EP1531867A1 - Metastable pharmaceutical compositions - Google Patents
Metastable pharmaceutical compositionsInfo
- Publication number
- EP1531867A1 EP1531867A1 EP03729714A EP03729714A EP1531867A1 EP 1531867 A1 EP1531867 A1 EP 1531867A1 EP 03729714 A EP03729714 A EP 03729714A EP 03729714 A EP03729714 A EP 03729714A EP 1531867 A1 EP1531867 A1 EP 1531867A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- composition according
- active agent
- volatile solvent
- physiologically active
- 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- Withdrawn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
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- 239000002904 solvent Substances 0.000 claims abstract description 55
- 239000013543 active substance Substances 0.000 claims abstract description 52
- 238000001704 evaporation Methods 0.000 claims abstract description 15
- 230000008020 evaporation Effects 0.000 claims abstract description 15
- 230000037317 transdermal delivery Effects 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 56
- 210000003491 skin Anatomy 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 22
- 238000002844 melting Methods 0.000 claims description 17
- 230000008018 melting Effects 0.000 claims description 17
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 claims description 12
- 229960002428 fentanyl Drugs 0.000 claims description 12
- IVLVTNPOHDFFCJ-UHFFFAOYSA-N fentanyl citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 IVLVTNPOHDFFCJ-UHFFFAOYSA-N 0.000 claims description 12
- 210000000434 stratum corneum Anatomy 0.000 claims description 11
- 239000007921 spray Substances 0.000 claims description 10
- 210000002615 epidermis Anatomy 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000003380 propellant Substances 0.000 claims description 9
- 229960003604 testosterone Drugs 0.000 claims description 8
- 238000010521 absorption reaction Methods 0.000 claims description 7
- 239000003623 enhancer Substances 0.000 claims description 7
- 230000035515 penetration Effects 0.000 claims description 7
- 239000000443 aerosol Substances 0.000 claims description 6
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 claims description 5
- 150000001298 alcohols Chemical class 0.000 claims description 5
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 claims description 5
- 229960002495 buspirone Drugs 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 230000000699 topical effect Effects 0.000 claims description 5
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical group FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 4
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 claims description 3
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims description 3
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 claims description 3
- 229960004046 apomorphine Drugs 0.000 claims description 3
- 229960002568 ethinylestradiol Drugs 0.000 claims description 3
- 229960004136 rivastigmine Drugs 0.000 claims description 3
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 claims description 3
- 229960000425 rizatriptan Drugs 0.000 claims description 3
- 229960001879 ropinirole Drugs 0.000 claims description 3
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- YSGQGNQWBLYHPE-CFUSNLFHSA-N (7r,8r,9s,10r,13s,14s,17s)-17-hydroxy-7,13-dimethyl-2,6,7,8,9,10,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-one Chemical compound C1C[C@]2(C)[C@@H](O)CC[C@H]2[C@@H]2[C@H](C)CC3=CC(=O)CC[C@@H]3[C@H]21 YSGQGNQWBLYHPE-CFUSNLFHSA-N 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000000812 cholinergic antagonist Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000002562 thickening agent Substances 0.000 claims 3
- RFRMMZAKBNXNHE-UHFFFAOYSA-N 6-[4,6-dihydroxy-5-(2-hydroxyethoxy)-2-(hydroxymethyl)oxan-3-yl]oxy-2-(hydroxymethyl)-5-(2-hydroxypropoxy)oxane-3,4-diol Chemical compound CC(O)COC1C(O)C(O)C(CO)OC1OC1C(O)C(OCCO)C(O)OC1CO RFRMMZAKBNXNHE-UHFFFAOYSA-N 0.000 claims 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims 1
- 230000000717 retained effect Effects 0.000 claims 1
- 239000003814 drug Substances 0.000 description 24
- 229940079593 drug Drugs 0.000 description 23
- 238000009792 diffusion process Methods 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000003961 penetration enhancing agent Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010040880 Skin irritation Diseases 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 210000004207 dermis Anatomy 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 230000036556 skin irritation Effects 0.000 description 3
- 231100000475 skin irritation Toxicity 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000004411 aluminium Substances 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000010952 in-situ formation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000037311 normal skin Effects 0.000 description 2
- 231100000435 percutaneous penetration Toxicity 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000000935 solvent evaporation Methods 0.000 description 2
- 238000000638 solvent extraction Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 229940041677 topical spray Drugs 0.000 description 2
- 238000013271 transdermal drug delivery Methods 0.000 description 2
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- 102000011782 Keratins Human genes 0.000 description 1
- 108010076876 Keratins Proteins 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 229960002677 darifenacin Drugs 0.000 description 1
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 230000036267 drug metabolism Effects 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- -1 fluoro hydrocarbon Chemical class 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
-
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
-
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
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- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
Definitions
- the present invention relates to compositions for the transdermal delivery of physiologically active agents, to uses of those compositions, and to methods for the transdermal delivery of physiologically active agents.
