CN109498611B - Medicine for treating diabetic peripheral neuralgia and application thereof - Google Patents
Medicine for treating diabetic peripheral neuralgia and application thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
The invention belongs to the field of medicines, and particularly relates to a medicine for treating diabetic peripheral neuralgia and application thereof. The medicine for treating diabetic peripheral neuralgia is prepared by combining sulfacetamide sodium and one of levetiracetam, pregabalin and gabapentin. The preferable dosage form of the medicine for treating the diabetic peripheral neuralgia is an oral tablet, and the preferable pharmaceutic adjuvant comprises lactose, povidone K90, sodium carboxymethyl starch and magnesium stearate. The analgesic effect of the drug for treating diabetic peripheral neuralgia by intragastric administration on a diabetic peripheral neuralgia model of a rat is superior to that of the single administration of levetiracetam, pregabalin and gabapentin. Has certain application potential in the treatment of the diabetic peripheral neuralgia.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a medicine for treating diabetic peripheral neuralgia and application thereof.
Background
Diabetic peripheral neuralgia is a kind of neuropathic pain, and is a disease caused by peripheral nerve injury by a pathological process secondary to hyperglycemia, and is manifested by spontaneous pain, hyperalgesia, abnormal pain or paresthesia. Patients with diabetic peripheral neuralgia often feel stabbing pain, ant walking feeling or burning feeling, and have the feeling of wearing socks and gloves; is extremely sensitive to cold, heat and touch, and has the expression of pain sensitization. According to statistics, the patients with diabetic peripheral neuralgia account for about 10% of the diabetic population. The disease is one of three major complications of diabetes.
Despite the differences in pathophysiology between type 1 and type 2 diabetes, to date, the academia still considers the same mechanism by which both cause neuropathic pain around diabetes. However, it has also been found that type 2 diabetes, although it accounts for about 90% to 95% of the population with diabetes, has a lower incidence of neuropathic pain around diabetes. While type 1 diabetes has a low incidence, the incidence of diabetic peripheral neuralgia is high. In contrast, the incidence of diabetic peripheral neuralgia in type 1 diabetes can be significantly reduced by the approach of blood sugar control, but the effect of controlling the incidence of diabetic peripheral neuralgia in type 2 diabetes is very limited. From this point of view, in addition to blood glucose factors, there should be other factors unrelated to blood glucose level involved in the development and progression of diabetic peripheral neuralgia, and type 2 diabetic patients are more exposed to these other factors unrelated to blood glucose level. To date, however, the academia is still poorly understood with respect to these complex factors and their interplay. It has been thought in the past that diabetic peripheral neuralgia occurs only when exposed to hyperglycemia for a long period of time, but recent observations have revealed that diabetic peripheral neuralgia occurs even in patients with blood sugar control.
The pathogenesis of diabetic peripheral neuralgia is extremely complex, and the exact mechanism thereof has not yet been elucidated. It is currently speculated that factors involved in the development of diabetic peripheral neuralgia may include the following classes:
first, inflammation is thought to be involved in the development of diabetic peripheral neuropathic pain, a concept that has been confirmed by a number of preclinical and clinical findings. Although the inflammatory process is very complex, activation of the IKK β/NF- κ B axis is thought to play an important role. In the diabetes model induced by streptozotocin, ischemia reperfusion injury leads to the over-expression of NF-kB of sciatic nerve endothelial cells, which indicates that the activation of NF-kB is possibly involved in the enhancement of the neuroinflammatory reaction of diabetes.
Secondly, oxidative stress is also thought to be involved in the development of diabetic peripheral neuropathic pain. Glycolysis processes may produce oxygen free radicals, and oxidative stress can damage mitochondrial DNA, proteins, and membranes; neurotrophic factors are also reduced by mitochondrial damage and thus oxidative stress may cause nerve damage to be involved in the development of diabetic peripheral neuropathic pain.
Again, central and peripheral hyperalgesia is one of the factors that contribute to diabetic peripheral neuralgia. Typical hyperalgesia is that caused by abnormal activation of calcium ion channels in the dorsal horn of the spinal cord.
Finally, hyperglycemia-induced end microcirculation disturbance can also lead to peripheral nerve ischemia and hypoxia, so that peripheral nerves are damaged to cause pathological pain.
