FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"DELAYED RELEASE PHARMACEUTICAL COMPOSITIONS OF
PREDNISONE"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivali (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION:
The present invention relates to a delayed release formulation with a core comprising a drug and a delayed release coating. In particular, it relates to a delayed release formulation for a drug for delivering to the intestine. The active ingredient for the pharmaceutical compositions in delayed release system according to present invention is prednisone or a pharmaceutically-acceptable salt thereof. Prednisone is the most common prescribed steroid for chronic conditions.
BACKGROUND OF THE INVENTION:
The present invention relates to delayed release prednisone dosage form.
This invention relates to delayed release prednisone dosage form, their preparation, and pharmaceutical use.
Prednisone is a glucocorticoid having anti-inflammatory effect. Prednisone is indicated for conditions like Endocrine Disorders, Rheumatic Disorders, Dermatologic Diseases and Allergic conditions like allergic rhinitis etc.
The molecular formula for prednisone is C21H26O5. The chemical name for prednisone is 17,21-dihydroxypregna-l,4-diene-3,11,20-trione, and the structural formula is:

It is further considered highly desirable to provide such delayed release formulations with dissolution profile and pharmacokinetic properties which provide the most effective anti-inflammatory properties in patients.
Delayed release preparations containing pharmaceutical active ingredients are highly useful preparations capable of controlling blood concentrations of pharmacologically active ingredients and sustaining pharmacological effects.
U.S. Patent No. 5,792,476 discloses a sustained-release formulation of a glucocorticoid such as prednisone comprising 2.5-7 mg of the glucocorticoid releasing at least 80% by weight of the glucocorticoid into the small intestine of a

mammal during a period of about 40-80 min. The '476 patent also claims method of treating rheumatoid arthritis using a sustained-release formulation of a glucocorticoid.
PCT publication No. WO 2004/093843 discloses a tablet comprising prednisone with a specific core geometry to release the active ingredient in a specific delayed release manner.
U.S. Pat. No. 6,488,960 discloses a pharmaceutical dosage form for controlled release of prednisone. The formulation comprises 0.25 mg to 2 mg of prednisone which releases at least 90% by weight of the corticosteroid 2 hours to 8 hours after administration. The '960 patent also claims method of treating rheumatoid arthritis using controlled release formulation of prednisone.
U.S. Patent No. 8,168,218 discloses press-coated tablet comprising a core containing 5 mg of prednisone and a coating around the core. Formulation is adapted to provide a lag time of about 2 to 6 hours during which substantially no drug substance is released.
Indian application No. 1403/DELNP/2006 exemplifies delayed release oral solid dosage form of prednisone. The '403 application covers delayed release composition wherein compression coating delays the release of drug until after a period of time from about 2 to about 18 hours after exposure of the dosage form to an aqueous solution.
There is a continual need for delayed release compositions that provide stable and reliable delivery of prednisone to targeted areas of the gastrointestinal tract.
It is therefore an object of the present invention to provide a delayed release formulation of prednisone which has a rate of release of prednisone over a long period of time with delay of at least 2 hours.
However, the prior arts disclosed above did not provide formulations as described herein.
SUMMARY OF INVENTION:
The present invention relates to a delayed release formulation with a core comprising a drug and a delayed release coating. In particular, it relates to a delayed release formulation for a drug for delivering to the intestine. Accordingly, it is an object of the present invention to provide an improved delayed release compositions containing prednisone.
Specifically, the invention provides a delayed release oral dosage form comprising

