WO2007075408A2

WO2007075408A2 - Effervescent compositions for triptans

Info

Publication number: WO2007075408A2
Application number: PCT/US2006/047897
Authority: WO
Inventors: Marshall Hayward
Original assignee: Effrx, Inc.
Priority date: 2005-12-16
Filing date: 2006-12-18
Publication date: 2007-07-05
Also published as: WO2007075408A3

Abstract

The invention provides effervescent compositions comprising an analgesic agent and highly buffered, possibly carbonated solutions that are rapidly ejected from the stomach and absorbed by the body.

Description

EFFERVESCENT COMPOSITIONS FOR TRIPTANS

TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates generally to effervescent compositions comprising triptans as an active agent.

BACKGROUND OF THE₁ INVENTION

[0002] Many orally-administered drugs have slow onset of action due to the time required to absorb the drug from the stomach into the blood stream. Such a time delay is extremely undesirable in patients who seek an immediate relief of their symptoms. One approach is to administer such drugs in a highly buffered form, including effervescent forms. However, typical effervescent formulations contain only enough of an acid/alkaline buffer system to cause rapid dissolution of the drug in water, without regard to the subsequent behavior of the solution in the stomach. We have found that heavily buffered effervescent systems with high acid neutralizing capacity cause rapid ejection of selected active ingredients from the stomach, thus further decreasing the time for absorption thereby accelerating the onset of action. Delivery of the high buffering capacity that stimulates ejection from the stomach is not restricted to effervescent solutions, as the buffering components can also be delivered from swallow tablets, fast melt tablets, capsules, syrups, elixirs, or any orally administered dosage form.

A specific aim of this invention is to deliver sumatriptan to patients suffering from ailments accompanied by gastric stasis. Gastric stasis commonly occurs in conjunction with certain gastrointestinal maladies, and in disease states such as diabetes. Gastric stasis is often an early symptom or manifestation of migraine headache. If an individual that suffers from migraine recognizes the onset of symptoms (commonly known as 'aura') it is possible to abort the onset of migraine attack by the administration of analgesics or triptans, alone or in combination. Unfortunately, drugs administered orally during the onset of migraine accompanied by stasis may not be ejected from the stomach, in which case the therapeutic agents are thus not available for absorption from the gastrointestinal tract. Triptans can be effective in aborting acute migraine attack if delivered to the patient fast enough, as this class of drug must be delivered systemically to be effective. Sumatriptan, for example, generally shows a maximal plasma level (T_max) 2 hours after dosing, which can increases to an average of 2.5 hours or longer after dose administration during acute migraine. As an average, 2.5 hours is probably inadequate to abort a migraine attack. For those individuals experiencing a Tj_nax longer that 2.5 hours, the medication is not able to exert a therapeutic benefit in time to be useful in the blockage of a migraine attack.

We have found that highly buffered solutions enhance the absorption of the triptans, in particular the succinate salt of sumatriptan, at doses corresponding to normally accepted dose of such drugs in orally administered forms. For sumatriptan, this dose is calculated as the free base, at preferred amounts of at or between 25 mg and 50 mg per dose. The invention also relates to other drugs such as analgesic agents that can abort or shorten a migraine attack if the medicament is absorbed rapidly enough including triptans alone, analgesics alone or combinations that can ameliorate a migraine attack.

SUMMARY OF THE INVENTION

[0003] An object of the invention is to provide an improved effervescent composition comprising as the active agent and which, upon dissolution in water, has a buffered pH in the range of about 3.0 to about 6.0, and an acid neutralizing capacity (ANC) per dose of a minimum of 2 mEq or more, preferably 4 mEq or more, and more preferably 8 to 20 mEq per dose. [0004] The dosage form includes powders, tablets, granules or other forms that are dissolved in water prior to ingestion, or that are dissolved or dispersed in the mouth before swallowing, or that are swallowed whole as granules, tablets, capsules or the like that generate a buffered solution in the stomach which leads to rapid ejection of the administered dose from the stomach into the small intestine.

