JP2003523933A - Compositions and formulations and their use as analgesics, anxiolytics and anabolic agents - Google Patents

Abstract

  (57) [Summary] 【Task】 A first drug such as folinic acid, a pharmaceutically acceptable salt thereof, or a mixture thereof and an analgesic, a muscle relaxant, a mood disorder, an anti-inflammatory, an anti-migraine, an anti-nausea, a diuresis. And compositions comprising a second agent, such as an agent, a high protein complex. The product is suitable as an analgesic and for the treatment of wasting disorders, bulimia, anorexia nervosa, anxiety, irritability and other symptoms associated with premenstrual syndrome and is administered with steroids or adenosine deficiency And / or is administered to treat or prevent abnormal behavior or aggression common to steroid users.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a composition containing folinic acid, a pharmaceutically acceptable salt thereof or a mixture thereof, and other drugs such as analgesics, anti-inflammatory agents, muscle relaxants, anti-migraine agents, anti-nausea agents and diuretics. Products and formulations. This product is a wasting disord
er), anxiety, for treating hypersensitivity associated with premenstrual syndrome, and for administration with steroids, or for supplementing adenosine deficiency common to steroid users, it is suitable as a nociceptive agent.

[0002]

[Prior art]

Folinic acid is an intermediate product of folic acid metabolism and is considered to be an active form of folic acid converted in the body. Ascorbic acid or vitamin C is required as a necessary factor in the conversion of folic acid to folinic acid. Folinic acid has been used therapeutically as an antidote to antifolates such as methotrexate, which blocks the conversion of folic acid to folinic acid. In addition, folinic acid has the ability to fight folate deficiency,
Used as an anti-anemic agent. To date, folinic acid has not been used in patients suffering from adenosine deficiency, nor has it been used as a treatment to elevate adenosine levels in the brain or other organs.

Adenosine is a purine involved in intermediate metabolism. Adenosine is involved in the regulation of physiological activity in various mammalian tissues and in many local regulatory mechanisms, including those occurring at the central nervous system (CNS) junctions and the peripheral effector neuroeffector junctions. ing. In the CNS, adenosine blocks the release of various neurotransmitters such as acetylcholine, noradrenaline, dopamine, serotonin, glutamate and GABA, inhibits neurotransmission, reduces neuronal firing and induces spinal analgesia, and , Relieve anxiety. In the heart, adenosine suppresses pacemaker activity, delays AV conduction, has antiarrhythmic and arrhythmogenic effects, regulates autonomic control, and induces prostaglandin synthesis and release.
In addition, adenosine has potential vasodilatory effects and regulates vascular conditions. inferior,
Adenosine is clinically used in the treatment of supraventricular tachycardia (SVT) and other cardiac abnormalities, and in testing cardiovascular function. Adenosine analogs have also been investigated for use as anticonvulsants, anxiolytics and neuroprotectants. Adenosine also protects tissues that have undergone ischemia (oxygen block), and these tissues, such as,
At risk of brain after stroke or other acute or chronic cerebral ischemic episodes and diseases, heart after heart attack or acute or chronic ischemic episodes or diseases, and risk of ischemia involved in the course of the disease and symptoms Other organs, namely acute and chronic physiological events, help reperfusion in transplantable organs as well as already transplanted organs, especially during the harvest and transplantation stages prior to transplantation. Adenosine analogs have also been investigated for use as anticonvulsants, anxiolytics and neuroprotective agents. Furthermore, adenosine is, for example, a natural anti-inflammatory agent known to mediate the anti-inflammatory effect of methotrexate. Adenosine also promotes and accelerates wound healing, and
It regulates neutrophils via the activity of serine / threonine phosphatases. Although adenosine has a variety of therapeutic uses mentioned above, it has a very short half-life (about 1 second). The short half-life of adenosine and its propensity to produce angina-like pain renders therapeutic options poorly selected.

From the above description, a large decrease in adenosine levels or adenosine deficiency leads to a wide range of adverse symptoms, and the ability to treat, reverse and prevent adenosine deficiency is a highly beneficial tool for therapeutic intervention. It's easy to see. Drugs with longer half-lives are useful as pain relievers and as therapeutic and prophylactic treatments for various diseases and conditions such as anxiety, hypersensitivity and wasting disorders associated with premenstrual syndrome, among others, the effects of steroids. Will bring great advantages to counter.

[0005]

DISCLOSURE OF THE INVENTION

The present invention relates to compositions, formulations and methods for inhibiting and treating wasting disorders including anxiety, nausea, hypersensitivity associated with premenstrual syndrome, bulimia and anorexia nervosa and increasing muscle (protein). The method provides a subject in need of such treatment with a first drug and other anxiolytic agent selected from the group consisting of folinic acid, pharmaceutically acceptable salts thereof, and mixtures thereof. Administering a pharmaceutical composition that includes, inter alia, an agent, an antidepressant, an anti-inflammatory agent, and a second agent such as an analgesic.
The composition may also include a formulation component and a physiologically acceptable carrier.

That is, this method, regardless of its origin, or whether the disease is accompanied by a decrease in adenosine levels (whether due to an endogenous abnormality or as a result of an exogenous administered substance) It can be applied to preventive and therapeutic treatment of diseases and symptoms and reduction of severity. Treats and blocks diseases and conditions affecting the central nervous system (CNS) such as nausea, anxiety, and signs of premenstrual syndrome, treats steroid-related CNS problems, wasting disease, and reduces anorexia nervosa and The application of the compositions and formulations of the present invention to induce weight gain in bulimia and to increase body weight in general and muscle mass in particular is of particular importance. The drug of the present invention is in the form of bulk or unit tablets, or as various pharmaceutical formulations such as energy bar, chewing gum, candy, drink, cake, salad dressing, and other edible ingredients such as pasta in the form of food and the like. May be provided.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention blocks wasting, anorexia nervosa or bulimia, anxiety, hypersensitivity associated with premenstrual syndrome, nausea, anxiety and other related conditions often associated with adenosine deficiency in the central nervous system (CNS) and It arises from the desire of the inventor to improve on the prior art of treatment. The treatment of the present invention, regardless of the presence or absence of significant adenosine depletion or deficiency, and whatever the cause is, for example, by the use of steroids and other adenosine deficient drugs, defective adenosine synthesis, high adenosine metabolism or Effective for any other cause.

Adenosine is known to be a natural drug with analgesic, anti-inflammatory, anti-ischemic, hypnotic and anxiolytic effects. The present inventors have unexpectedly found that the first drug also shows sustained activity as a nociceptive anxiolytic agent to treat and prevent adverse symptoms associated with steroid intake, such as abnormal behavior, madness and aggression. I found that The inventor has also found that the first drug is hypersensitivity and other abnormal emotional behavior associated with premenstrual syndrome, wasting syndrome (the first drug acts as an anabolic agent)
And from studies that have, inter alia, substantial activity to treat and prevent bulimia and anorexia nervosa. In particular, in the case of premenstrual syndrome, the inventor has found that this condition is often associated with a cyclical change in adenosine levels, probably due to fluctuations in neuronal steroid levels.

Adenosine has an extremely short half-life (about 1 second) and tends to produce angina-like pain, which in itself is anxiety, premenstrual syndrome (PMS) signs, wasting disorders, anorexia nervosa and It is inferior to the choice of hyperphagic treatment and the adverse side effects of steroid intake. The inventor has the ability to produce adenosine synthesis,
Agents such as folinic acid, which has a longer half-life than adenosine and does not cause angina-like pain, were hypothesized to be more suitable for administration to subjects suffering from these conditions.

