WO2016166767A1

WO2016166767A1 - Pharmaceutical formulation comprising low melting, highly lipophilic drugs

Info

Publication number: WO2016166767A1
Application number: PCT/IN2016/000096
Authority: WO
Inventors: Anwar Siraj DAUD; Nidhi SAPKAL; Shamsuddin JAMALUDDIN
Original assignee: Zim Laboratories Limited
Priority date: 2015-04-14
Filing date: 2016-04-13
Publication date: 2016-10-20
Also published as: BR112017021995A2

Abstract

This invention comprises a pharmaceutical dosage form of, and method of improving dissolution in a substantially aqueous environment/medium of, a low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts, comprising a solid dispersion further comprising of at least one low melting highly lipophilic drug, at least one surfactant, at least one water soluble dispersant and at least one oxide/s of third row element of periodic table or other pharmaceutically acceptable inert solid powder that is non- cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces. The pharmaceutical dosage form of this invention comprises dissolution rate more than 80% in 15 minutes of the low melting highly lipophilic drug Orlistat from its adsorbates in a dissolution test in 900ml of 0.5% of Sodium Chloride containing 3.0% Sodium Lauryl Sulphate, pH 6.0; containing 1-2 drops of n-octanol/10 litres, in a USP 2 Type apparatus (Paddle) with coil wire sinker at a speed of 75 RPM and temperature of 37.0°C± 0.5°C.

Description

PHARMACEUTICAL FORMULATION COMPRISING LOW MELTING, HIGHLY LIPOPHILIC DRUGS

TECHNICAL FIELD

The invention pertains to the method/process of making a pharmaceutical dosage form containing Low melting, highly lipophilic drug/s or its/their pharmaceutically acceptable salts and the dosage form made by using the method/process of the invention.

BACKGROUND OF THE INVENTION

Highly lipophilic drugs obviously have poor dispersibility as well as poor water solubility. Adequate water solubility is the prerequisite for dissolution. In the case of systemica!ly acting drugs, dissolution is the indicator of bioavailability, if the drug has good permeability. For the drug molecules that act locally, improved dissolution increases the effectiveness of the drug as it increases its chances to interact with the contents of the targets in their immediate vicinity. An example in this context is the contents of a digesting bolus in the gastrointestinal (Gl) tract, wherein in the case of lipase inhibitors their target is to attach to the lipase enzyme and inhibit its action on the fats and oils contained in the digesting food. Another example relates to the interaction of each particle of many locally acting anti-inflammatory drugs to the receptors located along the inner lining of Gl tract. Different methods of improving solubility are reported in literature e.g. solid dispersions with hydrophilic excipients, use of surfactants, change of physical form from crystalline to amorphous, size reduction etc. But these techniques of improving solubility/dissolution have limitations when used for low melting highly lipophilic drugs. Because of their low melting nature they can't be spray dried; can't be converted to efficient solid dispersions using known methods, size can't be reduced because of aggregate forming tendency of these molecules.

Orlistat, an illustrative low melting highly lipophilic drug, also known as tetrahydrolipstatin, is a drug designed to treat obesity. It is a .white to off white crystalline powder, a lipophilic substance with very low solubility in water within the physiological pH range. This causes Orlistat to exhibit a low rate of dissolution in aqueous media (including gastrointestinal fluids) which results in inadequate bioavailability (absorption into systemic circulation) after oral ingestion.

In order to make a composition comprising Orlistat it is necessary to enable maximum dissolution of the drug in the gastrointestinal fluids.

Various compositions are disclosed that contain Orlistat as an ingredient. US6004996 Discloses a pharmaceutical composition of tetrahydrolipstatin (Orlistat) comprising a plurality of pellets having a diameter in the range of from about 0.25 mm to about 2 mm, and at most only a trace amount of pellets outside this range, each pellet comprising about 50% by weight tetrahydrolipstatin; polyvinylpyrrolidone; microcrystalline cellulose; and at least one pharmaceutically acceptable excipient. Excipients used comprise PVP, sodium lauryi sulphate, sodium dioctylsulfosuccinate, sucrose, corn starch, sodium starch glycolate, cross PVP. Cross croscarmellose sodium, hydroxypropyl cellulose, mierocrystalline cellulose, lactose, medium chain triglyceride, skim milk powder, sodium carboxymethyl cellulose and magnesium stearate. However, this patent does not disclose any improvement in solubility.

