CN108703946A - A kind of transdermal absorption formulation for treating diabete peripheral herve pain - Google Patents

Abstract

The invention belongs to the field of chemical medicines, in particular to a transdermal absorption preparation for treating diabetic peripheral neuralgia. The transdermal absorption preparation is made of γ-aminobutyric acid analog analgesics and small molecule tricarbonyl nitrogen-containing compounds, and the pharmaceutical excipients of the preparation are carbomer 940, glycerin, Tween 80, triethanolamine, lauryl nitrogen Drone and distilled water. The external administration of the transdermal absorption preparation has a significant analgesic effect on diabetic peripheral neuralgia. And can reduce the dosage of GABA analog analgesics.

Description

A transdermal absorption preparation for treating diabetic peripheral neuralgia

technical field

The invention belongs to the field of chemical medicines, in particular to a transdermal absorption preparation for treating diabetic peripheral neuralgia.

Background technique

Diabetes is a metabolic disease characterized by elevated blood sugar. The disease, cardiovascular and cerebrovascular diseases, and tumors are the three major chronic diseases that threaten human health at present. In recent years, with the improvement of living standards and the acceleration of the pace of life, the incidence of diabetes has also shown an obvious upward trend, and the current incidence has reached 12%; and the population of pre-diabetes is also increasing day by day. And blood sugar control requires long-term medication.

Diabetic peripheral neuralgia is one of the main complications of diabetes, and its patients account for about 7.5-24% of the total number of diabetics. As early as the mid-19th century, European and American countries had noticed the high incidence of peripheral neuralgia in diabetic patients. The pathogenesis of diabetic peripheral neuralgia is still unclear. It is speculated that it may be related to the joint action of multiple factors such as metabolic disorder caused by hyperglycemia, ischemia and hypoxia in neurotrophic vessels, reduction of neurotrophic factors, and autoimmune factors. Patients with diabetic peripheral neuralgia often manifest as limb pain, hypoesthesia, numbness, burning, cold, etc., and may also manifest as spontaneous pain and hyperalgesia. Abnormal sensations include numbness, ants walking, insects crawling, fever, electric shock-like sensations, etc. Abnormal pain can reach up to the knee from the distal toes, and the patient feels like wearing socks and gloves. Patients with severe sensory impairment may develop lower extremity arthropathy and foot ulcers. When diabetic foot ulcers develop, amputation is often required, which seriously affects the quality of life of patients. In my country, patients with diabetic peripheral neuralgia account for 85% of the total number of diabetic patients. Pain seriously affects the quality of life of patients, and the rate of disability and death is high.

Because its pathogenesis and mechanism are still not very clear, clinical treatment can only be symptomatic. At present, the clinical treatment of diabetic peripheral neuralgia generally adopts the way of blood sugar control combined with analgesics. The analgesic drugs include opioid analgesics, tricyclic antidepressants, selective serotonin and norepinephrine reuptake inhibitors, γ-aminobutyric acid analogs, etc. Among them, opioid analgesics have risks of tolerance, withdrawal syndrome and abuse. Tricyclic antidepressants have been used in the treatment of neuralgia as early as 1977, and its mechanism is to block sodium channels and calcium channels, increase the release of monoamines and block NDMA receptors. However, due to the strong and high incidence of side effects (such as drowsiness, orthostatic hypotension, anticholinergic side effects, etc.), patients cannot tolerate it, which limits its application. Selective serotonin and norepinephrine reuptake inhibitors such as duloxetine are also effective for neuralgia, but are less effective alone. GABA analogues are mainly pregabalin and gabapentin. Gabapentin reduces pain by binding to voltage-gated calcium channels to block the depolarization of primary afferent neurons. Experiments have shown that it is more effective in treating diabetic peripheral neuralgia than other neuralgia; pregabalin is a homologous compound of gabapentin , especially effective for diabetic peripheral neuralgia and postherpetic neuralgia. The above two drugs have high curative effect, low side effects and broad prospects for clinical application, but they are expensive and cannot be used as first-line routine drugs. The current clinical treatment options for diabetic peripheral neuralgia are mostly duloxetine alone or pregabalin, duloxetine combined with barpentin.

At present, a few topical preparations have been approved for the treatment of diabetic peripheral neuralgia. Theoretical advantages of topical administration are reduced side effects, no drug-drug interactions, and generally no dose titration is required. For example, lidocaine skin patch, capsaicin ointment, and Xiaoxintong spray have been approved by the US Food and Drug Administration.

