DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10; rule 13]

PRESS-COATED PREDNISONE TABLETS AND PROCESS FOR ITS PREPARATION

PIRAMAL PHARMA LIMITED, an Indian company incorporated under the Companies Act 2013, of Ground floor, Piramal Ananta, Agastya Corporate Park, Kamani Junction, LBS Marg, Kurla West, Mumbai - 400070, State of Maharashtra, India

The following specification particularly describes the invention and the manner in which it is to be performed
Field of the Invention
The present invention relates to a press-coated pharmaceutical composition having a core comprising of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating comprising a coating agent and one or more pharmaceutical excipient(s). The invention further relates to a process for preparation of said pharmaceutical composition in the form of a tablet having a core comprising prednisone and a coating around the core having a defined thickness which attributes to the timely and effective drug release of the active ingredient.

Background of the Invention
Prednisone belongs to a class of drugs known as corticosteroids. Corticosteroids are adrenocortical steroids, both naturally occurring and synthetic. The molecular formula for prednisone is C21H26O5. The chemical name for prednisone is 17,21-dihydroxypregna-1,4-diene-3,11,20-trione, and the structural formula is:

Prednisone is a white to practically white, odorless, crystalline powder and has a molecular weight of 358.43. Prednisone is very slightly soluble in water; slightly soluble in alcohol, chloroform, dioxane, and methanol. Prednisone is used as an anti-inflammatory or an immunosuppressant medication. It treats many different conditions such as allergic disorders, skin conditions, ulcerative colitis, arthritis, lupus, psoriasis, or breathing disorders.
RAYOS® a delayed-release prednisone tablet marketed in US is intended for oral administration. It consists of a prednisone-containing core tablet in an inactive shell, which delays the onset of in vitro drug dissolution by approximately 4 hours. Each tablet contains 1 mg, 2 mg, or 5 mg of prednisone, with the following inactive ingredients: dibasic calcium phosphate dihydrate, colloidal silicon dioxide, croscarmellose sodium, glycerol dibehenate, lactose monohydrate, magnesium stearate, povidone, yellow ferric oxide, and red ferric oxide.
US Patent No. 8,168,218 provides 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, and is adapted to provide a lag time of between about 2 to 6 hours during which substantially no drug substance is released.
PCT Publication No. WO2016114726 relates to a time-controlled delayed release tablet comprising prednisone whose release active ingredient from core after a lag time wherein said, time- controlled delayed release tablets are press-coated tablets comprising a core and a coating covering said core.
US Publication No. 20130243861 claims a press-coated tablet comprising a core comprising prednisone, and a coating around the core, said core being disposed within said coating such that the coating thickness about an axis (A-B) is equal to or thicker than the coating thickness about an axis (X-Y) orthogonal to (A-B), wherein the axis (A-B) is the axis of the direction of movement of the punch used in the press-coating of the tablet.
Drug Design, Development and Therapy; 2016:10, 1047-1058, Marco Krasselt et al, “Efficacy and safety of modified-release prednisone in patients with rheumatoid arthritis” reports that the existing data on Modified-Release prednisone suggest a superior efficacy in reducing Rheumatoid Arthritis-related morning stiffness while bearing a safety profile comparable to conventional prednisone formulations.
Rheumatol Ther (2017) 4:363–374, Ara H. Dikranian et al., “Switching From Immediate-Release to Delayed-Release Prednisone in Moderate to Severe Rheumatoid Arthritis: A Practice-Based Clinical Study” analyzes the incremental benefit of better timed and lower dose glucocorticoid therapy.
Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that can cause cartilage and bone destruction if left untreated. Upon confirming a diagnosis of RA, a variety of treatment approaches are typically considered, including non-steroidal anti-inflammatory drugs (NSAIDs), synthetic disease-modifying anti-rheumatic drugs (DMARDs), biologic DMARDs, and glucocorticoids.
Patients with RA – a disease that can painfully swell joints – often wake to crippling stiffness caused by an overnight increase in inflammation. Since many RA medications activate within one to two hours, patients must take their prescriptions in the early morning to minimize pain. RA is commonly treated with low-dose immediate-release prednisone (IR-prednisone) in the morning upon awakening. This timing may not optimize control of inflammation and disease symptoms because inflammatory cytokines peak before awakening, typically around 2–4 a.m. Administering a delayed-release prednisone (DR-prednisone) tablet at bedtime enables timed delivery of prednisone before and during this circadian peak of inflammatory cytokine release and thereby potentially influences disease symptoms.
Hence it is important that the drugs that work well for the disease need to be present in the body in the early morning hours. The concept of time-controlled or delayed release formulations are known in the art that are able to deliver drug substances with a defined release rate after a lag time during which no drug substance is released. The coating acts as a barrier to the ingress of aqueous media into an active-agent-containing core and thereby creating a lag time during which no drug substance is released. The coating act as a medium through which drug is released in a delayed or modified manner. These formulations are completely independent of pH. In other words, releases the active ingredient after a lag time regardless of the physiological pH environment in the gastrointestinal tract.
