WO2009146537A1

WO2009146537A1 - Multilayer control-release drug delivery system

Info

Publication number: WO2009146537A1
Application number: PCT/CA2009/000763
Authority: WO
Inventors: Alain Desjardins; Najiba Dernaoui
Original assignee: Pharmascience Inc.
Priority date: 2008-06-02
Filing date: 2009-06-01
Publication date: 2009-12-10

Abstract

The present invention relates to a continuous, controlled-release tablet, comprising at least one centered release layer, wherein said release layer is of equal thickness along the length of the tablet or has a zero-order dissolution profile, for dissolution of at least one pharmaceutically active agent, and whereby dissolution of said centered release layer is peripheral.

Description

MULTILAYER CONTROL-RELEASE DRUG DELIVERY SYSTEM

BACKGROUND OF THE INVENTION

(a) Field of the Invention

[0001] The present invention relates to a continuous, controlled-release multilayer tablet comprising at least one centered release layer, wherein the release layer is of equal thickness along the length of the tablet or has a zero- order dissolution profile, for dissolution of at least one pharmaceutically active agent, and whereby dissolution of the centered release layer is peripheral. By minimizing the change in surface area exposed to dissolution media with time, this particular construction allows dissolution of the enclosed pharmaceutically active agent only from the periphery of the tablet, therefore leading to its constant release in the environment.

(b) Description of Prior Art

[0002] A problem with the control release of round shaped tablets is that they usually give a first-order release profile. Several approaches have been studied to correct this behavior. Some of those approaches involved coating the round tablets on one or several surfaces with insoluble film coating in order to obtain linearity. One approach was to synchronize release and erosion from the central layer and that of the outer layers such that the reduction in the surface area of the core is compensated by additional surface exposition following dissolution of the coating. Other approaches involved balancing the swelling rate and the drug dissolution rate to achieve linear release. In any case, the formulation of the products using these technologies requires quite a lot of fine-tuning in order to obtain target release profile. The following patents are various examples of the recent developments in the continuous, controlled-release of a pharmaceutically active agent.

[0003] U.S. Patent No. 3,317,394 describes a cylindrical multilayer tablet with a central layer containing the pharmaceutically active agents and coated with coating material forming porous channels as dissolution proceeds. The pharmaceutically active agent dissolves by diffusion from the periphery of the tablet and eventually also diffuses through the pores of the coating. Balancing diffusion of the enclosed pharmaceutically active agent from the periphery and from across the coating is the only way to obtain regular release of the enclosed agent which, by modifying the thickness and porosities of the coating layer, can be very intricate.

[0004] U.S. Patent No. 4,839,177 relates to a core tablet coated with an insoluble coating on several surfaces, leaving only one face for the release of the pharmaceutically active agent. The core tablet contains the active ingredient and at least one swelling and one gelling agent, plus other adjuvants. The coating is applied to the core in order to suitably direct and quantitatively regulate the release of the active ingredient from the core. Swelling and gelling of the core material are the driving forces for release of the active ingredient, whereas the geometry of the coating limits the swelling of the core and direct emission of material from it. The application of the coating by an economical mean is not provided, and the real benefit of the coating applied is not clear, as release profiles reported differ from a zero- order diffusion profile. The purpose of the coating should have been to modulate the swelling so as to obtain a constant drug release.

[0005] US Patent No. 5,114,719 consists of an insoluble polymeric matrix containing biologically active, water-soluble agents of low molecular weight covered with an impermeable coating. The polymer device is constructed in order that, when placed in a fluid environment, fluid is absorbed by the device and water soluble molecules diffuse into the fluid environment leaving behind pores and channels in the matrix, the rate of diffusion being limited by the impermeable coating. Therefore, diffusion of the biologically active molecules out of the matrix is directly connected to the matrix's load of molecules and to the thickness of the polymeric matrix and of the coating. However, the problem with such system consists in the often too fast formation of pores and channels through the matrix, which frequently result in non-linear diffusion rate. [0006] US Patent No. 5,393,765 consists of an erodible matrix tablet containing a dispersed pharmaceutically active agent of a solubility not greater than 80 mg/ml. The matrix is constituted of a hydroxypropyl methylcellulose derivative and erosion modifiers depending on drug solubility and drug loading, such as lactose and polyoxyalkylene derivatives of propylene glycol, as well as other inert materials such as binders and lubricants. When placed in a physiologic environment, the construction forms two layers: an outer layer of hydrated matrix which is eroding and an inner core of unchanged matrix. Drug diffusion is either negligible or comparable to the erosion rate of the matrix, drug concentration in the hydrated layer remaining constant. Such construction is not optimal, drug diffusion being unstable as well as limited to pharmaceutically active agents of lower solubility.

[0007] US Patent No. 5,422,123 consists of a deposit-core of defined geometrical form comprising a pharmaceutically active agent and, either a polymeric material swelling on contact with water or aqueous liquids and combined to a gellable polymeric material, or a single polymeric material having both swelling and gelling properties. A support-platform, consisting of an elastic support, is applied to the deposit-core, covering one or more of its surfaces and following changes due to hydration of the deposit-core as well as being slowly soluble and/or slowly gellable in aqueous fluids. The support- platform is made of a less soluble material than the polymeric material of the deposit-core, therefore allowing diffusion of the active agent only from the non-covered surfaces of the core. However, since the shape and thickness of the deposit-core is variable, the amount of pharmaceutically active agent in contact with the environment will vary as the diffusion front moves forward in the tablet, therefore affecting the rate of the diffusion. Moreover, coating only one surface, as it is proposed, will provide only negligible control on drug diffusion: at least two surfaces have to be covered to manage an active agent's release. [0008] US Patent No. 5,549,913 consists of multilayer tablets comprising at least one swelling and gelling layer, containing one or more active principle, and at least one erodible or soluble layer possibly containing an active principle. The geometrical modifications of the system generate a gradual increase in total release surface, which compensates the reduction of release rate caused by the increase of gelled layer thickness. The gradual increase in total release surface is brought about by dissolution of the erodible layer, which exposes progressively more of the swelling layer. This system requires a careful synchronization of the swelling and erodible layers in order to obtain constant release of the enclosed active agent. The release kinetic may be highly dependant on dissolution conditions, which might vary from an individual to another.

[0009] US Patent No. 5,626,874 consists of a construction having a lenticular form consisting of three layers. The top and bottom layers are barriers made of gellable and/or erodible polymeric material, and being similar or different with respect to thickness and composition. The central layer withholds the active material to be dissoluted in the physiological environment. The layering of the tablet is such that the exposition of the central layer to fluid on its periphery is minimized, resulting in slow initial release of drug. The erosion and/or solubilisation or progressive hydration of at least one of the external coating results in ultimate release of the drug to the surrounding. However, such construction is not intended to offer a zero- order dissolution profile.

[0010] US Patent No. 5,681 ,583 relates to the use of multilayered tablets comprising at least one layer used for the rapid release of a drug and a second layer used for the control release of the same or different drug. A third layer can also be used for the controlled-release of the same or different drug. The presence of the several layers is not intended to provide a particular release profile from the physical interaction of the different layers. The superficial release layer(s) do not remain on the tablet for long enough to provide any control over the release of the long acting layer(s). [0011] US Patent No. 5,738,874 is a triple layer tablet, or core-coated tablet comprising a central layer containing the active ingredient with slow release characteristics, a first outer layer consisting of a continuous, controlled-release layer and a second outer layer being of low permeability and acting as barrier type coating. The superficial layer serves the purpose of limiting the drug release of the central slow release layer. The triple layer is not aimed at providing zero-order release. The tablet can release the same drug at different release rate (burst followed by controlled release), or release several drugs at different times.

