WO2006123354A2

WO2006123354A2 - Oral pharmaceutical composition

Info

Publication number: WO2006123354A2
Application number: PCT/IN2006/000042
Authority: WO
Inventors: Vijaya Kumar Velidi; Chancharusiri Apichai; Snehal Mukund Mehta; Wongpayak Pornchai; Madhav Pai Rajesh; Torane S. Jyotsna; Ratilal Vavia Pradeep; Satyen Torne; Shankar Swaminathan; Aradee Kunchom
Original assignee: Mega Lifesciences Pvt. Ltd.
Priority date: 2005-02-02
Filing date: 2006-02-01
Publication date: 2006-11-23
Also published as: EP1848407A2; WO2006123354A3; WO2006123354B1

Abstract

An oral pharmaceutical composition comprising about 0.1 to about 25% by weight of selective hydrophobic drug , about 0.5 to about 90% by weight of a lipophilic naturally occurring wetting agent, solubilizer and stabilizer comprising rice oil, about 0.5 to about 90% by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic co-surfactant and about 0.5 to about 90% by weight of a surfactant, wherein the relative proportion of selective hydrophobic drug, hydrophilic components, lipophilic components and surfactants in said composition is such that upon dilution with water to a ratio of 1 part by weight of said composition to 100 parts by weight of water, an oil-in-water microemulsion having average particle size below 100 nm is spontaneously formed.

Description

ORAL PHARMACEUTICAL COMPOSITION

FIELD OF INVENTION

The present invention relates to oral pharmaceutical composition comprising hydrophobic drugs in a homogenous alcohol free, transparent self emulsifying drug delivery system for oral administration. More specifically it comprises poorly water soluble selective hydrophobic drugs like cyclosporin, tacrolimus, hydrophilic component, surfactant having suitable HLB value, lipophilic component along with naturally occurring wetting agent, , solubilizer and stabilizer in the form of selective vegetable oil namely rice bran oil and rice germ oil. The formulation upon dilution forms microemulsion spontaneously with average particle size of below 100 nm.

BACKGROUND AND PRIOR ART

Cyclosporin has a narrow therapeutic index and the condition of patient to be treated with cyclosporin is generally unstable. Therefore, it is very difficult to establish an optimum drug dosage regimen for survival of transplanted patient through maintenance of efficient and constant blood concentration that can prohibit side effects and rejection. Numerous studies have been conducted to overcome the said properties and to develop an improved pharmaceutical formulation. Such studies have been mainly focused on the means that are used to solubilize cyclosporin. Typical examples include not only mixed solvent systems consisting of vegetable oil and surfactant, but also microspheres, the formations of powdery composition using adsorption, inclusion complexes, solid dispersions, and other numerous formulations. An oral preparation containing cyclosporin as the primary active ingredient has been commercialized in a solution form and a soft capsule formulation. A microemulsion preconcentrate intended to form microemulsion upon ingestion is an established way to improve bioavailability of cyclosporin with reduced inter subject variability.

Cyclosporin is a highly lipophilic drug which is sparingly soluble in water, but dissolves readily in organic solvents, such as methanol, ethanol, chloroform etc.

One of the liquid compositions was formulated into a soft capsule preparation, which is now commerecially available as SANDIMMUNE. In this preparation the cyclosporin soft capsule contains a large amount of ethanol as a co-surfactant in order to solubilize the cyclosporin. However, since ethanol peremeates the gelatin shell of the capsule and is volatile even at normal temperatures, the constitutional ratio of the contents of the soft capsules may greatly vary during storage. The resulting reduced ethanol content may in turn result in crystallization of the cyclosporin and thus results in a significant variation in the bioavailability of cyclosporin. The variation in cyclosporin in concentration in this formulation makes it quite difficult to determine the dosage needed to provide a desired therapeutic effect.

Tacrolimus (also FK-506 or Fujimycin) is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the fungus Streptomyces tsukuhaensis. It is an immunosuppressive drug whose main use is after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. Tacrolimus is another hydrophobic immunosuppressant drug which is insoluble in water. Various solvents and methods have been tried to solubilize the drug without diminishing the bioavailablity.

Most of the available documents teach of single and/or various combinations of surfactants namely reaction products of natural and hydrogenated castor oil polyoxyethylene sorbitan fatty esters, Tweens, spans etc. along with lipophilic component.

A microemulsion comprises two or more immiscible liquid materials together with surfactant like emulsion, but is a thermodynamically stable and optically transparent unlike emulsion. The microemulsion has very low surface tension and small particle size, which together result in high absorption and permeation properties of drug delivered. The microemulsion is, especially, very useful in solubilization and absorption improvement of insoluble drugs like cyclosporin. Lipophilic phase, hydrophilic phase and surfactant are the preliminary components of any microemulsion preconcentrate formulation. Hence they are present in various ratios in microemulsion preconcentrate formulations. In most of the available documents for cyclosporin coming under microemulsion preconcentrate formulation single as well as various combinations of surfactants with various lipophilic phases are reported. In general, because the cyclosporin are hydrophobic, pharmaceutical compositions containing them in the form of microemulsion preconcentrate usually comprise lipophilic materials.

