KR19980701896A - Treatment of diabetic neuropathy - Google Patents

Abstract

Topical use of insulin in the treatment of diabetic neurological disorders.

Description

Treatment of diabetic neuropathy

Neuropathy (also known as diabetic neuropathy) in diabetic patients is a pain that many diabetic patients suffer, especially in the limbs of the body such as the toes and feet.

Table 1 summarizes the classification and stages of neurological disorders in diabetic patients based on the recommendation of the 1988 American Diabetes Association. The first of two major pathological disorders of normal neurological function in diabetes is the elevated blood glucose level (hyperglycemia), the polyhydric alcohol pathway (which produces alcohol-sugars, termed polyhydric alcohols as final products, and biochemical path), myo-inositol (cell energy-storage substrate), Na ⁺ / K ⁺ ATPase (ion-pump enzyme) means a mutual relationship is assumed between an active and neurobehavioral, i.e., nerve impulse transmission rate (Greenwich, etc. ²⁾ do.

The second hypothesized sick-physiological mechanism of normal neurological function impairment in diabetes is the lack of oxygen in the nerve fibers, which leads chemically to elevated blood glucose levels and activation of the polyhydric alcohol pathway, changes in blood flow through the microtubules in the nerve (Williamson et al. ³ ).

Neuropathy of diabetic patients ¹ Classification and stages (1988. American Diabetes Association's recommendation basis). Class 1: Asymptomatic neuropathy A. Abnormal electrodiagnostic test: 1. Neurological symptom rate reduction 2. Decrease in width of induced muscle or nerve activity potential B. Abnormal Quantitative Perceptual Test: 1. Vibration / Tactile 2. Heat warming / cooling C. Abnormal autonomic function test: 1. Reduction of synchronous arrhythmia (stroke against changes in heart rate) 2. Reduced sweating and irritation 3. Increased childhood potential

Class 2: Pathological neuropathy A. Diffuse neuropathy: 1. In situ symmetric perception. Autonomic nervous disorders a. Abnormal Childhood Potential b. Sweating irritant function c. Genitourinary autonomic disorders ⅰ. Bladder dysfunction Ⅱ. Sexual dysfunction d. Gastrointestinal autonomic disorder ⅰ. Gastric relaxation ⅱ. Gallbladder relaxation ⅲ. Diabetic diarrhea e. Cardiovascular autonomic dysfunction f. Neglect of hypoglycemia B. Lesional neuropathy: 1. Single neurological disorder / single neurological disorder 2. Multiple Neurotoxic disorder 3. Neuromuscular disorders 4. Cranial nerve disorder

Direct (via the inner cell of the blood vessel) and indirect (via the best skin-sensory nerves) method and measurement of the blood leak (by the laser Doppler velocimeter) are known to stimulate skin flushing reactions using current (iontophoresis) , These methods have been used by others ⁴ , ⁵ , ⁶ and inventors and colleagues ⁷ ,

Previously used treatments for diabetic neuropathy management have recently been reviewed by Papers ^{9, 10} (1993) describing three different disease patterns and detailed algorithms for their diagnosis and management.

Some of the most commonly used treatments for pain or neurological disorders in diabetic neuropathies (some of which are referred to by papers ^{9 and 10} ) include:

(a) The physical therapies used for affected areas of pain may sometimes be provided as symptom relief, for example:

I. TENS, interference, vibration, ultrasonic

Ii. Massage and massage

Iii. Water treatment

Iv. Use warmth, heat or cold

V. Acupuncture or acupressure

Vi. Use of face-to-face dressing films ^{11, 12} .

