CA2098196C - Method and systems for administering drugs transdermally using sorbitan esters as skin permeation enhancers - Google Patents
Method and systems for administering drugs transdermally using sorbitan esters as skin permeation enhancersInfo
- Publication number
- CA2098196C CA2098196C CA002098196A CA2098196A CA2098196C CA 2098196 C CA2098196 C CA 2098196C CA 002098196 A CA002098196 A CA 002098196A CA 2098196 A CA2098196 A CA 2098196A CA 2098196 C CA2098196 C CA 2098196C
- Authority
- CA
- Canada
- Prior art keywords
- pharmacologically active
- active agent
- skin
- unsaturated
- sorbitan
- 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.)
- Expired - Lifetime
Links
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- 229940079593 drug Drugs 0.000 title abstract description 102
- 238000000034 method Methods 0.000 title abstract description 35
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- 239000000203 mixture Substances 0.000 claims abstract description 69
- -1 sorbitan ester Chemical class 0.000 claims abstract description 51
- 239000013543 active substance Substances 0.000 claims abstract description 44
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- 239000000006 Nitroglycerin Substances 0.000 claims description 67
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000002131 composite material Substances 0.000 claims description 21
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical group FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims description 20
- 239000001593 sorbitan monooleate Substances 0.000 claims description 20
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- 229940055577 oleyl alcohol Drugs 0.000 description 11
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- 239000004147 Sorbitan trioleate Substances 0.000 description 8
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 8
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- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2r)-2-[(3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 description 5
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
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- 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 3
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- 125000003438 dodecyl group Chemical group [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])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000013536 elastomeric material Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229940068939 glyceryl monolaurate Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002648 laminated material Substances 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 229960003639 laurocapram Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 125000005644 linolenyl group Chemical group 0.000 description 1
- 125000005645 linoleyl group Chemical group 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000002648 merrit Nutrition 0.000 description 1
- 244000087976 merrit Species 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 201000003152 motion sickness Diseases 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000001421 myristyl 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])[H] 0.000 description 1
- 229960002289 nicardipine hydrochloride Drugs 0.000 description 1
- AIKVCUNQWYTVTO-UHFFFAOYSA-N nicardipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 AIKVCUNQWYTVTO-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003605 opacifier 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
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000002445 parasympatholytic effect Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920006267 polyester film Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000003368 psychostimulant agent Substances 0.000 description 1
- 230000000541 pulsatile effect Effects 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
- 239000001570 sorbitan monopalmitate Substances 0.000 description 1
- 229940031953 sorbitan monopalmitate Drugs 0.000 description 1
- 239000003381 stabilizer Substances 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
- 239000000758 substrate Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 229940064707 sympathomimetics Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
Abstract
Skin permeation enhancer compositions are provided which increase the permeability of skin to transdermally adminis-tered pharmacologically active agents. The compositions contain a sorbitan ester in addition to the selected pharmacologically ac-tive agent and may also contain Cl-C4 aliphatic alcohol. Methods and drug delivery systems are provided which systems have a laminated matrix or a drug reservoir. In the drug reservoir type of Figure 1, designated (10) there is provided a backing layer (12), a drug reservoir (14) and a two piece release liner (16a) and (16b). In the laminated type, designated (18) in Fi-gure 2, there is provided a backing film (20), a reservoir (22), a ring shaped layer (24) of an adhesive, a membrane layer (26) and a sealable inner liner.
Description
~) 92/10154 ~ PCr/US91/0921S
-1- 20~
.
METHOD ANn SYST} MS FOR ADMINISTT`RTNG DRUG5 T~RANSD~RM~T T V
USING SORBITAN EsTER~ AS ST~TN pE~MT~'A TIIQN. ~N~IANr'~R.C:
Desc~i~tion 10 Trhn i cal Field The present invention relates generally to the transdermal administration of pharmacologically active agents, and more particularly relates to methods and compositions for enhancing the permeability of the skin 15 to such agents.
~3ackaro-ln,~ _ The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a 20 comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e. g., gastrointes-tinal irritation and the like--are eliminated as well.
25 Transdermal drug delivery also makes possible a high degree af control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment 30 into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must 35 overcome a different resistance to penetratio in each W0 92/101S4 2 0 9119 ~ PCl/US91/09~
type of tissue. Transport across the skin membrane is thus a complex rh~-n~ ~nnn. However, it is the celis of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally 5 administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body.
In order to increase skin pe~ --hjl;ty~ and in particular to increase the permeability of the stratum 10 corneum ( i . e., 60 as to achieve enhanced penetration, through the skin, of the drug to be administered transdermally~, the skin may be pretreated with a penetration ~nhAnr;n~ agent (or "permeation F~nhAn~c~r", as 60metimes referred to herein) prior to application of a 15 drug. Alternatively, and preferably, a drug and a permeation ~nhAnc~r are delivered concurrently.
The present invention is directed to a novel composition for enhancing the penetration of pharmacologically active agents through skin, the 20 composition based on a sorbitan ester as will be described herein. The composition may or may not contain an aliphatic alcohol as an additional component. The sorbitan ester compositions of the invention have been found by the inventors herein to be particularly 25 effective in enhancing the penetration of pharmaceutically active agents through skin.
While there are a number of patents and publications available which relate to the trAncdl~rr- 1 administration of drugs and to skin permeation ~nhAnr~r , 30 compositions, applicants are unaware of any art which suggests that sorbitan esters are useful as permeation ~nhAnC~rs in the absence of additional permeation enhancing compounds or which describes the sorbitan ester/aliphatic alcohol compositions as described and 35 claimed herein.
.
_ _ _ _ _ _ . _ _ _ _ . . . ., . .... , . .... . ... _ .. _ ~ . , _ . _ ....
0 92/10154 ~ PCr/US91/09215 _3_ ~098196 The systems and methods of the present invention are useful for administering a wide variety of drugs and drug types. For example, one focus of the invention is on the enhanced trAnc-lPr~-l administration 5 of steroids.
In another Pmhodir~nt, the systems and methods of the present invention relate to the transdermal administration of nitroglycerin at PnhAnrP-l tr~nl:~Prr-1 f luxes . Nitroglycerin is a drug that has been lO administered as a prompt-acting vasodilator in the relief and treatment of angina pectoris. Nitroglycerin has also been used at somewhat higher doses in the treatment of congestive heart failure. The principal pharmacological action of nitroglycerin is relaxation of vascular smooth 15 muscle, so as to produce a vasodilator effect on both peripheral arteries and veins.
Nitroglycerin was originally administered orally and, later, bucally. More recently, transdermal systems have been developed which have been f ound to 20 improve the systemic bioavailability of the drug. The Nitro-Dur~ Transdermal Infusion system manufactured and sold by Key Pharmaceuticals, Inc. (Kenilworth, New Jersey), the Nitrodisc3 made by searle Pharmaceuticals, Inc. (Chicago, Illinois), the Nitroglycerin Tr~n~dPrr-l 25 System of Bolar Pharmaceutical Co., Inc. (Copiague, New York), the Transderm-Nitro~ system distributed by CIBA
Pharmaceutical Co. (Summit, New Jersey), and the Minitran~ system of Riker Pharmaceuticals (St. Paul, I~innesota) are examples of the currently available 30 transdermal nitroglycerin systems.
Several problems which have been encountered with the trAn~Prr- 1 administration of nitroglycerin include the tolerance to the drug which results from prolonged administration. Higher and higher doses are 35 required for patients on long-term nitroglycerin therapy,
-1- 20~
.
METHOD ANn SYST} MS FOR ADMINISTT`RTNG DRUG5 T~RANSD~RM~T T V
USING SORBITAN EsTER~ AS ST~TN pE~MT~'A TIIQN. ~N~IANr'~R.C:
Desc~i~tion 10 Trhn i cal Field The present invention relates generally to the transdermal administration of pharmacologically active agents, and more particularly relates to methods and compositions for enhancing the permeability of the skin 15 to such agents.
~3ackaro-ln,~ _ The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a 20 comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e. g., gastrointes-tinal irritation and the like--are eliminated as well.
25 Transdermal drug delivery also makes possible a high degree af control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment 30 into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must 35 overcome a different resistance to penetratio in each W0 92/101S4 2 0 9119 ~ PCl/US91/09~
type of tissue. Transport across the skin membrane is thus a complex rh~-n~ ~nnn. However, it is the celis of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally 5 administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body.
In order to increase skin pe~ --hjl;ty~ and in particular to increase the permeability of the stratum 10 corneum ( i . e., 60 as to achieve enhanced penetration, through the skin, of the drug to be administered transdermally~, the skin may be pretreated with a penetration ~nhAnr;n~ agent (or "permeation F~nhAn~c~r", as 60metimes referred to herein) prior to application of a 15 drug. Alternatively, and preferably, a drug and a permeation ~nhAnc~r are delivered concurrently.
The present invention is directed to a novel composition for enhancing the penetration of pharmacologically active agents through skin, the 20 composition based on a sorbitan ester as will be described herein. The composition may or may not contain an aliphatic alcohol as an additional component. The sorbitan ester compositions of the invention have been found by the inventors herein to be particularly 25 effective in enhancing the penetration of pharmaceutically active agents through skin.
While there are a number of patents and publications available which relate to the trAncdl~rr- 1 administration of drugs and to skin permeation ~nhAnr~r , 30 compositions, applicants are unaware of any art which suggests that sorbitan esters are useful as permeation ~nhAnC~rs in the absence of additional permeation enhancing compounds or which describes the sorbitan ester/aliphatic alcohol compositions as described and 35 claimed herein.
.
_ _ _ _ _ _ . _ _ _ _ . . . ., . .... , . .... . ... _ .. _ ~ . , _ . _ ....
0 92/10154 ~ PCr/US91/09215 _3_ ~098196 The systems and methods of the present invention are useful for administering a wide variety of drugs and drug types. For example, one focus of the invention is on the enhanced trAnc-lPr~-l administration 5 of steroids.
In another Pmhodir~nt, the systems and methods of the present invention relate to the transdermal administration of nitroglycerin at PnhAnrP-l tr~nl:~Prr-1 f luxes . Nitroglycerin is a drug that has been lO administered as a prompt-acting vasodilator in the relief and treatment of angina pectoris. Nitroglycerin has also been used at somewhat higher doses in the treatment of congestive heart failure. The principal pharmacological action of nitroglycerin is relaxation of vascular smooth 15 muscle, so as to produce a vasodilator effect on both peripheral arteries and veins.
Nitroglycerin was originally administered orally and, later, bucally. More recently, transdermal systems have been developed which have been f ound to 20 improve the systemic bioavailability of the drug. The Nitro-Dur~ Transdermal Infusion system manufactured and sold by Key Pharmaceuticals, Inc. (Kenilworth, New Jersey), the Nitrodisc3 made by searle Pharmaceuticals, Inc. (Chicago, Illinois), the Nitroglycerin Tr~n~dPrr-l 25 System of Bolar Pharmaceutical Co., Inc. (Copiague, New York), the Transderm-Nitro~ system distributed by CIBA
Pharmaceutical Co. (Summit, New Jersey), and the Minitran~ system of Riker Pharmaceuticals (St. Paul, I~innesota) are examples of the currently available 30 transdermal nitroglycerin systems.
Several problems which have been encountered with the trAn~Prr- 1 administration of nitroglycerin include the tolerance to the drug which results from prolonged administration. Higher and higher doses are 35 required for patients on long-term nitroglycerin therapy,
2 ~ 9 6 PCI/US9~/09--,~
. 4 neces6itating the use of larger and larger transdermal patches. This is obviously inconvenient and undesirable.
Accordingly, the present invéntion is directed to a method and system for administering nitroglycerin transdermally at a relatively high tr~ncr~ flux, using a more conveniently sized, smaller patch. The invention may also ~e useful to treat indications other than angina pectoris, e.g., congestive heart failure or production of controlled hypotension during surgery and perioperative to surgery, which require higher doses of nitroglycerin. The invention involves the transdermal administration of nitroglycerin in combination with a low irritation skin permeation enhancer as will be discussed in detail herein.
CitatiQn Qf ~rt l'he f ollowing ref erences relate to one or more aspects of the present invention.
Skin permeation enhancers, generally: Various ~ ''- for enhancing the permeability of skin are known in the art. U. s . Patent Nos . 4, 006, 218, 3, 551, 554 and 3,472,931, for example, respectively describe the use of dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA) to enhance the absorption of pharmacologically active agents through the stratum corneum. Other compounds which have been used to enhance skin permeability include: decylmethylsulfoxide (C1oMSO); diethylene glycol monoethyl ether; polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Patent No.
4,568,343); glycerol monolaurate (U.S. Patent No.
4,746,515); propylene glycoI monolaurate; ethanol (e.g., as in U.S. Patent No. 4,379,454); eucalyptol (U.S. Patent No. 4,440,777); lecithin (U.S. Patent No. 4,783,450); the l-substituted azacycloheptan-2-ones, particularly l-n-dodecylcyclazacycloheptan-2-one (available under the 92/10154 PCI/US9l/09215 , _5_ 20~g196 trademark Azone0 from Nelson Research & Development Co., Irvine, CA; see U.S. Patent Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); propylene glycol in combination with a fatty acid such as linoleic acid (European Patent PUblication No. 261429); "cell envelope disordering - c~ such as methyl laurate or oleic acid in combination with N-(hydL~J~yt!l.hyl) pyrrolidone (U.S.
Patent No . 4 , 537 , 776); C3 -C4 diols (U. S . Patent No.
4, 552, 872, European Patent Application Publication No .
043738); or a binary system of oleic acid, oleins or oleyl alcohol in combination with a lower alcohol (U. S .
Patent No. 4, 863, 970) .
