WO2009055925A1 - Enhanced nsaid formulations - Google Patents

Abstract

The application is directed to a composition and its use for treating inflammation comprising a non-steroidal anti-inflammatory active agent, a metasilicate, a first disintegrant and a second disintegrant, resulting in increased absorption of said active in mammals with suppressed vagal systems The preferred composition includes a non-steroidal anti-inflammatory active, sodium bicarbonate, tartaric acid and metasilicate.

Description

Enhanced NSAID Formulations

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This invention claims priority of US. Serial No. 60/991 ,179, filed

November 29, 2007 and U.S. Serial No. 60/984,058, filed October 31 , 2007; and are continuation-in-parts of U.S. Serial No. 11/118,773, filed May 2, 2005, 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 pharmaceutical formulations having increased absorption rate in suppressed mammalian vagal systems (i.e., in pain).

DESCRIPTION OF RELATED ART

[0003] In the treatment of acute pain rapid absorption of orally administered analgesics is desirable. There appears to be a positive relationship 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 active agent. 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 analgesics and other active agents have been claimed to be superior over the products of the same drug with respect to onset of action when the gastrointestinal function is compromised (e.g., pain). 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] Jamali & Kunz, Brit J. CHn. Pharmacol., 47:391 -396 (1999) have reported that, using dental 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 suggested to be caused by suppression of the vagal nervous system. The vagus nerve, nervus vagus, is the 10^th 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, bioavailability tends to be highly variable as well as low. The physicochemical properties of a drug govern its absorptive potential, but the properties of the dosage form (which partly depend on its design and manufacture) can also largely determine drug bioavailability. Differences in bioavailability among formulations of a given drug can have clinical significance. 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 growing evidence that vagal suppression conditions, namely, reduction in stomach motility, stomach secretion diminution, and reduced absorption appear to be present also in the elderly, or what shall be termed herein, the geriatric stomach. [0009] Mere increased solubility and in vitro dissolution as described by

Gupta et al (J Pharm Sci. 2003 Mar;92(3):536-51 ; Pharm Dev Technol. 2002 Jan;7(1):103-12.; Pharm Res. 2002 Nov; 19(11): 1663-72) are not sufficient to increase the in vivo absorption rate of drugs, i.e., shorter onset of action, when the patient is in pain. The formulation needs to quickly disintegrate to allow efficient dissolution. The present invention presents optimal combination of various excipients that yield both rapid breakdown of the formulation and increased rate of dissolution as the same time. [0010] Ketamine (2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone is the common name for a drug that is widely used as a surgical anesthetic. Two of its more important traits are: (i) it is cleared from circulating blood fairly rapidly, which enables anesthesiologists to bring an unconscious patient out of anesthesia more rapidly than can be achieved by using other types of anesthetics with longer durations of action; and, (ii) it is an NMDA antagonist drug, which means that it exerts anesthetic effects by suppressing and reducing activity at the so-called NMDA class of neuronal receptors. The term "NMDA antagonist" is used interchangeably herein with terms such as "NMDA receptor blocker" or "NMDA blocker drug".

SUMMARY OF THE INVENTION

[0011] It is desirable to provide an active agent formulation that can deliver drugs into the blood stream despite a suppressed vagal system. It would be advantageous to provide a composition having enhanced absorption of active agent, as well as providing an improved concentration of the drug at the cellular level at the site of its action. The formulations include one or more active agents, said active agents being effective against or suitable for treating pain; at least one dissolution and/or disintegration agent, such as a bicarbonate; and one or more excipients, such as tartaric acid. The formulations also may include one or more diluents or fillers; one or more binders or adhesives; one or more additional disintegration agents; one or more lubricating agents; and one or more adjunct agents, including but not limited to colorants, flavor enhancers; solubilizers; and extended release agents. The preferred formulation is a tablet suitable for oral ingestion. [0012] 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.

[0013] Prior applications and inventions by the present inventors have shown formulations for increasing the disintegration and bioavailability NSAIDs, meloxicam, and a few other analgesics. With the present invention, applicant shows that the formulations of the present invention, specifically the inclusion of a bicarbonate and tartaric acid as taught below, results in rapid disintegration and absorption of a wide variety and range of active agents. [0014] In accordance with one embodiment of the present invention, the composition contains an active agent; 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 tablet, caplet, or solid form, to produce formulations that have enhanced disintegration into particles and subsequently enhanced dissolution of the particles into dispersed molecules in solution.

[0015] In accordance with the present invention, the bicarbonate is a disintegrator or disintegrating agent that increases the solubility and/or bioavailability of the active agent. One of the important effects of sodium bicarbonate ingestion is that the reaction takes place in the stomach. This results in 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. Mere exposure of ibuprofen with bicarbonate in the aqueous environment of stomach results in the reaction. However, this reaction is accelerated with the addition of a soluble acid such as tartaric acid. 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 therein. [0016] While not intending to be limited to a particular mechanism of action, the inventors believe that the bicarbonate increases solubility by promoting the formation of sodium ibuprofen, a salt that is readily converted to ibuprofen; ibuprofen 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. Mesoporous silicate matrix has been used by Cavallaro et al (Drug Deliv. 2004 Jan-Feb;11 (1):41 -6) to delay drug release in stomach rather than maintain solubility of the released molecules. [0017] The compositions and methods of the present invention achieve chemically what happens biologically when one or more active agents are administered and absorbed in vagally suppressed 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.

[0018] 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 soluble salt of ibuprofen leading in part to quicker absorption, thereby, faster onset of action. [0019] 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. [0020] 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.

[0021] 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.

[0022] As shown in Examples 11 -14, delayed absorption in rats with suppressed gastrointestinal secretion and motility (an animal model mimicking the human in pain condition) can be, beside ibuprofen, extrapolated to drugs such as diclofenac, naproxen, naratriptan, metoclopramide, ketamine, and many other active agents noted below.

DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 illustrates significantly increased absorption of

Diclofenac when used as an active agent in a formulation of the present invention. [0024] Figure 2 illustrates significantly increased absorption of meloxicam when used as an active agent in the formulation described in Example 12. [0025] Figure 3 illustrates significantly increased absorption of

Diclofenac when used as an active agent in the formulation described in Example 12. [0026] Figure 4 illustrates significantly increased absorption of naratriptan when used as an active agent in the formulation described in Example 14. [0027] Figure 5 shows that the absorption of naproxen acid is reduced in an animal model in pain. [0028] Figure 6 shows that the absorption of naproxen sodium salt is substantially similar when comparing an animal model in pain to a healthy animal.

[0029] Figure 7 shows that there is no significant difference between naproxen acid in a formulation of the present invention, as compared to a sodium salt of naproxen in a conventional formulation.

[0030] Figure 8 shows that there is no significant difference between a sodium salt of naproxen in a formulation of the present invention, as compared to a sodium salt of naproxen in a conventional formulation

DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention is a method and composition of treating pain and/or inflammation 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 metasilicate, wherein the first disintegrant comprises sodium bicarbonate; and wherein said second disintegrant comprises tartaric acid.

[0032] In accordance with the present invention, the active agent is preferably selected from the group consisting of diclofenac, naproxen, naratriptan, ketamine, and metoclopramide.

[0033] The present invention is also a method and composition 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.

[0034] 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 tablet. [0035] 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 Chemical

Industry Co., Ltd.; Trade-name: NEUSILIN).

[0036] The present invention is also any of the above compositions, further comprising one or more lubricating agents, one or more 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.

[0037] The present invention is also a method for increasing the absorption of an active agent -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 vagally suppressed system.

[0038] The present invention is also a method of treating acute pain in humans comprising administering a composition according to the present invention.

[0039] Our invention is a rapidly bursting solid dosage form that, after entering stomach and upon exposure to the fluid therein, bursts open and makes the active ingredient available for dissolution and absorption. This formulation does not have to be in a special form such as microsphere as shown in U.S. Patent 5,840,334 and U.S. Patent 6,086,920, nano particulate as shown in U.S. Patent 6,165,506 or contain soluble salts of low solubility drugs as shown in WO 97/30699.

[0040] 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.

[0041] The present invention further relates to tablets and granules, formulated in accordance with the present invention, which are fast dissolving and fast acting. The granulation and tablet composition also includes normal excipients useful for the preparation of tablets.

[0042] The present invention is also a composition and method of treatment comprising 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 following: 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 gallate; 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.

[0043] 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. The formulation of the present invention is especially useful for oral delivery of bio-active agents and may comprise any bio-active compound that is suitable for oral drug administration; examples of the various therapeutic classes of bio-active agents that can be administered while using the present dosage forms include, but are not limited to: analgesic agents; anesthetic agents; antiarthritic agents; respiratory drugs; anticancer agents; anticholinergics; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihelminthics; antihistamines; antihyperlipidemic agents; antihypertensive agents; anti-infective agents such as antibiotics and antiviral agents; antiinflammatory agents; antimigraine preparations; antinauseants; antineoplastic agents; anti-Parkinson drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; antitubercular agents; antiulcer agents and other gastrointestinally active agents; antiviral agents; anxiolytics; appetite suppressants; attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD) drugs; cardiovascular preparations including calcium channel blockers, CNS agents, and vasodilators; beta-blockers and antiarrhythmic agents; central nervous system stimulants; cough and cold preparations, including decongestants; diuretics; genetic materials; herbal remedies; hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents; leukotriene inhibitors; mitotic inhibitors; muscle relaxants; narcotic antagonists; nutritional agents, such as vitamins, essential amino acids and fatty acids; parasympatholytics; peptide drugs; psychostimulants; sedatives; steroids; sympathomimetics; and tranquilzer. [0044] 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 invention, the composition and method include an active agent selected from the group consisting of diclofenac, naproxen, naratriptan, ketamine, and metoclopramide. [0045] Thus other active substances which may be used for the combinations mentioned above include for example the non-steroidal antiinflammatories aceclofenac, acemetacin, acetylsalicylic acid, azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indometacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulphasalazine, tenoxicam, zomepirac or the pharmaceutically acceptable salts thereof as well as meloxicam and other selective COX2-inhibitors, such as for example rofecoxib and celecoxib. [0046] It is also possible to use candesartan, eprosartan, irbesartan, losartan, olmesartan, tasosartan, telmisartan, valsartan, duloxetine, ergotamine, dihydro-ergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, pizotifen, botox, gabapentin, topiramate, riboflavin, montelukast, lisinopril, prochloroperazine, dexamethasone, flunarizine, dextropropoxyphene, meperidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramin, carbamazepine, phenyloin, valproate, amitryptiline, lidocaine or diltiazem and other 5-HT.sub.1 B/1 D-agonists such as, for example, almotriptan, avitriptan, donitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan and the physiologically acceptable salts thereof. [0047] Categories of active agents that may be used in accordance with the present invention include, but are not limited to, e.g. angiotensin Il receptor antagonists, .alpha.-agonists and .alpha.-antagonists, 5- HT.sub.1 B/1 D agonists, AMPA antagonists, mild analgesics, antidepressants, antiemetics, anticonvulsants, antimuscarinics, .beta.-blockers, calcium antagonists, corticosteroids, ergot alkaloids, histamine-H1 receptor antagonists, neurokinine antagonists, neuroleptics, non-steroidal antiinflammatories, NO-synthase inhibitors, prokinetics, selective serotonin reuptake inhibitors or other anti-migraine agents, which may be formulated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories.