[0005] Another object is to provide effervescent compositions that contain citric acid or a similar organic acid in the acidic component, and an alkaline effervescing component comprising a carbonate salt and a bicarbonate salt, wherein the composition, when dissolved or dispersed in water provides an effervescent composition that contains the active agent, 10-60 % of citric acid (and/or citrate salts) based on the total weight of the composition, 10-40% carbonate salt and about 25% to about 50% bicarbonate salt based on the total weight of the acidic component and alkaline effervescing component.

[0006] Another object is an improved method for administering selected drugs in effervescent solution, comprising: administering to a subject in need thereof an effervescent solution having a buffered pH of 3.5 to about 6.0, obtained by dissolving 1 to about 6 grams of a solid composition in water; wherein said solid composition comprises

(a) an effective amount of an active ingredient (which may require modification to flavor or taste so that it is palatable, if the dosage form is delivered as a solution or mouth dispersing form. Sumatriptan is representative of the triptan class and" is described in US Patent No. 4,816,470; CAS number 103628-46-2 (for sumatriptan base), a suitable dosage range is 25-100 mg/dose, noting that this dose may be delivered in 5 to 25 mg increments).

(b) about 45 — 60 wt.% of an acidic component selected from the group consisting of citric acid, tartaric acid and alkali metal salts thereof,

(c) about 30 — 55 wt.% of an alkaline component selected from the group consisting of an alkali metal bicarbonate, an alkali metal carbonate and mixtures thereof.

(d) Tableting compression aids, processing or flow aids, flavors, sweeteners, lubricants, viscosity builders, desiccants, humectants, or other excipents to improve the processing or aesthetic properties of the dosage form.

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention provides a buffered effervescent composition comprising a therapeutically effective amount of an active agent , an acid component comprising citric acid and/or citrate salts, an alkaline effervescing component comprising a carbonate salt and a bicarbonate salt, and optionally a sweetener and/or a flavorant, wherein the addition of the composition to water provides an aqueous composition having a pH of about 3 to about 6.0 and a large amount of acid neutralizing capacity (ANC) per dose from 2 to about 20 mEq. [0002] Among other advantages, this type of composition gives improved onset of action of the triptans by causing rapid ejection of the solution from the stomach, leading to improved absorption and bioavailability of the active agent, and reduced side effects associated with the active agent. In this respect, it is believed that the effervescent composition provides an acid mediating effect on the stomach pH and the vigorous bubbling action provided by the high buffering capacity aids in moving the active agent rapidly into the intestinal tract and then into the bloodstream.

[0003] Because the absorption of the active agents into the blood stream is improved through the use of heavily buffered effervescent compositions compared to traditional formulations, the amount of active agent can optionally be reduced from that normally required. Thus, the effervescent composition of the invention may contain only 90 wt.% to about 75 wt.%, or even about 50 wt.% or less than the amount of active agent required in traditional formulations, without changing the amount of the active agent delivered to the bloodstream of the patient. [0004] The active agent can be any triptan, or an analgesic intended for the treatment of headache especially migraine headache. For example, the active agent can be a drug having low solubility in water, poor absorption into the blood stream, and/or low bioavailability. The active agent also can be a drug associated with a high occurrence of undesirable side effects, in particular gastrointestinal side effects.

[0005] It is not a specific objective of this disclosure to describe combination therapies, but in such instances where combinations of therapeutic agents can provide an improved therapeutic outcome if delivered from the rapid active preparation otherwise described herein, such combinations are embraced. Such combinations for the treatment of migraine include analgesics (including centrally acting and peripherally acting agents, whether narcotic or non-narcotic, and including the NSAIDs as well as acetaminophen, triptans, other CNS active agents, vasodilators, vasoconstrictors, and muscle relaxants. The ratios and specific combinations of the various agents is dependent upon the specific patient requirements in different therapeutic situations. [0006] The acid component comprises citric acid (e.g., citric acid anhydrous) and optionally other suitable acid components. The additional acid component(s) can be any suitable acid component. For example, the acid component can comprise citric acid in combination with any suitable organic or mineral acids, or salts thereof, that are safe for consumption and which provide for effective and rapid effervescent disintegration upon contact with water and the alkaline effervescent component. Suitable acid components can be selected from the group consisting of tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides, acid salts (e.g., sodium salts and potassium salts), mixtures of acid salts; acid salts of disodium dihydrogen pyrophosphate, acid citrate salts (e.g., monosodium citrate and disodium citrate) and other related organic acids and their salts, and combinations thereof. Preferably, the acid component comprises citric acid and an organic acid or salt, the latter preferably being monosodium citrate and/or monopotassium citrate. The use of non-sodium acid components is desirable for use with patients requiring electrolyte maintenance, e.g., hypertensive and other cardiac patients.