Sorbitan analogs as permeation ~nhAn~m~rs~
specifically: T. Ogiso et al., J. Pharmacobio-Dvn., 9:517-5Z5 (1986), presents studies on percutaneous absorption ~ v vo and the penetration n vitrQ of indomethacin. Sorbitan monooleate was tested as a permeation ~nhAnc~r in combination with a dimethyl sulfoxide (DMSO) gel and was ~ound to have no F-nhAn.
effect. T. Ogiso et al., J. Pharm. Sci., 78(4) :319-323 (1989), describes the combined use of laurocapram and sorbitan monooleate in a permeation c~nhAnr~r composition also containing a DMSO gel, for the transdermal administration of indomethacin. W.-W. Shen et al., J. Pharm. Sci~, 65(12) :1780-1783 (1986), describes the effect of various nonionic surfactants, including sorbitan r-nopAlm;tate and sorbitan trioleate, on the percutaneous absorption of salicylic acid. As with the latter two references, the sorbitan esters are used in conjunction with DMSO. U.S. Patent No. 4,637,930 to Konno et al. describes a trAncfl~rr~l formulation for the administration of nicardipine hydrochloride which contains a mixed liquid composed of urea and an additional compound which may be a sorbitan "middle chain" (6-12 carbon atom) fatty acid ester.
W0 92/10154 PCI~US91/09--2~8~g~ ' ~
Transdermal administration of nitroglycerin, generally: U.S. Patent No. 4,751,087 to Wick describes an acrylate-based adhesive tape for delivering nitroglycerin transdermally. The system optionally 5 inc~ Pc as a skin penetrat1on PnhAnr;r~ combination (i) a fatty acid ester, and (ii)- glyceryl monolaurate. Patent No. 4,615,699 to Gale et al. déscribes a transdermal delivery system for administering nitroglycerin in con~unction with ethanol as a skin permeation Pnh~n~-Pr.
U.S. Patent No. 4,764,381 to Bodor et al. describes nitroglycerin compositions for transdermal administration, containing oleic acid as a permeation Pnh~nr~Pr U.S. Patent No. 4,~59,222 to Enscore describes a matrix composition for transdermal drug administration, 15 the matrix containing mineral oilf polyisobutylene, and colloidal silicon dioxide. U. S . Patent No . 4, 698, 062 to Gale et al. relates to a transdermal drug delivery device which effects "pulsatile" delivery of nitroglycerin to a patient. U. S. Patent No. 4, 814, 168 to Sablotsky et al.
20 describes transdermal drug delivery systems stated to be useful in the administration of nitroglycerin, the systems containing a "multipolymer" drug reservoir of vinyl acetate, polyethylenel rubber, and a tackifying agent. PCT Publication No. W083/00093, inventors Keith 25 et al., relates to a polymeric diffusion matrix for the transdermal administration of nitroglycerin which contains two polyvinyl alcohol components and glycerol.
PCT Pùblication No. W086/00814, inventors Sablotsky et al., relates to an adhesive bilayer transdermal delivery 30 system for the administration of nitroglycerin.
c ry of the Invention -- ~ Accordingly, it is a primary object of the invention to provide a method for enhancing the rate of
. 4 neces6itating the use of larger and larger transdermal patches. This is obviously inconvenient and undesirable.
Accordingly, the present invéntion is directed to a method and system for administering nitroglycerin transdermally at a relatively high tr~ncr~ flux, using a more conveniently sized, smaller patch. The invention may also ~e useful to treat indications other than angina pectoris, e.g., congestive heart failure or production of controlled hypotension during surgery and perioperative to surgery, which require higher doses of nitroglycerin. The invention involves the transdermal administration of nitroglycerin in combination with a low irritation skin permeation enhancer as will be discussed in detail herein.
CitatiQn Qf ~rt l'he f ollowing ref erences relate to one or more aspects of the present invention.
Skin permeation enhancers, generally: Various ~ ''- for enhancing the permeability of skin are known in the art. U. s . Patent Nos . 4, 006, 218, 3, 551, 554 and 3,472,931, for example, respectively describe the use of dimethylsulfoxide (DMSO), dimethyl formamide (DMF) and N,N-dimethylacetamide (DMA) to enhance the absorption of pharmacologically active agents through the stratum corneum. Other compounds which have been used to enhance skin permeability include: decylmethylsulfoxide (C1oMSO); diethylene glycol monoethyl ether; polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Patent No.
4,568,343); glycerol monolaurate (U.S. Patent No.
4,746,515); propylene glycoI monolaurate; ethanol (e.g., as in U.S. Patent No. 4,379,454); eucalyptol (U.S. Patent No. 4,440,777); lecithin (U.S. Patent No. 4,783,450); the l-substituted azacycloheptan-2-ones, particularly l-n-dodecylcyclazacycloheptan-2-one (available under the 92/10154 PCI/US9l/09215 , _5_ 20~g196 trademark Azone0 from Nelson Research & Development Co., Irvine, CA; see U.S. Patent Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); propylene glycol in combination with a fatty acid such as linoleic acid (European Patent PUblication No. 261429); "cell envelope disordering - c~ such as methyl laurate or oleic acid in combination with N-(hydL~J~yt!l.hyl) pyrrolidone (U.S.
Patent No . 4 , 537 , 776); C3 -C4 diols (U. S . Patent No.
4, 552, 872, European Patent Application Publication No .
043738); or a binary system of oleic acid, oleins or oleyl alcohol in combination with a lower alcohol (U. S .
Patent No. 4, 863, 970) .
Sorbitan analogs as permeation ~nhAn~m~rs~
specifically: T. Ogiso et al., J. Pharmacobio-Dvn., 9:517-5Z5 (1986), presents studies on percutaneous absorption ~ v vo and the penetration n vitrQ of indomethacin. Sorbitan monooleate was tested as a permeation ~nhAnc~r in combination with a dimethyl sulfoxide (DMSO) gel and was ~ound to have no F-nhAn.
effect. T. Ogiso et al., J. Pharm. Sci., 78(4) :319-323 (1989), describes the combined use of laurocapram and sorbitan monooleate in a permeation c~nhAnr~r composition also containing a DMSO gel, for the transdermal administration of indomethacin. W.-W. Shen et al., J. Pharm. Sci~, 65(12) :1780-1783 (1986), describes the effect of various nonionic surfactants, including sorbitan r-nopAlm;tate and sorbitan trioleate, on the percutaneous absorption of salicylic acid. As with the latter two references, the sorbitan esters are used in conjunction with DMSO. U.S. Patent No. 4,637,930 to Konno et al. describes a trAncfl~rr~l formulation for the administration of nicardipine hydrochloride which contains a mixed liquid composed of urea and an additional compound which may be a sorbitan "middle chain" (6-12 carbon atom) fatty acid ester.
W0 92/10154 PCI~US91/09--2~8~g~ ' ~
Transdermal administration of nitroglycerin, generally: U.S. Patent No. 4,751,087 to Wick describes an acrylate-based adhesive tape for delivering nitroglycerin transdermally. The system optionally 5 inc~ Pc as a skin penetrat1on PnhAnr;r~ combination (i) a fatty acid ester, and (ii)- glyceryl monolaurate. Patent No. 4,615,699 to Gale et al. déscribes a transdermal delivery system for administering nitroglycerin in con~unction with ethanol as a skin permeation Pnh~n~-Pr.
U.S. Patent No. 4,764,381 to Bodor et al. describes nitroglycerin compositions for transdermal administration, containing oleic acid as a permeation Pnh~nr~Pr U.S. Patent No. 4,~59,222 to Enscore describes a matrix composition for transdermal drug administration, 15 the matrix containing mineral oilf polyisobutylene, and colloidal silicon dioxide. U. S . Patent No . 4, 698, 062 to Gale et al. relates to a transdermal drug delivery device which effects "pulsatile" delivery of nitroglycerin to a patient. U. S. Patent No. 4, 814, 168 to Sablotsky et al.
20 describes transdermal drug delivery systems stated to be useful in the administration of nitroglycerin, the systems containing a "multipolymer" drug reservoir of vinyl acetate, polyethylenel rubber, and a tackifying agent. PCT Publication No. W083/00093, inventors Keith 25 et al., relates to a polymeric diffusion matrix for the transdermal administration of nitroglycerin which contains two polyvinyl alcohol components and glycerol.
PCT Pùblication No. W086/00814, inventors Sablotsky et al., relates to an adhesive bilayer transdermal delivery 30 system for the administration of nitroglycerin.
c ry of the Invention -- ~ Accordingly, it is a primary object of the invention to provide a method for enhancing the rate of
3 5 ~
~92/10154 - - --PCI`/US91/0921~
2~ 96 penetration of a rh~rr~rologically active agent through the skin.
It is another object of the invention to provide such a method which involves applying to a selected area of intact skin a therapeutically effective amount of the selected pharmacologically active agent in combination with a permeation Pnh~nrPr composition containing a sorbitan ester.
It is still another object of the invention to provide such a method wherein the permeation Pnh~nr~r composition consists essentially of: (l) a sorbitan ester; or (2) a sorbitan ester in combination with an aliphatic alcohol as will be described in detail herein.
It is a further object of the invention to provide a skin permeation Pnh~ncPr composition comprising the pharmacologically active agent and a permeation Pnh~nrPr composition which consists essentially of: (l) a sorbitan ester; or (2) a sorbitan ester in combination with an aliphatic alcohol.
It is still a further object of the invention to provide a tr~nqdPrr~1 system in the form of a laminated composite designed to adhere to the skin. The composite contains, in addition to the selected pharmacologically active agent to be administered, a permeation Pnh~nrPr composition containing a sorbitan ester, and, optionally, an aliphatic alcohol.
It is another object of the invention to provide such a method for administering nitroglycerin transdermally which involves administration of the drug 3 0 in combination with a low irritation skin permeation Pnh~nr~ Pr.
It is still another object of the invention to provide a method for administering nitroglycerin transdermally involving administration of the drug with a
~92/10154 - - --PCI`/US91/0921~
2~ 96 penetration of a rh~rr~rologically active agent through the skin.
It is another object of the invention to provide such a method which involves applying to a selected area of intact skin a therapeutically effective amount of the selected pharmacologically active agent in combination with a permeation Pnh~nrPr composition containing a sorbitan ester.
It is still another object of the invention to provide such a method wherein the permeation Pnh~nr~r composition consists essentially of: (l) a sorbitan ester; or (2) a sorbitan ester in combination with an aliphatic alcohol as will be described in detail herein.
It is a further object of the invention to provide a skin permeation Pnh~ncPr composition comprising the pharmacologically active agent and a permeation Pnh~nrPr composition which consists essentially of: (l) a sorbitan ester; or (2) a sorbitan ester in combination with an aliphatic alcohol.
It is still a further object of the invention to provide a tr~nqdPrr~1 system in the form of a laminated composite designed to adhere to the skin. The composite contains, in addition to the selected pharmacologically active agent to be administered, a permeation Pnh~nrPr composition containing a sorbitan ester, and, optionally, an aliphatic alcohol.
It is another object of the invention to provide such a method for administering nitroglycerin transdermally which involves administration of the drug 3 0 in combination with a low irritation skin permeation Pnh~nr~ Pr.
It is still another object of the invention to provide a method for administering nitroglycerin transdermally involving administration of the drug with a
4 PCI/I'S91/09~
~81~6 skin permeation Pnh~nrPr composition as will be defined herein .
It is a fùrther object of the invention to provide such a method in which the nitroglycerin and the
~81~6 skin permeation Pnh~nrPr composition as will be defined herein .
It is a fùrther object of the invention to provide such a method in which the nitroglycerin and the
5 skin permeation Pnh~n--Pr are administered simult~nP~ cly using a laminated composite as a transdermal patch which contains drug and the selected permeation Pnh 1n~Pr in one or more drug reservoir layers.
It is still a further object of the invention lO to provide a transdermal system for the administration of nitroglycerin which provides f or a drug f lux of at least - about 50% higher than that obtained in the absence of a skin permeation enhancer.
It is yet another object of the invention to lS provide methods and compositions for the enhanced transdermal administration of steroid drugs.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become 20 apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention .
In one aspect, the invention is a method f or administering a pharmacologically active agent 25 transdermally so as to achieve relatively high transdermal fluxes, by administering, through a predetermined area of intact skin and for a predetermined period of time, (l) the agent, and (2) a permeation PnhAnoPr consisting essentially of a sorbitan ester, or a 30 sorbitan ester in combination with a Cl-C4 aliphatic alcohol. In a preferred embodiment, the skin permeation ~-nh~nrPr and the drug are administered in a single composition. As the clearance rate of many drugs from ... . '' .~ .. . ~....
~ -9- 2098196 administration be substantially continuous throughout the time period chosen for patch application.
In another aspect of the invention, a composition of matter is provided that is useful for the 5 delivery of a pharmacologically active agent through the skin, comprising:
(a) a therapeuticaliy effective amount of the pharmacologically active agent to be administered; and (b) an amount of a permeation ~nh~nr~r 10 composition effective to enhance the penetration of the pharmacologically active agent through the skin, wherein the ~nh~nt ~r consists essentially of a sorbitan ester or a sorbitan ester combined with a Cl-C4 aliphatic alcohol.
In still another aspect of the invention, a 15 therapeutic system is provided for administering a drug transdermally, at relatively high fluxes as noted above, in the form of a skin patch. The skin patch is - pref erably in the f orm of a matrix-type laminated composite containing an upper backing layer that is 20 substantially imp~L --hle to the drug, and at least one drug/-~nh~n~ c~r reservoir, one of which forms the basal surface of the device and is designed to adhere to the skin during use. The reservoir is a matrix which contains both the drug and a permeation ~nh~nr~r as 25 described above. Such a laminated composite preferably i n~ s a strippable protective release liner laminated to the basal surface of the drug reservoir. The release liner is a disposable element designed to protect the exposed reservoir surface prior to use. In an 30 alternative embodiment, a transdermal therapeutic system is provided in the form of a liquid reservoir-type laminated composite, e.g., as described in commonly assigned U. S . Patent No . 4, 849, 224 to Chang et al .
i' .
~j) 92/10154 PCI/US91/09!--- ~ -lO- 2098196 In yet another aspect, the invention is a method for administering nitroglycerin transdermally so as to achieve relatively high transdermal fluxes, by co-administering, through a predetPrm;nPd area of intact skin and for a predetPrm;nPcl period of time, (l) nitro-glycerin, and tz~ a permeation Pnh~nrPr as described herein . In a pref erred Pmho~l i r -~t, the skin permeation Pnh;lnrPr and the drug are administered in a single composition which contains both components. As the clearance rate of nitroglycerin from the body is quite high, it is preferred that administration be continuous throughout the time period chosen for patch application.
