CN101119705A - Combination of a NMDA receptor antagonist and a MAO-inhibitor or a GADPF-inhibitor for the treatment of central nervous system-related conditions - Google Patents
Combination of a NMDA receptor antagonist and a MAO-inhibitor or a GADPF-inhibitor for the treatment of central nervous system-related conditions Download PDFInfo
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Abstract
The present invention provides a method for treating the disease relative to the aphronesia, such as Parkinsonism and Alzheimer's disease, etc., and a composition which is formed by a NMDA receptor antagaonists and a monoamine oxidase (MAO) inhibitor and a GADPH inhibitor.
Description
Technical field
The present invention relates to treat central nervous system (CNS)-relevant disease, as the compositions and the method for parkinson disease and Alzheimer.
Background technology
Oxidase inhibitor (MAOi, A or B) is used to the treatment of neurological and neuropsychiatry disease symptoms clinically, comprises parkinson disease (PD) depression and two depression of sex.Its superiority is removed active owing to and undefined freedom-Ji active for the inhibition of amine (for example, dopamine, serotonin, tyramine and 2-benzene-(base) ethamine) digestive enzyme.Recently, it is reported that aforementioned second kind of activity is relevant with the apoptotic resistance of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mediation.Obviously, GAPDH is found and shifts nucleus and interior level and the multiple disease of its nuclear that enters apoptotic cell, comprises parkinson disease, and Alzheimer is relevant with Huntington Chorea.Yet, monoamine oxidase, MAO (MAO) thus the treatment of inhibitor is relevant with many weak side effect to have limited its use.These side effect comprise, for example, regurgitation, dizzy, giddy swoons, stomachache, confusion, hallucination, xerostomia, dreaminess, the dyskinesia, headache.
Like this, need a kind of curative drug, its reservation or strengthened MAO inhibitor (MAOi) and the curative effect of the compositions of the apoptosis (GAPDHai) that other antagonisms GAPDH mediates and reduce or eliminate these adverse side effects.
Summary of the invention
Generally speaking, the apoptotic antagonist that the invention provides by giving patient N-methyl D-aspartic acid (NMDA) receptor antagonist and MAO inhibitor (referring to " MAOi ") or GAPDH mediation (refers to " GAPDHai; (for example; selegiline (selegiline) and Lei Sajilan (rasagiline)) combination; treatment CNS-relevant disease is as the compositions and the method for parkinson disease and Alzheimer.Bonded treatment described here can slow down or prevent CNS-relevant disease or dull-witted relevant or by it symptom that causes, for example, and disppointment, loss of balance, hallucination, depression, illusion, excitement, depression, communication disorder, cognitive disappearance, personality change, entanglement, and insomnia.
Exist or do not exist mediation to discharge under the situation of composition, nmda receptor antagonist, MAO inhibitor or GAPDHai, or two kinds of medicines can be prepared into controlled slow release form, thus obtain maximum curative effect and reduce adverse side effect.In a word, this type produced the more stable C ratio (Cratio) as time function, and wherein the C ratio is represented the concentration ratio measured between two kinds of active component.When relating to a kind of medicine, term " C " refers to the drug level in the patient's sample (for example, blood, serum, cerebrospinal fluid) at any time.Like this, a kind of " C average (Cmean) " of medicine referred in a period of time, by the mean concentration of this medicine in patient's sample of any standard method mensuration in this area." C maximum (Cmax) " of medicine refers to the Cmax of this medicine that any time records in the regulation time limit.In a word, this type produced the more stable Cratio as time function, and wherein Cratio represents the concentration ratio measured between two kinds of active component.Like this, the Cratio that nmda receptor antagonist and MAO inhibitor or GAPDHai are relevant is between 0.4-2.5.
In the preferred embodiments of the invention, after administration 1 hour, be less than 50% nmda receptor antagonist, MAO or GAPDHai, or the both is transported into circulation or nervous system.Ingredient can be prepared into be suitable for oral, topical transdermal, subcutaneous, intravenous, nasal cavity, or the transporting pattern that sucks.At random, ingredient can be prepared into suspension, capsule, tablet, suppository, lotion, sheet, or device (for example acceptable conveyer device of subcutaneous transplantation or suction pump).
Though the method and composition among the present invention can use any nothing-malicious nmda receptor antagonist, but lower and nmda receptor antagonist medium affinity be more suitable for (see, for example, Parsons et al., Neuropharmacology 34:1239-58,1995).The toxicity of these nmda receptor antagonists obviously reduces than high affine nmda receptor antagonist tool, and this toxicity arrives or can show its spiritual side effect during near therapeutic dose.Like this, nmda receptor antagonist can be, for example, the aminoadamantine derivatives comprises Memantine hydrochloride (1-amino-3,5-dialkyl group diamantane (obsolete)), rimantadine (1-(1-amino-ethyl) diamantane (obsolete)), or Buddha's warrior attendant (alkane) amine (1-amino-ethyl-diamantane (obsolete)).MAO inhibitor or GAPDHai suppress to choose the apoptotic drug categories from having shown, comprise that those are considered to similar with the effect of MOA mortifier, free radical scavenger or tool demonstration can suppress the medicine of GAPDH mediating apoptosis and (see, for example, Chuang et al., Annual Review of Pharmacology andToxicology, 45:269-290,2004), comprise L-deprenyl/SELEGILINE
TM, desmethyldeprenyl, N-propargyl-I (R)-aminoindan/Rasagaline
TM, phenelzine/NARDILTM, tranycypromine/PARNATE
TM, CGP3466, Furazolidone, Isocarboxazid/MARPLAN (Oxford Pharm), Pargyline HCl, Pargyline HCl and methyclothiazide, ProcarbazineHCl/Matulane (Sigma Tan).By injectivity optimizing being provided or discharging regulation and control, be the difference part of the present invention and previous research to reduce the relevant side effect of every kind of medicine.
In some embodiment, the nmda receptor antagonist that gives patient can be equal to for medication amount, or is less than the nmda receptor antagonist that typically gives patient and gives medication amount.For example, with typical non-slow release or do not have MAOi or active situation following every day of the 10-20mg of GAPDHai dosage is compared, the Memantine hydrochloride dosage that causes patient's effecting reaction (comprising side effect) is 2.5-40mg every day.Similarly, in some embodiment, the dosage that gives patient MAOi or GAPDHai to be less than ought not exist control or delay to discharge and the nmda receptor antagonist situation under in order to obtain MAOi or the GAPDHai dosage that the identical therapeutic effect at the CNS-relevant disease gives patient.Certainly, in some embodiment, the dosage of uniting use nmda receptor antagonist and MAOi or GAPDHai is less than it and divides other independent use amount, and has similar or higher curative effect.These effects may be additional or synergic, as described below.
In some embodiment, with respect to not existing discharging, mode of administration control and the nmda receptor antagonist situation under the MAOi that gives or the dosage of GAPDHai, the dosage that gives patient's MAOi or GAPDHai can be higher.In some embodiment, with respect to not existing discharging, mode of administration control and the situation of MAOi or GAPDHai under the nmda receptor antagonist dosage that gives, the dosage that gives patient's nmda receptor antagonist can be higher.In preferred embodiments, nmda antagonist and MAOi or GAPDHai can be mixed into single compositions and be prepared into orally, and form is received in tablet or saturating snuffing.
Alternatively, at one hour, two hours, three hours, six hours, 12 hours, or in the twenty four hours, two kinds of medicines can be respectively carried in succession with form independently.If respectively administration, two kinds of medicines can be with identical or different administrations, and by one day three times, one day twice, once a day, or two days single administrations.
Unless otherwise defined, all technology used herein and scientific terminology are same as the meaning that the those of ordinary skill in the affiliated field of the present invention is recognized altogether.Though can be used for practice of the present invention or test with similar or identical method and material described here, suitable method and material are as described below.All publications, patent application, patent, the list of references of other citation is all by all being incorporated in text in this citation.If conflict is arranged, will comprise that definitional part is as the criterion with this description.In addition, material, method, and embodiment is only as illustration and non-limiting.Unless otherwise defined, all distributions and percent are all according to itemize of weight.
Other characteristics of this method and advantage will embody in following detailed description and claim.
Description of drawings
Fig. 1 has shown the result who reduces as dC/dt, the sketch map that the nmda receptor antagonist regulation and control discharge.