[0012] US Patent No. 5,780,057 describes a gastro-retentive device in the form of a bilayer or trilayer tablet consisting of one layer which rapidly swells and increases in volume, a second layer that contains the active ingredient to be released in a controlled-release fashion, and optionally a third layer acting as a barrier modulating the release of the pharmaceutically active agent. In order to obtain a zero-order release profile, the erosion of the third layer must be adjusted to compensate the decreasing concentration of the pharmaceutically active agent in the release layer.

[0013] US Patent No. 5,783,212 is a trilayer tablet consisting of two barrier layers on either side of a central drug layer. The barrier layer erodes more rapidly than the drug layer in the course of dissolution. In order to obtain a constant drug-release, the drug layer area has to be exposed in an approximately constant manner.

[0014] US Patent No. 6,033,685 describes a tablet containing a drug embedded into a non-swelling, non-gelling hydrophobic matrix. The tablet is laminated on one or both sides by a barrier layer. The barrier is either a swellable and gellable/erodable layer or a non-erodable hydrophobic layer. Such construction being cylindrical in shape, the central matrix releases the drug with a decreasing rate due to increase path length from the sidewall, unless the surface area exposed to surroundings increased in the process of dissolution, as for example, by the erosion of barrier(s). [0015] None of the above-mentioned inventions succeeded in developing an efficient system allowing a continuous, constant drug-release of active agents in a physiological environment, and most of the inventions have the following drawbacks. They are complex to formulate, as the kinetics of release depends on the synchronization of events taking place in the core tablet and external layers. Moreover, the cost and commercial manufacture of some propositions is an issue. The development of a tablet providing a steady rate of delivery, easy to formulate and to produce is essential, and the present invention focuses on the resolution of this challenge.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Fig. 1 is a top view of a round shaped trilayer tablet showing the decrease in surface of the drug releasing central layer as a function of time.

[0017] Fig. 2a is a top view of a possible configuration of a tablet of an elongated shape.

[0018] Fig. 2b is a cross-section plan view of the internal configuration of the tablet of Fig. 2a: two outer coating layers, as well as a central release layer are displayed.

[0019] Fig. 3a is a top view of an elongated shaped trilayer tablet showing the change in dimension of the drug relasing core (central layer) as dissolution progresses. Change in surface area of the releasing faces is limited to erosion of the tips.

[0020] Fig. 3b is a cross-section plan view of an elongated shaped trilayer tablet showing the change in dimension of the drug releasing core (central layer) as dissolution progresses. As seen in Fig. 3a, change in surface area of the releasing faces is limited to erosion of the tips.

[0021] Figs. 4-10 show the dissolution profiles of the tested tablets.

SUMMARY OF THE INVENTION

[0022] In accordance with the present invention, there is provided an approach to improve the dissolution profile of tablets through structural modifications. In fact, one of the aimed goals is to minimize the negative effects associated with the decrease in a construction's exposed surface occurring when releasing enclosed pharmaceutically active agents in an environment. This can be exemplified typically by Fig. 1 , showing a round tablet which diameter is decreasing in the course of dissolution, by an erosion mechanism for example, resulting in a net decrease in surface area exposed to the dissolution medium with time. Such negative effects consist in, particularly, a diminution of the dissolution rate of the enclosed pharmaceutically active agent in proportion with the diminution of the exposed surface area of a tablet.

[0023] The present invention is based on the elaboration of a tablet generating a zero-order dissolution profile obtained by minimizing the change in surface area in the course of dissolution. This can be made possible by using an elongated shaped tablet, as exemplified in Fig. 2a, instead of a round shaped tablet, as in Fig. 1. Furthermore, the elongated shaped tablet can be multilayered, as exemplified in Fig. 2b, which shows a trilayered tablet. The releasing layer in Fig. 2b is the central layer. The outer top and bottom layers do not contain and do not release any pharmaceutically active agent, and act merely as barriers forcing interaction of the release central layer only from the periphery. By allowing release of the enclosed active agent from the periphery only, the exposed surface area remains almost constant during the entire course of the dissolution, as exemplified from Fig. 3a and Fig. 3b. Indeed, the dissolution from the tips of the tablet will introduce some first order release, but as the surface of the tips is much smaller than the overall surface of the lateral sides, the release will be predominantly zero-order for the delivery of water-soluble drugs over a long period of time and at a nearly constant rate. Such construction presents major advantages compared to already marketed products, which dissolution patterns are too often characterized by uneven and irregular distribution in time and in quantity of the enclosed active ingredient, therefore possibly leading to unwanted side- effects. [0024] In accordance with the present invention, there is provided a continuous, controlled-release tablet comprising at least one centered release layer, wherein the release layer is of equal thickness along the length of the tablet or has a zero-order dissolution profile, for dissolution of at least one active substance, and whereby dissolution of the centered release layer is peripheral.

[0025] In accordance with the present invention, there is provided a continuous, controlled-release tablet with a zero-order dissolution profile of at least one pharmaceutically active agent, the tablet comprising a variable geometry multilayer tablet for continuous, constant drug delivery, at least one centered release layer, wherein the release layer is of equal thickness along the length of the tablet or has a zero-order dissolution profile for dissolution of at least one pharmaceutically active agent, and a top and a bottom external coating layer preventing dissolution of the centered release layer therefrom, whereby dissolution of the centered release layer is from the periphery.

[0026] In accordance with the present invention, there is provided a continuous, controlled-release tablet with a zero-order dissolution profile for at least one pharmaceutically active agent, the tablet comprising a variable geometry for continuous, constant drug delivery, at least one centered release layer comprising the at least one pharmaceutically active agent, wherein the release layer is of equal thickness along the length of the tablet or has a zero- order dissolution profile for dissolution of the at least one pharmaceutically active agent, and a top and a bottom external coating layer preventing dissolution of the centered release layer therefrom, whereby dissolution of the centered release layer is from the periphery.

[0027] In accordance with the present invention, there is provided a continuous, controlled-release tablet with a zero-order dissolution profile for at least one pharmaceutically active agent, the tablet comprising: a) a variable geometry for continuous, constant drug delivery;

b) at least one centered release layer comprising at least one pharmaceutically active agent, wherein the release layer has a top portion; a bottom portion; and a periphery; and the centered release layer has a constant thickness along the length of the tablet or has a zero-order dissolution profile, for dissolution of the least one pharmaceutically active agent; and

c) a top external coating layer disposed over the top portion of the centered layer and a bottom external coating layer disposed over the bottom portion of the centered layer;

whereby the top external coating layer and the bottom external coating layer limits the dissolution of the centered release layer therefrom, to the periphery thereof.

[0028] In accordance with a preferred embodiment of the present invention, the continuous, controlled-release tablet may be of a pharmaceutically acceptable size and may have a geometry which comprises either a construction with an elongated shape, such as an oblong, or rectangular construction with a length at least two to three times greater than its width.

[0029] In accordance with a preferred embodiment of the present invention, the tablet's form may vary from a very large pharmaceutically acceptable size to a very small pharmaceutically acceptable size.

[0030] In accordance with another embodiment of the present invention, the centered release layer may be a single layer or multiple layers of equal thickness along the length of the tablet or a single layer or multiple layers having a zero-order dissolution profile.

[0031] In accordance with a preferred embodiment of the present invention, the single or multiple layers of the centered release layer of the continuous controlled-release tablet are each constituted of a blend of a pharmaceutically active agent with a pharmaceutically acceptable carrier.

[0032] In accordance with still a preferred embodiment of the present invention, each of said multiple layers of the centered release layer of the continuous controlled-release tablet may enclose identical or different pharmaceutically active agents and/or pharmaceutically acceptable carriers.

