CN106692120A

CN106692120A - Medicine composition of lidocaine and application of medicine composition

Info

Publication number: CN106692120A
Application number: CN201611162754.2A
Authority: CN
Inventors: 刘力
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-12-15
Filing date: 2016-12-15
Publication date: 2017-05-24

Abstract

The invention provides a lidocaine medicine composition for preparing local anesthetic for preventing or treating surgical pain of human and mammals, and application of the lidocaine medicine composition in preparation and application of a medicine. Therefore, a corresponding product has a quicker and better treating effect, higher safety and higher treating compliance in a clinical process.

Description

The medical composition and its use of lidocaine

Technical field

The present invention relates to pharmaceutical technology field, prevention or the local anaesthesia for the treatment of surgical pain are specifically to provide The light lidocaine menthol pharmaceutical composition of the quick-acting potent side effect of medicine and its preparation and use.

Background technology

To imitate local anaesthetics in amide-type, Central nervous system has obvious excited and suppresses lidocaine after blood absorption Biphasic effect, and can the excitement without pioneer, when blood concentration is relatively low, there is analgesia and the drowsy, threshold of pain improved；With dosage plus Greatly, effect or toxicity enhancing, have anticonvulsant action during the poisoning blood concentration of Asia；When blood concentration is more than 5 μ gml^-1Can shy Faint.This product can promote k in cardiac muscle cell in low dosage⁺Outflow, reduces by 4 phase slopes, slows down diastolic spontaneous depolarization, drops The self-disciplining of low cardiac muscle, and there is anti-ventricular arythmia to act on；In therapeutic dose, electrical activity, chamber to cardiac muscle cell Conduction and the contraction of cardiac muscle have no significant effect；Blood concentration is further raised, and cardiac conduction speed can be caused to slow down, Atrioventricular Conduction Retardance, suppresses myocardial contractive power and declines cardiac output.Lidocaine can also cause hypersusceptibility and allergic reaction；To breathing Patient Dao Gaomin, can cause bronchial spasm；Dosage is excessive, absorb and can cause very much toxic reaction soon, show as tinnitus, excitement, It is fidgety to wait central nervous excitation symptom, and it is drop in blood pressure etc. of twitching, go into a coma that can develop rapidly；Blood concentration is too high, can cause Atrium conduct velocity, atrioventricular block, room are quivered and sudden arrest of heart beat.

Average 5 minutes of lidocaine hydrochloride onset time, effect is maintained 1~2 hour, and its fat-soluble, protein binding rate is equal Higher than procaine, action intensity is 4 times of procaine.Clinical practice is in infiltration anesthesia, caudal anaesthesia, surface anesthesia (being used as mucous membrane anesthesia when being included in thoracoscopy or abdominal operation) and nerve block, and need per urethra to implement inspection Look into and treatment needs local anaesthesia person.The product can be used for VPB, Ventricular Tachycardia and the room that takes place frequently after acute myocardial infarction Property premature beat, also can be used for digitalis poisoning, the VA that causes of cardiac operation and cardiac catheter.Surface anesthesia, Caudal block is used for inhibiting pain in parturition, epidural anesthesia, infiltration anesthesia or intravenous regional block, peripheral blockade, sympathetic god Anesthesia adult's usual amounts such as warp knuckle retardance are described in lidocaine hydrochloride injection specification.

Parenteral solution of the Compound Lidocaine Hydrochloride parenteral solution with lidocaine hydrochloride and menthol as Main Ingredients and Appearance, is country The new drug of Ministry of Public Health's approval, but indication in Compound Lidocaine Hydrochloride parenteral solution specification is only limitted to anorectum department and surgery hand The local infiltration anesthesia of art cutting part：Surgery anesthesia, Postoperative Analgesia After etc..Clinic is also used for treating pruritic, painful skin Disease, pain etc. after treatment herpes zoster；Because of its side effect etc. so that it is considerably restricted using scope or indication, it should With on the contrary not as lidocaine hydrochloride injection or lidocaine carbonate injection；The Compound Lidocaine Hydrochloride note of prior art Penetrate liquid and be not also suitable for external preparation.Ethanol content is high in injection, brings some side effects, if unexpected penetrate blood vessel, because of second Alcohol can inherently occur hemolytic reaction, cause the serious adverse reactions such as haemolysis, injected shallow or too deep had trouble.Such as monopersulfate compound Refer to that ethanol allergy sufferers are used with caution in lidocaine hydrochloride injection specification, injected shallow, it is possible to create local scleroma, patient injection After there is local edema, local application can excessively cause oedema or superficial necrosis.It is unsuitable too deep when being injected under crissum operative incision, In case being formed, hard (document 1, Xing Guoliang, the Wu great thinker of the past, Du Zonghao, Ke Zepu makees the effect of anal operation of postop. Lente anesthetic and bad Response analysis, Colon and rectum anus surgery, 2006,12 (5):286-288；Document 2, a kind of injection of lidocaine hydrochloride compound medicine Liquid and preparation method thereof CN 104274434A).Compound Lidocaine Hydrochloride parenteral solution pH value still has one with Human Physiology pH value Determine gap, add because using ethanol solution, excitant is stronger, most of patients has transient " burning tingling sensation "；Crissum infiltration fiber crops Liquor-saturated too deep, ethanol etc. causes crissum liquefaction of fat to be possible to cause abscess to be formed.Compound Lidocaine Hydrochloride parenteral solution for The deep subcutaneous administration in nerve pain is also seriously restricted, even more so that patient incision's infection need to perform the operation again.Additionally, In clinical practice, although carrying out preemptive analgesia using Compound Lidocaine Hydrochloride parenteral solution can mitigate postoperative short-term, at a specified future date Pain, but postoperative defecation, dressing still have many patient pains heavier, and some patients' analgesic timeliness is not enough satisfied with, document report Realized for common ring-shaped mixed hemorrhoids also only about 55% patient painless, to the anal fistula of complexity, also only about 40% patient realizes nothing Bitterly, preferably postoperative whole process is not implemented painless, how makes this analgesia method more perfect, need further clinical research, this The situation of kind is further improved and lifted for a long time.

Additionally, menthol is slightly soluble in water, too low its consumption of concentration of ethanol solution is just big even can not under limited consumption The abundant menthol of dissolving, causes to separate out white point etc. in injection causing that preparation is unqualified, and the water solubility of lidocaine is also bad, Lidocaine is used as the ultimate constituent of Pharmaceutical composition, the practical feasibility or stability of its compound injection are also not Know；Even without Tween-80 in document 2, still there is ethanol etc., improvement lifting is very limited, prepared in the system scope Preparation, injection adverse reaction is larger under the state, range of application be limited.Ethanol is injected in Compound Lidocaine Hydrochloride Menthol being uniformly distributed in local organization can be promoted in liquid, and strengthen itself and neurilemmal adhesion, reduce or get rid of second After alcohol, whether its validity reduces also unknown, reduces or get rid of the new pharmaceutical compositions after rear, lifting pH value such as ethanol etc., Whether the preparation process of parenteral solution or emulsion under new system goes wrong or injection whether occur it is muddy or separate out crystallization or Unstable or degraded, or its security etc. is also unknown.When GMP management is high current with Control of drug quality requirement as strict as possible Generation, any quality problems of injection all can manufacture enterprise and make troubles or even huge blow to one.

The content of the invention

The present invention provides lidocaine or its pharmaceutical salts with menthol or the drug regimen of its isomers or its inclusion compound The ratio between weight number or parts by weight of main ingredient component in the said composition of thing, a UD or unit formulation or unit volume For：It is 20~100 (with lidocaine weight calculation amounts), L- thin containing lidocaine or its pharmaceutically acceptable salt or its inclusion compound One or more in lotus alcohol or menthol or its isomers or its inclusion compound or its eutectic is for 2~20 (with menthol Weight meter)；Or contain above-mentioned each main ingredient in the said composition of said one UD or unit formulation or unit volume 0.20~5 times of the weight number of component；The pharmaceutical composition and pharmaceutically acceptable auxiliary material or excipient or vehicle group patent medicine Thing preparation, including but not limited to injection or solution or emulsion for injection；The preparation of above-mentioned composition can be in solution or liquid PH value is measured under state or suspension or semisolid, or the said composition of a UD or unit formulation or unit volume is dissolved in Or be woven into the water of 20ml and measure pH value, it is between pH value 5.8-9.5；More preferably pH value is in the range of 6.001~8.5； PH value is more preferably in the range of 6.3~7.8.

Furtherly, in lidocaine pharmaceutical composition of the present invention, a UD or unit formulation or list The ratio between weight number or parts by weight of main ingredient component can be in the said composition of position volume：Containing lidocaine or its pharmaceutically may be used The salt of receiving or its inclusion compound be 20~100 or 20~100mg (with lidocaine weight calculation amount), MENTHOL or menthol or One or more in its isomers or its inclusion compound or its eutectic is 2~20 or 2~20mg (with the weight of menthol Meter)；Or contain above-mentioned each main ingredient component in the said composition of said one UD or unit formulation or unit volume 0.20~5 times of weight number；Wherein, lidocaine or carbonic acid or bicarbonate are selected from, but not limited to, lidocaine, carbonic acid benefit Cacaine, lidocaine bicarbonate, lidocaine sodium acid carbonate or lidocaine ammonium hydrogen carbonate or their hydrate or they Inclusion compound in one or more；The pharmaceutical composition and pharmaceutically acceptable auxiliary material or excipient or vehicle group are into medicine Preparation, between 5.8-9.5, more preferably pH value is in the range of 6.001~8.5 for its pH value；PH value is more preferably to 6.3~7.8 models In enclosing.

Lidocaine pharmaceutical composition of the present invention, can be with effective dose adrenaline or adrenalin hydrochloride or wine On stone acid adrenaline or norepinephrine or Arterenol (Hoechst), noradrenaline bitartrate or deoxidation kidney Parathyrine, aramine or pharmaceutically acceptable salt or derivatives thereof or a- adrenoceptor agonists are combined into Composition.More preferably, the preparation of the lidocaine menthol pharmaceutical composition of a unit formulation or UD can include but 50 a ten thousandths are not limited to the adrenaline or adrenalin hydrochloride or Adrenaline Tartrate of a ten thousandth or are gone on first kidney Parathyrine or Arterenol (Hoechst), noradrenaline bitartrate or neo-synephrine, aramine or medicine Acceptable salt or derivatives thereof or a- adrenoceptor agonists on.

It is stated another way, in the preparation of lidocaine menthol pharmaceutical composition of the invention, per 1000ml or 1000g Said composition preparation in contain sulfuric acid lidocaine or lidocaine or its pharmaceutically acceptable salt or its different knot Brilliant or amorphous article or its solvate or its inclusion compound or they in it is any one or more of, weight in terms of lidocaine or Ratio of weight and number can be 2-20wt ‰ or 2-20 or 2-20g, MENTHOL or menthol or its isomers or its inclusion compound Or any one or more of weight or ratio of weight and number is calculated as 0.2-2wt ‰ or 0.2~2 or 0.2~2g in its eutectic； Remaining is pharmaceutically acceptable carrier；In lidocaine menthol drug combination preparation of the invention, composition solution or The pH value of composite preparation is in the range of 6.0~9.5；More preferably pH value is in the range of 6.001~8.5；PH value is more preferably to 6.3 In the range of~7.8【Bibliography：Xie Jingping, Jinghong army, soldier, the research of the preferred beta-schardinger dextrin inclusion menthol of Orthogonal Method _ Chinese Journal of Modern Applied Pharmacy magazine, 1999,16 (1):28-29；Yong Guoping, virgin red military Li Guang water polishings menthol β-ring paste The research of inclusion compounds, Food Science .2002,23 (10):40-41；】.

Lidocaine menthol pharmaceutical composition of the invention, a UD or unit formulation or unit volume should The ratio between weight number or parts by weight of main ingredient component are in composition：Containing lidocaine or its pharmaceutically acceptable salt or its bag Compound be 6.0~100.0mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion compound or One or more in its eutectic is 0.80~20.00mg (with menthol weight calculation amount)；Or in said one UD Or 0.2~10 times of weight number containing above-mentioned each main ingredient component in the said composition of unit formulation or unit volume；Wherein, profit Many cacaines or carbonic acid or bicarbonate are selected from lidocaine, lidocaine carbonate, lidocaine bicarbonate, lidocaine carbonic acid One or more in hydrogen sodium or lidocaine ammonium hydrogen carbonate or their hydrate or their inclusion compound；The pharmaceutical composition With pharmaceutically acceptable auxiliary material or excipient composition injection.

The said composition of lidocaine pharmaceutical composition of the invention, a UD or unit formulation or unit volume The ratio between weight number or parts by weight of middle main ingredient component are：Containing lidocaine or its pharmaceutically acceptable salt be 60.3~ In 76.2mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion compound or its eutectic One or more be 11.0~14.3mg (with menthol weight calculation amount)；Or in said one UD or unit formulation or list 0.25~5 times of weight number containing above-mentioned each main ingredient component in the said composition of position volume；Wherein, lidocaine or carbonic acid or Bicarbonate is selected from lidocaine, lidocaine carbonate, lidocaine bicarbonate, lidocaine sodium acid carbonate or lidocaine One or more in ammonium hydrogen carbonate or its pharmaceutically-acceptable salts or their hydrate；The pharmaceutical composition with pharmaceutically may be used Into pharmaceutical preparation, the pH value of its injection or solution and other preparations is in 6.01- for the auxiliary material or excipient or vehicle group of receiving Between 9.5.

The said composition of lidocaine pharmaceutical composition of the invention, a UD or unit formulation or unit volume The ratio between weight number or parts by weight of middle main ingredient component are：It is 86mg or 43mg containing lidocaine or its pharmaceutically acceptable salt In the inclusion compound or its eutectic of (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or cyclodextrin One or more is 13mg or 6.5mg (with menthol weight calculation amount)；Or in said one UD or unit formulation or unit 0.25~5 times of weight number containing above-mentioned each main ingredient component in the said composition of volume；Wherein, lidocaine or carbonic acid or carbon Sour hydrogen salt is selected from lidocaine, lidocaine carbonate, lidocaine bicarbonate, lidocaine sodium acid carbonate or lidocaine carbon One or more in sour hydrogen ammonium or its pharmaceutically-acceptable salts or their hydrate；The pharmaceutical composition can connect with pharmaceutically Into pharmaceutical preparation, the pH value of its injection or solution and other preparations is in 6.01-9.5 for the auxiliary material or excipient received or vehicle group Between.

The said composition of lidocaine pharmaceutical composition of the invention, a UD or unit formulation or unit volume The ratio between weight number or parts by weight of middle main ingredient component are：Containing lidocaine or its pharmaceutically acceptable salt be 69.22895 or The inclusion compound of 69.229 or 69.23 or 69.2 or 69.3mg (with lidocaine weight calculation amount), MENTHOL or menthol cyclodextrin Or one or more in its eutectic is 13mg (with menthol weight calculation amount)；Or in said one UD or the system of unit 0.25~5 times of weight number containing above-mentioned each main ingredient component in the said composition of agent or unit volume；Wherein, lidocaine or Carbonic acid or bicarbonate are selected from lidocaine, lidocaine carbonate, lidocaine bicarbonate, lidocaine sodium acid carbonate or profit One or more in many cacaine ammonium hydrogen carbonate or its pharmaceutically-acceptable salts or their hydrate；The pharmaceutical composition and medicine Into pharmaceutical preparation, the pH value of its injection or solution and other preparations exists for acceptable auxiliary material or excipient or vehicle group on Between 6.01-9.5.

Lidocaine pharmaceutical composition of the invention, it is characterised in that：One UD or unit formulation or unit bodies The ratio between weight number or parts by weight of main ingredient component are in long-pending said composition：Containing lidocaine or its pharmaceutically acceptable salt It is 34.614476mg or 34.61448 or 34.6145 or 34.615 or 34.614 or 34.61 or 34.62mg or 34.6mg (with profit Many cacaine weight calculation amounts), be 6.5mg one or more in the inclusion compound or its eutectic of MENTHOL or menthol cyclodextrin (with menthol weight calculation amount)；Or containing above-mentioned in the said composition of said one UD or unit formulation or unit volume 0.25~5 times of the weight number of each main ingredient component；Wherein, lidocaine or carbonic acid or bicarbonate are selected from lidocaine, carbonic acid Lidocaine, lidocaine bicarbonate, lidocaine sodium acid carbonate or lidocaine ammonium hydrogen carbonate or its is pharmaceutically acceptable One or more in salt or their hydrate；The pharmaceutical composition and pharmaceutically acceptable auxiliary material or excipient or carrier The pH value of composition pharmaceutical preparation, its injection or solution and other preparations is between 6.01-9.5.

Lidocaine pharmaceutical composition of the invention more preferably, a UD or unit formulation or unit volume should The ratio between weight number or parts by weight of main ingredient component are in composition：Containing lidocaine or its pharmaceutically acceptable salt or its bag Compound is 6.0~19.0mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its urea or sulphur One or more in the inclusion compound of urea or cyclodextrin etc. or its eutectic is 0.80~1.80mg (with menthol weight calculation amount)； Or contain the weight of above-mentioned each main ingredient component in the said composition of said one UD or unit formulation or unit volume Several 0.2~30 times；Wherein, lidocaine or carbonic acid or bicarbonate are selected from lidocaine, lidocaine carbonate, lidocaine Bicarbonate, lidocaine sodium acid carbonate or lidocaine ammonium hydrogen carbonate or its pharmaceutically-acceptable salts or their hydrate or One or more in their inclusion compound；The pharmaceutical composition and pharmaceutically acceptable auxiliary material or excipient composition injection Agent.

