CN107773560A - A kind of Pharmaceutical composition with analgesic and antiinflammation - Google Patents

Abstract

The present invention relates to a kind of pharmaceutical composition, specifically a kind of new pharmaceutical composition with analgesic and anti-inflammatory and its production and use.Said composition is made up of active constituents of medicine and pharmaceutically acceptable carrier, and the active constituents of medicine is made up of brufen or its pharmaceutically acceptable salt or its enantiomter or its enantiomter pharmaceutically acceptable salt and Pridinol or its pharmaceutically acceptable salt.Present invention discover that said composition has the function that Synergistic, performance analgesia and antiinflammation can be cooperateed with, there is good clinical value.

Description

A kind of Pharmaceutical composition with analgesic and antiinflammation

Technical field

The present invention relates to a kind of pharmaceutical composition with analgesic and antiinflammation, specifically include by brufen or its pharmacy Upper acceptable salt or its enantiomter or its enantiomter pharmaceutically acceptable salt and Pridinol or its pharmaceutically Acceptable salt and pharmaceutically acceptable carrier composition.Provide the preparation method of said composition and in anti-inflammatory and antalgic simultaneously The purposes of aspect.

Background technology

Brufen, also known as brufen, Chinese are 2- (- 4- isobutyl phenenyls）Propionic acid, structural formula are shown in Fig. 1, are With analgesic, anti-inflammatory and antipyretic common drug, at present extensive use in the world, turn into the best-selling OTC in the whole world One of medicine, and aspirin, paracetamol are listed as three big pillar product of analgesic-antipyretic together.Brufen is as prescription medicine It is mainly used in treating various rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, postoperative pain, post-partum pain With the pain agent diseases associated with inflammation of soft tissue injury, general dosage is up to 3200mg/ days.Brufen is main as non-prescribed medicine It is used for the pain for treating various headache, antimigraine, rheumatalgia, courbature, backache, neuralgia, dysmenorrhoea, toothache and colds and flu Pain and fever symptoms, general dosage are up to 1200mg/ days.

Fig. 1：Brufen

Brufen is most earlier than 1964 by Britain Stewart doctors Adams and the team scientific research expert of its leader ColinBurrows, chemist John doctors Nicholson have found synthesis jointly.By Britain cloth thatch（BOOTS）Company is first First patented and industrialized production, Patent No. US 3385886.Oral solid formulation is in 1969 first in Britain City, 1974 in U.S.'s Initial Public Offering.The effect of due in terms of antipyretic-antalgic, is notable, and be particularly suitable for use in children, is world health Children's first choice antipyretic of Organisation recommendations, and toxicity is low, and better than aspirin and paracetamol, thus market expands rapidly. Due to the effect of brufen is preferable and there is less adverse reaction, the U.S., the successive approval of Britain switch to it with prescription medicine non- Prescription medicine.Nineteen eighty-three turns into OTC in Britain, turns into OTC in the U.S. within 1984.To in the early 1990s, world market cloth Lip river The sales volume of fragrant preparation has broken through 1,000,000,000 dollars of high pointes, is the earliest analgesic-antipyretic product for breaking through 1,000,000,000 dollars.Brufen is The derivative of aromatic series benzenpropanoic acid, and a kind of conventional NSAIDs (NSAIDs).Its main function approach is non-choosing Selecting property suppresses cyclooxygenase（COX）, so as to suppress the synthesis of prostaglandin and release, while adjust leukocyte activity, reduce carefully Intracellular cytokine produces, suppresses that the approach such as free radical and signal transduction is reached and play antiinflammatory action.

It is safe in brufen clinical practice.One is intended to by comprehensive high quality by the WHO meta-analysises initiated Research, there is provided gastrointestinal complication report special and relevant with Time of Administration length a comprehensive assessment NSAIDs.Research 32 random experiments and 13 cohort studies have been collected, 5325 has been shared and at least takes a kind of NSAID, control group shares 3453 people. Intestinal complications are defined as：Ulcer, bleeding, perforation, be in hospital or associated death in any one.Meta-analysis result shows Show, in the NSAIDs of 7 assessed kind, gastrointestinal complication relative risk the lowest is brufen, and relative risk rate RR is 1.1995%, cumulative morbidity CI are 0.93~1.54.

One large-scale research Medical data analyses show that brufen is heart infarction least risk in traditional NSAIDs.Should Research is carried out based on a large sample arthritis crowd, and it analyzes several Selective COX-2 inhibitors and non-selection Property NSAIDs occur acute myocardial infarction risk.This research conclusion is rofecoxib, Meloxicam, the significant acute heart of increase of sulindac Flesh infarct（AMI）Occurrence risk, especially when high dose is applied.Rather than Nabumetone, naproxen, cloth in selective N SAIDs Ibuprofen is relatively low with respect to AMI risks.