- transdermal drug delivery has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation.
- transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.
- the skin consists of two principle parts, a relatively thin outermost layer (the 'epidermis') and a thicker inner region (the 'dermis').
- the outermost layer of the epidermis (the 'stratum corneum') consists of flattened dead cells which are filled with keratin.
- the region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.
- the agent For effective transdermal delivery of a physiologically active agent that is applied to the surface of the skin ('topical application'), the agent must be partitioned firstly from the vehicle into the stratum corneum, it must typically then be diffused within the stratum corneum before being partitioned from the stratum corneum to the viable epidermis and dermis and then into the bloodstream.
- the physiologically active agent to be present as a saturated solution or mass.
- physiologically active agents are commonly formulated with incorporation of one or more drug penetration enhancers.
- aqueous ethanol is commonly used as a vehicle in formulations for topical application and it is known that ethanol can act as a penetration enhancer that can increase the flux of an active agent across the skin due to a solvent drag effect (Berner et al., 1989, J. Pharm. Sci, 78(5), 402-406.
- Penetration enhancers are known to cause skin irritation in some individuals.
- ethanol is unlikely to act as a penetration enhancer since, due to the small quantity applied to the skin, the ethanol acts as an intermediary solvent which spreads the drug and enhancer over the skin. Since the drying time of the compositions in question is less than 2 minutes, and in vitro weight loss measurements have previously confirmed that the ethanol evaporates off pig skin with a surface temperature of 32 °C within 1 minute all that remains is the drug. The short exposure time, less than 2 minutes, of ethanol or similar lipid extracting solvents to the skin is unlikely to alter the barrier function of the skin (Abrams et al., 1993, J. Invest. Dermatol, 101 , 609-613).
- U.S. Patent Number 6444234 combines particular solvents and solute modifiers with skin stabilisers in a transdermal delivery system to form a true solution and thus minimizing irritation to the skin.
- US Patent Number 6299900 describes the non-occlusive delivery of a physiologically active agent across the skin however, this composition relies on a penetration enhancer to achieve an increased flux.
- Compositions formulated without the use of a penetration enhancer are generally not effective enough to deliver significant amounts of the physiological active through the skin.
- Compositions containing alcohol and acetone vehicles have been used for topical delivery of antibiotics, as seen in U.S. Patent Number 6017912, which describes the use of fluoroquinolone in the topical treatment of skin infections and inflammatory conditions.
- such compositions have inherently low permeabilities of the physiological active.
- the physiological active In order to overcome the low permeability, the physiological active must have a maximised thermodynamic activity.
- U.S. Patent Number 6528094 the use of stable shaped particles is particularly well-suited to the fabrication of pharmaceutical formulations, particularly where sustained release and uniform bioavailability are desired. It has been shown that to achieve high permeation rates across the skin, the concentrations of the drug dissolved may need to be high such that it possesses a high tendency to crystallise. As a result transdermal patches are often thermodynamically unstable because the drug shows a tendency to recrystallise during storage (Xinghang et al., 1996, Int. J. Pharm., 142(1), 115-119 and Latsch et al., 2003, Eur. J. Pharm. & Biopharm., In Press, Corrected Proof).
- the present invention arises from the inventor's studies of volatile sprays and aerosols and in particular from the realisation that, for finite dose formulations, appreciable enhancement of percutaneous absorption can be attained from the in situ formation of a metastable deposit within the skin using a volatile vehicle, such as a spray or aerosol.
- the present invention arises, at least in part, from the realisation that an increase in the percutaneous absorption of the physiologically active agent may be achieved by the deliberate formation of a metastable drug in situ that has a lower melting point than would be otherwise achieved from the range of crystalline polymorph(s) routinely supplied by the commercial manufacturer. This reduction in melting point translates to an increase in the diffusion of the drug across the epidermis and dermis and into the bloodstream.
- the present inventor's have found that some combinations of physiologically active agent and volatile solvent form a metastable solid in situ when they are applied topically.
- the present invention provides a composition including: - one or more physiologically active agents; and - a volatile pharmaceutically acceptable solvent wherein the physiologically active agent forms a metastable deposit upon evaporation of the volatile solvent.
- the lower melting point metastable deposit arises, at least in part, from either a metastable pseudopolymorph such as an alcohol solvate, a metastable polymorph, a metastable amorphous solid, or a mixture of these.