In the treatment of diabetic peripheral neuralgia, analgesic drugs are commonly used clinically for symptomatic treatment. Among them, the nonsteroidal anti-inflammatory analgesic drugs have not been satisfactory in effect, and thus the national guidelines do not recommend them for the treatment of diabetic peripheral neuralgia. Other analgesic drugs such as duloxetine, pregabalin and gabapentin are more commonly used. Wherein pregabalin and gabapentin are structural analogues, and the effect of pregabalin is superior to that of gabapentin. Duloxetine is commonly used in combination with pregabalin or gabapentin. Levetiracetam has also been shown to have a good effect on treating diabetic peripheral neuralgia. However, duloxetine, pregabalin, gabapentin and levetiracetam are used as potent drugs in the central nervous system, have large side effects, and are relatively common in drug withdrawal caused by adverse reactions.
Disclosure of Invention
In view of the above problems, an object of the present invention is to provide an analgesic for neuropathic pain, in particular, a medicament for diabetic peripheral neuralgia. In order to solve the problems, the technical scheme adopted by the invention is as follows:
a medicine for treating diabetic peripheral neuralgia is prepared from the following components:
1) a substituted derivative of sulphamoyl or sodium sulphamoyl or sulphamoyl;
2) an antiepileptic drug for diabetic peripheral neuralgia;
3) and (3) a medicinal auxiliary material.
Wherein the antiepileptic drug for diabetic peripheral neuralgia is preferably one of levetiracetam, pregabalin and gabapentin.
As a preferable scheme, the medicine for treating the diabetic peripheral neuralgia is prepared from sulfacetamide sodium, levetiracetam and pharmaceutic adjuvants. Wherein the weight part ratio of the sulfacetamide sodium to the levetiracetam is 1 weight part of the sulfacetamide sodium and 2.5-5.5 weight parts of the levetiracetam.
Further preferably, the weight ratio of the sulfacetamide sodium to the levetiracetam in the medicine for treating diabetic peripheral neuralgia is 1 part by weight of the sulfacetamide sodium, 2.5 parts by weight of the levetiracetam or 5 parts by weight of the levetiracetam sodium.
As another preferable scheme, the medicine for treating the diabetic peripheral neuralgia is prepared from sulfacetamide sodium, gabapentin and pharmaceutic adjuvant, wherein the weight part ratio of the sulfacetamide sodium to the gabapentin in the medicine for treating the diabetic peripheral neuralgia is 1 part by weight of the sulfacetamide sodium and 5 parts by weight of the gabapentin.
Preferably, the dosage form of the medicament for treating the diabetic peripheral neuralgia is an oral solid preparation. Oral tablets are preferred.
Further preferably, the pharmaceutical excipients of the oral tablet comprise: lactose, povidone K90, sodium carboxymethyl starch and magnesium stearate. The dosage of lactose, povidone K90, sodium carboxymethyl starch and magnesium stearate in the oral tablet is preferably as follows: the dosage of the lactose is 0.5-0.9 time of the weight of the sulfacetamide sodium; the dosage of the povidone K90 is 1/3 times of the weight of the sodium sulfacetamide, the dosage of the sodium carboxymethyl starch is 0.4 time of the weight of the sodium sulfacetamide, and the dosage of the magnesium stearate is 1/9 times of the weight of the sodium sulfacetamide.
In another preferred embodiment, the dosage form of the medicament for treating diabetic peripheral neuralgia is external gel, and the pharmaceutical excipients of the external gel comprise: sodium carboxymethylcellulose, propylene glycol, ethanol and distilled water. The dosage of the sodium carboxymethyl cellulose, the propylene glycol and the ethanol in the external gel is preferably as follows: the dosage of the sodium carboxymethyl cellulose is 0.75 time of the weight of the sodium sulfacetamide; the dosage of the propylene glycol is 5 times of the weight of the sulfacetamide sodium; the amount of ethanol is 6.5 times of the weight of the sulfacetamide sodium.
The invention also provides application of the medicine for treating the diabetic peripheral neuralgia in preparing a medicine for treating the diabetic peripheral neuralgia.
The sulfacetamide sodium in the technical scheme is also called sulfacetamide sodium, and has the English name of sulfacetamide sodium; the eye drop has anti-inflammatory and antibacterial effects, is mainly used for eye infection caused by conjunctivitis, keratitis, dacryocystitis, trachoma and other sensitive bacteria at present, and is mainly used for skin infection symptoms such as skin infection, seborrheic dermatitis and the like.