Lipophilic component generally comprises of single or comibinations of transesterification product of a natural vegetable oil with a glycerol, wherein said transesterification product comprises a mixture of monoglycerides, diglycerides and triglycerides forming oil phase, Medium chain triglycerides, various vegetable oils (olive oil, castor oil, arachis oil), refined fish oil, monoglyceride of fatty acid, esterified fatty acid and primary alcohol fatty acids etc.

There are three basic fatty acid types. Saturated fatty acids (SFA), polyunsaturated fatty acids (PUFA) and mono unsaturated fatty acids (MUFA).

Saturated fatty acids (SFA) have great stability. But they raise blood cholesterol levels.

The second type, polyunsaturated fatty acids, have been linked to lower incidences of heart disease. But they lack strong stability traits. They are also prone to oxidation and development of unstable molecules called free radicals. Omega-6 and Omega-3 are types of polyunsaturated fatty acids which helps in reducing risk of coronary heart disease and gastrointestinal, kidney and heart functions respectively.

As a monounsaturated fatty acid, the third type, oleic acid has higher stability than the polyunsaturated acids. And it has good characteristics, similar to those of the polyunsaturated fatty acids, when it comes to prevention of cholesterol and heart disease. Fatty acid composition of various oils is as shown in table 1.

Table 1 : Fatty acid composition of various oils

Oils are mainly composed of triglycerides along with some minor components diglycerides, monoglycerides, free fatty acids etc. Oxidative stability of oils is of paramount importance in any formulation. The more unsaturated the oil the greater will be its susceptibility to oxidative rancidity. Hence unsaturated oils like soyabean oil, corn oils possess very less stability.

Asian rice bran and germ oil is rich in linoleic acid Omega-6 Essential Fatty Acids (35%), oleic acid (Omega-9 monosaturated fats) (40%) and Vitamin E (32.3mg/100g). The oil is also extremely rich in phytosterols (1190mg/100g or 167 mg/tbsp), mainly beta sitosterol. Phytosterols have been shown to be as effective as conventional drugs for relieving frequent urination in aging men suffering from prostate conditions and quickly lower cholesterol. The oil also contains a compound called gamma oryzanol that reduces absorption and increases excretion of cholesterol. Gamma oryzanol is also an effective antioxidant. (Herb & Supplement Encyclopedia). There is no indication that such oil could be used for dissolving drugs and yet provide stable composition where the viscosity is low and the microemulsion formed with the drug has defined particle size. Also there is no indication that such oil could be useful in stabilizing the microemulsion without the use of added antioxidants, which are the common excipients in any microemulsion formulation. The rice oil is also not reported to have good dispersing properties, wetting properties in addition to being good solubilizer for the drug cyclosporine.

EP 0650721 b1 suggests use of dimethylisosorbide still has the properties which have such undesirable property like reactivity with gelatin shell of soft capsule and the volatility and shows the limit as hydrophilic solvent.

Moreover, US Patent No. 56,342,625 suggests the use of solvents such as Glycofurol and Transcutol which are restricted for pharmaceutical use by several regulatory agencies worldwide, including the FDA, because they are not considered "Generally Recognized As Safe" (GRAS) for oral use. Further, with such solvents there is always an added risk of precipitation of the cyclosporin on exposure to gastrointestinal fluids in vivo.

US 6028067 teaches cyclosporin-containing pharmaceutical composition, adapted for oral administration as a microemulsion preconcentrate and comprising a cyclosporin as an active ingredient; a lipophilic solvent chosen from an alkyl ester of polycarboxylic acid and a carboxylic acid ester of polyols; an oil; and a surfactant. It teaches use of refined vegetable oils for improved solubilisation of the drug. Additionally it teaches use of viscosity control agent and antioxidant to provide the composition in gelatinous capsules. Examples of the refined vegetable oils, which are preferable oils of the composition according to the present invention, are super-refined corn oil, borage oil, sesame oil, primrose oil, peanut oil and olive oil, which are on the market as trade name

Super-refined oil (Croda Co.). The more preferable oil that can be used in the composition according to the present invention is the form that the content of high gamma linolenic acid in the oil is increased in more than 50%, and example of that oil is concentrated borage oil of trade name Crossential (Croda Co.). It teaches solubilization effect sufficient for cyclosporin, and also provide advantages that lipophilic solvent neither changes the capsule's appearance nor causes precipitation of the active ingredient cyclospprin, because said lipophilic solvent does not react with gelatin shell of soft capsule and is not volatile. However the solubilization of drug achieved by the oils used in US '067 and solubility rate kinetics study at various time intervals are not very high and neither is the dissolution rate high. Hence the ease of preparation of the composition is less.

