HK1084025B - Sexual desire and performance enhancement with meal from plants containing protein-bound tryptophan - Google Patents

Description

Enhancing sexual desire and performance with meal from plants containing protein-bound tryptophan

Technical Field

The present invention relates to compositions comprising tryptophan from natural sources, in particular protein-bound tryptophan from plants; a process for preparing the composition; physical formulations of said compositions (physical formulations); and the use of said compositions for enhancing sexual desire and performance in mammals.

Background

Tryptophan is an essential amino acid found in a variety of naturally occurring plant proteins and has a variety of interesting medicinal values, including for the treatment of insomnia and adjunctive treatment of various psychiatric disorders. After absorption, tryptophan circulates in the blood with approximately 80% bound to plasma albumin and the remaining 20% circulating as free tryptophan and, where appropriate, tryptophan is transported to the brain. Once across the Blood Brain Barrier (BBB), tryptophan is metabolized to 5-hydroxytryptamine, a neurotransmitter that is involved in mood and sleep regulation (Boman, 1988). 5-hydroxytryptamine, in turn, is metabolized to melatonin, a sleep-related hormone found in the pineal body, a small globular-like structure in the upper thalamus of the brain responsible for regulating the circadian rhythm of a person over 24 hours. Ingestion of sufficient amounts of tryptophan per se consistently reduces sleep latency, i.e., the time from "lights out" to falling asleep, and improves the overall quality of sleep by improving sleep architecture (Boman, 1988). The metabolism of tryptophan to 5-hydroxytryptamine is also very helpful in some cases where there is depletion of 5-hydroxytryptamine levels, such as anxiety, depression, obsessive compulsive disorder, some painful conditions, aggressive behavior, and eating disorders.

The hypnotic effect of tryptophan was studied extensively, following a fairly flat dose-response curve, with a plateau at approximately 1000 mg (reviewed in Schneider-Helmut and Spinweber, 1986). If used alone, only 250 mg of tryptophan is sufficient to improve sleep in mildly insomniac or those with sleep latency longer than average (Hartmann and Spinweber, 1976; Hartmann 1982). A dose of 1000 mg gives more consistent results (Schneider-Helmut and Spinweber, 1986), but the additional benefit of higher doses (2,000-12,000 mg) is very limited, and in fact, the highest dose (12,000 mg) is accompanied by a disorganization of sleep, although sleep latency can be reduced (Griffiths et al, 1972).

PCT application WO01/89319 to Hudson, Susan p. and Hudson, Craig J, published 11/29 2001, discusses the aforementioned conditions. The aforementioned WO01/89319 discloses a composition comprising an at least partially defatted meal of a plant material, preferably pumpkin seeds (squash seeds), containing protein-bound tryptophan, and optionally a carbohydrate source, in an amount sufficient to facilitate transport of the tryptophan produced in vivo across the blood-brain barrier. Dietary supplements, foods and beverages comprising the composition are also disclosed for inducing sleep, for anxiety, depression, obsessive compulsive disorder, aggression, chronic pain and eating disorders, or for providing tryptophan supplementation to an individual in need thereof.

It is generally believed that drugs that increase 5-hydroxytryptamine levels in the brain reduce libido and reduce overall sexual performance (Bradford 2001). Drugs associated with decreased libido include antidepressants, particularly those belonging to the class of selective 5-hydroxytryptamine reuptake inhibitors (SSRIs), as well as the 5-hydroxytryptamine precursor, tryptophan (Young 1986).

The sexual desire/function is enhanced by ingestion of large doses of tryptophan, i.e. more than 6 grams per day, which has been rarely reported in the past.

In addition, it has been previously reported that essentially all persons who claim enhanced sexual desire or performance when using tryptophan are taking other drugs at the same time. There has been no report of the enhancement of sexual desire or performance by the use of relatively low doses of tryptophan alone as a single agent.

Furthermore, at least no report has been made on the role of tryptophan-binding proteins in enhancing sexual desire or performance.

Disclosure of Invention

We have surprisingly found that the at least partially defatted flour composition described in WO01189319, supra, enhances the sexual desire and performance of mammals.

