WO2020049588A1

WO2020049588A1 - Technology for enhancing bioavalaibility of selective estrogen receptor modulator (serm)

Info

Publication number: WO2020049588A1
Application number: PCT/IN2019/050632
Authority: WO
Inventors: Hetal Paresh Thakkar; Gargi NANDA
Original assignee: THAKKAR Hetal Paresh; Nanda Gargi
Priority date: 2018-09-05
Filing date: 2019-09-02
Publication date: 2020-03-12

Abstract

The present invention relates to a technology to enhance the bioavailability of Selective Estrogen Receptor Modulator (SERM) class of drugs. The present invention provides enhanced bioavailability by increasing its dissolution using liquisolid compacts and/or reducing first pass metabolism (glucuronidation) by incorporating bio enhancers like Naringin and Piperine or combination of both.

Description

TECHNOLOGY FOR ENHANCING BIOAVALAIBILITY OF SELECTIVE ESTROGEN RECEPTOR MODULATOR (SERM)

FIELD OF THE INVENTION

The present invention relates to a technology to enhance the bioavailability of Selective Estrogen Receptor Modulator (SERM) class of drugs. The present invention provides enhanced bioavailability by increasing its dissolution using liquisolid compacts and/or reducing first pass metabolism (glucuronidation) by incorporating bio enhancers like Naringin and Pipeline or combination of both.

BACKGROUND OF THE INVENTION

Osteoporosis is a medical condition in which the bones become brittle and fragile due to loss of tissue, typically as a result of hormonal changes or deficiency of calcium or vitamin D. Postmenopausal Osteoporosis develops after menopause, when estrogen levels drop precipitously. These changes lead to loss of bone mineral density, usually in the spongy bone inside the hard cortical bone. Various conditions like age, heredity, lifestyle, menstrual history and body type, play major role in postmenopausal osteoporosis. As per survey conducted by WHO, 1 out of 4 women of age 30 years suffer from Post-Menopausal Osteoporosis.

For the treatment of post-menopausal osteoporosis, Antiresorptive drugs (Biphosphonates, calcium, serotonin, SERM) and Anabolic agents (Teriparatide) are available. Out of available therapies, Selective Estrogen Receptor Modulator (SERM) are gaining preference over other treatment options due to cost effectiveness, higher stability profile, easy handling and lesser chances of accumulation. Drugs like tamoxifen, raloxifene, lasofoxifene, toremifene, clomiphene, ospemifene, bazedoxifene and nafoxidine etc are classified as SERMs, out of which, Raloxifene Hydrochloride [2-(4-hydroxyphenyl)-3-{4-[2-(piperidin-l-yl)ethoxy]benzoyl}-l- benzothiophen-6-ol hydrochloride] is an FDA-approved drug for its usage in Osteoporosis. In ETSA, Raloxifene is marketed as EVISATA^® as tablet formulation of 60 mg strength. EVISTA^® (raloxifene hydrochloride) is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical structure is as below;

EVISTA^® is supplied in a tablet dosage form for oral administration. Each EVISTA® tablet contains 60 mg of raloxifene HC1, which is the molarequivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, camauba wax, crospovidone, FD&C Blue No. 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide.

As per pharmacokinetic information published in leaflet of EVISTA^®, it is mentioned that“Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites.”

Therefore use of Raloxifene Hydrochloride is severely limited by its poor bioavailability. It is a BCS Class II drug, with aqueous solubility of l00pg/mL. Absolute bioavailability of Raloxifene Hydrochloride is 2% due to its poor water solubility and extensive first-pass metabolism, yielding non-toxic, inactive metabolites. It has a half-life of about 28 hours, with volume of distribution of 2348L/kg, protein binding of 95% and is eliminated 6% in urine and mainly in the feaces after hepatic metabolism. The side-effects associated with administration of Raloxifene Hydrochloride include leg swelling, chest pain and severe headache. Enhancement of Oral Bioavailability results in lowering of dose required to attain Minimum Effective Concentration, which leads to reduction in side-effects and improved patient compliance. Raloxifene Hydrochloride, a BCS Class II drug, has very low solubility in aqueous media, i.e. l00pg/mL. Though it manages to dissolve upto 60%, its extensive first-pass metabolism (hepatic glucuronidation) by enzymes ETGT1A1, ETGT1A8 and ETGT1A10 leads to absolute bioavailability upto 2%. Marketed formulations available for Raloxifene Hydrochloride possesses same issues and these formulations are unable to overcome it.