Lidocaine pharmaceutical composition of the invention more preferably, a UD or unit formulation or unit volume should The ratio between weight number or parts by weight of main ingredient component are in composition：Containing lidocaine or its pharmaceutically acceptable salt or its bag Compound is 6.2~8.8mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its urea or thiocarbamide Or one or more in the inclusion compound or its eutectic of cyclodextrin etc. is 1.0~1.50mg (with menthol weight calculation amount)；Or The weight number containing above-mentioned each main ingredient component in the said composition of said one UD or unit formulation or unit volume 0.2~30 times；Wherein, lidocaine or carbonic acid or bicarbonate are selected from lidocaine, lidocaine carbonate, lidocaine carbon Sour hydrogen salt, lidocaine sodium acid carbonate or lidocaine ammonium hydrogen carbonate or its pharmaceutically-acceptable salts or their hydrate or it Inclusion compound in one or more；The pharmaceutical composition and pharmaceutically acceptable auxiliary material or excipient composition injection.

In lidocaine drug combination preparation of the invention in every milliliter of parenteral solution or solution, containing lidocaine 6.0 One kind or many in~20.0mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion compound It is 0.80~2.00mg to plant (with menthol weight calculation amount)；Or in said one UD or unit formulation or unit volume should 0.25~30 times of weight number containing above-mentioned each main ingredient component in composition；

For injection or solution, can be expressed as (expression below is similar)：Lidocaine medicine group of the invention Containing 6.0~20.0mg/ml of lidocaine (with lidocaine weight calculation amount), MENTHOL or menthol or its isomery in compound preparation One or more in body or its inclusion compound or its eutectic is 0.80~2.00mg/ml (with menthol weight calculation amount)；Or The weight number containing above-mentioned each main ingredient component in the said composition of said one UD or unit formulation or unit volume 0.25~30 times；

For injection or solution, can be expressed as：More preferably contain in lidocaine drug combination preparation of the invention 6.0~19.0mg/ml of lidocaine (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion One or more in thing is 0.80~1.80mg/ml (with menthol weight calculation amount)；Or in said one UD or unit 0.25~30 times of weight number containing above-mentioned each main ingredient component in the said composition of preparation or unit volume；

In lidocaine drug combination preparation of the invention in every milliliter of parenteral solution or solution more preferably containing 6.0~ In 10.0mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion compound or its eutectic One or more be 0.80~1.80mg (with menthol weight calculation amount)；Or in said one UD or unit formulation or list 0.25~30 times of weight number containing above-mentioned each main ingredient component in the said composition of position volume；

For injection or solution, can be expressed as：More preferably contain in lidocaine drug combination preparation of the invention 6.0~10.0mg/ml (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion compound or its One or more in eutectic is 0.80~1.80mg/ml (with menthol weight calculation amount)；Or in said one UD or 0.25~30 times of weight number containing above-mentioned each main ingredient component in the said composition of unit formulation or unit volume；

For injection or solution, can be expressed as：More preferably contain in lidocaine drug combination preparation of the invention 6.0~10.0mg/ml (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion compound or its One or more in eutectic is 1.00~1.50mg/ml (with menthol weight calculation amount)；Or in said one UD or 0.25~30 times of weight number containing above-mentioned each main ingredient component in the said composition of unit formulation or unit volume；

For injection or solution, can be expressed as：More preferably contain in lidocaine drug combination preparation of the invention 6.3~8.8mg/ml (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion compound or its One or more in eutectic is 1.00~1.50mg/ml (with menthol weight calculation amount)；Or in said one UD or 0.25~30 times of weight number containing above-mentioned each main ingredient component in the said composition of unit formulation or unit volume；

For injection or solution, can be expressed as：More preferably contain in lidocaine drug combination preparation of the invention 6.9229mg/ml or 6.923mg/ml or 6.92mg/ml or 6.9mg/ml (with lidocaine weight calculation amount), MENTHOL or peppermint (counted weight with menthol for 1.30mg/ml one or more in brain or its isomers or its inclusion compound or its eutectic Amount)；

For injection or solution, can be expressed as：Can contain in lidocaine drug combination preparation of the invention 17.2mg/ml or 17.3mg/ml (with lidocaine weight calculation amount), menthol or menthol or its isomers or its inclusion compound or One or more in its eutectic is 1.30mg/ml (with menthol weight calculation amount)；

Menthol in composition or menthol or its isomers in the present invention is including but not limited to MENTHOL or L- Menthol etc., the eutectic of menthol is including but not limited to xylitol and the eutectic of menthol or menthol or its isomers Deng.

Lidocaine pharmaceutical composition of the present invention, for preparing pharmaceutically acceptable pharmaceutical preparation, including but It is not limited only to injection, solution, tincture, ointment, cream, gel, paste, suppository.It is pharmaceutically acceptable preparing Pharmaceutical preparation can contain one or more pharmaceutically acceptable carrier.

Aforementioned pharmaceutical compositions and pharmaceutically acceptable auxiliary material or excipient composition injection or solution.

Pharmaceutically acceptable auxiliary material includes water or water for injection or pure water or deionized water etc., described pharmaceutically acceptable Auxiliary material may also comprise the cosolvent that pharmaceutically receives or solubilizer, stabilizer, antioxidant, isotonic regulator, pharmaceutically receive PH adjusting agent and stabilizer, cosolvent or solubilizer or stabilizer are selected from but are not limited only to polyethylene glycol oxide list oleic acid sorbierite Acid anhydride ester, Tween-80, VE succinic acid macrogol ester (vitamin E TPGS), glycerine-polyethylene glycol epoxide stearate, PEG-32 glyceryl palmitostearates, lauryl sodium sulfate, Sorbitan monolaurate, polyethylene glycol, polyethylene glycol 400-6000, polyethylene glycol-hydroxy stearic acid ester, HS15, polyethylene glycol -15- hydroxy stearates It is acid esters, polyvinylpyrrolidone, polyvinyl alcohol, amino acid or its pharmaceutical salts, pharmaceutically acceptable alcohols, pharmaceutically acceptable many First alcohol, poloxamer, PLURONICS F87, poloxamer188, azone, laurocapram, cyclodextrin or cyclodextrin pharmaceutically may be used The derivative of receiving, amide-type or urea and derivative, inorganic acid or inorganic acid salt, pharmaceutically acceptable organic acid or organic acid Salt, pharmaceutically acceptable carbohydrate or sugar lime, pharmaceutically acceptable amine etc. or their chiral isomer etc. or they in One or more.

Amino acid or its pharmaceutical salts are more preferably selected from but are not limited only to D- or the lysine of L- or DL- types, the bad ammonia of acetic acid certainly Acid, methionine, arginine, acetic arginine, L-aminobutanedioic acid, Monosodium L-aspartate, glutamic acid, glycine, taurine, valine, Threonine, cysteine hydrochloride, cysteine, cystine, glutamine, 5- oxylysines, histidine, 3- hydroxy-prolines, 4- hydroxy-prolines, proline, ornithine, citrulling, creatine, 3- alanine, theanine, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- amino-2-methyls propionic acid, 2- methyl -3- alanines, 2,6- diaminopimelic acids, 2- amino-3-phenyl butyrics, 4- hydroxyls Arginine, 4- hydroxyls ornithine, 4- hydroxyhomoarginines, 2,4-diamino-butanoic etc. or its pharmaceutical salts or its hydrate or they Chiral isomer in one or more；

Pharmaceutically acceptable amide-type, urea derivative, amine, inorganic acid or inorganic acid salt, organic acid or acylate, Carbohydrate or sugar lime are more preferably selected from but are not limited only to certainly：Niacinamide, urethane, acetamide, urea, thiocarbamide, saccharin sodium, a second Hydramine, diethanol amine, triethanolamine, boric acid or Boratex, nicotinic acid, L-AA, citric acid, sodium citrate, lactic acid, lactic acid Sodium, sodium taurocholate, lactobionic acid, sodium lactonic, gluconic acid, sodium gluconate, threonic acid, sucrose, trehalose, ethanol, propane diols, 1,2- propane diols, butanediol, 1,3 butylene glycol, glycerine, phenmethylol, maltitol, sorbierite, mannitol, lactitol, xylose One kind or many in alcohol, antierythrite or its hydrate or their pharmaceutically acceptable salt etc. or their chiral isomer etc. Kind；

As used herein, cyclodextrin can be cyclodextrin or cyclodextrin pharmaceutically acceptable derivates or pharmacy Upper acceptable substituted cyclodextrin, the cyclodextrin of term substitution refer in its structure one or more hydroxyls by by ehter bond The α that the different chemical substituents of attachment replace-, β-or gamma-cyclodextrin.Substituted cyclodextrin can be in same cyclodextrin molecular Chemical substituents comprising single type or more than one types.For example, a hydroxyl of cyclodextrin can be replaced by sulfoalkyl Base replaces and another hydroxyl is replaced by hydroxyalkyl substituted groups.Substituted cyclodextrin compound includes, but not limited to, e.g. sulfoalkyl Ether ring dextrin (SAE-CD), hydroxyalkyl ether cyclodextrin (HAE-CD), sulfoalkyl ether-alkyl ether cyclodextrin (SAE-AE-CD) or sulphur The ring of known other substitutions of the ordinary skill of alkyl ether-hydroxyalkyl ether cyclodextrin (SAE-HAE-CD) and the art Dextrin.

The cyclodextrin can be cyclodextrin or cyclodextrin pharmaceutically acceptable derivates, cyclodextrin or derivatives thereof choosing From but be not limited only to natural cyclodextrin, methyl flamprop, ethyl cyclodextrin, hydroxypropyl cyclodextrin, butyl cyclodextrin, sulphur butyl ring Dextrin, sulphonic acid ester cyclodextrin, full sulfydryl Alpha cyclodextrin, single sulfydryl betadex, full sulfydryl betadex, amino ring Dextrin, cyclodextrin phosphate, hydroxyethyl cyclodextrin, front three cyclodextrin, acetyl cyclodextrin, carboxylate cyclodextrin, nitrate Cyclodextrin, sulfuric ester cyclodextrin, glucosyl group cyclodextrin, malt-base cyclodextrin, galactolipin cyclodextrin, succinyl cyclodextrin Deng；The natural cyclodextrin is including alpha-cyclodextrin, beta-schardinger dextrin, gamma-cyclodextrin etc.；Wherein described cyclodextrin more preferably from but not Be only limitted to HP-β-CD, sulfobutyl ether beta-schardinger dextrin, (- the O- of 2,6- bis-) second group-beta-cyclodextrin, (2- carboxy ethyls)- Beta-schardinger dextrin sodium salt, (2- hydroxyethyls)-beta-schardinger dextrin, sulfobutyl ether-beta-cyclodextrin, (2- hydroxypropyls)-beta-schardinger dextrin, (3- hydroxypropyls)-beta-schardinger dextrin, 6- monodeoxy -6- monoamines group-beta-cyclodextrin, 6-O- α-malt sugar group-beta-cyclodextrin, fourth Group-beta-cyclodextrin, butyl-gamma-cyclodextrin, carboxymethyl group-beta-schardinger dextrin, methyl-B-cyclodextrin, succinyl-beta-cyclodextrin, three Acetyl group-beta-cyclodextrin, succinyl-alpha-cyclodextrin, (2- hydroxypropyls)-alpha-cyclodextrin, alpha-cyclodextrin, beta-schardinger dextrin and γ- Cyclodextrin etc..

Present invention encompasses including with beta-schardinger dextrin, SAE-CD, HAE-CD, SAE-AE-CD or SAE-HAE-CD etc. in One or more inclusion or compound menthol or L- menthols or other isomers, the present invention also contemplated including being pasted with β-ring One or more in essence, SAE-CD, HAE-CD, SAE-AE-CD or SAE-HAE-CD etc. inclusion or compound lidocaine or Lidocaine carbonic acid or bicarbonate or their hydrate, it can be used as Narcotic analgesic drug preparation.

Present invention encompasses including with urea, thiocarbamide, beta-schardinger dextrin, SAE-CD, HAE-CD, SAE-AE-CD or SAE- One or more inclusion or compound menthol or L- menthols or its isomers in HAE-CD etc., the present invention also contemplated bag Include and one or more bag in urea, thiocarbamide, beta-schardinger dextrin, SAE-CD, HAE-CD, SAE-AE-CD or SAE-HAE-CD etc. Close or compound lidocaine or lidocaine carbonic acid or bicarbonate or their hydrate, they or their compositions can As Narcotic analgesic drug preparation.

Menthol or menthol include menthol or menthol or its raceme or its isomers or chiral isomer or it The one or more of which, such as D- menthols, L- menthols such as inclusion compound.The Benexate Hydrochloride of menthol or peppermint Brain hydroxypropyl-beta-cyclodextrin inclusion or menthol sulfobutyl ether Benexate Hydrochloride or L- menthols 3- hydroxy propyl-Betas-ring Cyclodextrin inclusion compound can come from commercialized product or own product, and inclusion method can refer to or (Yong Guoping grinds with reference to polishing etc. The research of mill method menthol Benexate Hydrochloride, Food Science, 2002,23 (10)：40-41).

Pharmaceutically acceptable auxiliary material in pharmaceutical compositions of the invention may include pharmaceutically acceptable antioxidant and Stabilizer, they can be sulfurous acid and its salt, bisulfites, pyrosulfite, dithionite, thiosulfate, Organosulfur compound thiocarbamide, glutathione, dimercaprol dimercaptopropanol, TGA and its pharmaceutical salts, thiolactic acid and its pharmaceutical salts, sulphur For dipropionic acid and salt, phenol compound, such as gallic acid and its pharmaceutical salts, caffeic acid and its pharmaceutical salts, forulic acid and its medicine With salt, di-t-butyl Pyrogentisinic Acid, DHB and its pharmaceutical salts；Amino acid and its pharmaceutical salts；Ascorbic acid and Its pharmaceutical salts, arabo-ascorbic acid and its pharmaceutical salts, niacinamide, tartaric acid, nitrate, acetic acid, malic acid, citrate, lactic acid, Sodium lactate, sodium taurocholate, lactobionic acid, sodium lactonic, gluconic acid, sodium gluconate, EDTA and edta salt, such as EDETATE SODIUM, The sodium of EDTA tetra-, Ethylenediaminetetraacetic Acid Calcium Salt salt (including sodium ethylene diamine tetracetate calcium or the hydrate of sodium ethylene diamine tetracetate calcium 2, ethylenediamine tetrem The sour hydrate of sodium calcium 4), (2- ethoxys) glycine of N- bis- or its isomers or their pharmaceutical salts or its solvated compounds etc. In one or several；The salt of above-mentioned substance selects its pharmaceutically acceptable salt or its hydrate.

Pharmaceutically acceptable auxiliary material in pharmaceutical compositions of the invention may include pharmaceutically acceptable isotonic regulation Agent, they can be glucose, fructose, xylitol, sorbierite, mannitol, inverted sugar, maltose, dextran, sodium chloride, One or more in potassium chloride, sodium lactate or its isomers etc..

Pharmaceutically acceptable pH adjusting agent can be pharmaceutically acceptable inorganic acid or organic acid, inorganic base or organic The lewis acid or alkali of alkali, or broad sense, can contain one or several, can be carbonic acid or bicarbonate, dioxy Change carbon, sodium acid carbonate, sodium carbonate, phosphoric acid, sodium dihydrogen phosphate, dibastic sodium phosphate or sodium phosphate, acetic acid and acetate, such as sodium acetate Deng the pharmaceutical salts such as lactic acid and sodium lactate, tartaric acid or its pharmaceutical salts, citric acid pharmaceutical salts, sodium citrate, sodium citrate 2 are hydrated Thing, benzoic acid, Sodium Benzoate, butanedioic acid, sodium succinate, NaOH, trihydroxy aminomethane, diethanol amine, monoethanolamine, two Isopropanolamine, 2- amino -2- (methylol) 1,3-PDs amine, N- methyl glucoses amine and their salt, multi-hydroxy carboxy acid and Pharmaceutical salts, such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, threonic acid, glucoheptonic acid, amino acid or its isomers or One or several in their sodium salt or their other pharmaceutically acceptable salts or its hydrate etc..

In the preparation process of injection, it can add the activity with liquid measure 0.005~3% to go thermal source and degerming mode Charcoal removes thermal source, and miillpore filter is degerming and pressure sterilizing, it would however also be possible to employ heat sterilization, remove thermal source.Miillpore filter can be mixing Cellulose microporosity filter membrane, cellulose acetate miillpore filter, nylon-type miillpore filter, polysulfones miillpore filter, PP type micropore Filter membrane etc..In hyperfiltration process, ultrafilter can select flat, rolling, tubular type, hollow fiber form or circle boxlike etc., preferably rolling With hollow fiber form ultrafilter, retention relative molecular mass is used to remove most of heat generation material for 50,000 to 300,000 filter membrane After bacterium, then using the remaining thermal source of milipore filter removing of retention relative molecular mass 3000~60000, preferably average molecular matter The milipore filter of amount 3000~20000.

