EP0684834A1 - Mikroemulsionen, die therapeutische peptide enthalten - Google Patents
Mikroemulsionen, die therapeutische peptide enthaltenInfo
- Publication number
- EP0684834A1 EP0684834A1 EP94909810A EP94909810A EP0684834A1 EP 0684834 A1 EP0684834 A1 EP 0684834A1 EP 94909810 A EP94909810 A EP 94909810A EP 94909810 A EP94909810 A EP 94909810A EP 0684834 A1 EP0684834 A1 EP 0684834A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- medium
- fatty acid
- die
- hlb surfactant
- chain fatty
- 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- Withdrawn
Links
- 239000004530 micro-emulsion Substances 0.000 title claims abstract description 139
- 108090000765 processed proteins & peptides Proteins 0.000 title claims description 72
- 102000004196 processed proteins & peptides Human genes 0.000 title description 31
- 230000001225 therapeutic effect Effects 0.000 title description 4
- 239000004094 surface-active agent Substances 0.000 claims abstract description 116
- 239000000203 mixture Substances 0.000 claims abstract description 108
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 83
- -1 polyol ester Chemical class 0.000 claims abstract description 68
- 229920005862 polyol Polymers 0.000 claims abstract description 38
- 150000004667 medium chain fatty acids Chemical class 0.000 claims abstract description 34
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical class OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 claims abstract description 31
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 16
- 239000008346 aqueous phase Substances 0.000 claims abstract description 14
- 150000008050 dialkyl sulfates Chemical class 0.000 claims abstract description 6
- 239000012071 phase Substances 0.000 claims description 43
- 239000003814 drug Substances 0.000 claims description 38
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 35
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000001931 aliphatic group Chemical group 0.000 claims description 26
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 21
- 239000002202 Polyethylene glycol Substances 0.000 claims description 21
- 229920001223 polyethylene glycol Polymers 0.000 claims description 21
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 20
- 239000000194 fatty acid Substances 0.000 claims description 20
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 18
- 229930195729 fatty acid Natural products 0.000 claims description 18
- 150000003077 polyols Chemical class 0.000 claims description 16
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 229940124597 therapeutic agent Drugs 0.000 claims description 13
- 150000004665 fatty acids Chemical class 0.000 claims description 12
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 11
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 11
- 229960002446 octanoic acid Drugs 0.000 claims description 11
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 10
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 8
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- 238000010521 absorption reaction Methods 0.000 claims description 7
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 claims description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 6
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 6
- 102000004877 Insulin Human genes 0.000 claims description 5
- 108090001061 Insulin Proteins 0.000 claims description 5
- 229940125396 insulin Drugs 0.000 claims description 5
- CTYRPMDGLDAWRQ-UHFFFAOYSA-N phenyl hydrogen sulfate Chemical compound OS(=O)(=O)OC1=CC=CC=C1 CTYRPMDGLDAWRQ-UHFFFAOYSA-N 0.000 claims description 5
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- 230000000699 topical effect Effects 0.000 claims description 5
- 108060001064 Calcitonin Proteins 0.000 claims description 4
- 102000055006 Calcitonin Human genes 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 claims description 4
- 229960004015 calcitonin Drugs 0.000 claims description 4
- 238000013268 sustained release Methods 0.000 claims description 4
- 239000012730 sustained-release form Substances 0.000 claims description 4
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- GXBMIBRIOWHPDT-UHFFFAOYSA-N Vasopressin Natural products N1C(=O)C(CC=2C=C(O)C=CC=2)NC(=O)C(N)CSSCC(C(=O)N2C(CCC2)C(=O)NC(CCCN=C(N)N)C(=O)NCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(CCC(N)=O)NC(=O)C1CC1=CC=CC=C1 GXBMIBRIOWHPDT-UHFFFAOYSA-N 0.000 claims description 3
- 108010004977 Vasopressins Proteins 0.000 claims description 3
- 102000002852 Vasopressins Human genes 0.000 claims description 3
- 150000001413 amino acids Chemical group 0.000 claims description 3
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 claims description 3
- 150000005690 diesters Chemical class 0.000 claims description 3
- 229960000878 docusate sodium Drugs 0.000 claims description 3
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 3
- 229940043264 dodecyl sulfate Drugs 0.000 claims description 3
- 229960003726 vasopressin Drugs 0.000 claims description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 125000003450 decanoic acid ester group Chemical group 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- 150000005846 sugar alcohols Polymers 0.000 abstract description 4
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- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 22
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- 239000000523 sample Substances 0.000 description 20
- CDOUZKKFHVEKRI-UHFFFAOYSA-N 3-bromo-n-[(prop-2-enoylamino)methyl]propanamide Chemical compound BrCCC(=O)NCNC(=O)C=C CDOUZKKFHVEKRI-UHFFFAOYSA-N 0.000 description 19
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 19
- 150000002148 esters Chemical class 0.000 description 18
- 238000010587 phase diagram Methods 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
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- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
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- 102100033367 Appetite-regulating hormone Human genes 0.000 description 8
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- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 6
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000006557 surface reaction Methods 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- WBWWGRHZICKQGZ-HZAMXZRMSA-M taurocholate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-M 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940093609 tricaprylin Drugs 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 239000002996 urinary tract agent Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- QYEFBJRXKKSABU-UHFFFAOYSA-N xylazine hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1NC1=NCCCS1 QYEFBJRXKKSABU-UHFFFAOYSA-N 0.000 description 1
- 239000002888 zwitterionic surfactant Substances 0.000 description 1
- WHNFPRLDDSXQCL-UAZQEYIDSA-N α-msh Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(N)=O)NC(=O)[C@H](CO)NC(C)=O)C1=CC=C(O)C=C1 WHNFPRLDDSXQCL-UAZQEYIDSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
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
- A61K38/39—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
- Microemulsions Comprising Therapeutic Peptides.
- This invention relates to pharmaceutically acceptable water-in-oil (w/o) self-emulsifyi microemulsions containing therapeutic agents, 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, an oil, water, a surfactant, a cosurfactant and an electrolyte.
- the tendency towards a water-in-oil (w/o) or an oil-in-water (o/w) microemulsion is dependent on the properties of the oil and die surfactant.
- Surfactants are conveniently classified on an empirical scale known as the hydrophilic-lipophilic balance (HLB) which runs from 1 to 45.
