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WO1996023522A1 - Traitement de la neuropathie diabetique - Google Patents

Traitement de la neuropathie diabetique Download PDF

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Publication number
WO1996023522A1
WO1996023522A1 PCT/AU1996/000046 AU9600046W WO9623522A1 WO 1996023522 A1 WO1996023522 A1 WO 1996023522A1 AU 9600046 W AU9600046 W AU 9600046W WO 9623522 A1 WO9623522 A1 WO 9623522A1
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WO
WIPO (PCT)
Prior art keywords
insulin
treatment
cream
neuropathy
diabetic neuropathy
Prior art date
Application number
PCT/AU1996/000046
Other languages
English (en)
Inventor
Roderick Alan Westerman
Paul Zev Zimmet
Original Assignee
Cortecs Limited
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 Cortecs Limited filed Critical Cortecs Limited
Priority to JP8523119A priority Critical patent/JPH11502513A/ja
Priority to KR1019970705293A priority patent/KR19980701896A/ko
Priority to EP96901190A priority patent/EP0808170A1/fr
Priority to AU45315/96A priority patent/AU4531596A/en
Publication of WO1996023522A1 publication Critical patent/WO1996023522A1/fr
Priority to NO973548A priority patent/NO973548L/no
Priority to FI973216A priority patent/FI973216L/fi