Lidocaine and the assay of menthol in solution or injection, can refer to standard number：WS1- (X- 109) standard of the Compound Lidocaine Hydrochloride parenteral solution of -2000Z is measured.

The preparation of lidocaine pharmaceutical composition ointment or emulsifiable paste or gel or suppository formulations

Lidocaine carbonate or lidocaine or its pharmaceutically acceptable salt or different crystal forms or amorphous article or its is molten One or more in agent compound or its inclusion compound and menthol or its isomers or its inclusion compound or its eutectic, with ointment Or the matrix and pharmaceutically acceptable bleeding agent, emulsifying agent or surfactant of emulsifiable paste or suppository etc. is well mixed and obtain, its To in the range of 6.001~9.5, more preferably pH value is in the range of 6.5~7.5 for pH value；If being used in ointment or emulsifiable paste or gel Lidocaine hydrochloride, the pharmaceutically acceptable pH value of pH value application of its solution is adjusted in the range of 6.001~9.5, more preferably PH value is in the range of 6.5~7.5.Pharmaceutically acceptable pH adjusting agent can be one or more specified in this specification. The need for during local skin external application analgesia, can the size etc. of basis determine consumption, general one day 1-3 times.

The ointment or emulsifiable paste or gel or suppository of lidocaine pharmaceutical composition ointment of the present invention or emulsifiable paste or gel preparation Matrix and pharmaceutically acceptable bleeding agent, emulsifying agent or surfactant etc. be selected from but be not limited only to：Water, ethanol, propane diols, 1,2- propane diols, butanediol, 1,3 butylene glycol, glycerine, lanolin, vaseline, spermaceti, cera alba, paraffin, ceresine, vegetable oil, Hydrogenated vegetable oil, axunge, cholesterol, isopropyl myristate, hexadecanol, octadecyl alcolol, the fat of polyoxyethylene stearate 40, polyethylene glycol 100-20000, PEG-4000, PEG-4000, PEG-4000, atoleine, sodium stearyl sulfate, list Tristerin, polyglycerol stearate, glycerin gelatine, sodium alginate, the series of polyethylene glycol, the series of poloxamer, Polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, Carbomer series (carbomer 934, carbomer940, Acritamer 940, Carbopol 941, CARBOPOL 974P, Carbopol etc.), sodium carboxymethylcellulose, Tween-80, polyethylene glycol oxide list oleic acid sorb Alcohol acid anhydride ester, VE succinic acid macrogol ester (vitamin E TPGS), glycerine-polyethylene glycol epoxide stearate, PEG-32 Glyceryl palmitostearate, azone, laurocapram, lauryl sodium sulfate, Sorbitan monolaurate, shitosan, PLURONICS F87, poloxamer188, hydroxyethyl cellulose, glucose phosphate ester, glucose phosphate ester derivant, xanthans, Carboxyl vinyl polymer, Sodium Polyacrylate, cellulose derivative, polysaccharide, chondroitin sulfate, hyaluronic acid or hyaluronic acid Sodium, guar gum, alginic acid etc. or pharmaceutically acceptable auxiliary material or carrier.When ointment or emulsifiable paste or gel preparation are prepared, In the range of 6.001~9.5, more preferably pH value is to 6.001~7.5 models for the pH value of its ointment or emulsifiable paste or gel or suppository formulations In enclosing.

The preparation method of lidocaine menthol drug combination injection of the invention or solution：Or 1. method A divides One or more in injection sodium acid carbonate or sodium carbonate are not dissolved in appropriate water for injection, lidocaine hydrochloride or benefit Cacaine pharmaceutical salts are dissolved in appropriate water for injection, and 2. the inclusion compound (cyclodextrin inclusion compound etc.) of menthol dissolves in appropriate injection In water, cosolvent or stabilizer or antioxidant or additives enter in appropriate water for injection, and two kinds of solution are mixed；3. by carbon In sour hydrogen sodium or aqueous sodium carbonate or pharmaceutically acceptable solution of Lewis base one or more slowly with hydrochloric acid benefit card Because of aqueous solution mixing, stir and evenly mix, 4. will add cold water for injection to full dose during 2. 3. solution be added to solution, or with liquid measure 0.005~3% activated carbon decolorizing removes thermal source (more preferably with the activated carbon of liquid measure 0.03~1%), stirring, and uses titanium dioxide Carbon gas and/or add one kind or several in sodium bicarbonate aqueous solution or aqueous sodium carbonate or pharmaceutical acceptable acid or aqueous slkali To in the range of 6.001~9.5, more preferably pH value is in the range of 6.5~7.5 for the pH value of kind of regulation solution；5. solution filter mistake Filter or circulating filtration or 0.85 μm~0.2 μm micro-pore-film filtration or circulating filtration or ultrafiltration；6. sample, the middle product content of measure, PH, visible foreign matters, qualified rear embedding；7. sterilize：Using 100~121 DEG C of 10~30min of flowing steam sterilization, leak detection, sterilizing knot Treat that ampoule temperatures are down to 15~35 DEG C ± 2 DEG C after beam；8. the ampoule that will sterilize takes out, cooling, inspection, packaging.

Or method B：1. during cosolvent, stabilizer or antioxidant etc., added into appropriate water for injection, plus recipe quantity profit Many cacaines or lidocaine pharmaceutical salts, lead to carbon dioxide or add one kind or several in pharmaceutical acceptable acid or aqueous slkali Kind, stirring to dissolving, 2., during the inclusion compound (cyclodextrin inclusion compound etc.) that takes menthol etc. dissolves in water for injection, 3., will 2. solution Slowly mix with 1. solution, stir evenly, benefit adds to the full amount of water for injection, or with the activated carbon decolorizing with liquid measure 0.005~3% or go Thermal source (more preferably with the activated carbon of liquid measure 0.03~1%), stirring, and with carbon dioxide and/or add sodium bicarbonate aqueous solution Or the pH value of one or more the regulation solution in aqueous sodium carbonate or pharmaceutical acceptable acid or aqueous slkali to 6.001~ In the range of 9.5, more preferably pH value is in the range of 6.5~7.5；5., solution filter circulating filtration or filtering or 0.85 μm~ 0.2 μm of micro-pore-film filtration or circulating filtration or ultrafiltration；6., sample, determine middle product content, pH, visible foreign matters, qualified rear filling Envelope；7., sterilize：Using 100~121 DEG C of 10~30min of flowing steam sterilization, leak detection, sterilizing treats that ampoule temperatures are down to after terminating 15~35 DEG C ± 2 DEG C；8. the ampoule that, will sterilize takes out, or vibration, cooling, inspection, packaging.

Or method C：1. the menthol and cosolvent for, weighing recipe quantity are added in ethanol, and 2. stirring, takes salt to dissolving Lidocaine hydrochloride or lidocaine pharmaceutical salts and/or antioxidant or stabilizer are dissolved in water for injection, 3., 2. solution will slowly be fallen Enter 1. solution mixing, stir evenly, benefit adds to the full amount of water for injection, or with the activated carbon decolorizing with liquid measure 0.005~3% or reduces phlegm and internal heat Source, stirring, and with carbon dioxide and/or plus sodium bicarbonate aqueous solution or aqueous sodium carbonate or pharmaceutical acceptable acid or To in the range of 6.001~9.5, more preferably pH value is to 6.5~7.5 scopes for the pH value of one or more the regulation solution in aqueous slkali It is interior；5., solution filter circulating filtration or filtering or 0.45 μm~0.2 μm micro-pore-film filtration or circulating filtration or heat sterilization, Remove thermal source；6., sample, determine middle product content, pH, visible foreign matters, qualified rear embedding；7., sterilize：Using 100~121 DEG C of streams 10~30min of logical steam sterilizing, leak detection, sterilizing treats that ampoule temperatures are down to 15~35 DEG C ± 2 DEG C after terminating；8., will sterilize peace Small jar takes out, inspection, packaging.

Or method D：1. the menthol or its isomers for, taking recipe quantity are dissolved with appropriate ethanol, then logical with cyclodextrin Cross stirring mixing method or saturated water solution method or polishing or colloid mill polishing or high-speed organization smashs method or rotary evaporation to pieces Or one or more in the methods such as ultrasonic method are included, 2., by cosolvent, lidocaine or lidocaine pharmaceutical salts And/or during antioxidant or stabilizer enter water for injection, 2. 3. stirring, solution will be mixed to dissolving with 1. solution, and note is added in stirring Penetrate with water to full dose, or with the activated carbon decolorizing with liquid measure 0.005~3% or remove thermal source, stir, and with carbon dioxide with Or add one or more regulations in sodium bicarbonate aqueous solution or aqueous sodium carbonate or pharmaceutical acceptable acid or aqueous slkali molten To in the range of 6.001~9.5, more preferably pH value is in the range of 6.5~7.5 for the pH value of liquid；5., solution with filter circulating filtration or Filtering or 0.45 μm~0.2 μm micro-pore-film filtration or circulating filtration or heat sterilization, remove thermal source；6., sample, determine middle product Content, pH, visible foreign matters, qualified rear embedding；7., sterilize：Using 100~121 DEG C of 10~30min of flowing steam sterilization, hunt leak, Sterilizing treats that ampoule temperatures are down to 15~35 DEG C ± 2 DEG C after terminating；8. the ampoule that, will sterilize takes out, and vibrates and cools down, and checks, bag Dress.

Or method E：Take cosolvent or stabilizer or additives are added in appropriate water for injection, stirring is extremely dissolved, plus The lidocaine carbonate of recipe quantity or the carbonate of lidocaine or bicarbonate or lidocaine or lidocaine pharmaceutically may be used One or more in the salt of receiving, lead to carbon dioxide add or pharmaceutical acceptable acid or aqueous slkali in one kind or several Kind, to dissolving, the inclusion compound (cyclodextrin inclusion compound etc.) and antioxidant or stabilizer for taking menthol dissolve in water for injection for stirring, Above-mentioned solution, stirring are mixed, benefit adds to the full amount of water for injection, or with the activated carbon decolorizing with liquid measure 0.005~3% or goes Thermal source, stirring, and with carbon dioxide and/or sodium bicarbonate aqueous solution or aqueous sodium carbonate or pharmaceutical acceptable acid or To in the range of 6.001~9.5, more preferably pH value is to 6.5~7.5 scopes for the pH value of one or more the regulation solution in aqueous slkali It is interior；Solution filter circulating filtration or filtering or 0.65 μm~0.2 μm micro-pore-film filtration or circulating filtration or heat sterilization, go Thermal source；Sampling, determines middle product content, pH, visible foreign matters, qualified rear embedding；Sterilizing：Gone out using 100~121 DEG C of flowing steams 10~30min of bacterium, leak detection, sterilizing treats that ampoule temperatures are down to 15~35 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize takes out, inspection, Packaging.

Or method F：Successively by inclusion compound (cyclodextrin inclusion compound etc.) of menthol etc., lidocaine hydrochloride or its pharmaceutically The salt of receiving, cosolvent or stabilizer or antioxidant or additives etc. are dissolved in appropriate water for injection, are stirred, and use carbon dioxide Gas and/or add in sodium bicarbonate aqueous solution or aqueous sodium carbonate or pharmaceutical acceptable acid or aqueous slkali one or more The pH value of solution is adjusted in the range of 6.001~9.5, more preferably in the range of 6.5~7.5, benefit injects water to full pH value Amount (or with the activated carbon decolorizing with liquid measure 0.005~3% or thermal source being removed, more preferably with the activated carbon of liquid measure 0.03~1%), it is molten Liquid is filtered or circulating filtration or 0.45 μm~0.2 μm micro-pore-film filtration or circulating filtration or ultrafiltration with filter；Sampling, in measure Between product content, pH, visible foreign matters, qualified rear embedding；Sterilizing：Using 100~121 DEG C of 10~30min of flowing steam sterilization, inspection Leakage, sterilizing treats that ampoule temperatures are down to 15~35 DEG C ± 2 DEG C after terminating；8. the ampoule that will sterilize takes out, inspection, packaging.

Corresponding or correlation step or process that method made above can also forgive but be not limited in above-mentioned A-F distinct methods In preparation method or program interaction or alternately or used interchangeably, medicinal bottle and the solution such as ampoule of injection and cillin bottle Medicinal bottle can be exchange.

Additives in the present invention can be with pharmaceutically acceptable auxiliary material or carrier component.

Manufacture uses Compound Lidocaine Hydrochloride parenteral solution and sodium bicarbonate injection or carbonic acid sodium injection or injection Agent or the combination of its aseptic powder injection, or lidocaine carbonate injection belong to the combination of menthol parenteral solution or assembly packaging In in concept of the invention, the formulation of composition of the invention contains but is not limited to solution ointment or cream or gel The pharmaceutically acceptable formulation such as agent or suppository.

The present invention is not only for the one kind in a kind of lidocaine or lidocaine carbonic acid or bicarbonate or its non-hydrochloride Or one or several the pharmaceutical compositions in several, menthol or MENTHOL or peppermint Alkanol isomer or its inclusion compound Thing.The present invention also provides a kind of lidocaine or lidocaine carbonic acid or bicarbonate or lidocaine pharmaceutical salts or its inclusion One or more in thing, one or more in menthol or MENTHOL or peppermint Alkanol isomer or their inclusion compound Pharmaceutical composition, including the composition with one or more pharmaceutically acceptable excipient, diluent or carrier.The present invention Composition formed injection cause to play a role faster, act on it is stronger；The present invention also provides a kind of lidocaine or benefit In cacaine carbonic acid or bicarbonate or its non-hydrochloride or its inclusion compound one or more, menthol or MENTHOL or peppermint The injection of the Pharmaceutical composition of one or more in Alkanol isomer or their inclusion compound, is free of in the injection or contains less Ethanol or glycerine or tween or Tween-80.The analgesia of composite preparation of the invention and local anesthetic action are stronger, but reducing stimulates Property and reduce adverse reaction pharmaceutical composition, the need for more meeting clinical practice, and will to clinical application or treatment bring More preferable compliance, or for clinic provides new selection or new valuable preparation, the present invention further provides the medicine system of preparation The new method of agent.We have found that in the case where pH value is lifted, injection stable system can lift analgesic activity, not shadow Stability is rung, but also the generation of adverse reaction can be reduced.

After compound lidocaine menthol injection injection of the invention, even if without CO₂Effusion and CO₂Quick diffusion can Produce following two aspects effect：Have direct repression to nerve, and by the influence to pH promote the disperse of local anaesthetics with Capture, strengthens neural depression effect, and also the effect than existing Compound Lidocaine Hydrochloride menthol injection is better.

The present invention, similarly will be to clinical application or treatment not only for a kind of or ointment or emulsifiable paste or gel or suppository formulations Bring new selection or preferably compliance；Or for clinic provides new selection or new valuable preparation, the present invention is further carried New method for preparing pharmaceutical preparation.

Exploitation this product can provide a kind of safety, more effective local anaesthetics for clinic.The present invention is for preparing local infiltration Anesthesia, surgery anesthesia, Postoperative Analgesia After, caudal block, epidural block, teeth groove are mended and hindered through retardance, peripheral blockade, brachial plexus Stagnant, sympathetic block, infiltration local anaesthesia or intravenous regional block etc.；And all kinds of pruritic, painful skins are sick, band is treated The medicine of prevention or the treatment of shape post herpetic neuralgia.

Pharmaceutical composition of the invention is to mouse writhing reaction experiment

1st, test objective

The power of compound lidocaine pharmaceutical composition writhing response after intraperitoneal administration of the invention is observed, to investigate not With the degree of the adverse reaction of the pharmaceutical composition of group.

2nd, animal subject：Adult healthy white mouse, male and female half and half, body weight 18-22g.

3rd, test method：Mouse writhing method

Mouse 80 is taken, male and female half and half, fasting (can't help water) 12h is randomly divided into 8 groups, respectively vehicle control group, compound The parenteral solution of the existing CNS of lidocaine hydrochloride is Compound Lidocaine Hydrochloride parenteral solution control group (compound hydrochloric acid profit Many cacaine parenteral solutions), the method group of embodiment 2, the method group of embodiment 3, the method group of embodiment 6, the method group of embodiment 11, the method group of embodiment 12 and The method group of embodiment 18.Administering mode is intraperitoneal injection, and the normal saline solution of vehicle control group 0.9% is given respectively 0.2ml/20g, Compound Lidocaine Hydrochloride parenteral solution control group (0.2ml/20g is injected in intraperitoneal injection), and benefit of the present invention During cacaine parenteral solution group (each group intraperitoneal injection embodiment solution injects 0.2ml/20g) injection 0.2h and 3h, then intraperitoneal injection 0.5% glacial acetic acid solution 0.2ml/20g, timing immediately, mouse produces the secondary of writhing response generation in 15min after observation administration Number, calculates the inhibiting rate of writhing response, inhibiting rate (%)=(the administration group writhing number of times of vehicle control group writhing number of times one)/solvent Control group writhing number of times × 100% [bibliography：Wang Congqing, Wu Yongjie, Wu Bin, etc.；The analgesic activity and mechanism of pain peace capsule Research, Pharmacology and Clinics of Chinese Materia Medica, 2008,24 (3):95-97；].

