HK1158058B - Method of treating migraine using guava - Google Patents

Description

Method for treating migraine by using guava

Background

The invention relates to the treatment of migraine with guava.

People with migraine headaches often describe this pain as a pulsatile or throbbing sensation in an area of the head. Blood vessels contract and dilate in migraine. Common migraine headache persists for 4-72 hours. Humans are very sensitive to light and sound during migraine. Some people with migraine headache experience warning signs such as flashing lights, zig-zag, blind spots, temporary visual loss, or aura in the form of unpleasant odors. These symptoms are often referred to as "auras" and these types of migraine are referred to as "classic migraine". Migraine headache is often accompanied by nausea, vomiting, and increased sensitivity to light and noise. In many cases, migraine headache has disability. A number of stimuli have been described that contribute to the development of migraine, including certain foods and beverages (e.g., chocolate or wine), stress, and menstruation.

Common migraine ("common migraine") is the most common migraine, and is characterized by painful headaches that are more severe and persist for a longer period of time than general headaches. People with common migraine do not experience the pre-headache aura, but many do complain of paresthesia fatigue, inability to concentrate and mood changes. To be classified as 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 as to interfere with normal activity, or pain that may be caused or exacerbated by normal physical activity.

Migraine is more common in women, three times as common as men. Menstrual-related migraine (MRM) is common in women and is associated with a number of disabilities. MRM attacks are more severe, longer lasting and less responsive to analgesics than non-menstrual migraine.

There is currently no known cure for migraine. Migraine treatment may include pain-relieving medication, known as acute or abortive treatment. Pain relief medications are taken at the time of a migraine attack and are designed to arrest the symptoms that have already begun. Examples of pain relief drugs include nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and aspirin, and marketed drugs specifically for migraine use such as acetaminophen (acetaminophen), aspirin and caffeine in combination. NSAIDs can cause ulcers, gastrointestinal bleeding, and rebound headaches if taken too frequently or for an extended period of time.

It is also common to reduce the severity and frequency of migraine headaches by taking prophylactic medications regularly on a daily basis. Many people with severe migraine attacks take triptans (triptans). Triptans are reported to be effective in relieving pain, nausea, and sensitivity to light and sound associated with migraine. Examples of triptan-like drugs include sumatriptan (sumatriptan), rizatriptan (rizatriptan), naratriptan (naratriptan), zolmitriptan (zolmitriptan), almotriptan (almotriptan), frovatriptan (frovatriptan), and eletriptan (eletriptan). Side effects of triptans include nausea, dizziness, muscle weakness, and less common strokes and heart attacks. Ergotamine and dihydroergotamine have also been used as prescriptions for migraine.

The guava plant (psidium guajava L) has been used by many cultures as a source of nutrition, and its fruit can be made into juice and jelly for consumption, as well as in other food products. Guava plant parts have been used by various cultures to treat diarrhea and gum pain (sore gums). Guava plants have also been studied to determine their effects on various human conditions including diabetes and obesity. Guava extracts have been used to reduce, prevent or inhibit hangover effects (including headache) and to reduce blood alcohol levels in drunk individuals. Such use is described in U.S. patent No. 7,247,324 (Wehling et al).

Migraine headache differs from a common headache, such as a hangover headache, in that the pain of migraine headache is significantly more severe than the pain of a common headache, which is not accompanied by the other features of migraine headache mentioned above, and the pain of migraine headache is often aggravated by physical strain, whereas the pain of a common headache is not. Conventional headaches can also be successfully treated with standard over-the-counter medications such as aspirin, acetaminophen, and ibuprofen.

Summary of The Invention

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

In one aspect, the present invention relates to a method of using guava extract, comprising administering guava extract to an individual experiencing at least one symptom of migraine to reduce migraine. In one embodiment, the individual has migraine headache with aura. In another embodiment, the method comprises administering the guava extract daily.

In some embodiments, the guava extract is an extract of a leaf 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 embodiments, the guava extract is in a unit dosage form comprising from about 500 to about 2000 milligrams of guava extract. In other embodiments, the guava extract is in a unit dosage form comprising at least about 1000mg of guava extract.

