CN115364229B - Pharmaceutical composition for preventing or treating pain - Google Patents

Pharmaceutical composition for preventing or treating pain Download PDF

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CN115364229B
CN115364229B CN202211174273.9A CN202211174273A CN115364229B CN 115364229 B CN115364229 B CN 115364229B CN 202211174273 A CN202211174273 A CN 202211174273A CN 115364229 B CN115364229 B CN 115364229B
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pregabalin
flupirtine
pain
retigabine
pharmaceutical composition
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CN115364229A (en
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庄涛
黄超男
朱瑾
张桂森
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Jiangsu Ocean University
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Jiangsu Ocean University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • 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]

Abstract

The invention discloses a pharmaceutical composition for preventing or treating pain, which comprises a Kv7/KCNQ channel opener and a voltage-gated calcium channel blocker; the Kv7/KCNQ channel opener comprises flupirtine, retigabine or pharmaceutically acceptable salts and solvates thereof; the voltage-gated calcium channel blocker is selected from pregabalin or pharmaceutically acceptable salts and solvates thereof, and further comprises a pharmaceutically acceptable carrier or excipient; the embodiment of the invention proves that the Kv7/KCNQ potassium channel opener and the voltage-gated calcium channel blocker are combined, so that various pains can be effectively prevented or treated, especially the pain can be effectively prevented and treated, the synergistic analgesic effect is better than that of single medicine, the dosage and frequency of the single medicine can be reduced, and the side effect of single medicine dosage dependence can be reduced.

Description

Pharmaceutical composition for preventing or treating pain
Technical Field
The invention relates to the field of medicines, in particular to a pharmaceutical composition for preventing or treating pain.
Background
Pain is an unpleasant sensory and emotional experience associated with or similar to actual or potential tissue damage, one of the important reasons for people to actively seek medical assistance. With the increasing population and the increasing trend of aging society, the incidence of pain increases, and about 20% of the population worldwide is affected at present, thus causing a huge social burden. Pain can be classified into various types, and acute and chronic pain according to the duration of pain; according to pathogenesis, inflammatory pain, neuropathic pain, cancer pain, etc. are also classified. Inflammatory pain, resulting from an increased excitability of peripheral nociceptive sensory fibers by inflammatory mediators; neuropathic pain is caused by injury or lesions of the somatosensory system, and is associated with serious health problems including poor sleep, reduced quality of life, anxiety and depression. Due to the complexity of pathogenesis and the lack of clinically available therapeutic regimens, pain therapy has become an important medical area of increasing clinical demand but still unmet.
Clinical studies have shown that pregabalin has a certain analgesic effect on neuropathic pain as a voltage-gated calcium channel blocker, but its analgesic response rate is not high (about 40-60%), and the onset of pregabalin is relatively high with dose-dependent side effects such as dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and inattention. Kv7/KCNQ channels are widely found in the nervous system and play an important role in regulating neuronal excitability. Kv7/KCNQ channel openers (e.g., flupirtine and retigabine) are a new approach for clinical use in the treatment of diseases associated with neuronal hyperexcitability (epilepsy and pain). Unfortunately, flupirtine is only short-term due to dose-dependent hepatotoxicity, whereas long-term use of retigabine can lead to serious skin and retinal pigmentation side effects.
In view of the deficiency of single analgesic drugs, multi-mode analgesic strategies are currently recommended in clinic, that is, analgesic drugs and methods with different action mechanisms are jointly applied to ensure that the drugs and methods exert the optimal analgesic effect, and the multi-mode analgesic strategy is an effective analgesic strategy for reducing adverse reactions caused by single drugs or methods. For example: the combination of a non-steroidal anti-inflammatory drug with an opioid for the treatment of moderately severe pain patients; tramadol is combined with strong opioid receptors for the treatment of patients with severe pain, and the combination effectively reduces the dosage of opioid and the dose-dependent side effects thereof while enhancing analgesic effectIs used. Preclinical studies can evaluate drug-drug synergy, addition or antagonism by isoradiometric analysis, which is a gold standard for measuring drug-drug interactions. The principle of this method is simply to assume ED for the separate use of two drugs in pharmacological experiments 50 Values of A, B, Z respectively t ED obtained for combination administration experiments 50 Value, r=a/B, P 1 ＝A/(A+B),P 2 ＝B/(A+B),Z add (co-administration of theory ED 50 Value) =a/(P 1 +R×P 2 )。λ＝Z t /Z add λ < 1 indicates interaction as synergy, λ=1 indicates interaction as addition, and λ > 1 indicates interaction as antagonism.
