CA2589079A1 - Nsaid compositions exhibiting clinical superiority - Google Patents

Abstract

The invention is directed to a composition and its use in treating pain, pyrexia and inflammation comprising an NSAIS as the active ingredient, a metasilicate, a first disintegrant and second disintegrant resulting in increased absorption of poorly soluble NSAIS~s and increased absorption in suppressed vagal systems. The preferred composition comprises ibuprofen on a metasilicate matrix, sodium bicarbonate as the first disintegrant and tartaric acid as the second disintegrant. The composition may also contain additional pharmaceutically acceptable excipients.

Description

NSAID Compositions Exhibiting Clinical Superiority CROSS-REFERENCE TO RELATED APPLlCATIONS
10001a This is a continuation-in-part of U.S. Serial No.10/119,313, filed April 10, 2002; and U.S. Serial No. 10/119,303, filed April 10, 2002; and U.S. Serial No.
10/166,050, filed June 11, 2002, and U.S. Serial No. 60/624,806, filed November 3, 2004.

BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
[0002] The present invention is directed to solid NSAID formulations having increased absorption in rate suppressed vagal systems. One of the primary NSAIDs, (d)-2-(4-lsobutylphenyi) propionic acid, ibuprofen, is a potent and well tolerated anti-inflammatory, analgesic, and anti-pyretic compound.

DESCRIPTION OF RELATED ART

[0003] In the treatment of acute pain rapid absorption of orally administered analgesics is desirable. For non-steroidal anti-infiammatory drugs (NSAIDs), such as ibuprofen, meloxicam, and ketoprofen, there appears to be a positive relatiohship between plasma drug concentration and analgesic activity. Any delay in absorption or reduction in the circulating drug concentration may result In treatment failure or in reduced activity of the analgesic. After oral administration of regular-release tablet preparations to healthy subjects, ibuprofen is almost completely absorbed from the gastrointestinal tract. it is, therefore, expected that, typically, peak serum concentrations and maximal analgesic effect normally occur within I to 2 hours of administration. One skilled in the art readily recognizes that analgesic formulations with enhanced absorption rates are expected to be more effective in treating acute pain.

[0004] However, none of the widely available solid dosage forms of NSAIDs have been claimed to be superior over the products of the same drug with respect to onset of action. This is despite differences in apparent rate of absorption usually measured in healthy volunteers. It appears that rapid absorption observed in healthy subjects does not necessarily result in a quick onset of action in patients experiencing pain.

[0005] Jamall & Kunz, BritJ. Clin. PharmacoL, 47:391-396 (1999) have reported that, using denta( surgery as a pain marker, pain or its associated trauma causes reduced rate of absorption of ibuprofen. Surgery resulted in a two hour delay In the mean time to peak concentration, significant decreases in serum ibuprofen concentrations following both doses, and a fall to sub-optimal serum concentrations.

[0006] The observed reduced absorption Is believed to be caused by suppression of the vagal nervous system. The vagus nerve, nervus vagus, is the 10t' cranial nerve;
suppressing the activity of the vagus nerve causes reduced gastric juice secretion and motility, both of which are associated with decreased absorption of NSAIDs.
Sufficient fluid and a rather quick exit from stomach (hence entry to small intestine, the major site of absorption) is needed for efficient absorption.

[0007] If an active agent does not dissolve readily or cannot penetrate the epithelial membrane (e.g., if it is highly ionized and polar), residence time at the absorption site may be insufficient. In such cases, bloavaiiabiiity tends to be highly variable as well as low. The physicochemical properties of a drug govem its absorptive potential, but the properties of the dosage form (which partly depend on its design and manufacture) can also largely determine drug bloavailability. Differencesr in bioavallabiiity among formulations of a given drug can have clinical signi6cance. Thus, the concept of equivalence among drug products is important in making clinical decisions.

[0008] The problem of decreased absorption in vagally suppressed mammals is further exacerbated by the low solubility of NSAIDs in an aqueous or gastric (acidic) environment. Finally, there is growing evidence that these conditions, namely, reduction in stomach motility, stomach secretion diminution, and reduced absorption appear to be present also in the elderly, or what shail be termed herein, the geriatric stomach.

[0009] Some prior art formulations, such as U.S. Patents 6,197,336 and 4,834,966, dissolve the ibuprofen formulation prior to administering the composition.

Other prior art formulations, e.g., PCT/EP97100841, incorporate an alkali metal bicarbonate into the ibuprofen formulation to enhance the compressibility of the solid dosage form. These formulations Include ibuprofen as the active agent, the bicarbonate as a compressibility enhancer, a compressible filler, and a disintegrant (preferably croscarmellose sodium or sodium starch glycollate).
[00101 Alkali metal carbonates and bicarbonates are solubie materials which have previously been proposed for use in effervescent tablets, for example to react with the acid component in an effervescent couple (see for example WO 94/10994) or to prevent initiation of the effervescent reaction e.g. during storage.
Effervescent tablets disintegrate by means of the reaction between acid and base particularly in the presence of water leading to the production of carbon dioxide. The system of disintegration of non-effervescent dosage forms according to the present Invention, which are arranged to be swallowed and for which an effervescent reaction is not desired, is different to that of effervescent formulations. In the present dosage form the soluble acidic component is not intended to react with the alkali metal carbonate or bicarbonate to produce an effervescent reaction prior to administering the tablet. That is, the solid dosage form of the present invention does not need to be dissolved in water prior to taking the tablet.
[0011] US Patent 5,681,583 describes a multilayer tablet in which one layer is designed to accelerate release of active ingredients. The patent discloses compounds that "can produce effervescence and disintegration". As stated in claim 1, however, the same layer contains several other excipients that are included to facilitate dissolution and disintegration independent of the effervescent. In contrast, the present invention relies on the acid-base reaction to enhance disintegration and dissolution.
[0012] The '583 patent also teaches the need, in the first layer, for coating reagents. The present deals wfth an uncoated compressed tablet. Indeed, the coating action will be detrimental to a rapid disintegration and dissolution in the stomach of a patient under pain due to low agitation, emptying and fluid. Acute pain suppresses gastric emptying, agitation and juice.

SUMMARY OF THE INVENTION
10013] It is desirable to provide an NSAID and other analgesic formulation that can deliver drugs into the blood stream despite a suppressed vagal system.
[0014] It would be advantageous to provide a composition having enhanced absorption of NSAIDs and other drugs that tend to be poorly water soluble, as well as providing an improved concentration of the drug at the cellular level at the site of its action.
[0015]. It would also be advantageous to provide a,method and composition for increasing the absorption rate of such poorly water-soluble active agents by increasing the disintegration efficiency of the composition in tablet form, by accelerating the time and speed of the tablet disintegrating into molecules in solution, and by increasing the speed by which active agent is available in solution for absorption.
[0016] Ibuprofen Is a relatively weak acid (pka 4.4) and has poor solubility in water: less than I part of drug will dissolve in 10,000 parts of water.
However, it is fairly soluble in simple organic solvents. lbuprofen solubility is particularly low in acidic environment where it wiil have a reiatively long residence time when the patient is in pain. This slows down absorption.
[0017] In comparison with standard ibuprofen tablet formulations, which contain the active ingredient as the free acid, liquid formulations or faster dissolving ibuprofen salts (e.g. lysine or arginine salts) demonstrate faster absorption and higher peak serum concentrations when. given to healthy subjects.
[0018] NSAIDs are weak organic acids and are not ionized in the acidic environment of the stomach. Therefore, NSAIDs are able to diffuse freely into the mucosal cells. Once inside the mucosal cell, the more neutral intracellular pH
causes NSAIDs to ionize, resulting in a diminished ability to passively diffuse back through the mucosal cells. Mucosal cell ion trapping causes NSAIDs to accumulate, resulting in elevated intracellular concentrations and direct cellular injury. .
[0019] Since the cell membranes on the stomach wall contain lipids, they offer little resistance to the lipid-soluble NSAID. The NSAID acts against the cell membrane, increasing its permeability. This results in cell swelling and death. The local acid effect ..4..