In another aspect, the invention relates to a method of using guava extract, comprising administering guava extract (e.g., extract derived from the leaves of a guava plant) to an individual susceptible to migraine to prevent migraine. In one embodiment, the guava extract is administered in an amount of at least 500 mg. In some embodiments, the administering comprises administering to the individual a guava extract (e.g., at least about 500mg of guava extract) daily beginning at least about seven days prior to the onset of menstruation for a duration of at least until the onset of menstruation. In another embodiment, the administration is for a period of at least two days after the onset of menstruation. In other embodiments, the administration is for a period of at least three days after onset of menstruation. In other embodiments, the administering comprises administering at least about 500mg of guava extract per day to an individual susceptible to menstrual-related migraine.

In some embodiments, the guava extract is in the form of an oral effervescent dosage form comprising guava extract and an effervescent conjugate comprising an acid and a base, a binder, and a lubricant.

In another embodiment, the guava extract comprises a water-soluble extract of guava leaves. In one embodiment, the guava extract comprises at least one of an organic solvent-soluble extract of guava leaves and an oil-soluble extract of guava leaves.

In another aspect, the present invention relates to the use of guava extract in the preparation of a composition for alleviating pain associated with migraine headache in a mammal.

The present invention relates to a therapeutic method for preventing migraine and reducing the severity of migraine pain in some individuals and for reducing or eliminating migraine-associated pain and other associated symptoms in some individuals. In some individuals, the treatment methods may also reduce the frequency of migraine.

Other features and advantages will be apparent from the following description of the preferred embodiments and the appended claims.

Glossary

For the purposes of the present invention, these terms have the following meanings:

the term "migraine" as used herein refers to pain in the head: 1) wherein the pain occurs on only one side of the head, 2) with increased sensitivity to light, sound, or a combination thereof, 3) with aura (e.g., flashing lights, zig-zag meanders, blind spots, temporary visual loss, unpleasant odors, or a combination thereof), 4) with nausea, 5) with vomiting, 6) so severe as to interfere with normal activities, 7) caused or exacerbated by normal physical activities, or a combination thereof.

The term "unit dose" as used herein refers to a physically discrete unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect.

The term "oral dosage form" as used herein is generally used to refer to products for oral administration.

The term "carrier" as used herein means a substance used in conjunction with guava to facilitate administration of guava.

The term "pharmaceutically acceptable" when used as an adjective herein means substantially non-toxic and substantially non-injurious to a recipient.

Detailed Description

The methods of using guava extract include administering to an individual an amount of guava extract sufficient to reduce, preferably eliminate, more preferably prevent, at least one symptom associated with migraine (e.g., pain, sensitivity to light, sound, and odor, nausea, and loss of vision), frequency of migraine, and combinations thereof. The methods can be used to treat individuals suffering from migraine, susceptible to migraine, and combinations thereof.

The guava extract can be administered either neat, prophylactically, or in a combination thereof, depending on the individual need. A useful method of treating migraine headache comprises administering guava extract at an onset of an indication (i.e., warning) indicative of an impending migraine headache, at the onset of symptoms of migraine headache, and combinations thereof. In cases where migraine headache occurs repeatedly or periodically in an individual, a useful treatment involves administering guava extract daily. Another useful treatment involves administering guava extract daily beginning at least two days, at least five days, or even at least seven days prior to the predicted onset of migraine symptoms when an individual experiences migraine headaches on a periodic basis and the period is relatively predictable (e.g., based on the individual's history of migraine headaches). For the amount and frequency, the guava extract can be ingested daily for a period of time that is typically experienced with migraine headache, and then altered or stopped by the individual after the predicted migraine pain has ended, e.g., at least one, at least two, or even at least three days after the day on which migraine should occur, or after the day on which migraine should disappear, depending on the past experience of the individual.

Preferably, administration of guava extract is gradually reduced in frequency, amount, or a combination thereof after a period of time during which the guava extract treatment is effective. The rate and nature of the reduction is preferably associated with a reduction in migraine frequency and severity.

