CN105919990A - Medicine composition used for preventing and treating neuropathic pain and application thereof - Google Patents
Medicine composition used for preventing and treating neuropathic pain and application thereof Download PDFInfo
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- CN105919990A CN105919990A CN201610496300.2A CN201610496300A CN105919990A CN 105919990 A CN105919990 A CN 105919990A CN 201610496300 A CN201610496300 A CN 201610496300A CN 105919990 A CN105919990 A CN 105919990A
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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
- A61K31/185—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
Abstract
The invention discloses a medicine composition for treating neuropathic pain, especially neuropathic pain caused by diabetes mellitus. The medicine composition takes retigabine and gabapentin as active pharmaceutical ingredients, wherein the weight ratio of retigabine to gabapentin in the medicine composition is 1 to (0.01-500), preferably 1 to (0.2-300) and further preferably 1 to (1.5-24). The medicine composition has the advantages that the medicine composition is preferably taken orally when being used for treating neuropathic pain caused by diabetes mellitus; retigabine and gabapentin in the medicine composition show obvious synergistic effects on treatment of neuropathic pain; and the medicine composition has clear ingredients, definite treatment effects, small adverse effects and good medical values.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of Western medicine medical composition and its use, be specifically related to a kind of containing retigabine with the medical composition and its use of gabapentin.
Background technology
Neuropathic pain is one of two kinds of main Types of chronic pain.When producing chronic nociceptive/inflammatory pain, body tissue sustains damage, and is formed the chronic transmission of pain signal by the nervous pathway of conduction nociception sexual stimulus.And neuropathic pain usually not tissue injury, or occur after peripheral nerve injury, pain transduction access function is disorderly, causes the chronic transmission of exception of pain signal.In some cases (such as cancer), can have both types of pain simultaneously.
When forming neuropathic pain, can there is obvious nerve injury, it is also possible to do not have.The nerve injury not involving Motor nerve fibre is generally difficult to diagnosis.Damage is it may happen that around or any level of maincenter nociception nervous pathway, but due to the reason of distributing position, perineural damage is the most common.The generation mechanism of neuropathic pain is the most at present, but the research of this aspect is the most active.May have the participation of number of mechanisms in this case in many patients, this situation is similar with the chronic disease of some other complexity, such as asthma or chronic heart failure, it is thus possible to the different pharmaceutical being required for various mechanism is treated.
Gabapentin (gabapentin, trade name Neurontin), chemistry entitled 1-(aminomethyl) Cyclohexaneacetic acid, molecular structure is similar to γ-aminobutyric acid (GABA), a kind of new antiepileptic drugs, 1994 FDA (FDA) ratify this medicine and be used clinically for treating various epilepsy.Research in recent years finds, gabapentin has good therapeutic effect to neuropathic pain (neuropathicpain), with opiates medicine use in conjunction, treatment postoperative pain is had obvious synergy.The untoward reaction of this medicine is few, is therefore expected to become promising analgesic.Apply at present and only have oral formulations at clinical gabapentin, at small intestinal mainly by L amino acid transport Systemic absorption after being administered orally.One notable pharmacology of gabapentin is to degrade without liver, do not induce and the most do not suppress hepatomicrosome enzyme, extremely low with protein bound rate, therefore have substantially no effect on other antuepileptics and the metabolism of opiates medicine, but other drug may affect the elimination of gabapentin.
Gabapentin (gabapentin) is secondary antuepileptic, is most commonly used to treat neuropathic pain.Extensive double blinding, random, placebo-controlled trial prove, after gabapentin therapy diabetic peripheral neuropathic pain and herpes zoster, pain is effective.In this experiment, the dosage of gabapentin titrated by 900mg/ day, until maximum tolerable dose (up to 3600mg/ day), and keep stable in the test maintenance stage.With sleep, emotion and the improvement of quality of life while pain scores improvement.It is the most effective that gabapentin is used for treating the neuropathic pain that cancer, phantom pain, Guillain Barre syndrome (Guillain-Barr é syndrome) and spinal cord injury causes.