Contents of the invention

In view of the existing problems above, the object of the present invention is to provide a transdermal absorption preparation for treating diabetic peripheral neuralgia. Above-mentioned technical problem is not solved, and the technical scheme that the present invention adopts is as follows:

A transdermal absorption preparation for treating diabetic peripheral neuralgia, made of γ-aminobutyric acid analogs, compound (I) represented by the following formula, and pharmaceutical excipients:

In the compound (I), R is one of H, methyl and ethyl; the γ-aminobutyric acid analogue is one of pregabalin and gabapentin.

Preferably, the γ-aminobutyric acid analogue is pregabalin, and R in the compound (I) is H.

Preferably, the γ-aminobutyric acid analogue is pregabalin, and R in the compound (I) is methyl.

Preferably, the γ-aminobutyric acid analogue is pregabalin, and R in the compound (I) is ethyl.

Preferably, the γ-aminobutyric acid analogue is gabapentin, and R in the compound (I) is H.

Preferably, when R in the compound (I) is H, the γ-aminobutyric acid analogue and the compound

The weight ratio of (I) is 6 to 9 parts by weight of γ-aminobutyric acid analogs and 1 part by weight of compound (I);

Further preferably, the weight ratio of the γ-aminobutyric acid analog to the compound (I) is 9 parts by weight of the γ-aminobutyric acid analog and 1 part by weight of the compound (I).

As another further preferred solution, the weight ratio of the γ-aminobutyric acid analog to the compound (I) is 7 parts by weight of the γ-aminobutyric acid analog and 1 part by weight of the compound (I).

For the above-mentioned transdermal absorption preparation for treating diabetic peripheral neuralgia, the dosage form of the transdermal absorption preparation is preferably a gel, and the pharmaceutical excipients include carbomer 940, glycerin, Tween 80, triethanolamine and distilled water.

Further, the pharmaceutical excipients also include laurocaprazine.

Wherein, when R in compound (I) is H, methyl, or ethyl, the structural formulas of compound (I) are shown in the following formulas IA, IB, and IC, respectively:

The preparation method of compound (IA) has been disclosed in patent documents such as CN200710036109.0; compound (IB) and compound (IC) are respectively dimethyl ester and diethyl ester of compound (IA), which can be Basically formed by reacting with methanol and ethanol. For those skilled in the art, the esterification reaction is a typical organic synthesis reaction, which can be found in the "Handbook of Fine Organic Unit Reaction Synthesis Technology" edited by Zhang Daguo and published by Chemical Industry Press in 2014.

In a preferred scheme, the transdermal preparation for treating diabetic peripheral neuralgia is made of compound (IA), pregabalin, carbomer 940, glycerin, Tween 80, triethanolamine, laurocaprolactone and distilled water. The specific composition was as follows: 70g of pregabalin, 10g of compound (IA), 21g of carbomer 940, 78g of glycerin, 32g of triethanolamine 21g of Tween 80, 7g of laurocaprolactone and 1261g of distilled water. The specific preparation method is as follows: take the prescribed amount of carbomer 940 and add 1029 g of distilled water, and let it stand overnight to fully swell; add the prescribed amount of glycerin to grind to make it moist, and add the prescribed amount of triethanolamine to grind to form a transparent gel matrix. Take the remaining amount of distilled water, prescription Tween 80, laurocaprazine, compound (IA), and pregabalin and stir, add to the gel base and stir for 5 to 20 minutes at 60 to 90 rpm, then pour into medicinal ointment tubes That's it.

In another preferred embodiment, the transdermal absorption preparation for treating diabetic peripheral neuralgia is made of compound (IA), gabapentin, carbomer 940, glycerin, Tween 80, triethanolamine, laurocaprolactone and distilled water , the specific prescription is as follows: gabapentin 90g, compound (IA) 10g, carbomer 940 21g, glycerin 78g, Tween 80 21g triethanolamine 32g, laurocaprolactone 7g and distilled water 1241g. The specific preparation method is as follows: take the prescribed amount of carbomer 940 and add 1029 g of distilled water, and let it stand overnight to fully swell; add the prescribed amount of glycerin to grind to make it moist, and add the prescribed amount of triethanolamine to grind to form a transparent gel matrix. Take the remaining amount of distilled water, prescription amount of Tween 80, laurocaprazine, compound (IA), gabapentin and stir, add to the gel base and stir at 60-90 rpm for 5-20 minutes, then put it into medicinal ointment tubes .

The English name of the aforementioned Pregabalin is Pregabalin, and the English name of Gabapentin is Gabapentin.