US6358522B1 provides a pharmaceutical composition in unit dosage form, said composition comprising an inhibitor of gastrointestinal lipase and at least one additive selected from the group consisting of substantially non-digestible, substantially non-fermentable, hydrophilic and hydrocolloidal food grade thickeners, emulsifiers and mixtures thereof, wherein said composition contains 1 to 300 parts by weight of the thickener, emulsifier or mixtures thereof per 1 part by weight of an inhibitor of gastrointestinal lipase. Also provided is a method of reducing anal leakage of oil in a patient to whom orlistat is being administered, which comprises orally administering to the patient 1 to 3 tablets per meal consumed by the patient, each of the tablets containing (i) 50 mg to 150 mg of orlistat and (ii) at least one additive selected from the group consisting of karaya gum and xanthan gum, the karaya gum or xanthan gum being present in the amount of 3 parts to 30 parts by weight of karaya gum or xanthan gum per 1 part by weight of orlistat. Excipients used include Sorbitol, Avicel C L 611 , Citric Acid, Parahydroxybenzoic acid methyl ester, parahydroxybenzoic acid propyl ester, passion fruit flavour, avicel PH 105, Monosodium citrate, Saccharine Sodium, pvp, avicel C E - 15, talc, stearic acid, MCC, sodium starch glycolate, sodium lauryl sulphate and Ryoto sugar ester- S-170. However, there is no disclosure on any improvement in solubility of Orlistat.

US6534087B2 discloses method for preparing a pharmaceutical composition containing orlistat, which comprises: a) preparing a solution or a homogeneous dispersion, which contains a liquid, orlistat, and one or more pharmaceutically suitable excipients; b) expanding the solution or homogeneous dispersion by exposing it to a reduction in pressure to between about 30 and about 150 Torr under conditions such that the solution or homogeneous dispersion does not boil; and c) stabilizing the expanded solution or homogeneous dispersion to form the pharmaceutical composition. The result is a product in the form of expanded, mechanically stable, lamellar, porous, sponge like or foam structures out of solutions and dispersion. This invention does not mention the extent of improvement in dissolution.

US6756364B2 discloses method of reducing the gastrointestinal side effects associated with Orlistat treatment, which comprises administering to a patient being treated with Orlistat an amount of a bile salt sequestrant selected from the group consisting of cholestyramine, colestipol, colestimide, co!esevelam, sevelamer, DEAE-cellulose, .beta.-cyclodextrin, .gamma.-cyclodextrin, guanidinoethylcel!ulose, and DEAE-Sephadex, effective to reduce the side effects associated with the orlistat treatment. Excipients used include microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulphate, aspartame, maltodextrine, silicium dioxide, saccharose, lactose, pvp and talc. Process of preparation includes conventional granulation and extruder spheronization to form pellets and granules. This patent also does not touch to the problem of dissolution and does not disclose improvement in dissolution rate.

WO2003039516A1 discloses a method for improving dissolution of poorly dispersible medicament, which comprises mixing the poorly dispersible medicament with a floating agent and granulating the mixture. Surfactant may also be added to above mixture before granulation. In WO2003039516, the floating agent is non-water-soluble cellulose, sodium alginate, propylene glycol alginate, tragacanth powder or xanthan gum; the surfactant is sodium lauryl sulfate, polyoxyl 40 stearate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropyiene glycol or polyoxyethylene sorbitan fatty acid ester; the poorly dispersible medicament is 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,f][l,4]-thiazepine or a salt thereof. The floating agent is crystalline cellulose and the surfactant is sodium lauryl sulfate. In WO2003039516, the dissolution of the poor dispersible medicament is improved by the floating agent or by the floating agent and the surfactant. The granulated product is manufactured by an extrusion granulation. The granulated product is in a form of fine granules. The dosage form is a capsule which comprises the granulated product or a tablet which comprises the granulated product. The surfactant is sodium lauryl sulfate, polyoxyl 40 stearate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol or polyoxyethylene sorbitan fatty acid ester.

US2010/0317642A1 discloses a stable pharmaceutical composition comprising dispersion blend comprising 20 to 60% by weight of orlistat and 20% to 80% by weight of water soluble polymer carrier selected from hydroxypropyl methyl cellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and the like. Excipients include pregelatinized starch (0.5 to 2%) and Silicon dioxide as antitack (0.5%).

