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WO1994008605A1 - Microemulsions therapeutiques - Google Patents

Microemulsions therapeutiques Download PDF

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Publication number
WO1994008605A1
WO1994008605A1 PCT/US1993/009963 US9309963W WO9408605A1 WO 1994008605 A1 WO1994008605 A1 WO 1994008605A1 US 9309963 W US9309963 W US 9309963W WO 9408605 A1 WO9408605 A1 WO 9408605A1
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WO
WIPO (PCT)
Prior art keywords
fatty acyl
hlb surfactant
long
medium
composition according
Prior art date
Application number
PCT/US1993/009963
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English (en)
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WO1994008605A9 (fr
Inventor
Panayiotis Pericleous Constantinides
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Smithkline Beecham Corporation
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Publication date
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Priority to JP6510336A priority Critical patent/JPH08502492A/ja
Priority to EP93923933A priority patent/EP0666752A4/fr
Publication of WO1994008605A1 publication Critical patent/WO1994008605A1/fr
Publication of WO1994008605A9 publication Critical patent/WO1994008605A9/fr

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    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/095—Oxytocins; Vasopressins; Related peptides
    • 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
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]

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 the ⁇ nodynamically 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, an 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.
  • Surfactants are conveniently classified on an empirical scale known as the hydrophilic-lipophilic balance (HLB) which runs from 1 to 20.
  • HLB hydrophilic-lipophilic balance
  • microemulsions are formed using surfactants (or emulsifiers) which have an HLB value in the range of about 3 to 6 whilst (o/w) microemulsions are formed using surfactants which have an HLB value in the range of about 8 to 18.
  • 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. When 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 200 nm in size and this gives rise to their optical transparency. These particles may be spherical although other structures are feasible.
  • the role of the cosurfactant 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 cosurfactant 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 etal., 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 surfactant-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 bioavailabity.
  • WO 88/00059 discloses controlled release compositions for biologically active materials comprising an "L2-phase” and containing an unsaturated (C16-22)- fatty acid monoglyceride and an unsaturated (Ci6-22Matty acid triglyceride, in a ratio of from 1:1 to 3:1, and a polar liquid such as water.
  • an unsaturated (C 16-22)- fatty acid monoglyceride is a low HLB surfactant.
  • the present invention provides a pharmaceutical composition comprising:
  • a lipophilic phase having an oil which is a medium- or a long-chain fatty acyl triglyceride or a mixture thereof and a low HLB surfactant which is a medium- or a long-chain fatty acyl mono- and or diglyceride, a sorbitan long-chain fatty acid ester or a mixture thereof, such that lipophilic phase comprises a mixture of medium- and long-chain fatty acyl moieties;
  • the pharmaceutical composition upon admixing forms a stable, self-emulsifying, water-in-oil (w/o) microemulsion which is liquid or a gel at room temperature.
  • Figure 1 Illustrates a Pseudo Ternary Phase Diagram of aW/O Microemulsion
  • Figure 2 Illustrates a Pseudo Ternary Phase Diagram of theW/O Microemulsion
  • FIG. 1 Illustrates a Pseudo Ternary Phase Diagram of theW/O Microemulsion Existence Field in the System comprising Captex 355 and sorbitan monooleate (ratio 3:1), Tween 80 and saline;
  • Figure 4 Illustrates a Pseudo Ternary Phase Diagram of theW/O Microemulsion
  • Figure 5 Illustrates a Pseudo Ternary Phase Diagram of theW/O Microemulsion
  • Figure 6 Illustrates a Pseudo Ternary Phase Diagram of theW/O Microemulsion
  • the instant invention comprises a pharmaceutical composition which has a) a lipophilic phase having an oil which is a medium- or a long-chain fatty acyl triglyceride or a mixture thereof and a low HLB surfactant which is a medium- or a long-chain fatty acyl mono- and/or diglyceride, a sorbitan long-chain fatty acid ester or a mixture thereof, such that lipophilic phase comprises a mixture of medium- and long-chain fatty acyl moieties; (b) a high HLB surfactant; (c) an aqueous hydrophilic phase; and
  • a water-soluble therapeutic agent which upon admixing form a stable, self- emulsifying, water-in-oil (w/o) microemulsion which is liquid or a gel at room temperature.
