CN115364229A - A pharmaceutical composition for preventing or treating pain - Google Patents
A pharmaceutical composition for preventing or treating pain Download PDFInfo
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- CN115364229A CN115364229A CN202211174273.9A CN202211174273A CN115364229A CN 115364229 A CN115364229 A CN 115364229A CN 202211174273 A CN202211174273 A CN 202211174273A CN 115364229 A CN115364229 A CN 115364229A
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- China
- Prior art keywords
- pregabalin
- pain
- retigabine
- flupirtine
- pharmaceutical composition
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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
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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
- A61K31/197—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 or pantothenic acid
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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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
- A61K31/435—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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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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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- Animal Behavior & Ethology (AREA)
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Abstract
The invention discloses a pharmaceutical composition for preventing or treating pain, which comprises a Kv7/KCNQ channel opener and a voltage-gated calcium ion 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 invention has synergistic analgesic effect on inflammatory and neuropathic pains, the effect is better than that of a single medicine, the dosage and frequency of the single medicine can be reduced, and the side effect of the single medicine depending on the dosage can be reduced.
Description
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 and is one of the important reasons people are actively seeking medical help. With the increasing population and the increasing aging trend of society, the incidence of pain also increases, which affects about 20% of the population of the world and causes huge social burden. Pain can be divided into various types, and according to the duration of pain, acute pain and chronic pain can be divided; according to the pathogenesis, the pain can be divided into inflammatory pain, neuropathic pain, cancer pain and the like. Inflammatory pain, caused by increased excitability of peripheral nociceptive sensory fibers by inflammatory mediators; neuropathic pain, which is caused by injury or pathology to the somatosensory system, 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 treatment regimens, pain treatment has become an important medical field with an ever-increasing clinical need that remains unmet.
Clinical studies show that pregabalin has a certain analgesic effect on neuropathic pain as a voltage-gated calcium ion channel blocker, but the analgesic response rate is not high (about 40-60%), and the pregabalin has a relatively high effective dose and has certain dose-dependent side effects, such as dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and inattention. Kv7/KCNQ channels are widely present in the nervous system and play an important role in regulating neural excitability. Kv7/KCNQ channel openers (such as flupirtine and retigabine) are a new approach for clinical treatment of diseases associated with neuronal hyperexcitability (epilepsy and pain). Unfortunately, flupirtine is only used for a short period due to dose-dependent hepatotoxicity, whereas retigabine is used for a long period with severe skin and retinal pigmentation side effects.
In view of a single analgesic drugThe existing clinical multi-mode analgesic strategy is recommended, namely, a plurality of analgesic drugs with different action mechanisms and methods are combined to play the best analgesic effect, and the multi-mode analgesic strategy is an effective analgesic strategy for reducing adverse reactions caused by a single drug or method. For example: the combination of the non-steroidal anti-inflammatory drug and the opioid is used for treating patients with moderate and severe pain; tramadol is combined with strong opioid receptors for treating severe pain patients, and the combination effectively reduces the dosage of opioid drugs and the side effects of dose dependence while enhancing the analgesic effect. Preclinical studies can evaluate synergy, additivity, or antagonism between drugs by isoradiometric analysis, which is a gold standard for measuring interactions between drugs. Briefly, the principle of this approach is to hypothesize the ED used alone for two drugs in pharmacological experiments 50 Values of A, B, Z t ED derived for combined drug administration experiments 50 Value, R = A/B, P 1 ＝A/(A+B),P 2 ＝B/(A+B),Z add (Combined dosing theory ED 50 Value) = a/(P) 1 +R×P 2 )。λ＝Z t /Z add λ < 1 means that the interaction is synergistic, λ =1 means that the interaction is additive, and λ > 1 means that the interaction is antagonistic.
Aiming at the pharmacodynamic characteristics of pregabalin, flupirtine and retigabine, the invention screens the drug dosage and the drug combination to obtain a drug composition for preventing or treating pain, enhances the analgesic effect after combined use, can effectively reduce the use dosage of a single drug, and solves the problems of large administration dosage, dose-dependent side effect and the like existing in the single drug; the invention provides a new thought for clinical medication and has important significance.
Disclosure of Invention
The present invention is directed to overcoming the problems set forth in the background above by providing a pharmaceutical composition for preventing or treating pain that addresses the deficiencies of the prior art.