The invention screens the drug dosage and the drug combination aiming at the pharmacodynamics characteristics of pregabalin, flupirtine and retigabine to obtain a drug composition for preventing or treating pain, and the drug composition has the advantages that the analgesic effect is enhanced after the drug composition is combined, the dosage of a single drug can be effectively reduced, and the problems of large dosage, dose dependence side effect and the like of the single drug are solved; the invention provides a new thought for clinical medication and has important significance.
Disclosure of Invention
The present invention is directed to solving the above-mentioned problems of the prior art by providing a pharmaceutical composition for preventing or treating pain.
In order to achieve the above purpose, the present invention provides the following technical solutions: a pharmaceutical composition for preventing or treating pain, the pharmaceutical composition comprising a Kv7/KCNQ channel opener and a voltage-gated calcium channel blocker; also included are pharmaceutically acceptable carriers or excipients.
As a preferred technical scheme of the invention, the Kv7/KCNQ channel opener comprises flupirtine, retigabine or pharmaceutically acceptable salts and solvates thereof.
As a preferred embodiment of the present invention, the voltage-gated calcium channel blocker is selected from pregabalin or pharmaceutically acceptable salts and solvates thereof.
As a preferable technical scheme of the invention, the weight ratio of flupirtine to pregabalin is 0.1-10:1, preferably 1-5:1; the weight ratio of the retigabine to the pregabalin is 0.1-10:1, preferably 1-4:1.
As a preferred technical scheme of the invention, the amount of flupirtine or pharmaceutically acceptable salt and solvate thereof is equivalent to 5-250 mg flupirtine base, the amount of retigabine or pharmaceutically acceptable salt and solvate thereof is equivalent to 10-400 mg retigabine base, and the amount of pregabalin or pharmaceutically acceptable salt and solvate thereof is equivalent to 30-350 mg pregabalin base.
As a preferable technical scheme of the invention, the pharmaceutical composition is prepared into oral solid preparations, including granules, tablets, capsules, powder, sustained-release tablets and sustained-release capsules.
As a preferred embodiment of the present invention, the pharmaceutical combination is used for the treatment or prevention of pain-related diseases, including cancer pain, inflammatory pain, neuropathic pain, acute and chronic pain.
The invention has the beneficial effects that: the pharmaceutical composition has a synergistic effect in treating pain, effectively reduces the dosage of a single drug, and reduces the toxic and side effects of the dosage dependence; the invention confirms the synergic analgesic effect among the medicaments by an isoradiometric analysis method, has no obvious toxic or side effect while playing the analgesic effect, and has good clinical application prospect.