  • 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 1993).
  • w/o water-in-oil
  • a lipophilic phase which is a mixture of medium and long-chain fatty acyl mono-, di- and triglycerides.
  • the term “mixture” refers to an enriched blend of components, preferably where the other component is admixed in an amount greater than 10%.
  • the medium chain fatty acyl moiety is present in an amount of 20% or greater, preferably about 50% and most preferably about 80% of the total mixture.
  • mixtures within the scope of the present invention include the medium- and long-chain components in a ratio of from 10:90 to 90: 10, preferably from 50:50 to 70:30, more preferably 50:50 to 80:20.
  • compositions according to the present invention comprise in the lipophilic phase, for instance, a mixture of a medium-chain fatty acyl triglyceride and a low HLB surfactant having a long-chain fatty acyl moiety or a long-chain fatty acyl triglyceride and a low HLB surfactant having a medium-chain fatty acyl moiety.
  • Another useful lipophilic phase comprises a mixture of a long-chain and a medium-chain fatty acyl triglyceride and a medium-chain fatty acyl mono- and/or diglyceride.
  • intermediate-chain fatty acyl refers to a fatty acyl moiety 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 fatty acyl refers to a fatty acyl moiety which may be saturated, mono-unsaturated or poly-unsaturated, having from 14 to 22, preferably 14 to 18, carbon atoms which may be branched or unbranched, preferably unbranched, and which may be optionally substituted.
  • Suitable medium and long-chain fatty acid triglycerides for use in the present invention may be of natural, semi-synthetic or synthetic origin and may include blends of different fatty acid triglycerides. Suitable triglycerides for use herein are readily available from commercial suppliers.
  • Preferred medium-chain fatty acyl triglycerides 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 MYRITOL; CAPTEX (Karlshams Lipid Specialties, Columbus OH), for instance CAPTEX 355, CAPTEX 300, CAPTEX 350, CAPTEX 850, CAPTEX 800 and CAPTEX 8000; MIGLYOL
  • MIGLYOL 810 for instance the grades MIGLYOL 810, MIGLYOL 812 and MIGLYOL 818 (which also comprises a linoleic acid triglyceride) and MAZOL 1400 (Mazer Chemical, Gumee, H.).
  • the fatty acid content of representative products is: CAPTEX 355 - caproic acid (2%), caprylic acid (55%) and capric acid (42%); CAPTEX 8000 - at least 98% caprylic acid, MYGOL 810 - caproic acid (2%), caprylic acid (65-75%), capric acid (25-35%) and MIGLYOL 812 - caproic acid (3%), caprylic acid (50- 65%), capric acid (30-45%) and lauric acid (5%) (manufacturer's data). . .
  • Suitable long-chain fatty acid triglycerides may also be conveniently obtained from neutral plant, vegetable and fish oils such as shark oil, olive oil, sesame oil, peanut oil, castor oil, safflower oil, sunflower oil and soybean oil which 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
  • 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 Cig-monounsaturated or polyunsaturated fatty acids.
  • mixtures of medium- and long-chain fatty acyl triglycerides are obtained by physically admixing triglycerides which essentially have medium-chain fatty acyl moieties with triglycerides which essentially have long-chain fatty acyl moieties, to create a ⁇ ificial mixtures of medium- and long- chain fatty acyl triglycerides in the desired ratios.
  • the present invention is directed towards microemulsions which are liquids or gels at room temperature (that is below about 23°C) and therefore does not include microemulsions which are solid at room temperature. Accordingly, in formulating microemulsions of the present invention, oils such as coconut oil (mp 25°C) and palm oil (mp about 30°C) or blends thereof should be avoided as the use thereof will tend to give formulations which are solid at room temperature.
