KR20000023819A - Appetite suppression - Google Patents

Abstract

PURPOSE: Provided are compositions for suppression of appetite and desire for carbohydrates and method thereof using precursors of neurotransmitter such as sertonin, dopamine, epinephrine and histamine. CONSTITUTION: A composition containing precursors of neurotransmitter such as sertonin,dopamine, epinephrine and histamine. The precursors contain amino groups and comprise tryptophan for serine, phenylalanine and tyrosine for dopamine and epinephrine, and histidine for histidine. The precursors improve appetite suppression of the neurotransmitter by combination with one another or xanthin. The xanthin is provided from a natural source of supply. Especially, cocoa provides combination of xanthin containing theobromine and caffeine, and amine, especially, phenylamine in an organism. Tryptophan is administrated in the form of hydrolyzed protein by protease.

Description

Appetite suppression {APPETITE SUPPRESSION}

One major component of a successful weight loss program is appetite suppression. Appetite suppression can be achieved by administration of amphetamines, antidepressants, insoluble and soluble fibers, serotonin precursors, and prescription drugs that enhance serotonin activity. All of these technologies currently in use have significant disadvantages.

Amphetamines are well known to suppress appetite. Dexedrin and related medications, including ephedrine and pseudoephedrine, reduce appetite. These drugs cause irritability, addictive poisoning or nerve damage (dexedrin), or a rapid decay of effect (ephedrine or pseudoephedrine). Amphetamine molecules, phentermines, have been approved as appetite suppressants but must be administered by prescription. This leads to increased costs associated with having to see a doctor. In addition, phentermine may only be used for a short time when administered alone. Amphetamines, including phentermines, are known to partially suppress appetite through their effects on brain dopamine. Pentamine may also cause high blood pressure, heart rate irregularities and irritability. Thus amphetamines and related drugs can be used to reduce appetite at substantial cost, but, as is known, often involve unacceptable side effects.

One approach, introduced in 1978 by Wurtman et al., Was to reduce the appetite for carbohydrates using precursors of brain serotonin. Serotonin in the brain hypothalamic region is known to reduce the desire for carbohydrates. U.S. Patent No. At 4,210,637 Wurtman et al. Describe compositions and methods for selectively inhibiting appetite for carbohydrates. This method involves administration of tryptophan, a serotonin precursor, along with carbohydrates that cause insulin secretion. Insulin secretion transfers amino acids other than tryptophan from the bloodstream to tissues. This removes amino acids that compete with tryptophan for transport across the blood brain barrier from the blood. This carbohydrate-initiated insulin effect on the amino acid cycle maximizes tryptophan delivery to the hypothalamus.

The dose of tryptophan proposed by Wurtman is between 10 and 100 mg per kg of rat. For a 70 kg person, the dosage to potentially achieve similar effects will range from 700 to 7,000 mg. When Wurtman applied tryptophan to humans in an amount of 2,300 mg / day, there was no consistent effect on appetite suppression. Moreover, the Food and Drug Administration (FDA), a US regulatory agency, has found that tryptophan administration above 100 mg / day is not safe. The FDA has stated that administration of tryptophan over 100 mg / day may potentially cause muscle damage. Thus tryptophan cannot be used alone or as a carbohydrate as an appetite aid.

U.S. Patent No. At 4,309,445 Wurtman et al. Described compositions and methods using d-phenfluramine to block intermittent carbohydrate cravings. This method discloses that d-phenfluramine and the related isomer 1-phenfluramine selectively reduce carbohydrate desire. Wurtman et al. US Patent No. At 4,687,763, it was disclosed that tryptophan can increase brain serotonin levels when administered with melatonin. In this patent, Wurtman et al. Disclosed that oral administration of tryptophan may increase brain serotonin and that increased brain serotonin causes a decrease in carbohydrate cravings. The amount of tryptophan used by Wurtman et al. Was consistent between 2 and 100 mg / kg body weight per dose. These amounts are significantly above the amount of supplemental tryptophan of less than 1.6 mg / kg per day, the current FDA safety guideline, especially if tryptophan is from a bacterial synthesis source.

The FDA only accepts naturally occurring proteins as a source of supplemental tryptophan. Native, naturally occurring protein forms of the "predigested" (enzymatic hydrolyzed) form can also be used. Naturally occurring proteins contain approximately 1.6% tryptophan. The amount of tryptophan in a naturally occurring protein is previously thought to be insufficient to cause a reduction in carbohydrate cravings. This is due to the presence of other amino acids that compete with the small amount of tryptophan present in the protein for absorption. A recent FDA report concluded that there is not enough evidence that tryptophan reduces appetite at a dose that is considered safe. There is no known prior art suggesting the use of pre-digested proteins as a tryptophan source for appetite suppression.

Tyrosine is a precursor of brain dopamine. Amphetamines stimulate release of dopamine. Brain dopamine is associated with the appetite suppressing effects of amphetamines. To date, no food supplement has been used to enhance the release of dopamine without the use of amphetamines or amphetamines such as ephedrine or pseudoephedrine. Wurtman et al. US Patent No. 4,673,689 discloses that tyrosine can be used to enhance sympathomimetic agents such as ephedrine or pseudoephedrine. However, this patent does not contain any disclosure or suggestion of utility or synergistic effects for the purpose of combining tyrosine with any other drug having activity in the central nervous system.

Histidine is a precursor of histamine in the brain. Histamine and its precursor histidine, when administered by intraperitoneal injections, are reported to reduce food intake in experimental animals (rats) ("Manipulation of Central Nervous System Histamine, Histaminergic Receptors (H1) Affects Food Intake in Rats). ", Mercer et al., J. of Nutrition, 1994, Mol. 24, pp 1029-1036)). However, the effectiveness of histamine or its precursor histidine or its known side effects on appetite suppression by oral administration has not been clarified.

Chocolate, in particular cocoa powder, contains, among other active ingredients, xanthine theobromine and caffeine along with in vivo amines such as phenylethylamine. These drugs affect the activity of both serotonin and dopamine. Xanthine is known to increase the release of both dopamine and serotonin. Chocolate or cocoa powder has never been used as an appetite suppressant, alone or in combination with neurotransmitter precursors such as tryptophan or tyrosine. Phenylethylamine is also known to promote the release of serotonin and dopamine. Phenylethylamine is also known to act as an inhibitor of monoamine oxidase (MAO), which breaks down serotonin and dopamine. Chocolate has been used, directly and indirectly, as a mood enhancer. The appealing mechanism of chocolate is not clearly defined so far. Most common sense suggests that the cause of the appeal of chocolate is in its taste and not in the neurotransmitter effect.