[0048] Gastrointestinally active agents can be administered using the present dosage forms. These types of drugs include agents for inhibiting gastric acid secretion such as, but not limited to, the H2 receptor antagonists cimetidine, ranitidine, famotidine, and nizatidine, the H+ or K+-ATPase inhibitors (also referred to as "proton pump inhibitors") omeprazole and lansoprazole, and antacids such as, but not limited to, calcium carbonate, aluminum hydroxide and magnesium hydroxide. Also included within this general group are agents for treating infection with Helicobacter pylori (H. pylori) such as, but are not limited to, metronidazole, tinidazole, amoxicillin, clarithromycin, tetracycline, thiamphenicol and bismuth compounds (e.g. bismuth subcitrate and bismuth subsalicylate). Other gastrointestinally active agents that can be administered while using the present dosage forms include, but are not limited to, pentagastrin, carbenoxolone, sulfated polysaccharides such as sucralfate, prostaglandins such as misoprostol, and muscarinic antagonists such as pirenzepine and telenzepine. Additionally included are antidiarrheal agents, antiemetic agents and prokinetic agents such as, but are not limited to, ondansetron, granisetron, metoclopramide, chlorpromazine, perphenazine, prochlorperazine, promethazine, thiethyl- perazine, triflupromazine, domperidone, trimethobenzamide, cisapride, motilin, loperamide, diphenoxylate and octreotide.

[0049] Anti-microbial agents that may be used in this invention include tetracycline antibiotics and related compounds (e.g. chlortetracycline, oxy- tetracycline, demeclocycline, methacycline, doxycycline, minocycline and roli- tetracycline); macrolide antibiotics such as, but not limited to, erythromycin, clarithromycin, and azithromycin; streptogramin antibiotics such as, but not limited to, quinupristin and dalfopristin; beta-lactam antibiotics, including penicillins (e.g., penicillin G, penicillin VK), antistaphylococcal penicillins (e.g. cloxacillin, dicloxacillin, nafcillin and oxacillin), extended spectrum penicillins (e.g. aminopenicillins such as ampicillin and amoxicillin, and antipseudomonal penicillins such as carbenicillin), cephalosporins (e.g. cefadroxil, cefepime, cephalexin, cefazolin, cefoxitin, cefotetan, cefuroxime, cefotaxime, ceftazidime and ceftriaxone) and carbapenems such as, but not limited to, imipenem, meropenem and aztreonam; aminoglycoside antibiotics such as, but not limited to, streptomycin, gentamicin, tobramycin, amikacin and neomycin; glycopeptide antibiotics such as teicoplanin; sulfonamide antibiotics such as, but not limited to, sulfacetamide, sulfabenzamide, sulfadiazine, sulfadoxine, sulfamerazine, sulfamethazine, sulfamethizole and sulfamethoxazole; quinolone antibiotics such as, but not limited to, ciprofloxacin, nalidixic acid and ofloxacin; anti-mycobacterials such as, but not limited to, isoniazid, rifampin, rifabutin, ethambutol, pyrazinamide, ethionamide, aminosalicylic and cycloserine; systemic antifungal agents such as, but not limited to, itraconazole, ketoconazole, fluconazole and amphotericin B; and miscellaneous antimicrobial agents such as, but not limited to, chloramphenicol, spectinomycin, polymyxin B (colistin), bacitracin, nitrofurantoin, methenamine mandelate and methenamine hippurate. [0050] Anti-diabetic agents that may be used in this invention include, by way of example, acetohexamide, chlorpropamide, ciglitazone, gliclazide, glipizide, glucagon, glyburide, miglitol, pioglitazone, tolazamide, tolbutamide, triampterine, and troglitazone.

[0051] Non-opioid analgesic agents that may be used in this invention include, but are not limited to, apazone, etodolac, difenpiramide, indomethacin, meclofenamate, mefenamic acid, oxaprozin, phenylbutazone, piroxicam and tolmetin. Opioid analgesics that may be used in this invention include, but are not limited to, alfentanil, buprenorphine, butorphanol, codeine, drocode, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, sufentanil and tramadol.

[0052] Anti-inflammatory agents that may be used in this invention include non-steroidal anti-inflammatory agents, e.g. propionic acid derivatives such as, but not limited to, ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, fenbufen, apazone, diclofenac, difenpiramide, diflunisal, etodolac, indomethacin, ketorolac, meclofenamate, nabumetone, phenylbutazone, piroxicam, sulindac and tolmetin. Suitable steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, hydrocortisone-21 -monoesters (e.g. hydrocortisone-21 -acetate, hydrocortisone-21 -butyrate, hydrocortisone-21 - propionate, hydrocortisone-21 -valerate), hydrocortisone-17,21 -diesters (e.g. hydrocortisone-17,21 -diacetate, hydrocortisone-17-acetate-21 -butyrate, hydrocortisone-17,21 -dibutyrate), alclometasone, dexamethasone, flumethasone, prednisolone and methylprednisolone. [0053] Anti-convulsant agents that may be used in this invention include, by way of example, azetazolamide, carbamazepine, clonazepam, clorazepate, ethosuximide, ethotoin, felbamate, lamotrigine, mephenyloin, mephobarbital, phenyloin, phenobarbital, primidone, trimethadione, vigabatrin, topiramate, and benzodiazepines.

[0054] CNS and respiratory stimulants that may be used in this invention include, but are not limited to, xanthines such as caffeine and theophylline; amphetamines such as amphetamine, benzphetamine hydrochloride, dextroamphetamine, dextroamphetamine sulfate, levamphetamine, levamphetamine hydrochloride, methamphetamine, and methamphetamine hydrochloride; and miscellaneous stimulants such as methylphenidate, methylphenidate hydro-chloride, modafinil, pemoline, sibutramine and sibutramine hydrochloride.

