CN101060830A - Combination of a NMDA receptor antagonist and an anti-depressive drug mao-inhibitor or a gadph-inhibitor for the treatment of psychiatric conditions - Google Patents

Abstract

To obtain a noise filter having a more improved noise elimination effect.First ends of inner conductors 22, 24 having meandering parts 22C, 24C are led out to the end of a lower ceramic layer 12A, and second ends of the conductors 22, 24 are led out to the end of an upper center ceramic layer 12A.Planar inner conductors 21, 23, 25 are led out to the end of a lower center ceramic layer 12A. A signal terminal electrode connected to a leading part 22A of the inner conductor 22 is disposed rightwards on the lower side, and a signal terminal electrode connected to the leading part 24A of the inner conductor 24 is disposed leftwards on the lower side. Grounding terminal electrodes connected to leading parts 26 of the inner conductors 21, 23, 25 are disposed on the central area of the lower side. Connecting electrodes connected to leading parts 22B, 24B of the inner conductors 22, 24 are disposed on the upper side, respectively.

Description

Nmda receptor antagonist associating anti-depression drug oxidase inhibitor or glyceraldehyde phosphate dehydrogenase inhibitor for treating mental sickness

Invention field

The invention relates to the method and composition of treatment mental sickness such as depression.

Background of invention

The recurrent mental maladjustment can have long-term destructive effects, and cost, the productivity and the health care of suffering from the people of these diseases are huge.For many patients, recognize that now the long-term results of incomplete outbreak interval rehabilitation is usually even worse than previous idea, and observed comprehensive function fails gradually.Undoubtedly, according to the research of global disease burden, mental maladjustment is one of incapabitated pathogenesis of the global people of making, and becomes health, society and the economic problems that become big day by day probably in the future several years.

Present many antidepressants are used for the treatment of severe depression.Up to decades ago, tricyclics (TCAs) is only medicine that is used for the treatment of depressive illness.Some novel drugs of succeeding in developing rapidly subsequently, selective serotonin reuptake inhibitor among them (SSRIs) and 5-hydroxy tryptamine/NRI (SNRIs) extensively are used now.Though the pharmacological treatment of selecting depression in the past few decades between as if exponentially increase, there is the limitation of effect and toleration aspect in the existing means of depression always.

Therefore, the particularly obstinate type melancholia's treatment of significant need development severe melancholy treatment, bipolarity treating depression and depression worsen novelty and the better therapy of treatment.

Summary of the invention

In general, the invention provides the method and composition of patient's drug combination being treated central nervous system's associated conditions (as psychosis and pain), this drug combination comprises nmda receptor antagonist and anti-depression drug (ADD).Drug combination described herein causes relevant or the alleviating and prevent by the syndrome of its initiation of central nervous system, comprise, for example, but be not limited to depression, bipolarity depression, anxiety headache, pain, neuropathy, cereborischemia, dementia, the dyskinesia, multiple sclerosis disease and other mental sickness.Active pharmacopedics medicine can be according to a certain mode to patient's administration, and the ratio that reduces active medicine concentration during certain hour changes, thereby has maximized therapeutic effect and minimized side effect.The present invention is different from existing research, novel drug combination is provided and instructs the dosage optimization or discharges improvement to reduce the drug combination preparation of relevant each adverse effect.

Nmda receptor antagonist, anti-depression drug (ADD), or two kinds of medicaments can be by with discharging composition or provide maximizing each therapeutic effect without the controlled release form that discharges composition immediately or slow release formulation immediately, and reduce the side effect that each need not.When these medicines were provided by the peroral dosage form of not benefiting from controlled release composition or slow release composition, behind a few minutes or several hrs, these medicines were released to and are transported in the body fluid.

Nmda receptor antagonist, anti-depression drug, or two kinds of medicines can carry out administration by the dosage that is similar to the general administration of receptor.Not necessarily, nmda receptor antagonist, anti-depression drug, or the dosage of two kinds of medicines can carry out administration by the dosage that is greater than or less than the general administration of receptor.For example, if there is not improved formulations described herein, the dosage that need positively influence the memantine (Memantine) of patient's reaction (containing untoward reaction) can be by 2.5-80mg administration every day rather than general 10-20mg administration every day.The nmda receptor antagonist of higher dosage can be used to the disease as non-neuropathy degeneration pain among the present invention, however nmda receptor antagonist and anti-depression drug unite when using, it is enough than low dosage to the therapeutic effect that reaches the patient.Not necessarily, when carrying out administration,, in unit dose, use than low dosage or the nmda receptor antagonist and the anti-depression drug that are reduced dosage with respect to the dosage of each medicine as single therapy.

Here use, " C " system refers to active medicine in the biological sample with the concentration of composition, for example patient's sample (as, blood, serum and cerebrospinal fluid).The concentration of biological sample Chinese medicine can adopt standard detecting method known in some this areas to determine.Term " Cmax " system refers to the Cmax that reaches of given dose medicine in the biological sample.Term " Cmean " system refers to the medicine mean concentration in time in the sample.Cmax and Cmean can be further defined as system and refer to concrete time period with respect to drug administration.The time system that requires in concrete patient's sample to reach Cmax (" Cmax ") refers to " Tmax ".Therefore the medicine of coupling carries out administration in preparation, this preparation has reduced the variation of active medicine concentration ratio a period of time of after, has maximized therapeutic effect and has minimized side effect.

In case of necessity, dosage form with dose increase progressively form, twice of every day or once a day form provide.In this case, concentrate gradient (or Tmax effect) to such an extent as to can be reduced concentration change (dC/dT) and be changed and reduce or eliminate the needs that increase progressively drug dose as time function.For example, the minimizing of dC/dT can realize by increase Tmax by relative proportional mode.Therefore, increase twice Tmax value and can reduce dC/dT by about 2 the factor.Therefore, follow the delay of Tmax, nmda receptor antagonist can be provided, and the dC/dT that is reduced with significance after rapid release (so-called IR) dosage form discharges.Pharmacy composite can be mixed with at the Tmax by 24 hours, 16 hours, 8 hours, 4 hours, 2 hours or 1 hour change in the time at least.The relevant minimizing of dC/dT can be undertaken by about 0.05,0.10,0.25,0.5 or 0.8 factor at least.In certain embodiments, this can be less than 30%, 50%, 75%, 90% or 95% nmda receptor antagonist, anti-depression drug by release and realize, or in hour of this administration, the both enters in blood circulation or the nervous system and realizes.

Two kinds of drug concentrations ratios of coupling are referred to as " Cratio ", and it is fluctuateed because medicine of coupling is released, enters blood circulation or central nervous system, metabolism, discharge.An object of the present invention is to stablize the Cratio of coupling medicine described herein.Useful is, Cratio changes and (is described as that " Cratio, var ") should be low as much as possible.

Therefore, the invention describes to reducing the coupling preparation at optimization dosage or release modification of each medicament untoward reaction that administration is relevant respectively.Picture is described below, and the coupling of nmda receptor antagonist and anti-depression drug can cause summation action or cooperative effect.

Therefore, an aspect the invention provides pharmaceutical composition, and this pharmaceutical composition comprises second kind of medicine and nonessential of nmda receptor antagonist, anti-depression drug (ADD), medicine carrier.In some embodiments, at least one in nmda receptor antagonist or the second kind of medicine provides with slow release formulation.

In one aspect of the method, the invention describes the method for prevention or treatment central nervous system associated conditions, this method is by being needed this method receptor to carry out the nmda receptor antagonist of dose therapeutically effective and the administering drug combinations of second kind of medicament anti-depression drug.In some embodiments, at least one in the nmda receptor antagonist of coupling or the second kind of medicament provides with slow release formulation.

