CN1972685A - Compositions and methods to treat recurrent medical conditions - Google Patents

Abstract

The invention describes methods and compositions for alleviating recurrent medical afflictions for which anxiety may cause or exacerbate the affliction. A subject suffering from the affliction is treated with a combination of a pharmaceutical that enhances learning, and a second pharmaceutical recognized to be useful for treatment of the affliction. Representative afflictions include insomnia, erectile dysfunction, female sexual dysfunction, neuropathic pain, attention deficit disorder, and depression.

Description

The compositions and the method for the disease of the needs treatment of treatment recurrent

The mutual reference of relevant application

The application is based on following U.S. Provisional Patent Application and as basis for priority:

U.S. Provisional Patent Application is numbered 60/533,003, and the applying date is December in 2003 29 days; U.S. Provisional Patent Application is numbered 60/625,253, and the applying date is on November 5th, 2004.

Technical field

The present invention relates to technical field of pharmaceuticals.

Background technology

As insomnia, erection disturbance, widely used medicine only at the biochemical physiology factor of misery, has been ignored psychological factor for some health diseases.Can waste chance like this, because the spin-off of curing on the physiology as success, be used for the treatment of medicine temporarily reduction of patient and the concurrent anxiety of disease as insomnia, erection disturbance, this but physiological " reparation " is temporary transient, and existing Drug therapy has been ignored the chance of catching and consolidating favourable psychoreaction.On the contrary, ridden patient thinks that the anxiety that disease may recur but stimulates or aggravate the recurrence of disease through regular meeting.

When the neutral stimulus of band emotion is accompanied by deleterious dislike stimulation (unconditioned stimulus (US)), typical frightened symptom can take place, for example foot trembles.Then, previous neutral stimulus (that is, present stimulation with good conditionsi (CS)) just can cause various spontaneous in human body, hormone and reactions skeleton, and follows the sensation of conscious fear, and this also often is operated the fear that is used for judgment experiment chamber animal.Lacking under the situation of US, can eliminate the characteristic of bringing out anxiety of CS by CS is provided repeatedly.There's a widespread conviction that for people, disappears to cause association originally to disappear from memory, but can be absorbed in the formation of the association that new and previous conditioned response compete mutually.

Cognition neural is learned the nearest result of study in field and is proved, and the cognitive medicine of enhancing can be consolidated the useful psychoreaction that stimulates (WO02/078629 quotes in full in the lump at this).The research result is extremely important to treating frightened obstacle, because nearest clinical research is verified, be combined in the medicine of using the enhancing cognitive competence in the course of treatment if accept the patient of cognitive-behavioral therapy, in the short course of treatment, can reach clinical cure (such as, be less than 75%) (Davis, Arch Gen Psychiatry.2004; 61:1136-1144).A kind of suitable medicine that is used to strengthen cognitive competence is D-cycloserine (" DCS ").DCS be being used for the treatment of of a kind of FDA approval lungy off-patent, (commodity are called Seromycin  to two wires (second-line) medicine, be abbreviated as " DCS ", Eli Lilly is on sale), have to strengthen cognitive secondary role, although chronic administration is tending towards limiting this effect even has the opposite effect.Other cognitive enhancer, the particularly agonist of other the incomplete nmda receptor of glycine (glycine partial NMDA receptor agonists) believe it also is effective.

Therefore, described the therapy for the treatment of frightened obstacle in the prior art, comprised in conjunction with should acutely using the behavior cognitive therapy that strengthens cognitive medicine.

Prior art has also been described the chronic NMDA of using agonist chronic treatment senile dementia and neuropsychiatric disorders.U.S. Patent No. 6,228,875 dosage of having described with 105-500mg are that chronic administration basis amount is used DCS (or other nmda receptor agonist) treatment schizophrenia, the not enough obstacle of attention and other neuropsychiatric disorders.But it does not instruct the advantage of using the DCS acute dose in conjunction with other medicines.

Do not describe in the prior art and be used in combination acute administration and strengthen cognitive medicine and carry out Drug therapy and treat as other obstacles such as depression, insomnia, erection disturbance, chronic pains.

For a long time, need a kind of the reinforcement to the disease with anxiety factor and the pharmaceutical composition and the method for the treatment of dysfunction always.The present invention has satisfied this needs.

Summary of the invention

The invention describes a kind of alleviate because of anxiety cause or aggravation the method and composition of the misery that need treat of recurrent.Suffer this painful patient to accept following therapeutic alliance:

(1) a kind of can strengthen cognitive medical compounds (ancillary drug) and

(2) known to alleviating the effective second kind of medical compounds of a certain special misery (main medicine).

Our technology is to adopt the agonist of one or more incomplete nmda receptors as a kind of ancillary drug that strengthens cognition, improves the effect of main medicine by the fixing psychological benefit that is produced by main Drug therapy.With respect to only using second kind of medical compounds, promptly only use the patient of main Drug therapy, on average, utilize the treatment that contains the pharmaceutical composition that strengthens cognitive chemical compound to alleviate patient's misery to a greater extent.Because the beneficial effect of method and composition of the present invention has considered that conventional biochemical analysis does not often observe this beneficial effect on the simple biochemical indicator of whole psychology/somatic reaction of patient rather than molecule or cellular level.

The representational obstacle that the method according to this invention and compositions can be treated comprises insomnia, erection disturbance, female sexual disorder, neuralgia, distractibility hyperkinetic syndrome (attentiondeficit-hyperactivity disorder), depression and anxiety neurosis.For the misery that some recurrents need be treated, misery is temporary transient, then can should acute using treat by medicine.Outstanding example is erection disturbance and female sexual disorder.Other some have the misery of relevant potential factor at heart and treat by multiple medication every day usually.Wherein representational misery comprises insomnia (also adopt sometimes and answer acute treatment), chronic pain, neuralgia, anxiety, depression and distractibility hyperkinetic syndrome.The present invention described here has considered to be used to alleviate the method and composition of the misery that recurrent need treat, and comprises the patient is used:

(1) a kind of chemical compound that can alleviate characteristic symptom (specific condition); With

(2) a kind of chemical compound that can strengthen cognition,

The chemical compound that wherein is used for the treatment of characteristic symptom was taken once on average per at least 24 hours, and wherein strengthened cognitive chemical compound, was preferably the agonist of the incomplete receptor of a kind of NMDA,, was no more than weekly twice patient's administration with the frequency that reduces.

DCS is used as in the specific embodiment that strengthens cognitive chemical compound therein, if the administration number of times of DCS is more frequent, i.e. every day, or on every Wendesdays time or more times, the reinforcing agent as a kind of cognition will not have significant positive-effect so, and have negative interaction.

Implement mode of the present invention

Use as this place, each following term has its described related meanings.

The object of article is one or more than one (promptly being at least one) on the article " a " that use in this place and " an " finger speech method.For example, the meaning of " composition " is a kind of composition or more than a kind of composition.

Use as this place, " plural number " means and is at least two.

Use as this place, " FDA " means U.S. food and FAD.

Any scope that quote in this place is an inclusive, comprises the composition of 50mg and 100mg as " approximately 50mg-100mg ".

Use as this place, " acute " administration of a treatment means in patient's duration disposable use and strengthens cognitive and or the medicine of the treatment effective dose of regulating action.Relevant with " acute " definition, duration was defined as four days or the longer time, such as administration DCS should acute administration with regard to constituting weekly.The patient has taken the DCS of doses, and then takes medicine for the second time after 24 hours, and this administering mode does not constitute acute administration.Answer acute administration if the single administration of DCS intravital DCS of patient in 12 hours reaches the blood peak value with regard to constituting, the existing immediate release profile of the dose that is made into wherein also has the characteristic of slow release.

" disease " is that a kind of animal (mammal) can not keep homeostatic a kind of health status, and if this disease can not be enhanced, the health of animal will continue to worsen so.On the contrary, animal intravital " obstacle " is that a kind of animal can moderately keep homeostatic health status, but the health status of the health status of this animal when accessible is favourable.If do not treat, this obstacle is unlikely the further deterioration that causes the animal health state.

Use as this place, " misery that recurrent need be treated " refers to a kind of recurrent or chronic obstacle in the human body, and this obstacle can be owing to the anxiety of obstacle or constrain and cause or aggravation at least in some patients.Define from this, " anxiety " or " constraining " is a kind of concern to obstacle, worry, worry, the uncomfortable state of psychology.Anxiety or constrain and to be recognized by the patient that perhaps the patient does not discover.The anxiety relevant with obstacle may not be present among each patient who is defined as the painful obstacle that recurrent need treat; On the contrary, if some patients some the time obstacle felt concern or pressure, this obstacle is fit to definition like this.For purposes of the invention, above-mentioned have the patient of the misery that recurrent need treat should have the obstacle that one or more can use method treatment of the present invention.Like this, a patient has single obstacle or a plurality of obstacle that method described here is treated.The misery that the recurrent that the present invention considers need be treated comprises, but be not limited to erection disturbance, female sexual disorder, chronic pain, neuralgia, insomnia, distractibility hyperkinetic syndrome, habit-forming, fatigue, anxiety neurosis, depression, migraine and eating disorder (eating disorder).

Use as this place, when the obstacle of the needs treatment of attempting to alleviate the patient in earnest or disease, the patient is exactly a quilt " treatment ", or has accepted " treatment ".For example, it is exactly to treating dysfunction that the patient has taken the medicament that can alleviate obstacle, whether can successfully alleviate obstacle with this treatment and have nothing to do.

Use as this place, if the order of severity of a certain symptom of the misery that a kind of disease, obstacle or recurrent need be treated, the patient stands the frequency of this symptom, and perhaps the both has descended, and " has alleviated " misery that disease, obstacle or recurrent need be treated exactly.

" patient " that diagnosed or treat refers to the people.

" on the therapeutics " treatment means to the individual drug administration that shows the pathology sign with in order to reduce or to remove the processing that those signs are purpose.

" the treatment effective dose " of chemical compound is meant that chemical compound that the patient takes is enough to provide the amount of beneficial effect.

Use as this place, " compound vitamin B " is one or more vitamin that are selected from following group, comprises thiamine (B1), riboflavin (B2), nicotinic acid (B3), pyridoxol (B6), folic acid (B9), cyanocobalamin (B12), pantothenic acid and biotin.

What be worth promotion is, when using integrated processes of the present invention, strengthen cognitive chemical compound and it has been generally acknowledged that all should be in reasonable period of time to alleviating painful useful main medical compounds that recurrent need treat (such as, in 12 hours, in preferred 4 hours) patient is used.These chemical compounds can be included on the identical pharmacopedics in the acceptable carrier so that administration simultaneously.Also can be included in the separated drug carrier as conventional oral agents form, take simultaneously.As used above, the term combination refers to that also these chemical compounds are included in the dosage form separately, is successively taken, and takes in 12 hours as them, preferably in 4 hours.