Exactly because brufen has stronger anti-inflammatory as described above and antipyretic effect and less side effect, from Since 1969 are developed by Britain, clinic it has been widely used in always.There is a chiral carbon on the side chain of brufen Atom, so two optical isomers of R (-) brufen and S (+) brufen be present.At this in enantiomer, suppressing prostaglandin The pharmacological activity of generation mostlys come from d-isomer S（+）Brufen, and through the external experiment card for suppressing prostaglandin synthesis Bright, the ability that S (+) brufen suppresses prostaglandin synthesis is about 160 times of R (-) enantiomer.The suppression of raceme brufen The effect that platelet aggregation and thromboxane are formed is pure S（+）The half of brufen.In vivo studies shows S (+) brufen Activities present is 1.4 times of R (-) brufen.

Having studied simultaneously confirms S（+）Brufen be brufen main active, and R (-) brufen substantially without Imitate, after oral raceme brufen, R (-) brufen that there are about 50 ~ 60% is converted to S（+）Brufen.And work as the outer used time, then In the absence of this conversion.Therefore S (+) d-isomer has the effect of higher compared with waiting dosage brufen raceme, and smaller dose is It can reach therapeutic action.Effect and purposes of S (+) brufen with brufen are identical, and there are some researches show only need raceme cloth The (S)-ibuprofen of the half-value dose of ibuprofen one can be obtained by and the former identical clinical efficacy.200mg and 400mg dextrorotation cloth Ibuprofen piece, (.1 of Tmax 2~2 .2 hours) can be absorbed after oral in human body rapidly and reach the .4mg/ ml of peak concentration 12 (200mg)、12.0mg/ ml (400mg)。

The metabolic characteristic of (S)-ibuprofen and left-handed brufen is also different, and left-handed brufen is relevant with fat metabolism path, And be incorporated into together on triglyceride with Endogenous fatty acid, and (S)-ibuprofen and these special metabolic responses without Close, therefore, (S)-ibuprofen is than racemic ibuprofen from removing more thorough in vivo.

Compared with other NSAID, (S)-ibuprofen has good tolerance:Racemic ibuprofen rate of side effects is 30%, double chloric acid phenol are then up to 90 %.Long-term safety experiment shows that the rate of side effects of (S)-ibuprofen is only 15.2 %, the wherein .7% of digestive tract reaction 11, the % of reaction of central nervous system 1.3, dermoreaction 1.3%, other 0.9%, tolerance is good It is good.After open application, the investigation of larger samples amount then shows rate of side effects for the % of 2.3 %~2.7.Therefore dextrorotation cloth Ibuprofen is better than brufen in terms of security and pharmacodynamics.

(S)-ibuprofen is entitled in Austrian traded commodity by Gebro Broscheck companies most earlier than 1994 Seraetil, specification are 150 mg and 300 mg.Thereafter, (S)-ibuprofen is multiple national as a kind of new non-steroidal anti-inflammatory Medicine lists, and such as (S)-ibuprofen tablet has listing in Australia, Germany, Italy and country of Britain.

Therefore except with racemate form, brufen can also brufen activity form-(S)-ibuprofen（S（+）Bu Luo It is fragrant）In the presence of.Brufen or (S)-ibuprofen are also likely to be the form of salt simultaneously, as the lysine of brufen or (S)-ibuprofen, The forms such as arginine salt.

Pridinol is that R.W.Cunningham in 1949 is synthesized first with 3- piperidine propanoic acids ethyl ester with phenyl-magnesium-bromide, Its chemical name is 1,1- diphenyl -3- piperidines -1- propyl alcohol, and structural formula is shown in Fig. 2, and it is a kind of with skeletal muscle relaxation effect Central anticholinergic agent.Afterwards, R.W.Cunningham has found that Pridinol has obvious relaxation effect to muscle cramp.Its salt Hydrochlorate preparation and mesylate preparation then list, applied to muscle cramp and with pain or the motor disorder of contraction (such as pain in back and loin, neck shoulder wrist syndrome, omarthritis, deformity of spinal column etc.) and Parkinson's.

Fig. 2：Pridinol

Pridinol is a kind of central anticholinergic agent with skeletal muscle relaxation effect.Acetylcholine is as wide in nervous system A kind of general existing neurotransmitter, is discharged by presynaptic membrane in the form of vesica, and with the nicotine receptor of cell surface (N-type by Body) or muscarinic receptors (M receptors) with reference to and play a role.Pridinol is a kind of M receptors antagonist, by Ml and The effect of M4 receptor subtypes, cholinergic neurotransmitter excitement acceptor is hindered, the reflex activity to spinal motion neuron produces suppression Make and use.

Pridinol can act on the bone and muscle of central nervous system and peripheral neverous system, to strychnine, can Mouse shock convulsions has inhibitory action caused by La Zuo and nicotine, and rat stretch reflex caused by electro photoluminescence is excessively increased There is inhibitory action, have relexation to muscle.Gu Chuan it is quick it is virtuous he wait by Magnus methods discovery Pridinol there is anti-acetyl courage The effect of alkali, antihistamine and anti-barium chloride, for three kinds of spasmodic contractions caused caused by convulsion agent, there is depression effect.In addition, Pridinol also has the function that anti-oxytocins and anti-slow sharp skin, also has relaxation effect to the abdominal muscles spasm of frog.

