WO2017137894A1

WO2017137894A1 - Compositions comprising absorption augmenting agent

Info

Publication number: WO2017137894A1
Application number: PCT/IB2017/050669
Authority: WO
Inventors: Jayant Deshpande; Manutosh ACHARYA; Ashok KANDPAL; Shankaranarayanan JEYAKODI; Prakash Bhanuse; Laxman Kate; Sachin AWARI
Original assignee: Omniactive Health Technologies Limited
Priority date: 2016-02-11
Filing date: 2017-02-08
Publication date: 2017-08-17

Abstract

The invention relates to compositions comprising lipophilic active, effective amount of an absorption augmenting agent and suitable excipients and the process for preparation thereof. More particularly, the fine free flowing powder composition described herein is comprised of effective amount of lipophilic active such as coenzyme Q10, absorption augmenting agent and other suitable excipients which is formulated by emulsification and size reduction. The size reduced emulsion is spray dried to get fine free flowing powder of lipophilic active which may be further filled in sachets or formulated into solid dosage forms or suspended in oil medium. Oil suspension can be encapsulated in soft gel capsules and/or filled in sachets and is useful for treatment of health ailments. Use of salacia as absorption augmenting agent in coenzyme Q10 formulation resulted in more than 2 times enhanced bioavailability in aqueous medium as compared to unformulated coenzyme Q10.

Description

COMPOSITIONS COMPRISING ABSORPTION AUGMENTING AGENT

Field of the Invention

The invention relates to compositions comprising lipophilic active, an absorption augmenting agent and at least one more excipient and the process for preparation thereof. More particularly, the composition described herein is comprised of coenzyme Q10 which is uniformly mixed with absorption augmenting agent and formulated in the form of fine free flowing powder using suitable size reduction technique along with emulsification. The composition as described herein is prepared by emulsifying solvent phase comprising coenzyme Q10 as lipophilic active with aqueous phase comprising absorption augmenting agent with suitable excipients like matrix carriers and subjecting the emulsion to effective size reduction. The size reduced emulsion formulated with absorption augmenting agent is spray dried to get fine free flowing powder of lipophilic active which may be further filled in sachets or formulated into solid dosage forms such as beadlets, sachets, tablets, capsules or suspended in oil medium. Use of salacia as absorption augmenting agent results into coenzyme Q10 formulation having more than 2 times enhanced bioavailability in aqueous medium as compared to unformulated coenzyme Q10. Composition as described herein can be utilized as nutritional supplement, human or veterinary drug or food product. Background

When we consume a food, drink or drug, the actives contained are released from the matrix, absorbed into the bloodstream and transported to their respective target tissues. However, not all actives can be utilized to the same extent or made available in blood stream for absorption. In other words, they differ in their bioavailability. Understanding active bioavailability helps optimize doses for drugs and set appropriate recommendations for nutrients. A number of actives have lipophilic characteristics and although these have higher solubility in organic solvents, they exhibit poor water solubility and therefore poor absorption in body.

The oral bioavailability of many lipophilic bioactive agents such as drugs, vitamins, and nutraceuticals is limited due to various other physicochemical and physiological processes such as low solubility in gastrointestinal fluids; metabolism or chemical transformation within the gastrointestinal tract; low epithelium cell permeability and the like. The bioavailability of these agents can be improved by specifically designing the compositions that control their release, solubilization, transport, metabolism, and absorption within the gastrointestinal tract.

Coenzyme QIO, which is also called as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times as COQJO is one of the lipophilic actives which is crystalline powder , insoluble in water. It suffers from low solubility as well as bioavailability. Coenzyme QIO resembles a vitamin and it is present in most eukaryotic cells, primarily in the mitochondria. It is a component of the electron transport chain and participates in aerobic cellular respiration, which generates energy in the form of ATP. It is used as dietary supplement and it is not approved by the U.S. Food and Drug Administration (FDA) for the treatment of any medical condition.

Although various approaches such as complexation with cyclodextrin, use of solubilizers and surfactants, particle size reduction are being tried in prior art for enhancing solubility of lipophilic actives, it is always challenging to achieve desired and consistent bioavailability from such compositions. Also some other novel carrier systems such as liposomes, nanoparticles, dendrimers, etc. may be used to increase the bioavailability of CoQie,. However, none of the approaches have been proved to be very successful with CoQio.

Prior art search shows several references which deal with efforts for formulation development and the bioavailability enhancement of lipophilic actives for use as nutraceutical, human or veterinary drug products or food products. Patent application CN1969833 describes a dry powder composition with lipophilic active such as coenzyme QIO and preparing method, which comprises coenzyme QIO, use of excipients selected from sucrose, glucose, maltodextrin or microcrystalline cellulose, 10%-80% hydrophilic wall material (such as modified starch, arabic gum, casein, caseinate, gelatin, polyvinyl pyrrolidone alkone or hydroxy methyl cellulose), antioxidant and water. It also describes process for preparation of dry powder composition comprising emulsion preparation, homogenization and spray drying to get dry powder. However this reference does not give any dissolution or bioavailability data for coenzyme Q10 formulation. US6740338 discloses a method for increasing the bioavailability of ubiquinone from an orally administered composition comprising administering to a subject a composition comprising an effective amount of ubiquinol obtained from the in situ reduction of ubiquinone to ubiquinol in oral dosage form, said composition comprising ubiquinol and an amount of ascorbyl palmitate as a reducing agent effective to reduce ubiquinone to ubiquinol; said composition further comprising an amount of a surfactant, triglyceride, vegetable oil or mixture thereof, and optionally a solvent, effective to solubilize said ubiquinone, ubiquinol and said reducing agent.