of NSAIDs has been reduced by enteric-coating the drug, delaying dissolution until later in the digestive process. However, not all NSAIDs are enteric-coated as it increases cost. In addition, enteric-coating does little rimore than improve the symptoms of upset stomach.
[0020] In healthy subjects, ibuprofen is well absorbed and extensively bound to plasma proteins in vivo. It is prescribed for rheumatic arthritis and other musculoskeletal disorders, as well as acute gout. The dosage of the drug is typically from 600 to 1200 mg daily in divided doses, with 2,400,mg per day being the maximum.
[0021] lbuprofen is also indicated for use in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, seronegative arthropathies, periarticular disorders and soft tissue injuries. Ibuprofen may also be used in the treatment of postoperative pain, postpartum pain, dental pain, dysmenorrhoea, headache, musculoskeletal pain or the pain or discomfort associated with the following: respiratory infections, colds or influenza, gout or moming stiffness.
[0022] A critical factor relating to the use of ibuprofen to treat the above disorders concerns, as noted above, improving the onset of action of ibuprofen, particularly in the treatment of pain. This issue partially concems improving the amount and speed of achieving a certain blood.serum level of ibuprofen. It is believed that ideally a rapid disintegration of a formulation, beginning in the mouth, but primarily In the stomach in which 100% of the formulation is disintegrated results in the release the drug into the body more quickly, thereby leading to a more rapid onset of therapeutic action, as compared with a standard dosage form or with dosage forms calibrated against healthy individuals. Accordingly, it is desired to produce a solid dosage form for oral administration adapted to disintegrate quickly in the gastro-intestinal tract.
it is also preferred that the dosage form is manufactured by compression on standard tabletting machines.
[0023] In accordance with one embodiment of the present Invention, the composition contains an NSAID, preferably ibuprofen (hereinafter referred to as IB); a disintegration and dissolution agent, such as a bicarbonate, preferably sodium bicarbonate; tartaric acid as an additional excipient; and neusilin as a matrix. The composition may optionally also include starch. These ingredients are formed into a ..g..

tablet, caplet, or solid form, these forms having enhanced disintegration into particles and subsequently enhanced dissolution of the particles into dispersed molecules in solution.
[0024] In accordance with the present invention, the bicarbonate is a disintegrator or disintegrating agent that increases the solubility of the NSAID. One of the important effects of sodium bicarbonate ingestion is that the acid-base reaction takes place in the stomach. This results is production of carbon dioxide in a bubbling fashion.
This motion results in rapid disintegration of the formulation and the rapid drug dissolution in aqueous environments.
100251 Mere exposure of ibuprofen with bicarbonate in the aqueous environment of stomach results in the acid-base reaction. However, this reaction is accelerated with the addition of a soluble acid such as tartaric acid.
[0026] The acid-base reaction results in the break down of the formulation integrity and exposes the contained maize to water. This results a bursting effect that further accelerates disintegration and dissolution of the drug thereiri.
[0027] While not intending to be limited to a particular mechanism of action, the inventor believes that the bicarbonate increases solubility by promoting the formation of sodium ibuprofen, a salt that is readily converted to ibuprofen; ibuproÃen precipitates under gastric conditions, so the anti-precipitation agent prevents precipitation by increasing the solubility of the ibuprofen in the gastric environment. This is achieved by addition of solubilizing agents such,as Neusilin.
[0028] The compositions and methods of the present Invention achieve chemically what happens biologically when NSAIDS are administered and absorbed in healthy subjects. Biologically, the stomach has a certain amount of movement or motility, as well as gastric juice that contribute to a tablet disintegrating into particles, and then dissolving into molecules.
[0029] The compositions and methods of the present invention provide a formulation whereby the solid dosage form provides it own movement through the acid-base reaction and is disintegrated in the stomach at a faster rate, it subsequently presents itself in the stomach as a solubie salt of ibuprofen leading in part to quicker absorption, thereby, faster onset of action.

[0030] In a vagally suppressed human, i.e., a human in pain, both the motility and gastric juice extraction are reduced. Also in the geriatric population stomach emptying and gastrointestinal transit time are delayed. These conditions result in delayed absorption, . The present invention accelerates the time line of disintegration Into particle form by chemically mimicking the agitation provided by the motility function, by initiating the disintegration from tablet form into particles as soon as the tablet is exposed to a very limited amount of fluid. In the presence of some moisture, the incorporated bicarbonate starts reacting with acids. The result is breaking down of the larger solid particles, enhancing solubility, and providing a greater amount of active agent earlier in the process, thereby accelerating the absorption rate, and thereby providing more relief, faster.
[0031] The compositions and methods of the present invention achieve this result by surrounding, capturing, or formulating active agent particles, such as ibuprofen, in a.
matrix or the like of a metasilicate, such as Neusilin. The composition may further include a disintegrating agent that, upon exposure to an aqueous environment, promotes the break-up of the tablet into smaller particles of active agent, thereby increasing the availability of the active agent for absorption.
[0032] The solid dosage forms according to the invention are adapted for direct administration to a patient to obtain the desired therapeutic 'effect. They are not -intended to be dissolved or dispersed in water prior to administration.
Furthermore, the compressed dosage forms according to the present invention need no further processing, e.g. coating, after compression of a composition comprising a mixture of the ingredients to produce a solid dosage form.
[0033] The accompanying drawings show illustrative embodiments of the invention from which these and other of the objectives, novel features and advantages will be readily apparent.

DESCRIPTION OF THE DRAWINGS
Figure 1 shows the mean serum concentration versus time for S-ibuprofen generated by a formula of the present invention (n=12 patients) compared to Motrin (n=14 patients).

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Figure 2 shows mean serum concentration for R-ibuprofen generated by a formula of the present invention (n=12 patients) compared to Motrin (n=14 patients).
Figure 3 shows the pharmacokinetic parameters for total (S+R) concentration of ibuprofen generated by a formula of the present invention (n=12 patients) R-ibuprofen compared to Motrin (n=14 patients).
Figure 4 shows the mean incremental area under the curve (AUC) for S-lbuprofen in plasma concentrations following administration of either a formula of the -present invention (n=12 patients) or Motrin (n+14 patients).
Figure 5 shows the mean incremental area under the curve (AUC) for R-ibuprofen in plasma concentrations following administration of either a formula of the present invention or Motrin.
Figure 6 shows the mean incremental area under the curve (AUC) for total ibuprofen In plasma concentrations following administration of either a formula of the present invention or Motrin.
Figure 7 shows the mean cumulative (incremental) AUC of ibuprofen (o-1 h).
following administration of the formula (open bars) or Motrin (closed bars) to patients after dental surgery.
Figure 8.shows the mean cumulative (incremental) AUC of ibuprofen (0-6 h) following administration of the formula (open bars) or Motrin (closed bars) to patients after dental surgery.
Figure 9 shows the man pain intensity score (PIS) over time using a categorical pain intensity scale for patients after dental surgery following administering either the formula or Motrin. There was no statistically significant differences between the two products due to the small number of subjects tested. However, there was consistent trend for greater P!S for Motrin IB.
Figure 10 shows the mean pain intensity difference (PID) between the two products over time using a visual analogue scale (VAS) after dental surgery following administering either ZAG-1701 or Motrin.
Figure 11 shows the percent of patients who recorded meaningful relief following a dose of either Motrin or ZAG-1701.

