WO2008006216A1

WO2008006216A1 - Anti-inflammatory and cytoprotectant chronotherapy

Info

Publication number: WO2008006216A1
Application number: PCT/CA2007/001241
Authority: WO
Inventors: Bertrand Bolduc; Alain Desjardins; Nevine Rizkalla
Original assignee: Mistral Pharma, Inc.
Priority date: 2006-07-14
Filing date: 2007-07-12
Publication date: 2008-01-17

Abstract

The present invention relates to a chronotherapy tablet comprising: a substantially round core having a first end and a second end, the core being comprised of at least two superposed layers of different compositions with an interface between each layer; wherein at least one of said layers comprises a pharmacologically active anti-inflammatory composition and at least one of said layers comprises a pharmacologically active cytoprotective composition; a coating which envelops the core except for at least one exposed release face of the core at at least one end of the core; whereas upon oral administration the chronotherapy tablet allows proper timing of delivery of said pharmacologically active anti-inflammatory composition and said pharmacologically active cytoprotective composition relative to the time of oral administration

Description

Title: Anti-inflammatory and cytoprotectant chronotherapy

BACKGROUND OF THE INVENTION

(a) Field of the Invention The present invention relates to an anti-inflammatory and cytoprotectant chronotherapy which may be used in cases of arthritis and/or osteoarthritis therapy.

(b) Description of Prior Art

Inflammatory conditions of the joint are often chronic joint diseases which afflict and disable, to varying degrees, millions of people worldwide.

Arthritis is one of the most common disabling diseases. It has been estimated that about 10 percent of the Western population suffers from one or many forms of arthritis. There are over 75 types of different diseases of the joint, classified according to their specific symptoms and causes. Representatives of the more common disorders are rheumatoid arthritis (RA) and osteoarthritis (OA).

Prostaglandins and leukotrienes are lipid mediators produced in a variety of inflammatory disease states, including inflammatory conditions of the joint. Both are products of metabolism of arachidonic acid. Cyclooxygenases (COX-1 and COX-2) are the enzymes that catalyze the conversion of arachidonic acid to prostaglandins. 5-Lipoxygenase (5-LO) catalyzes the conversion of arachidonic acid to leukotrienes.

Patients suffering from arthritis often have relatively high prostaglandin E2 (PGE₂) levels. PGE₂ induces inflammation and causes the sensation of pain. In addition PGE₂ is involved in deterioration of the cartilage.

Arthritis pain is caused by several factors, such as:

• Inflammation: the process that causes the redness and swelling in joints; • Damage to joint tissues: which results from the disease process or from stress, injury or pressure on the joints; • Fatigue that results from the disease process: which can make pain seem worse and harder to handle;

• Depression or stress: which results from limited movement or no longer doing activities. Arthritis patients can get caught in a cycle of pain, limited/lost abilities, stress and depression that makes managing pain and arthritis seem more difficult.

Most therapeutic agents are directed at reducing the inflammation and relieving pain. NSAIDs (non-steroidal anti-inflammatory drugs) are a large class of medications used to treat arthritis pain and inflammation. There are three types of NSAIDs: Salicylates (acetylated, such as aspirin, and non-acetylated), the traditional NSAIDs, and COX-2 selective inhibitors.

Non-steroidal anti-inflammatory drugs (NSAIDs) are the first line of treatment for arthritis, but chronic long-term use can lead to gastric or duodenal ulcers.

NSAIDs are among the most widely prescribed drugs for chronic inflammatory diseases, such as rheumatoid arthritis. Their effectiveness is related to inhibition of prostaglandin (PG) synthesis, which also accounts for their main side effects, which include gastric and duodenal ulcer. During the last few years, selective COX-2 inhibitors producing less gastrointestinal irritation have been developed, but many of them have been recently withdrawn from the market, e.g. Bestra™ (valdecoxib) and Vioxx™ (rofecoxib), due to increased cardiovascular risks. This has generated a renewed interest in traditional NSAIDs but the issue of gastric and duodenal ulcer formation associated with their chronic use remains problematic for numerous patients. A new trend in the management of arthritic pain is based upon the circadian rhythm of the disease: it has been reported that pain in most arthritic patients attains its peak in the morning. On the other hand, natural protection of gastric mucosal lining was also found to follow a circadian variation, with lower levels of mucus, bicarbonate and prostacycline occurring in the morning. This explains the rationale for the evening administration of a delayed chronotherapeutic form containing the NSAID, along with a cytoprotective agent.

The rationale of a NSAID chronotherapeutic dosage form for arthritis is to deliver the drug in accordance with the circadian rhythm of the disease. Morning pain is a very characteristic symptom of rheumatoid arthritis. Also, gastric and duodenal ulceration represents a major side effect associated with NSAID administration in the morning, due to a limited protection of the mucous membrane of the upper gastrointestinal tract at this time. The formulation strategy offers a time delayed delivery of the NSAID, in addition to a concurrent release of a cytoprotective agent which will compensate for the natural drop in the protective factors occurring in the morning. It is hypothesized that the pulsative release profile of the ingredients, which respects the chronopharmacology of the condition, could provide effective pain management, along with reduced side effects.

Furthermore, patients suffering from arthritis or osteoarthritis experience pain at a different time of the day. The pain is usually more intense in the morning for RA patients and in the afternoon to evening from OA patients.

Chronobiological patterns are commonly observed with many diseases such as asthma, arthritis (e.g., osteoarthritis and rheumatoid arthritis, for example), gastrointestinal disorders, cardiovascular disease (e.g., hypertension, angina, myocardial infarction, and stroke), and cancer. Coordinating medical treatment with biological rhythms is called chronotherapy.

United States application published in the name of Chopra under

No. 20004/0137062 describes a chronotherapy tablet which includes pulse delivery of an anti-inflammatory composition. There is no suggestion of the possibility or feasibility of a combination chronotherapy tablet for the delivery of an anti-inflammatory composition with another therapeutic agent.

It would be highly desirable to be provided with a chronotherapy for the release of an anti-inflammatory active ingredient at a time when the pain is more intense depending on the inflammatory condition while combined with the cytoprotectant effect of a different therapeutic agent to ease the side effect of the anti-inflammatory agent on the stomach.

SUMMARY OF THE INVENTION

In accordance with the present invention there is provided a chronotherapy for the release of an anti-inflammatory active ingredient at a time when the pain is more intense depending on the inflammatory condition while combined with the cytoprotectant effect of a different therapeutic agent to ease the side effect of the anti-inflammatory agent on the stomach. For the purpose of the present invention the following terms are defined below.

