EP0671937A1 - Compositions pour emulsions pharmaceutiques - Google Patents

Compositions pour emulsions pharmaceutiques

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Publication number
EP0671937A1
EP0671937A1 EP93923918A EP93923918A EP0671937A1 EP 0671937 A1 EP0671937 A1 EP 0671937A1 EP 93923918 A EP93923918 A EP 93923918A EP 93923918 A EP93923918 A EP 93923918A EP 0671937 A1 EP0671937 A1 EP 0671937A1
Authority
EP
European Patent Office
Prior art keywords
medium
composition
chain fatty
fatty acyl
oil
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Withdrawn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
EP93923918A
Other languages
German (de)
English (en)
Other versions
EP0671937A4 (fr
Inventor
Panayiotis Pericleous Constantinides
Seang Huoth Yiv
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.)
Affinity Biotech Inc
SmithKline Beecham Corp
Original Assignee
Affinity Biotech Inc
SmithKline Beecham Corp
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 Affinity Biotech Inc, SmithKline Beecham Corp filed Critical Affinity Biotech Inc
Publication of EP0671937A1 publication Critical patent/EP0671937A1/fr
Publication of EP0671937A4 publication Critical patent/EP0671937A4/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Withdrawn legal-status Critical Current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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/23—Calcitonins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • 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

Definitions

  • This invention relates to pharmaceutical compositions in the form of water-in-oil (w/o) self-emulsifying microemulsions, processes for their preparation and their use.
  • Microemulsions can be defined in general as thermodynamically stable, isotropically clear dispersions of two immiscible liquids stabilized by interfacial films of surface-active molecules.
  • the formation of microemulsions usually involves a combination of three to five components, namely, ; ; ; oil, water, a surfactant, a cosurfactant and an electrolyte.
  • the tendency to form either a water-in-oil (w/o) or an oil-in-water (o/w) microemulsion is influenced by the properties of the oil and the surfactant.
  • HLB hydrophilic-lipophilic balance
  • the surfactant should preferably exhibit low solubility in both the oil and water phases, and be preferentially absorbed at the water-oil interface with concomitant lowering of interfacial tension.
  • interfacial tension is less than 2 x 10-2 dyn/cm, a stable microemulsion can form.
  • Microemulsions are typically substantially non-opaque, that is they are transparent or opalescent when viewed by optical microscopic means. In the undisturbed state, they are optically isotropic (non-birefringent) when examined under polarized light.
  • the dispersed phase typically comprises particles or droplets which are normally between 5 and
  • co-surfactant usually a short-chain alcohol
  • the role of the co-surfactant is to increase the interfacial fluidity by penetrating the surfactant film and consequently creating a disordered film due to the void space among surfactant molecules.
  • the use of a co-surfactant in microemulsions is however optional and alcohol-free self-emulsifying emulsions and microemulsions have been described in the literature (see for instance, Pouton et al., Int. Journal of Pharmaceutics, 27, 335-348, 1985 and Osborne et al., J. Disp. Sci. Tech., 9, 415-423, 1988).
  • Microemulsions form spontaneously, without the need for a high input of energy and are therefore easy to prepare and scale up for commercial applications; they have thermodynamic stability due to their small particle size and therefore have a long shelf life; they have an isotropically clear appearance so that they may be monitored by spectroscopic means; they have a relatively low viscosity and are therefore easy to transport and mix; they have a large interfacial area which accelerates surface reactions; they have a low interfacial tension which permits flexible and high penetrating power and, lastly, they offer the possibility of improved drug solubilization and protection against enzymatic hydrolysis.
  • microemulsions may undergo phase inversion upon addition of an excess of the dispersed phase or in response to a temperature change and this is a property of these systems that can affect drug release from microemulsions both in vitro and in vivo. The reasons for this improved drug delivery are not however well understood.
  • lipid-based microemulsions to enhance the bioavailability of different drugs, including peptides.
  • GB 2222770-A (Sandoz Ltd) describes microemulsions and corresponding microemulsion "pre-concentrates" for use with the highly hydrophobic cyclosporin peptides.
  • a suitable pre-concentrate comprises 1,2-propylene glycol as the hydrophilic component, a caprylic-capric acid triglyceride as the lipophilic component and a mixture of a polyoxyethylene glycolated hydrogenated castor oil and glycerin monooleate (ratio 11 : 1 ) as the surf actant-cosurfactant
  • Such formulations may then be diluted with water, to give oil-in-water rather than water-in- oil microemulsions.
  • GB 2098 865A (Sandoz Ltd) describes topical compositions in the form of microemulsions comprising a water-immiscible organic solvent, an emulsifier, a co- emulsifier, water and a (non-peptide) therapeutic agent. These formulations are said to have improved skin penetrating properties.
  • Suitable organic solvents include mono- or diesters of glycerol with a (C6-22) carboxylic acid, such as glyceryl caprylate (which may also act as a co-emulsifier).
  • US 4712239 (Muller et al.) describes multi-component systems for pharmaceutical use comprising an oil, a nonionic surfactant with an HLB value above 8 and a co-surfactant which is a partial ether or ester of a polyhydroxyl alcohol and a (C6-22) fatty alcohol or acid, which components form a "single phase" on mixing.
  • the special properties of the system are attributed to the particular blend of surfactant and co-surfactant selected.
  • An aqueous phase is an optional extra and the therapeutic agent may be lipophilic or hydrophilic. Such systems are said to give enhanced transdermal delivery characteristics.
  • one (example 1, formulation I) has PEG (20 EO)-oleic acid glycerol partial esters (40%), caprylic-capric acid glycerol partial esters (42% monoglyceride, 24%), medium-chain triglycerides (16%) and water (20%).
  • GB 1 171 125 (Glaxo Laboratories Ltd.) describes microemulsions comprising a hydrophilic oil, a blend of low and high HLB surfactants and an aqueous phase, for use as injectable preparations.
  • example 15 thereof contains in the lipophilic phase a mixture of coconut oil and sorbitan monooleate. The patent is concerned with improved formulations and is silent on bioavailability.