US20040175420 a U.S. patent application is now a patented case, US8.012,494 having following granted claim: "1. A pharmaceutical dosage form comprising (i) Orlistat (ii) at least one non-ionic or zwitterionic surfactant selected from the group consisting of vitamin E polyethylene glycol 1000 succinate, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene stearates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polyglycolyzed glycerides, transesterified and (poly)ethoxylated oils, sorbitan fatty acid esters, poloxamers, lecithins, sugar esters, and mixtures thereof, and (iii) at least one dispersant.".

US20110275706 claims; "1. A pharmaceutical dosage form comprising (i) Orlistat (ii) at least one non-ionic or zwitterionic surfactant selected from the group consisting of vitamin E polyethylene glycol 1000 succinate, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene stearates, polyoxyethylene alkyl ethers, polyoxyethylene castor oils, polyglycolyzed glycerides, transesterified and (poly)ethoxylated oils, sorbitan fatty acid esters, poloxamers, lecithins, sugar esters, and mixtures thereof, and (iii) at least one water-soluble dispersant." This claim differs from the granted patent claim in the dispersant being further narrowed down to "water soluble dispersant".

In a corresponding patent EP1216025, the granted claim is:

"A pharmaceutical composition comprising at least one lipase inhibitor, at least one surfactant selected from the group consisting of vitamin E(polyethylene glycol 1000)succinate (TPGS), polyethylene stearates, polyoxyethylenealkyle ethers, polyoxyethylenecastro oils, polygycolyzed glycerides and lecithins and mixtures thereof and at least one dispersant.

WO2001019378: Claims a pharmaceutical composition comprising at least one inhibitor of lipases and at least one fatty acid ester of polyols, characterized in that the fatty acid ester has a melting point above the body temperature and the polyols are chosen from the group consisting of glycerol, sugars, sugar derivatives and mixtures thereof.

WO2001019340: Discloses a pharmaceutical composition comprising at least one lipase inhibitor, at least one surfactant and at least one dispersant. The "dispersants" or "dispersing agents" are defined as materials that facilitate the initial disintegration of the composition and promote further fine distribution in the environment. Dispersants can be chosen from water and lipid soluble compounds. They are usually present in an amount of at least 5% of the total -weight of the composition, preferably in amounts varying between 5 and 70% of the total weight of the composition. According to WO2001019340, water soluble dispersants can be found in a group consisting of sugars, sugar alcohols, alcohols, effervescents, disintegrants, and mixtures thereof. More preferred dispersants may be chosen from the group consisting of glucose, sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylenglycol, glycerol, triacetin, glycofurol, effervescents, e.g. NaHC03/acid mixtures, e.g. NaHC03/citric acid, and mixtures thereof. Most preferred water soluble dispersants are sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylenglycol, e.g. polyethylenglycol 100 - 10000, more preferably polyethylenglycol 400 - 6000, e.g. polyethylenglycol 400, glycerol, triacetin, glycofurol and mixtures thereof. Gammascintigraphic studies have shown that effervescent mixtures (NaHC0₃ /citric acid) have pronounced effects on the dispersion of content of hydroxyl propyl methylcellulose (HPMC) capsules in the stomach. According to the present invention, dispersants can also be chosen from the lipid soluble dispersing agents which are preferably applied in amounts varying between 20 and 90% of the total weight of the compositions and must be liquid at the body temperature (i.e. >37°C). The lipid soluble dispersants can be chosen among the group consisting of triglycerides, diglycerides, monoglycerides, mixtures of di/mono/triglycerides, vitamin E, tocophero acetate, terpenes, squalene and mixtures thereof, more preferably the lipid soluble compound is chosen from the group consisting of triglycerides, diglycerides, monoglycerides, mixtures of di/mono/triglycerides, vitamin E, tocopherol acetate, and mixtures thereof. Preferred examples are medium chain triglycerides or mixtures of medium chain triglycerides, e.g. fractionated coconut oil (Medium Chain Triglycerides, MCT, e.g. Miglyol 812, Hiils AG, Neobee M-5, Stepan, Captex 355, Abitec). Preferably, the compositions according to the present invention may further comprise an additional surfactant (co-surfactant). Example 5 of WO2001019340 illustrates a method of making the dosage form of this invention which discloses:"A composition consisting of 1700 mg TPGS and 300 mg orlistat were added to a planet-mixer in which the metal beaker was warmed to 60°C. After melting, the mixture was stirred and 10 g of solid sorbitol was added while continuously stirring at 150 rpm. The stirring was continued for 30 minutes during which time the preparation cooled down to room temperature. Afterwards, the solid mixture was sieved through a 2mm sieve. Hydroxypropylmethylcellulose capsules containing each 30 mg of oriistat in the above composition were applied to human volunteers" The instant invention has achieved an alternative method for achieving a novel method of achieving a novel solid dispersion of low melting, highly lipophilic drugs.