In case of necessity, nmda receptor antagonist is discharged in the acceptor sample by the lower speed of rapid release (IR) preparation than observed same dose antagonist, wherein during 0 of quick releasing formulation arrives the one section setting of Tmax in the time, rate of release is measured by dC/dT, and dC/dT speed is less than about 80% of rapid release speed.In some embodiments, dC/dT speed is less than about 60%, 50%, 40%, 30%, 20% or 10% of quick releasing formulation speed.Similarly, anti-depression drug also can be discharged in patient's sample by the lower speed of rapid release (IR) preparation than observed same dose antagonist, wherein during 0 of quick releasing formulation arrives the one section setting of Tmax in the time, rate of release is measured by dC/dT, and dC/dT speed is less than about 80%, 60%, 50%, 40%, 30%, 20% or 10% of quick releasing formulation speed.

In case of necessity, of the present invention all aforementioned aspect in, in the pharmaceutical composition at least 50%, 90%, 95% or basic all nmda receptor antagonists can be provided by controlled release form.In some embodiments, after in pharmaceutical composition enters receptor one hour, at least 99% nmda receptor antagonist keeps continuing dosage form.The back is about 2 hours at least 8 hours, 12 hours, 16 hours, 24 hours in nmda receptor antagonist enters receptor, and nmda receptor antagonist can have about 1.6,1.5,1.4,1.3 or Cmax/Cmean ratio still less.

Of the present invention all aforementioned aspect in, second medicament also can provide by the controlled release preparation form.Therefore, at least 50%, 60%, 70%, 80%, 90%, 95% or basic all anti-depression drugs can be used as controlled release preparation and provide.If provide by this, after second medicament enters in the receptor about 2 hours at least 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, second medicament has the ratio about 1.6,1.5,1.4,1.3 of Cmax/Cmean or still less.

Not necessarily, medicine reach after the limit or medication after first during 24 hours, the Cratio.Var of nmda receptor antagonist, anti-depression drug or two kinds of medicines is less than 100%, for example, less than 70%, 50%, 30%, 20% or 10%.In some embodiments, in first 4 hours, 6 hours, 8 hours or 12 hours, Cratio.Var is less than about 90% (for example, about 75% or 50%) of the rapid release administration Cratio.Var of identical active pharmaceutical ingredient after the administration.

According to the present invention, the central nervous system's associated conditions that can be treated can be, as, psychosis (as epilepsy, panic syndrome, general anxiety imbalance, all types of phobic syndrome, demented, anxiety neurosis, hot-tempered strongly fragrant psychosis, excited disease, unipolarity depression, depression, bipolarity depression, stress disorders, posttraumatic stress disorder (PTSD), somatoform disorder, personality disorder, psychosis and schizophrenia) and pain (as, acute pain, chronic pain, chronic neuralgia).

Therapeutic alliance of the present invention is favourable for other treatment of conditions and prevention also, and it comprises syndrome behind headache, cerebrovascular disease, motor neuron, dementia, neurodegenerative diseases, apoplexy, the dyskinesia, its Ji dysfunctional syndrome, sympathetic nervous system disorder, cranial nerve disorder, myelopathy, traumatic brain injury and spinal cord injury, radiation brain injury, multiple sclerosis disease, meningitis, protein disease, myelitis, radiculitis, neuropathy, pain syndrome, aixs cylinder brain injury, encephalopathy, chronic fatigue syndrome, mental sickness and drug dependence.

Of the present invention aforementioned aspect in, nmda receptor antagonist can be present in aminoadamantan derivant memantine (1-amino-3,5-dimethyladamantane), rimantadine (1-(1-aminoethyl) diamantane (obsolete)) or amantadine (1-amino-diamantane (obsolete)).Second medicament can be GABA transmaminase inhibitor, GABA reuptake inhibitor, carbonic anhydrase inhibitor, Benzodiazepines or sodium channel inhibitor.Perhaps, second medicine can be antidepressants, and it comprises, for example, for example, 5-hydroxy tryptamine reuptake inhibithors (SSRIs), 5-hydroxy tryptamine and norepinephrine inhibitor (SNRIs), act on dopamine receptor medicine or dopamine and reclaim inhibitor (TCAs, other) again.The embodiment of anti-depression drug is that 5-hydroxy tryptamine reclaims inhibitor (for example, fluoxetine/PROZAC again ^TM, citalopram and Escitalopram/CELEXA ^TMAnd LEXAPRO ^TM, Sertraline/ZOLOFT ^TM, paroxetine/PAXILTM), 5-hydroxy tryptamine/noradrenaline reuptake inhibitor (for example, duloxetine/CYMBALTA ^TM, and venlafaxine/EFFEXOR ^TM), dopamine reclaims inhibitor (for example, desipramine/NORPRAMIN again ^TM, imipramine/TOFRANIL ^TM, clomipramine/ANAFRANIL ^TM, nortriptyline/PAMELOR ^TM, and amitriptyline/ELAVIL ^TM), amfebutamone/WELLBUTRIN ^TM, and buspirone/BUSPAR ^TMTherefore, nmda receptor antagonist can be memantine and second medicine can be fluoxetine, Escitalopram, citalopram, duloxetine or paroxetine.

Nmda receptor antagonist, second medicine or both can make oral administration, parenteral, rectally, oral administration, percutaneous plaster administration, nose administration, topical, locally see through administration or inhalation under epithelial cell administration, the corium down by prescription.Therefore, medicine described herein can be made suspension, capsule, tablet, suppository, washing liquid, paster or device (for example, corium drug delivery implant equipment or suction pump) by prescription.In case of necessity, nmda receptor antagonist and anti-depression drug can be mixed into single compositions.Perhaps, two kinds of medicines with separate formulation continuously or in 1 hour, in 2 hours, in 3 hours, in 6 hours, in 12 hours or administration in 24 hours.If separate administration, two kinds of medicines can adopt identical or different approach by once carrying out every day 2 times, every day 1 time or per two days administration.

Not necessarily, the nmda receptor antagonist and second medicine provide with the unit dose form.

In case of necessity, the dosage of nmda receptor antagonist is less than the dosage that when nmda receptor antagonist is not having administration under second drug condition treatment central nervous system associated conditions obtains the nmda receptor antagonist that needs in the unit dose of identical treatment effect in the pharmaceutical composition.Perhaps, the dosage of second medicine is less than the dosage that obtains second medicine that needs in the unit dose of identical treatment effect when second medicine administration time treatment central nervous system associated conditions under no nmda receptor antagonist situation in the pharmaceutical composition.

Perhaps, the dosage of nmda receptor antagonist in pharmaceutical composition is not have under second drug condition the receptor administration for to the virose dosage of people's receptor.In case of necessity, the dosage of second medicine in pharmaceutical composition be under no nmda receptor antagonist situation to the receptor administration for to the deleterious dosage of people's receptor.

If there is not other explanation, technology that all here use and scientific terminology have can be by the identical meanings of technical staff's understanding in the field under the present invention.Though, being similar to or being equal to method described herein and material and can in practice of the present invention or in the test, use, suitable method and material are described below.The publication of above-mentioned all references, patent application, patent, and other reference materials all by being incorporated in this paper in this citation.Under situation about clashing, will comprise definition and be as the criterion with this description.In addition, material, method and embodiment only are used to illustrate the present invention rather than restriction the present invention.As not having other detailed description, all equal portions and percentages are calculated.

Brief description of drawings

Fig. 1 is a curve chart, and it has shown that the controlled release of nmda receptor antagonist has caused the minimizing of dC/dt.

Fig. 2 A is a series of curve charts, and it has shown the API concentration after 24 hours and 10 days after the rapid release administration.Memantine 10mg bid (Tmax is 3 hours, and T1/2 is 60 hours) and duloxetine 60mg qd (Tmax is 6 hours, and T1/2 is 12 hours).

Fig. 2 B is a series of curve charts, and it has shown controlled release preparation 1 first API concentration after 24 hours and 10 days of back.Memantine 25mg qd (Tmax is 12 hours, and T1/2 is 60 hours) and duloxetine 60mg qd (Tmax is 12 hours, and T1/2 is 12 hours).

