EP2300027A1

EP2300027A1 - Method of treating migraine using guava

Info

Publication number: EP2300027A1
Application number: EP08817304A
Authority: EP
Inventors: Fred Wheling
Original assignee: Amerilab Technologies Inc
Current assignee: Amerilab Technologies Inc
Priority date: 2008-07-10
Filing date: 2008-07-10
Publication date: 2011-03-30
Also published as: CN102088987A; WO2010005438A1; CN102088987B

Abstract

A method of using guava extract that includes administering guava extract to an individual experiencing the symptoms of migraine or prone to migraine.

Description

METHOD OF TREATING MIGRAINE USING GUAVA

BACKGROUND

The invention is directed to treating migraine with guava. People who get migraines often describe the pain as pulsing or throbbing in one area of the head. During migraine blood vessels contract and dilate. A typical migraine lasts for from four to 72 hours. During migraines people are very sensitive to light and sound. Some people who experience migraines experience a warning sign such as an aura in the form of a flash of light, zigzag lines, a blind spot, a temporary loss of vision, or an unpleasant smell. These symptoms are often referred to as an "aura" and these types of migraines are referred to as "classic migraine." Migraines are often accompanied by nausea, vomiting, and a heightened sensitivity to bright lights and noise. In many cases migraines are incapacitating. A variety of triggers that precipitate an episode of migraine have been described including certain foods and beverages (e.g., chocolate or alcohol), stress and menstruation.

A "common migraine," is the most typical kind of migraine and is characterized by a painful headache that is more severe and longer in duration than the average headache. People who experience common migraines do not experience the pre-headache aura, but many do complain of feeling unusually tired, being unable to concentrate, and mood changes. In order to be classified as a common migraine, the headache must also be accompanied by two of the following symptoms: nausea, pain on only one side of the head, pain that is so severe that it prevents normal activity, or pain that is brought about or worsened by normal physical activity.

Migraine is three times more common in women than in men. Menstrual related migraine (MRM) headache is common in women and associated with substantial disability. Compared to non-menstrual migraine, MRM attacks are more severe, longer in duration, and have a poorer response to analgesics.

Currently there is no known cure for migraine. Treatment of migraine can include pain-relieving medications, which are referred to as acute or abortive treatments. Pain- relieving medications are taken during migraine attacks and are designed to stop symptoms that have already begun. Examples of pain-relieving medications include nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin, and drugs marketed specifically for migraine, such as the combination of acetaminophen, aspirin and caffeine. If taken too often or for long periods of time, NSAIDs can lead to ulcers, gastrointestinal bleeding, and rebound headaches.

There are also preventive medications, which are taken regularly, often on a daily basis, to reduce the severity or frequency of migraine. Many people with severe migraine attacks take triptans. Triptans are reported to be effective in relieving the pain, nausea and sensitivity to light and sound that are associated with migraines. Examples of triptans include sumatriptan, rizatriptan, naratriptan, zolmitriptan, almotriptan, frovatriptan and eletriptan. The side effects of triptans include nausea, dizziness, muscle weakness and, rarely, stroke and heart attack. Ergotamine and dihydroergotamine have also been prescribed for migraine.

The guava plant, psidium guajava L. , has been used as a source of nutrition by many cultures; its fruit is eaten as is, made into juices and jellies, and used in other food products. Parts of the guava plant have been used by various cultures to treat diarrhea and sore gums. The guava plant has also been studied to ascertain its effects on various conditions of the human body including diabetes and obesity. The extract of guava has been used to alleviate, prevent or inhibit the effects of a hangover (including headache) and to decrease the blood alcohol level of an individual who has consumed alcohol. Such use has been described in U.S. Patent 7,247,324 (Wehling et al.). A migraine differs from a regular headache, such as a headache from a hangover, in that the pain of a migraine is significantly more severe than the pain of a regular headache, a regular headache is not accompanied by the other characteristics described above with respect to migraine, and migraine pain often gets worse with physical exertion, whereas the pain of a regular headache does not. Regular headaches also can be successfully treated with standard over the counter medications such as aspirin, acetaminophen, and ibuprofen.

SUMMARY

The invention features a method of treating an individual suffering from or prone to migraine. The method includes administering guava to the individual. In some embodiments, the guava is administered on a daily basis (e.g., administering at least about 500 mg, or even at least about 1000 mg, guava extract on a daily basis). In one embodiment, the guava extract is administered prior to the onset of migraine. In other embodiments, the guava extract is administered after onset of migraine. In another embodiment, the guava is administered prior to the onset of menstruation.

In one aspect, the invention features a method of using guava extract that includes administering guava extract to an individual experiencing at least one symptom of a migraine to alleviate the migraine. In one embodiment, the individual is experiencing migraine with aura. In another embodiment, the method includes administering the guava extract on a daily basis.