- the reduction in melting point (at atmospheric pressure) provided by the metastable deposit will be in the range of from 1 to 50 e C and preferably from 2 to 30 Q C.
- the metastable deposit is readily partitioned into the skin upon evaporation of the volatile solvent and rapidly diffuses across the stratum corneum.
- the formation of the higher melting point crystalline deposits in the skin leads to a higher propensity toward skin irritation and a decrease in percutaneous absorption efficiency (due to the need for greater energy to dissolve the crystal prior to diffusional transport).
- the metastable deposit also has excellent skin feel and touch when in some instances it may be desirable to rub the metastable deposit into the skin of a human.
- the composition of the invention is essentially free of penetration enhancers.
- Penetration enhancers have the effect of increasing skin permeability by reversibly damaging or altering the physiochemical nature of the stratum corneum to reduce its diffusion resistance.
- Penetration enhancers are generally lipophilic, non-volatile compounds with a molecular weight greater than 100 and a vapour pressure below 10mm Hg at atmospheric pressure and normal skin temperature of 32 S C.
- the composition of the invention may also provide lower irritancy than some other delivery systems such as benzyl alcohol sprays, because the irritating penetration enhancer is removed.
- the composition of the present invention may avoid problems with crystallisation and/or supersaturation that are encountered with storage of existing type transdermal patches because the pharmaceutical compositions of this invention exist as stable, single phase solutions and hence have no crystalline nature (or polymorphic memory) during their pharmaceutical shelf life.
- Another advantage of the present invention is the rapid partitioning into the skin from these in-situ forming metastable compositions which means the skin can act as a natural crystalline inhibitor for the physiologically active agent, further improving the stability of the metastable deposit within the skin.
- the present invention also provides a method of delivering a metastable drug formulation to a host, the method including the steps of applying a topical spray composition containing one or more physiologically active agents, and a volatile pharmaceutically acceptable solvent to the skin of the host so that the volatile solvent evaporates to form a metastable deposit containing the active agent.
- the present invention further provides a composition for spray application to the skin of a subject for transdermal administration of a physiologically active agent, the composition comprising: (i) a physiologically active agent;
- a propellant preferably a fluoro hydrocarbon
- composition when applied to the skin as a spray forms a metastable deposit in the skin of the subject.
- the invention also provides a spray device for transdermal administration of a physiologically active agent comprising a chamber for maintaining the composition under pressure, a mixture contained within the chamber comprising the physiologically active agent, a pharmaceutically acceptable solvent which is volatile when applied to skin and a propellant which is preferably maintained at least partially in liquid form under pressure within the chamber and valve means for providing delivery of the mixture and wherein the mixture provides a metastable deposit of physiologically active agent on the skin.
- the propellant is preferably a hydrofluorocarbon such as HFC-134a or HFC-227. HFC-134a is the most preferred propellant.
- the hydrofluorocarbon propellant is preferably from 15 to 50% by volume of the total pharmaceutical composition and more preferably from 20 to 40% by volume of the total composition.
- the invention further provides the use of an active agent for manufacture of a medicament for treatment or prophylaxis disease in a subject wherein the composition includes a physiologically active agent and a volatile carrier and is topically applied to the skin of the subject for transdermal administration wherein the volatile solvent evaporates to form a metastable deposit containing the active agent.
- metastable composition avoids the disadvantage of spray nozzle blockage seen with existing film-forming sprays or aerosols.
- the invention also provides a composition as described above contained in a chamber wherein the propellent is HFC-134a.
- the volatile solvent and active will preferably provide a single phase solution of the active.
- amorphous means substantially non-crystalline. It will be appreciated that, unless specified otherwise, the term amorphous includes within its scope a phase that does display some crystallinity.
- physiologically active agent and volatile solvent of the present invention is limited functionally to those that together form a metastable deposit with a melting point lower than that seen from the range of crystalline polymorph(s) routinely supplied by the commercial manufacturer or obtained from crystallisation from methanol or chloroform.
- active agent is relatively non-volatile relative to the volatile solvent so that upon application of the composition to the skin of the host, only the volatile solvent evaporates at physiological temperatures.
- the physiologically active agent may selected from a range of potent, lipophilc, physiologically active agents with a molecular weight less than 600 Daltons and a melting point less than 200°C with the list including apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergics such as oxybutynin, tolterodine and darifenacin, testosterone, MENT (7-methyl-19-testosterone), ethyinyl estradiol, or an pharmaceutically acceptable salt or derivative of any one of the aforementioned.