However, adenosine has a very short half-life (about 1 second) and therefore cannot be reasonably administered as a therapeutic agent. This fact and the tendency to cause angina-like pain precludes adenosine itself as a therapeutic agent for pain and inflammation. Agents such as folinic acid that can cause adenosine synthesis are more suitable for administration to subjects afflicted with these conditions. The inventor has shown that administration of folinic acid induces new synthesis of adenosine. The inventor has shown that oral administration of folinic acid causes a dramatic increase in adenosine concentrations in the brain of an animal model. Since folinic acid has a longer half-life than adenosine itself and is not involved in the induction of angina-like pain, this first drug shows an unexpected improvement over adenosine that increases cerebral adenosine levels. It is suitable as a nociceptive, anxiolytic, and antibulimic agent, and for the treatment of anorexia nervosa, wasting disease, gaining weight and countering the CNS side effects of steroids. Folinic acid, its salts and their mixtures are effective in the prevention and treatment of these and other syndromes and conditions, and increasing adenosine levels have therapeutic value.

The agents of the present invention are combined with the agents currently used to treat the above-mentioned diseases, conditions, signs and syndromes and to treat other comparable signs encountered by these patients. It is provided as a pharmaceutical composition. The technique of the present invention can be applied to existing treatments that are only partially effective, even if the treatments are initially effective but their effectiveness declines over time. It is extremely useful for the examiner. The methods of the invention are effective in stimulating adenosine synthesis, thereby therapeutically using or using steroids, for example to treat or control anxiety, nausea, and hypersensitivity (such as in premenstrual syndrome). The subject being treated is treated to gain weight, treat wasting disorders, and prevent marked weight loss in anorexia nervosa and bulimia nervosa. The term "adenosine deficiency" means
It is intended to include diseases and conditions such as nausea, anxiety and weight loss, which may be compared to previous adenosine concentrations in the same subject or to one or more of the normative norms (passing score) of that species. It is associated with a significant reduction or depletion of adenosine levels in tissues. However, from other symptoms and changes in the patient, therapeutic benefit is achieved in the patient by increasing the adenosine concentration compared to the previous concentration. The method of the present invention treats a subject having a decreased adenosine concentration, for example, about 5%, about 10%, about 20%, about 3 compared to the previous adenosine concentration that was completely depleted.
0% or more. Although the present invention relates primarily to the treatment of human subjects, it also has general use in the treatment of vertebrates, particularly mammals. Some of the animals treated are domestic and wild animals, house pets (cats, dogs, etc.), zoo animals, race horses, farm animals (cattle, sheep, etc.) and others for veterinary purposes. There are large and small animals, including many of them.

Folinic acid and its pharmaceutically acceptable salts (hereinafter “active compounds”) are known and are prepared according to known methods. See, generally, Merck Index, Research Paper No. 4141 (11th edition, 1989), US Pat. No. 2,741,608.

The second agent of the composition of the present invention is one or more of a variety of therapeutic and diagnostic agents suitable for administration to humans and / or animals. Some of the categories of agents suitable for incorporation into the compositions and formulations of the present invention include: analgesics, premenstrual medications, anti-menopausal agents such as hormones, anti-aging agents, anxiolytics, nociceptive agents, Mood disorders, antidepressants, anti-bipolar mood agents, anti-schizophrenia agents, anti-cancer agents, alkaloids, blood pressure regulators, hormones, anti-inflammatory agents, arthritis, burns, wounds, chronic bronchitis, chronic obstructive pulmonary disease (COPD)
), Inflammatory bowel diseases such as Kron's disease and ulcerative colitis, other agents suitable for the treatment and prevention of diseases and conditions associated with or associated with pain and inflammation such as autoimmune diseases, muscle relaxants, Steroids, hypnotics, anti-ischemic agents, anti-arrhythmic agents, contraceptives,
Vitamins, minerals, tranquilizers, neurotransmitter control agents, wound and burn healing agents,
Anti-angiogenic agent, cytokine, growth factor, anti-metastatic agent, anti-acid agent, anti-histamine agent,
Antibacterial agents, antiviral agents, anti-toxic gas agents, reperfusion injury agents, neutralizing appetite suppressants, sunscreens, emollients, skin temperature lowering agents, radioactive phosphorescence and fluorescence contrast diagnostics and imaging agents, libido change agents, Bile acids, laxatives, anti-diarrheal agents, skin renewal agents, hair growth agents and the like.

Hormones include female and male sex hormones such as premarin, progesterone, androsterone and its analogs, thyroxine and glucocorticoids, and libido-altering agents include viagra and other NO-level regulators. There are, as analgesics, over-the-counter drugs such as ibuprofen, orda, aleb and acetaminophen, and controlled drugs such as morphine and codeine, and as antidepressants, tricyclics, MAO inhibitors and epinephrine, γ-aminobutyric acid. (
GABA), dopamine and serotonin concentration increasing agents such as prozac, amitriptyline, wellbutyrin and zoloft, and skin regenerating agents include
There are hair growth agents such as retin-A and rogaine, anti-inflammatory agents include non-steroidal anti-inflammatory drugs (NSAIDs) and steroids, and hypnotic agents include melatonin and diazepam, cytoprotective agents, anti-ischemic agents. There are wound healing agents such as and enadrine, and many others. Examples of drugs in different groups include:
Some are listed below. Examples of analgesics include acetaminophen,
Anierldine, aspirin, buprenorphine, butavitar, butorphanol, choline salicylate, codeine, dezocine, diclofenac, diflunisal, dihydrocodeine, elcatoninine, etodolac, fenoprofen, hydrocodeine, hydromorphone, ibuprofen, ketoprofen, ketorolac, revorfa, revorfa, revolfa, revolfa, levorfa. Meclofenamate, mephenamic acid, meperidine, methadone, methotrimeprazine, morphine, nalbuphine, naproxen, opium, oxycodone, oxymorphone, pentazocine, phenobarbital, proxyphene, salsalate, sodium salicylate, tramadol and above In addition there are narcotic analgesics. Mosby's
See Physician's GenRx. Examples of anxiolytics include, inter alia, arpazolam, bromazepam, buspirone, chlordiazepoxide, chlormezanone, chlorazepate, diazepam, harazepam, hydroxyzine, ketazozocam, lorazepam, meprobamate, oxazepam and prazepam. Examples of anxiolytic agents associated with psychodepression include, among others, chlordiazepoxide, amitriptyline,
There are loxapine, maprotiline and perphenazine. As anti-inflammatory agents, non-rheumatic aspirin, choline salicylate, diclofenac, diflunisaal, etodolac, fenoprofen, floctafenin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, magnesium salicylate, meclofenamate, mephenamine acid, nabumetone, There are naproxen, oxaprozin, phenylbutazone, proxycam, salsalate, sodium salicylate, sulindac, tenoxicam, thiaprofenic acid, tolmethine. Examples of anti-inflammatory agents for eye treatment include diclofenac, flurbiprofen, indomethacin, ketorolac, rimexolone (usually for postoperative treatment). Examples of anti-inflammatory agents for non-infectious nasal treatment include beclomethaxone, budesonide, dexamethasone, flunisolide, triamicinolone. Examples of hypnotics (anti-insomnia / sleep inducers), such as those used in the treatment of insomnia, include alprazolam, bromazepam, diazepam, diphenhydramine, doxylamine, estazolam, flurazepam, harazepam, ketazolam, corazepam, nitrazepam, among others. There are prazepam, quazepam, temazepam, trazolam, zolpidem and sopiclone. Examples of sedatives include diphenhydramine, hydroxyzine, metrotrimeprazine, promethazine, propofol, melatonin, trimeprazine and the like. Examples of analgesics and especially drugs for small seizures and tremors are amitriptyline HCl, chlordiazepoxide, amobarbital, secobarbital, aprobarbital, butabarbital, esthiorubinol, glutethimide, L-tryptophan, mefobarbital, methohether Na, There are Midzolam HCl, Oxazepam, Phenotobarbital Na, Secobarbital, Thiamylal Na and many others. Treatment of head trauma (brain injury / ischemia) includes enadrine HCl (eg, for treatment of severe head injury, rare condition, Warner Lambert). Examples of cytoprotective agents and remedies for menopause and menopause syndrome include ergotamine, belladonna alkaloids and phenobarbital. Examples of drugs for the treatment of menopausal vasomotor symptoms include clonidine, conjugated estrogens and medroxyprogesterone, estradiol, estradiol
There are cypionate, estradiol valerate, estrogen, conjugated estrogens, esterified estrone, estropipeto and ethinyl estradiol. Examples of agents that treat the symptoms of premenstrual syndrome (PMS) include progesterone, progestin, gonadotropin-releasing hormone, oral contraceptives, danazol, luprolide acetate and vitamin B6. Examples of mood / psychological therapeutic agents include amitriptyline HCl (eravir), amitriptyline HC
There are tricyclic antidepressants including 1, perphenazine (triavir) and doxepin HCl (Sinequan). Examples of tranquilizers, antidepressants and anxiolytics are diazepam (barium), lorazepam (achiban), alprazolam (Xanax), SSRI's (selective serotonin reuptake inhibitor), fluoxetine HCl (prozac), sertaline. HCl (Zoloft), paroxetine HCl (
Paxil), fluvoxamine maleate (lubox), venlafaxine H
There are Cl (effector), serotonin, serotonin agonists (fenfluramine), and other over the counter medicines (OTCs). Examples of anti-migraine agents include Imitrex.

