CN105612155A - Compositions and methods for the treatment of local pain - Google Patents

Compositions and methods for the treatment of local pain Download PDF

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Publication number
CN105612155A
CN105612155A CN201380030659.5A CN201380030659A CN105612155A CN 105612155 A CN105612155 A CN 105612155A CN 201380030659 A CN201380030659 A CN 201380030659A CN 105612155 A CN105612155 A CN 105612155A
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Prior art keywords
pain
pharmaceutical composition
composition
treatment
dispenser
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Chinese (zh)
Inventor
M·坎杜拉
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Cellix Bio Pvt Ltd
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Cellix Bio Pvt Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for the treatment of local pain may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of infiltration, nerve block, epidural, intrathecal anesthesia, pain, severe pain, chronic pain, chemotherapy-induced pain, neuropathic pain, post-herpetic neuralgia, neuralgia, motor neurone disease, diabetic neuropathy, postheipetic neuralgia, injury, post-operative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cord injury, migraine, HIV-related neuropathic pain, cancer pain and low back pain.

Description

Composition and the method for the treatment of local pain
Priority
The application requires in the power of the India temporary patent application No.1843/CHE/2012 of submission on May 10th, 2012Benefit, depend on whole disclosures of this temporary patent application, and these whole disclosures is by drawing for all objectsWith being incorporated in the application.
Technical field
Present disclosure relates in general to the compound and the composition that are used for the treatment of local pain. More specifically, the present inventionRelate to compound, crystal, polymorph, ester, salt, stereoisomer, enantiomter, hydrate, front with pharmaceutically acceptable dosageMedicine or their mixture carry out treatment target.
Background technology
Pain is that the subjectivity that is subject to physiology, psychology, society and mental element impact is experienced. The concept accreditation institute of entirety painThere are the importance of these aspects and good pain relief can pay close attention to every aspect. The disease of pain and for example cancerNot synonym: in the process of disease that takes a disease, at least 2/3 patient can experience pain during one's sickness sometime, and absolutelyGreat majority are by antalgesic strong needs.
Severe pain (as pain), depression, fibromyalgia, rheumatic arthritis, restless leg syndrome, anxiety disorder are one groupThere is very different etiologic etiological brain, spinal cord and the peripheroneural neural various disease of comprising. Much there is something lostTransmissibility; Having some is results of toxicity or metabolic process. Free radical is can self-existent high activity molecule or chemical substance.The generation of highly reactive form of oxygen (ROS) is that normal cell function is as the group of mitochondrial respiratory chain, phagocytosis and arachidonic acid metabolicBecome key element. During being reported in recovery stage of the multiple pathology noxious stimulation to brain tissue, discharge oxygen radical. SomeThe nervous disorder relevant with pain comprises damage, postoperative pain, osteoarthritis, rheumatoid arthritis, multiple sclerosis, spinal cordDamage, antimigraine, neuropathic pain, PHN, diabetic neuropathy, cancer pain, fiber that HIV is relevantMyalgia and pain in the back.
Process acute pathology and often depend on the basic pathology and the symptom that solve disease. At present, this area needs new combinationThing is treated local pain.
Summary of the invention
The composition that the invention provides compound, contain these compounds and use their treatment, prevention and/or alleviateSuch as the method for the impact of the symptom of local pain.
The present invention provides contained I or its officinal salt, hydrate, solvate, prodrug, enantiomter or stands at thisThe composition of body isomers. The present invention also provides the compound or its intermediate and a kind of or many that comprise one or more formulas IPlant the pharmaceutical composition of pharmaceutically suitable carrier, medium or diluent. These compositions can be used for the treatment of local pain and relevantComplication.
In certain embodiments, the present invention relates to compound and the composition of formula I, or its officinal salt, hydrate,Solvate, prodrug, enantiomter or stereoisomer.
Wherein,
R1Represent independently D ,-CH3、-OCH3、H、
R2Represent independently
A is 2,3 or 7 independently;
Each b is 3,5 or 6 independently;
E is 1,2 or 6 independently;
C and d are H, D ,-OH ,-OD, C independently of one another1To C6Alkyl ,-NH2Or-COCH3；
N is 1,2,3,4 or 5 independently.
In exemplary, the example of formula I compound is listed below:
The application also provides the kit that comprises in pharmaceutical composition disclosed herein any one. Described reagentBox can comprise the operation instruction that is used for the treatment of local pain or its related complication.
Disclosed herein as well is and comprise pharmaceutically suitable carrier and the pharmaceutical composition of described any compound herein. OneA little aspects, described pharmaceutical composition be formulated for whole body dispenser, oral dispenser, sustained release, parenteral dispenser, injection,Subcutaneous dispenser or through skin dispenser.
Herein, the application provides the kit that comprises described pharmaceutical composition herein in addition. Described kit also canTo comprise the operation instruction that is used for the treatment of local pain or its related complication.
Described composition has some purposes herein. The application provides for example to suffering from local pain or showing as generationDecline office, invitation, etc. on account of illness shape, serious disease or disorderly related complication, hepatopathy, cancer, blood, orthopaedics, cardiovascular, kidney, skin, nerve orThe method that the patient of ocular complications treats.
Detailed description of the invention
Definition
As used herein, term below and phrase should have implication hereinafter described. Unless otherwise defined, otherwise thisThe whole scientific and technical terminologies that use in literary composition have the identical meanings of conventionally understanding with those of ordinary skill in the art.
Compound of the present invention can exist with the form of officinal salt. Compound of the present invention also can be with pharmaceutically acceptable esterForm there is (, treating sour methyl and ethyl ester as the formula I of prodrug). Compound of the present invention can also be by solventChange i.e. hydration. Solvation can be during manufacture process, i.e. the hygroscopic nature of the initial anhydrous compound of factor I and workingOr generation (hydration).
There is same molecular formula but arrange different chemical combination in character or its atom order of connection or its atomic spaceThing is called as " isomer ". On its atomic space is arranged, different isomers is called as " stereoisomer ". Non-Enantiomter be and diastereoisomer there is the stereoisomer of opposite configuration with one or more chiral centres. Mirror imageThe stereoisomer with one or more center of asymmetries that each other can not be overlapping is called as " enantiomter ". Work as compoundWhile thering is center of asymmetry, for example, if a carbon atom group different from four connects, likely form a pair of mappingIsomers. Enantiomter can characterize by the absolute configuration of its center of asymmetry or multiple center of asymmetries, and logicalCross R and the S ordering rule of Cahn, Ingold and Prelog or by molecule, the mode of polarized light flat rotation retouchedState and be appointed as dextrorotation or left-handed (being appointed as respectively (+) or (-) isomer). Chipal compounds can be with single kindEnantiomter or the form of their mixture exist. The mixture of the enantiomter that contains equal proportion is called as" racemic mixture ".
As used herein, term " metabolism symptom " refers to inborn errors of metabolism (or inherited metabolic disease shape), and it isThe genetic disease causing because of the defect in one or more metabolic pathway; Particularly, the function of enzyme is affected,Cause the shortage of enzyme or do not exist completely.