It should also be noted that the present invention is directed to the administration of nitroglycerin to individuals in need of nitroglycerin therapy, generally, and thus Pn _ -C~PC tr;~n~CIPrr-1 methods and systems designed for a variety of indications , e . g ., the relief and treatment of angina pectoris, congestive heart failure, and the like.
In still another aspect of the invention, a therapeutic system is provided for administering nitroglycerin transdermally, at relatively high fluxes as noted above, in the form of a skin patch. The skin patch is a laminated composite containing an upper backing layer that is substantially impermeable to the drug, and at least one drug/enhancer reservoir, one of which forms the basal surface of the device and is designed to adhere to the skin during use The reservoir contains both the nitroglycerin and a permeation Pnh~nrPr as described 3 0 herein .
In still another aspect of the invention, such a laminated composite is provided which further includes a strippable protective release liner laminated to the basal surface of the drug reservoir. The release liner is a disl~osable element designed to protect the exposed :.
.. _ _ . . . ... _ _ _ _ , , .
~ 92/10154 PCr/US91/09215 2~98~96 - reservoir surface prior to use. The release liner, for ease of removal, is preferably a two-part structure in which a f irst strippable protective sheet partially overlaps a second strippable protective sheet, giving 5 rise to a tab extending from the basal surface of the patch .
Brief ~escriPtiQn of the Drawinq Figure l is a schematic sectional view through lO a laminated matrix-type transdermal system of the invention .
Figure Z is a schematic sectional view through a laminated liquid reservoir-type tr~nc~rr~l system of the invention.
Detailed PescriPtion of the Invention Before describing the present compositions, systems and methods of the invention in detail, it is to be understood that this invention is not limited to the 20 particular drugs, sorbitan esters, aliphatic alcohols, or laminate materials described herein as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular omho-lir tS only, and is not intended to be 2 5 l imiting .
It must ~e noted that, as used in this specification and the appended claims, the singular forms "a, " "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, 30 reference to a laminated structure containing "a drug"
includes a mixture of two or more drugs, reference to "an adhesive" includes reference to one or more of such adhesives, and reference to 1'a sorbitan ester" includes reference to a mixture of two or more sorbitan esters.
_ _ _ _ _ , WO 92/10154 PCI/US91/09~
209819~
..=_ In describing and rlilim;n~ the present invention, the following terminology will be used in accordance with the def initions set out below.
"Penetration enhancement" or "permeation 5 Pnh inr~--nt" as u8ed herein relates to an increase in the permeability of skin to a pharmacologically active agent, i . e., 50 as to increase the rate at which the agent permeates into and through the skin. A "permeation ~nh~nrPr" is a material which achieves such permeation lO enhancement, and a "penetration enhancing amount" of an ~nh~nrPr as used herein means an amount effective to enhance skin penetration of a selected agent to a desired degree .
By "transdermal" drug delivery, applicant is lS using the term in its conventional sense, i.e., to indicate delivery of a drug by passage through the skin and into the blood stream. By "tr~n c05~ drug delivery, applicant intends aelivery of a drug by passage of a drug through the mucosa~ tissue into the blood 20 stream. "Topical" drug deiivery is used to mean local administration of a topical drug as in, for example, the treatment of various skin disorders. These terms will sometimes be used interchangeably herein, i . e., aspects of the invention which are déscribed in the context of 25 "transdermal" drug delivery, unless otherwise specified, can apply to tr~ncm11ooc~l or topical delivery as well.
That is, the compositions, systems, and methods o~ the invention, unless explicitly stated otherwise, shouid be 1 to be equally applicable with any one of these 3 0 three modes of drug delivery .
The term "drug" or "pharmacologically active agent" as used herein is intended to mean a compound or composition of matter which, when administered to an organism (human or animal) induces a desired 35 pharmacologic and/or physiologic effect~by local andlor .
~0 92/10154 PCI/US91/09215 13 2~81~
systemic action. In general, the terms include the therapeutic or prophylactic agents in all major therapeutic/prophylactic areas of medicine. Examples of drugs useful in conjunction with the present invention 5 include: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations;
anorexics; antih~1minthics; antiarthritics; antiasthmatic agents; anticholinergic agents; anticonvulsants;
antidepressants; antidiabetic agents; antidiarrheals;
lO antihistamines; anti-inf lammatory agents, antimigraine preparations; anti-motion sickness drugs; antinauseants;
antineoplastics; antiparkinsonism drugs; antipruritics;
antipsychotics; antipyretics; antispasmodics;
anticholinergics; sympathomimetics; xanthine derivatives;
15 cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics;
vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and 20 cold preparations, including decongestants; steroids;
hypnotics; immunosuppressives; muscle relaxants;
parasympatholytics; psychostimulants; sedatives; and tranquilizers. For purposes of the aforementioned definition, "drugs" as used herein also include locally 25 administered topical medicaments such as antibacterial agents, antifungals, antimicrobials, cutaneous growth enhancers, antipsoriatics, anti-acne medicaments, and the l ike .
"Carriers" or "vehicles" as used herein refer 30 to carrier materials without pharmacological activity which are suitable for administration in conjunction with the presently disclosed and claimed compositions, and include any such carrier or vehicle materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, 35 solubilizer, or the like. The carriers and vehicles .
WO 92/l0l54 PCI/US91/09~
~9819~
~ --14--suitable herein are "pharmaceutically acceptable" in that they are nontoxic, do not interfere with drug delivery, and are not for any other reasons biologically or otherwise undesirable. Examples of specific suitable 5 carriers and vehicles for use herein include water, mineral oil, silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes, petroleum jelly, and a variety of other oils and polymeric materials.
By a "therapeutically effective" amount of a 10 drug or pharmacologically active agent is meant a nontoxic but suf f icient amount of the drug or agent to provide the desired therapeutic effect.
"Nitroglycerin" shall mean 1,2,3-propanetriol trinitrate, i . e., the compound having the structural 15 formula , The invention is thus in one Pmho~ nt a 25 method for enhancing the rate of penetration of a pharmacologicaily active agent through the skin, wherein the method involves co-administration of the agent through a predetermined area of intact skin, and for a predetermined period of time, the selected agent and a 30 permeation f~nhAnr~r consisting essentially of a sorbitan ester or a sorbitan ester in combination with a C1-C4 aliphatic alcohol. The sorbitan esters which are useful in con~unction with the present invention have the structure _ CEit--R, E~O--CH O
l/
H~/
10 wherein the substituent Rl has the structure -O(CO)R', where R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated and tri-u:lsa~uLated aliphatic hydrocarbon substituents of 7 to Z1 carbon atoms, preferably 11 to 21 carbon atoms, 15 and may be substituted with 1 to 3 hydroxyl groups. The substituents R2 and R3 may be the same or different and are selected from the group consisting of hydroxyl and -O(CO~R' as defined above. Rl, R2 and R3, may be, for example, lauryl, myristyl, palmityl, stearyl, 20 palmitoleyl, oleyl, linoleyl, linolenyl, or ricinoleyl esters, or the like. Exemplary sorbitan esters are long-chain sorbitan Donoesters, wherein R1 is as defined above, R' is hydrocarbon of 11 to 21 carbon atoms, and R2 and R3 are both hydroxyl. Particularly preferred 25 ~_ u.-ds within the class of sorbitan monoesters are sorbitan monooleate and sorbitan monolaurate.
In addition to a sorbitan ester, the permeation Pnh IncPr composition of the invention may also include an aliphatic alcohol r~ nt. Preferred aliphatic 30 alcohols are the Cl-C4 alcohols such as ethanol, n-propanol, isopropanol, t-butanol, and mixtures thereof.
However, longer chain alcohols (typically C8-C22) such as oleyl alcohol may also be used (see, e.g., Examples 8 and 9 ) herein .
' ~ .
~) 92/10154 PC~/US91/09~
, _ , The method of delivery of the present compositions may vary, but necessarily involves application of drug and PnhAncPr to a selected intact surface of the skin or other tissue for a period of time 5 sufficient to provide the desired blood level of drug.
The method preferably involves administration of drug and PnhAnrPr simultaneously, in a single composition, i.e., as an ointment, gel, cream, or the like, or may involve use of a drug delivery device as taught, f or example, in U.S. Patent Nos. 4,849,224, 4,983,395, 4,568,343, 3,797,494 or 3,742,951.
When the drug to be administered and the permeation PnhAnl-~r as described above are applied in the form of an ointment, gel, cream or the like, the amount 15 of drug contained within the composition will depend on a variety of factors, including the desired rate of delivery, the desired dosaqe, the disease to be treated, the nature and activity of the drug, the desired effect, possible adverse reactions, the ability and speed of the 2 0 drug selected to reach its intended target, and other factors within the particular knowledge of the patient and the physician. The amount of enhancer will typically be in the range of O .1 wt . % to 4 0 wt . % relative to the total composition, more preferably on the order of about 25 2 . 5 wt. % to 15 wt. %. The composition may, in addition to drug and PnhAncPr ~ include one or more selected carriers or excipients, and/or various agents and ingredients commonly employed in dermatological ointments and lotions. For example, fragrances, opacifiers, 30 preservatives, antioxidants, gelling agents, perfumes, thickening agents, stabilizers, surfactants, emollients, coloring agents, and the like may be present so long as they are pharmaceutically acceptable and compatible with the drug and enhancer.
_ ~ -17- 2098196 A trAncdPrr-l delivery system for the administration of a drug can be constructed with the drug/enhancer composition described hereinabove.
Preferred tr~nC~rr l drug delivery systems for use .
S herein are laminated composites which contain one or more drug/permeation ~nhAncP~ reservoirs, a backinq layer and, optionally, one or more additional layers ~e.g., additional drug and/or ~nh~nc~r reservoirs) as those skilled in the art of trAnc-lPrr- 1 drug delivery will 10 readily appreciate. Figure 1 depicts an exemplary system, generally designated 10, that when applied to skin administers a selected pharmacologically active agent as outlined above. System 10 is a laminated composite in which the top layer 12 is a backing layer, 1~ its face forming the top surface of the composite. The drug reservoir, containing drug, enhancer as described herein, and optional carriers or vehicles, is shown at 1~, immediately below and adjacent to the backing layer.
Prior to use, the laminate also includes a strippable protective release liner. In a preferred ~ ' ~; L, the release liner is in the form of two sheets 16zl and 16b, the first sheet 16a partially overlapping the second sheet 16b. Additional structural layers and/or additional drug/enhancer reservoirs may also be present.
The drug reservoir is preferably comprised of a contact adhesive which is a pressure-sensitive adhesive suitable for long-term skin contact. It must also be physically and fh~ri~Ally compatible with the drug and enhancer employed, and with any carriers or vehicles incorporated into the drug/enhancer composition.
Further, the adhesive selected for use as the reservoir ~ 92/10154 PCI`/US91/09~
=
-18- 2a98l96 layer must be such that the drug and ~hAnrPr are at least somewhat soluble in the adhesive. The drug reservoir will generally be in the ranqe of about 2 to 4 mils in thickness . Suitable adhesives f or use as the 5 drug reservoir include polysiloxanes, polyacrylates, polyurethanes, tacky rubbers such as polyisobutylene, and the like. Particularly preferred contact adhesives for use as the drug reservoir herein are cross-linked acrylates (e.g., the Durotak~ adhesives, available from lO National Starch & Chemical Co., New York, NY, or the Gelva~19 adhesives, available from Monsanto Co., St. Louis, M0) .
The backing layer, which is, as shown, adhered to the drug reservoir and serves as the upper layer of 15 the device during use, functions as the primary structural element of the device. The backing layer is made of a sheet or film of a preferably flexible elastomeric material that is substantially impermeable to the drug/~nhAnrpr composition. The layer will typically 20 be on the order of l.0 to about 4.0 mils in thickness, and is preferably of a material that permits the device to follow the contours of the skin, such that it may be worn comfortably on any skin area, e.g., at joints or other points of flexure. In this way, in response to 25 normal mechanical strain, there is little or no likelihood of the device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device. Examples of polymers useful for the backing layer herein are polyethylene, polypropylene, 30 polyesters, polyurethanes, polyethylene vinyl acetate, polyvinylidene chloride, block copolymers such as PEBAX, and the like. The backing layer may also comprise laminates of one or more of the f oregoing polymers .
The release liner is a ~;crnsAhle element which 35 serves only to protect the device prior to application.
-0 92/10154 PCI`/US91/09215 Typically, the relea6e liner is formed from a material -~.hle to the drug, vehicle, and adhesive, and which is easily stripped from the contact adhesive that serves as the drug reservoir layer. Preferred release liners 5 for use herein are those which are generally suitable for use in conjunction with pressure-sensitive adhesives.
Silanized polyester films are presently preferred.
In a preferred Pmho~l;r-nt, as noted above, a two-part release liner is used, wherein a first lO strippable protective sheet (shown as 16a in Figure l) partially overlaps a second strippable protective sheet 16b, such that the area of overlap gives rise to a tab which extends from the basal surface of the laminate, enabling ready removal of the strippable sheets from the 15 reservoir Iayer.
The preferred laminated composites of the invention are as shown in Figure l, having a backing layer, a drug reservoir, and a two-piece release liner;
the drug reservoir contains a drug/~nh~nc~r composition 2 0 as described above, with the quantity of the drug therein, and with the r~--inrll~r of the drug reservoir comprised of adhesive and optional carriers, vehicles or the like. To use these laminated composites, one is applied directly to the skin of a patient, to release the 25 drug/~nh;lnc~r composition to the skin, allowing the drug to permeate into the circulation. The adhesive layer which serves as the drug reservoir should be in f irm contact with the skin.
In general, such devices are fabricated using 30 methods standard in the art, e.g., solvent-evaporation f ilm casting in which all components of the drug/enhancer composition are admixed with the adhesive which will serve as the drug reservoir, and cast onto a substrate which is either the backing layer or release liner.
3 5 ~ ~
.
~ -20- 2098196 Other layers are then laminated to this initial structure .
In an alternative ~mhQ~ t, laminated composites containing drug in a liquid reservoir, as des,cribed in U. S. Patent No. 4, 849, 224, may be used. As described in that patent, such devices shown generally at 18 in Figure 2 are comprised of an uppermost layer of a heat-sealable backing film 20 having an inverted, cup-shaped recess that serves the reservoir 22 for the drug-~nhAnaer formulation. The underside of the outer edge of the backing film carries a ring-shaped layer 2~ of a :~UL- ~cnsitive adhesive peripheral to the reservoir.