Fig. 2 A-2C the has been series of displays release characteristic of chemical compound of modulated release and the sketch map of Cratio.
Fig. 3 A and 3B are the comparison sketch map that regulation and control in 12 hours in advance discharge and regulation and control in 24 hours in advance discharge.
The specific embodiment
The invention provides treatment or prevent the CNS-relevant disease, as parkinson disease, the method and composition of Alzheimer.The apoptosis mortifier of--nmda receptor antagonist and second kind of composition---MAO mortifier or GAPDH mediation that this combination comprises first kind of composition.Give the treatment of this combination, thereby reduce or prevent symptom, or alternatively, slow down the development of CNS-relevant disease.Ideally, a kind of in these two kinds of medicines, or two kinds, be prepared to the slow release form, thereby in desired period, provide a kind of for treatment sufficiently high concentration of effect and suitable concentration rate, but for preventing that its level is enough low for the multilevel excessively side effect that causes of any ingredient among the patient.
The effect of glutamate, Glu in nervous disorder
Excitatory amino acid receptor is the topmost mediation person of excited synapse conduction (for example, neural stimulation) in the brain, participate in normal and improper central nervous system (CNS) function various aspects.Main excited receptor, calcium (Ca2+) the permeability ion channel that N-methyl D-aspartic acid (NMDA) receptor is relevant with it be by glutamate, Glu and its common-the activation glycine is activated.It is that potentiation in length-period (learning and memory is relevant) is necessary that nmda receptor Ca2+ active and subsequently flows into.
Unusual glutamate receptor activity is associated with a large amount of nerve degeneration situation.In this relation, may can cause the continuous activity (continuing several minutes usually but not millisecond) of acceptor ions passage, thereby Ca2+ is risen because glutamate, Glu rising level causes improper nmda receptor activity.Too much Ca2+ flows into the increase that causes intracellular reactive NO usually, the increase of free radical, and the decay of cell-cell-cell communication, the excessive release of excitatory amino acid, contiguous neuronic incorrect stimulation causes cell death (apoptosis) at last.Like this, the strategy that reduces the excited poison of glutamate, Glu mediation is necessary, and particularly those can suppress the result of overstimulation and keep the active strategy of normal glutamate, Glu.
Nmda receptor antagonist
Specific nmda receptor antagonist has the active ability of high-level glutamate, Glu of weakening and does not influence normal glutamate activity in the brain not conversely.Wherein most owing to be called as nocompetitive antagonist with Ca2+ passage interaction under open state.Wherein safest form (for example, Memantine hydrochloride, (memantine)) role is in some sense for stopping up and leave fast passage.These medicines have good systemic security of system characteristic, have quite accurate sphere of action.
MOA mortifier and GAPDHai
The known specific active medicine of adjusting MOA, and other have shown the apoptosis inhibitory action or have shown that the inhibiting medicine of apoptosis of GAPDH mediation is a theme of the present invention by removing free radical.A kind of member of this apoplexy due to endogenous wind is selegiline (deprenyl)/Selegiline
TM, it is considered to threaten neuronic free radical to generate by inhibition, reduces apoptotic danger thereby weaken the oxidation load, and the GAPDH transfer of inhibition trigger cell apoptosis enters in the nucleus.These medicines have shown good living features, thereby but are subjected to its toxicity and have limited it with the reciprocal action of food and used.Instead-chain oligonucleotide and RNAi oligonucleotide since its obvious regulating power also as the other drug of theme of the present invention.
Unique joint effect
One aspect of the present invention is that these medication preparation are become certain form, has enough associating active effects and reduces side effect.Obtain ratio between appropriate ingredients by new synergism between these pharmaceutically active mechanism in this case.Specific nmda receptor antagonist can stop unnecessary Ca2+ effectively, thereby alleviates apoptosis by destructiveness that reduces free radical in the cell and the effect that may reduce intracellular reactive NO kind.We have found that the mechanism that reduces the level of Ca2+ in the cell by specific MAO mortifier and GAPDHais and specific nmda receptor antagonist synergism.The apoptotic mortifier of these MAO or GAPDH mediation stops in the Cytoplasm GAPDH to enter nucleus by nuclear membrane to transport/translate.Like this, chemical compound of the present invention can carry out two at identical biological approach-directly interfere, and it has that expect and synergic effect in patient.
The quantity of nmda receptor antagonist and MAO mortifier or GAPDHai and ratio can be various, and its treatment effect maximization and toxicity or safety issue are minimized.In specific embodiments, nmda receptor antagonist can change in 20% to 100% scope by its normal dose, and MAO mortifier or GAPDHai can change in 20% to 100% scope by its normal dose.Ratio will be according to the situation change of treatment accurately.In specific embodiments, the dosage of Memantine hydrochloride can for every day 2.5 to 40mg, and 1-selegiline dosage is 1 to 10mg/ day.
The advantage of this form
Specific nmda receptor antagonist, as Memantine hydrochloride, its penetrable blood-brain barrier can have similar concentration in the serum of the extracellular of cerebral tissue body fluid and whole body.Ideally, nmda receptor antagonist should exist with certain concentration, reduces the symptom of disease and does not cause debilitating side effect.Yet under present dosage form, these medicines, some of them have the quite long half-life, predose progressively need be upgraded or " titration " side effect to prevent that initial administration is relevant.This causes being difficult to the patient compliance that reaches appropriate, and the medication amount program of giving that is used for the treatment of the complexity of regulating nerve or neuropsychiatric disease (neuropyschiatric) will further make its deterioration.
Therefore, need design drug release especially, reduce and delay the plasma peaks level, and do not influence the scope of validity of medicine with control.When usually relevant with rapid releasing pattern weak side effect is in the drug level that will obtain medical treatment when minimum.In addition, be the result that the serum peak value on the serum levels that obtains to have curative effect and potential lag phase carry out slow release, administration frequency will be reduced to usually, for example, be administered once every day or twice, thereby improve patient's adaptability and patience.
Correspondingly, the present invention with nmda receptor antagonist and MAO mortifier or GAPDHai combination medicine-feeding to improve curative effect and to prevent the side effect of two kinds of non-expectations in the medicine.For example, can be by using the treatment of release-control method and synergistic combinations, it has all embodied aspect of the present invention, makes to comprise that spirit relevant with the nmda receptor antagonist medication and the side effect of cognitive disappearance reduce to some extent on severity and occurrence frequency.And, the side effect relevant with using MAO mortifier or GAPDHai reduced on severity and frequency to some extent.In addition, the control-release of the active pharmaceutical ingredient of this form can obtain that continue and activity component concentration ratio the best during the Cmax/Cmean eigenvalue expected during the administration and the treatment.
The pattern of administration
Chemical compound of the present invention can be with part or whole body form, or supply or sustained release form administration.In the embodiment of first-selection, nmda receptor antagonist, MAO mortifier or GAPDHai, or two kinds of medicines can be prepared to controlled, slow release form (as described here).For example, the controlled release nmda receptor antagonist is provided, MAO mortifier or GAPDHai, or its both ingredient can make up and be produced with desired medicine or the medicine with one or more extra compositions, when to patient's administration, corresponding medicine is discharged in special time period with targeted rate.These medicines can be by oral, transdermal or intranasal administration.
Aptly, these two kinds of compositions are to provide the form administration of desired effects, and this effect is derived from first kind and second kind of composition in the chemical compound.Alternatively, before entering in the patient body, first kind and second kind of medicine be mixed into a kind of single form.This combination can be easily finished by inferior-unit dose of being separated into first kind and the second kind medicine that comprises suitable quantity.Unit dosage form can be, for example, and a kind of capsule or tablet, or contain this parcel form of a little compositions of suitable quantity.The quality of active component can change according to the special requirement of the situation of being treated or adjust in the unit dosage form.
Alternatively, can get along well MAO mortifier or GAPDHai of the nmda receptor antagonist in the compositions mixes, in they enter the patient body.Like this, term " compositions " has comprised nmda receptor antagonist and MAO mortifier or GAPDHai to be prepared into the isolating form and the form of administration respectively.For example, nmda receptor antagonist and MAO mortifier or GAPDHai can be at two days, and one day, 18 hours, 12 hours, 1 hour, half an hour, 15 minutes, or administration respectively in the shorter time.Every kind of medicine can be by multiple, single capsule or tablet are distinguished administration to patient.Alternatively, nmda receptor antagonist and MAO mortifier or GAPDHai can exist with unpack format in pharmaceutical composition, and they do not mix before in pharmaceutical composition enters the patient body.Mixing can occur in before patient's administration.