In the case of menstruation-related migraine headaches, one useful treatment involves administering guava extract daily beginning at least about one, at least about two, at least about three, or even at least about seven days before the first day of menstruation and continuing daily administration of guava extract at least on the first day of menstruation, up to the second day of menstruation, or even up to the third day of menstruation. Administration of guava extract may optionally be stopped for a period of time and then restarted as described above. Alternatively, guava extract may be administered daily to individuals predisposed to menstrual-related migraine.

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

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

For ease of reference, the guava is referred to herein as guava extract. However, it is to be understood that the guava can take a variety of forms including, for example, the fruit, leaves, roots, stems of the guava plant, components derived from the above parts (e.g., fruit juice), and combinations thereof.

Preferably, the guava extract is administered in a dosage form comprising a suitable carrier. Useful carriers include, for example, excipients, diluents, binders, lubricants, disintegrants, colorants, sweeteners, and combinations thereof including, for example, carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic materials, hydrophobic materials, gelatin, oils, organic solvents, water, and combinations thereof. The choice of carrier depends on the mode of administration of the guava extract.

The effective amount of guava extract varies depending on a number of factors, including, for example, the physical characteristics of the individual (e.g., height, weight, age, and physical health), the source and form of guava, the severity, nature, and frequency of migraine pain. Preferably, the guava extract is provided in a unit dosage form that can be administered in a single dose or in multiple doses. The effective dose for a given individual will generally be set at the discretion of the individual. The guava extract is generally effective over a wide dosage range. Useful amounts have been found to include administration of at least about 100mg guava extract per 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 per day.

The dose may optionally be administered more than once per day, including, for example, at least two times a day, at least three times a day, or even at least five times a day. More than one dose may also be administered in each administration (e.g., at least two 250mg guava extract dosage units or even at least two 500mg guava extract dosage units per day).

The guava extract medicament may comprise pure guava extract, i.e. the medicament does not contain other components, or it may comprise components other than guava, including, for example, various carriers. Preferably, the medicament comprises 0.1-100%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40% by weight guava extract.

The guava extract medicament may optionally comprise wetting agents, lubricating agents, emulsifying agents, suspending agents, preservatives, sweetening agents, stabilizing agents, flavoring agents, coloring agents and combinations thereof, useful examples of which are described below.

The guava extract medicament may be provided in a variety of packages including foil pouches, tubes (e.g., plastic and metal tubes), ampoules, multi-dose containers. The package is preferably air-tight and moisture-impermeable.

The guava extract can be administered in any convenient manner, including, for example, by oral, intravenous, subcutaneous, intramuscular, subcutaneous routes, and combinations thereof. Oral administration can be in any suitable dosage form, including, for example, powders (e.g., effervescent powders and powdered beverage mixtures), tablets (e.g., fast dissolving tablets), granules (e.g., effervescent granules, chewable granules), pills, capsules, soft gelatin capsules, composites (e.g., stacked tablet structures, structures comprising a continuous phase and a discontinuous phase), chewable dosage forms including chewable and chewable tablets, wafers (e.g., disintegrating and dissolving tablets), liquid formulations (e.g., solutions and dispersions), e.g., beverages such as canned and bottled beverages, dry or liquid aerosols that can be inhaled or sprayed, and combinations thereof. The guava extract may be provided in the form of a sterile solution by direct injection into the bloodstream of the subject being treated. The guava extract is preferably formulated to provide a dose-controlled guava extract, an easily ingestible, and easily manipulable dosage form.

One example of a useful effervescent composition of guava extract includes guava extract and an effervescent agent (also referred to as an effervescent conjugate) that includes an acid and a base. The effervescent composition forms a gas when placed in a suitable volume of water. The effervescent composition also disintegrates, preferably dissolves, when placed in a sufficient amount of water. Preferably, the guava extract is dried and sieved to a suitable particle size (e.g., using a No. 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 sachet of tablets or powder particles) comprising at least about 250mg, at least about 500mg, at least about 800mg, at least about 1000mg, at least about 1500mg, or even at least about 2000mg of guava extract.