In order to achieve the purpose, the invention provides the following technical scheme: a pharmaceutical composition for preventing or treating pain, comprising a Kv7/KCNQ channel opener and a voltage-gated calcium channel blocker; also comprises a pharmaceutically acceptable carrier or excipient.
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 preferred technical solution of the present invention, the weight ratio of flupirtine to pregabalin is 0.1-10, preferably 1-5; the weight ratio of the retigabine to the pregabalin is 0.1-10, preferably 1-4.
As a preferred technical scheme of the invention, 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.
As a preferable technical scheme, 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 treating or preventing pain-related disorders, including the treatment of 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, so that the use dosage of a single medicament is effectively reduced, and the toxic and side effects of dose dependence are reduced; the invention proves the synergistic analgesic effect among the medicaments by an isoradiometric analysis method, has no obvious toxic or side effect while exerting the analgesic effect, and has good clinical application prospect.
Drawings
Figure 1 is clystering pregabalin, flupirtine, retigabine reverse Paclitaxel induced mechanical hyperalgesia in mice (P <0.05, P <0.01, P <0.001, P <0.0001vs Paclitaxel/velocle);
figure 2 is a dose-dependent reversal of Paclitaxel-induced mechanical allodynia in combination with dapagliptin ([ P <0.05, [ P <0.01 ], [ P <0.001 ], [ P <0.0001 ] vs Paclitaxel/Vehicle);
FIG. 3 is a graph showing that flupirtine relatively reverses paclitaxel-induced mechanical allodynia in mice 90min after administration, whereas pregabalin in combination with flupirtine is superior to flupirtine in efficacy;
FIG. 4 is an isobolographic analysis of the interaction of pregabalin with flupirtine in a model of paclitaxel-induced neuropathic pain in mice;
figure 5 is a dose-dependent reversal of Paclitaxel-induced mechanical allodynia in combination with retigabine (. P <0.05,. P <0.01,. P <0.001,. P <0.0001vs Paclitaxel/velocle);
figure 6 is a graph showing the relative reversal of paclitaxel-induced mechanical allodynia 120min after retigabine administration. The effect of the combination of the pregabalin and the retigabine is obviously superior to that of the retigabine;
FIG. 7 is an isobolographic analysis of the interaction of pregabalin and retigabine in a model of paclitaxel-induced neuropathic pain in mice;
figure 8 is the administration of pregabalin, flupirtine, retigabine reversed carrageenan-induced inflammatory pain (. P <0.05,. P <0.01,. P <0.001,. P <0.0001 vs. Paclitaxel/Vehicle);
figure 9 is a dose-dependent reduction of carrageenan-induced inflammatory pain in combination with pregabalin and flupirtine (. P <0.05,. P <0.01,. P <0.001,. P <0.0001 vs. Paclitaxel/Vehicle);
FIG. 10 is a graph showing that pregabalin significantly reduces carrageenan-induced inflammatory pain at 90min post-administration, and that pregabalin combined with flupirtine is superior to pregabalin in efficacy;
FIG. 11 is an isobologram of the interaction of pregabalin with flupirtine in carrageenan-induced inflammatory pain in mice;
figure 12 is a dose-dependent reduction of carrageenan-induced inflammatory pain in combination with pregabalin and retigabine (. P <0.05,. P <0.01,. P <0.001,. P <0.0001 vs. Paclitaxel/Vehicle);
fig. 13 is a graph showing that pregabalin significantly reduces carrageenan-induced inflammatory pain at 90min after administration, and that pregabalin and retigabine combined have superior effects to pregabalin;
FIG. 14 is a graph of isoradiometric analysis of the interaction of pregabalin with retigabine in carrageenan-induced inflammatory pain in mice;
figure 15 is a combination of pregabalin and flupirtine at different ratios-the model of mouse neuropathic pain induced by the paclitaxel model (× P <0.05, × P <0.01, × P <0.001, × P <0.0001vs pre (1));
figure 16 is a model of neuropathic pain in mice induced by the combination-paclitaxel model with different ratios of pregabalin to retigabine (× P <0.05, × P <0.01, × P <0.001, × P <0.0001vs pre (1;
figure 17 is an assessment of side effects of pregabalin in combination with flupirtine/retigabine-rotarod test (. P <0.05,. P <0.01,. P <0.001,. P <0.0001vs Control).