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Figure 12 shows the comparative dissoiution profiles among lbuprofen alone;
ibuprofen and sodium bicarbonate; and ibuprofen, sodfum bicarbonate, and Geiucire .
DETAILED DESCRIPTION OF THE INVENTION
[0034] The present invention Is a method of treating pain and{for inliammation comprising administering a solid dosage formulation comprising an active agent in a matrix, and a first and second disintegrant; wherein said active agent is an NSAID;
wherein said matrix Is a metasiiicate, wherein the first disintegrant comprises sodium bicarbonate; and wherein said second disintegrant comprises tartaric acid.
100351 The present invention is also a method of treating pain and or inflammation by administering a solid dosage formulation having a fast onset of action, wherein the solid dosage formulation comprises a formulation of the present invention.
[00361 The present invention is also a method of increasing the onset of action of a solid formulation, e.g., a tablet, comprising blending tartaric acid and a diluent to form a first blend; adding at least one diluent and a binder to said first blend to form a second blend; blending an active agent and a metasilicate matrix to form a third blend; adding sodium bicarbonate to said third blend to form a fourth blend; and compressing said fourth blend into a tabiet.
[0037] The present invention is a. compositian cflntaining an NSAID as an active agent, said composition having increased absorption and onset of action in vagaiiy suppressed systems. The composition comprises an NSAID and a disintegration and dissolution agent, such as a bicarbonate, in a matrix or carrier, such as a metasilicate.
The preferred NSAID is ibuprofen. The composition may further include an anti-precipitation agent e.g. Gelucire .
[0038] The composition may further Include tartaric acid as an additional disintegrating agent, Examples of a porous carrier include, for instance, aluminum magnesium metasilicate (available from Fuji Chemicai Industry Co., Ltd.; Trade-name:
NEUSILIN).
(0039] The present invention Is also a composition comprising ibuprofen on a matrix comprising a metasilicate, and a disintegration and dissolution agent, such as a bicarbonate. The invention also includes a method of treating inflammation or alleviating pain comprising administering a composition as described in this paragraph.
[0040] The present invention is also a composition comprising ibuprofen and a matrix comprising a metasilicate, a disintegration and dissolution agent, such as a bicarbonate. Such a composition is characterized by having earlier onset of action and increased absorption of the active agent, as compared to other compositions when the comparison assesses the absorption of the active agent under pain conditions.
The invention also includes a method of treating inflammation or alleviating pain comprising administering a composition as described in this paragraph.
[0041] The present invention is also any of the above compositions, further comprising one or more lubricating agents, one or ore binders, one or more additional disintegrating agents, one or more flow aids, one or more preservatives, and/or one or more colorants and/or flavorants.
[0042] The present invention is also a method for increasing the absorption of an NSAID-containing composition, said method comprising providing a composition, -such as one of the compositions described above, whose ingredients are specifically formulated to increase absorption under pain conditions, i.e;, In a vagaily suppressed system.
[0043] The present invention is also a method of treating acute pain in humans comprising administering a composition according to the present invention.
[0044] It will be appreciated that the present invention provides a method of treating inflammation, pain and pyrexia by administration of a pharmaceutical composition comprising racemic ibuprofen, together with a pharmaceutically acceptable carrier to a mammal, e.g. a human, in need thereof. Preferably the ibuprofen is present in one or more of its well known forms, namely, ibuprofen, its S(+) and R(-) enantiomers, including different enantiomeric ratios thereof, salts, hydrates, and other derivatives. The preferred form is a dihydrate. The most preferred form is the acid form.
[0045] The ibuprofen may be also present in the form of any salt or other derivative of ibuprofen or its enantiomers. If necessary, the ibuprofen may comprise one or more ibuprofen active ingredients such as racemic ibuprofen and S(+)-ibuprofen in combination. However, we prefer that the ibuprofen comprises a single ibuprofen active ingredient. The (buprofen active agent may also be present in different degrees of hydration. The present invention applies to both anhydrous and hydrated forms, for example the monohydrate or the dihydrate. The most stable anhydrous or hydrated form wil) generally be used. Preferably, the ibuprofen is in the form of a salt of racemic or S(+)-ibuprofen. Representative examples include alkali metal salts, for example the sodium or potassium salts of ibuprofen; aikaline earth metal salts, e.g. the calcium or magnesium salts of ibuprofen; metal salts, e.g. the aluminum salt of ibuprofen; amino acid salts for example the lysine or arginine salts of ibuprofen: or amine salts, e.g. the meglumine salt of ibuprofen. Preferably the ibuprofen is a single salt selected from alkali metal salts, amino acid salts and amine salts.
[0046] These soluble ibuprofen salts also have the advantage that, as they are more soluble in an aqueous medium, on release from the formulation they have improved absorption, thus leading to an improved onset of action compared to the substantially insoluble forms of. ibuprofen. The sodium salt of ibuprofen is particulariy preferred, especially the sodium salt of racemic ibuprofen. It has been found that the dihydrate of the sodium salt of racemic ibuprofen is a particularly stable hydrated form, accordingly we prefer to use the sodium salt dihydrate in a compressed dosage form according to the present invention.
10047] The compositions and methods of the present invention are particularly suited to forming non-aqueous granulations and to solid dosage formulations, preferably dosage formulations that are non-effervescent prior to administration or prior to in vivo delivery. In preferred embodiments of the invention, one or more of the disintegrants burst the tablet or caplet apart in the stomach, thereby presenting a greater amount of active agent.
[0048) The present invention further relates to tablets and granules, formulated in accordance with the present invention, that are fast dissolving and fast acting. The.
granulation and tabletting composition also includes normal excipients useful for the preparation of tablets.
[0049] The present invention is also a composition and method of treatment comprising an NSAID as an active agent, blended with a metasilicate matrix and a bicarbonate as a disintegrating agent. The composition may further comprise one or more of the fo(lowing: one or more disintegrating agents, preferably sodium bicarbonate and/or tartaric acid; one or more diluents or fillers; one or more binders or adhesives;
one or more additional disintegrating agents; one or more lubricating agents;
one or more preservatives, preferably propyl gailate; and one or more miscellaneous adjuncts, such as colorants and/or flavorants, any of said adjuncts being well known to those skilled in the art.
[0050] Any number of pharmaceutically active agents may be employed in the formulations of the present invention. These active agents may exist as either solids or liquids at standard temperature and pressure. Exemplary pharmaceutically active agents suitable for use herein include, but are not limited to, the non-steroidal anti-inflammatory agents such as piroxicam, indomethacin, fenoprofen, meloxicam, and ibuprofen. In a preferred embodiment of the fnvention, the composition and method includes ibuprofen as the active agent.
[0051] The compositions of the invention may include about 15 to about 99% by weight of an active agent, such as lbuprofen, preferably up to about 80% by weight, more preferably from about 15% to about 70% by weight; about 10% to about 60%
by weight of a first disintegrant, such as a bicarbonate, preferably between about 12% and 30%, and more preferably between about 12% and 20%.
[0052] The compositions of the present invention may include up to about 30%
by weight of a second disintegrant, such as tartaric acid, preferably up to about 15%, more preferably between about 1% and about 10%.
[0053] The compositions of the present invention may include up to about 30%
by weight of a matrix, such as a metasilicate, preferably up to about 2%, more preferably between about 1% and about 15%.
[0054] The compositions of the present invention may Include up to about 80%
by weight of one or more diluents, such as microcrystalline cellulose and sodium starch glycolate, preferably up to about 40%, more preferably between about 5% and about 20%.
[0055] The compositions of the invention are generally prepared in unit dosage form. The unit dosage of ibuprofen is in the range.of 5-1200 mg in a pre-calculated amount to provide doses which are equivalent by weight to doses of for example mg, 200 mg, 400 mg or 800 mg of ibuprofen. The amount of an NSAID substance in a quick release, sustained release, or modified release composition according to the invention may be selected so that is corresponds to about I mg, 2 mg, 3 mg, 4 mg, 5 mg, 8 mg, 10 mg, 12 mg, 16 mg, 20 mg, 24 mg, 25 mg, 30 mg, 32 mg, 50 mg, 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, I g, 1.1 g, 1:2 g, 1.3 g or 1.6 g of NSAID substance which are dosages generally known in the art.
[0056] The preferred dosage form according to the invention is In the form of a capsule, tablet, sachet etc. The size of the dosage form may be adapted to the amount of the active drug substance contained in the composition.
[00371 The above suggested dosage amounts should not be regarded as a limitation of the scope of the invention as It is obvious for the skilled person that any desired amount of the active drug substance may be appiied and is only limited by the size.of the composition and the type bf the active drug substance;
[00581 The bicarbonate is preferably an alkali metal carbonate, more preferably any bicarbonate salt that is pharmaceutically acceptable, preferably sodium.or potassium bicarbonate. The alkali metal carbonates may be supplied anhydrous or in varying degrees of hydration, e.g., the monohydrate and decahydrate. Any of these forms may be used.
[0059] In therapeutic use, the composltions of the present invention may be administered orally, rectally, or topically, preferably orally or topicaliy.
In the present invention, the preferred mode of administration is orally, i.e. as a solid tablet easily dissolved in the gastric environment. Suitably the therapeutic compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, or topical administration.
[0060) Solid compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, capiets, and capsules.
[0061] Within the context of the present description the identity of the components and amounts thereof refer to the weight and identity of the starting materials used in preparing the composition. It is possibie that during preparation of the cornposition and/or tablets, some interaction or reaction may occur between two or more components. To the extent that such interaction or reaction occurs the present invention is intended to cover such occurrences.
[0062] Normai excipients useful in the preparation of the tabiets include, but are not limited to: lubricants such as magnesium stearate, sodium stearyl fumarate and sodium benzoate; anti-adherents such as taic and polyethylenglycoi; glidants such as colloidal silica; diiuents such as dicalcium phosphate, cellulose (for example microcrystalline cellulose) and its derivatives, carbohydrates and polyalcohols such as saccharose, xylitol and lactose; disintegrants such as crosslinked vinylic polymers (such as crosslinked PVP), derivatives of starch and of cellulose such as sodium carboxymethyl-starch and sodium croscarmelose; wetfing agents such as TWEEN 80 -(Trademark registered by ICI of Americas for polysorbate) and sodium lauryl sulphate.
[0063] Suitable exciplents and their amounts can be readily determined by those of ordinary skill in the art according to the methods normally used in pharmaceutical technology. However, in the present invention, it is important to avoid excipients that would cause a significant decrease in tablet dissolution rate.
[0064] Further, excipients should allow a good workability of the tablet. In preparing the tablet of the present invention, simple mixing may be sufficient. One skilled in the art will readily recognize that a number of mixing and tabletting protocols may be used. For example, it may be desirable to prepare an IB granulate, to mix it with the bicarbonate and the excipients, and then to compress. An exempiary method of preparing a composition of the present invention comprises dissolving ibuprofen in an alkaline solution; mix with neusitin; change the pH (e.g., by adding glacier acid) so that the ibuprofen re-crystallizes; and remove the soiution. The ibuprofen is thereby loaded on the neusilin matrix. It should then be dried, e.g., overnight. Other processes that lead to a workable tablet are shown in the Examples.
[0065] Preferably the diluent includes lactose, calcium phosphate, dextrin, microcrystalline cellulose, sucrose, starch, calcium sulphate, sodium bicarbonate, or mixtures thereof.