The effervescent agent is activated upon contact with an aqueous liquid such as water (e.g., when the powder or tablet is placed in a glass of water). The water releases the acid and base, which react with each other to produce carbon dioxide gas, which carbonates the aqueous composition. Examples of acids useful for the effervescent conjugates include citric acid, ascorbic acid, aspartic acid, malic acid, adipic acid, tartaric acid, fumaric acid, succinic acid, sodium acid pyrophosphate, lactic acid, cyclohexanesulfonic acid, amino acids, acid salts and anhydrides of the above acids, and mixtures thereof. Examples of useful anhydrides include citraconic anhydride, glucono-D-lactone, and succinic anhydride. Examples of useful acid salts include potassium hydrogen tartrate, acid citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium hydrogen sulfite, and combinations thereof. Preferably, the acid is present in the effervescent composition in an amount of from 10 wt% to about 60 wt%, from about 15 wt% to about 50 wt%, or even from about 25 wt% to about 40 wt%.

The base of the effervescent conjugate is preferably capable of generating a gas such as carbon dioxide. Examples of suitable carbonate bases include sodium bicarbonate, sodium carbonate, trisodium dicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, magnesium oxide, sodium glycine carbonate, L-lysine carbonate, arginine carbonate, zinc oxide, amino acid carbonates, and mixtures thereof. Preferably, the effervescent composition comprises a base in an amount of 10 wt.% to about 60 wt.%, about 15 wt.% to about 50 wt.%, or even about 25 wt.% to about 40 wt.%.

The effervescent composition can optionally include various other active agents including, for example, vitamins, amino acids, medicaments, minerals, food supplements, and combinations thereof. Suitable vitamins include, for example, ascorbic acid (vitamin C), aspartic acid, thiamine, riboflavin, niacin, pantothenic acid, pyridoxine, biotin, folic acid, niacin, vitamin B12, lipoic acid, vitamin a, vitamin D, vitamin E, vitamin K and its coenzymes, choline, carnitine and alpha-, beta-, gamma-carotene. Examples of coenzymes include thiamine pyrophosphate, flavin mononucleotide, flavin adenine dinucleotide, nicotinamide adenine dinucleotide phosphate coenzyme A pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme B12, lipoic acid lysine, 11-cis-retinal, 1, 25-dihydroxycholecalciferol, and mixtures thereof.

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

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

Suitable food supplements include, for example, bee pollen, bran, wheat germ, seaweed, cod liver oil, ginseng, fish oil, amino acids, proteins, vitamins, minerals, alpha-glycerophosphorylcholine, acetyl-L-carnitine and salts thereof, docosahexaenoic acid, cranberry (cranberry) extract, chondroitin, methylsulfonylmethane, and mixtures thereof.

The effervescent composition may also contain other ingredients including, for example, flavoring agents, fillers, surfactants (e.g., polysorbate 80 and sodium lauryl sulfate), coloring agents including, for example, dyes and pigments, sweeteners, and flow agents.

Useful flavoring agents include natural and artificial flavoring agents including, for example, volatile oils, synthetic flavoring oils, flavoring aromatics, oils, liquids, oleoresins, and extracts of plants, leaves, flowers, fruits, stems, and combinations thereof. Useful flavoring agents include, for example, lemon oil such as lemon, orange, grape, lime and grapefruit, fruit essences including, for example, apple, pear, peach, grape, strawberry, raspberry (raspberry), cherry, plum, pineapple, apricot, and other fruit flavors, ice tea flavors, and combinations thereof. Other useful flavoring agents include, for example, 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), C-8 aldehyde (citrus fruit), C-9 aldehyde (citrus fruit), C-12 aldehyde (citrus fruit), tolualdehyde (cherry, almond), 2, 6-dimethyloctanal (green fruit), 2-dodecenal (citrus, Chinese orange), and mixtures thereof. Preferably, the effervescent composition comprises at least about 100mg, at least about 200mg, no more than about 500mg, or even no more than about 400mg of flavoring agent.

Useful colorants include, for example, food, pharmaceutical and cosmetic (FD & C) colorants, including, for example, dyes (e.g., FD & C No. 40 red), lakes, and certain natural and derived colorants. Useful lakes include dyes absorbed onto aluminum hydroxide and other suitable vehicles.