Gabapentin chemical constitution is similar to GABA, synthesis and release on GABA have some to affect, but itself is not combined with GABA receptor, do not affect picked-up and the metabolism of endogenous GABA, its quick effect of anti-pain is not affected by GABA receptor antagonist, it is taken as that mechanism of action may be unrelated with GABA receptor.It is now recognized that the analgesic activity of gabapentin may with following several respects mechanism about: 1. gabapentin may reduce the flow of calcium ions of neuron by suppression P/Q type calcium channel, and then reduces gentleman's propylhomoserin (AMPA) receptor activation and the release of norepinephrine in cerebral tissue.2. gabapentin plays a role probably as the antagonist at a kind of NMDA-glycine position, and D-Ser may be relevant with suppression excitatory amino acid release by the analgesic activity of competitive displacement gabapentin performance reverse effect 3. gabapentin.
Retigabine is a kind of new antiepileptic medicine, GlaxoSmithKline PLC and Valeant company develop cooperatively, be the opener simultaneously as potassium-channel and the reinforcing agent of γ-aminobutyric acid (GABA).The double action mechanism of retigabine, can control the outbreak of epilepsy from different mechanisms, alleviates the state of an illness.For neuron potassium channel openers.The epilepsy partial seizure of neuron potassium channel openers retigabine (retigabine) treatment intractable epilepsy patient has good therapeutic effect.At present on international market, the Hot spots for development of antiepileptic is concentrated mainly on efficiently, in low-risk and low side effect.The appearance of retigabine, is the potential major progress being interrupted ictal epilepsy therapy, brings new hope to the ictal epileptic of interruption.
In the medicine of existing treatment neuropathic pain, there is no the pharmaceutical composition as active component with gabapentin and retigabine.
Summary of the invention
In order to overcome existing neuropathic pain treatment medication effect undesirable, the defect that side effect is big, the present invention provides a kind of new neuropathic pain treatment pharmaceutical composition, the advantage of this pharmaceutical composition is that component is clear and definite, definite effect, therapeutic effect is notable, and toxic and side effects is low.
Pharmaceutical composition of the present invention contains active constituents of medicine retigabine and gabapentin, by a large amount of pharmacological evaluation, the present inventor finds that this pharmaceutical composition shows significant therapeutic effect when treating neuropathic pain.The embodiment of the present invention 7 proves that retigabine gabapentin drug compositions is significantly better than each single medicine group therapeutic effect to neuropathic pain to the therapeutic effect of various neuropathic pain, and two kinds of medicines embody obvious synergism to the treatment of neuropathic pain.After the embodiment of the present invention 8 shows retigabine and gabapentin composition compound recipe, no matter compared with retigabine list medicine group, or compared with gabapentin list medicine group, it all shows significant therapeutic effect to diabetes nerve pathologic pain rat model, and this therapeutic effect is obviously enhanced along with the prolongation for the treatment of time.Retigabine and gabapentin show significant synergism in terms of the neuropathic pain that treatment diabetes cause.
In the present invention after retigabine and gabapentin use in conjunction composition compound recipe, ingredient clearly, stable in properties, influence each other less, it is simple to the foundation of pharmaceutical preparation quality control, when being conducive to producing preparation, the control of quality, is especially suitable for industrialized great production.
Pharmaceutical composition of the present invention comprises two kinds of active constituents of medicine:
1) retigabine；
2) gabapentin.
In pharmaceutical composition as above, the weight ratio of retigabine and gabapentin is 1:0.01-500, it is preferable that the weight ratio of retigabine and gabapentin is 1:0.2-300；It is further preferred that the weight ratio of retigabine and gabapentin is 1:1.5-24.