Compound lidocaine pharmaceutical composition of table 1 etc. to the Body writhing test result of mouse (N=10)

4th, result finds that the display Compound Lidocaine Hydrochloride parenteral solution control group of table 1 produces the number of times or right of writhing response The inhibiting rate of mouse writhing reaction has notable with the difference of each embodiment group of compound lidocaine pharmaceutical composition of the present invention Property, as a result shows, the action intensity degree of pharmaceutical composition of the invention is apparently higher than the control group of prior art.

Specific embodiment

Except in embodiment and when indicated otherwise, all of numerical value used should be by specification and claims It is interpreted as being modified with term " about " in all of example, therefore, unless the contrary indication, this specification and appended The numerical parameter gone out given in claims is approximation, the required property that it can be according to sought by by present disclosure Matter and change, at least, and not be intended to limit the application of doctrine of equivalents right, each numerical parameter takes an examination The number and routine for considering significant digits round up method to explain.

Although the number range and parameter that set the wide scope of disclosure are approximations.But institute in a particular embodiment The numerical value for being given is reported as precisely as possible, and any number is substantially comprising some by the discovery in their own test The error that standard deviation is necessarily led to.

It is pointed out that unless clearly explanation in addition in text, uses in this specification and the appended claims Singulative " one ", " one kind " and " being somebody's turn to do " include the plural form of referring to thing, so, for example.Contain " one if referred to Mixture including two or more compounds during the composition of kind compound ", it is further noted that unless herein clearly Ground explanation in addition, term "or" generally includes "and/or".

Pharmaceutical composition

" pharmaceutical composition " used herein refers to the composition of medicine, and described pharmaceutical composition can contain at least one Pharmaceutically acceptable carrier.

" pharmaceutically acceptable carrier " used herein refers to be applied to that the compound that occasionally provides herein is administered medicinal Excipient or pharmaceutic adjuvant or solvent, it is included well known to a person skilled in the art suitable for any such of specific administration mode Carrier.

In the preparation technology of specification of the invention or each embodiment, the prescription particularly in embodiment has limited each group In the case of the title divided, for simplicity for each component in prescription, can carry out simplifying appellation or the property omitted address, for example, The hydrate of lidocaine hydrochloride 1 in prescription can be referred to as lidocaine hydrochloride hydrate or lidocaine hydrochloride, lemon The hydrate of sour sodium 2 is referred to as sodium citrate or vice versa referred to as, and the L- menthols in prescription are referred to as into menthol, and other components are equal Can or the rest may be inferred.

The concentration unit used in description of the invention has molar concentration (M) or (mol/L) or equivalent concentration (N), or hundred Divide specific concentration etc., chronomere can use second (s), minute (min), hour (h) etc., and volume unit can use liter (l or L), milli (ml), microlitre (μ l) are risen, mass unit can use gram (g), milligram (mg) etc..And for example, w/v：0.01% (weighing body Product ratio：W/V,0.01g/100ml).

" appropriate water for injection ", " appropriate sodium chloride ", " appropriate sodium bicarbonate aqueous solution ", " 5% sodium bicarbonate aqueous solution Appropriate each meaning in " appropriate citric acid solution and sodium citrate solution " etc. can be by the treatment such as raw material or preparation to institute in right amount " Need the suitable less consumption or minimum dosage or optimal consumption or preferably consumption of state.

In order to further appreciate that the present invention, the preferred embodiment of the invention is described with reference to embodiment, but It should be appreciated that these descriptions are simply to further illustrate the features and advantages of the present invention, rather than to the claims in the present invention Limitation.

Effect of the invention is illustrated with specific embodiment below, but protection scope of the present invention is not limited by following examples System.

Specific embodiment

Preparation (the specification of the compound lidocaine carbonate drug combination injection of embodiment 1：5ml/ branch)

Prescription：The hydrate 34.61g of lidocaine hydrochloride 1 (weight is in terms of lidocaine net content), the 2- hydroxypropyls of menthol Group-beta-cyclodextrin inclusion compound 6.5g (in terms of menthol net content), L-aminobutanedioic acid 20g, glycerine 250.0ml, VE succinic acid Macrogol ester 10g, disodium ethylene diamine tetraacetate 0.05g, 5% sodium bicarbonate solution is appropriate, appropriate carbon dioxide, note Penetrate and add to 5000ml with water；

Preparation process：1. L-aminobutanedioic acid, glycerine, VE succinic acid macrogol ester, the ethylenediamine of recipe quantity are taken respectively Tetraacethyl disodium and menthol hydroxypropyl-beta-cyclodextrin inclusion, lidocaine hydrochloride dissolve in and fill 4000ml waters for injection In stainless steel cask, stir and evenly mix；The pH value of solution is adjusted in the range of 7.0~7.4 with appropriate sodium bicarbonate aqueous solution；2. add Cold water for injection to full dose, plus during 0.05% needle-use activated carbon adds above-mentioned solution, stirring and adsorbing 20 minutes；3. solution is filtered with titanium Device circulating filtration 15 minutes, filtrate is again through 0.45 μm of filtering with microporous membrane；And the pH value of filling CO 2 gas regulation solution is extremely In the range of 7.0~7.5；4. sample, determine middle product content, pH, visible foreign matters, qualified rear embedding；5. sterilize：Using 100 DEG C Flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize takes out, inspection Test, pack, obtain final product.

Sample shading prepared by the above method, the dark cold place specified in Chinese Pharmacopoeia standard is preserved 24 months, and solution is protected Hold clear and bright, the content of main ingredient lidocaine is in the range of the 90-110% of the labelled amount of this recipe quantity.

Preparation (the specification of the compound lidocaine carbonate pharmaceutical composition ejection preparation of embodiment 2：10ml/ branch)

Prescription：The hydrate 69.23g of lidocaine hydrochloride 1 (in terms of lidocaine net content), the 2- hydroxypropyls of L- menthols Group-beta-cyclodextrin inclusion compound 13.0g (in terms of menthol net content), urea 20g, citric acid 15g, sodium citrate 15g, glycerine 350.0ml, VE succinic acid macrogol ester 20g, the hydrate 1g of disodium ethylene diamine tetraacetate 2, saturated sodium bicarbonate solution In right amount, appropriate carbon dioxide, water for injection adds to 10L；

Preparation process：1. urea, citric acid, sodium citrate, glycerine, the poly- second of VE succinic acid of recipe quantity are taken respectively Diol ester, disodium ethylene diamine tetraacetate and menthol hydroxypropyl-beta-cyclodextrin inclusion, lidocaine hydrochloride dissolve in and fill In the stainless steel cask of 4000ml waters for injection, stir and evenly mix；With appropriate saturated sodium bicarbonate aqueous solution adjust solution pH value to In the range of 7.1~7.5；2. plus cold water for injection is to full dose, plus during 0.05% needle-use activated carbon adds above-mentioned solution, stirring and adsorbing 20 minutes, and the pH value of solution is adjusted in the range of 7.0~7.4 with carbon dioxide；3. solution titanium filter circulating filtration 15 minutes, filtrate was again with 0.45 μm of filtering with microporous membrane；4. sample, determine in the middle of product contents, pH, visible foreign matters, it is qualified after press 10ml/ branch embeddings；5. sterilize：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 after terminating ℃±2℃；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine carbonate drug combination injection of embodiment 3：5ml/ branch)

Prescription：The hydrate 34.62g of lidocaine hydrochloride 1 (in terms of lidocaine net content), menthol hydroxy propyl-Beta-ring Cyclodextrin inclusion compound 6.5g (in terms of menthol net content), thiocarbamide 20g, sodium lactate 18g, glycerine 100.0ml, VE succinic acid Macrogol ester 30g, the hydrate 0.6g of disodium ethylene diamine tetraacetate 2,5% sodium bicarbonate solution is appropriate, carbon dioxide In right amount, water for injection adds to 5L；

Preparation process：1. thiocarbamide, sodium lactate, glycerine, the hydrate of disodium ethylene diamine tetraacetate 2, the dimension of recipe quantity are taken respectively Raw element E butanedioic acids macrogol ester and menthol hydroxypropyl-beta-cyclodextrin inclusion, lidocaine hydrochloride dissolve in and fill 4000ml In the stainless steel cask of water for injection, stir and evenly mix；The pH value of solution is adjusted to 7.1~7.5 models with appropriate sodium bicarbonate aqueous solution In enclosing；2. plus cold water for injection is to full dose, (w/v is W/V, g/100ml) needle-use activated carbon of plus 0.03% adds above-mentioned In solution, stirring and adsorbing 20 minutes, and the pH value of solution is adjusted in the range of 7.0~7.3 with carbon dioxide；3. solution is used Titanium filter circulating filtration 15 minutes, filtrate is filtered with 0.45 μm of microporous barrier cartridge filter again；4. sample, determine middle product and contain Amount, pH, visible foreign matters, it is qualified to press 5ml/ branch embeddings afterwards, sterilize, inspection, packaging is obtained final product.

Sample shading prepared by the above method, the dark cold place specified in Chinese Pharmacopoeia standard is preserved 27 months, and solution is protected Hold clear and bright, the content of main ingredient lidocaine is in the range of the 90-110% of the labelled amount of this recipe quantity.

Preparation (the specification of the compound lidocaine carbonate pharmaceutical composition ejection preparation of embodiment 4：10ml/ branch)

Prescription：The hydrate 34.6g of lidocaine hydrochloride 1 (in terms of lidocaine net content), injection sodium acid carbonate 12.7g, the hydroxypropyl-beta-cyclodextrin inclusion 6.5g (in terms of menthol net content) of menthol, glycerine 50.0ml, thiocarbamide 30g, Niacinamide 10g, sodium citrate 20g, polyethylene glycol -15- hydroxy stearic acid ester 30g, calcio-disodium edetate 0.5g, saturated carbon Appropriate acid sodium aqueous solution, appropriate carbon dioxide, water for injection adds to 5L

Preparation process：1. it is hard that the thiocarbamide of recipe quantity, niacinamide, sodium citrate, glycerine, polyethylene glycol -15- hydroxyls are taken respectively The hydroxypropyl-beta-cyclodextrin inclusion of resin acid ester, calcio-disodium edetate and menthol, lidocaine hydrochloride, injection carbon Sour hydrogen sodium dissolves in the stainless steel cask for filling 4000ml waters for injection successively, is stirred to dissolve mixing；Use appropriate saturated sodium carbonate The pH value of aqueous solution regulation solution is in the range of 7.1~7.5；2. cold water for injection is added to full dose, plus 0.03% pin activity Charcoal is added in above-mentioned solution, stirring and adsorbing 20 minutes, and adjusts the pH value of solution to 7.0~7.4 scopes with carbon dioxide It is interior；3. solution titanium filter circulating filtration 15 minutes, filtrate is filtered with 0.45 μm of filtering with microporous membrane and 0.22 μm of micropore respectively again Membrane filtration；4. sample, determine in the middle of product contents, pH, visible foreign matters, it is qualified after the loading amount propped up by 10ml/ carry out embedding；5. go out Bacterium：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；To sterilize Ampoule is taken out, inspection, and packaging is obtained final product.

Sample shading prepared by the above method, preserves 27 months in dark cold place, and solution keeps clear and bright, main ingredient lidocaine Content in the range of the 90-110% of the labelled amount of this recipe quantity.

Preparation (the specification of the compound lidocaine carbonate pharmaceutical composition ejection preparation of embodiment 5：10ml/ branch)

Prescription：The hydrate 34.6g of lidocaine hydrochloride 1 (in terms of lidocaine net content), injection sodium acid carbonate 12.71g, the hydroxypropyl-beta-cyclodextrin inclusion 6.5g (in terms of menthol net content) of menthol, 2-HP-BETA-CD 6.0g, Pidolidone 30g, thiocarbamide 30g, VE succinic acid macrogol ester 100g, the hydrate of disodium ethylene diamine tetraacetate 2 0.6g, 5% aqueous sodium carbonate is appropriate, and appropriate carbon dioxide, water for injection adds to 5L

Preparation process：1. thiocarbamide, Pidolidone, the hydrate of disodium ethylene diamine tetraacetate 2, the vitamin of recipe quantity are taken respectively The hydroxypropyl-beta-cyclodextrin inclusion of E butanedioic acids macrogol ester and menthol, lidocaine hydrochloride, injection sodium acid carbonate In the stainless steel cask for filling 4000ml waters for injection, stir and evenly mix；The pH value of solution is adjusted with appropriate aqueous sodium carbonate To in the range of 7.0~7.5；2. cold water for injection is added to full dose, plus in the above-mentioned solution of 0.03% needle-use activated carbon addition, stirring Absorption 15 minutes, and the pH value of solution is adjusted in the range of 6.8~7.3 with carbon dioxide；3. solution titanium filter is circulated Filtering 15 minutes, filtrate is again respectively with 0.45 μm of filtering with microporous membrane and 0.22 μm of filtering with microporous membrane；4. sample, determine middle Product content, pH, visible foreign matters, it is qualified after by 10ml/ prop up loading amount carry out embedding；5. sterilize：Using 100 DEG C of flowing steam sterilizations 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine carbonate pharmaceutical composition ejection preparation of embodiment 6：10ml/ branch)

Prescription：The hydrate 38.08g of lidocaine hydrochloride 1 (in terms of lidocaine net content), menthol 4.0g, hydroxypropyl- Beta-schardinger dextrin 100g, lemon sodium 5.0g, L- threonic acid 20.0g, thiocarbamide 20g, VE succinic acid macrogol ester 100g, second The hydrate 0.5g of edetate disodium 2, appropriate absolute ethyl alcohol, appropriate saturated sodium carbonate solution, appropriate carbon dioxide, note Penetrate and add to 5L with water；

Preparation process：1. the menthol fine powder for taking recipe quantity dissolves in appropriate ethanol, by the hydroxy propyl-Beta-ring of recipe quantity Dextrin is ground into pasty state after distilling water dissolves in right amount, then mixes stirring, then is fully ground 1h, then by said mixture in commercially available Ultrasound three times in supersonic cleaning machine, 15 minutes every time, taking-up was fully ground 1h again, and then decompression boils off most of ethanol, then will 50-60 DEG C of drying of solids 3 hours, then be transferred in the stainless steel cask for filling 3000ml waters for injection, strong stirring makes dissolving； 2. the thiocarbamide of recipe quantity, the hydrate of disodium ethylene diamine tetraacetate 2, VE succinic acid macrogol ester are taken respectively is dissolved in note Penetrate with water；3. will 1. with 2. mix, stir and evenly mix；4. take the lemon sodium of recipe quantity, threonic acid, lidocaine hydrochloride be dissolved in it is suitable In amount water for injection, the pH value of lidocaine hydrochloride solution to 7.0~7.5 scopes is adjusted with appropriate sodium bicarbonate aqueous solution It is interior, then 3. solution will be added to wherein, cold water for injection is added to full dose, plus 0.02% needle-use activated carbon adds above-mentioned solution In, stirring and adsorbing 20 minutes, and adjust the pH value of solution to 6.9 with carbon dioxide and appropriate saturated aqueous sodium carbonate In the range of~7.3；5. solution titanium filter circulating filtration 15 minutes, filtrate is again respectively with 0.45 μm of filtering with microporous membrane and 0.22 μm filtering with microporous membrane, and the pH value of solution is adjusted in the range of 6.8~7.2 with carbon dioxide；6. sample, determine middle Product content, pH, visible foreign matters, it is qualified after by 10ml/ prop up loading amount carry out embedding；7. sterilize：Using 100 DEG C of flowing steam sterilizations 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；8. the ampoule that will sterilize takes out, and uses high-capacity industrial Hydro-extracting cage vibrates 5 minutes repeatedly in rotating speed 150-250rpm, obtains final product.

Sample shading prepared by the above method, preserves 24 months in dark cold place, and solution keeps clear and bright, main ingredient lidocaine Content in the range of the 90-110% of the labelled amount of this recipe quantity.

Preparation (the specification of the compound lidocaine carbonate drug combination injection of embodiment 7：10ml/ branch)

Prescription：The hydrate 34.62g of lidocaine hydrochloride 1 (in terms of lidocaine net content), menthol sulfobutyl ether β-ring Cyclodextrin inclusion compound 6.5g (in terms of menthol net content), sulfobutyl ether beta-schardinger dextrin 20.0g, L- cysteine hydrochloride 5.0g, sulphur Urea 20g, the hydrate 10g of sodium citrate 2, the hydrate 0.5g of disodium ethylene diamine tetraacetate 2, the sodium bicarbonate solution of saturation are appropriate, Appropriate carbon dioxide, water for injection adds to 5L；

Preparation process：Take respectively the menthol sulfobutyl ether Benexate Hydrochloride of recipe quantity, sulfobutyl ether beta-schardinger dextrin, L- cysteine hydrochlorides, thiocarbamide, the hydrate of disodium ethylene diamine tetraacetate 2, lidocaine hydrochloride, sodium citrate are dissolved in appropriate injection With in water, stir and evenly mix, the pH value of lidocaine hydrochloride solution is adjusted to 7.0~7.5 with appropriate saturated sodium bicarbonate aqueous solution In the range of；Cold water for injection is added to full dose, plus in the above-mentioned solution of 0.02% needle-use activated carbon addition, stirring and adsorbing 20 minutes； Solution titanium filter circulating filtration 15 minutes, filtrate is filtered with 0.45 μm of filtering with microporous membrane again, and is adjusted with carbon dioxide The pH value of solution is saved in the range of 6.5~7.0；Sampling, determine in the middle of product contents, pH, visible foreign matters, it is qualified after by 10ml/ branch Loading amount carry out embedding；Sterilizing：Using 115 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to after terminating 30 DEG C ± 2 DEG C, the ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Sample shading prepared by the above method, preserves 24 months in dark cold place, and solution still keeps clear and bright, main ingredient benefit The content of cacaine is in the range of the 90-110% of the labelled amount of this recipe quantity.