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

The effervescent composition may be provided in various forms including, for example, powders, granules, tablets, capsules, pellets, and composites. Preferred effervescent tablets have a hardness of at least 3 kilopounds (Kp), preferably at least 5Kp, from about 5Kp to about 10Kp, or even from about 5Kp to about 8Kp, as measured using a standard hardness tester equipped with a strain gauge.

When in the form of a tablet, the effervescent composition also preferably includes a binder, a lubricant, and combinations thereof. Examples of suitable binders include, for example, starch, natural gums, carboxymethylcellulose, microcrystalline cellulose, methylcellulose, cellulose ethers, sodium carboxymethylcellulose, ethylcellulose, gelatin, dextrose, lactose, sucrose, sorbitol, mannitol, polyethylene glycol, polyvinylpyrrolidone, pectin, alginate, polyacrylamide, polyvinyloxoazodone (polyvinyoxazolidone), polyvinyl alcohol, and mixtures thereof. Preferably, the binder is water soluble.

When 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 binder is preferably present in the composition in an amount of from 10 wt% to about 60 wt%, from about 15 wt% to about 50 wt%, or even from about 20 wt% to about 40 wt% or even 20-30 wt%.

Various lubricants are suitable for use in the effervescent compositions, 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 may also comprise water insoluble lubricants including, for example, stearates (e.g., magnesium stearate, calcium stearate, and zinc stearate), oils (e.g., mineral oil, hydrogenated and partially hydrogenated vegetable oil, cottonseed oil), and combinations thereof. Other water-insoluble lubricants include, for example, animal fats, polyoxyethylene monostearate, talc and combinations thereof.

The effervescent composition preferably includes a sufficient amount of lubricant to allow the composition to be formed into tablets and released from a high speed tablet press in tablet form. When present, the lubricant is preferably present in the composition in an amount of from 1 wt% to about 15 wt%, from about 1 wt% to about 12 wt%, from about 2 wt% to about 10 wt%, or even from about 3 wt% to about 8 wt%.

The components of the effervescent composition are preferably dried and sieved as required prior to formulation.

Preferably, the effervescent composition is stored in a moisture-proof package, including, for example, sealed metal foil pouches, blister packs, and dry lidding tubes. Useful packaging materials also include metal foils, plastic films, and blister packs.

The effervescent composition may be administered by adding the composition to an excess of water, such as a cup of 8 ounces of tap water, or vice versa, to form an aqueous composition for subsequent ingestion. After the effervescent composition is added to the aqueous liquid, the composition may optionally be stirred to facilitate dispersion and/or dissolution of the composition in the aqueous liquid.

The effervescent composition formulated for tableting is well suited for mass production of effervescent tablets without the need for sorting, die wall etching, capping and lamination. Any suitable tablet mass production equipment and process may be used. Examples of useful tableting processes for effervescent compositions are described in Pharmaceutical Dosage Forms (Pharmaceutical Dosage Forms) volume 1 (edited by Herbert a. lieberman et al, 2 nd edition 1989), which is incorporated herein. The tablets may be manufactured via an automated process in which a plurality of dies of a tablet press are filled sequentially or simultaneously with the effervescent composition, two punches compress the effervescent composition to form a tablet, and the tablet is then ejected from the dies. The tablets are then placed in a packaging material and then sealed to form a hermetically sealed package. The packaged tablets may be further processed by being transported to other processing stations including, for example, other packaging stations for further packaging such as boxing and bagging.

The manufacturing and initial packaging operations of the tablets are preferably performed in a controlled environment with controlled temperature and humidity. Preferably the controlled environment has less than 18 grains (grains), less than 16 grains, or even less than 15 grains of moisture.

Other useful methods for making effervescent tablets, as well as coated tablets, sustained release tablets, coated granules, and chewable tablets are described in Pharmaceutical Dosage Forms, Vol.1-3 (ed. Lieberman et al, 2 nd edition 1989), which is incorporated herein. U.S. patent No. 6,368,625, which is incorporated herein, discloses a useful method for making a fast dissolving tablet.

