CN1311665A - Novel analgesic, anti-inflammatory and wound healing agent - Google Patents

Abstract

Composition and formulations comprise a brain, heart, lung and/or vascular system protecting amount of a first agent such as folinic acid, pharmaceutically acceptable salts thereof or mixtures thereof and a carrier, and optionally a second agent such as analgesics, heart medicines, anti-inflammatory agents, soporifics, muscle relaxants, anti-pyretic agents, anti-fibrillation agents, heart, brain, lung and vascular drugs, anxiolytic agents, mood controlling agents, and many others. The products are suitable for the treatment of previous mood disorders, symptoms and sequelae of menopause, pain, inflammation, insomnia, restless sleep, trauma, surgery, burns, conditions and diseases which bring these symptoms, ischemia, Supra Ventricular Tachycardia (SVT), heart conditions and heart failure, Acute Respiratory Distress Syndrome (ARDS), COPD, allergic rhinitis, and other conditions, and for reducing the number and severity of heart attacks, as well as for alleviating other diseases associated with the heart, and more generally, for the assessment of heart function. An edible product is prepared with the agent of the invention.

Description

A kind of new pain relieving, antiinflammatory and wound healing agent

The background technology of invention

Invention field

The present invention relates to contain the compositions and the preparation of folinic acid, its salt or its mixture and carrier, wherein optionally contain other treatment system.Described product is applicable to the treatment of for example following various diseases and imbalance: insomnia, insomnia, inflammation, pain, ischemia, wound, burn, mood disorders, menopausal symptom and sequela and various heart disease, reduce the number of times and the intensity of cardiac infarction and apoplexy, induce loss of consciousness, sleep and anesthesia.In addition, wherein also comprise these products are used for assess cardiac function, protect, cure and reindoctrinate in bodily tissue.This medicament also can be made into the medicine box of edible product and its preparation.

The description of background technology

Adenosine is a kind of purine that occurs when intermediate supersession.In addition, it also participates in the adjusting of various mammalian tissues physiologically actives, and participates in many regional regulatory mechanisms, for example can appear at synapse, appear at the neural effector joint portion in central nervous system (CNS) and the peripheral nervous system.In addition, know that adenosine also has effect to other system.The example for example has the active effect that suppresses cardiac pacemaker and slows down the AV conduction, be anti-arrhythmic and have an arrhythmogenic effect, regulate prostaglandin is synthetic and discharge Autonomous Control and triggering, have effective vasorelaxation action and scalable vascular tone.At present, use adenosine clinically with treatment sulfamethoxypyridazine ventricular tachycardia (SVT) and other heart abnormality, and be used for heart function test.Existing research is used as anticonvulsant, antianxiety drugs and neuroprotective with neplanocin.And; adenosine also can be protected the tissue of ischemia (oxygen loss) and help to inculcate treatment, for example apoplexy or other are acute or the symptom of chronic cerebral ischemia and disease, cardiac infarction after or after the symptom that produced of other acute and chronic heart ischemia and the disease and have other organ of the ischemia danger relevant, acute or chronic physiological process and the collection before transplanting and the transplantation organ in haulage stage and inculcating of having carried out in the transplanted organ with disease and pathological process.Existing research is used as anticonvulsant, antianxiety drugs and neuroprotective with neplanocin.Adenosine can also be natural anti-infective, and for example it can mediate the anti-infectious function of methotrexate, and can be by the function that activation serine/threonine phosphate promotes and neutrophilic granulocyte is cured and regulated in acceleration.In the central nervous system, known adenosine can suppress the release of neurotransmitter such as acetylcholine, norepinephrine, dopamine, 5-hydroxy tryptamine glutamate, Glu and GABA.Adenosine also demonstrates and can suppress itself, thereby may discharge the pain that reduces spinal column by reducing neuronal, with and have an anxiety performance.Though adenosine has above-mentioned various therapeutical effect, its half-life is extremely lacked (approximately being in second).Because the short-half-life of adenosine and the character of himself are caused like anginal pain, people are difficult to select it to use as treatment.

Folinic acid is the intermediate product of folic acid metabolism, be sure of that it is the activity form that folic acid changes in health.Know that change in the process of folinic acid at folic acid, ascorbic acid or vitamin C are necessary.Existing folinic acid is used for the treatment of as the antidote of antifol such as methotrexate, and methotrexate folic acid capable of blocking is to the conversion of folinic acid.Folinic acid can also be used as anti-anemia agent, because it has the ability that folate lacks that overcomes.But folinic acid both had been not used in because the patient that the adenosine disappearance causes suffering also is not used in the Therapeutic Method that improves adenosine level in brain, heart or other organ.

Affective disorder is very different as depression and depression clinically, and everyone once felt, and even forfeiture grief.They are very weak and dangerous, and under many circumstances, irresistible sadness and other various symptoms combine.Some people can will commit suiside intently, and some other people's emotion (experience) is high, may cause dangerous behavior, and a lot of people is perplexed by guilty-feeling and skimble-skamble sensation.Some people usually is difficult to clearly think deeply, remember or is difficult to treat giocoso every thing.They can experience anxiety and physical ability weakens, and feed and dyskoimesis perhaps conversely, are felt more than happy and eaten excessively and sleep.The height that the spreading rate of various types of affective disorder is surprising.In the U.S., the male has 5-12%, and the women has 10-20% to suffer from this disease, mainly shows as Hypoemotivity in some time of its life.Except depressive patient, in these people, there be half (approximately being American 1-1.5%) can become than more oppressive in the past, and have people up to 10% (approximately being American 1.0-1.5%) have mad dry performance and known be mad dry-symptom of depressive illness or bipolar disorder.The feature of mania be to sleep need reduce, speech fast, the delusion of grandeur, superactivity and carry out activity, excessive drinking or the crude driving that some have other self-destruction of confusion tendency.Except that pain and anergy affective disorder, they still are potential murderer.Statistics shows annual have among them nearly 15% to suffer from depression or bipolar disorder disease is committed suiside.1996, disease prevention and control centre (Centers for Disease Control and Prevention) at 30,862 philtrums, listed the death that the U.S. has 9 examples to be caused by suicide, only a little less than AIDS virus infection.And be sure of that this numeral has been underestimated, because the situation that has at least some death to be attributed to other disease and in some vehicle accident, under cover commit suiside.

Have enough evidences to show, no matter what initial starting point is, the biochemistry that causes depressed last approach to relate in the brain changes.These change the marked feature that finally causes being absorbed in easily deep feeling of grief or remorse and other depression.All these various contents still among exploring, still in nearest decades, particularly in recent years, have had the progress that reaches very much to its effort of identifying.Psychotherapy and antidepressant are widely used, and other Therapeutic Method such as galvanic shock no longer are used.Though the antidepressant that uses is littler than previously used side effect at present, and is effectively under many circumstances, depression still causes huge misery, forfeiture viability and reduces the productivity.The geneticist provides the most primary proof that produces the biological components of depression in a lot of people, and depression and mad dry type depression usually are familials.As the geneticist the continuous institute of criminal's gene is shown that other the neuro chemistry approach that concentrates on particularly concentrates on neurotransmitter.More particularly, depression is to produce owing to cerebral circulation has the part imbalance at least significantly under many circumstances, and this cycles through the neurotransmitter transmission signal of some monoamines.These biochemicalses, promptly all amino acid whose derivants comprise 5-hydroxy tryptamine, norepinephrine and dopamine.Wherein, only, the evidence relevant with norepinephrine and 5-hydroxy tryptamine is a lot, in addition, also shows the insufficiency of accommodation of depression and hypothalamic hypophysis adrenal gland (HPA) axle on evidence, and relevant to the system of the response of anxiety with the control health.To health or mental health appearance threat the time, hypothalamus makes its amplification and produces corticotropin releasing factor (CRF) (CRF), and it induces the ACTH secretion of hypophysis, and ACTH sends instruction to discharge hydrocortisone to the adrenal gland top of each kidney then.All these variations make health make the reaction of resistance or escape, and cause stopping to disturb the activity of autoprotection.For example, the hydrocortisone transmission of thing that can have additional nutrients to muscle.Simultaneously, CRF can reduce appetite and libido, and improves agility.But the chronic activity of hpa axis lowly can cause sick, and may be depression.It should be noted that studies show that compare with collator or the patient that suffers from other mental sickness, the concentration of CRF improves in the cerebrospinal fluid of patients with depression.And observation experiment animal CRF finds its behavior that produces response and depression arranged when the transmission of brain, i.e. insomnia, appetite descend, libido descends and the mankind of anxiety seemingly.The accumulative total material shows that serious depression also can improve dying danger after cardiac infarction and the apoplexy.And can reduce the quality of life and the life span of cancer patient.

Heart is the pump of one four ventricle, at each circulation correct time of heartbeat, controls flowing of blood by the open and close of a series of valve.For most people, the function of these valves is a no problem in this life process of people.Cardiac valve can go wrong in the sub-fraction people, and modal is mitral valve prolapse, and it is more than the man that this problem occurs in the woman.The blood flow in the left upper and lower atrium of left atrioventricular valve control heart, last atrium (left atrium) accepted fresh oxygenated blood fluid and is delivered to left ventricle (the main suction chamber of heart) by left atrioventricular valve from lung.Then, left ventricle is shunk, and by Arterial system fresh blood is sent, and oxygen and various nutrient are transported to whole body.Under the situation of mitral valve prolapse, there is one or two valve left atrioventricular valve to increase, the oversize or elongation too easily of connective tissue string is upwards pushed valve to ventricle when shrinking in the chamber.Under serious situation more, inappropriate the closing of valve makes part blood can not return ventricle, i.e. mitral incompetence fully.But in general, the left atrioventricular valve prolapsus also is not enough to serious in causing very big problem.But when if what symptom is the problems referred to above do not cause, modal is cardiopalmus or " cross and jump " to occur, or other cardiac rhythm is irregular.Second kind of modal problem is chest pain, rapid breathing or tired easily.

Statistics shows that 35% American dies from heart disease, finds that the feature of its risk factor is age, family's medical history, sex, body weight, smoking, cholesterol levels and diabetes in the potential people that cardiac problems arranged.Heart disease is very general in the old man, usually is diagnosed between 45 to 55 years old.Sickness rate increased if parents had heart disease in the past at 50 years old.The man is than the easier heart disease that occurs of woman before 50 years old.After this, the woman has cardiopathic chance identical.With regard to height, if body weight surpasses 20% of normal value, and overweight part concentrates on the middle part of health, then has cardiopathic probability to increase.The danger that the smoker has a heart disease is two times of normal person, and the danger of the apoplexy higher slightly than normal arterial pressure is two times.The amount of cholesterol is ideal less than 200, the boundary between 200 to 240, and greater than 240 just high, last, diabetes are potential, and cardiopathic danger is arranged is normal two times, or more little easily going wrong more of age.

