EP0671929A1 - Zusammensetzungen - Google Patents
ZusammensetzungenInfo
- Publication number
- EP0671929A1 EP0671929A1 EP93923917A EP93923917A EP0671929A1 EP 0671929 A1 EP0671929 A1 EP 0671929A1 EP 93923917 A EP93923917 A EP 93923917A EP 93923917 A EP93923917 A EP 93923917A EP 0671929 A1 EP0671929 A1 EP 0671929A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- fatty acyl
- hlb surfactant
- chain fatty
- long
- composition
- 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- Withdrawn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
- 239000000203 mixture Substances 0.000 title claims abstract description 93
- 239000004530 micro-emulsion Substances 0.000 claims abstract description 112
- 239000004094 surface-active agent Substances 0.000 claims abstract description 103
- -1 sorbitan long-chain fatty acid ester Chemical class 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 38
- 150000002190 fatty acyls Chemical group 0.000 claims abstract description 37
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 14
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 68
- 239000012071 phase Substances 0.000 claims description 56
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 claims description 23
- 238000010587 phase diagram Methods 0.000 claims description 23
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical class CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 14
- 239000000194 fatty acid Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 11
- 229930195729 fatty acid Natural products 0.000 claims description 11
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- 108010077689 gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide Proteins 0.000 claims description 10
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
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- OYHQOLUKZRVURQ-HZJYTTRNSA-N linoleic acid group Chemical group C(CCCCCCC\C=C/C\C=C/CCCCC)(=O)O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 claims description 6
- 235000021313 oleic acid Nutrition 0.000 claims description 6
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 6
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 5
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- 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
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- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
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- 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
- 239000002736 nonionic surfactant Substances 0.000 claims description 3
- 229960003726 vasopressin Drugs 0.000 claims description 3
- 241000124008 Mammalia Species 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
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000000539 amino acid group Chemical group 0.000 claims 1
- 239000003921 oil Substances 0.000 description 34
- 102000004196 processed proteins & peptides Human genes 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 26
- 235000019198 oils Nutrition 0.000 description 26
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- 239000011780 sodium chloride Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- LDVVMCZRFWMZSG-UHFFFAOYSA-N captan Chemical compound C1C=CCC2C(=O)N(SC(Cl)(Cl)Cl)C(=O)C21 LDVVMCZRFWMZSG-UHFFFAOYSA-N 0.000 description 17
- 239000000523 sample Substances 0.000 description 17
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 15
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 14
- 229920000053 polysorbate 80 Polymers 0.000 description 14
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 13
- 238000002474 experimental method Methods 0.000 description 10
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- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
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- PCJGZPGTCUMMOT-ISULXFBGSA-N neurotensin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 PCJGZPGTCUMMOT-ISULXFBGSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000002889 oleic acids Chemical class 0.000 description 1
- 125000001117 oleyl 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])/C([H])=C([H])\C([H])([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 1
- XNOPRXBHLZRZKH-DSZYJQQASA-N oxytocin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@H](N)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)NCC(N)=O)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 XNOPRXBHLZRZKH-DSZYJQQASA-N 0.000 description 1
- 229960001723 oxytocin Drugs 0.000 description 1
- 239000002540 palm oil Substances 0.000 description 1
- 125000000913 palmityl 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])C([H])([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 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002263 peptidergic effect Effects 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
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- 229940068965 polysorbates Drugs 0.000 description 1
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- 235000010388 propyl gallate Nutrition 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].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 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000004079 stearyl 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])C([H])([H])C([H])([H])C([H])([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 1
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- 229940093609 tricaprylin Drugs 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 239000002996 urinary tract agent Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011800 void material 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
- This invention relates to pharmaceutical compositions in the fo ⁇ n of water-in-oil (w/o) self-emulsifying microemulsions, processes for their preparation and their use.
- Microemulsions can be defined in general as thermodynamically stable, isotropically clear dispersions of two immiscible liquids stabilized by interfacial films of surface-active molecules.
- the formation of microemulsions usually involves a combination of three to five components, namely, 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 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, 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 consequendy 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 et al., J. Disp. Sci. Tech., 9, 415-423, 1988).
- Microemulsions form spontaneously, without the need for a high input of energy and are therefore easy to prepare and scale up for commercial applications; they have thermodynamic stability due to their small particle size and therefore have a long shelf life; they have an isotropically clear appearance so that they may be monitored by spectroscopic means; they have a relatively low viscosity and are therefore easy to transport and mix; they have a large interfacial area which accelerates surface reactions; they have a low interfacial tension which permits flexible and high penetrating power and, lastly, they offer the possibility of improved drug solubilization and protection against enzymatic hydrolysis.