  • Suitable low HLB surfactants for use in the present invention include fatty acid monoglycerides and diglycerides, as well as mixtures thereof, and may also comprise a small amount by weight of free fatty acid.
  • the mono- and di-glycerides may each include blends of different fatty acid mono- and di-glycerides.
  • Suitable medium chain fatty acid mono- and di-glycerides are formed from caprylic and capric acids.
  • Suitable blends comprise from about 50 to 100% caprylic acid and from about 0 to 50% capric acid mono and/or diglycerides.
  • Suitable commercial sources of these include the products available under the trade name CAPMUL (Karlsham Lipid Specialties, Columbus OH), for instance the products CAPMUL MCM which comprises monoglycerides (77.4%), diglycerides (21 %) and free glycerol (1.6%), with a fatty acid composition of caproic acid (3.2%), caprylic acid (66.8%), capric acid (29.6%), lauric acid (0.3%) and palmitic acid (0.1%) and CAPMUL C8 which has monoglycerides (70 - 90%), diglycerides (10 - 30%) and . .
  • Suitable long-chain fatty acid 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, and 18-99, MYVATEX and MYVAPLEX, respectively, from Eastman Kodak Chemicals, Rochester, New York.
  • a further useful long-chain fatty acid monoglyceride-containing product is ARLACEL 186 (available from ICI Americas Inc.) which includes, in addition to glycerol monooleate, propylene glycol (10%).
  • the main fatty acids 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 C ⁇ -saturated, monounsaturated or polyunsaturated fatty acid, preferably a Cis-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.
  • sorbitan long-chain fatty acid esters such as 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.
  • the low HLB surfactant will have an HLB value in the range of about 2.5 to 6.
  • 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.
  • Suitable high HLB surfactants for use in the present invention include non-ionic surfactants such as
  • polyoxyethylene fatty acid 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);
  • polyoxyetheylene-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 high HLB surfactant preferably has an HLB value in the range of 13 to 20.
  • the blend of low and high HLB surfactants will have an HLB value in the range of from about 7 to about 15.
  • the term "therapeutic agent” refers to any compound which has biological activity, is soluble in the hydrophilic phase and has an HLB value of at least that of the high HLB surfactant used in the formulation, to ensure that the drug is preferentially dissolved in the hydrophilic rather than the lipophilic phase.
  • drug refers to any compound which has biological activity, is soluble in the hydrophilic phase and has an HLB value of at least that of the high HLB surfactant used in the formulation, to ensure that the drug is preferentially dissolved in the hydrophilic rather than the lipophilic phase.
  • Suitable peptides include not only small peptides but also larger peptides/polypeptides and proteins. Suitable such peptides preferrably 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
  • 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)-N a -acetyl-Cys-(N a -methyl)Arg- Gly-Asp-Pen-NH2 (AH et al., EP 0341 915, whose disclosure is herein incorporated by reference in its entirety) and the peptide cyclo(S,S)-(2-mercapto)benzoyl-(N a - 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 0275 748; 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 600mg/g of the hydrophilic phase or from 0.1 to 60 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 89/10933 (PCT/US89/01829); the peptide Ala-His-D-Nal-Ala-Trp-D-Phe-Lys-NH 2 (in which Nal represents ⁇ -naphthylalanine) and the peptides disclosed by Momany, US 4,228,158, US 4,228,157, US 4,228,156, US 4,228,155, US 4,226,857, US 4,224,316, US 4,223,021, US 4,223,020, US 4,223,019 and US 4,410,512.
  • RGD containing peptides such as those disclosed by Momany, US 4,411,890 and US 4,410,513;
  • Suitable peptides include hexapeptides such as the growth hormone releasing peptide (GHRP) His-D-Trp-Ala-Trp-D-Phe-Lys-NH , (Momany, US 4,411,890) and related analogs thereof, such as but not limited to, His-D-Phe-Ala-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 and porcine somatostatin as well as analogs and homologs thereof.