Preparation (the specification of the compound lidocaine carbonate drug combination injection of embodiment 8：5ml/ branch)

Prescription：The hydrate 86.0g of lidocaine hydrochloride 1 (in terms of lidocaine net content), menthol sulfobutyl ether β-ring Cyclodextrin inclusion compound 16.0g (weight is in terms of menthol net content), sulfobutyl ether beta-schardinger dextrin 10.0g, glutamic acid 20.0g, nicotinoyl Amine 20.0g, VE succinic acid macrogol ester 300g, appropriate saturated sodium bicarbonate solution, appropriate carbon dioxide, note Penetrate and add to 10L with water；

Preparation technology：Take respectively the menthol sulfobutyl ether Benexate Hydrochloride of recipe quantity, sulfobutyl ether beta-schardinger dextrin, Glutamic acid, niacinamide, glycerine and VE succinic acid macrogol ester, lidocaine hydrochloride are dissolved in appropriate water for injection, are stirred Mixing is mixed, the pH value of lidocaine hydrochloride solution is adjusted in the range of 7.0~7.5 with appropriate sodium bicarbonate aqueous solution, mixed, mended Plus cold water for injection is to full dose, plus in the above-mentioned solution of 0.05% needle-use activated carbon addition, stirring and adsorbing 20 minutes, and use titanium dioxide The pH value of carbon gas and appropriate sodium bicarbonate aqueous solution regulation solution is in the range of 6.5~7.3；Solution titanium filter circulating filtration 15 minutes, filtrate was again with 0.45 μm of filtering with microporous membrane；Sampling, determine in the middle of product contents, pH, visible foreign matters, it is qualified after be used in combination The CO 2 gas-shielded lower loading amount embedding for pressing 5ml/ branch is in ampoule；Sterilizing：Using 100 DEG C of flowing steam sterilization 30min, inspection Leakage, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating, the ampoule that will sterilize takes out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine carbonate drug combination injection of embodiment 9：20ml/ bottles, 25ml/ bottles)

Prescription：The hydrate 34.62g of lidocaine hydrochloride 1 (in terms of lidocaine net content), injection sodium carbonate 12.7g, Menthol hydroxypropyl-beta-cyclodextrin inclusion 6.5g (in terms of menthol net content), thiocarbamide 20.0g, sodium pantothenate 10.0g, L- half Cystine 3.0g, VE succinic acid macrogol ester 5g, appropriate saturated sodium carbonate solution, appropriate carbon dioxide, injection 5L is added to water；

Preparation process：Menthol hydroxypropyl-beta-cyclodextrin inclusion, thiocarbamide, sodium pantothenate, the Guangs of L- half of recipe quantity are taken respectively Propylhomoserin, glycerine and VE succinic acid macrogol ester, lidocaine hydrochloride, sodium carbonate are dissolved in 4000ml waters for injection, are stirred Mixing is mixed, the pH value of solution is adjusted in the range of 7.0~7.5 with appropriate carbon dioxide and sodium bicarbonate aqueous solution, added Cold water for injection to full dose, plus during 0.02% needle-use activated carbon adds above-mentioned solution, stirring and adsorbing 20 minutes, and with appropriate two The pH value of carbon oxide gas and saturated sodium carbonate solution regulation solution is in the range of 7.0~7.5；Solution titanium filter circulating filtration 15 minutes, filtrate was filtered with 0.45 μm of microporous barrier cartridge filter and 0.22 μm of microporous barrier cartridge filter respectively again；Sampling, surveys Product content, pH, visible foreign matters, qualified after embedding in ampoule bottle in the middle of fixed；Sterilizing：Using 100 DEG C of flowing steam sterilizations 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine drug combination injection of embodiment 10：2ml/ branch, 5ml/ branch, 10ml/ Branch, 20ml/ branch)

Prescription：Lidocaine 34.62g, urethane 20g, citrulling 5g, menthol hydroxypropyl-beta-cyclodextrin inclusion 6.5g (in terms of menthol net content), thiocarbamide 30.0g, glycerine 200.0ml, polyethylene glycol -15- hydroxy stearic acid ester 80g, second two Amine tetraacethyl disodium 0.2g, 3M citric acid solution and 2M sodium citrate solutions are appropriate, and water for injection adds to 5L；

Preparation process：1. citrulling, thiocarbamide, disodium ethylene diamine tetraacetate, the lidocaine of recipe quantity are taken in appropriate injection In keg with the stainless steel of water, adding citric acid solution is stirred to dissolve, and 2. takes the urethane of recipe quantity respectively, glycerine and poly- Ethylene glycol -15- hydroxy stearic acid esters are stirred to dissolve in the keg of the stainless steel of appropriate water for injection, then molten by two kinds Liquid mixes, and with the pH value of appropriate citric acid solution and sodium citrate solution regulation solution to 7.2 or so；Benefit is injected water to In full dose, plus the above-mentioned solution of 0.05% needle-use activated carbon addition, stirring and adsorbing 20 minutes；3. solution titanium filter circulating filtration 15 Minute, filtrate is again with 0.45 μm of filtering with microporous membrane；4. sample, determine in the middle of product contents, pH, visible foreign matters, in ampoule bottle Embedding, sterilizing, inspection, packaging is obtained final product.

Preparation (the specification of the pharmaceutical composition ejection preparation of embodiment 11：10ml/ bottles, 25ml/ bottles)

Prescription：Lidocaine 80g, urethane 10g, glutamic acid 10g, L- menthol 3- hydroxypropyl-beta-cyclodextrin inclusions 6.5g (in terms of menthol net content), thiocarbamide 30g, glycerine 100ml, disodium ethylene diamine tetraacetate 0.5g, 3M gluconic acid solution In right amount, 3M sodium gluconate solutions are appropriate, and water for injection adds to 5L；

Preparation process：1. the lidocaine of recipe quantity is taken in the keg of the stainless steel of appropriate water for injection, plus glucose Acid solution, is stirred to dissolve, and L- menthol 3- hydroxypropyl-beta-cyclodextrin inclusions, the urethane, sulphur of recipe quantity are 2. taken respectively Urea, glutamic acid, glycerine, disodium ethylene diamine tetraacetate are stirred to dissolve in the keg of the stainless steel of appropriate water for injection, then Will 1. 2. both mixing, and with the pH value of gluconic acid solution and sodium gluconate solution regulation solution to 6.9~7.4 scopes It is interior；Benefit adds to the full amount of water for injection, plus in the above-mentioned solution of 0.05% needle-use activated carbon addition, stirring and adsorbing 20 minutes；3. solution With titanium filter circulating filtration 15 minutes, filtrate was again with 0.45 μm of filtering with microporous membrane；4. sample, determine in the middle of product contents, pH, can See in foreign matter, filling cillin bottle, jump a queue, gland is sealed, sterilizing, inspection, packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 12：10ml/ bottles)

Prescription：Lidocaine 34.6g, L-ASPARTIC ACID 5g, urethane 10g, lysine 5g, L- menthol 3- hydroxypropyls- Benexate Hydrochloride 6.5g (in terms of menthol net content), thiocarbamide 30.0g, calcio-disodium edetate 0.6g, 2M malic acid Appropriate solution, 2M sodium gluconate solutions are appropriate, and water for injection adds to 5L；

Preparation process：1. take the lidocaine of recipe quantity, L-ASPARTIC ACID in 2000ml waters for injection stainless steel it is small In bucket, stir 20min, plus appropriate malic acid solution, stirring make it is molten, 2. take respectively the L- menthol 3- hydroxypropyls of recipe quantity- Benexate Hydrochloride, urethane, thiocarbamide, lysine, calcio-disodium edetate are in the stainless steel of 2000ml waters for injection In keg, it is stirred to dissolve, then mixes two kinds of solution, and solution is adjusted with malic acid solution and sodium gluconate solution PH value is in the range of 6.9~7.4；Benefit adds to the full amount of water for injection, plus in the above-mentioned solution of 0.05% needle-use activated carbon addition, stirring Absorption 20 minutes；3. solution titanium filter circulating filtration 15 minutes, filtrate is again with 0.45 μm of filtering with microporous membrane；4. sample, survey Product content, pH, visible foreign matters in the middle of fixed, then in filling cillin bottle, jump a queue, gland sealing, sterilizing, inspection, packaging obtains final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 13：2ml/ branch, 5ml/ branch, 10ml/ branch, 20ml/ branch)

Prescription：Lidocaine 34.62g, urethane 20g, niacinamide 10g, L-aminobutanedioic acid 10g, menthol hydroxy propyl-Beta-ring Cyclodextrin inclusion compound 6.5g (in terms of menthol net content), thiocarbamide 30.0g, glycerine 10.0ml, polyethylene glycol -12- hydroxy stearic acids Ester 20g, 3M phosphoric acid solution and 2M sodium citrate solutions are appropriate, and water for injection adds to 5L；

Preparation process：1. the lidocaine of recipe quantity is taken in the keg of the stainless steel of 1000ml waters for injection, plus in right amount Phosphoric acid solution, be stirred to dissolve, menthol hydroxypropyl-beta-cyclodextrin inclusion, urethane, the nicotinoyl of recipe quantity are 2. taken respectively Amine, L-aminobutanedioic acid, thiocarbamide, glycerine and HS15 are in the keg of the stainless steel of 3000ml waters for injection In, it is stirred to dissolve, then two kinds of solution are mixed, and solution is adjusted jointly with appropriate phosphoric acid solution and sodium citrate solution PH value in the range of 6.9~7.4；Benefit adds to the full amount of water for injection, plus in the above-mentioned solution of 0.05% needle-use activated carbon addition, stirs Mix absorption 20 minutes；3. solution titanium filter circulating filtration 15 minutes, filtrate is again with 0.45 μm of filtering with microporous membrane；4. sample, Product content, pH, visible foreign matters in the middle of determining, qualified after embedding in ampoule bottle, sterilizing, inspection, packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol ejection preparation of embodiment 14：5ml/ branch, 10ml/ branch)

Prescription：The hydrate 3.81g of lidocaine hydrochloride 1 (in terms of lidocaine net content), injection sodium carbonate 1.4g, L- Menthol 0.71g (in terms of L- menthol net contents), HP-β-CD 30g, thiocarbamide 10g, meglumine 1g, glycerine 50.0ml, ethanol 50ml, Tween-80 4.0ml, appropriate saturated sodium carbonate solution, appropriate carbon dioxide, injection Water adds to 1000ml；

Preparation process：1. the HP-β-CD of recipe quantity, thiocarbamide are taken respectively is dissolved in the stainless of appropriate water for injection In steel keg；2. during L- menthols dissolve in the stainless steel keg of ethanol, glycerol adding and Tween-80 are stirred to dissolve；3. take respectively The lidocaine hydrochloride of recipe quantity, injection sodium carbonate, meglumine are added in the stainless steel keg of appropriate water for injection, stirring Mix, 4. 1. 2. mix solution with solution, stir, then 3. mix with solution, stir, add cold water for injection To full dose, plus in the above-mentioned solution of 0.01% needle-use activated carbon addition, stirring and adsorbing 20 minutes, and use appropriate saturated sodium carbonate solution In the range of the pH value that carbon dioxide adjusts solution to 6.5~7.5；5. solution titanium filter circulating filtration 15 minutes, filter Liquid is again with 0.45 μm of filtering with microporous membrane；6. sample, determine middle product content, pH, visible foreign matters, qualified rear embedding；7. sterilize： Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；8. will sterilize Ampoule is taken out, vibration, cooling, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 15：5ml/ branch, 10ml/ branch)

Prescription：The hydrate 3.11g of lidocaine hydrochloride 1 (in terms of lidocaine net content), injection sodium carbonate 1.14g, Menthol 3- hydroxypropyl-beta-cyclodextrin inclusions 0.72g (by terms of menthol net content), thiocarbamide 5g, meglumine 1g, glycerine (weight ratio is 1 for 40.0ml, polyethylene glycol -15- hydroxy stearic acid ester 3g, sodium chloride and sodium lactate:1) it is appropriate, carbon dioxide gas Appropriate body, water for injection adds to 1000ml；

Preparation process：Thiocarbamide, menthol 3- hydroxypropyl-beta-cyclodextrin inclusions, glycerine and the poly- second of recipe quantity are taken respectively Glycol -15- hydroxy stearic acid esters, lidocaine hydrochloride, meglumine, injection sodium acid carbonate in 850ml water for injection not In rust steel keg, it is stirred to dissolve, stirs evenly, then (weight ratio is 1 with appropriate sodium chloride and sodium lactate:1) solution is adjusted Osmotic pressure is about 300mOsmol/k, adds cold water for injection to full dose, plus in the above-mentioned solution of 0.02% needle-use activated carbon addition, Stirring and adsorbing 20 minutes, and the pH value of solution is adjusted in the range of 6.5~7.5 with carbon dioxide；Solution titanium filter is followed Ring is filtered 15 minutes, and filtrate is again with 0.45 μm of filtering with microporous membrane；Sampling, determines middle product content, pH, visible foreign matters, qualified Embedding afterwards, potting process filling CO 2 gas shield；Sterilizing：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing knot Treat that ampoule temperatures are down to 30 DEG C ± 2 DEG C after beam；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the lidocaine menthol drug combination injection of embodiment 16：10ml/ branch, 20ml/ branch)

Prescription：Lidocaine hydrochloride 9.0g (in terms of lidocaine net content), injection sodium acid carbonate 3.4g, menthol 3- Hydroxypropyl-beta-cyclodextrin inclusion 2.0g (in terms of menthol net content), thiocarbamide 10g, niacinamide 5g, mannitol 2g, ethylenediamine Tetraacethyl disodium 0.07g, appropriate sodium lactate, appropriate carbon dioxide, water for injection adds to 1000ml；

Preparation process：Thiocarbamide, menthol 3- hydroxypropyl-beta-cyclodextrin inclusions, the hydrochloric acid benefit card of recipe quantity are taken respectively Cause, niacinamide, mannitol, injection sodium acid carbonate, disodium ethylene diamine tetraacetate are in the stainless steel keg of the water for injection of 900ml In, stirring and evenly mixing, the osmotic pressure for then adjusting solution with appropriate sodium lactate is about 300mOsmol/k, adds cold water for injection To full dose, plus in the above-mentioned solution of 0.03% needle-use activated carbon addition, stirring and adsorbing 20 minutes；Solution titanium filter circulating filtration 15 Minute, filtrate is again through 0.45 μm of filtering with microporous membrane；Then the pH value of filtrate is adjusted to 6.8~7.2 models with carbon dioxide In enclosing；4. sample, determine middle product content, pH, visible foreign matters, qualified after embedding in ampoule bottle, potting process fills titanium dioxide Carbon gas shield；Sterilizing：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C after terminating ±2℃；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 17：2ml/ branch, 10ml/ branch, 15ml/ branch, 25ml/ branch)

Prescription：The hydrate 5.6g of lidocaine hydrochloride 1 (in terms of lidocaine net content), injection sodium acid carbonate 2.06g, Menthol 3- hydroxypropyl-beta-cyclodextrin inclusions 1.6g (in terms of menthol net content)), thiocarbamide 10g, morpholine 5g, sodium pantothenate 2g, PEG400 2g, disodium ethylene diamine tetraacetate 0.01g, appropriate sodium chloride, appropriate carbon dioxide, water for injection is added to 1000ml；

Preparation process：Thiocarbamide, menthol 3- hydroxypropyl-beta-cyclodextrin inclusions, the polyethylene glycol of recipe quantity are taken respectively 400th, lidocaine hydrochloride, morpholine, sodium pantothenate, sodium acid carbonate, disodium ethylene diamine tetraacetate are successively in the water for injection of 890ml In stainless steel keg, stir and evenly mix, the osmotic pressure for then adjusting solution with appropriate sodium chloride is about 300mOsmol/k, fill Penetrate and be settled in full dose, plus the above-mentioned solution of 0.05% needle-use activated carbon addition with water, stirring and adsorbing 20 minutes；And use carbon dioxide The pH value of gas regulation solution is in the range of 6.5~7.5；Solution titanium filter circulating filtration 15 minutes, filtrate is again with 0.45 μm Filtering with microporous membrane；Sampling, determine in the middle of product contents, pH, visible foreign matters, it is qualified after press 2ml/ branch, 10ml/ branch, 15ml/ respectively Branch, 25ml/ branch carry out embedding in ampoule bottle, potting process filling CO 2 gas shield；Sterilizing：Steamed using 100 DEG C of circulations Vapour sterilizing 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize takes out, inspection, bag Dress, obtains final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 18：1ml/ branch, 2ml/ branch, 5ml/ branch, 10ml/ branch)

