BACKGROUND OF THE INVENTION All references, including any patents or patent applications, cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

Peripheral sensory neuropathy is a relatively frequent and often debilitating complication of diabetes mellitus (Greene et al, 1990,) but its aetiology and underlying pathophysiology are uncertain (Ward, 1992).

Diabetes is associated with hyperglycaemia as a consequence of inadequate insulin activity, but the relative contributions of hyperglycaemia and of the reduced insulin activity per se to the genesis of neuropathy are not clear.

The inventors have recently demonstrated that defects in insulin action independent of glycaemic levels may be implicated in the development of diabetic neuropathy. Sensory nerve function was measured by warm and cold perception threshold determination in lean and obese non-diabetic human subjects. Insulin sensitivity was measured in these subjects, both directly using the short intravenous insulin tolerance test (Akinmokun et al. 1992),

and by inference from fasting insulin levels. Sensory nerve function was found to be impaired, as indicated by elevated thermal thresholds in non-diabetic subjects in whom insulin sensitivity was reduced despite normoglycaemia (Delaney et al, 1994a ; Delaney et al, 1994b; Delaney et al, 1995) An important question remains as to the mechanism by which reduced insulin action in concert with hyperglycaemia contributes to the pathogenesis of diabetic neuropathy.

The process may involve interactions between insulin and neurotrophic growth factors, proteins that promote the survival and differentiation of nerve cells.

Insulin-like Growth Factor-I (IGF-I) and Insulin-like Growth Factor-II (IGF-II) are members of this neurotrophic family of growth factors, and have extensive structural and functional similarities. Each is capable of activating the type 1 IGF membrane receptor, and both have been demonstrated to elicit similar responses from nerve cells in vitro (US Patent No. 5,817,623). For the purposes of this invention, they are considered to be equivalent, and are referred to collectively herein as"IGF"or"IGFs"; this term also encompasses biologically active analogues of IGFs. IGFs have been shown to be reduced in both hypoinsulinaemic and hyperinsulinaemic states. The level and activity of insulin can potentially modify that of IGF- I in a variety of ways, and it has been suggested that the development of neuropathy may in fact involve the combined loss of insulin and IGF activity (Ishii, 1995).

Decreased serum levels of IGF-I have been demonstrated in both Type 1 and Type 2 diabetic subjects, as well as in diabetic animal models (Dills et al, 1990; Dills et al, 1991; Rogers et al 1991; Graubert et al, 1991). Many studies have shown an inverse correlation between measures of glycaemic control and IGF-I levels (Winter et al, 1979; Amiel et al, 1984; Dills et al, 1990), and reduced IGF-I levels in diabetic humans and animals have been shown to be at least partially restored with

improved metabolic control and/or insulin treatment (Maes et al, 1983A Amielet alE 1984o Graubert et al, 1991; Tamborlane et al; 1981). For example, reduced IGF-I levels during conventional insulin therapy were shown to be partially restored toward non-diabetic levels upon institution of intensified insulin therapy (Amiel et al, 1984) In spontaneous obesity-associated diabetes in the rhesus monkey, it has been shown that IGF-I levels progressively decline in parallel with the metabolic changes, including weight gain, hyperinsulinaemia and impaired glucose tolerance, but are not correlated with the glycaemic state (Bodkin et al, 1991). Hyperinsulinaemia may also inhibit the mitogenic activity of IGF-I (Conover et al, 1994). Consistent with this, systemic treatment with recombinant human IGF-I has been shown to reduce hyperglycaemia in patients with extreme insulin resistance (Schoenle et al, 1991).

Peripheral nerves appear to possess receptors for both insulin (Waldbillig and LeRoith, 1987) and IGF (Kanje et al, 1989), and IGF is axonally transported (Hansson and Rozell, 1987). The affinity of insulin for binding to the type 1 IGF receptor is approximately 1% of that of IGF-I (Steele-Perkins et al, 1988).

In view of the apparent involvement of IGF in some of the metabolic derangements associated with diabetes, this neurotrophic factor may be of direct relevance in the pathogenesis of diabetic neuropathy, and may provide the link between glycaemic control, reduced insulin activity and unfavorable body fat distribution in the degenerative process.