[0033] In accordance with another embodiment of the present invention, the continuous, controlled-release tablet's pharmaceutically acceptable carrier may be a hydrophilic, water-soluble, polymeric carrier chosen from crosslinked polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, hydroxyethylcellulose, crosslinked sodium carboxymethylcellulose, carboxymethyl starch, acrylic and methacrylic acid polymers and copolymers, polyesters, polyethylene glycol, polyethylene oxide, polyanhydrides copolymers polymethylvinylether/anhydride, potassium methacrilate- divinylbenzene copolymer, polyvinylalcohols, polyvinylpyrrolidone, glucan, scleroglucan, mannan, starchs, pregelatinised starch and other starchs derivatives, betacyclodextrins and cyclodextrins derivatives containing linear and/or branched polymeric chains and mixtures thereof.

[0034] In accordance with another embodiment of the present invention, the continuous, controlled-release tablet's pharmaceutically acceptable carrier may be a carrier that is used to adjust or modify the release characteristics of the centered layer chosen from lactose, mannitol, sucrose, sorbitol, xilitol, polyethylene glycols, polyols, low molecular weights HPMC, low molecular weights HPC, low molecular weight polyvinylpyrrolidone, ionic and non-ionic surfactants, polyoxyalkylene derivatives of propylene glycol (Pluronics™), organic acids, buffering agents, starch, fillers, lubricants, superdisintegrants, calcium carbonate, calcium phosphate, microcrystalline cellulose, hydrogenated castor oil, glyceryl palmitostearate, talc and mixtures thereof. [0035] In accordance with another embodiment of the present invention, the single or multiple layers of the centered release layer of equal thickness along the length of the tablet may be in each case of a pharmaceutically acceptable thickness.

[0036] In accordance with another embodiment of the present invention, the tablet is a variable geometry multilayer tablet.

[0037] In accordance with still another embodiment of the present invention, the multiple layers may each be of the same or of different thicknesses.

[0038] In accordance with another embodiment of the present invention, the single or multiple layers of the centered release layer may be disposed in a crosswise, longitudinal position and in a pharmaceutically acceptable shape along the length of the construction.

[0039] In accordance with still another embodiment of the present invention, the top and a bottom external coating layer may be of the same or of different material and are disposed apart from one another.

[0040] In accordance with still another embodiment of the present invention, the top and bottom external coating layers may be of a material chosen from water-insoluble cellulose, such as ethylcellulose and cellulose ester, cellulose acetate-proprionate, water-insoluble polyvinylacetate, or blends of polyvinyl acetate with other material such as in Kollidon SR, water- insoluble polyacrylate such as water-insoluble acrylate polymer, water- insoluble methacrylate polymers, water-insoluble methylmethacrylate polymers, water-insoluble ethylacrylate polymers, copolymers comprising a combination of a preceding water-insoluble polyacrylate, a quaternary ammonium functional group containing derivative of the preceding polymers and copolymers, copolymers based on acrylic and methacrylic acid esters such as Eudragit NEm RS, RS30D, RL, or RL30D. [0041] In accordance with still another embodiment of the present invention, the top and bottom external coating layers may be of a material that is highly less water-soluble that the material of the coating layer.

[0042] In accordance with still another embodiment of the present invention, the pharmaceutically active agent contained in the release layer may be selected from peptidomimetics, peptides, proteins, toxoids, antibodies, nucleosides, nucleotides, nucleic acids, polysaccharides, analgesics and anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anticoagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, antimigraine agents, anti-muscarinic agents, anti-neoplastic agents and immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics and neuroleptics, β-blockers, cardiac inotropic agents, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine H,-receptor antagonists, keratolyses, lipid regulating agents, muscle relaxants, anti-anginal agents, nutritional agents, analgesics, sex hormones, stimulants, and cytokines.

[0043] In accordance with still a preferred embodiment, the pharmaceutically active agent may be salbutamol, labetalol, sumatriptan, ondansetron, cyclobenzaprine, dantrolene sodium, methocarbamol, metaxalone, carisoprodol, orphenadrine citrate, baclofen, chlorophenesin carbamate, chlorzoxazone, mephenesin, diazepam, nitrazepam, flurazepam, oxazepam, chlordiazepoxide, medazepam, lorazepam, ibuprofen, naproxen, naproxen sodium, flurbiprofen, fenoprofen, fenbufen, ketoprofen, ketoprofen, pirprofen, carpofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, ndomethacin, sulindac, tolmetin, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazae, clidanac, oxepinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, CP- 14,304, 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1 H- pyrodo[4,3b]indol-1 -one, (+)-1 ,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1 H- imidazol-4-yl)methyl]-4H-carbozol-4-one, 6-fluoro2,3,4,5-tetrahydro-5, methyl- 2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1 H-pyrido[4,3-b]indol-1 -one or a pharmaceutical acceptable salt, solvate or derivative thereof.

[0044] In accordance with still another embodiment of the present invention, the centered release layer comprises two or more layers for the dissolution of two or more active agents.

[0045] In accordance with a preferred embodiment of the present invention, the tablet may be film-coated.

[0046] In accordance with still a preferred embodiment of the present invention, the film-coating may be for esthetic purposes.

[0047] In accordance with still a preferred embodiment of the present invention, the film-coating may modify the release properties of the tablet.

[0048] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble upon ingestion.

[0049] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble in the dissolution medium.

[0050] In accordance with still a preferred embodiment of the present invention, the film-coating may be insoluble upon ingestion.

[0051] In accordance with still a preferred embodiment of the present invention, the film-coating may be insoluble in the dissolution medium.

[0052] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble depending on the pH of the dissolution medium.

[0053] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble in acidic conditions. [0054] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble in basic conditions.

[0055] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble depending on the position of the tablet in the gastro-intestinal tract.

[0056] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble in the colon.

[0057] In accordance with still another embodiment of the present invention, there is provided a method for making the tablet of the present invention, the method comprising preparing one or more blend of a pharmaceutically active agent and a pharmaceutically acceptable carrier in an appropriate manner to form a mix for the at least one centered release layer, preparing a second blend of a material in an appropriate manner to form a mix for the coating layers, compressing the blends for the top and bottom coating layers with one or more blends for the central release layer in a die and producing a tablet out of the one or more compressed mixes.

[0058] In accordance with still a preferred embodiment of the present invention, the pharmaceutically acceptable carrier may be a hydrophilic, water-insoluble, polymeric carrier chosen from hydroxypropyl methycellulose (HPMC), methylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyethylene glycol, polyethylene oxide, polyvinyl alcohols, pregelatinised starch and mixtures thereof.

[0059] In accordance with still a preferred embodiment of the present invention, the pharmaceutically acceptable carrier may be a carrier that is used to modulate the pharmaceutically active agent release and that is chosen from lactose, mannitol, sucrose, sorbitol, xilitol, polyethylene glycols, polyols, low molecular weights HPMC, low molecular weights HPC, low molecular weight polyvinylpyrrolidone, ionic and non-ionic surfactants, polyoxyalkylene derivatives of propylene glycol (Pluronics™), organic acids, buffering agents, starch, fillers, lubricants, superdisintegrants, calcium carbonate, calcium phosphate, microcrystalline cellulose, hydrogenated castor oil, glyceryl palmitostearate, talc and mixtures thereof.

[0060] In accordance with still a preferred embodiment of the present invention, the material for the coating layers may be chosen from water- insoluble cellulose, such as ethylcellulose and cellulose ester, cellulose acetate-proprionate, water-insoluble polyvinylacetate, or blends of polyvinyl acetate with other material such as in Kollidon SR, water-insoluble polyacrylate such as water-insoluble acrylate polymer, water-insoluble methacrylate polymers, water-insoluble methylmethacrylate polymers, water- insoluble ethylacrylate polymers, copolymers comprising a combination of a preceding water-insoluble polyacrylate, a quaternary ammonium functional group containing derivative of the preceding polymers and copolymers, copolymers based on acrylic and methacrylic acid esters such as Eudragit NEm RS, RS30D, RL, or RL30D.