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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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • This invention relates to the treatment of diabetic neuropathy, and in particular it relates to a novel method and composition for the topical treatment of this condition.
  • Diabetic neuropathy also known as diabetic neuritis
  • diabetic neuritis is a painful condition suffered by many diabetic patients, and arises from nerve dysfunction particularly at the extremities of the body such as the toes and feet.
  • Table 1 outlines the Classification and Staging of Diabetic Neuropathy, based on the recommendations 1 of the American Diabetes Association, 1988.
  • the first of two main pathological disturbances of normal nerve function in diabetes involves a postulated relationship between raised blood glucose levels (hyperglycaemia), the polyol pathway (the biochemical pathway triggered by high glucose levels and producing alcohol-sugars called polyols as the end-products), myo-inositol (a cell energy-storage substrate), Na7K + ATPase (ion-pump enzyme) activity and nerve conduction, that is, the speed of nerve impulse transmission (Greene et al. 2 ).
  • the second postulated patho-physiological mechanism of disturbance of normal nerve function in diabetes relates to lack of oxygen within the nerve fibres, which is chemically-induced by raised blood sugar levels and activation of the polyol pathway, leading to changes in blood flow through micro-vessels within the nerves (Williamson et al. 3 ). TABLE 1 Classification and staging of diabetic neuropathy 1 (based on recommendations of the American Diabetes Association, 1988).
  • Autonomic neuropathy a. abnormal pupillary function, b. sudomotor dysfunction, c. genitourinary autonomic neuropathy, i bladder dysfunction ii sexual dysfunction d. gastrointestinal autonomic neuropathy i gastric atony ii gall bladder atony iii diabetic diarrhoea e. cardiovascular autonomic neuropathy f. hypoglycaemic unawareness.
  • Physical therapies applied to the affected painful region may sometimes provide symptomatic relief, e.g. i electrical stimulation such as TENS, interferential, vibration, ultrasound ii massage and rubbing iii hydrotherapy iv application of warmth, heat or cold v acupuncture or acupressure vi application of Opsite dressing film 11,12 .
  • i electrical stimulation such as TENS, interferential, vibration, ultrasound ii massage and rubbing iii hydrotherapy iv application of warmth, heat or cold v acupuncture or acupressure vi application of Opsite dressing film 11,12 .
  • Drugs and medications to be taken by mouth for pain relief include i non-steroidal analgesics (e.g. aspirin, paracetamol, ibuprofen, ketoprofen, etc.); ii narcotics, e.g codeine, morphine, pethidine, and sustained release morphine preparations; iii antidepressants including tricyclics such as amrtryptilline, etc.; iv anticonvulsants with inhibitory effects on relay of pain signals, such as carbamazepine, clonazepam; v antiarrhythmic compounds which reduce electrical excitability of cells such as mexilitene, lignocaine; vi aldose reductase inhibitors, such as Sorbinil, ponalrestat (ICI), epalrestat (Ono), tolrestat (Wyeth-Ayerst), zopolrestat (Pfizer) which may improve the levels of intraneural energy substrate
  • GLA gamma-linolenic acid
  • Topical treatments to desensitise superficial nerve fibres conveying pain signals, e.g. i capsaicin cream or ointment (usually as 0.025% or 0.075%) which is a neurotoxin and has been used for post-herpetic neuralgia 15,16,17 , and for painful diabetic neuropathy 18 .
  • ii aspirin in vanishing cream or sorbolene has been reported by Kassirer 19 to relieve post-herpetic neuralgia, and has been used by the present inventors (Westerman and Zimmet, unpublished) and found to be sometimes effective in the burning painful diabetic neuropathy.
  • Topical insulin therapy has not been reported previously, particularly in treatment of diabetic neuropathy. ln 1980, Snyder & Kim 20 made the first suggestion that insulin may be a nerve survival factor. Soon after, Low et a/. 4 described the reduced responses to sudomotor axon reflex tests as a small fibre dysfunction in neuropathy, and electrically evoked axon reflex responses were found to be reduced in diabetes mellitus 7 , and largely restored by a single dose of insulin in rat experimental STZ-diabetes 21 .
  • transdermal iontophoresis in dermatology 25 has been shown to be effective in facilitating transport of peptides 26 , including insulin 2728 .
  • the present inventor has conducted studies of the short-term effects of insulin on small nerve and axon reflex function in both animal studies in streptozotocin- induced diabetic rats and insulin-dependent diabetic patients 29 .
  • the size of the skin flushing response to noxious stimulation was significantly reduced, although responses of small blood vessels themselves were not reduced. This indicates that the reduced inflammation was due to sensory nerve dysfunction rather than microvascular impairment.
  • iontophoresis Topical application of insulin by six minutes of cathodal electrical current, termed iontophoresis, resulted in highly significant restoration of the size of the axon reflex, both in humans with IDDM and in rats made diabetic chemically with streptozotocin.
  • the immediate restorative effect of the insulin iontophoresis indicates that the decline in the axon reflex is reversible, and therefore due to functional changes in the nerves mediating the response, rather than any structural defects.
  • Mechanisms by which insulin produces these acute effects on nerves are now known, but the rapid time- course of the effect (in minutes) suggests some ionic or excitability changes, such as calcium levels within the nerves based on other indirect evidence of such actions of insulin 30,31 .
  • the present invention provides the topical use of insulin in the treatment of diabetic neuropathy in a patient.
  • the present invention provides a method for the treatment of diabetic neuropathy in a patient which comprises the topical administration of a therapeutically effective amount of insulin to the affected area of skin of the patient.
  • the present invention provides a composition for the treatment of diabetic neuropathy in a patient, which comprises a therapeutically effective amount of insulin in a topical, pharmaceutically acceptable diluent or carrier.
  • the present invention provides the use of a therapeutically effective amount of insulin in the manufacture of a medicament for topical use in the treatment of diabetic neuropathy in a patient.
  • the insulin used in accordance with this invention is human insulin (available, for example, as Humulin R, Velosulin or Actrapid). It is to be understood, however, that the present invention also extends to the use of porcine insulin, bovine insulin or insulin from other non-human animal species.
  • insulin as used herein is intended to encompass not only insulin per se, but also the a- or 7-subchains of insulin, separately or in combination.
  • the insulin is administered in therapeutically effective amounts.
  • a therapeutically effective amount means that amount necessary at least partly to attain the desired effect, or to delay the onset of, inhibit the progression of, or halt altogether, the onset or progression of the diabetic neuropathy condition being treated. Such amounts will depend, of course, on the particular condition being treated, the severity of the condition and individual patient parameters including age, physical condition, size, weight and other concurrent treatment. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a minimum effective dose be used according to sound medical judgement. It will be understood by those of ordinary skill in the art, however, that a higher dose may be administered for medical reasons, psychological reasons or for virtually any other reasons.
