid pharmaceutical composition containing progesterone as the active substance, wherein the first and the second pharmaceutical composition are present as separate entities in a single solid dosage form and wherein the preferred solid dosage form is capsule.
In an embodiment, the invention provides a pharmaceutical composition for oral administration comprising a first solid pharmaceutical composition containing Aspirin as the active substance and second solid pharmaceutical composition containing progesterone as the active substance, wherein the first and the second pharmaceutical composition are present as separate entities in a single solid dosage form and wherein the preferred solid dosage form is capsule and wherein the first and second pharmaceutical composition further comprises pharmaceutically acceptable excipients.
In a preferred embodiment, the first solid pharmaceutical composition and/or the second solid pharmaceutical composition is in the form of mini-tablets, granulate, granules, grains, beads or pellets, which are mixed and filled into capsules or sachets or are compressed to tablets by conventional methods.
In a preferred embodiment, the mini-tablets, granulate, granules, grains, beads or pellets containing Aspirin are in targeted drug release form.
In a preferred embodiment, the mini-tablets, granulate, granules, grains, beads or pellets containing the progesterone are in sustained drug release form.
But it is well known in the pharmaceutical art, that the formulation of multiple pharmaceutically active compounds into usable dosage forms, in which the release of one or more active ingredients is different from one another, may be challenging and, frequently, unpredictable. Although various methods have been suggested in the art to improve the drug release from the fixed dose combination formulations, it is highly uncertain to devise an ideal formulation of a particular drug combination by legitimate selection of excipients. The inventors of the present invention have been able to overcome the same by formulating a formulation comprising separate solid pharmaceutical composition comprising individual active ingredients wherein the separate pharmaceutical composition doesn’t affect the release profile of one another.
Thus in an embodiment, the invention provides a pharmaceutical composition for oral administration comprising a first solid pharmaceutical composition containing Aspirin in targeted drug release form and second solid pharmaceutical composition containing progesterone in sustained drug release form, wherein the first and the second pharmaceutical composition are present as separate entities in a single solid dosage form and wherein the preferred solid dosage form is capsule and wherein the first and second pharmaceutical composition doesn’t adversely affect the release profile of one another.
The targeted drug release profile of the first solid pharmaceutical composition comprising Aspirin is obtained by coating a core comprising the active ingredient with a seal coat followed by an enteric coat layer over the seal coat. In an embodiment the core comprising active ingredient further comprises filler, disintegrant and lubricants. In an embodiment the seal coat comprises film forming agent, plasticizer and coating solvent. In an embodiment the enteric coat layer comprises of film forming agent and coating solvent.
In an embodiment, Aspirin is present in the first solid pharmaceutical composition in range of 50% to 90% by weight of the composition.
The sustained release drug profile of the second oral pharmaceutical composition comprising progesterone, with the desired dissolution bioavailability profile, has been obtained by using a novel mixture of sustained release agent in specific ratio which allows the sustained release of the progesterone that meets the required bioavailability of the drug.
Thus, in an embodiment the second solid pharmaceutical composition comprising progesterone comprises a mixture of sustained release polymer in specific ratios, which provides sustained or modified release of progesterone.
In another embodiment, the second solid pharmaceutical composition comprising progesterone is in sustained or modified release form, wherein the sustained or modified release is obtained with a novel mixture of sustained release polymers in specific ratios and wherein the second pharmaceutical composition further comprises additional pharmaceutically acceptable excipient.
In a preferred embodiment, the novel mixture of sustained release polymers comprises two or more, preferably three sustained release polymers, wherein the sustained release polymers are present in the ratio of 2:1:1 to 10:5:5.
In an embodiment, progesterone in the second solid pharmaceutical composition is present in the range of 40% to 80% by weight of the composition.
The additional objective of preparing pharmaceutical composition wherein the first and/or second pharmaceutical composition doesn’t adversely affect the release profile of one another was obtained by using a synergistic combination of additional pharmaceutical excipients in specific ratios.