(b) Oral medication for pain relief:

I. Non-steroidal analgesics (e.g., aspirin, paracetamol, ibuprofen, ketoprofen, etc.);

Ii. Anesthetics such as codeine, morphine, petidine and sustained-release morphine preparations;

Iii. Anti-depressants including tricyclics such as amitriptyline and the like;

Iv. An anticonvulsant agent having an inhibitory effect on pain signaling such as carbamazepine and clonazepam;

V. Antiarrhythmic compounds that decrease the electrical excitability of cells such as Mexylitene and lignocaine;

Vi. (ICI), ephorestat (Ono), which improve the level of neuronal energy substrate (myinositol), reduce polyhydric alcohol sugar accumulation (sorbitol) and improve Na ⁺ / K ⁺ ATPase function, , Aldose-reductase inhibitors such as tolestat (Upo-Ieelst), Joopolestat (piza);

Ⅶ. Essential fatty acids (which reduce diabetes), for example, supplemental agents that supply gamma-linolenic acid (GLA) such as evening primrose oil.

(c) compounds that promote nerve regeneration (i.e., treatment, regrowth and relapse) (by injection);

- such as gangliosides (cronosaccharides), vitamin B12 (cyanocobalamin) and insulin-like growth factors.

(d) topical treatment that removes the sensitivity of the surface nerve fibers that transmit pain signals , e.g.,

I. Neurotoxin and post-herpetic neuralgia^{15, 16, 17}And pain in diabetic patients nervous disorders¹⁸Capsaicin creams or ointments (typically 0.025% or 0.075%) that have been used in the art.

Ii. Aspirin or solvolenes in vanishing creams have been reported by Cassirer as good for post-herpetic neuralgia and have been used by the present inventors (Westermann and Zimet, not reported) and sometimes effective for neuropathy in patients with thermal pain diabetes Was found.

Topical use of insulin is currently known to be available for the special treatment of diabetic neuropathy in patients with pain. Local insulin therapy has not been previously reported, especially in diabetic neurological disorders.

In 1980, Cynthia And Kim ²⁰ predicted that insulin was a nerve survival factor. Shortly thereafter, Low et al. Described a reduction in response to sweating-induced axon reflex tests such as small fiber dysfunction in neurological disorders, particularly in the axillary reflex response induced by diabetes mellitus ⁷ , and in rat experiments STZ-diabetes ²¹ It was found that the single dose of insulin significantly restored. In searching for possible ways of working for insulin, Worldville and Lloyd's demonstration of insulin receptors in the peripheral nerve ²² and localization of lysolein in these ²³ have shown that the inventors of the present invention for insulin role in normal sensory nerve function ²⁴ Research.

²⁵ medical skin Tufi ion penetration therapy techniques shown to be effective to facilitate transport of peptides, including insulin, ^{26, 27, 28.} The present inventors have studied the short-term effect of insulin on apoptosis and axon reflex function in two animal studies of streptozotocin-induced diabetic rats and ²⁹ insulin-dependent diabetics. In both diabetic patients and rats, the size of the skin flushing reaction (called the axonal reflection flare) for infiltration stimuli was significantly reduced, even though the small blood vessels themselves did not decrease. This indicates that the reduced inflammation is due to sensory dysfunction rather than microtubule dysfunction. Localized use of insulin by a 6 minute cathodic current called iontophoresis has significantly increased the recovery of axonal reflection size in chemically diabetic rats with IDDM and streptozotocin. The immediate recovery effect of insulin in insulin infusion therapy is due to the functional changes of the nerves that mediate the response rather than any structural linkage, as axon reflexes can reverse. Although insulin is the mechanism lays these practical effect in the nerve is known, quick time of the effect-course (in minutes) are some of the ions, such as calcium levels within the nerves one based on other indirect evidence of such actions of insulin ^{30, 31} Castle Or excitatory changes.

In general, the special treatment of neuropathy in patients with pain diabetes is not present until now. All therapies currently in use are intended to provide symptom relief. Some of these are aimed at identifying physiological disorders that range from diabetes to diabetes and that do not require special testing or evaluation.

SUMMARY OF THE INVENTION

The present invention provides for topical use of insulin in the treatment of diabetic neurological disorders in its broad character.