In 1992, Wientraub discovered that when used together, phentermin and fenfluramine induce long-term weight loss, reduce appetite and reduce carbohydrate cravings. Fenfluramine is a mixture of fenfluramine in the form of dextrose and levo. The combination of phentermine and fenfluramine was attributed to their respective effects on serotonin and dopamine. Using this combination of prescription drugs, weight loss could last from months to years. Thus there has been a substantial increase in the use of the phentermine-phenfluramine approach to weight loss despite the lack of regulatory approval for combinations. Many regulatory agencies limit the use of any of these drugs to short periods of time ranging from 7 days to 1 month. In addition, the use of fenfluramine is rarely associated with side effects of pulmonary hypertension and reflux disease. The use of d-fenfluramine is expensive for US $ 5.00 per day for the drug and induces grogginess in many subjects. Add to this cost the number of visits to the doctor several times to review treatments that may last for months or years. Pentamine is also an amphetamine-like drug whose long-term effects are unknown. Therefore, there is a need for a low cost program that is comparable to the effectiveness of phentermine-phenfluramine treatment, which can be applied to the majority of individuals without repeated physician review. Ideally, the components of such a program would be formulated from low cost components, not drugs.

The present invention generally relates to dietary supplements for reducing appetite and reducing carbohydrate cravings. Obesity is associated with increased mortality, diabetes mellitus, hypertension, heart disease and angina, and attention to weight control is increasing.

With attention to reducing obesity, the introduction of sugar- and fat-free foods, diet plans, weight loss programs, artificial fats, and pharmaceutical preparations to alter both appetite and carbohydrate needs have begun. Despite the desirability of weight loss and the proliferation of weight loss supplement products, people's weight continues to increase. Now over 40% of the population is estimated to be overweight. At any given time, approximately 25% of the population is on a diet, going from repeated diets to an undesirable "yo-yo" effect. Failure of weight loss products to achieve and maintain weight loss can be attributed to several factors. This includes relatively ineffective personal access, side effects of weight loss products, and the cost of continuing the weight loss program. Therefore, effective programs based on safe and naturally occurring drugs are needed. Such a program will enable the reduction of side effects and the reduction of costs in addition to weight loss.

The present invention aims to achieve appetite suppression and reduced carbohydrate desire without much administration of fiber, amphetamines, antidepressants, or other prescription drugs. The present invention also aims to enable the use of ready-to-use, low cost, safe, plant-derived drugs, and to provide appetite suppression with reduced dosages of such drugs to minimize the likelihood of side effects. .

The present invention provides methods and compositions for inhibiting appetite based on the discovery that in appetite suppression and carbohydrate desire reduction, certain neurotransmitter precursors will act synergistically with each other and with certain neurotransmitter enhancers, in particular amino acids. The neurotransmitter precursors to the neurotransmitters of serotonin, dopamine, norepinephrine and histamine, containing tryptophan, phenylalanine, tyrosine and histidine, are one or more xanthines that effectively inhibit appetite, and in particular caffeine and / or Together with theobromine, it is administered orally at reduced dosages. When these neurotransmitter precursors are administered alone, they require an unacceptable high dose for appetite suppression.

In another aspect of the invention, histidine is administered with or without the administration of xanthine, with tryptophan, phenylalanine or tyrosine having a synergistic effect of appetite suppression. Tryptophan is associated with phenylalanine or tyrosine, which have a beneficial effect, so that they can be administered separately on the same day but at least 20 minutes apart to avoid competition between them to cross the blood brain barrier.

Another feature of the present invention is that the neurotransmitter precursors and enhancers are administered in accordance with the present invention in naturally occurring forms that are believed to be safe for long intake as food.

The neurotransmitter precursor tryptophan may be administered in the form of a natural protein that hydrolyzes to release amino acid residues, including tryptophan. Pre-digested proteins can deliver free amino acids to produce a quick effect. Hydrolyzed proteins advantageously have an empty stomach (ie, an hour after eating) with carbohydrates that remove competing amino acids from the bloodstream that induce insulin secretion and thereby block the passage of tryptophan across the blood brain barrier. Administration to a subject having, thereby maximizing the absorption of naturally occurring tryptophan. Insulin-mediated effects on these amino acids allow sufficient tryptophan to be delivered to the brain to achieve the desired effect.

In a related embodiment, rather than administering the pre-hydrolyzed protein, the protein source for tryptophan may be administered in unhydrolyzed form with proteolytic enzymes to cause hydrolysis to occur in the gastrointestinal tract to release tryptophan. .

Xanthine is also advantageously derived from natural sources that have been used for a long time as food, such as cocoa, tea, coffee and the like. Cocoa in particular provides the only source of the combination of both xanthine caffeine and theobromine and provides phenylethylamine which is considered to be tasty and safe.

Dosage forms are provided to advantageously and conveniently perform the aforementioned methods at reduced dosages compatible with effective appetite suppression. A single dosage form consists of pills, caplets, and other forms that are individually adapted to administer an appropriate single dose of the selected component. The amount of tryptophan in the dosage form is about 2.5 to 100 milligrams, the amount of tyrosine is about 10 to 700 milligrams and the amount of histidine is about 1 to 500 milligrams. Xanthine Theobromine is in the range of about 1 mg to 2 gm or more when present in the dosage form. When cocoa is employed as a xanthine source, it may be present in an amount of about 1 mg to 2 grams or more in a single dosage form. When the hydrolyzed protein is a source of tryptophan, the amount of hydrolyzed protein is 0.5 grams and 30 grams. May be between grams or more. Preferably, the amount of hydrolyzed protein is chosen to be able to provide tryptophan in an amount of 2.5 to 100 milligrams.

The combination of these drugs makes it possible to reduce the dose of individual neurotransmitter precursors due to their surprising synergistic effects, thus reducing side effects and allowing the administration of the component to a level normally considered safe by a regulatory body such as the FDA. To reduce it. They further enable the use of naturally occurring proteins and the use of plant-derived materials instead of drugs.