Drug regimen species of the present invention can also be prepared as suitable drug formulation containing acceptable auxiliary material excipient on preparation process.The medicine composition dosage form of the present invention is preferably oral Pharmaceutical dosage forms.Oral Pharmaceutical dosage forms can be tablet, slow-release tablet agent, capsule, oral liquid, granule etc..Described tablet contains one or more following adjuvants: starch, dextrin, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline Cellulose, hydroxypropyl cellulose, starch slurry lactose, mannitol, micropowder silica gel, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone.Described capsule or granule contain one or more following adjuvants: amylum pregelatinisatum, lactose, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, micropowder silica gel.Described slow releasing agent or controlled release agent contain one or more following adjuvants: amylum pregelatinisatum, lactose, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, micropowder silica gel, carbomer, sodium alginate, calcium alginate, chitin.
According in the pharmaceutical dosage form that pharmaceutical composition provided by the present invention is prepared as, the effective dose that in described preparation, each preparation unit contains gabapentin is 10mg-500mg, and the effective dose containing retigabine is 10mg-250mg.
It is another object of the present invention to open pharmaceutical composition purposes in preparation treatment neuropathic pain medicine.Pharmaceutical composition of the present invention achieves good therapeutic effect to neuropathic pain, especially achieves obvious synergism when treating the neuropathic pain that diabetes cause, is significantly better than therapeutic effect when gabapentin and the independent medication of retigabine.During the nerve pathological pain that medicine composite for curing neuropathic pain of the present invention, especially diabetes cause, preferably oral administration.In pharmaceutical composition, the dosage of gabapentin is 5mg/kg.d-40mg/kg.d, preferably 10mg/kg.d-40mg/kg.d；The dosage of retigabine is 1mg/kg.d-3mg/kg.d, preferably 1.5mg/kg.d-2.5mg/kg.d.
The advantage of this pharmaceutical composition is embodied in following aspect:
(1) in pharmaceutical composition of the present invention, retigabine and gabapentin, when treating the neuropathic pain that neuropathic pain especially diabetes cause, are significantly better than each single therapy group, embody the strongest synergism.It addition, pharmaceutical composition of the present invention embodies effect build-up effect during long-term prescription, therefore it is desired that long-term prescription can significantly improve neuropathic pain, and may thoroughly reach the purpose cured.
(2) over the course for the treatment of; merge the medicine using mechanism of action different and can strengthen the therapeutic effect to neuropathic pain; make Other Risk Factors or cohesive disease be optimally controlled, be conducive to the neural system structure and function of protection, reduce toxic and side effects incidence rate further.
(3) due to when forming immobilised compound, each single pharmaceutical quantities has reduced, and makes side effects of pharmaceutical drugs reduce, and medical expense greatly reduces, therefore immobilised compound is administered and the benefit/expense ratio for the treatment of is significantly improved, so that the curative compliance of patient is greatly improved.
(4) neuropathic pain that diabetes are especially caused by pharmaceutical composition of the present invention is effective, effectively alleviates the pain of such patient, and diabetes itself also function to certain and mitigation, so that the quality of life of patient is substantially improved.
Detailed description of the invention
Now being further illustrated by the following examples present disclosure, wherein embodiment 1～6 is formulation embodiment, and embodiment 7～8 is pharmacodynamics embodiment, but the range of application of the present invention is not limited only to the following example.
The preparation of embodiment 1 gabapentin retigabine compound tablet
Preparation technology: first gabapentin and cyclodextrin are put into ground and mixed in mortar uniform, it is sequentially added into carboxymethyl starch sodium, amylum pregelatinisatum mix homogeneously, it is eventually adding retigabine mixing, make binding agent with the ethanol solution of 5%PVP to pelletize, 40 DEG C are dried, granulate, add magnesium stearate mixing, tabletting, to obtain final product.
The preparation of embodiment 2 gabapentin retigabine compound tablet
Preparation technology: first gabapentin and cyclodextrin are put into ground and mixed in mortar uniform, it is sequentially added into carboxymethyl starch sodium, amylum pregelatinisatum mix homogeneously, it is eventually adding retigabine mixing, make binding agent with the ethanol solution of 5%PVP to pelletize, 40 DEG C are dried, granulate, add magnesium stearate mixing, tabletting, to obtain final product.