Various techniques are available for solubility enhancement like use of Surfactants, pH adjustment, Salt Formation, Particle Size Reduction, Co-grinding/co-micronisation, Super Critical Fluid Technology, ETltra-Rapid Freezing, Solid Solution/Dispersion, Co- evaporate system/Co-precipitation, Inclusion Complexes & Liquisolid Systems.

Among all the above techniques, Particle Size Reduction, Solid Dispersion, Inclusion Complexes with b-cyclodextrins, and use of Surfactants have been reported for Raloxifene Hydrochloride.

ETS Patent No. ETS5811120 relates to solid orally administerable pharmaceutical formulations comprising raloxifene hydrochloride, a surfactant being sorbitan fatty acid ester or a polyoxyethylene sorbitan fatty acid ester, polyvinylpyrrolidone, and a water soluble diluent which is polyol or sugar.

ETS Patent No. US 5972383 A, titled “Solid Orally Administrable Raloxifene Hydrochloride Formulation”, discloses about formulation of Raloxifene, its esters or ethers, or pharmaceutically acceptable salt, in combination with surfactant, water- soluble diluents, and hydrophilic binder.

Patent No. WO 2009/146097 Al, titled“Raloxifene Pharmaceutical Formulations”, discloses about formulation comprising of Raloxifene Hydrochloride, at least one surfactant, at least one water insoluble diluents, with definite PDI in range of 60pm to 150m_§.

European Patent No. EP 2253627 Al, titled “Inclusion Complex of Raloxifene Hydrochloride and b-Cyclodextrin”, discloses about the invention which relates to process for obtaining raloxifene hydrochloride inclusion complex with b-cyclodextrin for the treatment of postmenopausal osteoporosis.

WO2013132512 discloses a pharmaceutical composition comprising a crystalline non- solvated raloxifene hydrochloride, having improved dissolution even with higher particle size of raloxifene hydrochloride having a mean particle size of at least about 25 microns & 90 percent of particles having about 50 to about 80 microns and process for preparation thereof.

JP2016160196 describes about producing a solid dispersion in which the weight ratio of raloxifene hydrochloride to a solubilizing agent is preferably 1.0:0.5-1.5 enables the stable production of amorphous raloxifene and the long-lasting storage thereof, the raloxifene hydrochloride being produced through the step of dissolving a raloxifene hydrochloride and the solubilizing agent to a solvent. Preferably, the solubilizing agent is selected from povidone, hypromellose, propylene glycol, and the like

WO2007133476 discloses a method and composition for orally administering to a patient in need thereof a therapeutic amount of the drug (raloxifene, arzoifene, troglitazone, and fenofibrate.) in combination with a suitable competitive inhibitor (hersperidin, eriodictyl, quercetin, rutin, hesperitin, 7-hydroxyflavone, chrysin, apigenein, fisetin, naringenin, and geni stein and mixtures thereof) in an amount sufficient to effectively compete with the drug for at least one metabolizing enzyme.

Various techniques for avoiding first pass metabolism are used namely Lymphatic approach, Prodrugs, Polymeric Excipients and Enzyme Inhibitors. For circumvention of First Pass Metabolism, usage of techniques like Lymphatic Approach and Polymeric Excipients has been reported for Raloxifene Hydrochloride. However, these techniques require large amount of excipients, which increase the cost and toxicity of the formulation.