We have surprisingly found that human subjects who ingest a high protein food composition enriched for protein-bound tryptophan reported enhanced sexual desire and performance in a selected sleep study. Studies that achieve these results may provide much lower amounts of tryptophan per se (< 250 mg) calculated as tryptophan-bound protein ingested relative to the amounts of the prior art described above (> 6 g/day).

It is therefore an object of the present invention to provide a plant material for tryptophan for use in enhancing sexual desire and performance in mammals.

Accordingly, in one aspect, the present invention provides a composition for enhancing sexual desire and performance in a mammal comprising a meal derived from a plant source containing protein-bound tryptophan, and a physiologically acceptable diluent or carrier therefor.

More preferably, the meal is at least partially defatted.

It has now been found that tryptophan-rich compositions derived naturally by concentrating the protein-bound tryptophan component of a tryptophan-rich protein source according to WO01/89319 enhance sexual desire and performance in mammals. The compositions used in the present invention comprise plant material which naturally contains protein-bound tryptophan, preferably pumpkin seeds (squash seed), such as Butternut squash seeds, Peppercorn squash seeds and pumpkin seeds. Preferably, the plant material is at least partially defatted to concentrate the content of protein-bound tryptophan. Preferably, the composition further comprises a carbohydrate source, such as glucose, in an amount sufficient to enhance uptake of tryptophan across the blood brain barrier and to overcome competition for BBB transport sites into the Central Nervous System (CNS). The composition may further optionally comprise physiologically acceptable carriers, flavouring agents, colours and other nutritional agents, for example vitamins, preferably vitamin B3 and/or vitamin B6.

In a preferred embodiment, the composition comprises at least partially defatted squash seeds (in particular Butternut squash seeds, pumpkin seeds and pepercorn squash seeds), glucose and vitamins B3 and B6.

The invention further relates to dietary additives, for example in the form of tablets, powders, suspensions, liquids, capsules or gels; food products such as dietary bars, biscuits, baked goods; snacks, candies, candy bars, beverages and similar food products comprising the compositions of the present invention.

The aforementioned WO01/89319 discloses the use of second derivative spectroscopy of specific plant materials, and in particular plant seeds containing relatively high levels of protein-bound tryptophan, and discloses that these materials can be used to provide tryptophan in vivo. A method is provided for producing edible compositions having high levels of protein-bound tryptophan as a natural protein source of tryptophan in higher amounts than known natural sources. Plants using arundoin generally contain high levels of tryptophan and can be used as the plant material of the present invention. It is desirable, but not necessary, that the starting plant material contains at least 200 mg/100 g or at least 0.2% protein-bound tryptophan. Tryptophan concentration can be determined by known methods including, for example, High Pressure Liquid Chromatography (HPLC), second derivative spectroscopy, or any other known method. Second derivative spectroscopy is the preferred method for quantitative analysis of tryptophan levels because it eliminates background adsorption.

According to one embodiment of the present invention, a series of steps may be employed to remove oil from the plant material to partially degrease the material and increase the level of protein-bound tryptophan in the plant material. The plant material may be a seed, such as, but not limited to, Butternut squash seed, pepercorn squash seed, pumpkin seed, lentil seed, sunflower seed, linseed, watermelon seed, garlic mustard seed, cottonseed, sesame seed, Canola seed, evening primrose seed, safflower seed, alfalfa (alfalfalfalfalfa) seed, barley, soybean, and combinations thereof. Preferably, the seed is a Butternut squash seed, since Butternut squash seed is believed to contain the highest ratio of tryptophan to total protein compared to other seeds. The plant material may also be a vegetative part of a plant (e.g. alfalfa, seaweed or kelp). While it is preferred to defat the plant material to increase the level of protein-bound tryptophan, defatting is not essential to the practice of the invention.

The aforementioned WO01/89319 discloses a method for producing a concentrated, natural source of tryptophan comprising identifying a naturally occurring protein-bound source of tryptophan in a plant material; compressing the plant material under conditions sufficient to release the oil contained therein; and at least partially removing the oil contained therein to produce a partially defatted plant material having a higher tryptophan source than the starting material.