In some embodiments, the guava extract is an extract of the leaves of a guava plant.

In one embodiment, the guava extract is in an oral effervescent dosage form. In some embodiments, the oral effervescent dosage form is an effervescent tablet. In other embodiment, the guava extract is in a unit dosage form that includes from about 500 to about 2000 milligrams guava extract. In other embodiments, the guava extract is in a unit dosage form that includes at least about 1000 milligrams guava extract.

In another aspect, the invention features a method of using guava extract that includes administering guava extract (e.g., an extract derived from the leaves of a guava plant) to an individual prone to migraines to prevent migraine. In one embodiment, the amount of guava extract administered is at least 500 mg. In some embodiments, the administering includes administering guava extract (e.g., at least about 500 mg guava extract) to the individual on a daily basis starting at least about seven days before the onset of menstruation in the individual, and continuing the administration at least until menstruation starts. In another embodiment, the administration continues for a period of at least two days after menstruation starts. In other embodiments, the administration continues for a period of at least three days after menstruation starts. In other embodiments, the administering includes administering at least about 500 mg guava extract on a daily basis to a individual prone to menstrual related migraine.

In some embodiments, the guava extract is in the form of an oral effervescent dosage form that includes guava extract and an effervescent couple that includes an acid and a base, a binder and a lubricant. In another embodiment, the guava extract includes a water-soluble extract of guava leaves. In one embodiment, the guava extract includes at least one of an organic solvent soluble extract of guava leaves and an oil soluble extract of guava leaves.

In another aspect, the invention features a use of guava extract for the preparation of a composition for decreasing the pain associated with a migraine in a mammal.

The invention features a method of treatment that prevents migraine, decreases the severity of migraine pain in some individuals, and alleviates or eliminates the pain and other related symptoms associated with a migraine in some individuals. In some individuals, the treatment method also decreases the frequency of migraines. Other features and advantages will be apparent from the following description of the preferred embodiments and from the claims.

GLOSSARY

In reference to the invention, these terms have the meanings set forth below: As used herein, the term "migraine" refers to a pain in the head 1) in which the pain occurs on only one side of the head, 2) that is accompanied by enhanced sensitivity to light, sound or a combination thereof, 3) that is accompanied by an aura (e.g., a flash of light, zigzag lines, a blind spot, a temporary loss of vision, an unpleasant smell or a combination thereof), 4) that is accompanied by nausea, 5) that is accompanied by vomiting, 6) that is so severe that it prevents normal activity, 7) that is brought about or worsened by normal physical activity, or a combination thereof.

As used herein, the term "unit dose" or "unit dosage" refers to physically discrete units that contain a predetermined quantity of active ingredient calculated to produce a desired therapeutic effect.

As used herein the term "oral dosage form" is used in a general sense to reference a product that is administered orally.

As used herein the term "carrier" means a substance used in association with guava for aiding in the administration of guava.

The term "pharmaceutically acceptable" when used herein as an adjective, means substantially non-toxic and substantially non-deleterious to the recipient. DETAILED DESCRIPTION

The method of using guava extract includes administering guava extract to the individual in an amount sufficient to decrease, preferably eliminate, more preferably prevent, at least one of the symptoms associated with migraine (e.g., pain, sensitivity to light, sound, and smells, nausea, and loss of vision), the frequency of migraine and combinations thereof. The method is useful for treating an individual suffering from migraine, prone to migraine, and combinations thereof.

The guava extract can be administered abortively, prophylactically, or in a combination thereof, depending on the needs of the individual. One useful method of treating migraines includes administering guava extract at the onset of indications (i.e., warnings) that a migraine is going to occur, while experiencing the symptoms of a migraine, and combinations thereof. Where migraine occurs in the individual on a repeated or periodic basis, a useful method of treatment includes administering guava extract on a daily basis. Where an individual experiences migraines on a periodic basis and the periodicity is relatively predictable (e.g., based on the individual's migraine history), another useful method of treatment includes administering guava extract on a daily basis starting at least two days, at least three days, at least five days or even at least seven days before the predicted onset of migraine symptoms. The daily intake of guava extract in terms of amount and frequency can be continued through the period over which the migraine is usually experienced and then altered or stopped by the individual after the predicted end of migraine pain, e.g., at least one day, at least two days, or even at least three days after the day on which the migraine would have occurred, or the day on which the migraine would have gone away, based on the past experience of the individual.

After the guava extract treatment has been effective over a period of time, the administration of guava extract is preferably gradually decreased in terms of frequency, amount, or a combination thereof. The rate and nature of the decrease is preferably correlated with the decrease in the frequency and severity of the migraine.

For menstrual related migraine, one useful method of treatment includes administering guava extract on a daily basis starting at least about one day, at least about two days, at least about three days or even at least about seven days before the first day of menstruation and continuing the daily administration of guava extract during at least the first day of menstruation, through the second day of menstruation, or even through the third day of menstruation. The administration of guava extract optionally can be stopped for a period of time and then restarted as described above. Alternatively, guava extract can be administered on a daily basis to an individual prone to experiencing menstrual related migraine.