a) a core comprising prednisone or its pharmaceutically acceptable salts;
b) delayed release coating comprising a polymeric material;
c) citric acid derivatives;
along with one or more pharmaceutically acceptable excipient(s).
According to one embodiment of the present invention there is provided a delayed release pharmaceutical preparation which comprises prednisone, the delayed release of which in the intestinal tract of a patient is desired, and citric acid derivatives. The citric acid derivative is preferably sodium citrate.
In a preferred embodiment of the present invention there is provided a delayed release oral dosage form comprising
a) a core comprising prednisone or its pharmaceutically acceptable salts;
b) delayed release coating comprising a polymeric material;
c) citric acid derivatives;
along with one or more pharmaceutically acceptable excipient(s);
wherein the dosage form provides a dissolution rate (measured by USP. paddle method in 500 ml water at 37 °C) of not more than about 25% after 3 hours and not less than 70% after 7 hours.
Thus it is an object of the present invention to provide a delayed release dosage form comprising prednisone wherein the dosage form provides a dissolution rate (measured by USP. paddle method at 50 rpm in 500 ml water at 37 °C) of not more than about 25% after 3 hours and not less than 70% after 7 hours.
It is another object of the present invention to provide method for preparing said compositions.
The invention is based on the finding that providing a functional outer coating of cellulose or acrylic polymer material along with citric acid derivatives enhances the release characteristics of the composition.
DETAILED DESCRIPTION OF THE INVENTION
The above and other objects and features of the present invention will become apparent from the following description of the invention.

The present invention relates to a delayed release drug delivery system comprising a core composition and a delayed release coating composition.
In one embodiment the present invention relates to a delayed release drug delivery system comprising a core composition comprising an active ingredient and a delayed release coating composition.
The active ingredient for the pharmaceutical compositions in delayed release system according to one embodiment of the invention is prednisone or a pharmaceutically-acceptable salt thereof.
In order to achieve delayed release profile, development was directed toward delayed release coated tablets having a quickly disintegrating core with a polymeric coating which allows release of the prednisone in a very specific time.
In one embodiment the present invention relates to a delayed release drug delivery system comprising a core composition comprising prednisone and a delayed release coating composition.
In another embodiment the present invention relates to a core composition comprising prednisone and pharmaceutically acceptable excipients. The present invention also relates to delayed release dosage form comprising a core composition of prednisone in the range about 0.1% to 10% w/w, preferably about 0.1 to 5% w/w. In one aspect of the invention the core may be prepared by granulating the drug and one or more pharmaceutically acceptable excipients together using any conventional techniques for example dry granulation, direct compression, wet granulation, melt granulation and extrusion-spheronization. Among the above-mentioned processes, wet granulation is the preferred one. The core may additionally comprise one or more pharmaceutically acceptable excipients. The pharmaceutical excipients include but are not limited to binders, lubricants, glidants, fillers, diluents, disintegrants and the like.
Diluents may be, for example, any pharmaceutically acceptable, non-toxic diluent. Particular examples include lactose, dextrose, sucrose, maltose, microcrystalline cellulose, starch, calcium hydrogen phosphate, mannitol and the like. The core comprises the diluent from about 10-90% w/w, preferably about 15 to 70% w/w, and most preferably about 20 to 50% w/w. In preferred embodiments, the diluent is lactose.
Binders may be, for example, starch, sugars, glims, low molecular weight hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose, hydroxyethyl cellulose or the like. The core comprises the binder from about 0.1-40% w/w, preferably about 1 to 30% w/w, and most preferably about 2.5 to 20% w/w.

Lubricants may be, for example, talc, magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sodium benzoate or the like. The core comprises the lubricants from about 0.05- 20% w/w, preferably about 0.1 to 10% w/w, and most preferably about 0.5 to 5% w/w. In preferred embodiments, the lubricant is magnesium stearate.
Antiadherents and Glidants may be, for example, colloidal silicon dioxide, talc or the like. The core comprises the antiadherents and glidants from about 0.1- 20% w/w, preferably about 0.5 to 10% w/w, and most preferably about 1 to 5% w/w. In preferred embodiments, the antiadherent is aerosol 200.
Disintegrants may be, for example, croscarmellose sodium, crospovidone, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium starch glycolate, starch or the like. The core comprises the disintegrants from about 1-50% w/w, preferably about 5 to 40% w/w, and most preferably about 10 to 30% w/w. In preferred embodiments, the disintegrant is crospovidone.
In one embodiment the present invention relates to delayed release dosage form comprising a core composition comprising prednisone and a citric acid derivative. In preferred embodiments, the citric acid derivative is sodium citrate. The core comprises the citric acid derivatives from about 0.1-50% w/w, preferably about 1 to 40% w/w, and most preferably about 5 to 30% w/w.
In accordance with a first aspect of the present invention, there is provided a delayed release drug composition for oral administration to deliver prednisone, said composition comprising a core and a coating for the core, the core comprising prednisone and the coating comprising a polymeric material.
In one embodiment the present invention relates to delayed release oral dosage form comprising:
a) a core comprising prednisone in the range about 0.1 to 5% w/w,
b) delayed release coating comprising the ammonio methacrylate copolymer dispersion of Type A (Eudragit RL 30D) or Type B (Eudragit RS 30D) or mixtures thereof in the range about 1% to 40% w/w; and
c) citric acid derivative in the range about 0.1% to 50% w/w.
In one embodiment the present invention relates to delayed release dosage form comprising a delayed release coating, wherein the delayed release coating comprises a polymeric material. The delayed release coating comprising the polymeric material which is capable of delaying the release of Prednisone from the