SUMMARY OF THE INVENTION

This invention comprises a pharmaceutical dosage form comprising a solid dispersion, the solid dispersion comprising of at least one therapeutically effective amount of low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts, at least one surfactant, at least one water soluble dispersant and at least one pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces.

The pharmaceutical dosage form of this invention comprises of the dosage form selected from the group consisting of a powder, a tablet, pills, capsules, pellets, mini tablets, dispersible tablets, fast disintegrating tablets, effervescent tablets extrudates and granules. The pharmaceutical dosage form of this invention may also comprise one or more pharmaceutically permitted excipient/s.

This invention also comprises a method of improving dissolution of a low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts in a substantially aqueous environment/medium by making its adsorbates in high concentration on at least one pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces.

In one embodiment, this invention comprises a pharmaceutical dosage form comprising at least one therapeutically effective amount of low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts having dissolution more than 80% in 15 minutes of the low melting highly lipophilic drug Orlistat from its adsorbates in a dissolution test in 900ml of 0.5 % of Sodium Chloride containing 3.0 % Sodium Lauryl Sulphate, pH 6.0; containing 1-2 drops of n-octanol per 10 litres, in a USP Type 2 apparatus (Paddle) with coil wire sinker at a speed of 75 RPM and temperature of 37.0°C ± 0.5°C as mentioned in USP 37. The pharmaceutical dosage form comprises a solid dispersion, the solid dispersion comprising of at least one low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts, at least one surfactant, at least one water soluble dispersant and at least one pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces.

In one embodiment of this invention, the pharmaceutical dosage form the solid dispersion comprises adsorbate of the low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts on the pharmaceutically acceptable inert solid powder, the lipohilic ingredients comprise the lipophilic drug/s or or its/their pharmaceutically acceptable salts, oils, surfactants with lipophilic ends, the water soluble dispersant comprises one or more selected from the group consisting of mannitol, sucrose, dextrose, fructose and maltodextrin, the low melting highly lipophilic drug is selected from the group consisting of Orlistat, fenofibrate, nitroglycerin, amyl nitrate, simethicone, Cholecalciferol, and any other low melting highly lipohilic drug, the surfactant is selected from the group consisting of Polysorbate 80 (Tween 80^®), Polysorbate 20 (Tween 20^®), polyethoxylated castor oil (Cremophor EL^®), sorbitan monostearate 20 (Span 20^®), and sorbitan monostearate 80 (Span 80^®). The pharmaceutically acceptable inert comprises any one of or a mixture of oxide/s of third row element of periodic table. The oxide or mixture of the oxides of third row of periodic table is selected from the group consisting of oxides of Aluminium, Magnesium & Silicon. The mixture of oxides of aluminium, magnesium & silicon comprises a ratio ranging from [(1 :1:1) to (0.5:1.5:1)], or [(0.5-3.5):(0.5-10): (0.25-10)] more preferably to [(1-2.5): (3.5-6):( 0.5-6)].

In a further embodiment of this invention, concentration of the low melting highly lipophilic drug/s or or its/their pharmaceutically acceptable salts is 20 - 80%, the water soluble dispersant used as dispersant is 1-45%, the surfactant/s is/are 0.05 - 45%, concentration of the drug adsorbates prepared using the pharmaceutically acceptable inert solid powder is 20- 80% and concentration of pharmaceutically acceptable inert solid powder used in solid dispersion is 0.1 to 45%. DETAILED DESCRIPTION OF THE INVENTION

