AAntihistamines In Combination With A Range Of Substances For Improved Health

Abstract

The present invention provides for novel combinations comprising an antihistamine with selected pharmaceutical and nutraceutical agents which alleviate some of the symptoms experienced by menopausal women, optionally combined further with a range of indole-based natural products such as L-tryptophan, 5-hydroxytryptophan and melatonin. These mixtures may be enriched further with pharmaceutically acceptable calcium and magnesium salts as well as selected B vitamins. These combinations have utility in providing a medicament for improving health in mammals, especially for the improvement of menopausal symptoms as well as sleep in women.

Claims

1-9. (canceled)

10. A pharmaceutical composition for the treatment of sleep disorders and inducing restorative sleep function comprising a mixture of an antihistamine drug and at least two indole-based dietary supplements.

11. A composition according to claim 10 comprising: doxylamine or its pharmaceutically acceptable salts; L-tryptophan and melatonin or their pharmaceutically acceptable salts; a pharmaceutically acceptable calcium salt; a pharmaceutically acceptable magnesium salt; vitamin B.sub.3 or its pharmaceutically acceptable salts; and a pharmaceutically acceptable carrier.

12. A composition according to claim 11 wherein the doxylamine is present in its substantially pure single enantiomer form, or a pharmaceutically acceptable salt thereof.

13. The composition in claim 11 further including vitamin B6 or its pharmaceutically acceptable salts.

14. The composition in claim 13 further including amino acids from a group consisting of theanine, GABA, and combinations thereof.

15. The composition in claim 13 further including substances that ameliorate symptoms of the menopause.

16. A composition according to claim 11 wherein the melatonin is provided in a slow-release formulation.

17. A method of treating a sleep disorder comprising administering a sleep-inducing amount of a composition comprising an antihistamine drug, at least one dietary supplement and substance(s) that have effect in the treatment of a range of symptoms related to the menopause.

18. The method of claim 1 wherein the composition is in a form from a group consisting of a tablet, a fast dissolving tablet, capsule and beverage.

19. A pharmaceutical composition for the treatment of sleep disorders and the induction of restorative sleep function comprising: A. At least one indole-based dietary supplement, and B. At least one substance with beneficial effect in the treatment of menopausal symptoms.

20. A method of claim 1 wherein the sleep disorder is from a group consisting of occasional sleeplessness, acute insomnia, chronic insomnia, transient/temporary insomnia, inducing restorative sleep function, sleep-related breathing disorders, obstructive sleep apnea, non-restorative sleep, insomnia associated with jet lag disorder, sleep difficulties related to circadian rhythm steep disorders, sleep problems relating to shift work disorder, subjects experiencing difficulty falling asleep, subjects experiencing difficulty maintaining sleep, and combinations thereof.

21. A pharmaceutical composition for the treatment of sleep disorders and the induction of restorative sleep function comprising: A. At least one antihistamine, and B. At least one substance with beneficial effect in the treatment of menopausal symptoms.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0052] The present invention is directed to novel combinations of sedating antihistamines and certain indole-based dietary supplements, with substances that alleviate the symptoms experienced by menopausal women and to their use for improving the health of human subjects, including the treatment of insomnia and other sleep-related problems such as issues with circadian rhythm and Jet Lag Disorder (JLD). A further embodiment of the invention is for specific combinations of a pharmacologically active and bioavailable antihistamine (H.sub.1 receptor antagonist), a melatonin component and a tryptophan component.

[0053] A further embodiment of the invention is for specific combinations of a pharmacologically active and bioavailable antihistamine (H.sub.1 receptor antagonist), with substances that alleviate the symptoms experienced by menopausal women, optionally with a melatonin component and a tryptophan component, optionally combined with one or more vitamins such as B.sub.3 and B.sub.6, and one or more minerals such as calcium and magnesium. These compositions, and methods of use thereof, are useful for to provide a more effective formulation for sleep improvement, thereby alleviating the symptoms experienced by menopausal women and more directly inducing restorative sleep and its benefits.

[0054] Various documents including, for example, publications and patents, are recited throughout this disclosure. All such documents are hereby incorporated by reference. Trade names for products or components including various ingredients may be referenced herein. The inventors herein do not intend to be limited by materials under a certain trade name.

[0055] In the description of the invention various embodiments or individual features are disclosed. As will be apparent to the ordinarily skilled practitioner, all combinations of such embodiments and features are possible and can result in preferred executions of the present invention. The compositions herein may comprise, consist essentially of, or consist of any of the elements as described herein.