In some embodiments, molecule bond comprises and is selected from LA (CASNo.1200-22-2), two bigcatkin willowEster (CASNo.552-94-3), acetylcysteine (CASNo.616-91-1), eicosapentaenoic acid (CASNo.10417-94-4), the compound in DHA (CASNo.6217-54-5).
Term " polymorph " is for approving and refer to the one crystalline substance of given compound in this area as used in this articleBody structure.
Phrase " parenteral dispenser " and " non-enteron aisle dispenser " refer to except in intestines and local dispenser as used in this articleDispenser pattern (for example injection), and include, without being limited in intravenous, muscle, in pleura, in blood vessel, in pericardium, arteryIn, in sheath, in capsule, in socket of the eye, in heart, in intracutaneous, peritonaeum, under tracheae, subcutaneous, epidermis, in joint, under capsule, under arachnoid,In backbone and intrasternal injection and transfusion.
Treat " patient ", " object " or " host " of being treated by this subject methods can refer to the mankind or non-human animal as long in spiritClass, mammal and vertebrate.
Phrase " pharmaceutically acceptable " is by being approved this area. In certain embodiments, this term is included in abundant medical judgmentIn scope, be applicable to organize and contact and there is no overdosage toxicity, excitant, allergy or its with mammal, human and animalComposition, polymer and other material and/or the formulation of its problem or complication, it matches with rational income/risk ratio.
Phrase " pharmaceutically suitable carrier " is by being approved this area, and for example comprise organ from body or part toAnother organ of body or part deliver or carry pharmaceutically acceptable material, composition or matchmaker related in any theme compositionMatter, filler, diluent, solvent or the coating material of for example liquid or solid. Every kind of carrier must be from theme compositionIn the meaning of other component compatibility, say so " acceptable ", and harmless for patient. In certain embodiments, pharmaceutically acceptableCarrier is nonthermal. Can comprise as some examples of pharmaceutically suitable carrier: (1) sugar, as lactose, dextrose plus saccharose; (2)Starch, as cornstarch and farina; (3) cellulose and derivative thereof, as sodium carboxymethylcellulose, ethyl cellulose andCellulose ethanoate; (4) powdery tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum; (8) cocoa butter and suppository wax; (9) oil, asPeanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycol, as propane diols; (11) manyUnit's alcohol, as glycerine, D-sorbite, mannitol and polyethylene glycol; (12) ester, as ethyl oleate and ethyl laurate; (13) fine jadeFat; (14) buffer, as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apirogen water; (17) isotonic saline solution; (18)Ringer's mixture (Ringer'ssolution); (19) ethanol; (20) PBS; And (21) are at pharmaceutical formulationsOther nontoxic compatible substances of middle use.
Term " prodrug " is intended to be included in the compound that is converted into therapeutic activity medicament of the present invention under physiological condition. MakeThe common methods of prodrug is to comprise the selected part to discharge desired molecule that is hydrolyzed under physiological condition. In other enforcement sideIn case, transform prodrug by the enzymatic activity of host animal.
Term " preventative or therapeutic " is treated as being approved this area, and comprises that host is used to one or more to leadTopic composition. If clinical manifestation go out undesirable symptom (disease of for example host animal or other undesirable state) itFront dispenser, treatment, for preventative, protects host to avoid developing undesirable symptom; And if do not wished showingSymptom after dispenser, treatment (is intended to reduce, alleviates or stablize and existingly do not wish that symptom or its are secondary and do for curativeWith).
Term " prediction " refers in the future time window (prediction window) of specifying as used in this article, for relevantDisease will suffer deformity or complication and/or end platelet aggregation or exhaustion and/or dead probability (i.e. deathRate) assess. The described death rate can be caused by central nervous system or complication. Described prediction window is that object is according to pre-Survey probability will develop the time interval of one or more above-mentioned complication. In the time analyzing by method of the present invention,Prediction window can be whole residual lifes of object.
Term " treatment " is by being approved this area, and comprises and prevent that disease, disorder or symptom from sending out can tend in advanceGive birth to this disease, disorder and/or symptom but be not yet diagnosed as in the animal that suffers from this disease, disorder or symptom and occur; Suppress instituteState disease, disorder or symptom, for example, hinder the development of this disease, disorder or symptom; And alleviate described disease, disorder or sickShape, for example, cause disappearing of this disease, disorder and/or symptom. It is basic that treatment disease or symptom are included in even without having influence onVenereal disease is managed in physiological situation, alleviates at least one symptom of specified disease or symptom, for example, by using medicament, evenThis medicament is not treated in the situation of the symptom origin cause of formation, and object is carried out to local anaesthesia, comprises outside infiltration, nerve block, dura materGod after pain that anesthesia, intravertebral anesthesia, pain, severe pain, chronic ache, chemotherapy cause, neuropathic pain, herpes zosterDysmenorrhoea, neuralgic treatment. Term " treatment " comprises healing property, prevention property (for example preventative), auxiliary as used in this articleThe treatment of property and palliative.
Phrase " treatment effective dose " is the term of approving for this area. In certain embodiments, this term refers to thisThe amount of disclosed salt or composition in literary composition, described amount is to be applicable to the reasonable income/risk of any therapeutic treatment than producing certainThe effect of expection. In certain embodiments, this term refers within a period of time necessary to medical symptom elimination or minimizing instituteOr enough amounts. Effective dose can be according to disease or symptom such as in treatment, particular target in using to construct, objectThe factor of the seriousness of size or disease or symptom and changing. Those of ordinary skill in the art can be empirically trueDetermine particular composition effective dose and without undo experimentation.
In certain embodiments, herein described pharmaceutical composition to make the described composition can be to treat effectivelyThereby amount is delivered to patient and prepares as mode preventative or therapeutic treatment part. Required to patient to be administeredAmount of composition will depend on absorption, inactivation and the discharge rate of medicine and salt and the composition speed of sending by theme compositionRate. It should be noted that dose value also can change along with the seriousness of symptom to be slowed down. It should be further understood that,For any specific object, should and use or instruct the people's who uses composition professional judgement according to individual need, along withPassage of time regulates concrete dosage. Typically, dosage will utilize technology known to those of skill in the artDetermine.
In addition, can regulate to fit to the optium concentration of any specific salt or composition and/or amount or dosageShould treat the variation of parameter. These treatment parameters comprise the clinical application (for example position for the treatment of) of preparation trend of purchasing, patient's classType (for example mankind or non-human, adult or children), and the character of disease or symptom.
The dosage of the theme composition providing herein in certain embodiments, can be by reference to therapeutic combination orThe PC of other coating material is determined. For example, can use maximal plasma concentration (Cmax) and PC-timeUnder curve from the time be 0 to infinitely-great area.
In the time using aspect pharmaceutical composition or other material, term " sustained release " is by being approved this area. For example,With the single that the material disposable biological of all dosage can be used fast (bolus) type use contrary, through time h substance masterTopic composition can demonstrate the characteristic of sustained release. For example, in specific embodiment, (comprising blood, ridge with body fluidMarrow liquid, mucus secretion or lymph liquid etc.) when contact, one or more pharmaceutically acceptable excipient can be in the time that continues or extendIn (compared with discharging fast with single) degraded (for example, by being hydrolyzed) of carrying out progressively or postponing, discharge simultaneously and wherein compriseAny material (for example medicine and/or bioactive salts and/or composition). This release can make disclosed hereinThe treatment effective dose of any healing potion extends sends.