This invention comprises a pharmaceutical dosage form which comprises a therapeutically effective amount of low melting, highly lipophilic drug/s or its/ their pharmaceutically acceptable salts, a surfactant, at least one water soluble dispersant and at least one pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces. The invention is illustrated with using oxide of third row element of periodic table as the inert solid powder. It is possible to consider use of other inert soluble powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces. In a further aspect, the said dosage form comprises a solid dispersion of low melting, highly lipophilic drug, one or more surfactant/s, one or more water soluble dispersants and one or more oxide/s of third row element of periodic table that serves as an inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces. In a further aspect, this invention comprises a dosage form comprising, without limitation, tablet, a pills, a capsules, pellets, mini tablets, dispersible tablets, fast disintegrating tablets, effervescent tablets, extrudates, granules and the like, further comprising a solid dispersion of low melting, highly lipophilic drugs, one or more surfactant/s, one or more water soluble dispersant and either one or more oxide/s of third row element of periodic table or any other pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces. In a still further aspect, pharmaceutically permitted excipients are also added to the dosage form. This invention comprises a method of improving dissolution of illustrative low melting highly lipophilic drug Oriistat by making its adsorbates on either one or more oxide/s of third row element of periodic table or any other pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces in high concentration, more preferably 60% of the total composition. In one embodiment, the method comprises adsorbing Oriistat as the lipophilic drug. Surprisingly, the adsorbates made in this way led to dissolution of more than 95% of labelled claim of the low melting highly lipophilic drug Oriistat from its adsorbates in a USP type 37 dissolution test, which complies to the limit given on label of Oriistat capsules. Conditions used for USP type 37 dissolution test are:

Dissolution Conditions:

Medium 900 ml_, 0.5 % of Sodium Chloride containing 3.0 % Sodium Lauryl Sulphate, pH 6.0; containing 1-2 drops of n-octanol per 10 litres

Apparatus USP 2 (Paddle) with coil wire sinker;

Speed 75 RPM;

e Temperature 37.0°C ± 0.5°C; Orlistat can be replaced with any other low melting highly lipophilic drug for making adsorbates The method described for making adsorbates of Orlistat can also be used for making adsorbates of any other low melting highly lipophilic drug. The lipophilc drug/s or its/their pharmaceutically acceptable salts may be selected from the group, in addition to Orlistat, comprising, without limitation, fenofibrate, choline fenofibrate, nitroglycerin, amyl nitrate, simethicone, Cholecalciferol, and any other low melting highly lipohilic drug/s or its/their pharmaceutically acceptable salts to achieve substantial improvement in dissolution of these lipophlic drug/s or its/their pharmaceutically acceptable salts in an aqueous environment.

It was found surprisingly that as compared to prior art dosage forms of these low melting, highly lipophilic drugs that did not contain one or more oxide/s of third row element of periodic table, the dissolution of Orlistat improved in the dosage form of this invention.

The method/process of this invention of making the said solid dispersion of low melting highly lipophilic drugs comprises steps of heating and melting the low melting the highly lipophilic drug/s or its/their pharmaceutically acceptable salts, blending the surfactant/s into the molten drug, adsorbing the molten dispersion on mixture of mannitol and oxide/s of third row elements of the Periodic Table and solidifying the mixture by cooling. In place of Mannitol, an equivalent alternative water soluble dispersant may also be used, such as, without limitation, Maltodextrin, mannitol, sucrose, dextrose, fructose and the like. An oxide of third row elements may be selected from a group consisting of oxides of Aluminium, magnesium & silicon Most preferred oxide is Magnesium oxide. The oxide may also be replaced by any other pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces. This solidified mixture can be processed into tablets, pellets, capsules and other solid dosage forms after the addition of suitable excipients.

Additionally, In the case of liquid or highly volatile drugs, the procedure is carried out at room temperature without requiring heat.

The solidified mixture is further granulated with water and extruded followed by drying of extrudate at a temperature below the melting point of the drug. These extrudates can be processed further to make elongated pellets or granules for filling them in capsules.

It is preferred to use two or more oxides, more preferably oxides of aluminium, magnesium & silicon in ratio ranging from (1:1:1) to (0.5:1.5:1) or (0.5-3.5):(0.5-10): (0.25-10), more preferably (1-2.5): (3.5-6):( 0.5-6). Without binding to any theory, it is contemplated that because of the very intimate mixing achieved by mixing the surfactant with the drug in the molten state, which is further dispersed on the oxide/s of third row element of the Periodic Table, it follows that each granule or particles of the solid dispersion will be an approximately uniform mixture of the low melting highly lipophic drug and surfactants which is finely dispersed and adsorbed on mixture of mannitol (or any other water soluble dispersant) and oxides of third row element of periodic table (or any other pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces.) ; which shall have better probability to reach up to the lipases in the digestive tract for inhibiting their action.