[0061] In accordance with still a preferred embodiment of the present invention, the material for the coating layers may be a material that is highly less water-soluble than the material of the centered release layer.

[0062] In accordance with still a preferred embodiment of the present invention, blending the pharmaceutically active agent and the pharmaceutically acceptable carrier in an appropriate manner to form a mix may be effected using an appropriate mixing device.

[0063] In accordance with still a preferred embodiment of the present invention, compressing one or more mixes may consist of piling up one or more layers of blends of a pharmaceutically active agent and of a pharmaceutically acceptable carrier in a mold.

[0064] In accordance with still a preferred embodiment of the present invention, compressing one or more mixes in a die may be done using a manual or automated multilayer press. [0065] In accordance with still a preferred embodiment of the present invention, the die used for compressing the mix may be a die of an elongated shape.

[0066] In accordance with still a preferred embodiment of the present invention, the die used for compressing the mix may have a length two to three times more important than its width and may be of a size that can vary from a very large pharmaceutically acceptable size to a very small pharmaceutically acceptable size.

[0067] In accordance with still a preferred embodiment of the present invention, producing a tablet out of the one or more compressed mixes may consist of pressing a tablet out of the mix.

[0068] In accordance with still a preferred embodiment of the present invention, pressing a tablet out of the mix may be done by using a tablet punch.

[0069] In accordance with still a preferred embodiment of the present invention, the method for making the tablet of the present invention may further comprise the step of film-coating the produced tablet.

[0070] In accordance with still a preferred embodiment of the present invention, the film coating may consist in vaporizing the produced tablet with a coating solution and drying the coating in appropriate equipments.

[0071] In accordance with still a preferred embodiment of the present invention, the tablet may be film coated for esthetic purposes.

[0072] In accordance with still a preferred embodiment of the present invention, the tablet may be film coated in order to modulate the pharmaceutically active agent release.

[0073] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble upon ingestion.

[0074] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble in the dissolution medium. [0075] In accordance with still a preferred embodiment of the present invention, the film-coating may be insoluble upon ingestion.

[0076] In accordance with still a preferred embodiment of the present invention, the film-coating may be insoluble in the dissolution medium.

[0077] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble depending on the pH of the dissolution medium.

[0078] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble in acidic conditions.

[0079] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble in basic conditions.

[0080] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble depending on the position of the tablet in the gastro-intestinal tract.

[0081] In accordance with still a preferred embodiment of the present invention, the film-coating may be soluble in the colon.

[0082] For the purpose of the present invention the following terms are defined below.

[0083] The expression "pharmaceutically active agent" is intended to mean a compound, which is enclosed in a tablet in order to be transported, and dissolved in an environment wherein it will induce a physiological effect.

[0084] The expression "pharmaceutically acceptable shape" is intended to mean the shape of an oral dosage form that presents various characteristics providing benefits in terms of the release and diffusion of an enclosed pharmaceutically active agent.

[0085] The expression "pharmaceutically acceptable carrier" is intended to mean a compound that presents certain benefits in terms of diffusion, release and interaction with the surrounding environment. [0086] The expression "pharmaceutically acceptable size" is intended to describe the size of an oral dosage form that is appropriate for the type(s) of component(s) it is intended to enclose, for the type of the structure and disposition of the enclosed component(s) and for the type of administration it is destined to.

[0087] The expression "forming a tablet out of the mix" consists of the general method for producing a tablet out of various blended components known by the person skilled in the art.

[0088] The term "zero-order" describes the ability of an oral dosage form to release the pharmaceutically active agent it encloses in a continuous and proportionate rate in time.

[0089] The expression "dissolution medium" describes the gastric juices and the various liquids or substances present in the gastro-intestinal tract and in which the tablet may dissolve.

[0090] All references referred herein are hereby incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

[0091] In accordance with the present invention, there is provided a continuous, controlled-release tablet comprising at least one centered release layer, wherein the release layer is of equal thickness along the length of the tablet or has a zero-order dissolution profile, for dissolution of at least one pharmaceutically active agent, and whereby dissolution of the centered release layer is peripheral. Diffusion originates out of the one or more centered hydrophilic release layers, constituted of a blend of a pharmaceutically acceptable carrier and of a pharmaceutically active agent. The one or more centered hydrophilic layers are positioned in a crosswise and longitudinal position in the tablet and can be arranged in various pharmaceutically acceptable shapes in the composition. The centered layer is either of equal thickness along the length of the construction or has a zero- order dissolution profile, the layer being disposed laterally in any pharmaceutically acceptable shapes. The tablet also comprises top and bottom insoluble coating layers on its inferior and superior surfaces made of various types of materials. The tablet is specifically produced with a geometry supporting a continuous, constant drug delivery. This precise geometry consists in a tablet with an elongated geometry, for example having a length being at least two to three times more important than its width.

[0092] Preparation of the tablet

[0093] A first blend for the central drug layer was prepared. The blend for the central layer comprises a pharmaceutically active agent, a hydrophilic polymer and optionally an excipient. Water soluble, hydrophilic, polymeric carriers referenced to in regard to this invention are those that dissolve completely in water at 25^CC within 24 hours in a preferred embodiment. Such carrier can be chosen from crosslinked polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, hydroxyethylcellulose, crosslinked sodium carboxymethylcellulose, carboxymethyl starch, acrylic and methacrylic acid polymers and copolymers, polyesters, polyethylene glycol, polyethylene oxide, polyanhydrides copolymers polymethylvinylether/anhydride, potassium methacrilate-divinylbenzene copolymer, polyvinylalcohols, polyvinylpyrrolidone, glucan, scleroglucan, mannan, starchs, pregelatinised starch and other starchs derivatives, betacyclodextrins and cyclodextrins derivatives containing linear and/or branched polymeric chains and mixtures thereof. Also, other ingredients used to adjust or modify the release characteristics of the centered layer can be used as pharmaceutically acceptable carrier: such ingredients can be chosen from lactose, mannitol, sucrose, sorbitol, xilitol, polyethylene glycols, polyols, low molecular weights HPMC, low molecular weights HPC, low molecular weight polyvinylpyrrolidone, ionic and non-ionic surfactants, polyoxyalkylene derivatives of propylene glycol (Pluronics™), organic acids, buffering agents, starch, fillers, lubricants, superdisintegrants, calcium carbonate, calcium phosphate, microcrystalline cellulose, hydrogenated castor oil, glyceryl palmitostearate, talc and mixtures thereof. The pharmaceutically active agent of the central release layer may be chosen from peptidomimetics, peptides, proteins, toxoids, antibodies, nucleosides, nucleotides, nucleic acids, polysaccharides, analgesics and anti-inflammatory agents, anthelmintics, antiarrhythmic agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anti-coagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, antimigraine agents, anti-muscarinic agents, anti-neoplastic agents and immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics and neuroleptics, β-blockers, cardiac inotropic agents, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine H, -receptor antagonists, keratolyses, lipid regulating agents, muscle relaxants, anti-anginal agents, nutritional agents, analgesics, sex hormones, stimulants, and cytokines. More specifically, the pharmaceutically active agent may be salbutamol, labetalol, sumatriptan, ondansetron, cyclobenzaprine, dantrolene sodium, methocarbamol, metaxalone, carisoprodol, orphenadrine citrate, baclofen, chlorophenesin carbamate, chlorzoxazone, mephenesin, diazepam, nitrazepam, flurazepam, oxazepam, chlordiazepoxide, medazepam, lorazepam, ibuprofen, naproxen, naproxen sodium, flurbiprofen, fenoprofen, fenbufen, ketoprofen, ketoprofen, pirprofen, carpofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, ndomethacin, sulindac, tolmetin, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazae, clidanac, oxepinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, CP- 14,304, 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1 H-imidazol-4- yl)methyl]-1 H-pyrodo[4,3b]indol-1-one, (+)-1 ,2,3,9-tetrahydro-9-methyl-3-[(5- methyl-1 H-imidazol-4-yl)methyl]-4H-carbozol-4-one, 6-fluoro2, 3,4,5- tetrahydro-5, methyl-2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1 H-pyrido[4,3- b]indol-1 -one or a pharmaceutical acceptable salt, solvate or derivatives thereof.

