EP0178321A1 - Topische behandlung von diabetes mit insulin und mit einem auf die haut verabreichten und mit einem pflaster bedeckten penetrationsverbesserer - Google Patents
Topische behandlung von diabetes mit insulin und mit einem auf die haut verabreichten und mit einem pflaster bedeckten penetrationsverbessererInfo
- Publication number
- EP0178321A1 EP0178321A1 EP19850902306 EP85902306A EP0178321A1 EP 0178321 A1 EP0178321 A1 EP 0178321A1 EP 19850902306 EP19850902306 EP 19850902306 EP 85902306 A EP85902306 A EP 85902306A EP 0178321 A1 EP0178321 A1 EP 0178321A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- skin
- layer
- insulin
- gel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 90
- 102000004877 Insulin Human genes 0.000 title claims abstract description 50
- 108090001061 Insulin Proteins 0.000 title claims abstract description 50
- 229940125396 insulin Drugs 0.000 title claims abstract description 45
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 39
- 239000003623 enhancer Substances 0.000 title claims description 16
- 238000011282 treatment Methods 0.000 title abstract description 9
- 230000000699 topical effect Effects 0.000 title description 8
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 239000000463 material Substances 0.000 claims abstract description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 80
- NZJXADCEESMBPW-UHFFFAOYSA-N 1-methylsulfinyldecane Chemical compound CCCCCCCCCCS(C)=O NZJXADCEESMBPW-UHFFFAOYSA-N 0.000 claims description 20
- -1 hydroxypropylmethyl Chemical group 0.000 claims description 16
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 230000001464 adherent effect Effects 0.000 claims description 5
- 230000002708 enhancing effect Effects 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000004698 Polyethylene Substances 0.000 claims description 4
- 229920000573 polyethylene Polymers 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 3
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 2
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 2
- 241001307210 Pene Species 0.000 claims 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims 1
- 150000002334 glycols Chemical class 0.000 claims 1
- 239000000853 adhesive Substances 0.000 abstract 1
- 230000001070 adhesive effect Effects 0.000 abstract 1
- 239000008188 pellet Substances 0.000 abstract 1
- 239000003961 penetration enhancing agent Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 description 17
- 239000008280 blood Substances 0.000 description 17
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 14
- 239000008103 glucose Substances 0.000 description 14
- 241000699670 Mus sp. Species 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 108010081368 Isophane Insulin Proteins 0.000 description 5
- LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3N=CN=C3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 102000005237 Isophane Insulin Human genes 0.000 description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 4
- 235000019271 petrolatum Nutrition 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 208000002874 Acne Vulgaris Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 206010000496 acne Diseases 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000008311 hydrophilic ointment Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 235000019388 lanolin Nutrition 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 2
- 230000000474 nursing effect Effects 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 229960004063 propylene glycol Drugs 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000003871 white petrolatum Substances 0.000 description 2
- 229930003347 Atropine Natural products 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 208000005615 Interstitial Cystitis Diseases 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 108010077977 Lente Insulin Proteins 0.000 description 1
- 241001082241 Lythrum hyssopifolia Species 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 208000004210 Pressure Ulcer Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- 206010058679 Skin oedema Diseases 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- RKUNBYITZUJHSG-SPUOUPEWSA-N atropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-SPUOUPEWSA-N 0.000 description 1
- 229960000396 atropine Drugs 0.000 description 1
- 108010043605 beef-pork regular insulin Proteins 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000002642 intravenous therapy Methods 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- 229940069265 ophthalmic ointment Drugs 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
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- 235000019364 tetracycline Nutrition 0.000 description 1
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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
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
Definitions
- Exogenous insulin is the mainstay of therapy for human diabetics.
- a major disadvantage is the necessity to administer the drug parenterally, e.g., with a needle and syringe.
- the need for at least daily injections of insulin is an important factor in patient compliance and comfort.
- Penetrant enhancers other than DMSO are known. [Dugard,
- the present invention overcomes these difficulties and provides a method for treating diabetes involving topical application of a composition to the surface of the skin or a diabetic subject.
- a composition which when applied to the surface of the skin of a diabetic subject or patient is useful in the treatment of diabetes, comprises a first layer in contact with the skin surface and a second layer covering the first layer.
- the first layer includes an effective diabetes-treating amount of insulin, an effective enhancing amount of a penetrant enhancer such as dimethyl sulfoxide or n-decyl-methyl sulf- oxide and a suitable carrier.
- the second layer comprises a suitable adherent, nonporous patch material such as poly ⁇ ethylene.
- the first layer is in the form of a gel and includes a suitable gel material such as hydroxymethyl cellulose, hydroxypropylmethyl cellulose or hydroxypropyl cellulose.
- compositions which when applied to the surface of a diabetic patient's or subject's skin are useful in treating diabetes.
- such a composition includes a first layer in contact with the skin surface and a second layer covering the first layer.