..~ 4~-[0066] Preferably the lubricating agent includes magnesium stearate, stearic acid, calcium stearate, sodium bicarbonate, or mixtures thereof. More preferably the lubricating agent is magnesium stearate or stearic acid.
[0067] Preferably the disintegrating agent includes microcrystalline cellulose, maize starch, sodium starch glycolate, low substituted hydroxypropyl cellulose, alginic acid or croscarmelose sodium, sodium bicarbonate, or mixtures thereof.
[0068] Preferably the binder includes polyvinyl, pyrrolidone, gelatin, Gelucire , hydroxypropylmethyl cellulose, starch, or mixtures thereof.
[0069] Suitable flow aids include, but are not limited to talc and colloidal silicon dioxide.
[0070] The compositions of the present invention may additionally comprise a taste masking component for example a sweetener, a flavoring agent, arginine, sodium carbonate or sodium bicarbonate.
[0071] Solid non-effervescent compositions are preferred compositions of the present invention. The preferred compositions are preferably formed into a tablet. In the most preferred compositions and methods, disintigarion occurs in stomach through the acid/base reaction.
[0072] In the compositions of the present invention the NSAID, such as ibuprofen, may, if desired, be associated with other compatible pharmacologically active ingredients and/or enhancing agents. Thus, for example, ibuprofen may be combined with any ingredient commonly used in a cough or cold remedy, for example, an antihistamine, caffeine or another xanthine deryvative, a cough suppressant, a decongestant, an expectorant, a muscle relaxant, or combinations thereof.
Exemplary compatible pharmacologically active ingredients include, but are not limited to codeine, oxycodone, hydrocodone, and/or hydromorphone.
[0073] Suitable antihistamines which are preferably non-sedating include acrivastine, astemizole, azatadine, azelastine, bromodiphenhyrdramine,.
brompheniramine, carbinoxamine, cetirizine, chlorpheniramine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, ebastine, ketotifen, lodoxamide, loratidine, levocubastine, rnequitazine, oxatomide, phenindamine, phenyftoloxamine, pyrilamine, sefastine, tazifylline, temelastine, terfenadine, .w~ ~~

tripelennamine or triproildine. Suitable cough suppressants include caramiphen, codeine or dextromethorphan. Suitable decongestants include pseudoephedrine, phenylpropanolamine and phenylephrine. Suitable expectorants include gualfensin, potassium citrate, potassium gualacoisulphonate, potassium sulphate and terpin hydrate.
[0074] The disintegration time of the tablet formed in accordance with the present invention is less than 30 minutes as measured by the method described in the European Pharmacopoeia 1986, Ref V .5.1.1 (updated 1995) (A. Disintegration Test for Tablets and Capsules). Preferred disintegration times are less than 6 minutes (e.g. 1-10 minutes), more preferably less than 5 minutes (e.g. 1-5 minutes) and most preferably 3 minutes or less (e.g. 1-3 minutes). Consequently the release is faster with respect to the commercially available ibuprofen based analgesic tablets (see the examples below).
[0075] in the present invention the tablet size Is between 100-700 mg preferably between 400-600 mg (in the Examples, the typical size of a tablet of the present invention is 570 mg) for a tablet containing 200 mg racemic IB. Considering the need for acid/base reaction, this size tablet is favorable due to the ease of swallowing.
[0076] As used herein, a diluent or filler is used in its conventional pharmacological definition, and refers to an ingredient that adds necessary bulk to a formulation to prepare tablets of a desired slze.
[0077] As used herein, a binder or adhesive is used In its conventional pharmacological definition, and refers to an ingredient that promotes the adhesion of the particles of the formulation.
[0078] As used herein, a disintegrator or disintegrating agent is used in its conventional pharmacological definition, and refers to an ingredient that promotes the post-administration break-up of the tablets into smaller particles for more ready drug availability.
[0079] As used herein, a lubricant or lubricating agent is used. in its conventional pharmacological definition, and refers to an ingredient that enhances the flow of the tabletting material into the tablet dies, and prevents the tabletting material from sticking to punches and dies.

..16..

[0080] - As used herein, enhanced absorption or similar terms and phrases relating to the relative speed, rate, and/or quantity of the bioavailability of the active agent. In accordance with the present invention, enhanced absorption Is measured in reference to the standard in the industry, Motrin. In essence, the compositions of the present invention provide, to a patient in pain, a greater concentration of active agent faster, as compared to the bioavailability curve for Motrin. For example, see Figures 1-3. In graphical or mathematical terms, enhanced absorption may be determined or quantified by using the area under the curve (AUC). As shown in Figures 4-6, the extent and rate of absorption, as represented by the AUC, for the formulations of the present invention, delivers a greater amount of active agent in a shorter time frame as compared to Motrin. In accordance with the teachings of the present invention, it is 'important to determine enhanced absorption of a particular composition as it applies to a patient in pain, or data obtained from a patient or subject in pain.
100813 In therapeutic use the dosage forms of the present invention are administered orally, thus the therapeutic dosage forms are presented in solid dosage form, preferably as a tablet. The dosage forms may be coated with a sugar or film coating, which dissolves substantially Immediately the dosage form comes into contact with an aqueous medium. The composition may aiso be compressed onto a solid core of another material to form a solid formulation with a quick reiease outer coating.
Alternatively, the compressed composition may be present in one or more layers of a multi-layer solid dosage Ãorm. In such formulations the remaining layers or core may comprise standard excipients to provide conventional, fast or slow release and are well within the knowledge of a person skilled in the art (e,g., see Remington's Pharmaceutical Sciences, t7th Edition, Ed Gennaro et al; or Ansel's "Introduction to Pharmaceutical Dosage Forms", 2"d edition, Henry Kimpton Publishers).
[0082] Although not wishing to be held to any particular theory of action, the inventor believes that a tablet or capiet of the present invention functions as follows:
after swallowing a capiet with a glass of water, the sodium bicarbonate reacts with tartaric acid and (buprofen in the stomach. This appears to provide stomach agitation or movement that breaks the caplet into finer pieces and solubilizes the ingredients. A
weak resultant solution of sodium ibuprofen may be formed, which may eventually react with stomach acid resulting in its conversion to crystallized ibuprofen. To prevent crystaliization and precipitation, Neusilin acts as a solubilizer due to its lingering alkaline nature.
j00833 The following Examples illustrate specific formulations comprehended by the present invention, and methods for their preparation. The Examples are not intended to be limiting to the scope of the invention in any respect and should not be so construed.

EXAMPLES
Example 1. Description of Manufacturing Process Due to the sensitivity of the product to moisture, the relative humidity during the manufacturing process should be maintained below about 40%.
Milling 1. Pass tartaric acid (98.0 g) and microcrystalline cellulose (98.0 g) through the Quadro Comil at 1800:L50 rpm speed into a labeled container lined with double polyethylene bags.
Pre-Blend 2. Place the milled blend, microcrystalline cellulose (98.0 g), hydroxypropyl cellulose (279.3 g), and sodium starch glycolate (420.0 g) into a 16 qt Gallay Blender.
3. Blend for 5 minutes at 25 rpm.
4. Add ibuprofen, colloidal silicon dioxide (39.9 g), and Neusilin UFL2 (245.0 g) into a 16 qt. Gallay Blender.
5. Purge the 16 qt. Gailay Blender with Nitrogen gas for 30 seconds and blend for 10 minutes at 25 rpm.
6. Discharge the Pre-Blend into appropriate containers lined with double polyethylene bags.
7. Pass the pre-blend through 30-mesh hand screen into labeled containers lined with double polyethylene bags.

Screened Blend 8. Place screened blend and sodium bicarbonate (728.0 g) into 16 qt. Gallay Blender.

Purge blender with nitrogen gas for 30 seconds. Blend for 10 minutes at 25 rpm.
9. Add talc (59.$5 g) and magnesium stearate (39.9 g) to the blender and purge w'ith nitrogen gas for 30 seconds before blending for 2 minutes at 25 rpm.

10. Discharge the final blend into a labeled container with double polyethylene bags, place 15 desiccants between the bags and tightly seal each bag with a twist-tie.
Tablet.Compression 11. Ecisure correct tooling set-up (Upper and Lower Punch: 0.5650" x 0.2671", capsule shape, plain) and set up Tablet Deduster in-line with the tablet press.

12. Compress blend according to the specifications.

13. Store the finished tablets in tared, labeled containers lined with double polyethylene bags. Place 15 desiccants between the bags and tightly seal each bag with a twist tie.
In-Process Controls ' Table 1: Tablet Compression Specifications Parameter Specification Average weight of 10 Target: 5.70 g tablets Range: 5.50-5.90 g Check average weight of 10 tablets every 10 minutes Individual weight Target: 570.0 mg Range: 541.5-598.5 mg At start-up check (n+5) tablets, when n= no. of stations. During run check 10 tablets every 20 minutes Hardness Target: 10kp Range: 5-11 kp* (Target 8 kp) At start-up check (n+5) tablets, when n= no. of stations. During run check 10 tablets every 20 minutes.
*Guidefine only: Adjust hardness to achieve friability NMT 0.7%
in 4 minutes Thickness Cornpiie ait thickness data and record minimum and maximum as range.
At start-up check (n+5) tablets, when n= no. of stations. During run check* 10 tablets every 20 minutes.