Useful sources of guava include various parts of the guava plant, psidium guajava L, including, e.g., the fruit, leaves, stems, and roots thereof. A useful form of guava is guava extract (i.e., an extract of a part of a guava plant), which can be derived from the fruit, leaves, stems, and roots of the guava plant. Preferably the guava extract is obtained from guava leaves. Useful methods of obtaining guava extract include, e.g., solvent extraction, wherein at least a portion of the guava plant is contacted with a liquid including, e.g., an organic solvent (e.g., methanol, ethanol, butanol and isopropanol), water (e.g., tap water, room temperature water, elevated temperature water (e.g., boiling water) and combinations thereof), oil (e.g., mineral oil, elevated temperature oil, vegetable oils, animal oils and combinations thereof), and combinations thereof. The resulting extract is then gathered for use. The guava plant or a portion thereof can also be treated prior to extraction. Useful pre- and post-extraction treatments include, e.g., drying, lyophilizing, freeze drying, humidifying, and combinations thereof.

The guava extract can be in a variety of states including, e.g., dry guava extract (e.g., in the form of a powder or granulation), wet guava extract (e.g., in the form of a liquid, a tincture (i.e., a solvent (e.g., organic and aqueous) in which the extract is dissolved or dispersed), a wetted mass), and combinations thereof.

For ease of reference, the guava is referred to herein as a guava extract. It is to be understood, however, that the guava can be in a variety of forms including, e.g., the fruit, leaves, roots, and stems of the guava plant, components derived from the foregoing (e.g., juice of the fruit), and combinations thereof. The guava extract is preferably administered in a dosage form that includes a suitable carrier. Useful carriers include, e.g., excipients, diluents, binders, lubricants, disintegrants, coloring agents, sweetening agents, and combinations thereof including, e.g., carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic materials, hydrophobic materials, gelatin, oils, organic solvents, water, and combinations thereof. The selection of the carrier will depend upon the means by which the guava extract is to be administered. The effective amount of guava extract will vary depending on a number of factors including, e.g., the physical characteristics of the individual (e.g., height, weight, age, and physical health), the source and form of guava, and the severity, nature and frequency of the migraine pain. The guava extract is preferably provided in a unit dosage form and can be administered in a single dose or in multiple doses. The effective dose for a given individual is usually set by the judgment of the individual. The guava extract is generally effective over a wide dosage range. Amounts that have been found to be useful include at least about 100 mg guava extract/dose, at least about 250 mg/dose, at least about 500 mg/dose, at least about 800 mg/dose, at least about 1000 mg/dose, at least about 1500 mg/dose, at least about 2000 mg/dose, at least about 3000 mg/dose, at least about 5000 mg/dose, or even at least about 10,000 mg/dose administered on a daily basis.

The dose can optionally be administered more than once daily including, e.g., at least two times a day, at least three times a day, or even at least five times a day. More than one dose can also be administered during each dosing (e.g., at least two 250 mg guava extract dosage units, or even at least two 500 mg guava extract dosage units, administered once a day).

The dose of guava extract can include neat guava extract, i.e., the dose is free of other components, or it can include components in addition to guava extract including, e.g., a variety of carriers. The dose preferably includes from 0.1 % to 100 % by weight, at least about 10 % by weight, at least about 20 % by weight, at least about 25 % by weight, at least about 30 % by weight, at least about 40 % by weight guava extract.

The dose of guava extract can optionally include wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, sweeteners, stabilizers, flavoring agents, coloring agents, and combinations thereof, useful examples of which are set forth below. The dose of guava extract can be provided in a variety of packages including metal foil pouches, tubes (e.g., plastic and metal tubes), ampoules, in multidose containers. The packaging preferably is air tight and impermeable to moisture.

The dose of guava extract can be administered in any convenient manner including, e.g., by oral, intravenous, subcutaneous, intramuscular and subcutaneous routes, and combinations thereof. Oral administration can be by any suitable dosage form including, e.g., powder (e.g., effervescent powders, and powdered drink mixes), tablet (e.g., quick dissolve tablets), granulations (e.g., effervescent granulations, chewable granulations), pill, capsule, gel caps, composite (e.g., a layered tablet construction, a construction that includes a continuous phase and a discontinuous phase), chewable dosage forms including chewing gum and chewable tablets, wafer (e.g., disintegrating tablets and dissolving tablets), and liquid formulations (e.g., solutions and dispersions), e.g., beverages, e.g., canned and bottled beverage, a dry or liquid aerosol that can be inhaled or sprayed, and combinations thereof. The guava extract can be provided in the form of a sterile solution by direct injection into the bloodstream of the individual to be treated. The guava extract is preferably formulated into a dosage form that provides an easily controllable dose of guava extract, is easy to ingest, and is easy to handle.