[0055] Neuroleptic agents that may be used in this invention include antidepressant drugs, antimanic drugs and antipsychotic agents. Suitable antidepressant drugs include: (a) tricyclic antidepressants such as, but not limited to, amoxapine, amitriptyline, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline and trimipramine, (b) serotonin re-uptake inhibitors such as, but not limited to, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine, [c) monoamine oxidase inhibitors such as, but not limited to, phenelzine, tranylcypromine and (-)-selegiline, and (d) other atypical antidepressants such as, but not limited to, nefazodone, trazodone and venlafaxine. Suitable anti-manic and antipsychotic agents include: (a) phenothiazines such as, but not limited to, acetophenazine, acetophenazine maleate, chlorpromazine, chlorpromazine hydrochloride, fluphenazine, fluphenazine hydro-chloride, fluphenazine enanthate, fluphenazine decanoate, mesoridazine, mesoridazine besylate, perphenazine, thioridazine, thioridazine hydrochloride, trifluoperazine, and trifluoperazine hydrochloride, (b) thioxanthenes such as, but not limited to, chlorprothixene, thiothixene, and thiothixene hydrochloride, and (c) other heterocyclic drugs such as, but not limited to, carbamazepine, clozapine, droperidol, haloperidol, haloperidol, decanoate, loxapine succinate, molindone, molindone hydrochloride, olanzapine, pimozide, quetiapine, risperidone and sertindole.

[0056] Hypnotic agents and sedatives that may be used in this invention include, but are not limited to, clomethiazole, ethinamate, etomidate, glutethimide, meprobamate, methyprylon, Zolpidem and barbiturates (e.g. amobarbital, apropbarbital, butabarbital, butalbital, mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital and thiopental). [0057] Anxiolytics and tranquilizers that may be used in this invention include, but are not limited to, benzodiazepines (e.g. alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam, lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam and triazolam), buspirone, chlordiazepoxide and droperidol. [0058] Anticancer and antineoplastic agents that may be used in this invention include, but are not limited to, paclitaxel, docetaxel, camptothecin and its analogues and derivatives (e.g. 9-aminocamptothecin, 9- nitrocamptothecin, 10-hydroxycamptothecin, irinotecan, topotecan and 20-O- .beta.-glucopyranosyl camptothecin), taxanes (e.g. baccatins, cephalomannine and their derivatives), carboplatin, cisplatin, interferon- . alpha. 2A, interferon-.alpha. 2B, interferon-. alpha. N3 and other agents of the interferon family, levamisole, altretamine, cladribine, tretinoin, procarbazine, dacarbazine, gemcitabine, mitotane, asparaginase, porfimer, mesna, amifostine, mitotic inhibitors including podophyllotoxin derivatives such as, but not limited to, teniposide and etoposide, and vinca-alkaloids such as, but not limited to, vinorelbine, vincristine and vinblastine.

[0059] Antihyperlipidemic or lipid-lowering or hyperlipidemic agents that may be used in this invention include, but are not limited to, HMG-CoA reductase inhibitors such as atorvastatin, simvastatin, pravastatin, lovastatin and cerivastatin, and other lipid-lowering agents such as, but not limited to, clofibrate, fenofibrate, gemfibrozil and tacrine.

[0060] Anti-hypertensive agents that may be used in this invention include, but are not limited to, arnlodipine, benazepril, darodipine, dilitazem, diazoxide, doxazosin, enalapril, eposartan, losartan, valsartan, felodipine, fenoldopam, fosinopril, guanabenz, guanadrel, guanethidine, guanfacine, hydralazine, metyrosine, minoxidil, nicardipine, nifedipine, nisoldipine, phenoxybenzamine, prazosin, quinapril, reserpine and terazosin. [0061] Cardiovascular preparations that may be used in this invention include, by way of example, angiotensin converting enzyme (ACE) inhibitors such as, but not limited to, enalapril, 1 -carboxymethyl-3-1 -carboxy-3-phenyl- (1 S)-propylamino-2,3 ,4,5-tetrahydro-- 1 H-(3S)-1 -benzazepine-2-one, 3-(5- amino-1 -carboxy-1 -S-pentyl)amino-2,3,4,5-tetrahydro-2-oxo-3-S-1 -H-be- nza- zepine-1 -acetic acid or 3-(1 -ethoxycarbonyl-3-phenyl-(1 S)-propylamino)- 2,3,4,5-tetrahydro-2-oxo-(- 3S)-benzazepine-1 -acetic acid monohydrochloride; cardiac glycosides such as, but not limited to, digoxin and digitoxin; inotropes such as amrinone and milrinone; calcium channel blockers such as, but not limited to, verapamil, nifedipine, nicardipene, felodipine, isradipine, nimodipine, bepridil, amlodipine and diltiazem; beta-blockers such as, but not limited to, atenolol, metoprolol; pindolol, propafenone, propranolol, esmolol, sotalol, timolol and acebutolol; antiarrhythmics such as, but not limited to, moricizine, ibutilide, procainamide, quinidine, disopyramide, lidocaine, phenyloin, tocainide, mexiletine, flecainide, encainide, bretylium and amiodarone; cardioprotective agents such as dexrazoxane and leucovorin; vasodilators such as nitroglycerin; and diuretic agents such as, but not limited to, hydrochlorothiazide, furosemide, bumetamide, ethacrynic acid, torsemide, azosemide, muzolimine, piretanide and tripamide.