Friabiiity NMT 0.7% in 4 minutes.
(Determine at start-up and compietlon of run) Disintergration NMT 15 minutes In water at 37 C without disks.(Determine at start-up and completion of run) .-1 g-.

Example 2. Exemplary Process for producing 200 mg tablets Pass tartaric acid and microcrystalline cellulose through Quadro Comil at 1800 1:50 rpm. Add microcrystalline cellulose, hydroxypropyi cellulose and sodium starch glycolate; blend for 5 minutes at 25 rpm. Add ibuprofen, colloidal silicon dioxide, and Neusilln UFI.2; blend for 10 minutes at 25 rpm. Screen blend through 30 mesh hand screen. Add sodium bicarbonate and blend for 10 minutes at 25 rpm. Add talc and magnesium stearate; blend for 2 minutes at 25 rpm. Compress into tablets.

Example 3. The ZAG - 1701 formulation Drug Product Components and Composition (Per Tablet and Per Batch) Component Quantity per unit % Quantity per batch ibuprofen (active agent) 200,00 mg 35.1 1400.0 g Sodium Bicarbonate (disintegrant) 104.00 mg 18.2 728.0 g Tartaric Acid (disintegrant) 14.00 mg 2.5 98.0 g Microcrystalline Cellulose 200 97.15 mg 17.0 680.1 g (diluent) Hydroxypropyl cellulose EXF 39.90 mg 7.0 279.3 g (binder) Sodium Starch glycolate (diluent) 60.00 mg 10:5 420.0 g Colloidal silicon dioxide (300) 5.7 mg 1.0 39.9 g (glidant) Neusilin UFL2 (mat(x) 35.00 mg 6.1 245.0 g Talc (lubricant and glidant) 8.55 mg 1.5 59.85 g Magnesium Sterate (non-bovine) 5.7 mg 1.0 39.9 g (iubricant) Total 570.00 mg 100 3.99 kg Specification and Analyticat Methods for Inactive Ingredients Listed in the table below is each excipient with its compendial status. With the exception of Neusifin UFL2, all exciplents meet current USP/NF
requirements.

Inactive Ingredient Compendial Funcfiion Desi nation Sodium Bicarbonate USP Disintegrant Tartaric Acid NF Disintegrant Microcrystalline cellulose USP/NF/EP/JP Diluent Hydroxypropyi cellulose USP Binder EXF
Sodium starch glypplate USP/NF Diluent Colloidal silicon dioxide NF Hydrophilic water-insoluble (300) iidant Neusilin UFL2 JP Absorbent and disintegrant Talc USP Hydrophilic water-insoluble lubricant and glidant Magnesium Stearate (non- USP/NF/EP/JP Hydrophilic water-insoluble bovine) lubricant The specification for the inactive ingredient Neusilin UFL2 is as follows:
Test Specification Desc(tion White powder or granules identification 1) The solution responds to the qualitative tests for aluminum salt.
2) The filtrate responds to the qualitative tests for magnesium salt.
3) The residue becomes blue.
Soluble saifi The residue weighs NMT 0.020g.
Aikali The solution is colourless.
Chloride - NMT 0.053%
Sulfate NMT 0.480%
Heavy metais NMT 30 ppm Iron The solution has no more colour than the control solution.
Arsenic NMT 5 m Loss on D in NMT 20.0%
..29..

Test Specification Acid-consuming capacity The amount of HCI consumed is not less than 210 mL per g of Magnesium Aluminometasilicate on dried basis).
Assay 1) Sificon Dioxide: 29.2-35.6%
2) Aluminum Oxide: 29.1-35.5%
3) Magnesium Oxide: 11.4-14.0%
(All values calculated on dried basis) Example 4.

The purpose of this experiment is to produce tablets that disintegrate in 15-30 min with no external agitation.

(mg) Ibuprofen 200 Sodiurm bicarbonate 104.3 Getucire@ 44114 12.0 Maize 62.9 Results: Acceptable disintegration time for small batches and when tablets were prepared under low compression pressure. Increased compression pressure required for optimal friability test resulted in unacceptable dissolution times.

Example S.
(mg) lbuprofen 200 Sodium bicarbonate 104.3 Gelucire 44114 12.0 Maize 62.9 Tartaric acid . 14.3 The above ingredients were mixed according to the procedure described in examples I or 2, and were then subjected to direct compression.
Results: Acceptable disintegration time (15 min) for small batches even under optimal compression pressure. The mixer was found unsuitable for larger batches. It was unable to properly chop and mix GelucireO.

..22..

Examate B.
(mg) (burpofen 200 Sodium bicarbonate 104.3 Getucire 44114 12.0 Maize 62.9 Tartaric Acid 14.3 Mg-Stearate 4.3 The above ingredients were mixed according to the procedure described in examples I or 2, and were then subjected to direct compression.
Results: Problems were noticed during compression due to poor powder flow and sticking to punch and die.

Exampte 7:

(mg) Ibuprofen 200 Sodium bicarbonate 104.3 Gelucire 44/14 12.0 Maize 62.9 Tartaric acid 14.3 Mg-Stearate 4.3 Neusilin 8.6 The above ingredients were mixed according to the procedure described in examples I or 2, and were then subjected to direct compression.
Results: Problems were noticed during compression due to melting of Gefucire .

Example 8:
(mg) Ibuprofen 200 Sodium bicarbonate 104.3 Gelucire 44/14 12.0 Maize 62.9 Tartaric acid 14.3 Mg-Stearate 4.3 Neusilin 8.6 The above ingredients were mixed according to the procedure described in examples I or 2, and were then subjected to direct compression. The bulk was kept at 4 C to cool down before compression.
Results: Compression was satisfactory. Clinical batch was prepared.
Problem: After storage for a few days tablets failed the disintegration test (15 min). Exposure to moisture was blamed for the failure.

Example 9:
(mg) lbuprofen 200 Sodium bicarbonate 104.3 Maize (sodium starch giycoiiate) 60.0 Tartaric acid 14.3 Mg-Stearate 5.4 Neusilin 34.9 The above ingredients were mixed according to the procedure described in examples I or 2, and were then subjected to direct compression. The bulk was compressed directly to form tablets.
Results: Compression was satisfactory, Clinical batch was prepared. After storage for six months, tablets failed due to lack of stability and loss of potency.
This was unexpected for ibuprofen, as based on previous experiences the method of dry mixing and granulation was expected to yield a stable formulation.
The presence of alkaline materials or exposure to humidity might have caused degradation.

Example 10:
(mg) ibuprofen 200 Sodium bicarbonate 104.3 Maize. (sodium starch glycolate) 60.0 Tartaric acid 14.3 Mg-Stearate 5.4 Neusilin 34.9 Propyl gallate 11.4 The above ingredients were mixed according to the procedure described in examples I or 2, and were then subjected to direct compression.
Results: Compression was satisfactory. Tablets had satisfactory stability.

Example 11:
(mg) Ibuprofen 200 Sodium bicarbonate 104.3 Maize (sodium starch glycolate) 60.0 Tartaric acid 14.3 Mg-Stearate 5.4 Neusilin 34.9 EDTA 0.6 The above ingredients were mixed according to the procedure described in examples I or 2, and were then subjected to direct compression.
Results: Compression was satisfactory. A batch was prepared. The stability of the tablet did not improve to a satisfactory level.

Examale 12:
(mg) ibuprofen 200 Sodium bicarbonate 104.3 Maize (sodium starch glycolate) 60.0 Tartaric acid 14.3 Mg-Stearate 5.4 Neusilin 34.9 Propyl gallate 11.4 EDTA 0.6 The above Ingredients were mixed according to the procedure described in examples I or 2, and were then subjected to direct compression.
Results: Compression was satisfactory. The tablets have satisfactory stability.
Examples 10 and 12 are suitable for manufacturing in bulk quantities.
Example 13. Accelerated stability test:

An accelerated stability test was carried out on tablets containing the ingredients described below. Tablets of each formulation were piaced at 22 C, 45 C, and 60 C. Three tablets of each formulation were sampled after 0, 3, 7, days,1, 3 and 6 months. Samples were analyzed using an HPLC method (Paul.
A. Asmus, J. of Chromatogr. 331 (1) 1985, P: 169-176) with minor modifications.
--25-- .

The potency of ibuprofen and impurity was determined simultaneously. The impurity of interest due to thermal degradation of lbuprofen was 4-isobutyiacetophenone.

Formula A:
(mg) Ibuprofen 200 Sodium bicarbonate 104.3 sodium starch glycolate 60.0 Tartaric acid 14.3 Mg-Stearate 5.4 Neusilin 8.6 Formula B:
(m9) lbuprofen 200 Sodium bicarbonate 104.3 sodium starch glycolate 60.0 Tartaric acid 14.3 Mg-Stearate 5.4 Neusilin 34.9 Propyl gailate 11.4 Formula C:
(mg) lbuprofen 200 Sodium bicarbonate 104.3 sodium starch glycolate, 60.0 Tartaric acid 14.3 Mg-Stearate 5.4 Neusilin 34.9 EDTA 0.6 The result of accelerated stability test during the first 3 months and extrapolating assessment indicate that the formulation without any antioxidants, Formula A, is only stable for 20 days. However, formulations with propyl gailate (Formula B) and EDTA (Formula C) will be stable at least for 2.8 years and 243 days, respectively.