There have been several time-release, delayed-release or modified-release formulations techniques reported in the art. Delayed drug release is commonly achieved by the application of an enteric coating on dosage forms such as tablets, capsules and multiparticulates. The main function of an enteric coating is to confer protection. Film and sugar coatings have the number of disadvantages; most important one is the utilization of aqueous or organic solvent that leads to toxicity. To overcome the trouble of film or sugar coating, Tablet in Tablet or compress coating introduces as alternating coating technique. It is also recognized as a dry coating or press coating and was one of the first solvent free-coating techniques. In general, a Tablet in Tablet or compression-coated tablet consists of two parts; one is an internal drug core, and another is an outside coating shell. The outer layer surrounds the inner core, and it mainly controls the strength of the film coating, the release of the drug, and the stability. It is intended to be used mainly in the therapy of those diseases which depend on circadian rhythms.
For the time controlled release system from compression coated tablets, the amount of the outer shell is a key factor for controlling the lag time. Higher amount of outer coating added would prolong the lag time of drug release. Insufficient amount of polymer coat would result in absence of the lag time, since the drug might be released through the incomplete form of compression coat. The main difficulty in the manufacture of press-coated tablets is how to center the inner core tablet under rapid processing conditions. Eccentric localization may alter lag time and release profile, leading to the changes in drug bioavailability. Reproducibility of drug release from press-coated tablets becomes uncertain with off center placement of the core tablet. Hence, there is a need to have a strategic coating technique that will produce tablets with consistent bioavailability of the drug in comparison to the drug formulation currently in market.
In consideration of the need as indicated above, the inventors of the present invention after extensive research and experimentation have found that by carefully selecting the geometry of the core within its coating and/or ingredients in coating such that tablets achieve predefined lag times and drug release consistently, it is possible to adjust the composition and coating thickness at specific points on the tablet which releases the drug with desired rate after specific lag time. The inventors of the present invention have found that the press-coated tablets of prednisone having a coating thickness about an axis (A-B) almost equal to an axis (X-Y) orthogonal to axis (A-B), will release the drug after desired lag time. The inventors of present invention have carried out extensive research to evaluate the right process, and right excipients to ultimately give a robust, high productivity and regulatory compliant product of good quality.
Summary of the Invention
In one aspect, the present invention relates to a press-coated pharmaceutical composition having a core comprising of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating comprising of a coating agent and one or more pharmaceutical excipient(s).
In yet another aspect, there is provided a press coated pharmaceutical composition comprising prednisone, one or more diluent(s), one or more binder(s), one or more disintegrant(s), one or more lubricant(s), one or more glidant(s), one or more colorant(s) and one or more coating agent(s).
In another aspect, there is provided a process for the preparation of a press-coated pharmaceutical composition having a core comprising of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating comprising of a coating agent and one or more pharmaceutical excipient(s).
In another aspect, there is provided a process for the preparation of a press-coated pharmaceutical composition in the form of a tablet, wherein the tablet contains a core comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s); having a defined thickness which attributes to the timely and effective drug release of the active ingredient.
In another aspect, there is provided a process for the preparation of a press-coated pharmaceutical composition in the form of a tablet, wherein the tablet contains a core comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s); wherein the core being disposed within said coating such that the coating thickness about an axis (A-B) is almost equal to the coating about an axis (X-Y) orthogonal to axis (A-B).
In another further aspect, there is provided a method for treating or preventing various conditions, diseases, disorders, comprising administering to a subject in need thereof any one of the compositions of the present invention in an amount effective to treat or prevent a condition, a disease or a disorder.
In another further aspect, there is provided use of a press-coated pharmaceutical composition having a core comprising of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating comprising a coating agent and one or more pharmaceutical excipient(s); for the manufacture of a medicament for treating or preventing various conditions, diseases or disorders.
In a still further aspect, the present invention relates to a pharmaceutical kit comprising: (a) prednisone and one or more pharmaceutical excipient(s); and (b) optionally a package insert comprising instructions for using the said pharmaceutical composition.
These and other aspects and advantages of the present invention will be apparent to those skilled in the art from the following description.
Brief Description of Drawings of the Invention
Figure 1: Shows that the thickness of X-Y and A-B axis are similar/comparable
Figure 2: Comparative drug release profile of Prednisone DR Tablets Test formulations with Reference product provided in Table 4.