- physiologically active agent may selected from a range of potent, lipophilc, physiologically active agents with a molecular weight less than 600 Daltons and a melting point less than 200°C with the list including apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergics such as oxybutynin
- the drug and solvent generally have the ability to intimately mix, such that the solvent will interact with the crystal face of the drug. Therefore, the drug will typically have a saturated solubility in the solvent of greater than or equal to 0.05% w/w, more preferably greater than or equal to 0.1% w/w.
- the volatile solvent has a vapour pressure is above 35mm Hg at atmospheric pressure and normal skin temperature of 32°C.
- the volatile solvent will preferably comprise a lower alcohol. More preferably the volatile solvent will comprise at least 60% by weight of the total volatile solvent component of lower alcohol.
- the volatile solvent component will consist essentially of one or more lower alcohols.
- the preferred lower alcohols are ethanol, isopropanol and mixture thereof.
- the composition is a topical spray composition that contains the physiologically active agent and the volatile solvent and the method includes the step of spraying the composition onto the skin of the host to form the metastable deposit containing the physiologically active substance.
- the metastable deposit is preferably formed in the epidermis of the host.
- Figure 1 shows a plot of the cumulative amount of drug penetrating across the skin from the metastable composition compared to a saturated solution of drug.
- Figure 2 gives an example of base DSC profiles before and after evaporation from ethanol.
- Figure 3 shows a plot of the melting point of each model drug, before and after evaporation from a volatile solvent after a time period of 24 hours.
- Figure 4 shows a plot of the diffusion profile for fentanyl through human epidermis, after evaporation from ethanol and isopropyl alcohol.
- a benefit of the present invention is that the composition is stable, which means that it is not prone to supersaturation or crystallisation during its pharmaceutical shelf life. This may be contrasted with transdermal patches in which crystallisation of the active agent has presented a problem in the past.
- the composition of the present invention can be held in a primary container during the shelf life without encountering shelf-life problems of the prior art transdermal patches.
- composition of the present invention may contain from about 0.1% to about 10% of the physiologically active agent, and from about 85% to about 99.8% of the volatile solvent.
- the vehicle may have additional pharmaceutical excipients, for example gelling agents, such as CARBOPOL and cellulose derivatives.
- gelling agents such as CARBOPOL and cellulose derivatives.
- the formation of a metastable deposit of drug within the stratum corneum can be expected to increase the penetration of a drug across the skin relative to a saturated solution of a drug or a simple dispersion of the solid drug on the surface of the skin as shown in figure 1 (levels not detected).
- the active agents chosen represent a diverse range of physicochemical properties as shown in the following table:
- the pans were maintained at ambient temperature and 33% relative humidity for 24 hours. After this time the pans were covered and hermetically sealed. DSC was then performed under a stream of nitrogen and at 10 Q C/minute and within a temperature range that depended on the drug.
- the choice of solvent used in a composition can be selected on the basis of the desired transdermal delivery profile as measured by percutaneous penetration
- Ethanol Acetone or lPA or Chloroform 60-90 : 10-40; or a mixture thereof.
- Fentanyl diffusion profile through human epidermis, demonstrates a change in delivery profile which is solvent dependent (Figure 5).
- fentanyl After evaporation from ethanol, fentanyl showed a sigmoidal, first order diffusion profile indicating that the initial burst across the skin is limited.
- fentanyl shows a zero order release rate profile. Therefore, the leaving tendency may be modified to suit the desired delivery rate by altering the volatile solvent vehicle.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Inorganic Chemistry (AREA)
- Rheumatology (AREA)
- Gynecology & Obstetrics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Diabetes (AREA)
- Dermatology (AREA)
- Psychology (AREA)
- Urology & Nephrology (AREA)
- Psychiatry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPS317302 | 2002-06-25 | ||
AUPS3173A AUPS317302A0 (en) | 2002-06-25 | 2002-06-25 | Metastable pharmaceutical compositions |
