CN1178471A - Treatment of diabetic neuropathy - Google Patents

Abstract

Treatment of diabetic neuropathy by using trypsin partly.

Description

Treatment of diabetic neuropathy

The field of the invention

The present invention relates to treatment of diabetic neuropathy, particularly it relates to a kind of new method and the compositions that is used for this disease of topical therapeutic.

Technical background of the present invention

Diabetic neuropathy (also being the diabetes nerve inflammation) is a kind of painful diseases that many diabeticss suffer from, and is particularly caused by the dysneuria of body extremity such as toe and foot.

Table 1 is according to the introduction of ADA in 1988, summarized the classification of diabetic neuropathy and by stages.In the main pathology imbalance of two of the normal neuro-function of diabetes, at first comprise blood sugar content (hyperglycemia), polyol pathway (being called the biochemical route that the pure sugar of polyhydric alcohol brings out), inositol (a kind of cell energy storage substrate), the Na of rising by the finished product of sugared content of height and generation ⁺/ K ⁺Adenosine triphosphatase (ionic pump enzyme) active with nerve conduction be that supposition between the speed transmitted of neural impulse concerns (Greene et al. ²).

Second supposition pathophysiological mechanism of the normal neuro-function imbalance of diabetes is relevant with anoxia in the nerve fiber, it is inductive by the activation of blood sugar content that raises and polyol pathway, causes neural interior by microvascular blood flow change (Williamson et al. ³).

Table 1 diabetic neuropathy ¹Classification and (according to the introduction of ADA in 1988) by stages.

The 1st class: the electrodiagnostics test that subclinical neuropathy A. is unusual:

1. the nerve conduction velocity that reduces

2. the quantitative sensory test that the amplitude B. that brings out muscle or nerve action potential that reduces is unusual:

1. shake/tactile.

2. the autonomy function test that warm hot/cold C. is unusual:

1. the sinus arrhythmia that weakens (dancing heart rate change)

2. the sudomotor function that weakens

3. pupil incubation period of Zeng Jiaing

The 2nd class: the neuropathy of clinical neuropathy A. diffusion:

1. the symmetric sensorimotor polyneuropathy of tip.

2. infrapsychic neuropathy

A. unusual pupillary function,

B. urge the antiperspirant malfunction,

C. genitourinary autonomy neuropathy,

I bladder function obstacle

Ii sexual disorder

D. gastrointestinal autonomy neuropathy

The i gastroatonia

The ii gallbladder tension lacks

The iii diabetic diarrhea

E. cardiovascular autonomy neuropathy

F. hypoglycemic unconsciousness B. kitchen range neuropathy

1. mononeuritis/polyneuritis,

2. clump is sick,

3. radiculopathy,

4. cranial nerve disease

With the method for electric current (ionotherapy) direct (by the lining cell of blood vessel) and indirect (by the thinnest dermal sensation nerve) chafe generation flare reaction and the mensuration (using laser Doppler velocimetry (LDV)) that dermal blood flow changes is known, and these technology are by other people ^4,5,6And the inventor and colleague ^7,8Adopt.

People such as Pfeifer ^9,10(1993) looked back the therapy that is used to handle diabetic neuropathy in the prior art recently, they have described three kinds of different Clinical types and have been used to the detailed steps diagnosing and dispose.

That below list is type (the some of them pfelfer of the most common therapeutic method in management of pain diabetes nerve inflammation or the neuropathy ^9,10Mention): (a) physiotherapy that is used for affected painful area sometimes can mitigation symptoms, for example:

The i electricity irritation is such as TENS, interference, vibrations, ultrasonic

The ii massage

The iii hydrotherapy

Iv utilization temperature, heat or cold

V acupuncture therapy or acupreesion

Vi uses relative dressing thin film ^11,12(b) be oral drugs and the medicament of easing the pain:

I on-steroidal analgesic (for example, aspirin, acetaminophen, ibuprofen,

Ketoprofen, etc.);

Ii analgesic, for example codeine, morpholine, Pethidine and the lasting morpholine that discharges

Preparation;

The antidepressants that iii comprises tricyclic antidepressants are amitriptyline etc. for example;

