Patent Application: US-33584199-A

Abstract:
numerous studies have documented that medications which increase brain serotonin are effective anorectic agents which help obese patients lose weight and which also decrease craving for sweets and carbohydrates . evidence from other studies also indicate that increases in brain 5 - ht may help decrease craving for alcohol and cocaine . 5 - hydroxy - l - tryptophan , abbreviated 5 - htp , is the immediate precursor of serotonin . when administered in combination with an inhibitor of peripheral decarboxylase such as carbidopa , 5 - htp increases brain serotonin . increases in synaptic 5 - ht decreases the firing rate of 5 - ht neurons via stimulation of inhibitory 5 - ht1a receptors located on the cell bodies in the raphe . this serves as a negative feedback loop . the clinically available beta adreneric receptor antagonist medication pindolol is also a 5 - ht1a antagonist , and can be used to increase the ability of 5 - htp to increase brain 5 - ht . previous studies with 5 - htp used doses exceeding 50 mg per day . when 5 - htp was used in combination with carbidopa , the dose of carbidopa was in excess of 50 mg per day . one novel aspect of the invention are the doses of the 5 - htp and carbidopa : much lower daily doses than have been used before are effective in decreasing appetite , decreasing craving for food and for promoting weight loss . the second novel aspect of the invention relates to the concurrent use of pindolol along with the 5 - htp / carbidopa , which enhances the effectiveness of the 5 - htp / carbidopa combination .

Description:
the pharmaceutical compounds according to the invention are found in three different classes of therapeutically active substances , i . e . one class comprising the precursor of the neurotransmitter serotonin , such l - 5 - hydroxytryptophan , the second class comprising inhibitors of the enzyme peripheral decarboxylase , such as carbidopa , and the third class comprising compounds which block the 5 - ht1a receptor in the brain , such as pindolol . the term “ therapeutically active substance ” as used herein is intended to mean any physiologically or pharmacologically active substance that produce a localized or systemic effect in animals , in particular in mammals , including humans , primates and domestic animals . examples of peripheral decarboxlyase inhibitors include drugs such as carbidopa and benserazide , or any prodrug which yields a peripheral decarboxylase inhibitor . examples of 5 - ht1a inhibitors include pindolol , but could also include any other drugs blocks activation of 5 - ht1a receptor . examples of 5 - ht1a inhibitors also include any prodrug which yields a drug which blocks activation of 5 - ht1a receptor . in this context , the term “ prodrug ” denotes a bioreversible derivative of the drug , the bioreversible derivative characterized in being therapeutically inactive per se but being able to convert to the active drug within the organism either by an enzymatic or non - enzymatic process . pharmaceutically acceptable salts of the compounds according to the present invention include salts of strong inorganic acids or week organic acids , for example a hydrochloride , sulfate , nitrate and acetate salt . examples of suitable prodrugs of the compounds according to the present invention include compounds obtained by suitable bioreversible derivatization of one or more reactive groups of the parent drug . the composition according to the present invention can be formulated for administration by any suitable route such as the oral , rectal , nasal , topical ( dermal ) or parenteral administration route . thus , the composition may be in the form of tablets , capsules , suspensions , emulsions , solutions , injectables , suppositories , sprays , aerosols and in other suitable form . formulations for oral use include tablets which contain the active ingredient in admixture with non - toxic pharmaceutically acceptable excipients . these excipients may be , for example , inert diluents , such as calcium carbonate , sodium chloride , lactose , calcium phosphate or sodium phosphate ; granulating and disintegrating agents , for example , potato starch or alginic acid ; binding agents , for example , starch , gelatin or acacia ; and lubricating agents , for example , magnesium stearate , stearic acid or talc . other pharmaceutically acceptable excipients can be colorants , flavouring agents , plasticizers , humectants etc . the tablets may be uncoated or they may be coated by known techniques , optionally to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period . for example , a time delay material such as glyceryl monostearate or glyceryl distearate may be employed . formulations for oral use may also be presented as chewing tablets , or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent , for example , calcium carbonate , calcium phosphate or kaolin , or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium , for example , peanut oil , liquid paraffin , or olive oil . powders , dispersible powders or granules suitable for preparation of an aqueous suspension by addition of water are also convenient dosage forms of the present invention . formulation as a suspension provide the active ingredient in admixture with a dispersing or wetting agent , suspending agent and one or more preservatives . suitable