  • Other suitable larger polypeptides include those disclosed by Pierschbacher et al, US 4,589,881 (>30 residues); Bitde et al, US 4,544,500 (20-30 residues); and Dimarchi et al, EP 0204 480 (>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 hematopoetic 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 antagonists;
  • Non-peptide therapeutic agents such as antibiotics, antimicrobial agents, antineoplastic agents, cardiovascular and renal agents, antiinflammatory, 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), vasopressin, a calcitonin or an insulin, more preferably the fibrinogen receptor antagonist peptides cyclo(S,S)-N a -acetyl-Cys-(Na-methyl)Arg-Gly-Asp-Pen-NH 2 or cyclo(S,S)-(2- mercapto)benzoyl-(N a -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
  • vasopressin a calcitonin or an insulin
  • 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.
  • the ionic strength and pH (within the range 3 to 10) may be adjusted to aid dissolution, without compromising the integrity 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.
  • compositions of the present invention may be avoided.
  • a mono- or polyhydroxyalcohol co-surfactant such as ethanol, butanol or propylene glycol
  • the hydrophilic phase of compositions of the present invention may be essentially aqueous and comprise less than 10%, preferrably less than 5% and more preferrably less than 2% by weight of the phase of an alcohol.
  • (1) represents the mixture of the oil and the low HLB surfactant, at a fixed ratio X
  • (3) the high HLB surfactant represents the point "A” represents a mixture 50% oil plus low HLB surfactant, 20% aqueous phase and 30% high HLB surfactant.
  • 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 low HLB surfactant (in a fixed ratio) against the high HLB surfactant and the hydrophilic phase, noting points of phase separation, turbidity and transparency. Clear, transparent formulations are indicative of the formation of a stable microemulsion. Liquid and gel formulations may be obtained at room temperature according to the specific nature of the components employed.
  • microemulsions are an (o/w)- or a (w/o)-type.
  • a water-soluble dye will disperse in an (o/w) microemulsion whilst 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 polarised light.
  • the microemulsions being micellar in nature are isotropic and therefore non-birefringent when examined under polarised light
  • a representative pseudo-ternary phase diagram of a system containing in the lipophilic phase a medium-chain triglyceride oil (CAPTEX 355) and a long-chain fatty acid mono-glyceride (ARLACEL 186, low HLB surfactant) (in the ratio 3:1), high HLB surfactant (Tween 80) and saline is shown as Fig 2.
  • the mixture of oil plus the low HLB surfactant is indicated as component (1), saline as component (2) and the high HLB surfactant as compontent (3).
  • This sub-division is based primarily on differences in conductance, viscosity and dilutability in the presence of excess water (at least 5-fold). Both the viscosity and conductance increase from region (A) to (C), with major changes observed between (B) and (C). In the presence of excess of the dispersed phase (saline or water), microemulsions of regions (A) and (B) are inverted to turbid (o/w) emulsions . In contrast, microemulsions from region (C) remains clear upon dilution.
  • the calculated final HLB values for the blend of low and high HLB surfactants in the regions (A), (B) and (C) are 7 to 11, 11 to 13 and 13 to 15, respectively.
  • Microemulsions within the scope of the present invention are those falling within regions (A), (B) and (C) of the pseudo-ternary phase diagram.
  • 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 regions (A), (B) and (C), preferably (A) and (B), more preferably (A), of a pseudo-ternary phase diagrams such as Fig 2.
  • the lipophilic phase comprising fatty acyl triglyceride and the 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 fatty acyl triglyceride and the low HLB surfactant may be combined and mixed at various ratios.