Iv is to the inhibited anticonvulsant of the transmission of pain signal, for example Karma

Xiping, clonazepam;

V reduces the antiarrhythmic compounds of the electrostimulation of cell, for example U.S. west

Rule, lignocaine;

Vi aldose reductase inhibitor, for example sorbinil, Ponalrestat

(ICI), epalrestat (Ono), holder end department he (Wyeth-Ayerst),

Zepolrestat (Pfizer), they can improve intranueral energy substrate (flesh

Alcohol) content reduces polyhydric alcohol sugar and assembles (Pyrusussuriensis (sugar) alcohol), and

Strengthen Na ⁺/ K ⁺The function of adenosine triphosphatase;

Vii provides the complementary medicine of basic fatty acid (reducing in the diabetes), for example uses

Make the gamma-Linolenic acid (GLA) of Radix Oenotherae erythrosepalae oil ^13,14(c) promote the chemical compound (through injecting) of neuranagenesis (as reparation, regrowth and is connected again);

For example ganglioside (Cronassial), vitamin B ₁₂(cyanogen cobalt ammonium) and insulin-like growth factor.(d) make the local treatment of the surperficial nerve fiber desensitization of transmitting pain signal, for example:

I capsaicin Emulsion or ointment (being generally 0.025% or 0.075%), it

Be a kind of neurotoxin, be used for the neuralgia behind the herpes zoster ^15,16,17

And the diabetic neuropathy of painful ¹⁶

Ii Kassirer ¹⁹Report can alleviate behind the herpes zoster neuralgic A Si

Woods vanishing cream or Sorbolene and it are by the inventor (Westerman

And Zimmet, undocumented) use, find that it is to extreme pain sometimes

Diabetic neuropathy effective.

Have now found that the local insulin that uses can be as the local treatment of painful diabetic neuropathy.The local insulin therapy was not appeared in the newspapers in the past, particularly aspect the diabetic neuropathy treatment.

1980, Snyder and Kim ²⁰At first proposing insulin may be a kind of neural Survival Factor.In the near future, people such as Low ⁴Discussed and owing to the fubril malfunction reaction of urging the antiperspirant axon reflex to test has been reduced in the neuropathy, and found that the axon reflex that electricity brings out in the diabetes reacts decline ⁷, the insulin major part with single dose in rat experiment streptozotocin diabetes is restored ²¹In the process of the method for seeking possible utilization insulin, Waldbillig and LeRoith are about the demonstration of the Insulin receptor INSR in the peripheral nerve ²²And the correlated positioning mode of Liewellyn ²³Make the inventor to insulin the effect in normal threshold of feeling function of nervous system study ²⁴

Found dermatological ²⁵The iontophoresis law technology of middle percutaneous is promoting polypeptide ²⁶Comprise insulin ^27,28Transport in be effective.The inventor has studied inductive diabetes rat of streptozotocin and insulin-dependent diabetics ²⁹Middle insulin is to the shortterm effect of nervelet and axon reflex function.In diabetics and rat, though the reaction of little blood vessel itself does not reduce, the size (being called " axon reflex flushing ") that the erubescence that destructive stimulus is produced reacts significantly reduces.This shows that it is because sensory nerve parasthenia rather than microvascular lesions that inflammation reduces.Through being called the local insulin that uses of iontophoretic cathode current in six minutes, the big or small utmost point that causes the insulin-dependent diabetes patient and chemically bring out the axon reflex in the rats with diabetes with streptozotocin recovers significantly.The iontophoretic this restitution immediately of insulin shows that it is reversible that axon reflex goes down, and its reason is because the changes of function of the nerve of transfer reaction, rather than any structure is damaged.Insulin is known to mechanism of these violent effects that nerve produces, but according to other indirect foundations of these effects of insulin ^30,31, the quick time course of this effect (in minute) is pointed out some ionic or excitatoty change, for example intranueral calcium content.

It is generally acknowledged the particularity therapy that does not also have the painful diabetic neuropathy up to now.All Therapeutic Method (above-mentioned) that use all are at mitigation symptoms at present.Some of them at the confirmable disorder that appears in the diabetes, and wherein do not exist special test or evaluation yet on indefinite degree.