For seeds, it is not necessary to remove the skin or hull of their seeds to expose the seeds prior to processing. In one embodiment, the seeds are preferably first passed through a series of smoothing rollers to produce a sheet, a process known as sheeting. This step at least partially disrupts the oil cells and increases the surface area of the seed for further treatment.

The flaked seeds are then heat treated, a process known as cooking or conditioning, to further rupture the oil cells and increase the viscosity of the oil for subsequent defatting. The conditioning step may be carried out by, for example, a microwave oven, an oven or indirect steam. The temperature of the conditioning step should be sufficient to rupture the cells of the oil and increase the viscosity of the oil, but not to cause deleterious damage to the proteins contained in the plant material. Preferably, the temperature is from about 40 ℃ to about 50 ℃. The conditioning step is performed for a time sufficient to reach the target temperature.

Prior to cooling, the heated seed flakes are mechanically pressed to at least partially remove the oil contained therein. Any known mechanical Press or presser may be used, for example a Gusta Lab Press: the default of default depends in part on the flash and viewing relating, temperature and oil vision and the pressure experienced in the described. Generally, it is preferred to remove from about 2/3 to about 3/4 of grease.

The further processing of the pressed plant material depends on the end user. For example, the plant material may be ground using any conventional means, such as, but not limited to, a disc mill, hammer mill, or pin mill. The mill selected will depend in part on the desired product density, for example, a pin mill will produce a product having a flour-like density, while a disc mill or hammer mill will produce a product having a particle density.

The above method produces a natural source of protein-bound tryptophan having a higher tryptophan content than the original plant source. Preferably, the material should provide at least 0.2% by weight tryptophan. The resulting, at least partially defatted seed flour can then be incorporated into compositions for enhancing sexual desire and performance.

In addition to the partially defatted flour, the composition used in the present invention preferably also comprises a carbohydrate source having a high glycemic index (glycemic index), preferably glucose, although sucrose and other sugars degradable to glucose may also be used. Without being bound by theory, it is believed that the carbohydrate source may facilitate uptake of tryptophan per se across the blood brain barrier, which may then be metabolized to 5-hydroxytryptamine. Humans have a barrier that functionally shields the brain from the environment elsewhere in the body in order to protect the sensitive CNS. This barrier is formed by countless tight junctions between brain endothelial cells at the blood-brain interface that act to limit the diffusion of substances into the brain (Saunders et al, 1991). The multiple diffusion resulting from tight junctions is a cascade of transport mechanisms into and out of the brain that regulate the internal environment of the brain, with a large number of molecules involved including dielectrics, glucose, vitamins and amino acids. Other Large Neutral Amino Acids (LNAA) also use the tryptophan transport mechanism (Lajtha, 1974; Betz and Goldstein, 1978). It is believed that competition for these transport sites results in a diet containing high amounts of high protein, despite the presence of sufficient tryptophan (Moller, 1983), which does not induce a hypnotic effect. In contrast, in the same study, a high carbohydrate diet with relatively small amounts of tryptophan lacked induction of a modest hypnotic effect. The explanation for this apparent conflict is that, at relatively high serum insulin levels, competitive LNAA shunts to liver and muscle tissue (Fernstrom and Wurtman, 1971). Tryptophan is not shunted in this way, and therefore any free tryptophan gains a competitive advantage over insulin induction through the transport sites of the BBB.

The amount of carbohydrate source is preferably sufficient to induce an increase in blood insulin levels in an individual ingesting the composition. The tryptophan/LNAA ratio increased with increasing insulin levels, increasing from 15 to 60 micro units/ml causing an increase in the tryptophan/LNAA ratio of about 35%. This increase in level is sufficient, however, a less pronounced increase is also beneficial. Preferably, the amount of glucose in the composition is from about 25 grams to about 150 grams, most preferably 75 grams. The amount of tryptophan will remain the same, but an increase in carbohydrate will result in an increase in tryptophan/LNAA ratio. Other carbohydrate feedstocks may include maltose, sucrose, etc., but are preferably not fructose because of its low glycemic index. For obese individuals or individuals with type 2 diabetes, higher amounts of carbohydrate, such as 100 grams, may be required due to the abnormal glucose insulin response.