core. The polymeric material may be, for example, hypromellose (HPMC), high and low molecular weight cross linked polyacrylic acid polymers (Carbopol polymers) and various grades of copolymer of ethyl acrylate, methyl acrylate and low content of methacrylic acid ester with quaternary ammonium groups (Eudragit polymers) or the like. Preferably the polymeric material may be Eudragit® RL 30 D and Eudragit® RS 30 D known under the commercial names —chemically referred to as an ammonio methacrylate copolymer dispersion of Type A and Type B, respectively. The delayed release coating comprises the polymeric material from about 1-40% w/w, preferably about 2 to 30% w/w and most preferably about 5 to 20% w/w. Preferably the delayed release coating comprises ammonio methacrylate copolymer dispersion of Type A or Type B from about 1-40% w/w, preferably about 2 to 30% w/w and most preferably about 5 to 20% w/w.
The delayed release coating may additionally comprise one or more pharmaceutically acceptable excipients. The pharmaceutical excipients include but are not limited to binders, lubricants, fillers, diluents, plasticizer and the like. The binders, lubricants, fillers, diluents are described as supra.
Preferably, the plasticizer is selected from the group consisting of dibutylsebacate, triethyl citrate, tributyl citrate, glyceryl triacetate, propylene glycol, acetyltriethyl citrate, diethyl phthalate, copolymers of propylene oxide and ethylene oxide, poloxamers and a mixture thereof. In preferred embodiments, the plasticizer is triethyl citrate.
In another embodiment the present invention relates to a delayed release oral dosage form comprising a core comprising prednisone or its pharmaceutically acceptable salts, a delayed release coating comprising a polymeric material and citric acid derivatives along with one or more pharmaceutically acceptable excipient(s). The core composition comprises prednisone in the range about 0.1% to 10% w/w, preferably about 0.1 to 5% w/w. The core composition of prednisone additionally comprises a citric acid derivative. In preferred embodiments, the citric acid derivative is sodium citrate. The core comprises the citric acid derivatives from about 0.1-50% w/w, preferably about 1 to 40% w/w, and most preferably about 5 to 30% w/w. The delayed release coating comprising the polymeric material which is capable of delaying the release of Prednisone from the core. The polymeric material may be Eudragit® RL 30 D and Eudragit® RS 30 D known under the commercial names —chemically referred to as an ammonio methacrylate copolymer dispersion of Type A and Type B, respectively. The delayed release coating comprises ammonio methacrylate copolymer dispersion of Type A or Type B from about 1-40% w/w, preferably about 2 to 30% w/w and most preferably about 5 to 20% w/w. The delayed release oral dosage form additionally comprise one or more pharmaceutically acceptable excipients. The pharmaceutical excipients