The present invention, in one aspect, provides a method for treating neurological disorders in a diabetic patient by topically administering a therapeutically effective amount of insulin to the skin region of the suffering patient.

In another aspect, the invention provides a composition for the treatment of neurological disorders in a diabetic patient comprising locally an effective amount of insulin, a pharmaceutically acceptable diluent or carrier.

In another aspect, the invention provides a therapeutically effective amount of insulin for the manufacture of a medicament for topical use in the treatment of neurological disorders in diabetic patients.

The present invention relates to the treatment of neurological disorders in diabetic patients, in particular the present invention relates to novel methods of local treatment of such symptoms and compositions therefor.

Preferably, the insulin used in accordance with the present invention is human insulin (e.g., can be used as human insulin, belochulins or actraids). However, it will be appreciated that the present invention may extend to the use of insulin from pig insulin, bovine insulin or other non-human animal species.

As used herein, the term insulin includes not only insulin itself, but also insulin of the [alpha] - or [beta] -sub chain separated or combined.

In accordance with the present invention, insulin is administered in a therapeutically effective amount. A therapeutically effective amount refers to an amount that is at least partially required to delay the onset or inhibit the onset of neurological dysfunction in a diabetic patient to be treated, to arrest its onset or progression together, or to achieve the desired effect . Of course, this amount is well known for the particular symptoms to be treated, the severity of the symptoms and the individual patient parameters including age, physical condition, size, weight and other current treatments, and should be known by routine experimentation only. Generally, the minimum amount of active drug is preferably used according to normal medical judgment. However, those of ordinary skill in the art will appreciate that dosages may be administered more for medical, mental, or any other practical reasons.

Formulations of formulations or compositions for topical administration are well known to those skilled in the art. Suitable pharmaceutically acceptable carriers and / or diluents include any and all conventional solvents, dispersion media, fillers, aqueous solutions, antibacterial and antifungal agents, absorption promoters, and the like. The use of such media and medicaments as pharmaceutically active substances is well known in the art and is exemplified in Remington ' s Pharmaceutical Sciences , 18th ed., Pennsylvania, USA. Except insofar as the generic media or agents are incompatible with the active ingredient, their use in the pharmaceutical compositions of the present invention should be considered. In addition, the supplemental active ingredient can be mixed into the composition.

Topical preparations contemplated by the present invention include creams, ointments, gels, lotions, ball pen liquids, sprays, glass bead wound sacks, synthetic polymer sacks impregnated with insulin, or other insulins. The creams include buffering agents and hydrophobic components. Also, for these agents, compounds such as DMSO (dimethylsulfoxide), which facilitate the passage of insulin across the cutaneous horny barrier, can be used.

Since creaming has proven to be most effective in promoting the delivery of insulin active ingredients to the affected skin, the method of making the creams will be described in detail in the following examples.

Topical insulin creme 70 g vanishing creme substrate contains purified water, stearic acid, dimethicone, isopropyl myristate, cetyl alcohol, triethanolamine, polysorbate 80, aloe vera extract, methyl paraben, propyl paraben, (Such as home remedial skin creams, solvolene creams or seto-Merck rosace creams). 70 IU, or 210 IU, all of which are insulin, a neutral person. 100 IU / mg is added to sodium sulphate buffer, which is preserved by 0.3% meta-cresol in vellosulin or actraid. This represents the final concentration of 1 or 3 IU per finished Crree grams.

In the preliminary test, the final formulation of Vanishing Cream base shows that it is relatively insignificant in Creep Hyposility. Other forms of Solvolenment are also used as excipients and are effective. It contains deionized water, glycerin, sorbitol, light mineral oil, cetyl alcohol, cetomercurogol 1000, stearic acid, triethanolamine, tocopheryl acetate, imidazolidinyl urea, methylparaben, EDTA, para-cresol. Similar but more hydrophobic and pH-buffering creams are currently being developed.