US 6063762 teaches cyclosporin-containing microemulsion preconcentrate composition which comprises: a cyclosporin as an active ingredient; a lipophilic solvent chosen from the group consisting of triacetin, triethyl citrate, tributyl citrate, acetyltributyl citrate and acetyltriethyl citrate; an oil; and a surfactant in defined ratio. Examples of the refined vegetable oils, which are preferable oils of the composition according to this invention, are super-refined corn oil, borage oil, sesame oil, primrose oil, peanut oil and olive oil, which are on the market as trade name Super-refined oil (Croda Co.). The more preferable oil that can be used in the composition according to the present invention is the form that the content of high gamma linolenic acid in the oil is increased in more than 50%. Example of that oil is concentrated borage oil of trade name Crossential (Croda Co.). It was identified that the microemulsion preconcentrate using lipophilic solvent instead of hydrophilic solvent can overcome the various problems of prior arts, mainly those of stability of the gelatinous capsules. This composition is characterized in that it dissolves in an external phase such as water, artificial gastric fluid and artificial intestinal fluid by controlling the mixing ratio of the components thereby to get the microemulsion form of inner phase diameter of 100 nm or below. There is no direction that even with use of hydrophilic components the stability could be achieved and high solubility as well low viscosity could be attained wherein the components are in the defined ratio as taught in this art and micoemulsion size is below 100nm. This prior art makes use of the super refined oils alongwith the added antioxidant, US 6551619 teaches vehicle matrix of tri/di glyceride for cyclosporin, glycerol myristate, palmlate, and further stabilizers like ethoxylated lipids. The basic objective of this prior art is to formulate the compositions for the cyclosporine transport through dermis in order to effective topical treatment. The formulation is nanoemulsion in the form of solid lipid nanoparticles.

US 6486124 teaches cyclosporin, PEG monoester and mohohydric and polyhydric alcohols are taught. This prior art makes use of ethanol as solubilizer.. Ethanol is volatile, so that the soft gelatin capsules have to be packaged individually in metallic pouches to prevent evaporation of the ethanol. Ethanol contributes to an undesirable taste of the microemulsion preconcentrate, so that, even after dilution into a sweetened drink, there is still a somewhat unpleasant taste.

New Zealand Patent Application No. 280689 teaches preconcentrate of cyclosporin in solvent system comprising lypophillic solvents like tocol, tocophenol and tocotricenol and specific Vitamin A alongwith hydrophilic solvents and surfactants. This is the microemulsion preconcentrate where the tocol, tocophenol and tocotricenol and specific Vitamin A are externally added to the formulation. Lipophilic solvent such as Vitamin E are relatively expensive.

US 6258783 teaches cyclosporin A alongwith acetylated monoglycerides and surfactant and preferred features include propylene glycol and this art avoids the use of ethanol. It is also mentioned that the preferred surfactant is vegetable oil like castor oil. The present prior art is considering acetylated monoglycerides available from Eastman Chemical Product Inc. under the designations Myvacet 9-08 and Myvacet 9-45. The source for these acetylated monogycerides is hydrogenated coconut oil which has high viscosity and hence difficult to formulate into composition

US 6159933 teaches cyclosporin A, propylene carborate , lipophilic surfactant including mono, di and tri glyceride and surfactant like hydrogenated vegetable oil like castor oil has been taught. The lipophilic solvent, which is mixed mono- di- and tri-glycerides, is relatively expensive. However, it is generally known that mono- and di-glycerides have detergent properties which enhance irritation and damage to tissues. Propylene carbonate is an organic solvent which is needed for the solubilization of cyclosporine. Also propylene carbonate is susceptible degradation by oxidizing agents which may necessitate the formulation to have an antioxidant.

US 6008192 describes binary pharmaceutical compositions comprising drug tacrolimus, a hydrophilic phase and a surfactant provide bioavailability of the active ingredient which is equivalent to that provided by ternary compositions, but without the need for a lipophilic phase.

EP0943327 relates to a pharmaceutical composition comprising a water- insoluble medicinally active substance, tacrolimus, surfactant(s) and solid carrier(s), which has very satisfactory dissolution property, oral absorbability and so on.

US 6248363 provides solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein including tacrolimus or separately administered. In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients, hydrophilic surfactant, lipophilic surfactants and triglycerides. In another embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier being formed of different combinations of pharmaceutical active ingredients, hydrophilic surfactants, lipophilic surfactants and triglycerides.

US 6294192 describes Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents including tacrolimus. US 6451339 describes triglyceride-free pharmaceutical compositions for delivery of hydrophobic therapeutic agents including tacrolimus.

US 6469132 relates Diblock copolymer and use thereof in a micellar drug delivery system for drugs including tacrolimus.

