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 penetrationsverbesserer

Info

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Withdrawn
Application number
EP19850902306
Other languages
English (en)
French (fr)
Inventor
Collin J. Weber
Michael Kazim
Keith Reemtsma
John F. Nicholson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Columbia University in the City of New York
Original Assignee
Columbia University in the City of New York
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Columbia University in the City of New York filed Critical Columbia University in the City of New York
Publication of EP0178321A1 publication Critical patent/EP0178321A1/de
Withdrawn legal-status Critical Current

Links

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)
EP19850902306 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 Withdrawn EP0178321A1 (de)

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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3576120D1 (de) * 1984-06-09 1990-04-05 Hoechst Ag Insulinzubereitungen, verfahren zu deren herstellung und deren verwendung.
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
US6139868A (en) * 1986-08-28 2000-10-31 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Transdermal therapeutic system, its use and production process
US5820876A (en) 1986-08-28 1998-10-13 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Transdermal therapeutic system
US6126963A (en) * 1986-08-28 2000-10-03 Lts Lohmann Therapie-Systeme Gmbh & Co. Kg Transdermal therapeutic system, its use and production process
US6117448A (en) * 1986-08-28 2000-09-12 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
RU2358753C2 (ru) 2003-08-07 2009-06-20 Хилор Лтд. Фармацевтические композиции и способы для ускорения заживления ран
WO2005112889A2 (en) * 2004-05-20 2005-12-01 Recordati Ireland Limited Transmucosal delivery formulations
RU2012134041A (ru) 2010-01-11 2014-02-20 Хилор Лтд. Способ лечения воспалительного заболевания и расстройства
EP3348272B1 (de) * 2011-05-11 2020-06-24 Veloce BioPharma LLC Zusammensetzungen zur verwendung in der behandlung von paronychie

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
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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Inventor name: KAZIM, MICHAEL

Inventor name: WEBER, COLLIN, J.

Inventor name: REEMTSMA, KEITH

Inventor name: NICHOLSON, JOHN, F.