include but are not limited to binders, lubricants, glidants, fillers, diluents, disintegrants and the like. The binders, lubricants, glidants, fillers, diluents, disintegrants are described as supra. The delayed release oral dosage form provides a dissolution rate (measured by USP. paddle method in 500 ml water at 37 °C) of not more than about 25% after 3 hours and not less than 70% after 7 hours.
Dissolution study
Another object of the invention is to provide dissolution profile of a delayed release dosage form of the invention comprising prednisone wherein the dosage form provides a dissolution rate (measured by USP. paddle method at 50 rpm in 500 ml water at 37 °C) of not more than about 25% after 3 hours and not less than 70% after 7 hours. In preferred embodiments, the dosage form provides a dissolution rate (measured by USP. paddle method at 50 rpm in 500 ml water at 37 °C) of not more than about 15% after 3 hours and not less than 90% after 7 hours.
The inventors have now developed a delayed release dosage form of Prednisone, which surprisingly exhibits improved dissolution. The core comprises prednisone which may be mixed with citric acid derivative which acts as dissolution enhancer. Prednisone, citric acid derivative and other pharmaceutically acceptable excipients are mixed to provide a homogeneous mixture and subsequently compressed to form a tablet.
In an alternative to the first aspect, the present invention relates to a delayed release drug delivery system comprising a core composition and a delayed release coating composition. The coating comprising an outer layer and an inner layer, wherein the outer layer comprises a polymeric material for delayed release and the inner layer comprising a hydrophilic polymer. The inner layer is coated on the core. The outer layer is disposed around the inner layer. The core comprises prednisone and pharmaceutically acceptable excipients.
In one embodiment the present invention relates to delayed release oral dosage form comprising
a) a core comprising prednisone in the range about 0.1 to 5% w/w,
b) inner layer coated around the core, wherein the inner layer comprises a hydrophilic polymer in the range about 1 to 10% w/w;
c) outer layer disposed around the inner layer, wherein the outer layer comprises a polymeric material in the range about 1% to 40% w/w; and
d) citric acid derivatives in the range about 0.1% to 50% w/w.

In one embodiment the present invention relates to delayed release dosage form comprising an inner layer, wherein the inner layer comprises a hydrophilic polymer. The inner layer is coated on the core. The hydrophilic polymer may be, for example, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose or the like. The inner layer comprises the hydrophilic polymer from about 0.1-20% w/w, preferably about 0.5 to 15% w/w, and most preferably about 1 to 10% w/w. The inner layer may additionally comprise one or more pharmaceutically acceptable excipients. The pharmaceutical excipients include but are not limited to binders, lubricants, fillers, diluents, disintegrants, plasticizers and the like. The binders, lubricants, fillers, diluents, disintegrants, plasticizers are described as supra. Depending on the dissolution profile desired, the weight gained with the inner layer might vary from about 1 to 30% of the weight of the core. Preferably, the weight gain after the inner layer is approximately 5 to 20% of the weight of the core.
In the invention, when two layers are "adjacent", that means the two layers are in physical proximity with each other. Preferably, the two layers are in direct contact atleast at one point.
In one embodiment the present invention relates to delayed release dosage form comprising an inner layer comprising a hydrophilic polymer and a citric acid derivative. In preferred embodiments, the citric acid derivative is sodium citrate. The inner layer comprises the citric acid derivatives from about 0.1-20% w/w, preferably about 0.5 to 15% w/w, and most preferably about 1 to 10% w/w.
In one embodiment the present invention relates to delayed release dosage form comprising an outer layer, wherein the outer layer comprises a polymeric material. The outer layer comprising the polymeric material is capable of delaying the release of Prednisone from the core. The outer layer is coated on the inner layer. The polymeric material may be, for example, hypromellose (HPMC), high and low molecular weight cross linked polyacrylic acid polymers (Carbopol polymers) and various grades of copolymer of ethyl acrylate, methyl acrylate and low content of methacrylic acid ester with quaternary ammonium groups (Eudragit polymers) or the like. Preferably the polymeric material may be Eudragit® RL 30 D and Eudragit® RS 30 D known under the commercial names —chemically referred to as an ammonio methacrylate copolymer dispersion of Type A and Type B, respectively. The outer layer comprises the polymeric material from about 1-40% w/w, preferably about 2 to 30% w/w and most preferably about 5 to 20% w/w. Preferably the outer layer comprises ammonio methacrylate copolymer dispersion of Type A or Type B from about 1-40% w/w, preferably about 2 to 30% w/w and most preferably about 5 to 20% w/w.