[0056] While various embodiments and individual features of the present invention have been illustrated and described, various other changes and modifications can be made without departing from the spirit and scope of the invention. As will also be apparent, all combinations of the embodiments and features taught in the foregoing disclosure are possible and can result in preferred executions of the invention.

[0057] With respect to dosing preferences, dosage levels are developed based on typical human subjects (e.g. a 70 kg subject). If the present composition is used in other mammals or in various human subjects, it may be necessary to modify the dosage. Modification of dosages based on the needs of the subject is well within the skill of the ordinary artisan. It is therefore understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors. The specific dosage of the compound to be administered, and the duration of treatment are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, gender, and medical condition of the subject), and compliance with the treatment regimen.

[0058] In a further embodiment of this invention, novel compositions of antihistamines, indole-based dietary supplements such as tryptophan, 5-HTP, melatonin along with substances that alleviate the symptoms experienced by menopausal women, further in combination with niacin (also known as vitamin B.sub.3, nicotinic acid or vitamin PP) are claimed for the treatment of insomnia and other sleep-related problems such as issues with circadian rhythm and jet lag. Co-dosing of vitamins, for example niacin, assists in the metabolism of tryptophan to serotonin in human subjects.

[0059] In a further embodiment of this invention, novel compositions of antihistamines, indole-based dietary supplements such as tryptophan, 5-HTP and melatonin along with substances that alleviate the symptoms experienced by menopausal women in combination with vitamin B.sub.6 are claimed for the treatment of insomnia and other sleep-related problems such as issues with circadian rhythm and jet lag. Co-dosing of vitamins, for example B.sub.6, assists in the metabolism of tryptophan to serotonin in human subjects.

[0060] In a further embodiment of this invention, novel compositions of antihistamines, indole-based dietary supplements such as tryptophan, 5-HTP and melatonin along with substances that alleviate the symptoms experienced by menopausal women in combination with pharmaceutically acceptable calcium salts and substance(s) with utility in the treatment of menopausal symptoms, are claimed for the treatment of insomnia related to and derived from menopausal symptoms and other sleep-related problems such as issues with circadian rhythm and jet lag. Representative pharmaceutically acceptable calcium salts are calcium hydrochloride, calcium tartrate, calcium maleate, calcium citrate, calcium phosphate, calcium acetate, calcium lactate calcium fumarate, calcium sulfate, calcium bromide, calcium mesylate, calcium palmoate, calcium iodide, calcium nitrate and calcium methylsulfate.

[0061] These novel combinations of sedating antihistamines and indole-based dietary supplements along with substances that alleviate the symptoms experienced by menopausal women together with calcium salts have utility in the treatment of insomnia and other sleep-related problems such as issues with circadian rhythm, shift work disorder and jet lag. It is known that calcium stimulates the metabolism of tryptophan and the presence of calcium salts will bring about more rapid formation of serotonin (Boadle-Biber, M. C. Effect of calcium on tryptophan hydroxylase from rat hind brain. Biochem. Pharmacol., 1975, 24, 1455-1460).

[0062] In a further embodiment of this invention, compositions of antihistamines and indole-based dietary supplements with optional addition of niacin and calcium salts combined with substance(s) having utility in the treatment of menopausal symptoms, are provided in a liquid form as a drink to be taken at bedtime to improve sleep. In a preferred embodiment the liquid formulation can be ingested either before or during or after a long aircraft flight to aid rest and sleep as well as treating the symptoms of jet lag including issues with circadian rhythm. The presence of vitamins, sugars, sources of complex carbohydrates and other ingredients and formulations are also added, familiar to those skilled in the art of preparing beverages.

METHODS OF USE

[0063] The methods of the present invention comprise orally administering (i.e., through ingestion) a composition of the present invention to a mammal, preferably a human, to provide various health benefits, including treatment of insomnia and inducing restorative sleep function and combinations thereof. The compositions of the present invention are most preferably ingested by consumers primarily desiring restorative sleep function while taking advantage of the restorative actions of the mammalian body during rest sleep. The compositions of this invention may also be ingested as a supplement to normal dietetic requirements.