As needs, nmda receptor antagonist and MAO mortifier or GAPDHai can unite the other treatment form administration, as, medicine, surgery, or other interfere Therapeutic Method.When unite comprised non--during Drug therapy, as long as can obtain the associating-effect curative effect of compositions and other treatment form, non--Drug therapy can be operated in any suitable time.For example, in appropriate circumstances, when after giving medicine, temporarily removing non--Drug therapy a couple of days even a few weeks longer, still can obtain useful effect.
The nmda receptor antagonist composition
Usually, as long as it is avirulent when using in compositions, any nontoxic nmda receptor antagonist can use in method and composition of the present invention.Term " avirulence " uses by a kind of relative understanding, and it means and anyly be used for human body therapy by U.S. food Drug Administration (" FDA ") approval, or is still setting up adjustment standard and operation, allows to be used for the material of human body administration through FDA.
Desirably, nmda receptor antagonist is a kind of aminoadamantan chemical compound.Suitable aminoadamantan chemical compound is known in this field, for example, and Memantine hydrochloride (1-amino-3,5-dialkyl group diamantane (obsolete)), rimantadine (1-(amino-ethyl) diamantane (obsolete)), Buddha's warrior attendant (alkane) amine (1-amino-ethyl-diamantane (obsolete)), and drug acceptable salt.Memantine hydrochloride is at United States Patent (USP) 3,391, describes to some extent in 142,5,891,885,5,919,826,6,187,338.Buddha's warrior attendant (alkane) amine is at United States Patent (USP) 3,152, describes to some extent in 180,5,891,885,5,919,826,6,187,338.At United States Patent (USP) 4,346, extra aminoadamantane chemical compound has been described in 112,5,061,703,5,334,618,6,444,702,6,620,845,6,662,845.All these patents are by all being incorporated in text in this citation.
If needed, nmda receptor antagonist can comprise one or more aminoadamantan chemical compounds, and it is avirulent when using as the part in the compositions.Correspondingly, the aminoadamantan chemical compound when with compositions in second kind of medicine be avirulent when using jointly, it then is deleterious giving patient's aminoadamantan chemical compound during second kind of medicine in the disappearance compositions.Term " avirulence " uses by a kind of relative understanding, and it means and anyly be used for human body therapy by U.S. food Drug Administration (" FDA ") approval, or is still setting up adjustment standard and operation, allows to be used for the material of human body administration through FDA.
More nmda receptor antagonist comprises, for example, restrains his life, eliprodil, ifenprodil, two Suo Xiping, remacemide, lamotrigine, riluzole, Ah Ti adds naphthalene, phencyclidine, fluorine pyridine, selfotel, non-ammonia ester, spermine spermidine, assistant emopamil, dextromethorphan ((+)-3-hydroxy-n-methylmorphinan) and its metabolite, dextromethorphan ((+)-3-hydroxy-n-methylmorphinan) drug acceptable salt or ester, or any above-mentioned metabolic precursor thereof.
When nmda receptor antagonist is provided, nmda receptor antagonist enters about 2 to 8 hours of the interior back of patient body, and it is about 2 ratio release with the Cmax/Cmean value.Pharmaceutical composition can be prepared into a kind of form, and the Memantine hydrochloride that shows quantity in the example 4 is provided, and can be 1 to 80mg/ day, and 5 to 40mg/ days, or 10 to 20mg/ days; The consumption of amantadine is 25 to 500mg/ days, 25 to 300mg/ days, or 100 to 300mg/ days; The dextromethorphan consumption is 1 to 5000mg/ day, 1 to 1000mg/ day, and 100 to 800mg/ days, or 200 to 500mg/ days.Child dose should be lower than adult's using dosage.
The medicine of selected NMDAr antagonist is for kinetics in table 1. mankind and the rat
| Chemical compound | Human PK | List of references |
| Memantine hydrochloride | 56 hours | Namenda NDA submission 21-487 |
| Rimantadine | 25 hours | Chladek et al，In.J.Clin Pharm 39：179-184 |
| Amantadine | 16 hours | Aoki，et al.Clin Pharm.26：729-736 (1979) |
Second kind of ingredient: the apoptotic mortifier of MAO mortifier or GAPDH mediation
Suitable MAO mortifier or GAPDHai comprise, for example, and L-selegiline/SELEGILINE
TM, nor-selegiline, N-propilolic alcohol-I (R)-aminoidan/Rasagaline
TM, nor-selegiline, phenelzine/NARDILTM
TM, tranylcypromine/PARNATE
TM, CGP3466, furazolidone, isocarboxazid/MARPLAN (Oxford Pharm), pargyline, pargyline and methyclothiazide, procarbazine hydrochloride/Matulane (Sigma Tan).[come from above-mentioned TF and insert tabulation], the antisense strand of GAPDH or RNAis.
The dosage of MAO mortifier or GAPDHai depends on the specific medicine of use in the compositions, shown in following example 4, typically is 1mg/ days to 200mg/ days.For example, the L-selegiline in the compositions can be 1 to 10mg/ day in the adult, and Lei Sajilan is 1 to 20mg/ day.Anti--apoptosis dosage can be lower than these typical use amounts.Child dose should be lower than adult's using dosage.
The medicine of selected MAO mortifier/GAPDHai is for kinetics in table 2. mankind and the rat
| Chemical compound | Human PK | List of references |
| Selegiline/selegiline | 1.5-8.6 hour | Barret et al.，Am.J.of Ther.，m 4：298-313，1996 |
| Nor-selegiline | 3.8-9.5 hour | Barret et al.，Am.J.of Ther.，m 4：298-313，1996 |
| N-propilolic alcohol-1 (R)-aminoidan/Lei Sajilan | 1.8 hour | Stern et al.，Movement Disorders，19：916-923，2004 |
In representative embodiment, when (for example giving main body, a kind of mammal such as the mankind) nmda receptor antagonist in when treatment at least 50% provides with the sustained-release dosage form, and in about 2 to 8 hours or longer time, the Cmax/Cmean value of nmda receptor antagonist is about 1.5 after the administration.As through the design, the release of nmda receptor antagonist can be monophasic or heterogenetic (for example, biphase).In addition, MAO mortifier or GAPDHai can be prepared into the slow release form, after administration about 2 to 8 hours or the longer time in its Cmax/Cmean value be about 2.In addition, the sustained release form can cause its initial Concentraton gradient (dC/dt) to be less than releasing pattern immediately, and 90% less than releasing pattern (see figure 1) immediately aptly.
The optimal proportion of composition
Except that the specific combination of narration here, compositions by first kind of aminoadamantan chemical compound and MAO mortifier or GAPDHai preparation, can be identified by the ability that the compositions of selected aminoadamantan chemical compound and MAO mortifier or GAPDHai preparation weakens dementia-relevant disease (for example, parkinson disease and Alzheimer) symptom by test.Described the embodiment that selects this ratio in the example 1, wherein the best of two kinds of compositions associating ratio is tested by extracorporeal neuron, or the body inner model in the example 2 is assessed.Compare with the same dose of MAO mortifier or GAPDHai with independently measuring the required nmda receptor antagonist of the identical curative effect of acquisition respectively, suitable compositions is those nmda receptor antagonist and MAO mortifier or GAPDHai of having improved curative effect or having obtained the some of lower treatment side effect.The curative effect by here we obtained enhanced at the curative effect of disease or symptom and/or the side effect of minimizing.
For each medicine, dosage is an important factor for the success of treatment and patient's health.In any case, at particular range, the doctor will be according to patient's sex, age, body weight, pathology stage and the best dosage of other parameters decision.In some cases, may need to give patient with the dosage that exceeds the drug packages scope.These situations are tangible for medicine teacher and veterinary.
The form that is used for special route of administration
Combination can provide with pharmaceutical composition, and it is best for special conveying type.For example, be used for oral pharmaceutical composition and can accept preparing carriers with this field known drug.Can the medication preparation in the compositions be become with carrier, for example, tablet, pill, capsule, solution, suspension, sustained release form; The powder of patient's orally ingestible, liquid or gel.
