Description
The present invention discloses a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the dosage form delays the release of the corticosteroid from the core for a period of about 2h to 10h after oral administration.

Circadian rhythms are physical, mental and behavioral changes that follow a roughly 24-hour cycle, responding primarily to light and darkness in an organism’s environment. Circadian rhythms are produced by natural factors within the body, but they are also affected by signals from the environment. Light is the main cue influencing circadian rhythms, turning on or turning off genes that control an organism’s internal clocks. Circadian rhythms can change sleep-wake cycles, hormone release, body temperature and other important bodily functions. For example, an asthmatic attack generally happens in the early morning, the stomach pH decreases during the night and in some hypertension diseases the pressure value is higher during the daytime, while a decrease occurs during the night.

The biological clocks that control circadian rhythms are groupings of interacting molecules in cells throughout the body. A “master clock” in the brain coordinates all the body clocks so that they are in synch. The master clock network is composed of the paired suprachiasmatic nuclei (SCN) that are situated in the hypothalamus and the pineal gland. This circadian clock is a combination of an input pathway (photoreceptors and projections of retinal ganglion cells), circadian pacemakers generating the circadian signal and an output pathway manifesting circadian behaviors. Circadian rhythms in gastrointestinal, liver, kidney and other bodily processes and functions are of great importance for therapeutics, for example, in choosing when to administer medications in relation to rhythm influences on their pharmacokinetics, effect-duration, efficacy, adverse effect and beneficial outcomes.

In a number of diseases involving chronic inflammation and pain, such as rheumatoid arthritis (RA), severe asthma and polymyalgia rheumatica (PMR), symptoms are linked to sufferers’ circadian fluctuations in pro-inflammatory cytokines. For example, a nocturnal rise in pro-inflammatory cytokine levels such as IL-6 is responsible for the morning stiffness associated with RA, which for some, is a disabling symptom of the disease.

Corticosteroids, such as prednisone, are used to suppress these autoimmune, inflammatory and allergic disorders by inhibiting the production of various pro-inflammatory cytokines, such as interleukin 6, or IL-6, and TNF-α. High-dose oral corticosteroid treatment is not a viable long-term treatment option due to side effects including, among others, osteoporosis, cardiovascular disease and weight gain. However, clinical studies have shown that the long-term use of low-dose prednisone does not dramatically increase total adverse events. In addition, low-doses, typically less than 10 mg daily, of corticosteroids such as prednisone have been shown to treat the symptoms of RA while slowing the overall progression of the disease.

Prednisone is a corticosteroid, more specifically a glucocorticoid. Glucocorticoids are adrenocortical steroids, both naturally occurring and synthetic, which are readily absorbed from the gastrointestinal tract. The chemical name for prednisone is pregna-1,4-diene-3,11, 20-trione, 17, 21-dihydroxy.

Prednisone is marketed under the brand name of Lodotra®, which is developed utilizing SkyePharma’s proprietary GeoClock™ and GeoMatrix™ technologies. Lodotra® is a proprietary programmed release formulation of low-dose prednisone, a well-established drug used to inhibit the production of various pro-inflammatory cytokines which are proteins associated with joint inflammation in RA. By synchronizing the prednisone delivery time with the patient’s elevated cytokine levels in the early morning hours, Lodotra exerts its effect at a physiologically optimal point to inhibit cytokine production and thus significantly reduce the signs and symptoms of RA.

To fulfill the specific therapeutic needs of such diseases, which depend on circadian rhythmicity, new drug delivery systems are required for the time-programmed administration of the active ingredients. Such dosage forms should release the drug both at the rate and time, which is in sync with the circardian rhythm. For example, the assumption in the evening of a dosage form able to start releasing the dose some hours after ingestion at a proper rate could be a suitable therapeutic regimen for all diseases, which show a night symptomatic recrudescence.

Various attempts have been made by several researchers for development of a delivery system modifying the release of the active ingredient providing desired therapeutic effect to overcome the symptoms that are linked to circadian fluctuations and achieve better patient compliance.

Recently various chronopharmaceutical technologies have emerged, such as, Oros® Technology, Ceform® Technology, Contin® Technology, Diffucaps® Technology, Chronotopic® Technology, Egalet® Technology, Codas® Technology, GeoClock® Technology, Port® Technology, Three Dimensional Printing® (3DP) Technology, TimeRx® Technology, Chronomodulated infusion pump and Controlled Release Microchip.

There are various approaches to obtain programmed release of the corticosteroid from a dosage form. Some approaches involve use of coating of multiparticulate active ingredients with polymethacrylate polymers, use of multiple layer tablets, press coating, use of various rate controlling polymers, etc.

Inorganic salt of calcium ion is available as Emcompress® (Edward mendell, USA), A Tab® (Rhodia, USA), Di Tab® (Rhodia, USA), Fujicalin® (Fuji Chemical Industry, Japan), Calstar (FMC Biopolymer) which contains dicalcium phosphate; Tricalcium phosphate is available as Tri Tab® (Rhodia, USA); Calcium sulphate is available as Delaflo® (JWS Delavau, USA); Calcium lactate pentahydrate is available as Puracal DC® (Purac, USA); Calcium lactate trihydrate is available as Puracal TP® (Purac, USA).