[0064] Frequency of administration is not limited. However, such administration for treatment of insomnia is typically at least once weekly, more preferably at least 3 times weekly, and most preferably at least once daily around bedtime. As used herein, “restorative sleep function” refers to alleviation of any circadian rhythm phase-shifting effect, jet lag, winter depression, shift work-related desynchronies, sleep phase disorders, and other sleep disorders, improvement in sleep quality, improvement of sleep duration, and combinations thereof.

[0065] As used herein, the term “orally administering” with respect to the mammal (preferably, human) means that the mammal ingests or is directed to ingest (preferably, for the purpose of providing one or more of the health benefits described herein) one or more compositions of the present invention. In one embodiment, the composition is formulated as a tablet, capsule, food or beverage composition. Wherein the mammal is directed to ingest one or more of the compositions, such direction may be that which instructs and/or informs the user that use of the composition may and/or will provide one or more general health and/or general physiological benefits including, but not limited to, restorative sleep function.

[0066] The following are non-limiting examples of Methods which can be utilized to provide tablet formulations of the novel combinations which are useful in providing a medicament for improving sleep in mammals, especially humans.

[0067] Method A

[0068] A capsule formulation is prepared for use in treating sleep disorders in mammals comprising 0.001 g to 0.05 g of a suitable sedating antihistamine, for example doxylamine as its pharmaceutically acceptable salt, for example its succinate salt form, between 0.0025 g and 0.5 g of progesterone, 0.0001 g to 0.01 g of melatonin, 0.001 g to 1.0 g of L-tryptophan, 0.01 g to 0.05 g of niacin, 0.001 g to 0.01 g of pyridoxine, 0.01 to 1.0 g of a suitable mineral salt of calcium, for example calcium citrate and 0.005 to 0.5 g of a magnesium compound such as magnesium oxide. Suitable excipients for this tablet formulation include dicalcium phosphate, acceptable dyes such as FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The tablet is dosed to human subjects in order to improving their health, especially in the treatment of sleep problems, including inducing restorative sleep function, in the treatment of insomnia and other sleep-related problems such as issues with circadian rhythm, shift work disorder and jet lag.

[0069] Method B

[0070] A capsule formulation is prepared for use in treating sleep disorders in mammals comprising 0.001 g to 0.05 g of a suitable sedating antihistamine, for example doxylamine as its pharmaceutically acceptable salt, for example its succinate salt form, 50 mcg to 0.015 g estriol, 0.0001 g to 0.01 g of melatonin, 0.001 g to 1.0 g of L-tryptophan, 0.01 g to 0.05 g of niacin and 0.001 g to 0.01 g of pyridoxine. Suitable excipients for this tablet formulation include dicalcium phosphate, calcium citrate, acceptable dyes such as FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The tablet is dosed to human subjects in order to improving their health, especially in the treatment of sleep problems, including inducing restorative sleep function, in the treatment of insomnia and other sleep-related problems such as issues with circadian rhythm, shift work disorder and jet lag.

[0071] Method C

[0072] A capsule formulation is prepared for use in treating sleep disorders in mammals comprising 0.001 g to 0.05 g of a suitable sedating antihistamine, for example doxylamine as its pharmaceutically acceptable salt, for example its succinate salt form, 10 mcg to 0.015 g of estradiol, 0.0001 g to 0.01 g of melatonin, 0.001 g to 1.0 g of L-tryptophan, 0.01 g to 0.05 g of niacin and 0.01 g to 0.1 g of theanine. Suitable excipients for this tablet formulation include dicalcium phosphate, calcium citrate, acceptable dyes such as FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The tablet is dosed to human subjects in order to improving their health, especially in the treatment of sleep problems, including inducing restorative sleep function, in the treatment of insomnia and other sleep-related problems such as issues with circadian rhythm, shift work disorder and jet lag.

[0073] Method D

[0074] A capsule formulation is prepared for use in treating sleep disorders in mammals comprising 0.005 g to 0.01 g of a suitable sedating antihistamine, for example diphenhydramine as its pharmaceutically acceptable salt, for example its hydrochloride or citrate salt form, 0.0005 g to 0.5 g black cohosh, 10 mcg to 0.015 g estrone, 0.0001 g to 0.01 g of melatonin, 0.001 g to 1.0 g of L-tryptophan, 0.01 g to 0.05 g of niacin, 0.001 g to 0.01 g of pyridoxine, 0.01 to 1.0 g of a suitable mineral salt of calcium, for example calcium citrate and 0.005 to 0.5 g of a magnesium compound such as magnesium oxide. Suitable excipients for this tablet formulation include dicalcium phosphate, acceptable dyes such as FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The tablet is dosed to human subjects in order to improving their health, especially in the treatment of sleep problems, including inducing restorative sleep function, in the treatment of insomnia and other sleep-related problems such as issues with circadian rhythm, shift work disorder and jet lag.