Because Pridinol is a kind of central anticholinergic agent with skeletal muscle relaxation effect, have to muscle cramp substantially Relaxation effect, be clinically used for muscle cramp and parkinsonism etc. with pain and the motor disorder of contraction（Such as waist Back pain, neck shoulder wrist syndrome, omarthritis, deformity of spinal column etc.）.In addition, general anesthesia adjuvant is alternatively arranged as, shallower Under general anesthesia, the degree of flaccid muscles needed for surgical operation is obtained, so as to reduce the dosage of GENERAL ANESTHETICS.

The tolerance of Pridinol is good, and adverse reaction rate is relatively low.More typical adverse reaction, which occurs mainly in, to disappear (including poor appetite, stomach burns for the adverse reaction of change system, Neurotoxicity and some allergic symptoms, wherein digestive system Heat, dry etc.) it is most commonly seen.In a clinical test, in 974 patients for taking Pridinol ordinary tablet, suffer from for totally 135 There is adverse reaction (13.8%) in person, wherein 53 patients's (5.4%) occur including the digestive functions such as Nausea and vomiting, poor appetite Disorder symptoms；There is sleepy grade for psychiatric system symptom in 32 patients's (3.3%)；There are the diseases such as dizziness, dizziness in 21 patients's (2.2%) Shape；There are the symptoms such as burnout, weakness in 17 patients's (1.7%).It is random to carry out clinical examination, in the trouble that 10 are taken Pridinol A Neuroleptic Leukocytopenia is found in person.

At present, the medicinal forms of Pridinol mainly have two kinds of hydrochloride and mesylate, in Japan, South Korea, Argentina Deng country and Taiwan listing for many years, its preparation mainly has common compressed tablets, coating tablet, enteric coatel tablets, parenteral solution and injection Powder pin etc..Such as the methylsulfonic acid pridinol piece of Argentinian Laboratorios Bago S.A companies exploitation, trade name Relaxedan, specification 4mg.The Pridinol mesylate injection that Nippon Shinyaku Co., Ltd. (JP) Tokyo To, Japan develops, specification:lmL:2mg, The methylsulfonic acid pridinol injection freeze-dried powder that Argentinian CASAASCO companies develop, specification:2.2mg.

Methylsulfonic acid pridinol is prepared into composition with brufen, has collaboration pharmacological action, is keeping methanesulfonic acid general vertical On the basis of ground promise bone and myorelaxant effects, collaboration enhances analgesia and anti-inflammatory effects, is more beneficial for muscle cramp and companion There is a treatment of the illnesss such as pain, effect is than alone methylsulfonic acid pridinol or alone brufen more preferably.It can be additionally used in arthritis, god Heating etc. caused by dysmenorrhoea, courbature, dysmenorrhoea, various inflammation.

On the drug combination of brufen, one kind is disclosed in patent EP388125, EP535841, CN1083265C Pharmaceutical composition containing brufen and codeine, and describe said composition be used for treat Acute Pain as have a headache and toothache, It can be additionally used in pain such as osteoarthritis, rheumatoid arthritis, rheumatoid, scapulohumeral periarthritis, the tenosynovitis of chronic disease With the pain symptom such as cancer.But the codeine in said composition is opium kind analgesicses, prolonged application can produce tolerance, habituation Property, be discontinued after withrawal symptom, easily there are the adverse reactions such as respiration inhibition, bronchial spasm, be suitable only for clinically acute control Treat moderate and severe pain.And a kind of pharmaceutical compositions containing brufen and domperidone are disclosed in patent CN1115150C Thing, the pharmaceutical usage of narration is treatment antimigraine, it is impossible to treats other kinds of pain, indication is more single, limits this The application of composition.A kind of pharmaceutical composition comprising brufen and pseudoephedrine is disclosed in US5100675, can be mitigated Flu-like symptom and flu, fever, the symptom of nasosinusitis or nasal obstruction, headache and general malaise, but said composition is mainly used in Symptom in terms of influenza of catching a cold, not including myalgia, backache, neuralgia, dysmenorrhoea, have a toothache, rheumatic arthritis ankyloses Indication, the limitations such as property spondylitis, osteoarthritis, postoperative pain and soft tissue injury are very big.

The content of the invention

It is an object of the invention to provide one kind to contain by brufen or its pharmaceutically acceptable salt or its enantiomerism Body or its enantiomter pharmaceutically acceptable salt and Pridinol or its pharmaceutically acceptable salt are combined to be stopped for anti-inflammatory The Pharmaceutical composition of pain.Said composition is on bone and exposure basis of flaccid muscles is made, collaboration enhancing analgesia and antiinflammation. Said composition is made up of active constituents of medicine and pharmaceutically acceptable carrier, wherein the active constituents of medicine is by by brufen Or its pharmaceutically acceptable salt or its enantiomter or its enantiomter pharmaceutically acceptable salt and Pridinol or Its pharmaceutically acceptable salt forms.

Another object of the present invention there is provided the preparation method and purposes of the Pharmaceutical composition.