Phrase " systemic administration ", " general is used ", " use periphery " and " periphery property is used " be by being approved this area, andAnd be included in away from treatment disease location place and use theme composition, medicine or other material. For being used for the treatment of diseaseThe using of medicament, (for example pass through subcutaneous administration) unless be applied directly in central nervous system, even otherwise this medicament withRear general ground distributes, and still can be called as " local ", " part " or " regionality " uses, thereby enters patient body system,And carry out thus the processes such as metabolism.
Phrase " treatment effective dose " is the term of approving for this area. In certain embodiments, this term refers to thisThe amount of disclosed salt or composition in literary composition, described amount is to be applicable to the reasonable income/risk of any therapeutic treatment than producing certainThe effect of expection. In certain embodiments, this term refers within a period of time necessary to medical symptom elimination or minimizing instituteOr enough amounts. Effective dose can be according to disease or symptom such as in treatment, particular target in using to construct, objectThe factor of the seriousness of size or disease or symptom and changing. Those of ordinary skill in the art can be empirically trueDetermine particular composition effective dose and without undo experimentation.
Present disclosure has also thought over the prodrug of composition disclosed herein, and described prodrug is pharmaceutically acceptableSalt.
Disclosed herein as well is the pharmaceutical composition that comprises pharmaceutically suitable carrier, and can prepare the group of the compound of formula ICompound is for whole body, part or Orally administered. Also can by the preparation of this pharmaceutical composition for Orally administered, oral solution,Injection, subcutaneous administration or applied dermally. Described pharmaceutical composition can also comprise pharmaceutically useful stabilizing agent, diluent, surperficial livingAt least one in property agent, filler, adhesive and lubricant.
In a lot of embodiments, described pharmaceutical composition is by with enough compounds to patient's delivery type I hereinOr the amount of the treatment effective dose of composition comprises disclosed compound to be delivered and composition (formula I), as preventative or controlThe part of the property treated treatment. Required formula I or the concentration of its officinal salt by the absorption, inactivation and the discharge rate that depend on medicine withAnd salt and composition are by the delivery rate of theme composition. It should be noted that dose value also can be along with symptom to be slowed downSeriousness and changing. It should be further understood that, for any specific object, should and use or refer to according to individual needLead the people's who uses composition professional judgement, along with passage of time regulates concrete dosage. Typically, dosage is by profitDetermine by technology known to those of skill in the art.
In addition, can regulate to fit to the optium concentration of the compound of any specific formula I and/or amount or dosageShould treat the variation of parameter. These treatment parameters comprise the clinical application (for example position for the treatment of) of preparation trend of purchasing, patient's classType (for example mankind or non-human, adult or children), and the character of disease or symptom.
Can for example, by animal (mouse) is made regular check on, adopt suitably test to check a series of of material to be determinedConcentration and/or dosage, easily determine concentration and/or the dosage of the compound of any formula I. Known method also can be used for inspectionFix on the diffusion rate of local organization concentration, salt or composition before using medicine preparation disclosed herein and afterwardsAnd RBF. One of such method is micro-dialysis, if T.E.Robinson etc. was at the Techniques of 1991Described in the microdialysisintheneurosciences of the 7th volume the 1st chapter. In brief, described in RobinsonMethod can be implemented as follows. Micro-dialysis ring original position is placed in experimental animal. Carry dislysate by this ring with pump. When leaning onWhen nearly this ring is injected the compound of for example formula I disclosed herein, the medicine discharging is with proportional with its local organization concentrationBe gathered in dislysate. Thus, can utilize the concentration of known salt or composition, determine by suitable correction programThe diffusion process of salt or composition.
The dosage of the compound of the subject-type I providing herein in certain embodiments, can be by reference to therapeuticThe PC of composition or other coating material is determined. For example, can use maximal plasma concentration (Cmax) and blood plasmaUnder concentration time curve from the time be 0 to infinitely-great area.
Generally speaking, in the time implementing the method describing in detail in the application, the effective dose of the compound of formula I is single dose or dividesDosage at about 0.01mg/kg/ days to about 100mg/kg/ days, for example single dose or divided dose at 0.01mg/kg/ days to about 50mg/In the scope of kg/ days. The compound of formula I can be according to being for example less than 0.2mg/kg/ days, 0.5mg/kg/ days, 1.0mg/kg/ days,The dosage of 5mg/kg/ days, 10mg/kg/ days, 20mg/kg/ days, 30mg/kg/ days or 40mg/kg/ days is used. The compound of formula IAlso can according between for example 0.1mg and 1000mg, between 5mg and 80mg or be less than 1.0,9.0,12.0,20.0 every day,50.0,75.0,100,300,400,500,800,1000,2000, the dosage of 5000mg is applied to human patients. In some enforcementIn scheme, composition herein be less than obtain the required formula I of identical treatment income compound 95%, 90%, 80%,70%, 60%, 50%, 40%, 30%, 20% or 10% amount is used.
The effective dose of the compound of described formula I refers to and can suppress or the described salt of prophylactic one or group hereinThe amount of compound.
Exist because of neurotrosis or demyelinate and/or the rising of reactive oxidants-nitrogenize kind and/or the autologous adjusting of physiologyExtremely cause in the patient of complication risk, effective dose can be enough to stop, treat, alleviate, alleviate, suspend, suppress, delayOr reverse the development of this type of complication, or reduce the order of severity of this complication. Thus, these methods optionally comprise doctorLearn using of therapeutic (acute) and/or preventative (prevention). Dosage and the time of certainly, using composition will be depended on acceptanceThe object for the treatment of, the ailing order of severity, the mode of using and prescriber's judgement. Therefore, due to the difference between patient,Above given dosage is a kind of guidance, and the dosage that doctor can titration of medicines is realized doctor and thought and be suitable for patientTreatment. In the time considering the treatment degree of expection, doctor must weigh many factors, for example patient's age, existing diseaseThe existence of existence and Other diseases.
The composition being provided by the application can pass through various conventional drug delivery routes, comprises oral, local, parenteral (exampleAs intravenous injection, hypodermic injection or intramedullary injection) and be applied to the object that needs treatment. And, described composition can nose in,Use as rectal suppository or use " fast " formula (even if medicine dissolves in oral cavity without making water). In addition, shouldComposition can pass through Controlled release formulation type, privileged site drug delivery, transdermal drug delivery, paster (active/passive) mediationDrug delivery, by three-dimensional locating injection, or is applied to the object that needs treatment with the form of nano particle.