Summary of the present invention

Topmost aspect the invention provides the local diabetic neuropathy that uses insulin to be used for the treatment of the patient.

On the one hand, the invention provides the method for treatment patient's diabetic neuropathy, it is included in the insulin that effective dose is gone up in the interior topical administration treatment of the affected skin scope of patient.

On the other hand, the invention provides treatment patient's the compositions of diabetic neuropathy, it comprises the insulin of effective dose in the treatment in partial, the pharmaceutically acceptable diluent or carrier.

Also have on the one hand, the invention provides the purposes of medicine that the insulin of will treatment going up effective dose is used to make topical therapeutic patient's diabetic neuropathy.Detail specifications of the present invention

The preferred insulin human of insulin that the present invention uses (obtainable, for example, the greenweed element, Velosulin, Actrapid).Yet, know that very the present invention also expands to use Iletin II (Lilly), bovine insulin or derives from other inhuman animal kind insulin.

" insulin " speech meaning of using here is not only to comprise insulin itself, and comprises the α of independent or bonded insulin-or β-Ya chain.

According to of the present invention, insulin is to go up the effective dose administration by treatment.The effective dose meaning is meant and reaches the required effect of part at least in the treatment, perhaps postpone the diabetic neuropathy of being treated generation, stop its development, perhaps stop its generation simultaneously or develop needed quantity.Certainly, these quantity comprise the different and different of age, health, stature, body weight and other treatment of carrying out simultaneously according to the specified disease, severity of disease and the patient's that are treated individual parameter.These factors are well-known to those skilled in the art, and only just can draw by normal experiment.According to the preferred usually effective dose of using minimum of rational medical judgment.But those of ordinary skill in the art knows owing to medical reasons, psychological reason or because any other actual cause can give higher dosage.

The preparation of topical administration or the prescription of compositions are well-known to those skilled in the art.The pharmaceutically acceptable carrier and/or the diluent that are fit to comprise all any common solvent, disperse medium, filler, aqueous solution, antibacterial and antifungal, promotion absorbent etc.The active substance that these media and reagent are used for pharmaceutically is well known in the art, for example, in Mack publishing company, Pennsylvania, on the books in the 18th edition Remington ' s pharmaceutics of U.S.A.Except with inconsistent any typical media of active component or reagent, all can be used in the pharmaceutical compositions of the present invention.Also supplementary active ingredients can be used for compositions.

The topical formulations that plan of the present invention is used comprises aqueous emulsions, ointment, gel, lotion, rolling liquid, spray, bead wound dressing, with the synthetic polymer varnish of insulin dipping, or any other percutaneous uses the method for insulin.Emulsion comprises buffer agent and hydrophobic ingredient.These preparations also can comprise the chemical compound that uses DMSO (dimethyl sulfoxide) and so on, and they can make insulin unimpeded through the passage that skin keratin barrier enters epidermis.

Since confirmed Emulsion promote to transport the insulin active composition by and enter may be the most effective aspect the affected skin, the method for preparing Emulsion is described in detail in this mode with embodiment and has comprised.

Local insulin Emulsion.70g contain purify waste water, the vanishing cream substrate (for example Home board skin repair Emulsion, Sorbolene, Polyethylene Glycol Emulsion) of stearic acid, dimethicone, isopropyl myristic acid ester, hexadecanol, triethanolamine, many ethylaminos ether 80, Aloe extract, methyl butex, propyl parabene and spice.With 70IU or 210IU greenweed element, Velosulin, Actrapid, they are neutral Human Actrapid Penfill, and 100IU/ml adds in the sodium phosphate buffer, preserves with 0.3% cresol. obtain the ultimate density of every gram Emulsion 1-3IU like this.

From preliminary test, as if with respect to the effect of Emulsion, the end formulation of vanishing cream substrate is unimportant.A kind of dissimilar Sorbolene lotion also is used as excipient and effective.It comprises deionized water, glycerol, Pyrusussuriensis (sugar) alcohol, light mineral oil, hexadecanol, cetomacrogol 1000, stearic acid, triethanolamine, alpha-tocopherol acetate, imidazolidinyl urea, nipagin, ethylenediaminetetraacetic acid, paracresol.A kind of similar but hydrophobicity is better and the buffered Emulsion of PH has just been made now.