One example of a useful effervescent composition for guava extract includes guava extract and an effervescent agent (which is also referred to as an effervescent couple) that includes an acid and a base. The effervescent composition evolves gas when placed in a suitable volume of water. The effervescent composition also disintegrates, and preferably dissolves, when placed in a sufficient amount of water. The guava extract is preferably dried and sieved to a suitable particle size (e.g., using a number 12 sieve) prior to combining with the other ingredients of the effervescent composition. The effervescent composition preferably is in a dosage form (e.g., a tablet or a sachet of a powdered granulation) that includes guava extract in an amount of at least about 250 mg, at least about 500 mg, at least about 800 mg, at least about 1000 mg, at least about 1500 mg, or even at least about 2000 mg.

The effervescent agent is activated when contacted with an aqueous liquid, e.g., water (e.g., when the powder or tablet is placed in a glass of water). The water liberates the acid and base and enables the acid and base to react with each other to produce carbon dioxide gas, which imparts carbonation to the aqueous composition. Examples of useful acids of the effervescent couple include citric acid, ascorbic acid, aspartic acid, malic acid, adipic acid, tartaric acid, fumaric acid, succinic acid, sodium acid pyrophosphate, lactic acid, hexamic acid, amino acids, and acid salts and acid anhydrides thereof, and mixtures thereof. Examples of useful acid anhydrides include citraconic anhydride, glucono-D- lactone, and succinic anhydride. Examples of useful acid salts include potassium bitartrate, acid citrate salts, sodium dihydrogen phosphate, disodium dihydrogen phosphate, sodium acid sulfite, and combinations thereof. Preferably acid is present in the effervescent composition in an amount of from 10 % by weight to about 60 % by weight, from about 15 % by weight to about 50 % by weight, or even from about 25 % by weight to about 40 % by weight. The base of the effervescent couple preferably is capable of generating a gas such as carbon dioxide. Examples of suitable carbonate bases include sodium bicarbonate, sodium carbonate, sodium sesquicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium carbonate, magnesium oxide, sodium glycine carbonate, L- lysine carbonate, arginine carbonate, zinc carbonate, zinc oxide, amino acid carbonates, and mixtures thereof. The effervescent composition preferably includes base in an amount of from 10 % by weight to about 60 % by weight, from about 15 % by weight to about 50 % by weight, or even from about 25 % by weight to about 40 % by weight.

The effervescent composition can optionally include a variety of additional active agents including, e.g., vitamins, amino acids, pharmaceutical agents, minerals, dietary supplements, and combinations thereof. Suitable vitamins include, e.g., ascorbic acid

(vitamin C), aspartic acid, thiamin, riboflavin, nicotinic acid, pantothenic acid, pyridoxine, biotin, folic acid, niacin, vitamin B 12, lipoic acid, vitamin A, vitamin D, vitamin E and vitamin K and coenzymes thereof, choline, carnitine, and alpha, beta, and gamma carotenes. Examples of coenzymes include thiamine pyrophosphates, flavin mononucleotide, flavin adenine dinucleotide, nicotinamide adenine dinucleotide, nicotinamide adenine dinucleotide phosphate coenzyme A pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B 12, lipoyllysine, 11-cis-retinal, and 1,25- dihydroxycholecalciferol and mixtures.

Suitable amino acids include, e.g., L-tyrosine, isoleucine, ornithine, glutamine, phenylalanine, leucine, lysine, methionine, threonine, taurine, tryptophan , valine, alanine, glycine, arginine, histidine, cysteine, asparagine, proline and serine, and mixtures thereof.

Examples of minerals include iron, zinc, selenium, copper, iodine, phosphorus, chromium and mixtures thereof.

Suitable dietary supplements include, e.g., bee pollen, bran, wheat germ, kelp, cod liver oil, ginseng, and fish oils, amino-acids, proteins, vitamins, minerals alpha- glycerylphosphorylcholine, acetyl-L-carnitine and salts thereof, docosahexaenoic acid, cranberry extract, chondroitin, methylsulfonylmethane, and mixtures thereof.

The effervescent composition can also include other ingredients including, e.g., flavor agents, fillers, surfactants (e.g., polysorbate 80 and sodium lauryl sulfate), color agents including, e.g., dyes and pigments, sweeteners, and flow agents.

Useful flavor agents include natural and artificial flavor agents including, e.g., volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins and extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. Useful flavor agents include, e.g., citric oils, e.g., lemon, orange, grape, lime and grapefruit, fruit essences including, e.g., apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot, and other fruit flavors, ice tea flavoring, and combinations thereof. Other useful flavor agents include, e.g., aldehydes and esters (e.g., benzaldehyde (cherry, almond)), citral, i.e., alpha-citral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C- 12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanal (green fruit), 2-dodedenal (citrus, mandarin), and mixtures thereof. Preferably the effervescent composition includes at least about 100 mg, at least about 200 mg, no greater than about 500 mg or even no greater than about 400 mg flavor agent.