PCT application WO2015069974 relates to nutritional supplement formulations containing lipophilic nutrients with improved bioavailability comprising at least about 80% by weight of lipophilic mono-diglyceride carrier oil, as agent for increasing absorption in body system.

European patent application EP2457451 provides a complex coacervate delivery system which encapsulates lipophilic nutrients such as, fatty acids, fat soluble vitamins, vitamin A, vitamin D, vitamin E, vitamin K, tocotrienols, carotenoids, xanthophylls, lycopene, lutein, astaxanthin, zeazanthin, fat-soluble nutraceuticals, phytosterols, stanols and esters thereof, Coenzyme Q10, ubiquinol, hydrophobic amino acids and peptides, essential oils and extracts, omega-3 fatty acids. It also discloses that the controlled release of the encapsulated lipophilic nutrient in the lower gastrointestinal tract enhances bioavailability and overall physiological efficacy of the lipophilic nutrient.

US patent 7588781 discloses a method for increasing bioavailability of a lipophilic bioactive compound to a subject upon administration, wherein whey protein is used to increase the bioavailability of the lipophilic bioactive compound. US20130190252A1 relates to an improved pharmaceutical composition for oral administration comprising a therapeutically effective quantity of a lipophilic active ingredient with milk as a solubilizing/dispersing agent; wherein milk is used as a solubilizing/dispersing agent to enhance bioavailability and/or improve solubility of the composition.

US20070026072A1 provides benzoquinone compositions of enhanced solubility and bioavailability, wherein the benzoquinone is coenzyme Q10 and solubility-enhancing carrier is a hydroxyalkylalkyl cellulose derivative, and the composition is produced by dry blending and solvent spray drying.

Xuyi Gaoa et al (Asian Journal of Pharmaceutical Sciences 2006, 1 (2): 95-1020) describes improved solubility and dissolution of CoQIO due to complexation with γ-CyD and/or nanometer-sized particle formation.

US Patent 5989583 relate to solid lipid compositions of lipophilic compounds for enhanced oral bioavailability wherein lipophilic substances are mixed with at least one solid fat and phospholipid to obtain a dried solid composition suitable as an oral dosage form. The solid lipid compositions are exemplified for food additives or dietary supplements such as Coenzyme Q10 and for pharmaceuticals such as dexanabinol. The Coenzyme QlO-dry lipid mixtures shows improved drug release in vitro and enhanced oral bioavailability in vivo compared to a commercial formulation.

PCT application WO2016101317A1 relates to a processing method for increasing the solubility and bioavailability of a fat-soluble active component, the processing method comprising the following steps: (1) dissolving water-soluble starch particles in a sodium acetate buffer to prepare a homogeneous solution; (2) dissolving a fat-soluble active component in an ethanol solution to prepare another homogeneous solution; (3) mixing the two homogeneous solutions and simultaneously performing uninterrupted agitating at 30-70°C; (4) placing the solutions into an ultrasonic device; and (5) performing a centrifugal treatment and performing a vacuum drying treatment of an obtained supernatant, so as to obtain a starch particle complex of a fat-soluble active component having good solubility and bioavailability.

Although the prior art relates to various approaches for development of soluble compositions comprising lipophilic actives such as coenzyme Q10, there is no teaching till date about the compositions which exhibit significantly enhanced bioavailability in aqueous medium. Thus there is an unmet need for compositions of lipophilic actives such as coenzyme Q10, which are convenient to administer and provide desired absorption and enhanced bioavailability in the body system.

Summary

The applicant has carried out rigorous experimentation trials to formulate compositions comprising lipophilic active such as coenzyme Q10 by proper selection of excipients and techniques, in order to design the formulation having enhanced bioavailability. The compositions described herein, are formulated in the form of fine free flowing powder using effective amount of salacia extract as absorption augmenting agent and suitable excipients such as matrix carriers. The composition of the invention is prepared by emulsifying solvent phase comprising coenzyme Q10 as lipophilic active with aqueous phase comprising effective amount of absorption augmenting agent along with pharmaceutically and/or nutraceutically acceptable excipients like matrix carriers and subjecting the emulsion to effective size reduction by suitable techniques.

Although prior art relates to size reduction or suspension in oil medium as one of the techniques to enhance bioavailability of coenzyme Q10, these approaches are not sufficient to enhance bioavailability in aqueous body fluids. Therefore it is desirable to design a formulation having enhanced bioavailability in water medium. Instant invention achieves enhanced bioavailability of coenzyme Q10 in water, when formulated using salacia as absorption augmenting agent. The composition described herein, relates to use of salacia as absorption augmenting agent and use of suitable size reduction technique to form fine free flowing coenzyme Q10 powder formulation. The compositions are evaluated for particle size, dissolution and bioavailability. The composition in the form of fine free flowing powder can be filled in sachets or formulated in beadlets, tablets, capsules or suspended in suitable oil medium to form the dispersion which can be administered as such or encapsulated to form soft capsules. Use of salacia as absorption augmenting agent results in coenzyme Q10 formulation having more than 2 times enhanced bioavailability in aqueous medium as compared to unformulated coenzyme Q10.