Underlying the reservoir, just inward of the peripheral ring of adhesive, is a membrane layer 26 that is permeable to the drug-anhAnc~r formulation. A peel sealable inner liner 28 underlies membrane 26 and portions of backing film 20. A peel-s~llAhla release liner 30 covers the entire underside of the assembly and forms the basal surface of the device. Device 18 has a heat seal 3Z between the membrane and backing f ilm and a peelable (impermanent) heat seal 34 between the backing film and the inner liner 28. An alternative liquid reservoir-type device which may be used in conjunction with the present compositions is described in U. s . Patent No. 4,983,395.
Preferred daily dosages obtained with the present methods and systems will, similarly, vary with the drug administered. The targeted daily dosage will depend on the individual being treated, the indication addressed, the length of time the individual has ~een on the drug, and the like.
Turning now to the administration of nitroglycerin, specifically, it is preferred that the drug and the selected permeation ~nhAncr~r or enhancers are administered to the individual simultaneously, in a D 92/10154 PCr/US91/0921~
- ~2-0~8196 ~ingle composition. As with other drugs, a preferred mode of administration, however, is via a trAn-~lPrr-1 patch, wherein the pref erred quantities of the various ~; ts will be outlined below.
In a preferred embodiment, the nitroglycerin and the selected permeation ~nh~nrPr or PnhAnc~rs are administered such that f lux is increased by at least about 50% relative to that which would be achieved in the absence of a permeation Pnh~ncPr, that is, typically, a flux on the order of at least about lO ~g/cm2/hr, preferably at least about 20 ~ug/cm2/hr, most preferably at least about 30 ~Lg/cm2/hr, is achieved. It will be appreciated by those skilled in the art of transdermal drug delivery that the foregoing numbers are approximate, as trAncdprr~l flux may vary with the individual undergoing treatment as well as the particular skin site chosen for transdermal drug delivery.
It is also preferred that the time period for nitroglycerin administration be on the order of 12 to 36 hours, optimally about 12 to 24 hours, during which time drug delivery is substantially continuous.
Preferred daily dosages obtained with the present methods and systems are typically in the range of 2.5 to 50 mg, more typically in the range of about 2.5 to 20 mg, for nitroglycerin. ~he targeted daily dosage will, however, depend on the particular drug being administered, the individual being treated, the indication addressed, the length of time the individual has been on the drug, and the like. Generally, and as 3 0 noted above, the present methods and systems enable transdermal administration of nitroglycerin at somewhat higher transdermal fluxes than enabled with the majority of previously known transdermal nitroglycerin systems, and may thus be useful for treating disorders which require a higher daily dosage than is typical (e.g., .
WO 92/10154 PCI/US91/09~
~8196 congestive heart failure), or for treating patients who have developed some tolerance for the drug. The invention also enables the use of conveniently sized small patches.
~r~nR~or~ 1 delivery of nitroglycerin with the permeation ~nh In-~rs of the invention enable the use of a skin area for drug administration in the range of approximately 1. 0 cm2 to about 100 cm2 . At higher transdermal fluxes, smaller skin areas within the aforementioned range may be targeted, i.e., less than about 25 cm2 or, more preferably, less than about 10 cm2.
r~çri~ -ntal The following examples are put forth so as to provide those with ordinary skill in the art with a complete disclosure and description of how to formulate compositions and systems of the invention, and are not intended to limit the scope of what the inventors regard as their invention . Ef f orts ~have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures , etc . ), but some experimental errors and deviations should be allowed for. Unless indicated otherwise, parts are parts by weight, temperatures are in degrees Centigrade, and pressure is at or near ai ~rh~ric.
Es~radiol, norethindrone acetate, progesterone and pindolol were-obtained from Sigma Chemical Co., St.
Louis, M0. Polyacrylate adhesive solutions were obtained from National Starch & Chemical Co., New Jersey (Durotak~D
80-1194, 80-1054, 80-1070) and fro~n Monsanto Corporation, St. Louis, M0 (Gelva~ 737). Sorbitan monooleate, sorbitan monolaurate and sorbitan trioleate were all obtained from ICI Americas.~ Ethanol (USP 95~) was obtained from Fisher Scientific.
.~ f ;) 92/1 OW -- PCT/US91/0921~
--2~9~196 Adhesive laminates were formulated by mixiny the selected polyacrylate solutions with drug and/or ~.nh~n~ r, followed by evaporation of solvent. The concentrated solution was cast onto the silanized surface 5 of a polyester release liner (Release Technologies, 2-EST-A-S242M), using a 10 mil gap Gardner knife. The cast adhesive was then dried at 80C for 15 minutes in a convection oven to yield a final 0. 050 inch thick adhesive coating. A 0. 0075 inch thick low density 10 polyethylene film (Schoeller Technical Paper Co., New York) was then laminated onto the dried adhesive surface to produce a three-layer transdermal matrix system construction .
The in vitro skin f lux of the particular drugs 15 tested was evaluated across human cadaver skin as described by Merrit and Cooper (J. CQntrolled Release (1984) 1:161) using a high-performance liquid chromatography (HPLC) assay. For these studies the release liner was removed from a previously cut section 20 of the above tr~nc~rr~ 1 matrix construction. The adhesive matrix was then positioned onto the stratum corneum surface of heat separated human epidermis and the skin, with the adhering transdermal system, was then immediately mounted onto the diffusion cell. The steady 25 state flux (~Lg/cm2/hr~ of drug was determined by linear regression analysis of the cumulative amount of drug permeating (~g/cm2) across the skin as a function of the t ime ( hr ) .
WO 92/10154 PCI`/US91/09.
20981 g6 }
2 ~--l;y;~ nle 1 The aforementioned pLocedu~_ was used to evaluate the effect of increasinq sorbitan ester levels on estradiol flux from acrylic adhesives. The sorbitan 5 ester used was sorbitan monolaurate ("SML"); the acrylic adhesive used was Durotak~ 80-1194 ("1194").
Results are set forth in Table I. As may be seen, the flux obtained was found to increase with increasing quantities of sorbitan monolaurate.
Table I
F~fect of Incraasina-sorbitan Monolaura~e Levels on Estradiol Flux from an Acrvlic Adhesive -Estradiol Conc. Flux Enh~nr~r Svstem fmq/ml) ~ua/cm2/hr) None 2 wt.96 0.26 + 0.05 5 wt.% SML 2 wt.% 0.34 + 0.09 10 wt.% SML 2 wt.96 0.43 + 0.08 EYPI le 2 ~ ~
The procedure of Example 1 was followed to evaluate the effect of sorbitan monooleate ("SM0") and sorbitan monolaurate on estradiol f lux from three 25 different acry~ic adhesive matrices, Durotak~ 80-LL94 ("1194"), Durotak~ 80-1054 ("1054") and Durotak~ 80-1070 ("1070"). All systems tested contained 4 wt.% estradiol.
As may be deduced from the results set forth in the following table, the two sorbitan esters were found to 30 siqnificantly increase flux in all three types of adhesive matrices.
092/lOlS4 PCI/US9l/0921 -25- 2!39813 Table II
Effect of Sorbitan Esters on Estradiol F~
From Three Differorlt Acrvlic ~h~cive Matrices Formulation Flt~ Lq/cm2/hr~
1194 0.38 + 0.36 1194/15% SMO 1.69 + 0.58 1194/15% SML 0.96 + 0.47 1054 o . 55 + o . 12 1054/15% SMO 0.95 + 0.40 1054/15% SML 1.07 + 0.07 15 1070 0.41 + 0.07 1070/15% SMO 0. 68 + 0.13 1070/15~ SMO O . 99 + O. 31 2 0 Exam~le 3 The procedure above was f ollowed to prepare additional acrylic adhesive matrices containing estradiol (both with and without a sorbitan ester), so as to evaluate the effect of drug loading on estradiol flux.
The acrylic adhesive used was Durotak~ ~30-1070 ("1070"), and the sorbitan ester used was sorbitan monooleate.
Results are set forth in Table III. Sorbitan monooleate was found to increase estradiol flux in both of the systems tested.
WO 92/10l54 PCI/US91/09~
2~98196~ -26-T~hlç III
~ffect Qf Druq Loadinq on Estradiol F1llY from ~n ACXYliC Adhesive Matrix Wi~h ;~n~l Without Sorbitan Monooleate Skin 1 Skin 2 Formulation (~Lq/cm2/hr~ q/cm2/hr~
1 wt.% estradiol, no f~nhAn-~Pr 0.22 + 0.08 0.34 + 0.03 2 wt. % e6tradiol, no ~nhAncor O . 56 + O . 08 0 . 72 + O . 09 10 1 wt.% estradiol, 5 wt.% SMO 0.43 + 0.18 0.55 + 0.07 2 wt. % estradiol, 5 wt . % S~O 1. 00 + 0 .16 Q=. 98 + O . 08 . .
FY;~ le 4 The procedure above was folIowed to prepare additional acrylic adhesive matrices (Durotak$ 80-1194) containing estradiol. One 6ystem was prepared with sorbitan trioleate ("STO") as an ~nhAnr~r, and a second system was prepared without sorbitan trioleate. The flux obtained with the sorbitan trioleate system was approximately 52% higher than that obtained with the control system. Results are set forth in Table IV.
T;~hle IV
Effect of Sorbitan Trioleate on ~stradiol Flux (~Lq/cm2/hr) from An AcrYliç Adhesive Ma~rix FQrmulation ~ Flux (ILq/cm2/hr) 4 wt.% estradiol, no enhancer 0.78 + 0.13 4 wt.% estradioI, 10 wt.% STO 1.19 + 0.13 ) 92/10154 PCr/US91/0921~
209~196 r le 5 The ~loc:euuL~ above was followed to prepare acrylic - adhesive matrices (Durotak~ 80-1194 and 80-1054) containing 10 wt. % norethindrone acetate. Systems were 5 prepared with and without 15 wt. % sorbitan ester; both sorbitan monooleate and sorbitan monolaurate were tested, as shown in Table V. As may be concluded from the results summarized in the table, both sorbitan monooleate and sorbitan monolaurate significantly increased 10 norethindrone acetate flux in both adhesive systems.
Table V
Ef~ects of Sorbitan Esters on l~orethintlrone Acetate Fl~ rom Acrvlic Ar1h~ives Matrices Skin 1 Skin 2 lAtion (ua/cm2/hr~ (ILq/cm2/hr) 1194/no enhancer 0.21 + 0.02 0.24 + 0.02 1194/15% SM0 0.38 + 0.20 0.31 + 0.01 20 1194/15% SNL 0.43 + 0.09 0.60 + 0.03 1054/no enhancer - 0.27 + 0.06 1054/15% SM0 - 0.40 + 0.11 1054/15% SML -- 0.54 + 0.06 ~xam~le 6 The procedure above was ~ollowed to prepare acrylic adhesive matrices using Gelva~ 737 ("737") containing 5 wt. ~ pindolol. Systems were prepared with 30 15 wt.% sorbitan monooleate, 15 wt.% sorbitan mono-laurate, and 15 wt. % sorbitan trioleate, and compared with a system not containing any sorbitan ester. Again, the flux of arug was found to be significantly higher for all of the systems formulated with the sorbitan esters, WO 92/10154 PCr/US9i/09~
20981~
--~~ ~ 2 8 relative to the control. Results are set forth in Table VI.
I'Ahle VI
E~fects of Sorbitan Esters on Pindolol Flu~ from Acrylic Adhesive Matrices F~ lRtion Fl~ 71~q/cm2/hrl 737/no enhancer 0 . 23 + 0 . 05 10737/15% SMO 0.55 737/15% SML 0.75 + 0.26 737/15% ST0 0.55 + 0.19 15 EYA le 7 Flux of progesterone from ethanolic solutions of the drug was evaluated as ~ollows.
- Ethanol/water/glycerin/sorbitan ester ointments were prepared as summarized in Table VII, and the flux of 20 the drug therefrom evaluated.
TAhle VII
PrQc~esterone Pl~ From Ethanolic s01utinnc Containinq SQrbitAn Ester Flux 1~20 Glvcerin SM0 SML l~q/cm2/hr ---- 88 10 2 --- o. 61 + C. 03 ---- 88 lO -- 2 1.21 + 0.19 : -- -- 6.29 + 0.77 30 60 28 10 ~ 2 __ 13.04 + 1.52 28 10 -- 2 ; 10 . 33 + 4 . 02 The data summarized in Table 7 clearly demonstrates a synergistic enhancement f or progesterone 0 92/10154 PCr/US91/09215 -29- 2~8196 when ethanol is combined with sorbitan monolaurate or sorbitan monooleate.
r le 8 Nitroglycerin in ethanol (lO vol . %) was obtained from ICI Americas, Inc., Delaware; polyacrylate adhesive solution (Durotak~ 80-1194) was obtained from National Starch & Chemical Co., New Jersey. Oleyl alcohol was obtained from Henkel corp., La Grange, Illinois (HD Eutanol, ultra pure grade). The polyacrylate adhesive solution, nitroglycerin solution and oleyl alcohol were mixed in the required proportion to provide a final solution which upon solvent evaporation would contain 37.5 wt.% nitroglycerin, 5 wt.%
oleyl alcohol and 57 . 5 wt. % polyacrylate adhesive. This solution was rotoevaporated to increase its viscosity to facilitate casting as a film. The concentrated solution was cast onto the silanized surface of a polyester release liner (Release Technologies, 2-EST-A-S242N), using a 10 mil gap Gardner knife. The cast adhesive was then dried at 80C for 15 minutes in a convection oven to yield a f inal 0 . 0025 inch thick adhesive coating. A
0 . 0025 inch thick low density polyethylene f ilm (Schoeller Technical Paper Co., New York) was then laminated onto the dried adhesive surface to produce a three-layer tr~n~d~rr~l matrix system construction.
Following the same procedure outlined above, another transdermal matrix system with the final composition of 35 wt. % nitroglycerin and 65 wt. % polyacrylate adhesive was prepared. This matrix did not contain any ~nhiin~-Pr.