When the blood supply wretched insufficiency of cardiac muscle (myocardium) part or when stopping, cardiac infarction takes place, one of tremulous pulse of giving cardiac muscle (coronary artery) supply blood this moment blocks or stops up.This obstruction may be because atherosclerosis (accumulation of lipoid material deposit), clot (coronary artery thrombosis), or combine the crown vascular spasm of generation with near blocking.If the blood supply of cardiac component stops, this part will can not received again and finish necessary oxygen of its function and nutrition, thereby cause death.If there is enough big part to suffer damage, the damage of irreversibility can cause death.Pain is serious, sharp keen and perforation formula during cardiac infarction, and it can cause heart tissue ischemia (minimizing blood supply).Feel uncomfortable in chest normally and be radiated between the arm and scapula of cervical region, jaw portion, one or both sides.These symptoms are understood last very long usually, and can not alleviate with nitroglycerin, and as cardiopalmus or " cross and jump ", or other cardiac rhythm is irregular.Another modal problem is chest pain, rapid breathing or tired easily.The long-term cardiac studies of country thinks nearly in four cardiac infarction does not once have symptom, or is not have dead person relevant with cardiac problems at least.These are exactly so-called like asymptomatic cardiac infarction (Asilent heart attacks@), only having opposite extreme situations to be called as like asymptomatic ischemia (Asilent ischemia@) in the more common symptom, is oxygen and the chronic deficiency of nutrition that blood is carried to heart.Both of these case makes the victim that great danger be arranged.Ischemia, reason asymptomatic or other situation are atherosclerosiss under many circumstances, because the accumulation of cholesterol piece causes gradual narrow of heart arter.The minimizing of this blood supply causes that the reaction of heart is that convulsive pain is angina pectoris.But, there is the cardiac infarction patient of 25-30% not have these significantly thromboembolism symptoms gradually, Framingham is to 4 of the Massachusetts, what 000 man more than 40 years old carried out discovers, wherein have 25% people every year to their reaction after EKO do not notice their cardiac infarction before detecting.But, do not have pain not mean and do not damage.Heart have certain reserve capacity make contributions again can, make it can under the situation that cicatrization and ability weaken, also can satisfy the needs of health.But ischemia again or cardiac infarction are even light moderate also has a life danger, in default of reserve capacity.Even they survive in another time cardiac infarction, the danger that they become the cardiac increases, and congestive heart failure or arrhythmia can occur, and promptly pulse is irregular.Have no idea to foretell for certain that they are asymptomatic ischemia patients, still, from statistics, coronary artery disease is very big risk factor, the person of choosing after they more like.These risk factors comprise some uncontrollable factors such as age, sex and atherosclerotic heredodiathesis, and can control as diabetes, hypertension, hypercholesterolemia, smoking, do not get enough athletic exercise and obesity.Undiscovered ischemia screened by medical history, physical examination and cardiac stress test undertaken: in treadmill, detect cardiac function.

Sometimes sudden cardiac death appears in the patient, but does not have anatomy and electrophysiological heart disease evidence.Asymptomatic (asymptomatic) ischemia that is caused by coronary vasospasm in these patients may cause asystole owing to triggering ventricular fibrillation.Silent ischemia appears among the patient who has defined coronary artery disease usually.Angina pectoris is usually being arranged and having that silent ischemia is recurrent among the patient of myocardial infarction, what follow therewith is that heart disease takes place, and comprises that the danger of sudden death increases.But silent ischemia also can occur on one's body the normal patient of coronary artery, and can be seriously the ST ripple is improved and trigger serious arrhythmia to being enough to.Serious ST ripple improves and serious arrhythmia, and prognosis mala when following repeatedly angina pectoris.Ventricular fibrillation is the symptom of electrical activity imbalance, and it can cause ventricular systole with quick, asynchronous, ataxic form.When this thing happens, do not have or seldom have blood to flow out, under the situation that does not have medical rescue timely, collapse or sudden death can occur from heart.If that handles is timely, under the situation of electric shock, chamber tachycardia and ventricular fibrillation can change into normal rhythm.Rapid heart beat can carry out Drug therapy by detecting or destroy the heart rate imbalance.Recently, a kind of effective method is to be called the implanted defibrillator is corrected threat to life the rhythm of the heart by use.Continue studies show that have family the mobile without limits sometimes coronary artery infringement of the patient that quivers, do not have angina pectoris, do not have myocardial infarction (MI) omen and do not have asystole can take place under the unusual situation of heart tissue yet.But the frequency of of short duration outbreak changes relevant with ST ripple spontaneous or that the inductive coronary vasospasm of ergometrine causes.Under many circumstances, be counter inculcate rather than the ischemia of self relevant with ARR generation.Counter to inculcate inductive arrhythmia may be because calcium overload ischemia after, and it may cause the asystole of short time, owing to may cause asymptomatic ischemia and coronary vasospasm during motion, so this situation to occur be N/R.According to some clinicians' viewpoint, even without early stage chest pain with define coronary artery disease, because the of short duration ischemia that coronary vasospasm causes also should be considered when diagnostic evaluation patient's asystole.In these patients, myocardial ischemia can be seriously to being enough to bring out life-threatening arrhythmia.The ischemia resisting treatment can protect the patient to avoid asymptomatic arrhythmia and ventricular arrhythmia.The ventricular tachycardia patient that the cardiac muscle cicatrization causes needs additional carry out pharmacology or non-pharmacological antiarrhythmic therapy usually.

Apoplexy is also referred to as " apoplexy ", and is insufficient and take place when causing brain cell dead at blood flow.Cerebral infarction is to take place when being stopped up by clot or other particulate matter to the angiorrhexis of brain delivering oxygen and nutrition or blood vessel.Owing to such break or stop up, the part brain can not get its needed blood flow.After forfeiture oxygen, the neurocyte in the affected brain area can't be brought into play its function, and death in several minutes.After these neurocytes can not be brought into play its function, the corresponding part health of being controlled by these cells had also just lost function.The destructive effects of apoplexy usually is nonvolatil, because dead brain cell can not recover.Annual apoplexy makes about 150,000 American's death, and is the reason that the adult paralyses.

Paroxysmal supraventricular tachycardia (SVT) is pregnant woman's common arrhythmia.Wherein nearly 50% the ventricular tachyarrhythmia of overrunning does not have effect with vagal Therapeutic Method, and adopts other method, comprises electric Cardioversion and drug treatment.Propranolol, verapamil and food is arranged and the adenosine of medicine permission flag has the emergency treatment effect to supraventricular tachycardia.Verapamil is the most frequently used medicines of common people, but it has some shortcoming, as might cause or aggravate hypotension, congestive heart failure, the bradycardia companion rhythm of the heart is irregular and quiver in the chamber.In addition, verapamil passes Placenta Hominis easily, and demonstrates and can cause fetus bradycardia, heart block, contraction inhibition and hypotension.In addition, in the influence to Tachyarrhythmia, experiment shows that adenosine can reduce the infringement that reindoctrinates after myocardial ischemia, and can reduce the size of thromboembolism and prevent " not resurgent phenomenon " (" no-reflow phenomenon ").Therefore, during MI, it can be used for protecting heart.Adenosine now has been used to the non-infringement evaluation of myocardial ischemia, because it can increase coronary flow.Estimate in adenosine transfusion available thallic absorption in back and reallocation, can identify the infringement area of ischemia and cardiac muscle thus.The vasodilator effect of its sensitivity, specificity and repeatability and motion-load experiment (exercise-stress testing) or persantin mediation is similar.At last, there is the proof adenosine to can be used for epilepsy.Propranolol, verapamil and adenosine have the food and the drug licence of emergency treatment supraventricular tachycardia (SVT).The adenosine of sign has the emergency treatment effect to supraventricular tachycardia.Verapamil is the most frequently used medicines of common people, but it has some shortcoming, as might cause or aggravate hypotension, congestive heart failure, the bradycardia companion rhythm of the heart is irregular and quiver in the chamber.In addition, verapamil passes Placenta Hominis easily, and demonstrates and can cause fetus bradycardia, heart block, contraction inhibition and hypotension.Compare with verapamil, adenosine has some advantages, comprise fast play a role, of short duration side effect, theoretic safety and may not have the transfer of Placenta Hominis.The final certification adenosine is the preferred therapeutic agents to the paroxysmal supraventricular tachycardia of gravid woman (SVT).But, because half-life (approximately in second) that it is extremely short and might cause pain like the angina pectoris, to treating above-mentioned arbitrary disease and symptom, and for the various body ﹠ mind symptom treatments relevant with symptom with the affective disorder disease, adenosine is not good selection.

Obviously, in the heart disease of high mortality, it is very important that dangerous individuality is detected, because early diagnosis can the early treatment.Electrocardiogram stress test in the time of can carrying out individual exercises for this purpose, but the method lacks high sensitivity and specificity.Particularly all the more so under the anginal patient's of asymptomatic and atypical chest pain situation.In the case, except carrying out exercise stress test, also should carry out angiography with ray such as 201Th and 99mTc.But, have a considerable amount of coronary artery patients can not be, for example serious arthritis and the patient of peripheral blood vessel and symptom is arranged, and other situation in acceptable horizontal movement obtaining effective result of the test.Measure suitable pulse and carry out with regard to the effective stress test with regard to when motion, the hypertensive patient who uses blocker and calcium-channel antagonists also has problem.For these patients that can not move, the drug load test is the most useful.In the U.S., nearly 1/3rd patient's cardiac muscle is inculcated test and is undertaken by drug test.For this reason, to participating in the general patient who takes exercise, can use two kinds of medicines: coronary artery vasodilator and myotility had the medicament that is just influencing.

The only two kinds of coronary artery dilators that be can be used for this test by the FDA proof are two ancymidols (dipyrimidol) and adenosine, and both all can come coronary artery dilator by improving the level of adenosine in blood and making blood flow rate coronarius improve 4 or 5 times.Give use in the venous patient radioreagent as ²⁰¹Th and ^99mTc carries out the radioactivity radiography and knows this variation.Though being evenly distributed of normal person's radioactive marker, the tremulous pulse that has a place or many places experimenter narrow and that stop up to pass through at the radioactive marker with varying strength in coronary artery demonstrates zone and Adefects@, and it can illustrate ischemia or myocardial necrosis.Observed opposite during with motion, observed hemodynamics and Electrocardiographic variation are very little after giving the pharmaceutical preparation of adenosine class.Usually pulse can improve 10% to 20%, and system arterial pressure improves 5% to 10%, suppresses to have pointed out the specific and serious signal of coronary artery disease at the CT section Electrocardiogram of Electrocardiogram (ECG).Therefore, concerning a lot of patients, the ability of bearing pharmacology's stress test is very important.But have a lot of patients that second effect (side effect) is arranged, this can cause serious bronchospasm, myocardial infarction and death under many circumstances.With regard to individual, the adenosine inappropriate medication can make the patient that bronchoconstriction takes place, comprise that asthma, hypotension and two degree or the tridimensional chamber of unknown cause stop up when carrying out pharmacology's stress test.A lot of SVT patients and other were accepted the adenosine medicine has too high response with the experimenter who estimates its cardiovascular function in air flue, therefore the tendency of bronchoconstriction is arranged after using adenosine.For fear of the bronchoconstriction that life is had threat, should not allow them use adenosine.