Use as this place, term " depression " comprises the depressive type obstacle, as single sporadic or the main depressive disorder of recurrent, spirit depressing obstacle, depressive type neurasthenia and nerve depression; The inhibitable type depression comprise anorexia, weight loss, insomnia and morning early awakening, psychomotor slow; Atypical depression (response type depression) comprises that appetite strengthens, drowsiness, mental excitation or irritability, anxiety and fear, seasonal affective disorder, bipolar nerve cell obstacle or manic depression, for example bipolar nerve cell I type obstacle, bipolar nerve cell II type obstacle and cycloophrenia obstacle.

Use as this place, term " neuralgia " means and is derived from pain neural or neural breaking-up or dysfunction initiation." chronic pain " means pain and continues 3 months at least, causes serious psychology and emotion influence usually and limited the ability of a people's whole functional.

Use as this place, " insomnia " be defined as falling asleep or normally during the sleep in keep regaining consciousness for a long time.It comprises acute insomnia and chronic insomnia temporary transient or short-term.It also comprises the initial stage insomnia, and it is defined as and is difficult to fall asleep; The insomnia in mid-term, sleeping subsequently but very difficult after it is defined as and wakes up midnight; The insomnia in late period, it is defined as more early than the time of normally waking up awake, can not fall asleep again.

Use as this place, " attention that hyperactivity causes not enough obstacle (hyperkinetic syndrome) " refers to absent minded obstacle sometimes, be defined as herein have personal feature for the obstacle of careless, wholwe-hearted, that impulsion is relevant with hyperactivity difficulty serious and that continue.

Use as this place, " erection disturbance " is meant the sexual impotence that can't reach or keep erection to cause owing to the male.

Use as this place, the symptom of " female sexual disorder " is for lacking desire, excitement or orgasm.APA (APA) divides women's problem into ideological stumbling-block have: lack that libido is hoped or excited, sexual intercourse is uncomfortable, vagina ischemia, the property dislike relevant with wound and can't come to orgasm.

Use as this place, the chemical compound of " strengthening cognitive " or " cognitive enhancer " be that those skilled in the art can recognize, use any medicine that can improve cognitive function in conjunction with method of the present invention.For example, the class in this pharmaceutical preparation is to improve the chemical compound of levels of acetylcholine in the brain, comprises the chemical compound that for example can block the acetylcholine disintegrate.The example of such chemical compound includes, but not limited to the tacrine that donepezil hydrochloride, E2020 and inhibition cholinesterase enzyme are lived.The another kind of chemical compound that can strengthen cognition is the medicine that can strengthen (NMDA) receptor active of N-methyl-D-aspartate in the brain or transmission (anionic current).It is useful especially can strengthening (NMDA) receptor active of N-methyl-D-aspartate in the brain or transmission (anionic current) but can not cause significant neurovirulent medicine.Available method well known to those skilled in the art detects the transmission that strengthens nmda receptor.For example, measure the nmda receptor activity with lutropin (LH) secretions and (see people (1997) Neuropsychopharm 16 (5) such as van Berckel: 317-324).Other method comprises that electrophysiology and chemical method are (referring to people such as Mothet (2000) Proc.Natl.Acad.Sci.USA 97 (9): 4926-4931).Neurovirulent detection is for example available, the neural method of cultivation cerebellar granule that Boje etc. (1993) BrainRes.603 (2): 207-214 describes.

Use as this place, term " nmda receptor " or " NMDA passage " refer to glutamate receptor passage NMDA hypotype (Yamakura and Shimoji (1999) Prog.Neurobiol.59 (3): 279-298).Term " agonist " comprises by ionotropic receptor such as nmda receptor, i.e. channel opener improves any chemical compound of anionic current, and these chemical compounds do not observe during by identical receptor anionic current is reduced." antagonist " comprises can be by ionotropic receptor such as nmda receptor, i.e. passage occlusive agent can reduce any chemical compound of anionic current, and these chemical compounds do not observe anionic current by identical receptor and increase.Term " not exclusively agonist " refers to whether exist based on the part in main site, be whether known and the bonded endogenous ligands of acceptor site exist, regulate the allosteric site of ionotropic receptor such as nmda receptor, increase or reduce a kind of chemical compound by the cation flow of part catwalk.When lacking the part in main site, not exclusively agonist increases the cation flow by the part gallery, but lower than the flow of realizing by the part in main site.Not exclusively agonist is just partly opened receptor channel.When the part in main site existed, not exclusively agonist reduced the cation flow by the part gallery, and it is lower than the flow of realizing by the part in main site under the normal condition.Use in this place, and " nmda receptor agonist ", " nmda receptor antagonist " and " the incomplete receptor stimulating agent of NMDA " can refer to " NMDA agonist ", " nmda antagonist " and " the incomplete agonist of NMDA " respectively." the incomplete agonist of NMD receptor " also can exchange with " not exclusively nmda receptor agonist ".The present invention considers the multiple molecule that plays the effect of incomplete nmda receptor agonist.Such exemplary agents comprises, but be not limited to, act on the chemical compound of the glycine regulatory site of nmda receptor, comprise that (l-am inocyclopropane-carboxylicacid ACPC) (sees U.S.Patent Nos.5,086 to DCS, D-serine and α-ring alanine, 072 and 5,428,069, incorporated by reference in the lump here).The incomplete agonist of nmda receptor is to strengthen cognitive chemical compound, and particularly useful when using in conjunction with method and composition of the present invention.

It is about 20 years that DCS is used for the treatment of tuberculosis by the FDA approval.In the past in the period of 10 as a kind of cognitive enhancer clinically through test several times.For tuberculosis, the common taking dose of DCS chronic treatment is 500-1000mg/ day, takes (PDR 1997) every day at twice.With the dosage of 500mg/ day every day, blood middle concentration is kept the level of 25-30mg/ml usually.Peak value in the blood appears at takes medicine back 3-8 hour, mainly discharges by kidney after 10 hours half-life.Patient's (have people lungy and be commonly referred to be chronic disease) is chronic to take that rarely found side effect comprises that drowsiness, headache, mental disorder, nerve are trembled, dizzy, memory difficulty, paresthesia of skin and epileptic outbreak (seizure).Side effect and taking dose are closely related.

In the U.S., it is 250mg (Seromycin , can available from EliLilly company) that DCS is used for the treatment of permission using dosage lungy.Need quite high effective ingredient concentration so that enough bactericidal activities to be provided.Yet the cognitive reinforced effects of DCS just can reach under low dosage.Therefore, method and composition of the present invention preferably includes the extremely about 100mg of the about 25mg of concentration that takes DCS to the patient, therefore avoids and has reduced the side effect of DCS, and the inferior antibiotic dosage (sub-antimicrobial dose) of pharmacotherapy is provided.

DCS also is in the news and has reduced the level of some important chemical substances in the blood samples of patients, comprises calcium, folic acid, magnesium, vitamin K, vitamin B6 and vitamin B12.Method and composition of the present invention is considered DCS and these compositions co-administered.Special consideration replenishes DCS with vitamin B6, B12, perhaps with its combination.In a specific embodiment, contain the vitamin B6 that also contains 50mg in the tablet of 50mgDCS.In other specific embodiment of the present invention, the magnitude of recruitment that vitamin B6 is fit to is 10 times of DCS dosage.

When preferred DCS conduct is used to strengthen cognitive chemical compound in method of the present invention or compositions, also considered other cognitive enhancer.Particularly considered other the incomplete receptor stimulating agent of NMDA.Method and composition of the present invention has also been considered analog and the prodrug of DCS, as DCS pharmaceutically acceptable salt class, comprise and the acylate that constitutes from physiologically acceptable anionic acidic materials, for example toluene fulfonate, methanesulfonates, acetas, citrate, malonate, tartrate, succinate, benzoate, Ascorbate, α-Tong Wuersuan and α-glycerophosphate, the acid that suitable mineral acid material is also arranged comprises hydrochlorate, sulfate, nitrate, bicarbonate and carbonate with salt.

Any those skilled in the art think to alleviate the effective medicine of recurrent medical conditions can both the method according to this invention or compositions as main medicine.

Erection disturbance

Any medicine that alleviates erection disturbance all can be used in the method and composition of the present invention.Erection disturbance is meant that penis can't reach or keep enough erection to satisfy sexual intercourse or other property expression.Some factors may make the patient be in the dangerous condition of this obstacle, for example, wound, pelvic surgical procedure, hypercholesterolemia, heart disease ischemia, external perihaemal canal disease, chronic renal failure, diabetes, the perhaps use of medicine such as antihypertensive drug treatment or digoxin, forbidden drug, tobacco and wine.The Therapeutic Method of erection disturbance comprises use vacuum equipment and penis implantation, use some medicines such as yohimbine, papaverine and apomorphine in addition, also useful phosphodiesterase-5 (PDE-5) inhibitor such as Vardenafil, tadalafil and sldenafil treatment.The PDE-5 inhibitor can strengthen the ability that the male reaches or keeps erecing.Also has the medicine that is in clinical experiment that is used for treating clinically erection disturbance at other physiological pathway.For example, originate from the PT-141 that Palatin Technologies company acts on the central nervous system.Endothelin antagonist is the another kind of chemical compound that is intended to be used for the treatment of erection disturbance.The Drug therapy erection disturbance is normally highly effective, but can not cure this misery or reverse potential problem; Comparatively speaking, they only have acute, temporary transient benefit.With respect to comprising the erection disturbance preparation but do not comprise the compositions of DCS, the medicine that comprises DCS and the combination of one or more erection disturbance preparations is formed and may be provided more significant effect to the patient.

Cause that erection disturbance has a lot of reasons, and be the 10-20% that psychogenic (that is all being spiritual) only accounts for case on the cause of disease stricti jurise.It is said that for many pathology that show the anxiety deterioration, its main cause is physiological.Sldenafil be successfully used to treat be considered to pure mental illness because of the patient.For example, Birk (Vol 60 (8) Birk, (2004) Journal of Clinical Psychology, 867-879) described one to the performance of libido paralysis and worried patient, to pure behavior intervention without any reaction.This patient responds to the sldenafil Drug therapy, and has improved the confidence to own futurity function gradually.The psychological result that the sldenafil treatment provides is very similar to the psychotherapy of successful implementation.

DCS and sldenafil are united and are helped consolidating the confidence reaction of patient to sexual state, have therefore reduced with more positive reaction substituting the required time of negative response to stimulating before.In other words, the number of times that reduces successful pharmaceutical intervention is that the psychological result of the requirement that reaches identical is necessary, and this has eliminated deleterious anxiety to performance.Through the DCS and the sldenafil therapeutic alliance of effective dose several times, can reduce or eliminate the anxiety of male to performance, the confidence sense that is helped to improve its performance ideally replaces.Need less pharmaceutical intervention because eradicate deleterious anxiety to performance, the chance of its make mistakes (it will destroy the psychoreaction of newly acquiring) still less.