dispersing or wetting agents are , for example , naturally - occurring phosphatides , as e . g . lecithin , or condensation products of ethylene oxide with e . g . a fatty acid , a long chain aliphatic alcohol or a partial ester derived from fatty acids and a hexitol or a hexitol anhydrides , for example , polyoxyethylene stearate , polyoxyethylene sorbitol monooleate , polyoxyethylene sorbitan monooleate etc . suitable suspending agents are , for example , sodium carboxymethylcellulose , methylcellulose , sodium alginate etc . the pharmaceutical formulation may also be administered parenterally ( intravenous , intramuscular , subcutaneous or the like ) in dosage forms or formulations containing conventional , non - toxic pharmaceutically acceptable carriers and adjuvants . the formulation and preparation of such compositions is well - known to those skilled in the art of pharmaceutical formulation . specific formulation can , however , be found in the text entitled “ remington &# 39 ; s pharmaceutical sciences ” ( 16 ). for parenteral use , the pharmaceutical compositions according to the invention may comprise the therapeutic compounds in the form of a sterile injection . to prepare such a composition , the therapeutic compounds are dissolved or suspended in a parenterally acceptable liquid vehicle . among acceptable vehicles and solvents that may be employed are water , water adjusted to a suitable ph by addition of an appropriate amount of hydrochloric acid , sodium hydroxide or a suitable buffer , 1 , 3 - butanediol , ringer &# 39 ; s solution and isotonic sodium chloride solution . the aqueous formulation may also contain one or more preservatives , for example , methyl , ethyl or n - propyl phydroxybenzoate . for the rectal application , suitable dosage forms for a composition according to the present invention include suppositories ( emulsion or suspension type ), and rectal gelatin capsules ( solutions or suspensions ). in a typical suppository formulation , the compounds are combined with an appropriate pharmaceutically acceptable suppository base such as cocoa butter , esterified fatty acids , glycerinated gelatin , and various water - soluble or dispersible bases like polyethylene glycols and polyoxyethylene sorbitan fatty acid esters . various additives like e . g . enhancers or surfactants may be incorporated . for the nasal application typical dosage forms for a composition according to the present invention include nasal sprays and aerosols for inhalation . in a typically nasal formulation , the active ingredients are dissolved or dispersed in a suitable vehicle . the pharmaceutically acceptable vehicles and excipients and optionally other pharmaceutically acceptable materials present in the composition such as diluents , enhances , flavouring agents , preservatives etc . are all selected in accordance with conventional pharmaceutical practice in a manner understood by the persons skilled in the art of formulating pharmaceuticals . the pharmaceutical compositions according to the invention may also be administered topically on the skin for percutaneous absorption in dosage forms or formulations containing conventionally non - toxic pharmaceutically acceptable carriers and excipients including microspheres and liposomes . the formulations include creams , ointments , lotions , liniments , gels , hydrogels , solutions , suspensions , pastes , plasters and other kinds of transdermal drug delivery systems . the pharmaceutically acceptable carriers or excipients may include emulsifying agents , antioxidants , buffering agents , preservatives , humectants , penetration enhancers , chelating agents , gelforming agents , ointment bases , perfumes and skin protective agents . examples of emulsifying agents are naturally occurring gums , e . g . gum acacia or gum tragacanth , naturally occurring phosphatides , e . g . soybean lecithin and sorbitan monooleate derivatives . examples of antioxidants are butylated hydroxy anisole ( bha ), ascorbic acid and derivatives thereof , tocopherol and derivatives thereof and cysteine . examples of preservatives are parabens and benzalkonium chloride . examples of humectants are glycerin , propylene glycol , sorbitol and urea . examples of penetration enhancers are propylene glycol , dmso , triethanoiamine , n , n - dimethylacetamide , n , n - dimethylformamide , 2 - pyrrolidone and derivatives thereof , tetrahydrofurfuryl alcohol and azone . rtm . examples of chelating agents are sodium edta , citric acid and phosporic acid . examples of gel forming agents are carbopol , cellulose derivatives , bentonit , alginates , gelatin and pvp . examples of ointment bases are beeswax , paraffin , cetyl palmitate , vegetable oil , sorbitan esters of fatty acids ( span ), polyethyleneglycols , and condensation products between sorbitan esters of fatty acids and ethylene oxide , e . g . polyoxyethylene sorbitan monooleate ( tween ). the formulation and preparation of the above - mentioned compositions is well - known to those skilled in the art of pharmaceutical formulation . specific formulation can be found in “ remington &# 39 ; s pharmaceutical sciences ” ( 16 ). preferably , the pharmaceutical composition of the present invention comprises a combination product containing the 5 - hydroxytryptophan in combination with the peripheral decarboxylase inhibitor , i . e . in the case of a