Detailed Description
The embodiments of the present invention will be described in detail below with reference to the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, and the scope of the present invention can be more clearly and clearly defined. It should be understood that these examples are for illustrative purposes only 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 ion channel blocker; further comprises a pharmaceutically acceptable carrier or excipient; 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, preferably 1-5; the weight ratio of the retigabine to the pregabalin is 0.1-10, preferably 1-4; 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 combination is 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 the efficacy of pregabalin in combination with flupirtine in a paclitaxel-induced neuropathic pain model;
experimental animals: adult female ICR mice, body weight (23 ± 5 g), purchased from eastern firms of febrifuge, certification mark: no.202235103.
Experimental materials: pregabalin, flupirtine maleate, polyoxyethylene castor oil EL were purchased from shanghai alatin biochem ltd; paclitaxel was purchased from Shanghai Maxin Biotechnology, inc.; the physiological saline is purchased from Jiangsu Huai' an double-crane pharmaceutical industry, inc.; anhydrous ethanol was purchased from shanghai saen chemical technology, ltd.
The medicine dispensing method comprises the following steps: dissolving pregabalin and flupirtine in normal saline; paclitaxel (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., maximum 14 days), and then diluted with physiological saline (0.9% NaCl) to a final concentration of 0.2mg/mL before administration.
The experimental method comprises the following steps: before the experiment, the mice are randomly grouped, each group comprises 8 mice, paclitaxel (2 mg/kg) or solvent (drug volume is 0.1mL/10 g) is injected into the abdominal cavity of the mice, 1 time per day is carried out for 5 consecutive days, the baseline value of the mechanical pain threshold of the mice is measured respectively on the day before the paclitaxel injection and the day after the paclitaxel injection (the mice are adapted to the environment for 30min before the test), and on the 7 th day, the pregabalin and flupirtine are administered to the mice by intragastric administration for single drug groups (the drug volumes are all 0.1mL/10 g) and measure the mechanical pain threshold of the mice at 30, 60, 90, 120min after administration. When administered in combination, the dosage is 1/2ED for each of the two drugs 50 ，1/4ED 50 ，1/8ED 50 And (4) administration.
Experimental dose groups are as in table 1:
TABLE 1 combination of Pregabalin and flupirtine-grouping of mouse neuropathic pain model induced by paclitaxel
p.o.: administration by intragastric administration
Data are expressed as mean ± s.e.m.; single or multi-factor analysis of variance with GraphPadPrism software and checked with Dunnett's multiple complexes test; analgesic inhibition rate (MPE%) = (mechanical threshold at peak-0 min)/(mechanical threshold at baseline value before molding-0 min) × 100%;
the experimental results are as follows:
after the paclitaxel administration is finished, the mechanical pain threshold of the mice is obviously reduced, which indicates that the molding is successful. Flupirtine maleate and pregabalin were administered alone in doses that positively correlated with reversal of hyperalgesia. The analgesic inhibition rates of flupirtine maleate at three doses of 4.3, 13 and 39mg/kg are respectively 38.09%, 49.53% and 65.41%, and the ED is 50 It was 11.97mg/kg. The analgesic inhibition rates of the pregabalin under the three doses of 6, 12 and 24mg/kg of low dose, high dose and high dose are respectively 42.4%, 65.6%, 70.1% and ED 50 It was 7.5mg/kg.
The pregabalin and the flupirtine maleate are respectively 1/2ED of the pregabalin and the flupirtine maleate 50 、1/4ED 50 、1/8ED 50 Dose combination, 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 (3mg/kg), MPE = 57.2%; pregabalin 1/8ED 50 (0.95 mg/kg) + Flupirtine maleate 1/8ED 50 (1.5 mg/kg), MPE =45%; after co-administration, ED 50 Theoretical value Z add =9.69mg/kg, ED calculated from experiment 50 Actual value Z t =3.229 mg/kg, gamma in isobologram (ED) 50 Actual value/ED 50 Theoretical) =0.33 < 1, indicating that both have synergistic analgesic effects, as shown in figures 1-4.