Since tryptophan is 80% bound to proteins in the blood in vivo, only a small amount of free tryptophan actually competes with other LNAAs for entry into the brain. Thus, in general, ingested plant protein-bound tryptophan is rapidly metabolized and stored in the "albumin pool" unless an supraphysiological amount is ingested, which has little effect on the bioavailability of CNS tryptophan. However, if tryptophan is available at elevated insulin levels, free fatty acids compete for the "albumin pool" and convert existing protein-bound tryptophan to free tryptophan, while preventing the incorporation of newly ingested tryptophan. Thus, when the serum levels of competing LNAA are reduced, free tryptophan is elevated by two different sources of tryptophan, the existing protein-bound tryptophan and the newly ingested tryptophan. In view of this, it would be desirable to provide a product containing at least some residual oil content so as to retain a portion of the fatty acids in the plant material or seed. For pumpkin seeds (squash seed), it is desirable to retain about 20% residual oil in the seed meal. For other seeds, it may be necessary to add further fatty acids to the partially defatted product in order to provide the best fatty acid balance. To this end, Hydrogenated oils (Hydrogenated oils) or other oils may be added, such as Canola oil, sunflower oil, safflower oil, palm kernel oil, corn oil or milk powder.

In a preferred embodiment, the composition for use in the present invention comprises: at least partially defatted squash seeds, particularly Butternut squash seeds, pumpkin seeds, Peppercorn seeds and combinations thereof; glucose in an amount sufficient to facilitate uptake of tryptophan from pumpkin seeds (squash seed) across the blood brain barrier in an individual ingesting the composition; and vitamins B3 and B6 in amounts that promote tryptophan uptake.

In another embodiment, the composition comprises at least partially defatted Butternut squash seed meal, for example, from about 50 grams to about 100 grams, in an amount sufficient to provide from about 250 milligrams to about 1000 milligrams of tryptophan, and from about 25 grams to about 200 grams of glucose. A more preferred composition comprises from about 25 grams to about 50 grams of defatted Butternut squash seed meal which has been reduced in oil content by 75% after pressing and comprises from about 75 grams to about 100 grams of glucose. Optionally, the composition comprises vitamin B3 and/or vitamin B6. Vitamin B3 in an amount from about 5 mg to about 50 mg; and vitamin B6 in an amount of about 0.5 mg to about 50 mg, preferably 50 mg of each of vitamins B3 and B6.

The compositions and dietary supplements of the invention are useful for daily oral administration. The composition is formulated to be administered preferably in a single dose before bedtime daily. Alternatively, the composition may be formulated in multiple portions to increase or decrease the frequency of administration as desired. A given dose may be divided into two, three or more tablets or capsules, and so forth, in order to make it of a size that is easy to swallow, or to enhance its bioabsorption or utilization before falling asleep or whenever desired. The daily dose may be administered in one tablet, in two tablets together. As noted above, the recommended amounts of the various ingredients can serve as a guide for formulating the additives of the present invention. The actual dosage of each component per unit dose depends on the number of units administered to the individual in need thereof. This relates to product design and is well known to dietary supplement formulators.

The compositions for use in the present invention may be formulated using any pharmaceutically acceptable form of vitamins, minerals, and other nutritional ingredients described above and salts thereof. The compositions may be formulated as capsules, tablets, powders, suspensions, gels or liquids, optionally containing physiologically acceptable carriers such as, but not limited to, water, milk, juice, starch, vegetable oils, salt solutions, hydroxymethylcellulose, carbohydrates. The compositions may be formulated as a powder, for example for mixing with a consumable liquid such as milk, juice, water, or a consumable gel or syrup for mixing into a dietary liquid or food product. The composition used in the present invention may be mixed with other food products or liquids to provide a predetermined amount of added food product, for example as a bar.

The composition can be made into various forms, such as baked goods such as biscuit, brownie, fudge, cake, bread, biscuit, cracker, pudding, confection, i.e., candy, snack food such as cracker, potato chip, diet drink, ice cream, frozen confection, and some fresh goods, or non-baked extruded products such as bar. A preferred form is a non-baked extruded nutritional bar.