Suitably, the topical formulation of the invention is used at least daily or daily for several hours on the affected area of the patient's skin. For example, two times daily (morning and evening) or three times daily.

It is effective to select patients with symptoms associated with diabetic neuropathy and fibrillary dysfunction with proper care and to initiate treatment. The most appropriate and most favorable clinical picture for topical insulin therapy is a specific neuropathy symptom complex involving an unpleasant superficial pyramidal form with a sensory or perceptual association (paper et al., ^{9, 10} ). It is most suitable for non-insulin dependent diabetes mellitus and patients who have not been previously treated with insulin.

Local insulin creams are used only twice daily for skin areas with superficial lacerations. This is usually best for lower parts of the toes, feet and legs.

A Medelek TTT device is used to re-measure the thermal perception threshold at the skin sites treated at monthly intervals according to the methods described by the dumbbells ^{32,33, 34} and Delaney et al. ^{8, 24} . Measure cold and warm perception threshold.

The clinically observable effect (symptom score) besides pain relief means a decrease in the thermal perception threshold, which can be understood as an improved thermal sensation sensitivity. This can be related to improved sensory nerve function. It is expected that the cold threshold will be improved faster than the warm threshold and there will be a greater advantage for the cold sensation mediated spinal A-delta nerve fibers.

Desirable characteristics of topical use of insulin in the treatment of neurological disorders in diabetic patients include:

I. The insulin concentration in the creams ranges from 0.01 to 20 IU per gram, preferably from 0.1 to 10 IU per gram, more preferably from 1 to 3 IU per gram.

Ii. The amount of crye used is usually 0.5 g per foot / leg. The desired crease density tends to be slightly diluted, and therefore it is easily dispersed and rubs on the skin until it is gone.

Iii. The recommended number of uses is from two to three times per day, but after a long-term test, less recovery, such as once daily, may be acceptable for maintenance therapy or skin ulcer prevention.

Iv. Patients with symptomatic patients, particularly those with type 2 (non-insulin dependent) diabetes mellitus, which are best suited for treatment with focal insulin creams, should be carefully monitored (see Paper Algorithms ^{9 and 10} ) . These include small sensory nervous function by tingling and facial sensibility, cold and warm perception thresholds from the waist and feet, and AC-current perception threshold (250 Hz or 5 Hz). Larger nerve fibers are more sensitive to sensations of lower limbs (calf, fibula TA, EDB), motor neuron / emergency studies and vibrotactile measurements, as well as AC-current perception at high frequencies such as 2000 Hz Threshold is measured and tested.

V. Body weight, height, body mass index (BMI), abdominal circumstance, fasting plasma glucose and insulin and hemoglobin A and C were also measured to show the insulin sensitivity of type 2 subjects and the quality of blood glucose control in two type 1 and type 2 subjects to provide. Blood glucose fixation measurements have not yet been used in these studies for logical reasons.

Vi. Warmth and cold thresholds are usually assessed when fibrillatory dysfunction causes lacerations of the lesion.

Ⅶ. The current perception threshold measured at the lower frequency stimulus (250 Hz, 5 Hz) provides another quantitative measurement of small sensory nerve fiber functions ^{35, 36, 37, 38} .

Suitable topical excipients for use in the administration of insulin according to the invention and their preparation are as follows:

1. Varnish Cream:

(I) Cetomarketing

Peptide sufficient

Seto Merck Root Milk Wax 15

Liquid paraffin (weight) 10

Chlorocresol 0.1

Propylene glycol 5

Distilled water up to 100

The cetomarc bean emulsion wax is melted with paraffin at about 70 ° C. Chlorocresol and propylene glycol are dissolved in about 50 parts of distilled water heated to the same temperature. Mix, weigh, and stir until cooled. Next, the peptide is added at an appropriate concentration and mixed thoroughly.