Useful color agents include, e.g., food, drug and cosmetic (FD&C) colors including, e.g., dyes (e.g., FD&C red no. 40), lakes, and certain natural and derived colorants. Useful lakes include dyes absorbed on aluminum hydroxide and other suitable carriers.

Useful sweetening agents include stevia, sugars such as sucrose, glucose, invert sugar, fructose, ribose, tagalose, sucralose, malitol, erythritol, xylitol, and mixtures thereof, saccharin and its various salts (e.g., sodium and calcium salt of saccharin), cyclamic acid and its various salts, dipeptide sweeteners (e.g., aspartame), acesulfame potassium, dihydrochalcone, glycyrrhizin, and sugar alcohols including, e.g., sorbitol, sorbitol syrup, mannitol and xylitol, and combinations thereof.

The effervescent composition can be provided in a variety of forms including, e.g., powder, granulation, tablet, capsule, pellet and composite. Preferred effervescent tablets have a hardness of at least 3 kilopounds (Kp), preferably at least 5 Kp, from about 5 Kp to about 10 Kp, or even from about 5 Kp to about 8 Kp₅ as measured on a Standard hardness tester fitted with a strain gauge.

When in the form of a tablet, the effervescent composition preferably also includes binder, lubricant, and combinations thereof. Examples of suitable binders include, e.g., starches, natural gums, cellulose gums, macrocrystalline cellulose, methylcellulose, cellulose ethers, sodium carboxymethylcellulose, ethylcellulose, gelatin, dextrose, lactose, sucrose, sorbitol, mannitol, polyethylene glycol, polyvinylpyrrolidone, pectins, alginates, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols and mixtures thereof. Preferably the binder is water soluble. Where present, the binder of the effervescent composition is present in an amount sufficient to assist in holding the components of the composition together in the form of a tablet. When present, the composition preferably includes binder in an amount from 10 % by weight to about 60 % by weight, from about 15 % by weight to about 50 % by weight, or even from about 20 % by weight to about 40 % by weight, or even 20 % by weight to 30 % by weight.

Various lubricants are suitable for use in the effervescent composition including water dispersible, water soluble, water insoluble lubricants and combinations thereof. Preferred lubricants are water soluble. Some lubricants also provide a binder function and vice versa. Examples of useful water soluble lubricants include sodium benzoate, polyethylene glycol, L-leucine, adipic acid, and combinations thereof. The composition can also include water insoluble lubricants including, e.g., stearates (e.g., magnesium stearate, calcium stearate and zinc stearate), oils (e.g., mineral oil, hydrogenated and partially hydrogenated vegetable oils, and cotton seed oil) and combinations thereof. Other water insoluble lubricants include, e.g., animal fats, polyoxyethylene monostearate, talc, and combinations thereof.

The effervescent composition preferably includes a sufficient amount of lubricant to enable the composition to be formed into tablets and released from a high speed tableting press in the form of a tablet. When present, the composition preferably includes lubricant in an amount of from 1 % by weight to about 15 % by weight, from about 1 % by weight to about 12 % by weight, from about 2 % by weight to about 10 % by weight, or even from about 3 % by weight to about 8 % by weight. The components of the effervescent composition are preferably dried and sieved as necessary prior to formulating.

The effervescent composition is preferably stored in a moisture-proof package including, e.g., sealed metal foil pouches, blister packs, and desiccant capped tubes. Useful packaging materials further include metal foil, plastic films, and blister packaging.

The effervescent composition can be administered by adding the composition to excess water or vice versa, e.g., an eight ounce glass of tap water, to form an aqueous composition, followed by ingestion. After addition of the effervescent composition to an aqueous liquid, the composition optionally can be stirred to facilitate dispersion and/or dissolution of the composition in the aqueous liquid.

The effervescent composition formulated for tableting is well suited to the mass production of effervescent tablets that are free from picking, die wall etching, capping and lamination. Any suitable tablet mass production equipment and processes can be used. Examples of useful tableting processes for effervescent compositions are described in Pharmaceutical Dosage Forms, Vol. 1, (Herbert A. Lieberman et al. eds, 2^nd ed. 1989) and incorporated herein. The tablets can then be manufactured in an automated process in which multiple dies of a tablet press are filled sequentially or simultaneously with the effervescent composition, two punches compress the effervescent composition to form the tablet(s), and then the tablet(s) is ejected from the die. The tablet is then placed in packaging material, which is then sealed to form an air tight sealed package. The packaged tablet can be further processed by conveying it to other processing stations including, e.g., additional packaging stations for further packaging, e.g., boxing and bagging.