Thus in a further embodiment the present invention provides a pharmaceutical composition comprising additional pharmaceutical excipients in specific ratio to obtain a pharmaceutical composition comprising a first solid pharmaceutical composition comprising aspirin with targeted drug release profile and second solid pharmaceutical composition comprising progesterone with sustained release profile, wherein the first and second solid pharmaceutical composition doesn’t adversely affects the release profile of one another.
In an embodiment, the first solid composition comprising Aspirin with targeted drug release profile, comprises:
i) a core comprising the active ingredient and pharmaceutical acceptable excipient;
ii) a seal coating over the core;
iii) an enteric coat over the seal coat layer.
In a most preferred embodiment, the first solid composition comprising Aspirin with targeted drug release profile comprises:
i) a core comprising Aspirin and pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipients are selected from filler, disintegrant and lubricants or combination thereof;
ii) a seal coating, over the core, wherein the seal coat comprises a mixture of film forming agent, plasticizer and one or more coating solvents;
iii) an enteric coating, over the seal coat layer, wherein the enteric coating comprises a mixture of Film forming agent and one or more coating solvents.
In an embodiment, the second oral pharmaceutical composition comprising progesterone with sustained release drug profile comprises:
i) active ingredient, wherein the active ingredient is progesterone;
ii) a mixture of two or more, preferably three sustained release agents;
iii) pharmaceutically acceptable excipients; wherein the pharmaceutically acceptable excipients are selected from filler, binder, disintegrant, glidant, lubricant or combination thereof and;
iv) Coating layer comprising a mixture of film former, plasticizer, opacifier, anti-tacking agent and two or more coating solvents.
Examples of fillers/diluents that can be used in the present invention are acacia, alginic acid, cellulose, dextrin, dextrates, sucrose, tylose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, gelatin, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, lactose, sucrose, glucose, mannitol, sorbitol, microcrystalline cellulose, pectin, polyacrylates, cellulose acetate, hydroxypropylmethyl cellulose, calcium carbonate, calcium carboxy methylcellulose, Colloidal silicon dioxide, Talc, Magnesium stearate and others including combinations thereof.
In a preferred embodiment filler/diluents are selected from Microcrystalline cellulose (MCC) PH 112 and MCC PH 102 or combination thereof.
Examples of sustained release agents that can be used in the present invention are polymers selected from methylcellulose, hydroxypropyl methylcellulose (Methocel) , carmellose sodium (sodium carboxymethylcellulose) and carbomer (polyacrylic acid), polyvinyl acetate, polyvinyl pyrrolidone, polymers and copolymers of acrylic acid and methacrylic acid and esters thereof, polyethylene glycol carrageenan, hydroxypropyl cellulose and gums such as acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, agar, pectin, carrageen, xanthan gum, soluble alginates methyl cellulose, hydroxy propylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose (Sodium CMC), carboxy polymethylene and others including combinations thereof.
In a preferred embodiment sustained release agents are selected from hydroxypropyl methylcellulose (Methocel K-200M Premium), Xanthan Gum and Sodium CMC or a combination thereof.
Examples of Binders that can be used in the present invention are water-soluble polymers, for example, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and the like; water-insoluble polymers, for example, ethyl cellulose, polyvinyl chloride, aminoalkyl and the like; and enteric polymers, for example, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer L, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxyvinyl polymer or combination thereof.
In a preferred embodiment binder is selected from ethyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone or a combination thereof.
Examples of Glidant that can be used in the present invention are colloidal silicon dioxide, magnesium trisilicate, talcum, powdered cellulose, starch, tribasic calcium phosphate, calcium stearate, glycerylbehenate, glycerylmonostearate, magnesium laurylsulfate, magnesium stearate, polyethyleneglycol, potassium benzonate, Sodium stearate, sodium stearyl fumarate, stearic acid or combination thereof. In most preferred embodiment glidant are colloidal silicon Dioxide and Talcum.
Examples of lubricant that can be used in the present invention are selected from stearic acid, magnesium stearate, calcium or zinc stearate, sodium stearyl fumarate and metal stearates or a combination thereof.