Detailed Description of the Invention
It should be understood that the detailed description and specific examples, while indicating embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art. One skilled in the art, based upon the definitions herein, may utilize the present invention to its fullest extent. The following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
Except as defined herein, all the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention relates.
Definitions:
For the purpose of the disclosure, listed below are definitions of various terms used to describe the present invention. Unless otherwise indicated, these definitions apply to the terms as they are used throughout the specification and the appended claims, either individually or as part of a larger group. They should not be interpreted in the literal sense. They are not general definitions and are relevant only for this application.
It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise.
It should be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
As used herein, the term "about" means approximately and in the context of numerical values the term “about” can be construed to estimate a value that is ±10% of the value or range recited for prednisone and excipients present in the composition and ±0.15 of the value indicated for the ratio of thickness of coating for axis (X-Y) and axis (A-B) respectively.
The term “excipient(s)” as used herein means a diluent, binder, disintegrant, glidant, lubricant, coating agent or the like, which is non-toxic, and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent (prednisone) to the target site without affecting the therapeutic activity of the said agent.
As used herein, the term “formulation” or “composition” or “pharmaceutical composition” or “dosage form” as used herein synonymously include solid dosage forms such as granules, multiunit particulate systems (MUPS), pellets, spheres, tablets, capsules, mini-tablets, layered tablets, beads, particles and the like; and liquid dosage forms such as solutions, suspensions, emulsions, colloids and the like, meant for oral administration. The active pharmaceutical compound is prednisone.
Within the context of the present invention and as used herein the term “prednisone” unless indicated otherwise in the entire specification, refers to prednisone in its free form.
Within the context of the present invention and as used herein, unless indicated otherwise, references to total weight of the pharmaceutical composition refers to the total weight of the active agent(s) and pharmaceutically acceptable excipient(s).
Within the context of the present invention and as used herein the term "subject" refers to an animal, preferably a mammal, and most preferably a human. In the context of the present invention, the term “mammal” is used interchangeably with the term “patient” or “subject”. In the context of the present invention, the phrase “a subject in need thereof” means a subject (patient) in need of the treatment of a disease or disorder for which prednisone is used.
Within the context of the present invention and as used herein the term 'diluent' refers to an agent used as filler in order to achieve the desired composition volume or weight. The diluent may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. Diluents are often added to tablet formulations to provide better tablet properties such as to improve cohesion, to allow direct compression manufacturing, to enhance flow and to adjust weight of tablet as per die capacity. Diluents are generally classified into three categories namely organic, inorganic and co-processed diluents. The organic diluents include but are not limited to, lactose such as a-lactose monohydrate, spray dried lactose and anhydrous lactose, starch such as potato starch, corn starch or maize starch, and pregelatinized starch, icing sugar with starch, sucrose, mannitol, sorbitol, cellulose such as powdered cellulose and microcrystalline cellulose. The inorganic diluents include but are not limited to calcium phosphates such as anhydrous dibasic calcium phosphate, dibasic calcium phosphate and tribasic calcium phosphate. Some of the insoluble diluents include but are not limited to starch, powdered cellulose, microcrystalline cellulose, calcium phosphate and the like. Some of the soluble diluents include but are not limited to lactose, sucrose, mannitol, sorbitol and the like.
Binders are dry powders or liquid which are added during granulation process to promote granules and cohesiveness. Binders are, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose, gelatin, liquid glucose, corn starch or maize starch, pregelatinized starch, hydrocolloids, sugars, polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth, xanthan, used either alone or combinations thereof.
Disintegrant as used in herein refers to any material that facilitates the break-up of a tablet prepared from the composition when placed in contact with an aqueous medium. Suitable disintegrants include, but are not limited to, crospovidone, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, carboxymethylcellulose sodium or calcium, croscarmellose sodium, pregelatinized starch, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium or calcium alginate, agar, guar gum, chitosan, alginic acid and mixtures thereof.
Glidants improve the flowability of the composition. Exemplary glidants are, but not limited to, fumed silica (colloidal silicon dioxide), colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, magnesium stearate, magnesium carbonate, mixtures thereof and the like.
Lubricants are added in small quantities to tablet formulations to improve certain processing characteristics. The role of the lubricants is to ensure that tablet formation and ejection can occur with low friction between the tablet ingredients and the die walls of the tableting machine. Lubricant prevents sticking to punch faces and enhances product flow by reducing interparticulate friction. The lubricant may be present in the pharmaceutical composition in the form of a single compound or in the form of a mixture of compounds. Lubricants are, but not limited to sodium oleate, sodium stearate, sodium benzoate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like.