As controls, the f lux of nitroglycerin from an ~nf~nh~n--ed nitroglycerin patch (NitroDur II, Key Pharmaceuticals) and an enhanced nitroglycerin patch (Minitran~, Riker Pharmaceuticals ) were evaluated in parallel.
, . . , . . . _ _ .. . .. .
WO 92/10154 PCr/US91/09~
- ~98~96 ~30-TAhle VIII
HPL~ Assav Method for Nitroqlvcerin 5 Mobile Phase: 50% (vol. ) acetonitrile 50% (vol. ) water Flow Rate: l . 3 ml/minute Column: Partisphere Cl8 (Whatman) Injection Volume: 20 ,Ll Wave Length: 210 nm Retention Time: 3 . 0 minutes Run Time: 5. o minutes Table IX provides the skin f lux in two different experiments obtained from the controls and the transdermal matrix patches prepared according to the method described above. The flux obtained from the oleyl alcohol matrix is much higher than that from the 20 11nPnhAnrPtl NitroDur II control patch and the 1~nPnh~nret~i nitroglycerin patch prepared as described above.
Furthermore, the oleyl alcohol matrix produced significantly higher nitroglycerin skin flux than the 25 enhanced control patch, M1nitran.
`
0 92/10154 DCI/US91/0921~
= 2098196 TAble IX
NitroqlYcerin ck i n F1I~Y
(~g/cm2/hr) a Form~ tion ~ia~ Skin 2 NitroDur II 20.58 + 2.60 29.92 + 4.02 Minitran 26 . 63 + 5 . 92 36. 69 + 2 . gl 65/3sb 24.21 + 2.84 30.68 + 2.80 57.5/37.5/5C 38.56 + 0.96 45.63 + 4.33 10 a N = 4, mean + standard deviation b weight percent of adhesive/nitroglycerin (no ~nhAnrPr) c weight percent of adhesive/nitroglycerin/oleyl alcohol FYA le 9 15 - Nitroglycerin was premixed into the National Starch Durotak~ 80-1194 polyacrylate adhesive by Atlas Powder Company to provide a f inal solution containing 22 .1 wt. 96 nitroglycerin, 35 . 8 wt. % solid acrylic adhesive and, 42 .1 wt. % total solvents. oleyl alcohol (Henkel) or 20 sorbitan monooleate ("ArlacelD 80"; ICI Americas) was then dissolved into the nitroglycerin/adhesive solution at various levels to provide f inal matrix compositions ranging from 0 to 7. 5 wt. 96 ~nhAn~ Pr upon drying. These solutions were then cast onto silanized release liners, 25 dried at 80OC for 15 minutes, and finally laminated onto the polyethylene backing film as described in the preceding example. Transdermal nitroglycerin delivery was then determined as a function of ~nhAnr~r loading as described in the Example 8 using the Minitran Patch 30 (Riker Labs) as a control. Results are presented in Table III.
WO 92/10154 PCI/US91/09*
I~9~19~
=
l~ablP III
NitroqlYcerin Skin Flux ~ g/cm2/hr) a Formulation OleYl Alcshsl Arlaeel 80 5 60.0/37.5/2.5b 39.61 + 1.94 39.18 + 4.28 58.75/36.25/5.0b 41.27 + 4.65 42.63 + 7.55 57.25/35.25/7.5b 47.02 + 2.63 36.04 + 8.13 Minitran Control 31.52 + 1.79 31.52 + 1.79 1 aN=4 bweight percent ratios of adhesive/nitroglycerin/enhancer In general, nitroglycerin flux was found to inerease with inereasing enhaneer (either oleyl aleohol 15 or Arlaeel 80) eontent. Further, higher nitroglyeerin ~lux values were observed with all PnhAnrPr loadings in the experimental matrix eompositions than with the Minitran eontrol.
EY~1e 10 The proeedure of Example 9 is repeated using sorbitan monolaurate in place of sorbitan monooleate (e.g., "Arlacel~D 20" from ICI Americas). ~nh;~nePrl transdermal flux relative to an unenhanced nitroglycerin 25 system is obtained.
~mnle 11 The ,u~u~ du~: of Example 9 is repeated using sorbitan monopalmitate in place of sorbitan monooleate 30 (e.g., "Arlacel~ 40" from ICI Americas). Enhanced transdermal flux relative to that obtained from with an unenhanced nitroglycerin system is obtained.
35 ~ ~ =
~ 92/10154 PCr/US91/09215 ~ le 12 The procedure of Example 9 is repeated using sorbitan trioleate in place of sorbitan monooleate (e.g., "Arlacel~ 85" from ICI Americas). As with the preceding examples, the transdermal f lux obtained is higher than that which would be obtained for an llnPnhAncPd nitroglycerin patch.
ExamPle 13 The enhanced transdermal delivery of nitroglycerin from acrylic matrices containing 5 wt. %
PnhAnf~Pr (oleyl alcohol or Arlacel~ 80) was evaluated using 3 different donor skins. FnhAnCPd nitroglycerin matrices were prepared as described in Example 9, nitroglycerin skin f lux was determined as described in Example 8 using the NitroDur II and Minitran as controls.
vitro skin f lux results are presented in Table X.
~k~
NitroqlYcerin Skin Flux (,ILg/cm2 /hr) Formulation ~ ~ki~ Skin 3 NitroDur II -- 26.06 + 5.65 16.34 + 4.64 25 Minitran 39 . 97 + 3 . 69 44 .14 + 5 . 95 20.17 + 1. 61 5% Oleyl Alcohola 55.99 + 4.80 50.57 + 6.53 30.63 + 5.04 5% Arla-cel 80a 57.45 + 3.81 51.86 + 10.?2 26.57 + 2.78 a 58.7% wt acrylic adhesive, 36.3% wt nitroglycerin, 5 . 0% wt enhancer The flux obtained from both oleyl alcohol and 35 Arlacel 80 PnhAn~pd matrices was nearly double that WO 92/lOlS4 PCI/US91/09~
--~819~
obtained from the lln~nhAnf~ NitroDur II control patch.
Further, both ~nhAnred matrix formulations produced consistently higher nitroglycerin skin flux than the ~nhAncF~-l control patch, Minitran.
E~ 21e 14 An easy to open release tab can be prepared by overlapping two sections of the release liner by approximately 1/8 inch. The adhesive/drug/~nhAn-~Pr lO solution can then be cast onto a f irst release liner, dried and laminated ~o the backing f ilm as described in the above examples . The f irst release liner is then removed and the overlapping release liner is then laminated onto the adhesive surface in its place. Final 15 transdermal patches are then die cut with the overlapping release liner section spatially within the f inal patch.
Alternatively, the f irst release liner can be control depth slit following the lamination of the backing film.
A section of the slit liner is then removed and a new 20 section relaminated onto the exposed adhesive area such that the new liner section overlaps the r~r~inin~, slit prior liner which was not removed from the original laminate. Final patches are then die cut as previously 25 described.
;
It is still a further object of the invention lO to provide a transdermal system for the administration of nitroglycerin which provides f or a drug f lux of at least - about 50% higher than that obtained in the absence of a skin permeation enhancer.
It is yet another object of the invention to lS provide methods and compositions for the enhanced transdermal administration of steroid drugs.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become 20 apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention .
In one aspect, the invention is a method f or administering a pharmacologically active agent 25 transdermally so as to achieve relatively high transdermal fluxes, by administering, through a predetermined area of intact skin and for a predetermined period of time, (l) the agent, and (2) a permeation PnhAnoPr consisting essentially of a sorbitan ester, or a 30 sorbitan ester in combination with a Cl-C4 aliphatic alcohol. In a preferred embodiment, the skin permeation ~-nh~nrPr and the drug are administered in a single composition. As the clearance rate of many drugs from ... . '' .~ .. . ~....
~ -9- 2098196 administration be substantially continuous throughout the time period chosen for patch application.
In another aspect of the invention, a composition of matter is provided that is useful for the 5 delivery of a pharmacologically active agent through the skin, comprising:
(a) a therapeuticaliy effective amount of the pharmacologically active agent to be administered; and (b) an amount of a permeation ~nh~nr~r 10 composition effective to enhance the penetration of the pharmacologically active agent through the skin, wherein the ~nh~nt ~r consists essentially of a sorbitan ester or a sorbitan ester combined with a Cl-C4 aliphatic alcohol.
In still another aspect of the invention, a 15 therapeutic system is provided for administering a drug transdermally, at relatively high fluxes as noted above, in the form of a skin patch. The skin patch is - pref erably in the f orm of a matrix-type laminated composite containing an upper backing layer that is 20 substantially imp~L --hle to the drug, and at least one drug/-~nh~n~ c~r reservoir, one of which forms the basal surface of the device and is designed to adhere to the skin during use. The reservoir is a matrix which contains both the drug and a permeation ~nh~nr~r as 25 described above. Such a laminated composite preferably i n~ s a strippable protective release liner laminated to the basal surface of the drug reservoir. The release liner is a disposable element designed to protect the exposed reservoir surface prior to use. In an 30 alternative embodiment, a transdermal therapeutic system is provided in the form of a liquid reservoir-type laminated composite, e.g., as described in commonly assigned U. S . Patent No . 4, 849, 224 to Chang et al .
i' .
~j) 92/10154 PCI/US91/09!--- ~ -lO- 2098196 In yet another aspect, the invention is a method for administering nitroglycerin transdermally so as to achieve relatively high transdermal fluxes, by co-administering, through a predetPrm;nPd area of intact skin and for a predetPrm;nPcl period of time, (l) nitro-glycerin, and tz~ a permeation Pnh~nrPr as described herein . In a pref erred Pmho~l i r -~t, the skin permeation Pnh;lnrPr and the drug are administered in a single composition which contains both components. As the clearance rate of nitroglycerin from the body is quite high, it is preferred that administration be continuous throughout the time period chosen for patch application.
It should also be noted that the present invention is directed to the administration of nitroglycerin to individuals in need of nitroglycerin therapy, generally, and thus Pn _ -C~PC tr;~n~CIPrr-1 methods and systems designed for a variety of indications , e . g ., the relief and treatment of angina pectoris, congestive heart failure, and the like.
In still another aspect of the invention, a therapeutic system is provided for administering nitroglycerin transdermally, at relatively high fluxes as noted above, in the form of a skin patch. The skin patch is a laminated composite containing an upper backing layer that is substantially impermeable to the drug, and at least one drug/enhancer reservoir, one of which forms the basal surface of the device and is designed to adhere to the skin during use The reservoir contains both the nitroglycerin and a permeation Pnh~nrPr as described 3 0 herein .
In still another aspect of the invention, such a laminated composite is provided which further includes a strippable protective release liner laminated to the basal surface of the drug reservoir. The release liner is a disl~osable element designed to protect the exposed :.
.. _ _ . . . ... _ _ _ _ , , .
~ 92/10154 PCr/US91/09215 2~98~96 - reservoir surface prior to use. The release liner, for ease of removal, is preferably a two-part structure in which a f irst strippable protective sheet partially overlaps a second strippable protective sheet, giving 5 rise to a tab extending from the basal surface of the patch .
Brief ~escriPtiQn of the Drawinq Figure l is a schematic sectional view through lO a laminated matrix-type transdermal system of the invention .
Figure Z is a schematic sectional view through a laminated liquid reservoir-type tr~nc~rr~l system of the invention.
Detailed PescriPtion of the Invention Before describing the present compositions, systems and methods of the invention in detail, it is to be understood that this invention is not limited to the 20 particular drugs, sorbitan esters, aliphatic alcohols, or laminate materials described herein as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular omho-lir tS only, and is not intended to be 2 5 l imiting .
It must ~e noted that, as used in this specification and the appended claims, the singular forms "a, " "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, 30 reference to a laminated structure containing "a drug"
includes a mixture of two or more drugs, reference to "an adhesive" includes reference to one or more of such adhesives, and reference to 1'a sorbitan ester" includes reference to a mixture of two or more sorbitan esters.
_ _ _ _ _ , WO 92/10154 PCI/US91/09~
209819~
..=_ In describing and rlilim;n~ the present invention, the following terminology will be used in accordance with the def initions set out below.
"Penetration enhancement" or "permeation 5 Pnh inr~--nt" as u8ed herein relates to an increase in the permeability of skin to a pharmacologically active agent, i . e., 50 as to increase the rate at which the agent permeates into and through the skin. A "permeation ~nh~nrPr" is a material which achieves such permeation lO enhancement, and a "penetration enhancing amount" of an ~nh~nrPr as used herein means an amount effective to enhance skin penetration of a selected agent to a desired degree .
By "transdermal" drug delivery, applicant is lS using the term in its conventional sense, i.e., to indicate delivery of a drug by passage through the skin and into the blood stream. By "tr~n c05~ drug delivery, applicant intends aelivery of a drug by passage of a drug through the mucosa~ tissue into the blood 20 stream. "Topical" drug deiivery is used to mean local administration of a topical drug as in, for example, the treatment of various skin disorders. These terms will sometimes be used interchangeably herein, i . e., aspects of the invention which are déscribed in the context of 25 "transdermal" drug delivery, unless otherwise specified, can apply to tr~ncm11ooc~l or topical delivery as well.
That is, the compositions, systems, and methods o~ the invention, unless explicitly stated otherwise, shouid be 1 to be equally applicable with any one of these 3 0 three modes of drug delivery .
The term "drug" or "pharmacologically active agent" as used herein is intended to mean a compound or composition of matter which, when administered to an organism (human or animal) induces a desired 35 pharmacologic and/or physiologic effect~by local andlor .
~0 92/10154 PCI/US91/09215 13 2~81~
systemic action. In general, the terms include the therapeutic or prophylactic agents in all major therapeutic/prophylactic areas of medicine. Examples of drugs useful in conjunction with the present invention 5 include: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations;
anorexics; antih~1minthics; antiarthritics; antiasthmatic agents; anticholinergic agents; anticonvulsants;
antidepressants; antidiabetic agents; antidiarrheals;
lO antihistamines; anti-inf lammatory agents, antimigraine preparations; anti-motion sickness drugs; antinauseants;
antineoplastics; antiparkinsonism drugs; antipruritics;
antipsychotics; antipyretics; antispasmodics;
anticholinergics; sympathomimetics; xanthine derivatives;
15 cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhythmics; antihypertensives; diuretics;
vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; cough and 20 cold preparations, including decongestants; steroids;
hypnotics; immunosuppressives; muscle relaxants;
parasympatholytics; psychostimulants; sedatives; and tranquilizers. For purposes of the aforementioned definition, "drugs" as used herein also include locally 25 administered topical medicaments such as antibacterial agents, antifungals, antimicrobials, cutaneous growth enhancers, antipsoriatics, anti-acne medicaments, and the l ike .