Prescription：The hydrate 17.2g of lidocaine hydrochloride 1 (in terms of lidocaine net content), L-arginine 12g, menthol 3- hydroxypropyl-beta-cyclodextrin inclusions 1.3g (in terms of menthol net content), sodium pantothenate 10g, 3- HP-β-CD 10g, The hydrate 0.05g of disodium ethylene diamine tetraacetate 2, appropriate sodium chloride, 2M citric acids and appropriate sodium citrate solution, water for injection add To 1000ml；

Preparation process：Menthol 3- hydroxypropyl-beta-cyclodextrin inclusions, the 3- hydroxy propyl-Betas-ring paste of recipe quantity are taken respectively Essence, lidocaine hydrochloride, sodium pantothenate, L-arginine, disodium ethylene diamine tetraacetate successively in 920ml water for injection stainless steel In keg, stir and evenly mix, the osmotic pressure for then adjusting solution with appropriate sodium chloride is about 300mOsmol/k, and citric acid and The pH value of sodium citrate solution regulation solution is to 7.3 or so, plus water for injection is settled to full dose, plus 0.05% needle-use activated carbon adds In entering above-mentioned solution, stirring and adsorbing 20 minutes；Solution is filtered with titanium filter, and filtrate is again with 0.45 μm of filtering with microporous membrane；Sampling, Product contents, pH, visible foreign matters in the middle of determining, it is qualified after respectively by 1ml/ branch, 2ml/ branch, 5ml/ branch, 10ml/ branch embeddings are in ampoule In bottle；Sterilizing：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating； The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 19：1ml/ branch, 2ml/ branch, 5ml/ branch, 10ml/ branch)

Prescription：The hydrate 17.2g of lidocaine hydrochloride 1 (in terms of lidocaine net content), the hydrate of trisodium citrate 2 7.6g, L- menthol 3- hydroxypropyl-beta-cyclodextrin inclusions 1.3g (in terms of menthol net content), thiocarbamide 10g, morpholine 5g are general Sour sodium 2g, PEG400 2g, the hydrate 0.075g of disodium ethylene diamine tetraacetate 2, appropriate sodium chloride, 2M citric acid solutions and 2M sodium citrate solutions are appropriate, and water for injection adds to 1000ml；

Preparation process：Thiocarbamide, L- menthol 3- hydroxypropyl-beta-cyclodextrin inclusions, the polyethylene glycol of recipe quantity are taken respectively 400th, lidocaine hydrochloride, morpholine, sodium pantothenate, the hydrate of trisodium citrate 2, the hydrate of disodium ethylene diamine tetraacetate 2 successively in In the stainless steel keg of the water for injection of 900ml, stir and evenly mix, and adjust molten with 2M citric acid solutions and 2M sodium citrate solutions To in the range of 6.9~7.3, the osmotic pressure for then adjusting solution with appropriate sodium chloride is about 300mOsmol/k to the pH value of liquid, plus Water for injection is settled in full dose, plus the above-mentioned solution of 0.05% needle-use activated carbon addition, stirring and adsorbing 20 minutes；Solution is filtered with titanium Device circulating filtration 15 minutes, filtrate is again with 0.45 μm of filtering with microporous membrane；Sampling, determines middle product content, pH, visible foreign matters, Respectively by 1ml/ branch after qualified, 2ml/ branch, 5ml/ branch, 10ml/ branch embeddings are in ampoule bottle；Sterilizing：Using 100 DEG C of flowing steams Sterilizing 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize takes out, inspection, packaging, Obtain final product.

Preparation (the specification of the compound lidocaine carbonate drug combination injection of embodiment 20：5ml/ branch, 10ml/ branch)

Prescription：Compound Lidocaine Hydrochloride parenteral solution 1000ml (in terms of lidocaine hydrochloride net content 80mg/ml, peppermint Brain 1.3mg/ml), thiocarbamide 10.0g, niacinamide 5.0g, appropriate sodium carbonate, appropriate carbon dioxide, appropriate water for injection；

Preparation technology：1. take respectively during the thiocarbamide of recipe quantity, niacinamide dissolve in Compound Lidocaine Hydrochloride parenteral solution, stirring Mix, and with the range of the pH value of sodium carbonate regulating solution to 6.8~7.5, the appropriate constant volume of water for injection to 1200ml, plus 0.02% needle-use activated carbon is added in above-mentioned solution, stirring and adsorbing 20 minutes, 2. solution titanium filter circulating filtration 15 minutes, filter Liquid is again with 0.45 μm of filtering with microporous membrane；And the pH value of solution is adjusted in the range of 6.9~7.3 with carbon dioxide；Sampling, Product content, pH, visible foreign matters in the middle of determining, qualified rear embedding is in ampoule bottle；Sterilizing：Using 100 DEG C of flowing steam sterilizations 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine carbonate menthol injection of embodiment 21：5ml/ branch, 10ml/ branch)

Prescription：Compound Lidocaine Hydrochloride parenteral solution 1000ml (in terms of lidocaine hydrochloride net content 80mg/ml, peppermint Brain 1.3mg/ml), urethane 10.0g, sulfobutyl ether-beta-cyclodextrin 20.0g, appropriate sodium acid carbonate, appropriate carbon dioxide, Appropriate water for injection；

Preparation technology：1. the compound hydrochloric acid benefit that the urethane of recipe quantity, sulfobutyl ether-beta-cyclodextrin dissolve in recipe quantity is taken In cacaine parenteral solution, and with the range of the pH value of manganese hydrogen sodium regulating solution to 6.8~7.5；The appropriate constant volume of water for injection is arrived In 1090ml, plus the above-mentioned solution of 0.04% needle-use activated carbon addition, stirring and adsorbing 20 minutes；2. solution titanium filter circulating filtration 15 minutes, filtrate again respectively with 0.45 μm of filtering with microporous membrane, and with carbon dioxide adjust the pH value of solution to 6.7~ In the range of 7.3；3. sample, determine in the middle of product contents, pH, visible foreign matters, it is qualified after CO 2 gas-shielded lower embedding in In ampoule bottle；Sterilizing：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 after terminating ℃；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 22：5ml/ branch, 10ml/ branch)

Prescription：Compound Lidocaine Hydrochloride parenteral solution 1000ml (in terms of lidocaine hydrochloride net content 80mg/ml, peppermint Brain 1.3mg/ml, meets the Chinese drug standards), 10% sodium citrate solution is appropriate, appropriate water for injection；

Preparation technology：1. the Compound Lidocaine Hydrochloride parenteral solution of recipe quantity is taken in stainless steel keg, uses sodium citrate , in the range of 6.9~7.4, the appropriate constant volume of water for injection is to 1100ml, plus 0.005% pin is active for the pH value of solution regulation solution Charcoal is added in above-mentioned solution, stirring and adsorbing 20 minutes；2. solution titanium filter circulating filtration 15 minutes, filtrate is micro- with 0.22 μm again Hole membrane filtration；3. sample, determine middle product content, pH, visible foreign matters, qualified rear embedding is in ampoule bottle；Sterilizing：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize takes Go out, check, packaging is obtained final product.

Preparation (the specification of the compound lidocaine drug combination injection of embodiment 23：5ml/ branch, 10ml/ branch)

Prescription：The Compound Lidocaine Hydrochloride menthol parenteral solution 1000ml (60mg/ in terms of lidocaine hydrochloride net content Ml, menthol 1.0mg/ml), 2-HP-BETA-CD 20.0g, lysine 10g, 15% sodium gluconate solution are appropriate, note Penetrate and use appropriate amount of water；

Preparation technology：1. Compound Lidocaine Hydrochloride parenteral solution, 2-HP-BETA-CD, the lysine of recipe quantity are taken In stainless steel keg, it is stirred to dissolve, adjusts the pH value of solution in the range of 6.9~7.4 with glucose sodium solution, injection Appropriate amount of water constant volume to 1160ml, plus during 0.005% needle-use activated carbon adds above-mentioned solution, stirring and adsorbing 20 minutes；2. solution is used Titanium filter circulating filtration 15 minutes, filtrate is again with 0.22 μm of filtering with microporous membrane；3. sample, determine in the middle of product content, pH, visible Foreign matter, qualified rear embedding is in ampoule bottle；Sterilizing：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing is waited to pacify after terminating Small jar temperature is down to 30 DEG C ± 2 DEG C；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 24：5ml/ branch, 10ml/ branch)

Prescription：Lidocaine carbonate injection 402.5ml (17.2mg/ml in terms of lidocaine net content) (pH value to 6.6 In the range of~7.0, meet the Chinese drug standards), 1.3g is (net with menthol for L- menthol 3- hydroxypropyl-beta-cyclodextrin inclusions Content meter), thiocarbamide 5.0g, glycerine 20ml, Ethylenediaminetetraacetic Acid Calcium Salt 0.02g, appropriate saturated sodium carbonate solution, water for injection is added to 1000ml；

Preparation technology：Take lidocaine carbonate injection, glycerine, the L- menthol 3- HP-β-CDs of recipe quantity Inclusion compound is stirred to dissolve in the stainless steel keg for filling 450ml waters for injection, and the pH value of solution is adjusted with sodium carbonate liquor To in the range of 6.9~7.4, plus water for injection is settled in full dose, plus the above-mentioned solution of 0.005% needle-use activated carbon addition, stirring Absorption 20 minutes；2. solution titanium filter circulating filtration 15 minutes, filtrate is again with 0.65 μm of filtering with microporous membrane；3. sample, survey Product content, pH, visible foreign matters in the middle of fixed, qualified rear embedding is in ampoule bottle；Sterilizing：Using 100 DEG C of flowing steam sterilizations 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 25：5ml/ branch, 10ml/ branch)

Prescription：(17.2mg/ml in terms of lidocaine net content, meets middle traditional Chinese medicines to lidocaine carbonate injection 402.5ml Product standard criterion) (in the range of pH value to 6.6~7.2), menthol 2-HP-BETA-CD inclusion compound 1.3g is (with menthol Net content meter), thiocarbamide 3.0g, 2-HP-BETA-CD 6.0g, Ethylenediaminetetraacetic Acid Calcium Salt 0.01g, 1M citric acid and 1M sodium gluconates Appropriate solution, water for injection adds to 1000ml；

Preparation technology：1. lidocaine carbonate injection 402.5ml, thiocarbamide, the 2- hydroxy propyl-Betas-ring paste of recipe quantity are taken Essence, menthol 2-HP-BETA-CD inclusion compound, Ethylenediaminetetraacetic Acid Calcium Salt are stirred in the stainless steel keg for filling 500ml waters for injection Mixing makes dissolving, and the pH value of solution is adjusted in the range of 7.0~7.4 with citric acid and sodium gluconate solution, plus water for injection is fixed Hold to full dose, plus in the above-mentioned solution of 0.005% needle-use activated carbon addition, stirring and adsorbing 20 minutes；2. solution titanium filter is circulated Filtering 15 minutes, filtrate is again with 0.45 μm of filtering with microporous membrane；3. sample, determine middle product content, pH, visible foreign matters, it is qualified Embedding is in ampoule bottle afterwards；Sterilizing：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures drop after terminating To 30 DEG C ± 2 DEG C；The ampoule that will sterilize is taken out, inspection, and packaging is obtained final product.

Preparation (the specification of the compound lidocaine menthol emulsion for injection of embodiment 26：10ml/ branch, 20ml/ branch)

Prescription：Lidocaine 34.62g, refined soybean oil 10g, refined egg yolk lecithin 1.2g, urethane 20g, citric acid 20g, L- menthol 3- hydroxypropyl-beta-cyclodextrin inclusions 6.5g (in terms of menthol net content), thiocarbamide 10.0g, glycerine 250.0ml, polyethylene glycol -15- hydroxy stearic acid ester 50g, Ethylenediaminetetraacetic Acid Calcium Salt 0.1g, 10% sodium gluconate solution are appropriate and 10% Citric acid solution it is appropriate, water for injection adds to 5L,

Preparation process：1. urethane, the Caledonia cacaine of recipe quantity, citric acid, glycerine, L- menthol 3- hydroxypropyls are taken respectively Group-beta-cyclodextrin inclusion compound, Ethylenediaminetetraacetic Acid Calcium Salt in 2000ml waters for injection, with 10% appropriate sodium gluconate solution and 10% Citric acid solution make dissolving；2. glycerine, VE succinic acid macrogol ester, refined soybean oil, the refined egg of recipe quantity are taken In 2000ml waters for injection, stirring makes emulsification to yellow lecithin；Then both are well mixed, add cold water for injection to complete Amount, needle-use activated carbon is added in above-mentioned solution, stirring and adsorbing, and with 10% appropriate sodium gluconate solution and 10% lemon The pH value of acid solution regulation solution is in the range of 6.5~7.5；Solution titanium filter circulating filtration 15 minutes, solution titanium filter, 1 μm of microporous membrane filters filtering；Sampling, determines middle product content, pH, visible foreign matters, and qualified rear embedding is in ampoule bottle；Go out Bacterium：Using 100 DEG C of flowing steam sterilization 30min, leak detection, sterilizing treats that ampoule temperatures are down to 30 DEG C ± 2 DEG C after terminating.

Preparation (the specification of the compound lidocaine menthol liquid agent of embodiment 27：50ml/ bottles)

Prescription：Lidocaine 34.62g, urethane 20g, L-aminobutanedioic acid 10g, L- menthol HP-β-CD inclusion Thing 6.5g (in terms of L- menthol net contents), thiocarbamide 30.0g, the 0.5g of polyquaternium -1, Ethylenediaminetetraacetic Acid Calcium Salt 0.2g, glycerine 200ml, Polyethylene glycol -15- hydroxy stearic acid esters 20g, 3M citric acid solution and 2M sodium citrate solutions are appropriate, and water for injection adds to 5L；

Preparation process：Take the lidocaine of recipe quantity lemon in the keg of the stainless steel of 4000ml ethanol plus appropriate Acid solution, is stirred to dissolve, then is separately added into menthol hydroxypropyl-beta-cyclodextrin inclusion, urethane, the door winter ammonia of recipe quantity Acid, thiocarbamide, polyquaternium -1, Ethylenediaminetetraacetic Acid Calcium Salt, glycerine and polyethylene glycol -15- hydroxy stearic acid esters, are stirred to dissolve, and with suitable The citric acid solution and sodium citrate solution of amount adjust the pH value of liquid in the range of 6.9~7.4 jointly；Benefit is injected water to Full dose, it is filling in medicinal bottle, add a cover, tamponade, using 100 DEG C of flowing steam sterilization 30min, cooling is taken out, inspection is packed, Obtain final product.

The preparation (specification 20ml/ branch) of the lidocaine menthol emulsifiable paste of embodiment 28

Preparation technology：1) single hard fatty acids glyceride, stearic acid and the hexadecanol for weighing recipe quantity mix in beaker, plus Heat makes fusing, standby；2) lidocaine of recipe quantity, sorbic acid, menthol hydroxypropyl-beta-cyclodextrin inclusion, poly- is taken respectively Quaternary ammonium salt -1, Ethylenediaminetetraacetic Acid Calcium Salt, glycerine and polyethylene glycol -15- hydroxy stearic acid esters are added in the container of the water for injection of 350ml, It is 6.001-6.8 to adjust pH with the citric acid and sodium citrate solution of 1mol/L, is stirred to dissolve；3) be stirred continuously it is lower will 1) plus To in solution 2), benefit is added to the full amount of water for injection, emulsification, crosses 200 mesh nylon mesh, and cooling, by 20ml/ bottles of packing, is sealed, i.e., .

The preparation (specification 10g/ bottles) of the lidocaine menthol ointment of embodiment 29

Prescription：Lidocaine 17.31g, menthol 3.25g, beeswax 50g, glycerine 50g, lanolin 30g, albolene add To 1000g；

Preparation method：Vaseline 800g, the beeswax of recipe quantity, glycerine, lanolin are taken respectively in beaker, it is heated to 60~ 70 DEG C make to melt, and then sequentially add the lidocaine of the recipe quantity of 100 mesh sieves, menthol and are sufficiently stirred for mixing, and packing is close Envelope, packaging.

The preparation (specification 5g/ bottles) of the lidocaine menthol ointment of embodiment 30

Prescription：Lidocaine 6.93g, L- menthol 1.3g, the fat 60g of polyoxyethylene stearate 40, glycerine 100g, lanolin 40g, hexadecanol 80g, albolene adds to 1000g；

Preparation method：Vaseline 650g, the fat of polyoxyethylene stearate 40 of recipe quantity, glycerine, lanolin, hexadecanol are taken respectively It is mixed in beaker, being heated to 60~70 DEG C makes to melt, lidocaine, the L- for then sequentially adding the recipe quantity of 100 mesh sieves are thin Lotus brain is sufficiently stirred for mixing, plus vaseline is to 1000g, mixes, packing, sealing, packaging.