One example of a suitable chewing gum formulation includes guava extract and a chewing gum base. Useful chewing gum bases comprise a water-soluble body portion, a water-insoluble chewable gum base portion, and optionally flavoring agents. Upon chewing, the water soluble portion is consumed with a portion of the flavoring agent over a period of time. The gum base portion is retained throughout the chew. Useful water-insoluble gum bases include, for example, elastomers, resins, fats, oils, softeners, inorganic fillers, and combinations thereof. The water-insoluble gum base may optionally comprise a wax. The chewing gum preferably comprises from about 5 wt% to about 95 wt%, from about 10 wt% to about 50 wt%, or even from about 25 wt% to about 35 wt% of a water-insoluble gum base.

Examples of useful water-insoluble gum bases include about 20% to about 60% by weight synthetic elastomer, about 0% to about 30% by weight natural elastomer, about 5% to about 55% by weight plasticizer, about 4% to about 35% by weight filler, about 5% to about 35% by weight softener, and optionally include small amounts (i.e., no more than about 1% by weight) of additives including, for example, colorants, antioxidants, flavorants, and combinations thereof.

Useful synthetic elastomers include, for example, polyisobutylene (e.g., polyisobutylene having a weight average molecular weight of about 10,000 to about 95,000 or even about 50,000 to 80,000), isobutylene-isoprene copolymer (butyl elastomer), styrene-butadiene copolymer having a styrene to butadiene ratio of about 1: 3 to about 3: 1 or even about 1: 1 to about 1: 3, polyvinyl acetate (e.g., polyvinyl acetate having a weight average molecular weight of about 2,000 to about 90,000 or even about 10,000 to about 65,000), polyisoprene, polyethylene, vinyl acetate-vinyl laurate copolymer (e.g., vinyl laurate copolymer having a vinyl laurate content of about 5 wt% to about 50 wt% or even about 10 wt% to about 45 wt%), and combinations thereof.

Useful natural elastomers include, for example, natural rubbers (e.g., smoked latex (smoothers), liquid latex, and guayule (guayule)), natural gums (e.g., jelutong (jelutong), lechi (colle caspi), coumar (perillo), sorva (sorva), massaranduba balata (massaranduba balata), massaranduba cholla (massaranduba chocteta), nispello (nispero), canary (rosindinha), chicle (chicle), gutta percha (gutta hang kang), and combinations thereof.

Useful elastomer plasticizers include, for example, natural glycerol rosin esters (e.g., partially hydrogenated rosin glycerol ester, polymerized rosin glycerol ester, partially dimerized rosin glycerol ester, partially hydrogenated rosin pentaerythritol ester, rosin methyl ester, and rosin partially hydrogenated methyl ester, rosin pentaerythritol ester), synthetic plasticizers include, for example, terpene resins derived from alpha-pinene, beta-pinene, hespertene (d-limonene), and combinations thereof.

Useful fillers and forming agents (texturizers) include, for example, magnesium carbonate, calcium carbonate, ground limestone, silicates (e.g., magnesium silicate and aluminum silicate), clay, alumina, talc, titanium dioxide, monocalcium phosphate, dicalcium phosphate, tricalcium phosphate, cellulosic polymers, and combinations thereof.

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

Useful colorants, including brighteners, include, for example, FD & C type dyes and lakes, fruit and vegetable extracts, titanium dioxide, and combinations thereof.

The gum base may optionally include a wax. An example of a non-wax containing gum base is disclosed in U.S. patent No. 5,286,500, the contents of which are incorporated herein by reference.

The water-soluble body portion can comprise a bulk sweetener, a high intensity sweetener, a flavoring agent, a softener, an emulsifier, a coloring agent, an acidulant, a filler, an antioxidant, and combinations thereof.

Softeners are added to the chewing gum to optimize the chewability and mouth feel of the gum. The softeners, also known as plasticizers, typically comprise from about 0.5% to about 15% by weight of the chewing gum. Suitable emollients include, for example, glycerin, lecithin, and combinations thereof. Aqueous sweetener solutions such as those containing sorbitol, hydrogenated starch hydrolysates, corn syrup, and combinations thereof may also be used as softeners and binding agents for chewing gum.