The method for preparation of fine free flowing powder compositions of coenzyme Q10, as described herein is simple, economic and employs commonly used equipments, thus it is industrially useful to prepare bioenhanced compositions of lipophilic actives. The process thus formulates poor water soluble lipophilic active into fine, free flowing bioenhanced compositions which are convenient to administer to the subjects.

Objectives

The main objective of the present invention is to provide composition comprising lipophilic active such as coenzyme Q10 with significantly enhanced bioavailability in aqueous medium comprising an effective amount of absorption augmenting agent and at least one more nutraceutically and/or pharmaceutically acceptable excipient which is prepared by employing suitable size reduction technique. Use of salacia as absorption augmenting agent in coenzyme Q10 formulation results into more than 2 times enhanced bioavailability in water as compared to unformulated coenzyme Q10.

According to one important objective, the present invention provides bioenhanced composition of lipophilic active comprising effective amount of salacia extract as absorption augmenting agent along with one more excipient selected from matrix carrier, antioxidant, stabilizer, filler, surfactant, solvents and the like or the combination thereof.

The invention also provides the process for preparation of composition comprising lipophilic active, absorption augmenting agent and at least one more nutraceutically acceptable excipient, in which the active is uniformly mixed with effective amount of absorption augmenting agent by emulsification and the emulsion is effectively size reduced with suitable technique before spray drying to get fine free flowing powder composition. As per one more objective of this invention, the composition is comprised of effective amount of salacia extract as absorption augmenting agent. It is used in such a way that the ratio of active: salacia is about 2: 1 to 14: 1. According to one more important objective of this invention, the composition is comprised of at least one more nutraceutically and/or pharmaceutically acceptable excipient. The excipient may be selected from the group consisting of, but not limited to, matrix carrier, oil, antioxidant, surfactant, emulsifier and the like or the mixtures thereof. Still one more objective of the present invention is to provide composition comprising lipophilic active, absorption augmenting agent and at least one matrix carrier, or the mixture of more than one matrix carrier thereof, such that the amount of carrier employed is about 35 to 75 % of the total composition. One more objective of the present invention is to provide the process for preparation of composition wherein coenzyme Q10 is dissolved in suitable organic solvent along with antioxidant and oil and it is added to aqueous phase comprised of absorption augmenting agent and other excipients, to form the emulsion. The emulsion is size reduced by suitable technique and spray dried to get fine free flowing powder composition which exhibit desired dissolution profile.

According to one more objective of the present invention, free flowing powder of lipophilic active is suspended in suitable oil medium to get oil suspension and can be used for evaluating bioavailability following single dose oral administration in animal model. The bioavailability may also be evaluated by administering the composition in free flowing powder form.

Another objective of the present invention is to evaluate the plasma pharmacokinetic profile of the test items such as the composition with salacia as absorption augmenting agent and to compare it with unformulated coenzyme Q 10 ingredient obtained from market. As per one more objective, composition described herein can be in the form of free flowing powder, which can be filled in sachet, formulated in tablets and capsules or can be suspended in suitable oil medium, which can be delivered in the form of soft capsules or the sachets, suitable for administration to subjects as per the requirement.

Detailed Description

The invention relates to compositions of lipophilic actives comprising absorption augmenting agent and at least one more nutraceutically and/or pharmaceutically acceptable excipient, which is formulated by emulsification and size reduction technique and exhibits significantly enhanced bioavailability as compared to regular unformulated lipophilic active. The invention also relates to process for preparation of bioenhanced composition of coenzyme Q10 comprising effective amount of salacia extract as absorption augmenting agent. The composition may be available as solid free flowing powder formulated in suitable solid dosage form or suspended in oil medium as per the requirement. The composition is comprised of effective amount of absorption augmenting agent in such an amount that ratio of lipophilic active: absorption augmenting agent is about 2:1 to 14: 1. The composition in the form of fine free flowing powder exhibits desired stability and dissolution profile. Fine free flowing powder composition of coenzyme Q10 may be suspended in suitable oil medium and evaluated for bioavailability. The composition comprising salacia as absorption augmenting agent exhibits significantly enhanced bioavailability, as compared with regular unformulated lipophilic active.

As used herein, the term "about" refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term "about" generally refers to a range of numerical values (e.g., +/-5-10% of the recited value) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). In some instances, the term "about" may include numerical values that are rounded to the nearest significant figure.

The term "fine free flowing powder" as used in the present invention can be defined as the dry particulate system prepared by suitable size reduction technique resulting into particle size which ranges from 10 to 22 micron with respect to measurement as d90 of total number of particles. The composition is comprised of lipophilic active uniformly mixed with effective amount of absorption augmenting agent and at least one more suitable excipient by emulsification process followed by size reduction to get fine free flowing powder composition.

The term "absorption augmenting agent" as used herein means excipient such as salacia, obtained from natural source genus Salacia, by process of extraction and which enhances absorption of lipophilic active in the body, thus resulting into significantly enhanced bioavailability.