US 6569463 relates solid carriers for improved delivery of hydrophobic active ingredients including tacrolimus in pharmaceutical compositions

US 6923988 relates solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients contained therein or separately administered. In one embodiment, the solid pharmaceutical composition includes a solid carrier, the solid carrier including a substrate and an encapsulation coat on the substrate. The encapsulation coat can include different combinations of pharmaceutical active ingredients including tacrolimus, hydrophilic surfactant, lipophilic surfactants and triglycerides.

US6761903 describes clear oil-containing pharmaceutical compositions containing a therapeutic agent including tacrolimus. US 6267985 describes clear oil-containing pharmaceutical compositions including tacrolimus for improved solubilization of triglycerides and improved delivery of therapeutic agents..

US6761903 describes clear oil-containing pharmaceutical compositions containing a therapeutic agent including tacrolimus.

Thus there is a need to provide stable composition without use of alcohol dimethylisosorbide, transcutol and glycofurol and hence free from associated problems in the formulation, yet solubilizing difficult to solubilize hydrophobic drugs like cyclosporin, tacrolimus and the like and free of additional antioxidant and at the same time providing the required size of microemulsion particle size using an oil which is hitherto not taught to provide stable composition with less viscous oil and higher saturation solubility and hence providing ease of formulation of the preconcentrate.

The inventors have now found a composition comprising hydrophobic drugs with rice oil such that use of a low viscous oil like rice oil which would make the composition with higher saturation solubility and higher stability for defined size of microemulsion and at the same time provide ease of formation of the composition in the form of miucroemulsion with use of hydrophilic phase as well. Further the oryzenol content in the rice oil eliminates the need of added antioxidants making the preconcentrate. Rice oil is a naturally occurring compound which with respect to hydrophobic drugs like cyclosporine, tacrolimus have shown a surprising combination of properties when formed into composition, not found in any other oils in the prior art and achieving the end result of ease of formulation of the compositionand better solubility kinetics of the composition. Unlike the prior art present composition with the rice oil provides additional advantage of not requiring the organic solvent for the solubilization of cyclosporine/tacrolimus along with its antioxidant content or ethanol which distorts the taste and does not require additional antooxidants while providing the

OBJECTS OF THE PRESENT INVENTION

It is an objective of the present invention to provide a stable, self-emulsifying microemulsion preconcentrate formulation and/or microemulsion comprising selective hydrophobic drug without using alcohol and added antioxidants.

A further object is to provide a stable microemulsion preconcentrate formulation comprising selective hydrophobic drug with rice oil such that the composition has higher saturation solubility and hence providing ease of formulation of the preconcentrate wherein the average particle below 100 nm is spontaneously formed. SUMMARY OF THE INVENTION

Thus according to the main aspect of the present invention there is provided an oral pharmaceutical composition comprising about 0.1 to about 25% by weight of comprising selective hydrophobic drug , about 0.5 to about 90% by weight of a lipophilic naturally occurring cosolvent comprising rice oil, about 0.5 to about 90% by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic co-surfactant and about 0.5 to about 90% by weight of a surfactant , wherein the relative proportion of all c comprising selective hydrophobic drug A, hydrophilic components, lipophilic components and surfactants in said composition is such that upon dilution with water to a ratio of 1 part by weight of said composition to 100 parts by weight of water, an oil-in-water microemulsion having average particle size below 100 nm is spontaneously formed.

DETAILED DESCRIPTION OF INVENTION Preferably the composition comprises about 0.1 to about 20% by weight of selective hydrophobic drug , about 3 to about 40% by weight of a lipophilic naturally occurring wetting, solubilizer and stabilizer comprising rice oil, about 3 to about 40% by weight of a lipophilic component, about 5 to about 40% by weight of a hydrophilic co-surfactant and about 10 to about 60% by weight of a surfactant, wherein the relative proportion of selective hydrophobic drug, hydrophilic components, lipophilic components and surfactants in said composition is such that upon dilution with water to a ratio of 1 part by weight of said composition to 100 parts by weight of water, an oil-in-water microemulsion having average particle size below 100 nm is spontaneously formed

The hydrophobic drug is selected from cyclosporine, tacrolimus and the like. The composition is preferably encapsulated in a soft gelatin capsule

The presently developed formulation also offers a formulation for cyclosporin that does not require expensive specialized packaging as against those formulations containing ethanol requiring specialized packaging and storage conditions. Further unlike the prior art compositions with tacrolimus the composition of the present invention include a carrier, where the carrier is formed from a combination of a triglyceride and at least two surfactants, at least one of which is hydrophilic. Upon dilution with an aqueous medium, the carrier forms a clear, aqueous dispersion of the triglyceride and surfactants and rice bran oil which dissolves the drug and adds to ease of formation of the composition. Further present invention relates to pharmaceutical compositions and methods for improved solubilization of triglycerides and improved delivery of therapeutic agents including tacrolimus..