"Carriers" or "vehicles" as used herein refer 30 to carrier materials without pharmacological activity which are suitable for administration in conjunction with the presently disclosed and claimed compositions, and include any such carrier or vehicle materials known in the art, e.g., any liquid, gel, solvent, liquid diluent, 35 solubilizer, or the like. The carriers and vehicles .
WO 92/l0l54 PCI/US91/09~
~9819~
~ --14--suitable herein are "pharmaceutically acceptable" in that they are nontoxic, do not interfere with drug delivery, and are not for any other reasons biologically or otherwise undesirable. Examples of specific suitable 5 carriers and vehicles for use herein include water, mineral oil, silicone, inorganic gels, aqueous emulsions, liquid sugars, waxes, petroleum jelly, and a variety of other oils and polymeric materials.
By a "therapeutically effective" amount of a 10 drug or pharmacologically active agent is meant a nontoxic but suf f icient amount of the drug or agent to provide the desired therapeutic effect.
"Nitroglycerin" shall mean 1,2,3-propanetriol trinitrate, i . e., the compound having the structural 15 formula , The invention is thus in one Pmho~ nt a 25 method for enhancing the rate of penetration of a pharmacologicaily active agent through the skin, wherein the method involves co-administration of the agent through a predetermined area of intact skin, and for a predetermined period of time, the selected agent and a 30 permeation f~nhAnr~r consisting essentially of a sorbitan ester or a sorbitan ester in combination with a C1-C4 aliphatic alcohol. The sorbitan esters which are useful in con~unction with the present invention have the structure _ CEit--R, E~O--CH O
l/
H~/
10 wherein the substituent Rl has the structure -O(CO)R', where R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated and tri-u:lsa~uLated aliphatic hydrocarbon substituents of 7 to Z1 carbon atoms, preferably 11 to 21 carbon atoms, 15 and may be substituted with 1 to 3 hydroxyl groups. The substituents R2 and R3 may be the same or different and are selected from the group consisting of hydroxyl and -O(CO~R' as defined above. Rl, R2 and R3, may be, for example, lauryl, myristyl, palmityl, stearyl, 20 palmitoleyl, oleyl, linoleyl, linolenyl, or ricinoleyl esters, or the like. Exemplary sorbitan esters are long-chain sorbitan Donoesters, wherein R1 is as defined above, R' is hydrocarbon of 11 to 21 carbon atoms, and R2 and R3 are both hydroxyl. Particularly preferred 25 ~_ u.-ds within the class of sorbitan monoesters are sorbitan monooleate and sorbitan monolaurate.
In addition to a sorbitan ester, the permeation Pnh IncPr composition of the invention may also include an aliphatic alcohol r~ nt. Preferred aliphatic 30 alcohols are the Cl-C4 alcohols such as ethanol, n-propanol, isopropanol, t-butanol, and mixtures thereof.
However, longer chain alcohols (typically C8-C22) such as oleyl alcohol may also be used (see, e.g., Examples 8 and 9 ) herein .
' ~ .
~) 92/10154 PC~/US91/09~
, _ , The method of delivery of the present compositions may vary, but necessarily involves application of drug and PnhAncPr to a selected intact surface of the skin or other tissue for a period of time 5 sufficient to provide the desired blood level of drug.
The method preferably involves administration of drug and PnhAnrPr simultaneously, in a single composition, i.e., as an ointment, gel, cream, or the like, or may involve use of a drug delivery device as taught, f or example, in U.S. Patent Nos. 4,849,224, 4,983,395, 4,568,343, 3,797,494 or 3,742,951.
When the drug to be administered and the permeation PnhAnl-~r as described above are applied in the form of an ointment, gel, cream or the like, the amount 15 of drug contained within the composition will depend on a variety of factors, including the desired rate of delivery, the desired dosaqe, the disease to be treated, the nature and activity of the drug, the desired effect, possible adverse reactions, the ability and speed of the 2 0 drug selected to reach its intended target, and other factors within the particular knowledge of the patient and the physician. The amount of enhancer will typically be in the range of O .1 wt . % to 4 0 wt . % relative to the total composition, more preferably on the order of about 25 2 . 5 wt. % to 15 wt. %. The composition may, in addition to drug and PnhAncPr ~ include one or more selected carriers or excipients, and/or various agents and ingredients commonly employed in dermatological ointments and lotions. For example, fragrances, opacifiers, 30 preservatives, antioxidants, gelling agents, perfumes, thickening agents, stabilizers, surfactants, emollients, coloring agents, and the like may be present so long as they are pharmaceutically acceptable and compatible with the drug and enhancer.
_ ~ -17- 2098196 A trAncdPrr-l delivery system for the administration of a drug can be constructed with the drug/enhancer composition described hereinabove.
Preferred tr~nC~rr l drug delivery systems for use .
S herein are laminated composites which contain one or more drug/permeation ~nhAncP~ reservoirs, a backinq layer and, optionally, one or more additional layers ~e.g., additional drug and/or ~nh~nc~r reservoirs) as those skilled in the art of trAnc-lPrr- 1 drug delivery will 10 readily appreciate. Figure 1 depicts an exemplary system, generally designated 10, that when applied to skin administers a selected pharmacologically active agent as outlined above. System 10 is a laminated composite in which the top layer 12 is a backing layer, 1~ its face forming the top surface of the composite. The drug reservoir, containing drug, enhancer as described herein, and optional carriers or vehicles, is shown at 1~, immediately below and adjacent to the backing layer.
Prior to use, the laminate also includes a strippable protective release liner. In a preferred ~ ' ~; L, the release liner is in the form of two sheets 16zl and 16b, the first sheet 16a partially overlapping the second sheet 16b. Additional structural layers and/or additional drug/enhancer reservoirs may also be present.
The drug reservoir is preferably comprised of a contact adhesive which is a pressure-sensitive adhesive suitable for long-term skin contact. It must also be physically and fh~ri~Ally compatible with the drug and enhancer employed, and with any carriers or vehicles incorporated into the drug/enhancer composition.
Further, the adhesive selected for use as the reservoir ~ 92/10154 PCI`/US91/09~
=
-18- 2a98l96 layer must be such that the drug and ~hAnrPr are at least somewhat soluble in the adhesive. The drug reservoir will generally be in the ranqe of about 2 to 4 mils in thickness . Suitable adhesives f or use as the 5 drug reservoir include polysiloxanes, polyacrylates, polyurethanes, tacky rubbers such as polyisobutylene, and the like. Particularly preferred contact adhesives for use as the drug reservoir herein are cross-linked acrylates (e.g., the Durotak~ adhesives, available from lO National Starch & Chemical Co., New York, NY, or the Gelva~19 adhesives, available from Monsanto Co., St. Louis, M0) .
The backing layer, which is, as shown, adhered to the drug reservoir and serves as the upper layer of 15 the device during use, functions as the primary structural element of the device. The backing layer is made of a sheet or film of a preferably flexible elastomeric material that is substantially impermeable to the drug/~nhAnrpr composition. The layer will typically 20 be on the order of l.0 to about 4.0 mils in thickness, and is preferably of a material that permits the device to follow the contours of the skin, such that it may be worn comfortably on any skin area, e.g., at joints or other points of flexure. In this way, in response to 25 normal mechanical strain, there is little or no likelihood of the device disengaging from the skin due to differences in the flexibility or resiliency of the skin and the device. Examples of polymers useful for the backing layer herein are polyethylene, polypropylene, 30 polyesters, polyurethanes, polyethylene vinyl acetate, polyvinylidene chloride, block copolymers such as PEBAX, and the like. The backing layer may also comprise laminates of one or more of the f oregoing polymers .
The release liner is a ~;crnsAhle element which 35 serves only to protect the device prior to application.
-0 92/10154 PCI`/US91/09215 Typically, the relea6e liner is formed from a material -~.hle to the drug, vehicle, and adhesive, and which is easily stripped from the contact adhesive that serves as the drug reservoir layer. Preferred release liners 5 for use herein are those which are generally suitable for use in conjunction with pressure-sensitive adhesives.
Silanized polyester films are presently preferred.
In a preferred Pmho~l;r-nt, as noted above, a two-part release liner is used, wherein a first lO strippable protective sheet (shown as 16a in Figure l) partially overlaps a second strippable protective sheet 16b, such that the area of overlap gives rise to a tab which extends from the basal surface of the laminate, enabling ready removal of the strippable sheets from the 15 reservoir Iayer.
The preferred laminated composites of the invention are as shown in Figure l, having a backing layer, a drug reservoir, and a two-piece release liner;
the drug reservoir contains a drug/~nh~nc~r composition 2 0 as described above, with the quantity of the drug therein, and with the r~--inrll~r of the drug reservoir comprised of adhesive and optional carriers, vehicles or the like. To use these laminated composites, one is applied directly to the skin of a patient, to release the 25 drug/~nh;lnc~r composition to the skin, allowing the drug to permeate into the circulation. The adhesive layer which serves as the drug reservoir should be in f irm contact with the skin.
In general, such devices are fabricated using 30 methods standard in the art, e.g., solvent-evaporation f ilm casting in which all components of the drug/enhancer composition are admixed with the adhesive which will serve as the drug reservoir, and cast onto a substrate which is either the backing layer or release liner.
3 5 ~ ~
.
~ -20- 2098196 Other layers are then laminated to this initial structure .
In an alternative ~mhQ~ t, laminated composites containing drug in a liquid reservoir, as des,cribed in U. S. Patent No. 4, 849, 224, may be used. As described in that patent, such devices shown generally at 18 in Figure 2 are comprised of an uppermost layer of a heat-sealable backing film 20 having an inverted, cup-shaped recess that serves the reservoir 22 for the drug-~nhAnaer formulation. The underside of the outer edge of the backing film carries a ring-shaped layer 2~ of a :~UL- ~cnsitive adhesive peripheral to the reservoir.
Underlying the reservoir, just inward of the peripheral ring of adhesive, is a membrane layer 26 that is permeable to the drug-anhAnc~r formulation. A peel sealable inner liner 28 underlies membrane 26 and portions of backing film 20. A peel-s~llAhla release liner 30 covers the entire underside of the assembly and forms the basal surface of the device. Device 18 has a heat seal 3Z between the membrane and backing f ilm and a peelable (impermanent) heat seal 34 between the backing film and the inner liner 28. An alternative liquid reservoir-type device which may be used in conjunction with the present compositions is described in U. s . Patent No. 4,983,395.
Preferred daily dosages obtained with the present methods and systems will, similarly, vary with the drug administered. The targeted daily dosage will depend on the individual being treated, the indication addressed, the length of time the individual has ~een on the drug, and the like.
Turning now to the administration of nitroglycerin, specifically, it is preferred that the drug and the selected permeation ~nhAncr~r or enhancers are administered to the individual simultaneously, in a D 92/10154 PCr/US91/0921~
- ~2-0~8196 ~ingle composition. As with other drugs, a preferred mode of administration, however, is via a trAn-~lPrr-1 patch, wherein the pref erred quantities of the various ~; ts will be outlined below.
In a preferred embodiment, the nitroglycerin and the selected permeation ~nh~nrPr or PnhAnc~rs are administered such that f lux is increased by at least about 50% relative to that which would be achieved in the absence of a permeation Pnh~ncPr, that is, typically, a flux on the order of at least about lO ~g/cm2/hr, preferably at least about 20 ~ug/cm2/hr, most preferably at least about 30 ~Lg/cm2/hr, is achieved. It will be appreciated by those skilled in the art of transdermal drug delivery that the foregoing numbers are approximate, as trAncdprr~l flux may vary with the individual undergoing treatment as well as the particular skin site chosen for transdermal drug delivery.
It is also preferred that the time period for nitroglycerin administration be on the order of 12 to 36 hours, optimally about 12 to 24 hours, during which time drug delivery is substantially continuous.
Preferred daily dosages obtained with the present methods and systems are typically in the range of 2.5 to 50 mg, more typically in the range of about 2.5 to 20 mg, for nitroglycerin. ~he targeted daily dosage will, however, depend on the particular drug being administered, the individual being treated, the indication addressed, the length of time the individual has been on the drug, and the like. Generally, and as 3 0 noted above, the present methods and systems enable transdermal administration of nitroglycerin at somewhat higher transdermal fluxes than enabled with the majority of previously known transdermal nitroglycerin systems, and may thus be useful for treating disorders which require a higher daily dosage than is typical (e.g., .
WO 92/10154 PCI/US91/09~
~8196 congestive heart failure), or for treating patients who have developed some tolerance for the drug. The invention also enables the use of conveniently sized small patches.
~r~nR~or~ 1 delivery of nitroglycerin with the permeation ~nh In-~rs of the invention enable the use of a skin area for drug administration in the range of approximately 1. 0 cm2 to about 100 cm2 . At higher transdermal fluxes, smaller skin areas within the aforementioned range may be targeted, i.e., less than about 25 cm2 or, more preferably, less than about 10 cm2.
r~çri~ -ntal The following examples are put forth so as to provide those with ordinary skill in the art with a complete disclosure and description of how to formulate compositions and systems of the invention, and are not intended to limit the scope of what the inventors regard as their invention . Ef f orts ~have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures , etc . ), but some experimental errors and deviations should be allowed for. Unless indicated otherwise, parts are parts by weight, temperatures are in degrees Centigrade, and pressure is at or near ai ~rh~ric.
Es~radiol, norethindrone acetate, progesterone and pindolol were-obtained from Sigma Chemical Co., St.