Under FDA regulations, supplemental tryptophan cannot be synthesized by artificial treatment and therefore must be derived naturally from proteins originating from animals or plants.

The FDA further states that the dose of tryptophan added may not exceed 100 mg per day or 1.43 mg / kg per day. Preferred sources in the present invention are plant proteins and the dosage of tryptophan is 45 mg / dose or 0.71 mg / kg / day. In embodiments using pre-digested protein, the amount of tryptophan may be as low as 15-40 mg / dose. Such administration of tryptophan that meets FDA's limitations will be ineffective in the absence of xanthine.

The following detailed description illustrates the means to which the principles of the invention apply, but do not conclude that it limits the scope of the invention.

Serotonin, dopamine, norepinephrine and histamine form a class of active neurotransmitters in the CNS that affect appetite, promoting the release of corticotropin-releasing factor (CRF) that inhibits appetite, or Inhibits the activity and / or release of neuropeptide Y which promotes appetite. Serotonin, norepinephrine and histamine all promote the release of CRF. Dopamine inhibits neuropeptide Y. Histamine promotes neuronal firing.

Precursors for this class of neurotransmitters that all contain amino groups include tryptophan for serotonin, phenylalanine and tyrosine for dopamine and norepinephrine, histidine for histamine, and the like. In the present invention, these precursors are employed in combination with each other and in combination with xanthine to enhance the effect on appetite suppression of each neurotransmitter of this class.

Precursors in the present invention are employed to enhance the synthesis of their respective neurotransmitters, and all of these precursors are enhanced because serotonin, phenylalanine, tyrosine, and histidine all increase the synthesis of neurotransmitters that stimulate the release of CRF. Thereby indirectly stimulating the release of CFR. In addition, phenylalanine and tyrosine indirectly inhibit neuropeptide Y by also enhancing the synthesis of dopamine. In addition, histidine promotes neuronal firing and thereby indirectly stimulates the synthesis of norepinephrine, tyrosine and serotonin.

Precursors are in the present invention, for example, purified extracts isolated from pure amino acids, such as exogenous substances synthesized or derived from animal or plant proteins, in particular from amino acid residues in enzymatic hydrolyzed proteins. However, a source for precursor tryptophan that is particularly useful in the present invention, because it is a natural food source and because of regulatory limitations, is a protein that is enzymatic hydrolyzed before administration to release tryptophan, or a proteolytic enzyme that will release tryptophan in the gastrointestinal tract. Unhydrolyzed protein administered together with. Commercial formulations of pre-digested proteins typically obtained from proteins derived from milk, such as casein or whey, are available and can be administered individually or in combination with histidine and / or xanthine.

If tryptophan is to be administered in the form of a pre-digested protein, or in the form of a protein to be enzymatically hydrolyzed after administration, in the present invention, other amino acids that cause release of insulin and compete with tryptophan across the cerebrovascular barrier, It is important to administer the protein in conjunction with carbohydrates, in particular sugars, dextrins, starches, etc. for removal from the body.

When non-hydrolyzed proteins are administered with proteolytic enzymes, soluble proteins such as albumin are preferred due to their ease of degradation. Whey, casein and soy are convenient sources of protein. Proteolytic enzymes can include papain, chemopapine, bromelain, trypsin, and pepsin.

Xanthine constitutes a class of non-selective adenosine antagonists, which include theobromine, caffeine and theophylline. They can promote the release of the neurotransmitters serotonin, dopamine and histamine. And they enhance neurotransmitter synthesis for each when administered according to the present invention. Combining xanthine and neurotransmitter precursors can achieve the desired effect with the administration of reduced and safe neurotransmitter precursors.

Xanthine can be used in the form of its free compound or as a salt, adduct or other derivative thereof, for example citrate addition caffeine, theophylline ethylenediamine, sodium theophylline acetate, sodium glycine, choline salt, theophylline derivative theophylline-meth Cumin and depilin, calcium theobromine salicylate, sodium acetate or sodium salicylate.

Particularly suitable xanthine sources for use in the present invention are those from natural sources. Cocoa provides a unique combination of xanthine, including theo and caffeine, with amines in vivo, in particular phenylethylamine, in a form that is generally readily ingested and acceptable by the subject. In addition to the strengthening effect of xanthine in cocoa, the MAO-inhibitory action of phenylethylamine prolongs the effects of serotonin, histamine and / or dopamine. Cocoa powder was originally included in preliminary preparations with neurotransmitter precursors to improve flavor because its mood enhancing effect has been appealing to people for centuries. The unexpected result was that cocoa powder significantly enhanced the effect of neurotransmitter precursors. This strengthening effect was confirmed by the present invention to be produced by naturally occurring xanthine and in vivo amines present in the cocoa powder.

Caffeine from coffee beans and caffeine and theophylline from tea leaves are in liquid form, such as coffee and tea, or in the form of dried extracts, alone or more uncomfortably in the form of neurotransmitter precursors, It can be employed as a natural source of xanthine. Chocolate, guarana and other food sources may be employed.

Combinations of neurotransmitter precursors of the present invention may be employed with the accompanying synergistic effect without incidental administration of xanthine, and may furthermore be enhanced by administering a combination of neurotransmitter precursors and xanthine. Combinations of neurotransmitter precursors include histidine administered with tyrosine, or histidine administered with tyrosine administered over time with tryptophan. Histidine does not compete with tyrosine or tryptophan when crossing the cerebrovascular barrier, so it can be administered with tyrosine or tryptophan in the same composition at the same time.

Tyrosine and phenylalanine may be advantageously used in conjunction with tryptophan in the present invention, but since they may interfere with the passage of tryptophan across the cerebrovascular barrier, they are separated from tryptophan and administered into the subject at least 20 minutes apart. do. Tryptophan or tyrosine and / or phenylalanine may be administered before the other. Administration in this manner to first allow absorption of phenylalanine and / or tyrosine from the blood stream can avoid interference with tryptophan absorption and result in improved effect of the precursor. In addition, neurotransmitter balance is facilitated by reducing the total dose of any single neurotransmitter over time.