Colorants or coloring agents are mainly used to impart a distinctive appearance to the pharmaceutical
dosage forms. We can also say that the colorants are the cosmetics for the pharmaceutical preparations,
because the aesthetic appearance of dosage forms can be enhanced by using suitable colorants.
Colorants are mainly used to impart appearance to the pharmaceutical dosage forms. There are many types of pharmaceutical preparations which need to be colored such as tablets, tablets coatings, capsules (hard gelatin, soft gelatin), liquid orals, tooth pastes, ointments and salves etc. The purpose of coloring varies with different formulations. Colorings may be required to increase the aesthetic appearance or to prolong the stability or to produce standard preparations or for identification of a particular formulation. Suitable examples of colorants are selected from, but are not limited to non-water soluble lake pigments; neutral pigments; yellow ferric oxide; red ferric oxide; black iron oxide and the like.
Coating agents comprise of a hydrophilic or a hydrophobic rate controlling material alone or in combination in the composition Suitable hydrophilic rate controlling materials are selected from, but are not limited to alkyl celluloses such as methyl cellulose; hydroxyalkyl celluloses, for example, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxybutyl cellulose; hydroxyalkyl alkyl celluloses such as hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose; carboxyalkyl cellulose or esters; microcrystalline cellulose, crosslinked cellulose derivatives such as crosslinked sodium carboxymethyl cellulose; crosslinked polyvinyl pyrrolidone and vinyl acetate; polysaccharides such as galactomannans, tragacanth, agar, guar gum, and polyfructans; polyvinyl alcohol; polyethylene glycol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; and polyalkylene oxides such as polyethylene oxide and polypropylene oxide and copolymers of ethylene oxide and propylene oxide, sodium alginate, alginic acid, polyox, carbopol; preferably cellulose ether derivatives such as hydroxypropyl methyl cellulose and hydroxypropyl cellulose, most preferred hydroxypropyl methyl cellulose and the like. Suitable hydrophobic rate controlling materials for coating are selected from, but are not limited to one or more of glyceride (e.g., glyceryl behenate, glyceryl trimyristate, glyceryl trilaurate, glyceryl tristearate, glyceryl monostearate, glyceryl palmitostearate, or glyceryl triacetate), stearic acid, hydrogenated castor oil, a hydrogenated vegetable oil, a water insoluble cellulose (e.g., ethyl cellulose, cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate butyrate, cellulose acetate propionate, nitrocellulose, cellulose diacetate, or cellulose triacetate), polymethacrylates such as Eudragit RS, Eudragit RL; polyvinyl acetate based such as Kollicoat SR; a wax or a wax-like substance (e.g., carnauba wax, cetyl esters wax, beeswax, castor wax, cationic emulsifying wax, cetrimide emulsifying wax, an emulsifying wax, microcrystalline wax, a nonionic wax, a nonionic emulsifying wax, paraffin, petroleum wax, petroleum ceresin wax, spermaceti wax, white wax, or yellow wax), a fat, an oil, a fatty acid, an emulsifier, a modified starch, a fatty alcohol, a protein (e.g., zein), shellac, or a polymer (e.g., a polyolefin, a polyurethane, a polyvinylchloride, a polyvinyl acetate, an acrylic acid polymer, a methacrylic acid polymer); cetostearyl alcohol, stearyl alcohol; and the like.
One or more of these excipients can be selected and used by the artisan having regard to the particular desired properties of the solid dosage form. The amount of each type of excipient employed, e.g. diluent, binder, disintegrant, glidant, lubricant, colorant may vary within ranges conventional in the art.
Suitable pharmaceutical compositions include, but are not limited to, capsules, tablets, granules, powders and unit dose pockets. Preferably the oral pharmaceutical composition is a tablet.
In an embodiment of the present invention, the press-coated pharmaceutical composition having a core comprises of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating comprising of a coating agent and one or more pharmaceutical excipient(s).
In an embodiment, the pharmaceutically acceptable excipient(s) is selected from the group consisting of diluent, binder, disintegrant, lubricant, glidant, colorant, coating material or a combination thereof.
In another embodiment, the press coated pharmaceutical composition comprises of prednisone, one or more diluent(s), one or more binder(s), one or more disintegrant(s), one or more lubricant(s), one or more glidant(s), one or more colorant(s) and one or more coating agent(s).
In an embodiment, the press-coated composition comprises a core composition and a coating composition.
In an embodiment, the core composition of the press-coated pharmaceutical composition comprises of prednisone one or more diluent(s), one or more binder(s), one or more disintegrant(s), one or more lubricant(s), one or more glidant(s), one or more colorant(s).
In an embodiment, the coating composition of the press-coated pharmaceutical composition comprises of coating agent, one or more diluent(s), one or more binder(s), one or more lubricant(s), one or more glidant(s), one or more colorant(s).
In an embodiment, the press-coated pharmaceutical composition contains prednisone as an active ingredient.
In an embodiment, the press-coated pharmaceutical composition contains prednisone in the range of about 0.1 % w/w to about 10 % w/w of the composition.
In an embodiment, the diluent is selected from the group consisting of lactose such as a-lactose monohydrate, spray dried lactose and anhydrous lactose, starch such as potato starch, corn starch or maize starch and pregelatinized starch, icing sugar with starch, sucrose, mannitol, sorbitol, cellulose such as powdered cellulose and microcrystalline cellulose, calcium phosphates such as anhydrous dibasic calcium phosphate, dibasic calcium phosphate and tribasic calcium phosphate and the like. The diluent may be used in the range of about 10-90 % by weight of the composition.