- HLB hydrophilic-lipophilic balance
- microemulsions are formed using surfactants (or emulsifiers) which have an HLB value in the range of about 3 to 6 while (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.
- interfacial tension is less than 2 x 10 ⁇ 2 dyn/cm, a stable microemulsion can form.
- Microemulsions are typically substantially non-opaque, i.e. are transparent or opalesce when viewed by optical microscopic means. In the undisturbed state, they are opticall isotropic (non-birefiringent) 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 consequendy creating a disordered film 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., InL
- 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.
- 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 but to give an oil-in-water rather than a water-in-oil microemulsion.
- 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 (C 10-22)- fatty acid esters of (C3-i8)-alcohols such as hexyl laurate, (Ci2-32)-hydrocarbons such as squalene and mono- or diesters of glycerol with a (C6-22) carboxylic acid such as glyceryl caprylate (which may also act as a co-emulsifier).
- C6-22 fatty acid esters of (C3-i8)-alcohols such as hexyl laurate, (Ci2-32)-hydrocarbons such as squalene and mono- or diesters of glycerol with a (C6-22) carboxylic acid such as glyceryl caprylate (which may also act as a co-emulsifier).
- US 4 712 239 (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 (C ⁇ - 2 2 ) 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 Ethylene oxide (20 EO)-oleic acid glycerol partial esters (40%), caprylic-capric acid glycerol partial esters (42% monoglyceride content, 24%), medium-chain triglycerides (16%) and water (20%). It is to be noted that the ratio of the medium-chain triglyceride to the caprylic-capric acid glycerol partial esters is 1:1.5. In comparison example 1, this is formulated widi the drug arecaidine /.-propyl ester HC1 salt.
- a further example incorporates a macromolecule, the polypeptide hirudin but in this, the oil is w ⁇ -propyl palmitate.
- WO 88/00059 discloses controlled release compositions for biologically active materials comprising an "L2-phase” and containing an unsaturated (Ci6-22)-fatty acid monoglyceride and an unsaturated (Ci6-22)-fatty acid triglyceride, in a ratio of from 1:1 to 3:1, and a polar liquid such as water.
- an unsaturated (Ci6-22Matty acid monoglyceride is a low HLB surfactant and there is no mention of the additional inclusion of a high HLB surfactant.
- a long-chain rather than a medium-chain derivative is used.
- DSS Dioctyl sodium sulfosuccinate
- Docusate Sodium or Aerosol OT is widely used as a solubilizing, wetting, emulsifying or dispersing agent.
- Known pharmaceutical uses of DSS include: a) as a therapeutic agent, alone or as an adjuvant in the prevention or treatment of constipation, b) as a tablet formulation adjuvant to facilitate tablet coating and improve tablet disintegration and dissolution characteristics, and c) as an absorption enhancer.
- DSS has been reported to increase the small intestinal absorption of heparin (Engel, R.H. ej a ; J. Pharm. Sci. 58, 706-710, 1969), insulin (Dupont, A.
- EP-387647 (Matouschek, R.) describes pharmaceutical microemulsion compositions containing acidic or basic drug and compound forming ion-pairs for nasal, rectal or transdermal delivery.
- Suitable oils included isopropyl myristate, 2-octyl dodecanol and paraffin oil with the surfactant comprising polyoxyethylene fatty acid ester and/or polyoxyethylene fatty alcohol ether.
- the cosurfactant used was polyoxyethylene glycerol fatty acid ester with water being the aqueous phase.
- the compound forming an ion-pair was sulphate.
- compositions which have improved solubility, stability and/or particle size for the oral delivery of therapeutic agents, in particular for peptides, is still needed.
- microemulsions having a lipophilic phase having certain relative amounts of medium-chain fatty acid propylene glycol and/or polyol esters and low HLB surfactant, in combination with a high HLB surfactant and an aqueous-based hydrophilic phase.
- the present invention provides a pharmaceutically acceptable, stable, self- emulsifying microemulsion comprising:
- a lipophilic phase comprising medium-chain fatty acid propylene glycol and/or polyol esters and a low HLB surfactant, in which the ratio of the medium-chain fatty acid propylene glycol and/or polyol esters to the low HLB surfactant is from 5:1 to 1.5:1;
- an admixture of a polyol and at least one high HLB surfactant which is i) a sulfate or pharmaceutically acceptable salt thereof, which is an aliphatic sulfate, an aryl sulfate, an aliphatic-aryl sulfate, or mixtures thereof; ii) a sulfonate or pharmaceutically acceptable salt thereof, which is an aliphatic sulfonate, or aryl sulfonate, an aliphatic-aryl sulfonate, or mixtures thereof; iii) a sulfosuccinate or pharmaceutically acceptable salt thereof, which
- Figure 1 illustrates a pseudo-ternary phase diagram reading of a microemulsion system containing an oil and a low HLB surfactant in a fixed ratio X, a high HLB surfactant and an aqueous phase.
- Figure 2 illustrates a pseudo-ternary phase diagram of the microemulsion system CAPTEX 200/CAPMUL C8 as the oil low HLB surfactant in a ratio of 2 to 1, labelled as component (1); DSS/PEG 400 (1:1) as the high HLB surfactant, labeled as component (3); and water as the aqueous phase, labeled as component (2).
- microemulsions of the present invention without a biologically therapeutic drug arc novel and useful as precursors to drug-containing microemulsions. Accordingly, the present invention provides for a stable, self-emulsifying water-in-oil (w/o) or oil-in-water (o/w) microemulsion comprising:
- a lipophilic phase comprising a medium-chain fatty acid propylene glycol ester and/or a medium-chain fatty acid polyol esters, or mixtures thereof, and a low HLB surfactant; in which the ratio of the medium-chain fatty acid propylene glycol and/or polyol esters to the low HLB surfactant is from 5:1 to 1.5:1;
- a polyol and at least one high HLB surfactant which is i) a sulfate or pharmaceutically acceptable salt thereof, which is an aliphatic sulfate, an aryl sulfate, an aliphatic-aryl sulfate, or mixtures thereof; ⁇ ) a sulfonate or pharmaceutically acceptable salt thereof, which is an aliphatic sulfonate, or aryl sulfonate, an aliphatic-aryl sulfonate, or mixtures thereof; iii) a sulfosuccinate or pharmaceutically acceptable salt thereof, which is an aliphatic sulfosuccinate, an aryl sulfosuccinate, an aliphatic-aryl sulfosuccinate, or mixtures thereof; or iv) a mixture of any of i), and/or ii), and or iii) above;
- the present invention provides for a pharmaceutically acceptable, stable, self -emulsifying microemulsion comprising each of (a), (b) and (c) above and (d) a water-soluble therapeutic agent.