Alternatively, the compositions among the present invention can be passed through many tactful transdermal administrations, comprises those at United States Patent (USP) 5,186,938,6,183,770,4,186,800 and WO89/09051 in the method narrated.The benefit that compositions is modified is that these two kinds of peak values all have quite high percutaneous permeability, side effect and pharmacokinetics variability then with MAO mortifier, selegiline selegiline
TMFirst metabolite relevant.
The pharmaceutical composition that contains second kind of medicine in nmda receptor antagonist and/or the compositions can be by pressure bottle, the aerosol drug delivery that aerosol apparatus or Diskus form.The suitable propelling material that is used for aerosol apparatus comprises, for example, and dichloro two fluoro-methane, trichlorine fluomethane, dichlorotetra-fluoroethane and carbon dioxide.Dosage can determine by valve is provided, thus the pressurised aerosol compositions of conveying some.
Suction or sprayed composition comprise acceptable water of medicine or organic phase solution, or dissolved solution of its mixed liquor or suspension, or powder.The liquid or solid compositions can comprise above-mentioned suitable medicine can accept excipient.Aptly, compositions is by oral, and intranasal or respiratory tract administration are brought into play part or systemic effect.Aptly, the compositions in the aseptic medicine acceptable solvent can be sprayed with noble gas.The vaporific solution that derives from sprayer unit can directly suck, or sprayer unit can with a kind of mask, cover or intermittent positive pressure breath device link to each other.Derive from the solution with the suitable method conveying of device, suspension or powder composition can pass through oral or nasal-cavity administration aptly.
In certain embodiments, for example, compare with inhalation, compositions can be carried by saturating nose and be arrived cribriform plate, can active medicine is conveyed into CNS and simplify whole body therapeutic by the olfactory sensation path.The device that is generally used for this route of administration comprises United States Patent (USP) 6,715,485.The compositions of carrying by this approach can increase the dosage among the CNS or reduce body burden, reduces the general toxicity relevant with certain drug and threatens.
The additional form that is suitable for other administration route comprises rectum capsule or stype.For stype, traditional set thing and carrier can comprise, for example, and poly alkylene glycol or triglyceride; These stypes can be become by preparation of compositions, and the active component scope that it comprises is 0.5% to 10%, aptly 1%-2%.
Combination can be the container transport form selectively, and continuous long-term delivery is provided, and for example, the conveying phase is 30 days, 60 days, and 90 days, 180 days, or 1 year.Container can be prepared from for the material such as the titanium of biological adaptation.The long-term delivery form is very useful for the patient of chronic disease, guarantees to have improved patient compliance, and increases the stability of compositions.The long-term delivery form is seen continuously, for example, and United States Patent (USP) 6,797,283,6,764,697,6,635,268,6,648,083.
As needs, these compositions can provide with kit form.Test kit can additionally comprise the description of using test kit.In certain embodiments, test kit comprises one or more containers that contain nmda receptor antagonist, and, independently, contain one or more containers of MAO mortifier or GAPDHai.In another embodiment, test kit provides the one or more containers that mixed nmda receptor antagonist and MAO mortifier or GAPDHai.Test kit has comprised the therapeutic effective dose of medicine thing of treatment dementia-relevant disease.
Oral control-releasing pattern
As mentioned above, nmda receptor antagonist, MAO mortifier or GAPDHai, or these two kinds of medicines can be with what control, and the slow release form provides.In one embodiment, at least 50%, 90%, 95%, 96%, 97%, 98%, 99%, or even over-drastic 99%
0Nmda receptor antagonist in the sustained-release dosage form, be provided.Release characteristics, for example, the release scope of nmda receptor antagonist and MAO mortifier or GAPDHai in expeced time, Cmax/Cmean value that can be by calculating special time in the scope in preset time process is easily measured.Like this, to main body (for example, a kind of mammal such as the mankind) administration the time, the Cmax/Cmean of the nmda receptor antagonist after administration between about 1,1.5,2 hours to 6,8,9,12,18,21,24 hours is about 2.5,2,1.5,1.0.As through the design, the release of nmda receptor antagonist can be monophasic or heterogenetic (for example, biphase).In addition, MAO mortifier or GAPDHai can be prepared into the slow releasing composition form, and the Cmax/Cmean after administration in about 1,1.5,2 hours to 6,8,9,12,18,21,24 hours is about 2.5,2,1.5,1.0.The personnel that have ordinary skill in this field can have the compositions of expectation release characteristics with nmda receptor antagonist and MAO mortifier or GAPDHai and following preparation method preparation.
As shown in table 2, the pharmacokinetic properties of each medicine of these kinds apoplexy due to endogenous wind changes in 3 hours to 60 hours scope.Like this, one aspect of the present invention is to select suitable form to make and obtain near stable concentration characteristic in period (being desirably 2 to 24 hours) widely, thereby keeps two kinds of constant ratios of composition to reach the optimum treatment effect.After administration, in about 1,1.5,2 hours to 6,8,9,12,18,21,24 hours, suit at 0.4 to 2.5 CRATIO.Carry this constantly, the form of the characteristic that can survey is one embodiment of the invention.The big metering method that obtains the expectation release characteristics is as described below.
The suitable method of preparation compositions, first kind of composition wherein, composition in second, or two kinds of compositions provide with slow release-form, have comprised United States Patent (USP) 4,606, the method described in 909 (by the full content of this patent being incorporated in this paper) in this citation.This list of references has been described the multiple unit form of a kind of sustained release, when this form (for example, pill or tablet) (is seen, for example during in the total disintegrate of animal stomach, 3 row, 26 row, 5 row, 10 row, 6 row, 29 row 9 row, 16 row), can form the independent packaging or the microcapsule unit of various ways.Each individual packages or microcapsule unit part-crosslinked abundant homology nuclear wherein comprises conservatively solvable active substance microgranule, this nuclear quilt can fully be resisted the stomach environment and can be in the small intestinal environment cracked wrappage packaging.
Alternatively, compositions can prepare with the method that United States Patent (USP) 4,769,027 is described.Correspondingly, comprise medicine acceptable material (for example, sugar/starch, salt, wax) the slow release form of microgranule can be wrapped up with the penetrating capable polymer matrix of the water that contains nmda receptor antagonist, and water-penetrating film further wraps up formation dispersible water-soluble special nucleus formation material.
One or both compositions in the compositions can be extraly according to United States Patent (USP) 4,897, and the method preparation of describing in 268 has comprised that a kind of biology is acceptable, biodegradable microcapsule induction system.Like this, nmda receptor antagonist can be prepared into a kind of composition forms, it comprises the compositions of the three-Tong spherical particle that obtains by the microcapsule of individually Memantine hydrochloride of some being packed into, for example, pack into the different copolymer thing excipient of friction speed degraded, enter blood circulation thereby discharge Memantine hydrochloride with predefined speed.This microgranule of some can be this analog copolymer excipient, and wherein the nuclear activity composition discharges after administration at once, thereby at initial time conveying active.The microgranule of second level some is such excipient, its ingredient that bull ladle wraps after medicine that first order quantity is carried begins to descend.The composition of third level quantity can wrap up with different excipient, and it has caused beginning to carry after the medicine that second level quantity is carried begins to descend.The speed of carrying can change, for example, and the ratio of lactide/glycolides in poly-by changing (D, L-lactide-co-glycolide) packing.Other operable polymers comprise polymethanal polymer, poly-former phosphide, polyesteramide, polycaprolactone and its copolymer, Merlon, polyhydroxybuterate and its copolymer, polymaleamides, copolyaxalates and polysaccharide.
Alternatively, compositions can be by United States Patent (USP) 5,395, the method preparation of describing in 626, and be feature with multilamellar sustained release pharmaceutical dosage forms.Dosage form comprises the parcel microgranule of purification, wherein every kind has multilamellar and a nuclear that contains nmda receptor antagonist and/or MAO mortifier or GAPDHai, make medicine contain nuclear and the controlled release barrier layer parcel of at least a other drug active component aspect, thereby make multilamellar parcel microgranule that the sustained release layer of at least two kinds of water soluble drugs is provided.