Example 14. in vitro dissolution test Using the U.S. Pharmacoipoeia Apparatus ii, the dissolution rates of ibuprofen alone, ibuprofen plus sodium bicarbonate (1:1 molar based), and .-26--ibuprofen plus sodium bicarbonate (1:1 molar based) plus Geluclre (5% total weight) were assessed. The apparatus contained 2 g of NaCI and 7 mL of concentrated HCI (pH 1.2) in 900 mL water. The medium was kept at 37 C, and was stirred with a rotating paddle at 75 rounds per minute. lbuprofen was detected at 232 nm. The amount dissolved per unit time is shown in Figure 12.
Examale 15. Formulation having improved dissolution rate and absorption of ibuprofen.
In this example, the solid dispersion and physical mixture of ibuprofen was tested for dissolution rate and improved rate of bioavailability. The Influence of the carrier and two other excipients (sodium bicarbonate and tartaric acid) in solid dispersion and the physical mixture as they affect drug dissolution behavior were also studied. Gelucire 44/14, sodium bicarbonate, tartaric acid, and ibuprofen were made into a physical mixture and solid dispersion. The soiid dispersion was prepared by the fusion method at 60 C, then cooled, then ground into granules of suitable size, then compressed as a tablet.
After optimization of the formulation, solid disperslon and physical mixture formulations were compared with a marketed product in healthy and treated rats.
(an animal model for pain; see f'CT/IB02/01139, incorporated herein by reference) in terms of rapid absorption and early exposure of the lbuprofen to the systemic circulation.
ln vitro dissolution test results showed that the rate of dissolution of the ibuprofen was considerably improved when formulated in solid dispersion or physical mixture with Gelucire 44/14, as compared to pure ibuprofen. In vivo studies showed that the early exposure of ibuprofen (AUC 0-0.5) was significantly higher in the physical mixture and solid dispersion than the brand formulation.

Examale % i=ormulation with tartaric acid.
A composition was formed using ibuprofen (1 mole), sodium bicarbonate (1.8 mole), tartaric acid (0.2 mole), and Gelucire 44/14 (5% of total mass).
First, the exact amount of Gelucire was weighed and dissolved in a small amount of isopropyl alcohol. The remaining ingredients were mixed together, ..27N

then mixed with the Geiucire solution to produce a fluffy paste. Using a sieve (mesh 20), granules with the size of 841 mm were produced. The granules were dried overnight at room temperature, then used to produce tablets using a single punch compressing machine with 500 kg (punch id no. 3/16N) of compressing pressure. It is preferred that the compression force should be minimal.
The formulation in this example may also include starch, and a portion of the sodium bicarbonate may optionally be used as a lubricant. In another alternative, the Gelucire dissolved in the isopropyl alcohol may be sprayed over the remaining mixture of ingredients.

Example 17. Clinical Trials The objective of this trial was to compare the rate of absorption on ibuprofen administered as ZAG 1701 (the present invention) with a commercialiy available product (Motrin IB). This study was conducted in patients after dental surgery, a FDA accepted test of analgesia.
This was tow-arm, doubie-biind study consisting of patients who needed dental extraction. Subjects were randomly'divided into two groups (n = 12-14/group), Dental extraction was carried out under local anesthesia. When a patient complained of pain and asked for analgesics, a single oral dose of 400 mg (2X200 mg) ibuprofen (the formulation shown- in Example 3) or Motrin !B
were administered randomly with a glass of water. Serial blood samples were collected for pharmacokinetic analysis; pain Intensity and relief were also measured. In addition, the time to meaningful pain relief and the request for rescue medications were recorded.
Plasma was separated from blood and ibuprofen enantiomers (S and R) were measured using an HPLC method. Plasma concentrations were plotted versus time, and the area under curve (AUC) for ibuprofen concentration over time was calculated. Incremental (cumulative) AUC values from the administration time (zero) to each subsequent collection time were calculated.
Incremental AUC during the absorption phase is the most reliable measure of absorption rate under conditions such those used in this trial.
All the avaiiable data collected for pharmacokinetic analyses from the 26 --2g-.

subjects who completed the study were used In the analyses. All pharmacokinetic calculations were performed using SAS (PC version 6.12). Any sample concentration reported less than the assay limit of quar<titation was set to zero for use in the pharmacokinetic and statistical analyses. Pharmacokinetic and statistical analyses were not conducted for samples labeled "pain relief', "onset and "prior to rescue". No concentration estimates were calculated for missing values.

Pharmacokinetic Procedures Pharmacokinetic parameters (areas, times to peak and elimination rates) were calculated using the actual, rather than the scheduled, times of sample collection. Graphical presentations of individual subject results also used the actual times of sample collection. Graphical presentations of mean results used the schedufed times. Pharmacokinetic analyses were conducted on the concentrations of R-ibuprofen, S-ibuprofen and total ibuprofen (sum of R-ibuprofen and S-ibuprofen). See Figure 3.
Peak concentration (Cmax) was the observed maximum value during the collection period of 0 (baseline) to 6 hours. The time to peak concentration (Tmax) was the time at which Cmax was observed (or first observed, if the peak value occurred at more than one time).
The apparent first-order elimination rate constant (Ke) was estimated as the negative value of the slope of the regression line for the terminal log-linear concentration-time values. A minimum of three terminal values was required to obtain an estimate. The values included in the regression analyses were determined by examination of the individual subject plots of natural logarithm of concentration against time. Whenever the terminal concentration-time values were not log-linear or the estimated rate would have been physiologically implausible (Ke<0.01), no elimination rate was estimated. Elimination half-life (T%2) was estimated as 1oge(2)/Ke.
Areas under the curve were calculated from time 0 to the scheduled time of each sample collection through the 6-hour collection sample. Area under the curve was calculated by the linear trapezoidal method. Area to infinite time --29w (AUCinf) was calculated by extrapolating AUC 0-6, by the addition of the quantity: Cg / Ke, where Ce is the concentration at the 6-hour collection time.
Area to infinity could only be calculated when an elimination rate constant had been estimated.

Statistical analyses Analysis of variance (ANOVA) was performed using the General Linear Models (GLM) procedure of the SAS statistical program (PC version 6.12).
The statistical model contained a main effect of treatment. F-ratios for testing treatment effect were constructed using the mean square term for treatment as the numerator and the mean square error term from the ANOVA as the denominator. Hypothesis testing was conducted at a=0.05. ANOVA was performed for each pharmacokinetic parameter estimate The intra-subject coefflcient of variation was estimated from the mean square error term (MSE) of the ln-transformed (loge) results as:

100% * SQRT(eMSE -1) Confidence Intervals (95%) for the area and peak concentration comparisons were calculated by the t-test approach (2,1-sided) at a= 0.05 overall, a = 0.025 each side:

Interval Lower Limit =(XT - XR )- Se * t./2 Interval Upper Limit =(XT - XR )+ Se * t,,,j2 Where:
XT and XR are the formulation of example 3[ZAG-1701] and Motrin IB
treatment least-squares means, respectively; Se is the standard error of the estimated difference between means from the SAS estimate statement; and t',2 is the critical value from the t-distribution with degrees of freedom that of the error term and a = 0.05.
For In-transformed data the interval was calculated from the ANOVA
. --30--results on the transformed values and then exponentiated to convert to the non-transformed scale:

Interval Limit = e{imtransf0r(ned lnterval Ilmit) The Intervals were computed for the "true" mean treatment differences, expressed as a percent of the reference mean, and true geometric mean ratios (from logarithmic transformation).