Fig. 2 C is a curve chart, and it has shown the ratio of the duloxetine concentration of rapid release administration and controlled release preparation 1 with respect to memantine concentration.

Fig. 2 D is a curve chart, and it has shown the ratio of the duloxetine concentration of rapid release administration and controlled release preparation 2 with respect to memantine concentration.

Fig. 3 A is a curve chart to 3F, and it has shown that the quick releasing formulation of embodiment 6 and the memantine of controlled release preparation and the PK of Escitalopram discharge and Cratios.

Fig. 4 A is a curve chart to 4C, and it has shown that the quick releasing formulation of embodiment 7 and the memantine of patch formulation and the PK of Escitalopram discharge and Cratios.

Detailed Description Of The Invention

The invention provides the method and composition for the treatment of or prevention central nervous system associated conditions, this illness comprise mental disease (as, panic syndrome, the general anxiety imbalance, all types of phobic syndromes, demented, anxiety disorder, hot-tempered strongly fragrant mental disease, excited disease, the unipolarity depression, depression, stress disorders, posttraumatic stress disorder (PTSD), somatoform disorder, personality disorder, mental disease, and schizophrenia), and pharmacological dependence (as, alcohol, psychoanaleptic (as, crack, cocaine, speed, meth), opium class medicine, and nicotine), epileptics, headache, Acute Pain, chronic ache, neuropathy, cereborischemia, dull-witted, dyskinesia, with multiple sclerosis disease. Drug combination comprises first composition and second composition, and wherein first composition is nmda receptor antagonist, and second composition is anti-depression drug (ADD).

Adopt drug combination so that syndrome is eased or prevents, perhaps, so that the development of central nervous system associated conditions weakens. Expectedly, this two kinds of medicines any, or even two kinds of medicines, be formulated as slow release formulation, therefore within the scheduled time, the concentration that obtains and optium concentration ratio are sufficiently high for result for the treatment of, but the bad reaction that the excessive levels of avoiding arbitrary composition in the acceptor is correlated with is enough low.

Nmda receptor antagonist

Any nmda receptor antagonist can use in method and composition of the present invention, particularly when in therapeutic alliance of the present invention, using avirulent those. Term " avirulence " is used in relative meaning and is used to specify some materials, this material via U.S. food Drug Administration (" FDA ") ratify to the people take or, consistent with the administrative standard of setting up and practice, the similar management organization that is easy to obtain U.S. food Drug Administration (" FDA ") or any country ratifies to take to the human or animal.

Nmda receptor antagonist can be amino-adamantane compound, this compound comprises, as, Memantine (1-amino-3, the 5-dimethyladamantane), Rimantadine (1-(1-aminoethyl) adamantane) or amantadine (amantadine), with and drug salt. Memantine exists, and such as United States Patent (USP) 3,391, is described in 142,5,891,885,5,919,826 and 6,187,338. Amantadine exists, and such as U.S.P. N.3, is described in 152,180,5,891,885,5,919,826 and 6,187,338. Amino-adamantane compound in addition exists, and such as United States Patent (USP) 4,346, is described in 112,5,06 1,703,5,334,618,6,444,702,6,620,845 and 6,662,845. All these patents are by being incorporated in this paper in this citation.

Further, spendable nmda receptor antagonist comprises, such as KET, Eliprodil, ifenprodil (Ifenprodil), Dizocilpine (dizocilpine), remacemide (remacemide), Lamotrigine (Iamotrigine), Riluzole (riluzole), Aptiganel (Aptiganel), Hog (phencyclidine), Flupirtine (Flupirtine), celfotel, non-ammonia ester (Felbamate), neramexane, spermine, spermidine, Levemopamil (Levemopamil), dextro-methorphan (Dextromethorphan) ((+)-3-hydroxy-n-methylmorphinan) and its metabolin, dextrorphan ((+)-3-hydroxy-n-methylmorphinan), neramexane drug salt or its ester, or the metabolism precursor of any aforementioned substances.

Follow at Tmax to postpone in the time, nmda receptor antagonist can be provided, and it discharges with the dC/dT speed that conspicuousness after quick-release (so-called IR) Types of Medicine reduces. Pharmaceutical composition can be mixed with at the Tmax through 24 hours, 16 hours, 8 hours, 4 hours, 2 hours or at least one hour and change in the time. The relevant minimizing of dC/dT can be about factor of 0.05,0.10,0.25,0.5 or at least 0.8. In addition, nmda receptor antagonist can be provided so that in nmda receptor antagonist enters acceptor after about 2 hours at least 8 hours, 12 hours, 16 hours, 24 hours, it so that Cmax/Cmean ratio about 1.6,1.5,1.4,1.3 or speed still less be released. Pharmaceutical composition can be mixed with to provide dosage at 1 to 80mg/ day, 5 to 40mg/ days or the Memantine that changed in the scope in 10 to 20mg/ days; Dosage was at 25 to 500mg/ days, 25 to 300mg/ days or the amantadine that changed in the scope in 100 to 300mg/ days; Dosage is 1 to 5000mg/ day, 1 to 1000mg/ day or 100 to 800mg/ days or the dextro-methorphan that changed in the scope in 200 to 500mg/ days. Child dose generally is lower than definite adult's dosage. Any technical staff in this area can find this representativeness dosage in U.S. clinician handbook (PDR).

Table 1 has shown exemplary pharmacokinetic properties (for example, Tmax and the T of Memantine, amantadine, Rimantadine_1/2)

Pharmacokinetics and the toxicology of the receptor antagonist of selecting in table 1 human body

Compound	People PK (t1/2) hour	Tmax hour	Common dose	Dosage is agreed to toxicity
					Memantine
	60	3	10-20mg/ days begin with 5mg	Require dosage escalation, hallucinate
					Amantadine	15	3	100-300mg/ days	Hallucinate
Rimantadine	25	6	100-200mg/ days	Insomnia

Anti-depression drug (ADDs)

Suitable anti-depression drug comprises, for example, serotonin reuptake inhibithors (SSRIs), serotonin and norepinephrine inhibitor (SNRIs), act on dopamine receptor medicine and dopamine reuptake inhibithors (TCAs, other). The embodiment of anti-depression drug is serotonin reuptake inhibithors (for example, desipramine/NORPRAMIN^TM, imipramine/TOFRANIL^TM, clomipramine/ANAFRANIL^TM, nortriptyline/PAMELOR^TM, and amitriptyline/ELAVIL^TM), Bupropion/WELLBUTRIN^TM, and buspirone/BUSPAR^TM Therapeutic dose commonly used can find in U.S. clinician handbook (PDR), and reflects below.

The pharmacokinetics of the anti-depression drug of selecting in table 2 human body

Compound	People PK (t1/2) hour	T maxHour	Common dose	The host amount is agreed to bad reaction
					The NORPRAMIN/ desipramine	22	3-6	100-200 mg/ days	The hypopiesia retention of urine, QTC
The LEXAPRO/ Escitalopram	30	5	10-20mg/ days	Sexual dysfunction
					P AXIL/ Paxil	21	5	20-50mg/ days	Sexual dysfunction
The CYMBALTA/ Duloxetine	12	6	40-60mg/ days	Feel dizzy
					The EFFEXOR/ Venlafaxine	5 parent/ 11 for ODV	2  parent/3  for  ODV	150-250 mg/ days	Feel sick, constipation, apocleisis, vomiting, drowsiness
The BUSPAr/ buspirone	7	1	20-30mg/ days	Sleepy, feel dizzy
					The WELLBUTRIN/ Bupropion	14	2	200-300 mg/ days	Apocleisis, constipation, epileptic attack (Bold Warning)

Except concrete drug combination disclosed herein, the nmda receptor antagonist that the drug combination of first nmda receptor antagonist and anti-depression drug can be chosen by test and being used for alleviates the ability of test drug combination of one or more anti-depression drugs of central nervous system associated conditions and determines. Preferred drug combination is that those work as each medicine when testing respectively, has nmda receptor antagonist and/or the anti-depression drug of low dose therapeutically effective with respect to the same dose nmda receptor antagonist that requires to obtain identical antidepressant effect and/or anti-depression drug.