  • Useful (w/o) microemulsions of relatively low viscosity may be obtained when the ratio of fatty acyl triglyceride to low HLB surfactant is in the range of about 5:1 to about 1.5: 1, preferably about 4: 1 to about 2:1.
  • microemulsions of the present invention comprise in the lipophilic phase at least 50% of medium-chain components.
  • the ratio of medium- to long-chain components is from about 9: 1 to 1 : 1 , more preferably from about 6: 1 to 1 : 1 , most preferably about 4: 1 to 1 : 1.
  • the high HLB surfactant is present in the range of 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. It will be readily appreciated by the skilled person that, in general, an increase in the relative amount of high HLB surfactant will have to be matched by an increase in the relative amount of hydrophilic phase.
  • the lipophilic phase comprises preferably about 10-90%, more preferably 40 to 90%, most preferably 60 to 90%, the high HLB surfactant preferably from about 5 to 75%, more preferably from 5 to 50%, most preferably 7.5 to 30% and the hydrophilic phase preferably less than 40%, more preferably less than 10% and most preferably less than 5% (w/w) of the microemulsion.
  • the ratio of fatty acyl triglyceride to low HLB surfactant is preferably between 4:1 and 2:1.
  • 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, ambient temperature, 37°C and at 50°C, preferably at 4°C or ambient temperatures.
  • Peptide-containing microemulsions of the present invention exhibit a similar stability (shelf life) profile to that of the corresponding peptide-free microemulsions.
  • Stable (w/o) microemulsions may be formed when the pH of the aqueous phase varies from a pH of approximately 3 to about 10, a property that can be beneficial for drugs exhibiting higher solubility at low or high pH.
  • the microemulsions are of varying viscosity, with formulations which are mobile liquids or gels at ambient temperature. Microemulsions with a relatively higher amount of a high HLB surfactant such as TWEEN 80 tend to be more viscous due to the greater viscosity of this material.
  • 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, in particular lecithins, 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-propyl gallate, butylated hydroxyanisole (BHA) and mixed isomers thereof, d-a-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); iii) bile salts, for instance as their alkali metal salts, such as sodium taurocholate; iv) stabilizers, such as hydroxypropyl cellulose, for instance in amounts less than 3, preferably less than 1% (w/w); v) antimicrobials, such as benzoic
  • 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.
  • the microemulsions may be readily prepared by the simple process of admixing appropriate quantities, with gentle 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 the low HLB surfactant with mixing, followed by the high HLB surfactant or vice versa.
  • a drug-free microemulsion may be initially prepared by admixing the oil, the low HLB surfactant, the high HLB surfactant and drug-free hydrophilic phase; to which may then be added further hydrophilic phase in which the drug is dissolved. Whilst higher temperatures (40-60°C) may be needed to solubilize all components during the preparation of the microemulsion, the preferred systems may be formulated at room temperature. Formulation at ambient temperature is particularly advantageous for thermolabile active ingredients such as peptides.
  • the pharmaceutical compositions of the present invention comprise a therapeutic agent and are intended for use in therapy, for administration 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 a fatty acyl triglyceride, a low HLB surfactant, a 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 used for oral, topical, rectal, intra-vaginal or other forms of systemic administration and accordingly will be presented in forms suitable for such.
  • pharmaceutical compositions intended for oral administration may be presented in soft gelatin capsules whilst the viscosity characteristics of some of the pharmaceutical compositions make them suitable for direct topical application.
  • Compositions suitable for oral or topical administration are especially prefered.
  • the present invention provides a composition
  • a composition comprising (a) a lipophilic phase having an oil which is a fatty acyl triglyceride and a low HLB surfactant which is a fatty acyl monoglyceride, a fatty acyl diglyceride, a sorbitan fatty acyl ester or a mixture thereof, in which the fatty acyl moieties are a mixture of medium and long chain fatty acyl moieties; (b) a high HLB surfactant; and (c) an aqueous hydrophilic phase in which each of (a), (b) and (c) are as hereinbefore defined and which on admixing form a stable, self-emulsifying water-in-oil (w/o) microemulsion which is liquid at room temperature.