As used within the scope of the invention, the term "salacia" refers to the salacia composition which is a product obtained by extraction from genus Salacia, using its aerial, sub aerial or underground plant parts. The extract is prepared by employing food grade non aqueous solvents, which are safe for human consumption. The composition is comprised of polyphenols, mangiferin and 25, 26-oxidofriedelane-l, 3-dione in certain percentage by weight of extract.

As used within present context, the term "significantly" means to meet the criteria in such measure that one skilled in the art would understand that the benefit to be achieved, or the condition or property value desired, is met.

As used within the scope of the invention, the term "lipophilic actives" refers to actives having good solubility in lipids, but very poor solubility in water. Such active agents may be vitamins, vitamin like substances, cancer chemotherapeutics, antimycotics, oral contraceptives, hormone supplements, analgesics, antacids, muscle relaxants, antihistamines, decongestants, anesthetics, antitussives, diuretics, anti-inflammatories, antibiotics, antivirals, psychotherapeutic agents, anti-diabetic agents, cardiovascular agents, bioengineered pharmaceuticals, nutraceuticals and nutritional supplements. Vitamins particularly that may be delivered using this invention include, and are not limited to the class of, fat soluble vitamins such as thiamin, riboflavin, pyridoxine, pantothenic acid, choline, carnitine, vitamin D and its analogs, vitamin A, vitamin like substance coenzyme Q10, ubiquinol and the carotenoids, retinoic acid, vitamin E and vitamin K. These lipophilic actives may include particularly nutrients like carotenoids, tocopherols, tocotrienols, plant sterols and stanols, and lecithins, select omega-3 fatty acids and poly-unsaturated fatty acids, pungent and odoriferous substances or the combinations thereof. Plant sterols or stanols are naturally occurring lipophilic compounds structurally related to cholesterol found in nuts, vegetable oils, seeds, cereals and beans. Lecithins are complex lipophilic mixtures of glyceride oils and phosphatides (including phosphaptidylcholine, or PC) which are widely used in food-processing, and are now being used as dietary supplements for their possible role as a source of choline which is required for cell-membrane integrity and for a wide variety of biochemical and neurochemical processes within the body.

Polyunsaturated fatty acids (such as linolenic acid, alpha-linoienic acid, and gamma- linolenic acid) and omega-3 fatty acids (such as AA, DHA and EPA) have a significant nutritional role to play with several metabolic processes and healthy body function. Vegetable oils such as soya oil, partially or fully hydrogenated soya oil, cotton oil, coconut oil, palm-kernel oil, maize oil, palm oil, sunflower oil, olive oil, sesame oil, linseed oil, hazelnut oil, walnut oils, safflower oil, corn oil, peanut oil, vegetable oils having an unsaturated long chain fatty acid content of about 30 wt. % to about 90 wt. %, or any blends or fractions of these vegetable oils also come within the scope of the invention. Lipophilic actives nutrient can also be lipophilic substances that have diuretic and cosmetic application such as the oils of avocado, pear, blackcurrant, borage, castor, evening primrose, wheat-germ, and the like. Pungent, oily and odoriferous substances such as capsaicinoids, ginegerois and actives obtained from capsicum, pepper, mustard and the like or the combinations thereof are also the lipophilic actives which can be considered within the scope of this invention. Of course, the lipophilic actives can comprise combinations of the above ingredients. For instance, various lipophilic actives could be diluted using one or more of the above vegetable oils. One having ordinary skill in the art would understand that this list of potential lipophilic actives substances is not exhaustive, and there are many other lipophilic actives that offer medicinal, nutritional, pharmaceutical, or some other health or cosmetic benefit, which may also be utilized in the current invention. Most preferably lipophilic active used in the present invention is coenzyme Q10, which is used in the amount ranging from 10 to 25% by total weight of the composition.

The applicants of the present invention have prepared composition comprising absorption augmenting agent and at least one more nutraceutically and/or pharmaceutically acceptable excipient, which exhibits significantly enhanced bioavailability in aqueous medium. The composition as described herein, uses coenzyme Q10 as lipophilic active and effective amounts of salacia extract as absorption augmenting agent. The composition may be in the form of free flowing powder, which is either formulated in suitable solid dosage form or suspended in suitable oil medium and evaluated for bioavailability study.

As per one embodiment of the invention, the absorption augmenting agent used in the composition is selected from the group of, but not limited to the excipients obtained from natural sources such as salacia, Japanese horse chestnut, peanut, green tea, black tea, nomame herba, coffee, wheel wingnut, yam, Siberian ginseng, sessiloside, cape jasmine, common hop, yerba mate, burning bush, apple extract, bayberry, sacred lotus, ginseng, doraji, roseroot, rosemary, corkscrew willow and the mixtures thereof.

As per one more embodiment of this invention, the composition is comprised of salacia as absorption augmenting agent. It is used in such a way that the ratio of coenzyme Q10: salacia is about 2: 1 to 14: 1.

According to one more embodiment, the composition is comprised of at least one more excipient. The excipient may be selected from the group consisting of, but not limited to, matrix carrier, oil, antioxidant, surfactant, emulsifier, filler, solvent and the like or the mixtures thereof.