The dosage of nmda receptor antagonist and anti-depression drug and ratio are convenient to change with the maximization result for the treatment of and are minimized toxicity or safety problem. Nmda receptor antagonist can it effective dose commonly used 20% to 200% between change, and anti-depression drug can its effective dose commonly used 20% to 200% between change. Accurately ratio can change according to the illness for the treatment of. In one embodiment, the dosage of Memantine changed between every day 2.5 to 40mg, and the dosage of Duloxetine changed in the scope at 10 to 60mg/ days.

Except concrete drug combination disclosed herein, the drug combination of nmda receptor antagonist such as aminoadamantan compound and anti-depression drug can be determined (referring to embodiment 1 and 2) for the ability of the test drug combination of the syndrome that alleviates the central nervous system associated conditions by test.

For concrete scope, doctor or other suitable health care personnel are that particular patient is determined best medicament according to patient's sex, age, body weight, pathological state and other parameter generally. In some cases, the dosage outside the treatment patient's who prints on the use drug packages the prescribed dose scope may be necessary. These cases are to the doctor in charge or main to examine the animal doctor will be apparent.

In some embodiments, drug combination of the present invention has reached treatment level, and has minimized debilitating side effect, and this side effect is often relevant with quick releasing formulation. In addition, owing to obtain potential time expand section of the blood plasma level of the delay of peak of plasma levels in the time and effectively treatment, medicine frequency can reduce to medication every day once or twice, therefore improves the compliance of patient treatment and the property followed.

Therefore, drug combination of the present invention allows nmda receptor antagonist and anti-depression drug administering drug combinations, and this administering drug combinations has improved effect and avoided two kinds of unnecessary side effects of pharmaceutical drugs. For example, by using controlled release method, change Tmax to the long period, thereby reduce the dC/dT of medicine, can alleviate seriousness and the frequency of the side effect that comprises the mental disease relevant with the nmda receptor antagonist administration and cognitive impairment. The minimizing of medicine dC/dT has not only increased Tmax, and reduced drug concentration when Tmax, and reduced Cmax/Cmean ratio, this ratio during preset time in for the treatment patient medicine of more lasting dosage is provided and has reduced the adverse events relevant with dosed administration. Similarly, also by controlled release method, seriousness and the frequency of using the side effect of antidepressant deposits yields can have been reduced.

In certain embodiments, drug combination has brought summation action. In no controlled-release technology situation, obtain additivity by the associating active agents. In other embodiment, especially when the pharmacokinetics of active pharmaceutical composition of associating is not identical, the controlled release preparation optimization pharmacokinetics of active pharmacy medicament reduce the in time changeability of Cratio. At the appointed time, the variable minimizing of Cratio has started the synergy of medicine in that time, the effectiveness of maximization associating. Cratio changeability (" Cratio.var ") is defined as the standard deviation of a series of Cratio that obtain in one period preset time, be respectively the mean value that those multiply by 100% Cratio. Picture shows in Fig. 2 A-2D and table 3, during any material time after comprising administration during at once with stable state in, the Cratio of controlled release preparation is more consistent than the Cratio of same medication combined quick releasing formulation. Data in the accompanying drawing are summed up in following table.

Memantine and Duloxetine Cratio and Cratio.var data in table 3. quick-release (IR) preparation and controlled release (CR) preparation

	Time: 22-24 hour		Time: 192-240 hour
					IR	CR	IR	CR
	The Cratio scope	0.40-1.98	0.39-0.84	0.14-0.38					0.14-0.24
Cratio mean value					1.04	0.62	0.24	0.19
	The Cratio standard deviation	0.57	0.14	0.07					0.03
Cratio.Var(％)					55％	23％	30％	16％

Administering mode

Drug combination of the present invention can arbitrary part or system mode or depot formulation or the administration of slow release mode.In a preferred embodiment, nmda receptor antagonist, anti-depression drug or two kinds of medicines can be formulated into and provide controlled, time-delay to discharge (as what describe) here.For example, provide the pharmaceutical composition of nmda receptor antagonist, anti-depression drug or two kinds of drug controllable release to make by associating expected drug or the medicine with one or more supplementary elements, when to the receptor administration, this supplementary element causes separately medicament or medicament to discharge concrete a period of time with target velocity.These medicaments can be preferably carried with oral, transdermal or per nasal form.

Two compositions are preferably to provide the mode administration of expection effect from first composition of drug combination and second composition.Not necessarily, before first medicament and second medicament entered in the receptor, they were mixed in the unitary agent.Drug combination can be divided into unit dose easily again, and this unit dose contains first medicament and second medicament of suitable dosage.Unit dosage forms can be, and for example, capsule or tablet or it can be this compositions of appropriate amount in the packing.The amount of the active component in the unit dosage forms can change or adjusts according to sanatory special requirement.

Perhaps, until after in they enter receptor, the nmda receptor antagonist of drug combination and anti-depression drug also can not be mixed.Therefore, term " associating " is round embodiment, and nmda receptor antagonist and anti-depression drug separate formulation provide and by successive administration.For example, nmda receptor antagonist and anti-depression drug can or still less be separated from each other to the receptor administration within the time 2 days, 1 day, 18 hours, 12 hours, 1 hour, half an hour, 15 minutes.Each medicament can a plurality of, single capsule or tablet provide, capsule or tablet are separately to the receptor administration.Perhaps, nmda receptor antagonist separates from pharmaceutical composition each other with anti-depression drug, makes that they do not have mixed afterwards in pharmaceutical composition enters into receptor.Mixing may be just in time before to the receptor administration, or takes place before to the receptor drug combination.

In case of necessity, nmda receptor antagonist and anti-depression drug can and be united other Therapeutic Method to patient's administration, for example, and medicine, operation or other interventional therapy scheme.Drug combination comprises non-drug therapy, as long as the cooperation of drug combination and other Therapeutic Method obtains favourable effect, non-drug therapy can be carried out under any appropriate time.For example, in suitable case, when the healing potion administration do not have temporarily non-drug therapy perhaps several days or even during several week, still obtain favourable effect.

The preparation of special route administration

Drug combination can be provided as pharmaceutical composition, and pharmaceutical composition is best for the administration of specific form.For example, pharmaceutical composition for oral administration uses medicine to make with carrier, and this medicine is well-known with carrier in the art.Carrier can make the medicament in the drug combination be mixed with, for example, and the tablet of receptor orally ingestible, pill, capsule, solution, suspension, slow releasing preparation, powder, liquid or gel.

Perhaps, compositions of the present invention can be by some strategies through transdermal administration, and those strategies that comprise are at United States Patent(USP) Nos. 5,186,938,6,183,770,4,861,800 and WO 89/09051 in be described.The combination medicine that provides in paster is special to be useful to those given medicaments with high relatively skin flux.

The pharmaceutical composition that contains second medicament of nmda receptor antagonist and/or drug combination also can pressurized package, the arosol spray preparation administration of atomized inhalation or solubility Foradil Aerolizer formoterol fumarate.The suitable propellant that is used in the atomized inhalation comprises, for example, and dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane and carbon dioxide.When being provided, press atomization carry the value of the chemical compound of prescribed dose to determine consumption.

