Application of a compound external paste in prevention and treatment of diabetic peripheral neuropathy

Abstract

The application relates to the technical field of compound medicines, and discloses application of a compound external-use patch for preventing and treating diabetic peripheral neuropathy, wherein the compound external-use patch comprises a gel base and dry extract and volatile oil doped into the gel base, the dry extract and the volatile oil are derived from a compound, and the compound is composed of 10-20 parts of cinnamon, 8-12 parts of asarum, 8-12 parts of evodia, 8-12 parts of chuanxiong and 0.2-0.8 parts of borneol in terms of weight parts. The compound external-use patch of the application is locally pasted on acupoints or joints of DPN rats, can reduce the blood sugar level of diabetic peripheral neuropathy rats, increase the insulin level, improve insulin resistance, prolong the latent period of hot stimulation foot withdrawal, increase the nerve conduction velocity, maintain the normal morphology and function of nerve cells, and therefore can prevent and inhibit the generation and deterioration of diabetic peripheral neuropathy; and the compound external-use patch improves the safety and convenience of patients in taking medicine compared with oral medicine.

Description

Technical Field

[0001] This invention relates to the field of compound drug technology, and in particular to the application of a compound external patch in the prevention and treatment of diabetic peripheral neuropathy. Background Technology

[0002] Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus (DM), severely impacting the quality of life and health of modern people. It also presents complex medical and nursing challenges and leads to recurrent episodes in diabetic patients. Approximately 55-85% of DM patients also have DPN. The clinical symptoms of DPN are complex, mostly due to involvement of sensory and autonomic nerves, accompanied by milder damage to motor neurons, especially peripheral nerve damage, primarily affecting the distal extremities. The upper limbs are less affected, while the lower limbs are more severely affected. Early symptoms are mainly sensory disturbances, typically manifesting as bilateral, symmetrical numbness, decreased sensation, coldness, electric shock sensation, and pain in the distal extremities. Some DPN patients may experience severe burning pain in the distal lower extremities, ultimately leading to death or disability.

[0003] The pathogenesis of diabetic nephropathy (DPN) is complex. Sustained hyperglycemia can induce inflammatory responses, oxidative stress, mitochondrial dysfunction, and dyslipidemia, leading to metabolic disorders, hypoxia and ischemia, and decreased levels of neurotrophic factors, ultimately resulting in staged demyelination and axonal atrophy. Currently, there are no drugs specifically for the prevention and treatment of DPN on the market, and clinically used drugs for treating DPN suffer from poor efficacy and significant side effects.

[0004] Therefore, existing technologies still need to be improved and developed. Summary of the Invention

[0005] In view of the shortcomings of the prior art, the purpose of this invention is to provide a compound external patch for the prevention and treatment of diabetic peripheral neuropathy, aiming to solve the problems of poor efficacy and obvious side effects of existing drugs for the prevention and treatment of DPN.

[0006] The technical solution of the present invention is as follows:

[0007] An application of a compound external patch in the prevention and treatment of diabetic peripheral neuropathy, wherein the compound external patch comprises a gel matrix and a dry extract and volatile oil incorporated into the gel matrix, the dry extract and volatile oil being derived from a compound, the compound being composed of 10-20 parts by weight of cinnamon, 8-12 parts of asarum, 8-12 parts of evodia, 8-12 parts of chuanxiong, and 0.2-0.8 parts of borneol.

[0008] The compound external patch is used to prevent and treat diabetic peripheral neuropathy. The compound is composed of 15 parts cinnamon, 10 parts asarum, 10 parts evodia, 10 parts chuanxiong and 0.5 parts borneol by weight.

[0009] The compound external patch is used to prevent and treat diabetic peripheral neuropathy. The compound is composed of 10 parts cinnamon, 8 parts asarum, 8 parts evodia, 8 parts chuanxiong and 0.2 parts borneol by weight.

[0010] The compound external patch is used to prevent and treat diabetic peripheral neuropathy. The compound is composed of 20 parts cinnamon, 12 parts asarum, 12 parts evodia, 12 parts chuanxiong, and 0.8 parts borneol by weight.