The outer layer may additionally comprise one or more pharmaceutically acceptable excipients. The pharmaceutical excipients include but are not limited to binders, lubricants, fillers, diluents, plasticizer and the like. The binders, lubricants, fillers, diluents, plasticizer are described as supra.
In one embodiment the present invention relates to delayed release dosage form comprising an outer layer comprising a polymeric material and a citric acid derivative. In preferred embodiments, the citric acid derivative is sodium citrate. The inner layer comprises the citric acid derivatives from about 0.1-20% w/w, preferably about 0.5 to 15% w/w, and most preferably about 1 to 10% w/w. The citric acid derivatives are added to polymeric solutions and dispersions to increase the flexibility or distensibility of the polymeric material.
Preferably, the combination of hydroxypropyl methyl cellulose can be used along with Eudragit RL or Eudragit RL to achieve the desired drug release.
According to the preferred embodiment, the total amount of Prednisone in the dosage form ranges from about 1 mg to about 15 mg, preferably in the amount of about 1 mg, 2 mg or 5 mg.
In one embodiment the present invention relates to a delayed release drug delivery system comprising a core composition comprising prednisone, a delayed release coating composition comprising a polymeric material and a citric acid derivative.
In another embodiment the present invention relates to a delayed release drug delivery system comprising a core composition comprising prednisone and pharmaceutically acceptable excipients, a delayed release coating composition comprising a polymeric material and pharmaceutically acceptable excipients and a citric acid derivative. The core comprising prednisone, a citric acid derivative and pharmaceutically acceptable excipients. The delayed release coating composition comprising a polymeric material, a citric acid derivative and pharmaceutically acceptable excipients.
In another embodiment the present invention relates to a delayed release drug delivery system comprising a core composition comprising prednisone and pharmaceutically acceptable excipients, a delayed release coating composition comprising a polymeric material and pharmaceutically acceptable excipients and a citric acid derivative. The core comprising prednisone, a citric acid derivative and pharmaceutically acceptable excipients. The delayed release coating comprising an outer layer and an inner layer, wherein the outer layer comprises a polymeric material for delayed release and the inner layer comprising a hydrophilic polymer. The outer layer comprising a polymeric material, a citric acid derivative and

pharmaceutically acceptable excipients. The inner layer comprising a hydrophilic material, a citric acid derivative and pharmaceutically acceptable excipients. The inner layer is coated on the core. Optionally, the dosage form is partially or completely surrounded by a film coating layer.
In a preferred embodiment, the invention provides a delayed release oral dosage form comprising
a) a core comprising prednisone or its pharmaceutically acceptable salts;
b) delayed release coating comprising a polymeric material;
c) citric acid derivatives;
along with one or more pharmaceutically acceptable excipient(s).
In another aspect, the invention provides a. delayed release oral dosage form comprising
a) a core comprising prednisone or its pharmaceutically acceptable salts;
b) inner layer comprising a hydrophilic polymer;
c) outer layer comprising delayed release coating comprising a polymeric material;
d) citric acid derivatives;
along with one or more pharmaceutically acceptable excipient(s).
The Core
In preferred embodiments, the delayed release composition comprises a core comprising prednisone or its pharmaceutically acceptable salts. The core can be any suitable dosage form, for example, a tablet, a pellet, a granule, a microparticle, a hard or soft capsule. In preferred embodiments, the core is a tablet. The core composition is prepared by mixing excipients in a granulator; wet granulating the mixed blend using prednisone dispersion; drying and milling the mixture; blending the mixture with lubricant and finally compressing the blended mixture to form core tablets.