Composition for inhalation or insufflation compositions comprise medicine with, solution and suspension in aqueous or organic solvent or its mixture and the powder.The liquid or solid compositions can comprise the appropriate drug excipient of listing above.For obtaining part or whole body effect, preferred composition Orally-administrable, intranasal administration or respiratory tract administration.Can spray by using noble gas with the compositions in the solvent at preferred disinfecting drug.Spray solution can directly suck from sprayer unit or sprayer unit can connect face shield, tent or intermittent positive pressure breathing respirator.Solution, suspension or powder composition can, preferred oral or nasal cavity, administration from the equipment of the preparation of carrying suitable mode.

In some embodiments, for example,, the compositions intranasal is better than making active component enter the central nervous system and reduce the whole body administration through the migration of olfactory sensation passage through suction but being transported to cribriform plate.The equipment that generally is used for this administration route is contained in United States Patent (USP) 6,715, in 485.The compositions that transmits through this route may increase central nervous system's dosed administration or reduce whole body burdens, reduces the general toxicity risk relevant with a certain medicament.

The additional formulations that is suitable for other administering mode comprises rectum capsule or suppository.For suppository, traditional binding agent and carrier can comprise, for example, and polyethylene glycols or triglyceride; This suppository can be from containing scope 05% to 10%, and the mixture of preferred 1% to 2% active component is processed into.

Drug combination can not necessarily be formulated into interior conveying of container that is used to provide continuous long-term delivery, for example, carried 30 days, 60 days, 90 days, 180 days, or 1 year.For example, container can be made with biocompatible material such as titanium.To raising patient's compliance, and improve the stability of combination, long-term delivery formulations is special effective in chronic disease patient body.The preparation of successive long-term delivery is as U.S.P.Ns.6, is suggested in 797,283,6,764,697,6,635,268 and 6,648,083.

In case of necessity, composition can be supplied with in test kit.Test kit comprises the description of using this test kit extraly.In some embodiments, test kit is included in one or more container, nmda receptor antagonist, and, separate, in one or more containers, anti-depression drug.In other embodiment, test kit provides the nmda receptor antagonist of mixture in one or more containers and the drug combination of anti-depression drug.Test kit comprises the medicine of dose therapeutically effective, and this medicament is used for the treatment of dull-witted associated conditions.

Nmda receptor antagonist, anti-depression drug or two kinds of medicines can be supplied with by controlled release, slow release formulation.In one embodiment, at least 50%, 90%, 95%, 96%, 97%, 98%, 99% or even surpass 99% nmda receptor antagonist with slow release formulation carry to.For example, after expeced time, the releasing degree of nmda receptor antagonist and anti-depression drug obtains specific acute or chronic stable state serum-concentration collection of illustrative plates and is determined easily by the Cmax/Cmean that calculates scope expeced time.Therefore, a pair of receptor (for example, mammal such as people) administration, in nmda receptor antagonist enters receptor about 2 hours of back, by at least 8 hours, 12 hours, 16 hours, 24 hours, nmda receptor antagonist has about 1.6,1.5,1.4,1.3 or Cmax/Cmean ratio still less.In case of necessity, the release of nmda receptor antagonist can be monophasic or heterogenetic (for example, biphase).In addition, anti-depression drug can be formulated as slow releasing composition, in nmda receptor antagonist enters receptor about 2 hours of back, by at least 8 hours, 12 hours, 16 hours, 24 hours, said composition has about 1.6,1.5,1.4,1.3 or Cmax/Cmean ratio still less.The those skilled in the art can use in this area nmda receptor antagonist known or that be described below and anti-depression drug and compound method to prepare the combination with expectation releasing properties.

Picture shows in table 1 and table 2, the pharmacokinetic property of two kinds of drug types from about 3 hours to greater than changing in 60 hours the scope.Therefore, one aspect of the present invention be used to select appropriate formulation obtain during prolonging in (preferably from 8 to 24 hours) thus almost constant concentration keeps the concentration of the optimum therapeuticing effect of two kinds of constant and acute administrations of components in proportions and chronic administration.

Preferred Cratio.Var value is less than about 100%, 70%, 50%, 30%, 20%, 10%.Preferred Cratio.Var value can be less than about 10%, 20%, 30%, 50%, 75% or 90% of the rapid release Cratio.Var value of first 4 hours, 6 hours, 8 hours, 12 hours identical active pharmaceutical compositions after the administration.

Drain the medicine of half-life with respect to extensive change, carry this preparation constant, measurability matter also to allow it to reach the acute dull rising of chronic ratio of comparing.This type of composition of the present invention and these combination treatments of use patient's method is embodiment of the present invention.Describe as following, many approach have reached the releasing properties of expection.

In the proper method of preparation drug combination, first composition, second composition or two kinds of compositions are to provide in the slow releasing preparation, and this slow releasing preparation is included in U.S. Patent No. 4,606, those disclosed in 909 (therefore by citation and be incorporated in herein).This list of references has been described independent overlay or the controlled release multiple unit formulation in its microcapsule unit of packing into, the decomposition of controlled release multiple unit formulation preparation in the stomach animal (for example, pill or tablet) just can obtain (referring to, for example 3 be listed as, 26 row are to 5 row, 10 row and 6 row, 29 row are to 9 row, 16 go).The unit of each independent overlay or microcapsule comprises the homogeneity internal layer, and this homogeneity internal layer contains the granule of slightly soluble active substance, and this internal layer has applied the coating of abundant acid-resisting environment, but can be etched under the environment in small intestinal.

Alternatively, this drug combination can use as U.S. Patent No. 4,769, and disclosed method is made in 027.Therefore, comprising medicine can adopt the permeable polymer matrix that contains nmda receptor antagonist to apply one deck and employing with the particulate slow releasing preparation of material (for example, sugar/starch, salt and wax) to contain the pervious bed repaste that dispersible water-soluble within it forms poromerics and cover one deck.

A kind of composition of drug combination or two kinds of compositions can be prepared as described in 268 additionally according to U.S. Patent No. 4,897, and this composition comprises bio-compatible, biodegradation microcapsule induction system.Therefore, nmda receptor antagonist can be formulated as the compositions that contains the free-flow spheroidal particle, said composition can obtain by some memantines in the microcapsule of packing into separately, for example, therefore threading discharges memantine and enters with in the circulation that pre-determines speed in the biodegradable different copolymer thing excipient with different rates.Some granules can have this copolymer excipient, and the internal layer active component is released rapidly after administration, so conveying active in during initial.Second batch of granule has such excipient, and the conveying of composition just begins when first conveying begins to reduce in the microcapsule of packing into.The 3rd batch of composition can be put in the microcapsule with different excipient, and it causes carrying when second batch conveying begins to reduce and just begins.The speed of carrying can be by changing lactic acid-ethanol copolymer (lactide/glycolides ratio in poly (D, the L-lactide-co-glycolide)) encapsulation.Other spendable polymer comprises polymethanal polymer, poly-former phosphide, polyesteramide, polycaprolactone and its copolymer, Merlon, poly butyric and its copolymer, poly-maleic amide, copolyaxalate, polysaccharide.

Perhaps, drug combination can be produced out as described in 626 according to U.S. Patent No. 5,395, and this U.S. Patent No. 5,395,626 is described out multilamellar controlled release pharmacy dosage form.Dosage form comprises many coating granules, wherein each has multilamellar around the internal layer that contains nmda receptor antagonist and/or anti-depression drug, contain whereby the medicine of internal layer and at least another layer of active medicine coated by the controlled release carrier layer, therefore at least two controlled release layer from the particulate water-soluble medicine of multiple coating layer are provided.