In an embodiment, the binder is selected from the group consisting of cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; gelatin, liquid glucose; corn starch or maize starch; pregelatinized starch; hydrocolloids; sugars; polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth and xanthan, used either alone or combinations thereof. The binder may be used in the range of about 1-25 % by weight of the composition.
In another embodiment, the disintegrant is selected from the group consisting of crospovidone, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, carboxymethylcellulose sodium or calcium, croscarmellose sodium, pregelatinized starch, polacrilin potassium, low-substituted hydroxypropylcellulose, sodium or calcium alginate, agar, guar gum, chitosan, alginic and the like used either alone or in combination thereof. The disintegrant may be used in the range of about 1-25 % by weight of the composition.
In another embodiment, the glidant is selected from the group consisting of fumed silica (colloidal silicon dioxide), colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, magnesium stearate, magnesium carbonate and the like used either alone or in combination thereof. The glidant may be used in the range of about 0.5-5 % by weight of the composition.
In another embodiment, the lubricant is selected from the group consisting of sodium oleate, sodium stearate, sodium benzoate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like used either alone or in combinations thereof. The lubricant may be used in the range of about 0.5-3 % by weight of the composition.
In another embodiment, the colorant is selected from the group consisting of yellow ferric oxide; red ferric oxide; black iron oxide and the like used either alone or in combinations thereof. The lubricant may be used in the range of about 0.1-5 % by weight of the composition.
In an embodiment, the coating agent is selected from the group consisting of methyl cellulose; hydroxymethyl cellulose; hydroxyethyl cellulose; hydroxypropyl cellulose; hydroxybutyl cellulose; hydroxyethyl methyl cellulose; hydroxypropyl methyl cellulose; microcrystalline cellulose; crosslinked sodium carboxymethyl cellulose; crosslinked polyvinyl pyrrolidone and vinyl acetate; galactomannans; tragacanth; agar; guar gum; polyfructans; polyvinyl alcohol; polyethylene glycol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate; combinations of polyvinyl alcohol and polyvinylpyrrolidone; polyethylene oxide; polypropylene oxide; copolymers of ethylene oxide and propylene oxide; sodium alginate; alginic acid; polyox; carbopol; glyceryl behenate; glyceryl trimyristate; glyceryl trilaurate; glyceryl tristearate; glyceryl monostearate; glyceryl palmitostearate, or glyceryl triacetate; stearic acid; hydrogenated castor oil; a hydrogenated vegetable oil; ethyl cellulose; cellulose acetate; cellulose acylate; cellulose diacylate; cellulose triacylate; cellulose acetate butyrate; cellulose acetate propionate; nitrocellulose; cellulose diacetate; or cellulose triacetate; polymethacrylates such as Eudragit RS, Eudragit RL; polyvinyl acetate based such as Kollicoat SR; carnauba wax; cetyl esters wax; beeswax; castor wax; cationic emulsifying wax; cetrimide emulsifying wax; an emulsifying wax; microcrystalline wax; a nonionic wax; a nonionic emulsifying wax; paraffin; petroleum wax; petroleum ceresin wax; spermaceti wax; white wax; or yellow wax; a fat; an oil; a fatty acid; an emulsifier; a modified starch; a fatty alcohol; a protein (e.g., zein); shellac; or a polymer (e.g., a polyolefin, a polyurethane, a polyvinylchloride, a polyvinyl acetate, an acrylic acid polymer, a methacrylic acid polymer); cetostearyl alcohol; stearyl alcohol; and the like used either alone or in combination thereof. The coating agent may be used in the range of about 20-60 % by weight of the composition.
In an embodiment, the diluent is selected from the group consisting of lactose, microcrystalline cellulose and dibasic calcium phosphate dihydrate or dibasic calcium phosphate anhydrous; or a combination thereof.
In an embodiment, the binder is polyvinyl pyrrolidone.
In an embodiment, the disintegrant is croscarmellose sodium.
In an embodiment, the disintegrant is intragranular and/or extragranular.
In an embodiment, the glidant is colloidal silicon dioxide.
In an embodiment, the lubricant is magnesium stearate.
In an embodiment, the colorant is selected from yellow ferric oxide or red ferric oxide; or a combination thereof.
In an embodiment, the coating agent is glyceryl behenate.
In another embodiment, the core composition of the press-coated pharmaceutical composition of the present invention comprises prednisone, lactose monohydrate, microcrystalline cellulose, red ferric oxide, croscarmellose sodium, polyvinyl pyrrolidone, colloidal silicon dioxide and magnesium stearate.
In yet another embodiment, the coating composition of the press-coated pharmaceutical composition of the present invention comprises dibasic calcium phosphate dihydrate, glyceryl behenate, polyvinyl pyrrolidone, colloidal silicon dioxide, magnesium stearate and yellow ferric oxide.
In another embodiment, the composition of the invention can be in standard-release, immediate-release, rapid-onset, delayed-release or dual-release form.
In another embodiment, the composition of the invention is delayed-release form.
Process for the preparation of Prednisone composition:
In an embodiment of the present invention, the process for the preparation of a press-coated pharmaceutical composition having a core comprises of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating comprising of a coating agent and one or more pharmaceutical excipient(s).
In an embodiment, the process may be performed by either direct compression or wet-granulation process.