[0075] Method E

[0076] A capsule formulation is prepared for use in treating sleep disorders in mammals comprising 0.05 g to 0.1 g of a suitable sedating antihistamine, for example promethazine as its pharmaceutically acceptable salt, for example its hydrochloride salt form, 0.01 g to 0.25 g red clover, 0.25 to 5 g Valerian root (crude herb), 0.0001 g to 0.01 g of melatonin, 0.001 g to 1.0 g of L-tryptophan, 0.01 g to 0.05 g of niacin, 0.001 g to 0.01 g of pyridoxine, 0.01 to 1.0 g of a suitable mineral salt of calcium, for example calcium citrate and 0.005 to 0.5 g of a magnesium compound such as magnesium oxide. Suitable excipients for this tablet formulation include dicalcium phosphate, acceptable dyes such as FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The tablet is dosed to human subjects in order to improving their health, especially in the treatment of sleep problems, including inducing restorative sleep function, in the treatment of insomnia and other sleep related problems such as issues with circadian rhythm, shift work disorder and jet lag.

[0077] Method F

[0078] A capsule formulation is prepared for use in treating sleep disorders comprising 0.0001 g to 0.01 g of melatonin, 0.001 g to 1.0 g of L-tryptophan, 0.05 g 0.5 g DHEA, 0.01 g to 0.25 g red clover, 0.25 to 5.0 g Valerian root (crude herb), 0.01 g to 0.05 g of niacin, 0.001 g to 0.01 g of pyridoxine, 0.01 to 1.0 g of a suitable mineral salt of calcium, for example calcium citrate and 0.005 to 0.5 g of a magnesium compound such as magnesium oxide. Suitable excipients for this tablet formulation include dicalcium phosphate, acceptable dyes such as FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose and sodium starch glycolate. The tablet is dosed to human subjects in order to improving their health, especially in the treatment of sleep problems, including inducing restorative sleep function, in the treatment of insomnia and other sleep related problems such as issues with circadian rhythm, shift work disorder and jet lag.

[0079] Method G

[0080] A composition of doxylamine succinate (0.025 g), the indole-based dietary supplements L-tryptophan (0.5 g) melatonin (0.003 g) were dissolved in pasteurized milk (250 mL) or a suitable fruit juice such as mango juice (250 mL), or a combination of juices, and Evening Primrose Oil (0.5 g), Siberian rhubarb extract (0.5 g), vitamin B6 (0.010 g), vitamin E (0.010 g) and glycine (1.0 g) were introduced. Niacin (0.25 g) and calcium citrate (2.5 g) were added, followed by a source of carbohydrate, with vitamin C (0.5 g) and a suitable approved flavoring. This scaleable formulation is in a beverage form as a drink, preferably to be taken at bedtime to improve sleep, or before, during or after a long aircraft flight to aid rest and sleep as well as treating the symptoms of jet lag, including disorders of circadian rhythm.

[0081] The following are non-limiting examples of the present compositions which are prepared utilizing conventional methods. The following examples are provided to illustrate the invention and are not intended to limit the scope thereof in any manner.

EXAMPLE 1

[0082] Doxylamine succinate (0.80 g), progesterone (5.0 g), L-tryptophan (32.50 g), melatonin (0.15 g) were all weighed on a Ohaus Explorer scale and combined with microcrystalline cellulose NF105 (Avicel™) (1.0 g). The ingredients were mixed thoroughly in a sterilized plastic container and the mixture was now ready for the capsule preparation procedure.

[0083] Utilizing a Jaansun® Capsule Machine 100, the mixture was carefully placed into “0” Clear Locking gelatin capsules (part # #30-1988-5000, obtained from PCCA USA, 9901 S. Wilcrest Drive, Houston, Tex. 77099-5132) as described below, following the manufacturer's instructions closely.

[0084] The loader filled with empty capsules was placed on top of the separator plate so that it could slide freely from left to right. The loader was positioned on the blue rails and slid to the left or right till it stopped against one set of the blue posts. The white plate was then gently pushed into the spring block, and the capsules were allowed to drop through the loader plates with the lid end up. The loader was lifted up and off the capsule machine.