PCT/AU2003/000785 WO2004000361A1 (en) | 2002-06-25 | 2003-06-24 | Metastable pharmaceutical compositions |
Publications (2)
Publication Number | Publication Date |
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EP1531867A1 true EP1531867A1 (en) | 2005-05-25 |
EP1531867A4 EP1531867A4 (en) | 2011-03-23 |
Family
ID=3836732
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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EP03729714A Withdrawn EP1531867A4 (en) | 2002-06-25 | 2003-06-24 | Metastable pharmaceutical compositions |
Country Status (9)
Country | Link |
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EP (1) | EP1531867A4 (en) |
JP (2) | JP2005534670A (en) |
KR (1) | KR20050120726A (en) |
AU (1) | AUPS317302A0 (en) |
BR (1) | BR0312003A (en) |
CA (1) | CA2490057A1 (en) |
EA (1) | EA012648B1 (en) |
NZ (1) | NZ537436A (en) |
WO (1) | WO2004000361A1 (en) |
Families Citing this family (1)
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JP2014508809A (en) * | 2011-03-22 | 2014-04-10 | ザ・ポピュレイション・カウンシル,インコーポレイテッド | Regeneration of myelin using androgen |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992006675A1 (en) * | 1990-10-18 | 1992-04-30 | Minnesota Mining And Manufacturing Company | Aerosol formulation comprising beclomethasone 17,21 dipropionate |
EP0803254A1 (en) * | 1996-04-25 | 1997-10-29 | LUITPOLD PHARMA GmbH | Alcoholic solutions containing acetylsalicylic acid for percutaneous administration, their use in antithrombotic therapy and medicaments |
WO2001002015A1 (en) * | 1999-07-01 | 2001-01-11 | The University Of Georgia Research Foundation, Inc. | Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0794378B2 (en) * | 1989-08-18 | 1995-10-11 | 久光製薬株式会社 | Aerosol |
JPH0383924A (en) * | 1989-08-28 | 1991-04-09 | Kanebo Ltd | Composition for percutaneous administration |
JP2974081B2 (en) * | 1990-07-26 | 1999-11-08 | 小池化学株式会社 | Aerosol composition for human body |
EP0581587A3 (en) * | 1992-07-31 | 1995-05-17 | Tanabe Seiyaku Co | Base for transdermal administration. |
AUPN814496A0 (en) * | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
US5968919A (en) * | 1997-10-16 | 1999-10-19 | Macrochem Corporation | Hormone replacement therapy drug formulations for topical application to the skin |
NZ513208A (en) * | 1999-02-05 | 2003-05-30 | Cipla Ltd | Topical sprays comprising a film forming composition |
EP1322336B1 (en) * | 2000-08-30 | 2013-07-03 | Unimed Pharmaceuticals, LLC | Method of increasing testosterone and related steroid concentrations in women |
TR200300776T2 (en) * | 2000-08-30 | 2005-10-21 | Unimed Pharmaceuticals, Inc. | A method for treating male sexual erectile dysfunction and increasing libido. |
-
2002
- 2002-06-25 AU AUPS3173A patent/AUPS317302A0/en not_active Abandoned
-
2003
- 2003-06-24 EP EP03729714A patent/EP1531867A4/en not_active Withdrawn
- 2003-06-24 WO PCT/AU2003/000785 patent/WO2004000361A1/en active Application Filing
- 2003-06-24 JP JP2004514438A patent/JP2005534670A/en not_active Withdrawn
- 2003-06-24 KR KR1020047020966A patent/KR20050120726A/en not_active Application Discontinuation
- 2003-06-24 BR BR0312003-1A patent/BR0312003A/en not_active IP Right Cessation
- 2003-06-24 NZ NZ537436A patent/NZ537436A/en not_active IP Right Cessation
- 2003-06-24 CA CA002490057A patent/CA2490057A1/en not_active Abandoned
- 2003-06-24 EA EA200500083A patent/EA012648B1/en not_active IP Right Cessation
-
2010
- 2010-07-30 JP JP2010172167A patent/JP2010248250A/en not_active Withdrawn
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1992006675A1 (en) * | 1990-10-18 | 1992-04-30 | Minnesota Mining And Manufacturing Company | Aerosol formulation comprising beclomethasone 17,21 dipropionate |
EP0803254A1 (en) * | 1996-04-25 | 1997-10-29 | LUITPOLD PHARMA GmbH | Alcoholic solutions containing acetylsalicylic acid for percutaneous administration, their use in antithrombotic therapy and medicaments |
WO2001002015A1 (en) * | 1999-07-01 | 2001-01-11 | The University Of Georgia Research Foundation, Inc. | Composition and method for enhanced transdermal absorption of nonsteroidal anti-inflammatory drugs |
Non-Patent Citations (1)
Title |
---|
See also references of WO2004000361A1 * |
Also Published As
Publication number | Publication date |
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CA2490057A1 (en) | 2003-12-31 |
KR20050120726A (en) | 2005-12-23 |
EA012648B1 (en) | 2009-12-30 |
JP2005534670A (en) | 2005-11-17 |
EA200500083A1 (en) | 2005-08-25 |
AUPS317302A0 (en) | 2002-07-18 |
EP1531867A4 (en) | 2011-03-23 |
JP2010248250A (en) | 2010-11-04 |
WO2004000361A1 (en) | 2003-12-31 |
NZ537436A (en) | 2007-01-26 |
BR0312003A (en) | 2005-03-22 |
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