The tablet manufacturing and initial packing operations are preferably performed in a controlled environment in which the temperature and humidity are controlled.

Preferably the controlled environment has less than 18 grains, less than 16 grains, or even less than 15 grains of moisture.

Other useful methods of making effervescent tablets, as well as coated tablets, sustained release tablets, coated particles, and chewable tablets, are disclosed in Pharmaceutical Dosage Forms, VoIs. 1-3, (Lieberman et al. eds. 2^d ed. 1989) and incorporated herein. A useful method of making quick dissolve tablets is disclosed in U.S. Patent No. 6,368,625 and incorporated herein.

One example of a suitable chewing gum formulation includes guava extract and a chewing gum base. A useful chewing gum base includes a water-soluble bulk portion, a water-insoluble chewable gum base portion, and, optionally, a flavor agent. The water- soluble portion dissipates with a portion of the flavoring agent over a period of time during chewing. The gum base portion is retained in the mouth throughout the chew. Useful water-insoluble gum bases include, e.g., elastomers, resins, fats, oils, softeners, inorganic fillers, and combinations thereof. The water-insoluble gum base may optionally include wax. The chewing gum preferably includes from about 5 % by weight to about 95 % by weight, from about 10 % by weight to about 50 % by weight, or even from about 25 % by weight to about 35 % by weight water-insoluble gum base.

An example of a useful water-insoluble gum base includes from about 20 % by weight to about 60 % by weight synthetic elastomer, from about 0 % by weight to about 30 % by weight natural elastomer, from about 5 % by weight to about 55 % by weight plasticizer, from about 4 % by weight to about 35 % by weight filler, from about 5 % to about 35 % by weight softener, and optionally minor amounts (i.e., no greater than about 1 % by weight) of additives including, e.g., coloring agents, antioxidants, flavor agents, and combinations thereof. Useful synthetic elastomers include, e.g., polyisobutylene (e.g., polyisobutylene having a weight average molecular weight of from about 10,000 to about 95,000, or even from about 50,000 to 80,000), isobutylene-isoprene copolymer (butyl elastomer), styrene- butadiene, copolymers of styrene-butadiene wherein the styrene to butadiene ratio is from about 1:3 to about 3:1, or even from about 1 :1 to about 1 :3, polyvinyl acetate (e.g., polyvinyl acetate having a weight average molecular weight of from about 2,000 to about 90,000, or even from about 10,000 to about 65,000), polyisoprene, polyethylene, vinyl acetate-vinyl laurate copolymers (e.g., vinyl laurate copolymers having a vinyl laurate content from about 5 % by weight to about 50 % by weight, or even from about 10 % by weight to about 45 % by weight), and combinations thereof. Useful natural elastomers include, e.g., natural rubber (e.g., smoked latex, liquid latex, and guayule), natural gums (e.g., jelutong, lechi caspi, perillo, sorva, massaranduba balata, massaranduba chocolate, nispero, rosindinha, chicle, gutta hang kang, and combinations thereof), and combinations thereof.

Useful elastomer plasticizers include, e.g., natural rosin esters (e.g., glycerol esters of partially hydrogenated rosin, glycerol esters of polymerized rosin, glycerol esters of partially dimerized rosin, glycerol esters of rosin, pentaerythritol esters of partially hydrogenated rosin, methyl and partially hydrogenated methyl esters of rosin, pentaerythritol esters of rosin), synthetic plasticizers including, e.g., terpene resins derived from alpha-pinene, beta-pinene, d-limonene, and combinations thereof, and combinations thereof. Useful fillers and texturizers include, e.g., magnesium carbonate, calcium carbonate, ground limestone, silicates (e.g., magnesium silicate and aluminum silicate), clay, alumina, talc, titanium oxide, mono-, di- and tri-calcium phosphate, cellulose polymers, and combinations thereof.

Useful softeners and emulsifiers include, e.g., tallow, hydrogenated tallow, hydrogenated and partially hydrogenated vegetable oils, cocoa butter, glycerol monostearate, glycerol triacetate, lecithin, mono-, di- and triglycerides, acetylated monoglycerides, fatty acids (e.g. stearic, palmitic, oleic and linoleic acids), and combinations thereof

Useful coloring agents including whiteners include, e.g., FD&C-type dyes and lakes, fruit and vegetable extracts, titanium dioxide, and combinations thereof.

The gum base can optionally include wax. An example of a wax-free gum base is disclosed in U.S. Pat. No. 5,286,500, the disclosure of which is incorporated herein by reference.

The water soluble bulk portion can include bulk sweeteners, high intensity sweeteners, flavoring agents, softeners, emulsifiers, colors, acidulants, fillers, antioxidants, and combinations thereof.