- microemulsion of an aliphatic, preferably a medium chain alkyl or dialkyl, sulfate or sulfonates or sulfosuccinate is believed to enhance the absorption of a biologically active agent when administered in d e above formulations, particularly in reference to field A in Figure 2.
- Suitable medium-chain fatty acid propylene glycol and/or polyol esters for use in the present invention may be of natural, semi-synthetic or synthetic origin and may include blends of different medium chain fatty acid esters, and/or medium and long chain fatty acid esters. Such blends include not only physical blends of medium- and long-chain fatty acid esters but also esters which have been chemically modified, by for instance, interesterification, to include a mixture of medium- and long-chain fatty acyl moieties. Suitable esters 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 esters.
- Prefered lipophilic phase medium chain esters for use herein include those which are either propylene glycol based or polyethylene based. Such examples include those available under the trade names MYRITOL; CAPTEX (Karlshams Lipid Specialties, Columbus OH), for instance CAPTEX 200; MIGLYOL (BASF), for instance the grades MIGLYOL 840; SOFITIGEN (Huls America Inc., Piscataway NJ), for instance SOFTIGEN 767; LABRAFAC and LABRASOL (Gattefosse Corp., Westwood, NJ), for instance LABRAFAC CM- 10.
- Propylene glycol examples are CAPTEX 200 and Miglyol 840 are propylene glycol dicaprylate/dicaprate systems.
- PEG based systems are Softigen 767, which is a PEG-6 Caprylic/Capric Glyceride system; LABRAFAC CM-10 are the glycerol and PEG esters of C ⁇ and Cio fatty acids, and LABRASOL is a PEG-8 Caprylate/Caprate glyceride ester system.
- polyol as in “polyol ester” in the lipophilic phase is a compound which contains one or more ester linkages derived from a polyhydric alcohol, i.e. a carbon backbone containing two or more hydroxyl groups.
- Such carbon backbones for making such esters include but not limited to, ethylene glycol, propylene glycol or polyethylene glycol (PEG).
- PEG is also referred to as a polyglycol widi ethylene glycol as a polymerized unit.
- the polyol is propylene glycol or a polyethylene glycol.
- intermediate-chain such as in “medium-chain fatty acid”
- “medium-chain fatty acid” refers to a carbon chain, which may be saturated, mono-unsaturated or poly-unsaturated, having from 6 to 12, preferably from 8 to 10 carbon atoms, which may be branched or unbranched, preferably unbranched, and which chain may be optionally substituted.
- Optional substituents include for instance, halogen, hydroxy, alkoxy, thioalkyl or halo substituted alkyl.
- Halogen as used herein includes F, Cl, Br and I.
- long-chain such as in “long-chain fatty acid”
- long-chain fatty acid refers to a carbon chain,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 as noted above for medium chain fatty acids.
- a non-ionic high HLB surfactant may be usefully included as an auxiliary high HLB surfactant
- the non-ionic high HLB surfactant has an HLB in the range of 15 to 45.
- the ratio of the aliphatic or aryl or aliphatic-aryl sulfate or sulfonate or sulfosuccinate to the non-ionic high HLB surfactant is at from 10:1 to 1:1. Preferably from 10:1 to 3:1 and most preferably about 10:1.
- Suitable low HLB surfactants for use in the present invention include fatty acyl monoglycerides, fatty acyl diglycerides, sorbitan medium or 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 acid 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 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 die 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 C8 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 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 IMWTTOR 308 (Huls America, Inc.) which has about 80-90% WL caprylic monoglycerides; and Glycerol Monocaprylin, manufactured as 1-monoctanoyl-rac- glycerol (Sigma Chemicals) having about 99% wt. caprylic monoglycerides; and Glycerol Monocaprate, manufactured as 1-monodecanoyl-rac-glycerol (Sigma Chemicals) having about 99% wt. capric monoglycerides.
- IMWTTOR 308 Huls America, Inc.
- Glycerol Monocaprylin manufactured as 1-monoctanoyl-rac- glycerol (Sigma Chemicals) having about 99% wt. caprylic monoglycerides
- Glycerol Monocaprate manufactured as 1-monodecanoyl-rac-glycerol (Sigma Chemicals) having about 99% wt. capric monoglycerides.
- 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) andl8-99 (a rapeseed oil monoglyceride), MYVATEX and MYVAPLEX, respectively, from Eastman Kodak
- a further useful long-chain fatty acyl 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 18-92 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 Cis-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 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 sorbitan medium-chain esters for use in the present invention include sorbitan caprylate, sorbitan caprate, sorbitan laurate.
- Suitable medium-chain fatty acids for use in the present invention include caprylic and capric acids and mixtures thereof.
- the low HLB surfactant will have an HLB value in the range of about 2 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.
- the estimated HLB of 1-monocaprylin is about 8.0.
- 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 200, Miglyol 840, Softigen 767, Labrafac CM-10, and Labrasol , and particularly CAPTEX 200, with CAPMUL MCM or CAPMUL C ⁇ , particularly CAPMUL C8-
- a self-emulsifying (w/o) microemulsion according to the present invention of a low HLB surfactant which is a medium-chain fatty acid monoglyceride and/or a medium- chain fatty acid diglyceride as hereinbefore defined and which is a component of the lipophilic phase provides for reduced droplet size and together with the high HLB surfactant this is believed to aid in the absorption of the therapeutic agent
- the present invention provides for a microemulsion in which the medium-chain fatty acid propylene glycol and/or polyol ester is a caprylic acid or a blend of caprylic and capric acids esters as hereinbefore defined and in which the low HLB surfactant is a medium-chain fatty acid monoglyceride or diglyceride or a mixture thereof in which the medium-chain fatty acid is caprylic acid or a mixture of caprylic and capric acids as hereinbefore defined, optionally admixed with a small amotmt of medium- chain fatty acid, in particular, a blend of caprylic acid triglyceride and caprylic acid monoglyceride or diglyceride or mixture thereof.