The term "pharmacologically active anti-inflammatory composition" is intended to mean any compositions containing at least one compound capable of exhibiting an anti-inflammatory activity, which include, without limitation, nonsteroidal anti-inflammatory agents such as aryl or N-aryl acetic acid derivatives, for example, sodium or potassium diclofenac, etodolac, indomethacin, ketorolac tromethamine, sulindac and tolmetin sodium; cyclooxygenase-2 inhibitors, for example, celecoxib and rofecoxib; fenamates, for example, mefenamic acid and floctafenine; oxicams, for example, meloxicam, piroxicam, piroxicam cyclodextrin, tenoxicam; propionic acid derivatives like aceclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, nabumetone, oxaprozin, tiaprofenic acid, and salicylic acid derivatives like acetylsalicylic acid and diflunisal, salsalate, choline salicylate, magnesium salicylate, salts thereof and mixtures thereof. The expression "delay composition" is intended to mean any composition having no particular pharmacological activity to create a delay between delivery of a first pharmacologically active composition and a second one. The expression "pharmacologically active cytoprotective agent" is intended to mean any compositions which include, without limitation omeprazole (Prilosec, Zegerid), pantoprazole, esomeprazole, rabeprazole, lansoprazole, leminoprazole, cimetidine, tamotidine, nizatidine, ranitidine, ranitidine bismuth citrate, single enantiomers thereof, alkaline salts thereof and mixtures thereof.

All references referred herein are hereby incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates an example chronotherapy tablet.

Fig. 2 illustrates the target release profile of the tablet of Fig. 1. Fig. 3 illustrates mean plasma concentrations of diclofenac 100 mg from fasting subjects and from simulation.

Fig. 4 illustrates mean plasma concentrations of omeprazole 40 mg from fasting subjects and from simulation

Fig. 5 illustrates percentage of enzyme inhibition from omeprazole 40 mg ER(b) according to simulation.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, a chronotherapy tablet (2) is provided for oral administration and the amelioration of at least one antiinflammatory condition within 24 hours comprising a substantially round core (4) having a first end (8) and a second end (10), the core (4) being comprised of at least two superposed layers (12) of different compositions with an interface (14) between each layer and wherein at least one of the layers (12) is a pharmacologically active anti-inflammatory composition and at least one of the layers (12) is a cytoprotective composition; a coating (16) which envelops the core (4), except for at least one exposed release face (18) of the core (4) at at least one end (20) of the core.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All publications and patents referred to herein are incorporated by reference.

Oral administration refers to oral administration of the chronotherapy tablet, per se.

Stages of drug delivery referred herein correspond to and are accomplished by dissolution of the different layers of the chronotherapy tablets of the present invention under physiological conditions.

A chronotherapy tablet of the present invention is configured structurally to deliver a specific dosage of at least one anti-inflammatory active agent at at least one predetermined period of time relative to the time of oral administration. Chronotherapy tablets of the present invention are specifically constructed for oral administration particularly to release at least one anti-inflammatory active agent in at least one coordinated pulse, particularly for treating arthritis (osteoarthritis and rheumatoid arthritis, for example) or osteoarthritis in combination with a cytoprotective agent. Embodiments of the present invention, for example, provide a plurality of pulses of pharmacological compositions (including combinations) within 24 hours.

Particularly, drug delivery devices of the current invention are constructed to effect proper timing of drug delivery relative to the time of oral administration and significantly increasing the efficiency and efficacy of the orally administered compounds to ameliorate arthritis or osteoarthritis conditions.

Drugs by means of the present invention are formulated and packaged and orally administered to be released in a variety of different stages and combinations thereof. A first stage of "delivery" begins, for example, immediately after oral administration of a chronotherapy tablet of the present invention. At least one pharmacological compound may immediately begin to be released. This immediate release stage may effect a rapid and short pulse, for example, a fifteen minute burst of drug delivery, or may effect a relatively long period of a substantially constant level of drug delivery. However, different chronotherapy embodiments of the present invention may not begin, for example, to release pharmacological compositions for a significant period of time after oral administration. Embodiments of the present invention even delay drug delivery for hours after oral administration of the chronotherapy tablet.

Preferred embodiment of chronotherapy tablets described herein intended for administration at bedtime, for example, are constructed to delay drug delivery for a variable number of hours to provide therapy when needed. Accordingly, the first stage of "delivery" may in fact be a delay stage lasting from about 5 to about 8 hours.

A second stage of delivery, and so forth, e.g., third, fourth, fifth, and the like, similar to the first stage described supra, and depending upon the nature of the first stage and chronobiological condition to be treated, may effect a rapid and short pulse, for example, a fifteen minute burst of drug delivery, or may effect a relatively long period of a substantially constant level of drug delivery, or may effect a period of delay by means of a "delay layer" further described infra. Oral administration of chronotherapy tablets of the present invention accomplishes drug delivery in as many stages as may be necessary or practical over, for example, a 24 hour period of time. Particularly, chronotherapy tablets of the present invention are able to, for example, (a) deliver one or two drugs three times a day at desired time intervals; (b) bypass the stomach and release drug in the intestine in two pulses (each one at a determined interval); (c) release a pharmacological composition instantly followed by a constant rate release for a desired period, followed by instant drug release, followed by a release at a constant rate for desired period, followed by instant release; and (d) deliver many different combinations of pulse release, delay, and constant release.

Chronotherapy tablets of the present invention are structurally configured dosage forms that fundamentally enable drug delivery to be synchronized with biological rhythms of disease activity. Embodiments of the invention are configured to deliver a predetermined dosage of drug at at least one certain predetermined period of time relative to the initial oral administration of the therapeutic entity. Embodiments of the invention also enable the delivery of at least one drug over a plurality of different periods of time. Chronotherapy tablets of the present invention also encompass embodiments wherein a plurality of different drugs are each delivered at a predetermined dosage at a plurality of periods of time relative to the time of oral administration. The therapeutic entity of the invention is capable of providing several pulses of drug delivery; three pulses, for example, of the same drug, different drugs, or the same or different combinations, in 24 hours. Pulses may be delayed as described herein; however, between pulses one or more drugs for example, can be released at a constant rate. Therapeutic entities described herein are structurally configured to effect various combinations of pulse release, constant release, and delayed release of compounds upon oral administration.