  • WO 88/00059 discloses controlled release compositions for biologically active materials comprising an "L2-phase” and containing an unsaturated (C16-22)-fatty acyl monoglyceride and an unsaturated (C 16-22)-f atty acyl triglyceride, in a ratio of from 1 : 1 to 3:1, and a polar liquid such as water.
  • an unsaturated (C16-22)-fatty acyl monoglyceride is a low HLB surfactant.
  • the present invention provides a pharmaceutical composition comprising:
  • a surfactant system comprising a mixture of high and low HLB surfactants in which the high HLB surfactant is a medium-chain fatty acid salt optionally admixed with a non- ionic high HLB surfactant;
  • composition upon admixing forms a stable, self-emulsifying, water-in-oil (w/o) microemulsion.
  • Figure 1 Illustrates a pseudo-ternary phase diagram of a system comprising (1) an oil and a second low HLB surfactant in a fixed ratio X, (2) an aqueous phase and (3) a free fatty acid and fatty acid salt in a fixed ratio Y.
  • Figure 2 Illustrates a pseudo-ternary phase diagram of the system comprising
  • Figure 3 Illustrates a pseudo-ternary phase diagram of the system comprising CAPTEX 8000 and CAPMUL C8 (ratio 2:1), caprylic acid and sodium caprylate (ratio 3:1) and de-ionized water.
  • Figure 4 Illustrates a pseudo-ternary phase diagram of the system comprising
  • FIG. 5 Illustrates a pseudo-ternary phase diagram of the system comprising
  • FIG. 6 Illustrates a pseudo-ternary phase diagram of the system comprising
  • Figure 7 Illustrates a pseudo-ternary phase diagram of the system comprising CAPTEX 200, IMWTrOR 308 (ratio 4.5: 1 ), caprylic acid and sodium caprate (ratio 2.5:1) and saline.
  • the present invention comprises a pharmaceutical composition which has
  • a surfactant system comprising a mixture of high and low HLB surfactants in which the high HLB surfactant is a medium-chain fatty acid salt optionally admixed with a non-ionic high HLB surfactant;
  • a surfactant system comprising a mixture of high and low HLB surfactants in which the high HLB surfactant is a medium-chain fatty acid salt optionally admixed with a non-ionic high HLB surfactant;
  • an aqueous hydrophilic phase comprising a mixture of high and low HLB surfactants in which the high HLB surfactant is a medium-chain fatty acid salt optionally admixed with a non-ionic high HLB surfactant.
  • useful (w/o) microemulsions may be prepared having a lipophilic phase which is either a mixture of a medium-chain fatty acyl triglyceride oil and a low HLB surfactant which is a medium-chain fatty acyl mono- or di- glyceride or a mixture thereof (Constantinides, P., WO93/02664, published 18 February 1993) or a mixture of a long-chain fatty acyl triglyceride oil and a low HLB surfactant which is a long-chain fatty acyl mono- or di-glyceride or a mixture thereof or a sorbitan long-chain fatty acyl ester (Constantinides, P., WO93/02665, published 18 February
  • microemulsions also included a high HLB surfactant which is a conventional non-ionic surfactant such as TWEEN 80.
  • microemulsion of a medium-chain fatty acid salt has unexpectedly been found to further enhance the absorption of a biologically active agent when administered in formulations according to the invention.
  • medium-chain refers to a fatty acyl chain having from 6 to 12, preferably 8 to 10 carbon atoms which may be branched or unbranched, preferably unbranched and which may be optionally substituted.
  • long-chain refers to a fatty acyl chain which may be saturated, mono-unsaturated or poly-unsaturated, having from 14 to 22, preferably 16 to 18 carbon atoms which may be branched or unbranched, preferably unbranched, and which may be optionally substituted.
  • Suitable oils for use in the lipophilic phase are those oils which are pharmaceutically acceptable and include fatty acyl triglycerides (fatty acyl triesters of glycerol), fatty acyl diesters of propylene glycol and mixtures thereof.
  • the fatty acyl moieties may be of medium-chain length or of long-chain length fatty acyl moieties or may be mixtures thereof.
  • Suitable fatty acyl triglycerides and fatty acyl diesters of propylene glycol for use in the present invention may be of natural, semi-synthetic or synthetic origin and may include blends of different fatty acyl triglycerides and or fatty acyl diesters of propylene glycol.
  • Such blends include not only physical blends of medium- and long-chain fatty acyl triglycerides and/or diesters but also triglycerides and/or diesters which have been chemically modified, by for instance, interesterification, to include a mixture of medium- and long-chain fatty acyl moieties.
  • Suitable such triglycerides and diesters are readily available from commercial suppliers.
  • the fatty acid composition comprises caprylic (C ⁇ ) acid optionally admixed with capric (Cio) acid, for instance from 50 to 100% (w/w) of caprylic acid and from 0 to 50% (w/w) of capric acid triglycerides.
  • Suitable examples include those available under the trade names MYRTTOL; CAPTEX
  • MIGLYOL (BASF), for instance the grades MIGLYOL 810, MIGLYOL 812 and MIGLYOL 818 (which also comprises a linoleic acid triglyceride) and MAZOL 1400 (Mazer Chemical, Gumee, II.).
  • MIGLYOL BASF
  • MIGLYOL 810, MIGLYOL 812 and MIGLYOL 818 which also comprises a linoleic acid triglyceride
  • MAZOL 1400 Mel Chemical, Gumee, II.
  • Suitable long-chain fatty acid triglycerides may be conveniently obtained from neutral plant, vegetable and fish oils such as shark oil, coconut oil, palm oil, olive oil, sesame oil, peanut oil, castor oil, safflower oil, sunflower oil and soybean oil, which oils may be in their natural state or partially or fully hydrogenated.
  • Soybean oil consists of oleic acid (25%), linoleic acid (54%), linolenic acid (6%), palmitic acid (11%) and stearic acid (4%) triglycerides while safflower oil consists of oleic acid (13%), linoleic acid (76%), stearic acid (4%) and palmitic acid (5%) triglycerides.