[0094] A second blend for the coating layers was prepared. Materials for the preparation of the coating layer may be chosen from water-insoluble cellulose, such as ethylcellulose and cellulose ester, cellulose acetate- propionate, water-insoluble polyvinylacetate, or blends of polyvinyl acetate with other material such as in Kollidon SR, water-insoluble polyacrylate such as water-insoluble acrylate polymer, water-insoluble methacrylate polymers, water-insoluble methylmethacrylate polymers, water-insoluble ethylacrylate polymers, copolymers comprising a combination of a preceding water- insoluble polyacrylate, a quaternary ammonium functional group containing derivative of the preceding polymers and copolymers, copolymers based on acrylic and methacrylic acid esters such as Eudragit NEm RS, RS30D, RL, or RL30D. The coating layer may also be made of a material that is highly less water-soluble than the material of the central layer.

[0095] Tablets were prepared on a single punch press of the make

Manesty F3. The die and punches were assembled on the press. A certain amount of the coating layer blend is introduced in the die, and the upper punch is lowered to touch the powder in the die with the objective of leveling the powder bed without compressing it appreciably. A certain amount of central drug layer blend is then introduced in the die on top of the coating layer already present, and the upper punch is lowered to touch the powder in the die with the objective of leveling the powder bed without compressing it appreciably. Additional center layers may be added, as the case may be. Finally, a certain amount of coating layer blend is introduced in the die, and the upper punch is lowered to apply high pressure on the layers and compress the tablet at a desired thickness and hardness.

[0096] The finish product is optionally film-coated, either to modify the esthetics of the tablet, or to modify its release properties.

[0097] Tablets may also be prepared in an automatic mode on commercial multilayer presses using highly automated compression procedures such as, for example, the Manesty-Layer press or the Korsch- Central Core Coater 3C.

[0098] Testing of the produced tablet

[0099] In general, for a tablet of a given size, drug release is governed by both the dissolution of the drug and by the erosion and/or swelling of the hydrophilic, polymeric carrier: such variables were modulated through this invention in order to obtain an ideal dissolution rate of a tablet's enclosed pharmaceutically active agent. Indeed, the present construction is distinctive due to the application of a top and bottom external coating layer as well as to its various structural characteristics, which were proven to be essential to lead to a constant release profile. The elongated shape of the tablet combined with the presence of a top and bottom coating layer permit to limit the dissolution of the enclosed pharmaceutically active agent from those particular surfaces. Because of those characteristics, dissolution is limited to the periphery of the tablet, inducing two favorable consequences. First, the delivery of the enclosed agent is less aggressive, the liberation originating from the periphery only whether than from the whole surface. Secondly, this characteristic permits an easier modulation of the pharmaceutically active agent's release rate: alteration of the shape and structure of the release layer induces direct consequences on dissolution. Those two factors significantly contributed in achieving the invention's objective and allowed the identification of an interesting configuration for the production of the tablets: a construction of an elongated geometry, being either oblong, rectangular or of any acceptable shape, with a length being at least two to three times more important that its width. This feature has the benefit of maintaining the exposition of the surface area to the dissolution medium constant throughout the whole dissolution process, as illustrated in Fig. 3a and in Fig. 3b. This is completely different from the situation encountered with round shaped tablet which exposed surface area decreases with time, as illustrated in Fig. 1.

[00100] The core material of the body comprises at least one pharmaceutically active agent and at least one pharmaceutically acceptable carrier such as a hydrophilic, water-soluble, polymeric carrier to facilitate the diffusion of the agent in the environment. A new and improved system for drug dissolution could especially be of interest for pharmaceutically active agents that are to be gradually diffused in the body through important laps of time. As already described, the pharmaceutically active agent is dispersed in at least one pharmaceutically acceptable carrier such as a hydrophilic, polymeric carrier which is water-soluble at body temperature, and is selected from the list already depicted. The combination of the active ingredient and the pharmaceutically acceptable carrier fill the centered layer of the tablet and will gradually diffuse from the periphery of the construction, as previously established, when introduced in the selected environment. Moreover, it is to be noted that the structure can be produced either with only one layer of a unique type of active ingredient or either with a multitude of layers of various compounds, each mixed with an identical or with a different hydrophilic, water- soluble, polymeric carrier.

[00101] Since the size and form of the releasing layer have major impacts on the dissolution rate of the loaded pharmaceutically active agent, those elements were used to develop the tablet of the present invention. In fact, since the top and bottom surface of the release layer are covered with a coating layer, diffusion is effected through the periphery of the tablet only. More precisely, the diffusing surface is limited to the surface of the centered release layer that is in contact with the surrounding medium, which consists in its periphery only. Therefore, if the size of the release layer varies as the diffusion front moves forward laterally in the tablet, the diffusion rate of the withheld pharmaceutically active agent will be proportionally influenced. The present invention distinguishes itself from the prior art mainly because the release layer exposed to dissolution medium remains of practically constant area with time. Such a feature prevents any variation in the diffusion rate of the pharmaceutically active agent, therefore allowing a constant delivery in the surrounding environment. [00102] The core of the tablet is coated with a top and bottom layer made either of a hydrophobic, water-insoluble material or of a very slowly soluble material in comparison to the solubility of the material of the core, in order to avoid influencing in any way the core release from the periphery. Such material can be chosen from one of the polymers lists already displayed. The material prevents the combined internal pharmaceutically acceptable carrier and pharmaceutically active agent to dissolve in the surrounding environment through the top and bottom surface of the oral dosage form. Therefore, the peripheral surface constitutes the only opening allowing diffusion, either from the surrounding exterior face of the compound or from the centered hole if there is one. Such coating is indispensable since it makes the linear diffusion rate of the withheld agent possible.

[00103] More precisely, in vitro dissolution was performed using USP type 1 (basket) dissolution apparatus, at 37°C, and 75 RPM. The dissolution medium was pH 6.8 USP phosphate buffer, unless indicated otherwise. Quantification of drug released in dissolution medium was performed by UV detection at the appropriate wavelength, by pumping dissolution medium through a UV spectrophotometer at suitable intervals. Each dissolution curve is the results of at least three replicates tablets. The dissolution data were fitted using the empirical formulation proposed by Korsmeyer and Peppas:

= log k+ n^*logt (1)

where M_t/ M∞ is the factional drug release at time t, k a kinetics constant, and n the release exponent. The release exponent n characterizes the release mechanism, where 0.89 < n >1.0 indicates a zero order release. Values of n for release profiles were obtained by performing a linear regression on the log transformed dissolution data following the logarithmic form of equation 1 , using dissolution data between at least 20% to 90% of drug release. The value of k and n were then used to generate the fitted curve which was reproduced alongside the actual dissolution curve, in order to evaluate visually the real dissolution profile and the fitted curve from equation 1.

EXAMPLE 1

[00104] Preparation and comparison of the release profiles of rectangular and round trilaver tablets and uncoated cores made with flat face tooling. Blends of 100g each of core formulation and coating formulation listed below were prepared by first blending all ingredients for one minute in a bag, and then adding sodium stearyl fumarate lubricant, and blending for an additional minute. Rectangular shaped tablets and round tablets were prepared from these blends. Trilayer tablets as well as uncoated cores were prepared for each tablet shape.