Example 2: the drug effect evaluation of the combined administration of pregabalin and retigabine in a model of mouse neuralgia induced by paclitaxel;
the experimental animal, the experimental material and the dispensing method are as follows: the procedure of example 1 was repeated, except that retigabine was purchased from Shanghai Michelin Biochemical technology Ltd and dissolved in physiological saline.
The experimental method comprises the following steps: the same procedure as in example 1 was followed, except that retigabine was administered by gavage alone, and that the mechanical pain threshold of the mice was measured 30, 60, 90 and 120min after administration. When used in combination, the two herbs are ED 50 、 1/2ED 50 、1/4ED 50 And (4) administration.
Experimental dose groups are as in table 2:
table 2: combination of pregabalin and retigabine-grouping condition of paclitaxel-induced mouse neuropathic pain model
p.o.: administration by intragastric administration
Data are expressed as mean ± s.e.m; single or multi-factor analysis of variance with GraphPadPrism software and checked with Dunnett's multiple complexes test; analgesic inhibition rate (MPE%) = (mechanical threshold at peak-0 min)/(mechanical threshold at baseline value before molding-0 min) × 100%;
the experimental results are as follows:
after the paclitaxel administration is finished, the mechanical pain threshold of the mouse is obviously reduced, and the model building is successful. The analgesic inhibition rates of the retigabine under three doses of low, medium and high doses of 5, 10 and 20mg/kg are respectively 29.0 percent and 5 percent7.8%, 87.4%, ED 50 It was 8.14mg/kg. Pregabalin ED as described above 50 It was 7.5mg/kg. Pregabalin and retigabine respectively use ED of pregabalin and retigabine 50 、1/2ED 50 、1/4ED 50 Dose combination, 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%. After co-administration, ED 50 Theoretical value Z add =7.83mg/kg, ED calculated by experiment 50 Actual value Z t =5mg/kg, and gamma =0.64 < 1 in the isobologram, both of which have synergistic analgesic effects, as shown in fig. 5-7.
Example 3: evaluation of the efficacy of pregabalin in combination with flupirtine maleate in a carrageenan-induced mouse model of inflammation;
experimental animals: the same as example 1;
experimental materials: pregabalin, flupirtine maleate, carrageenan were purchased from Shanghai Aladdin Biotech, inc.; the physiological saline is purchased from Jiangsu Huai' an double-crane pharmaceutical industry, inc.;
the medicine dispensing method comprises the following steps: pregabalin and flupirtine maleate take normal saline as a solvent; carrageenan: physiological saline is used as a solvent to prepare a solution with the mass fraction of 1%.
The experimental method comprises the following steps: before the experiment, the mice are randomly grouped, 6-8 mice are in each group, the inside of the instrument is adapted to the environment for 30min, the mechanical pain threshold of the mice is measured, and then 20ul of carrageenan solution with the mass fraction of 1% is injected subcutaneously on the soles of the mice; the mechanical pain threshold of the mice decreased significantly after 3 hours, after which pregabalin, flupirtine maleate (administration volume 0.1ml/10 g) were gavaged to the mice for the single drug group and measured at 30, 60, 90, 120min after administration. When used in combination, the two drugs are 1/2ED 50 ，1/4ED 50 ，1/8ED 50 The administration is combined.
Experimental dose groups are shown in table 3;
table 3: combination of pregabalin and flupirtine maleate with mouse inflammation model grouping condition induced by carrageenan
p.o.: administration by intragastric administration
Data are expressed as mean ± s.e.m.; single or multi-factor analysis of variance with GraphPadPrism software and checked with Dunnett's multiple complexes test; analgesic inhibition rate (MPE%) = (mechanical threshold at peak-0 min)/(mechanical threshold at baseline value before molding-0 min) × 100%;
the experimental results are as follows:
after 3 hours, the mechanical threshold of the mice decreased significantly. The single medicine is taken, and the dosage is positively correlated with the reversion to the mechanical hyperalgesia. The analgesic inhibition rates of the pregabalin at three doses of 6, 12 and 24mg/kg in low and high are 47.1%, 64.9% and 80.5%, respectively, and the ED thereof 50 =6.72mg/kg. The analgesic inhibition rates of flupirtine maleate under three doses of 4.3, 13 and 39mg/kg of low, medium and high doses are respectively 44.7%, 78.2% and 98.8%, ED 50 =5.056mg/kg. The 1/2ED of pregabalin and flupirtine maleate is respectively 50 、1/4ED 50 、 1/8ED 50 Dose combination, 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%. After co-administration, ED 50 Theoretical value Z add =5.9mg/kg, ED calculated by experiment 50 Actual value Z t =2.453mg/kg and γ =0.42 < 1, both of which have synergistic analgesic effects, as shown in fig. 8-11.