As used within the scope of the invention, the term "matrix carrier" as referred herein relates to the excipient employed in the aqueous phase while preparing emulsion and it offers a matrix for uniform mixing of absorption augmenting agent with the lipophilic active, when used in effective amounts ranging from 35 to 75 % by weight of the total composition. In one more embodiment, matrix carrier employed in the composition is selected from the group such as, but not limited to, cellulose derivatives, polyacrylates, polyethylene glycols, povidones, starch and starch derivatives, gums, sugars, and the mixtures thereof. The matrix carrier of the invention may be selected from the group such as cellulose and cellulose derivatives, but not limited to, alkyl cellulose (methyl cellulose), a hydroxyalkyl cellulose (e.g., hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose), carboxyalkyl cellulose (e.g., carboxymethyl cellulose and alkali metal salts thereof, such as sodium salts), a carboxyalkylalkyl cellulose (e.g., carboxymethylethyl cellulose), a carboxyalkyl cellulose ester (e.g., carboxymethyl cellulose butyrate, carboxymethyl cellulose propionate, carboxymethyl cellulose acetate butyrate, and carboxymethyl cellulose acetate propionate), and the mixture thereof. Cellulose derivatives of various viscosity ranges are also considered within the scope of this embodiment.

According to one more embodiment of the present invention, the matrix carrier may also be selected from the group such as polyacrylates, but not limited to polymethacrylate, a methacrylate copolymer (e.g., a methacrylic acid-methyl methacrylate copolymer, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, and a diethylaminoethyl methacrylic acid-methyl methacrylate copolymer), and an ethacrylate copolymer (e.g. methacrylic acid ethacrylate copolymer), and the mixture thereof.

According to still one more embodiment of the present invention, the matrix carrier may be selected from the group of povidones, but not limited to polyvinyl pyrrolidone (e.g., Povidone), polyvinyl acetate ester (e.g., polyvinyl acetate phthalate (PVAP), and a polyethylene glycol polyvinylacetate copolymer (e.g. polyethylene glycol- polyvinylcaprolactam-polyvinylacetate copolymer), and the mixture thereof. According to one more embodiment of the present invention, the matrix carrier may also be selected from the group such as polyethylene glycols, but not limited to, polyalkylene oxide (e.g., polyethylene glycols, such as PEG 300, PEG 400, PEG 4000, PEG 6000 and PEG 8000, and polypropylene glycols), a copolymer of ethylene oxide and propylene oxide (e.g., ethoxylated propoxylated block copolymers, and a polyethoxylated glyceryl ester (e.g., polyoxyl 35 castor oil and polyoxyl 40 castor oil having 40-45 moles of ethylene oxide), and the mixture thereof.

According to one more embodiment of this invention, the matrix carrier may be selected from the group such as starch and starch derivatives, but not limited to, dextrins, acid- treated starch, alkaline-treated starch, bleached starch, oxidized starch derivatives, enzyme-treated monostarch phosphate, distarch phosphate, phosphated distarch phosphate, acetylated distarch phosphate, starch acetate, acetylated distarch adipate, hydroxypropyl starch, hydroxypropyl distarch phosphate, hydroxypropyl distarch glycerol, starch sodium octenyl succinate, acetylated oxidized starch and the like and the mixture thereof.

As per one more embodiment of this invention, the matrix carrier may be selected from the group such as gums, but not limited to, pectin, alginate, carrageenan, agar, Gum arabic, Gum tragacanth, Gum karaya, Gum ghatti, Gum guar, Locust bean gum, Tara gum, Xanthan gum, Gellan gum, Welan gum and the like.

As per one more embodiment of the present invention, the matrix carrier may be selected from the group such as sugars and alcohols, but not limited to glycerol, sorbitol, glucose syrup, corn steep liquor, maltodextrin, mannitol, sucrose, glucose, sodium chloride, polyvinyl alcohol, and mixtures thereof and the mixture thereof.

As per preferred embodiment of the instant invention, the matrix carrier may be a single excipient or a combination of more than one excipients selected from the group consisting of cellulose derivatives, polyethylene glycol derivatives, dextrin and the like, as mentioned in earlier embodiments. As per one more embodiment of the invention, matrix carrier is used in such amounts that it provides a matrix in aqueous system with which lipophilic active is emulsified and mixed well before size reduction and emulsification steps. In certain preferred embodiments of the present invention, the matrix carrier is included in free flowing powder so that the percentage of matrix carrier is about 35 to 75% by weight of the total composition. Free flowing powder of the present invention typically may also include other food grade excipients such as, but not limited to, antioxidant, surfactant, emulsifier, oil and the like, and the mixture thereof. As is well known to those skilled in the art, these excipients are routinely incorporated into nutraceutical compositions, dietary supplements, human drug products, veterinary drug products, food products, botanical compositions and the products which are derived using actives from synthetic or natural sources and are meant for administration to mammals. This is done to ease the manufacturing process as well as to improve the performance of the composition in body of subjects.

As per one more embodiment of the instant invention, the antioxidant is selected from the commonly used excipients including, but not limited to a-Tocopherol, β-Tocopherol, γ- Tocopherol, mix Tocopherol, citric acid, Rosemary extract, ascorbyl palmitate, sodium ascorbate or the like and the combinations thereof.