[0007] The following example further illustrates the invention but, of course, should not be construed as in any way limiting its scope.

EXAMPLE

[0008] This example illustrates an effervescent composition of the invention, which produces a buffered pH of about 5 to about 6.5 upon dissolution in water.

[0009] An effervescent tablet is formed from the ingredients listed in Table 1.

[0010] Table 1:

Ingredients Amount Function

Sumatriptan succinate 50 mg (base) Active pharmaceutical ingredient citric acid anhydrous 422 mg acid component monosodium citrate 1822 mg acid component sodium bicarbonate 806 mg alkaline component potassium bicarbonate 691 mg alkaline component sodium carbonate 160 mg alkaline component polyethylene glycol 6000 50 mg Solubilizer aspartame 30 mg sweetener orange flavor 70 mg Flavorant

[0011] All processes are performed under approximately 20% relative humidity. A portion of citric acid, a portion of sodium bicarbonate, a portion of potassium bicarbonate, a portion of sodium carbonate, and a portion of polyethylene glycol (Macrogo 16000) are homogeneously mixed in a high-speed mixer. The powders are wetted with a small amount of water. This wetting initiates a slight effervescent reaction between the acidic and the alkaline components. The wetted powders are dried with heat in a vacuum at a very low humidity until the powder achieves approximately 0.15 % loss on drying. After sieving for particle size, the dried granulate is mixed in a tumbler with the remaining ingredients. The tablet mixture is compressed on a suitable commercially available rotary tablet press. The dies are lined with nylon inserts and/or are lubricated with a thin film of paraffin oil or magnesium stearate, which is applied by spraying.

[0012] Typically, the acid component is present in the effervescent composition in an amount of about 25% to about 75% based on the total weight of the composition and the alkaline effervescing component is present in the effervescent composition in an amount of from about 20 % to about 60 % based on the total weight of the composition. In a preferred embodiment, the amount of citric acid is 10 — 40 % based on the total weight of the acid component and the alkaline effervescing component. The amount of carbonate salt may be 1.0 — 60 % based on the total weight of the acid component and the alkaline effervescing component. The amount of bicarbonate salt may be 20- 55 % (e.g., about 25% to about 50%, or about 30% to about 45%) based on the total weight of the acid component and the alkaline effervescing component. [0013] Preferably, the weight ratio of bicarbonate to carbonate salt should be controlled to provide optional performance of the effervescent formulation. In this regard, it is advantageous that the amount of bicarbonate salt may be at least about 4 times (e.g., preferably at least about 6 times, or more preferably at least about 8 times) the amount by weight of carbonate salt. In an especially preferred embodiment, the effervescent composition comprises about 10% to about 25% citric acid, about 35% to about 60% monosodium citrate, about 0.1% to about 10% carbonate salt, and about 25% to about 50% bicarbonate salt, based on the total weight of the acid component and the alkaline effervescing component.

[0014] Advantageously, the inventive effervescent composition may comprise an active agent, an acid component comprising about 10% to about 45% citric acid by weight based on the total weight of the acid component and the alkaline effervescing component, and an alkaline effervescing component comprising about 0.1 % to about 10% by weight carbonate salt and about 25% to about 50% by weight bicarbonate salt based on the total weight of the acid component and the alkaline effervescing component, the effervescent composition, when dissolved in water, providing an aqueous composition having a buffered pH of about 3 to about 6.5 (e.g., about pH 4 to about pH 6.5, or about pH 5 to about pH 6.5). Such a composition may preferably further include the weight ratios of bicarbonate salt to carbonate salt described above. [0015] The effervescent composition of the invention desirably has a pleasing taste. The taste of a pharmaceutical composition is important as it enhances the willingness of patients to utilize the dosage form. Many active agents have an objectionable taste that must be masked by the formulation in which the active agents are delivered. Therefore, the effervescent composition preferably comprises a sweetener, a fiavorant, or a combination thereof. It was also found that the effect of the latter is enhanced relative to known effervescent compositions due to the inventive nature of the present effervescent composition.