- the high HLB surfactant for use in the present invention is an aliphatic, aryl or an aliphatic-aryl sulfate, sulfonate or sulfosuccinate.
- the aliphatic moiety is a medium or long chain alkyl or dialkyl group.
- the medium chain moiety contains C to 12- preferably 8 to 10 carbons, and the long chain moiety contains from C12 to 24 » preferably 14 to 18 carbons as previously defined.
- the aliphatic chain may be branched or unbranched, may be optionally substituted, and may be saturated, mono-unsaturated or poly-unsaturated.
- the aliphatic moiety is of medium chain length.
- linkages possible with the sulfate, sulfonate and sulfosuccinate groups for use herein.
- One is designated as a fatty acyl ester linkage and the other an ester linkage. If the aliphatic or aryl moiety forms an fatty acyl ester linkage with the sulfate, sulfonate or sulfosuccinate, i.e. contains an additional carbonyl [C(O)] group, the aliphatic (or aryl) group becomes known as the fatty acid portion of the ester linkage.
- a fatty acyl ester linkage is for instance, a C6-12-C (O) - O S(O)3Na+ .
- This is in contrast to the generally recognized linkage of C6-12 C-O - S(O)3Na+, referred to herein as the ester linkage.
- This terminology stems from the reaction of a C6-12 OH moiety with the sulfonic acid O-S(O)2 " Na + group forming a sulfonic ester.
- the linkage is an ester linkage and not a fatty acyl ester linkage. More preferably the linking group is a medium chain alkyl or dialkyl moiety.
- aryl sulfate, sulfonate or sulfosuccinate means a phenyl or naphthyl moiety.
- Suitable aryl sulfonates include, for instance, benzene sulfonate.
- aliphatic-aryr As more than one site for attachment is possible with the sulfates, sulfonates and sulfo ⁇ succinates another aspect of the invention is the use of mixtures of aliphatic and aryl linkages in the same moiety, such as dodecyl benzene sulfate. This combination as used herein is referred to as "aliphatic-aryr.
- the aliphatic moiety in this instance is a medium chain alkyl or dialkyl group.
- Suitable long chain alkyl or dialkyl sulfates, sulfonates and sulfosuccinates include, but are not limited to myristic (C14), palmitic (C16), palmitoleic (C16:l), stearic (C18), oleic (C18:l), vaccenic (trans oleic acid) or linoleic (C18:2) .
- the alkyl and dialkyl moieties may be mixtures of different medium and long chain moieties, such as a dialkyl sulfate having a C12 and a C16 group.
- the sulfates, sulfonates and sulfosuccinates are medium chain alkyl or dialkyl derivatives.
- Suitable medium chain moieties include, but are not limited to octyl (C ⁇ ), decyl (Cio), dodecyl (C12), iso-octoanoic, or di-octyl, di-decyl, or di-dodecyl.
- the medium chain moiety is octyl, decyl, dodecyl, or dioctyl.
- the high HLB is a octyl, decyl, dodecyl or di-octyl sulfosuccinate, or is a octyl, decyl, or dodecyl sulfate.
- Yet another aspect of the instant invention is the combination of mixtures of the different aliphatic, aryl or aliphatic-aryl sulfates, sulfonates and sulfosuccinates as the high HLB surfactant used herein.
- the sulfates, sulfonates, or sulfosuccinates will be pharmaceutically acceptable water-soluble salts, for instance alkali metal salts, such as sodium and potassium salts, or ammonium or quaternary ammonium salts also referred to as N(R)4 wherein R is an alkyl derivative, or is a primary and secondary (protonated) amine salt, such as ethanolamine or triethanolamine.
- the salts are the alkali metal salts.
- the salts are salts of the medium chain alkyl or dialkyl sulfates, such as octyl, decyl, dioctyl, or dodecyl sulfate; or the salts of the dialkyl sulfosuccinates such as noted above, of which the salts sodium dioctyl sulfosuccinate and sodium dodecyl sulfate are preferred.
- Sodium dioctyl sulfosuccinate (DSS) and sodium dodecyl sulfate (SDS) have estimated HLB values of 41 and 40 respectively.
- die term "polyol” is a polyhydric alcohol, i.e. containing two or more hydroxyl groups. Such as but not limited to, ethylene glycol, propylene glycol or polyediylene glycol (PEG). PEG is also referred to as a polyglycol with ethylene glycol as a polymerized unit. Preferably, the polyol has three or more alcoholic units and is glycerol or a PEG. More preferably, the polyol is a PEG having a molecular weight of 400 (PEG-400).
- Other suitable polyhydric alcohol's for use herein include, but not limited to, ediylene glycol (2-OH units), sorbitol (6-OH), and mannitol (6-OH).
- the ratio of the sulfates, sulfonates, or sulfosuccinates to the polyol is from about 10:1 to 1:1, preferably about 1:1.
- DSS Commerically available DSS includes all in USP grades DSS (100%), DSS 85% surfactant (with 15% sodium benzoate) or DSS (50%) in PEG 400 (1:1).
- the admixture for use herein is a polyol wim at least one high HLB surfactant which is a sulfate, or a sulfonate, or a sulfosuccinate or pharmaceutically acceptable salts thereof.
- the sulfate moiety, or a pharmaceutically acceptable salt thereof may be an aliphatic sulfate, an aryl sulfate, an aliphatic-aryl sulfate, or a mixture thereof.
- the sulfonate or pharmaceutically acceptable salt thereof may be an aliphatic sulfonate, aryl sulfonate, an aliphatic-aryl sulfonate, or a mixture thereof.
- the sulfosuccinate or pharmaceutically acceptable salt thereof may be an aliphatic sulfosuccinate, an aryl sulfosuccinate, an aliphatic-aryl sulfosuccinate, or a mixture thereof.
- the high HLB surfactant may be a mixture of any of the above noted sulfates, sulfonates or sulfosuccinates and tiieir pharmaceutically acceptable salts thereof. Such a mixture could be referred to as binary or ternary mixture of the sulfate groups, the sulfonate groups or sulfosuccinate groups.
- the preferred high HLB is a medium chain alkyl or dialkyl sulfate, sulfonate or sulfosuccinate or pharmaceutically acceptable salts thereof.