The use of IGF-I for the treatment of peripheral neuropathy associated with a wide variety of other conditions has been suggested; see International patent publication W093/25219 by Cephalon, Inc. and Albert Einstein College of Medicine, the entire contents of which is incorporated herein by this reference. This disclosed the use of IGF-I administered intravenously,

subcutaneously, or intraperitoneally for the treatment particularly of inherited peripheral neuropathy such as Charcot-Marie-Tooth disease. Studies have also demonstrated that IGF-I administered subcutaneously ameliorates the peripheral neuropathy induced by vincristine, a widely-used chemotherapy agent (Contreas et al, 1997). It is contemplated that the method of the present invention is suitable for the treatment of non- diabetic peripheral neuropathies, and in addition to those listed in W093/25219, it is particularly contemplated that the method of the invention is suitable for the treatment of AIDS-related peripheral neuropathies and non-inherited peripheral neuropathies such as that associated with post- polio syndrome or toxic agents such as anti-cancer chemotherapeutic agents.

Ishii (US Patent No. 5,817,623) has recently shown that systemically administered IGF-II is effective in restoring some nerve function in streptozotocin-induced diabetic rats. Ishii discloses administration of IGF-II by local infusion to a major nerve using implanted mini- osmotic pumps, and generalizes this to include" (other) pumps or other mechanical devices, slow release from encapsulation devices, and release from implanted tissues or cells". However, no direction is provided as to how these alternative methods of administration might be effected.

Moreover, systemic IGF treatment may carry a degree of risk (Kolaczynski and Caro, 1994). For example, IGF-I may accelerate the progression of diabetic microvascular disease, including nephropathy and proliferative retinopathy (Kolaczynski and Caro, 1994). In fact, in diabetic patients with proliferative retinopathy, serum IGF-I levels have been shown to be increased (Merimee et al, 1983), and higher levels of IGF-I are associated with an increased incidence of retinopathy (Dills et al, 1991). Thus systemic treatments with neurotrophic factors may be beneficial for nerve function, but in the process

may create new problems. Side-effects of systemic IGF treatment have been reported to include oedema in the face and hands, mild weight gain, occasional dyspnoea, bilateral jaw tenderness, hyperglycaemia, arthralgias and myalgias, fatigue, tachycardia, flushing, orthostatic hypotension and local burning at the injection site.

One solution which should avoid the risks of systemic IGF-I may reside in the topical route of administration, where the agent can be available locally for the nerves in high concentrations, without the danger of systemic effects because of the small total daily dose.

However, Ishii nowhere suggests that topical administration might be useful to treat peripheral sensory neuropathy. Nor does he suggest how effective topical administration might be achieved.

Moreover, there is no a priori basis for assuming that topically applied IGF would be effective at penetrating the skin epidermal layer in quantities effective to restore nerve function.

Importantly, Ishii discusses the problems associated with achieving penetration of IGFs through blood/brain and epineural barriers. Accordingly, Ishii appears to teach away from topical administration, as those skilled in the art would perceive such difficulties in epidermal penetration would exacerbate these problems.

Westerman et al (International Patent Publication No. W096/23522) have recently demonstrated that topically- applied insulin is effective in restoring some peripheral nerve function in non-insulin dependent diabetics. This is a deficient solution to the problem of peripheral sensory neuropathy, as it is not effective in all types of diabetes. Moreover, Westerman does not suggest that topical IGF would be effective in treating peripheral sensory neuropathy.

Insulin is distinct from IGF, in that insulin is a smaller molecule with a molecular weight around 5,800 Daltons, while IGFs are 30% larger, with molecular weights

around 7,600 Daltons. In addition, the amino acid sequence homology between insulin and the IGFs is low, being about 45%. While both insulin and IGFs have specific cellular receptors, and both these types of receptors are known to occur in the membranes of nerve cells, the cross-affinity between the molecules and receptors is very low. Thus there is no a priori basis for assuming that topical IGF would be effective merely because topical insulin is effective.