Drawings
Fig. 1 shows mechanical hyperalgesia in mice induced by intragastric pregabalin, flupirtine, retigabine reversed Paclitaxel (< P <0.05, < P <0.01, < P <0.001, < P <0.0001vs Paclitaxel/Vehicle);
fig. 2 shows dose-dependent reversal of Paclitaxel-induced mechanical hyperalgesia in combination of pregabalin and flupirtine (< P <0.05, < P <0.01, < P <0.001, < P <0.0001vs Paclitaxel/Vehicle);
FIG. 3 shows that flupirtine relatively reverses paclitaxel-induced mechanical hyperalgesia in mice 90min after administration, whereas pregabalin in combination with flupirtine is superior to flupirtine;
FIG. 4 is an isoradiometric analysis of the interaction of pregabalin and flupirtine in a paclitaxel-induced neuropathic pain model of mice;
fig. 5 shows dose-dependent reversal of Paclitaxel-induced mechanical hyperalgesia in combination of pregabalin and retigabine (< P <0.05, < P <0.01, < P <0.001, < P <0.0001vs Paclitaxel/Vehicle);
FIG. 6 is a graph showing the relative reversal of paclitaxel-induced mechanical hyperalgesia 120min after retigabine administration. The effect of the pregabalin and the retigabine after being combined is obviously better than that of the retigabine;
FIG. 7 is an isoradiometric analysis of the interaction of pregabalin and retigabine in a paclitaxel-induced neuropathic pain model of mice;
fig. 8 shows inflammatory pain induced by intragastric pregabalin, flupirtine, retigabine reversed carrageenan (< P <0.05, < P <0.01, < P <0.001, < P <0.0001vs Paclitaxel/Vehicle);
fig. 9 is a dose-dependent reduction of carrageenan-induced inflammatory pain in pregabalin in combination with flupirtine (< P <0.05, < P <0.01, < P <0.001, < P <0.0001vs Paclitaxel/Vehicle);
fig. 10 shows that pregabalin significantly reduced carrageenan-induced inflammatory pain 90min after administration, and that pregabalin combined with flupirtine was better than pregabalin;
FIG. 11 is an isoradiogram of the interaction of pregabalin and flupirtine in carrageenan-induced inflammatory pain in mice;
fig. 12 is a dose-dependent reduction of carrageenan-induced inflammatory pain in pregabalin in combination with retigabine (< P <0.05, < P <0.01, < P <0.001, < P <0.0001vs Paclitaxel/Vehicle);
fig. 13 shows that pregabalin significantly reduced carrageenan-induced inflammatory pain 90min after administration, and that pregabalin combined with retigabine was better than pregabalin;
FIG. 14 is an isoradiogram of the interaction of pregabalin and retigabine in carrageenan-induced inflammatory pain in mice;
fig. 15 is a model of neuropathic pain in mice induced by a combination-paclitaxel model with different proportions of pregabalin and flupirtine (< 0.05, <0.01, <0.001, <0.0001vs pre: flu (1:1));
fig. 16 is a model of paclitaxel model induced neuropathic pain in mice with different proportions of pregabalin and retigabine (< 0.05, <0.01, <0.001, <0.0001vs pre: ret (1:3));
fig. 17 is a side effect evaluation-stick test of pregabalin in combination with flupirtine/retigabine (< P <0.05, < P <0.01, < P <0.001, < P <0.0001vs Control).
Detailed Description
The following embodiments of the present invention will be described in detail with reference to the drawings so that the advantages and features of the present invention can be more readily understood by those skilled in the art, and thus the scope of the present invention is more clearly defined. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention.
The present invention provides a pharmaceutical composition for preventing or treating pain, comprising a Kv7/KCNQ channel opener and a voltage-gated calcium channel blocker; also included are pharmaceutically acceptable carriers or excipients; the Kv7/KCNQ channel opener comprises flupirtine, retigabine or pharmaceutically acceptable salts and solvates thereof; the voltage-gated calcium channel blocker is selected from pregabalin or pharmaceutically acceptable salts and solvates thereof;
the weight ratio of flupirtine to pregabalin is 0.1-10:1, preferably 1-5:1; the weight ratio of the retigabine to the pregabalin is 0.1-10:1, preferably 1-4:1; the amount of flupirtine or pharmaceutically acceptable salts and solvates thereof is equivalent to 5-250 mg of flupirtine base, the amount of retigabine or pharmaceutically acceptable salts and solvates thereof is equivalent to 10-400 mg of retigabine base, and the amount of pregabalin or pharmaceutically acceptable salts and solvates thereof is equivalent to 30-350 mg of pregabalin base; the pharmaceutical composition is prepared into oral solid preparations, including granules, tablets, capsules, powder, sustained-release tablets and sustained-release capsules; the pharmaceutical combinations are useful for treating or preventing pain-related disorders, including the treatment of cancer pain, inflammatory pain, neuropathic pain, acute and chronic pain.
Example 1: evaluation of efficacy of pregabalin in combination with flupirtine in paclitaxel-induced neuropathic pain models;
experimental animals: adult female ICR mice, body weight (23±5 g), purchased from eastern farm, usa, underwriters laboratories, inc.) were assigned to the following standard nos: no.202235103.