In sum, the decline significantly of adenosine level or the disappearance of adenosine can make CNS, heart and other tissue produce a series of deleterious symptoms, and treating, reverse and preventing this disappearance is extremely useful treatment intervention means.There is the medicament of longer half-life that very big advantage is arranged when treatment various central nervous system (CNS) disease than adenosine, described central nervous system disease for example is the affective disorder that comprises depression, schizophrenia, the two poles of the earth disease and other mood disorders, treatment and control menopausal symptom and sequela, and pain and inflammation.And, can prevent or reverse adenosine level reduction or adenosine disappearance simultaneously, the use of medicament that is arranged than adenosine the longer half-life is for prevention with treat various disease and symptoms such as insomnia, sleep deprivation, insomnia and other parahypnosis again, and assess cardiac function has very big advantage.In addition, such compositions also should be used for loss of consciousness and anesthesia.

The summary of invention

The present invention relates to prevention and treatment pain and inflammation, heart disease, CNS disease, wound and wound infringement, relate to sleep and anesthetic inducing and the evaluation of cardiac function.The example of the disease of CNS mediation is an affective disorder, comprise depression, schizophrenia, the two poles of the earth disease, compulsive disorder (COD), delirium, attention deficit (ADD), over-drastic aggressive behavior and other mood disorders, with menopausal symptom and sequela such as irritability and emotional lability, these can disturb, in most of the cases can hinder patient's daily life function, reduce the joy of giving birth to life of s/he greatly.Cardiovascular disease such as ischemia or anoxia, cardiac infarction, apoplexy, arrhythmia, supraventricular tachycardia (SVT), ARDS, heart failure and other disease.No matter these symptoms are former, or the reduction that is accompanied by adenosine level whether, and also no matter be that endogenous is unusual, still because used medicine caused, these symptoms can be with present Therapeutic Method and the processing of other method.Can also utilize compositions to carry out " stress test " to estimate experimenter's present function.Pharmaceutical composition of the present invention comprises carrier and is selected from first medicament of folinic acid, its pharmaceutical salts and their mixture, and optionally comprise the surfactant and/or second medicament, for example other emotion correction agent, antianxiety drug, nociception agent, sleep and anesthesia derivant, antiinflammatory, hormone, cardiac drug, diuretic and analgesic, and the formulation components that is suitable for various different approaches medications.First medicament that cardiovascular system protective agent amount or heart function test dosage are arranged in compositions usually is analgesia, antiinflammatory, treatment wound or burn, stabilizing the emotions, induced hypnotic and anesthetic medicament.

Injury of kidney and renal failure, cancer, burn, skin ulcer and other tissue injurys that the example of other symptom that the present invention can effectively treat is COPD, allergic rhinitis, emphysema, alveolar cysts (pulmonary vesocoustiction), chronic bronchitis and hypertension, caused by some drugs and video material, and improve individual's general quality of life and the probability that increases delight of life is arranged for the people who carries out orthobiosis with the invalid people of other Chinese medicines, impotentia.Second kind of effect is the quality of life of improving patient family, consequently improves health status, raising mobility, the prolongation in surging stage of derived emotion and recovers the hope of patient to life.Compositions can be made various preparations, can be large volume or unit dosage form, can be the form with other food component food prepared therefroms, for example energy bar, chewing gum, confection, beverage, cookies, be mixed into salad, flavoring agent, dough/pasta etc.Detailed description of the preferred embodiments

The inventor wishes the present invention's used prevention and treat the method for following disease before can improving: the dysthymic disorder, one pole or bipolar dysthymic disorder, cardiovascular disease such as heart disease, the urgency that particularly relevant with oxygen lack heart disease, sleep deprivation, nap, insomnia, any reason cause and chronic pain and inflammation and induce loss of consciousness, assess cardiac function.The variation of many medicable symptoms and adenosine level or adenosine disappearance are relevant, no matter and its how to form.The latter's example is decline, high adenosine metabolism and many other reason that the synthetic deficiency of use, adenosine, adenosine receptor sensitivity or the neuron of genetic diseases, adenosine disappearance medicine propagated.

Known adenosine is produced by heart, lung, kidney and brain, particularly with emotion and the stable natural agent that activity produced.But, because half-life (approximately in second) that it is extremely short and may cause similar anginal pain, therefore for the treatment of above-mentioned disease and symptom, and and pain, inflammation, wound, burn, oxygen deprive, have a sleepless night and other disease, adenosine is a bad selection in the treatment of the mental symptom relevant with heart function test.

The inventor thinks that the reagent such as folinic acid can cause the synthetic of adenosine, and than the long half time of adenosine, can not produce similar anginal pain, can be suitable for to bearing patient's medication that these diseases and other symptom torment.Unexpectedly, by these research, the inventor finds that folinic acid also has endurable emotion, heart is stable and regulate active, reduce pain and inflammation, no matter they are and wound, surgical operation, arthritis or the pain that causes by other reason, induce loss of consciousness, sleep and anesthesia that the ripple sample changes, therefore, can be used for treating pain, inflammation, skin is torn, organ and tissue injury, burn, the insomnia, there is not the sleep of having a rest, the cardiac fibers vibration, SVT, RDS is alleviated cardiac infarction and apoplexy, chronic bronchitis, COPD, allergic rhinitis, the order of severity of autoimmune disease and various other disease and symptom.He has reason to believe, because folinic acid and its salt can reach skin, brain and heart, improves adenosine level, and they also have and the adenosine similar activity.Therefore, the inventor proposes folinic acid and can be used for treating above-mentioned disease.Above-mentioned suggestion has not only been confirmed in the latter's work, but also points out that folinic acid has longer persistence than adenosine.Therefore, folinic acid and its salt can be used for treating emotion changes and obstacle such as depression (improving the emotion medicament), the two poles of the earth emotional disorder, compelling sex behavior, vainly hope, go mad, attention deficit and other spiritual pathological symptom.Folinic acid also can be used for treating the emotion changes of following menopause and its sequela is waken up too early as tired, insomnia and/or drowsiness, irritability, depression, when lacking appetite and/or excessive eating, sleep and/or the ripple sample changes sleep, to life have no interest and particularly indifferent to sexual life.

The inventor points out can induce the de novo synthesis of adenosine in the heart after the folinic acid medication, and can cause the rapid increase of adenosine level in heart, lung and the brain of animal model when oral.Because folinic acid is than the long half time of adenosine, can not induce similar anginal pain, when using as following treatment of diseases agent, it shows beat all improvement: analgesia, antiinflammatory, cardiac drug is (as fibrillation, ischemia resisting, prevention and treatment apoplexy, heart failure, cardiac infarction, SVT, ARDS, arrhythmia etc.), be used for the treatment of wound, other heart, lung and skeleton pathological symptom, and treatment also shows beat all improvement during anxiety neurosis, at surgical operation, arthritis or the pain that causes by other reason, induce loss of consciousness, sleep and anesthesia that the ripple sample changes, therefore, can be used for treating pain, inflammation, skin is torn, organ and tissue injury, burn, the insomnia, there is not the sleep of having a rest, the cardiac fibers vibration, SVT, RDS is alleviated cardiac infarction and apoplexy, chronic bronchitis, COPD, allergic rhinitis, the order of severity of autoimmune disease and various other disease and symptom.Have reason to believe that because folinic acid and its salt can reach skin, brain and heart, improve adenosine level, they also have and the adenosine similar activity.It can induce, prolongs and deepen the activity of sleep pattern in addition, therefore can be used as sleeping pill (sleep derivation agent) and be used for the treatment of and prevent insomnia, dyssomnias, nothing to have a rest sleep, sleep are of short duration, wake up too early when insomnia, sleep and low ripple is slept, with (improve emotion as the emotion control medicament, with smooth too high and low excessively emotion when the bipolar disease), the control choler, treat obsessive behavior (COB), paranoia, schizophrenia, depression, bipolar dysthymic disorder's disease etc., induce the scarce formula of sensation and be used for assess cardiac function.Folinic acid, its salt and their the mixture effectiveness when preventing and treat these diseases and need other disease that improves adenosine level and symptom has therapeutic value.Sometimes be called as the folinic acid of " reactive compound " hereinafter and its pharmaceutical salts is known, and can prepare in accordance with known methods generally can be referring to The Merck Index, MonographNo.4141 (11 editions, 1989); With USP 2,741,608.

Medicament of the present invention can only be a pharmaceutical composition, or selectively with other medicament and other medicament combination that is usually used in treating above-mentioned disease, situation, symptom, some of them are hereinafter listed.Product of the present invention is the effective receiver of fully invalid or part to existing treatment, though or effective when beginning, As time goes on its efficient situation about reducing is extremely valuable.Method of the present invention is stimulating the synthetic of adenosine, and thus directly or indirectly by gland glycoside action in other nervous pathway and/or neurotransmitter, so that the patient who for example suffers from medication and ethanol diseases associated and symptom is treated, and to lacking deep sleep, unusual aggressive behavior is arranged, it is very few or too much to take food, there be not long the lying up of taking exercise, the dysthymic disorder treats, no matter being immanent cause, described dysthymic disorder causes, still by other health reason such as sexual impotence, surgical operation, the injury that wound causes causes, and is other disorders such as cancers, wound pain, surgical operation, viral infection, infected by microbes, congested, inflammation, autoimmune disease, menopause, insomnia, operation back long-term bed, polyphagia, anorexia nervosa, consume disease, genetic diseases is caused with the unusual relevant symptom of other and emotion.And, treatment is suffered from the disease of cardiovascular system to compositions of the present invention and the patient of symptom is effective, for example treat and control the intensity and the frequency of cardiac infarction, heart failure, the fibrillation of heart, SVT, ARDS, COPD, general heart dysfunction and assess cardiac function, and treat other and the adenosine level relevant pathological symptom that descends, these are because other psychataxia, as infected by microbes, cancer, wound, operation, chronic pain, congested, inflammation, autoimmune disease and congenital diseases are caused, no matter described disease of patient and symptom are owing to press down wound, operation, the exogenous material that medication brought is still caused by other reason.Medicament of the present invention can be a pharmaceutical composition, can use separately, or the medicament commonly used of pain relevant with syndrome with treatment and any other disease, symptom and inflammation mixes and uses.The pain that will treat with medicament of the present invention and the described disease of inflammation-related, the example of symptom and syndrome is an arthritis, headache, ear is painful, head and periphery physical impairment, the operation before and after pain, have a back ache, pain relevant and antenatal pain in puerperal (partum pain) with baby due, athletic injury, myalgia and the overexertion relevant with exercise, with the relevant pain of absorption steroid, osteoporosis, wound, operation, burn, wound, chronic bronchitis, the chronic obstruction disease (COPD) of lung, allergic rhinitis, inflammatory bowel such as Chron disease and ulcerative colitis, autoimmune disease and other numerous disease.Moreover, folinic acid also has continuous activity to inducing, prolong and deepening sleep pattern, therefore can be used as sleeping pill (sleep derivation agent) and be used for the treatment of and prevent sleep, wake up too early when not having rest sleep, cat feel, insomnia, sleep and low ripple is slept and the pathological symptom of other sleep.Find that also folinic acid is to inducing consciousness, sleep and anesthesia effective.