Without wishing to be bound by any theory, the unexpected synergy found between these precursors is due to different mechanisms mediated by their respective neurotransmitters in promoting release of CRF and / or in the inhibition of neuropeptide Y. It can be explained at least in part.

Doses of each neurotransmitter precursor, when administered in combination with other neurotransmitters and / or xanthines used, enhance the synthesis of their respective neurotransmitters to stimulate release of CRF and thereby inhibit appetite. That's enough. The synergistic effect of these combinations will enable appetite suppression at lower dose levels than each other possible case of each neurotransmitter precursor, preferably avoiding those that limit the use of tryptophan, including possible side effects and especially staggering. This lower level is employed for this purpose.

For tryptophan, the desired single dose range is between 2.5 and 100 mg, usually 45 mg. The desired dosage range for phenylalanine or tyrosine is between 10 and 600 mg, usually 500 mg. However, up to 700 mg, or up to 1 gram or more, for example up to 3 grams, can be administered without the risk of severe side effects. These amounts, equivalent to 0.14 to 42.2 mg / kg, would be insufficient to suppress appetite if used alone. Histidine is preferably administered in a dosage range of 1 to 500 mg, usually in a dosage of 30 mg. However, if allowed by the subject, even higher doses may be given, for example up to 1 gram. Dosage ranges for each precursor apply to administration in combination with another precursor, or xanthine, or both and the precursor.

If the hydrolyzed protein or protein to be hydrolyzed in the gastrointestinal tract is employed as a source of tryptophan, the protein should be in an amount that provides the tryptophan dosage levels of the invention as described above. Typically this will be in the range between about 0.5 grams and 30 grams. The amount of enzyme employed can be 30-50 mg per gram of protein.

The insulin producing carbohydrate administered with the protein is preferably at a dosage level of about 0.5 grams to 5 grams.

Xanthine is employed in the present invention in a suitable dosage range to promote release of neurotransmitters and to avoid undesirable side effects. Theobromine and theophylline can be administered at dosages of 1 mg to 2 grams or more, respectively. Caffeine can be administered at a dosage of 1 to 200 mg or more, if it can be tolerated by the subject. Cocoa may be administered in dosages of 1 mg to 2 grams or more and 20 grams for an appropriate dosage of xanthine, with a preferred dosage of 400 to 800 mg. Intakes such as tea or coffee can be used in one or two cups to provide appropriate dosages. Rather high doses of these xanthines may be employed in subjects without severe discomfort.

The neurotransmitter precursors and neurotransmitter enhancers of the invention can be administered orally separately, or are administered together in the same composition to ensure proper ratios and dosages as well as convenience. The dosage forms for administration separately or in the same composition may be any of the conventional forms including capsules, caplets, chewable wafers, tablets, liquid suspensions, powders and the like. Xanthine administration can take the form of chocolate preparations, cocoa drinks, for example sachets such as coffee and tea, and cola drinks containing caffeine. Hydrolyzed protein sources of tryptophan are commercially available pre-digested protein tablets, such as LLP Concentrate Predigested Protein sold by Twin Laboratories, Inc., Ronkonkoma, New York, containing approximately 18 mg of tryptophan per gram of tablet. It may be taken separately in the form of tablets using.

The composition in powder or liquid form may be packaged in several dosage quantities with instructions to the user to relieve for appropriate intake, eg, one teaspoon or the like. However, the composition is preferably formulated in separate units, such as capsules, wafers, etc., each containing the neurotransmitter precursor and / or neurotransmitter enrichment in an appropriate dosage for a single administration, as described above. .

The composition may comprise common carriers, additives, excipients and adjuvants.

Advantageously, they include reinforcing agents contained in soluble fibers, insoluble fibers, neurotransmitter precursors and cocoa powder. The inclusion of dietary fiber initially results in satiety due to volume expansion, leading to the release of CCK, resulting in more appetite suppression. The appetite suppressing action of the dietary fiber component further enhances the neurotransmitter-related effects of the present invention.

It also contains folic acid and vitamin B6, which can increase the conversion of tryptophan to serotonin, tyrosine to dopamine, and histidine to histamine, respectively.

The preferred amount of folic acid is 200 mcg / dose and has a range of 1-800 mcg / dose. Preferred amounts of vitamin B6 are 10 mg, with a range of 1-50 mg / dose. Typical amounts of soluble fiber are 100 mg to 100 mg / administration. The best soluble fiber for producing appetite suppression is the pectin fiber of apples or tangerines. Typical dosages of insoluble fiber are 100 mg to 100 mg / administration. Preferred embodiments utilize insoluble fibers in the form of bran in these formulations. Other suitable insoluble fibers include, but are not limited to, cellulose, methyl-cellulose, chitosan, wheat, whole wheat fibers, and other wheat grain fibers. The concentration of insoluble fiber would not be effective as an appetite suppressant if given alone in these administrations. This fiber must be pre-mixed with water and dried at low temperatures until it is almost wet. Premixing will result in better gel and fat bonding than any fiber alone. Fibers that have not been premixed, heated and dried will reduce the effectiveness of the formulation.

In carrying out the present invention, when the subject's stomach is empty, it is usually important to administer at least one hour after the subject has eaten something, which is due to competition with other amino acids from the ingested food and the blood brain barrier. This is to avoid undesirably slow absorption across the surface. Administration can be repeated at intervals throughout the day if desired.

The effect of the formulations of the invention is usually strong enough so that the effect can be experienced after the first administration. The effects can be investigated by individuals using questionnaires to assess hunger and carbohydrate needs. This is in contrast to other appetite suppressants that require multiple administrations or require indirect methods such as weight loss to evaluate their effectiveness.

Various embodiments of the invention using tryptophan, phenylalanine, or tyrosine alone as neurotransmitter precursors or in combination with histidine may be used alone. Advantageously, however, these tryptophans and phenylalanine or tyrosine preparations are given to the subject at different times, each resulting in different appetite suppression. Phenylalanine or tyrosine-containing preparations are intended to enhance the production and release of dopamine. Appetite suppression is achieved by the dopamine activity produced and by the activity of histamine if histidine is included. Phenylalanine or tyrosine-containing preparations are comparable to the effects of amphetamine, phentermine, ephedrine and pseudoephedrine. Tryptophan-containing preparations are intended to reduce appetite for 2-4 hours and to enhance the production and release of serotonin, and histidine if histidine is included. Appetite suppression and carbohydrate desire reduction are achieved by the resulting serotonin activity. Tryptophan-containing preparations are comparable to the effects of fenfluramine, d-felfluramine and fluoxetine, and are typically intended to reduce appetite for 1-4 hours and reduce carbohydrate desire for 16-36 hours.