Suitable surfactants include, but are not limited to, anionic and non-ionic surfactants or a mixture thereof. The non-ionic surfactants employed in the composition may include, but are not limited to, ethoxylated fatty acid ester, ethoxylated fatty acid ethers, ethoxylated sorbitan ethers, ethoxylated alkyl-phenols, glycerol esters, glycerol sugar esters, polyoxyethylene glycerol monolaurate, polyoxyethylene glycerol monostearate, polyoxyethylene-20-cetyl stearate, polyoxyethylene-25-cetyl stearate, polyoxyethylene(25)-oxypropylene monostearate, polyoxyethylene-20-sorbitan monopalmitate, poly-oxyethylene-16-tert-octylphenol, polyoxyethylene-20-cetyl ether, polyethylene glycol(lOOO) monocetyl ether, ethoxylated castor oil, polyoxyethylene sorbitol-lanolin derivatives, polyoxyethylene(25)propylene glycol stearate, polyoxyethylenesorbitol esters, polyoxyethylene-20-sorbitan monopalmitate, polyoxyethylene- 16-tert-octylphenol, polyoxyethylene-20-cetyl ether, glycyeryl undecylenate and Polysorbate 60, capmul (medium chain glyceride), peceol(glyceryl monooleate), glyceryl laurate and glyceryl caprylate (Capmul MCM), PEG sorbitan fatty acid esters like PEG-20 sorbitan monolaurate (Tween 20), PEG-20 sorbitan monostearate (Tween 60), PEG-20 sorbitan monooleate (Tween 80), sorbitan fatty acid esters like sorbitan monolaurate (Span 20), glyceryl stearate (Cithrol GMS) or the like and mixtures thereof. Suitable anionic surfactants include, but are not limited to, fatty alcohol sulfates, alpha olefin sulfonates, sulfosuccinates, phosphate esters, carboxylates, sarcosinates, alkyl benzene sulfonates, alkyl sulfonates, olefin sulfonates, alkyl ethersulfonates, glycerol ethersulfonates, alpha-methyl estersulfonates, sulfonic fatty acids, alkyl sulfates, fatty alcohol ethersulfates, glycerol ethersulfates, mixed hydroxy ethersulfates, monoglyceride(ether)sulfates, fatty acid amide(ether)sulfates, sulfosuccinates, sulfosuccinamates, sulfotriglycerides, alkyl oligoglycoside sulfates, alkyl(ether)phosphates or the like and mixtures thereof. The composition of the invention may also optionally but preferably comprise an emulsifier. The emulsifier can be any of a number of food grade products such as gum Arabic, xanthan gum, guar gum, glycerine, mon-and di-glycerides, Tween 80 or lecithin (either egg or soy derived) and the combination thereof. The emulsifier should be one that is effective at achieving oil in water emulsion.

In another preferred embodiment the solvent employed in process for preparation of free flowing powders may be selected from the group such as, but not limited to, acetone, hexane, ethyl acetate, isopropyl alcohol, ethanol, dichloromethane, methanol, and a mixture thereof, more preferably from acetone, ethanol, dichloromethane and isopropyl alcohol, and the combination thereof.

In a preferred embodiment the non-polar solvents which may be used for preparing the composition include, but not limited to, methylene chloride, chloroform, petroleum ether (low boiling), petroleum ether (high boiling) and the like or the mixtures thereof.

As per one important embodiment of the invention, suitable oil medium may be used in the preparation of free flowing powder as well as for suspending the powder in oil medium for evaluation of bioavailability. Oil is used in solvent phase during the preparation of emulsion during preparation of free flowing powder. Oils employed for above purpose are edible or food-grade category and may be selected from animal, vegetable or synthetic source and are rich sources of medium chain triglycerides. Oils of the instant invention are selected from the group, such as, but not limited to sunflower oil, safflower oil, coconut oil, corn oil, cotton seed oil, canola oil, olive oil, palm oil, peanut oil, sesame oil, soybean oil, grape seed oil, pumpkin seed oil, argan oil, rice bran oil and other vegetable oils, as well as animal-based oils like butter and lard and the like. The oil may also be selected from processed vegetable oil, in which one or more than one oils are combined and processed to get oil such as medium chain triglyceride oil (MCT).

According to important embodiment of the invention, coenzyme Q10 composition comprising absorption augmenting agent and at least one more excipient may be prepared by emulsification and size reduction technique followed by spray drying method. As per this embodiment, solvent phase may be prepared by mixing lipophilic active such as coenzyme Q10 with other pharmaceutically and/or nutraceutically acceptable excipients in suitable amount of organic solvent, which may be added to aqueous phase comprising effective amount of absorption augmenting agent by continuous stirring. The mixture then may be homogenized and size reduced to form milky emulsion, which may be spray dried to get fine free flowing powder composition of the invention.

Suitable excipients such as oil and antioxidant may be used in solvent phase and the excipients such as matrix carrier, surfactant and emulsifier may be added in aqueous phase, to assist emulsion formation.