  • Suitable pharmaceutically acceptable carriers and/or diluents include any and all conventional solvents, dispersion media, fillers, aqueous solutions, antibacterial and antifungal agents, absorption promoting agents, and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art, and it is described, by way of example, in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Pennsylvania, USA. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the pharmaceutical compositions of the present invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • the topical preparations contemplated by the present invention include aqueous cream, ointment, gel, lotion, roll-on liquid, spray, glass bead wound dressing, synthetic polymer dressing impregnated with insulin, or any other method of transdermal application of insulin.
  • the cream will include buffering agents and hydrophobic ingredients.
  • These preparations may also include the use of compounds such as DMSO (dimethylsulfoxime) which would facilitate the passage of insulin across the skin keratin barrier and into epidermis.
  • Topical Insulin Cream 70g of vanishing cream base (such as Home Brand skin repair cream, Sorbolene cream, or Cetomacrogol cream) containing purified water, stearic acid, dimethicone, isopropyl myristate, cetyl alcohol, triethanolamine, polysorbate 80, aloe vera extract, methyl paraben, propyl paraben, fragrance.
  • vanishing cream base such as Home Brand skin repair cream, Sorbolene cream, or Cetomacrogol cream
  • vanishing cream base such as Home Brand skin repair cream, Sorbolene cream, or Cetomacrogol cream
  • purified water stearic acid, dimethicone, isopropyl myristate, cetyl alcohol, triethanolamine, polysorbate 80, aloe vera extract, methyl paraben, propyl paraben, fragrance.
  • Sorbolene lotion contains de-ionised water, glycerine, sorbitol, light mineral oil, cetyl alcohol, cetomacrogol 1000, stearic acid, triethanolamine, tocopheryl acetate, imidazolidinyl urea, methyl paraben, EDTA, para-cresol.
  • Sorbolene lotion contains de-ionised water, glycerine, sorbitol, light mineral oil, cetyl alcohol, cetomacrogol 1000, stearic acid, triethanolamine, tocopheryl acetate, imidazolidinyl urea, methyl paraben, EDTA, para-cresol.
  • the topical preparation of this invention is applied at least daily, or several times daily, to the affected area of the skin of the patient.
  • the application may be applied twice daily (morning and night), or even three times daily.
  • Effective treatment begins with careful selection of suitable patients having diabetic neuropathy and symptoms associated with small fibre dysfunction.
  • the clinical picture for which the topical insulin treatment is most appropriate and most likely to benefit is that particular neuropathy symptom- complex involving superficial burning type of discomfort with dysesthesia or paraesthesia (Pfeifer et a/. 9,10 ). Patients with non-insulin dependent diabetes and not previously insulin-treated are most suitable.
  • the topical insulin cream is applied at twice daily frequency restricted to skin areas with superficial burning discomfort. This is most commonly the toes, feet and lower parts of legs.
  • Re-measurement of thermal perception thresholds on treated skin zones at monthly intervals is performed according to the methods described by Jamal et a/. 323334 and Delaney et a/. 824 using the Medelec TTT device. Both cold and warm perception thresholds are measured.
  • thermal perception threshold which may be interpreted as an improved thermal sensory acuity. This may be related to an improved sensory nerve function. Cold threshold improves more rapidly than warm threshold, suggesting greater benefit for the myelinated A-delta nerve fibres mediating cold sensation.
  • Preferred aspects of the topical use of insulin in the treatment of diabetic neuropathy include the following:
  • the insulin concentration in a cream may range from 0.01-20 IU per gram, preferably 0.1-10 IU per gram, more preferably 1-3 IU per gram.
  • the amount of cream applied is usually about 0.5g on each foot/leg. The consistency of the preferred cream tends to be a little sloppy, and it is therefore easily spread and rubbed into the skin until it has vanished.
  • the recommended application frequency is twice to thrice daily, but after longer-term trials, a lesser frequency such as once daily might be acceptable for maintenance therapy or skin ulcer prophylaxis.
  • Symptomatic patients particularly those with type 2 (non-insulin- dependent) diabetes mellitus most suitable for treatment with topical insulin cream are identified after a careful history of symptoms (see Pfeifer algorithm 910 ) and testing for neuropathy with a group of investigations. These include testing small sensory nerve function by pinprick and cotton-wool sensibility, and warm and cold perception thresholds at wrist and foot dorsum, and AC-current perception thresholds
  • Body weight, height, body mass index (BMI), abdominial circumference, fasting plasma glucose and insulin and haemoglobin A ⁇ are also measured to provide an indication of insulin sensitivity in type 2 subjects and quality of glycemic control in both type 1 and 2 subjects.
  • Euglycemic clamp measurements have not yet been used in these studies for logistic reasons.
  • Suitable topical vehicles for use in administration of insulin accordance with this invention, and methods of preparation thereof, include the following:
  • Figures 1 to 3 show graphically the results of topical insulin treatment of painful burning feet in cases of diabetic neuropathy selected according to the criteria previously described (see page 10, paras, iv, v and Pfeifer 9,10 ).
  • Topical insulin cream of the composition described above (1 IU insulin per gram of finished cream) was provided to the patients, with instructions to apply about 0.5g on each foot/leg two or three times daily.
  • Figures 1 and 2 relate to a maximum number of 30 Type 2 diabetic subjects who had not been treated with systemic insulin.
  • Figure 3 depicts the results from a maximum of 16 subjects who had received systemic insulin treatment.
  • the vertical axis depicts the thermal threshold: open rectangles being the warm perception threshold, black filled rectangles being the cold threshold.
  • the severity of the painful burning symptoms on a 10 point visual analogue scale is also shown on the vertical axis by the filled black circles.
  • the horizontal axis shows the duration of treatment at which the tests and re-tests were performed.
  • the horizontal dotted line shows the upper limit of the normal 95% confidence margin (mean + 2.2 standard deviations).
  • Figure 1 shows the results from 12 weeks treatment, the number of subjects being 30 for weeks 0 and 4 and decreasing progressively to 16 at week
  • FIG. 2 graph shows on a time scale of months the same trends, and it will be noted that warm threshold has become significantly improved (i.e. WPT reduced) by 4 months of treatment.
  • Figure 3 shows the results of treatment of a smaller group of patients who had received systemic insulin treatment. These include some patients with Type 2 DM, whose deterioration ultimately required systemic insulin treatment; the remainder include patients with Type 1 DM.
  • the lack of improvement in thermal threshold results for warm and cold in this group contrasts markedly with those from the previous group, but also surprising is the symptomatic improvement noted by these patients.