US Patent No. US 5616593 A, titled“Compositions containing Piperine”, discloses about the invention of the compositions containing piperine as bioavailability enhancer for various drugs but Raloxifene and its class of drugs are not included. European Patent No. EP 935964 Al, titled“Pharmaceutical Compositions containing NSAIDs and Piperine”, discloses about the composition containing Piperine, its metabolites, analogues with atleast one NS AID, for bioavailability enhancement of NSAIDs thereof. Patent No. WO 2014168925 Al, titled “Compositions to alleviate Presystemic

Metabolism of Opiods”, discloses the invention providing novel combinations of compounds which comprises of at least one bioactive and one or more enzyme inhibitors, thus allowing the bioactive to absorb intact and increasing bioavailability. US Patent No. US 5877208, titled “Naringin and Naringenin as 3 Hydroxy-3-

Methylglutaryl CoA (HMG-CoA) Reductase Inhibitor”, discloses about the method for inhibiting the activity of HMG— CoA in mammal, which comprises of administering naringin or naringenin thereto. W02003055494 discloses a method of increasing the bioavailability of an orally administered pharmaceutical compound, which method comprises: orally coadministering to a mammal in need of treatment by said pharmaceutical compound, (1) said pharmaceutical compound (raloxifene, 2- methoxyestradiol, irinotecan, SN-38, estradiol, labetalol, dilevalol, zidovudine (AZT) or morphine) and (2) an inhibitor of a UDP- glucuronosyltransferase enzyme (epicatechin gallate, epigallocatechin gallate, octyl gallate, propyl gallate, quercetin, tannic acid, benzoin gum, capsaicin, dihydrocapsaicin, eugenol, gallocatechin gallate, geraniol, menthol, menthyl acetate, naringenin, allspice berry oil, N-vanillylnonanamide, clovebud oil, peppermint oil, silibinin, or silymarin) being present in an amount sufficient to provide bioavailability of said pharmaceutical compound in the presence of the inhibitor that is greater than the bioavailability of said pharmaceutical compound in the absence of said inhibitor.

It would be advantageous to have additional effective compositions or formulation technology which enhances bioavailability of SERM class drugs. The inventor(s) of the present invention have surprisingly found that technology using liquisolid compact and/or bio enhancers can provide enhanced bioavailability of SERM class drugs.

So, present invention is focused towards increasing solubility & reducing first pass metabolism in order to increase the bioavailability of Raloxifene through oral route of administration. SUMMARY OF THE INVENTION

The main aspect of the present invention provides a formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug comprising

a) A drug of Selective Estrogen Receptor Modulator (SERM) class,

b) At least one bio enhancer.

Another aspect of the present invention provides formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug comprising

a) A drug of Selective Estrogen Receptor Modulator (SERM) class and a) Solvent system comprising mixture of solvent and surfactant, wherein dissolution of 90% is achieved in 50 minutes. Yet another aspect of the present invention provides a formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug comprising a) A drug of Selective Estrogen Receptor Modulator (SERM) class, b) Solvent system comprising mixture of solvent and surfactant and

c) At least one bio enhancer. Another aspect of the present invention provides formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug wherein the metabolism of drug in liver homogenate is decreased by 5 to 29 times compared to marketed formulation. Yet another aspect of the present invention provides formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug wherein the bioavailability is enhanced by 20 to 55 times compared to marketed formulation.

DETATEED DESCRIPTION OF THE DRAWTNGS

Fig.l : Solubility study of Raloxifene hydrochloride in non-volatile solvent

Fig.2: Solubility Studies of Raloxifene hydrochloride in Surfactants

Fig.3: Solubility Studies of Raloxifene hydrochloride in different solvent system at different temperature

Fig.4: In-vitro Dissolution Studies of Marketed Formulation and Liquisolid Compacts Fig.5: Results of Rat Liver Homogenate studies

DETATEED DESCRIPTION OF THE TNVENTTON The present invention relates to a formulation technology to enhance the bioavailability of Selective Estrogen Receptor Modulator (SERM) class of drugs.

The term“SERM” as used herein is to be referred as Selective Estrogen Receptor Modulator which is a therapeutic class of drugs that act on the estrogen receptor.

Whenever term“SERM” is used, all the active ingredient or drug falling under this class to be considered. The drugs falling under this class is tamoxifen, raloxifene, lasofoxifene, toremifene, clomiphene, ospemifene, bazedoxifene and nafoxidine or pharmaceutically acceptable salts thereof.

As a pharmaceutically acceptable salt thereof any salts know in the art is to be considered.

In a preferred embodiment, the drug of SERM class is Raloxifene and more preferred is Raloxifene Hydrochloride. The term“Liquisolid” as used herein means a mixture of drug powder with solvent system comprises mixture of solvent and surfactant.