Example 4: the drug effect evaluation of the combination of pregabalin and retigabine in a carrageenan-induced mouse inflammation model;
the experimental animal, the experimental material and the dispensing method are as follows: the procedure of example 3 was repeated, except that retigabine was purchased from Shanghai Michelin Biochemical technology Ltd and dissolved in physiological saline.
The experimental method comprises the following steps: implementation details as in example 3, retigabine was administered by gavage when administered alone and mechanical pain thresholds of mice were measured at 30, 60, 90, 120min after administration. When used in combination, the ED of two herbs is used 50 ,1/2ED 50 ,1/4ED 50 The administration is combined.
Experimental dose groups are as in table 4:
TABLE 4 combination of Pregabalin and retigabine-grouping of carrageenan-induced mouse inflammation models
p.o.: administration by intragastric administration
Data are expressed as mean ± s.e.m; single or multifactor analysis of variance was performed using GraphPadprism software and checked using Dunnett's multiple complexes test. Analgesia suppression rate (MPE%) = (mechanical threshold at peak-0 min)/(mechanical threshold at baseline value before molding-0 min) × 100%;
the experimental results are as follows:
after 3 hours, the mechanical threshold of the mice decreased significantly. The single medicine is taken, and the dosage is positively correlated with the reversion to the mechanical hyperalgesia. Pregabalin ED as described in example 3 50 =6.72mg/kg. The analgesic inhibition rates of the retigabine at three doses of low, medium and high 5, 10 and 20mg/kg are respectively 41%, 58.02% and 75.8%, and ED 50 =7.14mg/kg. ED of pregabalin and retigabine respectively 50 、1/2ED 50 、1/4ED 50 Dose combination, 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 (168 mg/kg) + retigabine 1/8ED 50 (1.79 mg/kg), MPE = 37.7%. After co-administration, ED 50 Theoretical value Z add =6.94mg/kg, ED calculated by experiment 50 Actual value Z t =5.837, γ =0.84 < 1, indicating a synergistic analgesic effect, see figures 12-14.
Example 5: the drug effect evaluation of the combination of pregabalin and flupirtine maleate in different proportions in a paclitaxel-induced mouse neuropathic pain model;
experimental animals, experimental materials and a dispensing method are the same as those in example 1;
the experimental method comprises the following steps: molding was carried out as in example 1, the ED of flupirtine maleate in this model being as described in example 1 50 =11.97mg/kg, ED in this model for pregabalin 50 =7.5mg/kg, and the total dose of the combination is 4.8mg/kg when administered (ED for both) 50 1/4 of the sum), in combination with different dose ratios (dose ratio of pregabalin to flupirtine maleate 1:1. 1:3. 3: 1.6). Pregabalin: flupirtine maleate =1:1.6 is the two ED 50 Represents the ratio of pregabalin 1/4ED in example 1 50 + flupirtine 1/4ED 50 The combined effect is good.
Experimental dose groups are as in table 5:
table 5: grouping conditions of mouse neuropathic pain models induced by combined paclitaxel models with different ratios of pregabalin and flupirtine maleate;
p.o.: administration by intragastric administration
Data are expressed as mean ± s.e.m.; single or multifactor analysis of variance was performed using GraphPadprism software and checked using Dunnett's multiple complexes test.
The experimental results are as follows:
from the pharmacodynamic-time course curve, the pharmacodynamic sequence is pregabalin (Pre): flupirtine maleate (Flu) =1>1:3>3:1. Pregabalin: efficacy of flupirtine maleate (1): the drug effect of flupirtine maleate (3) 50 + Flupirtine maleate 1/4ED 50 The combined effect is best, and the details are shown in figure 15.