Levetiracetam in the technical scheme, the English name is Levetiracetam; has anti-epileptic effect, and belongs to fat-soluble medicines. The Pregabalin in the technical scheme has an anti-epileptic effect and is fat-soluble, wherein the English name is Pregabalin. Gabapentin, the name of English, gabapentin, and the like in the technical scheme; has antiepileptic effect and is liposoluble.
In the animal model of diabetic peripheral neuralgia, the medicament for treating diabetic peripheral neuralgia can obviously prolong the heat-shrinkable foot reflex latency of animals, and has better effect than the single use of levetiracetam, gabapentin and the like. Relatively speaking, the dosage of levetiracetam and gabapentin is more favorably reduced.
The oral administration dosage of the human body calculated according to the animal experiment dosage is 38-42 mg of sulfacetamide sodium per day calculated by 60kg of the body weight of the human body.
Detailed Description
The technical solution of the present invention will be further described with reference to the following examples. It should be noted that the formulation in the examples is only used for illustrating the technical solution of the present invention, and should not be construed as limiting the technical solution of the present invention.
Example 1 Compound tablet of sulfacetamide sodium/levetiracetam
Uniformly mixing 450g of sulfacetamide sodium, 2250g of levetiracetam, 360g of lactose and 180g of sodium carboxymethyl starch; adding 3600g of water into povidone K90150 g to prepare a solution which is used as an adhesive, carrying out wet granulation, drying, finishing granules, adding 50g of magnesium stearate, and pressing into 10000 tablets.
Example 2 Compound tablet of sulfacetamide sodium/levetiracetam
Uniformly mixing 450g of sulfacetamide sodium, 1125g of levetiracetam, 360g of lactose and 500g of starch;
adding 2400g of water into povidone K90100 g to prepare a solution, using the solution as an adhesive, performing wet granulation, drying, granulating, and pressing into 10000 tablets.
EXAMPLE 3 Sulfamidoyl sodium/gabapentin Compound tablet
Uniformly mixing 450g of sulfacetamide sodium, 2250g of gabapentin, 360g of lactose and 180g of sodium carboxymethyl starch; adding 3600g of water into povidone K90150 g to prepare a solution which is used as an adhesive, carrying out wet granulation, drying, finishing granules, adding 50g of magnesium stearate, and pressing into 10000 tablets.
Example 4 Sulfamidoyl sodium/levetiracetam Compound gel for external use
Taking 33.75g of sodium carboxymethylcellulose, dispersing in 292.5g of ethanol, adding 700ml of distilled water, stirring, standing overnight, and preparing blank gel; mixing 100 mL of distilled water and 45g of sodium sulfacetamide, adding blank gel in batches, and grinding uniformly; 225g of propylene glycol, 200mL of distilled water and 225g of levetiracetam are mixed and then added into the gel in batches to be ground uniformly, and the mixture is subpackaged and stored in a dark place.
EXAMPLE 5 analgesic Effect of drugs on type 1 diabetic rat peripheral neuralgia model
An SPF-grade healthy male Sprague Dawley rat, 180-200 g, is used for establishing a type 1 diabetes mellitus peripheral neuralgia rat model. The streptozotocin is dissolved in citrate buffer solution with pH of 4.0, the concentration is 4mg/ml, and the streptozotocin is prepared at present, stored at low temperature and transported to avoid the decomposition of the streptozotocin.
Rats were given a 24 hour fasting followed by a single intraperitoneal injection of 3mL streptozotocin citrate buffer. After 4 weeks of injection of streptozotocin, blood is collected from the tail vein of a rat to determine the blood sugar level, and the rat with the blood sugar of more than or equal to 16.7mmol/L is taken as a model rat with type 1 diabetes. The heat-shrinkable foot reflex latency of a type 1 diabetes model rat is determined by adopting a hot plate method, the heat-shrinkable foot reflex latency is determined by taking the time from the rat to the occurrence of foot licking, hoarseness and jumping reaction after the rat is placed on a hot plate, the temperature of the hot plate is (54 +/-1) DEG C, each rat is continuously determined for 2 times at an interval of 10 minutes each time, the mean value of the two heat-shrinkable foot reflex latencies is taken as the heat-shrinkable foot reflex latency of the rat, and 42 rats with the heat-shrinkable foot reflex latency lower than 15s are taken as type 1 diabetes surrounding neuralgia rat models. The model rats were randomly divided into 7 groups of 6 rats each. The administration was performed by gavage, and each rat was administered 1 time daily for 21 times. The following doses were given for each administration:
group A was a model group, and the stomach was drenched with distilled water, 1.5mL each.