  • the major fatty acid components are Ci8-saturated, monounsaturated or polyunsaturated fatty acids, preferably Ci 8-monounsaturated or polyunsaturated fatty acids, such as oleic, linoleic and linolenic acid.
  • triglycerides include interesterified triglycerides which may be derived synthetically by chemically reacting blends of medium- and long-chain triglycerides, for instance triglycerides containing caprylic and capric acid moieties and vegetable oils rich in oleic or linoleic acids.
  • Suitable such interesterified triglycerides include the products available from Karlshams Lipid Specialties, as CAPTEX 810A - D and 910A - D, which typically contain from 30 to 80% capric and caprylic acids, 10 to 50% linoleic acid (810 series) or 10 to 60% oleic acid plus up to 5% linoleic acid (910 series), and up to 25% of other acids.
  • Suitable fatty acyl diesters of propylene glycol include medium- and long-chain fatty acyl diesters.
  • the diester is formed from medium-chain fatty acids, more preferrably from caprylic and capric acids, most preferrably from caprylic acid.
  • Preferred diesters comprise from about 50 to 100% caprylic acid and from 0 to 50% capric acid.
  • a suitable thereof is the product CAPTEX 200 (Karlshams Lipid Specialties) which comprises caprylic acid (68%), capric acid (27%) and caproic acid (4%) (manufacturer's data).
  • Suitable medium-chain fatty acid salts will be pharmaceutically acceptable water- soluble salts, for instance alkali metal salts, such as sodium and potassium salts, or ammonium or quaternary ammonium salts.
  • the salt is a salt of caprylic or capric acid, of which the salts sodium caprylate and sodium caprate are preferred.
  • Sodium caprylate and sodium caprate have estimated HLB values of 23 and 21 respectively.
  • the salt form has an HLB value in the range of 20 to 25.
  • Suitable non-ionic high HLB surfactants include: (a) polyoxyethylene fatty acyl esters, for example polyoxyethylene stearic acid esters of the type available under the trade name MYRJ (ICI Americas, Inc.), for instance the product MYRJ 52 (a polyoxyethylene 40 stearate);
  • polyoxyethylene-sorbitan fatty acid esters for example the mono- and tri-lauryl, palmityl, stearyl and oleyl esters, for instance the polyoxyethylene sorbitan monooleates available under the trade name of TWEEN (ICI Americas Inc.), such as TWEEN 20, 21, 40, 60, 61, 65, 80, 81 and 85, of which class TWEEN 80 is especially preferred;
  • polyoxyethylene glycol long-chain alkyl ethers such as polyoxyethylated glycol lauryl ether
  • polyoxyethylene glycol long-chain alkyl esters such as PEG-monostearate.
  • the non-ionic high HLB surfactant preferably has an HLB value in the range of 13 to 20.
  • a non-ionic high HLB surfactant may be usefully included as an auxiliary high HLB surfactant to produce microemulsions which can solubilize a larger amount of aqueous phase.
  • Such microemulsions are, however, generally comparatively more viscous than those in which the non-ionic high HLB surfactant is absent.
  • the ratio of the fatty acid salt to the non-ionic high HLB surfactant is at least 1:1.
  • Suitable low HLB surfactants for use in the present invention include fatty acyl monoglycerides, fatty acyl diglycerides, sorbitan long-chain fatty acyl esters and medium- chain free fatty acids, as well as mixtures thereof.
  • Suitable mono- and di-glycerides may each include blends of different fatty acyl mono- and di-glycerides and the fatty acyl moieties may be medium- or long-chain or a mixture thereof.
  • Suitable medium chain fatty acyl mono- and di-glycerides are formed from caprylic and capric acids.
  • Suitable blends comprise from about 50 to 100% caprylic acid and from
  • capric acid 0 to 50% capric acid.
  • Mixtures of mono-and di-glycerides preferably comprise at least 50, more preferably at least 70% by weight of monoglycerides.
  • Suitable commercial sources of these include the products available under the trade name CAPMUL (Karlsham Lipid Specialties), for instance the products CAPMUL MCM which comprises monoglycerides (77%), diglycerides (21%) and free glycerol (1.6%), with a fatty acid composition which comprises caproic acid (3%), caprylic acid (67%) and capric acid (30%) and CAPMUL C% which has monoglycerides (70 - 90%), diglycerides (10 - 30%) and free glycerol (2 - 4%), with a fatty acid composition which comprises at least 98% caprylic acid (manufacturer's data for Capmul products is expressed as oleates; actual C8/10 mono- and diglyceride content of about 45%, respectively).
  • the low HLB surfactant contains a mixture of mono- and diglycerides having at least about 80% by weight, preferably at least about 90% by weight, and more preferably at least about 95% by weight of a caproic, caprylic, capric monoglyceride or mixtures thereof, preferably a caproic, caprylic, capric monoglyceride or mixtures thereof, more preferably a caprylic, capric monoglyceride or mixtures thereof.
  • surfactants include Imwitor 308 (Huls America, Inc.) which has about 80-90% wt caprylic monoglycerides; and Glycerol Monocaprylin, manufactured as 1-monoctanoyl-rac-glycerol (Sigma
  • Suitable long-chain fatty acyl monoglycerides include glycerol monooleate, glycerol monopalmitate and glycerol monostearate.
  • Suitable commercially available examples of such include the products available under the trade names MYVEROL, such as MYVEROL 18-92 (a sunflower oil monoglyceride) and 18-99 (a rapeseed oil monoglyceride), MYVATEX and MYVAPLEX, respectively, from Eastman Kodak Chemicals, Rochester, New York.
  • a further useful long-chain fatty acyl monoglyceride-containing product is ARLACEL 186 (available from IQ Americas Inc.) which includes, in addition to glycerol monooleate, propylene glycol (10%).
  • the main fatty acids of MYVEROL 18-92 are oleic acid (19%), linoleic acid (68%) and palmitic acid (7%) while those of MYVEROL 18-99 are oleic acid (61%), linoleic acid (21%), linolenic acid (9%) and palmitic acid (4%).