Composition of the present invention is mainly used in alleviating and treating pain and anti-inflammatory, including local soft tissue pain （Such as：Courbature, arthralgia, lumbago and strain, pull, strain caused by pain）, muscle cramp pain（Ache back Bitterly, neck shoulder arm syndrome, scapulohumeral periarthritis, morphotropism vertebra disease）, neuralgia, dysmenorrhoea, have a toothache, rheumatic arthritis, ankylosing Spondylitis, osteoarthritis and postoperative pain.

Clinically, brufen is analgesic, anti-inflammatory and antipyretic common drug, is a kind of conventional NSAIDs (NSAIDs), mechanism of action is non-selective suppression cyclooxygenase（COX）.And Pridinol to be a kind of there is skeletal muscle relaxation to make Central anticholinergic agent, there is obvious relaxation effect to muscle cramp.The maintenance maximum dose of brufen is 3200mg/ My god, its half-life period (t_1/2) it is 1.8 ~ 2 hours.The common usage of Pridinol is 2mg/ days, 1 day 1 time, its half-life period (t_1/2) be 0.48±0.05h.It is that performance makes bone and myorelaxant effects to Pridinol rapidly after being administered that both, which share synergy, afterwards Brufen gradually plays analgesic and antiinflammation.

Consider that We conducted drug compatibility experiment, examination from the science and reasonability for preparing drug combination preparation Verify that both bright medicines have preferable compatibility in nature in physics and chemistry in itself, therefore brufen and Pridinol are along with suitable The pharmaceutic adjuvant of amount can be made into compound preparation, and be confirmed through overtesting, work well.

The invention provides the purposes in terms of the preparation method of the composition and analgesic antiphlogistic, concrete technical scheme is： There is provided it is a kind of daily using effective dose be 25~3200mg brufen the pharmaceutical salts or enantiomer of its suitable dosage or its The enantiomer pharmaceutical salts of suitable dosage, and the Pridinol or the medicine of the pharmaceutical salts of its suitable dosage that effective dose is 1~40mg Thing.Both effective dose ratios are 3200:1~0.625:1.

Preferably daily apply comprising effective dose be 100~2400mg brufen or its suitable dosage pharmaceutical salts or The enantiomer pharmaceutical salts of enantiomer or its suitable dosage, and the Pridinol or its suitable dosage that effective dose is 2~20mg Pharmaceutical salts medicine.Preferable effective dose ratio is 1200:1~5:1.

The present invention contains the brufen that a kind of effective dose is 0.5%~40% (w/w) or the pharmaceutical salts of its suitable dosage Or the enantiomer pharmaceutical salts of enantiomer or its suitable dosage, and effective dose is 0.01%~20%（W/w Pridinol) or its The local topical formulation of the pharmaceutical salts composition of suitable dosage.

Preferably effective dose be 1%~20% (w/w) brufen or its suitable dosage pharmaceutical salts or enantiomer or The enantiomer pharmaceutical salts of its suitable dosage, and the Pridinol or its suitable dosage that effective dose is 0.05%~10% (w/w) The local topical formulation of pharmaceutical salts composition.

The present invention, brufen exist in the form of racemic modification or its enantiomeric form-(S)-ibuprofen, preferably dextrorotation cloth Ibuprofen form, its analgesic effect and clinically also have good tolerance much stronger than the brufen of racemate form.

Its pharmaceutically acceptable salt of the invention includes：

A) inorganic cation salt, including sodium, potassium, lithium, magnesium, calcium, caesium, ferrous iron, zinc, bivalent manganese, aluminium, iron, tin, copper and manganese sun from Alite；

B) brufen is pharmaceutically approved primary, secondary, uncle, the organic salt of quaternary ammonium, including：Triethylamine, tripropyl amine (TPA), 2- dimethylaminos Base ethanol, 2- DEAE diethylaminoethanols, lysine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, Hai Ba It is bright, choline, ethylenediamine, aminoglucose, TRIS（Hydroxymethyl）- aminomethane, methylglucosamine, theobromine, piperazine, piperidines, gather The primary, secondary of polyimide resin, uncle, quaternary ammonium salt；Or

C) their mixture.

In the present invention Pridinol pharmaceutically acceptable salt be mesylate, hydrochloride, sulfate, acetate, benzoate, Citrate, benzene sulfonate, maleate, fumarate, tartrate, esilate, para Toluic Acid's sulfonate, hydrobromic acid Salt, lauryl sulfonate, camsilate or DHB salt, preferably mesylate and hydrochloride.

The composition of the present invention is suitable for oral administration, sublingual administration, intestinal canal administration, parenterai administration, lung inhalation And topical routes of administration；The pharmaceutical dosage form that it is included is oral formulations, external preparation, ejection preparation, gas dispersant；Oral system Agent can be tablet, capsule, Orally-disintegrating tablet, pelliculae pro cavo oris, granule, supensoid agent, sustained-release preparation, and preferably peroral dosage form is Tablet, capsule；External preparation is preferably gel, ointment, liniment, patch, cataplasm, suppository；Gas dispersant is preferably Aerosol, spray;Ejection preparation is preferably intravenous fluid formulation.