In clinical trial at patient with special frightened disease, on average only need to reach clinical cure 2 courses of treatment with DCS in conjunction with psychotherapy treatment patient, and physiotherapy patient on average need 8 courses of treatment (Davis, Arch Gen Psychiatry.2004 diligently only; 61:1136-1144).The similar numeral of specific aim performance anxiety is determined in the clinical research that we also do not carry out the people.

Can be used for treating the erection disturbance chemical compound, particularly be selected from the PDE-5 inhibitor of sldenafil, Vardenafil, tadalafil, the promotion of physiological performance is provided usually, and this is enough to overcome the deleterious anxiety to performance of patient, has therefore produced successful libido result.When uniting the compound administration that uses the treatment erection disturbance, those strengthen cognitive chemical compound and have consolidated the positive psychology effect that is produced by the pharmacotherapy of success.

In a specific embodiment,, eliminated erection disturbance patient's deleterious anxiety basically to performance through one to ten therapeutic process of intervening with DCS and suitable substance P DE-5 inhibitor composition of medicine.In view of the above, the physiology that performance needs to the libido of success promotes just to have reduced.For the cause of disease mainly is psychogenic erection disturbance patient, and eliminating deleterious anxiety to performance may be enough to cure the patient, eradicates the needs to the pharmaceutical intervention in future.The erection disturbance patient that serious physiological barrier is arranged for reaching or keeping erecing may still need Drug therapy; In any case, the success rate of Drug therapy will be higher, because the performance obstacle that provides physiological promotion needn't overcome other passiveness by medicine.In other words, even without healing, DCS and one or more PDE-5 inhibitive factor are used in combination the effect that also can improve continued treatment by the negative influence of eliminating performance anxiety.Therefore, method and composition of the present invention can be used for treating most of erection disturbance patients, and being not limited to its misery mainly is psychogenic patient.

In a specific embodiment, the present invention considers DCS (10mg-500mg, 25mg-250mg preferably approximately) and the pharmaceutical composition of sldenafil, sldenafil citrate or pharmaceutically suitable other sldenafil salt (10mg-200mg, preferred 25mg, 50mg or 100mg).In another specific embodiment, the pharmaceutical composition that the present invention considers comprises DCS (10mg-500mg, preferred approximately 25mg-250mg) and tadalafil, or any its pharmaceutically suitable salt (2.5mg-50mg, preferred 5mg, 10mg or 20mg).In another specific embodiment, the pharmaceutical composition that the present invention considers comprises DCS (10mg-500mg, preferred approximately 25mg-250mg) and Vardenafil, Vardenafil hydrochlorate or other pharmaceutically suitable Vardenafil salt (2.5mg-50mg, preferred 5mg, 10mg or 20mg).In other specific embodiment, the pharmaceutical composition that the present invention has also considered comprises DCS and is selected from second chemical compound combination that yohimbine, PT-141, papaverine and apomorphine are formed.

The representational method of the present invention comprises that the patient to the hardship that is subjected to erection disturbance uses aforesaid pharmaceutical composition.In other method of the present invention, to patient's administration, wherein a kind of is to the effective medicine of treatment erection disturbance with two separated drug entities, and second kind of medicine is cognitive enhancer.In the preferred specific embodiment, be the PDE-5 inhibitor to the effective medicine of treatment erection disturbance, cognitive enhancer is the incomplete receptor stimulating agent of NMDA.One of them specific embodiment, the incomplete receptor stimulating agent of NMDA are DCS or its pharmaceutically acceptable salt.

In many specific embodiment, DCS and PDE-5 inhibitor co-administered.In other the specific embodiment, administration in DCS 12 hours before the administration of PDE-5 inhibitor or after the administration.Because DCS plays a part to consolidate knowledge behind the learning process, so be easy to expect after successfully with the PDE-5 inhibitor for treating, use DCS.

Female sexual disorder

Many gone through or be proposed to be used in the treatment male erectile dysfunction medicament also be proposed or attempt being used for the treatment of female sexual disorder.For example, test is used for the treatment of female sexual disorder to following medicament on the acute or chronic basis: Alprostadil, phentolamine, estradiol, fluorobenzene color woods, apomorphine, BUP, testosterone, sldenafil, PT-141, Vardenafil, yohimbine, tadalafil and its compositions to answer.These medicaments are oral administration sometimes, uses with ointment, suction spray or transdermal means in other cases.The method and composition that the present invention considers is used to alleviate female sexual disorder comprises to be used (i) one or more above-mentioned medicines of enumerating and (ii) strengthens cognitive chemical compound, the compositions of preferred DCS female patient.

Generally speaking, it is believed that with male erectile dysfunction and compare, psychological problem for female sexual disorder produce to influence meeting bigger.When DCS and significant feature mode are the medicament that acts on central nervous system rather than vascular flow when being used in combination, method and composition of the present invention is useful.The example of such medicament comprises apomorphine, BUP and PT-141.

In many specific embodiment of the present invention, before the romantic situation of expectation, DCS and the effectively main medicine of treatment female sexual disorder used jointly with emergent basis amount.In such specific embodiment, comprise DCS (10mg-500mg to alleviating the female sexual disorder drug composition effective, 25mg-250mg preferably approximately) and the pharmaceutically suitable salt (5mg-200mg, preferred 10mg-100mg) of sldenafil, sldenafil citrate or other sldenafil.In another specific embodiment, comprise DCS (10mg-500mg, preferred approximately 25mg-250mg) and tadalafil to alleviating the effective compositions of female sexual disorder, or its any pharmaceutically suitable salt (1mg-50mg, preferred 2mg-20mg).In another embodiment, the compositions that alleviates the effective medicine of female sexual disorder is comprised DCS (10mg-500mg, 25mg-250mg preferably approximately) and Vardenafil, Vardenafil hydrochlorate, perhaps other pharmaceutically suitable Vardenafil salt (1mg-50mg, preferred 2mg-20mg).In another specific embodiment, comprise DCS (10mg-500mg, preferably approximately 25mg-250mg) and PT-141 to alleviating the female sexual disorder drug composition effective, or its pharmaceutically acceptable salt class (2mg-20mg).In another specific embodiment, comprise DCS (10mg-500mg, preferably approximately 25mg-250mg) and apomorphine hydrochlorate (approximately 2g-25mg) to alleviating the female sexual disorder drug composition effective.In another specific embodiment, comprise DCS (10mg-500mg, preferably approximately 25mg-250mg) and BUP (about 30mg-300mg) or its pharmaceutically acceptable salt class to alleviating the female sexual disorder effective composition.

In another specific embodiment, the pharmaceutical composition that comprises BUP and DCS is based on acutely patient's administration, and when DCS and BUP when combination is not to patient's administration BUP or its pharmaceutically acceptable salt class be by the sky administration.The pharmaceutical kit of considering comprises two types pill:

Dosage form 1 comprises the BUP hydrochlorate (30mg-300mg) of effective dose, DCS of effective dose (10mg-500mg, preferably approximately 25mg-250mg) and nonactive component;

Dosage form 2 comprises the BUP hydrochlorate (30mg-300mg) and the nonactive component of effective dose.

Different dosage list agent are arranged in single agent in the packing, but continuous programming code makes the single agent of any two dosage forms 1 by single agent of at least 3 dosage forms 2 like this, and single agent of common 5 to 10 dosage forms 2 is separated.For example, representational packing places single agent of dosage form 1 the 1st day, and 8 days, the position of 15 days and administration in 22 days, single agent of dosage form 2 places all other day administration position.

In other method of the present invention, to patient's administration, wherein a kind of is to the effective medicine of treatment female sexual disorder with two separated drug entities, and wherein second kind of medicine is cognitive enhancer.

Insomnia

Efficacious agents to Cure for insomnia can be used in the method for the invention.Zaleplon (Zaleplon), zopiclone (zopiclone) zopiclone and zolpidem (zolpidem) all are the designated central nervous system's tranquilizer that is used for the treatment of insomnia.The benzene phenodiazine for example L0, clonazepam, oxazepan, flurazepam, triazolam, temazepam, alprazolam and its pharmaceutically acceptable salt class also be usually used in Cure for insomnia.Eszopiclone and indiplon are two kinds of other non-benzene two nitrogen compounds that carry out clinical experiment or conclusion has been arranged recently.

The method according to this invention and compositions, considered (i) one or more cognitive enhancer and (ii) one or more to the ataractic pharmaceutical composition of the effective CNS of Cure for insomnia.Effect to patient's applying said compositions can be consolidated insomnia drug reduces the possibility that causes the recurrent insomnia.In some embodiments, can use DCS (10mg-500mg to the patient, 25mg-250mg preferably approximately) in conjunction with one or more know usually to the Cure for insomnia efficacious agents, include but not limited to Zaleplon (5mg-40mg), zopiclone zopiclone (2.5mg-50mg), zolpidem (2.5mg-40mg), eszopiclone (1mg-10mg), indiplon (about 2.5mg-50mg), triazolam (about 0.05mg-1mg), clonazepam (about 0.1mg-2 mg), alprazolam (about 0.1mg-2.5mg), L0 (about 0.5mg-2.5mg) and its pharmaceutically acceptable salt.

Method and composition of the present invention has been considered polytype compositions.For example the dosage of eszopiclone routine is 2mg or 3mg.In a specific embodiment, the pharmaceutical kit of consideration comprises two types pill:

Dosage form 1 comprises the eszopiclone (1mg-10mg, preferred 2mg-3mg) for the treatment of effective dose, DCS (10mg-500mg, preferably approximately 25mg-250mg) and nonactive component; With

Dosage form 2 comprises the eszopiclone (1mg-10mg, preferred 2mg-3mg) and the nonactive component for the treatment of effective dose.Different dosage list agent is arranged, but continuous programming code makes so single agent of any two dosage forms 1 be separated single agent of common 6 to 10 dosage forms 2 at least by single agent of 3 dosage forms 2 in a packing.For example, representational packing places dosage form 1 single agent the 2nd day, and 8 days, 16 days and 25 days administration positions, dosage form 2 single agent are other day administration position at all.

Method of the present invention can also be implemented by two kinds of different medicine entities are provided.For example the patient to chronic insomnia can specify two kinds of different medicine entities.A kind of is the standard treatment of insomnia, for example, and indiplon 20mg every day, perhaps zolpidem tartrate 10mg every day; The second medicine entity is DCS, and it is formulated in one and comprises in two types the pharmaceutical kit of dosage:

Dosage form 1 comprises the DCS (10mg-500mg, preferably approximately 25mg-250mg) and the nonactive component of an effective dose; With

Dosage form 2 only comprises nonactive component.

Different dosage list agent can be arranged, but continuous programming code makes so any two dosage forms, 1 single agent by single agent of at least 3 dosage forms 2 separately, single agent of common 5 to 10 dosage forms 2 in a packing.For example, representational packing with dosage form 1 single agent at the 5th day, 12 days, 19 days and 26 days administration positions, dosage form 2 single agent are other administration position, sky at all.Also take second kind of pill that comprises DCS or placebo when taking two kinds of medicament purposes in the basis amount of patient every day and be the patient accepts a kind of routine in the amount of the basis of every day Insomnia therapy.