The above transdermal absorption preparation for treating diabetic peripheral neuralgia is applied to the skin of the affected area such as the forearm or lower leg. The dosage for human is calculated on the basis of 60kg body weight, calculated with pregabalin or gabapentin, and the daily dose is 100 mg to 200 mg. The dose of pregabalin or gabapentin can be significantly reduced, thereby helping to control the cost of drug use, and avoiding the adverse effects of oral drug administration on the gastrointestinal tract and liver. During the course of taking the medicine, patients can eat protein-containing food as usual. However, drug administration on damaged skin should be avoided to prevent the drug from irritating the damaged skin. The inventors have found through experimental research that compound (I) combined with pregabalin or gabapentin for external administration has a better therapeutic effect on diabetic peripheral neuralgia than pregabalin or gabapentin alone, and the safety of external administration is better than that of traditional Oral administration.

Detailed ways

The present invention will be explained in detail below in conjunction with specific examples, and the following examples are only for explaining the technical solution of the present invention, and the present invention is not limited to the following examples.

Example 1 Antidiabetic Peripheral Neuralgia Gel and Its Preparation

Gel formulation: Pregabalin 70g, compound (IA) 10g, carbomer 940 21g, glycerin 78g, Tween 80 21g triethanolamine 32g, laurocaprolactone 7g and distilled water 1261g.

Preparation method: Take the prescribed amount of Carbomer 940 and add 1029g of distilled water, let stand overnight to fully swell; add the prescribed amount of glycerin to grind to moisten, and add the prescribed amount of triethanolamine to grind into a transparent gel matrix. Take the remaining amount of distilled water, prescription Tween 80, laurocaprazine, compound (IA), and pregabalin, stir, add to the gel base and stir at 90 rpm for 8 minutes, and divide into medicinal ointment tubes to obtain.

Example 2 Antidiabetic Peripheral Neuralgia Gel and Its Preparation

Gel formulation: gabapentin 90g, compound (IA) 10g, carbomer 940 21g, glycerin 78g, Tween 80 21g triethanolamine 32g, laurocaprolactone 7g and distilled water 1241g.

Preparation method: Take the prescribed amount of Carbomer 940 and add 1029g of distilled water, let stand overnight to fully swell; add the prescribed amount of glycerin to grind to moisten, and add the prescribed amount of triethanolamine to grind into a transparent gel matrix. Take the remaining amount of distilled water, prescription Tween 80, laurocaprazine, compound (IA), and gabapentin and stir, add to the gel base and stir at 60 rpm for 12 minutes, then put them into medicinal ointment tubes.

Example 3 Investigation of Drug Effects of Antidiabetic Peripheral Neuralgia Prescription

Healthy male SD rats, weighing 190-200 g, were raised in the SPF laboratory. Streptozotocin was dissolved in sodium citrate buffer solution and prepared immediately. After the rats were fasted for 24 hours, each rat was intraperitoneally injected with 12 mg of streptozotocin. On the 14th day after streptozotocin injection, the diabetic rats were taken to measure the reaction time of licking, screaming and jumping in the rats by the hot plate method, that is, the heat shrinkage latency period before administration, and the temperature of the hot plate was 51- 52°C. Each rat was repeatedly measured 3 times, with an interval of 15 minutes between the two measurements, and the mean value of the 3 measurement results represented the thermal paw withdrawal latency of the rat before administration.

On the 15th day after streptozotocin injection, the rats were randomly divided into 6 groups, 6 in each group, the back of the rats was shaved, and the drug was applied on the shaved area:

The model group was smeared with normal saline, administered once a day for 7 consecutive days;

In the pregabalin group, pregabalin was added to dimethyl sulfoxide, and each rat was given 2.1 mg of pregabalin per smear, once a day, for 7 consecutive days;

In the gabapentin group, gabapentin was added to dimethyl sulfoxide, and each rat was given 2.7 mg of gabapentin per smear, once a day, for 7 consecutive days;

In the compound (IA) group, the compound (IA) was added to dimethyl sulfoxide, and each rat was given 0.3 mg of the compound (IA) per smear, once a day, for 7 consecutive days;

In the pregabalin+compound (IA) group, pregabalin and compound (IA) were added to dimethyl sulfoxide at a weight ratio of 7:1, smeared and administered once a day for 7 consecutive days. Based on pregabalin, the dosage per rat is 2.1 mg per administration.

In the gabapentin+compound (IA) group, gabapentin and compound (IA) were added to dimethyl sulfoxide at a weight ratio of 9:1, smeared, and administered once a day for 7 consecutive days. The dose for each rat was 2.7mg.

On the day after the last administration, the hot plate method was used again to measure the reaction time of the rats to lick paws, hissing, and jumping, that is, the latent period of thermal paw shrinkage after administration, and the temperature of the hot plate was 51-52°C. Each rat was repeatedly measured 3 times, with an interval of 15 minutes between the two measurements, and the mean value of the 3 measurement results was taken to represent the heat paw withdrawal latency of the rat after administration.