[0011] The compound topical patch is used for the prevention and treatment of diabetic peripheral neuropathy, wherein the preparation of the dry extract and volatile oil of the compound includes the following steps:

[0012] The compound was mixed with water to obtain a compound solution. The compound solution was then distilled using steam distillation to obtain a compound aqueous extract and a compound distillate. The compound residue was also recovered.

[0013] The compound medicinal residue was extracted with ethanol to obtain a compound ethanol extract;

[0014] The compound aqueous extract and the compound alcohol extract were combined and mixed evenly, the solvent was recovered to a thick paste, vacuum dried to a dry extract, and ground into powder for later use;

[0015] The compound distillate was extracted with diethyl ether, the oil layer was retained, and the oil was subjected to water bath heating to evaporate the diethyl ether, thus obtaining the compound volatile oil.

[0016] The compound external patch is used in the prevention and treatment of diabetic peripheral neuropathy, wherein the mass ratio of the compound to water in the compound solution is 1:8-12.

[0017] In the application of the compound external patch for the prevention and treatment of diabetic peripheral neuropathy, the step of ethanol extraction of the compound residue involves the following steps: the mass percentage of ethanol is 50-70%, and the ethanol extraction is performed twice. The first extraction is performed at a material-to-liquid ratio of 1:8 for 1 hour, and the second extraction is performed at a material-to-liquid ratio of 1:6 for 1 hour.

[0018] The compound external patch is used in the prevention and treatment of diabetic peripheral neuropathy, wherein the water bath heating temperature is 40-60℃ and the time is 5-8 hours.

[0019] The compound topical patch is used to prevent and treat diabetic peripheral neuropathy, wherein the gel matrix comprises a skeleton component, a moisturizer, a transdermal penetration enhancer, a cross-linking agent, a cross-linking regulator, a filler, a binder, and water.

[0020] The compound topical patch is used in the prevention and treatment of diabetic peripheral neuropathy, wherein the preparation of the compound topical patch includes:

[0021] The skeleton components, moisturizer, crosslinking agent, filler and transdermal penetration enhancer are mixed according to the feeding ratio to obtain phase A solution;

[0022] The crosslinking regulator and adhesive are added to water and mixed evenly to obtain phase B solution;

[0023] The A-phase solution and the B-phase solution are mixed, and the compound volatile oil and the compound dry extract are added under stirring conditions. Finally, the mixture is coated and cut using a coating machine to obtain the compound external patch.

[0024] Beneficial effects: Experimental verification shows that the compound external patch provided by this invention, when applied locally to acupoints or joints of diabetic peripheral neuropathy (DPN) patients, can reduce blood glucose levels, increase insulin levels, improve insulin resistance, prolong the latency of thermal stimulation withdrawal response, increase nerve conduction velocity, and maintain the normal morphology and function of nerve cells in rats with diabetic peripheral neuropathy. Therefore, this compound external patch can prevent and inhibit the occurrence and deterioration of diabetic peripheral neuropathy. Moreover, compared with oral medications, this compound external patch improves the safety and convenience of medication for patients. Attached Figure Description

[0025] Figure 1 This is an example diagram of the compound external patch of the present invention applied to acupoints in rats.

[0026] Figure 2 These are cross-sectional and longitudinal microscopic images of the sciatic nerve in rats from the normal group, model group, methylcobalamin group, and plaster group of this invention. Detailed Implementation

[0027] This invention provides an application of a compound topical patch for the prevention and treatment of diabetic peripheral neuropathy. To make the objectives, technical solutions, and effects of this invention clearer and more explicit, the invention is further described in detail below. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention.

[0028] This invention provides an application of a compound external patch in the prevention and treatment of diabetic peripheral neuropathy. The compound external patch comprises a gel matrix and a dry extract and volatile oil incorporated into the gel matrix. The dry extract and volatile oil are derived from a compound, which, by weight, consists of 10-20 parts of cinnamon, 8-12 parts of asarum, 8-12 parts of evodia, 8-12 parts of chuanxiong, and 0.2-0.8 parts of borneol.