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Abstract

L'invention se rapporte à l'utilisation topique de l'insuline pour le traitement d'une neuropathie diabétique chez un patient.
PCT/AU1996/000046 1995-02-02 1996-02-01 Traitement de la neuropathie diabetique WO1996023522A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
JP8523119A JPH11502513A (ja) 1995-02-02 1996-02-01 糖尿病性ニューロパシーの処置方法
KR1019970705293A KR19980701896A (ko) 1995-02-02 1996-02-01 당뇨병 환자의 신경장애 치료
EP96901190A EP0808170A1 (fr) 1995-02-02 1996-02-01 Traitement de la neuropathie diabetique
AU45315/96A AU4531596A (en) 1995-02-02 1996-02-01 Treatment of diabetic neuropathy
NO973548A NO973548L (no) 1995-02-02 1997-08-01 Behandling av diabetisk neuropati
FI973216A FI973216L (fi) 1995-02-02 1997-08-04 Diabeettisen neuropatian hoito

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPN0892 1995-02-02
AUPN0892A AUPN089295A0 (en) 1995-02-02 1995-02-02 Treatment of diabetic neuropathy

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WO1996023522A1 true WO1996023522A1 (fr) 1996-08-08

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EP (1) EP0808170A1 (fr)
JP (1) JPH11502513A (fr)
KR (1) KR19980701896A (fr)
AU (1) AUPN089295A0 (fr)
CA (1) CA2211450A1 (fr)
FI (1) FI973216L (fr)
NO (1) NO973548L (fr)
WO (1) WO1996023522A1 (fr)