Tryptophan and phenylalanine or tyrosine preparations may be planned for use with varying dosing regimens to individual needs. Each is preferably administered when the stomach is empty. When used together in accordance with the present invention, during the same day (24 hours), one should be administered at least 20 minutes away from the other. This is to avoid competition of precursors to cross the blood brain barrier. Usually, phenylalanine or tyrosine preparations are administered before lunch to suppress appetite during the day and afternoon. Tryptophan preparations are administered before dinner to reduce carbohydrate cravings and reduce appetite at dinner and during the evening. Late afternoon and evening hours are when many overweight people crave both food and carbohydrates during the day. Alternatively, the tryptophan preparation may be administered at 11 am and 4 pm while the phenylalanine or tyrosine preparation is administered at 10 am and 3 pm. The dosing regimen allows these food supplements to be comparable to the effects of the prescription drugs phentermine, fenfluramine, and d-fenfluramine.

If an individual fasts and becomes hungry, the administration of tyrosine causes appetite suppression to begin 15-30 minutes after ingestion and lasts for 2-4 hours. If hunger reappears, re-ingestion of this preparation begins to suppress hunger 15-30 minutes after ingestion and continues for 2-4 hours. Repeated administration of tyrosine preparations results in repeated suppression of appetite.

Administration of tryptophan-containing preparations after self-induced fasting starts appetite suppression 20-40 minutes after ingestion and continues for 2-4 hours. The decrease in carbohydrate cravings begins approximately 30 minutes after ingesting tryptophan preparations and continues for 18-36 hours. If the tryptophan preparation is administered 30-90 minutes prior to tryptophan, the onset of the tryptophan preparation effect will be shortened to 15-30 minutes.

The following Examples 1-7 illustrate preparations containing tyrosine as the sole neurotransmitter precursor, preparations containing tryptophan as the sole neurotransmitter precursor, and their independent and joint use. These examples also illustrate the use of various xanthines with precursors, and illustrate the use of hydrolyzed proteins as tryptophan sources.

Example 1

Useful tyrosine preparations for one dose are 295 mg tyrosine, 125 mg soluble fiber, 125 mg insoluble fiber, 20 mg cocoa, 5 mg vitamin B6 and 10 mcg folic acid. Useful tryptophan combinations for one dose are 175 mg of soluble fiber, 175 mg of insoluble fiber, 100 mg of protein powder, 45 mg of tryptophan, 5 mg of vitamin B6, and 100 mcg of folic acid. Another useful dose of tryptophan-containing formulation is 175 mg of soluble fiber, 175 mg of insoluble fiber, 2000 mg of pre-digested protein powder, 250 mg of cocoa, 250 mg of sugar, 5 mg of vitamin B6, and 100 mcg of folic acid. Preferred administration of the combination is two capsules of a tyrosine preparation before a lunch meal, two capsules of a tyrosine preparation at 4 pm, and two capsules of one of the tryptophan formulations 30 minutes before dinner. Another dosing plan includes administration of tyrosine at 10 am and 3 pm and tryptophan at 11 am and 4 pm. Other dosing regimens may also be used.

Example 2

This example illustrates the use of tyrosine as the sole neurotransmitter precursor with xanthine for appetite suppression. A 53 year old male fasted for 10 hours causing hunger. Two capsules of tyrosine preparation are administered, each containing 175 mg of soluble fiber in the form of apple pectin, insoluble fiber in the form of bran fiber, 295 mg of tyrosine, 20 mg of cocoa powder, 100 mg of folic acid and 5 mg of vitamin B6. Soluble and insoluble fibers are premixed, wet and dried. The material was placed in a capsule. The subject experienced an elimination of hunger that started 8 minutes after ingestion and lasted 2.5 hours. A second intake of 2 capsules of the formulation is also effective.

Example 3

This example illustrates the use of tryptophan as a neurotransmitter precursor alone with xanthine for suppressing appetite and carbohydrate cravings. A 44-year-old male fasted for 10 hours, causing hunger. The man then took 2 capsules of tryptophan preparation, each capsule 175 mg of soluble fiber in the form of apple pectin and psyllium, 175 mg of insoluble fiber in the form of bran fiber, 100 mg of non-bean vegetable protein, 45 mg of tryptophan, cocoa 250 mg of powder, 100 mcg of folic acid and 5 mg of vitamin B6 were contained.

The person's hunger began to disappear after 30 minutes and completely disappeared within 60 minutes. Eating this preparation will make you feel full sooner at your next meal. The carbohydrate desire disappeared and lasted 24 hours. Signs of appetite suppression following the ingestion of the preparation were associated with lasting 15 minutes of mental grogginess.

Example 4

This example illustrates the use of tryptophan preparations using pre-digested proteins as tryptophan sources. A 35-year-old woman fasted for 10 hours causing hunger. The woman is then 175 mg of soluble fiber in the form of apple factin and silium, 175 mg of insoluble fiber in the form of bran fiber, 2,00 mg of pre-digested protein in form of pre-digested casein, 250 mg of cocoa powder, 250 mg of sugar, 100 mcg of folic acid And 2 capsules of tryptophan formulation containing 5 mg of vitamin B6. The woman experienced a decrease in appetite and the disappearance of carbohydrate cravings. There was no dizziness caused by this preparation.

Example 5

This example illustrates the use of the tyrosine and tryptophan of the present invention for appetite suppression, reduced carbohydrate desire, and weight loss. A 53-year-old male took 2 capsules of the formulation of Example 2 at 10 am daily, 2 capsules of the formulation of Example 2 at 4 pm, and 2 capsules of the formulation of Example 3 at 5 pm . This curing was continued for 10 days. Both formulations decreased appetite for 2-4 hours after each ingestion for 10 days. Carbohydrate cravings decreased for 24 hours after tryptophan preparations. By day 3, it has been shown to have an improved effect in that the duration of action of the combined administration has been extended. By day 5, there was complete suppression of carbohydrate desire that persisted throughout the 10-day period. At day 1 and day 2 no side effects were observed except for 15 minutes of wobble caused by tryptophan preparations. During the first two days, signs of appetite suppression following the intake of tryptophan preparations are associated with dizziness that lasted for about 15 minutes. By day 3, the staggering effect disappeared. The subject, who initially weighed 159 pounds, lost weight to 150 pounds by day 10.