In certain embodiments, composition can be prepared into single or isolating pharmaceutical composition in first kind of composition of compositions described here and second." medicine or pharmacology can be accepted " comprise when to animal, or human administration is not have side effects, the molecular entity and the compositions of irritated or other untoward reaction." medicine acceptable carrier " comprises any and all solvents, dispersant, and wrappage, antibiotic and antifungal drug wait to blend to absorb to delay medicine and analog.The use in keeping pharmaceutically active of these media and medicine is well known in the art.Except any and inconsistent conventional media of active component or medicine scope, its effect in therapeutic composition is expected.Auxiliary active component also can be integrated in the compositions." the acceptable salt of medicine " comprises acid group salt, and it is formed by inorganic salt, for example, and hydrochloric acid or phosphoric acid, or organic acid such as acetic acid, oxalic acid, tartaric acid, phenylglycolic acid, and analog.The salt that is formed by the free carboxyl group group also can derive from inorganic group, for example, and sodium, potassium, ammonium, or hydrated ferric oxide. and organic group such as 2-aminopropane., trimethylamine, histidine, procaine and analog.
According to present discovery, preparation medicine or pharmacology method for compositions are known for those those of skill in the art.The preparation and the common technology of administration are seen " Remington:The Science and Practice of Pharmacy, TwentiethEdition, " Lippincott Williams﹠amp; Wilkins, Philadelphia, PA.Tablet, capsule, powder, granule, dragee, gel, slurry, ointment, solution suppository, injection, inhalant and aerosol are the embodiment of these forms.
Use method for example, the release oral form can prepare with other method as known in the art.For example, divide the suitable slow release form of other or common active pharmaceutical ingredient can be module tablet compositions.Appropriate module forms material and comprises, for example, and wax (for example, Brazil wax, Cera Flava, paraffin, ceresine, lacca, fatty acid, and aliphatic alcohol), oil, hard oil or fat are (for example, the hard oil Oleum Brassicae campestris, Oleum Ricini, Adeps Bovis seu Bubali, Petiolus Trachycarpi oil, and soybean oil), reach polymer (for example, hydroxy propyl cellulose, polyvinylpyrrolidone, HYDROXY PROPYL METHYLCELLULOSE, and Polyethylene Glycol).It is microcrystalline Cellulose that other appropriate module prepare material, cellulose powder, hydroxy propyl cellulose, ethane cellulose, other carriers, and implant.Tablet also can comprise granule, the powder of parcel, or bead.Tablet also can be many-layer.The tablet of many-layer is particularly suitable for the active component that obviously has different pharmacokinetic properties.Alternatively, last tablet can be parcel or non-parcel.
The parcel compositions typically comprises a kind of non-soluble module polymer (accounting for the 15-85% of parcel composition weight greatly) and a kind of water-soluble material (accounting for the 15-85% of parcel composition weight greatly).Alternatively, a kind of intestinal polymer (accounting for the 1-99% of parcel composition weight greatly) also can use or comprise wherein.Suitable water-soluble substance comprises polymer such as Polyethylene Glycol, hydroxy propyl cellulose, HYDROXY PROPYL METHYLCELLULOSE, polyvinylpyrrolidone, polyvinyl alcohol, low molecular weight material is as sugar (for example, lactose, sucrose, fructose, mannitol and analog), salt (for example, sodium chloride, potassium chloride and analog), organic acid (for example, fumaric acid, succinic acid, lactic acid, tartaric acid) and its compositions.Suitable intestinal polymer comprises HYDROXY PROPYL METHYLCELLULOSE, acetate succinate, HYDROXY PROPYL METHYLCELLULOSE, phthalate, polyvinyl acetate phthalate, cellulose ethylene phthalate, cellulose ethylene three mellites, lacca, zein and contain the polymethacrylates of carboxyl.
Characteristic according to the parcel barrier is wrapped up the main component of compositions or the glass conduction temperature of blending constituent or solvent as being used to, and the compositions of parcel can be a plasticizer.Suitable plasticizer can be added to the 0-50% of parcel composition weight, and comprises, for example, and diethyl phthalate, citrate, Polyethylene Glycol, glycerol, aceto-glyceride, dibutyl sebacate, Oleum Ricini.As through design, wrap up compositions and can comprise a kind of fill.According to the gross weight of parcel compositions, the quantity of fill can be for accounting for 1% to 99% of weight, and can be insoluble material such as silicon dioxide, titanium dioxide, Talcum, china clay, aluminium oxide, starch, cellulose powder, MCC, or polacrilin potassium.
The parcel compositions can be used as solution or emulsion in organic solvent or inorganic solvent or its compositions.If solution application, according to the gross weight of dissolved solid thing, solvent will account for the 25-99% of weight.Suitable solvent is a water, low-concentration ethanol, low concentration chlorinated hydrocarbon, ketone, or its compositions.If the application emulsion, according to the quantity of polymeric material in the emulsion, solvent will account for the 25-97% of weight.Main solvent is a water.
Pharmaceutical composition described here also can comprise a kind of carrier, as solvent, and dispersant, coating agent, antibiotic and antifungal drug wait to blend to absorb to delay medicine.The use in pharmaceutically active substance of these media and medicine is known in the art.The acceptable salt of medicine also can be used for said composition, for example, mineral salt such as hydrogen chlorate, hydrobromate, phosphate, or sulfate also can be acylate such as acetate, proprionates, malonic acid, or benzoate.Compositions also can comprise liquid, as water, and saline solution, glycerol, ethanol also can be wetting agent, emulsifying agent, or pH buffer.Liposome, as United States Patent (USP) 5,422,120, WO 95/13796, and WO 91/14445, or described in the EP 524968B1, also can be used as carrier.
The additive method of preparation sustained release form sees, for example, United States Patent (USP) 5,422,123,5,601,845,5,912,013,6,194,000, these lists of references are by all being incorporated in text in this citation.
Non-oral form
Prepare and carry the method for Transdermal absorption small pieces to be well known in the art, comprise following narration, for example, United States Patent (USP) 5,186,938 and 6,183,770,4,861,800,4,284,444.Owing to many MAO mortifiers, comprise the metabolic problems of the phase I of L-deprenyl, small pieces are useful especially in this case.Small pieces can be controlled the release of skin-osmotically active composition, and the persistent period is 12 hours, and 24 hours, 3 days, 7 days.In one embodiment, 2-doubly to day use amount nmda receptor antagonist inserted in non--volatilised liq with MAO mortifier or GAPDHai.According to the medication amount of testing, can in 12 to 72 hours, carry out suitable release here.
The transdermal prepared product of this form contains 1% to 50% active component.Compositions among the present invention is with stickiness, and non--volatilised liq form provides.Aptly, two kinds of compositions in the compositions have at least 10
-9Mole/cm
2/ hour infiltration rate.At least the active material of % will hour in infiltrate skin.The Transdermal absorption of particular form can be measured (for example, Franz et al., J.Invest.Derm.64:194-195 (1975)) by the method for standard in this area.
In certain embodiments, for example, compositions can be carried by saturating nose and be arrived cribriform plate, can active medicine is conveyed into CNS and simplify whole body therapeutic by the olfactory sensation path.The device that is generally used for this route of administration is included in United States Patent (USP) 6,715,485.The compositions of carrying by this approach can increase the dosage among the CNS or reduce body burden, reduces the general toxicity relevant with certain drug and threatens.
Preparation is well known in the art with the method for the pharmaceutical composition that transdermal device is carried, and is as described below, United States Patent (USP) 3,992,518; 5,660,848; 5756115.
Be suitable for the symptom that this compositions is treated
Any patient who has or be in dementia-relevant disease as parkinson disease and Alzheimer, can treat with the compositions and the method for narration here.Neuron-the relevant disease for the treatment of according to the present invention is the tremulous pulse dementia, senile Alzheimer type dementia, little cognitive sick damage of level, Lewy health dementia, Huntington ' s disease dementia, Pick ' s disease, PrPC disease-relevant dull-witted, HIV-is relevant dull-witted, volume temporo page or leaf dementia, hippocampal sclerosis-relevant dull-witted, encephalopathy-relevant disease, relevant with deterioration of neurons dull-witted, comprise neural demyelination (for example, multiple sclerosis (MS), multiple leukoencephalopathy (PML), disseminated necrotizing leukoencephalopathy (DNL), acute disseminated encephalomyelitis, schilder disease, central pontine myelinolysis (CPM), radionecrosis, Binswanger disease (SAE), Guillain-Barre syndrome, the brain protein malnutrition, acute disseminated encephalomyelitis (ADEM) acute transverse myelitis, acute viral encephalitis, adrenal gland's brain protein malnutrition (ALD), adrenomyeloneuropathy, AIDS-cavity myelopathy, experimental allergy myelitis (EAE), experimental autoimmune neuritis (EAN), the myelopathy that HTLV-is relevant, Leber ' s hereditary optic atrophy, subacute sclerosing panencephalitis and tropical lower limb spastic paralysis, Parkinson ' s disease, the Alzheimer disease, first malicious body-relevant disease, psychataxia is (for example, emotion, depression, worry is prevented the disappearance imbalance, autism, obstacle is done all one can in behavior/dystaxia, drinking and eating irregularly, fetal alcohol symdrome, learning capacity is lost, and intelligence delays, emotional maladjustment, speech and language, drug dependence is committed suiside, Tourette's syndrome (Tourette ' s disorder), with the posttraumatic stress disorder syndrome, shock and spastic imbalance (for example, epilepsy), pain is (for example, maincenter and periphery, comprise acute, chronic with neuropathic), migraine and acute inhibition nervous disorder such as wound and strike.Any situation can be treated with method and composition described here.