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WO1998024470A1 (fr) * 1996-12-03 1998-06-11 Dardai Zoltan Preparation locale destinee a l'introduction de medicaments peptidiques dans des organismes vivants
EP1383540A2 (fr) * 2000-07-31 2004-01-28 Bar-Ilan University Methodes et compositions pharmaceutiques de cicatrisation de lesions
US7638484B2 (en) 2003-08-07 2009-12-29 Healor Ltd. Methods for accelerating wound healing by administration of adipokines
US8093211B2 (en) 2000-07-31 2012-01-10 Bar-Ilan University Methods and pharmaceutical compositions for healing wounds
EP2646046A2 (fr) * 2010-11-30 2013-10-09 Joslin Diabetes Center, Inc. Compositions et méthodes de traitement de troubles nerveux associés au diabète
US9545487B2 (en) 2012-04-13 2017-01-17 Boehringer Ingelheim International Gmbh Dispenser with encoding means
US9682202B2 (en) 2009-05-18 2017-06-20 Boehringer Ingelheim International Gmbh Adapter, inhalation device, and atomizer
US9724482B2 (en) 2009-11-25 2017-08-08 Boehringer Ingelheim International Gmbh Nebulizer
US9744313B2 (en) 2013-08-09 2017-08-29 Boehringer Ingelheim International Gmbh Nebulizer
US9757750B2 (en) 2011-04-01 2017-09-12 Boehringer Ingelheim International Gmbh Medicinal device with container
US9827384B2 (en) 2011-05-23 2017-11-28 Boehringer Ingelheim International Gmbh Nebulizer
US9943654B2 (en) 2010-06-24 2018-04-17 Boehringer Ingelheim International Gmbh Nebulizer
US10004857B2 (en) 2013-08-09 2018-06-26 Boehringer Ingelheim International Gmbh Nebulizer
US10011906B2 (en) 2009-03-31 2018-07-03 Beohringer Ingelheim International Gmbh Method for coating a surface of a component
US10016568B2 (en) 2009-11-25 2018-07-10 Boehringer Ingelheim International Gmbh Nebulizer
US10099022B2 (en) 2014-05-07 2018-10-16 Boehringer Ingelheim International Gmbh Nebulizer
US10124125B2 (en) 2009-11-25 2018-11-13 Boehringer Ingelheim International Gmbh Nebulizer
US10124129B2 (en) 2008-01-02 2018-11-13 Boehringer Ingelheim International Gmbh Dispensing device, storage device and method for dispensing a formulation
US10195374B2 (en) 2014-05-07 2019-02-05 Boehringer Ingelheim International Gmbh Container, nebulizer and use
US10722666B2 (en) 2014-05-07 2020-07-28 Boehringer Ingelheim International Gmbh Nebulizer with axially movable and lockable container and indicator

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Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024470A1 (fr) * 1996-12-03 1998-06-11 Dardai Zoltan Preparation locale destinee a l'introduction de medicaments peptidiques dans des organismes vivants
AU744380B2 (en) * 1996-12-03 2002-02-21 Diabetic Trust Ag Topical preparation for introducing peptidaceous pharmacons in living organisms
AP1065A (en) * 1996-12-03 2002-04-30 Diabetic Trust Ag Topical preparation for introducing peptidaceous pharmacons in living organisms.
US6399566B1 (en) 1996-12-03 2002-06-04 Diabetictrust Ag Topical preparation for introducing insulin in living organisms
US8093211B2 (en) 2000-07-31 2012-01-10 Bar-Ilan University Methods and pharmaceutical compositions for healing wounds
EP1383540A4 (fr) * 2000-07-31 2004-06-30 Univ Bar Ilan Methodes et compositions pharmaceutiques de cicatrisation de lesions
US7402571B2 (en) 2000-07-31 2008-07-22 Bar-Ilan University Methods and pharmaceutical compositions for healing wounds
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AUPN089295A0 (en) 1995-03-02
MX9705920A (es) 1998-06-28
FI973216L (fi) 1997-10-01
JPH11502513A (ja) 1999-03-02
KR19980701896A (ko) 1998-06-25
EP0808170A1 (fr) 1997-11-26
NO973548D0 (no) 1997-08-01
NO973548L (no) 1997-10-02
CA2211450A1 (fr) 1996-08-08
FI973216A0 (fi) 1997-08-04

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