We have now surprisingly found that the topical application of IGFs can in fact be used as a specific treatment of peripheral sensory neuropathy. Topical IGF therapy has not been reported previously, particularly in the treatment of peripheral sensory neuropathy.

SUMMARY OF THE INVENTION In a first aspect, the invention provides a method of treating peripheral sensory neuropathy, comprising the step of topical administration of a pharmaceutical composition of IGF to the affected area of a subject in need of such treatment.

In an alternative aspect, the invention provides the use of IGF for the manufacture of a composition for the treatment of peripheral sensory neuropathy, in which the treatment comprises the step of topical administration of a pharmaceutical composition of IGF to the affected area of a subject in need of such treatment.

The composition may be applied to the affected area of the skin of the patient. The frequency of application will depend on the individual circumstances.

For example, the composition may be applied daily, twice daily, or even more frequently.

In a second aspect, the invention provides a composition for the treatment of peripheral sensory neuropathy, which comprises a therapeutically effective amount of IGF in a pharmaceutically acceptable diluent or carrier suitable for topical use.

In both aspects of the invention the IGF may be IGF-1, IGF-II, or a mixture of both IGF-I and IGF-II. The IGF may be any IGF. Preferably the IGF used in this invention is human IGF, more preferably recombinantly- produced human IGF. It is to be clearly understood that the present invention extends to biologically active fragments or functional analogues of human IGF, ie analogues of human IGF in which the wild-type IGF sequence contains additions, deletions or substitutions by another amino acid or an amino acid analogue, in which the biological activity of the IGF is retained. IGF analogues suitable for use in the invention include those described in United States patents U. S. 5,077,276, U. S. 5,164,370, U. S. 5,470, 828, and U. S. 5, 330, 971, all assigned to GroPep Ltd.

In one preferred embodiment the neuropathy is a diabetic neuropathy. It will be clearly understood that the diabetic neuropathy may be associated with Type 1 (insulin- dependent) diabetes, Type 2 (non insulin-dependent) diabetes, or both.

In a second preferred embodiment the neuropathy is a non-diabetic neuropathy. Such a non-diabetic neuropathy may be associated with an inherited condition, such as Charcot-Marie-Tooth syndrome, an infectious disease such as HIV, an infectious disease condition such as AIDS, or with side-effects caused by a chemotherapeutic agent such as taxol, vincristine, cisplatin, an agent used for the treatment of an infectious diseases such as streptomycin, didanosine or zalcitabine, or any other chemically toxic agent. Infectious disease conditions such as post-polio syndrome or AIDS-associated neuropathy are specifically contemplated.

The IGF is administered in therapeutically effective amounts. A therapeutically effective amount means the amount required at least partly to attain the desired effect, ie to alleviate or prevent the symptoms of the peripheral sensory neuropathy, or alternatively to

delay the onset of, inhibit the progression of, or halt altogether, the onset or progression of the peripheral sensory neuropathy 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, and will be at the discretion of the attending physician. 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 generally preferred that a minimum effective dose be determined according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a higher dose may be administered for medical, psychological or other reasons.

Methods and pharmaceutical carriers for preparation of pharmaceutical compositions, including compositions for topical administration are well known in the art, as set out in textbooks such as Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, Pennsylvania, USA.

Suitable pharmaceutically acceptable carriers and/or diluents include conventional solvents, dispersion media, fillers, aqueous solutions, antibacterial and anti- fungal agents, absorption-promoting agents, and the like.

Except insofar as any conventional medium 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. For example, the topical composition may additionally include one or more other cytokines, such as insulin, nerve growth factor and other neurotrophic factors.

The topical preparations contemplated by the present invention include any formulations suitable for transdermal application of IGF, such as aqueous creams,

ointments, gels, lotions, roll-on liquids, sprays, glass bead wound dressings, and synthetic polymer dressings impregnated with IGF. These preparations may also include compounds, such as dimethylsulfoxime, which would facilitate the passage of IGF across the skin keratin barrier and into the epidermis. Preferably the preparation is a cream.

Preferred aspects of the topical use of IGF in the treatment of diabetic neuropathy according to the invention include the following : (a) The IGF concentration in a cream may range from 0. 1-100 jug per gram, preferably 2.5-50 Rg per gram.