Disease that term " adenosine disappearance " relates to and symptom be cardiac infarction for example, apoplexy, heart failure, fibrillation, SVT, ARDS, burn, wound, operation, the dysthymic disorder, pain and inflammation, lack sleep or do not have the sleep of rest and heart, the caused disease of lung and disordered brain function, compare with the adenosine level before the same patient, or compare with similar crowd's standard average level (boundary point), these diseases reduce in one or more tissues with adenosine level and lack relevant, when patient's adenosine level and basic identical in the past, but when having other symptom or situation to change, reach therapeutic effect by making to increase on the former level of adenosine level.Method of the present invention is, preferably to its adenosine level with compared in the past reduced about 5%, about 10%, about 15%, about 20%, about 30% or the more depleted fully patient of as many as treat.Though the present invention relates generally to the treatment of human patients, also can be used for vertebrates, especially for mammal.For veterinary's purpose, in these animals of being treated, they can be domestic with wild, and are big or little, and comprise house pet (cat, Canis familiaris L. etc.), zoo animal, kind horse, farm-animals (cattle, sheep etc.) and many other animals.

In one embodiment, pharmaceutical composition of the present invention comprises above-mentioned folinic acid and/or its salt, and one or more surfactants.In order to increase the picked-up of antisense oligonucleotide of the present invention, suitable surfactant or surface active agent composition comprise synthetic or natural, and fully and cut segmental surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant protein E, di-saturated phosphatidylcholine (not being two palmityls), dipalmitoyl phosphatidyl choline, phosphatidylcholine, phosphatidyl glycerol, phosphatidylinositols, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidic acid, ubiquinone, lysophosphatidyl ethanolamine, LYSO-PHOSPHATIDYLCHOLINE LYSOPC, palmityl-LYSO-PHOSPHATIDYLCHOLINE LYSOPC, dehydroepiandrosterone, dolichol, sulfatide acid, 3-PGA, dihydroxyacetone phosphate, glycerol, glyceryl-3-phosphocholine, dihydroxy acetone, palmitate, cytidine diphosphate ester (CDP) diacylglycerol, cytidine diphosphocholine, choline, choline phosphate; And natural and synthetical platelet (1amelar) body is as the natural carrier of following substances: surface active agent composition, omega-3-fatty acid; polyenoic acid; lecithin; Palmic acid; the block copolymer of nonionic oxirane and expoxy propane; the monomer of poly(propylene oxide) and polymer; the monomer of poly(ethylene oxide) and polymer; the polyvinylamine that has glucosan and/or alkanoyl side chain; Brij 35; Triton X-100 and synthetic surfactant A LEC, Exosurf, Survan and atovaquone etc.In preparation, these surfactants can use separately, a part that also can a plurality of surface active agent compositions, or 5 of antisense oligonucleotide (oligos) ' and/or 3 ' position end group on the covalent bond addition.

Second or additional reagent of the present composition can be one or more all kinds of treatments and diagnostic agents, and they are suitable for people or non-human animal's medication.Some type, the reagent that is suitable for being used in combination with compositions of the present invention and preparation is analgesic; premenstruum medicine; anti-menopause medicament such as hormone; antidotal agent; antianxiety drug; other mood change agent; other antidepressant; other anti-bipolar dysthymic disorder's medicament; the antischizophrinic agent; anticarcinogen; alkaloids; cardiac drug; alkaloids; antianxiety drug; the induced hypnotic agent; blood pressure regulator; hormone; anti-infective; muscle relaxant; steroid; sleeping pill; the ischemia medicament; anti-arrhythmic; contraceptive; vitamin; mineral; tranquilizer; the neurotransmitter regulator; wound healing agent; the plain medicament of angiogenesis inhibitor; cytokine; somatomedin; the metastasis agent; antacid; hydryllin; antibacterial; antiviral agent; the gas roof agent; appetite is low; the sunlight protective agent; lubricant; reduce the product of skin temperature; radioactivity phosphorescence or fluorescence contrast diagnosis and imaging agent; the libido regulator; cholic acid; laxative; anti-diarrhea agents; the skin renewal agent; hair growth promoter etc.

Described hormone is female and androgen such as premarin, Progesterone, androsterone and their analog, thyroxine, glucocorticoid.The libido regulator is viagra (Viagra) and the agent of NO-horizontal adjustment.Analgesic is the OTC (over-the-counter) medication, as ibuprofen, oruda, aleve, to acetyl-amino phenol and in check medicament such as morphine and codeine.Antidepressants are that tricyclics, MAO inhibitor and epinephrine, aminobutyric acid (GABA), dopamine and 5-hydroxy tryptamine level improve medicament such as fluoxetine, Amytryptilin, Wellbutrin and Sertraline.The skin regeneration agent is a retin-A, and hair growth promoter is Rogaine.Anti-infective is non-steroid class anti-infective (NSAIDs) and steroid.Sleeping pill is a melatonin, and the sleep derivation medicine is as stabilizing cytoprotective, ischemia and head injury medicine such as enadoline and other multiple medicine.The example of inhomogeneity medicament is listed in hereinafter.Analgesic such as acetaminophen, anileridine, aspirin; buprenorphine; Butabital; Bu Tuofeinuo; choline salicylate; codeine; dezocine; voltaren see diclofenac; diflunisal; dihydrocodeine; elcatonin (Elcatoninin); etodolac; fenoprofen; dihydrocodeinone; hydromorphone; steroid; ibuprofen; ketoprofen; ketorolac; levorphanol; magnesium salicylate; Meclofenamate; mefenamic acid; pethidine; methadone; levometiomeprazine; morphine; nalbuphine; naproxen; Opium; oxycodone; Oxymorphone; pentazocine; phenobarbital; the third oxygen sweet smell; salsalate; sodium salicylate; tramadol; and except above-mentioned narcotic analgesics listed.Referring to Mosby ' s Physician ' sGenRx.Used antianxiety drugs comprises alprazolam, bromazepam, buspirone, chlordiazepoxide, chlomezanone, chlordiazepoxide, stable, halazepam, atarax, Ketaszolam, lorazepam, miltown, oxazepam and prazepam etc.Antianxiety drugs relevant such as chlordiazepoxide, amitriptyline, loxapine, maprotiline and perphenazine etc. with depression.Antiinflammatory such as non-rheumatism aspirin, choline salicylate, voltaren see diclofenac, diflunisal, etodolac, fenoprofen, floctafenine, Flurbiprofen, ibuprofen, indometacin, ketoprofen, magnesium salicylate, Meclofenamate, mefenamic acid, nabumetone, naproxen, dislike third Qin, Phenylbutazone, scorching pain happiness, salsalate, sodium salicylate, sulindac, tenoxicam, tiaprofenic acid, tolmetin, the antiinflammatory such as the voltaren see diclofenac that are used for the treatment of eyes, Flurbiprofen, indometacin, ketorolac, rimexolone (postoperative general treatment), that be used for the basic treatment of noninfective nose for example is beclomethasone (Beelomethaxone), budesonide, dexamethasone, flunisolide, triamcinolone etc.Sleeping pill (anti-insomnia agent/sleep derivation agent) for example is the used medicine of Cure for insomnia, comprises alprazolam, bromazepam, stable, diphenhydramine, doxylamine, estazolam, fludiazepam, halazepam, ketazolam, L0, nitrodiazepam, prazepam, quazepam, temazepam, triazolam, azoles pyrrole dawn and Sopiclone etc.Tranquilizer comprises diphenhydramine, atarax, methotrimeprazine, promethazine, diprivan see propofol, melatonin, alimemazine etc.Under other condition, be used for the treatment of epilepsy and the tranquilizer example hydrochloric acid amitriptyline that trembles, chlordiazepoxide, amobarbital, quinalbarbitone, allopropylbarbital, secbutabarbital, ethchlorvynol (Ethchiorvynol), glutethimide, L-tryptophan, enphenemal, brietal sodium, hydrochloric acid Midazolam, oxazepam, pentobarbital sodium, phenobarbital, barbose, sodium thiamylal etc.Medicament example hydrochloric acid enadoline in treatment head trauma (brain injury/ischemia) use; (for example treat serious head trauma; the drug addiction outbreak; Warner Lambert) cytoprotective and treatment menopause; employed medicament of the neat syndrome of menopause such as Ergotamine; belladonna alkaloids and phenobarbital, the employed medicament of treatment vasomotor symptoms in menopause for example is a clonidine; bonded estrogen (Conjugated Estrogens) and medroxyprogesterone; estradiol; Cypionate; estradiol valerate; estrogen; conjugated estrogens; the estrone of esterification; piperazine estrone sulfate and ethinyl estradiol.The example of the medicament of treatment premenstrual syndrome (PMS) is hormone, oral contraceptive, danazol, LuprolideAcetate, the vitamin B6 of Progesterone, progestogen, gonadotroph release.The example of medicament of treatment emotion/mental sickness for example is that tricyclic antidepressants comprises amitriptyline hydrochloride (Elavil), amitriptyline hydrochloride, perphenazine, (Triavil) and doxepin hydrochloride (Sinequan).The example of tranquilizer, antidepressant and antianxiety drug is stable (Valium), L0 (Ativan), alprazolam (Xanax), SSRI ' 5 (selectivity 5-hydroxy tryptamine reuptake inhibitor), fluoxetine Hydrochloride (fluoxetine), Sertaline HCl (Sertraline), paroxetine hydrochloride (paroxetine), fluvoxamine maleate (Luvox), Wy-45030 (Effexor),, 5-hydroxy tryptamine, serotonin agonist (fenfluramine) and other nonprescription drugs (OTC).Anti-migraine medicine is Imitrex etc.

Pharmaceutical salts is pharmacology and pharmaceutically acceptable salt, and these pharmacology and pharmaceutically acceptable salt can be prepared into alkali metal or alkali salt, as sodium, potassium or calcium salt, or the carboxylic acid group's of folinic acid salt.The calcium salt of folinic acid is a preferred pharmaceutical compositions salt.Organic salt or ester also are applicable to the present invention.Reactive compound of the present invention preferably uses to the patient with the form of pharmaceutical composition.The pharmaceutical composition that the present invention uses comprises system and the local preparation that uses, wherein preferably be suitable for sucking, oral, rectum, vagina, nose, ophthalmology, ear, in the body cavity, in the organ, local (comprising oral cavity, Sublingual, subcutaneous and ophthalmic), parenteral (comprising subcutaneous, intradermal, intramuscular, intravenous and intraarticular) and percutaneous dosing etc.Compositions can be made into single dose form or multiple dose form, and can be big medicated bag, and any known method preparation of available pharmaceutical field.Compositions of the present invention also can the generate a reagent box form, they can be preparations, and the description of preparation and application method is perhaps arranged.Described medicine box can also comprise other medicament as indicated above, and for example when parenteral, carrier can be in the container that another is sterilized.Also can in sterile chamber, add liquid-carrier before use and use compositions of the present invention, for example referring to USP 4,956,355; UKP 2,240, and 472; EPO number of patent application 429,187; PCT number of patent application 91/04030, this paper are quoted preparation relevant in the above-mentioned file and chemical compound part as a reference.In addition, also can consult Mortensen, S.A., etc., Int.J.Tiss.Reac.XII (3): 155-162 (1990); Greenberg, S., etc., J.Clin.Pharm.30:596-608 (1990); Folkers, K., etc., Proc.Nat=l.Acad.Sci.87:8931-8934 (1990), this paper quote preparation relevant in the above-mentioned file and chemical compound part as a reference.It is preferred being suitable for oral and preparation parenteral, and the preparation of suction is preferred.All methods have all comprised the step of reactive compound being introduced associated carrier, and described carrier is made of one or more supplementary elements.Usually, the preparation of preparation is by closely introducing associated liquid-carrier, meticulous solid carrier or among both, then, if desired, making product shaping is required preparation with reactive compound is all even.