Examples of film formers that can be used in the present invention are cellulose ethers such as ethyl cellulose, cellulose acetate, polyvinyl acetate, methacrylic acid esters neutral polymer, polyvinyl alcohol-maleic anhydride copolymers, cellulose esters, polyvinyl alcohol, ethyl celluloses, Hydroxypropyl methylcellulose (HPMC E-15), acrylic polymer, methylcellulose, hydroxypropyl cellulose, enteric coating agent selected from Instacoat EN (Hydroxypropyl methyl cellulose Phthalate. Polyethylene glycol, cellulose acetate phthalate). Methacrylate copolymer, shellac, sodium alginate, acetyltributyl citrate, carbomers, cellulose acetate phthalate, guar gum, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate, potassium chloride, glycerin, Sureteric, tributyl citrate, triethyl citrate, triolein, white wax, zein, with ethyl cellulose, chitosan, hydroxypropyl cellulose, polymethacrylates or combinations thereof. In most preferred embodiment, film formers are selected from HPMC E-15, Instacoat EN (I-EN) 670 or combination thereof.
Examples of plasticizer that can be used in the present invention are triethyl citrate, triacetin, dibutyl phthalate, diethyl phthalate, tributyl citrate, tributyl acetylcitrate, triethyl acetylcitrate, propylene glycol, dipropylene glycol, triacetin, diacetin, monoacetin, benzyl alcohol, glycerin phthalate, polyethylene glycol, polyoxyethylene alkyl ethers, polyethylene glycol fatty acid esters and propylene glycol fatty acid esters or combinations thereof. In most preferred embodiments, plasticizer is diethyl phthalate, PEG 600 or a combination thereof.
Examples of disintegrant that can be used in the present invention are sodium carboxymethyl starch, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose, sodium starch glycolate, alginates, pregelatinized starch, hydroy propyl cellulose (HPC), cross-linked PVP like collidone and crospovidone or combinations thereof. In most preferred embodiment, disintegrant used is selected from HPC, PVP, crospovidone or a combination thereof.
Examples of opacifier that can be used in the present invention are titanium dioxide, ferric oxide, talc, magnesium carbonate, barium sulfate, calcium carbonate or combinations thereof. In most preferred embodiments, opacifier is selected from titanium dioxide, calcium carbonate, magnesium carbonate or a combination thereof.
Examples of anti-tacking agent that can be used in the present invention are talcum, aluminum hydrate, silicon dioxide, silica gel, fumed silica, kaolin, glyceryl monostearate. In most preferred embodiments, anti-tacking agent is talcum.
Examples of Coating Solvent that can be used in the present invention are ethanol, methyl alcohol, n-butyl alcohol, acetonitrile water, acetone, isopropyl ketone, isopropyl alcohol, methylene chloride, ethyl acetate, chloroform, dichloromethane or combinations thereof. In most preferred embodiments, coating solvent is isopropyl alcohol, methylene chloride or combination thereof.
In an embodiment, the present invention provides a pharmaceutical composition for the treatment of recurrent early pregnancy loss, oligohydramnios, preeclampsia and/or fetal growth retardation in pregnant female, preterm pregnancy loss, miscarriage or other pregnancy related issues.
The pharmaceutical compositions of the present invention are prepared by dry and wet processing methods.