[0016] The fiavorant can be a natural or synthetic fiavorant. The fiavorant may be present in the effervescent composition in an amount of about 0.01% to about 10% (e.g., about 0.1 % to about 7.5%) based on the weight of the composition. Acceptable flavorants include members selected from the group consisting of volatile oils, synthetic flavor oils, oleoresins, plant extracts (e.g., green tea flavor), and combinations thereof. Desirable flavorants include a member selected from the group consisting of citrus oils such as lemon, orange, grape, lime and grapefruit; fruit essences such as apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, and apricot; and other fruit flavors. Other useful flavorants include aldehydes and esters such as benzaldehyde (cherry, almond), citral (lemon, lime), neral (lemon, lime), decanal (orange, lemon), C8-aldehyde (citrus fruits), C9aldehyde (citrus fruits), C12-aldehyde (citrus fruits), tolylaldehyde (cherry, almond), 2,6dimethyloctanal (green fruit), and 2-dodecenal (citrus, mandarin), and mixtures thereof. Preferably, the fiavorant is cherry, citrus, or orange. The fiavorant typically is present in the effervescent composition in an amount of about 10 mg to about 100 mg.

[0017] The sweetener can be any suitable natural or artificial sweetener, or a combination of natural and artificial sweeteners. Acceptable natural sweeteners include members selected from the group of glucose, dextrose, invert sugar, fructose, glycyrrhizic acid, and mixtures thereof. Typically, the natural sweetener may be present in the effervescent composition in an amount of S

about 10% to about 50% (e.g., about 20% to about 40%) based on the weight of the composition. Acceptable artificial sweeteners include members selected from the group consisting of saccharin; aspartame; chloroderivatives of sucrose such as sucralose, cyclamate, acesulfame-K; sugar alcohols such as sorbitol, mannitol, and xylitol; and mixtures thereof. Typically, the artificial sweetener may be present in the effervescent composition in an amount of about 0.01 to about 5% (e.g., about 0.1 to about 2.5%) based on the weight of the composition. Preferably, the sweetener is an artificial sweetener selected from the group consisting of aspartame, saccharin, acesulfame-K, xylitol, Splenda®, and combinations thereof. The effective concentration of a sweetener is determined by the strength of its sweetness, solubility, and masking ability for a specific active ingredient(s). For example, when the sweetener is aspartame, about 10 mg to about 50 mg aspartame is present in the effervescent composition. When the sweetener is saccharin, about 10 mg to about 30 mg saccharin is present in the effervescent composition. When the sweetener is acesulfame-K, about 10 mg to about 50 mg acesulfame-K is present in the effervescent composition. When the sweetener is xylitol, about 100 mg to about 400 mg xylitol is present in the effervescent composition. When the sweetener is Splenda®, about 10 mg to about 50 mg Splenda® is present in the effervescent composition.

[0018] The pH range of the buffered aqueous composition resulting from dissolution of the effervescent composition is desirably in the range of about 3 to about 6.5 (e.g., about 4 to about 6.5, or about 5 to about 6.5). Typically the upper limit of the stomach tolerance is about 10. However, the upper pH limit may further be limited by the pH tolerance of the ingredients included in the effervescent formulation. For example, the perceived flavor of a flavorant or sweetener can be affected by the pH of the buffered solution. Many flavorants undergo a chemical change causing the flavorants to lose or change their flavor at alkaline pH values (e.g., at pH values of about 7 or higher, or about 7.5 or higher). Thus, it has been found that selection of an appropriate buffered pH range for the effervescent composition of the invention requires a delicate balance of the pH considerations of the active agent (e.g., bioavailability and stability), as well as the considerations of the stomach tolerance and stability of inactive ingredients such as flavorants and sweeteners that are responsible for taste-masking.