Preferred Embodiments

A preferred embodiment of the present invention is a chronotherapy tablet comprised of a substantially round core comprising a first end and a second end. The core is comprised of at least two layers of different compositions, an anti-inflammatory composition and a cytoprotective composition, with an interface between each layer. The term "composition(s)", by itself, is used herein to refer to both delay compositions (inactive materials) without drug(s) and pharmacological compositions comprising one or more drugs for delivery. At least two of the layers is of a pharmacologically active composition, one being of an anti-inflammatory composition and one of a cytoprotective composition. The chronotherapy tablet further comprises a coating which completely covers the core except for one exposed release face of a first layer at one end of the core. "Release face" is used herein to refer to an exposed portion of a layer of the core composition. The initial release face, before administration of the chronotherapy tablet, may be any shape, including three-dimensional. Any exposed portion of the release face, however, that initially extends beyond the cover, dissolves in a relatively shorter period of time after oral administration, relative to a release face that does not extend beyond the cover, to yield a release face that is substantially perpendicular to the longitudinal axis of the core during dissolution of the core.

Accordingly, a chronotherapy tablet of the present invention is comprised of a substantially round core having a a first end and a second end, the core being comprised of at least two superposed layers of different compositions with an interface between each layer and wherein at least one of the layers is a pharmacologically active anti-inflammatory composition and at least one of the layers is a pharmacologically active cytoprotective composition; a coating which envelops the core; except for one exposed release face of the core at one end of the core. Preferred embodiments of the present invention are chronotherapy tablets described herein wherein at least one of the layers of compositions is a delay layer. Example embodiments of this type are chronotherapy tablets wherein a first exposed layer (by means of a release face) is a delay layer. Delay layers are in many different embodiments positioned within the "stack" of core of different pharmacologically active compositions to provide for proper timing of drug release to meet chronobiological needs.

Chronotherapy tablets of the present invention may comprise, for example, at least three layers of pharmaceutical compositions and two delay layers wherein the three layers of pharmaceutical compositions (not necessarily different) are each separated from each other by a delay layer. Arthritis

Chronobiological patterns have been observed with arthritis pain. People with osteoarthritis, the most common form of the disease, tend to have less pain in the morning and more at night. But for people with rheumatoid arthritis, the pain usually peaks in the morning and decreases as the day wears on. Recent animal studies showing that joint inflammation in rats fluctuates over a 24-hour period support these observations by both patients and physicians.

Chronotherapy for all forms of arthritis uses standard treatment, nonsteroidal anti-inflammatory drugs and corticosteroids; however, the dosages are timed to ensure that the highest blood levels of the drug coincide with peak pain and the presence of a cytoprotective drug when stomach is more fragile as a side effect of the anti-inflammatory drug.

Osteoarthritis tends to exhibit most symptoms in the afternoon to evening; whereas, symptoms of rheumatoid arthritis, however, peaks in the morning and decreases as the day wears on. Rheumatoid arthritis is a chronic inflammatory autoimmune disorder. The cardinal signs of rheumatoid arthritis are stiffness, swelling and pain of one or more joints of the body, characteristically most severe in the morning. Rheumatoid arthritis shows a marked circadian variation in its symptoms. Typically, within the population of rheumatoid arthritis sufferers, the severity of joint pain, swelling and stiffness is generally about 3 times higher between about 7AM to about 11AM when compared to normal bedtime. Hand strength is also generally lower by as much as 30% in these morning hours. Common treatments for arthritis, for example, are corticosteroids and nonsteroidal anti-inflammatory drugs. The usual dose of diclofenac, a nonsteroidal anti-inflammatory drug, for example, is 150-200 mg per day in divided doses. The dosage may be increased to 200 mg per day depending upon the patient's response. Increased dosages amplify the risk of adverse effects such as peptic ulcers, which has demonstrated fatalities, particularly in elderly. The present invention help alleviating the side effects of the anti-inflammatory to the stomach by the release of the cytoprotective agent when required.

Therapeutic efficacy of diclofenac is related to its synovial fluid concentration which has been reported to lag that of plasma [Reference: T. Bender, M. Schafer and J. Bariska, Clinical rheumatology (2000) 19:89-

91]. Release patterns from chronotherapy tablets are thus tailored to obtain, for example, optimal synovial levels in the needed hours of the morning to coincide with peak symptoms of RA, and of the afternoon to evening to coincide with those of OA. Materials

Materials to be used in forming delay layers, e.g., layer B in FIG. 1 , is not limited to any particular species. Preferred materials are therapeutically inactive and solubilize, dissolve, degrade, or erode relatively slowly under physiological conditions. The delay layer(s) are preferably substantially impenetrable to solvent or enclosed drug compounds within an adjacent layer until the delay layer has substantially completely dissolved. The delay layer(s) may be comprised of well known diluent/s, dissolution rate modifier/s, lubricant/s, polymer/s, surfactant/s and/or plasticizer/s commonly used in the art of pharmacy and formulations related thereto.

Layers A and C in FIG. 1 , for example, for slow release of a therapeutic compound, may be composed of the same or similar materials to Layer B in the same figure.

In a high shear blender/granulator of the Fielder type or Diosna type, the drug is blended with a slow dissolving polymer which comprises the shaped core. If required, a soluble diluent may also be added. The blend is subsequently granulated with water or an organic solvent or a mixture of water and an organic solvent. Alternatively a slow dissolving or colloidal dispersion forming polymer may be dissolved or dispersed in a solvent and added to the blend while mixing continuously. The mixture thus granulated is then dried at a suitable temperature and milled through a screen with an appropriate opening. The granules prepared are then mixed with a soluble or insoluble lubricant.

Layers B in FIG. 1 , for example, in addition to at least one therapeutic compound, may comprise well known therapeutically inactive diluent/s, and/or binder/s, and/or disintegrant/s, and/or lubricant/s, and/or dissolution rate modifier/s, and/or polymer/s, and/or surfactant/s commonly used in the art of pharmacy and formulations related thereto.