The composition may also contain other ingredients such as one or more other vitamins, minerals, antioxidants, fiber and dietary supplements or combinations thereof. The selection of one or more of these ingredients is related to formulation design, consumer and end-user preferences. The amounts of these ingredients added to the compositions for use in the present invention are readily known to those skilled in the art and guidance in this regard may be had with reference to U.S. adult RDA dosages. Vitamins and minerals that may be added include, but are not limited to, calcium phosphate or acetate, trivalent; potassium phosphate, divalent; magnesium sulfate or magnesium oxide; salt (sodium chloride); potassium chloride or potassium acetate; ascorbic acid; ferric orthophosphate; nicotinamide; zinc sulfate or zinc oxide; calcium pantothenate; copper gluconate; riboflavin; beta-carotene; pyridoxine hydrochloride; thiamine nitrate; folic acid; biotin; chromium chloride or chromium pyridine; potassium iodide; sodium selenate; sodium molybdate; vitamin K1; vitamin D3; vitamin B12; sodium selenite; copper sulfate; a vitamin A; a vitamin E; vitamin B6 and its hydrochloride; vitamin C; inositol; vitamin B12; and (3) potassium iodide.

Flavors, colors, spices, nuts, and the like may also be incorporated into the product. The flavoring agent may be in the form of a perfume, volatile oil, chocolate flavoring, peanut butter flavoring, cookie crumbs, crisp rice, vanilla or any commercially available flavoring agent. Examples of suitable flavoring agents include, but are not limited to, pure anise essence, artificial banana essence, artificial cherry essence, chocolate essence, pure lemon juice, pure orange juice, pure peppermint essence, artificial pineapple essence, artificial rum, artificial strawberry essence, or pure vanilla essence; or a volatile oil such as sesame oil, bay oil, bergamot oil, cedarwood oil, cherry oil, walnut oil, cinnamon oil, clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla cookie crumbs, butterscotch or toffee. In a preferred embodiment, the dietary supplement comprises non-caffeinated cocoa powder or chocolate, or chocolate substitutes such as carob beans. The food composition may also be coated, for example with yoghurt.

Emulsifiers may be added to stabilize the final product. Suitable emulsifiers include, but are not limited to, lecithin (e.g., from egg or soy), and/or mono-and diglycerides. Other emulsifiers will be apparent to those skilled in the art, and the selection of a suitable emulsifier will depend in part on the formulation and end product.

Preservatives can be added to the composition to extend the shelf life of the product. Preferably, preservatives such as potassium sorbate, sodium sorbate, potassium benzoate, sodium benzoate or calcium disodium edetate are used.

In addition to the carbohydrates described above, the compositions may contain artificial sweeteners such as sugars, cyclohexyl sulfamate, aspartame, acesulfame K, and/or sorbitol. Such artificial sweeteners would need to be added if the dietary supplement is intended for use in overweight or obese individuals, or in individuals with type 2 diabetes who are prone to hypoglycemia.

To produce such food bars, the liquid ingredients are cooked; mixing the dry ingredients with the liquid ingredients in a mixer until a dough is formed; placing the dough into an extruder for extrusion; cutting the extruded dough into suitable lengths; and the product is cooled. To produce other food or beverages, the ingredients comprising the composition used in the present invention may be added to conventional formulations, or may replace conventional ingredients. Those skilled in the art of food formulation will be able to design suitable foods/beverages to suit the objectives of the present invention.

Tryptophan additives were noted to have potential adverse reactions. Tryptophan at low doses rarely causes adverse effects, but has been reported to cause problems at high doses or in combination with certain antidepressants. Tryptophan is at risk for causing delirium and neurological dysfunction when used in combination with monoamine oxidase inhibitors (MAOI) (Thomas and Rubin, 1984). At higher doses (more than 12 grams per day), the most common complaints are daytime sedation and nausea (Hartmann, 1977). There are a few theoretical risks that have been demonstrated in animal models and not proven in humans alone. Large doses of 1-tryptophan cause lipogenesis in animals (Fears and Murrell, 1980), but this effect is not observed in humans (Sources, 1983). Similarly, there is theoretically a risk that Xanthurenic acid (Xanthurenic acid), a tryptophan metabolite, may cause diabetes (Kotake and Murakami, 1971). It is therefore an object of the present invention to limit the amount of protein-bound tryptophan administered to an individual daily to a level below about 12 grams of tryptophan a.i. per day to avoid these potential adverse effects. In another aspect, the present invention provides a method of manufacturing a pharmaceutical composition for enhancing sexual desire and performance in humans, said method comprising admixing a composition as defined above and one of its physiologically acceptable carriers.