Described composition can be executed individually or with pharmaceutically suitable carrier, medium or diluent combination with single dose or multiple doseWith. Suitable pharmaceutical carrier, medium and diluent comprises inert solid diluent or filler, aseptic aqueous solution and multiple organicSolvent. By pharmaceutical composition that above-mentioned composition and pharmaceutically suitable carrier, medium or mixing diluents are formed subsequently with respectivelyPlanting formulation such as tablet, powder, lozenge, syrup and injection solution etc. easily uses. If need these medicine groupsCompound can contain extra composition, such as flavor enhancement, adhesive and excipient etc. Therefore, for Orally administered object, canWith by contain multiple excipient as the tablet of L-arginine, natrium citricum, calcium carbonate and calcium phosphate and multiple disintegrant as starch,Alginic acid and specific composition silicate, together with adhesive as polyvinylpyrrolidone, sucrose, gelatin and gum arabicUse. In addition, lubricant is if dolomol, lauryl sodium sulfate and talcum are through being usually used in making the object of sheet. Also can be by phaseSolid composite like type is filled the filler in gelatine capsule as soft and hard. The suitable material of used as said purpose comprisesThe polyethylene glycol of lactose (lactose) or lactose (milksugar) and HMW. When for Orally administered and need to containWhen water suspension or elixir, can by essence active ingredient wherein and multiple sweet taste or flavor enhancement, coloring material or dyestuff withAnd emulsification or suspending agent (if needs), mix as water, ethanol, propane diols, glycerine and combination thereof together with diluent. AsKnown in pharmaceutical field, the compound of formula I can also comprise the enteric coating (enterically that contains multiple excipientcoated)。
For parenteral dispenser, the solution of described composition can for example, in () sesame or peanut oil, aqueous propylene glycolMiddle preparation, or can use aseptic aqueous solution. If necessary, should suitably cushion this aqueous solution, and shouldFirst make liquid diluent and enough physiological saline or glucose etc. ooze. These specific aqueous solution are particularly suitable for veinIn, in interior, the subcutaneous and peritonaeum of muscle, use. Thus, the sterile aqueous media using all can be passed through art technology peopleThe known standard technique of member easily obtains.
For example can contain 10 to 100,50 to 250,150 to 500mg or 350 to 800mg, for example such as the preparation of tablet10,50,100,300,500,700, the compound of 800mg formula I disclosed herein, the chemical combination of for example compound of formula I or formula IThe officinal salt of thing.
Typically, as described herein composition can be oral or parenteral (for example, in intravenous, muscle, subcutaneousOr in marrow) use. Also can indicate local application, for example, just suffer from patient the situation that hinders Orally administered gastrointestinal disordersUnder, or determine medicament administration in tissue or organ surface when the most suitable as attending doctor. Can also indicate spot application,For example, in the time that target tissue or organ place need higher dosage. Use for cheek, active compound can be taked in a usual mannerThe tablet of preparation or the form of lozenge.
The dosage of using will depend on the characteristic of metabolic disease; The type that relates to host (comprises its age, healthy shapeCondition and weight); The kind of synchronous therapeutic (if there is); Therapeutic frequency and treatment ratio.
Exemplarily, using the dosage level of active component based on host's body weight is: intravenous injection, 0.1 to about 200mg/Kg; Intramuscular injection, 1 to about 500mg/kg; Oral, 5 to about 1000mg/kg; In nose, instil, 5 to about 1000mg/kg; Spray,5 to about 1000mg/kg.
Explain with concentration, in skin periphery, nose, in throat, bronchus, vagina, the fixed point of rectum or eyeUse, the concentration that contains active component in composition of the present invention can be approximately 0.01 to about 50%w/w of said composition; PreferablyFor said composition approximately 1 to about 20%w/w; And use for parenteral, concentration can be said composition approximately 0.05 to approximately50%w/v; Be preferably approximately 5 to about 20%w/v.
The form that composition of the present invention preferably proposes the UD that contains appropriate active component is applied to people and movingThing, for example, for tablet, capsule, pill, powder, granule, suppository, aseptic injection solution or supensoid agent, aseptic non-injectionSolution or supensoid agent, and oral solution or supensoid agent etc. For oral dispenser, can be prepared into the list of solid or liquidThe form of position dosage.
As discussed above, label contains one or more hydrophilic polymers. Suitable hydrophilic polymer comprise butBe not limited to water-swellable cellulose derivative, PAG, thermoplastic poly alkylene oxide, acrylic polymer,Hydrophilic colloid, clay, gelatinized starch, swellable crosslinked polymer and their mixture. Suitable water-swellable celluloseThe example of derivative includes but not limited to sodium carboxymethylcellulose, crosslinked hydroxypropyl cellulose, hydroxypropyl cellulose (HPC), hydroxylPropyl methocel (HPMC), hydroxyl isopropyl cellulose, hydroxybutyl cellulose, hydroxyphenyl cellulose, hydroxyethylcellulose(HEC), hydroxyl amyl cellulose, Hydroxypropyl ethyl cellulose, hydroxypropyl butyl cellulose and Hydroxypropyl ethyl cellulose and itMixture. The example of suitable PAG includes but not limited to polyethylene glycol. Suitable thermoplastic poly alkylideneThe example of oxide includes but not limited to gather (oxirane). The example of suitable acrylic polymer includes but not limited to firstBase potassium acrylate-divinyl benzene copolymer, polymethyl methacrylate, high molecular weight crosslinked acrylate homopolymer and copolymer(for example can be purchased from the commodity of NoveonChemicals CARBOPOL by nameTMHigh molecular weight crosslinked acrylate homopolymer and altogetherPolymers). The example of suitable hydrophilic colloid includes but not limited to alginate, agar, guar gum, locust bean gum, κ-Irish mossGlue, ι-carrageenan, tara gum, gum arabic, tragacanth, pectin, xanthans, gellan gum, maltodextrin, galactomannan gatherSugar, pustulan (pusstulan), laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, Weilan gum(whelan), blue glue (methylan), chitin of neutral gum, zoogloea (zooglan), first, cyclodextrin, shitosan and itMixture. The example of suitable clay includes but not limited to that montmorillonite is as bentonite, kaolin and hectorite; Three silicic acidMagnesium; Aluminium-magnesium silicate; And their mixture. The example of suitable gelatinized starch includes but not limited to acidified starch, swelling shallow lakePowder is as sodium starch glycollate and derivative thereof, and their mixture. The example bag of suitable swellable crosslinked polymerDraw together but be not limited to PVPP, Cross-linked Agar and Ac-Di-Sol, and their mixture.
Described carrier can contain the preparation of one or more suitable excipient for tablet. Suitable excipientExample includes but not limited to filler, adsorbent, adhesive, disintegrant, lubricant, glidant, release modification excipient, superDisintegrant, antioxidant and their mixture.
Suitable adhesive includes but not limited to: dry adhesives, and as polyvinylpyrrolidone and hydroxypropyl methyl fiberElement; Wet type adhesive, for example water-soluble polymer, comprise hydrophilic colloid as gum arabic, alginate, agar, guar gum,Locust bean gum, carrageenan, carboxymethyl cellulose, tara gum, gum arabic, tragacanth, pectin, xanthans, gellan gum, brightGlue, maltodextrin, galactomannans, pustulan, laminarin, scleroglucan, inulin, Weilan gum, neutral gum, bacterium glueGroup, the blue glue of first, chitin, cyclodextrin, shitosan, polyvinylpyrrolidone, cellulosics, sugarcane sugar and starch, and theyMixture. Suitable disintegrant includes but not limited to sodium starch glycollate, PVPP, cross-linked carboxymethylCellulose, starch, microcrystalline cellulose and their mixture.
Proper lubrication agent include but not limited to LCFA and salt (for example dolomol and stearic acid) thereof, talcum,Glyceride, wax and their mixture. Suitable glidant includes but not limited to cataloid. Suitable release modificationExcipient includes but not limited to insoluble edible material, pH dependent polymers and their mixture.