The vegetable oil, namely rice oil of the present invention serves various purposes in that it contains mixture of triglycerides , diglycerides, monoglycerides along with phospholipids which will help to dissolve hydrophobic drug in the formulation thus further helps to improve bioavailability of the drug. It also acts as a powerful wetting agent at the time of manufacturing of preconcentrate thus reducing manufacturing time. The formulation contains rice oil containing naturally occurring antioxidants. Since proposed excipients itself poses antioxidant activity the composition will definitely have extended shelf life. The rice oil is present in the amount of 1 to 20%

The formulation is free of ethanol thus avoiding any induced instability of the soft capsules etc. will be totally nullified in the proposed formulation. The present invention provides a formulation that is designed to have improved bioavailability as compared to conventional formulations, thereby reducing amount of a hydrophilic solvents with minimum number of excipients in the form of microemulsion preconcentrate.

The present formulation provides a stable self-emulsifying preconcentrate and/or a microemulsion in which the poorly water soluble therapeutic agent is substantially soluble in the lipophilic phase, thus eliminating or drastically reducing the need for substantial amounts of a hydrophilic solvent system. The lipophilic naturally occurring wetting agent, solubilizer and stabilizer comprises a vegetable oil comprises antioxidants like Tocopherol, Tocotrienol, Oryzanol; C₁₄-C₂2 mainly Myristic, Palmitic, Stearic, Oleic, Linoleic, Arachidic, Behenic acids and from about 80-85% triglycerides, 1-5 % diglycerides, 3-10% monoglycerides. The vegetable oil is rice bran oil and/or Rice germ oil.

Rice oil is a product obtained from outer brown layers of rice or from germ portion of the grain by milling, utilized for edible as well as non-edible purposes. This oil is used in present invention and contains naturally occurring antioxidants such as Tocopherols, Tocotrienols and Oryzanol. Accordingly there is no need of adding antioxidants externally.

The lipophilic naturally occurring antioxidants used in present invention also helps in wetting of drug at the time of manufacturing of preconcentrate thus substantially reducing time required for manufacturing.

Comparison of other vegetable oil with rice oil is given below Table 2 : Compostion of common vegetable oils :

(SFA : Saturated fatty acid, MUFA : Mono unsaturated fatty acid, PUFA : Poly unsaturated fatty acid) By considering the effect of SFA, MUFA, PUFA levels on various body functions like cholesterol level, heart functioning etc. who has recommended certain level of these components. The recommended level of SFA is below 33% almost all oils mentioned above confirms this criterion. Whereas recommended MUFA level is above 33%. Mustered oil, ground nut oil and RBO fall in this category. The use of ground nut oil and RBO ensures optimal intake of MUFA. Among these three oils mustered oils shows very high percentage whereas Rice bran oil shows optimum amount. Recommended PUFA content is about 33%. Only groundnut and Rice bran oil confirms to this requirement. Recommended Omega6/Omega3 ratio is 5:10. Even though only Soyabean oil is confirming to this criteria but because of very high PUFA content it is quiet unstable towards oxidative degradation. RBO shows optimum level of Omega6/Omega3 ratio in comparison to Mustard oil, Sunflower oil, Safflower oil, Soyabean oil, Groundnut oil. Thus the present composition with RBO has best balance of saturated, monosaturated and polysaturated fats unlike some other examples like marine oils, soyabean oil, corn oil, sunflower seed oil etc. which contains very high level of polyunsaturates.

Rice Oil in the amount used also contains phospholipids as one of the components. Phospholipids because of its emulsification properties will further help in self emulsification of the oil. Thus it contributes for rapid emulsification of the oil.

The composition with rice oil having the natural source of Vitamin E group antioxidants such as Tocopherol, Tocotrienol and Oryzanol oil possess excellent oxidative stability and the composition is substantially free of any added antioxidants.

^' The composition mainly contains Rice Bran Oil/Rice Germ Oil and Oleic acid that is capable of dissolving the hydrophobic drug - cyclosporin. Thus it helps in enhancing the bioavailability of poorly water soluble therapeutic agent while minimizing the inter - and intra-patient or food variability in the bioavailability of the therapeutic agent.

Further the rice oil in the amount used in present composition has low viscosity it is very easy to mix it with other ingredients as compared to other oil like castor oil having very high viscosity. It is particularly important for in-vivo emulsification of preconcentrate hence rapidly forming microemulsion.

The lipophilic component of the composition comprises medium chain triglyceride containing 8-20 carbon atoms fatty acid chains.. And is present in the preferred amount of 1 to 40 %

The hydrophilic co-surfactant is propylene glycol.

The surfactant comprises a reaction product of natural or hydrogenated oil and ethylene oxide, polyethoxylated castor oils, polyethoxylated hydrogenated castor oils, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, Tweens, span.

Thus composition of present invention is free of any added antioxidant, added phospholipids, added alcohol, added viscosity building agent, added colours etc. The invention is now described with reference to following non limiting illustrative examples and figures

Brief Description of Accompanying Figures Figure 1a graphically represents entire patterns of viscosity change of Rice oil and mustard oil.