Dicalcium phosphate also known as calcium hydrogen orthophosphate dihydrate; calcium monohydrogen phosphate dihydrate; Di-Cafos; dicalcium orthophosphate; DI-TAB; E341; Emcompress; phosphoric acid calcium salt (1:1) dihydrate; secondary calcium phosphate. Dicalcium phosphate is the most common inorganic salt used in direct compression as a filler-binder. The milled material is typically used in wet-granulated, roller-compacted or slugged formulations. The ‘unmilled’ or coarse-grade material is typically used in direct-compression formulations. Dibasic calcium phosphate dihydrate is nonhygroscopic and stable at room temperature. However, under certain conditions of temperature and humidity, it can lose water of crystallization below 1000C. This has implications for certain types of packaging and aqueous film coating since the loss of water of crystallization appears to be initiated by high humidity and by implication high moisture vapor concentrations in the vicinity of the dibasic calcium phosphate dihydrate particles. However, dibasic calcium phosphate dihydrate is abrasive and a lubricant is required for tableting. Water of crystallization of dicalcium phosphate dihydrate could possible be released during processing and thus chemically interact with hydrolysable drug.

It is also well known that, dicalcium phosphate is insoluble and very abrasive, which generally leds to reduced tooling life due to wear on the equipment during tablet manufacture. High levels of lubricants are required to overcome the abrasiveness, but elevated levels of hydrophobic lubricants can impact the mechanical strength of the tablets and disintegration/dissolution performance. Further, due to the propensity of dicalcium phosphate towards brittleness, it tend to exhibit failure in a plane normal to the compaction axis, i.e. experience tablet capping and lamination phenomena.

Properties of dicalcium phosphate has been modulated by the use of glyceryl behenate. Such modified dicalcium phosphate has been used as an excipients in immediate and non-immediate release dosage forms. Use of these excipients in coating composition has not been explored.

Glyceryl dibehenate is a mixture of glycerol esters. It is also known as Compritol 888 ATO; 2,3-dihydroxypropyl docosanoate; docosanoic acid, 2,3-dihydroxypropyl ester; E471; glycerol behenate; glyceroli dibehenas; glyceryl monobehenate. It is a mixture of diacylglycerols, mainly dibehenoylglycerol, together with variable quantities of mono- and triacylglycerols.

Glyceryl behenate is used in cosmetics, foods, and oral pharmaceutical formulations. In pharmaceutical formulations, glyceryl behenate is mainly used as a lubricant in the preparation of oral tablets and capsules. It has also been investigated for use in the preparation of sustained-release tablets; as a matrix-forming agent for the controlled release of water-soluble drugs; and it can also be used as a hot-melt coating agent sprayed onto a powder or drug-loaded sugar beads and granules. It may also be incorporated via extrusion/spheronization into pellets, which can be further compressed into tablets.

One of the major problem associated with programmed release press-coated tablet is that they suffer from the disadvantages that sometimes neither the minimum quantity of active substance is released therefrom "in vitro" after fixed intervals (programmed-release profile with indication of the minimum amount to be released at fixed intervals), nor are they are immune to the influence and possible variations of the preparation during the aging or storage thereof (stability of the programmed-release rate of the preparation over time). Moreover, lag phase in most of the programmed release formulations is dependent on geometry of dosage form such as tablet geometry or presence of weak points in the tablet. This leads to uneven rupture of the coating, thus leading to variation in drug release. Undesired batch to batch variation in release of active ingredient is common with such type of dosage form. Prior art also discloses that the core should be correctly located within the coating to ensure that a tablet has an appropriate coating thickness. The coating thickness of the tablet directly affects the lag time. Thus improper positioning of the core will lead to intra-subject and inter-subject variance in bioavailability.

Though, there are various techniques known in the art for preparing a programmed release dosage form of various corticosteroids employing different polymeric excipients, still a need exists for a dosage form which is independent of the geometry of the tablet, free from lag phase variation and provides release of corticosteroid at a fixed duration. Further, such programmed release dosage form should have minimal variation.

U.S. Patent No. 7,364,755 discloses a modified calcium phosphate excipient with a fatty acid wax in a weight ratio of 50:50 to 95:5. The patent discloses use of excipient for formulating immediate and non-immediate release formulation, which can be further coated.

U.S. Patent No. 7,776,358 discloses an extended release coated tablet comprising a tablet core, which comprises at least 70% venlafaxine besylate; and a coating over said tablet core which comprises an ammonio methacrylate copolymer component, wherein said coating is in an amount within the range of 3% to 25% of the weight of said tablet core.

U.S. Patent Application No. 20050048118 discloses an modified release tablet having a core, which comprises a lipophilic matrix and an effective amount of venlafaxine hydrochloride; and a water insoluble, permeable coating over said core.

PCT Patent Application No. 2005013953, discloses an extended release tablet wherein the matrix material is co-processed with calcium phosphate and fatty acid wax having a ratio within the range of 85: 15 to 65: 35, respectively.