Being suitable for oral compositions can be discontinuous dosage form, for example capsule, cachet, lozenge or tablet, and each agent contains the reactive compound of scheduled volume; And for example powder and granule; Solution in water or on-aqueous liquid or suspending agent; As Water-In-Oil or oil in water emulsion.These compositionss can prepare with any suitable method in the pharmaceutical field, and described method has comprised reactive compound and suitable carrier-bound step.Usually, preparation of compositions of the present invention comprised with reactive compound and liquid-carrier, meticulous solid carrier or among both all even closely bonded step, then, if desired, the mixture that obtains is shaped.For example, will contain compacting of the powder of reactive compound or granule or compression molding and can make tablet, one or more annexing ingredients will wherein selectively be arranged.The tablet of compacting can be shaped with suitable mechanical compaction and prepare, wherein chemical compound exists with free-pouring form (free-lowing form), for example with binding agent, lubricant, inert diluent and/or blended powder of surfactant/dispersant selectivity or granule.The tablet of mold pressing can be preparing with suitable mechanical die forming with the moistening powder compound of inert liquid binder.The compositions of oral medication selectively is included in enteric coating known in the art, degrades under one's belt and medicine is discharged in small intestinal to prevent compositions.The compositions that is suitable for oral cavity (Sublingual) medication comprises lozenge, and wherein reactive compound is based on perfuming, normally sucrose, arabic gum or Tragacanth; The tablet that contains The compounds of this invention is base with the inert base, example gel and glycerol or sucrose and arabic gum.

The compositions that is suitable for parenteral comprises the sterilized water or the non-water injection solution of reactive compound, preferably makes with receiver's blood etc. to ooze.These preparations can contain antioxidant, buffer agent, antibacterial and can make preparation and the isoosmotic solute of receiver's blood.Water or non-aqueous suspension can comprise suspending agent and thickening agent.Compositions can be positioned in unit dose or the container to dosage, for example in Mi Feng ampoule and the vial, but and lyophilization store, only needing before use to add sterile liquid carrier such as saline or water is injectable.The solution of instant injection and suspension be sterilized powder, granule or preparation tablets by mentioned earlier.

The compositions that is suitable for the local skin application preferably adopts following form: emulsifiable paste, cream, lotion, paste, colloid, spray, aerosol or oil preparation.Operable carrier comprises vaseline, lanoline, Polyethylene Glycol, alcohols, transdermal enhancer and wherein two or more combination.The present composition that is suitable for percutaneous dosing can be the discontinuous patch that can contact closely with receiver's epidermis, to extend working time.The present composition that is suitable for percutaneous dosing also can discharge by iontophoresis, specifically optionally passes through the reactive compound aqueous solution of buffered, for example referring to Pharmaceutical Research 3:318 (1986).

The reactive compound amount is very wide in compositions of the present invention, folinic acid in compositions for example, and the content of its salt and their mixture can approximately be 0.001% of compositions, about 0.1%, about 1%, about 2%, about 5% to about 99.999%, about 98%, about 90%, about 40%, about 20%, about 10%, about 5%, preferably approximately be 1 to 99% of compositions, more preferably about 2 to 40% and more preferably about 2% to about 10%.If when adding or adding the overlapping active medicament of having of above being discussed, this amount can be adjusted.

According to patient's age, body weight and symptom, the dosage of reactive compound can change.Treatment can be from less than first kind of medicament of the present invention, and the low dose of the optimal dose of folic acid or its a kind of salt begins, and dosage can increase, up to being issued to the most desirable and/or optimum efficiency in described condition.In general, dosage is to be about 1, about 5, about 20, approximately 50mg is to about 100, about 200, about 500, about 1000mg/kg weight in patients, preferred dosage is about 5 to 500mg/kg body weight, more preferred dose is about 10 to 200mg/kg body weight, and more preferred dosage is about 50 to 100mg/kg body weight.Higher or lower dosage also can estimate, and also within the scope of this patent power.Usually, active agents preferably can not produce can produce useful effect under the concentration of unsuitable injury and deleterious side effect and use, and can the unit dose medication, or when needed, the reasonable time among the Yu Yitian be with the multidose administration of routine.The second treatment therapeutic agent is with the amount medication that can produce Expected Results known in the art.Have at second medicament and original medicament such as folic acid and its salt that overlapping they can amount known in the art use when active, the amount of one or both medicaments wherein can be adjusted obtaining ideal effect, and don't can surpass the dosage range that avoid side effect.Therefore, when for example adding analgesic and antiinflammatory in compositions, they can add by application quantity known in the art, or add to be lower than their use amounts own.

Usually, compositions of the present invention can be various systems and the local preparation that uses.That system of the present invention and the local preparation that uses are selected from is oral, in the oral cavity, in the lung, in the rectum, intradermal, part, skin, parenteral, tumor, in the intracranial, cheek, in Sublingual, nose, intramuscular, subcutaneous, intravenous, the film, can suction, in percutaneous, intraarticular, intracavity, implantable, percutaneous, iontophoresis, ophthalmic, medicament for the eyes, vagina, intraarticular, ear, intravenous, intramuscular, the gland, organ is interior, lymph is interior, implantable, slow release with the enteric coating preparation.The preparation of various these preparations and to be combined in this area be known does not here need to describe in detail.Reactive compound of the present invention can be in one day once or divide administration several times.The disclosed reactive compound of the application can be given patient's pulmonary administration by suitable mode, but preferably include the form medication that can suck particulate aerosol with formation, can suck and contain reactive compound of the present invention in the granule, these granules are sucked by the patient, i.e. inhalation.The granule that can suck can be a liquid or solid.In practice of the present invention, the granule that has comprised reactive compound should comprise the granule that can suck size: enough little of promptly particulate size be so that can through port and larynx when sucking, and enter the alveolar of bronchus and lung.Usually, the granular size scope that can suck is about 0.5 to about 10 microns, and more particularly, its size is less than 5 microns.The non-size that sucks comprises and can be stored in throat and deglutible aerosol that the non-particulate quality optimization that sucks is minimized in aerosol.Concerning intranasal administration, preferred particle size range is the 10-500 micron, to guarantee to rest on nasal cavity.

Be suitable for preparing aerosol reactive compound of the present invention composition of liquid medicine can by with reactive compound and stable for example aseptic, the pyrogen-free water of carrier in conjunction with preparing.Containing the dried particulate solid particle sub-portfolio thing that can suck the micronization reactive compound can be by grinding reactive compound and micronized compositions is crossed 400 mesh sieves with mortar and pestle, to smash and to separate big coagula and prepare.The solid particle composition that contains reactive compound selectively contains the dispersant that helps to form aerosol.Suitable dispersant is can any proper proportion and the blended lactose of reactive compound, and described ratio for example is 1: 1 weight ratio.

The liquid particles compositions that contains reactive compound can be with any suitable method, as the aerosol apparatus preparation, referring to USP 4,501,729.The equipment that aerosol apparatus normally can have been bought, it can change into the treatment aerosol to the solution of active component or suspension, perhaps by quickening Compressed Gas, air or oxygen makes it to handle by the mouth of pipe of narrow Venturi tube or by ultrasonic wave concussion specifically.The appropriate combination thing that is used for aerosol apparatus is made up of the active component that is present in liquid-carrier, active component comprises the nearly compositions of 40%w/w, but preferably less than 20%w/w, typical carrier is the alcoholic solution of water or dilute with water, and preference is made and the isoosmotic preparation of people's body fluid as adding sodium chloride.If it is aseptic that compositions is not made, then optionally additive comprises for example antiseptic of methyl hydroxybenzoate, antioxidant, aromatic, volatile oil, buffer agent and surfactant.

The aerosol that contains the solid particle of reactive compound can use the aerosol generator preparation of producing the solid particle medicine similarly.Can produce the aforesaid granule that sucks with the aerosol generator of solid particle administration for the patient, and can produce and contain aerosol predetermined dose, that be suitable for the certain volume of human body injection speed.The example of aerosol generator comprises gageable inhaler and insufflator.

Second medicament can with reactive compound in a conventional manner administration preferably in aforesaid same compositions, use with prevention and treatment affective disorder disease.Here word " conventional administration (concurrent administration) " is meant the mode administration with one of the following of folinic acid or its salt and second medicament (one or more): (a) administration simultaneously, preferably both and conventional pharmaceutical carrier preparation together, or (b) in a course of treatment both at different time administrations.Under latter event, two kinds of chemical compound multiple dosings make their complementation effective half-life, thereby offset the minimizing of another chemical compound peak value with the increase of a chemical compound peak value, with the minimizing of another compound activity of increase balance of a compound activity, just as another drug treatment.Reactive compound can be, can not be single administration perhaps, so that patient's adenosine level is enough to the former level that can return to.If compositions of the present invention or preparation a drug are enough to replenish adenosine level (if the level before the same patient reduces), with folinic acid, its salt or their mixture and second medicament make it reach the effective dose administration of expection level to be enough to improving adenosine level.Then, no matter second medicament and reactive compound have eclipsed activity, still has different activity, all can reduce the dosage of above-mentioned two or more medicaments, to keep adenosine level, in order to reduce the danger of recurrence, the dosage of second medicament can reduce with the minimizing of active compound doses.If the reactive compound a drug just is enough to replenish adenosine level, after reaching this level, whether continues to treat and depend on whether adenosine level can be kept under the situation that is with or without the continuation treatment.And whether the dosage of second medicament reduces depends on whether the patient needs to continue treatment or whether the state of an illness is stable.Need avoid recurrence if the doctor thinks, promptly adenosine level reduces, even disappearance, and/or needs to accept the continuation treatment of second medicament, and then treatment should be proceeded under tight monitoring.

Additional medicament mentioned above can itself administration, or with the form administration of pharmaceutical salts.As medicine the time, the salt of these medicines should be pharmacology or physiologically acceptable salt, but is that non-pharmaceutical salts can be used to prepare free reactive compound or its pharmaceutical salts, and these all can not be got rid of outside protection scope of the present invention.These pharmacology and physiologically acceptable salt include, but are not limited to the salt that is equipped with by following processed with acid: hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-methyl benzenesulfonic acid, tartaric acid, citric acid, methanesulfonic acid, formic acid, malonic acid, succinic acid, LOMAR PWA EINECS 246-676-2 and benzenesulfonic acid etc.