tablet , one tablet comprises a mixture of the two active components . however , the pharmaceutical composition of the present invention may also be presented in one package comprising two separate containers , one container comprising dosage form of the 5 - hydroxytryptophan and the other container comprising a dosage form of the peripheral decarboxylase inhibitor . in such cases , special instructions for substantially concomitant use of the two drugs should be enclosed with the product . the two dosage forms can be the same or they may be different , preferably the two dosage forms are the same . the pharmaceutical composition of the present invention also comprises a combination product containing the 5 - hydroxytryptophan in combination with the peripheral decarboxylase inhibitor and the 5 - ht1a receptor antagonist , i . e . in the case of a tablet , one tablet comprises a mixture of the three active components . however , the pharmaceutical composition of the present invention may also be presented in one package comprising three separate containers , one container comprising dosage form of the 5 - hydroxytryptophan , the second container comprising a dosage form of the peripheral decarboxylase inhibitor and the third container comprising a dosage form of the 5 - ht1a receptor antagonist . in such cases , special instructions for substantially concomitant use of the three drugs should be enclosed with the product . the three dosage forms can be the same or they may be different , preferably the three dosage forms are the same . in one aspect the present invention relates to a method for treatment of overweight or obesity in individuals , in particular in humans , or for reducing the adipose tissue mass / lean mass body mass ratio of an individual , in particular a human . in the present context the term “ overweight ” is used as an indication of a body with a weight exceeding the “ desirable weight ”, whereas the term “ obesity ” is used when the body weight is 20 % or more above the “ desirable weight ”. desirable weights for humans are defined as a body mass index less than or equal to 24 . in another aspect , the present invention relates to a method for the treatment of diseases which are complications to overweight or obesity . these diseases or conditions include diabetes mellitus type ii , hypercholesterolemia , hypertriglyceridaemia , hypertension , back pain caused by obesity , arthritis made worse by obesity , sleep apnea and psychological or psychiatric problems complicated by obesity . in another aspect , the present invention also relates to a method of reducing craving , or the desire to eat foods , consume alcohol or use stimulant drugs such as cocaine or amphetamine - type drugs . in a further aspect , the invention can be used along with other appetite suppressant drugs , such as amphetamine , phentermine , diethylpropion , phendimetrazine , ephedrine or similarly - acting agents , to enhance the effects of these medications , that is to increase the weight loss which would occur with the use of these agents alone . in a further aspect , the present invention also relates to the use of a combination of 5 - hydroxytryptophan and a peripheral decarboxylase inhibitor for the manufacture of a pharmaceutical composition for the treatment of overweight or obesity or diseases aggravated thereof . the weight loss experienced over the first month of treatment of patients treated with phentermine ( n = 29 ) was compared to patients treated with phentermine plus 5 - htp / carbidopa / pindolol ( n = 37 ). the patients were matched for starting weight . the average daily weight loss for the phentermine only group was 0 . 37 ± 0 . 03 pounds / per day vs . 0 . 57 ± 0 . 05 ( mean ± sem ) for the phentermine plus 5 - htp / carbidopa / pindolol group . study 2 . administration of 5 - hydroxytryptophan ( 5 mg )/ carbidopa ( 5 mg ) decreases craving for food and “ sweets ”. patients ( n = 3 ) were administered in a single blind manner placebo capsules three times a day for 1 week . in the next week , patients were administered identical capsules three times a day containing 5 - hydroxytryptophan ( 5 mg )/ carbidopa ( 5 mg ). patients &# 39 ; craving for food or sweets was rated before treatment , after one week of placebo treatment and after one week of treatment with 5 - hydroxytryptophan ( 5 mg )/ carbidopa ( 5 mg ). the rating scale ranged from 1 for no craving to 10 for the most craving ever . the results demonstrated that placebo treatment reduced craving by 14 ± 7 % ( mean + sem , n = 3 ) and 5 - hydroxytryptophan ( 5 mg )/ carbidopa ( 5 mg ) reduced craving by 82 ± 3 ( mean ± sem , n = 3 ). patients also reported the degree to which intake of foods they craved were reduced . in this questionnaire 1 = much reduced , 2 = a little reduced , 3 = no change and 4 = increased . the results were as follows : week 1 2 . 5 + 0 . 5 ( mean ± sem , n = 3 ) indicating little reduction by placebo . at the end of week 2 intake was rated as 1 ± 0 ( mean ± sem , n = 3 ), indicating a large reduction in the intake of craved foods . 1 . brauer , l . h . ; johanson , c . e . ; schuster , c . r . ; rothman , r . b . ; de wit , h . evaluation of phentermine and fenfluramine , alone and in combination , in normal , healthy volunteers . neuropsychopharmacol . 14 : 233 - 241 ; 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