In an embodiment the process of manufacture has the following steps:
1. Preparation of Sustained release progesterone tablets/granules
2. Preparation of enteric coated tablets/granules comprising Aspirin
3. Dispensing in Reverse laminar air flow (RLAF)
4. Capsule filling
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
Example 1: Formula for Progesterone SR tablets 100 mg
S.NO. INGREDIENTS MG/Tab % FUNCTION
DRY MIX
1 Progesterone 100.00 62.50 Active Pharmaceutical Ingredients
2 Microcrystalline cellulose 10.50 6.56 Filler
3 Hydroxypropyl methylcellulose 12.00 7.50 Sustained release agent
4 Xanthan Gum 2.00 1.25 Sustained release agent
5 Sodium carboxymethyl cellulose 2.00 1.25 Sustained release agent
BINDER SOLUTION
6 Ethyl cellulose 20cps 7.00 4.38 Binder
7 Isopropyl Alcohol 24.00 NA Binding solvent
8 Methylene Chloride 16.00 NA Binding solvent
LUBRICATION
9 Microcrystalline cellulose 12.00 7.50 Filler
10 Hydroxypropyl methylcellulose 5.00 3.13 Sustained release agent
11 Xanthan Gum 3.00 1.88 Sustained release agent
12 Sodium carboxymethyl cellulose 3.00 1.88 Sustained release agent
13 Talcum 2.00 1.25 Glidant
14 Colloidal Silicon Dioxide 0.50 0.31 Glidant
15 Magnesium Stearate 1.00 0.63 Lubricant
Weight of Uncoated Tablets 160.0 mg
COATING
16 HPMC E-15 3.00 1.88 Film Former
17 PEG 6000 0.50 0.31 Plasticizer
18 Titanium Dioxide 1.00 0.63 Opacifier
19 Talcum 0.50 0.31 Anti-tacking agent
20 Isopropyl Alcohol 27.00 NA Coating Solvent
21 Methylene Chloride 49.00 NA Coating Solvent
Weight of Coated Tablets 165.0 mg

Manufacturing process for Progesterone SR tablets:
Progesterone was shifted through #20 S.S. sieve and, Hydroxypropyl methylcellulose, Microcrystalline cellulose, Sodium carboxymethyl cellulose and Xanthan Gum were shifted through #40 S.S. sieve which fitted to a Mechanical Sifter and collected separately in double Polythene lined labelled container. Above shifted materials were added with binder solution containing Ethyl cellulose in Isopropyl alcohol and methylene chloride and granulated into Rapid Mixer Granulator (RMG). Granulated materials were dried at temperature of 60-65 °C for 10 min. Dry granules were added with colloidal silicon dioxide and magnesium stearate in blender. The lubricated blend was compressed by using suitable die and punches. The tablets were coated using coating composition comprising HPMC E-15, PEG 6000, Titanium Dioxide and Talcum in Isopropyl alcohol and methylene chloride.

Example 2: Formula for Aspirin EC tablets 75 mg
S.NO. INGREDIENTS MG/Tab % FUNCTION
1 Aspirin (Acetyl Salicyclic Acid) Granular 75.00 75.00 Active Pharmaceutical Ingredient
2 Microcrystalline cellulose 20.00 20.00 Filler
3 Hydroxy Propyl Cellulose (LH-11) 4.00 4.00 Disintegrants
4 Stearic Acid 1.00 1.00 Lubricant
Weight of uncoated tablets 100.00 mg
Seal Coating
5 HPMC E-15 2.80 2.55 Film former
6 Diethyl Phthalate 0.20 0.18 Plasticizer
7 Isopropyl Alcohol 20.00 18.18 Coating Solvent
8 Methylene chloride 37.00 33.64 Coating Solvent
Enteric Coating
9 Instacoat EN (I-EN) 670 7.00 6.36 Film Former
10 Isopropyl Alcohol 40.00 36.36 Coating solvent
11 Methylene Chloride 70.00 63.64 Coating solvent
Weight of coated tablets 110.00 mg

Manufacturing process for Aspirin EC tablet:
Aspirin, Hydroxypropyl methylcellulose, Microcrystalline cellulose, and steric acid were shifted through #20 S.S., #40 S.S., #40 S.S. and #60 S.S. sieve, respectively which fitted to a Mechanical Sifter and collected separately in double Polythene lined labelled container. Above shifted materials were mixed in a blender. The lubricated blend was compressed by using suitable die and punches. The tablets were seal coated using seal coating composition comprising HPMC E-15 and Diethyl Phthalate in Isopropyl alcohol and methylene chloride. The seal coted tablets were further coated using enteric coating composition comprises Instacoat EN (I-EN) 670 in Isopropyl alcohol and methylene chloride.
The Progesterone SR tablets, and Aspirin EC tablets were filled into "00" hard gelatin Capsule.