Experimental materials: pregabalin, flupirtine maleate, polyoxyethylene castor oil EL were purchased from shanghai ala Ding Shenghua technologies limited; paclitaxel was purchased from Shanghai Meilin Biochemical technologies Co., ltd; normal saline is purchased from Jiangsu Huaian Shuanghe pharmaceutical industry Limited liability company; absolute ethanol was purchased from shanghai saen chemical technologies limited.
The dispensing method comprises the following steps: pregabalin and flupirtine are dissolved in normal saline; paclitaxel: dissolved in a solution consisting of 50% polyoxyethylated castor oil EL and 50% absolute ethanol at a concentration of 6mg/mL (stored at-20 ℃ C. For a maximum of 14 days) and then diluted with physiological saline (0.9% NaCl) to a final concentration of 0.2mg/mL prior to administration.
The experimental method comprises the following steps: prior to the experiment, mice were randomized into groups of 8 mice each, were intraperitoneally injected with paclitaxel (2 mg/kg) or vehicle thereof (drug volume 0.1mL/10 g), 1 time daily for 5 consecutive days, baseline values of mechanical pain threshold of mice were measured on the day before paclitaxel injection and on the day after paclitaxel injection was completed (mice had been acclimatized for 30min before testing), and on day 7 mice were given intragastric administration of pregabalin, flupirtine (drug volumes were all calculated as 0.1mL/10 g) for the individual drug groups and mechanical pain threshold of mice were measured at 30, 60, 90, 120min post-drug administration. When combined, the dosage is 1/2ED of each of the two medicines 50 ，1/4ED 50 ，1/8ED 50 And (5) administration.
Experimental dose groupings are as in table 1:
TABLE 1 grouping of pregabalin and flupirtine combined-paclitaxel induced neuropathic pain models in mice
p.o.: gastric lavage administration
Data are expressed as mean ± s.e.m; analysis of single or multiple factor variance in GraphPadPrism software and testing with Dunnett's multiple comparisons test; analgesic inhibition rate (MPE%) = (mechanical threshold at peak time-0 min mechanical threshold)/(mechanical threshold at baseline before modeling-0 min) ×100%;
experimental results:
after the paclitaxel administration is finished, the mechanical pain threshold of the mice is obviously reduced, which indicates that the modeling is successful. Flupirtine maleate and pregabalin are administered alone at doses that are positively correlated with the reversal of hyperalgesia. The inhibition rate of analgesia of flupirtine maleate at three doses of low, medium and high 4.3, 13 and 39mg/kg is 38.09%, 49.53% and 65.41%, respectively, and ED thereof 50 11.97mg/kg. The analgesic inhibition rate of pregabalin at three doses of low, medium and high 6, 12 and 24mg/kg is 42.4%, 65.6%, 70.1% and ED respectively 50 7.5mg/kg.
Pregabalin and flubiplatine maleate are respectively treated with 1/2ED of pregabalin and flubiplatine maleate 50 、1/4ED 50 、1/8ED 50 Dose co-administration of pregabalin 1/2ED 50 (3.8 mg/kg) +Flupirtine maleate 1/2ED 50 (6 mg/kg), mpe=69.9%; pregabalin 1/4ED 50 (1.9 mg/kg) +Flupirtine maleate 1/4ED 50 (3 mg/kg), mpe=57.2%; pregabalin 1/8ED 50 (0.95 mg/kg) +flupirtine maleate 1/8ED 50 (1.5 mg/kg), mpe=45%; ED after co-administration 50 Theoretical value Z add =9.69 mg/kg, ED calculated experimentally 50 Actual value Z t =3.229 mg/kg, gamma (ED 50 Actual value/ED 50 Theoretical value) =0.33 < 1, indicating that the two have synergistic analgesic effect, see fig. 1-4.
Example 2: evaluation of drug efficacy of pregabalin in combination with retigabine in paclitaxel-induced model of mouse neuralgia;
experimental animals, experimental materials, dispensing method: example 1 was repeated except that retigabine was purchased from Shanghai microphone Biochemical technologies Co., ltd and dissolved in physiological saline.