More suitable is, topical preparation of the present invention at least once a day or be used for the affected area of patient skin in one day for several times.For example, can use twice in one day (sooner or later), or even three times on the one.

Effectively treatment at first is conscientiously to select to suffer from the diabetic neuropathy relevant with the fine fibre malfunction and the suitable patient of symptom.The local insulin therapy preferably is fit to and may the most effective clinical setting is special symptom plyability neuropathy, comprises with the extremely uncomfortable type (pfelfer etc. of insensitive or cacesthenic epidermis ^9,10).That be fit to the most is noninsulindependent diabetes and the former not patient of insulinize.

Local with the use twice in a day of insulin Emulsion, be confined to the extremely uncomfortable skin part of epidermis usually.The lower position of toe, foot and lower limb the most commonly.

According to Jamal etc. ^32,33,34With Delaney etc. ^6,24Described method uses MedelecT TT device to carry out every other month once the hotness threshold replication of being treated skin area.Measure two kinds of cold-peace temperature threshold of sensation.

Clinical observable effect also has the hotness threshold to descend except that pain relief (symptom score), and it may be interpreted as hotness sensitivity increases.This may be relevant with the sensory nerve increased functionality.Cold threshold increase temperature threshold is faster, shows that the effect that myelin A-δ nerve fiber is arranged to transmitting cold sensation is bigger.

Preferred part uses the neuropathic situation of insulin for treating diabetes to comprise following: the insulin concentration scope in the i Emulsion can be 0.01-20IU/g, preferred 0.1-

10IU/g better is preferably 1-3IU/g.The Emulsion amount that ii uses is about every foot/lower limb 0.5g usually.The concentration of preferred Emulsion is tended to

Light liquid, thereby be easy to spread and be rubbed in the skin until dissipation.The access times that iii recommends are every day two to three times, but through after the test of long term,

In order to keep treatment or prevention skin ulcer, less number of times is as once-a-day also being can

Accept.Iv (sees Pfelfer algorithm through understanding careful symptom history ^9,10) and with one

After the group investigation is tested neuropathy, can determine symptomatic patient, the spy

It not II type (the non-insulin dependence of those the most suitable local insulin Emulsion treatments

The property) diabetic.These researchs comprise by the sensitivity to acupuncture and absorbent cotton

And the gentle cold sensation threshold of wrist and instep portion and AC-electric current threshold of sensation

(250Hz or 5Hz) measures little sensory nerve function.Sensation by lower limb

With nervus motorius conduction/Electromyographic research (TA sura, fibula,

EDB), and measure vibrations sensitivity with biothesiometer, and higher

AC-electric current threshold of sensation when frequency such as 2000Hz can be tested bigger nerve

Fiber.V is treated for the insulin sensitivity that shows II type curee and I type and II type

The quality of both glucemia control of person, it is total also to have measured body weight, height, health

Index (BMI), abdominal circumference, fasting plasma glucose and insulin and hemoglobin

A1C。Owing to not using orthoglycemic clamping plate to survey in these researchs of logic reason

Fixed.If it is vi fubril malfunction causes the extremely uncomfortable of influenced skin, then warm usually

Raise with cold threshold.Measure electric current threshold of sensation (as 250Hz, 5Hz) when the vii low frequency stimulates other can be provided

The method of the little sensory nerve function of a kind of quantitative assay ^35,36,37,38

The topical vehicle that is fit to that is used for the administration of insulin of the present invention, and the method for preparation comprise as follows: 1. vanishing cream (I) Polyethylene Glycol Emulsion

Polypeptide is an amount of

Polyethylene Glycol emulsifing wax 15

Liquid Paraffin (weight) 10

Chlorocresol 0.1

Propylene glycol 5

Distilled water to 100

About 70 ℃ with melted paraffin wax Polyethylene Glycol emulsifing wax.Dissolved chlorine cresol and propylene glycol in about 50 parts of distilled water are heated to identical approximately temperature.Mix, adjust weight and be stirred to cooling.The polypeptide that adds debita spissitudo then thoroughly mixes again.(ii) aqueous emulsions APF