Be suitable as the insoluble edible material that discharges modification excipient include but not limited to insoluble polymer andLow melting point hydrophobic material, their copolymer and their mixture. The example of suitable insoluble polymer comprisesBut be not limited to ethyl cellulose, polyvinyl alcohol, polyvinyl acetate, polycaprolactone, cellulose ethanoate and derivative thereof, propyleneAcid esters, methacrylate, acrylic copolymer, their copolymer and their mixture. Suitable low melting point is hydrophobicProperty material includes but not limited to fat, fatty acid ester, phosphatide, wax and their mixture. Suitable fatty example comprisesBut be not limited to hydrogenated vegetable oil as cocoa butter, hydrogenated palm kernel oil, cotmar, hydrogenation sunflower oil and oil with hydrogenated soybean,Free fatty and salt thereof, and their mixture. The example of suitable fatty acid ester includes but not limited to sucrose-fattyEster, glycerine list, two and three ester ， behenic acid glyceride, palmitostearate, glycerin monostearate, three stearic acid are sweetGrease, laurin, myristic acid glyceride, GlycoWax-932, lauroyl polyethylene glycol-32 glyceride is hardFatty acyl group polyethylene glycol-32 glyceride and their mixture. The example of suitable phosphatide comprises phosphatid ylcholine, phosphatidylSerine (phosphotidylserene), phosphatidylinositols (phosphotidylenositol), phosphatidic acid and theyMixture. The example of suitable wax includes but not limited to Brazil wax, spermaceti, beeswax, candelila wax, shellac wax, crystalliteWax and solid paraffin; Fatty mixture is as chocolate, and their mixture. The example of super-disintegrant comprises but does not limitIn Ac-Di-Sol, sodium starch glycollate and PVPP (PVPP). In one embodiment,Label contains this super-disintegrant up to about 5 % by weight.
The example of antioxidant includes but not limited to tocopherol, ascorbic acid, sodium pyrosulfite, butylated hydroxytoluene, fourthBase BHA, ethylenediamine tetra-acetic acid and edetate, and their mixture. The example of anticorrisive agent comprise butBe not limited to citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid and sorbic acid, and their mixture.
In one embodiment, the average thickness that discharges immediately clad is at least 50 microns, for example, and from approximately 50 micronsTo approximately 2500 microns (such as from approximately 250 microns to approximately 1000 microns). In one embodiment, as passed through this specific layerWeight and volume is measured, discharges immediately clad and is conventionally compressed into density and exceedes about 0.9g/cc.
In one embodiment, discharge immediately clad and comprise Part I and Part II, wherein at least one portionDivide and contain the second pharmaceutically active medicament. In one embodiment, described two parts are in contact with one another at the central shaft of tablet. ?In an embodiment, Part I comprises the first pharmaceutically active medicament and Part II comprises the second pharmaceutically active medicament.
In one embodiment, Part I contains the first pharmaceutically active medicament and Part II and contains the second medicine and liveProperty medicament. In one embodiment, a described part contains the 3rd pharmaceutically active medicament. In one embodiment, oneIndividual described part comprise with label in the second release portion immediately of contained same medicine active agents.
In one embodiment, external coating part, being introduced into before coated label, is first made into dry blend materialMaterial. In another embodiment, external coating part comprises the dry granulation that contains pharmaceutically active medicament.
The preparation with above-mentioned different pharmaceutical releasing mechanism can be combined into and contain single or multiunit final formulation. ManyThe example of unit comprises multilayer tablet, the capsule of sheet, pearl or the particle that contains solid or liquid form. Typically, release immediatelyPutting preparation comprises compressed tablets, gel, film, clad, can be encapsulated in liquid and particle in gel capsule for example. A lotAll as known in the art for the preparation of the method for clad, covering or bound drug.
The unit of releasing dosage immediately in formulation, tablet, containing outside pearl, particle or the piller of multi-medicament or coated coreLayer formulation, contains and treats the active agents of effective dose and conventional drug excipient. Described releasing dosage immediately unit can be byOr be not wrapped by, and can with or do not mix with delayed release dosage device and (to be mixed into contain and to discharge immediately medicineThe encapsulation mixture of particle, piller or pearl and the particle that contains delayed release medicine or pearl).
Delayed release preparation is made into diffusion or osmosis system conventionally, for example, and as at " Remington-TheScienceandPracticeofPharmacy”(20th.Ed.,LippincottWilliams&Wilkins,Baltimore,Md.,2000) described in. Diffusion system is made up of one, container and matrix in two kinds of devices conventionally, and it is known in the artAnd record to some extent. Matrix device conventionally by being compressed into Tabules system by medicine together with slow dissolve polymer carrierStandby.
Can be coated or compression process coated immediate release layer on delayed release core by utilization, or for example containPostpone and discharge in the multiple-unit system of capsule of pearl immediately, release portion joins in delayed release system immediately.
Delayed release dosage particles is insoluble to stomach sour environment by use but is dissolved in the polymer of small intestine neutral environmentThe coated solid dosage forms of film make. The clad material coating medicine that delayed release dosage device can for example be selected by use orPrepare containing pharmaceutical composition. Described can be to add tablet in capsule, in " coated core " formulation, use containing pharmaceutical compositionMake the tablet of inner core, or add the pearl that contains multi-medicament, piller or particle in tablet or capsule.
Pulsed release dosage form is for simulating repeatedly dosing process but do not repeat dosing, and with the medicine of traditional dosing form(traditional solid dosage forms for example, discharging as solution or instant medicine) compared and conventionally can be made dosing frequency reduce twice at leastFormulation. Pulse release process is characterised in that, in a period of time, discharges without discharging (time delay) or decrement, then carries out fastMedicine discharges.
Every kind of formulation all contains the active agents for the treatment of effective dose. In the formulation of twice dosing process simulation every dayIn embodiment, in pulse for the first time, discharge the approximately 30wt.% to 70wt.% of active agents total amount in formulation, preferably40wt.% to 60wt.%, and the approximately 70wt.% that has correspondingly discharged active agents total amount in formulation in pulse is for the second time extremely30wt.%, preferably 60wt.% to 40wt.%. For the formulation of twice dosing process simulation every day, pulse for the second time preferably existsAfter dispenser approximately 3 hours to being less than 14 hours, more preferably approximately 5 hours to 12 hours in discharge.
Another kind of formulation contains compressed tablets or capsule, and described compressed tablets or capsule comprise the release immediately that contains medicineDosage device, delayed release dosage device and optional the second delayed release dosage device. In this formulation, releasing agent immediatelyAmount unit contains the pearl that much discharges in a large number immediately medicine after oral dispenser, particle, piller so that predose to be provided. Delay is releasedPut dosage device and contain the coated pearl of a lot of warps or particle, it discharges medicine to carry in approximately 3 hours to 14 hours after oral dispenserFor second-dose.