Its common oral preparation includes filler, adhesive, disintegrant, lubricant.Filler include starch, sucrose, can Pressure property starch, pregelatinized starch, microcrystalline cellulose, lactose, the one or more of inorganic salts；Adhesive may be selected from PVP, Hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch slurry, the one or more of sodium carboxymethylcellulose；Disintegrant may be selected from carboxylic first Base sodium starch, low-substituted hydroxypropyl cellulose, PVPP, Ac-Di-Sol, the one of calcium carboxymethylcellulose Kind is several；Lubricant may be selected from the one or more of magnesium stearate, sodium stearyl fumarate, superfine silica gel powder and talcum powder.

Its transdermal dosage form-patch or cataplasm are made up of back sheet, release-controlled film, load medicine pressure-sensitive adhesive layer and adherent layer； It carries medicine pressure-sensitive adhesive layer auxiliary material by pressure sensitive adhesive, EVA, colloidal silica, oleic acid, isopropyl myristate, azone, N- Methyl pyrrolidone, ethanol, propane diols, menthol, moon silicic acid glyceride, methyl laurate, ethyl oleate, hypromellose Element, lightweight oily paraffin, lactose, silicone oil, polyethylene glycol, carbopol, glycerine, one or more of groups of nonionic surfactant Into.

Its external use semi-solid preparation-gel or ointment mainly include carrier, cosolvent, solubilizer, NMF, transdermal suction Receive any of accelerator, preservative, emulsifying agent, antioxidant, aromatic or a variety of；Carrier is all scholars including oleaginous base Woods, stearic acid, paraffin, atoleine, beeswax, spermaceti, Brazil wax, lanolin, dimeticone, stearyl alcohol, monostearate One or more in glyceride, glycol stearate, hexadecanol, octadecyl alcolol, cetostearyl alcohol, vegetable oil, mineral oil；Water Property matrix is polyethylene glycols high-molecular compound and/or water；Emulsifying agent includes：Soda soap class（Such as potassium stearate）, fatty alcohol sulphur Acid（Ester）Sodium class（Such as lauryl sodium sulfate）, triethanolamine soaps（Such as triethanolamine stearic acid）, poly yamanashi esters（Such as poly- mountain Pear ester 80, polysorbate 60）, pegoxol 7 stearate, polyglyceryl fatty acid ester, oleic acid LABRAFIL M 1944CS, polyoxy The stearate of ethene 40, polyoxyethylene aliphatic alcohol ether, isopropyl myristate, the one or more of paregal O；NMF is sweet It is one or more in oil, propane diols, sorbierite；Preservative is oxybenzene esters（Such as methyl hydroxybenzoate, ethylparaben, nipalgin Propyl ester）, benzoic acid, sorbic acid, Phenoxyethanol, anesin, phenol, the one or more in BZK；Antioxidant is Butyl anisole（BHA）, dibutyl hydroxy toluene（BHT）, propylgallate（PG）And the one or more in tocopherol； Aromatic is strawberry essence, flavoring rose essence, flavoring pineapple essence, lavender oil, the one or more of neroli oil.

Its externally-applied liniment is made up of ethanol, oil or suitable solvent.

Its gas dispersant-aerosol or spray include medium, additives, propellant.Wherein propellant is hydro carbons, hydrogen The one or more of fluothane hydro carbons, diformazan ethers；Medium is ethanol or acetone；Additives include emulsifying agent, stabilizer, antioxygen Agent, the one or more of preservative.

Its ejection preparation includes 0.04~4% polyoxyethylene sorbitan monoleate, stabilizer, pH adjusting agent, needle-use activated carbon and injection Water；Stabilizer can be arginine, lysine.

Before making the present invention, there are no brufen or its pharmaceutically acceptable salt or its enantiomter or its mapping Isomers pharmaceutically acceptable salt is prepared into the report or related of composition to Pridinol or its pharmaceutically acceptable salt Patent or product, the present invention, which combines the two, is prepared into composition, belongs to the compound of innovation.

We have found that brufen and Pridinol pharmaceutical composition of the present invention is imitated in analgesia by pharmacodynamics test Fruit is significantly stronger than the effect that Isodose brufen is used alone, and synergic antalgic effect is presented.Antiinflammatory action is same with being used alone Deng the effect of dosage brufen, there was no significant difference, basically identical, and the antiinflammatory action of this and Pridinol is very weak consistent.

The present invention is creatively by brufen or its pharmaceutically acceptable salt or its enantiomter or its enantiomerism Body pharmaceutically acceptable salt and Pridinol or its pharmaceutically acceptable salt are prepared into composition, can be to muscle in drug effect Spasm has obvious relaxation, while can also cooperate with enhancing analgesic activity, can clinically be preferably applied to alleviate and treat pain and resist Inflammation, including local soft tissue pain（Such as：Courbature, arthralgia, lumbago and strain, pull, strain caused by pain）、 Muscle cramp pain（Pain in back and loin, neck shoulder arm syndrome, scapulohumeral periarthritis, morphotropism vertebra disease）, neuralgia, dysmenorrhoea, have a toothache, wind Wet arthritis, ankylosing spondylitis, osteoarthritis and postoperative pain.