Results Table 2 summarizes the statistical analyses comparing 200 mg ZAG-1701 capiets to 200 mg Motrin IB caplets with regard to incremental areas under the curve and time to peak. Incremental areas from time 0 to the time of the early sample collections are known to reflect the rate of drug absorption. Time of peak concentration is a direct function of this rate. ZAG-1701 caplets had statistically significantly (p<0.05) greater mean (up to 2.8 fold) incremental areas under the curve than Motrin iB through the first hour post-dose. This was true for R-ibuprofen, S-ibuprofen and Total ibuprofen. The mean time of peak for [ZAG-1701a was less than 60% that of Motrin iB . These results indicate that the rate of ibuprofen absorption for [ZAG-1701] is faster than that for Motrin !B .
Figures 1 and 2 show that during the first hour post-dose, when analgesics are most needed, the formula provides a significantly greater concentration of the drug into the blood stream thereby to the site of action. S-ibuprofen is the pharmacologically active enanitomer of racemic ibuprofen. R-ibuprofen converts S-ibuprofen once in the body. Figure 4-6 show that the extent of absorption is significantly greater following administration of the formula as compared with Motrin IB during the first hour post-dose when the analgesic effect is most needed. Figure 7 shows that there are significant differences between the two products were noticed during the first 60 minutes following a complaint of pain.
The formula demonstrated 2.8 fold greater extent of absorption during the first 15 minutes as compared with Motrin 1B. Figure 8 shows that signifcant differences between the two products were noticed during the first 60 minutes following a complaint of pain. The extent of absorption becomes equal for the two products in 6 hours. Figure 9 shows that there were no statistically significant differences between the two products due to the small number of subjects tested. However, there was a consistent trend for greater PIS for Motrin IB. Figure 10 shows that there was no statistically significant difference between the two prodUcts due to the small number of subjects tested. However, there was a consistent trend for greater PIS for Motrin IB after correction for the baseline pain. Figure 11 shows that in the first 80 minutes, over 90% of the patients recorded relief after taking the formula of the present invention, as compared with over 60% after Motrin !B.
Conclusion The rate of ibuprofen absorption from ZAG-1701 is significantly faster than that for Motrin IB . During the absorption phase (up to about 90 minutes after administration) the incremental extent of absorption of ibuprofen was up to 2.8 fold greater from ZAG-1701 as compared with Motrin. ZAG-1701 and Motrin IB
have comparable total ibuprofen absorption.

Table 2: Statisticat Comparisons to Evaluate Rates of ibuprofen Absorption Summary of statistical comparisons of arithmetic mean Incremental areas under the curve and time to peak for ZAG-1701 and Motrin IB (ZAG-1701: n=12 subjects, Motrin IB : n=14 subjects).

Arithmetic Means R-lbuprofen S-Ibuprofen Total Ibuprofen Parameter Ratio Significance Ratio Significance Ratio Si nificance z ;. e W '_ .~q = .s ~. ~.v AUC 0-0.25 ( g-hr/mL) 2.867* 0.0438 2.744 0.0544 2.811* 0.0481 AUC Q-0.5 ( g-hr/mL) 2.772* 0.0127 2.685* 0.0185 2.733* 0.0150 ( g hrg/mL)5 2.398* 0.0056 2.294* 0.0123 2.352* 0.0079 ~g hr0/mL) 2.052* 0.0058 1.948* 0.0140 2.006* 0.0085 AUC 0-1.5 (pg-hr/mL) 1.468 0.0752 1.380 0.1396 1.429 0.0972 AUC 0-2 1.368 0.0796 1.276 0.1691 1.327 0.1070 ( g-hr/mL) Al1C 0-3 (pg-hr/mL) 1.274 0.1163 1.173 0.2673 1.230 0.1554 ( g-hr/mL) 1.181 '0.2219 1.094 0.4398 1.143 0.2742 ( g-hrlmL) 1.096 0.4453 1.022 0.8196 1.063 0.5519 (pg-hr/mL) 1.049 0.6613 0.971 0.7166 1.013 0.8843 Tmax 0.569* 0.0390 0.575* 0.0448 0.575* 0.0448 * Comparison between products was detected as statistically sighificant by ANOVA (a=0.05).

Example 18. Secondary Pharmacokinetic Parameters for Bioequivaience Evaluations Summary of statistical comparisons for secondary pharmacokinetic parameters related to the determination of bloequivalence of EquiTech's 200 mg ZAG-1701 caplets and 200 mg Motrin IB caplets-when each was administered as a single 400 mg (2 X 200 mg) dose.
R-ibu rofen Arithmetic Mean Ratio Parameters ZAG-1701 Motrin IB

(ho~ 1.26 -2.22 0,569*
K/hour 0.6254 Ø6998 0.894 hour 1.14 1.03 1.110 S-1bu rofen Arithmetic Mean Ratio Parameters ZAG-1701 Motrin lB

houX 1.26 2.19 0.575*

(1lhaur 0.3088 0.3245 0.952 hour 2.48 2.38 1.046 Total ibu rofen Arithmetic Mean Parameters ~-G-1701 Motrin IB Ratio max hour 1.26 2.19 0.575*
1%hour 0.4526 0.4697 0.964 T'/z 1.57 1.51 1.034 hour * Comparison detected as statistically significant by ANOVA (a=0.05).
=-34-.

Facamale 19.
Patients who require rescue medication due to lack of response to either ZAG-1701 or Motrin. There were 12-14 patients/group. The time of request for the rescue medication and the corresponding S-ibuprofen serum concentration were recorded.
Rescue Medication mg/L
Subject Treatment (S) at, min 7 ZAG 2.63 60 25 MOT 2.66 180 37 MOT 0.67 240 Example 20. Analytical Methods for Drug Product Two analyfical testing procedures, Dissolution Assay of Ibuprofen Release in ZAG-1701 Tablets, and ADetermination of (buprofen and lmpurities in Ibuprofen Drug Product by HPLC are summarized below.

HPLC Parameters:
Column: Agilent Zorbax Eclipse XDB-C8, 5,um, 150 mm x 4.6 mm Flow rate:0.8 mi/min I n jection volume: 15 pL
Wavelength: 254 nm Column temperature: Ambient Mobile phase: i% chioroacetate buffer pH 3.0)/Acetonitrile 40/60 (v/v) Mobile Phase and Diiuent Preparation:
1% chloroacetate buffer solution (pH 3.0): Dissolve 10.0 g chioroacetic acid in 1000 ml of dionized watet. Adjust the pH to 3.0 with ammonium hydroxide solution.
Mobile phase: Combine 400 mL of 1% chioroactetate buffer (pH and 600 mL of acetonitrile and mix well. Filter the soiution through 0.45,um Nylon membrane filter and degas before use, Diluent (0.2% chioroacetate buffer, pH
Acetonitriie, 40/60 v/v): Dissolve 20.0 g of chioracetic acid in 1000 mL of deionized water.
Adjust the pH to 3.0 with ammonium hydroxide solution. Mix 400 rni of 02%
chioroactate buffer with 600 mL of CAN.
Standard Solution Preparation ibuprofen working Standard (4 mgJmL): Accurately weigh approximately 100 mg of ibuprofen reference standard, and transfer into a 25 mL volumetric flask. Dissolve in approximately 15 mL of the diluent with shaking, dilute to volume with diluent and mix well.
Resolution Solution Preparation Isobutylacetophenone stock solution (0.20 mglmL): Weigh approximately 20 mg of 4- lsobutyiacetophenone reference standard, and transfer into a 100 mL volumetric flask. Dissolve in approximately 80 mL of acetonitrile with shaking, dilute to volume with acetonitrile and mix well Resolution standard solution: Weigh approximately 100 mg of ibuprofen reference standard into a 25 mL volumetric flask. Pipette 1,0 mL of 4-isobutylacetophenone stock standard solution into the 25 mL volumetric flask.
Add approxirriately 15 mL of the diluent into the flask and shake until the standard is completely dissolved. Dilute to volume with the djluent and mix.
Sample Solution Preparation Potency and Related Substances: Accurately weigh 10 intact tablets and record the tablets weight. Transfer the 10 tablets into a 500 mL volumetric flask.
Add approximately 350 mL of the diluent Into the flask and shake mechanically for 30 minutes. Sonicate the mixture for 30 minutes with occasional shaking.
Allow to cool to room temperature. Dilute to volume with the diluent and mix well.
Centrifuge a portion of the resulting solution at about 3500 rpm for 10 minutes.
Content Uniformity: Weigh 10 individual intact tablets and record each tablet weight. Transfer each tablet into a 50 mL volumetric flask. Add approximately 30 mL of the diluent into the flask and shake mechanically for minutes. Sonicate the mixture for 30 minutes with occasional shaking. Allow to cool to room temperature. Dilute to volume with diluent and mix well.
Centrifuge a portion of the resulting solution at about 3500 rpm for 10 minutes.

Blend Uniformity: Accurately weigh and record the weight of the container with in process blend. This is gross weight. Depending on the weight of contents, transfer the entire contents into an appropriate volumetric flask. Add appropriate diluent in each volume flask, and shake mechanically for 30 minutes. Sonicate the mixture for 30 minutes with occasional shaking. Allow cooling to room temperature. Dilute to volume with the diluent and mix well. Centrifuge a portion of the resulting solution at about 3500 rpm for 10 minutes.
Identification: Accurately weigh 13 intact tablets and record the tablets weight. Transfer the 10 tablets into a 500 mL volumetric flask. Add approximately 350 mL of the diluent into the flask and shake mechanically for 30 minutes. Sonicate the mixture for 30 minutes with occasional shaking. Allow cooling to room temperature. Dilute to volume with the diluent and mix well, Centrifuge a portion of the resulting solution, at about 3500 rpm for 10 minutes.