Stability Study
Example 3 - Stability and dissolution study of formulation
Stability Condition: ACCELERATED STABILITY TESTING: 40°C, 75% RH
S. No. Duration of Study Initial 1 month 3 months 6 months
TEST Specification
1.0 Description Black Cap/Black body size "00" hard gelatin Capsule containing one white sustained release tablets (Progesterone) & one light pink coloured enteric coated Tablets (Aspirin). 10 capsule packed in Clear PVC & Plain aluminium foil. Complies Complies Complies Complies
2.0 Average weight (Filled Capsules) 395 mg ± 7.5% 397.05 mg 395.16 mg 396.76 mg 397.67 mg
3.0 Average fill weight 275 mg ± 10.0% 277.50 mg 273.25 mg 274.96 mg 274.02 mg
4.0 Disintegration Time (for capsule shell) Not more than 30 minutes. 02 min 55 sec 02 min 28 sec 02 min 59 sec 03 min 20 sec
5.0 Dissolution (By HPLC) For Progesterone
5.1 After 1 hours Not more than 15 % Min.- 9.45% Max.- 10.23%
Mean- 9.74% Min.- 08.76% Max.- 13.82%
Mean- 10.60% Min.- 03.11% Max.- 08.46%
Mean- 06.59% Min.- 04.44% Max.- 04.68%
Mean- 04.55%
5.2 After 5 hours Between 15% to 40% Min.- 22.40% Max.- 31.50%
Mean- 28.60% Min.- 27.60% Max.- 32.50%
Mean- 30.20% Min.- 29.90% Max.- 34.00%
Mean- 31.90% Min.- 21.60% Max.- 30.50%
Mean- 28.30%
5.3 After 11 hours Between 35% to 75% Min.- 50.63% Max.- 53.31%
Mean- 51.85% Min.- 49.66% Max.- 58.30%
Mean- 53.34% Min.- 54.26% Max.- 61.34%
Mean- 58.07% Min.- 56.47% Max.- 58.84%
Mean- 57.59%
5.4 After 24 hours Not less than 70% Min.- 91.85% Max.- 96.45%
Mean- 93.15% Min.- 88.31% Max.- 101.64%
Mean- 98.25% Min.- 88.182% Max.- 97.35%
Mean- 92.32% Min.- 96.96% Max.- 99.36%
Mean- 98.02%
6.0 Dissolution (By HPLC) For Aspirin (Light Pink Coloured Tablet)
6.1 In acidic medium NMT 10% in 120 minutes 0% 0% 0% 0%
6.2 In Phosphate buffer
(pH 6.8) NLT 70% (D) in 90 minutes Min.- 90.66% Max.- 99.92%
Mean- 94.7% Min.- 89.76% Max.- 95.63%
Mean- 92.70% Min.- 82.00% Max.- 94.00%
Mean- 90.00% Min.- 85.00% Max.- 101.00%
Mean- 94.00%

Stability Condition: LONG-TERM STABILITY TESTING: 30°C, 75% RH
S. No. Duration of Study Initial 1 month 3 months 6 months
TEST Specification
1.0 Description Black Cap/Black body size "00" hard gelatin Capsule containing one white sustained release tablets (Progesterone) & one light pink coloured enteric coated Tablets (Aspirin). 10 capsule packed in Clear PVC & Plain aluminium foil. Complies Complies Complies Complies
2.0 Average weight (Filled Capsules) 395 mg ± 7.5% 397.05 mg 394.38 mg 396.83 mg 396.69 mg
3.0 Average fill weight 275 mg ± 10.0% 277.50 mg 273.65 mg 276.09 mg 272.63 mg
4.0 Disintegration Time (for capsule shell) Not more than 30 minutes. 02 min 55 sec 02 min 58 sec 02 min 18 sec 02 min 38 sec
5.0 Dissolution (By HPLC) For Progesterone
5.1 After 1 hours Not more than 15 % Min.- 9.45% Max.- 10.23%
Mean- 9.74% Min.- 8.63% Max.- 12.77%
Mean- 10.34% Min.- 06.57% Max.- 09.08%
Mean- 08.42% MM.- 05.23% Max.- 06.04%
Mean- 05.49%
5.2 After 5 hours Between 15% to 40% Min.- 22.40% Max.- 31.50%
Mean- 28.60% Min.- 27.80% Max.- 32.80%
Mean- 30.40% Min.- 30.30% Max.- 34.50%
Mean- 32.20% Min.- 30.20% Max.- 36.80%
Mean- 31.70%
5.3 After 11 hours Between 35% to 75% Min.- 50.63% Max.- 53.31%
Mean- 51.85% Min.- 49.76% Max.- 58.46%
Mean- 53.49% Min.- 55.50% Max.- 62.57%
Mean- 58.62% Min.- 58.34% Max.-62.92%
Mean- 60.76% .