[0062] Anti-viral agents that can be delivered using the present dosage forms include, but are not limited to, anti-herpes agents such as acyclovir, famciclovir, foscamet, ganciclovir, idoxuridine, sorivudine, trifluridine, valacyclovir and vidarabine; anti-retroviral agents such as didanosine, stavudine, zalcitabine, tenovovir and zidovudine; and other antiviral agents such as, but not limited to, amantadine, interferon-alpha, ribavirin and rimantadine.

[0063] Sex steroids that may be used in this invention include progestogens such as, but not limited to, acetoxypregnenolone, allylestrenol, anagestone acetate, chlormadinone acetate, cyproterone, cyproterone acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone (17.alpha.-ethinyl-testosterone), ethynodiol diacetate, fluorogestone acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone, hydroxymethylprogesterone acetate, 3-ketodesogestrel, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate, melengestrol acetate, norethindrone, norethindrone acetate, norethisterone, norethisterone acetate, norethynodrel, norgestimate, norgestrel, norgestrienone, normethisterone and progesterone. Also included within this class are estrogens, e.g. .beta.-estradiol (i.e. 1 ,3,5-estratriene- 3,17.beta.-diol, or 17.beta.-estradiol) and its esters, including estradiol benzoate, valerate, cypionate, heptanoate, decanoate, acetate and diacetate; 17.alpha.-estradiol; ethinylestradiol (i.e. 17. alpha. -ethinylestradiol) and esters and ethers thereof, including ethinylestradiol-3-acetate and ethinylestradiol-3- benzoate; estriol and estriol succinate; polyestrol phosphate; estrone and its esters and derivatives, including estrone acetate, estrone sulfate, and piperazine estrone sulfate; quinestrol; mestranol; and conjugated equine estrogens. Androgenic agents, also included within the class of sex steroids, are drugs such as the naturally-occurring androgens androsterone, androsterone acetate, androsterone propionate, androsterone benzoate, androstenediol, androstenediol-3-acetate, androstenediol-17-acetate, androstenediol-3,17-diacetate, androstenediol-17-benzoate, androstenediol-3- acetate-17-benzoate, androstenedione, dehydroepiandrosterone (DHEA or prasterone), sodium dehydro-epiandrosterone sulfate, 4-dihydrotestosterone (DHT or stanolone), δ.alpha.-dihydrotestosterone, dromostanolone, dromostanolone propionate, ethylestrenol, nandrolone phenpropionate, nandrolone decanoate, nandrolone furylpropionate, nandrolone cyclohexanepropionate, nandrolone benzoate, nandrolone cyclohexanecarboxylate, oxandrolone, stanozolol and testosterone; pharmaceutically acceptable esters of testosterone and 4- dihydrotestosterone, typically esters formed from the hydroxyl group present at the C-17 position, including, but not limited to, the enanthate, propionate, cypionate, phenylacetate, acetate, isobutyrate, buciclate, heptanoate, decanoate, undecanoate, caprate and isocaprate esters; and pharmaceutically acceptable derivatives of testosterone such as, but not limited to, methyl testosterone, testolactone, oxymetholone and fluoxymesterone. [0064] Muscarinic receptor agonists that may be used in this invention include, by way of example, choline esters such as, but not limited to, acetylcholine, methacholine, carbachol, bethanechol (carbamylmethylcholine), bethanechol chloride, cholinomimetic natural alkaloids and synthetic analogues thereof, including pilocarpine, muscarine, McN-A-343 and oxotremorine. Muscarinic receptor antagonists that may be used in this invention include belladonna alkaloids or semi-synthetic or synthetic analogues thereof such as, but not limited to, atropine, scopolamine, homatropine, homatropine methyl bromide, ipratropium, methantheline, methscopolamine and tiotropium.

[0065] The phrase "pharmaceutically acceptable salt(s)," as used herein includes, but is not limited to, salts of acidic or basic groups that may be present in the compounds of the preferred embodiments of the invention. [0066] The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N.N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Salts derived from pharmaceutically acceptable acids include acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucuronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalene-1 ,5-disulfonic, naphthalene-2,6-disulfonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic and the like. Particularly preferred are citric, hydrobromic, hydrochloric, isethionic, maleic, naphthalene-1 ,5- disulfonic, phosphoric, sulfuric and tartaric acids.

[0067] Ketamine and butamben are basic in nature and are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable salts of such basic compounds are those that form salts comprising pharmacologically acceptable anions including, but not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, bromide, iodide, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, muscate, napsylate, nitrate, pantothenate , phosphate/diphosphate, polygalacturonate, salicylate, stearate, succinate, sulfate, tannate, tartrate, teoclate, triethiodide, and pamoate (i.e., 1 ,1 '- methylene-bis-(2-hydroxy-3-naphthoate)). Ketamine and butamben have an amino moiety and also can form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. [0068] In a preferred embodiment of the present invention, ketamine is in the form of ketamine hydrochloride. A physiologically tolerable salt of the ketamine may preferably be hydrochloride, hydrobromide, sulphate, sulphonate, phosphate, tartrate, embonate, formiate, acetate, propionate, benzoate, oxalate, succinate, citrate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate, lactate, mesylate or a mixture of at least two of these salts. [0069] The compositions of the invention may include about 15 to about

99% by weight of an active agent, 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%. [0070] 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%.

[0071] 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%. [0072] 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%.

[0073] 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 100 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 1 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, 1 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.

[0074] In general, the amount of ketamine in pharmaceutical compositions of the invention is within the range of from about 0.1 percent to about 20 percent by weight, from about 1 percent to about 10 percent by weight, or from about 2 percent to about 8 percent by weight. [0075] 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.

[0076] 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 applied and is only limited by the size of the composition and the type of the active drug substance.

[0077] 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.