Louis, M0. Polyacrylate adhesive solutions were obtained from National Starch & Chemical Co., New Jersey (Durotak~D
80-1194, 80-1054, 80-1070) and fro~n Monsanto Corporation, St. Louis, M0 (Gelva~ 737). Sorbitan monooleate, sorbitan monolaurate and sorbitan trioleate were all obtained from ICI Americas.~ Ethanol (USP 95~) was obtained from Fisher Scientific.
.~ f ;) 92/1 OW -- PCT/US91/0921~
--2~9~196 Adhesive laminates were formulated by mixiny the selected polyacrylate solutions with drug and/or ~.nh~n~ r, followed by evaporation of solvent. The concentrated solution was cast onto the silanized surface 5 of a polyester release liner (Release Technologies, 2-EST-A-S242M), using a 10 mil gap Gardner knife. The cast adhesive was then dried at 80C for 15 minutes in a convection oven to yield a final 0. 050 inch thick adhesive coating. A 0. 0075 inch thick low density 10 polyethylene film (Schoeller Technical Paper Co., New York) was then laminated onto the dried adhesive surface to produce a three-layer transdermal matrix system construction .
The in vitro skin f lux of the particular drugs 15 tested was evaluated across human cadaver skin as described by Merrit and Cooper (J. CQntrolled Release (1984) 1:161) using a high-performance liquid chromatography (HPLC) assay. For these studies the release liner was removed from a previously cut section 20 of the above tr~nc~rr~ 1 matrix construction. The adhesive matrix was then positioned onto the stratum corneum surface of heat separated human epidermis and the skin, with the adhering transdermal system, was then immediately mounted onto the diffusion cell. The steady 25 state flux (~Lg/cm2/hr~ of drug was determined by linear regression analysis of the cumulative amount of drug permeating (~g/cm2) across the skin as a function of the t ime ( hr ) .
WO 92/10154 PCI`/US91/09.
20981 g6 }
2 ~--l;y;~ nle 1 The aforementioned pLocedu~_ was used to evaluate the effect of increasinq sorbitan ester levels on estradiol flux from acrylic adhesives. The sorbitan 5 ester used was sorbitan monolaurate ("SML"); the acrylic adhesive used was Durotak~ 80-1194 ("1194").
Results are set forth in Table I. As may be seen, the flux obtained was found to increase with increasing quantities of sorbitan monolaurate.
Table I
F~fect of Incraasina-sorbitan Monolaura~e Levels on Estradiol Flux from an Acrvlic Adhesive -Estradiol Conc. Flux Enh~nr~r Svstem fmq/ml) ~ua/cm2/hr) None 2 wt.96 0.26 + 0.05 5 wt.% SML 2 wt.% 0.34 + 0.09 10 wt.% SML 2 wt.96 0.43 + 0.08 EYPI le 2 ~ ~
The procedure of Example 1 was followed to evaluate the effect of sorbitan monooleate ("SM0") and sorbitan monolaurate on estradiol f lux from three 25 different acry~ic adhesive matrices, Durotak~ 80-LL94 ("1194"), Durotak~ 80-1054 ("1054") and Durotak~ 80-1070 ("1070"). All systems tested contained 4 wt.% estradiol.
As may be deduced from the results set forth in the following table, the two sorbitan esters were found to 30 siqnificantly increase flux in all three types of adhesive matrices.
092/lOlS4 PCI/US9l/0921 -25- 2!39813 Table II
Effect of Sorbitan Esters on Estradiol F~
From Three Differorlt Acrvlic ~h~cive Matrices Formulation Flt~ Lq/cm2/hr~
1194 0.38 + 0.36 1194/15% SMO 1.69 + 0.58 1194/15% SML 0.96 + 0.47 1054 o . 55 + o . 12 1054/15% SMO 0.95 + 0.40 1054/15% SML 1.07 + 0.07 15 1070 0.41 + 0.07 1070/15% SMO 0. 68 + 0.13 1070/15~ SMO O . 99 + O. 31 2 0 Exam~le 3 The procedure above was f ollowed to prepare additional acrylic adhesive matrices containing estradiol (both with and without a sorbitan ester), so as to evaluate the effect of drug loading on estradiol flux.
The acrylic adhesive used was Durotak~ ~30-1070 ("1070"), and the sorbitan ester used was sorbitan monooleate.
Results are set forth in Table III. Sorbitan monooleate was found to increase estradiol flux in both of the systems tested.
WO 92/10l54 PCI/US91/09~
2~98196~ -26-T~hlç III
~ffect Qf Druq Loadinq on Estradiol F1llY from ~n ACXYliC Adhesive Matrix Wi~h ;~n~l Without Sorbitan Monooleate Skin 1 Skin 2 Formulation (~Lq/cm2/hr~ q/cm2/hr~
1 wt.% estradiol, no f~nhAn-~Pr 0.22 + 0.08 0.34 + 0.03 2 wt. % e6tradiol, no ~nhAncor O . 56 + O . 08 0 . 72 + O . 09 10 1 wt.% estradiol, 5 wt.% SMO 0.43 + 0.18 0.55 + 0.07 2 wt. % estradiol, 5 wt . % S~O 1. 00 + 0 .16 Q=. 98 + O . 08 . .
FY;~ le 4 The procedure above was folIowed to prepare additional acrylic adhesive matrices (Durotak$ 80-1194) containing estradiol. One 6ystem was prepared with sorbitan trioleate ("STO") as an ~nhAnr~r, and a second system was prepared without sorbitan trioleate. The flux obtained with the sorbitan trioleate system was approximately 52% higher than that obtained with the control system. Results are set forth in Table IV.
T;~hle IV
Effect of Sorbitan Trioleate on ~stradiol Flux (~Lq/cm2/hr) from An AcrYliç Adhesive Ma~rix FQrmulation ~ Flux (ILq/cm2/hr) 4 wt.% estradiol, no enhancer 0.78 + 0.13 4 wt.% estradioI, 10 wt.% STO 1.19 + 0.13 ) 92/10154 PCr/US91/0921~
209~196 r le 5 The ~loc:euuL~ above was followed to prepare acrylic - adhesive matrices (Durotak~ 80-1194 and 80-1054) containing 10 wt. % norethindrone acetate. Systems were 5 prepared with and without 15 wt. % sorbitan ester; both sorbitan monooleate and sorbitan monolaurate were tested, as shown in Table V. As may be concluded from the results summarized in the table, both sorbitan monooleate and sorbitan monolaurate significantly increased 10 norethindrone acetate flux in both adhesive systems.
Table V
Ef~ects of Sorbitan Esters on l~orethintlrone Acetate Fl~ rom Acrvlic Ar1h~ives Matrices Skin 1 Skin 2 lAtion (ua/cm2/hr~ (ILq/cm2/hr) 1194/no enhancer 0.21 + 0.02 0.24 + 0.02 1194/15% SM0 0.38 + 0.20 0.31 + 0.01 20 1194/15% SNL 0.43 + 0.09 0.60 + 0.03 1054/no enhancer - 0.27 + 0.06 1054/15% SM0 - 0.40 + 0.11 1054/15% SML -- 0.54 + 0.06 ~xam~le 6 The procedure above was ~ollowed to prepare acrylic adhesive matrices using Gelva~ 737 ("737") containing 5 wt. ~ pindolol. Systems were prepared with 30 15 wt.% sorbitan monooleate, 15 wt.% sorbitan mono-laurate, and 15 wt. % sorbitan trioleate, and compared with a system not containing any sorbitan ester. Again, the flux of arug was found to be significantly higher for all of the systems formulated with the sorbitan esters, WO 92/10154 PCr/US9i/09~
20981~
--~~ ~ 2 8 relative to the control. Results are set forth in Table VI.
I'Ahle VI
E~fects of Sorbitan Esters on Pindolol Flu~ from Acrylic Adhesive Matrices F~ lRtion Fl~ 71~q/cm2/hrl 737/no enhancer 0 . 23 + 0 . 05 10737/15% SMO 0.55 737/15% SML 0.75 + 0.26 737/15% ST0 0.55 + 0.19 15 EYA le 7 Flux of progesterone from ethanolic solutions of the drug was evaluated as ~ollows.
- Ethanol/water/glycerin/sorbitan ester ointments were prepared as summarized in Table VII, and the flux of 20 the drug therefrom evaluated.
TAhle VII
PrQc~esterone Pl~ From Ethanolic s01utinnc Containinq SQrbitAn Ester Flux 1~20 Glvcerin SM0 SML l~q/cm2/hr ---- 88 10 2 --- o. 61 + C. 03 ---- 88 lO -- 2 1.21 + 0.19 : -- -- 6.29 + 0.77 30 60 28 10 ~ 2 __ 13.04 + 1.52 28 10 -- 2 ; 10 . 33 + 4 . 02 The data summarized in Table 7 clearly demonstrates a synergistic enhancement f or progesterone 0 92/10154 PCr/US91/09215 -29- 2~8196 when ethanol is combined with sorbitan monolaurate or sorbitan monooleate.
r le 8 Nitroglycerin in ethanol (lO vol . %) was obtained from ICI Americas, Inc., Delaware; polyacrylate adhesive solution (Durotak~ 80-1194) was obtained from National Starch & Chemical Co., New Jersey. Oleyl alcohol was obtained from Henkel corp., La Grange, Illinois (HD Eutanol, ultra pure grade). The polyacrylate adhesive solution, nitroglycerin solution and oleyl alcohol were mixed in the required proportion to provide a final solution which upon solvent evaporation would contain 37.5 wt.% nitroglycerin, 5 wt.%
oleyl alcohol and 57 . 5 wt. % polyacrylate adhesive. This solution was rotoevaporated to increase its viscosity to facilitate casting as a film. The concentrated solution was cast onto the silanized surface of a polyester release liner (Release Technologies, 2-EST-A-S242N), using a 10 mil gap Gardner knife. The cast adhesive was then dried at 80C for 15 minutes in a convection oven to yield a f inal 0 . 0025 inch thick adhesive coating. A
0 . 0025 inch thick low density polyethylene f ilm (Schoeller Technical Paper Co., New York) was then laminated onto the dried adhesive surface to produce a three-layer tr~n~d~rr~l matrix system construction.
Following the same procedure outlined above, another transdermal matrix system with the final composition of 35 wt. % nitroglycerin and 65 wt. % polyacrylate adhesive was prepared. This matrix did not contain any ~nhiin~-Pr.
As controls, the f lux of nitroglycerin from an ~nf~nh~n--ed nitroglycerin patch (NitroDur II, Key Pharmaceuticals) and an enhanced nitroglycerin patch (Minitran~, Riker Pharmaceuticals ) were evaluated in parallel.
, . . , . . . _ _ .. . .. .
WO 92/10154 PCr/US91/09~
- ~98~96 ~30-TAhle VIII
HPL~ Assav Method for Nitroqlvcerin 5 Mobile Phase: 50% (vol. ) acetonitrile 50% (vol. ) water Flow Rate: l . 3 ml/minute Column: Partisphere Cl8 (Whatman) Injection Volume: 20 ,Ll Wave Length: 210 nm Retention Time: 3 . 0 minutes Run Time: 5. o minutes Table IX provides the skin f lux in two different experiments obtained from the controls and the transdermal matrix patches prepared according to the method described above. The flux obtained from the oleyl alcohol matrix is much higher than that from the 20 11nPnhAnrPtl NitroDur II control patch and the 1~nPnh~nret~i nitroglycerin patch prepared as described above.
Furthermore, the oleyl alcohol matrix produced significantly higher nitroglycerin skin flux than the 25 enhanced control patch, M1nitran.
`
0 92/10154 DCI/US91/0921~
= 2098196 TAble IX
NitroqlYcerin ck i n F1I~Y
(~g/cm2/hr) a Form~ tion ~ia~ Skin 2 NitroDur II 20.58 + 2.60 29.92 + 4.02 Minitran 26 . 63 + 5 . 92 36. 69 + 2 . gl 65/3sb 24.21 + 2.84 30.68 + 2.80 57.5/37.5/5C 38.56 + 0.96 45.63 + 4.33 10 a N = 4, mean + standard deviation b weight percent of adhesive/nitroglycerin (no ~nhAnrPr) c weight percent of adhesive/nitroglycerin/oleyl alcohol FYA le 9 15 - Nitroglycerin was premixed into the National Starch Durotak~ 80-1194 polyacrylate adhesive by Atlas Powder Company to provide a f inal solution containing 22 .1 wt. 96 nitroglycerin, 35 . 8 wt. % solid acrylic adhesive and, 42 .1 wt. % total solvents. oleyl alcohol (Henkel) or 20 sorbitan monooleate ("ArlacelD 80"; ICI Americas) was then dissolved into the nitroglycerin/adhesive solution at various levels to provide f inal matrix compositions ranging from 0 to 7. 5 wt. 96 ~nhAn~ Pr upon drying. These solutions were then cast onto silanized release liners, 25 dried at 80OC for 15 minutes, and finally laminated onto the polyethylene backing film as described in the preceding example. Transdermal nitroglycerin delivery was then determined as a function of ~nhAnr~r loading as described in the Example 8 using the Minitran Patch 30 (Riker Labs) as a control. Results are presented in Table III.
WO 92/10154 PCI/US91/09*
I~9~19~
=
l~ablP III
NitroqlYcerin Skin Flux ~ g/cm2/hr) a Formulation OleYl Alcshsl Arlaeel 80 5 60.0/37.5/2.5b 39.61 + 1.94 39.18 + 4.28 58.75/36.25/5.0b 41.27 + 4.65 42.63 + 7.55 57.25/35.25/7.5b 47.02 + 2.63 36.04 + 8.13 Minitran Control 31.52 + 1.79 31.52 + 1.79 1 aN=4 bweight percent ratios of adhesive/nitroglycerin/enhancer In general, nitroglycerin flux was found to inerease with inereasing enhaneer (either oleyl aleohol 15 or Arlaeel 80) eontent. Further, higher nitroglyeerin ~lux values were observed with all PnhAnrPr loadings in the experimental matrix eompositions than with the Minitran eontrol.
EY~1e 10 The proeedure of Example 9 is repeated using sorbitan monolaurate in place of sorbitan monooleate (e.g., "Arlacel~D 20" from ICI Americas). ~nh;~nePrl transdermal flux relative to an unenhanced nitroglycerin 25 system is obtained.