A pharmaceutically acceptable salt should be both pharmacologically and pharmaceutically acceptable. Such pharmacologically and pharmaceutically acceptable salts can be prepared as alkali metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group of folinic acid. The calcium salt of folinic acid is the preferred pharmaceutically acceptable salt. Organic salts and esters are also suitable for use in the present invention. The active compound is preferably administered to the subject as a pharmaceutical composition. The pharmaceutical compositions used in the present invention include systemic and topical formulations, especially inhalation, oral, intestine, vagina, nose, ear, eye, lumen, intra-organ, topical (oral, sublingual). , Including skin and intraocular), parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular) and transdermal administration. The compositions are conveniently provided in unit-dose or multi-dose form, as well as in bulk, and may be prepared by any of the methods well known in the art of pharmacy. The compositions of the present invention may already be formulated or may be provided in the form of a kit with instructions for its formulation and administration. The kit may also include other agents such as those mentioned above. For parenteral administration, for example, it may be contained in a separate container together with the carrier. that time,
The carrier is sterile. The compositions of the invention may be packaged in a sterile, separate container for addition of liquid carrier prior to administration. For example, U.S. Pat.No. 4,956,355,
See British Patent No. 2,240,472, European Patent Application No. 429,187, PCT Patent Application No. 91/04030, relevant preparation methods and compounds part introduced by the above references. Mortensen, SA, et al., Int. J. Tiss. Reac. XII (3); 155-162 (19
90); Greenberg, S., et al., J. Clin. Pharm. 30; 596-608 (1990); Folkers,
See K., et al., Proc. Natl. Acad. Sci. 87: 8931-8934 (1990), also relevant preparation methods and parts of compounds introduced by the literature. Formulations suitable for oral and parenteral administration are preferred, as well as inhalable preparations. All methods include the step of bringing the active compound into association with the carrier which constitutes one or more accessory ingredients. In general,
The formulations are prepared by uniformly and intimately admixing the active compound with liquid carriers, finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

Compositions suitable for oral administration include capsules, wafers, troches or tablets, as discrete unit tablets containing a predetermined amount of the active compound, as powders or granules,
It may be provided as a solution or dispersion of a water-soluble or water-insoluble liquid, or as an oil-in-water or water-in-oil emulsion. Such compositions may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound with a suitable carrier. In general, the compositions of the present invention are prepared by uniformly and intimately bringing into association the active compound with liquids or finely divided solid carriers or both, and then, if necessary, shaping the resulting mixture. . For example, a tablet is formed by pressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Pressed tablets may also be prepared by pressing, in a suitable machine, a free-flowing compound such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersant. Good. Molded tablets may be made by molding in a suitable machine a powdered compound moistened with an inert liquid binder. Compositions for oral administration optionally include an enteric coating known in the art to prevent degrading the composition in the stomach and resulting in release of the drug in the small intestine. Compositions suitable for buccal (sublingual) administration include flavor bases,
Usually mentioned are buccal agents containing the active compound in sucrose and acacia or tragacanth, troches containing the compound in an inert base such as gelatin and glycine or sucrose and acacia.

Compositions suitable for parenteral administration include sterile aqueous and non-aqueous injectable solutions of the active compound, the preparation of which is preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats, and solutes which make the blood of the intended recipient isotonic. Water-soluble and water-insoluble sterile dispersions
A dispersant and a thickener may be included. The compositions are provided in single-dose or multi-dose containers, such as sealed ampoules and vials, and frozen requiring the addition of a sterile liquid carrier, such as saline or water for injection, just before use. It may be stored in a dry state. Extemporaneous injection solutions and dispersions may be prepared from sterile powders, granules and tablets of the kind previously described.

Compositions suitable for topical application to the skin preferably take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Carriers used include petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. Compositions suitable for transdermal administration may be presented as discrete patches which are applied over time and in intimate contact with the epithelium of the recipient. Compositions suitable for transdermal administration may be released by iontophoresis (see, eg, Pharmaceutical Research 3, 318 (1986)) and usually take the form of an optionally buffered aqueous solution of the active compound.

The active compound (first agent) of the present invention is provided in the composition within a wide range of amounts. For example, folinic acid, its salts and mixtures thereof are present in the composition in an amount of about 0.00
1%, about 1%, about 2%, about 5% to about 99.999%, about 98%, about 90%, about 40%, about 20%, about 10%, about 5%, preferably the composition Medium, about 1 to about 99%
More preferably from about 2 to 40%, even more preferably from about 2 to about 10%. These amounts may be adjusted if they include another drug with overlapping activity as described above.

The dose of the active compound will vary according to the age, weight and condition of the subject.
Treatment is initiated with smaller sub-doses than the optimal dose of the first agent of this invention, whether folinic acid or one of its salts. This dose is increased until the desired and / or optimal effect is achieved under the conditions. Generally, the dose is about 1, about 5, about 10, about 20, about 50 mg / kg body weight to about 100, about 200, about 500.
Or about 1000 mg / kg body weight. Presently preferred doses are from about 5 to about 500 mg / kg of subject weight, more preferably from about 10 to about 200 mg / k.
g and more preferably about 50 to about 100 mg / kg of the body weight of the subject.
Is. However, higher or lower doses are also contemplated and therefore
These are also within the scope of this patent. In general, the active compounds are preferably administered at a concentration that will achieve effective results without any undue or harmful side effects, in a single dose or, if desired, per day. Administer any number of conventional subunits. The therapeutic or diagnostic second agent is administered in an amount known in the art to be effective in its intended use. If the second drug has an activity that overlaps with the base drug, folinic acid and its salts, the dosage of one or both of the other drugs should be within a dosage range that avoids abnormal side effects, It may be adjusted to obtain the desired effect. That is, for example, if other analgesics and anti-inflammatory agents are added to the composition, in amounts that are known in the art for their intended use, or in somewhat lesser amounts than when administered per se. It may be added.