In some embodiments, first composition and second composition of the drug combination of here describing provide in single or separated drug compositions." pharmacy can with or the pharmacology can with " comprise molecular entity and when the time to animal or people's administration suitable, produce the compositions of bad, allergy or other untoward reaction." pharmacy available support " comprise some and all solvents, disperse medium, coating, antimicrobial and antifungal drug, etc. open and the absorption delay medicine and similar medicine.This medium and medicine that use is used for pharmaceutically active substances are known in the art.But as some traditional sucroses or the incompatible exception that then belongs to active component of medicine, the use in the therapeutic combination is expected.Auxiliary active component also can join in the compositions." drug salt " comprises acid salt and this drug salt uses mineral acid, and example hydrochloric acid or phosphoric acid or organic acid such as acetic acid, tartaric acid, mandelic acid and class acidoid are processed into.Use salt that the free carboxy group shapes also may from inorganic base as, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or hydrated ferric oxide., from organic base as 2-aminopropane., trimethylamine, histidine, procaine and similar alkali.

According to the disclosure, pharmaceutical compositions or pharmacology's preparation of compositions are known by those skilled in that art.The preparation and the general technology of administration exist " Remington:TheScience and Practice of Pharmacy, Twentieth Edition, " LippincottWilliams ﹠amp; Amp; Wilkins, Philadelphia can find among the PA.Tablet, capsule, pill, powder, granule, dragee, gel, syrup, ointment, suppository solution, injection, inhalant and spray are the embodiment of this preparation.

Via embodiment, sustained-release oral preparation can use other the method in this area to be prepared.For example, arbitrary active pharmaceutical ingredient of Shi Yi slow release formulation or two kinds of compositions can be substrate tablet compositions.Suitable substrate rapidoprint comprises, as wax (as, babassu, Cera Flava, paraffin, ceresine, shellac wax, fatty acid and aliphatic alcohol), oil, castor oil, Adeps Bovis seu Bubali, Petiolus Trachycarpi oil and soybean oil) and polymer (as, hydroxy propyl cellulose, polyvinylpyrrolidone, hydroxypropyl emthylcellulose and Polyethylene Glycol.Other suitable substrate briquetting material is microcrystalline Cellulose, Powderd cellulose, hydroxypropyl cellulose, ethyl cellulose and other carrier and implant.That tablet also can comprise is granular, coating powder or bead.Tablet is also multiwalled.When active component made a marked difference pharmacokinetic property, the multilamellar tablet was especially preferred.Not necessarily, the tablet of making can be coated or do not coated one deck.

Coating composition generally comprises insoluble matrix polymer (forming the about 15-85% of weight in coating) and water-soluble substance (for example, forming the about 15-85% of weight in coating).Nonessential enteric polymer (forming weight about 1 to 99% in coating) can be used or contain.Suitable water-soluble material as sugar (for example comprises polymer such as Polyethylene Glycol, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, polyvinyl alcohol and monomer material, lactose, sucrose, fructose, mannitol and similar sugar), salt (for example, sodium chloride, potassium chloride and class are saloid), organic acid (for example, fumaric acid, succinic acid, lactic acid and tartaric acid) and its mixture.Suitable enteric polymer comprises hydroxypropyl emthylcellulose, acetic acid succinate, hydroxypropyl emthylcellulose, phthalate, polyvinyl acetate phthalate ester, cellulose acetate-phthalate, trimellitic acid cellulose acetate, Lac, zein and contains the polymethacrylates of carboxyl.

Coating composition can be according to the character of coating mix, as be used for the glass transition temperature of the main component of coating composition or mixture of ingredients or solvent and plastified.Suitable plasticizer can the coating combination from 0% to 50% the adding of weight meter; and plasticizer comprises; for example, diethyl phthalate, citrate, Polyethylene Glycol, glycerol, acetylation glyceride, acetylation citrate, decanedioic acid dibutylester and castor oil.In case of necessity, coating composition can comprise implant.The consumption of implant can coating combination total weight meter 1% to about 99%, and can be insoluble material such as silicon dioxide, titanium dioxide, Talcum, Kaolin, aluminium oxide, starch, Powderd cellulose, microcrystalline Cellulose (MCC) or polacrilin potassium.

Solution or latex that coating composition can be used as in organic solvent or aqueous solvent or its mixture are used.If solution is employed, the consumption of solvent can be in the about 25%-99% of dissolved solid total weight.The suitable solvent is water, lower alcohol, rudimentary chlorinated hydrocarbons, ketone or its mixture.If latex is employed, the consumption of solvent is the about 25-97% in the weight of some polymeric materials in the latex.Solvent is mainly water.

Here the pharmaceutical composition of Miao Shuing also can comprise for example solvent, disperse medium, coating, antimicrobial and antifungal, etc. open and the carrier of absorption delay agent.This medium and the vehicle that are used for pharmaceutically active substance are known in ability.Drug salt also can be used in the compositions, for example, and mineral salt such as hydrochlorinate salt, hydrobromate, phosphate or sulfate and acylate such as acetate, propionate, malonate or benzoate.Compositions also can comprise liquid, for example water, saline solution, glycerol and ethanol, and as the material of wetting agent, emulsifying agent or pH value buffer agent.Liposome, as in U.S. Patent No. 5,422,120, WO 95/13796, and WO 91/14445, and or EP524, those that describe among 968 B1 also can be used as carrier and use.

The other method of preparation controlled release preparation is as United States Patent(USP) Nos. 5,422, is described in 123,5,601,845,5,912,013 and 6,194,000, and all the elements are in this citation and be incorporated in herein.

The preparation of carrying in the percutaneous plaster can use method known in this area to realize that those methods are included in as United States Patent(USP) Nos. 5,186, those that describe in 938 and 6,183,770,4,861,800 and 4,284,444.Paster is special effective embodiment in the case that the absorption problem owing to many anti-depression drugs causes.Paster can be formed in 12 hours, 24 hours, 3 days and the release of 7 days saturating skin active component of inner control.In one embodiment, every day, 2 times of nmda receptor antagonists were thrown in the non-volatile fluid with anti-depression drug.The medicine of the prescribed dose of Shi Yonging here, preferred release will be carried out from 12 hours by 72 hours.

The preparation capable of permeating skin of this form will comprise from 1% to 50% active component.Compositions of the present invention provides with fluid form viscosity, non-volatile.Preferably, two of combination members will have at least 10 ^-9Mole/cm ²The percutaneous rate of/hour.At least 5% the active material skin of will in 24 hours, flowing through.The special preparation of transdermal can adopt the standard method in this area to measure (for example, Franz et al., J.Invest.Derm.64:194-195 (1975)).

In some embodiments, for example, compositions can be transported to brain by intranasal but not make active agents enter in the central nervous system through the olfactory sensation passage and reduced the whole body administration through suction.The equipment that is generally used for this administration path is included in United States Patent (USP) 6,715, in 485.Compositions through this delivery pathways can increase central nervous system's dosed administration or reduce the whole body burden, reduces the general toxicity risk relevant with certain drug.

The preparation of drug combination that subcutaneous implantation equipment is carried can use the method in this area to realize, as at United States Patent(USP) Nos. 3,992, and the method for describing in 518,5,660,848 and 5,756,115.