Group B is positive control group, and the stomach is irrigated with 1.5mL of mixed solution of sulfacetamide sodium, each containing 0.8mg of sulfacetamide sodium.
Group C is a positive control group, and the stomach is irrigated with levetiracetam water mixed liquor, 1.5mL of each group contains 4mg of levetiracetam.
Group D was a positive control group, and the stomach was perfused with 1.5mL of gabapentin aqueous mixture, each containing 4mg of gabapentin.
Group E is an experimental group, and 1.5mL of water mixed solution containing sulfacetamide sodium and levetiracetam is used for intragastric administration, and each group contains 0.8mg of sulfacetamide sodium and 4mg of levetiracetam.
And the group F is an experimental group, 1.5mL of water mixed solution containing sulfacetamide sodium and levetiracetam is used for intragastric administration, and each group contains 0.8mg of sulfacetamide sodium and 2mg of levetiracetam.
And group G is an experimental group, and 1.5mL of water mixed solution containing sulfacetamide sodium and gabapentin is used for intragastric administration, and the solution contains 0.8mg of sulfacetamide sodium and 4mg of gabapentin.
After administration of the drug to each group of rats is finished, fasting is carried out for 4h, the heat-shrinkable foot reflex latency of the rats is measured by adopting a hot plate method, the time from the rats to the occurrence of foot licking, hoarseness and jumping reaction is taken as the heat-shrinkable foot reflex latency, the temperature of the hot plate is (54 +/-1) DEG C, each rat is continuously measured for 2 times, each time interval is 10 minutes, and the average value of the two heat-shrinkable foot reflex latencies is taken as the heat-shrinkable foot reflex latency of the rat.
The heat-shrinkable foot reflex latency before and after administration of the drug to each group of rats is respectively counted to investigate the analgesic effect of the drug on model rats.
The heat-shrinkable foot reflex latency of each group is expressed by mean value and standard deviation, and the difference between the groups is compared by t test. P <0.05 judged the difference to be statistically significant.
Compared among groups, the blood sugar level of each group of rats at 4 weeks after injection of streptozotocin has no significant difference.
The results of the measurement of the latent phase of heat-shrinkable foot reflex before and after administration to each group of rats are shown in Table 1.
TABLE 1 Heat-shrinkable foot reflex incubation period(s) before and after dosing for each group of rats
And (3) displaying a statistical result:
before administration, each group has no significant difference in the heat-shrinkable foot reflex latency (p is greater than 0.05);
after administration, the heat-shrinkable foot reflex latency of the group B and the group A has no significant difference (p is more than 0.05), and the fact that the sulfacetamide sodium has no analgesic effect on the type 1 diabetic peripheral neuralgia model at the dose is suggested.
After administration, the heat-shrinkable foot reflex latency of C, D, E, F, G groups is obviously higher than that of A group (p is less than 0.01), and the condition that the composition of levetiracetam, gabapentin and sulfacetamide sodium has an analgesic effect on a type 1 diabetic peripheral neuralgia model is suggested under the condition of the dosage.
Further comparing group C with group E, and group D with group G, the heat-shrinkable foot reflex latency of group E is significantly higher than that of group C (p is less than 0.01), and the heat-shrinkable foot reflex latency of group G is significantly higher than that of group D (p is less than 0.01), which suggests that sulfacetamide sodium has certain improvement effect on the analgesic effect of levetiracetam and gabapentin.
In order to eliminate the influence caused by the difference of the baseline values, the difference of the heat-shrinkable foot reflex latency after the administration of the rats in each group is compared with that before the administration of the rats, the difference of the heat-shrinkable foot reflex latency in the group E is obviously higher than that in the group C (p is less than 0.05), the difference of the heat-shrinkable foot reflex latency in the group G is obviously higher than that in the group D (p is less than 0.01), and the improvement of the analgesic effect of the sulfacetamide sodium on the levetiracetam and the gabapentin is also prompted.
Because gabapentin and pregabalin are structural analogues, the analgesic effect of the sulfacetamide sodium on pregabalin can be reasonably predicted to have an improvement effect.
Claims (10)
1. A medicine for treating diabetic peripheral neuralgia is prepared from the following components:
1) sulfacetamide or sodium sulfacetamide;
2) one of the following antiepileptic drugs: levetiracetam, gabapentin;
3) and (3) a medicinal auxiliary material.