[0085] One of the retainer knobs was grasped and the separator plate was shaken to drop the capsules into the machine, ensuring that the capsules were sitting in the capsule machine so that the capsule tops could not rise above the blue metal ledge located just beneath the retainer knobs. Once the capsules had dropped into the machine, the capsules were gently tapped to ensure they were all at the required height; the procedure was then repeated for the remaining 50 capsules.

[0086] The loader was lifted up and off of the capsule machine, and all capsules were tapped gently to ensure they were sitting level in the capsule machine. The retainer plate was then placed on top of the separator plate with the beveled edges facing up, parallel to each set of retaining knobs. Each retainer knob was turned so that approximately ⅓ of the knob was covering the plate, and both pinch knobs were hand-tightened at the same time. The separator plate was then lifted up and off of the machine, and checked for capsule bases. Before setting the separator plate aside, it was ensured that the black retaining knobs were facing upwards.

[0087] The black pinch knobs were loosened and the capsules were allowed to drop down into the capsule machine so they were sitting flush with the top of the white pinch plate. The black pinch knobs were lightly tightened to hold the capsule bases in place during the filling process; the optional powder dam was placed on the top of the machine and the requisite clips applied over the powder dam and the short notch under the machine.

[0088] The thoroughly-mixed ingredients, as described above, were placed in powder form in the center of the machine and spread evenly over the top of the white pinch plate with a powder scraper. The machine was gently tapped in order to move the powders back and forth on the white pinch plate. The powders were tamped with a tamper to push air out of, and powder into the capsules, then the powder was redistributed over the capsules with a scraper as needed, checking for fill uniformity. This tapping, tamping, and scraping process was repeated until all the powder was neatly packed into the capsules.

[0089] Once it appeared that the majority of the powder has been packed into the capsules, the clips and powder dam were removed, and the tamper was used to check for capsule fill uniformity. If one end of tamper was sitting higher than the other end, the powder distribution was evened out using the tamper prongs as a scoop or manipulated with a plastic scraper/spatula if needed. The capsules were now ready to be reassembled by the following procedure: the separator plate was placed on the machine with the notches to the front door, and both pinch knobs were loosened, but with the retainer knobs holding the retainer plate in place. The depth plate was gently bounced while gradually applying pressure to raise the depth plate up. Pressure was applied to both the front and back of the plates to bring all the capsules back together.

[0090] The separator plate was then lifted up, and checked underneath to ensure that all capsule bases had been reattached to the lids; and the retainer knobs were checked again to ensure that they are still holding the retainer plate in place. The separator plate was turned over and each capsule locked by gently pressing down on each one individually. The retainer plate was removed by rotating the retainer knobs and lifting the plate up and off the separator plate. The capsules were removed from the separator plate by turning the plate over and guiding the capsules into a towel, then the four corners of the towel were brought together and the capsules were shaken, thereby cleaning the capsules and loading the capsule lids.

[0091] The batch of 100 capsules was then available for clinical evaluation, in a typical daily dose of 2 capsules at bedtime in subjects suffering from sleep problems related to menopausal symptoms, especially subjects who take dietary supplements ensuring healthy and adequate levels of the minerals calcium and magnesium.

EXAMPLE 2

[0092] Doxylamine succinate (0.80 g), DHEA (4.0 g), L-tryptophan (32.50 g), melatonin (0.15 g) were all weighed on a Ohaus Explorer scale and combined with microcrystalline cellulose NF105 (Avicel™) (1.0 g). The ingredients were mixed thoroughly in a sterilized plastic container and the mixture was now ready for the capsule preparation procedure as described in Example 1.

EXAMPLE 3

[0093] Doxylamine succinate (0.80 g), tibolone (2.5 g), L-tryptophan (32.50 g), melatonin (0.15 g) were all weighed on a Ohaus Explorer scale and combined with microcrystalline cellulose NF105 (Avicel™) (1.0 g). The ingredients were mixed thoroughly in a sterilized plastic container and the mixture was now ready for the capsule preparation procedure as described in Example 1.

EXAMPLE 4

[0094] Doxylamine succinate (0.80 g), veralipride (7.0 g), L-tryptophan (32.50 g), melatonin (0.15 g) were all weighed on a Ohaus Explorer scale and combined with microcrystalline cellulose NF105 (Avicel™) (1.0 g). The ingredients were mixed thoroughly in a sterilized plastic container and the mixture was now ready for the capsule preparation procedure as described in Example 1.