~mnle 11 The ,u~u~ du~: of Example 9 is repeated using sorbitan monopalmitate in place of sorbitan monooleate 30 (e.g., "Arlacel~ 40" from ICI Americas). Enhanced transdermal flux relative to that obtained from with an unenhanced nitroglycerin system is obtained.
35 ~ ~ =
~ 92/10154 PCr/US91/09215 ~ le 12 The procedure of Example 9 is repeated using sorbitan trioleate in place of sorbitan monooleate (e.g., "Arlacel~ 85" from ICI Americas). As with the preceding examples, the transdermal f lux obtained is higher than that which would be obtained for an llnPnhAncPd nitroglycerin patch.
ExamPle 13 The enhanced transdermal delivery of nitroglycerin from acrylic matrices containing 5 wt. %
PnhAnf~Pr (oleyl alcohol or Arlacel~ 80) was evaluated using 3 different donor skins. FnhAnCPd nitroglycerin matrices were prepared as described in Example 9, nitroglycerin skin f lux was determined as described in Example 8 using the NitroDur II and Minitran as controls.
vitro skin f lux results are presented in Table X.
~k~
NitroqlYcerin Skin Flux (,ILg/cm2 /hr) Formulation ~ ~ki~ Skin 3 NitroDur II -- 26.06 + 5.65 16.34 + 4.64 25 Minitran 39 . 97 + 3 . 69 44 .14 + 5 . 95 20.17 + 1. 61 5% Oleyl Alcohola 55.99 + 4.80 50.57 + 6.53 30.63 + 5.04 5% Arla-cel 80a 57.45 + 3.81 51.86 + 10.?2 26.57 + 2.78 a 58.7% wt acrylic adhesive, 36.3% wt nitroglycerin, 5 . 0% wt enhancer The flux obtained from both oleyl alcohol and 35 Arlacel 80 PnhAn~pd matrices was nearly double that WO 92/lOlS4 PCI/US91/09~
--~819~
obtained from the lln~nhAnf~ NitroDur II control patch.
Further, both ~nhAnred matrix formulations produced consistently higher nitroglycerin skin flux than the ~nhAncF~-l control patch, Minitran.
E~ 21e 14 An easy to open release tab can be prepared by overlapping two sections of the release liner by approximately 1/8 inch. The adhesive/drug/~nhAn-~Pr lO solution can then be cast onto a f irst release liner, dried and laminated ~o the backing f ilm as described in the above examples . The f irst release liner is then removed and the overlapping release liner is then laminated onto the adhesive surface in its place. Final 15 transdermal patches are then die cut with the overlapping release liner section spatially within the f inal patch.
Alternatively, the f irst release liner can be control depth slit following the lamination of the backing film.
A section of the slit liner is then removed and a new 20 section relaminated onto the exposed adhesive area such that the new liner section overlaps the r~r~inin~, slit prior liner which was not removed from the original laminate. Final patches are then die cut as previously 25 described.
;
Claims (26)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. The use of (a) a therapeutically effective amount of a pharmacologically active agent; and (b) a permeation enhancer consisting essentially of a sorbitan ester to enhance the rate of skin penetration of the pharmacologically active agent upon application to the skin.
2. The use of claim 1 wherein the sorbitan ester has the structural formula wherein R1 has the formula -O(CO)R', R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated or tri-unsaturated aliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, and R2 and R3 are independently selected from the group consisting of hydroxyl and -O(Co)R'.
3. The use of claim 2 wherein R ' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 11-21 carbon atoms optionally containing 1-3 hydroxyl groups, and R2 and R3 are both hydroxyl.
4. The use of claim 3 wherein the sorbitan ester is selected from the group consisting of sorbitan monooleate, sorbitan monolaurate, and mixtures thereof.
5. The use of claim 1 wherein the pharmacologically active agent is a steroid.
6. The use of claim 5 wherein the steroid is selected from the group consisting of estradiol, progesterone, norethindrone acetate, and mixtures thereof .
7. The use of claim 1 wherein the pharmacologically active agent is pindolol.
8. The use of claim 1, wherein the pharmacologically active agent is nitroglycerin.
9. The use of (a) a therapeutically effective amount of a pharmacologically active agent; and (b) a permeation enhancer consisting essentially of a sorbitan ester and a C1-C4 aliphatic alcohol to enhance the rate of skin penetration of the pharmacologically active agent upon application to the skin.
10. The use of claim 9 wherein the sorbitan ester has the structural formula wherein Rl has the ormula -O(CO)R', R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 7 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups, and R2 and R3 are independently selected from the group consisting of hydroxyl and -O(CO)R '.
11. The use of claim 10 wherein R' is selected from the group consisting of saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon substituents of 11-21 carbon atoms optionally containing 1-3 hydroxyl groups, and R2 and R3 are both hydroxyl.
12. The use of claim 11 wherein the sorbitan ester is selected from the group consisting of sorbitan monooleate, sorbitan monolaurate, and mixtures thereof.
13 The use of claim 9 wherein the Cl-C4 aliphatic alcohol is selected from the group consisting of ethanol, n-propanol, isopropanol, t-butanol, and mixtures thereof
14. The use of claim 9, wherein the pharmacologically active agent and the enhancer are present in a single pharmaceutical composition, and wherein the composition further includes a pharmaceutically acceptable inert vehicle
15. A composition of matter for the transdermal administration of a pharmacologically active agent, comprising: (a) a therapeutically effective amount of the pharmacologically active agent; and (b) a permeation enhancer consisting essentially of a sorbitan ester.
16. A composition of matter for the transdermal administration of a pharmacologically active agent, comprising: (a) a therapeutically effective amount of the pharmacologically active agent; and (b) a permeation enhancer consisting essentially of a sorbitan ester and a Cl-C4 aliphatic alcohol.
17. A laminated composite for administering a pharmacologically active agent through a selected area of skin over a sustained time period, comprising:
(a) a backing layer that is substantially impermeable to the pharmacologically active agent, (b) a reservoir layer comprising an adhesive polymer, the basal surface of the reservoir layer being adapted to be adhered to the skin, and (c) a therapeutically effective amount of the pharmacologically active agent, and (d) a permeation enhancer which consists essentially of a sorbitan ester.
(a) a backing layer that is substantially impermeable to the pharmacologically active agent, (b) a reservoir layer comprising an adhesive polymer, the basal surface of the reservoir layer being adapted to be adhered to the skin, and (c) a therapeutically effective amount of the pharmacologically active agent, and (d) a permeation enhancer which consists essentially of a sorbitan ester.
18. A laminated composite for administering a pharmacologically active agent through a selected area of skin over a sustained time period, comprising:
(a) a backing layer that is substantially impermeable to the pharmacologically active agent, (b) a reservoir layer comprising an adhesive polymer, the basal surface of the reservoir layer being adapted to be adhered to the skin, and (c) a therapeutically effective amount of the pharmacologically active agent, and (d) a permeation enhancer which consists, essentially of a sorbitan ester and a Cl-C4 aliphatic alcohol .
(a) a backing layer that is substantially impermeable to the pharmacologically active agent, (b) a reservoir layer comprising an adhesive polymer, the basal surface of the reservoir layer being adapted to be adhered to the skin, and (c) a therapeutically effective amount of the pharmacologically active agent, and (d) a permeation enhancer which consists, essentially of a sorbitan ester and a Cl-C4 aliphatic alcohol .
19. A laminated composite for administering a pharmacologically active agent selected from the group of sex steroid, pindolol, or nitroglycerin, through a selected area of skin over a sustained time period comprising:
a backing layer that is substantially impermeable to the pharmacologically active agent; and a matrix layer having a basal surface adapted to be adhered to said area of skin, said matrix layer comprising a mixture of:
a hydrophobic pressure sensitive adhesive polymer;
a therapeutically effective amount of the pharmacologically active agent, and a sorbitan ester of the formula:
wherein R1 has the structure -O (-CO) R', wherein R' is a saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon group of 11 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups and R1 and R3 are both hydroxyl.
a backing layer that is substantially impermeable to the pharmacologically active agent; and a matrix layer having a basal surface adapted to be adhered to said area of skin, said matrix layer comprising a mixture of:
a hydrophobic pressure sensitive adhesive polymer;
a therapeutically effective amount of the pharmacologically active agent, and a sorbitan ester of the formula:
wherein R1 has the structure -O (-CO) R', wherein R' is a saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon group of 11 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups and R1 and R3 are both hydroxyl.
20. The laminated composite of claim 19 wherein the sorbitan ester is sorbitan monooleate, sorbitan monolaurate or mixtures thereof.
21. The laminated composite of claim 19 wherein the mixture includes:
a Cl to C4 aliphatic alcohol.
a Cl to C4 aliphatic alcohol.
22 . The laminated composite of claim 19 wherein the hydrophobic pressure sensitive adhesive polymer is a crosslinked polyacrylate.
23. The use of a laminated composite to enhance the rate of skin penetration of a pharmacologically active agent through a selected area of skin over a sustained time period, the pharmacologically active agent selected from the group of pharmacologically active agents consisting of a sex steroid, pindolol or nitroglycerin, and the laminate comprising:
a backing layer that is substantially impermeable to the pharmacologically active agent; and a matrix layer having a basal surface adapted to be adhered to said area of skin, said matrix layer comprising a mixture of:
a hydrophobic pressure sensitive adhesive polymer;
a therapeutically effective amount of the pharmacologically active agent, and a sorbitan ester of the formula:
wherein Rl has the structure -0(-C0)R', wherein R' is a saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon group of 11 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups and R2 and R3 are both hydroxyl.
a backing layer that is substantially impermeable to the pharmacologically active agent; and a matrix layer having a basal surface adapted to be adhered to said area of skin, said matrix layer comprising a mixture of:
a hydrophobic pressure sensitive adhesive polymer;
a therapeutically effective amount of the pharmacologically active agent, and a sorbitan ester of the formula:
wherein Rl has the structure -0(-C0)R', wherein R' is a saturated, mono-unsaturated, di-unsaturated, or tri-unsaturated aliphatic hydrocarbon group of 11 to 21 carbon atoms optionally containing 1 to 3 hydroxyl groups and R2 and R3 are both hydroxyl.
24. The use of claim 23 wherein the sorbitan ester is sorbitan monooleate, sorbitan monolaurate or mixtures thereof.
25. The use of claim 23 wherein the mixture includes:
a C1 to C4 aliphatic alcohol.
a C1 to C4 aliphatic alcohol.
26. The use of claim 23 wherein the hydrophobic pressure sensitive adhesive polymer is a crosslinked polyacrylate.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US07/625,906 US5202125A (en) | 1990-12-10 | 1990-12-10 | Method and systems for administering nitroglycerin transdermally at enhanced transdermal fluxes |
US625,906 | 1990-12-10 | ||
US07/702,043 US5122383A (en) | 1991-05-17 | 1991-05-17 | Sorbitan esters as skin permeation enhancers |
US702,043 | 1991-05-17 |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2098196A1 CA2098196A1 (en) | 1992-06-10 |
CA2098196C true CA2098196C (en) | 1997-01-21 |
Family
ID=27090035
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002098196A Expired - Lifetime CA2098196C (en) | 1990-12-10 | 1991-12-06 | Method and systems for administering drugs transdermally using sorbitan esters as skin permeation enhancers |
Country Status (13)
Country | Link |
---|---|
US (2) | US5202125A (en) |
EP (1) | EP0561983B1 (en) |
JP (1) | JP2604097B2 (en) |
AT (1) | ATE167384T1 (en) |
AU (1) | AU656755B2 (en) |
CA (1) | CA2098196C (en) |
DE (1) | DE69129632T2 (en) |
DK (1) | DK0561983T3 (en) |
ES (1) | ES2117042T3 (en) |
GR (1) | GR3027652T3 (en) |
HK (1) | HK1013790A1 (en) |
PT (1) | PT99749B (en) |
WO (1) | WO1992010154A1 (en) |
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-
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- 1990-12-10 US US07/625,906 patent/US5202125A/en not_active Expired - Lifetime
-
1991
- 1991-12-06 DK DK92902108T patent/DK0561983T3/en active
- 1991-12-06 AT AT92902108T patent/ATE167384T1/en not_active IP Right Cessation
- 1991-12-06 JP JP4502721A patent/JP2604097B2/en not_active Expired - Lifetime
- 1991-12-06 DE DE69129632T patent/DE69129632T2/en not_active Expired - Lifetime
- 1991-12-06 CA CA002098196A patent/CA2098196C/en not_active Expired - Lifetime
- 1991-12-06 WO PCT/US1991/009215 patent/WO1992010154A1/en active IP Right Grant
- 1991-12-06 AU AU91413/91A patent/AU656755B2/en not_active Ceased
- 1991-12-06 EP EP92902108A patent/EP0561983B1/en not_active Expired - Lifetime
- 1991-12-06 ES ES92902108T patent/ES2117042T3/en not_active Expired - Lifetime
- 1991-12-10 PT PT99749A patent/PT99749B/en active IP Right Grant
-
1992
- 1992-07-24 US US07/919,296 patent/US5302395A/en not_active Expired - Lifetime
-
1998
- 1998-08-14 GR GR980401827T patent/GR3027652T3/en unknown
- 1998-12-24 HK HK98115310A patent/HK1013790A1/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
JP2604097B2 (en) | 1997-04-23 |
EP0561983B1 (en) | 1998-06-17 |
EP0561983A1 (en) | 1993-09-29 |
US5302395A (en) | 1994-04-12 |
PT99749A (en) | 1993-04-30 |
JPH06503576A (en) | 1994-04-21 |
WO1992010154A1 (en) | 1992-06-25 |
AU9141391A (en) | 1992-07-08 |
HK1013790A1 (en) | 1999-09-10 |
CA2098196A1 (en) | 1992-06-10 |
DE69129632D1 (en) | 1998-07-23 |
DK0561983T3 (en) | 1998-10-19 |
DE69129632T2 (en) | 1998-11-05 |
US5202125A (en) | 1993-04-13 |
ATE167384T1 (en) | 1998-07-15 |
GR3027652T3 (en) | 1998-11-30 |
PT99749B (en) | 1999-05-31 |
ES2117042T3 (en) | 1998-08-01 |
AU656755B2 (en) | 1995-02-16 |
EP0561983A4 (en) | 1993-10-20 |
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