Bulk sweeteners comprise sugar and a sugarless component. The chewing gum may comprise from about 5% to about 95%, from about 20% to about 80%, or even from about 30% to about 60% by weight bulk sweetener. Sugar sweeteners typically comprise sugar-containing components including, for example, sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose, galactose, corn syrup solids, and combinations thereof. Sugarless sweeteners include, for example, sugar alcohols such as sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, maltitol and combinations thereof.

The gums may optionally comprise artificial sweeteners including, for example, sucralose, aspartame, N-substituted APM derivatives such as neotame (neotame), acesulfame salts, alitame (alitame), saccharin and its salts, cyclamic acid and its salts, glycyrrhetate (glycyrrhetate), dihydrochalcones, thaumatin (thaumatin), monellin (monellin), and combinations thereof. To provide a 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. Techniques such as wet granulation, wax granulation, spray drying, spray cooling, fluid bed coating, coacervation, and fiber extension (fiber extension) may be used to achieve the desired release profile.

Combinations of sugar and sugarless sweeteners may be used in the chewing gum. In addition, the softener may also provide additional sweetness with, for example, aqueous sugar or sugar alcohol solutions.

Useful low calorie bulking agents include, for example, polydextrose, fructooligosaccharide (raftilose), inulin (raftilin), fructooligosaccharide, palatinose (palatinose) oligosaccharide, guar gum hydrolysate, indigestible dextrin, and combinations thereof.

Various flavoring agents are also suitable, including, for example, essential oils, synthetic flavors, and mixtures thereof, including but not limited to oils derived from plants and fruits, such as lemon oil, fruit essences, peppermint oil, spearmint oil, other mint oils, clove oil, wintergreen oil, anise oil, and the like. Artificial flavors and ingredients may also be used. Natural and artificial flavoring agents may be combined in any sensorially acceptable fashion. The flavoring agent is present in the gum in an amount of about 0.1% to about 15% or even about 0.2% to about 5% by weight.

Useful methods for making chewing gum bases and chewing gum end products are described, for example, in U.S. Pat. Nos. 6,949,264(McGrew et al), 3,995,064(Ehrgott et al), 4,459,311(DeTora et al), 5,045,325(Lesko et al), 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 and European patent publication No. 0,273,809 (General food company), French patent publication No. 2,635,441 (French General food company), which is incorporated herein.

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

Examples

Test method

The test methods for the examples include the following. All ratios and percentages are by weight unless otherwise indicated.

Formulation 1

Effervescent tablets were prepared by mixing the following ingredients by hand to form a uniform gum base. 900mg of instant sorbitol, 850mg of sodium bicarbonate # 5, 100mg of sodium carbonate grade 50 and 1000mg of dry guava leaf extract (boiling water soluble extract). The ingredients were sieved through a No. 12 sieve prior to mixing.

To 2850mg of the gum base was added 1500mg of anhydrous fine citric acid particles, 30mg of mineral oil, 25mg of sucralose, 150mg of natural orange flavoring, 35mg of natural citrus flavoring, 25mg of natural grapefruit flavoring, and 15mg of natural peach flavoring.

The composition was then formed into tablets having an average mass of 4.64g, an average thickness of 0.261 inch, and an average hardness of 8kP using a tablet press. At room temperature, the tablet is expected to disintegrate in tap water within 1 minute and 40 seconds to form a black guava suspension. Some settling at the bottom of the cup is expected. The taste is expected to be good.

Formulation 2

To 2850mg of the gum base prepared in formulation 1 above was added 1500mg of anhydrous fine citric acid particles, 25.2mg of mineral oil, 25mg of sucralose, 150mg of natural and artificial orange flavor blend, 35mg of natural citrus flavor, 25mg of natural grapefruit flavor, 15mg of natural peach flavor, and 5mg of fd & C food color No. 40 red.