- microemulsions may undergo phase inversion upon addition of an excess of the dispersed phase or in response to a temperature change and this is a property of these systems that can affect drug release from microemulsions both in vitro and in vivo. The reasons for this improved drug delivery are not however well understood.
- lipid-based microemulsions to enhance the bioavailability of different drugs, including peptides.
- GB 2222770-A (Sandoz Ltd) describes microemulsions and corresponding microemulsion "pre-concentrates" for use with the highly hydrophobic cyclosporin peptides.
- a suitable pre-concentrate comprises 1,2-propylene glycol as the hydrophilic component, a caprylic-capric acid triglyceride as the lipophilic component and a mixture of a polyoxyethylene glycolated hydrogenated castor oil and glycerin monooleate (ratio 11:1) as the 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 (C 6 -2 2 ) 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 ( -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 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 (Ci6-22)-fatty acid monoglyceride and an unsaturated (Ci6-2 2 )-fatty acid triglyceride, in a ratio of from 1:1 to 3:1, and a polar liquid su ⁇ h as water.
- an unsaturated (Ci 6 -22M att y acid monoglyceride is a low HLB surfactant.
- the present invention provides a pharmaceutical composition comprising:
- composition on admixing forms a stable, self-emulsifying, water-in-oil (w/o) microemulsion.
- Figure 1 Illustrates a Pseudo-Ternary Phase Diagram reading of a Microemulsion System containing the mixture of the oil and the low HLB surfactant, at a fixed ratio X, a hydrophilic (aqueous) phase and a high HLB surfactant.
- Figure 2 Illustrates a Pseudo Ternary Phase Diagram of the W/O Microemulsion
- FIG. 3 Illustrates a Pseudo Ternary Phase Diagram of the W/O Microemulsion
- Figure 5 Illustrates a Pseudo Ternary Phase Diagram of the W/O Microemulsion
- FIG. 7 Illustrates a Pseudo Ternary Phase Diagram of the W/O Microemulsion Existence Field in the System comprising Captex 910B/CAPMUL MCM (ratio 3: 1), a high HLB surfactant TWEEN 80 and saline.
- Figure 8 Illustrates a Pseudo Ternary Phase Diagram of theW/O Microemulsion
- the instant invention comprises a pharmaceutical composition which has
- a high HLB surfactant (b) a high HLB surfactant; (c) an aqueous hydrophilic phase; and (d) a water-soluble therapeutic agent; which on admixing form stable, self-emulsifying, water-in-oil (w/o) microemulsions.
- useful (w/o) microemulsions may be prepared using a medium-chain fatty acyl triglyceride 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 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).
- 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.
- interesterified triglyceride refers to a triglyceride which is formed synthetically from reacting together a physical admixture of medium- and long- chain fatty acyl triglycerides to form new synthetic triglycerides in which each triglyceride has a mixture of medium- and long-chain fatty acyl moieties. Suitable such triglycerides are readily available from commercial suppliers, having already found use in the food industry.
- oils such as coconut or palm oil comprise triglycerides formed randomly from a mixture of a number of different medium- and long-chain fatty acids and can therefore be distinguished over triglycerides that are enriched in long-chain fatty acyl chains useful in the present invention.
- Suitable interesterified triglycerides for use in the present invention include those in which the medium-chain fatty acyl moieties comprise caprylic and/or capric acids and the long-chain fatty acyl moieties comprise oleic and/or linoleic acids.
- the medium-chain fatty acyl moieties comprise from about 30 to 90%, more preferably from about 40 to 80%, most preferably from about 50 to 80% by weight of the fatty acyl moieties.
- the long-chain fatty acyl moieties comprise from aboutlO to 50%, more preferably from about 10 to 40%, most preferably about 10 to 30% by weight of the fatty acyl moieties.
- the medium-chain fatty acyl moieties comprise a majority of caprylic acid moieties.
- the ratio of caprylic acid and capric acid moieties is in the range of from about 1:1 to 9:1, more suitably about 1:1 to 3:1.
- Suitable triglycerides include the products available from Karlsham Lipid Specialties, Columbus OH under the trade marks CAPTEX 810A, B, C and D and CAPTEX 910A, B, C and D which are described as interesterified medium-chain triglycerides and high linoleic or oleic vegetable oil and comprise respectively mixtures of caprylic/capric and linoleic acids and caprylic/capric and oleic acids and essential fatty acids, as detailed in the following table (manufacturer's data, fatty acid % by weight):
- Suitable low HLB surfactants for use in the present invention include fatty acyl mono- and di-glycerides, as well as mixtures thereof, and may also include a small amount by weight (less than 5, preferably less than 2% 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 free glycerol (2- 4%), with a fatty acid composition which comprises at least 98% caprylic acid.