Figure 1b graphically highlights the clear difference of viscosity values of figure a at initial shear stress values.

Figure 2a graphically represents entire patterns of viscosity change of Rice oil and corn oil.

Figure 2b graphically highlights the clear difference of viscosity values of figure

2a at initial shear stress values. Figure 3a graphically represents entire patterns of viscosity change of Rice oil and ground nut oil.

Figure 3b graphically highlights the clear difference of viscosity values of figure

3a at initial shear stress values. Figure 4a graphically represents entire patterns of viscosity change of Rice oil and sunflower oil.

Figure 4b graphically highlights the clear difference of viscosity values of figure

4a at initial shear stress values.

Figure 5a graphically represents entire patterns of viscosity change of Rice oil and til oil.

Figure 5b graphically highlights the clear difference of viscosity values of figure

5a at initial shear stress values.

Figure 6a graphically represents entire patterns of viscosity change of Rice oil and palmolein oil. Figure 6b graphically highlights the clear difference of viscosity values of figure

6a at initial shear stress values.

Figure 7a graphically represents entire patterns of viscosity change of Rice oil and olive oil.

Figure 7b graphically highlights the clear difference of viscosity values of figure 7a at initial shear stress values.

Figure 8a graphically represents entire patterns of viscosity change of Rice oil and coconut oil.

Figure 8b graphically highlights the clear difference of viscosity values of figure

8a at initial shear stress values. Figure 9a graphically represents entire patterns of viscosity change of Rice oil and kardi oil.

Figure 9b graphically highlights the clear difference of viscosity values of figure

9a at initial shear stress values.

Figure 10a graphically represents entire patterns of viscosity change of Rice oil and soyabean oil.

Figure 10b graphically highlights the clear difference of viscosity values of figure

10a at initial shear stress values. Figure 11 a graphically represents entire patterns of viscosity change of Rice oil and castor oil.

Figure 11 b graphically highlights the clear difference of viscosity values of figure 11a at initial shear stress values. Figure 12 Graphical representation of solubility of cyclosporin in various oils

Figure 13 Graphical representation Saturation solubility of Cyclosporine in vegetable oils

Figure 14 Graphical representation Study of solubility rate kinetics of drug in selected oils Figure 15 Graphical representation of formation of microemulsion with size range below 100nm

EXAMPLE 1

^• The studies were conducted on various vegetable oils namely mustard oil, corn oil, ground nut oil, sunflower oil, til oil, palmolein oil, olive oil, coconut oil, kardi oil, soybean oil, castor oil in order to understand the behaviors of vegetable oil at different shear stress. The viscosity values were studied at different shear stress to select particular oil which will show low viscosity at low shear stress so that it can be used at manufacturing level successfully.

The instrument used for the purpose of determination of viscosity is Haake Rheometer and the data analysed by the Software Rheo Win Pro Job Manager

About 500 mg of oil was placed between the gap of sensor plate and base plate of the instrument. The gap between sensor plate and base plate was adjusted at 1mm.

The shear stress was adjusted from 0 to 50 and time set for the studies was 5 minutes. The graph was generated and the results were analyzed.

Mustard oil shows 0.09808 Pas viscosity at 50 Pa. Whereas comparable viscosity of 0.0988 Pas was achieved with Rice oil at 0.621Pa. Mustard oil shows very high viscosity whereas Rice oil shows very low viscosity at low shear stress values as shown in figures 1 a and 1b

With maximum shear stress of 50 Corn oil shows viscosity of 0.07191 as indicated in figures 2a and 2b. The lowest value achieved by Rice oil at the same shear stress is 0.09523. Even though the viscosity attained by Corn oil is less than Rice oil at shear stress of 0.333 viscosity of Corn oil is 2.251 whereas that of Rice oil is 0.381. Thus at very low shear stress values Rice oil shows rapid drop in viscosity which can be achieved very easily while manufacturing.

At shear stress of 50 groundnut oil shows 0.08527 value which is lower than 0.09523 of Rice oil as indicated in figures 3a and 3b. But at very low shear stress, viscosity fall of Rice oil is very faster than Ground nut oil. ^'

Sunflower oil and Rice oil gives comparable viscosities at all shear rate with slight lower viscosity with rice oil bellow shear stress upto 4 as indicated in figures 4a and 4b.

Til oil shows higher viscosity of about 1.0 till shear stress of 0.435 but Rice oil shows very low viscosities at low shear stress also as indicated in figures 5a and 5b.

The graphs (figures 6a and 6b) clearly show that viscosity attained by Palmolein is very low at higher shear stress values but rapid fall in viscosity is observed with Rice oil at Shear stress.

Rapid fall in the viscosity of Rice oil is observed at increasing shear rate of very low values as compared to Olive oil as indicated in figures 7a and 7b.