Pharmaceutical salts also can be prepared into the alkali metal or the alkali salt of hydroxy-acid group, as the salt of sodium, potassium or calcium.Pharmaceutical formulation of the present invention can be for animals, it also can be human, except that reactive compound and one or more additional medicaments, also can contain one or more pharmaceutical carriers, and selectively contain any other therapeutic component that is suitable for specified disease and symptom.Carrier must be a pharmaceutical carrier, is exactly compatible with other composition of preparation, and can undue detrimental effect not arranged to the receiver.

It can be discontinuous unit that invention is suitable for oral preparation, as capsule, cachet, tablet and lozenge, respectively contains the powder or the particulate predetermined medication of scheduled volume; Or the suspension in aqueous or on-aqueous liquid, as syrup, elixir, Emulsion or potus.

Tablet is optionally to prepare with one or more supplementary elements or compression molding.The tablet of compacting can be shaped with suitable mechanical compaction and prepare, and wherein chemical compound is with free-pouring form such as powder and granule, optionally with binding agent, disintegrating agent, lubricant, inert diluent, surfactant or dispersant.The mold pressing tablet that contains the mixture of Powdered reactive compound and suitable carrier can prepare with suitable mechanical die forming.

Syrup can prepare by add reactive compound in spissated sugar aqueous solution, and described sugar for example is sucrose, wherein can add other supplementary element.These supplementary elements can comprise aromatic, suitable preservatives, the delay crystalline reagent of sugar and increase the reagent such as the polyhydric alcohol of other composition dissolubility, for example glycerol or Sorbitol.

The preparation that is suitable for the parenteral medication generally includes the sterilized water preparation of reactive compound, and preferably the blood with the receiver is isoosmotic.

The spray agent of nose comprises the pure water solution of reactive compound, wherein contains antiseptic and isotonic agent.Preferably these preparations are adjusted to pH, and are adjusted to the state that oozes such as compatible with nasal mucosa.

Rectum or vaginal preparation can be the suppository that contains suitable carrier such as cocoa butter or hydrogenated fat or hydrogenated fatty acid.

The ophthalmic medication can be by preparing with the similar method of preparation nasal spray, and just its pH regulates consistently with eyes with the factor of oozing such as grade.As known in the art, aural preparations generally the thickness carrier as oil and analog in preparation, so just be easy to splash into ear, can not overflow but have.

Topical formulations contains dissolving or is suspended in the substrate that one or more media are gone into mineral oil, petroleum ether, polyhydroxy-alcohol or other local pharmaceutical formulations commonly used.It is ideal adding supplementary element as mentioned below.

Except mentioned component, preparation of the present invention can also comprise that one or more are selected from following supplementary element: diluent, buffer agent, surfactant, propellant, aromatic, binding agent, disintegrating agent, surfactant, thickening agent, lubricant, antiseptic (comprising antioxidant) etc.Other compositions known in the art also can use.

Medicament of the present invention can with the other treatment method, other chemicals is used in combination, or is not used in combination, this comprises psychotherapy, therefore the special treatment of mechanism is depended in its effect, provides the morbidity of treatment affective disorder multi-level Therapeutic Method.Therefore, medicament of the present invention can use separately, uses with carrier, uses with other Therapeutic Method or medicament, uses with food additive or with other form that is suitable for the human compositions that consumes.Therefore, the invention provides edible mood regulation product, this product comprises food or its composition; And first medicament of mood regulation effective dose.In these medicaments each can be used separately, or is used in combination with one or more second medicaments as herein described, or further is used in combination with food or personal dietary supplement ingredient.Medicament of the present invention also can medicine box form provide, in the container of cutting apart, contain other medicament.They comprise, but be not limited to second medicament, vitamin replenisher, mineral additive, other nourishing additive agent, buffer agent, salt, aromatic, diluent, thickening agent, emulsifying agent, antiseptic and antioxidant, these are that those of ordinary skills are familiar with, and the addition in compositions also is that those of ordinary skills are familiar with.The present composition or product also can contain binding agent such as Tragacanth, arabic gum, corn starch or gelatin, excipient such as dicalcium phosphate, anticoalescent such as corn starch, potato starch, alginic acid and its analog, lubricant such as magnesium stearate, sweeting agent such as sucrose, lactose or glucide, aromatic such as Herba Menthae, Fructus Citri tangerinae, wintergreen oil or Fructus Pruni pseudocerasi flavoring agent, and other known synthetical or natural aromatic.Dosage form that continue to discharge or preparation and can further contain component known in the art also within protection scope of the present invention.

The application has also comprised coated composition and different improvement dosage form, as coating forms such as lac, gelatin, sugar-coats.Any material that adds this product all should be pharmaceutically acceptable, and should be nontoxic substantially in its use amount.Other excipient that can add preparation is as employed among absorbable tablet, tablet, capsule, elixir, suspending agent, syrup and wafer etc., and described product can be made into these forms.Medicament of the present invention can be the form of edible product, and content wherein approximately is the 0.001-99.99wt% of product, preferably approximately 0.1-20.0wt%.But the medicament that other quantity also can be arranged in edible product.The quantity of medicament can change in pharmaceutical composition and edible product, and/or according to the order of severity, general health situation and the nutriture of patient's symptom, and whether there is the situation of other mood regulation medicine medication simultaneously to increase or reduce the frequency of medication.

The present invention is applicable to that the food as the emotion control product is milk, fruit juice, frumentum, chewing gum, soft battercake, confection, meat, vegetable and fruit, and blended or clothing alternate manner is as baby food such as cookies etc.But medicament of the present invention also can or add salad, meat, fish and poultry dish at the preparation consumable products on dining table, and adds dessert.

Medicament of the present invention also can make the mood regulation medicine box, the regulator of wherein being in a bad mood, heart, brain, lung and vascular tissue's protective agent, antiinflammatory, sleeping pill, anesthetis and cardiac function test composition wherein contain first medicament and selectivity and contain other therapeutic agent, carrier and food component; And at preparation operation instructions with the present composition and the blended medicine box of other component during food.This medicine box also can provide the component of the baking or the cooking together, and these are needed among specific recipe such as cake, pudding, cookies, flavoring agent, the beverage etc.In a particularly preferred embodiment, each component of medicine box is encapsulated in respectively in the different containers, and the recipe of one or more preparation Special foods is arranged.This medicine box can be used for being in a bad mood obstacle the patient or this dangerous patient's therapeutic treatment is arranged, described dysthymic disorder is relevant with adenosine and level.In food, can also add other component, this comprises vitamin replenisher, mineral additive, other nourishing additive agent, salt, buffer agent, aromatic, diluent, thickening agent, emulsifying agent, surfactant, antiseptic and antioxidant, and these are that those of ordinary skills are familiar with.Included in embodiments of the invention above-mentioned composition also further contains other component of varying number, for example food.Suitable is all food, comprises milk and milk additives.Compositions of the present invention and edible product also can improve, and clothing comprises the water of various quantity and is suitable for the various compositions of the clinical needs of patient.

The present composition can mix with beverage (liquid) or personal food.The emotion control agent that also can add effective dose in the compositions, heart, brain, lung and vascular tissue's protective agent, analgesic, antiinflammatory, sleeping pill, sleep derivation agent, anesthetis etc., and can be prepared into big medicated bag or unit dosage form.Be particularly suitable for travelling in the embodiment of using, compositions is the form of chewing gum or confection (hard or soft), or adds the form of powder of beverage before drinking.

Because the component of compositions is endogenic to human body, therefore medicament of the present invention also demonstrates other advantage when the above-mentioned all kinds of symptom of treatment.Therefore, medicament of the present invention unlikely causes toxicity, immunity and anaphylaxis to the patient who is treated.Because these medicaments are harmless, medicament of the present invention can also use under no skilled medical worker situation on the scene, for example it is added food etc., therefore can in convenience store, sell, or in the foreign material shop, sell as food supplement as nonprescription drugs.These people for the undeveloped country of the traveller of needs treatments or the shortage of medicine service facility have special significance.

Above the present invention has been done general description, can better understand the present invention with reference to some certain embodiments, the embodiment that this paper provides is just in order to illustrate the present invention, and do not limit the scope of the present invention or certain embodiment, except as otherwise noted.

Embodiment

In embodiment below and the whole patent, " DHEA " is meant dehydroepiandrosterone, and " F.A. " is meant folinic acid, and " M " is meant methyl testosterone, " s " refers to second, and " mg " refers to milligram, and " kg " refers to kilogram, " kw " refers to kilowatt, and " Mhz " refers to megahertz, and " nmol " refers to the milli nanomole.Embodiment 1 and 2: act in folinic acid and DHEA the body to adenosine level

With gavage give young bull Fischer 344 rats (120g) take in the carmellose dehydroepiandrosterone (DHEA) (300mg/kg) or methyl testosterone (40mg/kg), once a day, totally 14 days.Through intraperitoneal administration folinic acid (50mg/kg), once a day, totally 14 days.At the 14th day, (1.33kw, 2450MHZ 6.5s) put to death, and make all brain protein denaturations immediately, prevent the further metabolism of adenosine to give the irradiation of animal intracranial microwave pulse.Take out heart by animal body, after death, make its quick freezing in liquid nitrogen in 10 seconds.Liver and lung are taken out entirely, after death, make its quick freezing in liquid nitrogen in 30 seconds.Then cut apart cerebral tissue.Extraction adenosine tissue is derivatized to 1 with it, N6-ethylene adenosine, according to Clark and Dar (J.of Neuroscience Methods 25:243 (1988)), with high performance liquid chromatography (HPLC), adopt the fluorescence assessor to analyze, result of the test comprehensively is listed in the table below 2.The result compares Xp＜0.05 with " SEM " expression with matched group, compare ip＜0.05 with DHEA or methyl testosterone processed group.Table 2:DHEA, ^*～1～methyl testosterone and folinic acid are to the adenosine level of various rat tissues

Body in the effect

Intracellular adenosine (nmol/mg protein)
				Handle heart lung brain contrast 10.6 ± 0.6 3.1 ± 0.20.5 ± 0.04 (n=12) (n=6) (n=12)
DHEA (300mg/kg)	6.7±0.5?2.3±0.3 (n=12)	0.19±0.01 (n=6)	(n=12)
				Methyl testosterone (M) (40mg/kg)	8.3±1.0N.D. (n=6)	0.42±0.06	(n=6)
Methyl testosterone (M) (120mg/kg)	6.0±0.4?N.D. (n=6)	0.32±0.03	(n=6)
				Folinic acid (F.A.) (50mg/kg)	12.4±2.1 (n=5)	N.D.	0.72±0.09 (n=5)
DHEA+FA. (300mg/kg；50mg/kg)	11.1±0.6 (n=5)	N.D.	0.55±0.09 (n=5)
				M+FA. (120mg/kg；50mg/kg)	9.1±0.4?N.D. (n=6)		0.60±0.06 (n=6)
N.D.=does not examine

The multiple organ adenosine disappearance of every day with the rat of DHEA or methyl testosterone two weeks pointed out in these tests.The most significant disappearance is in brain (disappearance 34% when DHEA disappearance 60%, the methyl testosterone of high dose), heart (disappearance 22% when DHEA disappearance 37%, the methyl testosterone of high dose).There is not the adenosine disappearance during with the common medication of folinic acid fully.Folinic acid can be induced the increase of adenosine level in all organs of research when individually dosed.