Polypeptide is an amount of

Emulsifying ointment 30

Glycerol 5

Phenyl phenol 1

Distilled water to 100

At about 70 ℃ of fusing emulsifying ointment.In distilled water, dissolve phenyl phenol, be heated to uniform temp.Mix, adjust weight and be stirred to cooling.Add polypeptide, thoroughly stir.(iii) cushion Emulsion BPC 73

Polypeptide is an amount of

Citric acid 5

Sodium phosphate 25

Chlorocresol 1

Chlorination ointment 300

Distilled water 669

Mild heat fusing emulsifying ointment adds the chlorocresol that is dissolved in advance under sodium phosphate, citric acid and the uniform temp in the distilled water, is stirred to cooling more gently.Add polypeptide and thoroughly mixing.2. ointment (i) emulsifying ointment APF

Polypeptide is an amount of

Emulsifing wax 30

White soft wax 50

Liquid Paraffin (weight) 20

Together melt and stir until cooling.In a part of substrate, add the debita spissitudo polypeptide, slowly add remainder then, thoroughly mix.(ii) polypeptide ointment-with neomycin and Bacit White BPC 73

Polypeptide is an amount of

Liquid Paraffin 10

White soft wax to 100

Melt white soft wax, add liquid Paraffin, be stirred to cooling.With a part of substrate titration of medicines, add remaining substrate more gradually.3. gel (i) peptide-based gel together is used for lignocaine and chlohexidine gel APF person

Polypeptide is an amount of

Tragacanth 2.5

Glycerol 25

Distilled water to 100

Tragacanth is mixed with glycerol, and add most of distilled water.Be heated to boiling, cooling adds polypeptide, adjusts weight and mix homogeneously.Make the product lucifuge of gained.Spray (i)-be used for the identical of epinephrine and atropine spray BPC 73

Polypeptide is an amount of

Sodium metabisulfite 1

Chloretone 5

Propylene glycol 50

Distilled water to 1000 (ii)-be used for the identical of indole spray

Polypeptide is an amount of

Alcohol 95%5. lotions (i)-be used for the identical of aminobenzoic mordant BPC73

Polypeptide is an amount of

Glycerol 20

Alcohol 95% 60

Distilled water to 100 (ii)-Polyethylene Glycol lotion APF

Polypeptide is an amount of

Polyethylene Glycol emulsifing wax 3

Liquid Paraffin 10

Glycerol 10

SY 1007 solution 0.1

Distilled water to 100

About 60 ℃ with liquid Paraffin fusing Polyethylene Glycol emulsifing wax, under same temperature, it is joined then in advance in the chlohexidine solution with distilled water diluting to 50 part, stir fast simultaneously.Mix, adjust volume and be stirred to cooling.

Outside unless context requires, it is generally acknowledged " comprise " speech in the whole description of this piece, or its variant is meant as " Comprises " or " Comprising " meaning and comprises the whole or whole group who is set forth, but do not get rid of any other whole or whole group.

In the accompanying drawings,

Fig. 1-3 illustrates according to foregoing standard and (sees the 10th page, IV, V section and Pfeifer ^9,10) in the relevant diabetic neuropathy case selected the foot of sharp ache with the result of local insulin therapy.

Further characteristics of the present invention have more fully been described in the following examples.But obviously, this detailed explanation only is in order to demonstrate the invention, in no case should think the qualification to the main description of the invention described above.

Embodiment

Carried out the preliminary demonstration test of the local insulin treatment of painful Peripheral Neuropathy.

All experimenters are to use Pfeifer ' s Standard Selection, and suffer from the painful sensation polyneuropathy that causes because of diabetes.By one group of neuro physiology test this is verified, comprise with action potential incubation period and amplitude and measure sensation and motor nerve conduction velocity, measure vibrotactile threshold with biothesiometer, measure the warm threshold and the cold threshold of wrist and instep portion with Medelec TTT device, and in many patents, measure the electric current threshold of sensation of forefinger and hallux toe at 2000Hz, 250Hz, 5Hz with neural measuring device CPT.