(Ii) Water-based creaming APF

Peptide sufficient

Oily ointment 30

Glycerol 5

Phenoxyethanol 1

Distilled water up to 100

The ointment ointment is melted at about 70 ° C. Phenoxyethanol is dissolved in distilled water and heated to the same temperature. Mix, weigh, and stir until cooled. The peptide is added and stirred thoroughly.

(Iii) Buffered Crime BPC 73

Peptide sufficient

Citric acid 5

Sodium Phosphate 25

Chlorocresol 1

Oily ointment 300

Distilled water 669

The ointment ointment is melted with gentle heating, sodium phosphate, citric acid and chlorocresol are added, dissolved in distilled water at the same temperature in advance, and gently stirred until cooled. Add the peptides and mix well.

2. Ointment:

(I) ointment ointment APF

Peptide sufficient

Emulsion wax 30

White soft paraffin 50

Liquid paraffin (weight) 20

Melting together and stirring until cooled. The peptide is added to a portion of the substrate at an appropriate concentration, then the rest is gradually added and mixed thoroughly.

(Ii) Peptide Ointment - Neomycin and Bacitracin Ointment As in BPC 73

Peptide sufficient

Liquid paraffin 10

Up to 100 white soft paraffin

The white soft paraffin is melted, the liquid paraffin is mixed and stirred until cooled. The medicament is suitable for some substrates and the remaining substrates are gradually mixed.

3. Gel:

(I) Peptide gel -lignocaine and chlorhexidine gel As used in APF

Peptide sufficient

Tragacanth 2.5

Glycerol 25

Distilled water up to 100

Mix tragacanth with glycerol and add large amounts of distilled water. Heat to boiling, cool, add peptides, adjust weight and mix well. The final product is protected from light.

4. Spray:

(I) -Adrenalin and Atropine Spray As used in BPC 73

Peptide sufficient

Sodium metabisulfite 1

Chlorobutol 5

Propylene glycol 5

Distilled water up to 100

(Ii) - As used in Indian spraying

Peptide sufficient

Alcohol 95%

5. Loans:

(I) - As used in aminobenzoylation BPC 73

Peptide sufficient

Glycerol 20

Alcohol 95% 60

Distilled water up to 100

(Ⅱ) - Seto Merck Golation APF

Peptide sufficient

Seto Merck Root Emulsion Wax 3

Liquid paraffin 10

Glycerol 10

Chlorhexadine gluconate solution 0.1

Distilled water up to 100

The Seto Merck ointment wax is melted with liquid paraffin at about 60 ° C and added to the chlorhexidine solution pre-diluted to 50 parts with distilled water at the same temperature with rapid stirring. Mix, adjust the volume, and stir until cooled.

It should be understood that, unless the context requires otherwise, variations such as "comprise," "comprises," or "comprises" or "comprising" are intended to be inclusive of the stated integer or integer group, but not the exclusion of any other integer or integer group .

In the accompanying drawings,

Figures 1 to 3 illustrate the results of local insulin treatment of painful lacerations in the case of diabetic neuropathy selected according to already described criteria (see page 10, paragraphs, iv, v and papers ^{9 and 10} ) .

Other features of the invention will be more fully described in the following examples. It should be understood, however, that such detail is solely for the purpose of illustrating the invention and is not intended to limit the broad scope of the invention described above.

A preliminary open test of local insulin treatment of painful peripheral neuropathy is performed.

All subjects are selected using criteria ^{9 and 10} of the paper ^, and have sensory neuropathy of pain that aggravates their diabetes. This includes a series of neurophysiological tests involving sensory and motor NCVs with virtual potentials and amplitudes of activity, vibrational perception thresholds using a bio-sensor, warmth and frost heat thresholds at the waist and feet with the Medereck TTT device, The patient was identified by using neural gauge CPT at 2000 Hz, 250 Hz, and 5 Hz and by current perception threshold at the large toe.

Patients are instructed to administer a local insulin dose of the above composition (1 IU insulin per gram of final creme) to the patient twice or three times daily on each foot / leg approximately 0.5 g.