[0019] The effervescent composition optionally further comprises a solubilizing agent, which aids in the transition of the active agent from the gastrointestinal tract to the blood by solubilizing the active agent and facilitating its transfer into the mucosal interface of the gastrointestinal tract. The solubilizing agent may be any suitable solubilizing agent. For example, the solubilizing agent may be a polyvinylpyrrolidone, a polyethylene glycol, a dextran, or a combination thereof. The polyvinylpyrrolidone and polyethylene glycol can have any suitable molecular weight. For example, the polyvinylpyrrolidone can have a molecular weight of about 20,000 g/mol to about 40,000 g/mol, preferably about 25,000 g/mol to about 35,000 g/mol, more preferably about 28,000 g/mol to about 32,000 g/mol. The polyethylene glycol can have a molecular weight of about 2000 g/mol to about 10,000 g/mol (e.g., about 4000 g/mol, about 6000 g/mol, or about 8000 g/mol). The dextran can be any suitable branched poly-D- glucoside having predominantly Cl_6 glycosidic bonds. In some embodiments, the solubilizing agent comprises both polyvinylpyrrolidone and polyethylene glycol. The solubilizing agent may be present in the effervescent composition in an amount of from about 0.1 % or more based on the weight of the composition. For example, about 0.1% to about 10% (e.g., about 1% to about 5%) based on the weight of the composition polyvinylpyrrolidone and/or about 20 mg to about 100 mg polyethylene glycol may be present in the effervescent composition. When the solubilizing agent is a dextran, about 1% to about 20%, preferably about 5% to about 15% (e.g., about 10%) dextran based on the weight of the composition can be present in the effervescent composition.

[0020] The effervescent compositions described above optionally further comprise a colorant. The colorant can be any suitable colorant including natural colorants, food, drug and cosmetics (FD&C) colorants, and drug and cosmetic (DScC) colorants. Suitable natural colorants include red beet powder and beta-carotene powder. The colorant can be present in any amount suitable to provide the desired coloration.

[0021] The effervescent compositions described above optionally further comprise other ingredients to aid in the formulation of the composition and/or for aesthetic purposes. Such other ingredients include, for example, fragrances, dyes, fillers such as calcium sulfate, starch, and binders. Desirable binders assist in tablet compression and can include starches, pregelatinized starches, gelatin, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, and polyvinylpyrrolidone. The binder can be present in any suitable amount, e.g., about 0.1 wt.% to about 10 wt.%. [0022] The effervescent compositions described above can be formulated as a tablet, granulate, or a powder. Suitable methods for producing the effervescent compositions of the invention include those described in U.S. Patents 4,687,662, 4,942,039, 5,348,745, 5,415,870, 5,480,652, 5,853,759, and 6,284,272. The acid component and the alkaline effervescing • component may be at least partially reacted with each other during granulation with the active agent.

[0023] The effervescent compositions described above optionally further comprise a disintegrant to enhance the disintegration of the compressed tablet in water. The disintegrant can be any suitable disintegrant. For example, the disintegrant can be starch, alginic acid, guar gum, kaolin, bentonite, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose. The disintegrant can be present in any suitable amount, e.g., about 0.1 wt.% to about 25 wt.%. [0024] The effervescent compositions described above optionally further comprise a lubricant, which is applied to tableting dies before the granular mixture is compressed into the effervescent tablet. Lubricants can include hydrogenated or partially hydrogenated vegetable oils such as corn oil, canola oil, cottonseed oil, sesame oil, soybean oil, grape seed oil, sunflower oil, safflower oil, olive oil, peanut oil, and combinations thereof. Lubricants can also include calcium stearate, magnesium stearate, zinc stearate, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineral oil, and combination thereof. Lubricants can form a hydrophobic coating on an effervescent tablet and affect the dissolution rate of the tablet. The preferred embodiment of the invention uses paraffin oil or magnesium stearate as a lubricant. Paraffin oil or magnesium stearate dust imparts desirable dissolution characteristics to the tablets and facilitates the highspeed production of the tablets. The lubricant can be present in any suitable amount, e.g., about 0.01 wt.% to about 5 wt.%.

