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Definitions

• This invention relates to a composition and formulations comp ⁇ smg folinic acid, pharmaceutically acceptable salts thereof or mixtures thereof, and other agents such as analgesics, anti-inflam ato ⁇ es, muscle relaxants, anti-migraine agents, anti-emetics, diuretics, and the like
• the products are suitable as nociceptics, for treatment of wastmg disorders, anxiety, irritability associated with Pre Menstrual Syndrome and for administration either m conjunction with steroids or to compensate adenosme depletion common m steroid users.
• Folinic acid is an intermediate product of the metabolism of fo c acid, and is believed to be the active form into which fohc acid is converted in the body It is also known that ascorbic acid or Vitamin C is required as a necessary factor m the conversion of fo c acid to folinic acid Folinic acid has been used therapeutically as an antidote to fohc acid antagonists such as methotrexate which block the conversion of fohc acid into folinic acid Additionally, folinic acid has been used as an anti-anemic, because of its ability to combat folate deficiency Folinic acid has heretofore never been used m patients afflicted with adenosine depletion nor m a method to therapeutically elevate adenosine levels in the brain or other organ
• Adenosme is a pu ⁇ ne involved in intermediary metabolism
• Adenosine also participates in the regulation of physiological activity in a variety of mammalian tissues as well as m many local regulatory mechanisms, such as those occurring in synapses in the central nervous system (CNS) and at neuroeffector junctions in the peripheral nervous system
• CNS central nervous system
• adenosine inhibits the release of a variety of neurotransmitters, such as acetylchohne, noradrenahne, dopamine, serotonin, glutamate and GABA, depresses neurotransmission, induces spmal analgesia possibly by reducing neuronal firing and possesses anxiolytic properties
• adenosine suppresses pacemaker activity, slows AV conduction, possesses antiarrhythmic and arrhythmogenic effects, modulates autonomic control and triggers the synthesis and release of prostaglandms
• adenosine has potent vasodilatory effects and
• the present invention relates to a composition, formulations and a method of preventmg and treating anxiety, nausea, irritability associated with Pre Menstrual Syndrome, wastmg disorders, including bulimia and anorexia nervosa, as well as to increase muscle (protem) mass, which comprises administering to a sub j ect m need of such treatment a pharmaceutical composition comprising a first agent selected from the group consisting of folinic acid, pharmaceutically acceptable salts thereof and mixtures thereof and a second agent such as other anti- anxiolytic agents, nociceptis, anti-depressants, anti-inflammatory agents and analgesics, among others
• the composition may also comp ⁇ se formulation ingredients and a physiologically acceptable earner.
• compositions and formulations of the invention are applicable to the prophylactic and therapeutic treatment and reduction in severity of the diseases and conditions desc ⁇ bed above, regardless of their origin, or whether they are accompanied by a decrease in adenosine levels or not (whether due to endogenous abnormalities or the result of exogenously administered substances)
• CNS central nervous system
• the present agents may be provided as various pharmaceutical formulations in bulk or in unit form, as well as in the form of a foodstuff with other edible ingredients, e g energy bars, chewing gum, candy, drinks, cakes, salad dressings, pasta, etc Best Mode for Carrying Out the Invention
• the present invention arose from a desire by the inventor to improve on p ⁇ or technology for the prevention and treatment of wastmg disorders, anorexia nervosa or bulimia, anxiety, irritability associated with Pre Menstrual Syndrome, nausea, anxiety and other related pathologies which are often associated with adenosine depletion in the central nervous system (CNS)
• the present treatment is effective whether or not there is a marked adenosme reduction or depletion and whatever its cause, e g. due to use of steroids and other adenosine depletmg drugs, deficient adenosme synthesis, high adenosme metabolism or any other cause.
• Adenosine is known to be a natural agent provided with analgesic, anti-inflammatory, anti-ischemic, soporific and anti-anxiety properties
• the present inventor found, unexpectedly, that the first agent also exhibits sustamable activity as a nociceptic, anti-anxiety agent, to treat and prevent detrimental symptoms associated with the intake of steroids, such as playful behavior, crazmess and aggression He also found through his research that the first agent has substantial activity for treating and preventmg irritability and other abnormal mood behaviors associated with Pre Menstrual Syndrome, wasting syndrome (the first agent acts as an anabolic) and bulimia and anorexia nervosa, among others In the particular case of Pre Menstrual Syndrome, the inventor found that the symptoms are often associated with cyclic alterations m adenosme levels, perhaps due to fluctuations in levels of neuronal steroids.