[0021] Generally, the compositions of the present invention are provided in a variety of systemic or topical formulations. The systemic or topical formulation of the present invention may be oral, buccal, pulmonary, intestinal, intrauterine, intradermal, topical, cutaneous, parenteral, intratumoral, intracranial, buccal, sublingual, nasal, intramuscular. , Subcutaneous, intravascular, intrathecal, inhalable, transdermal, intraarticular, intraoral, transplantable, transdermal, iontophoretic, intraocular, eye, vagina, ear, intravenous, intramuscular, intraglandular, It is selected from the group consisting of intra-organ, intra-lymphocyte, implantable, low release, and enteric coating formulations. The actual preparation and mixing of these different formulations is well known in the art and need not be discussed at length here. The active compound may be administered once or several times a day. The active compounds described herein may be administered to the lungs of a subject by any suitable means, but are preferably administered by generating an aerosol consisting of respirable particles.
The respirable particles consist of the active compound and the subject inhales the particles by inhalational administration. The respirable particles may be liquid or solid. Particles of the active compound for carrying out the invention should be particles which are inhalable, i.e. particles of sufficiently small size to pass through the mouth and larynx upon inhalation and into the alveoli of the trachea and lungs. is there.
Generally, particles of about 0.5 to about 10 microns in size, especially about 5 microns or less in size are respirable. Non-breathable particles contained in the aerosol
Accumulates in the throat and tends to be swallowed. The amount of non-respirable particles in the aerosol is preferably minimized. For nasal administration, particles having a size of 10-500 μm are preferred to ensure retention in the nasal cavity.

Liquid pharmaceutical compositions of the active compound (s) for producing an aerosol may be prepared by mixing the active compound (s) with a stable vehicle, such as sterile pyrogen-free water. A solid particle composition comprising respirable dry particles of micronized active compound is prepared by milling the dry active compound using a mortar and pestle and then milling the micronized composition through a 400 mesh screen. Alternatively, a large lump is separated and prepared. Solid particle compositions of the active compound optionally contain a dispersant to help facilitate formation of the aerosol. A suitable dispersant is lactose, which has a suitable proportion, for example:
It may be blended with the active compound in a weight ratio of 1: 1.

Aerosols of liquid particles containing the active compound may be prepared by any suitable means, such as by a nebulizer. See, for example, U.S. Pat. No. 4,501,729. Nebulizers are commercially available devices that transform a solution or dispersion of the active ingredient into a therapeutic aerosol mist by passing it through a narrow Venturi orifice by accelerating a compressed gas, usually air or oxygen, or by ultrasonic agitation. A suitable composition for use in a nebulizer consists of the active ingredient in a liquid carrier, which active ingredient comprises 4 parts of the composition.
The carrier containing 0% w / w or more, but 20% w / w or less is preferably usually water or a dilute aqueous alcoholic solution, and is preferably isotonic with body fluids, for example, by adding salt. To do. Optional additives, if the composition is not prepared sterile, include preservatives, such as methylhydroxybenzoic acid, antioxidants, flavoring agents, volatile oils, buffers and surfactants.

Solid particle aerosols containing the active compound may also be prepared using any solid particle pharmaceutical aerosol generator. An aerosol generator for administering a solid particle medicine to a subject produces respirable particles as described above, and administers a prescribed dose of the medicine at a rate suitable for human administration. Generates a volume of aerosol, including. Examples of such aerosol generators include inhalers and ventilators.

The second drug may be administered at the same time as the active compound, and may also include insomnia, mood disorders, anxiety, irritability, wasting, bulimia, anorexia nervosa, cancer, viral and bacterial infections. , Inflammatory diseases such as heart abnormalities, ischemia, menopause, pain, inflammation, wounds and burns, muscle tone, low bone mineralization, autoimmune diseases, COPD and inflammatory bowel disease,
And many other inflammatory conditions, wound healing, ischemia and agents to prevent and treat reperfusion injury, preferably the same composition as described above to treat and prevent the secondary effects of steroid intake. , And improve weight and increase muscle mass. As used herein, the term "administered together" means that folinic acid or a salt thereof and the second drug are (a) simultaneously prescribed, and preferably, the two are mutually prescribed in a common pharmaceutical carrier, Or (b) different doses in the course of a common treatment plan. In the latter, the two compounds are administered at times that are effective in capturing their half-life, whereby alternating administration results in offsetting a decrease in the peak level of one with an increasing level of the other, and The decrease in the activity of is balanced with the increase in the activity of the other. That is, the active compound may or may not be administered for a time sufficient to bring the endogenous adenosine concentration back to the subject's previous concentration. If the composition or formulation of the invention is administered for a time sufficient to meet endogenous adenosine levels (
If lower than previous concentrations in the same subject), then folinic acid, its salts or mixtures thereof and the second agent are administered in an amount effective to increase adenosine concentrations to the desired concentration. Thereafter, the doses of two or more agents may be reduced to maintain adenosine levels. If the second drug may have overlapping activity with the active compound, or if it is of different activity, the dose of the second drug may be reduced according to the dose of the active compound if the risk of relapse is reduced. May be. If the active compound is administered for a time sufficient to meet the endogenous adenosine concentration and this is achieved, the continuation of treatment will depend on whether the adenosine concentration is maintained in the absence of treatment. Furthermore, whether the dose of the second drug is reduced will depend on whether it is necessary to continue administration or whether the subject is in a stable state. If the practitioner feels the need to offset future relapses, treatment should continue with closed monitoring as the adenosine concentration decreases, or its exhaustion and / or the need or benefit of continued administration of a second agent decreases. Good.

The additional agents, examples of which are given above, may be administered per se or in the form of pharmaceutically acceptable salts. When used as a medicament, the salts of these agents are pharmacologically and pharmaceutically acceptable, but the pharmaceutically unacceptable salts are used to prepare free active compounds or pharmaceutically acceptable salts. Used and not excluded from the scope of the invention. Such pharmacologically and pharmaceutically acceptable salts include, among others, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, maleic acid, acetic acid, salicylic acid, p-toluenesulfonic acid, tartaric acid, citric acid, Examples include, but are not limited to, methanesulfonic acid, formic acid, malonic acid, succinic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. Pharmaceutically acceptable salts may also be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. The pharmaceutical compositions of the present invention, for either veterinary or human application, in addition to the active compound and one or more additional agents,
It may contain one or more pharmaceutically acceptable carriers and, optionally, other therapeutic ingredients suitable for the particular disease and condition. The carrier is pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and must not be unduly harmful to the recipient.

Formulations of the present invention suitable for oral administration are provided as separate unit tablets such as capsules, wafers, tablets or troches, each of which is a powder or granules or syrup, elixir, emulsion or droat ( As a dispersion of a water-soluble liquid or a non-water-soluble liquid such as drought), it contains a predetermined amount of a strengthening agent.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are made by compression in a suitable machine with the active compound in free-flowing form such as a powder or granules mixed with a binder, disintegrant, lubricant, inert diluent, surfactant or dispersant. May be. Molded tablets consist of a mixture of the powdered active compound prepared by molding in a suitable machine with a suitable carrier.

Syrups are produced by adding the active compound to a concentrated aqueous solution of sugar, for example sucrose, to which auxiliary ingredients may be added. As such an accessory ingredient, a flavor substance, a suitable preservative,
Mention may be made of agents which delay crystallization of sugars and agents which increase the solubility of polyhydric alcohols, eg other ingredients such as glycerol or sorbitol.