Example 6

This example illustrates the co-use of tyrosine and tryptophan preparations of the invention in an open label study of five subjects consisting of three men and two women. Each subject took one capsule of tyrosine of Example 2 at 10 am and one capsule of tryptophan of Example 3 at 3:30 pm. All five subjects reported a decrease in hunger after taking either of these. All five patients experienced a decrease in carbohydrate cravings after taking tryptophan capsules.

Example 7

This example illustrates the use of tyrosine and tryptophan preparations in a randomized placebo double blind control experiment in 30 subjects. After all 30 subjects fasted for 10 hours, they completed a survey that judged hunger on five scales and also measured carbohydrate needs on five scales. The subjects then took two capsules of Example 2 or placebo capsules at 10 am and then surveyed at 11 am. The subjects again took the capsule or placebo of Example 2 at 4 pm and the capsule or placebo of Example 3 at 5 pm. They completed the survey at 4pm, 5pm, 6pm, and 10am the next day. Fifteen placebo subjects increased their hunger index from 2.2 to 2.9 after the first dose of tyrosine following intake of placebo (p <0.03). In 15 randomly receiving tyrosine, the Hunger Index dropped from 3.1 to 2.4 (p <0.03). Comparison of the active group to the placebo group shows a significant decrease in the hunger index. The carbohydrate desire index was also significantly reduced by tryptophan administration (p <0.01). In the active group, 85% of subjects had reduced thoughts about hunger or carbohydrate cravings, whereas only 45% of the placebo group experienced a decrease in hunger or carbohydrate cravings (p <0.03).

Examples 8 and 9 below illustrate the preparation and use of histidine and xanthine as the only neurotransmitter precursors.

Example 8

Preparations of histidine and cocoa can be prepared by mixing these two components in powder form in a ratio of 3 parts by weight of histidine and 50 parts by weight of cocoa. The product is then divided into gelatin capsules containing 30 mg of histidine and 500 mg of cocoa, respectively. One capsule of this preparation is best taken when the stomach is empty, at least an hour or two after eating. Alternatively, the mixed powder may be prepared by combining powdered bran, apple pectin and sweeteners in the form of chewable wafers of the same size containing the same dosage.

Example 9

Preparations of histidine and caffeine can be prepared in the same manner as described in Example 8 by mixing histidine and caffeine in a powder form at a ratio of 3 parts by weight of histidine and 10 parts by weight of caffeine. This mixture is then filled into capsules of one dose, each containing 30 mg of histidine and 100 mg of caffeine. This preparation is administered as in Example 8.

Examples 10-15 that follow illustrate the practice of the present invention using a combination of histidine and tyrosine and a combination of histidine and tryptophan as neurotransmitter precursors, with and without application of xanthine.

Example 10

The preparation of tryptophan and histidine can be prepared by mixing the two components in powder form at a ratio of 5 parts of tryptophan and 3 parts of histidine. This product is then divided into gelatin capsules containing 50 mg tryptophan and 30 mg histidine, respectively, and the capsules are administered as in Example 8.

Example 11

A preparation as in Example 10 containing caffeine in addition to tryptophan and histidine can be prepared by mixing 10 parts of caffeine, 5 parts of tryptophan and 3 parts of histidine in powder form. The powder mixture is filled in gelatin capsules so that each gelatin capsule contains 50 mg tryptophan, 30 mg histidine and 10 mg caffeine.

This preparation is administered as in Example 8.

Example 12

The preparation of tyrosine and histidine can be prepared by mixing the two components in powder form at a ratio of 50 parts of tyrosine and 3 parts of histidine. This product is then divided into gelatin capsules so that each capsule contains 500 mg tyrosine and 30 mg histidine and the capsules are administered as in Example 8.

Example 13

A preparation as in Example 12, containing cocoa in addition to tyrosine and histidine, can be prepared by mixing 50 parts of cocoa, 50 parts of tryptophan and 3 parts of histidine in powder form. The gelatin capsules are filled with this powder mixture so that each gelatin capsule contains 500 mg tyrosine, 30 mg histidine and 500 mg cocoa. This preparation is administered as in Example 8.

Example 14

Preparations of tryptophan and histidine in the form of enzyme hydrolyzed proteins can be prepared as follows. Enzymatic hydrolyzed milk protein (casein) in dry powder form containing approximately 18 mg of tryptophan per gram is mixed with histidine in powder form at a ratio of 200 parts of hydrolyzed protein and 3 parts of histidine. This product is then divided into gelatin capsules so that one capsule of 30 mg histidine and 2 gm of hydrolyzed milk protein providing about 32 mg tryptophan is contained in three capsules.

The capsule is administered as in Example 8.

Example 15

A preparation as in Example 14, containing cocoa in addition to hydrolyzed milk protein and histidine, can be prepared by mixing 200 parts of hydrolyzed milk protein and 50 parts of cocoa together with 3 parts of histidine in powder form. Can be.

The gelatin capsules are filled with a powder mixture, such that three capsules contain one dose: 30 mg histidine, 2 gm of hydrolyzed milk protein giving approximately 32 mg of tryptophan, and 500 mg of cocoa. This preparation is administered as in Example 8.

Examples 16 to 18, below, which, when accompanied and without the application of histidine and / or xanthine as additional neurotransmitter precursors, proteolytic enzymes that were not hydrolyzed as a source of tryptophan, the neurotransmitter precursor. Illustrates the practice of the invention for use with.

Example 16

An example illustrates the administration of tryptophan according to the present invention by orally administering to a subject a protein that has not been hydrolyzed and a proteolytic enzyme that will hydrolyze the protein when it enters the gastrointestinal tract to release tryptophan. do.