The experimental method comprises the following steps: details of the implementation are the same as in example 1, and retigabine is administered by gastric lavage alone, and the mechanical pain threshold of mice at 30, 60, 90, and 120min after administration is also measured. ED of the two medicines in combination 50 、 1/2ED 50 、1/4ED 50 And (5) administration.
Experimental dose groupings are as in table 2:
table 2: grouping of mouse neuropathic pain models induced by paclitaxel in combination of pregabalin and retigabine
p.o.: gastric lavage administration
Data are expressed as mean ± s.e.m; analysis of single or multiple factor variance in GraphPadPrism software and testing with Dunnett's multiple comparisons test; analgesic inhibition rate (MPE%) = (mechanical threshold at peak time-0 min mechanical threshold)/(mechanical threshold at baseline before modeling-0 min) ×100%;
experimental results:
after the paclitaxel administration is finished, the mechanical pain threshold of the mice is obviously reduced, and the modeling is successful. The analgesic inhibition rate of retigabine at three doses of low, medium and high 5, 10 and 20mg/kg is 29.0%, 57.8% and 87.4%, respectively, and ED thereof 50 8.14mg/kg. Pregabalin ED as described above 50 7.5mg/kg. ED of pregabalin and retigabine respectively 50 、1/2ED 50 、1/4ED 50 Dose co-administration of pregabalin ED 50 (7.5 mg/kg) +retigabine ED 50 (8.14 mg/kg), mpe=78%; pregabalin 1/2ED 50 (3.8 mg/kg) +retigabine 1/2ED 50 (4.07 mg/kg), mpe=58%; pregabalin 1/8ED 50 (1.9 mg/kg) +retigabine 1/8ED 50 (2.04 mg/kg), mpe=46.3%. ED after co-administration 50 Theoretical value Z add =7.83 mg/kg, ED calculated experimentally 50 Actual value Z t In the isoradiogram, gamma=0.64 < 1, and the two have synergistic analgesic effect, as shown in fig. 5-7.
Example 3: evaluation of efficacy of pregabalin in combination with flupirtine maleate in carrageenan-induced murine models of inflammation;
experimental animals: as in example 1;
experimental materials: pregabalin, flupirtine maleate, carrageenan were purchased from Shanghai a Ding Shenghua technologies limited; normal saline is purchased from Jiangsu Huaian Shuanghe pharmaceutical industry Limited liability company;
the dispensing method comprises the following steps: pregabalin and flupirtine maleate are taken as solvents; carrageenan: the physiological saline is used as a solvent to prepare a solution with the mass fraction of 1 percent.
The experimental method comprises the following steps: before the experiment, the mice are randomly grouped, 6-8 mice are in each group, the environment is adapted for 30min in an instrument, the mechanical pain threshold of the mice is measured, and 20ul of carrageenan solution with the mass fraction of 1% is subcutaneously injected into the subcutaneous sole of the mice; the mechanical pain threshold of mice was significantly reduced after 3 hours, after which, for the group alone, pregabalin, flupirtine maleate (administration volume 0.1ml/10 g) were given intragastrically and the mechanical pain threshold of mice was measured at 30, 60, 90, 120min post-administration. When combined, the two medicines are respectively used for 1/2ED 50 ，1/4ED 50 ，1/8ED 50 And (3) combined administration.