- the first layer includes an effective diabetes-treating amount of insulin, an effective enhancing amount of a penetrant enhancer and a suitable carrier.
- the second layer comprises a suitable adherent, nonporous patch material.
- the first layer may be formulated directly on the surface of the skin, it is generally preferable to first formulate the ingredients and then apply the formulated ingredients to the skin surface to form the layer.
- Effective diabetes-treating amounts of insulin may vary from the amounts normally required for subcutaneous or intravenous therapy. However, in the practices of the present invention it is contemplated that the amounts will be similar to those presently employed in the other treat- ment modes since one unit of protamine zinc insulin admin ⁇ istered subcutaneously is an appropriate dose for main ⁇ tenance of relative normoglycemia in diabetic rodents [Andersson, A., Diabetologia __ : 269 (1983)].
- the form of insulin may also vary and includes regular insulin, NPH, Lente and protamine zinc insulin. It is contemplated that insoluble repository forms of insulin may have longer dura ⁇ tions of action than regular insulin.
- the penetrant enhancer may be any of a number of agents known to enhance the penetration and increase the absorption of drugs across the skin. Examples include dimethyl sulfoxide, dimethyl acetamide, dimethylformamide and n-decyl-methyl sulfoxide. Additional such agents include propylene gly- col, glycerin, lanolins, alcohols, anionic emulsifiers (e.g. sodium lauryl sulfate) and surfactants (nonionic emulsifiers such as polyoxyethylene fatty alcohol ethers and esters; polyoxyethylene fatty acid esters, e.g.
- poly ⁇ oxyethylene stearate polyoxyethylene sorbitan fatty acid esters and sorbitan fatty acid esters, e.g. sorbitan mon- ostearate; polyoxyethylene glycol fatty acid esters; polyol fatty acid esters, e.g. glyceryl monostearate; and ethoxy- lated lanolin derivatives.
- DMSO dimethylacetamide, dimethylformamide and most particularly N-decyl-methyl sulfoxide
- NDMS N-decyl-methyl sulfoxide
- N-decyl-methyl sulfoxide is at least 15 times more effective than DMSO in skin penetrance enhancement [McCullough, J.L. et al., J. Invest. Dermatol. 6 ⁇ :103 (1976)], and in a less than 1% solution, applied topically, in amounts less than 1.3 ml per day, is safe and without side effects [Physicians Desk Reference, Medical Economics Company, Oradell, New Jersey- (1983)]. Substitution of NDMS for DMSO or lowering the amount of enhancing agent used is particularly desirable since DMSO has several undesirable, dose-related side ef ⁇ fects. [Harter, J., Annals of the New York Academy of Sciences, Vol. 411, Ed., J.C.
- DMSO in 50% aqueous solution is FDA approved for instillation in the bladder to treat interstitial cystitis [Stewart, B. et al., J. Urology Ll :36 (1976)]. It i expected that biological effects of DMSO in penetr-anc-, enhancement of insulin transport across the skin, even at concentrations as low as 1-5% will be effective since Whitworth and Stevenson.[J. Pharmaceut. Sci. 6 :48 (1971)]
- the amount of penetrant enhancer present in the first layer may vary over a wide range, depending upon the specific enhancer beinj used. In general, the amount will not exceed about 50% by volume of the first layer.
- the first layer also includes a suitable carrier.
- a suitable carrier is water, e.g., deionized dis ⁇ tilled water.
- Other carriers include alcohols such as methanol or ethanol or aqueous mixtures thereof.
- the carrier may be formulated in an emulsion or cream base.
- Hydrophilic Ointment USP a widely available oil-in-water emulsion.
- Hydrophilic Petrolatum USP a water- and-oil emulsion (Table 2).
- the first layer may also include additional materials such as emulsifying agents, suspending agents, preservatives and the like.
- the first layer is in the form of a gel.
- Suitable gel materials include hydroxymethyl cel ⁇ lulose, hydroxypropylmethyl cellulose or hydroxypropyl cellulose.
- the use of a gel permit easier application of the insulin and penetrant enhancer to the diabetic subject's skin. In addition, it permits better control over dosage amounts. Finally, it maintains the components of the firs- layer in contact with a defined area of the subject's ski; prior to application of the adherent, nonporous patch.
- the amount of gel material employed may vary widely depend ⁇ ing upon the identity of the gel material and the identity and amount of penetrant enhancer and carrier. In general, the amount of gel material will not exceed about 50% by volume of the first layer. In one preferred embodiment cf the invention the gel material and penetrant enhancer eacr comprise about 33% by volume of the first layer.
- the adherent, nonporous patch material may be any of th ⁇ various such materials known to be useful as a patch.
- a patch material useful in the practices of this invention is polyethylene. .