U.S. Patent No. 5,422,123 discloses tablets with zero order controlled-rate of release of the active substances, consisting of a core of defined geometrical form containing the active substance, polymer substances which swell on contact with aqueous liquids and polymer substances with gelling properties, and a support applied to said core to partly cover its surface, the support consisting of polymer substances which are slowly soluble and/or slowly gellable in aqueous liquids, plasticizing substances, and possibly substances with an adjuvant function.

U.S. Patent No. 4,839,177 discloses a system for the controlled-rate release of active substances, consisting of a deposit-core comprising the active substance and having defined geometric form and a support-platform applied to said deposit-core. Said deposit-core contains, mixed with the active substance, a polymeric material having a high degree of swelling on contact with water or aqueous liquids, a gellable polymeric material, said polymeric materials being replaceable by a single polymeric material having both swelling and gelling properties, and other adjuvants able to provide the mixture with suitable characteristics for its compression and for its intake of water.

U.S. Patent Application No. 20060057200 (‘200) discloses a pharmaceutical dosage form with site and time-controlled gastrointestinal release of active ingredient. The application discloses tablet composition wherein the ratio of the thickness of the press coating on the sides of the tablet to the upper side or lower side is preferably about 2.2-2.6mm (for side edges): about 1.2-1.6mm for the upper side and about 1.0-1.4 mm for lower side of the tablet. The ‘200 application discloses the use of glyceryl behenate, calcium phosphate and povidone in coating composition, by using wet granulation process, for delaying the release of active substance.

U.S. Patent Application No. 20070110807 (‘807) discloses a press-coated tablet comprising a core containing an drug substance, and a coating, the core being disposed within the coating such that the coating has a first thickness about an axis A-B and a thickness about an orthogonal axis X-Y, such that the coating about the axis X-Y is thicker than the coating about the axis A-B, to provide a lag time of between about 2 to 6 hours. The ‘807 application discloses the use of glyceryl behenate, calcium phosphate and povidone in coating composition, by using wet granulation process, for delaying the release of active substance.

U.S. Patent Application No. 20100196427 (‘427) discloses a method for treatment of a patient suffering from rheumatoid arthritis by administering a delayed-release dosage form of a glucocorticoid to a subject in need thereof. The release of the active substance is delayed for a time period of 2-10h after intake, preferably 2-6h, more preferably 3-5h. The ‘427 application disclose the use of glyceryl behenate, calcium phosphate and povidone in coating composition, by using wet granulation process, for delaying the release of active substance.

U.S. Patent Application No. 20100222312 (‘312) and PCT Publication No. 2010084188 disclose a method for treatment of asthma by administering a delayed-release dosage form of a glucocorticoid to a subject in need thereof. The release of the active substance is delayed for a time period of 2-10h after intake, preferably 2-6h, more preferably 3-5h. The release of the active substance is delayed for a time period of 2-10h after intake, preferably 2-6h, more preferably 3-5h. The ‘427 application disclose the use of glyceryl behenate, calcium phosphate and povidone in coating composition, by using wet granulation process, for delaying the release of active substance.

U.S. Patent Nos. 6,488,960 and 6,677,326 discloses a controlled release unit dose formulation comprising 0.25 to 2 mg of a corticosteroid. This small dose can be used to treat rheumatoid arthritis, especially if adapted to release at least 90% by weight of the corticosteroid, 2 to 8 hours after administration. The patents does not disclose the use of co-procesed glyceryl behenate and calcium phosphate in coating composition, for delaying the release of active substance.

U.S. Patent No. 5,464,633 discloses a tablet for oral administration suitable to release the active substance after a definite period of time, consisting essentially of, a core containing the active substance to be released in the gastric or intestinal tract, a polymeric substance which swells and/or gels and/or erodes on contact with water or aqueous liquids, a layer applied externally to said core by a compression process said layer being suitable to allow the release of the active substance contained in the core after a definite period of time i.e, after 2 to 3 hours.

U.S. Patent No. 5,279,832 and European Patent No. 0495349 discloses a delayed release dosage form with a core, which contains the active substance and a coating. The coating has selected areas which are thinner than the average thickness of the coating and/or areas which are predetermined rupture sites.

U.S. Patent No. 6,365,185 discloses a osmotic drug delivery system, which delivers the active agent in a substantially constant effective dose for the duration of the transit through the stomach and small intestine, followed by accelerated release when reaching the large intestine.

U.S. Patent No. 5,792,476 discloses a pharmaceutical composition for peroral treatment of rheumatoid arthritis and a treatment method therefor are described, wherein said composition comprises 2.5-7 mg of a glucocorticoid as active substance with a regulated sustained release such that at least 90% by weight of the glucocorticoid is released during a period of about 40-80 min, starting about 1-3 h after the entry of said glucocorticoid into the small intestine of a mammal.

U.S. Patent No. RE39,239 discloses methods of treating early morning pathologies using a time-specific controlled release dosage formulation which comprises a core including the pharmaceutically active agent effective for the treatment of the early morning pathology, and a swellable polymeric coating layer substantially surrounding the core.