• adenosine itself is a poor choice for the treatment of anxiety, Pre Menstrual Syndrome (PMS) symptoms, wasting disorders, anorexia nervosa and bulimia, and to counter the detrimental side effects of steroidal intake.
• PMS Pre Menstrual Syndrome
• the inventor posited that an agent such as folinic acid, which is capable of causing the synthesis of adenosine, has a significantly longer half life than adenosine and which does not produce angina-like pain, is better suited for administration to subjects afflicted with these conditions.
• Adenosine cannot be reasonably administered as a therapeutic, however, because it has an extremely short half life (about a second). This fact, and its propensity to cause angina-like pain make adenosine itself a poor choice for the treatment of pain and inflammation.
• An agent such as folinic acid which is capable of causing the synthesis of adenosine, is better suited for administration to subjects afflicted with these conditions.
• the inventor has shown that the administration of folinic acid induces the de novo synthesis of adenosine. He showed that the oral administration of folinic acid causes a dramatic increase in adenosine levels in the brain in an animal model.
• the first agent represents an unexpected improvement over adenosine for increasing brain adenosine levels and is thereby suitable as a nociceptic, anti-anxiolytic and anti-bulimic agent, as well as for the treatment of anorexia nervosa, wasting diseases, to increase body mass and to counter steroidal CNS side effects.
• Folinic acid, its salts and their mixtures are efficacious in the prevention and treatment of these and other syndromes and conditions, where an increase in the level of adenosine is of therapeutic value.
• the agent of the invention is provided as a pharmaceutical composition in combination with agents currently used to treat the diseases, conditions, symptoms and syndromes described above, and to address other co- symptoms encountered in these patients.
• the present technology is of extreme utility in subjects where existing treatments are partially effective at best or where, although the treatment may have been effective initially, its efficacy has eroded with time.
• the present method is effective in stimulating adenosine synthesis and, thereby, treat subjects who, for example, have used or been administered steroids therapeutically, for treating or controlling anxiety, nausea and irritability (such as is the case in Pre Menstrual Syndrome), to increase weight gain and treat wasting disorders, and to prevent extreme weight loss in anorexia nervosa and bulimia.
• adenosine depletion is intended to encompass both diseases and conditions such as nausea, anxiety, weight loss and the like, which are associated with adenosine levels which are significantly reduced or depleted in one or more tissues, as compared to previous adenosine levels in the same subject or to a standard average level for the species (cut-off point), and conditions where adenosine levels are essentially the same as previous adenosine levels in that subject but, because of some other condition or alteration in that patient, a therapeutic benefit is achieved in the patient by increasing the adenosine levels as compared to previous levels.
• the present method is carried out, preferably, on patients where adenosine levels are reduced, e.g., by more than about 5%, about 10%, about 15%, about 20%, about 30% and more, to fully depleted as compared to previous adenosine levels in the subject.
• the present invention is primarily concerned with the treatment of human subjects, it also is employed for the treatment of vertebrates in general, particularly mammals.
• the animals treated may be domesticated and wild animals, large and small, for veterinarian purposes, and including house pets (cats, dogs and the like), zoo animals, race horses, farm animals (cows, sheep and the like) and many others.