- the total amount of high HLB surfactant which is a sulfate, sulfonate and sulfosuccinate should comprise at least 50% of die total amount by weight of high HLB surfactant required to be present in the formulation. It is recognized tiiat other high HLB surfactants may be present in the formulation and are further described herein. Suitably, the total amount of high HLB surfactant present should range from about 5 % to about 30% (w/w) and from about 70% to less than 100% (w/w). It is of tiiese amounts that at least 50% (w/w) should be comprised of me sulfate, etc. surfactants. Any additional non-ionic, ionic and zwitterionic surfactants should comprise no more than 50% of the total high
- HLB surfactant present in the formulation, preferably 10% or less.
- the high HLB surfactant may contain additional excipients or co-surfactants and include, but are not limited to die
- non-ionic surfactants such as
- polyoxyethylene fatty acid esters for example polyoxyethylene stearic acid esters of the type available under d e trade name MYRJ (ICI Americas, Inc.), for instance the product MYRJ 52 (a polyoxyethylene 40 stearate);
- polyoxyetheylene-sorbitan fatty acid esters polysorbates
- polysorbates for example the mono- and tri-lauryl, palmityl, stearyl and oleyl esters, for instance the polyoxyethylene sorbitan monooleates available under die 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
- PEG glycerol ediers such as the polyethylene glycol long-chain alkyl ethers, which include polye ylated glycol lauryl etiier, and PEG fatty alcohol ethers; and
- PEG glycerol esters and PEG fatty acid esters such as the long-chain alkyl esters, which include PEG-monostearate;
- the surfactant system may contain additional surfactants and include, but not limted to:
- cationic surfactants such as cetyl ammonium bromide (CTAB) or benzalkonium bromide;
- anionic surfactants such as bile salts and die alkali metal salts thereof, including but not limited to cholate, deoxycholate, taurocholate, etc., sodium taurocholate and C6-18 fatty acyl carnitines; or
- low HLB surfactants such as other lipids, i.e., phospholipids which may be anionic, cationic or zwitterionic, in particular lecithins, such as soya bean lecithins, egg lecithin or egg phosphatide, cholesterol or long-chain fatty acids such as oleic acid.
- lecithins such as soya bean lecithins, egg lecithin or egg phosphatide, cholesterol or long-chain fatty acids such as oleic acid.
- the term "therapeutic agent” refers to any compound which has biological activity, is soluble in me 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 d e hydrophilic radier than the lipophilic phase.
- drug refers to any compound which has biological activity, is soluble in me 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 d e hydrophilic radier 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.
- peptides having from 2 to 35 amino acid moieties are especially preferred.
- 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 die fibrinogen receptor antagonists (RGD containing peptides) which are tetrapeptides witii 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-(N a -memyl)Arg-Gly-Asp-Pen-NH2 (Ali et al., EP 0 341 915, whose disclosure is herein incorporated by reference in its entirety) and d e peptide cyclo(S,S)-(2-mercapto)benzoyl-(N a -methyl)Arg-Gly-Asp-(2- mercapto)phenylamide (EP 0423 212, whose disclosure is herein incorporated by reference in its entirety).
- fibrinogen antagonists useful in the present invention are diose 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 die 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.
- Otiier peptides useful in die present invention include, but are not limited to, other RGD containing peptides such as tiiose disclosed by Momany, U.S. 4,411,890 and U.S. 4,410,513; Bowers et al, U.S. 4,880,778, U.S. 4,880,777, U.S. 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 die peptides disclosed by Momany, U.S. 4,228,158, U.S. 4,228,157, U.S. 4,228,156, U.S. 4,228,155, U.S. 4,226,857, U.S.
- Otiier suitable peptides include hexapeptides such as d e growth hormone releasing peptide (GHRP) His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2 , (Momany, US 4,411,890, the disclosure of which is herein incorporated by reference in its entirety). This may usefully be included in an amount up to about 250mg/g of the hydrophilic phase or from 0.1 to 25mg/kg 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 tiiereof.
- Odier suitable larger polypeptides include tiiose disclosed by Pierschbacher et al, U.S. 4,589,881 (>30 residues); Bitde et al, U.S. 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 endodielin 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;
- Otiier suitable drugs include non-peptide tiierapeutic agents such as antibotics, 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), a vasopressin, a calcitonin or an insulin, more preferably the fibrinogen receptor antagonist peptides cyclo(S,S)-N a -acetyl-
- a fibrinogen receptor antagonist 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
- fibrinogen receptor antagonist peptide cyclo(S,S)-N a -acetyl-
- the present invention provides microemulsions comprising a peptide which may be orally administered and which will retain biological activity, tiiereby overcoming the disadvantages of earlier formulations in which die bioavailability of the peptide has been less tiian satisfactory.
- die present invention provides formulations which by tiieir nature permit the preparation and administration of a peptide in suf ⁇ iciendy high concentration to allow not only convenient oral administration but also adequate bioavailability of the peptide.
- die degree of incorporation into die (w/o) microemulsions 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 d e proper modification of the PEG (400) and die high HLB surfactant salt ratio, in particular the medium chain alkyl/ dialkyl, sulfate or sulfonate or sulfosuccinates, 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 witii the selected lipophilic phase, such as polyediylene glycol, propylene glycol, sorbitol, mannitol and otiier mono- or di-saccharides.
- a pharmaceutically acceptable solvent which is non-miscible witii the selected lipophilic phase, such as polyediylene glycol, propylene glycol, sorbitol, mannitol and otiier mono- or di-saccharides.
- (1) represents the mixture of the oil and die low HLB surfactant, at a fixed ratio X, (2) die hydrophilic (aqueous) phase and (3) die high HLB surfactant.
- 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 die present invention exist may be determined by titrating a mixture of the oil and low HLB surfactant (in a fixed ratio) against die high HLB surfactant and die 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 die specific nature of the components employed.
- phase diagram of systems containing a medium-chain oil (CAPTEX 200TM) and low HLB surfactant (CAPMUL C8TM) in the ratios of 2:1, high HLB surfactant (DSS/PEG 400) in a ratio of 1 : 1, and water is shown in Figure 2.
- the mixture of oil plus the low HLB surfactant is indicated as component (1), water as component (2) and die high HLB surfactant as component (3).