2. The medicine for treating diabetic peripheral neuralgia according to claim 1, characterized in that the medicine for treating diabetic peripheral neuralgia is prepared from sulfacetamide sodium, levetiracetam and pharmaceutic adjuvant, wherein the weight ratio of the sulfacetamide sodium to the levetiracetam in the medicine for treating diabetic peripheral neuralgia is 1 weight part of sulfacetamide sodium and 2.5-5.5 weight parts of levetiracetam.
3. The medicament for treating diabetic peripheral neuralgia according to claim 2, wherein the ratio of the parts by weight of the sulfacetamide sodium to the levetiracetam in the medicament for treating diabetic peripheral neuralgia is 1 part by weight of the sulfacetamide sodium and 2.5 parts by weight of the levetiracetam.
4. The medicament for treating diabetic peripheral neuralgia according to claim 2, wherein the ratio of the parts by weight of the sulfacetamide sodium to the levetiracetam in the medicament for treating diabetic peripheral neuralgia is 1 part by weight of the sulfacetamide sodium and 5 parts by weight of the levetiracetam.
5. The medicine for treating diabetic peripheral neuralgia according to claim 1, characterized in that the medicine for treating diabetic peripheral neuralgia is prepared from sulfacetamide sodium, gabapentin and pharmaceutic adjuvant, wherein the weight ratio of the sulfacetamide sodium to the gabapentin in the medicine for treating diabetic peripheral neuralgia is 1 part by weight of the sulfacetamide sodium and 5 parts by weight of the gabapentin.
6. The medicament for treating diabetic peripheral neuralgia according to claim 1, wherein the dosage form of the medicament for treating diabetic peripheral neuralgia is an oral solid preparation.
7. The medicament for treating diabetic peripheral neuralgia according to claim 6, wherein the oral solid preparation is an oral tablet.
8. The medicament for treating diabetic peripheral neuralgia according to claim 7, wherein the pharmaceutical excipients of the oral tablet comprise: lactose, povidone K90, sodium carboxymethyl starch and magnesium stearate.
9. The medicament for treating diabetic peripheral neuralgia according to claim 8, wherein the amount of lactose used in the oral tablet is 0.5 to 0.9 times the weight of sulfacetamide sodium; the dosage of the povidone K90 is 1/3 times of the weight of the sodium sulfacetamide, the dosage of the sodium carboxymethyl starch is 0.4 time of the weight of the sodium sulfacetamide, and the dosage of the magnesium stearate is 1/9 times of the weight of the sodium sulfacetamide.
10. Use of the medicament for treating diabetic peripheral neuralgia according to claim 2 or 5 for the preparation of a medicament for treating diabetic peripheral neuralgia.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2009087682A2 (en) * | 2007-12-28 | 2009-07-16 | Intas Pharmaceuticals Limited | Stabilized injectable formulation of pregabalin |
| CN104244958A (en) * | 2011-11-23 | 2014-12-24 | 澳星医疗私人有限公司 | Improved synergistic anti-diabetic compositions |
| CN108703946A (en) * | 2018-08-28 | 2018-10-26 | 李建会 | A kind of transdermal absorption formulation for treating diabete peripheral herve pain |
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2019
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009087682A2 (en) * | 2007-12-28 | 2009-07-16 | Intas Pharmaceuticals Limited | Stabilized injectable formulation of pregabalin |
| CN104244958A (en) * | 2011-11-23 | 2014-12-24 | 澳星医疗私人有限公司 | Improved synergistic anti-diabetic compositions |
| CN108703946A (en) * | 2018-08-28 | 2018-10-26 | 李建会 | A kind of transdermal absorption formulation for treating diabete peripheral herve pain |
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| Synthesis, characterization, theoretical prediction of activities;Shilpa Agarwal et al.;《Bioorganic & Medicinal Chemistry Letters》;20160419;第2870-2873页 * |
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Address after: Nangang District of Heilongjiang city in Harbin province 150081 Yiyuan Street Fourth Affiliated Hospital of Harbin Medical University No. 37 Building 5, 8 floor of neurology ward Patentee after: Zhang Jingyu Address before: 150040 Room 1017, Bozhongyuan, Heilongjiang University of Traditional Chinese Medicine, No. 24, Xiangfang District, Harbin City, Heilongjiang Province Patentee before: Zhang Jingyu |
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