[0029] In this invention, the preparation of the compound dry extract and volatile oil includes the following steps: mixing the compound with water at a mass ratio of 1:8-12 to obtain a compound solution; distilling the compound solution using steam distillation to obtain a compound aqueous extract and a compound distillate, and recovering the compound residue; extracting the compound residue with ethanol to obtain a compound alcohol extract, wherein the mass percentage of ethanol is 50-70%, and the ethanol extraction is performed twice, the first extraction at a material-to-liquid ratio of 1:8 for 1 hour, and the second extraction at a material-to-liquid ratio of 1:6 for 1 hour; combining and mixing the compound aqueous extract and the compound alcohol extract, recovering the solvent to a thick paste, vacuum drying to a dry extract, grinding into powder for later use; extracting the compound distillate with diethyl ether, retaining the oil layer, and subjecting it to a water bath heating treatment at 40-60℃ for 5-8 hours to allow the diethyl ether to evaporate, thereby obtaining the compound volatile oil.

[0030] In this invention, the gel matrix comprises a skeleton component, a moisturizer, a transdermal penetration enhancer, a crosslinking agent, a crosslinking regulator, a filler, a binder, and water. The preparation of the compound topical patch includes: mixing the skeleton component, moisturizer, crosslinking agent, filler, and transdermal penetration enhancer according to the feeding ratio to obtain phase A solution; adding the crosslinking regulator and binder to water and mixing evenly to obtain phase B solution; mixing phase A solution and phase B solution; adding the compound volatile oil and compound dry extract under stirring conditions; and finally coating and cutting using a coating machine to obtain the compound topical patch.

[0031] In this invention, the skeleton component is one or more of sodium polyacrylate, sodium carboxymethyl cellulose, and polyvinyl alcohol; the moisturizer is one or more of glycerin, sorbitol, propylene glycol, and polyethylene glycol; the transdermal penetration enhancer is one or more of azone, propylene glycol, oleic acid, and borneol; the crosslinking agent is one or more of aluminum hydroxide, aluminum hydroxyl, aluminum oxide, aluminum trichloride, and aluminum sulfate; the filler is one or more of kaolin, titanium dioxide, zinc oxide, and calcium carbonate; and the binder is one or more of gelatin, sodium alginate, PVP, and carbomer.

[0032] The compound external patch provided by this invention has been experimentally verified to reduce blood glucose levels, increase insulin levels, improve insulin resistance, prolong the latency of heat-induced foot contraction response, increase nerve conduction velocity, and maintain the normal morphology and function of nerve cells when applied locally to acupoints or joints of diabetic peripheral neuropathy rats. Therefore, this compound external patch can prevent and inhibit the occurrence and deterioration of diabetic peripheral neuropathy. Moreover, this compound external patch improves the safety and convenience of medication for patients compared to oral medications.

[0033] In some specific embodiments, the compound is composed of 15 parts by weight of cinnamon, 10 parts of asarum, 10 parts of evodia, 10 parts of chuanxiong, and 0.5 parts of borneol.

[0034] In some specific embodiments, the compound is composed of 10 parts by weight of cinnamon, 8 parts of asarum, 8 parts of evodia, 8 parts of chuanxiong, and 0.2 parts of borneol.

[0035] In some specific embodiments, the compound is composed of 20 parts by weight of cinnamon, 12 parts of asarum, 12 parts of evodia, 12 parts of chuanxiong, and 0.8 parts of borneol.

[0036] The present invention will be further explained and illustrated below through specific embodiments:

[0037] Example 1

[0038] 1. The compound external patch of this embodiment includes a gel matrix and a dry extract and volatile oil mixed into the gel matrix. The dry extract and volatile oil are derived from a compound, which is composed of 15 parts cinnamon, 10 parts asarum, 10 parts evodia, 10 parts chuanxiong and 0.5 parts borneol by weight.

[0039] 2. Replication, grouping, and drug administration of the DPN rat model

[0040] SPF-grade male SD rats were acclimatized for 3 days and then randomly divided into two groups: a normal group and a model replication group. The normal group was fed a normal diet, while the model replication group was fed a high-fat, high-sugar diet. After 4 weeks of feeding, the rats were fasted but allowed free water for 12 hours and then injected intraperitoneally with a single dose of 1% STZ solution (35 mg / kg). -1 Three days later, random blood glucose levels in rats were measured using the tail tip blood sampling method. A random blood glucose level ≥16.7 mmol / L was considered normal. -1 To establish a standardized model of type 2 diabetes in rats, the successfully replicated rat models were randomly divided into three groups: the model group, the methylcobalamin group, and the compound plaster group.