In another embodiment of the present invention, the patient takes a kind of medicament effective to Cure for insomnia in the amount of the basis of every day, (for example, the zolpidem tartrate, 2.5-20mg, preferred 5mg-10mg), and the patient have one day weekly and take other DCS (10mg-500mg, preferably approximately 25mg-250mg).

In other the specific embodiment of the present invention, the patient takes DCS (10-500mg, preferred 25-250mg is more preferably 25-100mg) and the antidepressants of three-membered ring such as the compositions of amitriptyline hydrochloride (5mg-500mg, preferably approximately 10mg-100mg) composition.

Pain

Many people suffer from chronic pain disease, usually are chronic neuropathic pain.

Many non-pharmacological technology can be used to treat neuropathic pain, the electrical nerve stimulation (TENS), acupuncture physical therapy and the psychotherapy that comprise percutaneous, but pharmacotherapy may still be used most widely for treating the method for neuropathic pain, although its success rate instability.Be usually used in treating the medicine of neuropathic pain, comprise topical formulations (topical agents), derive from several different drug types, the antidepressants of three-membered ring, the special reuptake inhibitor (SSRIs) of 5-hydroxy tryptamine, anticonvulsant, and nonopioid analgesic.

Nearest research (Science, Vol 303,1162-1167 (2004)) shows that when it is believed that pain can alleviate, feeling of pain is different.The impression of pain comes from two physiological and psychological factors, comprises individual's conviction and expectation.Thus, there is not the placebo treatment of the pharmacotoxicological effect of essence to produce the analgesic effect by the expectation that changes a people.In two groups of functional MRI imaging (fMRI) test, research worker find the placebo pain relieving with in brain pain sensitizing range, comprise that the cerebral activity that reduces in thalamus, Reil's island, the preceding cingulate cortex is relevant, and also to shift to an earlier date between the apparition enhancing of cerebral activity relevant with prefrontal cortex pain, and this has just proved that placebo has changed pain experience.

These presentation of results, the patient obviously by multiple controlling factors, much is psychological to the reaction of pain stimulation.If the patient is to the pain anxiety, the pain of being experienced is more even worse than the patient who does not worry pain usually.Therefore, use cognitive-behavioral therapy treatment chronic pain not at all surprising.The patient takes the medicine that can reduce pain will change the reaction of patient to pain in useful mode.By taking DCS simultaneously, we can consolidate those useful reactions, reduce the probability of future to possible pain untoward reaction.

Use multiple Drug therapy neuropathic pain or chronic pain, comprised gabapentin, lyrica, desmethylimipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine, Sertraline, fluvoxamine, citalopram, venlafaxine, tramadol and dilantin.In specific embodiment more of the present invention, by using DCS (10mg-500mg, 25mg-250mg preferably approximately) is selected from gabapentin (every day 100mg-4000mg accumulated dose) with one or more medicines, lyrica (every day 50mg-1000mg accumulated dose), desmethylimipramine every day (accumulated dose of 10mg-300mg), amitriptyline (every day 5mg-500mg accumulated dose), nortriptyline (every day 5mg-400mg accumulated dose), paroxetine (the accumulated dose 5mg-100mg of every day, preferred every day 10mg-40mg), Sertraline (the accumulated dose 10mg-200mg of every day), (accumulated dose of every day is at 10-100mg for citalopram, preferred 20mg-60mg), fluoxetine (the accumulated dose 10mg-80mg of every day), fluvoxamine (the accumulated dose 25mg-300mg of every day), venlafaxine (the accumulated dose 5mg-300mg of every day), and the compositions of tramadol (the accumulated dose 10mg-200mg of every day) treats the patient, and the anxiety factor relevant with neuropathic pain can be eliminated potentially.The method according to this invention, other potential can combine with DCS or other cognitive enhancer with produce to the medicine that alleviates the neuropathic pain drug composition effective comprise any other to the efficacious agents of treatment chronic pain (for example, aspirin, acetaminophen, ibuprofen, and stronger analgesic, comprise anesthetis), provide these medicaments can not weaken the enhancing cognition that produces by strengthening cognitive compounds for treating significantly.

Multiple combination is considered and alleviates chronic pain or neuropathic pain by method and composition of the present invention.According to reaction, use gabapentin with different dosage usually.In a specific embodiment, pharmaceutical kit considers to comprise two types pill:

Dosage form 1 comprises the DCS (10mg-500mg, preferably approximately 25mg-250mg) and the nonactive component of gabapentin (100-1200mg) effective dose of effective dose; With

Dosage form 2 comprises the gabapentin and the nonactive component of effective dose.

Gabapentin is taken 3 times general every day, therefore in this case, different dosage list agent is arranged in a packing, but continuous programming code makes single agent of any two dosage forms 1 be separated single agent of common 21 to 30 dosage forms 2 at least by single agent of 9 dosage forms 2 like this.For example, representational packing with dosage form 1 single agent at the 2nd day, 8 days, 16 days and 25 days (correspondingly, for example, 6,23,47 and 75) administration position, dosage form 2 single agent are other day administration position at all.It is also conceivable that DCS is included in two successive pills, separately takes in 8 hours.

Method of the present invention can also be implemented by two kinds of different preparation medicaments are provided.For example, can specify two kinds of different preparation medicaments to the patient who stands neuropathic pain or other chronic pain.A kind of medicine is the standard care that is used for the treatment of pain, such as gabapentin, lyrica or amitriptyline.Second kind of medicine is included in the DCS in the test kit, and described test kit comprises two types dosage:

Dosage form 1 comprises the DCS (10mg-500mg, preferably approximately 25mg-250mg) and the nonactive component of an effective dose; With

Dosage form 2 only comprises nonactive component.

Different dosage list agent is arranged, but continuous programming code makes so single agent of any two dosage forms 1 be separated single agent of common 5 to 10 dosage forms 2 at least by single agent of 3 dosage forms 2 in a packing.

Day, measured on the basis, and the patient will take two kinds of medicaments, therefore take a kind of pill (for example, gabapentin, amitriptyline, lyrica) of pain and another pill (comprising DCS or placebo) in this pharmaceutical kit for the treatment of.

The method according to this invention has also been considered the spacetabs type gabapentin, and can unite use with DCS.

In another specific embodiment, pharmaceutical kit comprises two types compound pill:

Dosage form 1, (for example, 20mg) DCS of effective dose is (for example, 50mg) and nonactive component to comprise the amitriptyline of effective dose; With

The amitriptyline that dosage form 2 comprises effective dose (for example, 20mg) and nonactive component.

Different dosage list agent is arranged, but continuous programming code makes so single agent of any two dosage forms 1 be separated common 5 to 10 dosage form 1 single agent at least by single agent of 3 dosage forms 2 in a packing.For example, representational packing is placed on the 1st day, 8 days, 14 days and 23 days administration positions with single agent of dosage form 1; Single agent of dosage form 2 is other day administration position at all.

In another embodiment of the present invention, the patient takes a kind of medicament (for example, amitriptyline, approximately 5mg-100mg) that is used for the treatment of chronic pain on day, measured on the basis, and the patient also has one day weekly and takes DCS tablet (10mg-500mg, preferably approximately 25mg-250mg).

Depression

The important Drug therapy of treatment depression standard comprises uses selective serotonin reuptake inhibitor (SSRIs), such as fluoxetine, paroxetine, Sertraline and fluvoxamine.Because time ratio is more lasting, SSRIs is usually with day basis amount administration.Though with respect to independent use placebo, approved SSRIs has improved drug effect, but the health benefit for the patients with depression of Radix Satyrii nepalensis and clinical research is considered, many clinical researches show, take the FDA approval SSRIs the patient and take difference between the patient of placebo less than the patient who takes placebo with do not receive difference between the patient of any control treatment.In other words, many patients that take SSRIs, more important than the physiologic effect that the biological chemistry action by medicine produces by the patient to the psychological effects of the expectation generation of success.Other specifies the medicament that is used for the treatment of depression and anxiety neurosis to comprise the antidepressants of three-membered ring usually.

Method and composition of the present invention has been considered multiple combination.For example, the common dosage of Sertraline is 50mg, 100mg or 200mg.In a specific embodiment, pharmaceutical kit has considered to comprise two types pill:

Dosage form 1 comprises the Sertraline (preferred 10mg-200mg) of effective dose, DCS of effective dose (10mg-500mg, preferably approximately 25mg-250mg) and nonactive component; With

Dosage form 2 comprises the Sertraline (preferred 10mg-200mg) and the nonactive component of effective dose.

Different dosage list agent is arranged, but continuous programming code makes so single agent of any two dosage forms 1 be separated single agent of common 5 to 10 dosage forms 1 at least by single agent of 3 dosage forms 2 in a packing.For example, representational packing is that the single agent with dosage form 1 placed the 2nd day, 8 days, and the administration position of 16 days and 25 days, dosage form 2 single agent are other day administration position at all.

Method of the present invention can also be implemented by two kinds of different pharmaceutical preparatioies are provided.For example, can specify two kinds of different pharmaceutical preparatioies to depression or social phobia patient.First kind of preparation is the standard SSRI treatment that is used for this disease, for example, paroxetine, the whole dosage 5mg-100mg of people's every day, preferred every day 10mg-40mg; Perhaps Sertraline, the accumulated dose 10mg-200mg of every day; Perhaps citalopram, the accumulated dose 10-100mg of every day, preferred every day 20mg-60mg; Fluoxetine, the accumulated dose 10mg-80mg of every day; Perhaps fluvoxamine, the accumulated dose 25-300mg of every day; Second kind of medicine is the DCS in the pharmaceutical kit, and described test kit comprises two types dosage:

Dosage form 1 comprises the DCS (25-500mg, preferred 50-100mg) and the nonactive component of effective dose; With

Dosage form 2 only comprises nonactive component.

Different dosage list agent is arranged, but continuous programming code makes so single agent of any two dosage forms 1 be separated single agent of common 5 to 10 dosage forms 2 at least by single agent of 3 dosage forms 2 in a packing.For example, representational packing is that the single agent with dosage form 1 placed the 5th day, 12 days, and the administration position of 19 days and 26 days, dosage form 2 single agent are other day administration position at all.

The patient takes the medicine of basic amount of two kinds of days every day, and purpose is that the patient will take conventional SSRI medicament with day basis amount, in addition second kind of pill that comprises DCS or placebo.

In another embodiment of the present invention, the patient with day basis amount take a kind of SSRI medicament (for example, Sertraline, 100mg), and the patient to take the DCS tablet weekly.

In other specific embodiment of the present invention, use the compositions of the antidepressants of DCS and three-membered ring to the patient.In the preferred specific embodiment, the antidepressants of three-membered ring are selected from amitriptyline, imipramine, desmethylimipramine, nortriptyline and doxepin.