The use of compositions
Can adjust according to procedures known in the art patient's treatment with compositions.Effect with combination treatment can be assessed by measuring patient symptom with quantized method, for example, pays close attention to the minimizing of recurrence frequency, or delays the increase of the time of severity of symptoms.In a kind of successful treatment, patient's situation will have improvement (for example, the frequency of recurrence will reduce, or the time that delays severity of symptoms will increase).
Embodiment
The present invention will be illustrated with following non-limiting examples
Embodiment 1: the experiment in vitro of measuring synergy
We use the method that Parsons (Parsons, CG et al., Neuropharmacology 38:85-105,1999) and Weller (Weller et al., BrainResearch 613:143-148,1993) describe in this experiment.Briefly, the rat embryo cortex of 13-14-days initial incubation is injected towards the 11mm well culture plate, keeps 37 ℃, 95% air/5%CO
2The quantity of-neuronal cell non-for reducing is in adding 10 in the 3rd day of cell culture
-6The resisting mitosis cytosine galactoside (araC) of M concentration.Before glutamate, Glu was handled, culture medium was replaced by HEPES-buffering regulation and control saline solution Ph7.4 (HCSS).Cell adds subject composition or reference group compound with the 1mM glutamate, Glu, and MK-801 is hatched.After the incubated at room 10 minutes, remove this solution and also add subject composition or the replacement of reference group compound with the MEM of nothing-serum, cell was cultivated 24 hours in 37 ℃ under standard conditions.Cell is after morphologic detection, and the supernatant of contrast and test culture is collected and analyzes the LDH activity.
Dosage range research at first is used to measure the ED50 of Memantine hydrochloride, and the scope of expectation is 1-10um.The ED50 of selegiline measures with similar methods.Carried out the test of isobolic subsequently, its Chinese medicine with the mark of EDXXs to ED 100 unite (for example, ED50:ED50, ED25:ED75, etc.).Set up data drawing list.If the testing site is arranged under the straight line that figure ED50 orders, then this to unite be to have synergisticly, it is additional being positioned on the straight line, and suppresses above being positioned at straight line.The maximum synergistic point that is derived from the isobolic line is best ratio.This is best stabilization sub stage ratio (C
Ratio, ss) and will adjust according to the half-life of constituent.
Embodiment 2: measure best stabilized-stage concentration rate (C
Ratio, ss) body in method
Best stabilized-stage is dense will measure (Quack G and Archer is Neural Transm108:167-187 T.2001.J for FredrikssonA, Danysz W) according to the MPTP method of PD, but any corresponding C NS model may be used to this purpose.Briefly, mice is injected sc with MPTP, presses 80mg/kg every injection in 24 hours, continues 8-9 week to set up stable Parkinsonian symptom.Animal is handled with L-dopa, presses 20mg/kg sc, and the injection of every day injection totally 5 days/weekly is totally 5 weeks.L-dopa-resistance MPTP mice carries out administration with subject composition or saline solution before putting into a determination of activity room.Injected in mice L-dopa or saline solution also write down 3 hours locomotor activity.
Dosage range research at first is used to measure the ED50 that memantine is sighed, and the scope of expectation is 1-10um.The ED50 of 1-deprenyl measures with similar methods.Carried out the test of isobolic subsequently, its Chinese medicine with the mark of EDXXs to ED 100 unite (for example, ED50:ED50, ED25:ED75, etc.).Set up data drawing list.If the testing site is arranged under the straight line that figure ED50 orders, then this to unite be to have synergisticly, it is additional being positioned on the straight line, and suppresses above being positioned at straight line.The maximum synergistic point that is derived from the isobolic line is best ratio.This is best stabilization sub stage ratio (C
Ratio, ss) and will adjust according to the half-life of constituent.
The compositions of embodiment 3:NMDA receptor antagonist and MOA mortifier
The representational combination of ranges of compositions of the present invention is as follows
Adult's dosage of combined therapy
| MAO mortifier or GAPDHai (mg/ days) | |||
| NMDA medicine mg/ days | L selegiline/selegiline | Nor-selegiline | Lei Sajilan |
| Memantine hydrochloride/2.5-40 | 0.5-10 | 0.5-10 | 0.5-2.0 |
| Buddha's warrior attendant (alkane) amine/50-300 | 0.5-10 | 0.5-10 | 0.5-2.0 |
| Rimantadine/50-200 | 0.5-10 | 0.5-10 | 0.5-2.0 |
Embodiment 4: the release characteristics of Memantine hydrochloride and L-selegiline compositions
Following table has shown release characteristics.The accumulative total part is the ingredient quantity (for example, U.S.P.N.4,839,177) that is released into from the form module in serum or the internal organs.
| Memantine hydrochloride | The L-selegiline | |
| T1/2=60 hour | T1/2=1-4 hour | |
| Time | Cum. part A | Cum. part B |
| 0.5 | 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 |
| Memantine hydrochloride | The L-selegiline | |
| T1/2=60 hour | T1/2=1-4 hour | |
| Time | Cum. part A | Cum. part B |
| 0.5 | 0.2 | 0.30 |
| 2 | 0.3 | 0.40 |
| 4 | 0.4 | 0.50 |
| 8 | 0.5 | 0.60 |
| 12 | 0.6 | 0.70 |
| 16 | 0.7 | 0.80 |
| 20 | 0.8 | 0.90 |
| 24 | 0.9 | 0.99 |
Embodiment 5: the tablet that contains Memantine hydrochloride and L-selegiline compositions
The Memantine hydrochloride of treatment and the pulsation of L-selegiline discharge dosage form and are prepared to three independent parts.The three independently is prepared into tablet, and every kind has different release characteristics, the gel capsule and close and seal of subsequently three kinds of tablets being packed into.Shown in three kinds of tablets composed as follows.
Every contained dosage of composition function
Tablet 1 (discharging immediately)
Memantine hydrochloride active medicine 8mg
L-selegiline active medicine 5mg
Two aquation dicalcium phosphate diluent 26.6mg
Microcrystalline Cellulose diluent 26.6mg
Explotab disintegrant 1.2mg
Magnesium stearate lubricant 0.6mg
Tablet 2 (continuing to discharge in 3-5 hour after the administration)
Memantine hydrochloride active medicine 8mg
L-selegiline active medicine 5mg
Two aquation dicalcium phosphate diluent 26.6mg
Microcrystalline Cellulose diluent 26.6mg
Explotab disintegrant 1.2mg
Magnesium stearate lubricant 0.6mg
Eudragit RS30D slow release lapping 4.76mg
Talcum parcel composition 3.3mg
Triethyl group citric acid parcel composition 0.95mg
Tablet 3 (continuing to discharge in 7-9 hour after the administration)
Memantine hydrochloride active medicine 2.5mg
L-selegiline active medicine 5mg
Two aquation dicalcium phosphate diluent 26.6mg
Microcrystalline Cellulose diluent 26.6mg
Explotab disintegrant 1.2mg
Magnesium stearate lubricant 0.6mg
Eudragit RS30D slow release lapping 6.34mg
Talcum parcel composition 4.4mg
Triethyl group citric acid parcel composition 1.27mg
Tablet is by the wet particle of independent drug microparticles and other nuclear compositions, with the preparation of thermopnore granulator, or direct compressed compositions composition and preparing.Tablet 1 is a kind of releasing pattern immediately, and it is 1-2 hour release active medicine after administration.Tablet 2 and 3 is enclosed with the slow release lapping, prepares as spraying-parcel or similar approach with common technique for packing.The concrete composition of listing in the above-mentioned tablet can be substituted by other intimate compositions, for example, and diluent, sticking agent, lubricant, fill, wrappage, and analog.