- ester composition of capmul products provided by the manufacturer is expressed as oleates (C18); actual C8/C10 monoester content is about 45% of each.
- Another suitable blend of mainly caprylic acid mono- and di-glycerides is the product Imwit ⁇ r 308, from H ⁇ ls America, Piscataway NJ, which is similar to CAPMUL C8.
- 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
- a further useful long-chain fatty acid monoglyceride-containing product is ARLACEL 186 (available from Id 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 Cis-saturated, mono-unsaturated or polyunsaturated fatty acid, preferably a Ci8-mono-unsaturated 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.
- caprylic acid/capric acid mono- and di-glycerides in particular, caprylic and capric acid monoglycerides, is especially preferred.
- 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 (a) 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);
- non-ionic surfactants such as (a) 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.
- terapéutica 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 (Ali et al, EP 0 341 915, 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/US 89/01829); 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-NH2, (Momany, US 4,411,890) and related analogs or homologs thereof, such as but not limited to, His-D- Phe-Ala-D-Phe-Lys-Gln-Gly-NH2, Hong et al., USSN 07/951500 the disclosure of which are herein incorporated by reference in their entirety). This may usefully be included in an amount up to about 250mg g of the hydrophilic phase or from 0.1 to 25mg/g of the formulation.
- GHRP growth hormone releasing peptide
- Suitable larger polypeptides and proteins for use in microemulsions of the present invention include insulin, calcitonin, elcatonin, calcitonin-gene related peptide 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); Bittle et al, US 4,544,500 (20-30 residues); and Dimarchi etal, EP 0204480 (>34 residues).
- analogs or homologs of LHRH which display potent LH releasing activity or inhibit the activity of LHRH
- analogs or homologs of HP5 which possesses 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 immunosuppressiv ⁇ activity
- 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; hirudin analogs and homo
- 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-NH 2 ), a vasopressin, a calcitonin or an insulin, more preferably the fibrinogen receptor antagonist peptides cyclo(S,S)-N a -acetyl-Cys-(N a -methyl)Arg-Gly-Asp-Pen-NH2 or cyclo(S,S)-(2- mercapto)benzoyl-(N a -methyl)Arg-Gly-Asp-(2-mercapto)phenylamide orGHRP.
- a fibrinogen receptor antagonist peptide an RGD peptide
- GHRP His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2
- a vasopressin a calc
- the present invention provides compositions in the form of microemulsions comprising a peptide which may be orally admimstered 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.
- 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 while it will remain in its original form in a (w/o) microemulsion.
- (o/w) microemulsions are generally dispersible in water whereas (w/o) microemulsions are generally not.
- (o/w) microemulsions conduct electricity whereas (w/o) do not The isotropic nature of the system may be confirmed by examination thereof under 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 an interesterified medium-chain triglyceride oil (CAPTEX 810A) and a long-chain fatty acyl monoglyceride (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).
- microemulsion field (shaded areas) which field may be usefully be sub-divided into regions (A), (B) and (C).
- 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).
- microemulsions of regions (A) and (B) are inverted to turbid (o/w) emulsions. In contrast, microemulsions from region (C) remains clear up on 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 the pseudo-ternary phase diagrams as described herein, such as in Figure 2 for instance.
- the lipophilic phase comprising fatty acyl interesterified 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.
- 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 man 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 me 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 dieir 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 die 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 direcdy or by dilution of a stock solution diereof and this may then be added to a pre- mixed combination of the oil and die low HLB surfactant with mixing, followed by the high HLB surfactant or vice versa.
- a drug-free microemulsion may be initially prepared by admixing die 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. While 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.
- 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 dierapeutic effect will vary with the drug chosen, d e nature and severity of die condition and die animal undergoing treatment and is ultimately at the discretion of die physician.
- the 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 treated and tiiat such optima can be determined by conventional techniques. It will also be appreciated tiiat me 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 while 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 microemulsion compositions of the present invention widiout a drug are novel and useful as precursors to drug-containing microemulsions.
- the present invention provides a composition
- a composition comprising (a) a lipophilic phase having an oil which comprises an interesterified triglyceride 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; (b) a high HLB surfactant and (c) an aqueous hydrophilic phase which on admixing form a stable, self-emulsifying, water-in-oil (w/o) microemulsion.