Process A:
In an embodiment, the dry process comprises:
1. Dispensing all the raw materials as per formulation sheet. Sift the intragranular material through suitable sieve;
2. Blending the materials of core tablet in a blender;
3. Compressing core tablets as per attributes shown in Table of tentative tablet attributes;
4. Blending the excipients of press coating layer separately in a blender;
5. Compressing with core tablets to make tablet in tablet formulation and
6. Packing the coated tablets in bottle pack.

Process B:
In an embodiment, the wet granulation process comprises:
1. Adding active ingredient prednisone, lactose, polyvinyl pyrrolidone, croscarmellose sodium to rapid mixer granulator (RMG) and dry mix to form a blend;
2. Adding purified water preferably using nozzle to above dry mix in RMG and perform kneading;
3. Drying at inlet temperature of about 45°C with target LOD < 2.5%;
4. Milling the dried granules through suitable screen;
5. Putting half of granulate in RMG followed by colloidal silicon dioxide and then remaining half of granulate; mixing for 2 min and adding magnesium stearate and continue mixing for 2 min;
6. Compressing the blend obtained in step 5 as core tablets;
7. Separately, mixing dibasic calcium phosphate, glyceryl behenate, lactose and polyvinyl pyrrolidone in RMG;
8. Adding purified water to step 7 in RMG to granulate and perform kneading;
9. Drying at inlet temperature of about 45°C with target LOD < 2.5%
10. Milling the dried granules through suitable screen;
11. Putting half of granulate in RMG followed by colloidal silicon dioxide and then remaining half of granulate; mixing for 2 min and adding magnesium stearate and continue mixing for 2 min;
12. Compressing the blend obtained in step 11 and core tablets obtained from step 6 to make tablet in tablet formulation; and
13. Packing the coated tablets in bottle pack.

