EP1848407A2 - Composition pharmaceutique orale - Google Patents

Composition pharmaceutique orale

Info

Publication number
EP1848407A2
EP1848407A2 EP06780508A EP06780508A EP1848407A2 EP 1848407 A2 EP1848407 A2 EP 1848407A2 EP 06780508 A EP06780508 A EP 06780508A EP 06780508 A EP06780508 A EP 06780508A EP 1848407 A2 EP1848407 A2 EP 1848407A2
Authority
EP
European Patent Office
Prior art keywords
oil
composition
weight
lipophilic
surfactant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06780508A
Other languages
German (de)
English (en)
Inventor
Vijaya Kumar Medicap Ltd. 384 Soi 6 VELIDI
Chancharusiri Medicap Ltd. 384 Soi 6 APICHAI
Snehal Mukund Medicap Ltd. 384 Soi 6 MEHTA
Wongpayak Medicap Ltd. 384 Soi 6 PORNCHAI
Madhav Pai Medicap Ltd. 384 Soi 6 RAJESH
Torane S. Mumbai Uni. Inst. Chem. Tech. JYOTSNA
R. V. Mumbai Uni. Inst. Chem. Tech. PRADEEP
Satyen Univ.Dept.of Chemical Technology TORNE
Shankar Uni.Dept.of Chemical Technology SWAMINATHAN
Aradee Kunchom
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mega Lifesciences Pvt Ltd
Original Assignee
Mega Lifesciences Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mega Lifesciences Pvt Ltd filed Critical Mega Lifesciences Pvt Ltd
Publication of EP1848407A2 publication Critical patent/EP1848407A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins

Definitions

  • the present invention relates to oral pharmaceutical composition
  • 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.
  • 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.
  • cyclosporin soft capsule contains a large amount of ethanol as a co-surfactant in order to solubilize the cyclosporin.
  • 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.
  • 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.
  • 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.
  • SFA Saturated fatty acids
  • PUFA polyunsaturated fatty acids
  • MUFA mono unsaturated fatty acids
  • SFA Saturated fatty acids
  • 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.
  • the third type, oleic acid 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • GRAS Generally Recognized As Safe
  • 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.
  • 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.
  • a surfactant in defined ratio.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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
  • compositions with tacrolimus 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.
  • the carrier 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.
  • 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; C 14 -C 2 2 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.
  • SFA Saturated fatty acid
  • MUFA Mono unsaturated fatty acid
  • PUFA Poly unsaturated fatty acid
  • 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.
  • 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.
  • Rice Bran Oil/Rice Germ Oil and Oleic acid that is capable of dissolving the hydrophobic drug - cyclosporin.
  • 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.
  • composition of present invention is free of any added antioxidant, added phospholipids, added alcohol, added viscosity building agent, added colours etc.
  • 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 3a graphically represents entire patterns of viscosity change of Rice oil and ground nut oil.
  • Figure 4a graphically represents entire patterns of viscosity change of Rice oil and sunflower oil.
  • Figure 5a graphically represents entire patterns of viscosity change of Rice oil and til oil.
  • 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
  • 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 9a graphically represents entire patterns of viscosity change of Rice oil and kardi oil.
  • Figure 10a graphically represents entire patterns of viscosity change of Rice oil and soyabean oil.
  • 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
  • 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
  • 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
  • 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 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.
  • 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.
  • 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.
  • solubility rate kinetics of Cyclosporine at specific time intervals proved that rate of solubility of drug in Rice oil is faster than 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.
  • 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.
  • compositions are prepared according to formulations 1 , 2 and 3 which are within the range according to present invention
  • 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
  • oils for example caster oil 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.
  • 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.

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Abstract

La présente invention concerne une composition pharmaceutique orale comprenant d'environ 0,1 à environ 25% en poids d'un médicament hydrophobe sélectif, d'environ 0,5 à environ 90% en poids d'un agent mouillant naturel, d'un agent de solubilisation et d'un stabilisant comprenant de l'huile de riz, d'environ 0,5 à environ 90% en poids d'un composant lipophile, d'environ 0,5 é environ 90% en poids d'un co-tensioactif hydrophile et d'environ 0, 5 à environ 90% en poids d'un tensioactif. La proportion relative de médicament hydrophobe sélectif, de composants hydrophiles, de composants lipophiles et de tensioactifs dans la composition susmentionnée est telle qu'à dilution avec de l'eau selon un rapport d'une partie en poids de la composition pour 100 parties en poids d'eau, une micro-émulsion huile dans l'eau présentant une taille particulaire moyenne inférieure à 100 nm se forme spontanément.
EP06780508A 2005-02-02 2006-02-01 Composition pharmaceutique orale Withdrawn EP1848407A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN104MU2005 2005-02-02
PCT/IN2006/000042 WO2006123354A2 (fr) 2005-02-02 2006-02-01 Composition pharmaceutique orale

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EP1848407A2 true EP1848407A2 (fr) 2007-10-31

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US9486408B2 (en) 2005-12-01 2016-11-08 University Of Massachusetts Lowell Botulinum nanoemulsions
CN101848702B (zh) 2006-12-01 2013-07-17 安特里奥公司 两亲实体纳米粒子
TW200932240A (en) * 2007-10-25 2009-08-01 Astellas Pharma Inc Pharmaceutical composition containing lipophilic substance which inhibits IL-2 production
WO2009121069A2 (fr) * 2008-03-28 2009-10-01 University Of Massachusetts Compositions et procédés de préparation de nanoémulsions
EP2308468A1 (fr) 2009-10-08 2011-04-13 Novaliq GmbH Nouvelle composition pharmaceutique comportant un médicament contre l'immunosuppression macrolide
EP3541358A1 (fr) 2016-11-21 2019-09-25 Eirion Therapeutics, Inc. Administration transdermique de grands agents
WO2020056191A1 (fr) 2018-09-13 2020-03-19 Eirion Therapeutics, Inc. Utilisations d'inhibiteurs de l'inhibiteur de l'activateur du plasminogène 1 (pai-1)

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