[0078] In a further preferred embodiment, the medicament formulations according to the invention are in multi-particulate form, preferably as micro- tablets, micro-capsules, micro-spheroids, micro-pellets, ion exchange resinates, granulates, active ingredient crystals or pellets, particularly preferably as micro-tablets, granulates or pellets. Pellets in the meaning of the invention also include pellets manufactured by extrusion and/or spheronisation.

[0079] The medicament formulations are preferably suitable for oral, intravenous, intramuscular, subcutaneous, intrathecal, epidural, buccal, sublingual, pulmonary, rectal, transdermal, transmucal, nasal or intracerebroventricular administration, medicament formulations for oral, transdermal, transmucal or intravenous administration being particularly preferred.

[0080] For oral administration, the preparations preferably take the form of tablets, lozenges, gum, dragees, capsules, granulates, drops, juices and syrups. For buccal administration, a transmucal therapeutic system is preferred. For parenteral, topical and inhalation administration, preferably solutions, suspensions, emulsions, easily reconstituted dry preparations, micro-spheroids, sprays, suppositories or plasters (e.g. transdermal therapeutic systems) are suitable. Particularly preferable are suppositories or solutions for parenteral administration, transdermal therapeutic systems for topical administration and powders or solutions for inhalation administration. [0081] The preparation of the medicament formulations according to the invention may involve, apart from the combination of active ingredients according to the invention, further carrier materials, fillers, solvents, diluents, colorants, flavorings, binders or mixtures of at least two of these materials. The selection of excipients and the quantity thereof depends on how the medicament is to be administered. The appropriate excipients and the quantities thereof for each administration form are known to people skilled in the art. The medicament formulations according to the invention may be manufactured in accordance with the usual methods known to people skilled in the art.

[0082] The medicament formulations according to the invention may also contain at least one of the active components a) or b) in retarded (slow release) form.

[0083] In therapeutic use, the compositions of the present invention may be administered orally, rectally, or topically, preferably orally or topically. 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.

[0084] The compounds prepared according to the invention may be administered either on their own or optionally in combination with other active substances for the treatment of migraine by intravenous, subcutaneous, intramuscular, intrarectal, intranasal route, by inhalation, transdermal^ or orally, while aerosol formulations are particularly suitable for inhalation. The combinations may be administered either simultaneously or sequentially. [0085] Solid compositions for oral administration are preferred compositions of the invention and there are known pharmaceutical forms for such administration, for example tablets, caplets, and capsules. [0086] The oral route of drug administration is an important method of administering drugs for systemic effects. Solid oral dosage forms, like tablets and capsules, represent the preferred class of drug formulations for oral administration. The reason for this preference is that tablets and capsules represent unit dosage forms, which offer the greatest dose precision and the least content variability. Tablets and capsules represent the most convenient oral dosage forms, in which cases solid pharmaceutical carriers are employed.

[0087] Preferred formulations according to this invention contain the microporous matrix carrier/bio-active agent particles in capsules or compressed into a tablet. The encapsulating material is preferably highly soluble so that the microporous oxide bodies or particles can be delivered and rapidly dispersed into the gastrointestinal tract after the capsule is ingested. Such preferred dosage forms are prepared using conventional methods known to those in the field of pharmaceutical formulation and described e.g. by Gennaro in "The Science and Practice of Pharmacy" (ed. Remington). The bio-active agent/microporous matrix carrier particles of the invention may also be administered in packed capsules. Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like (e.g. see "The Science and Practice of Pharmacy", cited supra).

[0088] The preferred formulations of this invention are typically in the form of tablets or capsules. In comparison to capsules, tablets have a number of advantages. Tablet cost is lowest of all oral drug formulations. Tablets are the lightest and the most compact of all and they provide the greatest ease of swallowing with the least tendency for "hang-up" above the stomach. Tablets may be manufactured using standard tablet processing procedures and equipment such as direct compression wet-granulation or dry-granulation processes. Tablets may also be moulded rather than compressed, starting with a moist or otherwise tractable material, and using injection or compression moulding techniques using suitable moulds fitted to a compression unit. Tablets may also be prepared by extrusion in the form of a paste, into a mould, or to provide an extrudate to be cut into tablets. However, compression and granulation techniques are preferred, with direct compression being particularly preferred. Pore characteristics of the controlled release delivery system of the invention may be slightly but not substantially altered by high-pressure tableting. Hence, the sustained release pattern that is a characteristic of the crude loaded AMS or AMT is retained in the tablet formulation.

[0089] Tablets prepared for oral administration according to the invention, and manufactured using e.g. direct compression, will generally contain one or more other materials such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like. Binders are used to impart cohesive qualities to a tablet required for the bonding together of the granules under compaction, and thus ensure that the tablet remains intact after compression. Suitable binder materials include, but are not limited to, starch (including corn starch and pregelatinized starch), gelatin, sugars (including sucrose, glucose, dextrose and lactose), polyethylene glycol, waxes, and natural and synthetic gums, e.g. acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxy-propylmethylcellulose, methylcellulose, microcrystalline cellulose, ethyl cellulose, hydroxyethyl cellulose, and the like), and Veegum. Lubricants may be used to facilitate tablet manufacture, promoting powder flow and preventing particle capping (i.e., particle breakage) when pressure is relieved. They function by interposing a film of low shear strength at the interface between the tablet, the die wall and the punch face. Useful lubricants include magnesium stearate (in a concentration of from 0.25% to 3% by weight, preferably less than 1 % by weight), calcium stearate, stearic acid, and hydrogenated vegetable oil (preferably comprised of hydrogenated and refined triglycerides of stearic or palmitic acids at concentrations of about 1 % to 5% by weight, more preferably less than about 2% by weight). Disintegrants may be used to facilitate disintegration of the tablet, thereby increasing the erosion rate relative to the dissolution rate, and include starches, clays, celluloses, algins, gums, or crosslinked polymers (e.g. crosslinked polyvinylpyrrolidone). Basically, the disintegrant major function is to oppose the efficiency of the tablet binder and the physical forces that act under compression to form the tablet. Fillers are designed to make up the required bulk of the tablet when the drug dosage itself is inadequate to produce this bulk. Tablet formulations may contain a diluent for secondary reasons, for example to provide better tablet properties such as improved cohesion. Fillers include, for example, materials such as silicon dioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose, and microcrystalline cellulose, as well as soluble materials such as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, and sorbitol. Solubility- enhancers, including solubilizers per se, emulsifiers, and complexing agents (e.g., cyclodextrins or maltodextrins), may also be advantageously included in the present formulations. Known stabilizers may be used to inhibit or retard drug decomposition reactions, including oxidative reactions. [0090] Adequate tablet hardness and resistance to powdering and friability are necessary requisites for consumer acceptance. Tablets require a certain amount of strength to withstand mechanical shocks in manufacture and packaging and reasonable abuse when in the hands of the consumer. Tablet hardness is defined as the force required to break a tablet in a diametric compression test. To perform this test, a tablet is placed between two anvils, force is applied to the anvils, and the crushing strength that just causes the tablet to break is recorded.