(b) The amount of cream applied is usually about 0.5g on each affected site. The cream is easily spread and rubbed into the skin until it has vanished.

(c) The recommended application frequency is twice to thrice daily, but a lesser frequency such as once daily, or even less frequently, may be acceptable.

(d) Symptomatic patients are identified after a careful history of symptoms and testing for neuropathy with a group of investigations. These suitably include testing small sensory nerve function by pinprick and cotton-wool sensibility, and testing warm and cold perception thresholds at wrist and foot dorsum and AC-current perception thresholds. Larger nerve fibres are tested by sensory and motor nerve conduction/electromyographic studies of lower limb (sural, peroneal TA, EDB), and by measuring vibration sensitivity with a biothesiometer, as well as AC-current perception thresholds at higher frequencies.

(e) Body composition, fasting plasma glucose and insulin and haemoglobin A1C are also measured to provide an indication of insulin sensitivity in subjects with Type 2 diabetes, and quality of glycemic control in subjects with either Type 1 or Type 2 diabetes.

(f) Warm and cold thresholds are usually

elevated if small fibre dysfunction is provoking a burning discomfort of affected skin.

(g) Current perception thresholds determined at lower frequency stimulation are expected to provide another quantitative measure of small sensory nerve fibre function.

For the purposes of this specification it will be clearly understood that the word"comprising"means "including but not limited to", and that the word "comprises"has a corresponding meaning.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows improvements in cold threshold sensation in trial subjects as a consequence of topical IGF-I treatment. Sensation is measured in units of Just Noticeable Difference ("JND"). Improvement in sensation is indicated by a decrease in JND. Subjects DRB-003, CJH-004 and WMH-006 show improvement in cold sensation indicating an improvement in the function of small myelinated A8 sensory nerve fibres. Subject FCA-005 does not show an improvement in cold sensation.

Figure 2 shows improvements in cold threshold sensation and heat as pain threshold sensation in the trial subject FCA-005 as a consequence of topical IGF-I treatment. Sensation is measured in units of Just Noticeable Difference ("JND"). Improvement in sensation is indicated by a decrease in JND. In this subject, while there was no improvement in cold sensation there was an improvement in heat sensation, indicating an improvement in the function of small, unmyelinated C nerve fibres.

DETAILED DESCRIPTION OF THE INVENTION The invention will now be described in detail by way of reference only to the following non-limiting examples and to the figures.

Example 1 Topical IGF Formulations

Suitable topical vehicles for use in administration of IGF accordance with this invention, and methods of preparation thereof, include the following, in which"peptide"may be IGF-I or IGF-II : 1. Vanishing Creams : (i) Cetomacrogol Cream Peptide qs Cetomacrogol emulsifying wax 15 Liquid paraffin (by weight) 10 Chlorocresol 0.1 Propylene glycol 5 Distilled water to 100 Melt the cetomacrogol emulsifying wax with paraffin at about 70°C. Dissolve the chlorocresol and propylene glycol in about 50 parts of the distilled water warmed to about the same temperature. Mix, adjust to weight and stir until cool. Then add the peptide in appropriate concentration, and mix thoroughly.

In a particularly preferred embodiment, to 100g of cetomacrogol cream APF containing cetomacrogol emulsifying wax, liquid paraffin, chlorocresol, propylene glycol and water, add 700 Rg freeze-dried IGF-I to yield a final concentration of 7 Rg per gram of finished cream.

(ii) Aqueous Cream APF Peptide qs Emulsifying ointment30 Glycerol 5 Phenoxyethanol 1 Distilled water to 100 Melt the emulsifying ointment at about 70°C.

Dissolve the phenoxyethanol in the distilled water, warmed to about the same temperature. Mix, adjust to weight and

stir until cool. Add the peptide, stirring thoroughly.

(iii) Buffered Cream BPC 73 Peptide qs Citric acid 5 Sodium phosphate 25 Chlorocresol 1 Emulsifying ointment300 Distilled water669 Melt the emulsifying ointment with the aid of gentle heat, add the sodium phosphate, the citric acid and the chlorocresol, previously dissolved in the distilled water at the same temperature, and stir gently until cold.