5.4 After 24 hours Not less than 70% Min.- 91.85% Max.- 96.45%
Mean- 93.15% Min.- 90.15% Max.- 102.15%
Mean- 98.60% Min.- 87.53% Max.- 97.68%
Mean- 92.34% Min.- 96.30% Max.- 103.91%
Mean- 99.26%
6.0 Dissolution (By HPLC) For Aspirin (Light Pink Coloured Tablet)
6.1 In acidic medium NMT 10% in 120 minutes 0% 0% 0% 0%
6.2 In Phosphate buffer
(pH 6.8) NLT 70% (D) in 90 minutes MM.- 90.66% Max.- 99.92%
Mean- 94.7% Min.- 90.39% Max.- 102.75%
Mean- 94.30% Min.- 84.00% Max.- 99.00%
Mean- 91.00% Min.- 92.00% Max.- 100.00%
Mean- 96.00%

Stability Condition: REAL TIME STABILITY TESTING
S. No. Duration of Study Initial 1 month 3 months 6 months
TEST Specification
1.0 Description Black Cap/Black body size "00" hard gelatin Capsule containing one white sustained release tablets (Progesterone) & one light pink coloured enteric coated Tablets (Aspirin). 10 capsule packed in Clear PVC & Plain aluminium foil. Complies Complies Complies Complies
2.0 Average weight (Filled Capsules) 395 mg ± 7.5% 397.05 mg 398.05 mg 396.51 mg 396.51 mg
3.0 Average fill weight 275 mg ± 10.0% 277.50 mg 271.32 mg 275.75 mg 274.90 mg
4.0 Disintegration Time (for capsule shell) Not more than 30 minutes. 02 min 55 sec 03 min 15 sec 03 min 25 sec 03 min 25 sec
5.0 Dissolution (By HPLC) For Progesterone
5.1 After 1 hours Not more than 15 % Min.- 9.45% Max.- 10.23% Min.- 09.59% Max.- 11.17% Min.- 06.39% Max.-09.63% Min.- 04.58% Max.-04.69%
5.2 After 5 hours Between 15% to 40% Mean- 9.74% Mean- 10.39% Mean- 08.12% Mean- 04.63%
5.3 After 11 hours Between 35% to 75% Min.- 22.40% Max.- 31.50% Min.- 28.20% Max.- 33.90% Min.- 30.20% Max.- 34.20% Min.- 30.10% Max.- 30.70%
5.4 After 24 hours Not less than 70% Mean- 28.60% Mean- 31.70% Mean- 32.20% Mean- 30.40%
6.0 Dissolution (By HPLC) For Aspirin (Light Pink Coloured Tablet)
6.1 In acidic medium NMT 10% in 120 minutes 0% 0% 0% 0%
6.2 In Phosphate buffer
(pH 6.8) NLT 70% (D) in 90 minutes MM.- 90.66% Max.- 99.92% Min.- 88.26% Max.- 97.00% Min.- 90.00% Max.- 100.00% Min.-85.00% Max.- 97.00%
,CLAIMS:1. A pharmaceutical composition for oral administration comprising:
a) first solid pharmaceutical composition containing Aspirin as the active substance and;
b) second solid pharmaceutical composition containing progesterone as the active substance;
wherein the first and the second pharmaceutical composition are present as separate entities in a single solid dosage form.