[00105] Trilayers tablets labeled (L) 08049-2 were prepared using rectangular flat face tooling 14.8mm x 5.0mm onto a Manesty F3 press. The general method for tablet preparation is as follows. First, 125mg of coating blend was poured manually into the die, followed by slight tamping by lowering manually upper punch onto powder bed. Then, 250 mg of core blend were introduced, followed by slight tamping. Finally, 125mg of coating blend wwere introduced into the die, and a full compression cycle was carried-on in automatic mode. The compression force exerted for the final compression cycle was about 11 KN, and thickness was around 5.8mm. Core tablets labeled (L) 08048-2 were also prepared using rectangular flat face tooling 14.8mm x 5.0mm using 250mg of core blend. Compression force was also about 11 KN. Core thickness was about 2.6mm. Trilayer tablets labeled (L) 08049-1 were prepared using round flat face tooling with diameter of 10.0mm following the method described above for the trilayer rectangular tablet. Upper and lower coating layers were of 125 mg each, while the release core layer was of 250mg. Compression force was about 11 KN, and thickness was about 5.4mm. Core tablets labeled (L) 08048-1 were also prepared using round flat face tooling with diameter of 10.0mm using 250mg of core blend. Compression force was also about 11 KN. Core thickness was around 2.6mm.

[00106] Dissolution. Dissolution was performed at 37°C in USP type 1 apparatus (basket) at 75 RPM, in USP phosphate buffer at pH 6.8. Detection and quantification of glipizide was performed at 275nm, in cells with 10mm path length. The dissolution curves obtained from the different formulations are summarized in Fig. 4. The results with respect to the release exponent n are summarized in the tablet below. The n values for the different formulation show clearly that an improved release profile is obtained when cores are coated with upper and lower coating layers. Moreover, trilayer rectangular tablets release closer to zero-order, whereas trilayer round tablets deviate significantly from the range 0.89 < n >1.0 characterizing zero order release.

EXAMPLE 2 [00107] Preparation and comparison of the release profile of caplet and round trilayer tablets made with concave face tooling. Using the coating and core blends of Example 1 , trilayer tablets labeled (L) 08051-1 were prepared using caplet shaped standard concave face tooling 16.8mm x 5.6mm onto a Manesty F3 press, following the procedure and proportions of Example 1. The compression force exerted for the final compression cycle was about 11 KN, and thickness was around 5.6mm. Trilayer tablets labeled (L) 08051-2 were prepared using round standard concave face tooling with diameter of 11.2mm following the procedure and proportions of Example 1. Compression force was about 11 KN, and thickness was about 5.5mm.

[00108] Dissolution. Dissolution was performed as described in Example 1. The dissolution curves obtained are summarized in Fig. 5. The results with respect to the release exponent n are summarized in the tablet below. The n values show again that the trilayer caplet tablets prepared with concave face tooling release closer to zero-order, whereas trilayer round tablets deviate significantly from the range 0.89 < n >1.0.

EXAMPLE 3

[00109] Preparation and comparison of the release profile of caplet trilayer tablets of different dimensions. Using the coating and core blends of Example 1 , trilayer tablets labeled (L) 08051-1 were prepared using caplet shaped rectangular standard concave face tooling 16.8mm x 5.6mm as previously described in Example 2. Trilayer tablets labeled (L) 08053 were prepared using caplet shape standard concave face tooling 18.0mm x 6.0mm, using the coating and core blends of Example 1 , and following the procedures of Example 1. The mass of the coating blend use for the upper and lower external layers were 125mg. However, 260mg of core blend was used for the core. The compression force exerted for the final compression cycle was about 13KN, and thickness was around 5.0mm. Trilayer tablets labeled (L) 08054-1 were prepared using caplet shape standard concave face tooling 15.4mm x 5.1 mm, using the coating and core blends of Example 1 , and following the procedures of Example 1. The mass of the coating blend use for the upper and lower external layers were 125mg. However, 192mg of core blend were used for the core. The compression force exerted for the final compression cycle was about 9KN, and thickness was around 5.6mm.

[00110] Dissolution. Dissolution was performed as described in Example 1. The dissolution curves obtained are summarized in Fig. 6. The results with respect to the release exponent n are summarized in the tablet below. The n values show again that the trilayer caplet tablets release close to zero-order within the range of caplet dimension investigated.

EXAMPLE 4

[00111] Preparation and comparison of the release profile of caplet trilayer tablets with release core of different thickness. Using the coating and core blends of Example 1 , trilayer tablets labeled (L) 08051-1 were prepared using caplet shaped rectangular standard concave face tooling 16.8mm x 5.6mm as described previously in Example 2. Trilayer tablets labeled (L) 08061-2 are essentially similar to (L) 08051-1 , except that the mass of core blend used was 500mg instead of 250mg. The compression force exerted for the final compression cycle was about 15KN, and core layer thickness was about 5.0mm, with total tablet thickness of 7.50mm.

[00112] Dissolution. Dissolution was performed as described in Example 1. The dissolution curves obtained are summarized in Fig. 7. The results with respect to the release exponent n are summarized in the tablet below. The n values indicate that the trilayer caplet tablets release close to zero-order irrespective of the core thickness.

EXAMPLE 5

[00113] Preparation and evaluation of the release profile of of trilaver tablets with Minocycline HCI. Blends of 100g each of core formulation and coating formulation listed below were prepared by first blending all ingredients for one minute in a bag, and then adding sodium stearyl fumarate lubricant, and blending for an additional minute.

[00114] Trilayer tablets labeled (L) 08060-1 were prepared using caplet shaped rectangular standard concave face tooling 16.8mm x 5.6mm onto a Manesty F3 press, following the general procedure described in the other Examples. Coating layers weight were 125mg for each layer, and core weight was 250mg. The compression force exerted for the final compression cycle was about 11 KN, and thickness was around 5.6mm.

[00115] Dissolution. Dissolution was performed at 37°C in USP type 1 apparatus (basket) at 75RPM, in USP phosphate buffer at pH 6.8. Detection and quantification of minocycline was performed at 355nm, in cells with 10mm path length. The dissolution curve obtained is found in Fig. 8. The exponent n for the release profile was 0.90, indicating zero order release for minocycline as well.

EXAMPLE 6

[00116] Preparation and evaluation of the release profile of trilayer tablets with Cvclobenzaprine HCI. Blends of 5Og each of core formulation and coating formulation listed below were prepared by first blending all ingredients for one minute in a bag, and then adding sodium stearyl fumarate lubricant, and blending for an additional minute. Trilayers tablets labeled (L) 11-044 were prepared using caplet shaped standard concave face tooling 15.4mm x 5.1 mm following the approach described previously in Example 1. The mass of the coating blend use for the upper and lower external coating layers were 125mg, and 187.5mg of core blend was used for the releasing core. The compression force exerted for the final compression cycle was about 8KN, and thickness was around 5.8mm.

[00117] Dissolution. Dissolution was performed at 37°C in USP type 2 apparatus (paddle) at 50RPM, in USP phosphate buffer at pH 6.8. Detection and quantification of Cyclobenzaprine was performed at 290nm, in cells with 10mm path length. The dissolution curve obtained is found in Fig. 9. The exponent n for the release was 0.91 , indicating zero order release. EXAMPLE 7

[00118] Preparation and evaluation of the release profile of trilayer tablets with Cyclobenzaprine HCI. Blends of 5Og each of core formulation and coating formulation listed below were prepared by first blending all ingredients for one minute in a bag, and then adding sodium stearyl fumarate lubricant, and blending for an additional minute. Trilayer tablets labeled (L) 11-042 were prepared using caplet shaped standard concave face tooling 16.8mm x 5.6mm following the approach described previously in Example 1. The mass of the coating blend use for the upper and lower external coating layers were 150mg, and 250mg of core blend was used for the releasing core. The compression force exerted for the final compression cycle was about 10KN, and thickness was around 6.3mm.