The preparation (specification 5g/ branch, 50g/ branch) of the lidocaine menthol ointment of embodiment 31

Prescription：Lidocaine 30g, L- menthol 20g, the fat 60g of polyoxyethylene stearate 40, glycerine 100g, lanolin 40g, Hexadecanol 80g, octadecyl alcolol 20g, albolene adds to 1000g；

Preparation method：Vaseline 600g, the fat of polyoxyethylene stearate 40 of recipe quantity, glycerine, lanolin is taken respectively to be mixed in In beaker, being heated to 60~70 DEG C makes to melt, and lidocaine, the L- menthols for then sequentially adding the recipe quantity of 80 mesh sieves are abundant Stir and evenly mix, be sub-packed in medicinal flexible pipe, seal, packaging.

The preparation (specification 10ml/ branch, 20ml/ branch) of the compound lidocaine menthol gel of embodiment 32

Prescription：Lidocaine 6.93g, L- menthol hydroxypropyl-beta-cyclodextrin inclusion 2.0g (is counted weight with L- menthols Amount), Carbopol 20g, Macrogol 4000 80g, single hard fatty acids glyceride 30g, tocopheryl succinate acid polyethylene glycol Ester 2g, trehalose 4g, the 0.01g of polyquaternium -1, sodium ethylene diamine tetracetate 0.1g, appropriate sodium chloride, the citric acid solution of 2M or Appropriate with triethanolamine, water for injection adds to 1000ml

Preparation technology：1) Carbopol of recipe quantity is weighed in 800ml waters for injection, makes swelling dispersion, then add recipe quantity Macrogol 4000, single hard fatty acids glyceride, make dissolving, it is standby；2) lidocaine for weighing recipe quantity is injected in 100ml With in the stainless steel keg of water, adding citric acid solution is stirred to dissolve, plus recipe quantity trehalose, natrium adetate, polyquaternary amine Salt -1, VE succinic acid macrogol ester are stirred to dissolve in stainless steel keg, are adjusted with citric acid or with triethanolamine PH value to 6.7 is saved, plus water for injection is settled to 1000ml, stirs, and is distributed into the medicinal flexible pipes of 10ml, and seal, Check, obtain final product.

Preparation (the specification of the compound lidocaine menthol solution of embodiment 36：50ml/ bottles)

Prescription：Lidocaine 34.62g, L-ASPARTIC ACID 5g, urethane 20g, lysine 5g, L- menthol 3- hydroxypropyls- Benexate Hydrochloride 6.5g (in terms of menthol net content), thiocarbamide 30.0g, 2M malic acid solution is appropriate, 2M sodium gluconates Appropriate solution, water for injection adds to 5L；

Preparation process：Lidocaine, the L-ASPARTIC ACID of recipe quantity are taken in the keg of the stainless steel of 2000ml waters for injection In, stir 20min, plus appropriate malic acid solution, stirring makes molten, and the L- menthols 3- hydroxy propyl-Betas-ring of recipe quantity is taken respectively Cyclodextrin inclusion compound, urethane, thiocarbamide, lysine are stirred to dissolve in the keg of the stainless steel of 2000ml waters for injection, then Two kinds of solution are mixed, and with the range of the pH value of malic acid solution and sodium gluconate solution regulation solution to 6.9~7.4； Benefit adds to the full amount of water for injection, plus in the above-mentioned solution of 0.05% needle-use activated carbon addition, stirring and adsorbing 20 minutes；Solution is filtered with titanium Device circulating filtration 15 minutes, filtrate is again with 0.65 μm of filtering with microporous membrane；Sampling, determines middle product content, pH, visible foreign matters, Then in filling medicinal bottle, jump a queue, gland sealing, sterilizing, inspection, packaging obtains final product.

Preparation (the specification of the compound lidocaine menthol injection of embodiment 37：2ml/ branch, 5ml/ branch, 10ml/ bottles)

Prescription：Lidocaine 34.6g, Adrenaline Tartrate 0.1732mg, L-ASPARTIC ACID 5g, urethane 10g, rely ammonia Sour 5g, L- menthol 3- hydroxypropyl-beta-cyclodextrin inclusions 6.5g (in terms of menthol net content), thiocarbamide 30.0g, ethylenediamine tetraacetic Calcium acetate sodium 0.6g, 2M malic acid solution are appropriate, and 2M sodium gluconate solutions are appropriate, and water for injection adds to 5L；

Preparation process：1. lidocaine, Adrenaline Tartrate, the L-ASPARTIC ACID of recipe quantity are taken in 2000ml injections In the keg of the stainless steel of water, 20min, plus appropriate malic acid solution are stirred, stirring makes molten, and the L- that recipe quantity is 2. taken respectively is thin Lotus brain 3- hydroxypropyl-beta-cyclodextrin inclusions, urethane, thiocarbamide, lysine, calcio-disodium edetate are in 2000ml injections In the keg of the stainless steel of water, it is stirred to dissolve, then mixes two kinds of solution, and it is molten with malic acid solution and sodium gluconate The pH value of liquid regulation solution is in the range of 6.9~7.4；Benefit is added to the full amount of water for injection, plus 0.05% needle-use activated carbon is added In stating solution, stirring and adsorbing 20 minutes；3. solution titanium filter circulating filtration 15 minutes, filtrate is again with 0.45 μm of miillpore filter mistake Filter；4. sample, determine in the middle of product contents, pH, visible foreign matters, then in filling cillin bottle, jump a queue, gland sealing, sterilizing, inspection Test, pack, obtain final product.

Embodiment 38

The pharmaceutical composition safety testing result of compound lidocaine menthol injection of the invention

First, the pharmaceutical composition allergic reaction experiment of compound lidocaine menthol injection of the invention

1st, test objective

The pharmaceutical composition systemic administration for observing compound lidocaine menthol injection of the invention whether there is sensitization work With.

2nd, test material

2.1. animal subject：Adult healthy albino guinea-pig, male, body weight 200-300g.

2.2. tested material：The pharmaceutical composition of compound lidocaine menthol injection of the invention.

2.3. comparison medicine：Ovalbumin, is diluted with distilled water into 5% ovalbumin standby before use.

3rd, test method

3.1. sensitization contact：Cavy 32 is taken, 4 groups are randomly divided into, respectively vehicle control group, test medicine group 1, tested Medicine group 2 and positive controls.Every group of 8 animals.Each group animal distinguishes the chlorine of capacity (0.5ml) 0.9% such as intraperitoneal injection (ip) Change sodium solution, medicinal composition solution (method of embodiment 1, the method for embodiment 2 of compound lidocaine menthol injection of the invention Prepare) and 5% ovalbumin, the next day once, continuous 5 times.

3.2. provocative test：Each group animal is carried out into excitability injection on the 12nd day after the administration of last sensitization.Vehicle controls Group, test medicine group and positive controls cavy are respectively through the sodium chloride solution of jugular vein 0.9%, compound of the invention profit The medicinal composition solution of many cacaine menthol injections and 5% ovalbumin 1ml.Observe and record after administration at once to 15, 30th, in 60,120 and 180min there be but symptoms of allergic animal.

4th, result of the test

The sodium chloride solution of cavy abdominal cavity sensitizing injection 0.9%, the medicine of compound lidocaine menthol injection of the invention After compositions solution and 5% ovalbumin sensitization, animal ordinary circumstance is good, and diet, urination and faecal condition are normal.Animal Excitability injection is carried out after the administration of last sensitization within the 12nd day.Vehicle control group and test medicine group animal are excited after being administered at once Cough is showed no in 15,30,60,120 and 180min, is rolled up, is erected hair, the expiratory dyspnea even symptoms of allergic such as death, Therefore it is negative to be evaluated as allergic reaction.There is spasm and twitches, pants, has difficulty in breathing immediately after exciting administration in positive controls cavy And the phenomenon such as cyanosis, and it is dead in 5min after administration is excited, allergic reaction is the extremely strong positive, is shown in Table 2

The pharmaceutical composition of the compound lidocaine menthol injection of the invention of table 2 causes cavy allergic reaction and its degree

5th, conclusion (of pressure testing)

Cavy is injected intravenously the pharmaceutical composition of compound lidocaine menthol injection of the invention, and animal is not observed Cough, roll up, erecting the allergic reaction phenomenons such as hair, expiratory dyspnea.Show compound lidocaine menthol injection of the invention Pharmaceutical composition is to animal subject without sensitization.

The compound lidocaine menthol pharmaceutical composition hemolytic reaction test of embodiment 39

1st, test objective：The pharmaceutical composition for observing compound lidocaine menthol injection is added to red blood cell suspension In whether produce haemocylolysis and hemagglutination.

2nd, test material

Test medicine：The solution of the control group of lidocaine hydrochloride injection and compound lidocaine menthol of the invention The medicinal composition solution of injection

3rd, test method

3.1.2% prepared by red blood cell suspension：Healthy human blood 6ml is taken every time, and anticoagulant heparin constantly stirs blood with glass bar Liquid.About 10 times of physiological saline of amount are added, is shaken up, 1500rpm centrifugation 15min go the red blood cell of supernatant, precipitation to use physiology again Salt solution cyclic washing 3~4 times as stated above, not showing red to supernatant.Gained red blood cell is made into physiological saline 2% suspension, is for experiment.This red blood cell is prepared and can repeatedly carried out in the present embodiment.

3.2. test method：Clean tube 7 is taken, is numbered, No. 1-5 pipe is test sample pipe, No. 6 pipes are negative control Pipe, No. 7 pipes are positive control pipe.By sequentially adding 2% red blood cell suspension 2.5ml and different volume of saline table 4 Suo Shi, Mix, after 37 DEG C ± 0.5 DEG C incubates half an hour, 1-5 pipes add the control group of the not lidocaine hydrochloride injection of co-content Solution and compound lidocaine menthol injection of the invention medicinal composition solution it is (of the invention by each embodiment method Prepare), the 6th pipe adds physiological saline 2.5ml, the 7th pipe to add distilled water 2.5ml, after mixing, 37 DEG C of ± 0.5 DEG C of temperature are put immediately Educate.Each observation in 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours and 3 hours is once.If solution be in clear and bright red, ttom of pipe without Or there is a small amount of red blood cell to remain, show there is haemolysis；If having brownish red or rufous flocculent deposit in solution, after shaking regardless of Dissipate, then further cell agglutination phenomenon is judged.

4th, result of the test

Result see the table below 3, it is seen that 1~5 pipe supernatant in observed 3 hours is colourless bright, and without floccule.The 7 pipe solution are in clear and bright red, represent that positive control pipe has haemolysis to produce.

Effect of the lidocaine menthol pharmaceutical composition of table 3 to HRBC's suspension

5th, conclusion (of pressure testing)

The solution 0.1 of each embodiment method group of pharmaceutical composition of compound lidocaine menthol injection of the invention~ 0.5ml is added in 2% HRBC's suspension, Continuous Observation 3 hours, and as a result haemolysis and RCA occurs in each Guan Junwei Phenomenon, red blood cell is deposited on ttom of pipe, supernatant achromatism and clarity, without floccule.Show the medicine without hemolytic reaction and RCA Phenomenon.It is continuous to see and the solution 0.5ml of the control group of lidocaine hydrochloride injection is added in 2% HRBC's suspension Examine 3 hours, in clear and bright red, ttom of pipe there are some red blood cells to remain, and shows there is part haemolysis.

The compound lidocaine menthol injection medicine composition intravascular injection irritation test of embodiment 40

1st, test objective：Observation animal the physiological saline of drip-feed 0.9%, medicine composition injection of the invention and After comparison medicine parenteral solution, the vascular stimulation response situation of generation.

2nd, test material：2.1. animal：The white Female rabbits of the big ear of adult healthy New Zealand, 2.5~3.0kg of body weight.

2.2. tested material：Compound Lidocaine Hydrochloride injection control group [China National Drug Standard WS1- (X- 109)-2000Z]；Medicine composition injection (embodiment 9, embodiment 12, embodiment 16, the legal system of embodiment 18 of the invention It is standby)；

The parenteral solution of medicine composition injection of the invention and Compound Lidocaine Hydrochloride injection control group.

3rd, test method：Female rabbits 13, the 1st unused any medicine makees the observation of blank parallel control；Other 12 Divide respectively four groups respectively at auris dextra edge drip-feed Compound Lidocaine Hydrochloride injection contrast solution (according to the national drug standards WS1- (X-109) -2000Z prepare) and each embodiment method group solution；Administered volume is 0.8ml/kg, and drip velocity is 25~30 drops/min；Left auricular vein the capacity physiological saline such as gives and compares, and drip velocity is identical with by reagent.Daily one It is secondary, continuous drip 5 days.During instillation, the irritative response of auricular vein is observed in naked eyes timing daily.Put to death rabbit within 7th day, Bilateral auricular vein proximal part is drawn materials at injection site 1.0cm~1.5cm, is fixed with formaldehyde, does conventional organization section, is carried out Pathological examination.

4th, result of the test

4.1. naked eyes result：

Drip-feed the present embodiment each group solution, the vein of administration is compared with physiological saline to the slight expansion of lateral vein, drug withdrawal 24h Afterwards, it is seen that the oozing of blood at acupuncture forms subcutaneous induration around vein, administration side with to drip-feed physiological saline side without obvious Difference, other macroscopic results and physiological saline side no significant difference.

Compound Lidocaine Hydrochloride menthol injection control group animal during instillation repeatedly struggles, and points out control group There is certain excitant to body, can cause vascular pain, and it is rubescent to there is the congestion of blood vessel, vascular endothelial cell mild swelling, The inflammatory reaction situation such as peripheral tissue edema.

4.2. pathological examination：

Blank control group：See that venous blood tube chamber is complete under mirror, have no narrow, its tube wall has no inflammatory cell infiltration.

Physiological saline side：See that venous blood tube chamber is complete under (left auricular vein, instillation normal saline solution) mirror, its tube wall is shown in A little inflammatory cell infiltration.It is remaining to have no obvious lesion.

Test medicine group of the present invention：See venous blood tube chamber under (right auricular vein, instil pharmaceutical composition of the invention) mirror Completely, its tube wall is shown in a little inflammatory cell infiltration.It is remaining to have no obvious lesion.

Venous blood tube chamber swelling is seen under control drug group (right auricular vein, instillation control drug group solution) mirror, tube wall is scorching Property cellular infiltration is obvious.

5th, conclusion (of pressure testing)

Rabbit auricular vein instils the dilute solution after 5 days of pharmaceutical composition of the invention, injection site without Finding of naked eye irritative response, and there is the excitant of finding of naked eye in the control group of Compound Lidocaine Hydrochloride menthol injection Reaction.Microscopic pathology inspection result shows, has no blood vessel structure exception, endothelial injuries, thrombosis and other pathological changes, this Result is consistent with vehicle control group；Then there is the damage on pathology in control drug group.Prompting：Pharmaceutical composition of the invention is to blood Pipe is without obvious irritation, and the control group of Compound Lidocaine Hydrochloride menthol injection then has obvious excitant to blood vessel.

Industrial applicibility etc. and its explanation etc.：

The present invention is described in detail above by specific embodiment and embodiment, it will nevertheless be understood that these are said Bright that any limitation is not constituted to the scope of the present invention, person skilled substantially can be without departing from spirit of the invention and guarantor In the case of shield scope, technical solutions and their implementation methods of the present invention can be carried out with various modifications, improvement and replaced and group Close to realize the technology of the present invention, these are because falling within the scope of protection of the present invention.In particular, it will be understood that The change of many details is possible, and all similar replacements and change are for a person skilled in the art apparent , they are considered as being included in spirit of the invention, scope and content, and the present invention is not limited to above-described embodiment.

Claims

1. lidocaine pharmaceutical composition, it is characterised in that：The combination of one UD or unit formulation or unit volume The ratio between weight number or parts by weight of main ingredient component are in thing：Containing lidocaine or its pharmaceutically acceptable salt or its inclusion Thing be 20~100 (with lidocaine weight calculation amounts), MENTHOL or menthol or its isomers or its inclusion compound or its be total to One or more in crystal is 2~20 (in terms of the weight of menthol)；The pharmaceutical composition and pharmaceutically acceptable auxiliary material Or excipient or vehicle group are into pharmaceutical preparation, including but not limited to injection or solution；The preparation of above-mentioned composition is in solution Under pH value direct measurement or a UD or unit formulation or unit volume said composition, the pH value of its preparation exists Between 6.001-9.5.

2. the lidocaine pharmaceutical composition described in claim 1, it is characterised in that：One UD or unit formulation or list The ratio between weight number or parts by weight of main ingredient component are in the said composition of position volume：Containing lidocaine or its is pharmaceutically acceptable Salt or its inclusion compound be 20~100 (with lidocaine weight calculation amounts), MENTHOL or menthol or its isomers or its One or more in inclusion compound or its eutectic is 2~20 (in terms of the weight of menthol)；Or in said one unit dose 0.20~5 times of weight number containing above-mentioned each main ingredient component in the said composition of amount or unit formulation or unit volume；Wherein, Lidocaine or carbonic acid or bicarbonate are selected from, but not limited to, lidocaine, lidocaine carbonate, lidocaine bicarbonate, profit Many cacaine sodium acid carbonates or lidocaine ammonium hydrogen carbonate or lidocaine or its pharmaceutically-acceptable salts or their hydrate or One or more in their inclusion compound；The pharmaceutical composition is constituted with pharmaceutically acceptable auxiliary material or excipient or carrier The pH value of pharmaceutical preparation, its injection or solution and other preparations is between 6.01-9.5.