Distractibility hyperkinetic syndrome (ADHD)

In order to improve conventional ADHD therapy, can be known to alleviating the compounds effective of ADHD in conjunction with one or more, comprise that methylphenidate, tomoxetine and ADDERALL XR  (can be available from ShireU.S.Inc., Wayne, a kind of amphetamine salt mixture of PA) patient is used the chemical compound that one or more strengthen cognition.In these pharmaceutical compositions, strengthen cognitive chemical compound play consolidation by the ADHD Drug therapy occur the effect of preferable behavior reaction.

Method of the present invention can also be implemented by two kinds of different medicine entities are provided: for example, ADHD patient can take two kinds of different medicine entities.First kind is the standard SSRI therapeutic agent that is used for the treatment of this disease, for example, and methylphenidate (10-40mg, two doses of every days), tomoxetine (10-60mg, every day one or two doses), perhaps amphetamine salt mixture (5-30mg every day); Second medicine is the DCS in this pharmaceutical kit, and described test kit comprises two types dosage:

Dosage form 1 comprises the DCS (10-500mg, preferred 0.5mg/kg body weight-2.0mg/kg body weight) and the nonactive component of effective dose; With

Dosage form 2 only comprises nonactive component.

Different dosage list agent is arranged, but continuous programming code makes so single agent of any two dosage forms 1 be separated single agent of common 5 to 10 dosage forms 2 at least by single agent of 3 dosage forms 2 in a packing.For example, representational packing is that the single agent with dosage form 1 placed the 5th day, 12 days, and the administration position of 19 days and 26 days, dosage form 2 single agent place all other day administration position.

The patient with day basis amount take two kinds of medicines, purpose be the patient with day basis amount take the conventional medicine that is used for the treatment of ADHD and (mean that every day repeatedly, or once a day), also have second kind of medicament that comprises DCS or placebo for some lasting products that discharge.

In another specific embodiment of method of the present invention, patient every day take methylphenidate twice, and with week the basis amount take a DCS pill.

The preparation of pharmaceutical composition

Can prepare pharmaceutical composition that method and composition of the present invention considers and to having disease as described below and painful patient uses.

The present invention includes preparation of drug combination and use, described pharmaceutical composition contain as active ingredient, treatment disease disclosed herein and obstacle compounds effective (perhaps compound compositions).Pharmaceutical composition can only be made up of active ingredient like this, make the dosage form that is suitable for patient's administration, perhaps such pharmaceutical composition can comprise active component and one or more pharmaceutically acceptable carriers, and one or more add composition, perhaps some combinations of these compositions.Active component in the pharmaceutical composition can well known to a person skilled in the art that the physiology goes up acceptable ester or salt form exists, and goes up acceptable cation or anion such as the physiology.

Chemical compound preparation salify of the present invention also is effective.If chemical compound has enough alkalescence or acidity to stablize nontoxic acid or alkaline salt with formation, using so may be proper as the chemical compound of salt.The example of pharmaceutically acceptable salt is the organic acid addition salt of being made by physiologically acceptable anionic acid, for example toluene fulfonate, mesylate, acetas, citrate, malonate, tartrate, succinate, benzoate, Ascorbate or ester, α-Tong Wuersuan and α-glycerophosphate.Also can be made into the acid-addition salts of suitable mineral acid, comprise hydrochlorate, sulfate, nitrate, heavy carbonate and carbonate.Pharmaceutically acceptable salt can adopt standard technology well known in the art to obtain, for example, and by enough alkali compoundss such as amine and suitable provide physiologically acceptable anionic acid reaction.Also can obtain the alkali metal (for example, sodium, potassium or lithium) or alkaline-earth metal (for example calcium) salt of carboxylic acid.

Use as this place, term " pharmaceutically acceptable carrier " means a kind of chemical constituent, can be in conjunction with the chemical compound of active component, and in conjunction with after be used for active component is administered to the patient.

Use as this place, the ester of term " physiology is last to be accepted " or salt mean can with the ester of the active component of other any components compatibility in the pharmaceutical composition or the form of salt, these esters or salt can not damage the patient who uses this component.

The preparation of pharmaceutical composition as described herein can prepare by the known or after this improved method in any of medicine field.Generally speaking, such preparation method comprises other the bonded step of auxiliary composition of active component and carrier or one or more, then if desired or want, product made definite shape or be packaged into the single or multiple dose unit of wanting.

The pharmaceutical composition to human administration of suitable ethics has been provided in the description of this pharmaceutical composition that provides.

The pharmaceutical composition that is used for method of the present invention can be oral to be suitable for, in rectum, vagina, parenteral, partial, lung, intranasal, the oral cavity, eye usefulness, the sheath or in addition route of administration the dosage form preparation, pack or sell.Other preparation that can consider comprises injection microgranule, lipid formulations, comprises the reformation erythrocyte (resealed erythrocytes) and the immune formulation of active ingredient.

Pharmaceutical composition of the present invention can be with single single agent dose or a plurality of single single agent dose preparation, packing or sell by wholesale.Use as this place, one " single agent dose " is the dispersion amount that comprises the pharmaceutical composition of active component scheduled volume.The dosage of active component be generally equal to dosage or the suitable decrement of this dosage, for example half of dosage or 1/3rd of patient's administration.

Active ingredient compositions of the present invention can medicine the component form of compression provide.Two kinds of medicines can be prepared or separately preparation together by a people's dosage.

Active ingredient in pharmaceutical of the present invention, pharmaceutically acceptable carrier and the relative quantity of adding composition can and change according to route of administration further according to the patient's who is treated characteristic, body weight and situation.For example, compositions can comprise the active component between 0.1% and 100% (w/w).

The treatment effective dose of medicament can adopt any medically acceptable administering mode administration.Although those skilled in the art can consider the known administering mode of any those of ordinary skill, preferred still according to the administering mode of recommending, for example, in the commercial obtainable Drug packing in the incidental explanation listed administering mode come administration.

The control of pharmaceutical composition of the present invention or slow releasing preparation can adopt conventional technology preparation.

The preparation that the present invention is suitable for oral pharmaceutical composition can adopt the agent of dispersed solids dosage list with following form preparation, packing or sale, include but not limited to tablet (tablet), hard or soft capsule, cachet, tablet (troche) or lozenge, every kind of active component that all comprises scheduled volume.Other is suitable for suspending agent, water or oily solution or Emulsion that oral preparation includes but not limited to powder or granular preparation, water or oil.

Use as this place, " oil " body is meant a kind of carbonaceous liquid molecule, and polarity shows low than water.

The tablet that comprises active component is passable, for example, chooses any one kind of them or multiple interpolation composition, by compacting or moulding making.The compacting tablet can choose wantonly and one or more binding agents, lubricant, excipient, surfactant and dispersant, use suitable device, with active component compress into non-current form as powdery or granular preparation.Mould the film-making agent can with suitable device with active component,, pharmaceutically acceptable carrier and be enough to mixture that the liquid of moistening mixture forms at least and carry out moulding with mould and produce.The pharmaceutically acceptable excipient that is used to make tablet includes, but are not limited to inert diluent, pelletize and disintegrating agent, binding agent and lubricant.Known dispersant includes, but are not limited to, potato starch and sodium starch glycollate.Known surfactant comprises, but is not limited to SDS.Known diluent includes but are not limited to, calcium carbonate, sodium carbonate, lactose, microcrystalline Cellulose, calcium phosphate, calcium hydrogen phosphate and sodium phosphate.Known pelletize and disintegrating agent include, but are not limited to, corn starch and alginic acid.Known binding agent includes but are not limited to, gel, arabic gum, pre-gluing, corn starch, polyvinylpyrrolidone and hydroxypropyl emthylcellulose.Known lubricant includes, but are not limited to, magnesium stearate, stearic acid, silicon dioxide and Talcum.

Tablet is overlay film or use known method to carry out overlay film not, make to prolong in patient's gastrointestinal tract to decompose, so active component is continued to discharge and absorption.As an example, be used for the tablet overlay film such as materials such as glyceryl monostearate or stearic acid diglycerides.Further, can use U.S. Patent number 4,256,108; 4,160,452 and 4,265,874 described methods are carried out overlay film to tablet.For pharmaceutically attractive in appearance and good to eat preparation are provided, tablet can further comprise the compositions of sweeting agent, flavoring agent, coloring agent, antiseptic or above-mentioned substance.

Can utilize the physiology to go up degradable composition, prepare the hard capsule that comprises active component as gelatin.This hard capsule comprises active component, and also can further comprise the interpolation composition and comprise, for example, inert solid diluent such as calcium carbonate, calcium phosphate or Kaolin.

Can utilize the physiology to go up degradable composition, prepare the soft capsule that comprises active component as gelatin.The active component that this soft capsule comprises can with water or oils medium such as Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil.

The present invention be suitable for oral pharmaceutical composition liquid preparation can with liquid state or use before need water or another kind of the suitable carriers synthetic again preparation of dry labor thing form, packing and sell.

Can prepare liquid suspension with the method for routine, make active component be suspended in aqueous or the oil medium.Aqueous medium comprises, for example, and water and isotonic saline solution.Oil medium comprises, for example, and almond oil, grease, ethanol, vegetable oil such as Semen arachidis hypogaeae, Fructus Canarii albi, Semen Sesami or Oleum Cocois, fractionated vegetable oil and mineral oil such as liquid paraffin.Liquid suspension can comprise one or more interpolation compositions further and include, but not limited to suspending agent, dispersant or wetting agent, emulsifying agent, demulcent, antiseptic, buffer, salt, flavoring agent, coloring agent and sweeting agent.The oiliness suspending agent can comprise thickening agent further.Known suspending agent comprises, but be not limited to Sorbitol syrup, hydrogenation edible fat, sodium alginate, polyvinylpyrrolidone, gum tragacanth, Radix Acaciae senegalis and cellulose derivative such as sodium carboxymethyl cellulose, methylcellulose, hypromellose.Known dispersant or wetting agent comprise, but be not limited to, the phospholipid of natural generation such as lecithin, alkylene oxide and fatty acid, long chain aliphatic, derived from the incomplete ester of fatty acid and hexitol or the product that carries out condensation derived from the incomplete ester (for example, being respectively polyoxyethylene 8 stearate salt, heptadecaethyleneoxycetanol, octadecanoic acid ester of polyethylene glycol and polyoxyethylene sorbitan monooleate) of fatty acid and hexitol anhydride.Known emulsifying agent comprises, but is not limited to lecithin and arabic gum.Known antiseptic includes but are not limited to, methyl, ethyl or n-propyl group-right-hydroxy benzenes hydrochlorate, ascorbic acid and sorbic acid.Known sweeting agent comprises, for example, and glycerol, propylene glycol, sorbitol, sucrose and glucide.The known thickening agent that is used for oily suspensions comprises, for example, and Cera Flava, hard paraffin and spermol.