On this principle, a person skilled in the art would readily understand that, all low melting point, highly lipophilic drugs, including but not limited to Orlistat, lipstatin, Fenofibrate, Nitroglycerin, isosorbide mononitrate, amyl nitrite, Cholecalciferol and simethicone can also be made better bioavailable by the process described in this invention for improving bioavailability of Orlistat.

Solid dispersion does not always increase the dissolution to the desired extent due to the inherent limitation of the hydrophilic excipient; the process used for the preparation of solid dispersion is also important since it also influences the effect on dissolution. In addition, not all the methods mentioned in the literature can be employed for low melting drugs. Hence, this invention is also embodied in the method used for making the solid dispersion of this invention.

Similarly surfactants also give concentration dependent increase in dissolution but high concentration of surfactants are not permitted due to the associated toxicity and proper identification fo optimum concentration of the surfactants is critical. In addition, it has also been observed that surfactants cannot increase the solubility beyond a certain limit. In WO2009039157, for example, the solid filled capsules containing surfactant released less than 60% of Orlistat in 15 minutes; and the liquid solution filled capsules released between 60-70% in 15 minutes. While in the present invention he drug release was found to be more than 80% in 15 minutes. Since faster release of Orlistat is desired, and since a complete release is considered to be at least 80%, and for a lipase inhibitor to be effective, at least 80% content should be released before significant portion of the food has already passed through pylorus. Considering the fact that food starts passing through pylorus soon after an average meal consumption has started, and an average time for consumption of meal if about 15 minutes, it is preferred that the release of Orlistat starts soon after the meal starts and complete release occurs by about 15 minutes after start of the consumption of the meal. On this background it is clear that release of prior art dosage forms of Orlistat in stomach in 15 minutes of only 60% for solid filled capsules and 60-70% for liquid solution filled capsules is too short of the optimum requirement, and by the time full release happens, a lot of food would have passed through ileum and further to that point in the intestine with sub-optimal concentration of Orlistat. Hence, an improvement in rate of release of Orlistat was needed; and the same has been achieved in the instant invention.

Regarding other techniques of solubilization of low melting highly lipophilic drugs, the complex techniques like spray drying and freeze drying have been reported to convert less soluble crystalline form to more soluble amorphous form. However, apart from the complexity involved in scaling up of these techniques to industrial scale, change in physical form suffers from disadvantage of instability. Reversal of the physical form affects the performance of the formulation in worst manner. Higher the lipophilicity, worse will be the effect. Moreover, it is difficult to achieve a stable change in the form of low melting drugs.

Nanosizing, although very much advantageous in enhancing the solubility and hence dissolution greatly, also suffers from instability issues. Nano sized particles are notorious for their nature of forming aggregates upon keeping, which again will result in change in the formulation behaviour. The behaviour of re-aggregation is more common in low melting drugs that are waxy in nature.

It is an embodiment of this invention that dissolution of highly lipophilic, low melting drug molecules has been improved by a simple, novel, two step, one-pot technique involving no special equipments. This invention comprises a process of melting a highly lipophilic, low melting drug and making an intimate mixture of the molten drug with surfactants and adsorbing the intimate mixture on the water soluble dispersants and mixture of oxides of third row elements of the Periodic Table or any other pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces to result into a solid dispersion. It was surprisingly found that dissolution of the drug-surfactant mixture adsorbed on the mixture of the water soluble dispersant and oxides of third row elements of the Periodic table or any other pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces is significantly improved over the known techniques of dissolution improvement.

Upon adsorption on to the oxides of third row elements, without getting bound to the following theory, it seems that the non-cohesive powder properties of oxides of the third row metal elements are imparted to the drug surfactant mixture. Thus, it may be possible to replace Oxides of third row of Periodic Table by pharmaceutically acceptable inert solid powders that are non-cohesive in nature and have ability to adsorb lipophilic ingredients including lipophilic liquids on their surfaces.

For highly lipophilic liquid or volatile drug molecules, the process of this invention offers a novel method of converting them into easily handle-able solid form with reduced volatility. Drugs like nitroglycerine, amyl nitrate, isosorbide dinitrate etc. pose health problems on account of their volatility to the personnel involved in their production. These problems will be reduced because of reduced volatility and simultaneous enhancement in solubility.