Specifically, 10 grams of whey powder and approximately 40 mg of papain powder are administered orally to the subject when the stomach is empty. At this high dose, tryptophan in an amount that inhibits appetite was released in the gastrointestinal tract without administration of xanthine. However, the subject experienced a very noticeable stumble that lasted several hours.

Later, the same subject was administered 1-2 grams of whey powder, approximately 40 mg papain powder and 40 mg cocoa when the stomach was empty. This preparation caused appetite suppression in the subject and no stuttering was experienced.

This process provides an easy way to induce appetite suppression without excessive staggering by combining tryptophan and xanthine from natural food sources.

Administering the tryptophan source without xanthine or synergistic neurotransmitter precursors required such high levels of dosage with unacceptable side effects (stumble) to achieve appetite suppression.

Example 17

A preparation of tryptophan and cocoa in the form of a protein that is not hydrolyzed and a proteolytic enzyme that will hydrolyze the protein in the gastrointestinal tract can be prepared as follows. Whey of the dry powder is mixed with papain and cocoa in powder form, with a proportion of 200 parts by weight of hydrolyzed protein, 4 parts by weight of papain and 50 parts by weight of cocoa. The product is then divided into gelatin capsules, each containing 500 mg of cocoa, 2 gm of whey and 40 mg of papain. Hydrolysis of whey in the gastrointestinal tract gives a tryptophan dose of approximately 50 mg. This capsule is administered as in Example 8.

Example 18

Formulations are prepared and administered as in Example 17, with three portions of histidine added thereto, with an additional 30 mg of histidine per capsule dose.

As can be seen, the synergistic combinations of the present invention allow for a reduction in the dose of individual components, and in particular the dose of neurotransmitter precursors, which must be used to achieve the desired effect. Reducing the dose reduces the side effects caused by the large doses so far required to achieve the desired effect. The present invention enables appetite suppression and carbohydrate desire reduction to be achieved at dosages at levels deemed safe by regulatory agencies. Previous attempts to use that particular component separately have required administration of amounts that are ineffective or cause side effects.

For example, reduced dosages of tryptophan allow for a reduction in carbohydrate cravings without causing dizziness and worrying about safety associated with high dosages. Reduced doses of tyrosine allow appetite suppression without the irritability and anxiety caused by amphetamines. Reduced doses of histidine reduce or eliminate the potential side effects of histamine.

The compounds of the present invention enable the use of naturally occurring substances and thereby enhance regulatory approvals and market acceptance.

Although the above description contains many limitations, it should not be construed as limiting the scope of the invention, but should be considered as merely providing illustrations of some of the presently preferred embodiments of the invention. Various other embodiments and branches will be possible within the scope.

Missing industrial availability

Claims (73)