Formulations suitable for parenteral administration conveniently comprise a sterile water soluble preparation of the active compound that is isotonic with the blood of the recipient. Nasal spray formulations include purified aqueous solutions of the active compound with preservative agents and isotonic agents. Such formulations are preferably adjusted to pH and isotonic conditions compatible with the nasal mucosa. Formulations for enteral or vaginal administration may be presented as a suppository with a suitable carrier such as cocoa butter, or hydrogenated fats or fatty acids. Ophthalmic formulations are prepared in a manner similar to nasal sprays, except that the pH and isotonic factors are preferably adjusted to that of the eye. Ear formulations are prepared with viscous carriers, such as oils, which are well known in the art, and are easily administered into the ear without spilling. Topical formulations include the active compound dissolved or dispersed in mineral oil, petroleum, polyhydric alcohols or other bases used as topical pharmaceutical formulations. Addition of other subcomponents is desirable. See below. In addition to the above additives, the formulations of the present invention further include diluents, buffers, flavoring agents,
It contains one or more accessory ingredients selected from binders, disintegrants, surfactants, thickeners, lubricants, preservatives (including antioxidants) and the like. Other ingredients as known in the art may also be used. Although the invention has been generally described herein, the same will be better understood with reference to specific embodiments. The examples contained herein are for purposes of illustration only and are not intended to limit the invention or its embodiments unless otherwise stated.

[0031]

【Example】

In the examples below and in this patent, "DHEA" means dehydroepiandrosterone, "FA" means folinic acid, "M" means methyltestosterone, and "s" is Seconds, "mg" means milligrams, "kg"
"Means kilograms," kw "means kilowatts," Mhz "means megahertz, and" nmol "means nanomoles.

Examples 1 and 2 In Vivo Effects of Folinic Acid and DHEA on Adenosine Concentration Dehydroepiandrosterone in carboxymethylcellulose was administered to young adult male Fischer 344 rats (120 grams) once daily for 14 days by nutritional diet. (DHEA) (300 mg / kg) or methyltestosterone (
40 mg / kg). Folinic acid (50 mg / kg) was intraperitoneally administered once a day for 14 days. Ultrashort pulse (1.33kw, 2450MH) to the skull
Z, 6.5 s), animals were sacrificed on day 14 and immediately denatured all brain proteins to prevent further metabolism of adenosine. The heart was removed from the animal and snap frozen in liquid nitrogen within 10 seconds of death. The liver and lungs were removed en bloc and frozen instantly within 30 seconds of death. Brain tissue was subsequently dissected. Tissue adenosine was extracted, induced to 1, N6-ethenoadenosine, and subjected to high performance liquid chromatography (HPCL) using a spectrofluorometric detector according to the method of Clark and Dahl (J. of Neuroscience Methods 25: 243 (1988)). ). The results of these experiments are summarized in Table 2 below. Results are expressed as mean ± SEM, Xp <0.05 compared to control group and φp <0.05 compared to DHEA or methyltestosterone treated group.

[0033]

In vivo effects of DHEA, δ-1-methyltestosterone and folinic acid on adenosine concentrations in various rat tissues Intracellular adenosine (nmol / mg protein) Cardiopulmonary Brain control 10.6 ± 0.6 3.1 ± 0. 0.5 ± 0.04 (n = 12) (n = 6) (n = 12) DHEA 6.7 ± 0.5 2.3 ± 0.3 0.19 ± 0.01 (300mg / kg) (n = 12) (n = 6) (n = 12) Methyltestosterone (M) 8.3 ± 1.0 ND 0.42 ± 0.06 (40mg / kg) (n = 6) (n = 6) Methyltestosterone (M) 6.0 ± 0.4 ND 0.32 ± 0.03 (120mg / kg) (n = 0.6) (n = 6) Folin Acid (FA) 12.4 ± 2.1 ND 0.72 ± 0.09 (50mg / kg) (n = 5) (n = 5) DHEA + F. A. 11.1 ± 0.6 ND 0.55 ± 0.09 (300mg / kg; 50mg / kg) (n = 5) (n = 5) M + F. A. 9.1 ± 0.4 ND 0.60 ± 0.06 (120mg / kg; 50mg / kg) (n = 6) (n = 6) N.C. D. = Cannot be measured

The results of these experiments show that rats treated with DHEA or methyltestosterone daily for 2 weeks showed multi-organ adenosine loss. Loss of the brain (DHE
60% loss in A, 34% in high dose methyltestosterone) and heart (34%)
(37% loss in DHEA, 22% loss in high dose methotretestosterone). Co-administration with folinic acid completely suppressed adenosine loss. Administration of folinic acid alone induces an increase in adenosine levels in all organs studied. Having fully described the invention herein, it will be apparent to those skilled in the art that many changes or modifications can be made without departing from the spirit or scope of the disclosed invention. The preceding examples are illustrative of the invention and are not limiting. The invention is defined in the following claims and includes equivalents of these claims.

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Claims (147)