It is observed that, whereas, in the case of very low melting drug particles (including, without limitations, all the drugs listed above i.e. Orlistat, lipstatin, Fenofibrate, Nitroglycerin, isosorbide mononitrate, amyl nitrite, Cholecalciferol and simethicone) offer difficulty during processing; the solid dispersion of highly lipophilic, low melting drug obtained by process of this invention have good flow properties, which ensures its hassle free use in the manufacturing of formulations like tablets, capsules, pellets, etc, This is especially advantageous to those drug powders that are waxy (e.g. orlistat and fenofibrate) in nature and hence pose difficulty during processing. This process has dual advantages for them.

Thus, it is an embodiment of this invention that the solid dispersion of highly lipophilic, low melting drug obtained by process of this invention can be mixed with other pharmaceutically acceptable excipients and can be formulated into any pharmaceutical dosage form, comprising, without limitation, the powder, tablets, pills, capsules, pellets, mini tablets, dispersible tablets, fast disintegrating tablets, effervescent tablets, extrudates, granules and the like.

It is a further embodiment of this invention that solid dispersion of Jiighly lipophilic, low melting drug obtained by process of this invention remains stable and retains its dissolution enhancement property throughout the shelf life of the dosage form.

The solid dispersion of highly lipophilic, low melting drug obtained by process of this invention is also an embodiment of this invention.

In one embodiment, the solid dispersion of highly lipophilic, low melting drug obtained by process of this invention has following composition: A) Concentration of drug/s or its/their pharmaceutically acceptable salts is 20 - 80%,

B) A water soluble dispersant used as dispersant: 1-45%. Mannitol is an illustrative dispersant.

C) A surfactant/s: 0.05 - 45% .

D) drug adsorbates prepared using mixtures of oxides of third row elements of Periodic Table containing drug/s or its/their pharmaceutically acceptable salts: preferably20-80%

E) Concentration of oxides of third row elements of periodic table used in solid dispersion: 0.1 to 45%. F) The said mixture of oxides comprising a mixture of two or more oxides preferably of aluminium, magnesium & silicon in the ratio ranging from (1 :1 :1 ) to 0.5:1.5:1 , or (0.5-3.5):(0.5-10): (0.25-10) more preferably (1-2.5): (3.5-6):( 0.5-6)

The instant invention is illustrated by the following non-limiting illustrative examples.

Example 1 : 600gm of Orlistat was placed in a stainless steel pot, which was slowly heated under water bath until the Orlistat was melted. 50gm of Polysorbate 80 and Polyoxyl 40 hydrogenated castor oil was mixed and then blended into the molten Orlistat, and the mix was then adsorbed on a mixture comprising of mannitol 156gm, magnesium oxide 240gm, aluminium oxide 60gm, silicon dioxide 60gm and allowed to cool and solidify to form a solid dispersion. This solid dispersion so obtained is granulated with water and extruded, followed by drying of extrudates at 35°C and milled through screen to get granules of 16-25# size.

These granules were then filled into capsules with a net fill weight of 200mg per capsules. Eac capsule thus contains 120mg of Orlistat.

For these capsules dissolution test was performed as per method given under the monograph of Orlistat capsule, which is as follows: About 900 ml of dissolution Medium (3% Sodium lauryl sulfate and 0.5% sodium chloride in water containing 1-2 drops of n-Octanol per 10 lit of media) whose pH is adjusted to 6.0, with phosphoric acid was taken in USP dissolution apparatus 2 and capsules were added. Temperature was set to 37.0°C ± 0.5°C. A coiled wire sinker was used to dip the capsules in medium. The paddles were rotated at 75 rpm and drug release was measured by drawing samples after 15, 30 and 45 minutes. The samples were analysed using HPLC. About 96 % drug was released in first 15 minutes and complete dissolution was observed after 30 minutes.

Example 2:

Ingredients were taken in following proportion/percentages.

Orlistat, Tween 80 & Polyoxy! 40 hydrogenated castor oil were mixed & melted together at about 45°C. This was blended with Magnesium oxide, Silicon dioxide, Aluminium oxide & Mannitol and mixed well until it cooled. The granules were collected, milled and passed through 60# sieve. Water was added to make granules. These granules were extruded through 1 mm pore plate. Extrudate was collected & was dried at 35°C. The dried granules were passed through screen to get granules of 16-25#. These granules were then filled into capsules with a net fill weight of 200mg per capsule. Each capsule thus contained 120mg Orlistat. These capsules exhibited about 95% drug release in dissolution medium in 15 minutes when analysed using dissolutions conditions mentioned for dissolution test for Orlistat capsules in Example 1.