  • the major fatty acid component is a Ci 8- saturated, monounsaturated or polyunsaturated fatty acid, preferably a Ci8- monounsaturated or polyunsaturated fatty acid.
  • diacetylated and disuccinylated versions of the monoglycerides such as the product available under the trade name MYVATEX SMG are also useful.
  • Suitable sorbitan long-chain fatty acyl esters for use in the present invention include sorbitan monooleate, available commercially under the trade names SPAN 80 and ARLACEL 80 and sorbitan sesquioleate, available commercially under the trade names SPAN 83 and ARLACEL 83.
  • Suitable medium-chain fatty acids for use in the present invention include caprylic and capric acids and mixtures thereof.
  • microemulsions of the present invention comprise a medium-chain fatty acid salt and a medium-chain fatty acid which is preferably the corresponding free fatty acid, as herein before defined.
  • Suitable combinations include sodium caprylate/caprylic acid and/or sodium caprate/capric acid.
  • the ratio of free fatty acid to fatty acid salt is in the range of from about 10: 1 to 1: 1, more suitably from about 4: 1 to 1: 1.
  • the surfactant system also comprises, in addition to the free fatty acid, a further (second) low HLB surfactant, such as a fatty acyl monoglyceride, fatty acyl diglyceride, mixture of mono- and di-glycerides or a sorbitan long-chain fatty acyl ester, preferably a fatty acyl monoglyceride, as hereinbefore defined.
  • a further (second) low HLB surfactant such as a fatty acyl monoglyceride, fatty acyl diglyceride, mixture of mono- and di-glycerides or a sorbitan long-chain fatty acyl ester, preferably a fatty acyl monoglyceride, as hereinbefore defined.
  • the low HLB surfactant will have an HLB value in the range of about 2.5 to 8.
  • the HLB values of the products CAPMUL MCM, MYVEROL 18-99, ARLACEL 80, ARLACEL 83 and ARLACEL 186 are respectively about 5.5 to 6, 3.7, 4.3, 3.7 and 2.8 while the HLB of caprylic and capric acids are 5.8 and 4.8 respectively.
  • the estimated HLB of 1-monocaprylin is about 8.0.
  • the blend of the high and low HLB surfactants will preferably have an HLB value in the range of from about 5 to 14, preferably 7 to 13.
  • microemulsions comprise medium-chain fatty acyl components, such as those derived from caprylic and capric acids, especially those derived from caprylic acid.
  • preferred microemulsions include blends of CAPTEX 355, 810, CAPTEX 8000 or CAPTEX 200, particularly CAPTEX 8000; CAPMUL MCM or CAPMUL C8, particularly CAPMUL C$; and caprylic acid/sodium caprylate and/or capric acid/sodium caprate, particularly caprylic acid/sodium caprylate.
  • biologically active material refers not only compounds which have use as therapeutic and/or prophylactic agents (hereinafter referred to as "drugs") but also compounds which may be of use as diagnostic agents. Such materials will be soluble in the hydrophilic phase and have an HLB value of at least that of the high HLB surfactant(s) used in the formulation, to ensure that the drug is preferentially dissolved in the hydrophilic rather than the lipophilic phase. Such materials include both peptides and non-peptides. Suitable peptides include not only small peptides but also larger peptides/polypeptides and proteins.
  • Suitable such peptides preferably have a molecular weight from about 100 to 10,000, more preferably from about 100 to about 6,000. Especially preferred are peptides having from 2 to 35 amino acid moieties. Higher molecular weight peptides, even those with a molecular weight of above 10,000, up to about 50,000, may also be accommodated in microemulsions of the present invention.
  • Suitable small peptides have from about 2 to about 10, more preferably from about 2 to about 6 amino acid moieties.
  • Preferred small peptides include the fibrinogen receptor antagonists (RGD containing peptides) which are tetrapeptides with an average molecular weight of about 600. These peptide antagonists are highly potent platelet aggregation inhibitors at plasma levels as low as 1 pmol ml.
  • Preferred fibrinogen antagonists include the peptide cyclo(S,S)-Na-acetyl-Cys-(Na-methyl)Arg-Gly-Asp-Pen-NH2 (Ali et al., EP 0341 915, whose disclosure is herein incorporated by reference in its entirety) and the peptide cyclo(S,S)-(2-mercapto)benzoyl-(Na-methyl)Arg-Gly-Asp-(2-mercapto)- phenylamide (EP 0423212, whose disclosure is herein incorporated by reference in its entirety).
  • fibrinogen antagonists useful in the present invention are those peptides disclosed by Pierschbacher et al., WO 89/05150 (US/88/04403); Marguerie, EP 0275748; Adams et al., U.S. 4,857,508; Zimmerman et al., U.S.
  • the RGD peptide may be usefully included in the microemulsion formulation in an amount up to about 400mg g of the hydrophilic phase or from 0.1 to 40 mg/g of the formulation.
  • peptides useful in the present invention include, but are not limited to, other RGD containing peptides such as those disclosed by Momany, US 4,411,890 and US 4,410,513; Bowers et al., US 4,880,778, US 4,880,777, US 4,839,344; and WO
  • Suitable peptides include hexapeptides such as the growth hormone releasing peptide (GHRP) His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 , (Momany, US 4,411,890) and related analogs or homologs thereof, such as but not limited to, His-D-Phe-Ala-D-Phe-Lys- Gln-Gly-NH2, Hong et al., USSN 07/951500 the disclosure of which are herein incorporated by reference in their entirety). This may usefully be included in an amount up to about 250mg/g of the hydrophilic phase or from 0.1 to 25mg/g of the formulation.
  • GHRP growth hormone releasing peptide
  • Suitable larger polypeptides and proteins for use in microemulsions of the present invention include insulin, calcitonin, elcatonin, calcitonin-gene related peptide somatostatin such as porcineor bovine as well as analogs and homologs thereof of these peptides and proteins.