[0041] Drug intervention began on day 2. During this period, except for the normal group which was given a regular diet, all other groups of rats were given a high-fat, high-sugar diet. The normal group and the model group were given physiological saline solution (2 mL / kg) daily. -1 The group receiving oral gavage was given methylcobalamin solution (0.045 mg / kg). -1 (Gavage) Following the rat acupoint location diagram in *Experimental Acupuncture*, the compound plaster group rats underwent application of the plaster to the Dazhui (GV14) and bilateral Feishu (BL13), Pishu (BL20), and Shenshu (BL23) acupoints on the back, and bilateral Yanglingquan (GB34) and Zusanli (ST36) acupoints on the hind legs. Figure 1 As shown, the plaster is 2cm x 2cm in size, fixed with adhesive tape for 4 hours as usual, once a day, for 8 weeks.

[0042] 3. Effects of the compound on fasting blood glucose in DPN rats

[0043] The blood glucose levels of rats in the normal group, model group, and plaster group were measured, and the results are shown in Table 1.

[0044] Table 1 Comparison of blood glucose levels in rats of different groups

[0045]

[0046]

[0047] Note: Compared with the normal group at the same time point. ** p < 0.01; compared with the same period in the model group, # p < 0.05

[0048] As can be seen from the data in Table 1, compared with the normal group, the blood glucose level of the model group was significantly higher (p<0.01); compared with the model group, the blood glucose level of the plaster group was lower than that of the model group.

[0049] 4. Effects of the compound on total cholesterol (TC) and triglycerides (TG) in DPN rats

[0050] The levels of total cholesterol (TC) and triglycerides (TG) in rats in the normal group, model group, mecobalamin group, and plaster group were measured, and the results are shown in Table 2.

[0051] Table 2 Comparison of TC and TG levels in rats of different groups

[0052] Group <![CDATA[TC / (mmol·L -1 )]]> <![CDATA[TG / (mmol·L -1 )]]> normal group 1.33±0.11 0.71±0.17 Model group <![CDATA[2.10±0.60 * ]]> <![CDATA[1.36±0.85 * ]]> Methylcobalamin group 1.76±0.48 1.04±0.43 plaster set 1.69±0.87 0.85±0.44

[0053] Note: Compared with the normal group * p < 0.05

[0054] As can be seen from the data in Table 2, compared with the normal group, the TC and TG levels in the model group were significantly higher (p < 0.05); compared with the model group, the TC and TG levels in the plaster group were lower than those in the model group.

[0055] 5. Effects of the compound on insulin (FINS) and insulin resistance index (HOMA-IR) in DPN rats

[0056] The levels of insulin (FINS) and insulin resistance index (HOMA-IR) in rats in the normal group, model group, mecobalamin group, and plaster group were measured, and the results are shown in Table 3.

[0057] Table 3 Comparison of insulin levels and insulin resistance index among different groups of rats

[0058] Group <![CDATA[FINS / (mIU·L -1 )]]> HOMA-IR normal group 38.00±11.38 2.46±1.24 Model group <![CDATA[10.97±5.69 ** ]]> <![CDATA[16.73±8.37 ** ]]> Methylcobalamin group <![CDATA[10.13±4.16 ** ]]> <![CDATA[16.13±5.29 ** ]]> plaster set <![CDATA[19.71±6.40 **# ]]> <![CDATA[6.33±1.98 *# ]]>

[0059] Note: Compared with the normal group at the same time point.** p < 0.01, * p < 0.05; compared with the same period in the model group, # p < 0.05

[0060] As can be seen from the data in Table 3, compared with the normal group, the insulin level in the model group was significantly lower and the insulin resistance index was significantly higher (p<0.01); compared with the model group, the insulin level in the patch group was significantly higher and the insulin resistance index was significantly lower (p<0.05).