The coat layer comprises an insoluble or slowly soluble polymer and, optionally, a soluble component which leaches out of the coat rendering it porous, weak and susceptible to disintegration shortly after release of the active ingredient is complete. Layer D, the coat layer in FIG. 1 is composed of soluble and/or insoluble polymers, pore formers and lubricants. The coat layer may contain diluents and/or plasticizers. Examples of dissolution rate modifiers that either alone or in combination may be used in the present invention as polymers either as soluble polymers or polymers that produce clear colloidal dispersion in water, include but are not limited to hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose; polyvinylpyrrolidone, methyl cellulose, soluble modified starches, gelatin, acacia, polyethyleneoxide, and polyethyleneglycol. Water insoluble polymers that may be used in the present invention, includes but are not limited to cellulose acetate, cellulose acetate butyrate, polyvinyl alcohol, ethyl cellulose, methacrylic acid copolymers, insoluble modified starches, and polypropylene oxide. Biodegradable polymers that may be used in the present invention include but are not limited to polyglycolide, poly-L-lactide, poly-D,L-lactide, caprolactone, polyamino acids, polyorthoesters and polyanhydrides. One skilled in the art will recognize other polymers with similar properties which also may be used and the invention is not limited to the specific polymers listed herein. Examples of suitable soluble diluents for use in the present invention that may be incorporated into the core, include, but are not limited to, lactose, sucrose, carbowax, dextrates, glucose, fructose, soluble starch, sorbitol, mannitol, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, methyl cellulose, soluble modified starches, gelatin, acacia.

Examples of pH sensitive diluents include cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate and polymethacrylate. Examples of suitable insoluble diluents that may be used include, but are not limited to, calcium sulfate, dicalcium phosphate, microcrystalline cellulose, insoluble modified starches and starch.

Examples of suitable lubricants that may be used include, but are not limited to, stearic acid, sodium stearate, calcium stearate, magnesium stearate, sodium stearyl fumarate and sodium lauryl sulfate.

Manufacture of chronotherapy tablets of the present invention comprises the following basic steps.

Granulation

Layers for similar purpose or function can be prepared employing similar granulation compositions and methods described herein and/or known in the art. Delay composition layers, for example, may consist of standard tabletting excipients including binders, diluents, dissolution modifiers and lubricants. Therapeutically active composition layers generally contain at least one pharmacologically active agent (drug), excipients, diluents, disintegrants, binders and/or lubricants. Sustained release layers, particularly for hydrophilic drugs, for example, require the presence of dissolution regulators to prevent rapid and immediate dissolution of the entire core. Chronotherapy tablets of the present invention enable the release rate to be optimized for all types of drugs. Granulations may be prepared using well known wet or dry methods. All ingredients, including diluents and dissolution rate modifiers, are blended together in a dry method in an appropriate size blender, for example, to prepare a delay layer composition. To prepare pharmacologically active composition layers, drugs are included. The preparation of rapid release pharmacologically active composition layers involves the blending together of all ingredients including pharmacologically active agents, diluents and disintegrants. The blend may be milled and sieved, if desired, through a sieve with an appropriate size mesh, the mesh size is chosen according to the application. The blend is then mixed with an appropriate lubricant.

Delay layer compositions may be formulated in wet granulation by blending diluents with slow dissolving polymer/s. Pharmacologically active composition layers may similarly be formulated with active compound. The blend is subsequently granulated with water or an organic solvent or a mixture of water and an organic solvent.

Alternatively, a slow dissolving or dispersing polymer may be dissolved or dispersed in a solvent and added to the blend while mixing continuously. The mixture thus granulated is dried at a suitable temperature and milled through a screen with an appropriate opening. The granules prepared are then mixed with a soluble or insoluble lubricant.

Compression of Granulations

Prepared granulations are compressed into multi-layered cores on a conventional multi-layer press using appropriately shaped tooling. With the currently available equipment, like Elisabeth Hata HTAPSS-3L or Korsch TRP 900-5S, the number of core layers is limited to three o five, respectively. The number of core layers, however, can be increased with the availability of appropriate equipment in the future.

Compression Coating of the Multi-Layer Core

Pre-compressed multiple-layer cores bodies are compression coated using a core-coater fitted with a specially designed tooling for placing bodies precisely in the dies. The required coating material is transferred to the die and the core is placed precisely at the desired location on the top of the granules in the die. The core is then pushed into the coating material and final compression is then performed. Alternatively, the core is positioned in the die, and the coating is introduced over the core followed by compression. Any machine that can feed cores and position them precisely in the device to pick up the bodies for the precise placement in the center of the die can be used. Such press can be obtained from Korsch America Inc. or Elisabeth Hata in the USA, with a specially designed transfer mechanism. The coating material used to encase the active core is prepared by mixing a blend of soluble and insoluble polymers with appropriate plasticizers. The blend thus prepared is lubricated with lubricant/s. All ingredients used in this technology are pharmaceutically acceptable. There are consequently no toxicological issues with the technologies.

Although specific methods for manufacturing the chronotherapy tablets are described herein, numerous modifications and alternative process steps will be apparent to those skilled in the art. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art methods to prepare the invention. These processes may be varied substantially without departing from the spirit of the invention.

The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention rather than to limit its scope.

EXAMPLE 1 Materials and Methods

Study Design. The study will be an open-label, randomised, two- way crossover, comparative bioavailability / bioequivalence study conducted in 12 normal healthy non-smoking male subjects in the fasted state. Single oral doses of the combination test product will be compared to single oral doses of the two reference products. The dose of diclofenac and omeprazole administered for test and reference products will be the same. Objective. The objective of the study is to assess the comparative bioavailability / bioequivalence of diclofenac and omeprazole following a single dose of a diclofenac 100mg /omeperazole 40mg extended release (ER) combination test product and single doses of a diclofenac 100mg extended release (ER) reference product tablet plus two omeprazole 20mg immediate release (IR) reference product capsules (40mg in total).

Doses will be administered in the fasted state.

Products. Test (A) consists of Diclofenac 100mg / Omeprazole 40mg ER Tablets (diclofenac sodium 100mg + omeprazole magnesium equivalent to omeprazole 40mg) provided by Mistral Pharma Inc., Canada. In FIG. 1 , layer A contains about 50 mg of diclofenac which takes about 4-

6 hours to dissolve. In Fig. 1 , layer B contains about 40 mg of omeprazole releasable within 4-6 hours after dissolution of layer A. Layer C contains about 50 mg of diclofenac releasable at a constant rate of about 25 mg/hr over a period of about 4-6 hours. The coat D disintegrates after dissolution of Layer C is complete. The coat, layer D, comprises an insoluble or slowly soluble polymer and, optionally, a soluble component which leaches out of the coat rendering it porous, weak and susceptible to disintegration shortly after release of the active ingredient is complete. The target release profile of the tablet of Fig. 1 is illustrated in Fig. 2. A further advantage of this particular configuration is that Layer B being encased into the tablet, omeprazole active ingredient does not have to be protected by enteric coating, as it is usually the case to prevent degradation of the drug during gastric transit.

The Reference products (B) consist of Voltaren® SR 100mg Tablets (diclofenac sodium 100mg), a product of Novartis

Pharmaceuticals Canada Inc., Canada and Losec® 20mg Capsules (x2) (omeprazole, 40mg total), a product of Astrazeneca Canada, Inc., Canada.