Add the peptide and mix very well.

2. Ointments (i) Emulsifying Ointment APF Peptide qs Emulsifying wax30 White soft paraffin 50 Liquid paraffin (by weight) 20 Melt together and stir until cool. Add the peptide in appropriate concentration in a portion of the base and then gradually incorporate the remainder, mixing thoroughly.

(ii) Peptide Ointment-as in Neomycin and Bacitracin Ointment BPC 73 Peptide qs Liquid paraffin White soft paraffin to 100 Melt the white soft paraffin, incorporating the liquid paraffin, and stir until cold. Titurate the drug

with a portion of the base and gradually incorporate the remainder of the base.

3. Gels (i) Peptide Gel-as used in Lignocaine and Chlorhexidine Gel APF Peptide qs Tragacanth2.5 Glycerol 25 Distilled water to 100 Mix the tragacanth with the glycerol and add most of the distilled water. Heat to boiling, cool, add peptide, adjust to weight and mix well. Protect finished product from light.

4. Sprays (i)-as used in Adrenaline and Atropine Spray BPC 73 Peptide qs Sodium metabisulphite 1 Chlorbutol5 Prophylene glycol 50 Distilled water to 1000 (ii)-as used in Indospray Peptide qs Alcohol 95% 5. Lotions (i)-as used in Aminobenzoic Acid Lotion BPC 73 Peptide qs Glycerol 20 Alcohol 95% 60 Distilled water to 100

(ii)-Cetomacrogol Lotion APF Peptide qs Cetomacrogol emulsifying wax 3 Liquid paraffin Glycerol 10 Chlorhexidine gluconate solution 0.1 Distilled water to 100 Melt the cetomacrogol emulsifying wax with the liquid paraffin at about 60°C and add, with rapid stirring, to the chlorhexidine solution previously diluted to 50 parts with distilled water at the same temperature. Mix, adjust to volume and stir until cold.

Example 2 Topical IGF Reduces Symptoms of Diabetic Neuropathy A limited, open label trial of the topical IGF treatment for peripheral sensory neuropathy was conducted with six trial subjects, all of whom had given informed consent to the trial. All the subjects displayed Type 1 diabetes and objective evidence of peripheral sensory neuropathy as assessed by Pfeifer's algorithm (Pfeifer et al. 1993a, b), including superficial burning with numbness, dysaesthesia and/or paraesthesia; elevated cold perception threshold for the foot dorsum; and another confirming measure of sensory neuropathy such as hypoalgesia (decreased sensitivity) to noxious heat, abnormally elevated vibration perception thresholds, or abnormal sensory nerve conduction velocity.

A clinical assessment of the subjects'symptoms and nerve function was made on entry to the study and after three and six months of treatment. The clinical assessment included warm and cold perception thresholds at the forearm and foot dorsum using the CASE IV device and methods of Dyck et al (1993,1996). Improvement in cold threshold

sensation and heat as pain threshold sensation are accepted surrogate end-points for peripheral sensory neuropathy Dyck et al. (1993).

Topical IGF-I cream containing 7Rg IGF-I per gram of cetomacrogol cream APF was provided to the trial subjects, with instructions to rub about 0.5 gram on to each foot and ankle from below the malleoli until the cream vanished, twice per day.

Two of the trial subjects did not complete the trial. The topical IGF-I treatment resulted in improved nerve function in all four subjects who completed the trial. In three of these there was an apparent improvement in the function of small myelinated Ab sensory nerve fibres, as indicated by decreased cold perception thresholds. This is illustrated in Figure 1. In the remaining trial subject there was an apparent improvement in the function of small, unmyelinated C nerve fibres as indicated by decreased heat perception thresholds, as shown in Figure 2.

It will be apparent to the person skilled in the art that while the invention has been described in some detail for the purposes of clarity and understanding, various modifications and alterations to the embodiments and methods described herein may be made without departing from the scope of the inventive concept disclosed in this specification.

References cited herein are listed on the following pages, and are incorporated herein by this reference.

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