3. the lidocaine pharmaceutical composition described in claim 1~2, it is characterised in that：One UD or unit formulation Or the ratio between weight number or parts by weight of main ingredient component are in the said composition of unit volume：Containing lidocaine or its pharmaceutically may be used The salt of receiving be 30~90mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion compound or One or more in its eutectic is 3~15mg (with menthol weight calculation amount)；Or in said one UD or unit 0.25~5 times of weight number containing above-mentioned each main ingredient component in the said composition of preparation or unit volume；Wherein, lidocaine Or carbonic acid or bicarbonate be selected from lidocaine, lidocaine carbonate, lidocaine bicarbonate, lidocaine sodium acid carbonate or One or more in lidocaine ammonium hydrogen carbonate or its pharmaceutically-acceptable salts or their hydrate；The pharmaceutical composition with Pharmaceutically acceptable auxiliary material or excipient or vehicle group into pharmaceutical preparation, the pH value of its injection or solution and other preparations Between 6.01-9.5.

4. the lidocaine pharmaceutical composition described in claims 1 to 3, it is characterised in that：One UD or unit formulation Or the ratio between weight number or parts by weight of main ingredient component are in the said composition of unit volume：Containing lidocaine or its pharmaceutically may be used The salt of receiving is 60.3~76.2mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or its inclusion One or more in thing or its eutectic is 11.0~14.3mg (with menthol weight calculation amount)；Or in said one unit dose 0.25~5 times of weight number containing above-mentioned each main ingredient component in the said composition of amount or unit formulation or unit volume；Wherein, Lidocaine or carbonic acid or bicarbonate are selected from lidocaine, lidocaine carbonate, lidocaine bicarbonate, lidocaine carbon One or more in sour hydrogen sodium or lidocaine ammonium hydrogen carbonate or its pharmaceutically-acceptable salts or their hydrate；The medicine Composition and pharmaceutically acceptable auxiliary material or excipient or vehicle group into pharmaceutical preparation, its injection or solution and other systems The pH value of agent is between 6.01-9.5.

5. the lidocaine pharmaceutical composition described in claims 1 to 3, it is characterised in that：One UD or unit formulation Or the ratio between weight number or parts by weight of main ingredient component are in the said composition of unit volume：Containing lidocaine or its pharmaceutically may be used The salt of receiving is the bag of 86mg or 43mg (with lidocaine weight calculation amount), MENTHOL or menthol or its isomers or cyclodextrin One or more in compound or its eutectic is 13mg or 6.5mg (with menthol weight calculation amount)；Or in said one unit 0.25~5 times of weight number containing above-mentioned each main ingredient component in the said composition of dosage or unit formulation or unit volume；Its In, lidocaine or carbonic acid or bicarbonate are selected from lidocaine, lidocaine carbonate, lidocaine bicarbonate, benefit card Because of one or more in sodium acid carbonate or lidocaine ammonium hydrogen carbonate or its pharmaceutically-acceptable salts or their hydrate；Should Pharmaceutical composition and pharmaceutically acceptable auxiliary material or excipient or vehicle group are into pharmaceutical preparation.

6. the lidocaine pharmaceutical composition described in Claims 1 to 4, it is characterised in that：One UD or unit formulation Or the ratio between weight number or parts by weight of main ingredient component are in the said composition of unit volume：Containing lidocaine or its pharmaceutically may be used The salt of receiving be 69.22895 or 69.229 or 69.23 or 69.2 or 69.3mg (with lidocaine weight calculation amount), MENTHOL or One or more in the inclusion compound of menthol cyclodextrin or its eutectic is 13mg (with menthol weight calculation amount)；Or above-mentioned 0.25 of weight number containing above-mentioned each main ingredient component in the said composition of one UD or unit formulation or unit volume ~5 times；Wherein, lidocaine or carbonic acid or bicarbonate are selected from lidocaine, lidocaine carbonate, lidocaine bicarbonate One kind in salt, lidocaine sodium acid carbonate or lidocaine ammonium hydrogen carbonate or its pharmaceutically-acceptable salts or their hydrate Or it is various；The pharmaceutical composition and pharmaceutically acceptable auxiliary material or excipient or vehicle group are into pharmaceutical preparation.

7. the lidocaine pharmaceutical composition described in Claims 1 to 4, it is characterised in that：One UD or unit formulation Or the ratio between weight number or parts by weight of main ingredient component are in the said composition of unit volume：Containing lidocaine or its pharmaceutically may be used The salt of receiving be 34.614476mg or 34.61448 or 34.6145 or 34.615 or 34.614 or 34.61 or 34.62mg or One kind in the inclusion compound or its eutectic of 34.6mg (with lidocaine weight calculation amount), MENTHOL or menthol cyclodextrin or Various is 6.5mg (with menthol weight calculation amount)；Or in the combination of said one UD or unit formulation or unit volume 0.25~5 times of weight number containing above-mentioned each main ingredient component in thing；Wherein, lidocaine or carbonic acid or bicarbonate are selected from profit Many cacaines, lidocaine carbonate, lidocaine bicarbonate, lidocaine sodium acid carbonate or lidocaine ammonium hydrogen carbonate or they Hydrate in one or more；The pharmaceutical composition and pharmaceutically acceptable auxiliary material or excipient or vehicle group are into medicine Preparation.

8. the lidocaine pharmaceutical composition described in claim 1~7, it is characterised in that：Can be with effective dose in this composition Adrenaline or norepinephrine, isoprel or pharmaceutically acceptable salt or derivatives thereof are combined into composition.

9. the lidocaine pharmaceutical composition described in claim 1~8, it is characterised in that：Described or its inclusion compound be selected from but The inclusion compound of menthol cyclodextrin is not limited to, the cyclodextrin can be cyclodextrin or the pharmaceutically acceptable derivative of cyclodextrin Thing, cyclodextrin or derivatives thereof be selected from but be not limited only to natural cyclodextrin, α-, β-or gamma-cyclodextrin, methyl flamprop, ethyl Cyclodextrin, hydroxypropyl cyclodextrin, butyl cyclodextrin, sulphur butyl cyclodextrin, sulphonic acid ester cyclodextrin, Tanabe Seiyoku, cyclodextrin phosphorus Acid esters, hydroxyethyl cyclodextrin, front three cyclodextrin, acetyl cyclodextrin, carboxylate cyclodextrin, nitrate cyclodextrin, sulfuric ester Cyclodextrin, glucosyl group cyclodextrin, malt-base cyclodextrin, galactolipin cyclodextrin, succinyl cyclodextrin, hydroxy propyl-Beta-ring paste Essence, (- the O- of 2,6- bis-) second group-beta-cyclodextrin, (2- carboxy ethyls)-beta-schardinger dextrin sodium salt, (2- hydroxyethyls)-beta-schardinger dextrin, Sulfobutyl ether-beta-cyclodextrin, (2- hydroxypropyls)-beta-schardinger dextrin, 6- monodeoxy -6- monoamines group-beta-cyclodextrin, 6-O- α-malt Glycosyl-beta-cyclodexterin, fourth group-beta-cyclodextrin, butyl-gamma-cyclodextrin, carboxymethyl group-beta-schardinger dextrin, methyl-B-cyclodextrin, amber Amber acyl-beta-schardinger dextrin, triacetyl group-beta-cyclodextrin, succinyl-alpha-cyclodextrin, (2- hydroxypropyls)-alpha-cyclodextrin, α-ring paste Essence, beta-schardinger dextrin and gamma-cyclodextrin；Substituted cyclodextrin such as sulfobutyl ether beta-schardinger dextrin, sulfoalkyl ether cyclodextrin (SAE- CD), hydroxyalkyl ether cyclodextrin (HAE-CD), sulfoalkyl ether-alkyl ether cyclodextrin (SAE-AE-CD) or sulfoalkyl ether-hydroxyalkyl Ether ring dextrin (SAE-HAE-CD).

10. the lidocaine pharmaceutical composition described in claim 1~8, it is characterised in that：Pharmaceutically acceptable auxiliary material or tax Shape agent or carrier are selected from but are not limited only to water, pharmaceutically acceptable amides compound, amino acid or its pharmaceutical salts, pharmacy and can connect Unit or multicomponent alcoholics compound, pharmaceutically acceptable aminated compounds, pharmaceutically acceptable water-soluble polymer, the ring paste received Essence or cyclodextrin pharmaceutically acceptable derivates, pharmaceutically acceptable excipient, pharmaceutically acceptable pH adjusting agent, medicine Acceptable antioxidant or stabilizer, pharmaceutically acceptable chelating agent, pharmaceutically acceptable preservative or bacteriostatic agent on, Pharmaceutically acceptable solubilizing agent or cosolvent, pharmaceutically acceptable isotonic regulator, pharmaceutically acceptable lewis acid or One or more in alkali or its salt；

Pharmaceutically acceptable aminated compounds or amides compound or amino acid or its pharmaceutical salts are selected from but are not limited only to nicotinoyl Amine, Pyrazinamide, acetamide, ethoxy nutgall acid amides, urea, thiocarbamide, urethane, ethylenediamine, diethylamine, diethanol amine, Triethanolamine, meglumine, Portugal's ethamine, aminoguanidine, hydroxyethyltheophylline, theophylline -7- sodium acetates, Dyphylline, bis-hydroxypropyl tea Alkali, 1-METHYLPYRROLIDONE, D- or L- or DL-Lys or Lysine Acetate or arginine or acetic arginine or taurine or Glycine or L-aminobutanedioic acid or Monosodium L-aspartate or D- or L- or DL-histidine or cysteine or methionine, 5- hydroxyls rely Propylhomoserin, histidine, 3- hydroxy-prolines, 4- hydroxy-prolines, proline ornithine, citrulling, creatine, 3- alanine, tea ammonia Acid, 2-amino-butyric acid, 4-Aminobutanoicacid, 2- amino-2-methyls propionic acid, 2- methyl -3- alanines, 2,6- diaminourea heptan two Acid, 2- amino-3-phenyl butyrics, 4- hydroxyarginines, 4- hydroxyls ornithine, 4- hydroxyhomoarginines or its salt or theirs is different Structure body；Pharmaceutically acceptable unit or multicomponent alcoholics compound are selected from but are not limited only to ethanol, propane diols, 1,2- propane diols, fourth Glycol, 1,3 butylene glycol, glycerine, phenmethylol, sorbierite or mannitol or lactitol or xylitol, D-mannital, D- sorbs Sugar alcohol or antierythrite include one or more in its hydrate or their chiral isomer, and sorbierite includes anhydrous sorb It is one or more in alcohol or the water thing of sorbierite half or 1 water sorbierite or sorbitol instant etc., above-mentioned to include its chiral photo-isomerisation Body；Pharmaceutically acceptable water-soluble polymer is selected from, but not limited to, PEG400-6000, polyethylene glycol-12- hydroxy stearates Acid esters, poloxamer, Tween-80, azone, laurocapram, Vitamin E TPGS, cyclodextrin or cyclodextrin can pharmaceutically connect One or more of the derivative received；

Pharmaceutically acceptable pH adjusting agent is selected from but is not limited only to pharmaceutically acceptable inorganic acid or organic acid or its is medicinal The lewis acid or alkali of salt, inorganic base or organic base or its pharmaceutical salts, or broad sense, can be carbon dioxide, hydrochloric acid, sulphur Sour or its pharmaceutical salts, boric acid or its pharmaceutical salts, borax, phosphoric acid or its pharmaceutical salts, acetic acid or its pharmaceutical salts, such as sodium acetate, breast Acid and lactic acid pharmaceutical salts, citric acid or its pharmaceutical salts, tartaric acid or citric acid or its pharmaceutical salts, disodium hydrogen phosphate, biphosphate Sodium, potassium dihydrogen phosphate, benzoic acid, Sodium Benzoate, butanedioic acid, sodium succinate, ascorbic acid, sodium ascorbate, arabo-ascorbic acid, Sodium isoascorbate, NaOH, potassium hydroxide, sodium carbonate, sodium acid carbonate, trihydroxy aminomethane, diethanol amine, ethanol Amine, diisopropanolamine (DIPA), 2- amino -2- (methylol) 1,3-PDs amine, N- methyl glucoses amine and their salt, polyhydroxy carboxylic Acid and pharmaceutical salts, such as glucuronic acid, gluconic acid, sodium gluconate, lactobionic acid, sodium lactonic, malic acid, threonic acid, Portugal In heptonic acid, levulinic acid, levulinic acid sodium, amino acid or their pharmaceutically acceptable salt or its hydrate or its isomers One or several；

Pharmaceutically acceptable antioxidant and stabilizer are selected from but are not limited only to sulfurous acid and its salt, bisulfites, burnt sulfurous Hydrochlorate, dithionite, TGA and its pharmaceutical salts, thiolactic acid and its pharmaceutical salts, thio-2 acid and salt, monohydroxy Or multi-hydroxy carboxy acid and pharmaceutical salts, tartaric acid, sorbic acid or its pharmaceutical salts, nitrate, acetic acid pharmaceutical salts, citrate, EDTA And edta salt, including EDETATE SODIUM, the sodium of EDTA tetra-, Ca-EDTA sodium salt, sodium ethylene diamine tetracetate calcium or sodium ethylene diamine tetracetate The hydrate of calcium 2, the hydrate of sodium ethylene diamine tetracetate calcium 4, N- bis- (2- ethoxys) glycine, maltitol, xylitol, sorb Alcohol, mannitol, trehalose, vitamin E, beta carotene, Pyridoxamine Hydrochloride, taurine, amino acid or they pharmaceutically can connect One or several in its hydrate of the salt received or its isomers etc.；

Pharmaceutically acceptable carrier also includes cosolvent or solubilizer, and cosolvent or solubilizer are selected from but are not limited only to polyoxygenated Ethene list oleic acid sorbitan ester, TWEEN Series, Tween-20, tween -21, Tween-40, Tween-60, tween -61, tween - 80th, Tween-81, Tween-85, VE succinic acid macrogol ester (vitamin E TPGS), sorbitan oleate, glycerine- Polyethylene glycol epoxide stearate, PEG-32 glyceryl palmitostearates, lauryl sodium sulfate, mono laurate sorbitol anhydride Ester, polyethylene glycol, polyethylene glycol 100-8000, HS15, polyvinylpyrrolidone, polyethylene Alcohol, amino acid or its pharmaceutical salts, pharmaceutically acceptable unit or polyalcohols, poloxamer, PLURONICS F87, poloxamer 237th, poloxamer188, azone, laurocapram, cyclodextrin or cyclodextrin pharmaceutically acceptable derivates, pharmaceutically acceptable Unit or multicomponent alcoholics compound, amide-type or urea and derivative, inorganic acid or inorganic acid salt, pharmaceutically acceptable organic Acid or acylate, pharmaceutically acceptable carbohydrate or sugar lime, pharmaceutically acceptable amine etc. or their chiral isomer etc. Or one or more in their pharmaceutically acceptable salt；

Pharmaceutically acceptable carrier --- thickener or stabilizer or matrix, selected from but be not limited only to water-soluble polymer and ooze Saturating accelerator and the composition of their mixture composition；The water-soluble polymeric that can be used in pharmaceutical composition of the invention Thing include but is not limited to natural and synthesis polymer, polysaccharide, poly- aminoglycoside, cellulose derivative, guar gum, xanthans, Glucan, carboxyl vinyl polymer, Sodium Polyacrylate, hyaluronidase, hyaluronic acid, Sodium Hyaluronate, chondroitin sulfate, Locust bean gum, poloxamer, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, gellan gum, Pulan polysaccharide, alginic acid, Methylcellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyethylene One or more of derivative of alcohol or dextrin and dextrin etc. and their mixture；

Pharmaceutically acceptable isotonic regulator be selected from but be not limited only to sodium chloride, potassium chloride, sodium bromide, sodium phosphate, sodium sulphate, Sodium nitrate, glucose, boric acid, borax, glycerine, propane diols, polyethylene glycol, PEG-400, PEG300, PEG-200, glucose, Fructose, maltitol, xylitol, sorbierite, mannitol, inverted sugar, dextran, sodium lactate or sodium lactonic, gluconic acid Or one or more in its hydrate of sodium gluconate or its isomers；

One or more in pharmaceutically acceptable auxiliary material or excipient in addition to water for injection in UD Content more preferably 0.0010~0.040g in injection；Or can be expressed as：It is pharmaceutically acceptable in addition to water for injection Auxiliary material or excipient in one or more content in an injection for UD can be or selected from 0.0010 ~0.040g/ml.

Lidocaine pharmaceutical composition described in 11. claims 1~8, it is characterised in that：It is pharmaceutically acceptable for preparing Pharmaceutical preparation, includes but are not limited to injection, solution, tincture, ointment, cream, gel, paste, suppository.

Lidocaine pharmaceutical composition described in 12. claims 1~8, it is characterised in that：For preparing people or mammal institute Application in local anaesthesia and analgesic, include but are not limited to local infiltration anesthesia, surgery anesthesia, Postoperative Analgesia After, Caudal block, epidural block, teeth groove are mended through retardance, peripheral blockade, brachial plexus block, sympathetic block, infiltration office Fiber crops or intravenous regional block, all kinds of pruritic, painful skins are sick, the medicine of prevention or the treatment of pain after herpes zoster.