The preparation of embodiment 3 gabapentin retigabine compound tablet
Preparation technology: gabapentin and beta-schardinger dextrin-are first put into ground and mixed in mortar uniform, be sequentially added into carboxymethyl starch sodium, microcrystalline Cellulose, micropowder silica gel mix homogeneously, is eventually adding retigabine mixing, direct powder compression, to obtain final product.
The preparation of embodiment 4 gabapentin retigabine capsule
Preparation technology: gabapentin and beta-schardinger dextrin-are first put into ground and mixed in mortar uniform, be sequentially added into microcrystalline Cellulose, micropowder silica gel mix homogeneously, is eventually adding retigabine mixing, loads capsule shells, to obtain final product.
The preparation of embodiment 5 gabapentin retigabine granule
Preparation technology: first gabapentin is mixed homogeneously with beta-schardinger dextrin-, be subsequently adding retigabine, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, methylcellulose, sodium lauryl sulphate mix after crossing 16 mesh sieves, after mix homogeneously with orange flavor, aspartame again.Mixture is pelletized with 5% polyvidone ethanol, is dried, granulate, subpackage, to obtain final product.
The preparation of embodiment 6 gabapentin retigabine slow releasing tablet
Preparation technology: weigh the gabapentin of recipe quantity, retigabine, carbomer, hydroxypropyl cellulose, beta-schardinger dextrin-mix homogeneously.Separately take 8% starch slurry solution of Sq, add in mixed-powder, soft material processed after mix homogeneously, pelletized by 16 mesh sieves, less than 60 DEG C are dried.Carry out granulate with 18 mesh sieves after completing after drying, sift out the fine powder in dry granular, the magnesium stearate mixing with sieving, it is mixed evenly with dry granule the most again, tabletting, to obtain final product.
The embodiment 7 gabapentin retigabine pharmaceutical composition therapeutical effect to neuropathic pain
1. experiment modeling and administration
(1) the gabapentin retigabine pharmaceutical composition impact on rat formaldehyde induced pain
50 SD rats are randomly divided into 5 groups, often group 10, and male and female half and half, before modeling, 1h gavage gives each group of medicine (10ml/kg) (as shown in table 1), and model group gavage is to pure water.With l00L microsyringe at the formaldehyde 100 μ L of the left sufficient plantar subcutaneous injection 2% of rat, after injection of formaldehyde, observing behavioristics's change of each group of rat immediately, every 5min records 1 time, continues 1h, and observer does not knows the packet situation (double blinding) of experiment.Experimentation is avoided high light, keeps environment quiet.
It is that two hind paws lie in ground that rat pain is divided into 4 grades: 0 grade, movable without exception；1 grade is injection sole gentle touchdown ground, has limping time movable；2 grades are lifted for injection sole, not in contact with the ground；Lick for rat for 3 grades and sting or shake injection sole.
The computational methods of level (pain intensity scoring, PIS): PIS=(Tl+2 × T2+3 × T3)/(5 × 60), wherein Tl bitterly, T2, T3 are l occur in 5min respectively, the time of 2,3 grades.
The packet of table 1 experimental rat and dosage
(2) the gabapentin retigabine pharmaceutical composition impact on rat hotplate induced pain
Female sd inbred rats 50, is divided into 5 groups immediately, and each treated animal presses table 2 gastric infusion (10ml/kg), and model group fills pure water, and twice daily, the 3rd afternoon is administered half an hour after and is measured, and controls room temperature 18 DEG C～21 DEG C during experiment.Rat is placed on hot-plate instrument (hot plate temperature controls at 55 DEG C), is certainly placed on hot plate with stopwatch record rat and up to occurs licking metapedes required time, as the pain threshold of this Mus.Every rat measures 3 pain thresholds, and every rat measures time interval 40min 2 times.