The liquid solution that is dissolved in the active component in aqueous or the oil-based solvent can prepare with the same method of liquid suspension substantially, and its main difference is that those active component are dissolved rather than are suspended in the solvent.The liquid solution of pharmaceutical composition of the present invention can comprise the described every kind of component of liquid suspension, and suspending agent may not help the dissolving of active component in solvent certainly.Aqueous solvent comprises, for example, and water and isotonic saline solution.Oil-based solvent comprises, for example, and almond oil, grease, ethanol, vegetable oil such as Semen arachidis hypogaeae, Fructus Canarii albi, Semen Sesami or Oleum Cocois, fractionated vegetable oil and mineral oil such as liquid paraffin.

The powder of pharmaceutical preparation of the present invention and granular preparation can use known method preparation.This preparation can be directly to patient's administration, and type of service thinks, for example, and the solution of tablet, capsule, aqueous or oily suspensions, interpolation aqueous or oil medium.Each of these preparations all can further comprise one or more dispersants or wetting agent, suspending agent and antiseptic.Extra excipient as filler and sweeting agent, flavoring agent or coloring agent, also can be included in these preparations.

Pharmaceutical composition of the present invention also can be with form preparation, packing or the sale of oil-in-water emulsion or water in oil emulsion.Oil phase can be vegetable oil such as olive oil or Oleum Arachidis hypogaeae semen, mineral oil such as liquid paraffin, or their combination.This compositions can further comprise one or more emulsifying agents such as naturally occurring natural gum such as Radix Acaciae senegalis or gum tragacanth, spontaneous phospholipid such as Semen sojae atricolor or lecithin, derived from fatty acid and the bonded ester of hexitol anhydride or the not exclusively condensation product such as the polyoxyethylene sorbitan monooleate of ester such as dehydrated sorbitol mono-fatty acid ester and this incomplete ester and ethylene oxide.These Emulsions also can comprise the interpolation composition and comprise, for example, and sweeting agent or flavoring agent.

Pharmaceutical composition of the present invention can be to be suitable for dosage form preparation, packing or the sale of rectally.This compositions can be for example suppository, retention enema and be used for rectum or the dosage form of the solution of colon clysis.

Active component and non-irritating pharmaceutically acceptable excipient can be made up and prepare suppository, described excipient is a solid under room temperature (promptly about 20 ℃), and is liquid under patient's rectal temperature (be in the healthy human body about 37 ℃).Suitable acceptable excipient includes but are not limited to cocoa butter, Polyethylene Glycol and multiple glyceride.Suppository can further comprise multiple interpolation composition and include, but not limited to antioxidant and antiseptic.

Active component and pharmaceutically acceptable liquid-carrier can be made up and prepare the retention enema or be used for rectum or the solution of colon clysis.This area is well-known, and enema preparation can use the conveyer device that is adapted to patient's rectum structure to carry out administration, and medicament can be packaged in this device.Enema preparation can further comprise multiple interpolation composition and include, but not limited to antioxidant and antiseptic.

Pharmaceutical composition of the present invention can be to be suitable for dosage form preparation, packing or the sale of vagina administration.Said composition can be made, and for example, suppository, vagina that infiltrated or the bag quilt can insert material such as stopper thing, irrigation or gel, ointment, be used for the solution of vaginadouche.

Method with chemical compound infiltration or capsulating material is well known in the art, comprise, but be not limited to chemical compound deposition or be bonded to material surface method, between synthesis stage chemical compound mixed method in material (degradable material on promptly for example with the physiology) structure at material, and, carry out or do not carry out exsiccant method subsequently with in aqueous or oily solution or the suspension suction absorber material.

Active component and pharmaceutically acceptable liquid-carrier can be made up the solution for preparing irrigation or be used for vaginadouche.This area is well-known, and irrigation can use the conveyer device that is adapted to patient's vagina structure to carry out administration, and medicament can be packaged in this device.Irrigation can further comprise multiple interpolation composition and include, but not limited to antioxidant, antibiotic, antibacterial and antiseptic.

Use as this place, " the parenterai administration parenterai administration " of pharmaceutical composition comprises any to cause the physical cut of patient tissue, and pharmaceutical composition enters by this otch and is the route of administration of feature in the tissue then.Therefore, the parenterai administration parenterai administration includes, but not limited to by the pharmaceutical composition drug administration by injection, by the administration of operating otch application said composition, non-surgery operation wound application said composition administration by tissue penetration, or the like.Especially, the parenterai administration of consideration includes but are not limited to, subcutaneous, Intraabdominal, intramuscular, intrasternal injection and kidney dialysis input technology.

The drug combination preparation that is applicable to parenterai administration comprises the active component with pharmaceutically acceptable carrier such as sterilized water or aseptic isotonic saline solution combination.Pharmaceutical composition of the present invention can be to be suitable for concentrating form preparation, packing or the sale of administration or successive administration.Injectable preparation can for example be accompanied in the bottle in peace with the form of dosage unit, or is prepared, packs or sell in the container that comprises antiseptic of multiple dose.The preparation that is used for parenterai administration includes but are not limited to, suspension, solution, the Emulsion that is dissolved in oiliness or aqueous medium, paste and implantable slow release or biodegradable preparation.This preparation may further comprise one or more interpolation compositions and include, but not limited to suspending agent, stabilizing agent or dispersant.In the specific embodiment of non-intestinal drug delivery agent, active component provides with dried forms (being powdery or granular)), be used for reconfiguring with suitable medium (as aseptic no pyrogen water), the composition that this is reconfigured is through parenterai administration subsequently.

Pharmaceutical composition can be with form preparation, packing or the sale of aseptic injectable aqueous or oily suspensions or solution.Suspension or solution can also can comprise interpolation composition described herein such as dispersant, wetting agent or suspending agent except that active component according to technology preparation known in the art.Aseptic injectable preparation for example, can use nontoxic diluent or solvent such as water or 1 of can non-intestinal accepting, the preparation of 3-butanediol.Other acceptable diluent and solvent include but are not limited to, normal saline, isotonic sodium chlorrde solution and fixed oil such as synthetic list (monoor) two glyceride.It is microcrystalline form, liposome form or as the preparation of biodegradable polymers compositions that but other useful non-intestinal drug delivery agent comprises those active component wherein.The compositions that is used for lasting release or embedding can comprise pharmaceutically acceptable polymeric or hydrophobic material such as emulsion, ion exchange resin, sl. sol. polymer or sl. sol. salt.

The preparation that is applicable to topical includes but are not limited to, liquid or semi-liquid preparation such as liniment, lotion, oil-in-water or water in oil emulsion such as emulsifiable paste, ointment or paste, and solution or suspension.But the preparation of topical can, for example, comprise about 1%-about 10% (w/w) active component, although the concentration of active component can be high to the solubility limit of active component in solvent.The preparation that is used for topical can further comprise one or more interpolation compositions described here.

Pharmaceutical composition of the present invention can be to be suitable for the preparation of pulmonary administration dosage form, packing or the sale through the oral cavity.This preparation can comprise the dried particles that contains active component, about 7 nanometers of the about 0.5-of described particle diameter, preferably approximately about 6 nanometers of 1-.Come administration for the air-flow that utilizes a kind of its release device directly dispersed powders, that contain the dry powder reservoir, perhaps administration is to utilize a kind of device that contains self-propelled solvent/powder distributor disk, for example this device contains a sealed container, lower boiling propellant wherein dissolves or is suspended with active component, and this dry powder form compositions is very easily.Preferably, comprise in this powder by weight at least 98% particle diameter greater than 0.5 nanometer and by the particle diameter of quantity at least 95% less than 7 nanometers.Preferred, by weight at least 95% particle diameter greater than 1 nanometer and by the particle diameter of quantity at least 90% less than 6 nanometers.Dry powder composite preferably comprise the solid fines diluent as sugar and be single agent dose form of being convenient to provide.

Low-boiling propellant is usually included in the propellant that boiling point under the normal pressure is lower than 65 .Usually, propellant accounts for the 50-99.9% (w/w) of compositions, and active component accounts for the 0.1-20% (w/w) of compositions.Propellant can further comprise interpolation composition such as non-ionic or solid-state anion surfactant of liquid state or solid-state diluent (preferably its granular size is same progression with the granule that comprises active component).

The pharmaceutical composition that the present invention is used for lung diffusion also can be that the microdroplet form of solution or suspension provides active component.This preparation can be chosen the aseptic aqueous that comprises active component or solution form or formulated as suspensions, packing or the sale of alcohol,diluted wantonly, can use any suitable nebulization or atomising device administration easily.This preparation can further comprise one or more interpolation compositions and include, but not limited to flavoring agent such as saccharin sodium, volatile oil, buffer agent, surfactant or antiseptic such as methyl nipagin (methylhydroxybenzoate).The preferred average diameter of microdroplet that provides by this route of administration is in about 200 nanometers of about 0.1-.

The drug combination preparation that is used for lung diffusion described here also is used for intranasal and spreads pharmaceutical composition of the present invention.

Another is applicable to that the preparation of intranasal administration is the coarse powder that comprises active component and the about 0.2-500 micron of diameter.This preparation adopts the mode administration of snuffing, that is, suck rapidly from dust container by nasal passage.

The preparation that is applicable to nasal administration is passable, for example, comprises and arrives about 0.1% (w/w) less and the active component of as many as 100% (w/w) also can further comprise one or more interpolation compositions described here.

Pharmaceutical composition of the present invention can be to be suitable for dosage form preparation, packing or the sale of oral administration.This preparation is passable, for example, uses conventional method to make tablet or lozenge, and for example comprises 0.1-20% (w/w) active component, balancedly contains in the oral cavity soluble or degradable compositions and choosing any one kind of them or multiple interpolation composition described here.Perhaps, the preparation that is applicable to oral administration can comprise the powder that comprises active component, atomizing or atomizing solution or suspension.After disperseing, this powdered, atomizing or preferred average grain of atomizing preparation or drop size be in about 200 nanometers of about 0.1-, and may further include one or more interpolation compositions described here.

Pharmaceutical composition of the present invention can be to be suitable for dosage form preparation, packing or the sale of dosing eyes.For example, this preparation can be made the active component that is dissolved in aqueous or oil-based liquid carrier that comprises 0.1-1.0% (w/w) in eye drop such as solution or the suspension.This drop may further include buffer agent, salt or one or more other interpolation composition described here.It is the preparation of microcrystalline form, liposome form that but the preparation of the parenterai administration that other is useful comprises those active component.

Use as this place, " interpolation composition " comprises, but be not limited to following one or more: excipient, surfactant, dispersant, inert diluent, pelletize and disintegrating agent, binding agent, lubricant, sweeting agent, flavoring agent, coloring agent, antiseptic, degradable compositions such as gelatin on the physiology, aqueous medium and solvent, oil medium and solvent, suspending agent, disperse or wetting agent, emulsifying agent, demulcent, buffer, salt, thickening agent, filler, emulsifying agent, antioxidant, antibiotic, antibacterial, stabilizing agent and pharmaceutically acceptable polymeric or hydrophobic material.Other " the interpolation composition " in the pharmaceutical composition of the present invention of being included in is known in the field and for example Genaro chief editor, 1985, Remington ' s Pharmaceutical Sciences, Mack Publishing Co., Easton, the described interpolation composition of PA, here in the lump as a reference.