Coenzyme Q10 dissolved in solvent phase gets uniformly mixed with effective amount of salacia extract and matrix carrier such as cellulose polymer, polysaccharide and polyethylene glycol added in aqueous phase, during emulsion formation. The emulsion is size reduced using suitable technique such as colloid mill or microfluidizer and can be spray dried to remove organic solvent and water from aqueous phase, thus resulting into fine free flowing powder composition of coenzyme Q10. Fine free flowing powder of the present invention may be evaluated as such or suspended in suitable liquid vehicle so that ratio of free flowing powder to aqueous or oil vehicle is about 1 :0.5 to 1 : 10 to result into uniform suspension.

According to one embodiment of the present invention, fine free flowing coenzyme Q10 powder composition is evaluated for particle size, release of active in relevant dissolution medium and bioavailability by checking plasma pharmacokinetic profile in animal model and compared with unformulated lipophilic active, to evaluate effect of absorption augmenting agent and size reduction on bioavailability. Fine free flowing powder composition of the invention is prepared by using effective amount of absorption enhancer such as salacia extract and applying suitable size reduction technique. Use of salacia as absorption augmenting agent in coenzyme Q10 formulation results into higher bioavailability as compared to the formulation without salacia, when the study is carried out by using sterile water as medium for administering the formulation to experimental animal models. Such formulation exhibits more than 2 times enhanced bioavailability as compared to unformulated coenzyme Q10.

The details of the present invention are described in the Examples given below which are provided to illustrate the invention and therefore should not be construed to limit the scope of the present invention.

Experimental Details:

1. Composition of Fine free flowing powder

Table 1: Composition of Coenzyme Q10 free flowing powder composition with and without absorption augmenting agent and particle size reduction

Formulation 1 Formulation 2 Formulation 3 Formulation 4 (with salacia (without (with salacia (without

Sr. and use of Salacia and use and use of Salacia and use

Ingredients

o. microfluidizer) of microfluidizer) of

microfluidizer) microfluidizer)

%(w/w) %(w/w) %(w/w) %(w/w)

Coenzyme Q10 Active 12.00 12.00 24.06 24.06

Mixed Tocopherol 70% 1.00 1.00 0.75 0.75

MCT Oil 70% 12.00 12.00 9.02 9.02

Maltodextrin 24.00 24.00 5.52 7.78

Hydroxy propyl methyl

30.08 30.08 cellulose 40.00 40.00

Polyethylene Glycol

2.0 2.0 6000 6.00 10.00 Tween 80 1.00 1.00 0.75 0.75

Salacia Extract 3.00 - 2.26 -

Lecithin 1.00 - 0.75 0.75

Glycerol monostearate - - 24.81 24.81

Water 350.0 350.0 263.0 263.0

Methylene dichloride 25.00 25.00 48.0 48.0

Process for preparation of fine free flowing powder composition

Formulation 1

Coenzyme Q10 (purchased from supplier as CoQIO unformulated ingredient), Mixed tocopherol and MCT oil are dissolved in methylene dichloride to get organic phase.

Low viscosity hydroxyl propyl methyl cellulose is dispersed in to preheated (60^°C) purified water. Maltodextrin and Polyethylene Glycol 6000 are dissolved in cellulose dispersion and allowed to cool at room temperature. After cooling, polysorbate 80, lecithin and salacia extract are added to get an aqueous solution.

Organic phase is slowly added into aqueous phase under stirring and homogenized using IKA homogenizer at 17000 rpm.

This emulsion is passed through microfludizer at 27,000 PSI and it is spray dried using LU-227 Advanced spray dryer (Labultima) employing inlet temperature 165 C- 170 C and outlet temperature 70^°C.

Formulation 2

Coenzyme Q10, Mixed tocopherol and MCT oil are dissolved in to methylene dichloride. This is organic phase.

Low viscosity hydroxyl methyl propyl cellulose are dispersed into preheated (60^°C) purified water. Maltodextrin and Polyethylene Glycol 6000 are dissolved in cellulose dispersion and allowed to cool at room temperature. Polysorbate 80 is added to this aqueous solution.

Organic phase is slowly added into aqueous phase under stirring and homogenized using IKA homogenizer at 17000 rpm. This crude emulsion is again homogenized using colloid mill for 15 mins. Emulsion is spray dried using LU-227 Advanced spray dryer at inlet temperature 165 C- 170 C and outlet temperature 70^°C.

Formulation 3

Coenzyme Q10, Mixed tocopherol and MCT oil are dissolved in methylene dichloride to get organic phase.

This emulsion is passed through microfludizer at 24,000 PSI and it is spray dried using LU-227 Advanced spray dryer (Labultima) employing inlet temperature 165 C- 170 C and outlet temperature 70^°C.

Spray dried powder is further diluted with Glyceryl monostearate melted at 60^°C and mix to form uniform powder.

Formulation 4

Coenzyme Q10, Mixed tocopherol and MCT oil are dissolved in to methylene dichloride to get organic phase.

Organic phase is slowly added into aqueous phase under stirring and homogenized using IKA homogenizer at 17000 rpm. This crude emulsion is again homogenized using colloid mill for 15 mins.

Emulsion is spray dried using LU-227 Advanced spray dryer at inlet temperature 165^°C- 170 C and outlet temperature 70^°C.