The present invention now all narration finish, do not deviate from spirit of the present invention and on the basis of definite scope, those of ordinary skills obviously can make many changes and improvements to this.

Claims (94)

1. pharmaceutical composition; said composition contains regulates emotion, diet or aggression; induce quiet sleep, loss of consciousness and anesthesia; heart and vascular protection; first medicament of analgesic, antiinflammatory or pain relieving effective dose; described first medicament is selected from folinic acid, its physiologically acceptable salt and its mixture, and carrier pharmaceutically acceptable or for animals.

2. the compositions of claim 1, said composition also further contains second medicament that is selected from following medicament: analgesic, anti-premenstrual syndrome (PMS) medicine, the medicine of anti-menopause, antidotal agent, antianxiety drug, the emotion control agent, antidepressant, anti-bipolar dysthymic disorder's medicament, the antischizophrinic agent, anticarcinogen, the aggressive behavior controlling agent, the low disease medicament of anti-attention, anti-delirium medicine, the medicine of anti-obsessive-compulsive disorder (COD), antuepileptic, alkaloids, the controlling of blood pressure agent, hormone, anti-infective, muscle relaxant, steroid, sleeping pill, the ischemia medicament, anti-arrhythmic, contraceptive, vitamin, mineral, tranquilizer, the neurotransmitter regulator, wound healing agent, the plain medicament of angiogenesis inhibitor, cytokine, somatomedin, the metastasis agent, antacid, hydryllin, antibacterial, antiviral agent, the gas roof agent, appetite suppressant, anti-wasting diseases medicine, anti-polyphagia medicine, anti-anorexia nervosa disease drug, the brain injury medicine, the heart attack medicine, adenosine, adenosine releasing agent and adenosine receptor stimulant, the sun protection agent, lubricant, reduce the product of skin temperature, radioactivity phosphorescence or fluorescence contrast diagnosis and imaging agent, the libido regulator, cholic acid, laxative, anti-diarrhea agents, the skin renewal agent, hair growth promoter.

3. the compositions of claim 1, carrier wherein is selected from solid or liquid-carrier.

4. the compositions of claim 1, described compositions are cold do or cryodesiccated.

5. the compositions of claim 1; said composition further contains and is selected from following reagent: antioxidant; flavoring agent; volatile oil; buffer agent, dispersant, antiseptic or be selected from surfactant protein A; surfactant protein B; surfactant protein C; the activating agent of surfactant protein D and surfactant protein E and its active fragment; the di-saturated phosphatidylcholine of non-two palmityls; dipalmitoyl phosphatidyl choline, phosphatidylcholine, phosphatidyl glycerol; phosphatidylinositols; PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidic acid; ubiquinone; lysophosphatidyl ethanolamine, LYSO-PHOSPHATIDYLCHOLINE LYSOPC, palmityl-LYSO-PHOSPHATIDYLCHOLINE LYSOPC; dehydroepiandrosterone; dolichol, sulfatide acid; 3-PGA, dihydroxyacetone phosphate; glycerol; glyceryl-3-phosphocholine, dihydroxy acetone, palmitate; cytidine diphosphate ester (CDP) diacylglycerol; cytidine diphosphocholine, choline, choline phosphate; artificial laminar body carrier as surfactant; omega-3-fatty acid, polyenoic acid, polyenoic acid; lecithin; Palmic acid, the block copolymer of nonionic oxirane and expoxy propane, poly(propylene oxide); poly(ethylene oxide); the polyvinylamine that has glucosan and/or alkanoyl side chain, Brij35, TritonX-100; ALEC; Exosurf, Survan and atovaquone.

6. pharmaceutical preparation, said preparation contains the compositions of claim 3, and said preparation is the preparation that is selected from following system and topical use: oral, in the oral cavity, intravaginal, rectum, intrauterine, intradermal, local, skin, parenteral, in the tumor, intracranial, in the cheek, the Sublingual, intranasal, intramuscular, subcutaneous, in the blood vessel, in the sheath, suck, percutaneous, intraarticular, in the body cavity, implant, percutaneous, ionotherapy, ophthalmic, eye, vagina, intraarticular, ear, intravenous, intramuscular, in the gland, in the organ, in the lymph, implant, slow or lasting discharge and enteric coating preparation.

7. the pharmaceutical preparation of claim 6, wherein oral formulations is selected from capsule, cachet, lozenge, tablet, powder, granule, solution, suspension or Emulsion.

8. the oral formulations of claim 7, solution wherein and suspension are selected from water or non-aqueous solution and suspension, and Emulsion is selected from Water-In-Oil or oil in water emulsion.

9. the oral formulations of claim 7, wherein oral cavity and Sublingual medication preparation are selected from lozenge and lozenge, lozenge wherein also further contains the flavoring agent that is selected from sucrose, arabic gum and Tragacanth, and lozenge also contains the inert base that is selected from gel, glycerol, sucrose and arabic gum.

10. the oral formulations of claim 7 wherein further comprises enteric coating.

11. the pharmaceutical preparation of claim 6, wherein the preparation of parenteral is selected from injection solution and suspension, wherein further contains antioxidant, buffer agent, antibacterial and can make preparation and possibility receiver's isoosmotic solution of blood or suspension.

12. the parenteral formulations of claim 11, solution wherein and suspension are selected from aseptic water or non-water injection solution suspension, wherein also further contain suspending agent and thickening agent.

13. aseptic ampoule and vial wherein contain the preparation of the parenteral of claim 11.

14. the pharmaceutical preparation of claim 6, described preparation are single dose form or multiple dose form.

15. the pharmaceutical preparation of claim 6, described preparation are the forms of big medicated bag.

16. the pharmaceutical preparation of claim 6, described preparation are cold dried or cryodesiccated.

17. the pharmaceutical preparation of claim 6, wherein topical formulations is selected from: emulsifiable paste, cream, lotion, paste, colloid, spray, aerosol or oil preparation.

Be selected from following carrier 18. the topical pharmaceutical formulation of claim 17, described preparation further contain: vaseline, lanoline, Polyethylene Glycol, alcohols, percutaneous shift reinforcing agent.

19. the preparation of claim 6, described preparation are the preparations of percutaneous.

20. the preparation of the percutaneous of claim 19, said preparation are the solution or the form of suspension of first medicament, wherein also further contain buffer agent and one or more second medicaments.

21. the doser of percutaneous wherein contains the preparation of claim 19.

22. the doser of claim 21, this device is a patch.

23. the pharmaceutical preparation of claim 6, described preparation is an inhalable formulations.

24. the inhalable formulations of claim 23, wherein aerosol contains the granular medicament of liquid or solid, and further contains the reagent that is selected from following antiseptic, antioxidant, flavoring agent, volatile oil, buffer agent, dispersant.

25. containing can breathe maybe, the pharmaceutical preparation of claim 6, described preparation can suck granule.

26. the pharmaceutical preparation of claim 25, described preparation is an aerosol.

27. the pharmaceutical preparation of claim 6, carrier wherein comprises hydrophobic carrier.

28. the pharmaceutical preparation of claim 27, described preparation is a capsule.

29. the pharmaceutical preparation of claim 6, described preparation is a suppository.

30. the pharmaceutical preparation of claim 6, described preparation is an implant.

31. the pharmaceutical preparation of claim 6, described preparation are slow or sustained release formulation.

32. the pharmaceutical preparation of claim 6, described preparation is an ophthalmic preparations.

33. the pharmaceutical preparation of claim 6, described preparation is an aural preparations.

34. the pharmaceutical preparation of claim 6, described vaginal preparation is selected from emulsifiable paste, colloid, suppository and implant.

35. the pharmaceutical composition of claim 2, said composition contains first medicament, be selected from second medicament of analgesic, antiinflammatory, muscle relaxant, sleep derivation agent, antianxiety drug, diuretic, other mood regulation agent, vitamin, mineral, protein, hormone medicine, and physiologically acceptable carrier.

36. the pharmaceutical composition of claim 35, second medicament wherein comprise that one or more are different from the mood regulation agent of first medicament.

37. the pharmaceutical composition of claim 35, second medicament wherein comprises one or more diuretic.

38. the pharmaceutical composition of claim 35, second medicament wherein comprises vitamin and mineral.

39. the pharmaceutical composition of claim 35, second medicament wherein comprises one or more antianxiety drugs.

40. the pharmaceutical composition of claim 35, second medicament wherein comprises one or more analgesic and/or antiinflammatory.

41. the pharmaceutical composition of claim 35, second medicament wherein comprises one or more hormone medicines.

42. the pharmaceutical composition of claim 35, said composition contain first medicament, have the active hormone of estrogen and Progesterone, diuretic and analgesic or antiinflammatory.

43. the pharmaceutical composition of claim 1, wherein the compositions of food form also contains other comestible composition.

44. the pharmaceutical composition of claim 43, food wherein are selected from milk, fruit juice, frumentum, energy bar, chewing gum, cake, confection, soft battercake, beverage, cookies, dough/pasta, salad dressing, vegetable, meat, fish and fruit.

45. the pharmaceutical composition of claim 6, said composition is the ionotherapy percutaneous preparation form that adopts the ionotherapy transdermal delivery device to use, carrier wherein is selected from water and alcoholic solution, oil solution, suspension, with oil-in-water and water-in-oil emulsion, and said preparation also contains percutaneous transfer promoter.

46. implantable capsule or film wherein contain the percutaneous preparation of claim 45.

47. medicine box wherein contains the ionotherapy transdermal delivery device in the container that separates; The preparation of claim 6; With adding carrier and operation instructions.

48. comprising, the pharmaceutical composition of claim 4, carrier wherein be selected from liposome vesicle and particulate hydrophobic carrier.

49. the pharmaceutical composition of claim 48, somatocyst bubble wherein comprises that liposome and granule wherein comprise crystallite.

50. the pharmaceutical composition of claim 49, liposome wherein contains first medicament, and optionally contains one or more second medicaments.

51. the pharmaceutical composition of claim 50, vesicle wherein contain N-(1-[2,3-two oily acyloxy])-N, N, N-trimethyl methylsulfuric acid ammonium.