U.S. Patent Nos. 6,372,254 and 6,730,321 discloses a press coated, pulsatile drug delivery system having an immediate-release compartment, which contains a compressed blend of an active agent and one or more polymers, substantially enveloped by an extended-release compartment, which contains a compressed blend of the active agent and hydrophilic and hydrophobic polymers.

U.S. Patent Application No. 20070243253 disclose a delayed release drug formulation comprising a particle with a core and a coating for the core, the core comprising a drug and the coating comprising a mixture of a first material which is susceptible to attack by colonic bacteria and a second material which has a pH threshold at about pH 5 or above, wherein the first material comprises at least one polysaccharide.

The present inventors, while trying to develop press coated tablets, surprisingly found that, by modifying the geometry of the press coated tablets which comprises of a core and a coating comprising inorganic salts of calcium ions co-processed with glyceryl behenate, is press coated on the core such that the thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, delays the release of the active substances from the core for a period of about 2h to 10h. When this press coated tablet is exposed into aqueous media, the coating ruptures into two equal halves after a fixed time interval, thus releasing the corticosteroid contained in the core. The lag phase in the release of the corticosteroid from the core can be modulated by changing the ratio of glyceryl behenate to inorganic salts of calcium ions in the coating composition. To exemplify few, the present inventors found that when glyceryl behenate and dicalcium phosphate were co-processed in a ratio of 30:70, with 1.5mm thickness around the horizontal edge of the core and 1.75mm thickness around the vertical edge of the core, a lag phase of about 4h to 5h was observed. Further, when glyceryl behenate and dicalcium phosphate were co-processed in a ratio of 50:50, with 1.5mm thickness around both, the horizontal edge and the vertical edge of the core, a lag phase of about 9h to 10h was observed. Present inventors have thus surprisingly discovered that such a coating composition has reduced the batch to batch variation, variations of the formulation during the aging or storage thereof, and provides a consistent lag time with minimal variation. Further, the press coated tablets did not required specialized tooling for preparation.

Thus, the present inventors have now developed a programmed release press coated tablets comprising one or more corticosteroid, which helps to control initial burst release of the corticosteroid and achieves desirable dissolution profile and consistent release pattern after a lag phase of about 2 to about 10h hours.

The term “dosage form” as used herein refers to a pharmaceutical preparation in which dose or doses of one or more therapeutically active ingredients are included. It may be in form of a tablet, tablet in tablet, trilayer tablet, in-lay tablet, coated pellets, multiple unit pellet system, granules, particles or combinations thereof.

In the present invention, “coating thickness around the vertical edges of the core” of the tablet is used interchangbly with “length”. The term “length” of the tablet refers to the thickness of the tablet, or the sides which comes in contact with the upper and lower punch.

In the present invention, “coating thickness around the horizontal edges of the core” of the tablet is used interchangbly with “width”. The term “width” refers to diameter of the tablet, or the edges which are in contact to die while copmression.

The term “Programmed release” as used herein refers to the release of drug after a certain lag phase. The drug relase may be monophasic or biphasic. The site of the release may be programmed too.

“Modified release dosage forms” as used herein is defined (e.g. as by the United States Pharmacopoeia “USP”) as those whose drug release characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional immediate release dosage forms. The USP considers that the terms controlled release, prolonged release and sustained release are interchangeable. Accordingly, the terms “modified-release”, controlled-release”, “control-releasing”, “rate-controlled release”, “extended release”, “prolonged-release”, and “sustained-release” are used interchangeably herein, For the discussion herein, the definition of the term “modified-release” encompasses the scope of the definitions for the terms “extended release”, “enhanced-absorption”, “controlled release”, “sustained release” and “delayed release”.

The term “delayed release” is defined as any formulation, wherein the release of the drug is delayed for certain period of time. Conventional art known examples of such delayed release systems may include, but are not limited to timed-release tablets and capsules and enteric-coated tablets and beads.

“Lag time” is the time to disintegrate the tablet and to release the drug after administration of the programmed release press coated tablets.

The term “Co-processing” as used herein refers to a combination of two or more excipients by an appropriate process, which involves but is not limited to wet granulation, melt granulation, etc.

The terms “pore former”, “pore forming agent”, and “pore forming additive” as used herein are used interchangeably in this application, and are defined to mean an excipient that can be added to a coating, wherein upon exposure to fluids in the environment of use, the pore former dissolves or leaches from the coating to form pores, channels or paths in the coating, that can fill with the environmental fluid and allow the fluid to enter the core and cause core to disintegrate leading to open up of the coating in two halves, and modify the release characteristics of the formulation. The pore formers can be inorganic or organic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.

The term “bioavailable” as used herein, includes, but is not limited to the rate and extent to which the drug(s) become bioavailable to the site of action after administration.

The term "Cmax " is the highest plasma concentration of the drug attained within the dosing interval.

The term "Tmax " is the time period, which elapses after administration of the dosage form at which the plasma concentration of the drug attains the highest plasma concentration of drug attained within the dosing interval.