• Folmic acid and its pharmaceutically acceptable salts hereafter sometimes referred to as "active compounds/' are known and may be made in accordance with known procedures See generally, The Merck Index, Monograph No 4141 (11th Ed 1989), US Patent No 2,741,608
• the second agent of the present composition may be one or more of a variety of therapeutic and diagnostic agents which are suitable for administration to humans and/or animals
• agents suitable for incorporation into the present composition and formulations are analgesics, pre-menstrual medications, anti- menopausal agents such as hormones and the like, anti-agmg agents, anti-anxiolytic agents, nociceptic agents, mood disorder agents, anti-depressants, anti-bipolar mood agents, anti-schizophrenic agents, anti-cancer agents, alkaloids, blood pressure controlling agents, hormones, anti-inflammatory agents, other agents suitable for the treatment and prophylaxis of diseases and conditions associated or accompanied with pa and inflammation, such as arthritis, burns, wounds, chronic bronchitis, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease such as Chron's disease and ulcerative colitis, autoimmune disease, muscle relaxants, steroids, soporific agents, antt-ischemic agents, anti-arrhythmic agents,
• hormones are female and male sex hormones such as prema ⁇ n, progesterone, androsterones and their analogues, thyroxine and glucocorticoids, among the libido altermg agents are Viagra and other NO-level modulatmg agents, among the analgesics are over-the-counter medications such as lbuprofen, oruda, aleve and acetaminofen and controlled substances such as morphine and codeme, among the anti-depressants are t ⁇ cychcs, MAO inhibitors and epineph ⁇ ne, ⁇ -anuno butyric acid (GABA), dopamme and serotonin level elevating agents, e g Prozac, Amytryphlin, Wellbut ⁇ n and Zoloft, among the skin renewal agents are Retin-A, hair growth agents such as Rogame, among the anti-inflammatory agents are non-steroidal anti- inflammatory drugs (NSAIDs) and steroids, among the
• anti-inflammatories for ocular treatment are Diclofenac, Flurbiprofen, Indomethacin, Ketorolac, Rimexolone (generally for postoperative treatment).
• anti-inflammatories for non-infectious nasal applications are Beclomethaxone, Budesonide, Dexamefhasone, Flunisolide, Triamcinolone, and the like.
• soporifics anti-insomnia/sleep inducing agents
• soporifics are Alprazolam, Bromazepam, Diazepam, Diphenhydramine, Doxylamine, Estazolam, Flurazepam, Halazepam, Ketazolam, Lorazepam, Nitrazepam, Prazepam Quazepam, Temazepam, Triazolam, Zolpidem and Sopiclone, among others.
• sedatives are Diphenhydramine, Hydroxyzine, Mefhotrimeprazine, Promethazine, Propofol, Melatonin, Trimeprazine, and the like.
• Agents used in the treatment of head trauma include Enadoline HC1 (e.g.
• cytoprotective agents and agents for the treatment of menopause and menopausal symptoms are Ergotamine, Belladonna Alkaloids and Phenobarbitals.
• agents for the treatment of menopausal vasomotor symptoms are Clonidine, Conjugated Estrogens and Medroxyprogesterone, Estradiol, Estradiol Cypionate, Estradiol Valerate, Estrogens, conjugated Estrogens, esterified Estrone, Estropipate and Ethinyl Estradiol.
• agents for treatment of symptoms of Pre Menstrual Syndrome are Progesterone, Progestin, Gonadotrophic Releasing Hormone, oral contraceptives, Danazol, Luprolide Acetate and Vitamin B6.
• agents for the treatment of emotional/psychiatric treatments are Tricyclic Antidepressants including Amitriptyline HC1 (Elavil), Amitriptyline HC1, Perphenazine (Triavil) and Doxepin HC1 (Sinequan).
• Examples of tranquilizers, anti-depressants and anti-anxiety agents are Diazepam (Valium), Lorazepam (Ativan), Alprazolam (Xanax), SSRI's (selective Serotonin reuptake inhibitors), Fluoxetine HC1 (Prozac), Sertaline HC1 (Zoloft), Paroxetine HC1 (Paxil), Fluvoxamine Maleate (Luvox), Venlafaxine HC1 (Effexor), Serotonin, Serotonin Agonists (Fenfluramine), and other over the counter (OTC) medications.
• Examples of anti-migraine agents are Imitrex and the like.
• Pharmaceutically acceptable salts should be both pharmacologically and pharmaceutically acceptable. Such pharmacologically and pharmaceutically acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts, or the carboxylic acid group of folinic acid. The calcium salt of folinic acid is a preferred pharmaceutically acceptable salt. Organic salts and esters are also suitable for use with this invention.
• the active compounds are preferably administered to the subject as a pharmaceutical composition.
• compositions for use in the present invention include systemic and topical formulations and, among these, preferred are formulations suitable for inhalation, oral, rectal, vaginal, nasal, ophthalmic, otical, intracavitary, intraorgan, topical (including buccal, sublingual, dermal and intraocular), parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular) and transdermal administration, among others.