Softeners are added to the chewing gum in order to optimize the chewability and mouth feel of the gum. The softeners, which are also known as plasticizers and plasticizing agents, generally constitute from about 0.5 % by weight to about 15 % by weight of the chewing gum. Suitable softeners include, e.g., glycerin, lecithin, and combinations thereof. Aqueous sweetener solutions such as those containing sorbitol, hydrogenated starch hydrolysates, corn syrup, and combinations thereof, can also be used as softeners and binding agents in chewing gum.

Bulk sweeteners include both sugar and sugarless components. The chewing gum can include from about 5 % by weight to about 95 % by weight, from about 20 % by weight to about 80 % by weight, or even from about 30 % by weight to about 60 % by weight bulk sweetener. Sugar sweeteners generally include saccharide-containing components including, e.g., sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose, levulose, glactose, corn syrup solids, and combinations thereof. Sugarless sweeteners include, e.g., sugar alcohols such as sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, and combinations thereof.

The gum can optionally include artificial sweeteners including, e.g., sucralose, aspartame, N-substituted APM derivatives such as neotame, salts of acesulfame, altitame, saccharin and its salts, cyclamic acid and its salts, glycyrrhizinate, dihydrochalcones, thaumatin, monellin, and combinations thereof. In order to provide longer lasting sweetness and flavor perception, it may be desirable to encapsulate or otherwise control the release of at least a portion of the artificial sweetener. Such techniques as wet granulation, wax granulation, spray drying, spray chilling, fluid bed coating, coacervation, and fiber extension may be used to achieve the desired release characteristics.

Combinations of sugar and sugarless sweeteners may be used in chewing gum. Additionally, the softener may also provide additional sweetness such as with aqueous sugar or alditol solutions.

Useful low calorie bulking agents include, e.g., polydextrose, raftilose, raftilin, fructooligosaccharides, palatinose oligosaccharide, guar gum hydrolysate, indigestible dextrin, and combinations thereof. A variety of flavoring agents can are also suitable including, e.g., essential oils, synthetic flavors or mixtures thereof including, but not limited to, oils derived from plants and fruits such as citrus oils, fruit essences, peppermint oil, spearmint oil, other mint oils, clove oil, oil of wintergreen, anise and the like. Artificial flavoring agents and components may also be used. Natural and artificial flavoring agents may be combined in any sensorially acceptable fashion. The flavor agent can be present in the gum in amounts of from about 0.1 % by weight to about 15 % by weight gum, or even from about 0.2 % by weight to about 5 % by weight.

Useful methods of manufacturing chewing gum base and the chewing gum end product are disclosed in, e.g., U.S. 6,949,264 (McGrew et al), 3,995,064 (Ehrgott et al.) and 4,459,311 (DeTora et al.) U.S. 5,045,325 (Lesko et al.), and. 4,555,407 ( Kramer et al.), 4,968,511 (D'Amelia et al.), 5,543,160, 5,800,847, 5,397,580, 5,523,097, 5,419,919 and 5,571,543, European Publication No. 0,273,809 (General Foods France), French Publication No. 2,635,441 (General Foods France) and incorporated herein.

The invention will now be described by way of the following examples. EXAMPLES

Test Procedures

Test procedures used in the examples include the following. All ratios and percentages are by weight unless otherwise indicated.

Formula 1

An effervescent tablet is prepared by combining the following ingredients with manual mixing until uniform to form a base: 900 mg sorbitol instant, 850 mg No. 5 sodium bicarbonate, 100 mg sodium carbonate grade 50, and 1000 mg dried wild guava leaf extract (boiling water soluble extract). Each of the ingredients is sieved through a number 12 sieve prior to combining.

To 2850 mg of the base is added 1500 mg citric acid anhydrous fine granular, 30 mg mineral oil, 25 mg sucralose, 150 mg natural orange flavor, 35 mg natural tangerine flavor, 25 mg natural grapefruit flavor, and 15 mg natural peach flavor.

The composition is then formed into tablets using a tablet press to an average mass of 4.64 g, average thickness of 0.261 in, and average hardness of 8 kP. The tablets are expected to disintegrate in one minute 40 seconds in room temperature tap water to a black suspension of guava. Some sediment is expected on the bottom of the glass. The taste is expected to be good. Formula 2

To 2850 mg of the base prepared above in Formula 1 is added 1500 mg citric acid anhydrous fine granular, 25.2 mg mineral oil, 25 mg sucralose, 150 mg a natural and artificial orange flavor blend, 35 mg natural tangerine flavor, 25 mg natural grapefruit flavor, 15 mg natural peach flavor, and 5 mg FD&C Red food coloring number 40.

The composition is then formed into tablets using a tablet press to an average mass of 4.74 g, average thickness of 0.272 in and average hardness of 7.1 kP. The tablets are expected to disintegrate in two minutes in room temperature tap water to a dispersion having black foam on the surface includes particulate suspended throughout, and a deep red purple color.