Inner layer
In preferred embodiments, the delayed release composition comprises an inner layer comprising a hydrophilic polymer. The hydrophilic polymers that may be used in the present invention include methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methyl cellulose, and hydroxypropyl methyl cellulose. A preferred hydrophilic polymer is hydroxypropyl methylcellulose.
Outer layer
In preferred embodiments, the delayed release composition comprises an outer layer comprising a polymeric material for delayed release. The polymeric material is selected from hypromellose (HPMC), high and low molecular weight cross linked polyacrylic acid polymers (Carbopol polymers) and various grades of copolymer of ethyl acrylate, methyl acrylate and low content of methacrylic acid ester with quaternary ammonium groups (Eudragit polymers). A preferred polymer is Ammonio Methacrylate Copolymer Dispersion. Preferably ammonio methacrylate copolymer dispersion of Type A or Type B is about 1-40% w/w, preferably about 2 to 30% w/w and most preferably about 5 to 20% w/w. The presence of quaternary ammonium groups and citric acid derivatives increases permeability in aqueous media.
Citric acid derivatives
In preferred embodiments, the delayed release composition comprises a citric acid derivatives. In most preferred embodiments, the citric acid derivative is sodium citrate.
Each layer can contain other pharmaceutical excipients, so as to give suitable properties for compression, lubrication and/or binding as is well known to one skilled in the art.
A further technical advantage of the present invention is that substantially no drug is released for an extended period (while the coating is intact), following which the drug is released relatively quickly.
The Inventors have discovered that using the citric acid derivative in composition has superior intestinal release properties over comparative coatings designed for site-specific release.
The composition of the present invention further typically includes pharmaceutically acceptable excipients which are routinely incorporated into solid dosage forms. Common excipients include granulating aids, colorants, flavorants, surfactants, pH adjusters, anti-adherents and glidants etc.

Another preferred embodiment of the present invention includes compositions comprising a polymeric material, preferably about 5 to about 20% by weight of the composition and citrate derivatives, preferably about 5 to 30% w/w by weight of the composition.
In one embodiment the process for the preparation of delayed release dosage form of prednisone comprises the steps of:
1. Mixing excipients in a granulator;
2. wet granulating the mixed blend using prednisone dispersion;
3. drying and milling the mixture;
4. blending the mixture with lubricant and finally compressing the blended mixture to form core tablets;
5. Coating the tablets.
In another embodiment, delayed release dosage form of prednisone is prepared by:
1. Mixing citric acid derivative and other pharmaceutically acceptable excipients in a rapid mix granulator;
2. wet granulating the mixed blend with dispersion of prednisone with disintegrant in suitable vehicle;
3. drying and milling the mixture;
4. blending the mixture with magnesium stearate and finally compressing the blended mixture to form core tablets.
5. coating the tablets with release retarding polymeric agents.
6. optionally coating with color coating material
According to another embodiment, the present invention provides for a process for the preparation of a delayed release pharmaceutical composition of prednisone. The process includes the steps of:
1. Mixing citric acid derivative and other pharmaceutically acceptable excipients in a rapid mix granulator;
2. wet granulating the mixed blend with dispersion of prednisone with disintegrant in suitable vehicle;
3. drying and milling the mixture;

4. blending the mixture with magnesium stearate and finally compressing the blended mixture to form core tablets.
5. coating the dosage form of step 4 with a delayed release coating comprising a polymeric material.
7. optionally coating with film coating material
A fundamental feature of the process of the present invention is that it uses only water as solvent making it environment friendly and commercially viable.
The present invention provides a delayed release oral dosage form which has a suitable in-vitro release profile and improved stability.
In a further aspect of the present invention there is provided a solid oral dosage form containing the delayed release drug delivery system as described herein. Preferably, the solid oral dosage form is in the form of a capsule or tablet. More preferably, the solid oral dosage form is in the form of a tablet.
The term "pharmaceutical composition" as used herein includes solid dosage forms such as tablet, capsule, pellets, pill and the like.
The term "pharmaceutically acceptable excipients" as used herein includes diluents, lubricants, plasticizers, opacifiers, disintegrants, glidants, coloring agents and the like.
The term "polymeric materials" as used herein may include but not limited to methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, crosslinked sodium carboxymethyl cellulose, crosslinked polyvinyl pyrrolidone, galactomannans, tragacanth, guar gum, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinyl alcohol and polyvinylpyrrolidone, polyethylene oxide, polypropylene oxide and copolymers of ethylene oxide, propylene oxide, high and low molecular weight cross linked polyacrylic acid polymers (Carbomers) and various grades of copolymer of ethyl acrylate, methyl acrylate and low content of methacrylic acid ester with quaternary ammonium groups. Another exemplary combination can be found under the commercial names Eudragit® RL 30 D and Eudragit® RS 30 D—chemically referred to as an ammonio methacrylate copolymer dispersion of Type A and Type B, respectively. Preferably ammonio methacrylate copolymer dispersion of Type A or Type B is about 1-40% w/w, preferably about 2 to 30% w/w and most preferably about 5 to 20% w/w.