• the compositions may conveniently be presented in single or multiple unit dosage forms as well as in bulk, and may be prepared by any of the methods which are well known in the art of pharmacy.
• the composition of the invention may also be provided in the form of a kit, whether already formulated or with instructions for its formulation and administration regime.
• the kit may also contain other agents, such as those described above and, for example, when for parenteral administration, they may be provided with a carrier in a separate container, where the carrier may be ste ⁇ le.
• the present composition may also be provided in a separate contamer which may be ste ⁇ le for addition of a liquid earner p ⁇ or to admmistration. See, e.g. US Patent No 4,956,355, UK Patent No. 2,240,472; EPO Patent Application Serial No. 429,187, PCT Patent Application Senal No 91/04030, the relevant preparatory and compound portions of which are incorporated by reference above See, also Mortensen, S. A., et al , Int. J. Tiss. Reac.
• Formulations suitable for oral and parenteral admmistration are preferred, and inhalable preparations are also preferred. All methods include the step of bringing the active compound into association with a earner which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into desired formulations.
• compositions suitable for oral admmistration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound, as a powder or granules, as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-m-water or water-m-oil emulsion
• Such compositions may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable earner
• the compositions of the mvention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid earner, or both, and then, if necessary, shaping the resulting mixture.
• a tablet may be prepared by compressing or mold g a power or granules containmg the active compound, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispensing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
• compositions for oral admmistration may optionally include entenc coatings known m the art to prevent degradation of the compositions in the stomach and provide release of the drug in the small intestine
• compositions suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavored base, usually sucrose and acacia or tragacanth and pastilles compnsmg the compound m an inert base such as gelation and glycenn or sucrose and acacia
• compositions suitable for parenteral administration compnse sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient.
• preparations may contam antioxidants, buffers, bactenostats and solutes which render the compositions isotonic with the blood of the mtended recipient.
• Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents.
• compositions may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored m a freeze-dried (lyophilized) condition requiring only the addition of the stenle liquid earner, for example, salme or water-for-mjection immediately pnor to use.
• stenle liquid earner for example, salme or water-for-mjection immediately pnor to use.
• Extemporaneous injection solutions and suspensions may be prepared from stenle powders, granules and tablets of the kmd previously descnbed.
• compositions suitable for topical application to the skm preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
• Carners which may be used include vaseline, lanohne, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
• Compositions suitable for transdermal admmistration may be presented as discrete patches adapted to remam m mtimate contact with the epidermis of the recipient for a prolonged penod of tune.
• compositions suitable for transdermal admmistration may also be delivered by iontophoresis (see, e.g., Pharmaceutical Research 3, 318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound.
• the active compound of this mvention (first agent) is provided within broad amounts of the composition.
• folinic acid, its salts and their mixtures may be contamed in the composition in amounts of about 0 001%, about 1%, about 2%, about 5% to about 99.999 %, about 98%, about 90%, about 40%, about 20%, about 10%, about 5% of the composition, preferably about 1 to about 99%, more preferably about 2% to 40%, and still more preferably about 2% to about 10% of the composition.
• the dosage of the active compound may vary depending on age, weight, and condition of the subject.
• Treatment may be initiated with a small dosage which is less than the optimal dose of the first agent of the invention, be it folinic acid or one of its salts.
• the dose may be increased until a desired and/or optimal effect under the circumstances is reached.
• the dosage is about 1, about 5, about 10, about 20, about 50 mg/kg body weight and up to about 100, about 200, about 500 or about 1000 mg/kg body weight
• prefened are dosages of about 5 to about 500 mg/kg body weight of the subject, more prefened are dosages of about 10 to about 200 mg/kg, and still more prefened are dosages of about 50 to about 100 mg/kg body weight of the subject
• the active agent is preferably admmistered at a concentration that will afford effective results without causing any unduly harmful or deletenous side effects, and may be admmistered either as a single unit dose, or if desired m convenient subunits administered at suitable times
• the dose of one of the other or of both agents may be adjusted to attain a desirable effect without exceeding a dose range which avoids untoward side effects
• other analgesic and anti-inflammatory agents when added to the composition, they may be added in amounts known in the art for their intended application or in doses somewhat lower that when admmistered by themselves
• the present composition is provided in a vanety of systemic and topical formulations
• the systemic or topical formulations of the invention are selected from the group consisting of oral, intrabuccal, intrapulmonary, rectal, mtrautenne, intradermal, topical, dermal, parenteral, mtratumor, intracranial, buccal, sublingual, nasal, intramuscular, subcutaneous, mtravascular, mtrathecal, inhalable, transdermal, intraarticular, intracavitary, implantable, transdermal, lontophoretic, intraocular, ophthalmic, vagmal, otical, intravenous, intramuscular, mtraglandular, intraorgan, mtralymphatic, implantable, slow release and enteric coating formulations
• the actual preparation and compounding of these different formulations is known m the art and need not be detailed here.