[0025] Typically the effervescent composition of the invention has a total weight of about 3500 mg or more (e.g., about 4000 mg or more). In some embodiments, the effervescent composition has a total weight of about 5000 mg or more. Preferably, the effervescent composition has a total weight of about 500 mg to about 6000 mg (e.g., about 1500 mg to about 5000 mg). [0026] The effervescent composition of the invention, when formulated as a tablet, typically has a disintegration time of about 180 s or less (e.g., advantageously about 150 s or less, or preferably about 120 s or less) upon contact with about 60 ml of water. More preferably, the disintegration time of the effervescent tablet is about 90 s or less, and most preferably about 60 s or less. The disintegration time depends, at least in part, on the relative amounts of the "fast- reacting components" to the "slow-reacting components." Citric acid and carbonate salts react very fast with alkaline compounds and acid compounds, respectively, upon dissolution in water. Other effervescent components like monosodium citrate and bicarbonate salts react a bit slower with alkaline compounds and acid compounds, respectively, upon dissolution in water. It has been discovered that by balancing the relative amounts of the fast-reacting compounds to the slow-reacting compounds, an effervescent composition can be produced which has a fast disintegration time and, preferably also provides a clear solution that is substantially free or totally free of un-dissolved acid or alkaline effervescent components. Clear solutions are more aesthetically pleasing to patients than solutions containing suspended particles that can be seen by the naked eye.

[0027] The effervescent composition of the invention preferably is used in a method of treating a mammal. The method of treatment or prevention comprises combining an effective amount of the effervescent composition comprising the active agent with water to form at least a partial solution and administering the solution to the mammal (e.g., patient) orally. The amount of water typically is about 40 ml to about 250 ml (e.g., about 60 ml to about 200 ml). The effervescent composition can be administered to a mammal following a continuous schedule. The continuous schedule can be daily, once weekly, twice weekly, thrice weekly, biweekly, twice monthly, or monthly.

[0028] Desirably, administration of the buffer solution produced upon dissolution of the effervescent composition in water to a mammal (e.g., a patient) produces a stomach pH in the mammal of at least about 3 or greater (e.g., about 4 or greater), more preferably about 5 or greater (e.g., about 6 or greater). Typically, the pH of the mammal's stomach is not raised above about 7 (e.g., not above about 6.5).

[0029] The effervescent composition of the invention typically has an acid neutralizing capacity (ANC) of about 10 mEq or more of HCI. Preferably, the effervescent composition of the invention typically has an ANC of about 12 mEq or more (e.g., about 13 to about 20 mEq_HCI). The ANC can be determined by inflection point titration (IPT) method or by a Gran function plot method. IPT involves plotting the pH of a solution of the effervescent composition as a function of the volume of strong acid added and identifying the tinflection point of the titration. The Gran function plot method involves plotting a Gran function (e.g., the sum of the initial volume (V,,) and volume acid added (Vi) multiplied by the antilog of the change in pH (i.e., [(Vo + Vi)(IO-PH])) versus the volume of acid added (V;) and fitting a line through the data points (e.g., by regression analysis). The ANC value is determined by multiplying the normality of the acid by the linear constant (i.e., the point at which the line crosses the x-axis), and dividing by the sample volume.

[0030] The buffer solution that is generated upon dissolution of the acid and base components of the effervescent composition typically is capable of mediating the pH of a mammal's stomach (e.g., maintain the pH of the stomach at the initial value upon ingestion) for at least about 15 minutes or more. Preferably, the buffer solution is capable of mediating the pH of a mammal's stomach for up to about 30 minutes or more (e.g., up to about 45 minutes or more). Typically, about 15 minutes or more (e.g., about 30 minutes or more, or even 45 minutes or more) is required for the active agent to be absorbed into the bloodstream. [0031] All documents mentioned above are incorporated herein by reference.

Claims

WHAT IS CLAIMED IS:

1. An effervescent composition comprising:

(a) an active agent selected from the group consisting of triptans and analgesics, alone or in combination, effective for treatment of acute migraine, or mixtures thereof,

(b) an acidic and buffering component selected from organic acids and salts thereof,

(c) an alkaline effervescing component selected from a carbonate salt, a bicarbonate salt and mixtures thereof, and optionally a sweetener and/or a flavorant

(d) wherein the composition when dissolved in water produces a solution having a buffered pH of about 3 to about 6.5.

2. The composition of claim 1, wherein the active agent is a triptan in combination with an opioid analgesic, an NSAID, or acetaminiphen;

3. The composition of claim 1, wherein the composition when dissolved in water produces a solution having a buffered pH of about 4 to about 6.