Example 1

A female subject, over the prior eight month period, experiences migraine just prior to and during menstruation. The subject frequently experiences visual sensitivity (e.g., spots and sensitivity to light) and auditory sensitivity prior to the onset of the migraine. The migraines last for a period of from one to two days. The subject also experiences headaches during four out of every seven days.

The subject ingests 1000 mg guava extract each morning on a daily basis for a period of one week. The guava extract is in the form of the effervescent tablet of Formula 2. The effervescent tablet is first added to a glass of tap water (approximately 20 ounces), and allowed to disintegrate in the water prior to ingestion.

At the end of one week, menstruation starts. The subject experiences a dull headache (not a migraine headache) but does not experience visual sensitivity, does not see spots, is not sensitive to light, and does not experience auditory sensitivity, all symptoms that previously alert her to the fact that she is going to experience a migraine.

The subject continues to ingest 1000 mg guava extract in the manner described above on a daily basis. After four weeks the subject had not experienced a migraine.

Example 2 A female subject has a history of migraines (she experienced 61 days of migraines over a period of six months). The subject began ingesting a 1000 mg dose of guava extract each morning on a daily basis. On the second day, the subject did not have a migraine. On the third day the subject had a headache that turned into a migraine over days four and five. The subject did not experience another migraine over days 6-17. During days 1-7 the subject was also ingesting 50 mg amitriptyline and 175 mg TOPAMAX topiramate. During days 8-12 the subject was also ingesting 50 mg amitriptyline and 150 mg TOPAMAX. During days 13- 17 the subject was also ingesting 50 mg amitriptyline and 125 mg TOPAMAX.

The dose of guava extract ingested by the subject was in the form of the effervescent tablet of Formula 2. The effervescent tablet was first added to a glass of tap water, and allowed to disintegrate prior to ingestion.

Example 3

A female subject has a history of experiencing a migraine once every seven days. The subject begins ingesting a 1000 mg dose of guava extract, prepared according to Formula 2, each morning on a daily basis. After ten days of ingesting the guava extract the subject had not experienced a migraine.

Other embodiments are within the claims. Although the use of guava has been discussed herein with respect to the extract of a part of the guava plant, the use optionally includes administering a part of the guava plant that is a mechanically or chemically altered form of the guava plant part. Such alterations include, e.g., pulverized, powdered, and liquid parts of the guava plant. Such altered forms can also be formulated into a dosage form that also includes a suitable pharmaceutical carrier.

What is claimed is:

Claims

1. A method of using guava extract comprising: administering guava extract to an individual prone to experiencing the symptoms of a migraine.

2. The method of claim 2, wherein the individual is experiencing migraine with aura.

3. The method of claim 1 further comprising administering said guava extract to the individual on a daily basis.

4. The method of claim 1, wherein said guava extract is in an oral effervescent dosage form.

5. The method of claim 5, wherein said oral effervescent dosage form is an effervescent tablet.

6. The method of claim 1 , wherein said guava extract is in the form of a unit dosage comprising from about 500 to about 2000 milligrams guava extract.

7. The method of claim 1 , wherein said guava extract comprises an extract of the leaves of a guava plant.

8. The method of claim 1 , wherein said guava extract comprises a water- soluble extract of guava leaves.

9. The method of claim 1, wherein said guava extract comprises at least one of an organic solvent soluble extract of guava leaves and an oil soluble extract of guava leaves.

10. The method of claim 1 , wherein the individual is experiencing at least one symptom of a migraine.

11. The method of claim 1 , wherein said administering farther comprises administering said at least 500 mg guava extract to the individual on a daily basis starting at least about seven days before the onset of menstruation in the individual, and continuing said administration on a daily basis at least until menstruation starts.

12. The method of claim 11 , wherein said administration is continued on a daily basis for a period of at least two days after menstruation starts.

13. The method of claim 11, wherein said administration is continued on a daily basis for a period of at least three days after menstruation starts.

14. The method of claim 11 , wherein said guava extract is in an oral effervescent dosage form comprising said guava extract and an effervescent couple comprising an acid and a base, a binder and a lubricant.

15. The method of claim 14, wherein said oral effervescent dosage form is in the form of an effervescent tablet.

16. The method of claim 11 , wherein said guava extract is in a unit dosage form comprising from about 500 milligrams to about 2000 milligrams guava extract.

17. The method of claim 11 , wherein said guava extract is in a unit dosage form comprising at least about 1000 milligrams guava extract.

18. The method of claim 11 , wherein said guava extract comprises a water- soluble extract of guava leaves.

19. The method of claim 11, wherein said guava extract comprises at least one of an organic solvent soluble extract of guava leaves and an oil soluble extract of guava leaves.

20. A use of guava extract for the preparation of a composition for decreasing the pain associated with a migraine in a mammal.