The packet of table 2 experimental rat and dosage
(3) the gabapentin retigabine impact on rat hot water induced pain
50 SD rats divide 5 groups at random, often group 10, male and female half and half, and gavage gives each group of medicine (10ml/kg) 1h afterwards and measures pain threshold (such as table 2), and model group gavage gives pure water.First leica is spread out sheet machine temperature and is set in 48 DEG C, on the tail of all rats, a labelling is made with oil pen in advance before mensuration, this labelling is about 5cm with the distance of rat tail tip, then rat Mus bag is wrapped, expose tail, and the tail of rat is put into stand sheet machine water, liquid level is overlapped with the labelling on rat tail, clock with stopwatch at once when rat tail and hot water contacts, the time that record rat tail shrinks for the first time from hot water, every rat measures 3 induced pain times, and (it is 10min that every rat measures time interval for 2 times, otherwise easily by burned rats), take the threshold of pain that mean is this rat of 3 induced pain times.
(4) gabapentin retigabine causes the impact of mouse writhing test to glacial acetic acid
Mouse peritoneal injection acetic acid, cause abdominal cavity large area and more lasting pain stimulation, mice is caused to produce writhing response, 1h after administration, i.p 0.6% acetic acid normal saline solution 0.1ml/10g, the time of record writhing response that every mice occurs in 20min after injection acetic acid induced pain and number of times.
The packet of table 3 experimental rat and dosage
2 statistical analysis
All data all input SPSS l 1.5 and carry out t inspection, and each Sets of Measurement data all use scholar s to represent.
3 experimental results
The impact on rat formaldehyde induced pain of the 3.1 gabapentin retigabines
nullAfter 2% formaldehyde 0.1mL is injected in experimental group Rats With Unilateral vola，Injection part is the redst and the most swollen，After administration, animal occurs contracting foot immediately and licks the behaviors such as foot，Obvious biphasic reaction is shown in 1h，Test result indicate that each group of medicine all can not alleviate the scoring of rat the first phase，Compound recipe low dose group is in the second 15-20 minute period of phase、25-30 minute period alleviated (P ＜ 0.05 or P ＜ 0.01) with the scoring of 40-50 minute period compared with model group，The scoring of compound recipe high dose group 20-60 minute is below model group (P ＜ 0.05 or P ＜ 0.01)，Gabapentin group is substantially less than model group (P ＜ 0.01) the 25-35 minute and section scoring in 40-50 minute，Retigabine group 25-30 divide with 40-50 minutes section scoring significantly alleviate (P ＜ 0.05).Result shows that compound recipe group presents dose-dependent effect, and high dose group scoring, less than low dose group, wherein has significant 5-10 minute, 30-35 minute and 50-60 minute difference.The scoring of gabapentin group is higher than compound recipe high dose group, statistically significant in 55-60 time period difference.The scoring of retigabine group, also above compound recipe high dose group, has statistical significance the 25-40 minute section difference, and the time that the peak value being administered each group of scoring occurs all postpones than model group.
The impact on rat hotplate induced pain of the 3.2 gabapentin retigabines
Experimental result (such as table 4) shows: compound recipe low dose group is pain threshold significantly raised (P ＜ 0.01) compared with model group upon administration with compound recipe high dose group, pain threshold also has rising (P ＜ 0.05) compared with gabapentin list medicine a large amount group and retigabine list medicine a large amount group, shows that gabapentin and retigabine also exist obvious synergism in terms of raising pain threshold.After wherein compound recipe group is administered after 30min, 70min and 110min, pain threshold persistently raise show compound recipe group show in terms for the treatment of persistently effect build-up effect.Low group of compound recipe is better than gabapentin list medicine a large amount group and retigabine list medicine high group in terms of raising pain threshold, shows significant synergism.
The impact on rat hotplate induced pain effect of the table 4 gabapentin retigabine
Compared with model group*P ＜ 0.05,**P ＜ 0.01；With gabapentin group ratio#P ＜ 0.05,##P ＜ 0.01
Compared with retigabine group,&P ＜ 0.05,&&P ＜ 0.01；
The impact on rat hot water induced pain of the 3.3 gabapentin retigabines
Experimental result (such as table 5) shows: after administration, 1h surveys the Rat Tall Flick time as pain threshold, compound recipe low dose group, compound recipe high dose group, gabapentin group whipping time compare the most substantially shortening (P ＜ 0.01 with matched group, P ＜ 0.001, P ＜ 0.01).