The term "AUC0-t " as used herein, means area under plasma concentration-time curve from drug administration to last observed concentration at time t.

The term "AUC0-a" as used herein, means area under the plasma concentration-time curve extrapolated to infinite time.

The term "mean", when preceding a pharmacokinetic value (e.g. mean Tmax) represents the mean value of the pharmacokinetic value taken from a population of patients or healthy volunteers.

In one general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the dosage form delays the release of the corticosteroid from the core for a period of about 2h to 10h after oral administration.

In another general aspect of the invention, there is provided a method for delaying the release of one or more corticosteroid from the core for a period of about 2h to 10h, wherein the method comprise applying the coating composition to the core; wherein the coating composition comprises glyceryl behenate co-processed with one or more inorganic salts of calcium ion.

In another general aspect of the invention, there is provided a coating composition for delaying the release of one or more corticosteroid from the core for a period of about 2h to 10h; wherein the coating composition comprises glyceryl behenate co-processed with one or more inorganic salts of calcium ion optionally along with one or more pharmaceutically acceptable excipients.

The core is composed of either an immediate release or controlled release pharmaceutical composition consisting of the active ingredient in admixture with suitable excipients. If necessary, the core can be protected by a water-soluble or water-insoluble film before coating with the coating composition. The core may be prepared by various techniques known in the art such as direct compression, dry granulation, melt granulation, wet granulation.

Typically a core may contain 0.1 to 90% by weight of corticosteroid.

Coating is prepared by co-processing glyceryl behenate and dicalcium phosphate with one or more pharmaceutically acceptable excipients. The coating may be polymeric film and/or compression coating.

The tablets may also be compressed in the form of two or more layer tablet or press-coated in the form of tab-in-tab or tab-in-tab-in-tab.The penetration of aqueous fluid takes place through pores formed due to solubilization of the pore forming agent. For the purpose of present invention, pore forming agent include one or more inorganic salts of calcium ion.

Inorganic salts of calcium ion comprises but not limited to calcium phosphate, calcium phosphate dihydrate, calcium phosphate anhydrous, dibasic calcium phosphate, dibasic calcium phosphate monohydrate, dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate, monobasic calcium phosphate, tribasic calcium phosphate, calcium acetate, calcium carbonate, calcium chloride, calcium hydroxide, calcium pyrophosphate, calcium sulfate, calcium sulfate anhydrous, calcium sulfate dihydrate, or calcium sulfate hemihydrate.

In another general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein inorganic salt of of calcium ion is calcium phosphate dihydrate or dibasic calcium phosphate dihydrate.

In another general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the one or more inorganic salts of calcium ion are melt granulated with glyceryl behenate.

In another general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the co-processed mixture of glyceryl behenate and inorganic salts of calcium ion is in the ratio of 10:90 to 90:10.

In another general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the co-processed mixture of glyceryl behenate and inorganic salts of calcium ion is in the ratio of 15:85 to 55:45.

In another general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the coating may be applied as a film coating, spray coat, multiple layer compression coating or as press coating.

In another general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein coating composition further comprises hydrophilic or hydrophobic polymer.
The coating composition of the present invention may further comprises one or more hydrophilic polymer, hydrophobic polymer or non-polymeric rate controlling excipients.

Hydrophillic polymers is selected from the group consisting of one or more of cellulose derivatives; polyhydric alcohols; saccharides, gums and derivatives thereof; vinyl derivatives, polymers, copolymers or mixtures thereof; maleic acid copolymers; polyalkylene oxides or copolymers thereof; acrylic acid polymers and acrylic acid derivatives; or any combinations thereof.

Cellulose derivatives include, but are not limited to, ethyl cellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl ethylcellulose, carboxymethylethyl cellulose, carboxy- ethylcellulose, carboxymethyl hydroxyethylcellulose, hydroxyethylmethyl carboxymethyl cellulose, hydroxyethyl methyl cellulose, carboxymethyl cellulose (CMC), methylhydroxyethyl cellulose, methylhydroxypropyl cellulose, carboxymethyl sulfoethyl cellulose, sodium carboxymethyl cellulose, or combinations thereof.

Polyhydric alcohols include, but are not limited to, polyethylene glycol (PEG) or polypropylene glycol; or any combinations thereof.

Saccharides, gums and their derivatives include, but are not limited to, dextrin, polydextrin, dextran, pectin and pectin derivatives, alginic acid, sodium alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin, CMC agar; guar gum, locust bean gum, xanthan gum, karaya gum, tragacanth, carrageenan, acacia gum, arabic gum or gellan gum or the like; or any combinations thereof.

Vinyl derivatives, polymers, copolymers or mixtures thereof include, but are not limited to, polyvinyl acetate, polyvinyl alcohol, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (Kollidon SR), copolymers of vinyl pyrrolidone, vinyl acetate copolymers, polyvinylpyrrolidone (PVP); or combinations thereof.

Polyalkylene oxides or copolymers thereof include, but are not limited to, polyethylene oxide, polypropylene oxide, poly (oxyethylene)-poly (oxypropylene) block copolymers (poloxamers) or combinations thereof.