Example 3:

Ingredients were taken in following proportion:

Fenofibrate, Tween 80 & Propylene glycol were mixed & melted together at about 80°C. The mixture was blended with Magnesium oxide, Silicon dioxide, Aluminium oxide & Maltodextrin and mixed well. After the complete mixing it was cooled to room temperature. The so obtained granules were collected, milled and passed through 60# sieve. Water was added to make granules. These granules are ready for compression into tablets or filling into capsules after mixing with suitable excipients. Dissolution studies of these granules were carried out using conditions as described for dissolution test in Example 1 except that dissolution medium was 1000 mL of 0.05 M Sodium Lauryl Sulfate in deaerated water and the samples were analysed using HPLC.

In first 15 minutes more than 90% of the drug was released.

Claims

CLAIMS :

1. A pharmaceutical dosage form comprising a solid dispersion, the solid dispersion comprising of at least one therapeutically effective amount of low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts, at least one surfactant, at least one water soluble dispersant and at least one pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces.

2. The pharmaceutical dosage form of claim 1 wherein the dosage form is selected from the group consisting of a powder, a tablet, pills, capsules, pellets, mini tablets, dispersible tablets, fast disintegrating tablets, effervescent tablets, extrudates and granules.

3. The pharmaceutical dosage form of claim 2 further comprising one or more pharmaceutically permitted excipient/s.

4. A method of improving dissolution of a therapeutically effective amount of a low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts in a substantially aqueous environment/medium by making its adsorbates in high concentration on at least one pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces.

5. A pharmaceutical dosage form comprising at least one low melting > highly lipophilic drug having dissolution more than 80% in 15 minutes of the low melting highly lipophilic drug Orlistat or its pharmaceutically acceptable salts from its adsorbates in a dissolution test in 900ml of 0.5 % of Sodium Chloride containing 3.0 % Sodium Lauryl Sulphate, pH 6.0; containing 1-2 drops of n- octanol per 10 litres, in a USP Type 2 apparatus (Paddle) with coil wire sinker at a speed of 75 RPM and temperature of 37.0°C ± 0.5X.

6. The pharmaceutical dosage form of claim 5 comprising a solid dispersion, the solid dispersion comprising of at least one a therapeutically effective amount of low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts, at least one surfactant, at least one water soluble dispersant and at least one pharmaceutically acceptable inert solid powder that is non-cohesive in nature and has an ability to adsorb lipophilic ingredients on its surfaces.

7. The pharmaceutical dosage form of any one of claim 1 , claim 4 or claim 6 wherein:

a. the solid dispersion comprises adsorbate of the low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts on the pharmaceutically acceptable inert solid powder,

b. the lipohilic ingredients comprise the lipophilic drug/s, oils, surfactants with lipophilic ends, c. the water soluble dispersant comprises one or more selected from the group consisting of mannitol, sucrose, dextrose, fructose and maltodextrin,

d. the low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts is selected from the group consisting of Orlistat, fenofibrate, nitroglycerin, amyl nitrate, simethicone, Cholecalciferol, and any other low melting highly lipohilic drug/s or its/their pharmaceutically acceptable salts,

e. the surfactant is one or more selected from the group consisting of Polysorbate 80, Polysorbate 20, polyethoxylated castor oil, sorbitan monostearate 20, and sorbitan monostearate 80,

f. the pharmaceutically acceptable inert soild powder comprises any one of or a mixture of oxide/s of third row element of periodic table.

8. The pharmaceutical dosage form of claim 7 wherein: the oxide or mixt^ure of the oxides of third row of periodic table is selected from the group consisting of oxides of Aluminium, Magnesium & Silicon.

9. The pharmaceutical dosage form of claim 8 wherein the mixture of oxides of aluminium, magnesium & silicon comprises a ratio ranging from [(1 :1 :1) to (0.5:1.5:1)], or [(0.5-3.5):(0.5-10): (0.25-10)] more preferably to [(1-2.5): (3.5-6):( 0.5-6)].

10. The pharmaceutical dosage form of claim 9 wherein

a. concentration of the low melting highly lipophilic drug/s or its/their pharmaceutically acceptable salts is 20 - 80%, b. the water soluble dispersant used as dispersant is 1-45%, c. the surfactant/s is/are 0.05 - 45%,

d. concentration of the drug adsorbates prepared using the pharmaceutically acceptable inert solid powder is 20-80%, e. concentration of pharmaceutically acceptable inert solid powder used in solid dispersion is 0.1 to 45%.