In another embodiment, the dry blend can be performed in a suitable mixer, such as a container blender, fluid bed dryer, drum blender, v-blender, rapid mixer granulator or a high shear mixer.
In an embodiment, the granulating process can be performed using fluidized bed processor, fluid bed top spray granulator or fluidized spray drying.
In an embodiment, tablet compression can be performed in a tablet press.

In an embodiment, the process for the preparation of a press-coated pharmaceutical composition in the form of a tablet, wherein the tablet contains a core comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s); having a defined thickness which attributes to the timely and effective drug release of the active ingredient.
In another embodiment, the process for the preparation of a press-coated pharmaceutical composition in the form of a tablet comprises of the core being disposed within the coating such that the coating thickness about an axis (A-B) is almost equal to the coating about an axis (X-Y) orthogonal to axis (A-B).
In one embodiment, the press-coated composition comprises a core comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s); the core being disposed within the coating such that the thickness about the axis (A-B) and axis (X-Y) is between 2.0 to about 4.0 mm respectively.
According to the present invention, the thickness of the coating should not be so thick that it renders the final formulation too large to be swallowed by the patients or it should not be so thin that it renders the final formulation very weak and brittle which breaks during the mechanical handling. The coating thickness of the either side of the core on the axis (A-B) as well as axis (X-Y) should be almost equal.
In yet another embodiment of the present invention, a press-coated composition comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s); such that the coating thickness about the axis (A-B) is almost equal to the coating thickness about the axis (X-Y). The ratio of the thickness of the coating about the axis (A-B) to the thickness of the coating about the axis (X-Y) is about 1:1.
In further embodiment of the present invention, the ratio of the thickness of the coating about the axis (A-B) to the thickness of the coating about the axis (X-Y) is 0.85 to 1.15:0.85 to 1.15.
The thickness of the coating along and about the axis of the direction of movement of the punch (the “(A-B)” axis referred to above) is determined by the amount of coating material added to the die and the compaction force applied to form the tablet. On the other hand, the thickness of the coating along and about the “(X-Y)” axis is determined by the size of the core, its position within the die and the diameter of the die.
In an embodiment, the press-coated composition comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s), such that the coating thickness about the axis (A-B) is almost equal to the coating thickness about the axis (X-Y); wherein the thickness of the coating about the axis (A-B) is such that the coating is adapted to rupture upon immersion in an aqueous medium after a period of between about 2 to about 6 hours.
In an embodiment, the press-coated tablet comprises of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s), wherein said tablet releases more than 80% of prednisone within 3 to 7 hours of administration.
In an embodiment, the press-coated composition comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s), such that the coating thickness about the axis (A-B) is almost equal to the coating thickness about the axis (X-Y); wherein the composition exhibits no significant difference in both rate and extent of absorption of prednisone as compared to delayed release composition of prednisone marketed under trade name Rayos®.
In an embodiment, the press-coated composition comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s), such that the coating thickness about the axis (A-B) is equal to the coating thickness about the axis (X-Y); wherein the composition provides consistent drug release without unit-to-unit variation in tablets.
The compositions of the present invention can be packed into suitable containers such as bottles, blisters or pouch. Further, the packages may optionally contain a desiccant or an antioxidant or oxygen absorbant or combinations thereof.
In an embodiment, the present invention relates to use of a press-coated pharmaceutical composition comprising prednisone as a therapeutic agent for treatment of arthritis, blood disorders, breathing problems, severe allergies, skin diseases, cancer, eye problems, and immune system disorders, wherein the said composition is as described herein above in one or more embodiments of the present invention.
In another embodiment, the present invention relates to a method of treating arthritis, blood disorders, breathing problems, severe allergies, skin diseases, cancer, eye problems, and immune system disorders, comprising administering to a subject in need thereof a therapeutically effective amount of the prednisone composition; wherein the said composition is as described in one or more embodiments of the present invention as described herein above.
In another embodiment, the present invention relates to use of the composition of prednisone, for the manufacture of a medicament for treating arthritis, blood disorders, breathing problems, severe allergies, skin diseases, cancer, eye problems, and immune system disorders; wherein the said composition is as described herein above in one or more embodiments of the present invention.
In another embodiment, the composition of prednisone may be packaged in a suitable container depending upon the formulation and the method of administration of the composition. Suitable containers known to a person skilled in the art include blister pack or bottle pack.
In another embodiment, the present invention provides a pharmaceutical kit comprising prednisone and one or more pharmaceutically acceptable excipient(s). The kit may further comprise a package insert, including information about the indication, usage, doses, direction for administration, contraindications, precautions and warnings.
In another embodiment, the pharmaceutical compositions of the present invention can include all the dosage forms known to a person skilled in art, viz. formulations such as single unit dosage forms in the form of tablets, bilayer tablets, inlaid tablets, tablet in tablet, multilayered tablets, minitablets filled in capsules and the like; beads, pellets presented in a sachet, capsule or tablet capsules such as soft and hard gelatin; lozenges or sachets; granulates, microparticles, multiparticulates, powder and the like.
It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are included within scope of the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not to limit the scope of the present invention.
Examples

Table 1: FORMULATION 1

A - Core Tablet
Strength 1 mg 2 mg 5 mg
Sr. No. Ingredients Function % w/w mg/Tab % w/w mg/Tab % w/w mg/Tab
A – Core tablets
1 Prednisone API 1.67 1 3.33 2 8.33 5
2 Lactose Monohydrate Diluent 71.33 42.8 69.67 41.8 64.67 38.8
3 Ferric Oxide Red (optional) Colour 0.50 0.3 0.50 0.3 0.50 0.3
4 Croscarmellose sodium Disintegrant 18.33 11 18.33 11 18.33 11
7 Polyvinyl pyrrolidone Disintegrant 6.67 4 6.67 4 6.67 4
8 Colloidal silicon dioxide Glidant 0.50 0.3 0.50 0.3 0.50 0.3
9 Magnesium Stearate Lubricant 1.00 0.6 1.00 0.6 1.00 0.6
Total 100.00 60.00 100.00 60.00 100.00 60.00
B - Press Coating
Sr. No. Ingredients Function % w/w mg/Tab % w/w mg/Tab % w/w mg/Tab
1 Dibasic calcium phosphate Dihydrate Diluent 50.00 175.00 50.00 175.00 50.00 175.00
2 Glyceryl Behenate Coating agent 40.00 140.00 40.00 140.00 40.00 140.00
3 Polyvinyl pyrrolidone Binder 8.40 29.40 8.40 29.40 8.40 29.40
4 Ferric Oxide Yellow Colour 0.10 0.35 0.10 0.35 0.10 0.35
5 Colloidal silicon dioxide Glidant 0.50 1.75 0.50 1.75 0.50 1.75
6 Magnesium Stearate Lubricant 1.00 3.50 1.00 3.50 1.00 3.50
Total 100.00 350.00 100.00 350.00 100.00 350.00
Total weight of Press coated tablet 410.00 410.00 410.00