Example 6: the drug effect evaluation of the combination of pregabalin and retigabine in different proportions in a paclitaxel-induced mouse neuralgia model;
experimental animals, experimental materials and a dispensing method are the same as those in example 2;
the experimental method comprises the following steps: the molding method is the same as that of example 1; ED of retigabine in this model as described in example 2 50 =8.14mg/kg, pregabalin ED 50 =7.5mg/kg, total dose for fixed association of 7.8mg/kg at time of administration (ED of both) 50 1/2 of the sum of the values), in combination with different dose ratios (dose ratio of pregabalin to retigabine of 1:1. 1:3. 3) of the main component. 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 effect is good.
Experimental dose groups are given in Table 6
Table 6: combination of pregabalin and retigabine in different proportions-paclitaxel model induced mouse neuralgia model grouping
p.o.: administration by intragastric administration
Data are expressed as mean ± s.e.m.; single or multifactor analysis of variance was performed using GraphPadprism software and checked using Dunnett's multiple complexes test.
The experimental results are as follows:
from the pharmacodynamic-time course curve, the pharmacodynamic sequence is pregabalin (Pre): retigabine (Ret) =1> 3:1>1:3. Pregabalin 1/2ED 50 + retigabine 1/2ED 50 The combined effect is best, and the detail is shown in figure 16.
Example 7: the side effect evaluation of the combination of pregabalin and flupirtine maleate/retigabine-rotarod test experimental animal, experimental material and dosage method are as described above;
the experimental method comprises the following steps: the method comprises the steps of screening and training mice before experiment, firstly screening the mice with coordinated movement ability at the speed of 20r/min, then training the screened mice for two days, three times a day, 3-5min each time, 20r/min for the first day and 30r/min for the second day, and enabling the mice to adapt to the training intensity. In the formal experiment, flupirtine was administered alone or as the 2ED of each drug in a paclitaxel model 50 The dosage is combined, and the test is carried out at 30, 60, 90 and 120min, the rotating speed is 30r/min, and the running time is 5min.
Experimental dose groups are as in table 7:
table 7: side effect evaluation of pregabalin in combination with flupirtine maleate/retigabine-rotarod test grouping
p.o.: administration by intragastric administration
Data are expressed as mean ± s.e.m; single or multifactorial analysis of variance was performed using GraphPadPrism software and examined using Dunnett's multiple complexes test.
The experimental results are as follows:
it can be seen that flupirtine alone affects the motor coordination ability of mice, while the motor coordination ability of mice is hardly affected after the combination of large doses of flupirtine, and the combination of drugs is safe, as shown in fig. 17.
Example 8: preparing a pregabalin-flupirtine maleate tablet compound tablet;
table 8: pregabalin-flupirtine maleate tablet prescription composition (1000 tablets)
| Composition (I) | Every 1000 tablets |
| Pregabalin | 38g |
| Flupirtine maleate | 62g |
| Calcium hydrogen phosphate | 186.2g |
| Crosslinked polyvinylpyrrolidone | 12.0g |
| Sodium dodecyl sulfate | 0.4g |
| Magnesium stearate | 0.75g |
| Silica gel micropowder | 0.75g |
The preparation process comprises the following steps:
(1) 186.2g of calcium hydrophosphate and 12.0g of crosslinked polyvinylpyrrolidone are weighed, crushed and respectively sieved by a sieve (100 meshes);
(2) Then, 62g of flupirtine maleate raw material and 38g of pregabalin are weighed and evenly mixed with the auxiliary materials according to an equivalent gradual addition method;
(3) Preparing soft materials by using a proper amount of 50% ethanol solution as an adhesive, and sieving with a 20-mesh sieve for granulation; drying the wet granules by blowing at 60 ℃, and sieving with a 20-mesh sieve for size stabilization;
(4) Adding 0.75g of magnesium stearate sieved by a 100-mesh sieve and 0.75g of superfine silica gel powder, mixing uniformly, and tabletting.