[0061] 6. Effects of the compound on the latency of paw withdrawal under thermal stimulation in DPN rats

[0062] Determination of thermal withdrawal latency: Thermal withdrawal latency (TWL) was measured at the end of week 4 and week 8. A hot plate test was performed on rats using a smart hot plate apparatus to determine TWL. Rats were placed on a 23℃ operating table for 10-15 minutes beforehand. Once the rats were in a stable state, the hot plate temperature was set to 52℃±0.5℃. The time it took for the rats to begin licking their paws, jumping, or exhibiting other signs of pain was recorded. This was repeated three times, with 10-minute intervals between each test. The thermal withdrawal latency was the average of the three results. Rats that did not show signs of pain after 30 seconds were eliminated. The results are shown in Table 4.

[0063] Table 4 Comparison of latency of paw withdrawal response to thermal stimulation in rats of different groups

[0064]

[0065] Note: Compared with the normal group at the same time point. * p < 0.05 ** p < 0.01; compared with the same period in the model group, # p < 0.05 ## p < 0.01

[0066] As shown in Table 4, compared with the normal group, the latency of the thermal stimulation foot retraction response in the model group was significantly shortened (p < 0.01); compared with the model group, the latency of the thermal stimulation foot retraction response in the methylcobalamin group and the plaster group was significantly prolonged (p < 0.05 or p < 0.01).

[0067] 7. Effects of the compound on sciatic nerve conduction velocity in DPN rats

[0068] Measurement of sciatic nerve conduction velocity: Nerve conduction velocities (motor nerve conduction velocity, MNCV and sensory nerve conduction velocity, SNCV) were measured at the end of week 8. A concentration of 50 mg / mL was used. -1 Shutai-50 is an anesthetic, administered at a dose of 50 mg / kg based on rat body weight. -1The rat was anesthetized via intraperitoneal injection and fixed in a prone position after anesthesia. The skin at the ischial tuberosity and ankle joint, where the sciatic nerve passes, was incised to carefully expose the sciatic nerve. Under anesthesia, neurophysiological methods were used to detect MNCV and SNCV. For MNCV measurement, the stimulating electrode was placed proximally and distally to the sciatic nerve twice, with a difference of 2.0 cm between the proximal and distal ends. Recording electrodes were inserted into the rat's ankle and the space between the second toe on the left foot. For SNCV measurement, the stimulating electrode was placed on the ipsilateral dorsum of the foot, and recording electrodes were placed proximally and distally to the sciatic nerve twice. The bipolar recording electrodes transmitted a square wave pulse with a duration of 1 ms and an intensity of 2 mV. The BL-420F biomechanical experimental system was used to record the compound action potential; the time from the start of stimulation to the appearance of the evoked potential was the latency. The calculation formula was: MNCV (m·s) -1 ) = Distance between two recording electrodes / Difference between proximal and distal latency, SNCV (m·s) -1 = Distance between stimulating electrode and recording electrode / Difference between proximal and distal latencies. The test results are shown in Table 5.

[0069] Table 5 Comparison of sciatic nerve conduction velocity in rats of different groups

[0070]

[0071] Note: Compared with the normal group at the same time point. ** p < 0.01; compared with the same period in the model group, # p < 0.05 ## p < 0.01

[0072] As can be seen from the data in Table 5, compared with the normal group, the nerve conduction velocity in the model group was significantly reduced (p < 0.01); compared with the model group, the nerve conduction velocity in the mecobalamin group and the plaster group was significantly increased (p < 0.05 or p < 0.01).

[0073] 8. Effects of the compound on the pathological changes of the sciatic nerve in DPN rats

[0074] HE staining method for pathological changes of rat sciatic nerve: After sacrifice, the sciatic nerve was isolated on a sterile operating table, and a portion was fixed in 10% neutral formalin for 48 h. The sciatic nerve strips were dehydrated by graded ethanol, embedded in paraffin, and then cut into thin sections approximately 4 μm thick. After sectioning, dewaxing, hematoxylin-eosin staining, dehydration, clearing, and mounting, the morphological changes of the sciatic nerve were observed under an optical microscope. The results are as follows: Figure 2 As shown. From Figure 2It can be seen that structural abnormalities were observed in the model group, with disordered and loose nerve fiber arrangement, numerous scattered cavities, demyelination, and axonal atrophy. Compared with the model group, the plaster group showed varying degrees of improvement in the above conditions, with more regular nerve fiber arrangement and significant improvement in myelin loss and axonal atrophy.