Table 2: FORMULATION 2

A - Core Tablet
Strength 1 mg 2 mg 5 mg
Sr. No. Ingredients Function % w/w mg/Tab % w/w mg/Tab % w/w mg/Tab
1 Prednisone API 1.67 1 3.33 2 8.33 5
2 Starlac Diluent 92.83 55.7 91.17 54.7 86.17 51.7
3 Lycatab PGS Diluent 4.25 2.55 4.25 2.55 4.25 2.55
4 Magnesium stearate Lubricant 0.75 0.45 0.75 0.45 0.75 0.45
5 Ferric oxide red Colour 0.5 0.3 0.50 0.3 0.50 0.3
Total 100% 60.00 100% 60.00 100% 60.00
B - Press Coating
Methocel E50 (Methocel E50 Premium LV Hydroxypropyl) Diluent 80.00 280.00 80.00 280.00 80.00 280.00
Microcrystalline cellulose Diluent 18.00 63.00 18.00 63.00 18.00 63.00
Talc Glidant 1.00 3.500 1.00 3.500 1.00 3.500
Magnesium Stearate Lubricant 1.00 3.500 1.00 3.500 1.00 3.500
Total 100.00 350.00 100.00 350.00 100.00 350.00
Grand Total
410.00 410 410.00

Table 3: Tablet attributes for Formulation 1 and 2 – Tablet-in-Tablet

Tablet attributes Formulation 1 Formulation 2
Core tablet diameter 5.2 mm 5.2 mm
Core tablet thickness 2.1 mm 2.1 mm
Total tablet diameter 9 mm 9 mm
Total tablet thickness 5.5 mm 5.5 mm

Table 4: Dissolution data of different formulations in purified water in comparison with Reference drug (RAYOS).
Prednisone test tablet is released in Purified Water environment, under conditions of 500 mL of a dissolution medium at 37°C ±0.5°C, USP method-II (paddle with sinker), 100 rpm speed wherein the tablet exhibits a dissolution profile as follows:

Formulation RAYOS
(Reference) Formulation 1
Time (h) % Released
1 0 0
2 0 0
3 0 0
4 11 14
5 71 31
6 95 81

Results: From the above table, it can be found that the test formulations are able to delay the drug release similar to that of reference product
,CLAIMS:We claim:

1. A press-coated pharmaceutical composition having a core comprising of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating comprising of a coating agent and one or more pharmaceutical excipient(s).
2. The pharmaceutical composition as claimed in claim 1, wherein the composition comprises prednisone, one or more diluent(s), one or more binder(s), one or more disintegrant(s), one or more lubricant(s), one or more glidant(s), one or more colorant(s) and one or more coating agent(s).
3. The pharmaceutical composition as claimed in claim 1, wherein,
(i) the active ingredient is prednisone;
(ii) the diluent is selected from the group consisting of lactose, microcrystalline cellulose and dibasic calcium phosphate dihydrate or dibasic calcium phosphate anhydrous; or a combination thereof;
(iii) the binder is polyvinyl pyrrolidone;
(iv) the disintegrant is croscarmellose sodium either used as intragranular or extragranular or both;
(v) the glidant is colloidal silicon dioxide;
(vi) the lubricant is magnesium stearate;
(vii) the colorant is selected from yellow ferric oxide or red ferric oxide; or a combination thereof; and
(viii) the coating agent is glyceryl behenate.
4. A process for the preparation of a press-coated pharmaceutical composition having a core comprising of an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating comprising of a coating agent and one or more pharmaceutical excipient(s).
5. The process as claimed in claim 3, wherein the composition is formulated into a tablet containing a core comprising an active ingredient prednisone and one or more pharmaceutical excipient(s) and a coating around the core comprising a coating agent and one or more pharmaceutical excipient(s); having a defined thickness attributing to the timely and effective drug release of the active ingredient.
6. The process as claimed in claim 4, wherein the core being disposed within said coating is such that the coating thickness about an axis (A-B) is almost equal to the coating about an axis (X-Y) orthogonal to axis (A-B).
7. The process as claimed in claim 4, wherein the ratio of the thickness of the coating about the axis (A-B) to the thickness of the coating about the axis (X-Y) is about 1:1; wherein the term about means ±0.15 of the value indicated for the ratio of thickness of coating for axis (X-Y) and axis (A-B) respectively.
8. The process as claimed in claim 4, wherein the ratio of the thickness of the coating about the axis (A-B) to the thickness of the coating about the axis (X-Y) is 0.85 to 1.15:0.85 to 1.15.
9. The process as claimed in claim 4, wherein the thickness of the coating about the axis (A-B) is such that the coating is adapted to rupture upon immersion in an aqueous medium after a period of between about 2 to about 6 hours.
10. The pharmaceutical composition as claimed in claim 1, wherein the tablet releases more than 80% of prednisone within 3 to 7 hours of administration.