- TWEEN 80 as the high HLB surfactant
- saline as the hydrophilic phase
- 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 die high HLB surfactant and die aqueous phase, noting points of phase separation, turbidity and transparency.
- the resultant phase diagrams are shown as Figures 2 to 9.
- a wide range of clear, transparent, liquid (w/o) microemulsions as shown by regions (A), (B) and (C) were available. These are stable at room temperature and at 37°C.
- microemulsion existence regions for other systems may be readily determined by focussing on the ratios defined by regions (A), (B) and (C) ratiier than having to repeat the whole process and look at relative amounts well removed from these regions.
- microemulsions containing a therapeutic agent which was either GHRP or RGD were prepared according to the standard procedure outlined below and witii the proportions given in the following table:
- microemulsions were generally formulated by initially preparing die 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 die appropriate amounts (by weight) of a mixture of the oil and die low HLB surfactant, to which was then added die high HLB surfactant, with gentle stirring (magnetic hot plate stirrer).
- the hydrophilic phase containing d e drug was added to die 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 witii die corresponding drug-free microemulsion to adjust the concentration of die drug.
- Suitable rats for use in diis 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 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 die 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 of Examples 1 to 8, for instance 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 die microscope. The mucosal surface of both the stomach and duodenum of die animals that received microemulsions containing CAPTEX/CAPMUL or CAPTEX/ARLACEL are examined to see if tiiey are free of any lesions at naked eye. Oral Bioavailability of an RGD Peptide in Rats:
- 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 witii 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:
- Fasted rats are given an i.p. injection of anesthesia cocktail and surgically fitted with 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. The 0 min sample is taken 15 min prior to administration of the dose by duodenal catheter. Plasma is collected for analysis and d e blood returned to rats as described in die 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.
- active ingredients utilized herein is a fibrinogen receptor antagonist a platelet aggregation assay is employed to determine pharmacological activity of die peptide from microemulsions. These studies are carried out as shown below.
- Dogs used in this assay are male Mongrels (i.e. from mixed breeds). The dog(s) are fasted overnight die day before the experiment
- the cephalic vein of choice is prepared for the indwelling catheter in the following way: the area is first shaved and cleaned with a gauze soaked in 70% alcohol. An indwelling catheter is placed in die caphalic vein and attached to a luer lock adapter filled with 3.8% sodium citrate. The catheter is securely taped down.
- a 0.3 ml of blood is witiidrawn into a separate 1 cc syringe before the actual sample so that dilution of d e 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 gently inverted few times to mix components and tiien 1 ml is withdrawn for die whole blood aggregation assay.
- 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 the aggregometer and placed in a cuvette of saline solution and warmed in a side cuvette well in d e 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 die 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 settie for five minutes at which point 5 ⁇ l of collagen is added to the whole blood tiiat is being stirred to yield to a 5 ⁇ g/ml 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 d e 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, widi 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 independendy carried out earlier and serve as a useful comparison to die effects seen with the microemulsion-formulated peptide.
- a microemulsion with a composition (w/w) in accordance witii Formulas 1 to 8 above are made. Upon preparation, they are further stored in a stable form at ambient temperature for approximately 48 hrs before the in vivo evaluation.
- a control solution of a GHRP peptide, His-D-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.
- 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 die following way: a small incision 2-3 cm long is made on d e abdominal midline, and then a purse-string suture is placed on the duodenal muscle. A small hole is made in die center of die purse-string suture in which a blunt 23 G stub needle attached to a tuberculin syringe is inserted to deliver die dose. Upon completion of dosing, d e purse-string is tied to close d e opening.
- 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.
- 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 metiiod of treatment which comprises administering an effective amount of a pharmaceutical composition as defined herein to a patient in need diereof.
- 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 tiiereapeutic 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
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US5688761A (en) * | 1991-04-19 | 1997-11-18 | Lds Technologies, Inc. | Convertible microemulsion formulations |
US5948825A (en) * | 1993-04-19 | 1999-09-07 | Institute For Advanced Skin Research Inc. | Microemulsion preparation containing a slightly absorbable substance |
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- 1993-10-15 WO PCT/US1993/009915 patent/WO1994008603A1/en not_active Application Discontinuation
- 1993-10-15 EP EP93923917A patent/EP0671929A4/de not_active Withdrawn
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Also Published As
Publication number | Publication date |
---|---|
EP0671929A4 (de) | 1996-09-25 |
WO1994008603A1 (en) | 1994-04-28 |
JPH08502490A (ja) | 1996-03-19 |
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