- This system produces a wide range of clear, transparent microemulsions which are shown in the phase diagram as the microemulsion field whose field may be usefully be sub-divided into three fields or regions (A), (B) and (C).
- This sub-division is based primarily on differences in conductance, viscosity and dilutability in the presence of excess water. Both the viscosity and conductance increase from regions (A), (B) and (C). In the presence of excess of die dispersed phase (saline or water), microemulsions of regions (A) and (B) are inverted to turbid emulsions (o/w) indicative of their original (w/o) nature. In contrast, microemulsions from region (C) remain clear, characteristic of an oil-in-water isotropic system (microemulsion). Microemulsions within die scope of die present invention are those falling within regions
- the present invention provides for stable, self- emulsifying microemulsions as hereinbefore defined in which die relative proportions of the various components lie witiiin regions (A), (B) and (C) of die pseudo-ternary phase diagram in Figure 2.
- stable clear, transparent liquid microemulsions are obtained when die oil plus low HLB surfactant is present in the range from about 5% to less tiian 100% , die high HLB surfactant from about 5% to less than 100% and die aqueous hydrophilic phase, i.e. water or saline is from about 0.1% to less than 50% (w/w) of the microemulsion.
- the medium-chain fatty acid propylene glycol and/or polyol ester and die low HLB surfactant togedier comprise from about 5% to less than 100%, (w/w) of the microemulsion. Preferably, from about 30% to about less than 100%, more preferably from about 60% to less than 95%.
- the medium-chain fatty acid propylene glycol and/or polyol esters and die low HLB surfactant may be combined and mixed at various ratios.
- Useful (w/o) microemulsions may be obtained when die ratio of medium-chain fatty acid 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. It may be found that as die ratio of medium-chain fatty acid propylene glycol and/or polyol ester to low HLB surfactant is increased towards 5:1, region (C) of die microemulsion existence field becomes increasingly predominant
- the high HLB surfactant is present in the range of about 5 to less than 100%, prefeably from about 5% to less than 70%, and more preferably from about 5% to less than 40%.
- die high HLB surfactant will be admixed witii a polyol in a 10:1 to 1:1 ratio, preferably in a 5:1 to 1:1 ratio, more preferably in a 5:1 to 2:1, and most preferably 1:1 ratio.
- the hydrophilic phase comprises from just greater than 0 to about 50%, preferably from about 0.1 to about 20%, and more preferably from about 0.1% to about 10% (w/w) of the microemulsion. It will be readily appreciated by die 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.
- die ratio of medium-chain fatty acid fatty acid propylene glycol and/or polyol ester to low HLB surfactant is preferably between 4:1 and 2:1.
- microemulsions of the present invention are substantially non-opaque, that is tiiey 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, widiout 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 die corresponding peptide-free microemulsions.
- Stable (w/o) microemulsions may be formed when die pH of die aqueous phase varies from a pH of approximately 3 to about 8, a property that can be beneficial for drugs exhibiting higher solubility at low or high pH.
- the micro-emulsions are of varying viscosity.
- 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 die range 5 to 35 nm.
- the various phases may optionally contain minor amounts of further ingredients, such as, but not limited to: i) antioxidants such as n-propyl gallate, butylated hydroxyanisole (BHA) and mixed isomers thereof, d-a-tocopherol and mixed isomers tiiereof, ascorbic acid, propylparaben, methylparaben and citric acid (monohydrate); ii) stabilizers, such as hydroxypropyl cellulose; iii) antimicrobials, such as benozoic acid (sodium salt); and iv) protease inhibitors such as aprotinin.
- antioxidants such as n-propyl gallate, butylated hydroxyanisole (BHA) and mixed isomers thereof, d-a-tocopherol and mixed isomers tiiereof, ascorbic acid, propylparaben, methylparaben and citric acid (monohydrate); ii) stabilizers, such as
- microemulsions of the present invention form spontaneously or substantially spontaneously when their components are brought into contact, that is without die 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.
- die microemulsions may be readily prepared by die simple process of admixing appropriate quantities, widi gende hand mixing or stirring if necessary to ensure thorough mixing.
- the drug is dissolved in die hydrophilic phase, either directly or by dilution of a stock solution thereof and tiiis may then be added to a pre-mixed combination of die oil and die low HLB surfactant widi 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 tiien be added further hydrophilic phase in which the drug is dissolved. While higher temperatures (40-60°C) may be needed to solubilize all components during die preparation of die microemulsion, the preferred systems may be formulated at room temperature. Formulation at ambient temperature is particularly advantageous for thermolabile active ingredients such as peptides.
- Microemulsions of the present invention are pharmaceutical compositions which comprise a dierapeutic agent and are dierefore intended for use in therapy, for administration to animals, including man.
- die present invention provides a metiiod of treatment which comprises administering an effective amount of a microemulsion as hereinbefore defined comprising a dierapeutic agent to a patient in need thereof .
- Another aspect of die present invention is d e use of a formulation as hereinbefore defined for the controlled or sustained release of a dierapeutic agent where so desired to a patient in need tiiereof.
- the amount of drug required for therapeutic effect on administration will, of course, vary with the agent chosen, die nature and severity of the condition and the animal undergoing treatment, and is ultimately at die discretion of die physician.
- die optimal quantity and spacing of individual dosages of a drug will be determined by die nature and extent of die condition being treated, die form, route and site of administration, the particular patient being tteated and tiiat such optima can be determined by conventional techniques.
- tiiat die optimal course of treatment that is, die number of doses given, can be ascertained by tiiose skilled in the art using conventional course of treatment determination tests.
- the present invention also provides for d e use of a medium-chain fatty acid propylene glycol and/or polyol ester, a low HLB surfactant, a high HLB surfactant, a therapeutic agent and a hydrophilic phase as hereinbefore defined in the manufacture of a medicament.
- Microemulsions 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.
- microemulsions intended for oral administration may be presented in soft gelatin capsules while the viscosity characteristics of some of the microemulsions make them suitable for direct topical application.
- Compositions suitable for oral or topical administration are especially prefered.
- drug-free microemulsions examples and examples (drug-containing microemulsions) and biological examples.