• the active compounds may be admmistered once or several tunes a day.
• the active compounds disclosed herem may be admmistered to the lungs of a subject by any suitable means, but are preferably admmistered by generatmg an aerosol comp ⁇ sed of respirable particles, the respirable particles comprised of the active compound, which particles the subject inhales, i.e., by inhalation admmistration.
• the respirable particles may be liquid or solid.
• Particles compnsed of active compound for practicing the present mvention should include particles of respirable size, that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs.
• particles rangmg from about 0 5 to about 10 microns m size, more particularly, less than about 5 microns m size, are respirable Particles of non-respirable size which are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is preferably minimized
• a particle size in the range of 10-500 m is preferred to ensure retention m the nasal cavity
• Liquid pharmaceutical compositions of active compound for producmg an aerosol may be prepared by combmmg the active compound with a stable vehicle, such as stenle pyrogen free water
• Solid particulate compositions containing respirable dry particles of rmcronized active compound may be prepared by grinding dry active compound with a mortar and pestle, and then passing the micronized composition through a 400 mesh screen to break up or separate out large agglomerates
• a solid particulate composition compnsed of the active compound may optionally contam a dispersant which serves to facilitate the formation of an aero
• Aerosols of liquid particles compnsmg the active compound may be produced by any suitable means, such as with a nebulizer See, e g US Patent No 4,501,729 Nebulizers are commercially available devices which transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, through a nanow ventun orifice or by mens of ultrasonic agitation Suitable compositions for use m nebulizer consist of the active ingredient in liquid earner, the active ingredient compnsmg up to 40% w/w composition, but preferably less than 20% w/w earner being typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example sodium chlonde Optional additives mclude preservatives if the composition is not prepared ste ⁇ le, for example, methyl hydroxybenzoate, antioxidants, flavonng agents, volatile oils, buffering agents and surfactants
• Aerosols of solid particles compnsmg the active compound may likewise be produced with any sold particulate medicament aerosol generator Aerosol generators for admimstenng solid particulate medicaments to a subject product particles which are respirable, as explamed above, and generate a volume of aerosol contammg a predetermined metered dose of a medicament at a rate suitable for human admmistration Examples of such aerosol generators mclude metered dose inhalers and insufflators
• the second agent(s) may be admmistered concunently with the active compound, and may be an agent for preventmg and treating sleeplessness, mood disorders, anxiety, irritability, wasting disorders, bulimia, anorexia nervosa, cancer, viral and microbial mfections, heart conditions, ischemia, menopause, pain, inflammation, wounds and burns, muscle tension, low bone calcification, mflammatory diseases such as autoimmune diseases, COPD, and inflammatory bowel disease, and many more, mflammatory conditions, wound healmg, ischemia and reperfusion injury, to treat and prevent steroid mtake secondary effects and to improve body weight and mcrease muscle mass, preferably m the same composition as descnbed above
• concunently administering means that the folmic acid or its salt and the second agent(s) are admmistered either (a) simultaneously m tune, and preferably by formulating the two together m a common pharmaceutical
• the doses of the two or more agents may be reduced so as to maintain adenosine levels, whether the second agent has overlapping activity with the active compound or, if of different activity, the dose of the second agent may be reduced along with that of the active compound in cases of reduced risk of relapse. If the active compound is administered for a time sufficient to replenish endogenous adenosine levels, and this is attained, the continuation of treatment will depend on whether the adenosine levels are maintain in the absence of treatment or not. Moreover, whether the dose of the second agent(s) is reduced or not will depend on whether or not it is necessary to continue its administration or the subject remains stable.
• the treatment may be continued with close monitoring.