Drug Characteristics. Diclofenac and omeprazole both exhibit simple uncomplicated linear pharmacokinetics although absorption of omeprazole can be appreciably affected by food. The molecular structures of diclofenac and omeprazole are depicted below:

Diclofenac sodium Omeprazole magnesium

Diclofenac is a non-steroidal anti-inflammatory agent (NSAID) with analgesic, antirheumatic and antipyretic properties. These effects are caused by a reduction in cyclooxygenase activity which reduces levels of various prostaglandins. Diclofenac is prescribed for conditions such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, post-operative and post-traumatic pain associated with inflammation and swelling, pain associated with dental surgery and for the symptoms of primary dysmenorrhoea. Up to 150mg can be given daily in divided doses or in extended release products.

Omeprazole reduces secretion of gastric acid by parietal cells by specific inhibition of the proton pump i.e. H+ and K+-ATPase. As a weak base it preferentially concentrates in the acidic environment of parietal cells where it is converted to the active sulfenamide.

Regarding the pharmacokinetic parameters of the compounds, Diclofenac is well absorbed following oral administration, however, it is often administered in an enteric-coated dosage form to reduce gastric side effects. Maximum concentrations can be attained in less than an hour with dispersible dosage forms but can be significantly higher and variable following administration of an enteric-coated product. Absorption is rapid once the enteric-coating has been breached and peak concentrations are generally attained within an hour of the onset of absorption. Diclofenac is also rapidly excreted with a mean half-life of about 1-2 hours. It's pharmacokinetics are reported to be linear and it is also highly bound to plasma proteins. Diclofenac is extensively metabolized to a number of phenolic compounds which are excreted in the urine and bile as glucuronide or sulphate conjugates. Diclofenac, with rapid absorption and elimination characteristics, is an ideal candidate for incorporation into a sustained release dosage form. On the other side, Omeprazole is a chiral molecule and is administered as a racemic mixture. It is poorly stable in acid and even at pH 6.8 the half-life of the magnesium salt is only 8 hours at 37°C. When administered in an unprotected formulation, bioavailability is 40-50%. However, omeprazole is generally administered in a delayed release acid resistant formulation which limits its exposure to gastric acid and which increases bioavailability up to about 65%. In addition, bioavailability increases up to about 90% with repeated dosing. Administration with food, however, decreases its availability by about 50% although this is of less importance when administered in a sustained release formulation. Once released from the dosage form, omeprazole is rapidly absorbed and maximum plasma concentrations after dosing with oral solutions occur within 0.5 hours. Maximum concentrations are attained in about 1.5 - 2 hours after dosing with delayed release formulations. Omeprazole is extensively metabolized in the liver into inactive hydroxyl and desmethyl metabolites, predominantly by CYP2C19. A small portion is metabolized by CYP3A4 into the sulphone metabolite. Due to the major role played by CYP2C19, there is some polymorphic metabolism as 3% of Caucasians and 20% of Asians are poor metabolizers with respect to this enzyme. Less than 1 % is excreted unchanged in the urine and approximately 80% is excreted as inactive metabolites in the urine. The remainder is excreted as inactive metabolites in the feces.

Regarding adverse effects and contraindications, Diclofenac and omperazole are both safe and well tolerated drugs. The major adverse effect of diclofenac is peptic ulceration, particularly in susceptible individuals and during chronic treatment. Epigastric pain, nausea, diarrhea, vomiting, abdominal cramps, dyspepsia, flatulence, anorexia, vertigo, headache and slight dizziness are possible transient adverse effects which may be experienced at the start of treatment. Skin rashes, elevations in hepatic enzymes and a variety of other adverse events have been rarely reported. The most frequently adverse effects occurring with omeprazole are headache, diarrhea, nausea, flatulence, abdominal pain, constipation and dry mouth. Diclofenac and omperazole must not be administered to individuals who have an allergy to these compounds. In addition, diclofenac must not be administered to individuals with asthma, acute rhinitis or urticaria which is induced by diclofenac, aspirin or other prostaglandin synthetase inhibitors. The Diclofenac / Omeprazole combination ER test product

(A) is formulated to be administered once daily. The ER diclofenac reference product (B) is equivalent to the daily dose administered in the ER test product. Two capsules of the IR omeprazole reference product (B) is equivalent to the daily dose administered in the ER test product. The IR omperazole reference will be administered as there is no ER omeprazole reference product. In this study, equivalent total doses of diclofenac sodium and omeprazole will be administered for test and reference products. Description of the Test and Reference Products is provided in Table 1.

TABLE 1

Description of Test and References Product

Study design. Diclofenac if often administered in extended release tablets together with omeprazole in an immediate release tablet However, no extended release combination products are currently on the market. This test product is designed as a sustained release combination product of both diclofenac and omeprazole which provides for once daily dosing. It will be compared to equivalent doses administered in currently available formulations of diclofenac and omeprazole. The study will be an open-label, randomised, two-way crossover, comparative bioavailability / bioequivalence study conducted in normal healthy non-smoking male subjects. Doses will be administered to 12 subjects under fasted conditions in two different sequences as shown in TABLE 2 below: TABLE 2

Sequence of dose administration

One oral dose of the extended release test product will be compared to single doses of the two reference products with both reference products administered at the same time. All subjects will fast from 10 hours prior to dosing until 4 hours after dosing when they will be given a standard meal. Additional meals and snacks will be served as described: food and fluid intake will be standardised from the time subjects check in at the clinic until the 24 hour post-dose sample. Subjects will receive a well-balanced meal approximately 12 hours prior to the start of dosing (19h00) and a light snack and caffeine-free beverage no later than 10 hours prior to the start of dosing. Subjects will fast from 10 hours prior to the scheduled start of dosing until 4 hours post-dose, when they will be given a standard meal. Tap water will be permitted until 1 hour before dosing and restricted until 1 hour after dosing. However, 240 ml_ of flavoured water will be provided with each meal and snack and 24OmL of water will be administered at the time of dosing. Water will be allowed ad. libitum between restriction periods. Standard xanthine free meals and snacks will be provided as described in TABLE 3 below: TABLE 3

Administration of meals depending on time/event

Blood samples will be collected from study subjects at predetermined intervals after the administration of the test or reference products and samples will be analysed for diclofenac and omeprazole. Comparative bioavailability / bioequivalence will be assessed following determination of the pharmacokinetic parameters of AUC_O-_T and C_max by statistical analysis thereof.