Example 9: preparing a pregabalin-retigabine compound tablet;
table 9: pregabalin-retigabine tablet prescription composition
| Composition (A) | Every 1000 tablets |
| Pregabalin | 50g |
| Retigabine | 50g |
| Silica gel micropowder | 15g |
| Microcrystalline cellulose | 20g |
| 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 retigabine, pregabalin and superfine silica powder according to the prescription amount, adding one half of calcium phosphate according to the prescription amount, uniformly mixing, and crushing to pass through a 100-mesh sieve;
(2) Respectively sieving microcrystalline cellulose, lactose, polyethylene glycol 6000, hydroxypropyl methylcellulose, the rest of the calcium phosphate and the rest of the magnesium stearate in a 80-mesh sieve;
(3) Uniformly mixing the microcrystalline cellulose, the lactose, the polyethylene glycol and the calcium phosphate in the rest prescription amount obtained in the first step and sieved in the second step, uniformly mixing the mixture with hydroxypropyl methyl cellulose in the prescription amount, and wetting and granulating the mixture by using 50% ethanol;
(4) Drying at 60 ℃, finishing and sieving by a 60-mesh sieve;
(5) Finally, adding magnesium stearate with the prescription amount, and tabletting.
Combining the above results, the pharmaceutical combination of the present invention is safe and clinically valuable, and deserves further exploration and discussion.
The drug combination has a synergistic effect in treating pain, has a lasting drug effect, can avoid the problems of dosage and frequency of single drug administration, and reduces toxic and side effects; the invention proves the synergistic 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 above examples only show some embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the invention, and these changes and modifications are all within the scope of the invention.
Claims (7)
1. A pharmaceutical composition for preventing or treating pain, characterized by: the pharmaceutical composition comprises a Kv7/KCNQ channel opener and a voltage-gated calcium ion channel blocker; also comprises a pharmaceutically acceptable carrier or excipient.
2. A pharmaceutical composition for use in the prevention or treatment of pain according to claim 1, wherein: the Kv7/KCNQ channel opener comprises flupirtine, retigabine or pharmaceutically acceptable salts and solvates thereof.
3. A pharmaceutical composition for use in the prevention or treatment of pain according to claim 1, wherein: the voltage-gated calcium channel blocker is selected from pregabalin or pharmaceutically acceptable salts and solvates thereof.
4. A pharmaceutical composition for use in the prevention or treatment of pain according to claims 1 to 3, wherein: the weight ratio of flupirtine to pregabalin is 0.1-10, preferably 1-5; the weight ratio of the retigabine to the pregabalin is 0.1-10, preferably 1-4.
5. The pharmaceutical composition for preventing or treating pain according to claim 4, wherein: 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.
6. The 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, powder, sustained-release tablets and sustained-release capsules.
7. A pharmaceutical composition for use in the prevention or treatment of pain according to claim 1, wherein: the pharmaceutical combination is used for the treatment or prevention of pain related disorders, including the treatment of cancer pain, inflammatory pain, neuropathic pain, acute and chronic pain.
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| US20100190752A1 (en) * | 2008-09-05 | 2010-07-29 | Gruenenthal Gmbh | Pharmaceutical Combination |
| US20140112937A1 (en) * | 2011-04-05 | 2014-04-24 | Freistaat Bayern Represented By Julius- -Maximilians-Universitat Wurzburg | Use of an agent consisting of antibodies and/or insulin-like growth factor antagonists |
| US20150374647A1 (en) * | 2012-09-05 | 2015-12-31 | Pharnext | Therapeutic approaches for treating epilepsy and related disorders through reduction of epileptogenesis |
| US20150072005A1 (en) * | 2013-09-10 | 2015-03-12 | Vitalis Llc | Aspirin formulation for increased efficacy |
| CN109293566A (en) * | 2018-11-27 | 2019-02-01 | 武汉珈瑜科技有限公司 | Amide derivatives and its application |
| WO2022198114A1 (en) * | 2021-03-19 | 2022-09-22 | Xyzagen, Inc. | Prodrugs of kv7 channel openers |
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| CHAO-NAN HUANG ET AL.: "Pregabalin can interact synergistically with Kv7 channel openers to exert antinociception in mice", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 954, pages 1 - 11 * |
| 周文哲;周满红;: "国内临床镇痛药联合应用现状", 中华危重症医学杂志(电子版), no. 01, pages 1 - 4 * |
| 张桂森等: "普瑞巴林的合成", 中国医药工业杂志, vol. 38, pages 1 - 2 * |
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| CN117860727A (en) | 2024-04-12 |
| CN115364229B (en) | 2024-02-20 |
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