Compared with prior art, Pridinol (S)-ibuprofen compound cream provided by the invention in analgesia, anti-inflammatory and delays In terms of solving muscle cramp, curative effect is better than existing medicine, overcomes the defects of medicine analgesic curative effect is insufficient or side effect is big well, Effectively increase the quality of life of patient.

Embodiment

The present invention will be further illustrated by specific embodiment below, it should be understood, however, that, these embodiments are only It is to be used to specifically describe in more detail to be used, and is not to be construed as limiting the present invention in any form.

The drug compatibility of the brufen of embodiment 1 and methylsulfonic acid pridinol is tested

Chemically whether the purpose of this experiment be to verify brufen and methylsulfonic acid pridinol both medicines in physics and With good compatibility.By brufen and methylsulfonic acid pridinol both medicines in proportion（20:1）It is well mixed, put out In discharge surface ware, share equally as the thin layer thick less than 5mm, resulting mixture test sample, while individually placed unmixed group is made reference substance, Carry out tests below, i.e. 1. hot tests：It is placed in forced air drying, is placed 30 days at a temperature of 60 DEG C, 40 DEG C；2. high wet test： 25 DEG C of ± 5 DEG C/75%RH ± 5%RH are placed 30 days；3. strong illumination is tested：It is placed in lighting box, illumination is 4500Lx ± 500Lx Under conditions of place 11 days, make exposure experiments to light total illumination be not less than 1.2 × 10⁶Luxhr, near ultraviolet energy are not less than 200w·hr/m2.3 groups of samples carry out outward appearance, physical property, relevant material, hygroscopicity and detected respectively.As a result show this After two kinds of composition mixing, the physics and chemical property of the two still have good compatibility.

Composite tablet of the embodiment 2 containing brufen 200mg and methylsulfonic acid pridinol 4mg

Prescription：

Preparation method：Direct powder compression

Brufen is well mixed with 40g pregelatinized starch, 40g microcrystalline cellulose PH102,37.2g Lactis Anhydrouses；Again by first sulphur Sour Pridinol mixes with 10g pregelatinized starch, 10g microcrystalline cellulose PH102,10g Lactis Anhydrous, Ac-Di-Sol Close uniform；Two parts are well mixed again, add silica and magnesium stearate, it is common fully mix after, cross 12 mesh sieve whole grains, Particle rushes direct tablet compressing with 10mm, reuses Opadry film coating liquid and carry out film coating, coating through after the assay was approved Weightening 2~4%.

The 400mg containing brufen of embodiment 3 and methylsulfonic acid pridinol 4mg composite tablet

Prescription：

Preparation method：Wet granule compression tablet method

Brufen is well mixed with 90g pregelatinized starch, 70g lactose monohydrates, 50g sodium carboxymethyl starches；It is again that methanesulfonic acid is general On the spot promise is well mixed with 10g pregelatinized starch, 10g lactose monohydrates, 10g sodium carboxymethyl starches；Two parts are well mixed again, The granulation of the mesh sieve of povidone solution 20 is added, 50 DEG C of dryings to moisture are less than 3%, 18 mesh sieve whole grains, then additional silica and tristearin Sour magnesium, after common fully mixing, particle, with oval different in nature stamping, reuses Opadry film bag through after the assay was approved Clothing liquid carries out film coating, coating weight gain 2~4%.

The 300mg containing (S)-ibuprofen of embodiment 4 and methylsulfonic acid pridinol 12mg compound sustained release capsules agent

Prescription：

Preparation method：It is prepared by extrusion spheronization-fluidized bed coating

Methylsulfonic acid pridinol and microcrystalline cellulose, (S)-ibuprofen are mixed, using PVP ethanol solution as adhesive, prepared Wet stock, regulation extruded velocity is set to be 250r/min, extruded machine sieve plate（Aperture is 0.9mm）Extrusion, strip-shaped materials are put round as a ball In machine, round as a ball rotating speed 400r/min, round as a ball time 5min, make particle round as a ball；Micropill drying is taken out, it is micro- to filter out 20 ~ 40 purposes Ball is standby.Micropill is put in fluidized-bed coating machine, using bottom spraying type, micropill 3min is preheated in 30 DEG C before hydrojet, peristaltic pump is adjusted Section is coated to 1.0ml/min, and air blast frequency is 30Hz, is coated 25 ~ 30 DEG C of temperature, coating solution is Utech NE-30D30% Aqueous dispersion, fluidized bed coating have wrapped rearmounted 40 DEG C of oven dryings 24 hours, and filling capsule produces.

Embodiment 5 contains 5% (S)-ibuprofen and 0.1% methylsulfonic acid pridinol compound cream

Preparation method：

1. oil phase：TEFOSE is taken respectively^®63rd, hexadecanol, medium chain triglyceride, single bi-tristearin, methyl hydroxybenzoate add Heat stirs to 80 DEG C, standby.