[00119] Dissolution. Dissolution was performed at 37⁰C in USP type 2 apparatus (paddle) at 50 RPM, in USP phosphate buffer at pH 6.8. Detection and quantification of Cyclobenzaprine was performed at 290nm, in cells with 10mm path length. The dissolution curve obtained is found in Fig. 10. The exponent n for the release was 0.94, indicating zero order release. [00120] 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 continuous, controlled-release tablet with a zero-order dissolution profile for at least one pharmaceutically active agent, said tablet comprising:

a) a variable geometry for continuous, constant drug delivery;

b) at least one centered release layer comprising at least one pharmaceutically active agent, wherein said release layer has a top portion; a bottom portion; and a periphery; and said centered release layer has a constant thickness along the length of the tablet or has a zero-order dissolution profile, for dissolution of said least one pharmaceutically active agent; and

c) a top external coating layer disposed over the top portion of the centered layer and a bottom external coating layer disposed over the bottom portion of the centered layer,

whereby the top external coating layer and the bottom external coating layer limits the dissolution of said centered release layer therefrom, to the periphery thereof.

2. The tablet according to claim 1 , wherein said geometry comprises an elongated shape.

3. The tablet according to claim 2, wherein said elongated shape is chosen from oblong and rectangular.

4. The tablet according to claim 2, wherein said elongated shape has a length at least two to three times greater than its width.

5. The tablet according to any one of claims 1 to 4, wherein said the size of the tablet form ranges from a very large pharmaceutically acceptable size to a very small pharmaceutically acceptable size.

6. The tablet according to claim 1 , wherein said at least one centered release layer consists of a single layer of equal thickness along the length of the tablet or of a single layer having a zero-order dissolution profile comprising a single type of pharmaceutically active agent blended with a pharmaceutically acceptable carrier.

7. The tablet according to claim 1 , wherein said at least one centered release layer consists of multiple layers of equal thicknesses along the length of the tablet or of multiple layers having a zero-order dissolution profile, each one of said multiple layers comprising different pharmaceutically active agents and each blended with a pharmaceutically acceptable carrier.

8. The tablet according to claim 7, wherein each one of said multiple layers comprising different pharmaceutically active agents blended with the same pharmaceutically acceptable carrier.

9. The tablet according to claim 7, wherein said each one of said multiple layers comprising different pharmaceutically active agents blended with a different pharmaceutically acceptable carrier.

10. The tablet according to any one of claims 6 to 9, wherein said pharmaceutically acceptable carrier is chosen from a hydrophilic, water- swellable and/or water-erodible polymeric carrier consisting of a material chosen from crosslinked polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, hydroxyethylcellulose, crosslinked sodium carboxymethylcellulose, carboxymethyl starch, acrylic and methacrylic acid polymers and copolymers, polyesters, polyethylene glycol, polyethylene oxide, polyanhydhdes copolymers poiymethyivinylether/anhydride, potassium methacrilate- divinylbenzene copolymer, polyvinylalcohols, polyvinylpyrrolidone, glucan, scleroglucan, mannan, starchs, pregelatinised starch and other starchs derivatives, betacyclodextrins and cyclodextrins derivatives containing linear and/or branched polymeric chains and mixtures thereof.

11. The tablet according to any one of claims 6 to 9, wherein said pharmaceutically acceptable carrier is an ingredient used to adjust or modify the release characteristics of the centered layer chosen from lactose, mannitol, sucrose, sorbitol, xilitol, polyethylene glycols, polyols, low molecular weights HPMC, low molecular weights HPC, low molecular weight polyvinylpyrrolidone, ionic and non-ionic surfactants, polyoxyalkylene derivatives of propylene glycol (Pluronics™), organic acids, buffering agents, starch, fillers, lubricants, superdisintegrants, calcium carbonate, calcium phosphate, microcrystalline cellulose, hydrogenated castor oil, glyceryl palmitostearate and talc.

12. The tablet according to any one of claims 7 to 9, wherein said multiple layers of the centered release layer are each of different thicknesses.

13. The tablet according to claim 6, wherein said centered release layer consists of a single layer is disposed in a crosswise and longitudinal position at the center of the tablet.

14. The tablet according to any one of claims 7 to 9, wherein said centered release layer of multiple layers is disposed in a crosswise and longitudinal position at the center of the tablet.

15. The tablet according to claim 1 , wherein said at least one centered release layer of equal thickness along the length of the tablet or of a zero- order dissolution profile, is present in a pharmaceutically acceptable shape along the length of the construction.

16. The tablet according to claim 1 , wherein said top and bottom external coating layers are made of an insoluble material chosen from water-insoluble cellulose, such as ethylcellulose and cellulose ester, cellulose acetate- proprionate, water-insoluble polyvinylacetate, or blends of polyvinyl acetate with other material such as in Kollidon SR, water-insoluble polyacrylate such as water-insoluble acrylate polymer, water-insoluble methacrylate polymers, water-insoluble methylmethacrylate polymers, water-insoluble ethylacrylate polymers, copolymers comprising a combination of a preceding water- insoluble polyacrylate, a quaternary ammonium functional group containing derivative of the preceding polymers and copolymers, copolymers based on acrylic and methacrylic acid esters such as Eudragit NEm RS, RS30D, RL, or RL30D.

17. The tablet according to claim 1 , wherein said top and bottom external coating layers are made of a material that is highly less water-soluble than the material of the central layer.

18. The tablet according to claim 16 or 17, wherein said top and bottom external coating layers are of identical composition.

19. The tablet according to claim 1 , wherein said pharmaceutically active agent is chosen from peptidomimetics, peptides, proteins, toxoids, antibodies, nucleosides, nucleotides, nucleic acids, polysaccharides, analgesics and antiinflammatory agents, anthelmintics, anti-arrhythmic agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anti-coagulants, antidepressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, anti-malarials, anti-migraine agents, anti- muscarinic agents, anti-neoplastic agents and immunosuppressants, antiprotozoal agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics and neuroleptics, β-blockers, cardiac inotropic agents, diuretics, antiparkinsonian agents, gastrointestinal agents, histamine H,-receptor antagonists, keratolyses, lipid regulating agents, muscle relaxants, antianginal agents, nutritional agents, analgesics, sex hormones, stimulants, and cytokines.

20. The tablet according to claim 1 or 19, wherein said pharmaceutically active agent is chosen from salbutamol, labetalol, sumatriptan, ondansetron, cyclobenzaprine, dantrolene sodium, methocarbamol, metaxalone, carisoprodol, orphenadrine citrate, baclofen, chlorophenesin carbamate, chlorzoxazone, mephenesin, diazepam, nitrazepam, flurazepam, oxazepam, chlordiazepoxide, medazepam, lorazepam, ibuprofen, naproxen, naproxen sodium, flurbiprofen, fenoprofen, fenbufen, ketoprofen, ketoprofen, pirprofen, carpofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, ndomethacin, sulindac, tolmetin, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazae, clidanac, oxepinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, CP-14,304, 2,3,4,5- tetrahydro-5-methyl-2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1 H- pyrodo[4,3b]indol-1 -one, (+)-1 ,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1 H- imidazol-4-yl)methyl]-4H-carbozol-4-one, 6-fluoro2,3,4,5-tetrahydro-5, methyl- 2-[(5-methy!-1 H-imidazol-4-yl)methyl]-1 H-pyrido[4,3-b]indol-1 -one and a pharmaceutical acceptable salt, solvate and derivative thereof.

21. The tablet according to claim 20, wherein said pharmaceutically active agent is ranitidine or a pharmaceutically acceptable salt thereof.

22. The tablet according to claim 1 , wherein said at least one centered release layer comprises two or more layers for the dissolution of two or more active agents.