Spray dried powder is further diluted with glyceryl monostearate melted at 60^°C and mix to form uniform powder. 2. Particle Size Determination of fine free flowing powder composition

Particle size of free flowing powder composition was measured using Malvern size analyzer and the results found are tabulated below:

Table 2: Data on particle size of coenzyme Q10 powder compositions

It was observed that there was significant difference in particle size with respect to d90, d50 as well as dlO values when microfluidizer was used in case of Formulation 1 and 3 as compared to Formulation 2 and 4 respectively.

Particle size was effectively reduced when microfluidizer was used, thus resulting into fine particle coenzyme Q10 composition.

3. Dissolution study of fine free flowing powder composition

The dissolution study was carried out using 900 ml simulated gastric fluid with 2% SLS as dissolution medium and employing USP Type II Paddle apparatus at 50 rpm. Temperature of the medium was maintained at 37°C+/- 0.5 °C and the aliquots were drawn at definite intervals. Coenzyme Q10 contents were detected at 275 nm wavelength using UV spectrophotometer method. Table 3: Release of Coenzyme Q10 from powder compositions

It was observed that dissolution of coenzyme Q10 from Formulation 1 and 2 was complete within about 45 minutes; whereas Formulation 3 released coenzyme Q10 in 90 minutes. Release of Coenzyme Q10 was incomplete from Formulation 4. Slower or incomplete release of coenzyme Q10 from Formulations 3 and 4 can be co-related to use of glycerol monostearate.

4. Single dose oral bioavailability of Coenzyme Q10 composition in Animal Model

Adult Male Sprague Dawley rats aged 8-10 weeks were used for experimentation after a minimum 3 days of acclimation. Fasted animals were administered with suspension of test item of CoQlO formulations in recommended vehicle such as sterile water or MCT oil by oral route with a dose of 100 mg/kg body weight at dose volume of 10 mL/kg body weight and the results are compared with unformulated Coenzyme Q10 ingredient.

The Blood samples were collected staggered from retro-orbital plexus up to 36 h post- dose.

Plasma concentrations of Total CoQlO were quantified by LC-MS/MS method. Plasma Pharmacokinetic parameters were determined by noncompartmental analysis using Phoenix WinNonlin 6.3 software. Table 4:

Comparison of bioavailability of unformulated Coenzyme QIO and Fine free powder form of Coenzyme QIO - Measure of Total CoQIO in plasma

It was observed that coenzyme Q10 composition (Formulation 2) formulated without salacia exhibited 1.6 times bioavailability as compared to unformulated coenzyme Q10; whereas addition of salacia as absorption augmenting agent resulted into 2.2 times more bioavailability in aqueous medium than unformulated coenzyme Q10.

When formulation 1 was suspended in oil, it further resulted into enhanced bioavailability because of oil medium as an advantage.

Conclusion

Use of colloid mill for preparation of coenzyme Q10 formulation resulted into increasing bioavailability by 1.6 times in water as compared to unformulated coenzyme Q10 ingredient. Use of salacia as absorption augmenting agent in coenzyme Q10 formulation further enhanced the bioavailability more than 2 times as compared to unformulated coenzyme Q10, when the study is carried out by in aqueous medium for administering the formulation to experimental animal models.

Claims

1. Fine free flowing powder composition with enhanced bioavailability comprising; an effective amount of at least one lipophilic active agent;

an effective amount of absorption augmenting agent; and

at least one more suitable excipient.

2. Fine free flowing powder composition of claim 1, wherein effective amount of lipophilic active is selected from carotenoids, vitamins, omega fatty acids, glycerides, capsaicin, curcumin, terminalia, coenzyme Q10 and mixtures thereof.

3. Fine free flowing powder composition of claim 2, wherein lipophilic active selected is coenzyme Q10 which is employed in an amount of 10 to 25 % by weight of the total composition.

4. Fine free flowing powder composition of claim 1, wherein effective amount of absorption augmenting agent used is salacia extract.

5. Fine free flowing powder composition of claim 4, wherein amount of absorption augmenting agent used is such that ratio of lipophilic active and absorption augmenting agent ranges from 2: 1 to 14: 1

6. Fine free flowing powder composition of claim 1, wherein at least one more suitable excipient used is selected from the group of matrix carrier, antioxidant, stabilizer, solvents, fillers, oil vehicle either alone or in mixtures thereof.

7. A process for preparation of fine free flowing powder composition of lipophilic active agent, which is comprised of;

i. Dissolving lipophilic active such as coenzyme Q10 with one more suitable

excipient such as antioxidant in organic solvent;

ii. dissolving effective amount of absorption augmenting agent such as salacia

extract with at least one more excipient in water

iii. Adding organic solvent phase to aqueous phase with stirring and subjecting to homogenization

iv. passing the emulsion through suitable size reduction equipment such as mill or microfluidizer

v. spray drying the emulsion to get fine free flowing powder composition

8. Process for preparation of fine free flowing powder composition of claim 7, wherein at least one more excipient is selected from the group of matrix carriers, surfactant, antioxidant, oil vehicles and the mixture thereof.

9. Process for preparation of fine free flowing powder composition of claim 7, wherein the particle size of the powder ranges from 10 to 22 microns.

10. Fine free flowing powder composition of claim 1, wherein the bioavailability of the composition in aqueous medium is more than 2 times higher than the bioavailability of unformulated coenzyme Q10.