[0091] 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 possible that during preparation of the composition 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.

[0092] Normal excipients useful in the preparation of the tablets include, but are not limited to: lubricants such as magnesium stearate, sodium stearyi fumarate and sodium benzoate; anti-adherents such as talc and polyethylenglycol; glidants such as colloidal silica; diluents 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; wetting agents such as TWEEN 80 (Trademark registered by ICI of Americas for polysorbate) and sodium lauryl sulphate.

[0093] Suitable excipients 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.

[0094] 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 exemplary method of preparing a composition of the present invention comprises dissolving ibuprofen in an alkaline solution; mix with Neusilin; change the pH (e.g., by adding glacier acid) so that the ibuprofen re-crystallizes; and remove the solution. 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. [0095] Preferably the diluent includes lactose, calcium phosphate, dextrin, microcrystalline cellulose, sucrose, starch, calcium sulphate, sodium bicarbonate, or mixtures thereof. [0096] 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. [0097] 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.

[0098] Preferably the binder includes polyvinyl pyrrolidone, gelatin, gelucire, hydroxypropylmethyl cellulose, starch, or mixtures thereof. [0099] Suitable flow aids include, but are not limited to talc and colloidal silicon dioxide.

[00100] 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. [00101] 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, disintegration occurs in stomach through the acid/base reaction.

[00102] 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 derivative, 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.

[00103] 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, mequitazine, oxatomide, phenindamine, phenyltoloxamine, pyrilamine, setastine, tazifylline, temelastine, terfenadine, tripelennamine or triprolidine. Suitable cough suppressants include caramiphen, codeine or dextromethorphan. Suitable decongestants include pseudoephedrine, phenylpropanolamine and phenylephrine. Suitable expectorants include guaifensin, potassium citrate, potassium guaiacolsulphonate, potassium sulphate and terpin hydrate. [00104] Drugs can be included in these formulations alone or in combination. A unique combination will be that of a pain-killer (e.g., an NSAID or a for 5-hydroxytryptamine (5-HT) receptors, agonists, also known as triptans) plus a gastric motility enhancer such as metoclopramide. The latter combination will be rapidly disintegrated and dissolved in the stomach and will also be pushed out of stomach and in the intestine for a more efficient absorption. Metoclopramide given orally in conventional formulations will fail to rapidly disintegrate and dissolve when the patient is in pain rendering the use of the drug useless.

[00105] 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). [00106] In the present invention the tablet size is between 50-1000 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.

[00107] 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 size. [00108] 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.

[00109] 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.

[00110] 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. [00111] 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

[00112] 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 also be compressed onto a solid core of another material to form a solid formulation with a quick release outer coating. Alternatively, the compressed composition may be present in one or more layers of a multi-layer solid dosage form. 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, 17th Edition, Ed Gennaro et al; or Ansel's "Introduction to Pharmaceutical Dosage Forms", 2^nd edition, Henry Kimpton Publishers). [00113] Although not wishing to be held to any particular theory of action, the inventor believes that a tablet or caplet of the present invention functions as follows: After swallowing a caplet with a glass of water, the sodium bicarbonate reacts with tartaric acid and ibuprofen 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 crystallization and precipitation, Neusilin acts as a solubilizer due to its lingering alkaline nature.

[00114] 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.

[00115] 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±50 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. Gallay 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 (59.85 g) and magnesium stearate (39.9 g) to the blender and purge with 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. Ensure 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

Example 2. Exemplary Process for producing 200 mg tablets

Pass tartaric acid and microcrystalline cellulose through Quadra Comil at 1800 ± 50 rpm. Add microcrystalline cellulose, hydroxypropyl cellulose and sodium starch glycolate; blend for 5 minutes at 25 rpm. Add ibuprofen, colloidal silicon dioxide, and Neusilin 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. An lbuprofen formulation

Drug Product Components and Composition (Per Tablet and Per Batch)

Component Quantity per unit % Quantity per batch lbuprofen (active agent) 200.00 mg 35.1 1400.0 g

Sodium Bicarbonate 104.00 mg 18.2 728.0 g (disintegrant)

Tartaric Acid (disintegrant) 14.00 mg 2.5 98.O 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 60.00 mg 10.5 420.0 g (diluent)

Colloidal silicon dioxide (300) 5.7 mg 1.0 39.9 g (glidant)

Neusilin UFL2 (matrix) 35.00 mg 6.1 245.0 g

Talc (lubricant and glidant) 8.55 mg 1.5 59.85 g

Magnesium Sterate (non- 5.7 mg 1.0 39.9 g bovine) (lubricant)

Total 570.00 mg 100 3.99 kg

Specification and Analytical Methods for Inactive Ingredients

Listed in the table below is each excipient with its compendial status. With the exception of Neusilin UFL2, all excipients meet current USP/NF requirements.