The impact on rat hot water induced pain pain threshold of the table 5 gabapentin retigabine
Compared with model group,*P ＜ 0.05,**P〈0.01；
Diabetes are caused the treatment of neuropathic pain by embodiment 8 gabapentin retigabine pharmaceutical composition
1.1 laboratory animals and experimental article
Healthy male SD rat 120, body weight 180～220g, SPF level, Shandong New Times Pharmaceutical new drug An Ping center provides.Room temperature 20～25 DEG C, room ventilation is good, and ammonia density is less than 20 × 10-6mL/m3, and relative humidity is 40%～70%, illumination period 12h, rat feeding in rustless steel mouse cage, 4, every cage, freely ingest, drink water.
Streptozotocin (STZ, sigma company produces, the U.S.)；ZH LUO/B type rat-tail photo-thermal dolorimeter, YLS 3E type electronics tenderness instrument are purchased from Northern Huaihe River Anhui Zheng Hua biological Instrument and equipments company limited.
1.2 modelings and screening
120 rats are left and taken 10 at random and are only used as Normal group, after remaining 110 Rat Fast 12h, by 75mg kg-1 disposable celiac injection STZ solution, (STZ solution is prepared: be dissolved in by STZ in pH 4.2,0.1m mol/L citrate buffer solution, solution matching while using, concentration is 3.75% (W/V) i.e. 0.5mL/100g).
Blood sugar detection: surveying tail vein sugar after modeling 7d, blood glucose >=16m mol/L is then diabetes rat, has 47 rats successfully to build up DM model (model group) in experiment.STZ injection before and injection after the 7th, 21,35,49d detect blood glucose, blood glucose be less than 16m mol/L then abandon.
Machinery Determination of Pain Threshold: in STZ inject before (base state), injection after 21,35,49d measure machinery the threshold of pain.Rat is placed in the transparent organic glass equipped with audio frequency amplifier and fixes in cylinder, outside rat-tail dew cylinder, at labelling at tail point 5cm.Rat adapts to environment 15min, after rat combing and inquiry activity disappear, rat-tail mark is placed at electronics tenderness instrument pressure head, (increase 10g per second) is pressed to rat-tail, when rat occurs that pain reaction then stops pressure, record pressure data (g), METHOD FOR CONTINUOUS DETERMINATION 5 times as whinnied, struggling, every minor tick 10min, averages as machinery pain threshold.If force value is more than 500g, reject.
Hot Determination of Pain Threshold: minute point, preparation method are with the machinery threshold of pain.The heating-up temperature of ZH LUO/B type rat-tail dolorimeter is set as 49 DEG C, is directed at tail point 4cm by radiating light source, records and start the time (s) to rat-tail tilting from illumination after reaching setting value.If light application time tilts not yet more than 15s rat-tail, reject, measure 5 times, every minor tick 10min, take average as burning pain threshold value.
Modeling result: the rat of injection streptozotocin remains rat after blood sugar detection screening, the machinery threshold of pain and the screening of burning pain threshold and is modeling successful diabetes nerve pathologic pain rat, and rat modeling success 96, modeling success rate is 87.2%.
1.3 animal packet and administrations
Choosing successfully the diabetes nerve pathologic rat 60 of modeling, be randomly divided into six groups, often group ten, gives agents respectively, separately increases Normal group.