23. The tablet according to claim 1 , which is film-coated.

24. The tablet according to claim 23, wherein said film-coating is for esthetic purposes.

25. The tablet according to claim 23, wherein said film-coating modifies the release properties of the tablet.

26. The tablet according to claim 23, wherein said film-coating is soluble upon ingestion.

27. The tablet according to claim 23, wherein said film-coating is soluble in the dissolution medium.

28. The tablet according to claim 23, wherein said film-coating is insoluble.

29. The tablet according to claim 23, wherein said film-coating is insoluble in the dissolution medium.

30. The tablet according to claim 23, wherein said film-coating is soluble depending on the pH of the dissolution medium.

31. The tablet according to claim 23, wherein said film-coating is soluble in acidic conditions.

32. The tablet according to claim 23, wherein said film-coating is soluble in basic conditions.

33. The tablet according to claim 23, wherein said film-coating is soluble specifically in certain parts of the gastro-intestinal tract.

34. The tablet according to claim 33, wherein said film-coating is soluble in the colon.

35. A continuous, controlled-release tablet comprising at least one centered release layer, wherein said release layer is of equal thickness along the length of the tablet or has a zero-order dissolution profile, for dissolution of at least one pharmaceutically active agent, and whereby dissolution of said centered release layer is peripheral.

36. A method for making said tablet of claim 1 , said method comprising preparing one or more blend of a pharmaceutically active agent and a pharmaceutically acceptable carrier in an appropriate manner to form a mix for the at least one centered release layer, preparing a second blend of a material in an appropriate manner to form a mix for the coating layers, compressing the blends for the top and bottom coating layers with one or more blends for the central release layer in a die and producing a tablet out of the one or more compressed mixes.

37. The method according to claim 36, wherein said pharmaceutically active agent is chosen from peptidomimetics, peptides, proteins, toxoids, antibodies, nucleosides, nucleotides, nucleic acids, polysaccharides, analgesics and anti-inflammatory agents, anthelmintics, anti-arrhythmic agents, anti-asthma agents, anti-bacterial agents, anti-viral agents, anticoagulants, anti-depressants, anti-diabetics, anti-epileptics, anti-fungal agents, anti-gout agents, anti-hypertensive agents, antimalarials, antimigraine agents, anti-muscarinic agents, anti-neoplastic agents and immunosuppressants, anti-protozoal agents, anti-thyroid agents, anti-tussives, anxiolytic, sedatives, hypnotics and neuroleptics, β-blockers, cardiac inotropic agents, diuretics, anti-parkinsonian agents, gastrointestinal agents, histamine H, -receptor antagonists, keratolyses, lipid regulating agents, muscle relaxants, anti-anginal agents, nutritional agents, analgesics, sex hormones, stimulants, and cytokines.

38. The method according to claim 37, wherein said pharmaceutically active agent is chosen from salbutamol, labetalol, sumatriptan, ondansetron, cyclobenzaprine, dantrolene sodium, methocarbamol, metaxalone, carisoprodol, orphenadrine citrate, baclofen, chlorophenesin carbamate, chlorzoxazone, mephenesin, diazepam, nitrazepam, flurazepam, oxazepam, chlordiazepoxide, medazepam, lorazepam, ibuprofen, naproxen, naproxen sodium, flurbiprofen, fenoprofen, fenbufen, ketoprofen, ketoprofen, pirprofen, carpofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, bucloxic acid, ndomethacin, sulindac, tolmetin, diclofenac, fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxepinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, sudoxicam, isoxicam, CP-14,304, 2,3,4,5- tetrahydro-5-methyl-2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1 H- pyrodo[4,3b]indol-1-one, (+)-1 ,2,3,9-tetrahydro-9-methyl-3-[(5-methyl-1 H- imidazol-4-yl)methyl]-4H-carbozol-4-one, 6-fluoro2,3,4,5-tetrahydro-5, methyl- 2-[(5-methyl-1 H-imidazol-4-yl)methyl]-1 H-pyrido[4,3-b]indol-1 -one and a pharmaceutical acceptable salt, solvate and derivatives thereof.

39. The method according to claim 37, wherein said pharmaceutically acceptable carrier is a hydrophilic, water-insoluble, polymeric carrier chosen from hydroxypropyl methycellulose (HPMC), methylcellulose, hydroxypropylcellulose (HPC), hydroxyethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, polyethylene glycol, polyethylene oxide, polyvinyl alcohols, pregelatinised starch and mixtures thereof.

40. The method according to claim 37, wherein said pharmaceutically acceptable carrier is a carrier that is used to modulate the pharmaceutically active agent release and that is chosen from lactose, mannitol, sucrose, sorbitol, xilitol, polyethylene glycols, polyols, low molecular weights HPMC, low molecular weights HPC, low molecular weight polyvinylpyrrolidone, ionic and non-ionic surfactants, polyoxyalkylene derivatives of propylene glycol (Pluronics™), organic acids, buffering agents, starch, fillers, lubricants, superdisintegrants, calcium carbonate, calcium phosphate, microcrystalline cellulose, hydrogenated castor oil, glyceryl palmitostearate, talc and mixtures thereof.

41. The method according to claim 37, wherein said material is chosen from water-insoluble cellulose, such as ethylcellulose and cellulose ester, cellulose acetate-proprionate, water-insoluble polyvinylacetate, or blends of polyvinyl acetate with other material such as in Kollidon SR, water-insoluble polyacrylate such as water-insoluble acrylate polymer, water-insoluble methacrylate polymers, water-insoluble methylmethacrylate polymers, water- insoluble ethylacrylate polymers, copolymers comprising a combination of a preceding water-insoluble polyacrylate, a quaternary ammonium functional group containing derivative of the preceding polymers and copolymers, copolymers based on acrylic and methacrylic acid esters such as Eudragit NEm RS, RS30D, RL, and RL30D.

42. The method according to claim 37, wherein said material is a material that is highly less water-soluble than the material of the central layer.

43. The method according to claim 37, wherein blending the pharmaceutically active agent and the pharmaceutically acceptable carrier in an appropriate manner to form a mix is effected using an appropriate mixing device.

44. The method according to claim 37, wherein compressing one or more mixes consist of piling up one or more layers of blends of a pharmaceutically active agent and of a pharmaceutically acceptable carrier in a mold.

45. The method according to claim 37, wherein compressing one or more mixes in a die is effected using a manual or automated multilayer press.

46. The method according to claim 37, wherein said die used for compressing the mix is a die of an elongated shape.

47. The method according to claim 37, wherein said die used for compressing the mix has a length three times greater than its width and is of a size that ranges from a very large pharmaceutically acceptable size to a very small pharmaceutically acceptable size.

48. The method according to claim 37, wherein producing a tablet out of the one or more compressed mixes consists of pressing a tablet out of the mix.

49. The method according to claim 37, wherein pressing a tablet out of the mix is effected using a tablet punch.

50. The method according to claim 37, which further comprises the step of film-coating the produced tablet.

51. The method according to claim 37, wherein said film coating consists in vaporizing the produced tablet with a coating solution and drying the coating in appropriate equipments.

52. The method according to claim 37, wherein said tablet is film coated for esthetic purposes.

53. The method according to claim 50, wherein said tablet is film coated in order to modulate the pharmaceutically active agent release.

54. The method according to claim 50, wherein said film-coating is soluble upon ingestion.

55. The method according to claim 50, wherein said film-coating is soluble in the dissolution medium.

56. The method according to claim 50, wherein said film-coating is insoluble upon ingestion.

57. The method according to claim 50, wherein said film-coating is insoluble in the dissolution medium.

58. The method according to claim 50, wherein said film-coating is soluble depending on the pH of the dissolution medium.

59. The method according to claim 50, wherein said film-coating is soluble in acidic conditions.

60. The method according to claim 50, wherein said film-coating is soluble in basic conditions.

61. The method according to claim 50, wherein said film-coating is soluble depending on the position of the tablet in the gastro-intestinal tract.

62. The method according to claim 61 , wherein said film-coating is soluble in the colon.