- a Pseudo-ternary phase diagrams was constructed for d e representative system comprising: a) medium-chain fatty acid CAPTEX 200 diesters of propylene glycol (oil) b) low HLB surfactant CAPMUL C8 c) high HLB surfactant DSS/PEG 400 (1 : 1) d) aqueous phase water
- die high HLB surfactant may be DSS pure or DSS plus 15% sodium benzoate solublized in PEG 400 or another polylol in ratios ranging from 10: 1 to 1:1.
- phase diagram The regions of the phase diagram in which microemulsions according to the present invention exist were determined by titrating a mixture of the oil and low HLB surfactant (in a fixed ratio) against the high HLB surfactant and die aqueous phase, noting points of phase separation, turbidity and transparency.
- the resultant phase diagram is shown as figures 2. When examined under polarised light non-birefringent behaviour was observed.
- Formulations having the following compositions can be prepared in accordance widi die description below or as described herein.
- Examples 1-5 describe w/o microemulsions comprising CAPTEX 200 and CAPMUL C8
- Example 1 lies, for instance, in region A of a suitably prepared pseudo ternary phase diagram, Example 2 formulation within region C, Example 3 within region C and Examples 4 and 5 within region A.
- the aqueous phase can be an isotonic solution at pH ranging from 3 to 8.
- microemulsions were formulated by adding the hydrophilic phase to die solution of dioctyl sodium sulfosuccinate in PEG. To this mixture the oil plus the low HLB surfactant mixture was subsequently added and thoroughly mixed by hand shaking to produce a clear and transparent microemulsion.
- die hydrophillic phase can be added to die appropriate amounts by weight of a mixture of the oil and d e low HLB surfactant, to which was then added die high HLB surfactant, with gende stirring (magnetic hot plate).
- Active ingredient incorporating microemulsions can be prepared in a similar manner to mat shown above, by eimer dissolving die appropriate amoung of the drug in the appropriate amount of the aqueous phase or preferably, using a stock solution which was then further diluted if so required, and with vortex stirring if necessary to obtain complete diss solution.
- anodier aspect of the present invention is die use of a microemulsion formulation as herein before defined for use in the controlled release or sustained release of a thereaputic agent where desired.
- Intravenous (i.v.) or intraduodenal (i.d.) administration of the compound (in this instance Calcein) either from a solution of a microemulsion is carried out using conventional methods.
- fasted rats are anesthetized widi an intraperitoneal injection of a mixture of Rompun (5mg kg) and Ketset (35mg/kg) and a jugular catheter is implanted. Rats are allowed to recover from surgery for 1 day.
- Catherized rats were fasted for 18 hr prior to the administration of die compound. Each compound is administered by lateral tail-vein administration.
- Plasma samples of 0.5ml aliquots were collected at 0, 1, 3, 5, 15, 30, 45, 60, 90, 120, 150 and 180 minutes. The 0 min sample is taken 15 min prior to administration of the dose. Plasma is removed from whole blood by centrifugation at 1600x g for 5 min, and then stored at -20C in 250 ⁇ l aliquots per sample. The blood pellet is reconstituted with 12.5 units heparinized saline and returned to the appropriate rat via the jugular catheter. After die experiment, rats are euthanized widi i.v. administration of pentobarbital.
- duodenal cadieters are surgically implanted in anesthetized rats and die animals allowed to recover from surgery for 4-5 days.
- the compound is administered eitiier from a solution or microemulsion via the duodenal catheter.
- Blood samples of 0.5 ml aliquots are collected via jugular catheter in heparinized eppendorf tubes at 0, 10, 30, 60, 120, 180, 240 and 1440 min. The 0 min sample is taken 15 min prior to administration of the dose.
- Plasma is collected for analysis and die blood returned to rats as described for i.v. administration protocol.
- the stool of each rat over time is evaluated for consistency by a rank of soft, soft watery, or mucoid.
- %F (AUC id/AUC iv) X (Dose i v /Dose id) X 100
- the formulations of the present invention may be tested for GI irritation assessment with and widiout an active ingredient by die following mediod: Oral Dosing in Rats/GI Irritation Assessment
- 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 die experiment animals are euthanized widi 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 die GI tract upon oral administration.
- the present formulations may be given orally by gavage (preferably at three rats per formulation). After 24 hrs the animals are exsanguinated and upon abdominal incisions are examined botii by naked eye and under d e microscope.
- 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:
- Intraduodenal (i.d.) administration of peptide in microemulsion Fasted rats are given an i.p. injection of anesthesia cocktail and surgically fitted widi jugular and duodenal catiieters. 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.
- AUC area under die plasma concentration curve
- 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 men be obtained in die above noted manner.
- the formulations of the present invention are tested for in vivo activity.
- die active ingredients utilized herein is 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.
- Dogs used in tiiis assay are 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 cameter in the following way: the area is first shaved and cleaned widi a gauze soaked in 70% alcohol. An indwelling cadieter is placed in the caphalic vein and attached to a luer lock adapter filled widi 3.8% sodium citrate. The catheter is securely taped down.
- a 0.3 ml of blood is wididrawn into a separate 1 cc syringe before die actual sample so that dilution of the blood sample from the sodium citrate contained in me luer lock adapter is avoided. Then 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 widi die appropriate time point The tube containing the blood sample in 3.8% sodium citrate is gendy inverted few times to mix components and dien 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 is then frozen for subsequent HPLC analysis to determine peptide content.
- an appropriate dose of microemulsion with or widiout 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 die probe is cleaned with distilled water and a soft brush.
- the probe is attached to d e aggregometer and placed in a cuvette of saline solution and warmed in a side cuvette well in the aggregometer.
- 1 ml of tiie 2.7 ml of blood sample mixed widi die 0.3 ml 3.8% sodium citrate contained in die 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 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 die control.
- the control value is determined by die average of die -15 and die 0 time points. After each use the probe is removed and cleaned with distilled water and wiped widi a soft cloth and brush.
- a dog is considered a good model to assess die 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 independentiy 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 above is 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-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 die aforementioned microemulsion using 3 rats in each case. Prior to actual sampling and dosing, each rat is anesthetized with
- the rats stay anesthetized for the entire experiment.
- Dosing is achieved in die following way: a small incision 2-3 cm long is made on the abdominal midline, and dien a purse-string suture is placed on die duodenal muscle. A small hole is made in die center of the purse-string suture in which a blunt 23 G stub needle attached to a tuberculin syringe is inserted to deliver die dose.
- die purse-string is tied to close die opening. The incision is closed with wound clips.