Animal additionally comprising administering to the subject an amount of tryptophan effective to enhance the synthesis of serotonin in the brain at less than 100 mg of a single dose and an amount of xanthine effective to enhance the neuronal release of serotonin in the brain. How to suppress appetite in a subject. The method of claim 1 wherein the xanthine comprises caffeine. 3. The method of claim 2, wherein caffeine is administered in a single dose between 1 and 200 mg. The method of claim 1 wherein the xanthine comprises theobromine. 5. The method of claim 4, wherein theobromine is administered at a dosage between 1 and 2,000 mg. The method of claim 1 wherein the xanthine is in cocoa form. 7. The method of claim 6, wherein the cocoa is administered at a dosage between 1 and 2,000 mg. The method of claim 1, wherein the tryptophan is administered in the form of an enzyme hydrolyzed protein. The method of claim 8, comprising incidentally administering to the subject a single dose of carbohydrate sufficient to stimulate insulin production in the subject. To the subject, the precursors of dopamine and norepinephrine selected from phenylalanine and tyrosine are in an amount effective to enhance the synthesis of dopamine and norepinephrine in the brain, and xanthine is effective in increasing the neuronal release of dopamine and epinephrine in the brain. A method of inhibiting appetite in an animal subject, which additionally comprises administering. The method of claim 10, comprising administering tryptophan according to claim 1 at intervals of 20 to 24 hours from administration of the dopamine and norepinephrine precursors. The method of claim 10, wherein the dopamine and norepinephrine precursor are administered in a single dose of 10 to 700 mg. 13. The method of claim 12, wherein the dopamine and norepinephrine precursors are administered in a single dose of less than 600 mg. The method of claim 10 wherein the xanthine comprises caffeine. 15. The method of claim 14, wherein caffeine is administered in a single dose of 1 to 200 mg. The method of claim 10 wherein the xanthine comprises theobromine. The method of claim 16, wherein theobromine is administered in a single dose of 1 to 2,000 mg. The method of claim 10, wherein the xanthine is in the form of cocoa. 19. The method of claim 18, wherein the cocoa is administered at a dosage between 1 mg and 20 grams. Inhibiting appetite in an animal subject, concomitantly administering to the subject an amount of histidine effective to enhance the synthesis of histamine in the brain and an amount of xanthine effective to increase the neuronal release of histamine in the brain How to. The method of claim 20, wherein the histidine dose administered is between 1 and 500 mg. The method of claim 20 wherein the xanthine comprises caffeine. 23. The composition of claim 22, wherein the caffeine is administered in a single dose between 1 and 200 mg. The method of claim 20, wherein the xanthine comprises theobromine. The method of claim 24, wherein theobromine is administered in a single dose between 1 and 2,000 mg. 21. The composition of claim 20, wherein the xanthine is in cocoa form. 27. The method of claim 26, wherein the cocoa is administered in a single dose between 1 mg and 20 g. To the subject, the histamine precursor histidine, in an amount effective to enhance histamine synthesis in the brain, and a second neurotransmitter precursor selected from tryptophan, phenylalanine, and tyrosine, were prepared from the neurotransmitter synthesized from the second precursor. A method of inhibiting appetite in an animal subject, comprising administering in an amount effective to enhance synthesis in the brain. 29. The method of claim 28, wherein the histidine dose administered is between 1 and 500 mg. The method of claim 28, wherein the second precursor administered comprises tyrosine at a dosage of 1 to 600 mg. The method of claim 28, wherein the second precursor administered comprises tryptophan at a dosage of 1 to 100 mg. The method of claim 28, wherein the second precursor is tryptophan and the tryptophan is administered in the form of an enzyme hydrolyzed protein. 33. The method of claim 32 comprising administering to the subject a dose of carbohydrate sufficient to stimulate insulin production in the subject. 29. The method of claim 28, further comprising administering to the subject an amount of xanthine effective to increase cerebral neuronal release of the neurotransmitter and histamine synthesized from the second precursor. 35. The method of claim 34, wherein the xanthine comprises caffeine administered at a dosage of 1 to 200 mg. 35. The method of claim 34, wherein the xanthine comprises theobromine administered at a dosage of 1 to 2,000 mg. 35. The method of claim 34, wherein the xanthine is in cocoa form administered at a dosage of 1 mg to 20 grams. In enzymatic hydrolysis of the protein, an amount of protein containing sufficient tryptophan effective to enhance serotonin synthesis in the brain, a protease that hydrolyzes the protein to release tryptophan in the gastrointestinal tract, and serotonin in the brain A method of inhibiting appetite in an animal subject, comprising incidentally administering to the animal subject an amount of xanthine effective to enhance neuronal release of the subject. The method of claim 38, wherein the xanthine comprises theobromine administered at a dosage of 1 to 2,000 mg. 39. The method of claim 38, wherein the xanthine is in cocoa form. In enzymatic hydrolysis of proteins, an amount of protein containing sufficient tryptophan effective to enhance serotonin synthesis in the brain, proteolytic enzymes that hydrolyze the protein to release tryptophan in the gastrointestinal tract, and histamine synthesis in the brain A method of inhibiting appetite in an animal subject, comprising incidentally administering to the animal subject histidine, an amount of histamine precursor that is effective to enhance. 42. The method of claim 41 comprising administering to the subject an amount of xanthine effective to increase neuronal release of serotonin and histamine in the brain. A composition for inhibiting appetite in an animal subject, comprising, in a unit dosage form, an amount of tryptophan in an amount of 1 mg to 100 mg / dose and an amount of xanthine effective to enhance neuronal release of serotonin in the subject's brain. 44. The composition of claim 43, wherein the xanthine comprises theobromine in an amount of 1 to 2,000 mg / dose. 44. The composition of claim 43, wherein the xanthine comprises caffeine in an amount of 1 to 200 mg / dose. 44. The composition of claim 43, wherein the xanthine is in cocoa form. 44. The composition of claim 43, wherein the tryptophan is present in the composition in the form of an enzyme hydrolyzed protein. 48. The composition of claim 47, wherein the composition further comprises a dose of carbohydrate sufficient to stimulate insulin production in the subject. In a unit dosage form, comprising an amount of dopamine and norepinephrine precursor effective to enhance the synthesis of dopamine and norepinephrine in the brain, and an amount of xanthine effective to increase nerve release of dopamine and epinephrine in the brain, A composition for suppressing appetite in an animal subject. 50. The composition of claim 49, wherein the xanthine comprises theobromine in an amount of 1 to 2,000 mg / dose. 50. The composition of claim 49, wherein the xanthine comprises caffeine in an amount of 1 to 200 mg / dose. 50. The composition of claim 49, wherein the xanthine is in cocoa form in an amount of 1 to 2,000 mg / dose. 50. The composition of claim 49, wherein the precursor is tyrosine in an amount of 1 to 600 mg / dose. 54. The composition of claim 53, wherein the dose of tyrosine is less than 500 mg. A composition for inhibiting appetite in an animal subject, comprising, in a unit dosage form, an amount of histamine effective to enhance histamine synthesis in the brain and an amount of xanthine effective to increase neuronal release of histamine in the brain. 56. The composition of claim 55, wherein the xanthine comprises theobromine in an amount of 1 to 2,000 mg / dose. The composition of claim 55 wherein the xanthine comprises caffeine in an amount of 1 to 200 mg / dose. The composition of claim 55, wherein the xanthine is in cocoa form in an amount of 1 to 20 g / dose. 56. The composition of claim 55, wherein the amount of histidine per dose is 1 to 600 mg / administration. Within the unit dosage form, the histamine precursor histidine in an amount effective to enhance the synthesis of histamine in the brain and a second neurotransmitter precursor selected from tryptophan, phenylalanine, and tyrosine, the neuron synthesized from the second precursor A composition for inhibiting appetite in an animal subject, the composition comprising an amount effective to enhance intracellular brain synthesis of the delivery agent. 61. The composition of claim 60, wherein the amount of histidine per dose is 1 to 600 mg. 61. The composition of claim 60, wherein the second precursor administered comprises tyrosine in an amount of 1 to 200 mg / dose. 61. The composition of claim 60, wherein the second precursor administered comprises tryptophan in an amount of 1 to 100 mg / dose. 61. The composition of claim 60, wherein the second precursor is tryptophan in the form of an enzyme hydrolyzed protein. 65. The composition of claim 64, further comprising a dosage of carbohydrates sufficient to stimulate insulin production in the subject. 61. The composition of claim 60, wherein the composition further comprises an amount of xanthine effective to increase neurotransmitter synthesized from the second precursor and neuronal release of histamine in the brain. 67. The composition of claim 66, wherein xanthine comprises theobromine in an amount of 1 to 2,000 mg / dose. Claim 68 missing In a unit dry dosage form, an amount of powdered protein comprising sufficient tryptophan effective to enhance internal brain serotonin synthesis upon enzymatic hydrolysis, an amount of protease that hydrolyzes the protein in the gastrointestinal tract to release tryptophan, And xanthine in an amount effective to enhance neuronal release of serotonin in the brain. 70. The composition of claim 69, wherein the protein is in an amount of between about 0.5 grams and 30 grams per unit dose and the enzyme is in an amount between 30 and 50 mg per gram of protein. 71. The composition of claim 70, wherein the enzyme is papain. In a dry unit form, an amount of powdered protein comprising sufficient tryptophan effective to enhance serotonin synthesis in the brain upon enzymatic hydrolysis, an amount of protease that hydrolyzes the protein in the gastrointestinal tract to release tryptophan, and the brain A composition for inhibiting appetite in an animal subject, comprising histidine, an amount of histamine precursor effective to enhance histamine synthesis in the body. 75. The composition of claim 72, further comprising an amount of xanthine effective to increase neuronal release in the brain of histamine and serotonin.