  • Other suitable larger polypeptides include those disclosed by Pierschbacher et al., US 4,589,881 (>30 residues); Bittle et al., US 4,544,500 (20-30 residues); and Dimarchi et al., EP 0204480 (>34 residues).
  • analogs or homologs of LHRH which display potent LH releasing activity or inhibit the activity of LHRH
  • analogs or homologs of HP5 which possesses hematopoietic activity
  • analogs or homologs of endothelin which possess hypotensive activity
  • analogs or homologs of enkephalin which have antinociceptive activity
  • analogs or homologs of chlorecystokinin analogs or homologs of cyclosporin A which have immunosuppressive activity
  • analogs or homologs of atrial natriuretic factor analogs or homologs of atrial natriuretic factor
  • peptidergic antineoplastic agents analogs or homologs of gastrin releasing peptide
  • analogs or homologs of somatostatin gastrin antagonists
  • bradykinin antagonists neurotensin antagonists; bombesin antagonists; oxytocin ' agonists and antagonists; vasopressin agonists and
  • suitable drugs include non-peptide therapeutic agents such as antibiotics, antimicrobial agents, antineoplastic agents, cardiovascular and renal agents, anti- inflammatory, immunosuppressive and immunostimulatory agents and CNS agents.
  • the drug is a peptide such as a fibrinogen receptor antagonist peptide (an RGD peptide), GHRP (His-D-Trp-Ala-Trp-D-Phe-Lys-NH2), a vasopressin, a calcitonin or an insulin, more preferably the fibrinogen receptor antagonist peptides cyclo(S,S)-Na- acetyl-Cys-(Na-methyl) Arg-Gly- Asp-Pen-NH2 or cyclo(S ,S)-(2-mercapto)benzoyl-(Na- methyl)Arg-Gly-Asp-(2-mercapto)phenylamide or GHRP.
  • a fibrinogen receptor antagonist peptide an RGD peptide
  • GHRP His-D-Trp-Ala-Trp-D-Phe-Lys-NH2
  • a vasopressin a calcitonin or
  • the present invention provides compositions in the form of microemulsions comprising a peptide which may be orally administered and which will retain biological activity, thereby overcoming the disadvantages of earlier formulations in which the bioavailability of the peptide has been less than satisfactory.
  • the present invention provides compositions which by their nature permit the preparation and administration of a peptide in sufficiently high concentration to allow not only convenient oral administration but also adequate bioavailability of the peptide.
  • the degree of incorporation into (w/o) compositions of the present invention is limited only by its solubility in the hydrophilic phase.
  • isotonic aqueous phase in the physiological pH range (3 - 8) may be used to aid drug dissolution by the proper modification of the fatty acid/fatty acid salt ratio, without compromising the integrity of the active ingredient and stability of the composition.
  • the aqueous hydrophilic phase suitably comprises water or an isotonic saline solution and may also include a pharmaceutically acceptable solvent which is non-miscible with the selected lipophilic phase.
  • a pseudo-ternary phase diagram may be constructed by reducing the number of variables to three, by holding two pairs (free fatty acid fatty acid salt and oil second low HLB surfactant) each in a fixed ratio. Each of the three variables may then be represented by one side of the triangle.
  • (1) represents the mixture of oil and second low HLB surfactant, at a fixed ratio X
  • (3) the free fatty acid and fatty acid salt at a fixed ratio Y the point “A” represents a microemulsion of 40% oil plus second low HLB surfactant, 10% aqueous phase and 50% free fatty acid plus fatty salt. It will be appreciated by the skilled man that if either the second low HLB surfactant or the free fatty acid is omitted, then the variables (1) or (3) will no longer need to be a fixed ratio and corresponding phase diagrams may be constructed.
  • the regions of the phase diagram in which microemulsions according to the present invention exist may be determined by titrating a mixture of the oil and second low HLB surfactant (in a fixed ratio) against the free fatty acid plus fatty acid salt (in a fixed ratio) and the hydrophilic phase, noting points of phase separation, turbidity and transparency. Clear, transparent compositions are indicative of the formation of a stable microemulsion. These compositions may then be plotted on the phase diagram, to generate a microemulsion field, the boundary of which represents the transition from clear, transparent compositions (microemulsions) to turbid compositions, as shown in figure 1.
  • phase diagrams were also constructed using the total surfactant present in the system as one component; the oil as a second component; and the hydrophilic phase as third component
  • a representation of this phase diagram is illustrated as Figure 7 corresponding to Example 6 herein.
  • microemulsions are an (o/w)- or a (w/o)-type.
  • a water-soluble dye will disperse in an (o/w) microemulsion while it will remain in its original form in a (w/o) microemulsion.
  • (o/w) microemulsions are generally dispersible in water whereas (w/o) microemulsions are generally not.
  • (o/w) microemulsions conduct electricity whereas (w/o) do not The isotropic nature of the system may be confirmed by examination thereof under polarized light. The microemulsions are isotropic and therefore non-birefringent when examined under polarized light.
  • Microemulsions within the scope of the present invention are those falling within the microemulsion existence field of the pseudo-ternary phase diagrams herein.
  • the present invention provides compositions which form stable, self- emulsifying (w/o) microemulsions as hereinbefore defined in which the relative proportions of the various components lie within the microemulsion existence field of a pseudo-ternary phase diagram such as figure 1.
  • the oil comprises from about 5 to 95 , preferably from about 10 to 80% (w/w) of the microemulsion.
  • the low HLB surfactant comprises from about 15 to 85 , preferably from about 20 to 70% (w/w) of the microemulsion.
  • the high HLB surfactant comprises from about 5 to about 75%, preferably about 5 to about 50%, more preferably from about 7.5 to about 30% (w/w) of the microemulsion.
  • the hydrophilic phase comprises from just greater than 0 to about 40%, preferably from about 0.1 to 20%, more preferably from about 0.1 to 10% and most preferably from about 1 to 5% (w/w) of the microemulsion.