Be suitable for the indicator of combined therapy

Has or has central nervous system's associated conditions (as psychosis (as panic syndrome, the general anxiety imbalance, all types of phobic syndromes, demented, hot-tempered strongly fragrant psychosis, excited disease, the unipolarity depression, depression, stress disorders, posttraumatic stress disorder (PTSD), somatoform disorder, personality disorder, psychosis, and schizophrenia), and drug dependence (as, ethanol, psychostimulant (as, crack, cocaine, speed, meth), Opium class medicine, and nicotine), dull-witted associated conditions such as epileptics, epilepsy, acute pain, chronic pain, chronic neuralgia) some receptors of risk can use combination described herein and method to treat.Combination of the present invention is favourable for other treatment of conditions and prevention also, its disease comprise headache (as, migraine, tension headache, the mass-sending headache), cerebrovascular disease, motor neuron (as, amyotrophic lateral sclerosis, marrow motion atrophy, Tay-Sach ' s disease, the Sandoff disease, familial spastic), dull-witted (as, Alzheimer, Parkinson's disease, Pick's disease, volume temporal lobe dementia, the vascular type dementia, the water brain disease of normal pressure, Heng Dingdun chorea and demulcent cognitive impairment), neurodegenerative diseases (as, the familial alzheimer's is levied, the protein disease, cerebellar ataxia, Friedrich ' s ataxia, spinocebellar ataxia, Wilson's disease, resting potential, amyotrophic lateral sclerosis, adrenoleukodystrophy, Menke ' s Sx, the sick companion of brain autosomal dominant inheritance, AD cerebral arteries cortex is infraction (CADASIL) down; Spinal muscular atrophy, familial amyotrophic lateral sclerosis, duchenne muscular dystrophy, charcot marie tooth, the neural line fibromatosis, Von Hippel-Lindau disease, fragile X syndrome, spastic paraplesia, tuberous sclerosis, the WardenburgShi syndrome), apoplexy (as, embolic stroke, the embolus apoplexy, thromboembolic stroke, hemorrhagic apoplexy, the venoconstriction apoplexy, with the veins apoplexy) dyskinesia (as, myodystonia, optimum constitutional tremor, tardy muscle tonus degree deficiency, tardive dyskinesia, Tourette syndrome is waited group (tourette ' s Syndrome)), the ataxia syndrome, the sympathetic nervous system disorder is (as the Shy-Drager syndrome, the olivopontocerebellar degeneration, striatonigral degeneration, Parkinson's disease, the Heng Dingdun chorea, the Gullian-Barre syndrome, causalgia, I type and II type complex region pain syndrome, diabetic neuropathy, and alcoholic neuropathy), the cranial nerve disorder (as, trigeminal neuropathy, trigeminal neuralgia, Menier ' s syndrome, glossopharyngeal neuralgia, dysphagia, dysphonia, with the cranial nerve paralysis) myelopathy, traumatic brain injury and spinal cord injury, the radiation brain injury, multiple sclerosis disease, syndrome behind the meningitis, the protein disease, myelitis, radiculitis, neuropathy (as, the Guillian-Barre syndrome, the bad proteinemia diabetes of being correlated with, transthyretin inducing neural pathological changes, HIV related neural pathological changes, Lyme disease related neural pathological changes, herpes zoster related neural pathological changes, Carpel Tunnel Syndrome, the shank tunnel syndrome, starch inducing neural pathological changes, the leprosy neuropathy, bell's palsy, compressive neuropathy becomes, sarcoidosis inducing neural pathological changes, the brain polyneuritis, heavy metal inducing neural pathological changes, transition metal inducing neural pathological changes, drug-induced neuropathy), the pain syndrome (as, acute pain, chronic pain, neuropathic pain, nociceptive pain, inflammatory pain), the aixs cylinder brain injury, encephalopathy, and chronic fatigue syndrome.More any method and composition of here describing that uses in these diseases is treated.

Adopt the drug combination treatment can use method known in this area to monitor to receptor.Use the effect of drug combination treatment preferably to assess, for example by writing down the minimizing or the growth of syndrome extension deterioration time of recurrence frequency by the syndrome that detects a large amount of modes of receptor.Successfully treating in the case, the situation of receptor will improve (for example, the frequency of recurrence will reduce or postpone the progress time will improve).

The present invention will be illustrated in the non-restrictive example below.

Embodiment 1: and the method for definite best Css ratio in the body (Cratio, ss)

Dosage excursion research (for example, forced swimming experiment (FST)) in suitable depression model is used U.S. dollar to just come here to determine ED50 and is implemented, and ED50 is about 15 μ m.The ED50 of anti-depression drug (as fluoxetine) determines in a similar fashion.Thereby dose,equivalent experiment in the EDXX segment of medicine, be combined at them add up to ED100 (for example, ED50:ED50, ED25:ED75, etc.) situation under take place immediately.Data are handled.Experiment points out that the straight line on the curve chart between the ED50 point is the expression cooperative effect down, and point on line shows additive effect, and the point of online top shows depression effect.The point of maximum deviation dose,equivalent line is an optimum ratio.This is best stable state ratio (Cratio.ss) and adjusts according to the composition half-life.Similarly stipulations can be used in effective animal model of numerous species.

The drug combination of embodiment 2:NMDA receptor antagonist and anti-depression drug

The representative drug combination scope and the ratio that are lower than the present composition are presented.The preparation strategy of these scopes here to describe.

Adult's dosage and drug combination treatment ratio

	(ADD: NMDA) ratio is enclosed medicinal model to depression thing amount mg/day/
								NMDA medicine mg/ days	Desipramine/NORPRAMIN TM	Escitalopram/LEXAPRO TM	Paroxetine/PAXIL TM	Duloxetine/CYMBALTA TM	Venlafaxine/EFFEXOR TM	Buspirone/BUSPAR TM	Amfebutamone/WELLBUTRIN TM
Memantine 2.5-80	25-200 (0.3-80)	5-20 (0.05-10)	5-50 (0.05-20)	10-100 (0.1-40)	25-250 (0.25-100)	5-50 (0.5-20)	50-500 (0.5-200)
								Amantadine 50-400	25-200 (0.06-5)	5-20 (0.012-0.4)	5-50 (0.012-1)	10-100 (0.025-2)	25-250 (0.06-60)	5-50 (0.012-20)	50-500 (0.012-10)
Rimantadine 50-200	25-200 (0.3-80)	5-20 (0.05-10)	5-20 (0.05-20)	10-100 (0.1-40)	25-250 (0.25-100)	5-50 (0.05-20)	50-500 (0.5-200)

Embodiment 3: the releasing properties of memantine and paroxetine (paroxetine)

The release ratio of memantine and paroxetine drug combination shows in showing below.Running summary of the points scored is the amount (for example, U.S. Patent No. 4,839,177) that is discharged into the drug substance serum or the internal organs from preparation.

	Memantine T 1/2=60 hours	Paroxetine T 1/2=21 hours
			Time	Running summary of the points scored A	Running summary of the points scored B
1	0.2	0.2
			2	0.3	0.3
4	0.4	0.4
			8	0.5	0.5
12	0.6	0.6
			16	0.7	0.7
20	0.8	0.8
			24	0.9	0.9

Embodiment 4. contains the form of memantine and venlafaxine (venlafaxine) drug combination

The memantine of slow release formulation and venlafaxine are made three independently compressed tablets.These three compressed tablets independently, each has different releasing properties, subsequently three tablets is put in the gel capsules, shuts then and seal capsule.The composition of three tablets is as follows.

Composition	Function	Each tablet dosage
			Table 1 (directly discharging)
Memantine	Active component	0mg
			Venlafaxine	Active component	20mg
Dicalcium phosphate dehydrate	Diluent	26.6mg
			Microcrystalline Cellulose	Diluent	26.6mg
Sodium starch glycollate	Disintegrant	1.2mg
			Magnesium stearate	Lubricant	0.6mg

Composition	Function	Each tablet dosage
			Table 2 (discharging in 3-5 hour)
Memantine	Active component	10mg
			Venlafaxine	Active component	40mg
Dicalcium phosphate dehydrate	Diluent	26.6mg
			Microcrystalline Cellulose	Diluent	26.6mg
Sodium starch glycollate	Disintegrant	1.2mg
			Magnesium stearate	Lubricant	0.6mg
Eudragit RS30D	Time-delay discharges	4.76mg
			Talcum	Coat composition	3.3mg
Triethyl citrate	Coat composition	0.95mg

Composition	Function	Each tablet dosage
			Table 3 (slow release 7-10 hour)
Memantine	Active component	12.5mg
			Venlafaxine	Active component	60mg
Dicalcium phosphate dehydrate	Diluent	26.6mg
			Microcrystalline Cellulose	Diluent	26.6mg
Sodium starch glycollate	Disintegrant	1.2mg
			Magnesium stearate	Lubricant	0.6mg
Eudragit RS30D	Time-delay discharges	6.5mg
			Talcum	Coat composition	4.4mg
Triethyl citrate	Coat composition	1.27mg

Tablet is gone out by the wet granulation of single drug particles and other part can use fluidized bed pelletizer to make.Table 1 is a fast dissolving dosage form, discharges active component in 1-2 hour after administration.Thereby it does not contain the dC/dT influence that memantine has been avoided current dosage form.Table 2 and table 3 adopt the slow release clad material to carry out coating and finish as spraying and similar techniques as using the conventional bag coating technique.The concrete composition that is listed in the top form can use other the suitable composition of function to replace, for example, and diluent, binding agent, lubricant, implant, coating and analog.