[Claims] 1. An amount of folinic acid effective for anti-wasting, anti-bulimia, anorexia nervosa, anti-anxiety, anti-hypersensitivity, or antisteroid-related strange behavior or aggression,
A first drug selected from the group consisting of physiologically acceptable salts thereof, and a mixture thereof, and an analgesic, anti-premenstrual syndrome drug, anti-menopausal drug, anti-aging agent, anxiolytic other than the first drug Agents, mood disorders, antidepressants, anti-bipolar mood disorders, anti-schizophrenia agents, anti-migraine agents, alkaloids, blood pressure regulators, hormones, anti-inflammatory agents, muscle relaxants, first
Drugs other than drugs, steroids, hypnotics, anti-ischemic agents, anti-arrhythmic agents, contraceptives, vitamins, minerals, tranquilizers, neurotransmission regulators, wound healing agents, anti-angiogenic agents, cytokines, growth factors , Anti-metastatic agents, antacids, antihistamines, antibacterial agents, antiviral agents, anti-toxic gas agents, anorectic agents, anti-wasting agents, anti-bulimia agents, anorexia nervosa agents, brain damage agents, heart attack agents, Adenosine, adenosine release agent and adenosine receptor stimulant, sunscreen, emollient, skin temperature lowering agent, radioactive phosphorescence and fluorescence contrast diagnostic and imaging agent, libido change agent, bile acid, laxative, antidiarrheal agent, skin A pharmaceutical composition comprising a regenerating agent and a second agent selected from the group consisting of hair growth agents. 2. The composition according to claim 1, further comprising a carrier and / or an anticancer agent. 3. The composition of claim 2, wherein the carrier comprises a physiologically acceptable carrier. 4. The composition of claim 3, wherein the physiologically acceptable carrier comprises a pharmaceutically acceptable carrier. 5. The composition of claim 2, wherein the carrier is selected from the group consisting of solid carriers and liquid carriers. 6. Further comprising an agent selected from the group consisting of antioxidants, flavoring agents, colorants, fragrances, volatile oils, buffers, dispersants, surfactants, propellants and preservatives. The composition of claim 1. 7. The composition according to claim 4, which is a systemic formulation or a topical formulation. 8. Oral, buccal, intrapulmonary, rectal, intrauterine, intradermal, topical, skin, parenteral, intratumoral, intracranial, buccal, sublingual, nose, intramuscular, subcutaneous, intravascular, marrow Intracavitary, Inhalable, Transdermal, Intraarticular, Intracavitary, Implantable, Transdermal, Iontophoretic, Intraocular, Ocular, Vagina, Ear,
8. The composition of claim 7 selected from the group consisting of intravenous, intramuscular, intraglandular, intratissue, intralymphatic, implantable, low release, and enteric coating formulations. 9. The formulation according to claim 8, which is an oral formulation selected from the group consisting of capsules, wafers, troches, tablets, powders, granules, solutions, dispersions and emulsions. 10. Solutions and dispersions are selected from the group consisting of water-soluble and water-insoluble solutions and dispersions, and emulsions are selected from the group consisting of oil-in-water and water-in-oil emulsions. The formulation according to claim 9. 11. A lozenge further comprising a buccal agent further comprising a flavoring substance selected from the group consisting of sucrose, acacia and tragacanth, and an inert base material further selected from the group consisting of gelatin, glycerin, sucrose and acacia. The formulation according to claim 9, which is an oral or sublingual formulation selected from the group consisting of agents. 12. The oral formulation according to claim 9, which further comprises an enteric coating. 13. A parenteral formulation selected from the group consisting of injectable solutions or suspensions, further comprising antioxidants, buffers, bacteriostats and said solutions or suspensions. The formulation according to claim 8, which is a parenteral formulation that may contain a solute that isotonicly changed with the blood of the recipient. 14. The solution and suspension are sterile water-soluble and water-insoluble injection solutions and suspensions, which may further contain suspending agents and thickening agents. Parenteral prescription drug. 15. The parenteral formulation according to claim 13, which is a single or multiple dose contained in a container selected from the group consisting of sealed ampoules and vials. 16. A composition according to claim 7, which is in the form of single or multiple doses. 17. The composition according to claim 7, which is in a bulk form. 18. The composition according to claim 7, which is freeze-dried or lyophilized. 19. The formulation according to claim 8, which is a topical formulation selected from the group consisting of ointments, creams, lotions, pastes, gels, sprays, aerosols and oils. 20. The topical formulation according to claim 19, comprising a carrier selected from the group consisting of petrolatum, lanolin, polyethylene glycols, alcohols and transdermal enhancers. 21. The formulation according to claim 8, which is a transdermal formulation. 22. The transdermal formulation according to claim 21, which is a solution or suspension of a first drug, which may further contain a buffer and one or more second drugs. 23. The formulation of claim 21, which comprises a transdermal delivery device. 24. The formulation of claim 23, wherein the device is a patch. 25. The formulation according to claim 8, which is an inhalable formulation. 26. An azolol containing a liquid or solid particle drug, further comprising a preservative, antioxidant, flavoring agent, colorant, fragrance, volatile oil, buffer, dispersant and surfactant. 26. The inhalable formulation according to claim 25, which may be included. 27. The composition of claim 7, wherein the carrier comprises a hydrophobic carrier. 28. The formulation according to claim 27, which is contained in a capsule. 29. The formulation according to claim 8, which is a suppository. 30. The formulation according to claim 8, which is an implant. 31. The formulation according to claim 8, which is a delayed release formulation. 32. The formulation according to claim 8, which is an ophthalmic formulation. 33. The formulation according to claim 8, which is an ear formulation. 34. The formulation of claim 8, which is a vaginal formulation selected from the group consisting of creams, gels and vaginal suppositories and implants. 35. An analgesic other than the first drug, an anti-inflammatory drug, a muscle relaxant, an anti-migraine drug, an antidepressant, and a mood-altering drug other than the first drug, vitamins, minerals, proteins and physiologically acceptable. The composition according to claim 2, comprising a carrier. 36. The composition of claim 35, wherein the second drug comprises an analgesic. 37. The composition of claim 36, wherein the analgesic is selected from the group consisting of acetaminophen, salicylic acid, salts or esters thereof, naproxine, ibuprofen and narcotic analgesics. 38. The composition of claim 35, wherein the second agent comprises an antidepressant and / or an anti-migraine agent. 39. The composition of claim 35, wherein the second agent comprises a barbital acid salt and / or an anti-migraine agent. 40. The composition of claim 35, wherein the second agent comprises a muscle relaxant. 41. The composition of claim 35, wherein the second agent is an anti-premenstrual syndrome agent. 42. The composition of claim 4, further in the form of a food product that includes other edible ingredients. 43. The composition of claim 42, wherein the food product is selected from the group consisting of an energy bar, chewing gum, candy, drinks, cakes, pasta, and salad dressings. 44. An iontophoretic transdermal formulation wherein the carrier is selected from the group consisting of aqueous and alcoholic solutions, oily solutions, suspensions, and oil-in-water and water-in-oil emulsions. The composition of claim 7, wherein the agent further comprises a transdermal transport enhancer. 45. The composition according to claim 44, which is in the form of an implantable capsule or cartridge. 46. The composition of claim 4, wherein the carrier comprises a hydrophobic carrier. 47. The composition of claim 46, wherein the carrier comprises lipid vesicles or particles. 48. The composition of claim 47, wherein the vesicles comprise liposomes and the particles comprise crystallites. 49. The composition of claim 48, wherein the vesicles comprise liposomes containing a first drug and, optionally, a second drug. 50. The composition of claim 49, wherein the vesicles comprise N- (1- [2,3-dioleoxyloxy] propyl) -N, N, N-trimethyl-ammonium methylsulfate. 51. The composition of claim 8 comprising a respiratory or inhalable formulation. 52. The formulation of claim 51, which comprises an intrapulmonary formulation. 53. The formulation of claim 51 in the form of an aerosol. 54. The composition of claim 7, further in the form of a kit, which further comprises, in a separate container, instructions for addition and administration of the release device and carrier. 55. The composition of claim 54, wherein the delivery device comprises an inhaler which delivers a pre-measured dose of the formulation of the individual. 56. The composition of claim 54, wherein the inhaler comprises a nebulizer or an insufflator and further comprises a pierceable or releasable capsule or cartridge having the composition of solid particles. 57. The composition of claim 54, wherein the delivery device comprises a pressurized inhaler and the formulation comprises a suspension or solution of a water-soluble or non-water-soluble liquid or an oil-in-water or water-in-oil emulsion. object. 