  • the oil plus second low HLB surfactant together comprise from about 8 to about 95%, preferably about 10 to about 90%, more preferably about 40 to about 90%, most preferably about 60 to about 90% (w/w) of the microemulsion.
  • the oil and the second low HLB surfactant may be combined and mixed at various ratios.
  • Useful (w/o) microemulsions which have relatively low viscosity throughout the whole of the microemulsion field may be obtained when the ratio of oil to second low HLB surfactant is in the range of about 5:1 to about 1.5:1, preferably about 4:1 to about 2:1. It is found that as the ratio of oil to second low HLB surfactant is increased towards 5:1, the.microemulsion field tends to shrink towards the apex of the phase diagram formed by the sides representing (1) and (3).
  • the free fatty acid and the fatty acid salt are preferably present in the range of about 5 to about 75%, more preferably about 5 to about 50%, most preferably from about 7.5 to about 30% (w/w) of the microemulsion.
  • the free fatty acid and the fatty acid salt may be combined and mixed at various ratios, for instance in the range of from about 10: 1 to 1 : 1 , more preferably in the range of from about 4: 1 to 1 : 1 (w/w).
  • the microemulsions of the present invention are substantially non-opaque, that is they are transparent or opalescent when viewed by optical microscopic means. In their undisturbed state, they are optically isotropic (non-birefringent) when examined under polarized light. They exhibit excellent stability at low and ambient temperatures, without phase separation, clouding or precipitation, even over prolonged periods of time.
  • the formulations may be stored in a stable form at various temperatures, such as at 4°C, room temperature, 37°C and at 50°C, preferably at 4°C or room temperatures. On dilution with excess aqueous phase, the microemulsions of the present invention tend to invert to (o/w) emulsions.
  • the diameter of droplets or particles of the microemulsions of the present invention measured, for instance, as the number-average diameter by laser light scattering techniques, is less than 150 nm, more preferably less than 100 nm, yet more preferably less than 50 nm and most preferably in the range 5 to 35 nm.
  • the various phases may optionally contain further ingredients, such as, but not limited to: i) lipids, such as phospholipids which may be anionic, cationic or zwitterionic, in particular lecithin's, such as soya bean lecithins, egg lecithin or egg phosphatide, cholesterol or long-chain fatty acids such as oleic acid; ii) antioxidants such as n-pr ⁇ pyl gallate, butylated hydroxyanisole (BHA) and mixed isomers thereof, d- ⁇ -tocopherol and mixed isomers thereof, ascorbic acid, propylparaben, methylparaben and citric acid (monohydrate), for instance in amounts less than 3, preferably less than 1% (w/w); ⁇ i) bile salts and the alkali metal salts thereof, such as sodium taurocholate; iv) stabilizers, such as hydroxypropyl cellulose, for instance in amounts less than 3, preferably less than 1% (w
  • the present invention includes not only microemulsions which are liquids or gels at room temperature (about 23°C) but also microemulsions which, while liquid at the body temperature of the animal being treated, are solid at room temperature.
  • Such solid microemulsions may be readily prepared by using a high melting oil and, optionally, a high melting low HLB surfactant.
  • oils or low HLB surfactants will have a melting point above room temperature, preferably above 30°C and examples thereof are well known in the art.
  • Suitable high melting oils include hydrogenated coconut oil and palm oil and blends thereof, such as the HYDROKOTE oils available from Karlshamns Lipid Specialties, hydrogenated peanut oil and various hydrogenated vegetable oils.
  • Suitable high melting low HLB surfactants include sunflower oil monoglycerides such as the products MYVEROL 18-92 and 18-99.
  • the present invention provides for microemulsions which, upon addition of aqueous fluid, convert to both O/W emulsions and microemulsions.
  • the aqueous phase is preferably a 10-95%, preferably a 20-70%, more preferably a 20-50% by weight a solution of such compounds as sorbitol, polyethylene glycol (PEG), mannitol, propylene glycol, mono- and di-saccharides and mixtures thereof.
  • microemulsions of the present invention form spontaneously or substantially spontaneously when their components are brought into contact, that is without the application of substantial energy supply, for instance in the absence of high shear energy such as imparted by homogenization and/or microfluidization or other mechanical agitation. Accordingly, the microemulsions may be readily prepared at room temperature by the simple process of admixing appropriate quantities, with gende hand mixing or stirring, if necessary, to ensure thorough mixing.
  • the drug is dissolved in the hydrophilic phase, either directly or by dilution of a stock solution thereof and this may then be added to a pre-mixed combination of the oil and, if being used, the second low HLB surfactant with mixing, followed by the fatty acid salt and, if being used, the free fatty acid and non- ionic high HLB surfactant or vice versa.
  • a drug-free microemulsion may be initially prepared by admixing the oil and surfactants and drug-free hydrophilic phase; to which may then be added further hydrophilic phase in which the drug is dissolved.
  • Microemulsions which are solid at room temperature may be prepared by using higher temperatures, such that the various components are all liquids, for instance between 40 and 60°C, to facilitate mixing. Such microemulsions may then be allowed to cool down to room temperature, during which solidification occurs.
  • Microemulsions of the present invention may be pharmaceutical compositions comprising a therapeutic agent and which may be given to animals, including man.
  • the present invention provides a method of treatment which comprises administering an effective amount of a pharmaceutical composition as hereinbefore defined to a patient in need thereof.
  • the amount of drug required for therapeutic effect will vary with the drug chosen, the nature and severity of the condition and the animal undergoing treatment and is ultimately at the discretion of the physician.
  • the optimal quantity and spacing of individual dosages of a drug will be determined by the nature and extent of the condition being treated, the form, route and site of administration, the particular patient being treated and that such optima can be determined by conventional techniques. It will also be appreciated that the optimal course of treatment that is, the number of doses given, may be readily ascertained using conventional course of treatment determination tests.
  • the present invention provides for the use of an oil, a surfactant system comprising a mixture of high and low HLB surfactants in which the high HLB surfactant is a medium-chain fatty acid salt optionally admixed with a non-ionic high HLB surfactant a therapeutic agent and a hydrophilic phase, as hereinbefore defined, in the manufacture of a medicament.