The term "citric acid derivative" as used herein may include but not limited to sodium citrate.
A "delayed release" composition may be designed to delay the release of the drug for a specified period. It also includes compositions that only begin releasing the drug after a fixed period of time.
A "hydrophilic polymers" that may be used in the present invention may include but not limited to methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, crosslinked sodium carboxymethyl cellulose, crosslinked polyvinyl pyrrolidone, galactomannans, tragacanth, guar gum, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinyl alcohol and polyvinylpyrrolidone, polyethylene oxide, polypropylene oxide and copolymers of ethylene oxide and propylene oxide. A preferred hydrophilic polymer is hydroxypropyl methylcellulose.
Stability Study
The pharmaceutical compositions of the present invention are stable when tested over time upon storage under the recommended temperature conditions. The pharmaceutical formulation has a good stability.
A stability study on the pharmaceutical compositions identified as Example 1 is launched at 30° C ./65% RH and 40° C/75% RH (RH: relative humidity).
Table 1- 30° C./65% RH:

Sr. no Test Limit Period (Months)

Initial 03 06
1 Related substances : Any individual impurity Not more than 0.5% 0.260 0.390 0.436
2 Related substances : Total impurities Not more than 2.0% 0.954 1.388 1.683
3 Assay NLT 90.0 % and NMT 110.0% of the 101.9 100.8 99.3

labeled claim
Table 2- 40° C./75% RH :

Sr. no Test Limit Periods (Months)

Initial 01 02 03 06
1 Related substances : Any
individual impurity Not more than 0.5% 0.260 0.260 0.398 0.394 0.458
2 Related substances : Total impurities Not more than 2.0% 0.954 0.917 1.349 1.369 1.765
3 Assay NLT 90.0
% and
NMT
110.0% of
the
labeled
claim 101.9 101.3 101.0 99.8 98.7
This investigational study carried out in accelerated temperature conditions demonstrated the suitable stability of the proposed delayed release formulations with a very good Impurity Profile.
It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, that the description above as well as the examples which follow are intended to illustrate and not limit the scope of the invention.
Examples
The specific nature of the composition of the present invention will be more fully apparent from consideration of the following specific examples of preferred embodiments thereof. In the examples, as in the preceding description, all parts and percentages are given by weight unless otherwise indicated.

Table 3-

Ingredients % w/w

Ex 1 Ex 2 Ex 3 Ex 4 Ex 5 Ex 6 Ex 7 Ex 8 Ex 9 Ex 10 Ex 11 Ex 12
Core
Prednisone 2.11 2.14 2.07 1.87 1.62 1.92 2.14 1.92 2.21 1.85 0.33 0.73
Aerosil 200 0.84 0.86 0.82 0.74 0.64 0.76 0.86 0.76 0.88 0.74 0.66 0.72
Lactose monohydrate 34.45 34.83 33.82 30.47 26.40 31.23 43.38 40.80 36.06 30.07 27.85 30.67
Sodium starch
glycolate ■"* 21.37 ™~ 18.69 ™" ™" 12.82 ™~ ™~ 18.45 "™ ™~
Crospovidone 21.13 — 20.75 — 16.20 19.16 — 19.16 22.12 — 16.29 18.15
Sodium
chloride — 10.68 10.37 ~ -- -- -- — — -- -- --
Sodium Citrate 10.57 — — 9.35 8.10 9.58 10.68 ~ 11.06 9.23 8.14 9.07
Purified Water q.s. q.s. q.s. q.s. q.s q.s. q.s q.s q.s q.s q.s q.s
Low
substituted Hydroxypropyl cellulose 8.45 8.55 8.30 7.48 6.48 7.66 8.55 7.66 8.85 7.38 6.51 7.26
Magnesium Stearate 0.63 0.64 0.62 0.56 0.49 0.57 0.64 0.57 0.70 0.55 0.49 0.54

Seal coating (In ner layer)
Opadry Clear 03K19229 IH 3.8 3.85 3.73 3.36 2.92 3.45 3.85 3.45 3.98 — 2.93 3.27
Sodium
chloride — 3.42 3.34 — — — 3.42 - — ~ — --
Sodium Citrate 3.38 -- — 2.99 2.59 3.07 ~ 3.07 — — 2.61 2.90
Crospovidone 1.69 1.71 1.66 1.50 1.30 1.53 1.71 1.53 1.77 -- 1.30 1.45
Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. — q.s. q.s.