In order for example, to use through skin (local), (concentration is common can to prepare the aseptic moisture or partially aqueous solution of dilutionFor approximately 0.1% to 5%), other side is similar to parenteral solution mentioned above. For a person skilled in the art, preparationThe method of the various compounds of one or more formulas I that contain specified quantitative or the pharmaceutical composition of other active agents is known, or will be apparent according to present disclosure. For the example of the method for pharmaceutical compositions, refer toRemington'sPharmaceuticalSciences(MackPublishingCompany,Easton,Pa.,19thEdition(1995))。
In addition, in certain embodiments, the application's theme composition can be lyophilized or another suitable doing of processDry technology, for example spraying is dry. Described theme composition can be disposable employed, or can be partly according to the release of compositionSpeed and required dosage and be divided into multiple less dosage and use under the different periods.
Can be used for herein the preparation of institute's supplying method comprise be applicable to mouth, nose, part (comprising cheek and hypogloeeis), rectum,The preparation of vagina, spraying and/or parenteral administration. Described preparation can present with the form of UD easily, and canTo prepare by any method of knowing in pharmaceutical field. Can be combined to make with carrier material the subject combination of single doseThe amount of thing can change according to the object of receiving treatment and specific dispenser pattern.
The method of preparing these preparations or composition comprise make theme composition and carrier and optionally one or moreThe step that auxiliary element combines. Generally speaking, described preparation carries by the solid that makes theme composition and liquid-carrier, grindBody or both evenly and fully combinations, then if necessary, prepare the formed product of gained.
The compound of described formula I can be used with the form of suction or spray agent herein. Described suction or sprayMist preparation can comprise one or more and can be used for the medicament in inhalation therapy, for example adjuvant, diagnosticum, developer or treatmentAgent. Final spray agent with respect to the gross weight of said preparation can for example contain 0.005-90%w/w (as 0.005-50%,0.005-5%w/w or 0.01-1.0%w/w) medicine.
At the solid dosage forms for oral dispenser (capsule, tablet, pill, dragee, powder and particle etc.), make themeComposition and one or more pharmaceutically suitable carrier and/or following in any one mix mutually: (1) filler or extender, asStarch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) adhesive, as carboxymethyl cellulose, alginate, brightGlue, polyvinylpyrrolidone, sucrose and/or gum arabic; (3) NMF, as glycerine; (4) disintegrant, as agar, carbonic acidCalcium, potato or tapioca, alginic acid, specific silicate and sodium carbonate; (5) retarding solvent, as paraffin; (6) absorb and urgeEnter agent, as quaternary ammonium compound; (7) wetting agent, as acetyl ethanol and glycerin monostearate; (8) absorbent, as kaolin and swollenProfit soil; (9) lubricant, as talcum, calcium stearate, dolomol, solid polyethylene glycol, lauryl sodium sulfate and theyMixture; And (10) colouring agent. The in the situation that of capsule, tablet and pill, described pharmaceutical composition also can comprise bufferingAgent. The solid composite that can also use similar type is as polyethylene glycol etc. soft and hard that uses lactose and HMWFiller in the gelatine capsule that matter is filled.
For the liquid dosage form of oral dispenser comprise pharmaceutically useful emulsion, microemulsion, solution, supensoid agent, syrup andElixir. Except theme composition, described liquid dosage form can contain inert diluent conventional in this area, for example water orOther solvent, solubilizer and emulsifying agent, for example ethanol, isopropyl alcohol, diethyl carbonate, ethyl acetate, phenmethylol, Benzyl BenzoateEster, propane diols, 1,3-BDO, oils (particularly cottonseed, corn, peanut, sunflower seeds, soybean, olive, castor-oil plant and sesameOil), the fatty acid ester of glycerine, tetrahydrofurfuryl carbinol, polyethylene glycol and sorbitan, and their mixture.
Except theme composition, supensoid agent can contain suspending agent, for example ethoxylation isooctadecanol, polyoxyethyleneD-sorbite (polyoxyethylenesorbitol) and Isosorbide Dinitrate, microcrystalline cellulose, aluminium hydroxide, bentonite,Agar and tragacanth, and their mixture.
Preparation for rectum or medicine applicating vaginal can be rendered as suppository, this suppository by by theme composition with a kind of orMultiple suitable non-irritating carrier mixes to prepare, and described non-irritating carrier comprises for example cocoa butter, polyethylene glycol, suppositoryWax or salicylate, and at room temperature for solid is liquid under body temperature, thereby will in suitable body cavity, dissolve and releasePut sealed compound and composition. The preparation that is suitable for medicine applicating vaginal also comprises and contains known applicable carrier in this areaVaginal plug, tapon, emulsifiable paste, gel, paste, foam or spray agent.
Formulation for applied dermally comprises powder, spray, ointment, paste, emulsifiable paste, washing lotion, gel, solution, subsidesSheet and inhalant. Can by theme composition under aseptic condition with pharmaceutically suitable carrier, and any anticorrisive agent that may need,Buffer or propellant mix. For through skin dispenser, compound can comprise lipophilicity and hydrophilic radical to realizeWater-soluble and the transport properties needing.
Except theme composition, ointment, paste, emulsifiable paste and gel can contain other carrier, for example animal andPlant fat, oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicones, bentonite, silicic acid, talcumAnd zinc oxide, or their mixture. Except theme composition, powder and spray can contain excipient as breastSugar, talcum, silicic acid, aluminium hydroxide, calcium silicates and polyamide powder, or the mixture of these materials. Spray can also be anotherContain conventional propellant outward, for example CFC and volatile hydrocarbon (as butane and propane) that do not replace.
The method of carrying out delivering compositions by transdermal patch is as known in the art. Exemplary paster and paster are passedDelivery method is at U.S. Patent number 6,974, and 588,6,564,093,6,312,716,6,440,454,6,267,983,6,239,180With 6,103, be described in 275.
In another embodiment, transdermal patch can comprise: the substrate sheet that comprises composite membrane, described composite membrane is by containingThere is the tree of 100 weight portion polyvinyl chloride-polyurethane compositions and 2-10 parts by weight of styrene-ethene-butylene-styrene copolymerOil/fat composition forms; At the first adhesive layer of described composite membrane one side; Stick on composite membrane one side by described the first adhesive layerOn polyalkylene terephthalate film; Comprise saturated polyester resin and shape on described polyalkylene terephthalate film surfaceThe prime coat becoming; And the second adhesive layer forming on described prime coat, this second adhesive layer comprises and contains pharmaceutical agentStyrene-diene-styrene block copolymer. The method of preparing above-mentioned substrate sheet comprises: prepare above-mentioned resin combination; Pass throughThis resin combination is molded as composite membrane by rolling process; Then by adhesive layer, polyalkylene terephthalate film is sticked on to thisIn one side of composite membrane, form thus substrate sheet; And form and comprise on the outer surface of described polyalkylene terephthalate filmThe prime coat of saturated polyester resin.
The paster of another kind of type comprises directly to be introduced medicine in pharmaceutically acceptable adhesive, and by this adhesive containing medicineFor example be laminated in, on suitable substrate film (polyester substrate film). Described medicine should, not affect the character of adhesive, be passed simultaneouslySend the concentration of required clinical dosage to exist.
Transdermal patch can be passive or active. At present available passive transdermal drug delivery systems (for example nicotine,Estrogen and nitroglycerine paster) send small-molecule drug. A lot of protein and peptide drugs newly developed are excessive and cannot lead toCross by percutaneous plaster and send, they can adopt the macromolecular drug technology of for example electron assistant (ionotherapy) to enterRow is sent.