58. A pharmaceutical composition comprising administering to a subject having or prone to anxiety and / or hypersensitivity the pharmaceutical composition of claim 1 and optionally a carrier. Is an anti-anxiety and / or anti-hypersensitivity effective amount of the first agent, a method of preventing or neutralizing anxiety and / or hypersensitivity. 59. The method of claim 58, wherein the first agent is administered in an amount of about 1 to about 1,000 mg / kg body weight. 60. The method of claim 59, wherein the agent is administered in an amount of about 5 to about 500 mg / kg body weight. 61. The second drug is an analgesic, anti-premenstrual syndrome drug, anti-menopausal drug, anti-aging drug, anxiolytic drug, mood disorder drug, antidepressant drug, anti-bipolar mood disorder drug, anti-schizophrenic drug, Anti-migraine agents, pain relievers other than the first drug, anti-cancer agents, alkaloids, blood pressure regulators, hormones, anti-inflammatory agents, muscle relaxants, steroids, hypnotics, anti-ischemic agents, anti-arrhythmic agents, contraceptives, vitamins, Minerals, tranquilizers, neurotransmission regulators, wound healing agents, anti-angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, antihistamines, antibacterial agents, antiviral agents, antitoxic gas agents, appetite suppressants , Anti-wasting agents, anti-bulimia agents, anorexia nervosa agents, brain damage agents, heart attack agents, adenosine, adenosine release agents and adenosine receptor stimulants, sunscreens, emollients, skin temperature lowering agents, Radioactive phosphorescence and fluorescence contrast diagnostics and Imaging agents, libido-altering agents, bile acids, laxatives, anti-diarrheal agents,
59. The method of claim 58, selected from the group consisting of skin regenerating agents, and hair growth agents. 62. The method of claim 61, wherein the second agent comprises a mood disorder agent. 63. The method of claim 61, wherein the second agent comprises a muscle relaxant. 64. The method of claim 58, wherein the composition is administered by systemic or local route. 65. The method of claim 58, wherein the systemic or topical route is selected from the group consisting of oral, inhalable, topical, parenteral and transdermal. 66. The route of administration is the oral cavity, sublingual, skin, intraocular, subcutaneous, intradermal, intramuscular,
Intravenous, intraarticular, intrapulmonary, rectal, intrauterine, intradermal, topical, cutaneous, parenteral, intratumoral,
Intracranial, oral cavity, intranasal, intravascular, intrathecal, inhalable, percutaneous, intracavitary, transdermal, percutaneous, iontophoretic, intraocular, eye, vaginal, ear, intraglandular, intratissue 66. The method of claim 65, wherein the method is selected from the group consisting of: intralymphatic and transdermal. 67. The method of claim 66, wherein the composition is an oral formulation selected from capsules, wafers, troches, tablets, powders, granules, solutions, dispersions and emulsions. 68. The oral formulation further comprises an enteric coating.
The method described. 69. The composition comprises a buccal agent further comprising a flavoring agent selected from the group consisting of sucrose, acacia and tragacanth, and gelatin, glycerin,
66. The method of claim 65, administered as an oral or sublingual formulation selected from the group consisting of lozenges, which further comprises an inert matrix selected from the group consisting of sucrose and acacia. 70. The composition is a parenteral formulation selected from the group consisting of injectable solutions or suspensions, further comprising an antioxidant, a buffer, a bacteriostatic agent and the solution or suspension. 66. The method of claim 65, wherein the method is administered as a parenteral formulation that may include a solute that renders the fluid isotonic with the blood of the intended recipient. 71. The method of claim 70, wherein the parenteral formulation is in a multiple dose form selected from the group consisting of bulk or sealed ampoules or vials. 72. The method of claim 58, which is in the form of a single dose. 73. The formulation is in bulk or in multi-dose form.
8. The method according to 8. 74. The formulation is freeze-dried or lyophiliz.
66. The method of claim 65, wherein said method further comprises adding a sterile liquid carrier selected from the group consisting of saline or water prior to use. 75. The composition comprises an ointment, cream, lotion, paste, gel,
A topical formulation selected from the group consisting of sprays, aerosols and oils, which may further comprise a carrier selected from the group consisting of petrolatum, lanolin, polyethylene glycols, alcohols and transdermal enhancers. 66. The method of claim 65, which is administered as an agent. 76. The method of claim 65, wherein the composition is administered as a transdermal formulation in the form of a patch. 77. The method of claim 65, wherein the composition is administered as an iontophoretic formulation comprising a solution or suspension of the drug, and optionally a buffer and a second drug. 78. The method of claim 65, wherein the composition is administered as an inhalable formulation. 79. An inhalable formulation comprises liquid or solid particles of a drug and is further selected from the group consisting of preservatives, antioxidants, flavoring agents, volatile oils, buffers, dispersants and surfactants. 79. An aerosol, which may include a drug as defined above.
The method described. 80. The composition of claim 58, wherein the composition further comprises physiologically acceptable carriers, preservatives, antioxidants, flavoring agents, volatile oils, buffers, dispersants and surfactants. Method. 81. The method of claim 80, wherein the physiologically acceptable salt is selected from the group consisting of alkaline metals, alkaline earth salts, and organic salts. 82. The method of claim 81, wherein the physiologically acceptable salt of the drug is selected from the group consisting of sodium, potassium, calcium and carboxylates. 83. The method of claim 58, wherein the subject is a human. 84. The method of claim 58, wherein the subject is an animal. 85. The method of claim 58, which is a prophylactic method. 86. The method of claim 58, which is a therapeutic method. 87. The anxiety and / or hypersensitivity is premenstrual syndrome.
8. The method according to 8. 88. A pharmaceutical composition comprising a first drug selected from the group consisting of folinic acid, its salts and mixtures thereof, and optionally a physiologically acceptable carrier in an amount effective for weight gain. A method of increasing weight, comprising administering a composition comprising a first agent to a subject in need thereof. 89. The method of claim 88, wherein the patient is prone to or suffers from bulimia, anorexia nervosa and / or wasting disorders. 90. The method of claim 88, wherein the patient is or needs to take steroids. 91. The method of claim 88, wherein the first agent is administered in an amount of about 1 to about 1,000 mg / kg body weight. 92. The method of claim 91, wherein the agent is administered in an amount of about 5 to about 500 mg / kg body weight. 93. The second agent is an analgesic agent, anti-premenstrual syndrome agent, anti-menopausal agent, anti-aging agent, anxiolytic agent, mood disorder agent, nociceptive agent, anti-migraine agent, antidepressant agent, anti-bipolar agent. Mood disorder agents, anti-schizophrenia agents, anti-cancer agents, alkaloids, blood pressure regulators, hormones, anti-inflammatory agents,
Muscle relaxants, steroids, hypnotics, anti-ischemic agents, anti-arrhythmic agents, contraceptives, vitamins,
Minerals, tranquilizers, neurotransmission regulators, wound healing agents, anti-angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, antihistamines, antibacterial agents, antiviral agents,
Anti-poison gas, Appetite suppressant, Anti-wasting disorder, Anti-bulimia, Anti-anorexic, Brain damage, Heart attack, Adenosine, Adenosine release and adenosine receptor stimulant, Sunscreen, Emollient Agent, skin temperature lowering agent, radioactive phosphorescence and fluorescence contrast diagnostic and imaging agent, libido change agent, bile acid, laxative, antidiarrheal agent, skin regenerating agent,
89. The method of claim 88, selected from the group consisting of and a hair growth agent. 94. The method of claim 93, wherein the second agent comprises a mood disorder agent. 95. The method of claim 93, wherein the second agent comprises a steroid. 96. The method of claim 88, wherein the composition is administered by a systemic or local route. 97. The method of claim 88, wherein the systemic or topical route is selected from the group consisting of oral, inhalable, topical, parenteral and transdermal. 98. The route of administration is the oral cavity, sublingual, skin, intraocular, subcutaneous, intradermal, intramuscular,
Intravenous, intraarticular, intrapulmonary, rectal, intrauterine, intradermal, topical, cutaneous, parenteral, intratumoral,