  • the region of the phase diagram in which microemulsions were formed was determined by titrating a mixture of the oil and low HLB surfactant (in a fixed ratio) against the high HLB surfactant and the aqueous phase, noting points of phase separation, turbidity and transparency.
  • phase diagrams are shown as figures 2 to 8.
  • Figure 2 has already been mentioned. Phase diagrams were obtained for the systems nos. 8 and 9 but for these no clear and transparent (w/o) microemulsions were produced. A wide range of clear, transparent, liquid (w/o) microemulsions as shown by regions (A), (B) and (C) were available, for all but system no. 5 which gave only a (C) region. These were stable at room temperature and 37°C. When examined under polarized light, non-birefringent behaviour was observed.
  • phase diagrams show that microemulsions within the scope of the present invention are obtained for ratios of fatty acyl triglyceride to low HLB surfactant ranging from 4: 1 to 2: 1.
  • microemulsion existence regions for other systems may be readily determined by focussing on the ratios defined by regions (A), (B) and (C) rather than having to repeat the whole process and look at relative amounts well removed from these regions.
  • microemulsions were generally formulated by initially preparing the drug- containing hydrophilic phase, either by dissolving the appropriate amount of drug in the appropriate amount of saline solution or, more preferably, using a stock solution which was then further diluted if so required, 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 low HLB surfactant, to which was then added the high HLB surfactant, with gentle stirring (magnetic hot plate stirrer).
  • the hydrophilic phase containing the drug was added to the high HLB surfactant and following upon complete mixing, this was added to the oil plus low HLB surfactant mixture.
  • the drug-containing microemulsion was then diluted with the corresponding drug-free microemulsion to adjust the concentration of the drug. Batches were routinely prepared on a 5 or 10 g scale.
  • Example Drug Drug cone oil & low high HLB aqueous mg/g form.
  • HLB surfactant phase surfactant %(w/w) %(w/w)
  • formulations of the present invention are tested for GI irritation assessment with out an active ingredient by the following method:
  • Suitable rats for use in this assement are male Sprague-Dawley (Caesarian Delivery • Virus Antibody Free; Charles River Laboratories). The rats are fasted overnight the day before the experiment. Dosing with the microemulsion at the desired dose is done by gavage at a volume not exceeding 10 ml/kg. Upon termination of the experiment animals are euthanized with asphyxiation using carbon dioxide and exsanguinated. Abdominal incisions are then performed and gross observations of the gastric and duodenal mucosa are made at naked eyes and under a microscope (Nikon model SMZ-10 binocular microscope).
  • 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.
  • the formulations of the above noted Examples are given orally by gavage (preferably at three rats per formulation). After 24 hrs the animals are exsanguinated and upon abdominal incisions are examined both by naked eye and under the microscope. The mucosal surface of both the stomach and duodenum of the animals that received microemulsions containing CAPTEX/CAPMUL or CAPTEX/ARLACEL are examined to see if they are free of any lesions at naked eye.
  • microemulsions formulated as described above and containing, for instance, 3mg of peptide per gr of microemulsion are 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 ware allowed to recover from the surgery for 1 day.
  • Catherized rats are fasted for 18 hr prior to the experiment. Each rat receives 3mg of peptide by lateral tail- vein administration from a solution prepared as follows:
  • the 0 min. sample is taken 15 min prior to administration of the dose.
  • Plasma is removed from the whole blood by centrifugation at 16000Xg for 5 min, and then plasma is stored at -20°C in 250 ⁇ l aliquots per sample.
  • the blood pellet is reconstituted with heparinized saline and returned to the appropriate rat via catheter.
  • rats were euthanized with iv administration of pentobarbital.
  • Intraduodenal (i.d.) administration of peptide in microemulsion 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. c) Analysis of peptide plasma concentration
  • 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.