The component that active ingredient compositions of the present invention can be used as drug packages provides, and drug packages refers to " test kit " here.Two kinds of medicines can fit over together, or with independently separately preparation of dosage.

Especially, the present invention has considered to place a test kit that comprises two kinds of different dosage forms in packing to be convenient to continuously every day oral: dosage form 1, and comprise and strengthen cognitive chemical compound and dosage form 2, lack and strengthen cognitive chemical compound.The dosage of taking is single agent of taking dosage form 1 on day basis amount, and this list agent is by single agent of at least 3 dosage forms 2, and 5 to 10 dosage form 2 single agent separate with single agent of other dosage form 1 typically.

In the simplest specific embodiment, DCS is unique active component in single agent of dosage form 1, and single agent of dosage form 2 does not have active component.This specific embodiment is very effective, because preparation can combine with many different pharmaceutical treatments of taking every day effectively.Other representational specific embodiment is listed in the table below:

The active component of dosage form 1	The active component of dosage form 2
		Gabapentin, the DCS lyrica, the DCS methylphenidate, the DCS Zaleplon, the DCS zolpidem, the DCS lyrica, D-serine methylphenidate, D-serine Zaleplon, D-serine zolpidem, the ACPC zopiclone, DCS Indiplon, the DCS eszopiclone, the DCS fluoxetine, the DCS fluvoxamine, the DCS paroxetine, the DCS Sertraline, the DCS citalopram, the DCS escitalopram, the DCS amphetamine, dextroamphetamine, the DCS nortriptyline, the DCS amitriptyline, the DCS desmethylimipramine, the DCS BUP, DCS	Gabapentin lyrica methylphenidate Zaleplon zolpidem lyrica methylphenidate Zaleplon zolpidem zopiclone Indiplon eszopiclone Prozac Fluvoxamine Paxil Sertraline Citalopram escitalopram amphetamine, dextro-amphetamine nortriptyline amitriptyline desipramine BUP

Tomoxetine, DCS clonazepam, DCS alprazolam, DCS

Tomoxetine clonazepam alprazolam

Dosage

For strengthening cognitive chemical compound, the dosage of adult patients is about 0.1mg-5g.In a specific embodiment, when cognitive enhancer is the D-serine, the about 50mg-5g of dosage that adult patients is considered.

When cognitive enhancer is DCS, the about 5mg-1g of the dosage of adult patients, 25mg-500mg usually.The treatment effective dose of medicament can adopt medically acceptable any administering mode to come administration.Although those skilled in the art can consider any administering mode that the member of ordinary skill knows, preferably according to the administering mode of suggestion, for example, the administering mode of being enumerated on the commercial pharmaceutical products packing comes administration.In that approximately the DCS dosage level between 5mg and the 150mg may be relatively good, because the reaction that this dosage provides enough cognitive reinforced effects to expect with consolidation still seldom has side effect.The dosage level of the about 25mg-100mg of DCS may be more favourable, because the reaction that this dosage provides enough cognitive reinforced effects to expect with consolidation, but seldom have side effect.The dosage level of DCS is the concentration of little antimicrobial (that is, this dosage can not kill or limit significantly the growth of bacterium) for most bacterium at 25mg-100mg; Especially, dosage is little antimicrobial concentration at 25mg-75mg for the antibacterial of larger proportion, and dosage is little antimicrobial concentration at 25mg-50mg for the antibacterial of larger proportion.

The dosage level that is used to alleviate the main medicine of the misery that recurrent need treat comprises any treatment effective dose of FDA approval.Usually, these dosage are at about 0.1mg-5g.

Embodiment

Now in conjunction with describing the present invention with reference to the following specific embodiment.It only is in order to exemplify that these embodiment are provided, and the present invention must not be infer to is limited to these embodiment, and should be understood that to comprise any He all obvious improvement of instruction in view of the above.

Pharmaceutical composition of the present invention can be further with following embodiment explanation, to scope of invention without limits.Specific embodiment 5-16 is a preliminary experiment.

The medicament of the FDA approval of the following examples that are useful on all can obtain from the supplier and/or the pharmacy of commerce.All active component that are used for human patients among the following embodiment all are used for the people by the FDA approval.Comprise solid powder or the granule that the capsule of various active constituents mixt can be by weighing active component and incapsulate and obtain.

Embodiment 1

Treated by the amitriptyline hydrochloride of patient's medication every day 10mg of recurrent neuropathic pain torment seven days, pain is had slight curative effect.After seven days, the amount of amitriptyline is doubled to 20mg.Through high-dose therapy two days later, patient's pain has gone down basically.The patient is subsequently with containing 20mg amitriptyline, 25mg DCS and the pharmaceutically capsule list agent treatment of inert fraction.Subsequently, the patient takes 20mg amitriptyline (not containing DCS) again, reduces dosage gradually to stopping treatment, around continuing.

Embodiment 2

10mg zolpidem tartrate and 50mg DCS blend together powder, add following inert fraction: hydroxypropyl emthylcellulose lactose, magnesium stearate, microcrystalline Cellulose, Polyethylene Glycol, sodium starch glycollate and titanium dioxide incapsulate after the mixing.Capsule takes for the patient of the transient insomnia torment that is subjected to recurrent.After taking capsule, the patient begins to have a short and sleep that sleep quality is good.At 5 nights afterwards, the patient takes the capsule that comprises 5mg zolpidem tartrate, does not take DCS jointly.In the 7th evening, the patient takes and contains 5mg zolpidem tartrate and 50mg DCS, adds following inert fraction: the single capsule of hydroxypropyl emthylcellulose, lactose, magnesium stearate, microcrystalline Cellulose, Polyethylene Glycol, sodium starch glycollate and titanium dioxide.The patient stops further to treat.The patient is to sleep, and particularly the anxiety of awakening at midnight has descended, and the patient finds to be easy to recover sleep state.

Embodiment 3

Sldenafil citrate (50mg) and DCS (50mg) are mixed into powder, adding inert fraction comprises: microcrystalline Cellulose, Calcium monohydrogen phosphate, croscarmellose sodium, magnesium stearate, hydroxypropyl emthylcellulose, titanium dioxide, lactose and glyceryl triacetate incapsulate after the mixing.

Embodiment 4

Healthy volunteer takes and contains about 50mg sldenafil citrate and 50mg DCS, also has the capsule of inert fraction.Estimate pharmaceutical composition in intraindividual ill effect or effect, report wherein has no adverse reaction.Also estimated the effect of pharmaceutical composition to sexual function improving.

Embodiment 5

Following component is sieved and is fully mixed: DCS (200g), sldenafil citrate (50g), lactose and microcrystalline cellulose mixt (700g), polyvinylpyrrolidone (100g), cellulose ether (100g), silicon dioxide (4g).Magnesium stearate is also sieved and is mixed with the mixture of other component.Compositions is made tablet and every heavy 1.16g.Through extruding, use the moisture film coating.The thickness of film is variable.

Embodiment 6

DCS 50g, tadalafil 20g, lactose 75g and 100g Talcum with make granule and dry after the ethanol of q.s mixes.The granule that obtains or be squeezed into tablet or incapsulate wherein contains 50mg DCS and 20mg Vardenafil.This pharmaceutical composition can be used for alleviating erection disturbance.

Embodiment 7

DCS 125g, Vardenafil hydrochlorate 20g, lactose 75g and 100g Talcum with make granule and dry after the ethanol of q.s mixes.The granule that obtains or be squeezed into tablet or incapsulate contains 125mgDCS and 20mg Vardenafil.This pharmaceutical composition can be used for alleviating erection disturbance.

Embodiment 8

DCS 50g, zolpidem tartrate 5g, lactose 50g and 75g Talcum with make granule and dry after the ethanol of q.s mixes.The granule that obtains or be squeezed into tablet or incapsulate contains 50mg DCS and 5mg zolpidem tartrate.This pharmaceutical composition can be used for alleviating insomnia.

Embodiment 9

The tablet manufacturing technology of employing standard comprises the tablet of amitriptyline and DCS (75mg) with the drug excipient preparation of standard.This tablet can be used for alleviating the misery that following one or more recurrents need be treated: neuropathic pain, insomnia and depression.

Embodiment 10

Proved that erection disturbance responds to the Drug therapy with PDE-5 inhibitor such as sldenafil.In the clinical research of following placebo at random, the acute treatment that carries out with the incomplete receptor stimulating agent of NMDA strengthens the effect of using PDE-5 inhibitor for treating erection disturbance.

Research divides 3 processing, patient only to take that placebo, patient only take the PDE-5 inhibitor and the patient takes PDE-5 inhibitor and DCS compositions.Especially, the patient of therapeutic alliance is with the capsule administration that comprises sldenafil citrate (50mg) and DCS (75mg) compositions.The patient of single medicine therapy uses the capsule administration that comprises sldenafil citrate (50mg).Based on the cause of disease of patient's erection disturbance, the patient is divided into three types (bion, mental type, mixed types).All patients all are apprised of and will carry out clinical trial with different processing, and the research new drug is to alleviating the effect of erection disturbance.The research has continued 9 months.

Be similar to previous clinical research, to male's the ability of carrying out sexual activity and reach and the therapeutic effect that keeps being enough to finishing the erection of satisfied sexual activity is estimated to erection disturbance.The patient during when beginning research, research and the self evaluation of research back sexual function, be used to evaluate the successful property of therapy.The persistency of erecing in frequency that success is permeated during sexual activity and infiltration back is two important problem.After 6 months Drug therapy, Drug therapy finishes, and with same sexual function index evaluation patient, during 3 months subsequently, the patient does not take the medicine that is used for the treatment of erection disturbance.

Research subsequently can be at by the disease cause of disease, age or the erection disturbance patient who does not have carcinoma of prostate to divide into groups.

Embodiment 11

Proved that insomnia responds to the Drug therapy of carrying out with chemical compound such as zolpidem tartrate.In following placebo clinical research at random, the acute treatment that carries out with NMDA glutamate receptor agonist strengthens the effect for the treatment of chronic insomnia with the zolpidem tartrate.

Research divides 3 processing, patient only to take that placebo, patient only take zolpidem tartrate (10mg every day) and the patient takes zolpidem tartrate and DCS compositions.Especially, the therapeutic alliance patient takes a kind of in two kinds of medicaments every day.At 2-7,9-14,16-21 and 2 3-28 days, the patient took and comprises the capsule of zolpidem tartrate (10mg) as unique active component.The 1st, 8,15 and 29 days, the patient took the capsule that comprises zolpidem tartrate (10mg) and DCS (50mg).All patients all are apprised of and will carry out clinical trial with different processing, and the research new drug is to alleviating the effect of insomnia.Evaluate patient sleep required time (Sleep latency) and Sleep efficiency.

The patient also is used to estimate the successful property of therapy to the self evaluation of insomnia.Carry out patient's evaluation subsequently after three months.Final problem comprises the frequency of insomnia and the persistent period of insomnia.