According to explanation, use the local insulin Emulsion (Emulsion of every gram gained contains the 1IU insulin) of above-mentioned composition to be about every foot/lower limb 0.5g to the patient, every day two or three times.

The result as shown in the figure.Fig. 1 and 2 relates to the type ii diabetes patient who mostly is 30 routine virgin system insulinizes most.Fig. 3 has described the maximum 16 routine patients' that accept system's insulinize result.

Among all figure, vertical axis is represented hot threshold: hollow rectangle is the hotness threshold, and the solid black rectangle is cold threshold.Seriousness with the symptom of the sharp ache of 10 fens visual simulation standard evaluations is also represented with solid circles on vertical axis.Trunnion axis is represented test of carrying out and the treatment time of testing again.The dotted line of level is represented the upper limit (average+2.2 standard errors) of normal 95% confidence limit.

Fig. 1 represents the result of 12 weeks treatment, and 0-4 drops to 16 when week patient's number was 30,12 weeks.It shows that the raising of back symptom score and the increased functionality of δ nerve fiber all have statistical significance around the process, and raising exceeds this level gradually with the local insulin treatment.

Fig. 2 identical trend when illustrating monthly time standard, it shows that the treatment temperature threshold through four months significantly improves (inductive as WPT).

Therefore, see that from the data of Fig. 1 and 2 are clear in these noninsulindependent diabetes patients with the nervous symptoms that has an intense pain, alleviate and the heat sensitivity of symptom confirmed the sensory nerve increased functionality of the little Sensory nerve fibres of two classes.The most noticeable result is in cold fiber, has Most patients to tell simultaneously and recognizes that total sensation of their foot has strengthened, and numbness goes down and feels that the ability on the surface that socks, carpet and other foot are stepped on has strengthened.This may comprise the enhancing of some big sensory fiber function, but does not also measure.

Fig. 3 represents a therapeutic outcome than the patient of group of having accepted system's insulinize.These patients comprise some type ii diabetes patients, and the deterioration of this disease finally needs system's insulinize; Remaining comprise the type i diabetes patient.With last group form obvious contrast, warm threshold and cold threshold in this group are not seen rising, and have found these patient's doing well,improvings curiously.

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Claims (16)

1. method for the treatment of patient's diabetic neuropathy, it comprises the insulin of the affected skin area topical administration treatment of patient being gone up effective dose.

2. method according to claim 1, wherein insulin is an insulin human.

3. method according to claim 1, wherein insulin is Iletin II (Lilly), bovine insulin or the insulin that obtains from other inhuman animal kind.

4. according to the described method of the arbitrary claim of 1-3, wherein insulin comprises α-and/or β-Ya chain.

5. according to the described method of the arbitrary claim of 1-4, wherein insulin is local as Emulsion, ointment, gel, spray or lotion.

6. method according to claim 5, wherein the insulin part is used for vanishing cream substrate.

7. according to the described method of the arbitrary claim of 1-6, wherein insulin makes and comprises the 0.01-20IU/ gram, preferred 0.1-10IU/ gram, the most preferably Emulsion of 1-3IU/ gram.

8. method according to claim 7, wherein the amount of Emulsion use is about 0.5 gram, every day 2-3 time.

9. the purposes of the insulin of effective dose is gone up in treatment, is to be used to make the medicine that the part is used for the treatment of patient's diabetic neuropathy.

10. compositions for the treatment of patient's diabetic neuropathy, it comprises the insulin of effective dose in the pharmaceutically acceptable diluent of topical application or the carrier.

11. according to the compositions of claim 10, insulin wherein is an insulin human.

12. according to the compositions of claim 10, insulin wherein is an Iletin II (Lilly), bovine insulin or other non-human animal plant the insulin that obtains.

13. according to any one compositions among the claim 10-12, wherein insulin comprises α-and/or β-Ya chain.

14. according to any one compositions among the claim 10-13, wherein insulin is as Emulsion, ointment, gel, spray or lotion.

15. according to the compositions of claim 14, wherein insulin is used in the vanishing cream substrate.

16. according to any one compositions among the claim 10-15, wherein insulin comprises the every gram of 0.01-20IU, the preferred every gram of 0.1-10IU, the most preferably every gram of 1-3IU.

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