Normal group: gavage gives isopyknic distilled water
Model group: gavage gives isopyknic distilled water
Add Bagao group: gavage gives the gabapentin of 300mg/kg
Add low group of bar: gavage gives the gabapentin of 10mg/kg
Auspicious for high group: gavage gives the retigabine of 50mg/kg
Auspicious for low group: gavage gives the retigabine of 1mg/kg
Compound recipe one group: gavage gives the gabapentin of 10mg/kg and the pharmaceutical composition of the retigabine of 50mg/kg
Compound recipe two groups: gavage gives gabapentin and the pharmaceutical composition of 1mg/kg retigabine of 10mg/kg
Compound recipe three groups: gavage gives gabapentin and the 1mg/kg retigabine pharmaceutical composition of 300mg/kg
Compound recipe four groups: gavage gives gabapentin and the 50mg/kg retigabine pharmaceutical composition of 300mg/kg
Each administration group medicine dissolves with appropriate distilled water, and gastric infusion is administered once a day.After being administered 7d, 14d, 21d, measure mechanical pain threshold and the burning pain threshold value of each administration group rat.It is as shown in the table for each administration group measurement result.
Table 6 compound recipe therapeutical effect to diabetes nerve pathologic rat
Compared with normal group,**P〈0.01；Compared with model group,#P ＜ 0.05, ##P ＜ 0.01；
Compared with adding Bagao group,$P ＜ 0.05,$$P〈0.01；Compared with adding low group of bar,&P ＜ 0.05,&&P〈0.01；
With auspicious for compared with high group,@P ＜ 0.05,@@P〈0.01；With auspicious for compared with low group,%P ＜ 0.05,%%P〈0.01；
As can be seen from the above table, model group is compared with normal group, and the machinery threshold of pain and burning pain threshold decline notable (P ＜ 0.01), shows to use injection streptozotocin gained diabetes nerve pathologic pain rat model preferable, meets experiment needs.Gabapentin only has certain rising effect when high dose group to the diabetes nerve pathologic pain rat machinery threshold of pain and burning pain threshold, and its therapeutic effect does not extend with treatment time and strengthens.The high dose group of retigabine and low dose group the most do not cause the mechanical threshold of pain and the change of burning pain threshold of diabetes nerve pathologic pain rat.But when retigabine and gabapentin composition compound recipe, the neuropathic pain then caused diabetes shows significant therapeutic effect, and along with the prolongation of administration time, the mechanical threshold of pain and the burning pain threshold of diabetes nerve pathologic pain rat move closer to normal rat group.Compound recipe group (compound recipe one, two, three, four groups) is compared with retigabine list medicine group, or there is significant synergism in the notable significant therapeutic effect of equal table, i.e. retigabine and gabapentin in terms of the neuropathic pain causing diabetes in terms of the neuropathic pain that treatment diabetes cause compared with gabapentin list medicine group.
Claims (9)
1. a neuropathic pain medicine for treatment compositions, it is characterised in that its active constituents of medicine is retigabine and Jia Ba
Spray fourth.
2. pharmaceutical composition as claimed in claim 1, it is characterised in that retigabine and the weight of gabapentin in pharmaceutical composition
Ratio is 1:0.01-500.
3. pharmaceutical composition as claimed in claim 2, it is characterised in that retigabine and the weight of gabapentin in pharmaceutical composition
Ratio is 1:0.2-300.
4. pharmaceutical composition as claimed in claim 3, it is characterised in that retigabine and the weight of gabapentin in pharmaceutical composition
Ratio is 1:1.5-24.
5. pharmaceutical composition as claimed in claim 1, it is characterised in that pharmaceutical composition is oral drug preparation.
6. the pharmaceutical composition as described in claim 1-5, it is characterised in that described oral drug preparation is tablet, capsule, delays
Release tablet formulations, granule.
7. pharmaceutical composition as claimed in claim 5, it is characterised in that containing adding in each preparation unit of described oral drug preparation
The effective dose of bar spray fourth is 10mg-500mg, and the effective dose containing retigabine is 10mg-250mg.
8. the purposes in preparation treatment neuropathic pain medicine of the pharmaceutical composition described in claim 1.
9. pharmaceutical composition purposes as claimed in claim 8, it is characterised in that described neuropathic pain is that diabetes cause
Neuropathic pain.
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2016
- 2016-06-29 CN CN201610496300.2A patent/CN105919990A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1409632A (en) * | 1999-09-27 | 2003-04-09 | 维阿特里斯公司 | Use of retigabin for treating neuropathic pain |
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