  • a surfactant system comprising a mixture of high and low HLB surfactants in which the high HLB surfactant is a medium-chain fatty acid salt optionally admixed with a non-ionic high HLB surfactant a therapeutic agent and a hydrophilic phase, as hereinbefore defined, in the manufacture of a medicament.
  • compositions of the present invention may be administered parenterally, enterally or via a mucous membrane, for instance, by injection or by oral, topical, rectal, colonic or intra-vaginal administration. Accordingly the compositions will be presented in forms suitable for such. Thus for instance, pharmaceutical compositions intended for oral administration may be presented in soft gelatin capsules while the viscosity characteristics of some of the pharmaceutical compositions make them suitable for direct topical application-. Solid formulations are preferred for colonic and rectal administration.
  • microemulsion compositions of the present invention without a drug are novel and useful as precursors to drug-containing microemulsions.
  • the present invention provides a composition comprising an oil; a surfactant system comprising a mixture of high and low HLB surfactants in which the high HLB surfactant is a medium-chain fatty acid salt optionally admixed with a non-ionic high HLB surfactant and an aqueous hydrophilic phase which components on admixing form a stable, self- emulsifying, water-in-oil (w/o) microemulsion.
  • a pseudo-ternary phase diagram was constructed for the system comprising CAPTEX 8000 and CAPMUL C8 (ratio 3:1), caprylic acid and sodium caprylate (ratio 2:1) and aqueous phase (saline or deionized water).
  • the region of the phase diagram in which microemulsions were formed was determined by titrating a mixture of CAPTEX 8000 and CAPMUL C8 against a solution of caprylic acid and sodium caprylate and saline, noting points of phase separation, turbidity and transparency.
  • the resultant phase diagram is shown as figure 2.
  • a wide range of clear, transparent, liquid (w/o) microemulsions was available. These were stable at room temperature and 37°C. On dilution with excess aqueous phase, inversion to a turbid (o/w) emulsion was observed.
  • phase diagrams were constructed for the other systems given in the table and these are shown as figs. 3 to 6.
  • a similar range of microemulsion fields was obtained.
  • the microemulsions were found to have relatively low viscosity throughout the field.
  • higher levels of aqueous phase could then be . accommodated.
  • GHRP His-D-Trp-Ala-Trp-D-Phe-Lys-NH2
  • microemulsions were formulated by initially preparing the drug-containing hydrophilic phase, either by dissolving the appropriate amount of drug in the appropriate amount of the aqueous phase or, more preferably, using a stock solution which was then further diluted if so required, and with vortex stirring if necessary to obtain complete dissolution.
  • the hydrophilic phase containing the drug was then added to the appropriate amounts (by weight) of a mixture of the oil and the second low HLB surfactant, to which was then added a solution of fatty acid salt in free fatty acid, with gentle stirring (magnetic hot plate stirrer).
  • the hydrophilic phase containing the drug was added to the solution of fatty acid salt in free fatty acid.
  • Example 5 Solid Microemulsion A w/o microemulsion incorporating 3.2 mg of Calcein per g of formulation which is solid at room temperature but liquid at 37°C was prepared having the following composition (%, w/w): Witepsol H-15 (42.6%), Imwitor 308 (23.8%), Tween 80 (12.4%), Capric Acid (11.4%), Sodium Caprylate (4.8%) and 100 mM solution of Calcein in isotonic 10 mM Tris pH 7.4 (5.0%).
  • Example 6 (Convertible Microemulsion) A w/o microemulsion was prepared using the following components (%, w/w): Captex 200 (44.5%), Imwitor 308 (9.8%), Tween 80 (19.6%), Capric Acid (10.7%), Sodium Caprate (4.4%), aqueous phase containing a mixture of propylene glycol (4.9%), 100 mM calcein solution (4.9%) and 5N sodium hydroxide (1.2%).
  • Example 6 The w/o microemulsion of Example 6 upon a 20-fold dilution with deionized water was converted into an O/W clear microemulsion (final pH of the aqueous phase:6.9) with an effective particle diameter of 73 nm and polydispersity of 0.364 as determined by laser light scattering.
  • Example 7 Solid Microemulsion
  • Witepsol H-15 (42.75%)
  • Imwitor 308 (23.75%)
  • Tween 80 (12.35%)
  • Laurie Acid 11.4%
  • Sodium Laurate 4.75%
  • One aspect of the present invention are the formulations of w/o self-emulsifying microemulsions with or without peptide which produce little, if any, damage along the GI tract upon oral administration.
  • Formulations of the present invention will be given orally by gavage at a volume not exceeding 10 ml/kg (preferably at three rats per formulation). After 24 hrs the animals are exsanguinated and upon abdominal incisions the gastric and duodenal mucosa are examined both by naked eye and under the microscope (Nikon model SMZ-10 binocular microscope). The mucosal surface of both the stomach and duodenum of the animals that receive microemulsions are examined to see if they are free of any lesions at naked eye.
  • microemulsions formulated as hereinbefore and containing a peptide may be tested in the following manner for oral bioavailability.
  • Fasted rats are given an intraperitoneal (i.p.) injection and surgically fitted with femoral artery catheters. Rats are allowed to recover from the surgery for 1 day. Catheterized rats are fasted for 18 hr prior to the experiment Each rat receives 3 mg of peptide by lateral tail-vein administration from a solution prepared as follows:
  • Fasted rats are given an i.p. injection of anesthesia cocktail and surgically fitted with jugular and duodenal catheters. Rats are allowed to recover from the surgery for 4-5 days. Catherized rats are fasted 18-20 hrs. prior to the experiment. Each rat receives lOmg of peptide in either microemulsion or saline solution. Blood samples of 0.5ml aliquots are collected via jugular catheter in heparinized eppendorf tubes at 0, 10, 30, 60, 120, 180, 240 and 1440 minutes. The 0 min sample is taken 15 min prior to administration of the dose by duodenal catheter. Plasma is collected for analysis and the blood returned to rats as described in the i.v. administration (part a) above. After 1440 min, rats are euthanized by iv administration of pentobarbital, exsanguinated and the GI tract removed for gross observation.