• the additional agents may be administered per se or in the form of pharmaceutically acceptable salts.
• the salts of these agents should be pharmacologically and pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare the free active compound or pharmaceutically acceptable salts thereof and are not excluded from the scope of this invention.
• Such pharmacologically and pharmaceutically acceptable salts include, but are not limited to, those prepared from the hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p- toluenesulfonic, tartaric, citric, methanesulphonic, formic, malonic, succinic, naphthalene-2-sulphonic and benzenesulphonic acids, among others.
• Pharmaceutically acceptable salts also may be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group.
• the present pharmaceutical formulations may comprise, in addition to the active compound and one or more additional agents, one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients suitable for specific types of diseases and conditions.
• the carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof.
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the potentiating agent as a powder or granules or a suspension in an aqueous liquor or nonaqueous liquid such as a syrup, an elixir, an emulsion or a drought.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine, with the active compound being in a free-flowing form such as a powder or granules which is optionally mixed with a binder, disintegrant, lubricant, inert diluent, surface active agent or dispersing agent.
• Molded tablets comprised of a mixture of the powdered active compound with a suitable carrier may be made by molding in a suitable machine.
• a syrup may be made by adding the active compound to a concentrated aqueous solution of a sugar, for example sucrose to which may also be added any accessory ingredient(s).
• a sugar for example sucrose
• Such accessory ingredient(s) may include flavorings, suitable preservatives, an agent to retard crystallization of the sugar, and an agent to increase the solubility of any other ingredient, such as a polyhydric alcohol, for example glycerol or sorbitol.
• Formulations suitable for parenteral admmistration conveniently compnse a ste ⁇ le aqueous preparation of the active compound, which is preferably isotonic with the blood of the recipient.
• Nasal spray formulations compnse pu ⁇ fied aqueous solutions of the active compound with preservative agents and isotonic agents. Such formulations are preferably adjusted to a pH and isotonic state compatible with the nasal mucous membranes.
• Formulations for rectal or vagmal admmistration may be presented as a suppository with a suitable earner such as cocoa butter, or hydrogenated fats or hydrogenated fatty carboxylic acids.
• Ophthalmic formulations are prepared by a similar method to the nasal spray, except that the pH and isotonic factors are preferably adjusted to match that of the eye Otical formulations are generally prepared m viscous earners, such as oils and the like, as is known in the art, so that they may be easily administered into the ear without spilling
• Topical formulations compnse the active compound dissolved or suspended m one or more media such as mineral oil, petroleum, polyhydroxy alcohols or other bases used for topical pharmaceutical formulations
• media such as mineral oil, petroleum, polyhydroxy alcohols or other bases used for topical pharmaceutical formulations
• the formulations of this invention may further include one or more accessory ⁇ ngred ⁇ ent(s) selected from diluents, buffers, flavonng agents, binders, disintegrants, surface active agents, thickeners, lubncants, preservatives (including antioxidants) and the like
• accessory ⁇ ngred ⁇ ent(s) selected from diluents, buffers, flavonng agents, binders, disintegrants, surface active agents, thickeners, lubncants, preservatives (including antioxidants) and the like
• Other ingredients may also be utilized as is known m the art
• DHEA dehydroepiandrosterone
• F A folmic acid
• M methyltestosterone
• s means seconds
• mg milligrams
• kg means kilograms
• kw means kilowatts
• Mhz means megahertz
• nmol means nanomoles
• Young adult male Fischer 344 rats (120 grams) were admmistered dehydroepiandrosterone (DHEA) (300 mg/kg) or methyltestosterone (40 mg/kg) in carboxymethyl cellulose by gavage once daily for fourteen days
• Folmic acid 50 mg/kg was admmistered intrape ⁇ toneally once daily for fourteen days
• the animals were sacnficed by microwave pulse (1.33 kw, 2450 MHZ, 6 5 s) to the cranium, which mstantly denatures all bram protem and prevents further metabolism of adenosme.

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• 2000
  • 2000-01-05 JP JP2000591931A patent/JP2003523933A/ja not_active Withdrawn
  • 2000-01-05 CA CA002356368A patent/CA2356368A1/en not_active Abandoned
  • 2000-01-05 EP EP00904212A patent/EP1139913A4/en not_active Withdrawn
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