Experimental dose groupings are as in table 3;
table 3: group of mice inflammation model induced by pregabalin and flupirtine maleate in combination-carrageenan
p.o.: gastric lavage administration
Data are expressed as mean ± s.e.m; analysis of single or multiple factor variance in GraphPadPrism software and testing with Dunnett's multiple comparisons test; analgesic inhibition rate (MPE%) = (mechanical threshold at peak time-0 min mechanical threshold)/(mechanical threshold at baseline before modeling-0 min) ×100%;
experimental results:
after 3 hours, the mechanical threshold of the mice was significantly reduced. The doses were positively correlated with the reversal of mechanical hyperalgesia by administration alone. The analgesic inhibition rate of pregabalin at three doses of low, medium and high 6, 12 and 24mg/kg is 47.1%, 64.9% and 80.5%, respectively, and ED thereof 50 =6.72 mg/kg. The inhibition rate of analgesia of flupirtine maleate at three doses of low, medium and high 4.3, 13 and 39mg/kg is 44.7%, 78.2%, 98.8% and ED respectively 50 = 5.056mg/kg. Pregabalin and flupirtine maleate are respectively treated with 1/2ED of pregabalin and flupirtine maleate 50 、1/4ED 50 、 1/8ED 50 Dose co-administration of pregabalin 1/2ED 50 (3.36 mg/kg) +Flupirtine maleate 1/2ED 50 (2.53 mg/kg), mpe=70.2%; pregabalin 1/4ED 50 (1.68 mg/kg) +Flupirtine maleate 1/4ED 50 (1.26 mg/kg), mpe=52.1%; pregabalin 1/8ED 50 (0.84 mg/kg) +flupirtine maleate 1/8ED 50 (0.63 mg/kg), mpe=39.7%. ED after co-administration 50 Theoretical value Z add =5.9 mg/kg, ED calculated experimentally 50 Actual value Z t 2.453mg/kg, γ=0.42 < 1, and the two have synergistic analgesic effects, see fig. 8-11.
Example 4: evaluation of efficacy of pregabalin in combination with retigabine in a carrageenan-induced model of mouse inflammation;
experimental animals, experimental materials, dispensing method: example 3 was repeated except that retigabine was purchased from Shanghai microphone Biochemical technologies Co., ltd and dissolved in physiological saline.
The experimental method comprises the following steps: details of the implementation are the same as in example 3, retigabine was administered by gavage alone and the mechanical pain threshold of mice was measured at 30, 60, 90, 120min post administration. When combined, ED of the two medicines is adopted 50 ,1/2ED 50 ,1/4ED 50 And (3) combined administration.
Experimental dose groupings are as in table 4:
TABLE 4 grouping of the model of carrageenan-induced mouse inflammation with pregabalin in combination with retigabine
p.o.: gastric lavage administration
Data are expressed as mean ± s.e.m; analysis of single or multiple factor variance in GraphPadPrism software and testing with Dunnett's multiple comparisons test. Analgesic inhibition rate (MPE%) = (mechanical threshold at peak time-0 min mechanical threshold)/(mechanical threshold at baseline before modeling-0 min) ×100%;
experimental results:
after 3 hours, the mechanical threshold of the mice was significantly reduced. The doses were positively correlated with the reversal of mechanical hyperalgesia by administration alone. Pregabalin ED as described in example 3 50 =6.72 mg/kg. The analgesic inhibition rate of retigabine at three doses of low, medium and high 5, 10 and 20mg/kg is 41%, 58.02% and 75.8%, and ED is respectively 50 =7.14 mg/kg. ED of pregabalin and retigabine respectively 50 、1/2ED 50 、1/4ED 50 Dose co-administration of pregabalin ED 50 (6.72 mg/kg) +retigabine ED 50 (7.14 mg/kg), mpe=74.8%; pregabalin 1/2ED 50 (3.36 mg/kg) +retigabine 1/2ED 50 (3.57 mg/kg), mpe=51.2%; pregabalin 1/8ED 50 (1.68 mg/kg) +retigabine 1/8ED 50 (1.79 mg/kg), mpe=37.7%. ED after co-administration 50 Theoretical value Z add =6.94 mg/kg, ED calculated experimentally 50 Actual value Z t 5.837, γ=0.84 < 1, indicates a synergistic analgesic effect, see in detail fig. 12-14.