- This invention provides a method of treating diabetes which comprises applying to the surface of a diabetic subject' skin a composition of the type described herein for suitable period of time, such as 1-12 hours, to perm insulin present in the composition to penetrate across ____: skin, enter the bloodstream and effect blood sugar levels,
- Bovine-porcine regular insulin (Eli Lilly and Company, Indianapolis, Indiana) was topically applied to the skin of streptozotocin-diabetic male BO.BR mice, beneath a poly ⁇ ethylene patch (SteridrapeTM - 3M Company, Minneapolis, Minnesota), which was applied to the torso. Drug-skin contact occurred over approximately 1-2 cm ⁇ of body surface. Body hair was clipped 24-72 hours prior to each experiment. Mice were awake with free access to food and water. Animals were judged diabetic if they had more than three blood glucose values >40Q mg/dl over at least 10 days. Blood glucose was measured by the glucose oxidase technique on tail vein blood (Ames dextrometer) [Jarett, R. et al., Diabetes 3,9:7234 (1970)].
- dimethyl sulfoxide 33% or 50% (DMSO-Sigma) was mixedwith insulin.
- DMSO added to 100 units of regular insulin resulted in reductions of blood glucose in 8 of 13 mice.
- DMSO alone had no effect on blood sugar.
- NDMS n-decyl-methyl sulfoxide
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Dermatology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60560884A | 1984-04-30 | 1984-04-30 | |
US605608 | 1984-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0178321A1 true EP0178321A1 (de) | 1986-04-23 |
Family
ID=24424421
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19850902306 Withdrawn EP0178321A1 (de) | 1984-04-30 | 1985-04-17 | Topische behandlung von diabetes mit insulin und mit einem auf die haut verabreichten und mit einem pflaster bedeckten penetrationsverbesserer |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0178321A1 (de) |
AU (1) | AU4292585A (de) |
WO (1) | WO1985005036A1 (de) |
Families Citing this family (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE50502T1 (de) * | 1984-06-09 | 1990-03-15 | Hoechst Ag | Insulinzubereitungen, verfahren zu deren herstellung und deren verwendung. |
US6126963A (en) | 1986-08-28 | 2000-10-03 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
US6110488A (en) * | 1986-08-28 | 2000-08-29 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
USRE37934E1 (en) | 1986-08-28 | 2002-12-10 | Lts Lohmann Therapie-Systeme Ag | Transdermal therapeutic system |
US5820876A (en) * | 1986-08-28 | 1998-10-13 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system |
US6117448A (en) * | 1986-08-28 | 2000-09-12 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
US6139868A (en) * | 1986-08-28 | 2000-10-31 | Lts Lohmann Therapie-Systeme Gmbh & Co. Kg | Transdermal therapeutic system, its use and production process |
US5707641A (en) * | 1994-10-13 | 1998-01-13 | Pharmaderm Research & Development Ltd. | Formulations comprising therapeutically-active proteins or polypeptides |
US5858398A (en) * | 1994-11-03 | 1999-01-12 | Isomed Inc. | Microparticular pharmaceutical compositions |
AUPN089295A0 (en) * | 1995-02-02 | 1995-03-02 | International Diabetes Institute | Treatment of diabetic neuropathy |
US6667052B2 (en) * | 1997-05-29 | 2003-12-23 | Ben Gurion University Of The Negev Research And Development Authority | Transdermal delivery system |
IL120943A (en) * | 1997-05-29 | 2004-03-28 | Univ Ben Gurion | A system for administering drugs through the skin |
US5929055A (en) * | 1997-06-23 | 1999-07-27 | The Research Foundation Of State University Of New York | Therapeutic method for management of diabetes mellitus |
US20040037828A1 (en) | 2002-07-09 | 2004-02-26 | Bar-Ilan University | Methods and pharmaceutical compositions for healing wounds |
ATE429925T1 (de) | 2000-07-31 | 2009-05-15 | Univ Bar Ilan | Methoden und pharmazeutische zusammensetzungen zur wundheilung |
ATE529125T1 (de) | 2003-08-07 | 2011-11-15 | Healor Ltd | Pharmazeutische zusammensetzungen und verfahren zur beschleunigung der wundheilung |
WO2005112889A2 (en) * | 2004-05-20 | 2005-12-01 | Recordati Ireland Limited | Transmucosal delivery formulations |
CA2789972A1 (en) | 2010-01-11 | 2011-07-14 | Healor Ltd. | Method for treatment of inflammatory disease and disorder |
EP2707007B1 (de) * | 2011-05-11 | 2018-03-07 | Veloce BioPharma LLC | Fungizide zusammensetzungen zur behandlung von nägeln |
-
1985
- 1985-04-17 WO PCT/US1985/000695 patent/WO1985005036A1/en unknown
- 1985-04-17 EP EP19850902306 patent/EP0178321A1/de not_active Withdrawn
- 1985-04-17 AU AU42925/85A patent/AU4292585A/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO8505036A1 * |
Also Published As
Publication number | Publication date |
---|---|
WO1985005036A1 (en) | 1985-11-21 |
AU4292585A (en) | 1985-11-28 |
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