2. The pharmaceutical composition as claimed in claim 1, wherein the solid dosage from is selected from capsules, sachets, or tablets; wherein preferably solid dosage form is capsules.
3. The pharmaceutical composition as claimed in claim 1, wherein the first and the second solid pharmaceutical composition is in the form of mini-tablets, granulate, granules, grains, beads or pellets.
4. The pharmaceutical composition as claimed in claim 1, wherein the first solid pharmaceutical composition containing Aspirin are in targeted release form; and wherein the second solid pharmaceutical composition containing progesterone are in sustained release form.
5. The pharmaceutical composition as claimed in claim 1, wherein the first solid composition with targeted drug release profile, comprises:
a) a core comprising Aspirin and pharmaceutically acceptable excipients; wherein the pharmaceutically acceptable excipients are selected from filler, disintegrant and lubricants or combination thereof;
b) a seal coating over the core; wherein the seal coat comprises a mixture of film forming agent, plasticizer and one or more coating solvents;
c) an enteric coating over the seal coat layer; wherein the enteric coating comprises a mixture of Film forming agent and one or more coating solvents.
6. The pharmaceutical composition as claimed in claim 5, wherein aspirin is present in range of 50% to 90% by weight of the first solid pharmaceutical composition.
7. The pharmaceutical composition as claimed in claim 1, wherein the second solid composition with sustained drug release profile, comprises:
a) progesterone;
b) a mixture of two or more, preferably three sustained release agents;
c) pharmaceutically acceptable excipients; wherein the pharmaceutically acceptable excipients are selected from filler, binder, disintegrant, glidant, lubricant or combination thereof and;
d) coating layer comprising a mixture of film former, plasticizer, opacifier, anti-tacking agent and two or more coating solvents.
8. The pharmaceutical composition as claimed in claim 7, wherein progesterone is present in range of 40% to 80% by weight of the second solid pharmaceutical composition.
9. The pharmaceutical composition as claimed in claim 7, wherein the sustained release agents are selected from hydroxypropyl methylcellulose, Xanthan Gum and Sodium CMC or a combination thereof.
10. A process for preparation of a composition as claimed in any of the preceding claims comprising:
a) Process for preparation of first solid pharmaceutical composition containing Aspirin:
I. Sieving aspirin, hydroxypropyl methylcellulose, microcrystalline cellulose, and steric acid through #20 S.S., #40 S.S., #40 S.S. and #60 S.S. sieve, respectively;
II. Mixing sieved aspirin, hydroxypropyl methylcellulose, microcrystalline cellulose, and steric acid in a blender;
III. Compressing the dry mix blend to obtain tablets;
IV. Seal coating the tablets; wherein seal coating composition comprises HPMC E-15, Diethyl Phthalate, Isopropyl alcohol and methylene chloride;
V. Enteric coating the seal coated tablets; wherein enteric coating composition comprises Instacoat EN (I-EN) 670, Isopropyl alcohol and methylene chloride;
b) Process for preparation of second solid pharmaceutical composition containing progesterone:
I. Sieving progesterone through #20 S.S. sieve, and hydroxypropyl methylcellulose, Microcrystalline cellulose, Sodium carboxymethyl cellulose and xanthan Gum through #40 S.S. sieve;
II. granulating mixer of step (I) with binder solution in rapid mixer granulator; wherein binder solution comprises Ethyl cellulose, Isopropyl alcohol and methylene chloride;
III. drying the wet granulate at temperature of 60-65 °C for 10 minutes;
IV. mixing the colloidal silicon dioxide and magnesium stearate with dry granules;
V. compressing the mixer of step (IV) to obtain tablets;
VI. coating the tablets, wherein coating composition comprises HPMC E-15, PEG 6000, Titanium Dioxide and Talcum in Isopropyl alcohol and methylene chloride;
c) Capsule filing:
Filling the first solid pharmaceutical composition containing Aspirin and second solid pharmaceutical composition containing progesterone in hard gelatin capsules.