4. The composition of claim 1, wherein the dissolved buffered solution mediates the pH of the patient's stomach for about 15 minutes or more.

5. The composition of claim 1, wherein the acid component further comprises one or more organic acidic compounds selected from the group consisting of monosodium citrate, disodium citrate, monopotassium citrate, dipotassium citrate, tartaric acid and salts thereof, malic acid and salts thereof, fumaric acid and salts thereof, adipic acid and salts thereof, succinic acid and salts thereof, acid anhydrides, and combinations thereof.

6. The composition of claim 1, wherein the acidic component is present in an amount of from about 25% to about 75% by weight of the composition.

7. The composition of claim 1, wherein the alkaline component is selected from the group consisting of sodium carbonate, potassium carbonate, and mixtures thereof.

8. The composition of claim 1, wherein the alkaline effervescing component is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

9. The composition of claim 1, wherein the alkaline effervescing component comprises a carbonate or bicarbonate and one or more basic compounds selected from the group consisting of sodium glycine carbonate, calcium carbonate, calcium bicarbonate, lysine carbonate, arginine carbonate, and mixtures thereof.

10. The composition of claim 1, wherein the alkaline effervescing component is present in an amount of from about 20% to about 60% by weight of the composition.

11. The composition of claim 1, wherein the composition is in the form of a tablet, powder, granule, or capsule for reconstitution in water before ingestion, for dissolution in the mouth before swallowing, or that is swallowed as a solid with or without water.

12. The composition of claim 11 , wherein the tablet has a dissolution rate of about 60 seconds or less in 60 ml of water.

13. The composition of claim 1, wherein the acid component and the alkaline effervescing component are at least partially reacted with each other during granulation with the active agent.

14. The composition of claim 1, further comprising a solubilizing agent.

15. The composition of claim 14, wherein the solubilizing agent is selected from the group consisting of polyvinylpyrrolidones, polyethyleneglycols, dextrans, and mixtures thereof.

16. The composition of claim 1, wherein the dissolved composition comprises an amount of a fully deprotonated salt of the acid component that is at least about 1.5 times the amount of acid-base equivalents.

17. The composition of claim 1, wherein the dissolved solution has an acid neutralizing capacity of about 13 to about 20 mEq HCl.

18. The composition of claim 1, which is sumatriptan succinate 25 - 100 mg active pharmaceutical ingredient citric acid anhydrous 300 - 500 mg acid component monosodium citrate 1500 - 2000 mg acid component sodium bicarbonate 500 - 900 mg alkaline component potassium bicarbonate 500 - 900 mg alkaline component sodium carbonate 100 - 200 mg alkaline component solubilizer 25 - 100 mg sweetener 25 - 100 mg flavorant 5Q _ 100 mg

19. The composition of claim 18, which is Sumatriptan succinate 50 mg (base) Active pharmaceutical ingredient citric acid anhydrous 422 mg acid component monosodium citrate 1822 mg acid component sodium bicarbonate 806 mg alkaline component potassium bicarbonate 691 mg alkaline component sodium carbonate 160 mg alkaline component polyethylene glycol 6000 50 mg solubilizer aspartame 30 mg sweetener orange flavor 70 mg Flavorant

20. An effervescent composition comprising:

(a) an active agent,

(b) an acid component comprising about 10% to about 60% citric acid compound by weight based on the total weight of the acid component and the alkaline effervescing component, and

(c) an alkaline effervescing component comprising zero to about 10% by weight carbonate salt and about 25% to about 50% by weight bicarbonate salt based on the total weight of the acid component and the alkaline effervescing component, wherein the composition when dissolved in water produces a solution having a buffered pH of about 3 to about 6.5.

21. The composition of claim 18, wherein the acid component comprises about 35% to about 60% by weight monosodium citrate, based on the total weight of the acid component and the alkaline effervescing component.

22. The composition of claim 18, wherein the carbonate salt is selected from the group consisting of sodium carbonate, potassium carbonate, and combinations thereof.

23. The composition of claim 26, wherein the bicarbonate salt is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, and combinations thereof.

24. The composition of claim 26, further^'comprising a sweetener and/or a flavorant.

25. The composition of claim 26, further comprising a solubilizing agent.