The specification for the inactive ingredient Neusilin UFL2 is as follows:

Example 4. Clinical Trials

The objective of this trial was to compare the rate of absorption on the ibuprofen formulation of Example 1 (the present invention) with a commercially available product (Motrin IB). This study was conducted in patients after dental surgery, a FDA accepted test of analgesia.

This was tow-arm, double-blind 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 IB 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 available data collected for pharmacokinetic analyses from the 26 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 quantitation 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 scheduled times. Pharmacokinetic analyses were conducted on the concentrations of R-ibuprofen, S-ibuprofen and total ibuprofen (sum of R- ibuprofen and S-ibuprofen).

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 (T¹/2) was estimated as Iog_e(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 (AUCinf) was calculated by extrapolating AUC 0-6, by the addition of the quantity: C₆ / Ke, where Cβ 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 α=0.05. ANOVA was performed for each pharmacokinetic parameter estimate

The intra-subject coefficient of variation was estimated from the mean square error term (MSE) of the In-transformed (log_e) results as:

100% ^* SQRT(e^MSE -1)

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

Interval Lower Limit = (X_τ - XR ) - Se ^* W₂

Interval Upper Limit = (X_τ - XR ) + Se ^* t_α/2 Where:

XT and X_R 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 tα/2 is the critical value from the t-distribution with degrees of freedom that of the error term and α = 0.05.

For In-transformed data the interval was calculated from the ANOVA results on the transformed values and then exponentiated to convert to the non-transformed scale:

Interval Limit = _e ^(ln-^{transformed interval limit}>

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 caplets 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-1701] 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 IB^®.

The results 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. 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: Statistical Comparisons to Evaluate Rates of lbuprofen 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).

* Comparison between products was detected as statistically significant by ANOVA (α=0.05).

Example 5. Dissolution Assay of lbuprofen 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, 5μm, 150 mm x 4.6 mm

Flow rate: 0.8 mL/min

Injection volume: 15 μl_

Wavelength: 254 nm

Column temperature: Ambient

Mobile phase: 1% chloroacetate buffer (pH 3.0)/Acetonitrile 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 3.0. 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 μm nylon membrane filter and degas prior to use. Preparation of lbuprofen Standard Solution (110 uα/mϋ

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 μm PVDF syringe, discarding the first 2 mL, and collect the filtrate 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± 0.5⁰C.

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, 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 cannula, 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 μm PVDF syringe filter and collect the filtrate, discarding the first 2 mL. Dilute the filtrate 1 :1 with mobile phase and mix thoroughly.

Example 6

Diclofenac. The absorption was significantly increased in Gl- suppressed rats using the formulation of the present invention as compared with a conventional product (Figure 1).

Example 7

Diclofenac-meloxicam combination. The absorption was significantly increased in Gl- suppressed using the formulation of the present invention as compared with conventional products (Figure 2).

Example 8

Diclofenac-meloxicam-metoclopramid combination (Figure 3).

Example 9

Naratriptan (Figure 4).

Example 10

Naproxen as acid and sodium salt

Oral absorption of naproxen acid is reduced by suppression of gastrointestinal function in the rat when dosed as suspended pure powder. The results are shown graphically in Figure 5.

Oral absorption of naproxen sodium was not significantly reduced by suppression of gastrointestinal function in the rat administered as pure powder. The results are shown graphically in Figure 6.

These results suggest that the data from naproxen acid cannot be extrapolated to the sodium salt. Suppression of Gl function does not significantly reduce absorption of the drug when administered as sodium salt.

Example 11

Comparison of naproxen acid included in the formulation with a conventional formulation of naproxen sodium. No significant difference between products was observed (Figure 7).

C ornpo sition o f Naρro:xen_acid_FastAct formulation used in Example 6

Ingredients Amount (mg) %

Naproxen (acid) 30 37.6

Na- bicarbonate 19 23.8

Tartaric acid 4 5.0

Geluάre 2.5 3.1

C om starch 1 2 1 5.1

Micro crystalline cellos 1 0 12.5

Neusilin 2 2.5

Mg. Steaiate 0.2 0.3

Total F 79.7 100

Example 12

Comparison of naproxen sodium included in the FastAct formulation with a conventional formulation of naproxen sodium (Figure 8).

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

Claims

Claims:

1. A pharmaceutical composition comprising an active agent, at least one disintegration agent, and a metasilicate.

2. The pharmaceutical composition of claim 1 further comprising one or more lubricating agents, one or more binders, one or more additional disintegrating agents, one or more flow aids, and/or one or more colorants and/or flavorants.

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

4. The pharmaceutical composition of claim 3 wherein the alkali metal carbonate is sodium bicarbonate.

5. The pharmaceutical composition of claim 1 wherein at least one of the disintegration agents is a soluble acid.

6. The pharmaceutical composition of claim 1 wherein at least one of the disintegration agents is tartaric acid.

7. The pharmaceutical composition of claim 6 further comprising hypromellose, pre-gelatinized starch, microcrystalline cellulose, sodium croscarmellose, and magnesium stearate.

8. The pharmaceutical composition of claim 1 wherein the active agent is selected from then group consisting of diclofenac, naproxen, naratriptan, ketamine, and metoclopramide.

9. 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.

10. The method of claim 9 wherein in the active agent is selected from the group consisting of diclofenac, naproxen, naratriptan, ketamine, and metoclopramide.