  • Dogs used in this assay are male Mongrels (i.e. from mixed breeds). The dog(s) are fasted overnight the day before die 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. When a blood sample is withdrawn, a 0.3 ml of blood is withdrawn into a separate 1 cc syringe before the actual sample so that dilution of the blood sample from the sodium citrate contained in the luer lock adapter is avoided.
  • 2.7 ml of blood are drawn in a 3 cc syringe and placed in a Venoject vacuum tube containing 0.3 ml of 3.8% sodium citrate and labelled with the appropriate time point.
  • the tube containing the blood sample in 3.8% sodium citrate is gendy inverted few times to mix components and then 1 ml is withdrawn for the whole blood aggregation assay.
  • the rest of the blood sample is transferred to an eppendroff tube and upon centrifugation the supernatant plasma is removed and transferred to a new tube which wis then frozen for subsequent HPLC analysis to determine peptide content.
  • 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 rpm.
  • the probe is placed firmly into the test cuvette and the lid is shut.
  • the stirring cuvette is permitted to settle for five minutes at which point 5 ⁇ l of collagen is added to the whole blood that is being stirred to yield to a 5 ⁇ g l final solution in the cuvette.
  • 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 die 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.
  • a microemulsion with a composition (w/w) in accordance with the Examples illustrated above is made. Upon preparation, it is further stored in a stable form at ambient temperature for approximately 48 hrs before the vivo evaluation. A control solution of a GHRP peptide, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, in saline at 1.5 mg/ml is also prepared.
  • Dosing is done by single intraduodenal administration of GHRP at 3 mg kg in male rats in saline solution (control) and in the aforementioned microemulsion using 3 rats in each case.
  • each rat Prior to actual sampling and dosing, each rat is anesthetized with Pentobarbitol at 50 mg/kg i.p, diluted witii saline to a final volume of 1 ml. The rats stay anesthetized for the entire experiment. Dosing is achieved in the following way: a small incision 2-3 cm long is made on the abdominal midline, and then a purse- string suture is placed on the duodenal muscle.
  • a small hole is made in the center of the purse-string suture in which a blunt 23 G stub needle attached to a tuberculin syringe is inserted to deliver the dose.
  • the purser-string is tied to close the opening. The incision is closed with wound clips.
  • a 0.2 ml blood sample is obtained via jugular catheter at the following intervals: -15, 0, 5, 10, 15, 30, 45, 60, 90, and 120 minutes. Blood samples are stored on ice and subsequently analyzed for Growth Hormone by an RIA method. Analysis of the samples generated from the experiment mentioned above need to have determined the pharmacological activity of GHRP. Positive data will indicate that Growth Hormone Releasing Peptide is orally active from the microemulsion formulation of the present invention. However, blood levels and actual bioavailability need to be correlated to observed pharmacological activity.
  • 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

L'invention se rapporte à des microémulsions pharmaceutiquement acceptables qui ont une phase lipophile dans laquelle l'huile et des tensio-actifs à faible équilibre hydrophile-lipophile (EHL) sont un mélange de composants d'acides gras à chaînes moyennes et à chaînes longues, de tensio-actifs à équilibre hydrophile-lipophile élevé (EHL), et d'une phase hydrophile comprenant un agent thérapeutique.
PCT/US1993/009963 1992-10-16 1993-10-15 Microemulsions therapeutiques WO1994008605A1 (fr)

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JP6510336A JPH08502492A (ja) 1992-10-16 1993-10-15 治療用ミクロエマルジョン
EP93923933A EP0666752A4 (fr) 1992-10-16 1993-10-15 Microemulsions therapeutiques.