Example 5: drug efficacy evaluation of combinations of different proportions of pregabalin and flupirtine maleate in paclitaxel-induced neuropathic pain models in mice;
experimental animals, experimental materials and dispensing methods are the same as in example 1;
the experimental method comprises the following steps: method of molding the same embodimentED of flupirtine maleate in this model as described in example 1 50 ED in the pregabalin model =11.97 mg/kg 50 =7.5 mg/kg, the total dose of the combination of both fixed at the time of administration was 4.8mg/kg (both ED 50 1/4 of the sum) are co-administered at different dose ratios (the dose ratio of pregabalin to flupirtine maleate is 1:1. 1:3. 3:1, 1: 1.6). Pregabalin: flupirtine maleate = 1:1.6 is two ED 50 Represents the ratio of pregabalin 1/4ED in example 1 50 +flupirtine 1/4ED 50 The combined drug effect.
Experimental dose groupings are as in table 5:
table 5: grouping of mouse neuropathic pain models induced by the combination-paclitaxel model of different proportions of pregabalin and flupirtine maleate;
p.o.: gastric lavage administration
Data are expressed as mean ± s.e.m; analysis of single or multiple factor variance in GraphPadPrism software and testing with Dunnett's multiple comparisons test.
Experimental results:
from the efficacy-time course curve, the efficacy sequence is pregabalin (Pre): flupirtine maleate (Flu) =1:1.6>1:3>3:1. Pregabalin: drug efficacy of flupirtine maleate (1:1) with pregabalin: the drug effect of flupirtine maleate (3:1) is almost the same, pregabalin 1/4ED 50 +flupirtine maleate 1/4ED 50 The combined drug effect is best shown in figure 15.
Example 6: drug efficacy evaluation of the combination of pregabalin and retigabine in different proportions in paclitaxel-induced mouse neuralgia model;
experimental animals, experimental materials and dispensing methods are the same as in example 2;
the experimental method comprises the following steps: the molding method is the same as in example 1; ED of retigabine in this model as described in example 2 50 =8.14 mg/kg, pregabalin ED 50 =7.5 mg/kg, the total dose of the combination of both fixed at the time of administration was 7.8mg/kg (both ED 50 1/2 of the sum of the values), at different dose ratios (dose ratio of pregabalin to retigabine 1:1. 1:3. 3:1). Pregabalin: retigabine=1: 1 is two ED 50 Represents the ratio of pregabalin 1/2ED in example 2 50 +retigabine 1/2ED 50 The combined drug effect.
Experimental dose groupings are shown in table 6
Table 6: combination of pregabalin and retigabine in different ratios-paclitaxel model-induced mouse neuralgia model grouping
p.o.: gastric lavage administration
Data are expressed as mean ± s.e.m; analysis of single or multiple factor variance in GraphPadPrism software and testing with Dunnett's multiple comparisons test.
Experimental results:
from the efficacy-time course curve, the efficacy sequence is pregabalin (Pre): retigabine (Ret) =1:1>3:1>1:3. Pregabalin 1/2ED 50 +retigabine 1/2ED 50 The combined drug effect is best shown in figure 16.
Example 7: the side effect evaluation-stick rotation test experimental animal, experimental materials and dispensing method of the pregabalin and flupirtine maleate/retigabine combination are as described above;
the experimental method comprises the following steps: screening and training mice before experiment, firstly screening mice with coordinated movement capacity at 20r/min, then training the screened mice for two days, three times a day, 3-5min each time, 20r/min on the first dayThe following day, 30r/min, mice were allowed to adapt to the training intensity. In the formal experiment, flupirtine is singly used or 2ED of each drug in paclitaxel model 50 The doses were co-administered and tested at 30, 60, 90, 120min, rotational speed 30r/min, run time 5min.
Experimental dose groupings are as in table 7:
table 7: evaluation of adverse side effects of pregabalin in combination with flupirtine maleate/retigabine-rod-rotating test grouping conditions
p.o.: gastric lavage administration
Data are expressed as mean ± s.e.m; analysis of single or multiple factor variance in GraphPadPrism software and testing with Dunnett's multiple comparisons test.
Experimental results:
it can be seen that flupirtine alone has an effect on the motor coordination ability of mice, but the motor coordination ability of mice is hardly affected after large doses of the drugs are combined, and the drug combination is safe, as shown in fig. 17.