This capsule will obtain the release characteristics of three subpulses to patient's oral administration, initial Memantine hydrochloride and the L-selegiline that from first kind of tablet, discharges fully rapidly, Memantine hydrochloride that from second kind of tablet, discharged in 3-5 hour after the administration and L-selegiline, the Memantine hydrochloride that from the third tablet, discharged in 7-9 hour after the administration and L-selegiline.The curative effect characteristic is near linear in scope, and causes the concentration characteristic.
Embodiment 7: the microgranule that contains the combination of Memantine hydrochloride and L-selegiline
The method of embodiment 6 is repeated, except contain-microgranule of medicine substitutes tablet and uses.The first of microgranule, as lactose and prepares by medicine being wrapped up the inertia support material, and it can provide for the first time (discharging immediately) pulse.The second portion of microgranule wraps up immediately by the intestinal lapping with some that release microparticles prepares, and drug release-free stage of 3-7 hour can effectively be provided.The third part of microgranule with a large amount of intestinal lapping parcels, effectively provides drug release-free stage of 7-12 hour by will only having the release microparticles immediately of first kind of microgranule part half methylphenidate dosage.Three groups of microgranules can incapsulate as described in example 3 above, or compress under the situation that has the buffering medicine, are prepared into a pulse release tablet.Last release characteristics in 12 hours scopes near linear.
Alternatively, three groups of drug microparticles can be provided and wrap up the lactose particles into medicine-parcel as mentioned above.The release characteristics of demonstration is shown in Fig. 2 A-2C, and a series of figure have shown release composition release characteristics and CRATIO.This product can keep the ratio of almost stable between two kinds of compositions, and when the time scope was 2 to 16 hours, its excursion was 2 times to 0.5 times average Cratio (being set at 1).
Except that the release characteristics that obtains expectation, this cooperative programs will show that the concentration of first-selected 0.2v.0.5 increases.
| NMDAr Antag | ||
| IR | CR | |
| dC/dT(4hr) Cmax/Cmean2-16 | 0.54 1.10 | 0.20 1.38 |
| MAOi | ||
| IR | CR | |
| dC/dT(1hr) Cmax/Cmean2-16 | 1.04 3.11 | 0.13 1.35 |
Embodiment 8: the small pieces that Memantine hydrochloride and L-selegiline slow release are provided
As mentioned above, the slow release form of nmda receptor antagonist can be prepared into the topical form.Memantine hydrochloride transdermal small pieces form can prepare as stated above, for example, U.S.P.Ns.6,770,295 and 6,746,689, these documents are by all being incorporated in text in this citation.
Be preparation medicine-inherence-stickiness acrylates, the L-selegiline of the Memantine hydrochloride of 5g and 4g will be dissolved into 11g ethanol and add 20g Durotak387-2287 (National starch﹠amp; Chemical, U.S.A).With covering instrument (for example, RK PrintCoat Instr.Ltd, Type KCC 202control coater) drug gel is covered in (Scotchpak 1012 on the supporting film; 3M Corp., U.S.A.).Overburden cover is 400 μ m.Laminate put drying at room temperature 20 minutes, with rearmounted 40 ℃ 30 minutes.The polyester release liner is rolled on the dry drug gel.Be stored in 2-8 ℃ until using (using pouch-packaged) after being cut into small pieces.Memantine hydrochloride concentration range on the small pieces is 5.6-8mg/cm
2, L-selegiline concentration range is 2.8-6.5mg/cm
2
Fig. 3 A and 3B present embodiment are the comparison diagram of the sustained release (embodiment 7) of expection 12 hours and 24 hours.These figure show the subcontinuous conveying advantage of said composition, and (Cratio, importance ss) make it to reach optimization thereby adjust concentration dose to set up correct stable-stage ratio.
Embodiment 9: provide amantadine and 1-selegiline to continue the small pieces that discharge
The small pieces and the sele that can continue to discharge amantadine and 1-selegiline can prepare as follows.The module small pieces cover through the acrylates module forms the thick polyolefin foam (as a kind of closed holder) of 1mm, has comprised amantadine in this acrylate copolymer, 1-selegiline and a kind of transdermal-osmotic drug.By mixing amantadine (account for weight 20%); 1-deprenyl (account for weight 20%); Acrylate copolymer (Durotak.RTM.387-2052, account for weight 75%); Transdermal-osmotic drug; Acetylacetonate aluminum (Al (ACAC)
3, account for 0.4% of weight, as cross-linking agent) and prepare this module, and add ethanol until becoming the homogeneous state.The compositions of homogeneous is covered in polyolefin with manual glue spreader with average thickness 270 μ m and sets off.Covering is set off and is put 1 hour ethanol evaporation of 50 ℃ of dryings.Last dry small pieces weight is about 50g/m
2
Equivalent
Employing is no more than the means of normal experiment, and those skilled in the art will recognize a large amount of equivalents that maybe can be sure of concrete grammar described here.These equivalents are deemed to be within the scope of the present invention and are comprised by following claim.Under condit without departing from the spirit and scope of the present invention, can carry out various substituting, change and correction to the present invention.Other aspects, advantage and correction are also within the scope of the invention.All lists of references of being quoted in this application, the patent of mandate and the content of disclosed patent application are all by all being incorporated in text in this citation.At the present invention and its embodiment, can select these patents, the suitable composition in application and other document, process, and method.
Claims (56)
1. pharmaceutical composition, it comprises:
(a) nmda receptor antagonist;
(b) second kind of medicine, its described medicine are monoamine oxidase, MAO (MAO) mortifier or GADPH mortifier; And
(c) medicine acceptable carrier;
Nmda receptor antagonist wherein, described second kind of medicine, or both delay to discharge dosage form its.
2. according to the pharmaceutical composition of claim 1, wherein said nmda receptor antagonist provides to delay discharging dosage form.
3. according to the pharmaceutical composition of claim 2, wherein, after described nmda receptor antagonist enters in the patient body about 2 to 6 hours, the Cmax/Cmean value of described nmda receptor antagonist was about 2 or littler.
4. according to the pharmaceutical composition of claim 1, wherein said nmda receptor antagonist and described second kind of medicine corresponding C ratio value are 0.4-2.5.
5. according to the pharmaceutical composition of claim 2, wherein at least 50% described nmda receptor antagonist in described pharmaceutical composition provides to delay releasing pattern.
6. according to the pharmaceutical composition of claim 5, wherein at least 95% described nmda receptor antagonist in described pharmaceutical composition provides to delay releasing pattern.
7. according to the pharmaceutical composition of claim 6, wherein all the described nmda receptor antagonists basically in described pharmaceutical composition provide to delay releasing pattern.
8. according to the pharmaceutical composition of claim 2, wherein said pharmaceutical composition entered the patient body interior back 1 hour, and at least 99% described nmda receptor antagonist keeps described sustained-release dosage form.
9. according to the pharmaceutical composition of claim 1, wherein said second kind of medicine provides to delay releasing pattern.
10. according to the pharmaceutical composition of claim 9, wherein said second kind of medicine enters about 2 at least 6 hours of the interior back of patient body, and described second kind of medicine Cmax/Cmean value is about 2 or littler.
11. according to the pharmaceutical composition of claim 10, wherein said second kind of medicine enters about 2 at least 12 hours of the interior back of patient body, described second kind of medicine Cmax/Cmean value is about 2 or littler.
12. according to the pharmaceutical composition of claim 11, wherein said nmda receptor antagonist enters about 2 at least 6 hours of the interior back of patient body, described nmda receptor antagonist Cmax/Cmean value is about 2 or littler.
13. according to the pharmaceutical composition of claim 1, wherein said nmda receptor antagonist and described second kind of medicine provide to delay releasing pattern.
14. according to the pharmaceutical composition of claim 1, wherein said nmda receptor antagonist is a kind of aminoadamantine derivatives.