2. drug solution：(S)-ibuprofen, methylsulfonic acid pridinol are added in propane diols in 40-50 DEG C of water-soluble middle heating Stirring and dissolving, it is standby.

3. 80 DEG C of purified waters are will warm up in lower addition oil phase is stirred continuously, 70~80 DEG C of temperature control, lasting stirring 20min is emulsified, then is cooled the temperature under the conditions of 50~55 DEG C, lasting stir adds drug solution, after stirring 15min, adds Lavender oil, neroli oil are stirred for being cooled to room temperature,.

Case study on implementation 6 contains 5% (S)-ibuprofen and 0.1% methylsulfonic acid pridinol compound patch

Dissolved by medicine ibuprofen, methylsulfonic acid pridinol, with propane diols and add azone, menthol stirs, then with poly- third Olefin(e) acid ester pressure-sensitive is mixed evenly, and after ultrasonic 30min excludes bubble, is coated on using film applicator on adherent layer, natural After drying, it is placed in vacuum drying chamber in 40~50 DEG C of dry 1.5~2h, obtains drug storing layer, then back sheet is covered in storage medicine On layer, ibuprofen percutaneous release patch is obtained.

Embodiment 7 contains 5% (S)-ibuprofen and 0.1% methylsulfonic acid pridinol compound spray

Prescription：

Preparation method：

After the PVP of recipe quantity and glycerine, polyethylene glycol are mixed, (S)-ibuprofen, methylsulfonic acid pridinol are dissolved in afterwards In 3500ml ethanol, the Laurocapram of recipe quantity is added, ethanol is added to total amount 5000ml, stirs, use Aperture is 0.45 μm of filtering with microporous membrane, is dispensed, and sealing, is re-filled with HFA-134a（Hydrofluoroalkane hydrocarbon propellant）, bath inspection, Packaging, is produced.

The compound injection of the (S)-ibuprofen containing 400mg of embodiment 8 and 2mg methylsulfonic acid pridinols

Prescription：

Preparation method：

70 DEG C of fresh water for injection of 70% preparation total amount are taken in the material-compound tank after processing, lead to nitrogen 60min.Put into recipe quantity Arginine, polyoxyethylene sorbitan monoleate, being stirred under logical nitrogen protection makes its all dissolve；Add (S)-ibuprofen, the first sulphur of recipe quantity Sour Pridinol, stirring and dissolving, adjusts pH to 6.0-8.0 with sodium hydroxide, adds to the full amount of water for injection, stir under nitrogen protection Mix well mixed；Fluid temperature is down to 30 DEG C, continues logical nitrogen protection；Add and prepare total amount 0.1%（g/ml）Medical charcoal to medicine In liquid, 55% water-bath insulated and stirred is adsorbed 15 minutes under nitrogen protection, decarbonization filtering；Filtered with the micropore that aperture is 0.22 μm Film refined filtration, visible foreign matters inspection is done in sampling, after meeting regulation, is led to nitrogen embedding, 121 DEG C of pressure sterilizing 15min, is produced.

The compound iuprofen of embodiment 9（Brufen+methylsulfonic acid pridinol）Pharmacodynamics test

The analgesic activity of Dichlorodiphenyl Acetate induced mice writhing：Healthy mice 84 is taken, male and female half and half, is randomly divided into 7 groups, every group 12, the respectively isometric normal saline solution group (negative control) of equivalent, the high, medium and low dosage group of compound iuprofen (being respectively 101.18mg/kg, 25.59mg/kg, 12.80mg/kg), compound (S)-ibuprofen group are middle dose group（With compound The middle dosage of brufen group is consistent：25.59mg/kg）, folk prescription brufen group is (the same as compound iuprofen middle dosage-determination of ibuprofen： 25mg/kg), folk prescription methylsulfonic acid pridinol group is (the same as compound iuprofen middle dosage-methylsulfonic acid pridinol content：0.59mg/ kg)；The equal tail vein administration of each group, after 1h is administered, 0.7% acetic acid 0.2ml/ is injected intraperitoneally only in each mouse；Observe in 15min There is writhing response number of elements in each group, calculates each medicine analgesia percentage, and carry out the comparison of rate between group.To compound iuprofen group, The result of compound (S)-ibuprofen group, folk prescription brufen group and folk prescription methylsulfonic acid pridinol group carries out q inspections, calculates cloth Lip river Fragrant and methylsulfonic acid pridinol shares whether (i.e. compound iuprofen) acts synergistically.

As a result：1h is administered in compound iuprofen, and its mouse writhing reaction number of elements is considerably less than negative control group, shown multiple Square Nuprin Tablets Dichlorodiphenyl Acetate induced mice writhing has analgesic activity, and its percentage that eases pain is respectively 92%, 75% and 50%, is made With in dose-effect relationship；The analgesia percentage of compound (S)-ibuprofen middle dose group is 92% simultaneously, more than the compound cloth Lip river of same dosage The analgesia percentage of sweet smell group（75%）；Q assays, compound iuprofen group q>1, show that brufen and methanesulfonic acid are general on the spot Promise shares presentation synergy.It the results are shown in Table 1.