The releasing properties that will cause having three phases to the capsular oral administration of patient, with abundant instant initial release from first tablet venlafaxine, the main release that takes place to want tablet Sino-U.S. Buddha's warrior attendant and venlafaxine in 3-5 hour after the administration, and the release that memantine and venlafaxine from the 3rd tablet mainly took place after the administration in 7-9 hour from second.

Embodiment 5: contain memantine and and the pearl of venlafaxine drug combination

The method of embodiment 4 is repeated, and replaces tablet and is used unless contain the pearl medicine.First's glass bead is by coating the inertia backing material as making with the lactose of medicine, and this medicine provides first (rapid release) pulse.The second portion pearl a certain amount ofly fully provides the other inert material that concentrates on the memantine that discharged medicine in 3-7 hour and venlafaxine drug combination to coat pearl and makes by having.The third part pearl a certain amount ofly fully provides the other inert material that concentrates on another memantine that discharged medicine in 3-7 hour and venlafaxine drug combination to coat pearl and makes by having.Three groups of pearls can be put into capsule as embodiment 4, or are pressed into single tablet by buffer unit.Perhaps, three groups of drug particles can be provided and coat by top describing method, replace medication coat lactose pearl.

Embodiment 6: the releasing properties of rapid release and controlled release Escitalopram (escitalopram) preparation

Compare with the rapid release administration of existing market product, the anthropomorphic dummy PK release and the Cratio that make the controlled release drug combination product that is similar to embodiment 5 list in Fig. 3 A-3F.For the rapid release administration, oral dosed administration is 20mg memantine b.i.d. and 20mg Escitalopram qd.For controlled release preparation 1,20mg memantine and 20mg Escitalopram provide in controlled release oral is carried preparation, after 12 hours with the constant rate of speed release bioactive agent.This controlled release product will keep two kinds of almost constant Cratio of active component, and the time range Cratio.Var that surpasses 2-24 hour to 192-240 hour is 6% and 4% as calculated.

Except obtaining the expection releasing properties, this drug combination preparation will demonstrate the preferred reduction of dC/dT and C max/Cmean, even the preferred reduction of the nmda receptor antagonist dC/dT of higher dosage and Cmax/Cmean, therefore, do not having under other situation that requires to increase, for strengthening therapeutic effect, the present invention can provide more multiple dose.In addition, the dosage of increase allows the still less time administration of medicine.

DC/dT (4 hours) Cmax/Cmean2-16	Nmda receptor antagonist
			Rapid release (10mg)	Controlled release (20mg)
	4.0 1.6	3.1 1.4
			DC/dT (4 hours) Cmax/Cmean2-16	Escitalopram
Rapid release (20mg)	Controlled release (20mg)
		5.1 1.2		2.1 1.4

Embodiment 7: memantine and Escitalopram slow-release paster are provided

According to above-described, the nmda receptor antagonist slow releasing preparation is used for topical by preparation.The memantine transdermal plaster preparation is according to as United States Patent(USP) Nos. 6,770, and the method for describing in 295 and 6,746,689 is made.

For the preparation of medicine binding agent acrylate, 4.1g memantine and 3.6g Escitalopram are dissolved in the 11g ethanol and this mixture is added into 20g Durotak 387-2287 (National Starch﹠amp; Chemical, U.S.A.).Drug gel use filming equipment (as, RK Print Coat Instr.Ltd, Type KCC202 controls coater) (Scotchpak 1012 to be coated in the backing film; 3M Corp., U.S.A.) on.Wetting layer thickness is 400 μ m.Rolled at room temperature dry 20 minutes, then 40 ℃ of dryings 30 minutes.The polyester release liner is rolled on exsiccant drug gel.Thin slice is cut into paster and stores down until use (in the bag of packing into) at 2-8 ℃.The concentration range of memantine is at 4.6mg/cm in the paster ²And 6.6mg/cm ²Between, and the Escitalopram scope is at 4.0mg/cm ²And 6.0mg/cm ²Between.

Fig. 4 A, 4B and 4C are curve charts, with 24 hours release ratios of expection of current embodiment than rapid release character.These diagram shows are almost inculcated the advantage of component and set up correct stable state ratio that (Cratio, importance ss) are revised dosage form concentration then and obtained optimum therapeuticing effect continuously.

Other embodiments are included in claims.

Claims (16)

1. pharmaceutical composition, it comprises:

(a) nmda receptor antagonist;

(b) second medicine, wherein said medicine are anti-depression drug (ADD); With

(c) medicine carrier,

In wherein said nmda receptor antagonist or described second medicine at least one is to provide with slow release formulation.

2. pharmaceutical composition according to claim 1, wherein said nmda receptor antagonist have dC/dT less than about 80% of about quick releasing formulation speed.

3. pharmaceutical composition according to claim 1, wherein said nmda receptor antagonist back in it introduces receptor had about 1.6 or Cmax/Cmean ratio still less in about 2 hours at least 12 hours.

4. pharmaceutical composition according to claim 1, the relative Cratio.Var of the wherein above-mentioned nmda receptor antagonist and the second medicine anti-depression drug less than administration after from 2 hours to 12 hours 100%.

5. pharmaceutical composition according to claim 1, the relative Cratio.Var of the wherein above-mentioned nmda receptor antagonist and the second medicine anti-depression drug less than administration after from 2 hours to 12 hours 70%.

6. pharmaceutical composition according to claim 1, wherein said second medicine are 5-hydroxy tryptamine reuptake inhibithors (SSRIs), 5-hydroxy tryptamine/noradrenaline reuptake inhibitor (SNRIs), three ring resist melancholy agents (TCA).

7. pharmaceutical composition according to claim 1, wherein said nmda receptor antagonist are that the memantine and second medicine are desmethylimipramine, Escitalopram, paroxetine, venlafaxine, duloxetine, buspirone or pacify non-its ketone.

8. pharmaceutical composition according to claim 1, wherein said pharmaceutical composition are made into oral delivery, per nasal conveying, parenteral delivery, part down through carrying or the suction conveying under epithelial cell conveying, percutaneous plaster conveying, the corium.

9. pharmaceutical composition according to claim 9, wherein said pharmaceutical composition is configured to suspension, capsule, tablet, suppository, washing liquid or paster.

10. pharmaceutical composition according to claim 1, wherein said nmda receptor antagonist are that the memantine and second medicine are duloxetines.

11. method for the treatment of central nervous system's associated conditions, this method comprises the drug combination of its receptor of needs being taken dose therapeutically effective, this drug combination comprises the nmda receptor antagonist and second medicine, wherein second medicine is an anti-depression drug, and wherein nmda receptor antagonist provides with slow release formulation.

12. method according to claim 11, wherein said central nervous system's associated conditions are epilepsy, epilepsy or convulsive disease.

13. method according to claim 11, administration simultaneously of the wherein said nmda receptor antagonist and second medicine or administration in succession.

14. method according to claim 11, the wherein said nmda receptor antagonist and second medicine are as single compositions administration.

15. method according to claim 11, wherein said central nervous system's associated conditions are chronic injury susceptibility pain.

16. method according to claim 11, wherein said nmda receptor antagonist are that the memantine and second medicine are duloxetines.

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