In another aspect, the present invention provides a method of enhancing sexual desire and performance in a mammal by administering an effective amount of the above composition.

Detailed description of the preferred embodiments

Examples

The aforementioned WO01/89319 describes a process for obtaining a composition for use in the present invention.

The food bar (50 g) used in the present invention was prepared according to the conventional method described in the aforementioned WO01/89319, and had the composition:

26.3 g defatted pumpkin seeds (squash seed)

17.2 grams glucose ("glucose 43")

5.0 g Caramel (Carame) (New World flavors)

1.5 g dried apple slices

20.0 mg vitamin B3

20.0 mg vitamin B6

Case report

Three subjects spontaneously reported increased libido/sexual performance without direct inquiry by the investigator for changes in libido.

Each subject ingested their food bar approximately 1 hour prior to going to bed rest in the evening. Two subjects reported increased libido, manifested as persistent libido, while the other reported increased libido with improved quality of sexual life.

While preferred embodiments of the present invention have been described and illustrated herein, it should be understood that the invention is not limited to those particular embodiments. The invention includes all embodiments which are functionally equivalent to the specific embodiments and features described and illustrated herein.

Claims (13)

1. Use of a meal from a plant source containing protein-bound tryptophan, wherein the meal is at least partially defatted and has a higher tryptophan source than the plant source, for the preparation of a composition for enhancing sexual desire and performance in a mammal, wherein the plant source is selected from the group consisting of walnut pumpkin seeds, pepper pumpkin seeds, lentil seeds, sunflower seeds, linseed, watermelon seeds, garlic mustard seeds, cottonseed, sesame seeds, rapeseed, evening primrose seeds, safflower seeds, alfalfa seeds, barley, soybean, and combinations thereof.

2. Use according to claim 1, wherein the plant material is selected from walnut pumpkin seeds, pepper pumpkin seeds or pumpkin seeds.

3. The use of claim 1, wherein the composition further comprises a carbohydrate source having a high glycemic index.

4. The use of claim 3, wherein the carbohydrate source is selected from the group consisting of glucose, maltose, sucrose, and combinations thereof.

5. The use of claim 1 or 2, wherein the composition further comprises a vitamin selected from the group consisting of vitamin B3, B6, and combinations thereof, in an amount sufficient to increase uptake of tryptophan across the blood-brain barrier.

6. Use according to claim 1 or 2, wherein the composition is in the form of a tablet, powder, suspension, liquid, capsule or gel.

7. Use according to claim 1 or 2, wherein the composition is in the form of a dietary supplement.

8. Use according to claim 7, wherein the dietary supplement is in the form of a bar.

9. Use according to claim 1 or 2, wherein the composition comprises at least partially defatted walnut pumpkin seed meal comprising protein-bound tryptophan in an amount of from 25 mg to 1000 mg, from 25 mg to 200 mg of glucose and a physiologically acceptable diluent or carrier therefor.

10. Use according to claim 3, wherein the composition comprises at least partially defatted walnut pumpkin seed meal comprising protein-bound tryptophan in an amount of from 25 mg to 1000 mg, from 25 mg to 200 mg of glucose and a physiologically acceptable diluent or carrier therefor.

11. Use according to claim 1 or 2, wherein the composition comprises at least partially defatted walnut pumpkin seed meal providing 25 mg to 50 mg tryptophan, 75 mg to 100 mg glucose and a physiologically acceptable diluent or carrier.

12. Use according to claim 3, wherein the composition comprises at least partially defatted walnut pumpkin seed meal providing from 25 mg to 50 mg tryptophan, from 75 mg to 100 mg glucose and a physiologically acceptable diluent or carrier.

13. The use of claim 1 or 2, wherein the composition further comprises from 5 mg to 50 mg vitamin B3, from 0.5 mg to 50 mg vitamin B6, and combinations thereof.