15. pharmaceutical composition according to claim 14, wherein said aminoadamantine derivatives is a Memantine hydrochloride (1-amino-3,5-dialkyl group diamantane (obsolete)), rimantadine (1-(1-amino-ethyl) diamantane (obsolete)), or Buddha's warrior attendant (alkane) amine (1-amino-ethyl-diamantane (obsolete)).
16. according to the pharmaceutical composition of claim 15, wherein said aminoadamantine derivatives is Memantine hydrochloride (1-amino-3, a 5-dialkyl group diamantane (obsolete)).
17. according to the pharmaceutical composition of claim 1, wherein said second kind of medicine is selegiline, Lei Sajilan, demethyl selegiline, CGP3466, phenelzine, or tranylcypromine.
18. according to the pharmaceutical composition of claim 17, wherein said second kind of medicine is selegiline.
19. according to the pharmaceutical composition of claim 1, wherein said nmda receptor antagonist is a Memantine hydrochloride, wherein said second kind of medicine is selegiline.
20. according to the pharmaceutical composition of claim 1, wherein said preparation of pharmaceutical compositions becomes oral, intravenous, topical transdermal, nasal cavity, or the transporting pattern that sucks.
21. according to the pharmaceutical composition of claim 20, wherein said preparation of pharmaceutical compositions becomes suspension, capsule, tablet, suppository, lotion, or paster.
22. according to the pharmaceutical composition of claim 1, wherein said nmda receptor antagonist is to provide with unit dosage form with described second kind of medicine.
23. pharmaceutical composition according to claim 1, with compare with the required nmda receptor antagonist quantity of the therapeutic effect that obtains identical treatment CNS-relevant disease when nmda receptor antagonist administration when not having described second kind of medicine, wherein the quantity of the described nmda receptor antagonist in described pharmaceutical composition is still less.
24. pharmaceutical composition according to claim 1, with compare with second kind of required medication amount of the therapeutic effect that obtains identical treatment CNS-relevant disease when the administration when not having described nmda receptor antagonist of second kind of medicine, wherein the quantity of the described second kind of medicine in described pharmaceutical composition is still less.
25. pharmaceutical composition according to claim 1, wherein said nmda receptor antagonist is present in the pharmaceutical composition with doses, will be virose with this dosage to described main body administration at described nmda receptor antagonist under the situation of the described second kind of medicine of disappearance.
26. pharmaceutical composition according to claim 1, wherein said second kind of medicine is present in the pharmaceutical composition with doses, will be virose with this dosage to described main body administration at described second kind of medicine under the situation of the described nmda receptor antagonist of disappearance.
27. a method for the treatment of the CNS-correlation circumstance comprises the compositions that comprises nmda receptor antagonist and second kind of medicine of the main body therapeutic effective dose that needs, wherein said second kind of medicine is MAO mortifier or GADPH mortifier.
28. according to the method for claim 27, wherein said nmda receptor antagonist provides to delay releasing pattern.
29. according to the method for claim 28, wherein said nmda receptor antagonist enters about 2 at least 6 hours of the interior back of patient body, described nmda receptor antagonist Cmax/Cmean value is about 2 or littler.
30. according to the method for claim 29, wherein said nmda receptor antagonist enters about 2 at least 12 hours of the interior back of patient body, described nmda receptor antagonist Cmax/Cmean value is about 2 or littler.
31. according to the method for claim 27, wherein at least 50% described nmda receptor antagonist in described pharmaceutical composition provides to delay releasing pattern.
32. according to the method for claim 31, wherein at least 95% described nmda receptor antagonist in described pharmaceutical composition provides to delay releasing pattern.
33. according to the method for claim 32, wherein all the described nmda receptor antagonists basically in described pharmaceutical composition provide to delay releasing pattern.
34. according to the method for claim 31, wherein said pharmaceutical composition enters after the main body 1 hour, at least 99% described nmda receptor antagonist keeps described sustained-release dosage form.
35. according to the method for claim 27, wherein said second kind of medicine provides to delay releasing pattern.
36. according to the method for claim 25, wherein said second kind of medicine enters about 2 at least 6 hours of the interior back of patient body, described second kind of medicine Cmax/Cmean value is about 2 or littler.
37. according to the method for claim 36, wherein said second kind of medicine enters about 2 at least 12 hours of the interior back of patient body, described second kind of medicine Cmax/Cmean value is about 2 or littler.
38. according to the method for claim 27, wherein said nmda receptor antagonist enters about 2 at least 6 hours of the interior back of patient body, described nmda receptor antagonist Cmax/Cmean value is about 2 or littler.
39. according to the method for claim 27, wherein said nmda receptor antagonist is low offinity NMDA receptor antagonist.
40. according to the method for claim 27, wherein said nmda receptor antagonist is the aminoadamantine derivatives.
41. method according to claim 40, wherein said aminoadamantine derivatives is a Memantine hydrochloride (1-amino-3,5-dialkyl group diamantane (obsolete)), rimantadine (1-(1-amino-ethyl) diamantane (obsolete)), or Buddha's warrior attendant (alkane) amine (1-amino-ethyl-diamantane (obsolete)).
42. according to the method for claim 41, wherein said aminoadamantine derivatives is Memantine hydrochloride (1-amino-3, a 5-dialkyl group diamantane (obsolete)).
43. according to the method for claim 27, wherein said second kind of medicine is that wherein said second kind of medicine is selegiline, Lei Sajilan, demethyl selegiline, CGP3466, phenelzine, or tranylcypromine.
44. according to the method for claim 27, wherein said nmda receptor antagonist is a Memantine hydrochloride, wherein said second kind of medicine is selegiline.
45. according to the method for claim 27, wherein said CNS-relevant disease is parkinson disease, Alzheimer, or multiple sclerosis disease.
46. according to the method for claim 27, wherein said nmda receptor antagonist passes through oral, intravenous, and nasal cavity, or suck conveying.
47. according to the method for claim 27, wherein said second kind of medicine passes through oral, intravenous, and nasal cavity, or suck conveying.
48. according to the method for claim 27, wherein said nmda receptor antagonist and the administration simultaneously of described second kind of medicine.
49. according to the method for claim 27, wherein said nmda receptor antagonist and described second kind of medicine are with single compositions administration.
50. according to the method for claim 27, wherein said nmda receptor antagonist and described second kind of medicine administration in succession.
51. according to the method for claim 27, wherein said nmda receptor antagonist and described second kind of medicine administration in 24 hours.
52. according to the method for claim 27, wherein said nmda receptor antagonist and described second kind of medicine are with identical administration.
53. according to the method for claim 27, wherein said nmda receptor antagonist and described second kind of medicine are with different administrations.
54. according to the method for claim 27, wherein said nmda receptor antagonist, described second kind of medicine, or both are administered once to described main body every day.
55. according to the method for claim 27, wherein said nmda receptor antagonist, described second kind of medicine, or both were administered once to described main body in per three days.
56. according to the method for claim 27, wherein said main body is human.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200580006318XA CN101119705A (en) | 2005-01-31 | 2005-01-31 | Combination of a NMDA receptor antagonist and a MAO-inhibitor or a GADPF-inhibitor for the treatment of central nervous system-related conditions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200580006318XA CN101119705A (en) | 2005-01-31 | 2005-01-31 | Combination of a NMDA receptor antagonist and a MAO-inhibitor or a GADPF-inhibitor for the treatment of central nervous system-related conditions |
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| Publication Number | Publication Date |
|---|---|
| CN101119705A true CN101119705A (en) | 2008-02-06 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200580006318XA Pending CN101119705A (en) | 2005-01-31 | 2005-01-31 | Combination of a NMDA receptor antagonist and a MAO-inhibitor or a GADPF-inhibitor for the treatment of central nervous system-related conditions |
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| Country | Link |
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| CN (1) | CN101119705A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106668865A (en) * | 2017-01-23 | 2017-05-17 | 牡丹江医学院 | Medicinal composition for treating cerebral ischemia, preparation and application of medicinal composition |
-
2005
- 2005-01-31 CN CNA200580006318XA patent/CN101119705A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106668865A (en) * | 2017-01-23 | 2017-05-17 | 牡丹江医学院 | Medicinal composition for treating cerebral ischemia, preparation and application of medicinal composition |
| CN106668865B (en) * | 2017-01-23 | 2019-07-23 | 牡丹江医学院 | For treating pharmaceutical composition, preparation and its application of cerebral ischemia |
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