The graph clearly shows that rate of fall in viscosity of Rice oil with at low shear rate is very faster than Coconut oil as indicated in figures 8a and 8b. As seen from the graphs(Figures 9a and 9b) the rate of fall in viscosity of Rice oil is very faster than kardi oil.

As seen from the graphs (figures 10a and 10b) the rate of fall in viscosity of Rice oil is very faster than Soyabean Oil.

The lowest viscosity observed with Castor oil was 0.52 Pas at shear stress of 0.37 Pa. At the same shear stress PRV-1 oil shows viscosity of 0.111 Pas. The lowest viscosity value attained by Rice oil were never attained by Castor oil at any very high value of Shear stress as indicated in figures 11a and 11b

Thus it is evident that compared to other vegetacble oils usually used for purpose of solubilizing drugs the rice bran oil has low viscosity and hence it provide better ease of manufacture of composition where the same is used compared to other oils.

Example 2

The solubility of Cyclosporine in various vegetable oils was studied so as to select the components for the Microemulsion formulation. The solubility studies were divided in two parts,

1. Determination of saturation solubility of Cyclosporine in vegetable oils.

2. To study dissolution rate kinetics of drug in selected oils.

1. Determination of saturation solubility of Cyclosporine in vegetable oils. Solubility studies of Cyclosporine was carried out in various marketed vegetable oils. Saturation solubility was measured by adding excess weighed amount of drug (600 mg of Cyclosporine) in weighed vegetable oil (5 gm) in conical flask of 100ml capacity. The samples were subjected for continuous stirring for 48 hrs. The samples were withdrawn at the end of the study and visually observed. The samples were carefully removed and subjected for centrifugation at 10,000 RPM for 20 minutes for separation of oil. The supernatant oil was carefully removed, filtered and then the samples were analyzed for the content of dissolved

Cyclosporine.

2. Study solubility rate kinetics of Cyclosporine in selected oils.

From the results of first part of the study CASTOR OIL and RICE OIL were selected for the excipient selection. The oils were loaded with specified amount of drug (800mg of Cyclosporine) and subjected to stirring as above. Different flasks were kept for different time intervals and they were removed at 1, 5, 15, 30 and 60 min. time intervals. Further remaining flasks were removed at 2, 4, 6, 10, 16, 20 and 24 hrs. They were processed same as above. Visual Observation:

It has been observed that MUSTARD OIL and RICE OIL shows complete wetting of the drug forming fine suspension of drug whereas in remaining oils, excess drug remains as aggregates. Since microemulsion contains various excipients this property will definitely contribute at production level in reducing the time of processing. Since added drug remains uniformly suspended it will result into increased surface area hence it can easily dissolved by other added excipients.

Saturation solubility of Cyclosporine in vegetable oils.

Visual observations of oil samples were further confirmed with experimental evidence and surprisingly we have found that Cyclosporine shows maximum solubility that is 6.0702% w/w in CASTOR OIL and 5.947 % w/w in RICE OIL. Even though MUSTARD OIL shows good wetting of the drug, the saturation solubility was found to be only 3.0740 % w/w. Hence this oil was rejected for further studies.

Study of solubility rate kinetics of drug in selected oils.

Even though any oil shows higher solubility it is necessary that the maximum solubility should be achieved in optimum time frame, which can be practiced at production level. Hence solubility rate kinetics of drug in two oils that is CASTOR OIL and RICE OIL was conducted. The study of solubility rate kinetics of Cyclosporine at specific time intervals proved that rate of solubility of drug in Rice oil is faster than Castor oil. There is very rapid solubilization of drug in Rice oil at the point of addition immediately in 1 minute with 12.29 times faster solubilization than in Castor oil. Whereas at 15 minutes it is 2.45 faster than in Castor oil. The solubility of drug which can be achieved with Rice oil is very faster at the end of I hour thus the solubility pattern which we get by using Rice oil can be easily attained at production level.

Weighed amount of oil (30mg) was mixed with Propylene Glycol and Cremophor RH 40. The resultant mixture was shaken to ensure uniform mixing and allowed to equilibrate for two hours. The formed microemulsions were then diluted with ethanol to 10 ml, then suitably diluted further and injected in the chromatography system.

It is found out that the solubilization of drug achieved by RICE OIL and solubility rate kinetics study at various time intervals are far superior than any other oil studied.

Thus even though saturation solubility of the drug in RICE OIL and CASTOR OIL are very much comparable other parameters contributing to the uniqueness that are very rapid dissolution rate along with its superior suspending capability were far superior to consider RICE OIL as a oil of choice.

The data from Combining the studies from Viscosity measurement and solubility are provided in Table 3 below:

Thus the composition of present invention showed where the drug is dissolved in the rice bran oil, other components remaining name shows better attributes namely better dissolution rate and uniform suspension so that the manufacture of the formulation is easier.