[0075] In summary, the compound external patch provided by this invention has the effects of lowering blood sugar and blood lipids, improving insulin sensitivity, improving insulin resistance, prolonging the latency period of heat-induced foot contraction reaction, increasing nerve conduction velocity, maintaining the morphology and function of nerve cells, and inhibiting myelin loss and axonal atrophy. It has a certain therapeutic effect on diabetic peripheral neuropathy and can delay the development and deterioration of diabetic peripheral neuropathy.

[0076] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.

Claims

1. A compound external patch for the prevention and treatment of diabetic peripheral neuropathy, characterized in that, The compound external patch includes a gel matrix and a dry extract and volatile oil incorporated into the gel matrix. The dry extract and volatile oil are derived from a compound, which is composed of 10-20 parts by weight of cinnamon, 8-12 parts of asarum, 8-12 parts of evodia, 8-12 parts of chuanxiong, and 0.2-0.8 parts of borneol.

2. The compound external patch for preventing and treating diabetic peripheral neuropathy according to claim 1, characterized in that, The compound is composed of 15 parts cinnamon, 10 parts asarum, 10 parts evodia, 10 parts chuanxiong and 0.5 parts borneol by weight.

3. The compound external patch for preventing and treating diabetic peripheral neuropathy according to claim 1, characterized in that, The compound is composed of 10 parts cinnamon, 8 parts asarum, 8 parts evodia, 8 parts chuanxiong and 0.2 parts borneol by weight.

4. The compound external patch for preventing and treating diabetic peripheral neuropathy according to claim 1, characterized in that, The compound is composed of 20 parts cinnamon, 12 parts asarum, 12 parts evodia, 12 parts chuanxiong and 0.8 parts borneol by weight.

5. The compound external patch for preventing and treating diabetic peripheral neuropathy according to any one of claims 1-4, characterized in that, The preparation of the compound dry extract and volatile oil includes the following steps: The compound was mixed with water to obtain a compound solution. The compound solution was then distilled using steam distillation to obtain a compound aqueous extract and a compound distillate. The compound residue was also recovered. The compound medicinal residue was extracted with ethanol to obtain a compound ethanol extract; The compound aqueous extract and the compound alcohol extract were combined and mixed evenly, the solvent was recovered to a thick paste, vacuum dried to a dry extract, and ground into powder for later use; The compound distillate was extracted with diethyl ether, the oil layer was retained, and the oil was subjected to water bath heating to evaporate the diethyl ether, thus obtaining the compound volatile oil.

6. The compound external patch for preventing and treating diabetic peripheral neuropathy according to claim 5, characterized in that, In the compound solution, the mass ratio of the compound to water is 1:8-12.

7. The compound external patch for preventing and treating diabetic peripheral neuropathy according to claim 5, characterized in that, In the step of ethanol extraction of the compound medicinal residue, the mass percentage of ethanol is 50-70%, and the ethanol extraction is performed twice. The first extraction is performed at a material-to-liquid ratio of 1:8 for 1 hour, and the second extraction is performed at a material-to-liquid ratio of 1:6 for 1 hour.

8. The compound external patch for preventing and treating diabetic peripheral neuropathy according to claim 5, characterized in that, The water bath heating temperature is 40-60℃, and the time is 5-8 hours.

9. The compound external patch for preventing and treating diabetic peripheral neuropathy according to claim 1, characterized in that, The gel matrix comprises a skeleton component, a moisturizer, a transdermal penetration enhancer, a cross-linking agent, a cross-linking regulator, a filler, a binder, and water.

10. The compound external patch for preventing and treating diabetic peripheral neuropathy according to claim 9, characterized in that, The preparation of the compound external patch includes: The skeleton components, moisturizer, filler, crosslinking agent and transdermal penetration enhancer are mixed according to the feeding ratio to obtain phase A solution; The crosslinking modifier and adhesive are added to water and mixed evenly to obtain phase B solution; The A-phase solution and the B-phase solution are mixed, and the compound volatile oil and the compound dry extract are added under stirring conditions. Finally, the mixture is coated and cut using a coating machine to obtain the compound external patch.

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