Example 21. Dissolution Assay of Ibuprofen Release in Tablets Dissolution Parameters:
Dissolution Apparatus: USP Apparatus 2 (paddle) Temperature: 37 ~ 0.5 C
Dissolution volume: 900 mL
Rotation speed: 50 rpm Dissolution medium: 1% SDS in deionized water Sampling time: For release testing: sampling at 30 minutes only For stability testing: sampling at 5, 10, 20 and 30 minutes Sampling volume: 10 mL with dissolution medium replacement HPLC Parameters:
Column: Agilent Zorbax Eclipse XDB-C8, 5Nm, 150 mm x 4.6 mm Flow rate: 0.8 mUmin Injection volume: 15,uL
Wavelength: 254 nm Column temperature: Ambient Mobile phase: 1% chloroacetate buffer (pH 3.0)lAcetonitrile 40/60 (v/v) Preparation of Dissolution Medium Weigh and transfer approximately 10g of SDS into a suitable container, add 1000 mL of deionized water to dissolve and mix well. Degas by sonicating for 15 minutes before use.
Preparation of Diluent For the preparation of about one liter of diluent, combine 500 mL of mobile phase with 500 mL of dissolution medium and mix well.
Preparation of pH 3.0 Buffer For the preparation of one liter of pH 3.0 buffer, weigh approximately 10.0 g of chioroacetic acid and dissolve in 950 rnL of deionized water, adjust pH with NH4OH to 3Ø Dilute to 1000 mL with deionized water and mix thoroughly.
Preparation of Mobile Phase For the preparation of about one liter of mobile phase, combine 400 mL of pH
3.0 buffer with 600 mL of acetonitrile and mix well. Filter the mobile phase through a 0.45 ,um nylon membrane filter and degas prior to use.
Preparation of Ibuprofen Standard Solution (110 ualmL
Accurately weigh approximately 22 mg of lbuprofen reference standard and transfer into a 200 mL volumetric flask. Add about 150 mL of diluent to dissolve, sonicate if necessary. Dilute to volume with diluent once it is cooled to room temperature and mix well. Filter a portion of this solution through the 0.45 pm PVDF
syringe, discarding the first 2 mL, and collect the fiitrate for analysis.
Preparation of Dissolution Sample Solution 1. According to the dissolution conditions, place 900 mL of degassed dissolution medium Into each of six dissolution vessels, assemble the apparatus and equilibrate the dissolution medium to 37 0.5 C.
2. Weigh each of six tablets and record the individual tablet weight. Place each tablet Into a dissolution vessel, taking care to exclude air bubbles from the surface of the dosage-form unit and immediately operate the apparatus at a rotation speed of 50 rpm.
3. Sampling (For release) c Using a syringe fitted with a stainless steel cannula, ..38..

withdraw 10 mL of the solution from a zone midway between the surface of the dissolution medium and the top of the paddle, not less than 1 cm from the vessel wall at 30 minutes.
4. Sampling (For stability) . Using a syringe fitted with a stainless steel.
cannufa, withdraw 10 mL of the solution from a zone midway between the surface of the dissolution medium and the top of the paddle, not less than 1 cm from the vessel wall at 5, 10, 20, and 30 minutes time points for stability analysis, replace 10 mL of dissolution medium pre-wanned to 37 0.5 C back to dissolution vessel after every sampling point.
5. Filter the sample solution through the 0.45,um PVDF syringe filter and collect the filtrate, discarding the first 2 mL. Dilute the filtrate 1:1 with mobile phase and mix thoroughly, Test Specification Results physical appearance capiet shape, white to off-white conforms tablets potency 90-110% of label claim 108.1%

content uniformity meets USP<905> requirements 103.8 B 113.0%
Mean: 108:3%
%RSD: 2.3 related substances 1) 4-isobutylacetophenone NMT 0.25% 0:00%
2) individual unknown NMT 0.2% 0.05% (RRT 0.64) related substances 0.06% (RRT 0.82) 3) total related substances 0.11%

dissolution Q380% at 30 minutes 99.6%
(% dissolved 385%) %RSD = 2.0 loss on drying 2.9%
disintegration all tablets completely 2 min.13 sec.
disintegrated in NMT 15 minutes ..39...

Although the present invention has been described in terms of particular preferred embodiments, it is not limited to those embodiments. Alfiemative embodiments, examples, and modifications which would still be encompassed by the invention may be made by those skiiled in the art, particularly in light of the foregoing teachings.

Claims (31)

1. A pharmaceutical composition comprising a non-steroidal anti-inflammatory active agent, at least one disintegration agent, and a metasilicate.

2. A pharmaceutical composition comprising ibuprofen on a matrix comprising a metasilicate, and a disintegration and dissolution agent, such as a bicarbonate.

3. The pharmaceutical composition of claim I further comprising one or more lubricating agents, one or ore binders, one or more additional disintegrating agents, one or more flow aids, and/or one or more colorants and/or flavorants.

4. The pharmaceutical composition of claim 1 wherein the anti-inflammatory active agent is selected from the group consisting of piroxicam, meloxicam, indomethacin, fenoprofen, keterolac, naproxen, and ibuprofen.

5. The pharmaceutical composition of claim 1 wherein the disintegration agent is an alkali metal carbonate.

6. The pharmaceutical composition of claim 5 wherein the alkali metal carbonate is sodium bicarbonate.

7. The pharmaceutical composition of claim 1 further comprising an excipient comprising tartaric acid.

8. The pharmaceutical composition of claim 1 comprising ibuprofen, sodium bicarbonate, tartaric acid, and a metasilicate.

9. The pharmaceutical composition of claim 7 further comprising hypromellose, pre-gelatinized starch, microcrystalline cellulose, sodium croscarmellose, and magnesium stearate.

10. A method for the treatment of inflammation comprising supplying an anti-inflammation formulation, said formulation comprising a non-steroidal anti-inflammatory active agent, a disintegrating agent comprising an alkali metal carbonate, a metasilicate matrix, and an excipient comprising tartaric acid;
and administering said formulation.

11. The pharmaceutical composition of claim 1 wherein the active agent is ibuprofen.

12. The pharmaceutical composition of claim 11 wherein the ibuprofen is in the form of a salt of racemic or S(+)-ibuprofen.

13. The pharmaceutical composition of claim 12 wherein the ibuprofen is the hydrated form of sodium salt dehydrate in compressed dosage form.

14. The method of claim 10 wherein the formulation's standard dosage form of ibuprofen is in the range of 100-800 mg.

15. The method of claim 10 wherein the formulation dosage form is a tablet, capsule, or sachet.

16. The method of claim 15 wherein the formulation dosage form is a solid non-effervescent form.

17. A method of alleviating pain comprising preparing a formulation comprising a non-steroidal anti-inflammatory active agent, a disintegrating agent comprising an alkali metal carbonate, a metasilicate matrix, and an excipient comprising tartaric acid; and administering said formulation.

18. The method of claim 17 wherein the formulation comprises ibuprofen on a matrix comprising a metasilicate, a disintegration and dissolution agent, such as a bicarbonate, and an anti-precipitation agent.

bicarbonate, and an anti-precipitation agent.

19. The method of claim 18 wherein the anti-precipitation agent is Gelucire®.

20. The method of claim 17 wherein the formulation is in non-aqueous granulations and solid non-effervescent dosage.

21. A method of preparing the formulation comprises dissolving ibuprofen in an alkaline solution; mix with neusilin; change the pH (e.g., by adding glacier acid) so that the ibuprofen re-crystalizes; and remove the solution. The ibuprofen is thereby loaded on the neusilin matrix. It should then be dried, e.g., overnight.

22. A method of treating inflammation, pain and pyrexia by administration of a pharmaceutical composition comprising racemic ibuprofen, together with a pharmaceutically acceptable carrier to a mammal, e.g. a human, in need thereof.

23. The method of claim 22 wherein the ibuprofen is present in one or more of its well known forms, namely, ibuprofen, Its S(+) and R(-) enantiomers, including different enantiomeric ratios thereof, salts, hydrates, and other derivatives.

24. The method of claim 23 wherein the preferred form is a dihydrate.

25. A method for preparing a solid composition in tablet form, comprising an active ingredient such as ibuprofen is mixed with a bicarbonate, such as sodium bicarbonate under non-aqueous conditions and a diluent.

26. The pharmaceutical composition of claim 1 wherein the pharmaceutical composition percentage range by weight comprises 35% of ibuprofen, 6% of metasilicate, 18% sodium bicarbonate, 2.5% tartaric acid, 7% hyroxypropi cellulose,10% sodium starch glycolate, 17% microcrystalline cellulose, 1.5%
Talcum, 1-2% propyl gallate,0.5-1 % EDTA and 1.0% magnesium stearate,

27. A method of enhancing bioavailability in humans comprising forming non-aqueous granulations and to solid non-effervescent dosage forms prior to in vivo delivery.

28. The method of claim 27 wherein the non-aqueous granulations and solid non-effervescent dosage form is a tablet.

29. The pharmaceutical composition of claim 26 wherein the tablet size is 560-mg.

30. A method of accelerating the time line of disintegration into particle form by chemically mimicking the agitation provided by the motility function, by initiating the disintegration from tablet form into particles as soon as the tablet is exposed to a very limited amount of fluid.

31. A method of dissolution wherein the highest level of disintegration of the pharmaceutical composition is In the stomach of a patient in pain 5-30 min.