Analgesic activity (acetic acid writhing test) of the compound iuprofen of table 1 to mouse

With negative control group ratio, * P<0.05, * * P<0.01;Q is examined:ΔP >1 (enhancing)

The influence of rat paw edema caused by Carrageenan（Antiinflammatory action）：Choose rat 60, by sex body weight size with After machine is divided into five groups, the respectively isometric normal saline solution group (negative control) of equivalent, high, medium and low dose of compound iuprofen Amount group (152.36mg/kg, 76.18mg/kg, 13.1mg/kg), folk prescription brufen group are (the same as compound iuprofen middle dose group：Bu Luo Fragrant content, 75mg/kg), after surveying the left and right sufficient intestines normal volume of every rat with capillary amplifying method, tail vein approach is given 1% carrageenan 0.lml/ is subcutaneously injected only in medicine, the 20min after administration, left back vola pedis, and the difference of left foot plantar volume is before and after cause is scorching Swelling, relatively and its swelling inhibiting rate is calculated with negative control group, the results are shown in Table 2.

Influence of the compound iuprofen of table 2 to rat paw edema caused by Carrageenan

Note:Compared with negative control group, * P<0 .05, * * P<0.01 ;

As a result：Compound iuprofen each group is 1 after carrageenan is injected, 2,3,4h can significantly inhibit rat paw edema, Its antiinflammatory action has obvious dose-effect relationship；Wherein compound iuprofen 76.18mg/kg groups and with dosage folk prescription brufen pair According to group effect without the poor (P of conspicuousness>0 .05), this is little consistent with the antiinflammatory action of methylsulfonic acid pridinol.

Claims (7)

1. A kind of 1. pharmaceutical composition with analgesic and antiinflammatory action, by active constituents of medicine and pharmaceutically acceptable carrier group Into it is characterized in that the active constituents of medicine is by brufen or its pharmaceutically acceptable salt or its enantiomter or its mapping Isomers pharmaceutically acceptable salt and Pridinol or its pharmaceutically acceptable salt composition.
2. 2. according to the composition described in claims 1, there is provided be it is a kind of be daily 25~3200mg using effective dose, it is excellent Select 100~2400mg brufen or the pharmaceutical salts or enantiomer of its suitable dosage or the enantiomer pharmaceutical salts of its suitable dosage and Day effective dose is 1~40mg, the preferably pharmaceutical salts of 2~20mg Pridinol or its suitable dosage medicine；Both has It is 3200 to imitate dose ratio:1~0.625:1, preferably：1200:1~5:1.
3. 3. according to the composition described in claims 1, it is characterised in that it contains a kind of effective dose as 0.5%~40% (w/w), the mapping of preferably 1%~20% (w/w) brufen or the pharmaceutical salts or enantiomer of its suitable dosage or its suitable dosage Body pharmaceutical salts；It is 0.01%~20% with effective dose（w/w）, preferably 0.05%~10% (w/w) Pridinol or its suitable agent The local topical formulation of the pharmaceutical salts of amount.
4. 4. according to the composition described in claims 1, it is characterised in that the enantiomer of its brufen is (S)-ibuprofen, its medicine Acceptable salt and its enantiomer pharmaceutically acceptable salt include on：

   Inorganic cation salt, including sodium, potassium, lithium, magnesium, calcium, caesium, ferrous iron, zinc, bivalent manganese, aluminium, iron, tin, the cation of copper and manganese Salt；

   Primary, secondary, uncle that brufen is pharmaceutically approved, the organic salt of quaternary ammonium, including：Triethylamine, tripropyl amine (TPA), 2- dimethylaminos Ethanol, 2- DEAE diethylaminoethanols, lysine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, Hai Baming, Choline, ethylenediamine, aminoglucose, TRIS（Hydroxymethyl）- aminomethane, methylglucosamine, theobromine, piperazine, piperidines, polyamine tree The primary, secondary of fat, uncle, quaternary ammonium salt；Or

   Their mixture.
5. 5. according to the composition described in claims 1, it is characterised in that Pridinol pharmaceutically acceptable salt is mesylate, salt Hydrochlorate, sulfate, acetate, benzoate, citrate, benzene sulfonate, maleate, fumarate, tartrate, second sulphur Hydrochlorate, para Toluic Acid's sulfonate, hydrobromate, lauryl sulfonate, camsilate or DHB salt, preferably Mesylate and hydrochloride.
6. 6. according to the composition described in claims 1~5, it is characterised in that said composition be suitable for be administered orally, it is sublingual to Medicine, intestinal canal administration, parenterai administration, lung inhalation and topical routes of administration.
7. 7. according to the composition described in claims 1, for alleviating and treating pain and anti-inflammatory, including local soft tissue pain Bitterly（Such as：Courbature, arthralgia, lumbago and strain, pull, strain caused by pain）, muscle cramp pain（Ache back Bitterly, neck shoulder arm syndrome, scapulohumeral periarthritis, morphotropism vertebra disease）, neuralgia, dysmenorrhoea, have a toothache, rheumatic arthritis, ankylosing Spondylitis, osteoarthritis and postoperative pain.