As used herein, when an amount, concentration, or other value or parameter is given as either a range, preferred range, or a list of upper preferable values and lower preferable values, this is to be understood as specifically disclosing all ranges formed from any pair of any upper range limit or preferred value and any lower range limit or preferred value, regardless of whether ranges are separately disclosed. Where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range. It is not intended that the scope of the invention be limited to the specific values recited when defining a range.

As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains" or "containing," or any other variation thereof, are intended to cover a non-exclusive inclusion. For example, a composition, a mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. As used herein, the term "about" also encompasses amounts that differ due to different equilibrium conditions for a composition resulting from a particular initial mixture. Whether or not modified by the term "about", the claims include equivalents to the quantities. In one embodiment, the term "about" means within 10% of the reported numerical value, preferably within 5% of the reported numerical value.

The present invention provides enhanced bioavailability of Selective Estrogen Receptor Modulator (SERM) class of drugs by increasing its dissolution using liquisolid technique and/or reducing first pass metabolism (glucuronidation) by incorporating bio enhancers like Naringin and Pipeline or combination of both.

As per one embodiment, the present invention is a formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug comprising

a) A drug of Selective Estrogen Receptor Modulator (SERM) class and

b) At least one bio enhancer. Co-administration with Bio enhancers was employed for circumvention of first-pass metabolism. Bio enhancers, at low doses, promote and enhance bioavailability of drugs. They are capable of enhancing bioavailability of a specified drug at the low dose but they do not show typical pharmacological activity. As a bio enhancer there are many ingredients known for exhibiting enhancement in bioavailability of drugs by one or other mechanisms. Bio enhancers known are piperine, garlic, Carum carvi, Cuminum cyminum, lysergol, naringin, quercetin, niaziridin, glycyrrhizin and stevia. However selecting the effective bio enhancer for any particular drug and at effective concentration is a very complex and tedious work. The inventors have surprisingly found that piperine and naringin are showing promising effect of glucuronidation inhibition, for being potent inhibitors of ETGT action when used for preparing formulation of SERM class of drugs.

As per one embodiment, the bio enhancer is present in the range from about 1 to 20% of the drug, preferably in the range from 5 to 10% of the drug. Rat Liver Homogenate studies were performed on formulations prepared with bio enhancers as described in Examples.

As per another embodiment, the present invention is to provide a formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug comprising;

a) A drug of Selective Estrogen Receptor Modulator (SERM) class and

b) Solvent system comprising mixture of solvent and surfactant. Liquisolid Technique has emerged to be most promising approach to enhance the dissolution property of the drug and thereby enhancing its oral bioavailability. It is a promising technique because of the simple manufacturing process, utilization of less number of excipients, and the possibility of industrial production due to good flow and compaction properties of the liquisolid formulations, therefore it was applied to prepare liquisolid compacts of Raloxifene.

a) A drug of Selective Estrogen Receptor Modulator (SERM) class,

b) Solvent system comprising mixture of solvent and surfactant and

c) At least one bio enhancer.

At first solubility studies were performed for solvent system of Liquisolid, and the various solvent systems were studied at different ratios at varying temperatures 25 to 90 °C. The results of solubility studies were represented in Fig.l, Fig.2 and Fig.3.

As per one embodiment, the solvent system as per present invention comprises mixture of solvent and surfactant.

The solvent to be used for preparing solvent system is selected from group consisting of Polyethylene Glycols, Propylene Glycol, Highly purified diethylene glycol monoethyl ether, Glycerin, Glyceryl Caprylate, Linoleoyl macrogol-6 glycerides or mixture thereof. Preferably Propylene Glycol is to be used as solvent.

The surfactant as used herein for preparing solvent system is non-ionic surfactant selected from group consisting of polyoxyethylene sorbitan fatty acid esters like Polysorbate 20, Polysorbate 40, Polysorbate 60 and Polysorbate 80, fatty alcohols, glyceryl esters, fatty acid esters of fatty alcohols and alcohols. Preferably Polysorbate 80 is to be used as surfactant.