Ionotherapy is to be used for improving ionization material by the technology of the flux of film by applying electric current. IontophoresisAn example of the film of therapy is at U.S. Patent number 5,080, provides in 646 to Theeuwes. Ionotherapy strengthens moleculeTransdermal dominant mechanism is: (a) repel charged ion from the electrode of identical charges; (b) electro-osmosis, in the time applying electric fieldAs the response of counter ion preferred path, by the convective motion of charged hole generation solvent; Or (c) owing to applying electric currentImprove the permeability of skin.
In some cases, may use with the form of kit, described kit can comprise for holdingContainer, for example sectional bottle or the Foilpac (dividedfoilpacket) separating of composition separately. Typically, reagentThe explanation of using that box comprises independent component. When independent component preferably with different formulation (for example oral and parenteral) use, withDifferent dosing intervals is used or in the time that prescriber need to carry out titration to each component of composition, the form of kitEspecially favourable.
The example of this kit is so-called blister package. Blister package in Packaging Industry by people is known, andBe widely used in the packaging of pharmaceutical unit dosage forms (Tablet and Capsula etc.). Blister package is conventionally by the relatively hard material structure of a sliceBecome, it can be transparent plastic material paper tinsel that described material is coated with.
Be used for the treatment of the method and composition of local pain. Wherein, provide a kind of method for the treatment of local pain herein,Described method comprises to the compound of formula I of patient's administering therapeutic effective dose that has needs:
Wherein,
R1Represent independently of one another D ,-CH3、-OCH3、H，
R2Represent independently
A is 2,3 or 7 independently;
Each b is 3,5 or 6 independently;
E is 1,2 or 6 independently;
C and d are H, D ,-OH ,-OD, C independently of one another1-C6Alkyl ,-NH2Or-COCH3；
N is 1,2,3,4 or 5 independently.
The method of use formula I compound:
The present invention also comprises that treatment comprises infiltration, nerve block, caudal anaesthesia, intravertebral anesthesia, pain, serious painThe side of pain, neuropathic pain, PHN and neuralgic local pain that bitterly, chronic ache, chemotherapy causeMethod.
Preparation method
Example for the preparation of the synthesis path of formula I compound is listed and is summarised in scheme 1 with following example.
Scheme-1:
Step-1: compound 3 synthetic:
Under argon gas atmosphere, by the 2-pyridine carboxylic acid hydrochloride of 19.4g, DMF and the 225ml of 0.3mlCarrene put into the three neck round-bottomed flasks that are equipped with mechanical agitator, dropping funel and condenser. Then, at 20-25At DEG C, in 30 minutes, the solution that contains 11 milliliters of oxalyl chlorides (1.05 equivalent) in 4 milliliters of carrene is joined to mixtureIn. Reactant mixture remains at 20-25 DEG C and continues vigorous stirring 4.5 hours, is then cooled to-5 DEG C. In same temperatureUnder, in 1 hour, add in 15 milliliters of carrene, contain 15 milliliters 2,6-xylidine (1.0 equivalent) and 20 millilitersThe solution of pyridine (2.0 equivalent). Reactant mixture stirs 1 hour at-5 to 0 DEG C, is heated to 20 DEG C and also keeps making for 1 hour againReaction completes. In reaction mass, add the water of 200 milliliters, then stir 15 minutes, mixture is transferred in separatory funnel. SeparateOrganic layer, and with the water washing of 100 milliliters. Merge aqueous layer, and with the dichloromethane extraction of 50 milliliters once. Merge twoOrganic layer, uses MgSO4Be dried and filter, with rotary evaporator except desolventizing. The solid crude product (approximately 32 grams) obtaining is with 75The cyclohexane of milliliter is recrystallized and filters, and the cyclohexane washing of 15 milliliters for crystal obtains 26.0 grams yellowish after being dried2-pyridine carboxylic acid-the 2' of look, 6'-xylidine 3 crystal, productive rate is 94%. Fusing point: 104.2-104.5 DEG C.
Step-2: compound 4 synthetic
To being equipped with the 2-pyridine carboxylic acid-2' that adds 25 grams in the SS reaction bulb of mechanical agitator, 6'-xylidine 3,The Raney's nickel of the methyl alcohol of 625 milliliters, the acetic acid of 63 milliliters and 15 grams. Then, pass into argon gas 5 minutes in mixture, sealing alsoBe filled with hydrogen with 18Kg/cm (260psi). Reactant mixture is heated to 50 DEG C, and keeps under same pressure and temperature28-30 hour, until reacted. Filter reaction mass to remove catalyst and to use rotary evaporator concentrated mother liquor. Will be thickReaction mass is dissolved in the toluene of 250 milliliters, is transferred in separatory funnel, add the water of 250 milliliters, then uses 50 milliliters20% sodium hydrate aqueous solution alkalization. Separate organic layer, the toluene extracting twice of 100 milliliters for aqueous layer. After extraction, mergeAfter organic layer MgSO4Dry, and concentrated in rotary evaporator. The solid crude product obtaining is entered with the toluene of 70 millilitersRow is recrystallized, and obtains the solid chemical compound 4 of 18.5 grams of pale pinks, and productive rate is 72%, 116 DEG C of fusing points.
Step-3: compound 6 synthetic:
Potash (7.2 mMs), compound 4 (4.8 mMs) and 3-chloropropane-1-alcohol 5 (5.3 mMs) are existedIn DMF, be heated to 90 DEG C without water slurry, keep 5 hours. Reactant mixture filters by glass microfiber filters, and concentratedFiltrate. Residue is purified and is obtained 6 with silica gel column chromatography.
Step-4: compound 8 synthetic:
Under room temperature (RT), will be (200 milliliters of carrene (DCM); The pure level of LR) in contain compound 6 (18.0 millis rubYou; 1.0 equivalents) and (18.0 mMs of R-(+)-lipoic acids; 1.0 equivalents) solution; 1-ethyl-3-(3 ' dimethylamino thirdBase) (527.0 mMs of carbodiimide .HCl (EDCI.HCl); 1.5 equivalents) and DMAP (DMAP) (18.0 milli rubYou; 1.0 equivalents) mixture stir 24 hours. Monitor reaction by TLC. Once react reactant mixture DCM(200 milliliters) dilution, washes (2 × 300 milliliters) with water, then uses saline solution (300 milliliters) washing again, and through anhydrous slufuric acidSodium is dried and reduction vaporization. Crude product adopts ethyl acetate-benzinum and carries out column chromatography by 100-200 object silica gel pureChange, obtain compound 8. Molecular weight: 478.23;
Elementary analysis: C, 62.72; H, 8.00; N, 5.85; O, 10.03; S, 13.40
Embodiment
The Pharmacokinetic Evaluation of bupivacaine (BU) and formula I (1-1) in Sprague – Dawley rat freely:
The specified-pathogens free male Sprague – Dawley rat that weighs 350 grams of 300 – obtains from laboratory. ThisA little animals can free pickuping food and water. Before operation, the employing urethane of 1.0g/mL and the chloralose of 0.1g/mL (1ml/kg,Ip) anesthetized rat. Femoral venous catheter, for further dispenser, keeps rat temperature by heating cushion in experimentation. Experiment periodsBetween all rats remain on narcosis, simultaneously formula I (1-1) and the BU concentration in monitoring of blood, brain and bile. Off-testAfter, under narcosis, adopt excess carbon dioxide to implement euthanasia to it.