The results are shown in the drawings. Figures 1 and 2 relate to a maximum of 30 type 2 diabetic patients who are not treated with systemic insulin. Figure 3 shows the results from up to 16 patients who received systemic insulin therapy.

In all graphs, the vertical axis represents the thermal threshold; The blank rectangle is the warm threshold value, and the black rectangle is the cold threshold value. The depth of the laceration signs of pain in the 10-point visible superior scale was marked on the vertical axis as a black circle. The horizontal axis represents the treatment period for performing the test and the re-test. The horizontal dashed line represents the upper limit of the normal 95% confidence limit (mean +2.2 standard deviation).

Figure 1 shows the results from 12 weeks of treatment, the number of subjects is 30 at 0 and 4 weeks, and gradually decreases to 16 at 12 weeks. In the case of local insulin therapy, the symptom scale enhancement of the delta sensory fibers and the statistical significance of the improved function are achieved at 4 weeks and others are gradually improved.

Figure 2 shows a graph in the same direction on a time scale of several months, which shows that the warmth threshold is significantly improved (i.e. WPT reduction) by a four month treatment.

Thus, from the data of FIGS. 1 and 2, there is a thermosensitivity confirmation and symptom relief of the sensory nerve function improved in these two small sensory nerve fibers in these non-insulin dependent diabetic patients with signs of thermal pain neuropathy . ≪ / RTI > The most dramatic results are achieved by most patients who have reported improvements in generalized sensory awareness, decreased sensation in their feet, shocks they are walking on, and the ability to feel carpets and other surfaces on cold fibers. This may include a degree of improvement in the great sensory fiber function, but it has not yet been measured.

Figure 3 shows the treatment results of a smaller group of patients receiving systemic insulin therapy. These include some patients with type 2 DM where the reduction eventually requires systemic insulin therapy; The remainder includes patients with type 1 DM. The lack of improvement in the results of heat thresholds for warmth and cold in this group is significantly different from that in the previous group, but the surprise is that the signs improve in these patients.

references:

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Claims (15)

A method of treating a neurological disorder in a diabetic patient by administering a therapeutically effective amount of insulin topically to the affected skin area of the patient. 3. The method according to claim 1, wherein the insulin is human insulin. 3. The method of claim 1 wherein the insulin is insulin from pig insulin, bovine insulin or other non-human animal species. 4. The method according to any one of claims 1 to 3, wherein the insulin contains an alpha - and / or beta-subchain. 5. The method according to any one of claims 1 to 4, wherein the insulin is used topically with creams, ointments, gels, sprays or lotions. 6. The method according to claim 5, wherein the insulin is used topically in vanishing creams. 7. The use according to any one of claims 1 to 6, wherein the insulin is used as a cream containing from 0.01 to 20 IU per gram, preferably from 0.1 to 10 IU per gram, most preferably from 1 to 3 IU per gram Way. 8. The method according to claim 7, wherein the cream is used in an amount of about 0.5 grams every 2-3 times a day. Use of a therapeutically effective amount of insulin in the manufacture of a medicament for topical use in the treatment of neurological disorders. A composition for the treatment of neurological disorders in diabetic patients comprising a locally therapeutically effective amount of insulin, a pharmaceutically acceptable diluent or carrier. 11. The composition of claim 10 wherein the insulin is human insulin. 11. The composition of claim 10, wherein the insulin is insulin from pig insulin, bovine insulin or other non-human animal species. 13. The composition according to any one of claims 10 to 12, wherein the insulin contains an alpha - and / or beta-subchain. 14. A product according to any one of claims 10 to 13, wherein the insulin is made into creams, ointments, gels, sprays or lotions. 15. The composition of claim 14 comprising 0.01 to 20 IU of insulin per gram, preferably 0.1 to 10 IU per gram, most preferably 1 to 3 IU per gram.