Example 8: preparation of pregabalin-flupirtine maleate tablet compound tablets;
table 8: pregabalin-flupirtine maleate tablet prescription composition (1000 tablets)
Composition of the components Every 1000 tablets
Pregabalin 38g
Flupirtine maleate 62g
Dibasic calcium phosphate 186.2g
Crosslinked polyvinylpyrrolidone 12.0g
Sodium dodecyl sulfate 0.4g
Magnesium stearate 0.75g
Micro powder silica gel 0.75g
The preparation process comprises the following steps:
(1) Weighing 186.2g of calcium hydrophosphate and 12.0g of crosslinked polyvinylpyrrolidone, crushing, and sieving (100 meshes) respectively;
(2) Then weighing 62g of flupirtine maleate raw material and 38g of pregabalin, and uniformly mixing with the auxiliary materials according to an equivalent incremental method;
(3) Preparing soft materials by using a proper amount of 50% ethanol solution as an adhesive, and granulating through a 20-mesh sieve; drying wet granules by blowing at 60 ℃, and sieving the wet granules with a 20-mesh sieve to obtain granules;
(4) Adding 0.75g of magnesium stearate and 0.75g of micro powder silica gel which are sieved by a 100-mesh sieve, uniformly mixing, and tabletting.
Example 9: preparation of pregabalin-retigabine tablet compound tablets;
table 9: pregabalin-retigabine tablet prescription composition
Composition of the components Every 1000 tablets
Pregabalin 50g
Retigabine 50g
Micro powder silica gel 15g
Microcrystalline cellulose 20g
Lactose and lactose 16g
Calcium phosphate 10g
Hydroxypropyl methylcellulose 15g
Polyethylene glycol 6000 16g
Magnesium stearate 0.3g
The preparation process comprises the following steps:
(1) Uniformly mixing the prescription amount of retigabine, pregabalin and micro powder silica gel, adding one half of the prescription amount of calcium phosphate, uniformly mixing, and crushing to 100-mesh sieve;
(2) Respectively sieving microcrystalline cellulose, lactose, polyethylene glycol 6000, hydroxypropyl methylcellulose, the rest of the prescription amount of calcium phosphate and magnesium stearate with a 80-mesh sieve;
(3) Uniformly mixing the microcrystalline cellulose, lactose, polyethylene glycol and the residual calcium phosphate with the prescription amount obtained in the first step and sieved in the second step, uniformly mixing the mixture with the hydroxypropyl methylcellulose with the prescription amount, and wetting and granulating the mixture with 50% ethanol;
(4) Drying at 60 ℃ to obtain the third step, finishing, and sieving with a 60-mesh sieve;
(5) And finally adding the magnesium stearate with the prescription amount, and tabletting.
The medicine combination of the invention is safe and has clinical value and deserves further research and discussion.
The medicine composition has synergistic effect in treating pain, has lasting medicine effect, can avoid the problems of single administration dosage and frequency, and reduces toxic and side effects; the invention confirms the synergic analgesic effect among the medicaments by an isoradiometric analysis method, reduces the dosage of single administration, has no obvious toxic or side effect, and has good clinical application prospect.
The foregoing examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention.

Claims (5)

1. A pharmaceutical composition for preventing or treating pain, characterized by: the pharmaceutical composition consists of flupirtine or pharmaceutically acceptable salt thereof, pregabalin or pharmaceutically acceptable salt thereof and excipient.
2. A pharmaceutical composition for preventing or treating pain according to claim 1, wherein: the weight ratio of flupirtine to pregabalin is 0.1-10:1.
3. A pharmaceutical composition for preventing or treating pain according to claim 1, wherein: the amount of flupirtine or a pharmaceutically acceptable salt thereof corresponds to 5-250 mg of flupirtine base, and the amount of pregabalin or a pharmaceutically acceptable salt thereof corresponds to 30-350 mg of pregabalin base.
4. A pharmaceutical composition for preventing or treating pain according to claim 1, wherein: the pharmaceutical composition is prepared into oral solid preparations, including granules, tablets, capsules and powder.
5. Use of a pharmaceutical composition according to claim 1 for the preparation of a medicament for the treatment of pain, wherein the pain is selected from inflammatory pain and neuropathic pain.
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