EXAMPLE 5

[0095] Doxylamine succinate (0.80 g), clonidine (10.0 g), L-tryptophan (32.50 g), melatonin (0.15 g) were all weighed on a Ohaus Explorer scale and combined with microcrystalline cellulose NF105 (Avicel™) (1.0 g). The ingredients were mixed thoroughly in a sterilized plastic container and the mixture was now ready for the capsule preparation procedure as described in Example 1.

EXAMPLE 6

[0096] Doxylamine succinate (0.80 g), 17-hydroxy-6α-methyl-progesterone acetate (0.25 g), L-tryptophan (32.50 g), melatonin (0.15 g) were all weighed on a Ohaus Explorer scale and combined with microcrystalline cellulose NF105 (Avicel™) (1.0 g). The ingredients were mixed thoroughly in a sterilized plastic container and the mixture was now ready for the capsule preparation procedure as described in Example 1.

[0097] A method for assessing the effects of drugs on sleep time as well as differences in rapid eye-movement (REM) sleep, slow-wave sleep and wakefulness is illustrated in Example 7.

EXAMPLE 7

[0098] Twenty-five male Sprague-Dawley rats (300-350 g at the time of the surgery) were anesthetized with 2.5-3.0% halothane (Halocarbon Laboratories), and surgically implanted for sleep recordings. Two screw electrodes were placed in the parietal bone over the hippocampus (P=4.0; L=3.0), to record the electroencephalogram (EEG). Two wire electrodes were placed in the external and internal canthus of the orbit to record eye movements (EOG). Postural tone (EMG) was recorded through two wire electrodes inserted into the neck musculature. A stainless steel cannula (23 gauge) was stereotaxically implanted into the lateral ventricle. Rats were individually housed and the light-dark cycle was controlled (12:12, lights on at 06.30 h)

[0099] One week after the surgery, rats were habituated to the recording conditions for at least 2 days. Rats were recorded in a small cage (16×10×10″) placed inside of an environmental chamber (35×34×29″). Once the habituation period was completed, rats were divided into five groups (n=5). Each group was challenged with an intraventricular (ICV) administration of a solution of the desired proportions of doxylamine succinate/progesterone/L-tryptophan/melatonin or ethanol (EtOH, J. T. Baker). Control animals received 10 l of saline. Rats were continuously recorded for 8 h after the ICV injection (1000-1800 h). In addition, rats were observed for changes in spontaneous behavior through a one-way window. These methods are described in more detail in Prospero-Garcia, O.; Criado J. R. and Henricksen, S. J., A method for investigating sleep: Pharmacology of Ethanol and Glutamate Antagonists on Rodent Sleep: A Comparative Study. Pharmacology Biochemistry and Behavior, 1994, 49, 413-416.

[0100] Acid addition salts of the antihistamine and optional melatonin, 5-HTP and tryptophan combinations and other agents employed in the invention can be prepared in a conventional manner by treating a solution or suspension of the corresponding free base with one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration or crystallization techniques can be employed to isolate the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic and related organic or inorganic acids.

[0101] The antihistamine and optional melatonin, 5-HTP and tryptophan combinations and their pharmaceutically acceptable salts, may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions, oils (e.g. peanut oil, sesame oil) and various organic solvents. Enterically coated tablets are a preferred formulation when 5-HTP is utilized as one of the indole-based dietary supplements. The pharmaceutical compositions formed by combining the antihistamine and optional melatonin, 5-HTP and tryptophan combinations and pharmaceutically acceptable carriers can be readily administered in a variety of dosage forms such as tablets, powders, lozenges, emulsions, oil soft gels, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients, tastemasking agents and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions, elixirs or beverages are desired for oral administration, the essential active ingredient therein may be combined with a large range of various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.

[0102] For parenteral administration, solutions containing the antihistamine and optional melatonin, tryptophan and 5-HTP combinations or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

[0103] The effective dosages for the antihistamine, melatonin, 5-HTP and tryptophan combinations employed in the methods of this invention will depend on the intended route of administration and factors such as the age and weight of the patient. The dosages will also depend on the particular condition to be treated and will generally range from about 0.1 to about 300 mg/kg body weight of the patient per day, with administration carried out in single or divided dosages.