Embodiment 12

Proved that depression responds to the Drug therapy with SSRIs.Many patients that alleviated symptom with SSRIs treatment do not feel that symptomatic recurrence has just stopped Drug therapy.In following therapeutic scheme, there is the patient of clear reaction also intermittently to treat with DCS to Fluoxetine in Treatment.

Patients with depression with day basis amount take the treatment that two kinds of medicaments carry out 30 days:

1. comprise DCS (100mg) or the agent of placebo peridium patch; With

2. fluoxetine, 20mg.

But first kind of medicament places the pharmaceutical kit of continuous programming code, takes the DCS tablet at the 5th, 15 and 25 day, and other date is taken placebo tablet at all.Placebo tablet and DCS tablet are distinguished to be come out in appearance.

With respect to the patient who only uses Fluoxetine in Treatment, the patient who accepts therapeutic alliance has on average reduced anxiety, and seldom can feel and recur to the state of essential extra Drug therapy.

Embodiment 13

The chronic insomnia patient with day basis amount take the treatment that two kinds of medicaments carry out 30 days:

(1) comprises the tablet of the bag quilt of DCS (100mg) or placebo; With

(2)indiplon，20mg。

First kind of medicine (that is, containing the coated tablet of DCS or placebo) but place the pharmaceutical kit of the packing that contains continuous programming code, took the DCS tablet at the 3rd, 10,17 and 24 day, other date is taken placebo tablet at all.Placebo tablet and DCS tablet are distinguished to be come out in appearance.

With the patient of indiplon treatment, the patient who receives therapeutic alliance seldom can feel recurs to the state of essential extra Drug therapy with respect to only.

Embodiment 14

The patient of neuropathic pain patients and dyskoimesis with day basis amount take amitriptyline (20mg), totally 30 days.Per seven days, the patient used DCS (50mg) treatment in addition.With respect to the patient who only uses amitriptyline in treatment, the patient with the DCS acute treatment has more positive Drug therapy result in addition, has strengthened the remission effect of neuropathic pain and/or dyskoimesis.

Embodiment 15

But neuropathic pain patients is taken the medicinal tablet totally 30 days in the packing that places continuous programming code every day, and tablet comprises following two kinds of dosage forms:

(1) amitriptyline (20mg) and DCS (50mg)

(2) amitriptyline (20mg)

Two kinds of dosage forms of tablet are distinguished not come out.But the composition tablet that comprises amitriptyline and DCS in the packing of continuous programming code was taken the 3rd, 10 in 17 and 24 days, the Endep in this pharmaceutical kit (not containing DCS) at all other date take.

Temporary transient or long-term in, with respect to the patient who only uses amitriptyline in treatment, the patient who receives therapeutic alliance can alleviate neuropathic pain biglyyer.

Embodiment 16

One group 28 peridium patch agent places in the blister package of a coding.These 28 tablets of tablets comprise that 4 tablets of tablets that contain DCS (100mg) and conventional drug excipient and 24 comprise conventional drug excipient but do not contain the placebo tablet of DCS.All peridium patch agent are distinguished to be come out in appearance.The DCS tablet places the 1st, 9, in 18 and 27 the digital groove.Illustrate on the blister package, taken a slice tablet if the patient forgot in some day, correct method is to take two tablets of tablets subsequently one day so.

To those skilled in the art, described in this description and all publications and patent application be to be subordinated to of the present inventionly, be indicative.All publications and patent application, resemble each independent publication or patent application and are all pointed out the reference that is cited especially and individually with the equal extent reference that is cited at this.Although for the clear purpose of understanding, described the present invention in detail, obviously, in the representative specific embodiment scope of these these notions proposed below, can carry out some changes and improvements by the explanation and the specific embodiment.Dependent claims has a mind to comprise the specific embodiment and the equivalent variations that all are such.

Industrial applicibility

Described such as this place, method and composition of the present invention can be used for alleviating the misery of the needs treatment of human recurrent.

Claims (38)

1. the method for the misery of a needs treatment that is used to alleviate patient's recurrent comprises the patient is treated effective dose:

(i) at least a first medicament or its pharmaceutically acceptable salt that strengthens cognition; With

Second medicament or its pharmaceutically acceptable salt of the misery that the (ii) at least a needs that alleviate described recurrent are treated;

Wherein said first kind of medicament is with the amount administration of acute basis.

2. method as claimed in claim 1 is wherein united the misery that only more can alleviate the needs treatment of described recurrent to the method ratio of patient's administration with the second medicament administration effectively with described first medicament in conjunction with described second medicament.

3. the method for claim 1, wherein said first medicament is the incomplete receptor stimulating agent of NMDA.

4. the method for claim 1, wherein said first medicament comprises DCS or its pharmaceutically acceptable salt.

5. method as claimed in claim 4, the dosage of wherein said DCS or its pharmaceutically acceptable salt is about 0.25mg/kg-10mg/kg weight in patients.

6. method as claimed in claim 4, wherein compound vitamin B and described DCS or its pharmaceutically acceptable salt administering drug combinations.

7. method as claimed in claim 4, the misery of the needs treatment of wherein said recurrent is an erection disturbance.

8. method as claimed in claim 7, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from sldenafil, tadalafil and Vardenafil.

9. method as claimed in claim 4, the misery of the needs treatment of wherein said recurrent is a female sexual disorder.

10. method as claimed in claim 9, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from sldenafil, tadalafil, Vardenafil, PT-141, BUP and apomorphine.

11. method as claimed in claim 4, the misery of the needs treatment of wherein said recurrent is insomnia.

12. method as claimed in claim 11, wherein second medicament or its pharmaceutically acceptable salt comprise be selected from eszopiclone, indiplon, Zaleplon, zopiclone, zolpidem, L0, clonazepam, oxazepan, medicament or its pharmaceutically acceptable salt of flurazepam, triazolam, temazepam and alprazolam.

13. method as claimed in claim 4, the administration frequency of wherein said second medicament or its pharmaceutically acceptable salt more than or equal to once a day and wherein said second medicament or its pharmaceutically acceptable salt administration persistent period more than or equal to four days.

14. method as claimed in claim 13, the misery of the needs treatment of wherein said recurrent is selected from chronic pain and neuropathic pain.

15. method as claimed in claim 14, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from lyrica, gabapentin, nortriptyline and amitriptyline.

16. method as claimed in claim 13, the misery of the needs treatment of wherein said recurrent is insomnia.

17. method as claimed in claim 16, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from eszopiclone, indiplon, Zaleplon, zopiclone and zolpidem.

18. method as claimed in claim 13, the misery of the needs treatment of wherein said recurrent is to lax hyperkinetic syndrome.

19. method as claimed in claim 18, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from methylphenidate, tomoxetine, amphetamine and dextroamphetamine.

20. method as claimed in claim 13, the misery of the needs treatment of wherein said recurrent is a depression.

21. method as claimed in claim 20, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from desmethylimipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine, Sertraline, fluvoxamine and citalopram.

22. method as claimed in claim 13, the misery of the needs treatment of wherein said recurrent is a female sexual disorder.

23. method as claimed in claim 22, wherein second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from BUP, testosterone and estradiol.

24. a pharmaceutical kit comprises for the successive administration once a day of patient is provided with independently dosage list agent, comprising:

(i) 2-20 first dosage list agent, the wherein said first dosage list agent comprises:

A. medicine acceptable carrier;

B. at least a first medicament or its pharmaceutically acceptable salt that strengthens cognition;

C. alleviate second medicament or its pharmaceutically acceptable salt of treatment effective dose of misery of the needs treatment of recurrent;

(ii) 4-90 second dosage list agent, the wherein said second dosage list agent comprises:

A. pharmaceutically acceptable carrier; With

B. alleviate second medicament or its pharmaceutically acceptable salt of treatment effective dose of misery of the needs treatment of recurrent;

Wherein each first dosage list agent separates by the agent of at least 3 second dosage lists and the other first dosage list agent; Do not comprise described first medicament with the wherein said second dosage list agent.

25. pharmaceutical kit as claimed in claim 24, wherein said first medicament is DCS, or its pharmaceutically acceptable salt, and the about 25mg-500mg of treatment effective dose of DCS wherein.

26. pharmaceutical kit as claimed in claim 24, wherein said first dosage list agent and the described second dosage list agent are oral administrations.

27. the pharmaceutical composition of the misery of a needs treatment that is used to alleviate patient's recurrent comprises:

(i) a kind of first medicament or its pharmaceutically acceptable salt that strengthens cognition; With

Second medicament or its pharmaceutically acceptable salt of the misery that (ii) a kind of needs that alleviate described recurrent are treated; With

(iii) pharmaceutically acceptable carrier.

28. pharmaceutical composition as claimed in claim 27, the misery of the needs of wherein said recurrent treatment is selected from female sexual disorder and male erectile dysfunction, and wherein said first medicament or its pharmaceutically acceptable salt comprise DCS.

29. pharmaceutical composition as claimed in claim 28, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from sldenafil, tadalafil, PT-141, apomorphine, testosterone, BUP, estradiol and Vardenafil.

30. pharmaceutical composition as claimed in claim 27, the misery of the needs of wherein said recurrent treatment is selected from chronic pain and neuropathic pain, and wherein said first medicament or its pharmaceutically acceptable salt comprise DCS.

31. pharmaceutical composition as claimed in claim 30, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from lyrica, gabapentin, nortriptyline and amitriptyline.

32. pharmaceutical composition as claimed in claim 27, the misery of the needs of wherein said recurrent treatment is insomnia, and wherein said first medicament or its pharmaceutically acceptable salt comprise DCS.

33. pharmaceutical composition as claimed in claim 30, wherein said second medicament or its pharmaceutically acceptable salt comprise be selected from eszopiclone, indiplon, Zaleplon, zopiclone, zolpidem, L0, clonazepam, oxazepan, medicament or its pharmaceutically acceptable salt of flurazepam, triazolam, temazepam and alprazolam.

34. pharmaceutical composition as claimed in claim 27, the misery of the needs of wherein said recurrent treatment is the distractibility hyperkinetic syndrome, and wherein said first medicament or its pharmaceutically acceptable salt comprise DCS.

35. pharmaceutical composition as claimed in claim 34, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from methylphenidate, tomoxetine, amphetamine and dextroamphetamine.

36. pharmaceutical composition as claimed in claim 27, the misery of the needs of wherein said recurrent treatment is a depression, and wherein said first medicament or its pharmaceutically acceptable salt comprise DCS.

37. pharmaceutical composition as claimed in claim 36, wherein said second medicament or its pharmaceutically acceptable salt comprise medicament or its pharmaceutically acceptable salt that is selected from desmethylimipramine, amitriptyline, nortriptyline, fluoxetine, paroxetine, Sertraline, fluvoxamine and citalopram.

38. pharmaceutical composition as claimed in claim 27, wherein said first medicament or its pharmaceutically acceptable salt comprise DCS; Further comprise compound vitamin B with wherein said pharmaceutical composition.