Maleic acid copolymers include, but are not limited to, vinylacetate maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutyiether maleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate, styrene maleic acid anhydride copolymer or the like or any combinations thereof.

Suitable acrylic acid polymers include any suitable polyacrylic acid polymers or carboxyvinyl polymers such as those available under the brand name carbopol. Pharmaceutically acceptable acrylic polymer may be include one or more, but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate.

Hydrophobic polymer is selected from waxes, which are esters of fatty acids with long chain monohydric alcohols natural waxes are often mixtures of such esters, and may also contain hydrocarbons Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes, paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes Specific examples include, but are not limited to spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilla wax, castor wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, or mixtures thereof.

Waxes are also monoglyceryl esters, diglyceryl esters, or; glyceryl esters (glycerides) and derivatives and mixtures thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol are substituted by a fatty acid. Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyhstate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate (compritol), polyglyceryl diisostearate, lauroyl macrogolglycerides (Gelucire), oleoyl macrogolglycerides, stearoyl macrogolglycerides, mixtures of monoglycerides and diglycerides of oleic acid (Peceol), or combinations thereof.

Fatty acids include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil (Lubritab), hydrogenated cottonseed oil, and mixtures thereof. Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, or the like, or mixtures thereof.

Non-polymeric rate controlling excipients are selected from the group consisting of fat, wax, fatty acid, fatty acid ester, long chain monohydric alcohol or their ester or any combinations thereof.

In another general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the ratio of width of the tablet to the length of the tablet is less than the ratio of 1.33:1.

For the purpose of present invention, the programmed release press coated tablet of present invention further comprise one or more pharmaceutically acceptable excipient selected from the group consisting of diluents, fillers, binders, disintegrant, lubricants, glidants and colorant.

Examples of suitable diluents include but are not limited to one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, or metal carbonate.

Examples of suitable binders include, but are not limited to, starch, gums, pregelatinized starch, polyvinyl prrolidone (PVP), copovidone, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts.

Suitable lubricants include but are not limited to one or more talc, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oils, stearic acid, sodium stearyl fumarate, talc and sodium benzoate.

Compositions of the present invention may include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.

Suitable disintegrant may include but are not limited to one or more of starch, croscarmellose sodium, crospovidone, and sodium starch glycolate.

Moreover, the composition of the invention optionally include usual auxiliaries known in the art such as saliva stimulating agents like citric acid, lactic acid, malic acid, succinic acid, ascorbic acid, adipic acid, fumaric acid, tartaric acids; cooling sensation agents like maltitol, monomenthyl succinate, ultracool; stabilizers like gums, agar; taste masking agents like acrylic polymers, copolymers of acrylates, celluloses, resins; coloring agents like titanium dioxide, natural food colors, dyes suitable for food, drug and cosmetic applications; preservatives like alpha-tocopherol, citric acid, butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, fumaric acid, malic acid, sodium ascorbate or ascorbic acid palmitate or effervescing agents like citric acid, tartaric acid, sodium bicarbonate, sodium carbonate and the like.

In another general aspect of the invention, the programmed release press coated tablet of the present invention is in form of tablet, tablet in tablet, bilayer tablet, trilayer tablet, in-lay tablet, coated pellets, multiple unit pellet system, or combinations thereof.

The shape of the dosage form may be square, rectangular, circular, oval, donut, cylindrical, pentagonal, hexagonal, heptagonal, octagonal, pillowed shaped or a centrally notched round tablet.

One or more corticosteroids in the programmed release press-coated tablet of the present are selected from the group consisting of prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, budesonide, dexamethasone, fludrocortisone, fluocortolone, cloprednole, deflazacort and triamcinolone.

In another general aspect of the invention, there is provided a programmed release press-coated tablet, comprising of prednisone optionally with one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and a coating surrounding the said core comprising one or more inorganic salts of calcium ions coprocessed with glyceryl behenate, wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the dosage form delays the release of the prednisone from the core for a period of about 2h to 10h after oral administration.

In another general aspect of the invention a programmed release press-coated tablet is used for treating circadian phase dependent pathologies such as asthma, arthritis, chronic inflammation, pain, rheumatoid arthritis and polymyalgia rheumatica.

In another aspect, composition of the present invention is administered to host comprising human patients suffering from circadian phase dependent pathologies.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples
Example 1: Prednisone MR Tablets-1, 2 and 5 mg
Wet granulation process
Coating material composition

Core Shell Unit composition
Sr. No. Ingredients/Grade %w/w
Intragranular Ingredients
1. Calcium hydrogen phosphate dihydrate (Calipharm D) 70-80
2. Microcrystalline Cellulose(Avicel PH 101) 3.2-3.6
3. Glycerol dibehenate(Compritol 888 ATO) 10-20
4. Povidone K29/32 3-7
5. Purified Water q.s
6. Colloidal Anhydrous Silica 0.5-1.0
7. Magnesium Stearate 0.5-1.0

Procedure:
Intragranular ingredients were taken together and sifted. The sifted material was transferred to rapid mixer granulator. The sifted material in rapid mixer granulator was granulated using the prepared binder solution. The granules obtained were dried and then mixed with colloidal anhydrous silica and magnesium stearate.