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EP0753311A1 (fr) * 1993-04-19 1997-01-15 Institute For Advanced Skin Research Inc. Preparation en microemulsion contenant une substance difficilement absorbable
EP0788346A1 (fr) * 1994-03-18 1997-08-13 Pharmavene, Inc. Systemes d'administration de medicaments emulsionnes
EP0799620A1 (fr) * 1996-04-03 1997-10-08 Research Triangle Pharmaceuticals Ltd. Emulsions à base de cyclosporine
US5688761A (en) * 1991-04-19 1997-11-18 Lds Technologies, Inc. Convertible microemulsion formulations
WO1998000169A1 (fr) * 1996-07-02 1998-01-08 Cortecs (Uk) Limited) Preparations hydrophobes contenant des monoglycerides de chaine moyenne
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EP2098230A1 (fr) 1997-03-31 2009-09-09 Boston Scientific Scimed Limited Utlisation des inhibiteurs cytosquelettiques en forme cristalline pour l'inhibition ou la prévention de la resténose
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EP2292225A1 (fr) 1997-03-31 2011-03-09 Boston Scientific Scimed Limited Forme de dosage comprénant du taxol en forme cristalline
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CN101321472B (zh) * 2005-10-14 2013-09-18 天然香料公司 用于食品和饮料制品中的微乳剂
US8802087B2 (en) 2004-03-22 2014-08-12 Abbott Products Gmbh Pharmaceutical compositions of lipase-containing products, in particular of pancreation
WO2018159941A1 (fr) * 2017-03-02 2018-09-07 대화제약 주식회사 Composition pharmaceutique stable comprenant du zanamivir
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US5688761A (en) * 1991-04-19 1997-11-18 Lds Technologies, Inc. Convertible microemulsion formulations
US5444041A (en) * 1991-04-19 1995-08-22 Ibah, Inc. Convertible microemulsion formulations
US5633226A (en) * 1991-04-19 1997-05-27 Lds Technologies, Inc. Convertible microemulsion formulations
US5646109A (en) * 1991-04-19 1997-07-08 Lds Technologies, Inc. Convertible microemulsion formulations
EP0753311A1 (fr) * 1993-04-19 1997-01-15 Institute For Advanced Skin Research Inc. Preparation en microemulsion contenant une substance difficilement absorbable
EP0753311A4 (fr) * 1993-04-19 1997-05-21 Inst Advanced Skin Res Inc Preparation en microemulsion contenant une substance difficilement absorbable
US5948825A (en) * 1993-04-19 1999-09-07 Institute For Advanced Skin Research Inc. Microemulsion preparation containing a slightly absorbable substance
US5545569A (en) * 1993-05-13 1996-08-13 Neorx Corporation Prevention and treatment of pathologies associated with abnormally proliferative smooth muscle cells
US7094550B2 (en) 1993-05-13 2006-08-22 Neorx Corporation Method to determine TGF-beta
US5897876A (en) * 1994-03-18 1999-04-27 Shire Laboratories Inc. Emulsified drug delivery system
EP0788346B1 (fr) * 1994-03-18 2006-07-26 Shire Laboratories Inc. Systemes d'administration de medicaments emulsionnes
EP0788346A1 (fr) * 1994-03-18 1997-08-13 Pharmavene, Inc. Systemes d'administration de medicaments emulsionnes
US5952004A (en) * 1994-03-18 1999-09-14 Shire Laboratories Inc. Emulsified drug delivery systems
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US6187993B1 (en) 1995-02-25 2001-02-13 Imperial Cancer Research Technology Limited Transgenic animals as model of psoriasis
US5824638A (en) * 1995-05-22 1998-10-20 Shire Laboratories, Inc. Oral insulin delivery
US6008228A (en) * 1995-06-06 1999-12-28 Hoffman-La Roche Inc. Pharmaceutical compositions containing proteinase inhibitors
US5734770A (en) * 1995-06-29 1998-03-31 Minnesota Mining And Manufacturing Company Cleave and bevel fiber optic connector
EP0799620A1 (fr) * 1996-04-03 1997-10-08 Research Triangle Pharmaceuticals Ltd. Emulsions à base de cyclosporine
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