Phases will be separated by a minimum washout period of 7 days. A schedule of events and assessments undertaken during the study is presented in TABLE 4.

TABLE 4

Schedule of Events and Assessments

t Vital Signs - blood pressure, temperature (when required), pulse (check-in, pre-dose, 4 and 8 hours postdose)

$. Vital signs, wellbemg check with follow-up physical examination if appropriate, update on recent medication

$ Methaqualone only (HPLC)

# All drugs-of-abuse except methaqualone (urine dipstick) Subjects. This pilot study will be conducted to obtain preliminary comparative bioavailability data for purposes of product development, and to determine the number of subjects actually required for a pivotal study if results indicate that a pivotal study is appropriate. A standard number of 12 subjects will therefore be enrolled into the study.

Various inclusion criteria are observed for the choice of subjects. Only those subjects meeting the following criteria may be included in the study. First, subjects must be mentally competent and must be available for the entire study period and willing to adhere to the protocol requirements and able to give informed consent by signing the informed consent form, which is also signed by the person performing the informed consent discussion. The subjects must also be males between the ages of 18 and 55 years of age. They have to be volunteers with a body mass index (BMI) of between 19 and 30. They must be non-smoking volunteers who have not smoked for at least two months. The subjects must be normal in terms of medical history at the pre-study screening medical, or in the case of an abnormality, the medical practitioner considers the abnormality to be clinically insignificant. They subjects must also be normal in terms of physical examination at the pre-study screening medical, or in the case of an abnormality, the medical practitioner considers the abnormality to be clinically insignificant. And finally the subjects must be normal in terms of laboratory test values for the pre-study screening medical within the laboratory's stated normal range, or in the case of an abnormality, the medical practitioner considers the abnormality to be clinically insignificant. Subjects that are excluded are subjects with any history of hypersensitivity to diclofenac or omeprazole, any history of liver dysfunction, any history of renal dysfunction, any history of gastric ulceration, any history of adrenal or pituitary insufficiency, any history of asthma, bronchitis or other bronchospastic conditions, or asthma, acute rhinitis or urticaria induced by aspirin and other prostaglandin synthetase inhibitors, any history of epilepsy or other convulsive disorders, any history of mania, any history or other condition which the study physician regards as clinically significant to the study (including fainting upon blood sampling), any history of drug or alcohol abuse (>21 unitslweek on average) over the last 6 months, or the use of tobacco within two months of the study start date, treatment with any drug known to have a well- defined potential for toxicity to one of the major organs, particularly renal and hepatic toxicity, within 3 months of the study start date, treatment with any drug which could modify renal excretion of drugs (eg. probenicid) within 1 month of the study start date, the intake of a restricted or abnormal diet for longer than 1 week within 4 weeks of the study start date, maintence therapy with any drug or regular use of chronic medication, a major illness considered to be clinically significant by the study physician within 3 months of the study start date, participation in another study or the donation of one pint or more of blood within 1 month of the study start date, a positive test for Hepatitis B surface antigen, Hepatitis C or HIV, treatment with any prescription drug within one week of the study start date, unless the drug is considered to be clinically insignificant by the study physician, treatment with any OTC drug within one week of the study start date, unless the drug is considered to be clinically insignificant by the study physician, the consumption of alcohol or other enzyme inducing agents within 96 hours of the start of the study (all barbiturates, corticosteriods, phenylhydantoins etc), a positive urine test for any drug of abuse tested at the pre-study screening medical or at check-in.

Subjects are also submitted to a series of restrictions regarding concomitant medication, food, liquid ingestion and other variables. Indeed, regarding medication, no prescription medication or OTC medication (including cold preparations, vitamins, natural products, herbal or traditional remedies, antacids) will be allowed for at least one week prior to the study. Any medication taken between the screening medical and dosing will be assessed for its effect on the study and subjects may be excluded if necessary. With the exception of study drugs no concomitant medication may be taken by subjects during the study. Regarding alcohol, no alcohol may be taken by subjects from 96 hours prior to the initial dosing for each phase, then until the last sample of Phase 1 has been taken and until the post-study clinical investigations after Phase 2 have been completed. Regarding caffeine, no caffeine containing beverages and foods (e.g. tea, coffee, cola drinks, chocolate) may be taken by subjects from 48 hours prior to the initial dosing for each phase, then until the last sample of Phase 1 has been taken and until the post-study clinical investigations after Phase 2 have been completed. Regarding exercise, No strenuous physical activity may be undertaken by subjects from 24 hours prior to the initial dosing for each phase, then until the last sample of Phase 1 has been taken and until the post-study clinical investigations after Phase 2 have been completed. Subjects must not have smoked for at least 2 months prior to the start of Phase 1 and will refrain from smoking until the post-study clinical investigations after Phase 2 have been completed. Subjects will be informed of all restrictions and no restrictions other than those listed above and stated in the protocol will be placed on study subjects. Subjects will be specifically questioned on their adherence to restrictions prior to drug administration. Any deviations from the above restrictions which are made known to the investigators either voluntarily or on questioning will be recorded on the appropriate CRF. A decision as to whether the affected subject continues with the study will be taken by the study physician in consultation with the Principal Investigator.

Criteria for removal of any subject from the study at any time are the following: voluntary withdrawal by the subject for any reason, illness or injury during the study if regarded as clinically significant by the study physician, any adverse event or signs of toxicity if regarded as clinically significant by the study physician, failure of the subject to comply with or be uncooperative towards any study requirements if regarded as clinically significant by the study physician or investigators, failure to follow pre-study instructions regarding alcohol, drug use, fasting etc, if regarded as clinically significant by the study physician or investigators. A post- study medical on any subject who withdraws from the study and to conduct any necessary follow-up procedures if possible. Reasons for a subject's withdrawal will be documented in the subject's case report form and in the final study report. Samples collected from a subject who withdraws due to a drug adverse event will be analysed for the compound/s of interest and blood concentration data will be presented in the final report. However, samples collected from a subject who withdraws from the study voluntarily, or is removed from the study due to reasons other than an adverse event, will only be analysed and if needed.

Pharmacokinetics, statistics and standards for comparative bioavailability / bioequivalence

Standards for Comparative Bioavailability / Bioequivalence. Comparative bioavailability will be assessed objectively as well as according to the TPD guideline on the "Conduct and Analysis of Bioavailability and Bioequivalence Studies - Part B: Oral Modified Release Formulations, (Group Il Drug Products) for ER vs IR comparisons using omeprazole plasma concentration data:

1 - Cm_ax : The relative mean measured C_maχ of the test (A) to reference

(B) formulation should not exceed 125%.