Example 2: Core Tablet Unit Composition

Core Tablet Unit Composition
Sr. No. Ingredient/Grade %w/w
Intragranular Ingredients
1. Prednisone 1-10
2. Microcrystalline Cellulose(Avicel PH 101) 15-25
3. Lactose Monohydrate(Pharmatose 200 M) 65-75
4. Red Ferric Oxide E172 0.1-0.7
Binder Solution
5. Povidone (PVP K-30) 2-8
6. Purified Water q.s
Extragranular Ingredients
7. Croscarmellose Sodium (Ac-Di-Sol) 4-8
8. Colloidal Silicon Dioxide (Aerosil 200) 0.3-1.0
9. Magnesium Stearate 0.2-1.0

Procedure:
Intragranular ingredients were taken together and sifted except Red Ferric Oxide which was sifted seperately. All the ingredients were transferred into suitable rapid mixer granulator and dry mixed with impeller at a low speed. Wet granulation was carried out using the binder solution. The granules obtained were dried and collected in a pre-labeled container. Extragranular material were taken together, sifted and collected in a pre-labeled container. This mixture was then transferred into low shear blender and prelubrication was done.

Example 3:
Compression: (1mg Strength)
Tooling: 5.0mm round standard concave plain on both sides
Avg.Wt: 60.6 mg
Uniformity of Weight: 58.3-62.4 mg
Hardness: 40-43N
Thickness: 2.70-2.83 mm
Disintegration time: 1 min 12 sec
Friability: 0.07% w/w

Compression of Prednisone MR Tablets-1 mg
Tooling: 8.0 mm round Flat Faced Beveled Edges debossed with ‘45’ on one side and plain on other side.
Avg.Wt.: 457-461 mg
Uniformity of Weight: 458.3-463.2 mg
Hardness: 55-65 N
Thickness: 5.92-5.98 mm
Example 4: Dissolution Conditions:

Sr. No. Time points (h) 6.8 pH Phosphate Buffer % RSD
1 2 0 0
2 3 54 29.63
3 4 84 19.05
4 5 86 15.12
5 6 90 8.89

Example 5: Prednisone MR Tablets-1, 2 and 5 mg
Melt granulation process
Coating material composition
Core Shell Unit composition
Sr. No. Ingredient/Grade %w/w
Intragranular Ingredients
1. Calcium hydrogen phosphate dihydrate(Calipharm D) 55-75
2. Glycerol dibehenate(Compritol 888 ATO) 15-35
Extragranular Ingredients
3. Yellow ferric oxide 0.05-0.2
4. Povidone K29/32 2-8
5. Colloidal Silicon Dioxide(Aerosil 200) 0.5-1.0
Lubricants
6. Magnesium Stearate 0.5-2

Procedure:
Accurately weighed quantity of Glyceryl dibehenate was melted in SS vessel at a temperature of 65-750C to form a true liquefied wax. Calcium hydrogen phosphate dihydrate was sifted and added to melted glyceryl dibehenate. The mixture was then granulated while hot with vigorous mixing. The obtained material was then cooled. This was then passed through mesh and collected in a pre-labeled container. Yellow ferric oxide was sifted and collected in a pre-labeled container. Granules of glyceryl behenate and calcium hydrogen phosphate dihydrate along with yellow ferric oxide, povidone, Magnesium Stearate and colloidal silicon dioxide were transferred into double cone blender and prelubricated. Blend was unloaded and compressed.

Example 6: Core Tablet Unit Composition

Core Tablet Unit Composition
Sr. No. Ingredient/Grade %w/w
Intragranular Ingredients
1. Prednisone 1-10
2. Microcrystalline Cellulose(Avicel PH 101) 15-25
3. Lactose Monohydrate(Pharmatose 200 M) 65-75
4. Red Ferric Oxide E172 0.1-0.7
5. Maize Starch (Unipure FL) 5-15
Binder Solution
6. Purified Water q.s.
Extragranular Ingredients
7. Magnesium Stearate 0.2-1.0

Procedure:
All Intragranular ingredients were taken together and sifted except Red Ferric Oxide which was sifted seperately. All the ingredients were transferred into suitable rapid mixer granulator and dry mixed with impeller at a low speed. Wet granulation was carried out using the binder solution. The granules obtained were dried and collected in a pre-labeled container. Extragranular material were taken together, sifted and collected in a pre-labeled container. This mixture was then transferred into low shear blender and prelubrication was done.