The solvent system at different ratio of solvent and surfactant tried and evaluated as per Fig.3. As per preferred embodiment, solvent system comprises solvent and surfactant in ratio of 1 : 1 to 5:2. In a more preferred embodiment, the ratio of solvent to surfactant is 3: 1.

As per one embodiment of present invention the solvent system comprises Propylene Glycol and Polysorbate 80 in ratio of 1 : 1 to 5 :2, preferably in ratio of 3 : 1.

As per solubility study, highest solubility of Raloxifene Hydrochloride was achieved in Propylene Glycol: Polysorbate 80 with ratio 3: 1 at 70-80°C.

As per one embodiment the dry powder form obtained after processing of drug in liquidsolid techniques or with bio enhancer or with both is to be used for preparing final formulation as desired. As per one embodiment, the final formulation can be prepared in the form of powders, granules, tablets or capsules.

To prepare final formulations in the form of powders, granules, tablets or capsules, one or more other inactive excipients to be added. The inactive excipient is to be selected from diluent, disintegrant, binder, lubricant and anti-adherent. All these inactive excipients are very well known in the art and to be used as per selection of the final formulation. As per one embodiment, the final formulation is to be used for oral administration of human beings.

The formulation prepared as per technology of present invention is able to decrease metabolism of SERM class drug in liver homogenate is decreased by 5 to 29 times compared to marketed formulation.

The formulation prepared as per technology of present invention is able to enhance bioavailability of SERM class drug by 20 to 55 times compared to marketed formulation.

Further the formulation prepared as per technology of present invention is able to achieve faster dissolution compared to marketed formulation. The formulation of present invention is able to achieve more than 90% dissolution within 50 minutes.

The following Examples illustrate specific formulations and methods for their preparation. These examples are not intended to be a limitation on the scope of the invention in any respect and should not be so construed. In addition, the following examples are encompassed by the claims and their equivalents.

EXAMPLES

Example 1: Liquisolid compacts of Raloxifene

Drug (60 mg) is mixed in 0.39 ml of non-volatile solvent system and stirred at 70-80°C on Magnetic Stirrer with Heating Plate till homogenous solution obtained. To liquid medication prepared, 530 mg of Avicel pH 102 is added with constant mixing using blender. 7lmg Aerosil 200 is carefully added in blender and mixed constantly till dry powder formed. Final liquisolid blend formed is compressed into tablets using a single punch tablet machine with a compression force that provide acceptable tablet hardness.

Example 2: Liquisolid compacts of Raloxifene with Naringin

Drug (60 mg) is mixed in 0.39 ml of non-volatile solvent system and stirred at 70-80°C on Magnetic Stirrer with Heating Plate till homogenous solution obtained. To liquid medication prepared, 530 mg of Avicel pH 102 is added with constant mixing using blender. 7lmg Aerosil 200 is carefully added in blender and mixed constantly till dry powder formed. To the dry powder obtained, 5mg of Naringin is added and mixed uniformly, and final liquisolid blend formed is compressed into tablets using a single punch tablet machine with a compression force that provide acceptable tablet hardness. Example 3: Liquisolid compacts of Raloxifene with Piperine

Drug (60 mg) is mixed in 0.39 ml of non-volatile solvent system and stirred at 70-80°C on Magnetic Stirrer with Heating Plate till homogenous solution obtained. To liquid medication prepared, 530mg of Avicel pH 102 is added with constant mixing using blender. 7lmg Aerosil 200 is carefully added in blender and mixed constantly till dry powder formed. To the dry powder obtained, 5mg of Piperine is added and mixed uniformly, and final liquisolid blend formed is compressed into tablets using a single punch tablet machine with a compression force that provide acceptable tablet hardness. Example 4: Tablet of Raloxifene with Naringin

All the ingredients are taken as per the quantity specified. In blender, by the technique of geometric mixing, the ingredients were mixed uniformly so as to obtain tablet blend. The tablet blend is compressed into tablets using a single punch tablet machine with a compression force that provide acceptable tablet hardness.