2. AUC : The relative mean measured AUC_O-T of the test (A) to reference (B) formulation should be between 80% and 125%.

3. 90% Cl :ln addition, 90% confidence intervals will be calculated for Cmax, AUC₀-T and AUCo-∞.

and Part B: Oral Modified Release Formulations (Group III Drug Products) for ER vs ER comparison using diclofenac plasma concentration data:

1. C_max: The relative mean measured C_max of the test (A) to reference (B) formulation should be between 80% and 125%. 2. AUC: The 90% Cl of the relative mean measured AUCO-T of the test (A) to reference (B) formulation should be within 80% - 125%.

3. 90% Cl: In addition, 90% confidence intervals will be calculated for C_max and AUCo-∞.

Pharmacokinetics and Statistics. Diclofenac and omeprazole plasma concentration vs time profiles will be constructed from QA'd analytical data received from the analytical laboratory. Profiles will be assessed objectively and any data points which require confirmation (e.g.

Cm_ax value higher or lower than expected with respect to other data points in the profile) or which represent pharmacokinetic outliers (e.g. spurious peak in elimination phase) will be identified. These samples (pharmacokinetic repeats) will be re-analyzed and results reported and incorporated into the final data set for pharmacokinetic and statistical analysis according to the appropriate analytical site SOP. Samples re- assayed will be reported in the final report and an explanation as to why they were re-analyzed will be provided. Subject profiles will only be de- randomized once the analysis of pharmacokinetic repeats has been finalised.

Pharmacokinetic and statistical parameters will be determined by the BRI using the SAS statistical package. If any data points are missing, pharmacokinetic parameters will be calculated using actual data and missing data points will not be estimated in any way. Only data from subjects who complete the study will be used in pharmacokinetic and statistical analysis for the assessment of bioequivalence.

Pharmacokinetic and statistical analysis will be conducted on all subjects who complete the study. If possible, pharmacokinetic parameters will also be determined from plasma concentration data obtained from subjects who withdraw from the study if their samples are analyzed. Pharmacokinetic Analysis. The following pharmacokinetic parameters will be determined for both diclofenac and omeprazole: The following pharmacokinetic parameters will be determined for both diclofenac and omeprazole:

1- C_max The maximum concentration of analyte in a subject's plasma.

2. Ci_ast: The last measurable concentration

3. T_max : The sample time at which the C_max was attained. If this occurs at more than one time point, it is defined as the first time point with this value (hour).

4. Ti_ast : The time of last quantifiable concentration (hour).

5. T_Lιn : The time point where log linear elimination begins (hour).

6. AUCO-_T: The cumulative area under the plasma concentration vs. time curve from time zero to the last measured or measurable concentration, determined using the trapezoidal rule.

7. AUC₀-_X : The cumulative area under the plasma concentration vs. time curve from time zero to the last measured or measurable concentration, determined using the trapezoidal rule.

8. AUC₀- : The area under the extrapolated plasma concentration vs. time curve from time zero to infinity calculated as the sum of AUC ₀ - τ and Cι_ast / kel

9. AUCo-j/o - The percent ratio of AUC_0-T to AUC_0- as a measure of the extent to which the elimination of the drug was followed. 10. k_ei: The apparent first-order terminal elimination rate constant calculated by linear regression of the terminal linear portion of a semi- logarithmic plot of plasma concentration vs. time using at least the last three measurable concentrations.

11. T i/2ei : Mean elimination half-life (hour). kei, Tiι_2eι, AUC₀ - , AUC₀ - τ/0 - and Tu_n will not be estimated for concentration-time profiles that do not exhibit a terminal log-linear phase. Statistical Analysis. Statistical analysis will be conducted for both diclofenac and omeprazole. Descriptive statistical parameters of the mean, minimum, maximum, standard deviation (SD) and coefficient of variation (CV%), will be calculated for the demographic variables of age, height, weight and BMI. These statistical parameters will also be calculated for plasma concentrations at each individual time point. The mean, SD and CV% will be calculated for the pharmacokinetic parameters.

PK parameters will be determined to assess comparative bioavailability 1 bioequivalence as described in section 8.1. ANOVA analysis of pharmacokinetic parameters will be conducted and the 90% confidence intervals for the exponential of the difference between the test and the reference product will be calculated to facilitate the assessment of bioavailability 1 bioequivalence. Ln-transformed data for C_max, AUC_O-_T and AUC₀- and untransformed data for T max. and k_eι will be used for this purpose for parameters calculated from both diclofenac and omeprazole plasma concentrations.

Fixed factors included in the model will be the treatment received, the period in which it was given and the sequence in which each treatment was received. A random factor for the subject effect (nested within the sequence) will also be added. Sequence, period and treatment effects will be assessed at the 5% level. If a pharmacokinetic parameter for a subject cannot be determined for one period, the subject will be excluded for that particular statistical comparison. If, in the event that the statistical analysis of data as described above is deemed to be not appropriate due to any event occurring during the course of the study, the sponsor will be notified and alternative statistical methodologies agreed upon, in conjunction with the relevant regulatory agencies if necessary.

Study procedure

Blood Sampling, Processing and Storage. Blood samples (10 ml_) will be collected into syringes via an intravenous cannula inserted into an arm vein then transferred directly into 10 ml_ Vacutainer® tubes with K-EDTA. Samples will be collected by repeat venipuncture if necessary or if requested by the subject. Samples will be withdrawn at the time of cannulation (pre-dose, 0.0) then at the following time points: i) Following dosing with Test product (A): 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0,10,11 ,12,13,14,15,16,18,20,24 and 30 hours after dosing. A total of 23 samples will be collected from each subject for one phase. ii) Following dosing with the Reference products (B): 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0,6.0,7.0,8.0, 10, 12, 16,24 and 30 hours after dosing. A total of 17 samples will be collected from each subject for one phase.

The clock time of the blood draws will be recorded. Any deviation of more than 2 minutes from the scheduled sampling time will be reported. The total amount of blood collected from each subject over the entire study period, including blood samples withdrawn for pre- and post- study screening tests, will not be greater than 460 ml_. Blood samples will be stored in an ice-bath immediately after being taken until centrifugation commences. Centrifugation at 4°C will commence within 30 min. of the sampling time. Duplicate aliquots of harvested plasma for separate diclofenac and omeprazole analysis (4 aliquots in total) will be stored in polypropylene tubes at -80 +/-10°C until shipment. The tubes will be labeled with study number, phase number, subject number, sample number and sampling time.