  • the oral bioavailability data for the RGD peptide in rats after intraduodenal administration of a microemulsion containing the above formulations incorporating a fibrinogen receptor antagonist of a peptide dose may then be obtained in the above noted manner.
  • the formulations of the present invention are tested for in vivo activity.
  • a fibrinogen receptor antagonist a platelet aggregation assay is employed to determine pharmacological activity of the peptide from microemulsions. These studies are carried out as shown below. Oral Dosing in Dogs Platelet Aggregation Assay :
  • Dogs which may be used in this assay are, for instance, male Mongrels (i.e. from mixed breeds). The dog(s) are fasted overnight the day before the experiment.
  • the cephalic vein of choice is prepared for the indwelling catheter in the following way: the area is first shaved and cleaned with a gauze soaked in 70% alcohol. An indwelling catheter is placed in the caphalic vein and attached to a luer lock adapter filled with 3.8% sodium citrate. The catheter is securely taped down.
  • an appropriate dose of microemulsion with or without peptide is administered orally to the dog using a size 12 gelatin capsule.
  • the blood samples are then assayed for platelet aggregation inhibition using the Chromo-Log whole blood aggregometer.
  • the instrument is warmed to 37°C before samples are run and the probe is cleaned with distilled water and a soft brush.
  • the probe is attached to the aggregometer and placed in a cuvette of saline solution and warmed in a side cuvette well in the aggregometer.
  • 1 ml of the 2.7 ml of blood sample mixed with the 0.3 ml 3.8% sodium citrate contained in the Venoject vacuum tube is added to a cuvette and placed in the aggregometer well.
  • a stir bar is placed in the cuvette and set at 900 ipm.
  • the reaction is monitored for two minutes once the slope change reaches the baseline of the collagen addition, calculating the change in ohms per minute using the slope of the two minutes.
  • the change in ohms per minute is calculated as a % of the control.
  • the control value is determined by the average of the -15 and the 0 time points. After each use the probe is removed and cleaned with distilled water and wiped with a soft cloth and brush.
  • a dog is considered a good model to assess the pharmacological effect of one class of peptides of interest herein, the RGD containing fibrinogen receptor antagonists.
  • Experiments are conducted as described above, with a peptide dose of 3 mg kg or microemulsion dose of 0.5 ml kg. Control experiments where the peptide is given orally in a saline solution are independently carried out earlier and serve as a useful comparison to the effects seen with the microemulsion-formulated peptide.
  • Peptide the appropriate assay for in vivo activity is determined as shown below.
  • Microemulsions with a composition (w/w) in accordance with the present invention of Examples 1 and 2 are made. Upon preparation they are further stored in a stable form at ambient temperature for approximately 48 hrs before the in vivo evaluation. A control solution of a GHRP peptide, His-D-T ⁇ p-Ala-Trp-D-Phe-Lys-NH2, in saline at 1.5 mg/ml is also prepared.
  • Dosing was done by single intraduodenal administration of GHRP at 1.35 mg/kg in male rats in saline solution (control) and in the aforementioned microemulsion using 5 rats in each case. Prior to actual sampling and dosing, each rat was anesthetized with Pentobarbitol at 50 mg/kg i.p, diluted with saline to a final volume of 1 ml. The rats stayed anesthetized for the entire experiment. Dosing was achieved in the following way: a small incision 2-3 cm long was made on the abdominal midline, and then a purse-string suture was placed on the duodenal muscle.
  • the purse-string was tied to close the opening. The incision was closed with wound clips.
  • a 0.2 ml blood sample was obtained via jugular catheter at the following intervals: -15, 0, 5, 10, 15, 30, 45, 60, 90, and 120 minutes. Blood samples were stored on ice and subsequently analyzed for Growth Hormone by an RIA method.
  • the amount of active ingredient required for therapeutic systemic administration will, of course, vary with the compound chosen, the nature and severity of the condition, and the mammal, including humans, undergoing treatment, and is ultimately at the discretion of the physician.
  • the present invention also includes a method of treatment which comprises administering an effective amount of a pharmaceutical composition as defined herein to a patient in need thereof.
  • the thereapeutic agent is selected from fibrinogen receptor antagonist peptide, Growth Hormone Releasing Peptide, vasopressin, elcatonin, calcitonin, calcitonin-gene releated peptide, porcine somatostatin, or insulin.
  • fibrinogen receptor antagonist peptide is selected from fibrinogen receptor antagonist peptide, Growth Hormone Releasing Peptide, vasopressin, elcatonin, calcitonin, calcitonin-gene releated peptide, porcine somatostatin, or insulin.
  • the disease states and uses of each of the aforementioned thereapeutic agents is well known to those skilled in the art and for a number of the agents alerady cross referenced to their respective patents. For instance, use as platelet aggregation inhibitors, growth promote

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Abstract

Des compositions pharmaceutiques prenant la forme de micro-émulsions comprennent une huile, un mélange d'agents tensio-actifs à équilibres hydrophile-lisophile élevés et bas où celui à équilibre hydrophile-lisophile élevé comprend un sel d'acide gras à chaîne moyenne, une phase aqueuse et un agent biologiquement actif.
EP93923918A 1992-10-16 1993-10-15 Compositions pour emulsions pharmaceutiques. Withdrawn EP0671937A4 (fr)

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CA2369594A1 (fr) * 1999-05-07 2000-11-16 Pharmasol Gmbh Particules lipidiques a base de melanges de lipides liquides et solides et procede pour les produire
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IT1318539B1 (it) * 2000-05-26 2003-08-27 Italfarmaco Spa Composizioni farmaceutiche a rilascio prolungato per lasomministrazione parenterale di sostanze idrofile biologicamente
US6623765B1 (en) 2000-08-01 2003-09-23 University Of Florida, Research Foundation, Incorporated Microemulsion and micelle systems for solubilizing drugs
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