Example 5: Tablet of Raloxifene with Piperine

Example 6: In-vivo pharmacokinetic study

In-vivo study was performed to compare pharmacokinetic data of optimized formulation with suspension of marketed product, plain drug with naringin, and liquisolid compact blend. All the samples were administered orally to female Sprague-Dawley rats. Cmax, Tmax, AUC, and MRT of Liquisolid Compacts bearing Naringin were significantly higher than that of other samples. The relative bioavailability of the developed formulation was 41.85 folds higher that of the marketed preparation. Results are as provided below;

Various formulations were prepared by using bioenhancers-nari ngi n and pipeline at various levels, i.e. 3 mg(5%) to 6mg(l0%) per unit dosage of 60 mg raloxifene hydrochloride. 5 mg level per unit dosage form of 60 mg of raloxifene hydrochloride was optimized and further studied for in-vivo studies and results are provided below;

Example 7: Ex- Vivo Liver Homogenate Studies

Rat Liver Homogenate studies were performed to evaluate metabolism of Raloxifene. Raloxifene with Piperine, Raloxifene with Naringin and Raloxifene alone were evaluated in presence of liver homogenate in which, Raloxifene with Naringin & Raloxifene with Piperine showed less metabolism as compared to Raloxifene alone. Results are presented in Fig.5.

Example 8: Ex vivo studies on Raloxifene HC1, Naringin with Liver Extract Powder Solution

0.04, 0.08, 0.1, 0.12, 0.16 ml of Naringin stock solution (100 pg/ml) and 1 ml Liver Extract Solution was taken in 10 ml volumetric flask. 0.5 ml of Raloxifene HC1 stock solution (1000 pg/ml) was added and volume was made up to the mark with Methanol to precipitate liver proteins and extract drug. It was centrifuged. After centrifugation supernatant was filtered through 0.22pm syringe filter, and injected into HPLC for analysis and observations are as follows :

Claims

1. A formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug comprising

a) A drug of Selective Estrogen Receptor Modulator (SERM) class and b) At least one bio enhancer.

2. A formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug comprising

b) A drug of Selective Estrogen Receptor Modulator (SERM) class and c) Solvent system comprising mixture of solvent and surfactant, wherein dissolution of 90% is achieved in 50 minutes.

3. A formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug comprising

a) A drug of Selective Estrogen Receptor Modulator (SERM) class,

b) Solvent system comprising mixture of solvent and surfactant and

c) At least one bio enhancer.

4. The formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug according to any preceding claims, wherein drug is selected from group consisting of tamoxifen, raloxifene, lasofoxifene, toremifene, clomiphene, ospemifene, bazedoxifene and nafoxidine or pharmaceutically acceptable salts thereof.

5. The formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug according to claim 4, wherein drug is raloxifene hydrochloride.

6. The formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug according to any preceding claims, wherein solvent is selected from group consisting of Polyethylene Glycols, Propylene Glycol, Highly purified diethylene glycol monoethyl ether, Glycerin, Glyceryl Caprylate, Linoleoyl macrogol-6 glycerides or mixture thereof, preferably Propylene Glycol.

7. The formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug according to any preceding claims, wherein surfactant is non-ionic surfactant selected from group consisting of polyoxyethylene sorbitan fatty acid esters selected from Polysorbate 20, Polysorbate 40, Polysorbate 60 and Polysorbate 80, fatty alcohols, glyceryl esters, fatty acid esters of fatty alcohols and alcohols, preferably Polysorbate 80.

8. The formulation technology to improve bioavailability of Selective Estrogen

Receptor Modulator (SERM) class drug according to claim 8, wherein surfactant is The formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug according to any preceding claim, wherein solvent system comprises solvent and surfactant in ratio of 1 :1 to 5:2, preferably ratio is 3 : 1.

9. The formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug according to any preceding claims, wherein bio enhancer is selected from naringin and piperine present in the range from 1-10% of the drug.

10. The formulation technology to improve bioavailability of Selective Estrogen

Receptor Modulator (SERM) class drug according to any preceding claims, wherein the metabolism of drug in liver homogenate is decreased by 5 to 29 times compared to marketed formulation.

11. The formulation technology to improve bioavailability of Selective Estrogen Receptor Modulator (SERM) class drug according to any preceding claims, wherein the bioavailability is enhanced by 20 to 55 times compared to marketed formulation.