Subject Monitoring. The study physician will remain at the clinic from the commencement of dosing until 4 hours after the first dose has been administered, and be contactable by phone for the duration of the study. Blood pressure and pulse will be checked just prior to dosing then 4 and 8 hours after dosing. No other monitoring is required during the study. Subjects will be asked open-ended questions about their health at the time of each sample in order to obtain information on adverse events without making suggestions to subjects. Clinic nursing staff will observe and be in attendance to ensure that subjects adhere to the restrictions regarding posture, movement and the consumption of food and beverages while at the clinic. Study subjects will undergo a post-study medical as detailed the section entitled "Pre-and Post-Study Medical Screening" and test results will be assessed for out-of-range results and significant fluctuations compared to the pre-study test results. Clinically significant results will be followed until they are satisfactorily resolved. Sample analysis Analytical Method. Diclofenac and omeprazole plasma concentrations will be measured according to a suitably sensitive LC- MS/MS assays validated in the laboratory of the analytical facility prior to the start of the study.

Sample Analysis. The following samples will be analysed for diclofenac and omeprazole following administration of test and reference products: Test (A):

1. Diclofenac: 0.0, 0.5, 1.0, 1.5,2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10, 11 , 12, 13, 14, 15, 16, 18,20,24 and 30 hours after dosing i.e. all 23 samples.

2. Omeprazole: 0.0,2.0,4.0,5.0,6.0,7.0,8.0,9.0,10,11 ,12,13,14,16,18, 20,24 and 30 hours after dosing i.e. 18 samples.

Reference (B):

1. Diclofenac: 0.0,1.0,2.0,3.0,4.0,5.0,6.0,7.0,8.0,10,12,16,24 and 30 hours after dosing i.e. 14 samples.

2. Omeprazole: 0.0, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 10 and 12 hours after dosing i.e. 14 samples. Results

Simulation study is done to predict plasma profiles for both diclofenac and omeprazole and a PK/PD analysis for omeprazole

Observed in vivo data showed good bioavailability and demonstrated a pulsatile release over 24 hrs after a single administration of a chronotherapy tablet containing 100mg diclofenac (Fig. 3), as compared to Voltaren 100mg SR (% ratio of AUC_0-24 = 95.17%). Results were close to simulation, except for time lags which were deliberately changed in the formulation. In vivo data for omeprazole suggested slow absorption compared to the immediate release form though results were close to simulated values (Fig. 4). Pharmacodynamic simulation study demonstrated therapeutic efficiency in terms of % proton pump inhibition (Fig. 5). While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.

Claims

CLAIMS:

1. A chronotherapy tablet comprising:

• a substantially round core having a first end and a second end, the core being comprised of at least two superposed layers of different compositions with an interface between each layer; wherein at least one of said layers comprises a pharmacologically active anti-inflammatory composition and at least one of said layers comprises a pharmacologically active cytoprotective composition;

• a coating which envelops the core except for at least one exposed release face of the core at at least one end of the core; whereas upon oral administration the chronotherapy tablet allows proper timing of delivery of said pharmacologically active anti-inflammatory composition and said pharmacologically active cytoprotective composition relative to the time of oral administration.

2. The chronotherapy tablet according to claim 1 , comprising two layers of pharmacologically active anti-inflammatory composition separated by a layer of a pharmacologically active cytoprotective composition.

3. The chronotherapy tablet according to claim 2, wherein each of said two layers of pharmacologically active anti-inflammatory composition comprises a different pharmacologically active anti-inflammatory agent.

4. The chronotherapy tablet according to claim 2, wherein each of said two layers of pharmacologically active anti-inflammatory composition comprises a different dosage of same pharmacologically active anti-inflammatory agent.

5. The chronotherapy tablet according to claims 1 to 4, wherein said layer of a pharmacologically active cytoprotective composition further comprises a delay composition.

6. The chronotherapy tablet according to claims 1 to 5, further comprising at least one delay layer.

7. The chronotherapy tablet according to claims 1 to 6, wherein said pharmacologically active anti-inflammatory composition is chosen from an acetic acid derivative, acetylsalicylic acid, an indole derivative, sodium or potassium diclofenac, etodolac, indomethacin, ketorolac tromethamine, sulindac, tolmetin sodium, cyclooxygenase-2 inhibitor, celecoxib, rofecoxib, a fenamate, mefenamic acid, floctafenine, an oxicam, meloxicam, piroxicam, piroxicam cyclodextrin, tenoxicam, a propionic acid derivative, aceclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, nabumetone, oxaprozin, a tiaprofenic acid derivative, a salicylic acid derivative, diflunisal, salts thereof and mixtures thereof.

8. The chronotherapy tablet according to claims 1 to 7, wherein said pharmacologically active cytoprotective composition is chosen from omeprazole, pantoprazole, esomeprazole, rabeprazole, lansoprazole, cimetidine, famotidine, nizatidine, ranitidine, ranitidine bismuth citrate, salts thereof and mixtures thereof.

9. The chronotherapy tablet according to claims 1 to 8, wherein a first layer comprises therapeutically effective amount of diclofenac, a second layer comprises therapeutically effective amount of omeprazole and a third layer comprises a therapeutically effective amount of diclofenac.

10. The chronotherapy tablet according to claim 9, wherein said first layer comprises between about 25 mg to 100 mg of diclofenac, said second layer comprises between about 5 mg to 80 mg omeprazole and said third layer comprises between about 25 mg to 100 mg of diclofenac.

11. The chronotherapy tablet according to claim 10, wherein the first and third layers comprise about 50 mg diclofenac and the second layer comprises about 40 mg omeprazole.

12. The chronotherapy tablet having a dissolution profile of Fig. 2.

13. The chronotherapy tablet of claims 1 to 11 having a dissolution profile of Fig. 2.

14. A method of chronotherapy of an anti-inflammatory condition comprising orally administering a chronotherapy tablet of claims 1 to 13; whereas upon oral administration the chronotherapy tablet effects the amelioration of at least one anti-inflammatory condition within 24 hours while releasing a cytoprotective agent.

15. The method according to claim 14, wherein said anti-inflammatory condition is chosen from arthritis and osteoarthritis.

16. The method according to claim 14, wherein said anti-inflammatory condition is arthritis, said tablet is administered in the afternoon or in the evening for a peak effect of said anti-inflammatory composition when needed.

17. The method according to claim 14, wherein said anti-inflammatory condition is osteoarthritis, said tablet is administered in the morning or in the evening for a peak effect of said anti-inflammatory composition when needed.