Example 3

The average size of the particles in the micro emulsion was tested to confirm whether the composition form microemulsion. Compositions are prepared according to formulations 1 , 2 and 3 which are within the range according to present invention

Formulation 1

Cyclosporine 10%

Rice oil 6%

Propylene glycol 24%

Medium chain triglyceride 12% Cremophore 40 48%

Formulation 2

Cyclosporine 10%

Rice oil 12%

Propylene glycol 21%

Medium chain triglyceride 12%

Cremophor 40 45°/

Formulation 3

Cyclosporine 10%

Rice oil 10%

Propylene glycol 24% Medium chain triglyceride 10% Cremophor 40 46% It was found that the compositions with components with the amounts as in present invention formed microemulsion with average particle size of below 100 nm. The same is evident from figure 15 which represents formulation 1. This microemulsion had better stability and ease of production than those with higher particle size

Example 4

Various formulations were tested keeping the components as in present invention and varying oil in the composition. Formulation 1 has composition according to present invention with cyclosporine while formulations 4 and 5 have similar composition except other oils (castor oil and sunflower oil) are used

Formulation 1

Cyclosporine 10%

Rice oil 6%

Propylene glycol 24%

Medium chain triglyceride 12% Cremophore 40 48%

Formulation 4

Cyclosporine 10%

Castor oil 6%

Propylene glycol 24%

Medium chain triglyceride 12% Cremophore 40 48%

Formulation 5

Cyclosporine 10%

Sunflower oil 6%

Propylene glycol 24%

Medium chain triglyceride 12% Cremophor 40 48% It is found that spontaneous microemulsion preconcentrate is formed only with Rice oil of amount according to present invention as provided in formulation 1.

The other oils however face problems of higher globule size, not forming a clear preconcentrate, and gelling of cyclosporine in oil leading to its incomplete solubilization.

If the viscosity of the oils for example caster oil is very high it poses the problem of solubilizing the drug as the initial wetting of the drug is very difficult and time consuming. Also low viscosity oil such as sunflower oil is incapable of solubilizing the drug completely.

Example 5 A composition according to present invention is prepared with tacrolimus ( from the same category of immunosupressants as cyclosporine )also forms miroemulsion preconcentrate with the similar ease of preparation.

Formulation 6

Tacrolimus 2.22%

Rice oil 13.33%

Propylene glycol 22.22%

Medium chain triglyceride 17.77% Cremophor 40 44.44%

It is found that spontaneous microemulsion preconcentrate is formed. This composition is such that upon dilution with water to a ratio of 1 part by weight of said composition to 100 parts by weight of water, an oil-in-water microemulsion having average particle size belowl OO nm is spontaneously formed.

Claims

1. An oral pharmaceutical composition comprising about 0.1 to about 25% by weight of selective hydrophobic drug , about 0.5 to about 90% by weight of a lipophilic naturally occurring wetting agent, solubilizer and stabilizer comprising rice oil, about 0.5 to about 90% by weight of a lipophilic component, about 0.5 to about 90% by weight of a hydrophilic co- surfactant and about 0.5 to about 90% by weight of a surfactant, wherein the relative proportion of selective hydrophobic drug, hydrophilic components, lipophilic components and surfactants in said composition is such that upon dilution with water to a ratio of 1 part by weight of said composition to 100 parts by weight of water, an oil-in-water microemulsion having average particle size below 100 nm is spontaneously formed.

2. A composition as claimed in claim 1 comprising about 0.1 to about 20% by weight of selective hydrophobic drug, about 3 to about 40% by weight of a lipophilic naturally occurring wetting, solubilizer and stabilizer comprising rice oil, about 3 to about 40% by weight of a lipophilic component, about 5 to about 40% by weight of a hydrophilic co-surfactant and about 10 to about 60% by weight of a surfactant, wherein the relative proportion of selective hydrophobic drug, hydrophilic components, lipophilic components and surfactants in said composition is such that upon dilution with water to a ratio of 1 part by weight of said composition to 100 parts by weight of water, an oil-in-water microemulsion having average particle size below 100 nm is spontaneously formed

3. A composition as claimed in claim 1to 2 the hydrophobic drug is selected from cyclosporine, tacrolimus and the like.

4. A composition as claimed in any preceding claim wherein lipophilic wetting agent, solubilizer and stabilizer comprising rice oil has antioxidants selected from Tocopherol, Tocotrienol and Oryzanol and no added antioxidant

5. A composition as claimed in any preceding claim wherein the lipophilic component comprises of medium chain triglyceride containing 8-20 carbon atoms

6. A composition as claimed in any preceding claim wherein the hydrophilic co-surfactant is propylene glycol.

7. A composition as claimed in any preceding claim wherein the surfactant comprises a reaction product of natural or hydrogenated oil and ethylene oxide, polyethoxylated castor oils, polyethoxylated hydrogenated castor oils, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, Tweens_r span.

8. A composition as claimed in any preceding claim wherein the composition is in form of oral solution and gelatin capsule.