52. medicine box wherein contains first medicament of claim 1 in discontinuous container;

Doser;

With interpolation carrier and the medication instruction book accepted medicinal or for animals;

Selectively contain and be selected from surfactant protein A; surfactant protein B; surfactant protein C; the activating agent of surfactant protein D and surfactant protein E and its active fragment; the di-saturated phosphatidylcholine of non-two palmityls; dipalmitoyl phosphatidyl choline, phosphatidylcholine, phosphatidyl glycerol; phosphatidylinositols; PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphoric acid; ubiquinone; lysophosphatidyl ethanolamine, LYSO-PHOSPHATIDYLCHOLINE LYSOPC, palmityl-LYSO-PHOSPHATIDYLCHOLINE LYSOPC; dehydroepiandrosterone; dolichol, phosphoric acid; 3-PGA, dihydroxyacetone phosphate; glycerol; glyceryl-3-phosphocholine, dihydroxy acetone, palmitate; cytidine diphosphate ester (CDP) diacylglycerol; cytidine diphosphocholine, choline, choline phosphate; artificial laminar body carrier as surfactant; omega-3-fatty acid, polyenoic acid, polyenoic acid; lecithin; Palmic acid, the block copolymer of nonionic oxirane and expoxy propane, poly(propylene oxide); poly(ethylene oxide); have the polyvinylamine of glucosan and/or alkanoyl side chain, Brij 35, Triton X-100; ALEC; Exosurf, Survan and atovaquone.

Can suck or respirable preparation and comprise the doser of inhaler 53. the medicine box of claim 52, compositions wherein contain, this inhaler can single predetermined close with the preparation administration.

54. the medicine box of claim 53, wherein inhaler comprises aerosol apparatus or insufflator, and further comprise solid particle composition is housed can repairing or openable capsule or cartridge case.

55. the medicine box of claim 52, doser wherein comprises the pressure inhaler, and comprises following preparation: suspension in water or on-aqueous liquid or solution, or oil-in-water or water in oil Emulsion.

56. regulate patient's emotion, heart, kidney or brain function, pain, inflammation, sleep, the method of appetite or consciousness, use the pharmaceutical composition of claim 1 when this method is included in the needs of patients treatment to the patient, this comprises emotion, heart, sleep, kidney, brain, appetite, consciousness, pain or inflammation adjusting effective dose to the patient, or cardiac function is estimated first medicament of effective dose.

57. the method for claim 56, wherein the amount of application of first medicament is about 1 to about 1000mg/kg body weight.

58. the method for claim 57, the amount of application of wherein said medicament are about 5 to about 500mg/kg body weight.

59. also further comprising using to the patient, the method for claim 56, this method be selected from the second following medicament: analgesic, anti-premenstrual syndrome medicine, the medicine of anti-menopause, antidotal agent, antianxiety drug, the emotion control agent, antidepressant, anti-bipolar dysthymic disorder's medicament, the antischizophrinic agent, anticarcinogen, alkaloids, the controlling of blood pressure agent, the hormones medicament, anti-infective, muscle relaxant, steroid, sleeping pill, the ischemia medicament, anti-arrhythmic, contraceptive, vitamin, mineral, tranquilizer, sleeping pill, appetite suppressant, the neurotransmitter regulator, wound healing agent, the plain medicament of angiogenesis inhibitor, cytokine, somatomedin, the metastasis agent, antacid, hydryllin, antibacterial, antiviral agent, the gas roof agent, appetite suppressant, anti-wasting diseases medicine, anti-polyphagia medicine, anti-anorexia nervosa disease drug, the brain injury medicine, cardiotropic formulation, adenosine, adenosine releasing agent and adenosine metabolism inhibitor, the sun protection agent, lubricant, reduce the product of skin temperature, radioactivity phosphorescence or fluorescence contrast diagnosis and imaging agent, the libido regulator, cholic acid, laxative, anti-diarrhea agents, the skin renewal agent, hair growth promoter.

60. the method for claim 59, second medicament wherein comprises other mood regulation agent.

61. the method for claim 59, second medicament wherein comprises muscle relaxant and/or sleep derivation agent.

62. the method for claim 56, compositions wherein are to be administered systemically or topical.

63. the method for claim 62, compositions wherein be oral, suck, local, parenteral or percutaneous dosing.

64. the method for claim 63, wherein compositions is administration in the following manner: in cheek, Sublingual, percutaneous, ophthalmic, subcutaneous, Intradermal, intramuscular, intravenous, intraarticular, intravaginal, rectum, intrauterine, Intradermal, part, percutaneous, parenteral, the tumor, in the intracranial, cheek, nose, blood vessel, in the sheath, in the suction, percutaneous, body cavity, implant, percutaneous, ionotherapy, ophthalmic, eye, vagina, ear, in the gland, in the organ, interior, the implant of lymph.

65. the method for claim 64, compositions wherein is oral to be selected from following dosage form: capsule, cachet, lozenge, tablet, powder, granule, solution, suspension or Emulsion.

66. the method for claim 65, oral formulations wherein further comprises enteric coating.

67. the method for claim 63, compositions wherein is with oral cavity and sublingual formulation administration, and described preparation is selected from lozenge and lozenge,

Lozenge wherein also further contains the flavoring agent that is selected from sucrose, arabic gum and Tragacanth,

Lozenge wherein also contains the inert base that is selected from gel, glycerol, sucrose and arabic gum.

68. the method for claim 63, compositions wherein is with the parenteral administration administration, described preparation is selected from injection solution and suspension, wherein further contains antioxidant, buffer agent, antibacterial and/or can make solution and suspension and possibility receiver's the isoosmotic solute of blood.

69. the method for claim 68, preparation wherein are cold dried or cryodesiccated; And this method comprises that also adding before use is selected from the sterile liquid carrier of saline or water.

70. the method for claim 63, the dosage form administration that compositions is wherein used with the part, described preparation is selected from: emulsifiable paste, cream, lotion, paste, colloid, spray, aerosol or oil preparation; Wherein also can comprise the carrier that is selected from vaseline, lanoline, Polyethylene Glycol, alcohols and transdermal enhancer.

71. the method for claim 63, wherein the compositions as the percutaneous preparation administration is the form of patch.

72. the method for claim 63, compositions wherein are with iontophoretic preparation administration, said preparation comprises the solution or the suspension of described medicament, and selectively contains the buffer agent and second medicament.

73. the method for claim 63, compositions wherein is to suck the form administration of preparation.

74. the method for claim 73, suction preparation wherein is an aerosol, described aerosol contains the liquid or solid granule of medicament, and further contains the reagent that is selected from antiseptic, antioxidant, flavoring agent, volatile oil, buffer agent, dispersant and surfactant.

75. the method for claim 63, compositions wherein is by vagina or rectally.

76. the method for claim 63, compositions wherein is by eye or ear administration.

77. the method for claim 63, compositions is wherein passed through intra-articular administration.

78. further comprising, the method for claim 56, compositions wherein be selected from following reagent: physiologically acceptable carrier, antiseptic, antioxidant, flavoring agent, volatile oil, buffer agent, dispersant and surfactant agent.

79. the method for claim 56, patient wherein is an animal.

80. the method for claim 79, patient wherein is the people.

81. the method for claim 56, wherein emotional disorder is relevant with following disease or symptom: cancer, wound, pain, operation, viral infection, bacterial infection, hyperemia, inflammation, autoimmune disease, menopause, can't sleep, long-term bed, operation, voracity, anorexia nervosa, wasting diseases and gene genetic.

82. the method for treatment emotional disorder, this method comprises the method for claim 56, and first medicament wherein is with the administration of emotional disorder regulated quantity.

83. the method for claim 82, patient wherein tends to, perhaps existing depression, schizophrenia, over-drastic aggressivity, the low disease of attention, paranoea, obsessive-compulsive disorder or latah.

84. the method for claim 82, the operation of patient experience wherein or traumatic somatic damage, or suffer from chronic pain or cancer.

85. the method for claim 82, wherein the amount of application of first medicament is about 1 to about 1000mg/kg body weight.

86. the method for claim 85, the amount of application of wherein said medicament are about 5 to about 500mg/kg body weight.

87. also further comprising using, the method for claim 82, this method be selected from the second following medicament: analgesic, anti-premenstrual syndrome medicine, the medicine of anti-menopause, antidotal agent, antianxiety drug, the emotion control agent, antidepressant, anti-bipolar dysthymic disorder's medicament, the antischizophrinic agent, the low disease medicament of anti-attention, anticarcinogen, alkaloids, the controlling of blood pressure agent, the hormones medicament, anti-infective, muscle relaxant, steroid, sleeping pill, the ischemia medicament, anti-arrhythmic, contraceptive, vitamin, mineral, tranquilizer, the neurotransmitter regulator, wound healing agent, hormone medicine, anti-arthritic, anti-obsessive-compulsive disorder medicine, attack level decline medicine, the plain medicament of angiogenesis inhibitor, cytokine, somatomedin, the metastasis agent, antacid, hydryllin, antibacterial, antiviral agent, the gas roof agent, appetite suppressant and agonist, anti-wasting diseases medicine, anti-polyphagia medicine, anti-anorexia nervosa disease drug, the brain injury medicine, the heart attack medicine, adenosine, adenosine releasing agent and adenosine receptor agonist, the sun protection agent, lubricant, reduce the product of skin temperature, radioactivity phosphorescence or fluorescence contrast diagnosis and imaging agent, the libido regulator, cholic acid, laxative, anti-diarrhea agents, the skin renewal agent, hair growth promoter.

88. the method for claim 87, compositions wherein contains first medicament, and the active hormone of estrogen and Progesterone, diuretic, analgesic or antiinflammatory are arranged.

89. consumable products wherein contains first medicament of the claim 1 of food and mood regulation effective dose.

90. the consumable products of claim 89 wherein also contains and is selected from the second following medicament: analgesic, anti-premenstrual syndrome medicine, the medicine of anti-menopause, antidotal agent, antianxiety drug, the emotion control agent, antidepressant, anti-bipolar dysthymic disorder's medicament, the antischizophrinic agent, anticarcinogen, aggressive controlling agent, the low disease medicament of anti-attention, anti-latah medicine, anti-obsessive-compulsive disorder medicine, anti-aggressivity disease medicament, antuepileptic, alkaloids, the controlling of blood pressure agent, the hormones medicament, anti-infective, muscle relaxant, steroid, sleeping pill, the ischemia medicament, anti-arrhythmic, contraceptive, vitamin, hormone medicine, mineral, tranquilizer, the neurotransmitter regulator, wound healing agent, the plain medicament of angiogenesis inhibitor, cytokine, somatomedin, the metastasis agent, antacid, hydryllin, antibacterial, antiviral agent, the gas roof agent, appetite suppressant, anti-wasting diseases medicine, anti-polyphagia medicine, anti-anorexia nervosa disease drug, the brain injury medicine, the heart attack medicine, adenosine, adenosine releasing agent and adenosine receptor agonist, the sun protection agent, lubricant, reduce the product of skin temperature, radioactivity phosphorescence or fluorescence contrast diagnosis and imaging agent, the libido regulator, cholic acid, laxative, anti-diarrhea agents, the skin renewal agent, hair growth promoter.

91. the product of claim 89, wherein the amount of first medicament is 0.01-99.9 weight %.

92. containing, the product of claim 89, food wherein be selected from following secondary product: milk, fruit juice, frumentum, energy bar, confection, chewing gum, cake, confection, cookies, vegetable, meat and fruit.

93. the product of claim 89, food wherein is selected from infant foods, milk, baby food, cake and cookies.

94. treatment and diagnostic agent box, this medicine box is equipped with food component in the container that separates, first medicament of claim 1; And prepare the explanation of described food and use the explanation of this medicine box.