Example 7: Core Compression: (5 mg Strength)
Tooling: 5.0mm round standard concave plain on both sides
Avg.Wt: 60.6 mg
Uniformity of Weight: 59.6-61.4 mg
Hardness: 25-35
Thickness: 2.3-2.4 mm
Disintegration time: 20 sec
Friability: 0.07% w/w

Compression of Prednisone MR Tablets- 5 mg (Finished Product)
Tooling: 8.0 mm round FFBE embossed with W5 on one side and plain on other side.
Description: Round, yellow colored, press/compression coated FFBE debossed with W5 on one side and plain on other side.
Average Weight: 460.0 mg.
Layer-I: 200.0 mg, Layer-II 200.0 mg and Core tablet Weight: 60.0 mg
Thickness: 5.70-6.10 mm
Hardness: 45-80N
Friability: 0.021%w/w (At optimum Hardness)
Disintegration Time: 4 hrs 05 min in water
4 hrs 30 min in pH 6.8 Phosphate Buffer

Example 8: Dissolution Profile

No. of Units 6 24
Dissolution media 6.8 pH phosphate buffer 6.8 pH phosphate buffer
Apparatus USP -II ,Paddle USP -II ,Paddle
Speed 50 RPM 50 RPM
Volume 900 mL 900 mL
Lag Phase 3 h 35 min to 4 h 01 min (for optimum hardness- 50-60N)3 h 58 min to 4 h 52 min (for high hardness-70-75 N) 3 h 47 min to 5 h 04 min (for optimum hardness-50-60N)

We Claim-

1. A programmed release press-coated tablet, comprising of
a core comprising one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and
a coating surrounding the said core comprising one or more inorganic salts of calcium ion co-processed with glyceryl behenate,
wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the dosage form delays the release of the corticosteroid from the core for a period of about 2h to 10h after oral administration.

2. A method for delaying the release of one or more corticosteroid from the core for a period of about 2h to 10h, wherein the method comprise applying the coating composition to the core; wherein the coating composition comprises glyceryl behenate co-processed with one or more inorganic salts of calcium ion.

3. A coating composition for delaying the release of one or more corticosteroid from the core for a period of about 2h to 10h; wherein the coating composition comprises glyceryl behenate co-processed with one or more inorganic salts of calcium ion optionally along with one or more pharmaceutically acceptable excipients.

4. The programmed release press-coated tablet of claim 1, wherein the inorganic salts of calcium ion comprise one or more of calcium phosphate, calcium phosphate dihydrate, calcium phosphate anhydrous, dibasic calcium phosphate, dibasic calcium phosphate monohydrate, dibasic calcium phosphate dihydrate, anhydrous dibasic calcium phosphate, monobasic calcium phosphate, tribasic calcium phosphate, calcium acetate, calcium carbonate, calcium chloride, calcium hydroxide, calcium pyrophosphate, calcium sulfate, calcium sulfate anhydrous, calcium sulfate dihydrate or calcium sulfate hemihydrate.

5. The programmed release press-coated tablet as claimed in claim 4, wherein the inorganic salt of calcium ion is calcium phosphate dihydrate or dibasic calcium phosphate dihydrate.

6. The programmed release press-coated tablet of claim 1, wherein the one or more inorganic salts of calcium ion are melt granulated with glyceryl behenate.

7. The programmed release press-coated tablet as claimed in the preceding claims, wherein the co-processed mixture of glyceryl behenate and inorganic salts of calcium ion is in the ratio of 10:90 to 90:10.

8. The programmed release press-coated tablet as claimed in the preceding claims, wherein the coating may be applied as a film coating, spray coat, multiple layer compression coating or as press coating.

9. The programmed release press-coated tablet as claimed in the preceding claims, wherein coating composition further comprises hydrophilic or hydrophobic polymer.

10. The programmed release press-coated tablet as claimed in the preceding claims, wherein the ratio of width of the tablet to the length of the tablet is less than the ratio of 1.33:1.

11. The programmed release press-coated tablet as claimed in the preceding claims, the pharmaceutically acceptable excipients comprise one or more of diluents, fillers, binders, disintegrant, lubricants, glidants and colorant.

12. The programmed release press-coated tablet according to claim 1, wherein the composition is in form of tablet, capsule, tablet in tablet, tablet in capsule, bilayer tablet, trilayer tablet, in-lay tablet, microsphers, coated pellets, multiple unit pellet system, granules, particles or combinations thereof.

13. The programmed release press-coated tablet as claimed in the preceding claims, wherein one or more corticosteroids are selected from the group consisting of prednisone, prednisolone, methylprednisolone, cortisone, hydrocortisone, budesonide, dexamethasone, fludrocortisone, fluocortolone, cloprednole, deflazacort and triamcinolone.

14. A programmed release press-coated tablet, comprising of
a core comprising of prednisone optionally with one or more corticosteroid and optionally along with one or more pharmaceutically acceptable excipients, and
a coating surrounding the said core comprising one or more inorganic salts of calcium ion co-processed with glyceryl behenate,
wherein the said core is being disposed within said coating such that the coating thickness around the horizontal edges of the core is less than or equal to the coating thickness around the vertical edges of the core, wherein the dosage form delays the release of prednisone from the core for a period of about 2h to 10h after oral administration.

15. A method of treating circadian phase dependent pathologies such as asthma, arthritis, chronic inflammation and pain, such as rheumatoid arthritis and polymyalgia rheumatica wherein the method comprises administering a programmed release press coated tablets as defined in claim 1 to a host in need of said treatment.

Dated 18th day of August, 2011 For Wockhardt Limited

(Mandar Kodgule)
Authorized Signatory