- a 0.2 ml blood sample is obtained via jugular catheter at die 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.
- the amount of active ingredient required for therapeutic systemic administration will, of course, vary with die compound chosen, die nature and severity of the condition, and die mammal, including humans, undergoing treatment, and is ultimately at the discretion of die 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 diereof.
- the therapeutic agent is selected from a fibrinogen receptor antagonist peptide, a Growtii Hormone Releasing Peptide, a vasopressin, elcatonin, a calcitonin, a calcitonin-gene releated peptide, a porcine somatostatin, insulin or a homolog or analog thereof.
- the disease states and uses of each of the aforementioned tiiereapeutic agents is well known to those skilled in the art and for a number of the agents alerady cross referenced to ti eir respective patents. For instance, use as platelet aggregation inhibitors, growth promoters, for the treatment of osteoporosis, and diabetes.
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US1895693A | 1993-02-17 | 1993-02-17 | |
US18956 | 1993-02-17 | ||
PCT/US1994/002062 WO1994019003A1 (en) | 1993-02-17 | 1994-02-17 | Microemulsions comprising therapeutic peptides |
Publications (2)
Publication Number | Publication Date |
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EP0684834A1 true EP0684834A1 (de) | 1995-12-06 |
EP0684834A4 EP0684834A4 (de) | 1996-09-25 |
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EP94909810A Withdrawn EP0684834A4 (de) | 1993-02-17 | 1994-02-17 | Mikroemulsionen, die therapeutische peptide enthalten. |
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EP (1) | EP0684834A4 (de) |
JP (1) | JPH08507078A (de) |
WO (1) | WO1994019003A1 (de) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5981568A (en) | 1993-01-28 | 1999-11-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
JPH09510182A (ja) * | 1993-11-17 | 1997-10-14 | エルディーエス・テクノロジーズ・インコーポレーテッド | カプセル封入されたドラッグデリバリー用透明液 |
DE69535127T2 (de) * | 1994-03-18 | 2007-02-15 | Supernus Pharmaceuticals, Inc. | Emulgierte arzneistoffabgabesysteme |
GB9613858D0 (en) * | 1996-07-02 | 1996-09-04 | Cortecs Ltd | Hydrophobic preparations |
EP2292225B9 (de) | 1997-03-31 | 2012-06-27 | Boston Scientific Scimed Limited | Darreichungsform enthaltend Taxol in kristalliner Form |
SE9703691D0 (sv) | 1997-10-10 | 1997-10-10 | Astra Ab | Pharmaceutical compositions |
EP1498143A1 (de) * | 2003-07-18 | 2005-01-19 | Aventis Pharma S.A. | Selbstemulgierende und selbstmicroemulgierende Formulierungen zur oralen Verabreichung von Taxoiden |
US9028852B2 (en) * | 2004-09-07 | 2015-05-12 | 3M Innovative Properties Company | Cationic antiseptic compositions and methods of use |
EP2514406A1 (de) * | 2007-06-01 | 2012-10-24 | Novo Nordisk A/S | Spontan dispergierbare Vorkonzentrate mit einem Peptidwirkstoff in einem festen oder halbfesten Träger |
DK2910570T3 (en) | 2008-03-18 | 2017-01-30 | Novo Nordisk As | Protease-stabilized acylated insulin analogues. |
GB201107629D0 (en) * | 2011-05-06 | 2011-06-22 | Proxima Concepts Ltd | Hydrophobic preparations |
GB201107630D0 (en) * | 2011-05-06 | 2011-06-22 | Proxima Concepts Ltd | Microemulsions |
CN104364260B (zh) | 2012-04-11 | 2017-02-22 | 诺和诺德股份有限公司 | 胰岛素制剂 |
HUE055231T2 (hu) | 2016-12-16 | 2021-11-29 | Novo Nordisk As | Inzulint tartalmazó gyógyászati készítmények |
CN113164791B (zh) * | 2018-11-30 | 2024-05-17 | 舒万诺知识产权公司 | 含有荧光物质的局部抗微生物微乳液 |
WO2020109933A1 (en) * | 2018-11-30 | 2020-06-04 | 3M Innovative Properties Company | Topical antimicrobial microemulsions |
BR112021018817A2 (pt) * | 2019-04-11 | 2021-11-23 | Scherer Technologies Llc R P | Formulação para suprimento oral de proteínas, peptídeos e moléculas pequenas com pouca permeabilidade |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4146499A (en) * | 1976-09-18 | 1979-03-27 | Rosano Henri L | Method for preparing microemulsions |
EP0278660A1 (de) * | 1987-02-03 | 1988-08-17 | Stiefel Laboratories (Ireland) Limited | Mikroemulsionen |
EP0387647A2 (de) * | 1989-03-13 | 1990-09-19 | Desitin Arzneimittel GmbH | Hochdisperse pharmazeutische Zusammensetzung |
WO1993002664A1 (en) * | 1991-07-26 | 1993-02-18 | Smithkline Beecham Corporation | W/o microemulsions |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5110606A (en) * | 1990-11-13 | 1992-05-05 | Affinity Biotech, Inc. | Non-aqueous microemulsions for drug delivery |
-
1994
- 1994-02-17 EP EP94909810A patent/EP0684834A4/de not_active Withdrawn
- 1994-02-17 WO PCT/US1994/002062 patent/WO1994019003A1/en not_active Application Discontinuation
- 1994-02-17 JP JP6519300A patent/JPH08507078A/ja active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4146499A (en) * | 1976-09-18 | 1979-03-27 | Rosano Henri L | Method for preparing microemulsions |
EP0278660A1 (de) * | 1987-02-03 | 1988-08-17 | Stiefel Laboratories (Ireland) Limited | Mikroemulsionen |
EP0387647A2 (de) * | 1989-03-13 | 1990-09-19 | Desitin Arzneimittel GmbH | Hochdisperse pharmazeutische Zusammensetzung |
WO1993002664A1 (en) * | 1991-07-26 | 1993-02-18 | Smithkline Beecham Corporation | W/o microemulsions |
Non-Patent Citations (1)
Title |
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See also references of WO9419003A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP0684834A4 (de) | 1996-09-25 |
WO1994019003A1 (en) | 1994-09-01 |
JPH08507078A (ja) | 1996-07-30 |
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