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

Example 1

Female subjects experienced migraine headaches before and during menstruation within the first eight months. The subject often experiences visual (e.g., speckle and light sensitivity) and auditory sensitivity prior to a migraine attack. Migraine headache persists for a period of one to two days. The subject also experienced headache within four of every seven days.

The subject ingested 1000mg of guava extract daily in the morning for a week. The guava extract is in the form of effervescent tablets of formula 2. The effervescent tablet is first added to a glass of tap water (about 20 ounces) and allowed to disintegrate in water prior to ingestion.

At the end of the week, menstruation begins. The subject experienced mild headache (headache other than migraine) but did not experience visual sensitivity, no spotting, no light insensitivity and no auditory sensitivity, among other prior warnings that she would experience all symptoms of migraine.

The subject continued to ingest 1000mg of guava extract per day in the manner described above. After four weeks, the subject did not experience migraine.

Example 2

Female subjects had a history of migraine (migraine experienced for 61 days within six months).

The subject began ingesting a 1000mg daily dose of guava extract in the morning. The following day, the subject did not develop migraine. On day three, the subject developed headache, turning to migraine on day four and day five. The subject did not experience migraine again within days 6-17. The subject also ingested 50mg amitriptyline (amitriptyline) and 175mg Tolytidine (TOPAMAX) topiramate (topiramate) on days 1-7. The subject also ingested 50mg amitriptyline and 150mg tolbutate on days 8-12. The subject also ingested 50mg amitriptyline and 125mg tolbutate on days 13-17.

The guava extract medicament ingested by the subject is in the form of an effervescent tablet of formula 2. The effervescent tablet is first added to a glass of tap water, allowing it to disintegrate before ingestion.

Example 3

Female subjects had a history of experiencing migraine headaches every seven days. The subject began ingesting a 1000mg daily dose of guava extract prepared as described in formulation 2. 10 days after ingestion of the guava extract, the subject does not experience migraine.

Other implementations are within the scope of the following claims. Although the use of guava has been discussed herein with respect to the extraction of a portion of a guava plant, the use includes administering a portion of a guava plant that is a mechanically or chemically altered form of the guava plant. Such changes include, for example, pulverized, powdered, liquid portions of guava plants. Such modifications may also be formulated in a dosage form further comprising a suitable pharmaceutical carrier.

Claims (13)

1. Use of a water-soluble extract of guava leaf for the manufacture of a medicament for alleviating pain associated with migraine in a mammal, said medicament comprising at least 250mg of said water-soluble extract of guava leaf as the sole active ingredient.

2. The use of claim 1, wherein the medicament is in the form of an oral effervescent dosage form.

3. Use according to claim 2, wherein the oral effervescent dosage form is an effervescent tablet.

4. The use of claim 1, wherein said medicament is in a unit dosage form comprising at least about 500mg of a water-soluble extract of guava leaves.

5. The use of claim 1, wherein said medicament is in a unit dosage form comprising at least about 1000mg of a water-soluble extract of guava leaves.

6. The use of claim 1, wherein the medicament is in a unit dosage form comprising from about 500mg to about 2000mg of the water-soluble extract of guava leaves.

7. The use of claim 1, wherein the water soluble extract of guava leaf comprises a boiling water extract of guava leaf.

8. The use of claim 1, wherein the migraine-associated pain comprises at least one of head pain, light sensitivity, sound sensitivity, odor sensitivity, nausea, vomiting, visual loss, and combinations thereof.

9. The use of claim 1, wherein the migraine headache is a migraine headache that occurs with the onset of menstruation in an individual.

10. The use of claim 1, wherein the medicament is in an oral effervescent dosage form comprising a water soluble extract of the guava leaves and an effervescent conjugate comprising an acid and a base, a binder and a lubricant.

11. Use according to claim 10, wherein the oral effervescent dosage form is in the form of an effervescent tablet.

12. The use of claim 11, wherein said medicament is in a unit dosage form comprising at least about 500mg to about 2000mg of a water-soluble extract of guava leaves.

13. The use of claim 11, wherein said medicament is in a unit dosage form comprising at least about 1000mg of a water-soluble extract of guava leaves.