Intracranial, oral cavity, intranasal, intravascular, intrathecal, inhalable, percutaneous, intracavitary, transdermal, percutaneous, iontophoretic, intraocular, eye, vaginal, ear, intraglandular, intratissue 98. The method of claim 97, selected from the group consisting of: transplantability, intralymphatic, and transplantability. 99. The method of claim 98, wherein the composition is an oral formulation selected from capsules, wafers, troches, tablets, powders, granules, solutions, dispersions and emulsions. 100. The method of claim 99, wherein the oral formulation further comprises an enteric coating. 101. A buccal agent further comprising a flavoring substance selected from the group consisting of sucrose, acacia and tragacanth, and a troche further comprising an inert base material selected from the group consisting of gelatin, glycerin, sucrose and acacia. 98. The method of claim 97, which is an oral or sublingual formulation selected from the group consisting of agents. 102. The composition is a parenteral formulation selected from the group consisting of injectable solutions or suspensions, further comprising an antioxidant, a buffer, a bacteriostatic agent and the solution or suspension. 98. The method of claim 97, wherein the solution is administered as a parenteral formulation that may include a solute that renders the fluid isotonic with the blood of the intended recipient. 103. The method of claim 102, wherein the parenteral formulation is provided in the form of multiple doses selected from the group consisting of bulk or sealed ampoules and vials. 104. The method of claim 88, which is in the form of a single dose. 105. The method of claim 88, wherein the formulation is in bulk or in multiple dose form. 106. The formulation is freeze-dried or lyophilized.
98. The method of claim 97, further comprising the addition of a sterile liquid carrier selected from the group consisting of saline or water prior to use. 107. The composition is a topical formulation selected from the group consisting of ointments, creams, lotions, pastes, gels, sprays, aerosols and oils, further comprising petrolatum, lanolin, polyethylene glycol, alcohol and alcohol. 98. The method of claim 97, which may include a carrier selected from the group consisting of transdermal enhancers. 108. The composition is administered as a transdermal formulation in the form of a patch,
The method of claim 97. 109. The method of claim 97, wherein the composition is administered as an iontophoretic formulation comprising a solution or suspension of the drug and optionally a buffer and a second drug. 110. The method of claim 97, wherein the composition is administered as an inhalable formulation. 111. An inhalable formulation comprises liquid or solid particles of a drug and is further selected from the group consisting of preservatives, antioxidants, flavoring agents, volatile oils, buffers, dispersants and surfactants. 111. The method of claim 110, which may include a drug. 112. The composition further comprises a physiologically acceptable carrier, preservative,
89. The method of claim 88, comprising an agent selected from the group consisting of antioxidants, flavoring agents, volatile oils, buffers, dispersants and surfactants. 113. The method of claim 112, wherein the physiologically acceptable salt is selected from the group consisting of alkali metal, alkaline earth salts and organic salts. 114. A physiologically acceptable salt of a drug is sodium, potassium,
114. The method of claim 113, selected from the group consisting of calcium and organic acid salts. 115. The method of claim 88, wherein the subject is a human. 116. The method of claim 88, wherein the subject is an animal. 117. The method of claim 88, which is a prophylactic method. 118. The method of claim 88, which is a therapeutic method. 119. A pharmaceutical composition comprising a first drug selected from the group consisting of folinic acid, salts thereof and mixtures thereof, and optionally a physiologically acceptable carrier, in a pain effective amount. A method of inhibiting nausea comprising administering to a subject in need thereof a composition comprising the first agent of claim 1. 120. The method of claim 119, wherein the first agent is administered in an amount of about 1 to about 1,000 mg / kg body weight. 121. The method of claim 120, wherein the agent is administered in an amount of about 5 to about 500 mg / kg body weight. 122. The second drug is an analgesic, anti-premenstrual syndrome drug, anti-menopausal drug, anti-aging drug, anxiolytic drug, mood disorder drug, nociceptive drug, anti-migraine drug, antidepressant drug, anti-bipolar drug. Mood disorders, anti-schizophrenia agents, anti-cancer agents, alkaloids, blood pressure regulators, hormones, anti-inflammatory agents, muscle relaxants, steroids, hypnotics, anti-ischemic agents, antiarrhythmic agents, contraceptives, vitamins, minerals, tranquilizers Agents, neurotransmission regulators, wound healing agents, anti-angiogenic agents, cytokines, growth factors, anti-metastatic agents, antacids, antihistamines, antibacterial agents, antiviral agents, anti-toxic gas agents, appetite suppressants, anti-wasting disorders Agents, anti-bulimics, anorexia nervosa agents, brain damage agents, heart attack agents, adenosine, adenosine release agents and adenosine receptor stimulants, sunscreens, emollients, skin temperature lowering agents, radioactive phosphorescence and Fluorescence contrast diagnostics and imaging agents, 120. The method of claim 119, wherein the method is selected from the group consisting of a bide changing agent, a bile acid, a laxative, an anti-diarrheal agent, a skin regenerating agent, and a hair growth agent. 123. The method of claim 122, wherein the second agent comprises a mood disorder agent. 124. The method of claim 122, wherein the second agent is an anti-migraine agent, antidepressant agent, other nociceptive agent and / or muscle relaxant agent. 125. The method of claim 119, wherein the composition is administered by a systemic or local route. 126. The method of claim 119, wherein the systemic or topical route is selected from the group consisting of oral, inhalable, topical, parenteral and transdermal. 127. The administration route is oral, sublingual, skin, intraocular, subcutaneous, intradermal, intramuscular, intravenous, intraarticular, pulmonary, rectal, intrauterine, intradermal, topical, cutaneous, parenteral. , Intratumor, intracranial, buccal, intranasal, intravascular, intrathecal, inhalable, percutaneous, intracavity, implantable, percutaneous,
127. The method of claim 126, selected from the group consisting of: iontophoretic, intraocular, ocular, vaginal, ear, intraglandular, intratissue, intralymphatic and implantable. 128. The composition is a capsule, wafer, troche, tablet,
128. The method of claim 127, which is administered as an oral formulation selected from powders, granules, solutions, dispersions and emulsions. 129. The method of claim 128, wherein the oral formulation further comprises an enteric coating. 130. The composition comprises a buccal agent further comprising a flavoring agent selected from the group consisting of sucrose, acacia and tragacanth, and an inert base material selected from the group consisting of gelatin, glycerin, sucrose and acacia. 127. The method of claim 126, which is administered as an oral or sublingual formulation selected from the group consisting of lozenges further comprising: 131. The composition is a parenteral formulation selected from the group consisting of injectable solutions or suspensions, further comprising an antioxidant, a buffer, a bacteriostatic agent and the solution or suspension. 127. The method of claim 126, which is administered as a parenteral formulation that may include a solute that renders the fluid isotonic with the blood of the intended recipient. 132. The method of claim 131, wherein the parenteral formulation is in bulk or in multiple dose form selected from the group consisting of sealed ampoules and vials. 133. The method of claim 119, which is in the form of a single dose. 134. The method of claim 119, wherein the formulation is in bulk or in multiple dose form. 135. The formulation is freeze-dried or lyophilized.
127. The method of claim 126, wherein said method further comprises adding a sterile liquid carrier selected from the group consisting of saline and water prior to use. 136. The composition is a topical formulation selected from the group consisting of ointments, creams, lotions, pastes, gels, sprays, aerosols and oils, further comprising petrolatum, lanolin, polyethylene glycol, alcohol and alcohol. 127. A transdermal enhancer, which may comprise a carrier selected from the group consisting of: 126.
The method described. 137. The method of claim 126, wherein the composition is administered as a transdermal formulation in the form of a patch. 138. The method of claim 126, wherein the composition comprises a solution or suspension of the drug, and optionally a buffer and a second drug. 139. The method of claim 126, wherein the composition is administered as an inhalable formulation. 140. An inhalable formulation comprises liquid or solid particles of a drug and is further selected from the group consisting of preservatives, antioxidants, flavoring agents, volatile oils, buffers, dispersants and surfactants. 140. The method of claim 139, which may include a drug. 141. The composition further comprises a drug selected from the group consisting of physiologically acceptable carriers, preservatives, antioxidants, flavoring agents, volatile oils, buffers, dispersants and surfactants. 120. The method of claim 119, including. 142. The method of claim 141, wherein the physiologically acceptable salt is selected from the group consisting of alkali metal, alkaline earth salts and organic salts. 143. The physiologically acceptable salt of the drug is sodium, potassium,
143. The method of claim 142, selected from the group consisting of calcium and organic acid salts. 144. The method of claim 119, wherein the subject is a human. 145. The method of claim 119, wherein the subject is an animal. 146. The method of claim 119, which is a prophylactic method. 147. The method of claim 119, which is a therapeutic method.