The percentage increase of pain threshold of each rat was calculated according to the following formula: percentage increase of pain threshold (%)=1-(heat withdrawal latency period before administration-heat withdrawal latency period after administration)/heat withdrawal latency period before administration.

Statistical software was used to compare the heat withdrawal latency and the percentage increase in pain threshold of rats in each group before and after administration, and the t test was used for comparison between groups, and P<0.05 was considered significant difference.

The test results of heat withdrawal latency period before and after administration of rats in each group are shown in the table below

In the table: * indicates: P<0.01 compared with model group; # indicates: P<0.01 between pregabalin+compound (IA) group and pregabalin group or gabapentin+compound (IA) group and gabapentin group .

It can be seen from the results that there was no significant difference in the thermal paw withdrawal latency of rats in each group before administration. After administration, except the compound (IA) group, the thermal paw withdrawal latency and the percentage increase of pain threshold in other groups were significantly higher than those in the model group (P<0.01). Among them, the heat withdrawal latency and the percentage increase of pain threshold in the pregabalin+compound (IA) group and gabapentin+compound (IA) group were significantly higher than those in the pregabalin group and gabapentin group (P<0.01). It can be seen that there is no statistical difference in the indicators between the compound (IA) group and the model group, but compound (IA) combined with pregabalin or gabapentin for external administration can significantly improve the latter's pain relief in rats with diabetic peripheral neuralgia. Threshold, improve its analgesic effect.

The above embodiments have given examples to demonstrate the effects of the present invention. However, the above-mentioned embodiments are only used to explain the present invention, rather than to limit the protection scope of the present invention. For those skilled in the art, on the premise that the structure and activity of compound (IA) are disclosed, the analogues of compound (IA) after substituent changes or their esters, salts, etc., such as compound (IB) and compound (IC) have Similar activity to compound (IA) can reasonably be expected and confirmed by a limited number of experiments.

Claims (10)

1. a kind of transdermal absorption formulation for treating diabete peripheral herve pain, which is characterized in that by gamma-aminobutyric acid analog, The compound being shown below（I）It is made with pharmaceutic adjuvant：

The compound（I）Middle R is one kind in H, methyl, ethyl；The gamma-aminobutyric acid analog is Pregabalin, adds Bar spray fourth in one kind.

2. the transdermal absorption formulation for the treatment of diabete peripheral herve pain according to claim 1, which is characterized in that described Gamma-aminobutyric acid analog is Pregabalin, the compound（I）Middle R is H.

3. the transdermal absorption formulation for the treatment of diabete peripheral herve pain according to claim 1, which is characterized in that described Gamma-aminobutyric acid analog is Pregabalin, the compound（I）Middle R is methyl.

4. the transdermal absorption formulation for the treatment of diabete peripheral herve pain according to claim 1, which is characterized in that described Gamma-aminobutyric acid analog is Pregabalin, the compound（I）Middle R is ethyl.

5. the transdermal absorption formulation for the treatment of diabete peripheral herve pain according to claim 1, which is characterized in that described Gamma-aminobutyric acid analog is Gabapentin, the compound（I）Middle R is H.

6. the transdermal absorption formulation of the treatment diabete peripheral herve pain according to claim 2 and 5, which is characterized in that institute State gamma-aminobutyric acid analog and compound（I）Weight part ratio be 6~9 parts by weight of gamma-aminobutyric acid analog, compound （I）1 parts by weight.

7. the transdermal absorption formulation for the treatment of diabete peripheral herve pain according to claim 6, which is characterized in that described Gamma-aminobutyric acid analog and compound（I）Weight part ratio be 9 parts by weight of gamma-aminobutyric acid analog, compound（I）1 weight Measure part.

8. the transdermal absorption formulation for the treatment of diabete peripheral herve pain according to claim 6, which is characterized in that described Gamma-aminobutyric acid analog and compound（I）Weight part ratio be 7 parts by weight of gamma-aminobutyric acid analog, compound（I）1 weight Measure part.

9. according to the transdermal absorption formulation of the treatment diabete peripheral herve pain described in claim 6 to 8, which is characterized in that institute State transdermal absorption formulation dosage form be gelling agent, the pharmaceutic adjuvant include card pool nurse 940, glycerine, Tween 80, triethanolamine and Distilled water.

10. the transdermal absorption formulation for the treatment of diabete peripheral herve pain according to claim 9, which is characterized in that described Pharmaceutic adjuvant further includes Laurocapram.