In the sodium chloride solution of 0.9% (w/v), prepare bupivacaine (3mg/ml). Formula I (1-1) is equivalent to 3mg/ml'sBU. Rat is divided into following several groups (every group of sample number n=5), and accepts medicine intravenous injection: the 1st group adopts BU (3mg/kg)10 minutes (20mg/kg) processed in dispenser, and the 2nd group adopts formula I (1-1) (3mg/kg) to process.
Chromatographic system comprises: a PM-80 chromatogram pump (BAS, WestLafayette, IN, USA), off-line syringe(CMA/140, Stockholm, Sweden), syringe be furnished with 20L sample circulation syringe (Rheodyne model 7125) andWork under the room temperature Zi Wai – visible light detector (Soma, Tokyo, Japan) of (25 ± 2 DEG C). Be separated inOn LiChrosphere60RP-selectB post (4.6mm × 250mm, 5m, Merck), carry out. For blood plasma, brain homogenate, bloodThe mobile phase of dislysate and brain dislysate is made up of the Lin acid dihydride Jia – Yi Jing – triethylamine (67:33:0.01) of 10mM, uses phosphorusAcid is adjusted to pH4.3. The mobile phase of bile dislysate is made up of the Lin acid dihydride Jia – Yi Jing – triethylamine (60:40:0.01) of 10mM,Be adjusted to pH6.0 with phosphoric acid. The flow velocity of two mobile phases is set as to 1.0mL/min.
Result: the pharmacokinetic parameter of the BU in blood and brain and formula I (1-1) is as follows:
Blood
PK parameter BU Formula I (1-1)
AUC(min ug/mL) 82±16 98±29
T1/2(min) 4±2 7±6
Brain
PK parameter BU Formula I (1-1)
AUC(min ug/mL) 15±4 23±7
Cmax(ug/mL) 0.56±0.13 0.78±0.40
Term " sample " refers to humoral sample, refers to separated cell sample or refers to the sample from tissue or organProduct. Humoral sample can obtain by knowing technology, and preferably includes blood, blood plasma, serum or urine sample, more preferably bloodLiquid, blood plasma or blood serum sample. The sample of tissue or organ can obtain by for example biopsy from any tissue or organ. The cell separating can obtain as centrifugal or cell sorting by isolation technics from body fluid or tissue or organ. Preferably,Cell-, tissue-or organ samples obtain from expressing or being created in those cells, tissue or the organ of this related peptide.
Equivalent
Present disclosure provides the composition and the side that are used for the treatment of local pain and complication thereof except other sideMethod. Although the specific embodiments of present disclosure has been discussed, above description only plays illustrative effect and does not play limitProperty processed effect. Once browsing this description, many modification of system and method herein for those skilled in the art andSpeech will become apparent. The full breadth of system and method required for protection, should pass through with reference to claim together with itThe full breadth of equivalent, and this description is determined together with this class modification.
Quote and be incorporated to
As by each independent publication or patent specifically be appointed as be individually incorporated to by reference the same, hereinMentioned whole publications and patent, comprise the above project of enumerating, and its full content is incorporated to herein thus by reference.In the situation that there is conflict, the application, comprises any restriction of doing herein, will control its claimed scope.

Claims (12)

1. a compound of formula I, or its officinal salt, hydrate, polymorph, solvate, prodrug, enantiomter orStereoisomer:
Wherein,
R1Represent independently respectively D ,-CH3、-OCH3、H、
R2Represent independently
A is 2,3 or 7 independently;
Each b is 3,5 or 6 independently;
E is 1,2 or 6 independently;
C and d are H, D ,-OH ,-OD, C independently of one another1-C6Alkyl ,-NH2Or-COCH3；
N is 1,2,3,4 or 5 independently.
2. the pharmaceutical composition an of compound that comprises claim 1 and pharmaceutically suitable carrier.
3. pharmaceutical composition according to claim 2, this pharmaceutical composition is formulated with by oral dispenser, delayed releaseOr sustained release, thoroughly mucous membrane, syrup, part, parenteral dispenser, injection, subcutaneous, oral administration solution, rectum dispenser, cheek dispenser orThrough skin dispenser, effective dose is applied to the patient who needs and treats the potential cause of disease.
4. treat the method for local pain relevant disease as the potential cause of disease, the method comprises the claim of effective dose3 pharmaceutical composition is applied to the patient who needs.
5. method claimed in claim 4, is wherein selected from outside infiltration, nerve block, dura mater as the local pain of the potential cause of diseaseGod after pain that anesthesia, intravertebral anesthesia, pain, severe pain, chronic ache, chemotherapy cause, neuropathic pain, herpes zosterDysmenorrhoea, neuralgia, motor neuron disease, diabetic neuropathy, PHN, damage, postoperative pain, bone closeJoint inflammation, rheumatoid arthritis, multiple sclerosis, spinal cord injury, antimigraine, neuropathic pain that HIV is relevant, cancer pain andPain in the back.
6. the pharmaceutical composition of a molecule bond that comprises bupivacaine and LA.
7. the pharmaceutical composition of a molecule bond that comprises bupivacaine and eicosapentaenoic acid.
8. the pharmaceutical composition of a molecule bond that comprises bupivacaine and DHA.
9. the pharmaceutical composition of a molecule bond that comprises bupivacaine and salsalate.
10. a pharmaceutical composition that comprises bupivacaine and acetysalicylic molecule bond.
The pharmaceutical composition of 11. 1 kinds of molecule bonds that comprise bupivacaine and pantothenic acid.
The pharmaceutical composition of 12. 1 kinds of molecule bonds that comprise bupivacaine and pyridoxamine.
CN201380030659.5A 2012-05-10 2013-02-16 Compositions and methods for the treatment of local pain Pending CN105612155A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN1843CH2012 2012-05-10
IN1843/CHE/2012 2012-05-10
PCT/IB2013/051268 WO2013168006A2 (en) 2012-05-10 2013-02-16 Compositions and methods for the treatment of local pain

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Publication Number Publication Date
CN105612155A true CN105612155A (en) 2016-05-25

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CA3093398C (en) 2012-11-05 2022-05-24 Relievant Medsystems, Inc. Systems and methods for creating curved paths through bone and modulating nerves within the bone
US9724151B2 (en) 2013-08-08 2017-08-08 Relievant Medsystems, Inc. Modulating nerves within bone using bone fasteners
KR102422382B1 (en) * 2016-12-26 2023-01-25 셀릭스 바이오 프라이빗 리미티드 Compositions for Pain Treatment
WO2021050767A1 (en) 2019-09-12 2021-03-18 Relievant Medsystems, Inc. Systems and methods for tissue modulation

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CA2873138A1 (en) 2013-11-14
AU2013257727A1 (en) 2014-11-27
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WO2013168006A3 (en) 2016-09-01
AU2013257727B2 (en) 2016-04-28

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