Functional Coat ing (Oute r layer c >r delayed releas e coating)
Eudragit RL 30D -- — 5.18 5.35 16.68 9.85 ~ — — -- 16.94 12.34
Eudragit RS 30D 4.97 4.27 0.58 5.35 — — 4.27 — 4.42 — ~ —
Ethyl cellulose (Ethocel 10 cps) 14.76
Ethyl cellulose (Ethocel 45 cps) 9.85
Hydroxypropyl
methylcellulos
e 0.99 0.85 1.15 2.14 3.34 1.97 0.85 1.97 0.88 7.38 3.39 2.47
PEG 6000 — — — — 1.67 ~ .. — — ~ ~ —
Triethyl Citrate 0.25 0.43 0.58 1.07 — 0.49 0.43 0.49 0.44 1.48 0.85 0.62
Talc 2.49 2.14 2.88 5.35 8.34 4.93 2.14 4.93 2.21 4.43 8.47 6.17
Isopropyl alcohol -- -- -- ~_ __ ~~ " q.s. -- q.s. ~~ ~~

Methylene dichloride ~ — — — — ~ — q.s. — q.s. — --
Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. ~ q.s. — q.s. q.s.

Colour Coating
Instacoat Universal A05D02491 Orange IH 3.40 3.42 3.32 2.99 2.59 3.07 3.42 3.07 3.54 2.95 2.61 2.90
Sodium Citrate 0.85 0.85 0.83 0.75 0.65 0.77 0.85 0.77 0.88 0.74 0.65 0.74
Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Total weight of tablets % 100 100 100 100 100 100 100 100 100 100 100 100
Examples 1 to 12
TABLE 3 shows compositions of laboratory scale batches containing prednisone and various excipients. For each of the formulations,
Core:
a. Prednisone, sodium citrate and other pharmaceutically acceptable
excipients are sifted through a suitable sieve and thoroughly mixed for a
desired time;
b. Granulate the powder mix in granulator as prepared in step a) by using
water; subsequently dry the granules for a desired time;
c. Magnesium stearate is separately sifted through a suitable sieve;
d. Material of step b) is blended with the material of step c) for a suitable time;
and
e. The lubricated blend of step d) is compressed into tablets using appropriate
tooling to form a core.
Seal coating (inner layer):
f. Opadry and other pharmaceutically acceptable excipients are mixed in water
for a desired time to form a coating solution;
g. The coating solution as obtained above in step f) was coated on the core of
step e) in a conventional coating pan under appropriate coating conditions
for yielding defined results;
h. The seal coated tablets are obtained with desired weight gain.
Functional Coating (outer layer or delayed release coating):
i. Eudragit, HPMC and other pharmaceutically acceptable excipients are mixed in water for a desired time to form a coating solution;

j. The coating solution as obtained above in step i) was coated on the seal coated core of step h) in a conventional coating pan under appropriate coating conditions for yielding defined results;
k. The delayed release coated tablets are obtained with desired weight gain.
Film coating:
1. The delayed release coated tablets as obtained above in step k) are optionally film coated with excipients mentioned in the Table 2.
In vitro release
The in vitro release profile of the composition as prepared in Examples 1, 3, 6, 8 and 10 were analysed using USP dissolution Apparatus 2 (paddle). The following conditions were used: temperature 37.0 ±0.5°C; paddle speed 50 rpm. The level of release at particular time points were analysed.

Sampling time in Hours % of drug release

Example 1 Example
3 Example 6 Example 8 Example 10
2 0 2.1 0 0 3.2
3 1.3 8.7 2.3 1.6 9.9
5 69.0 73 75.3 59.4 66.7
7 99.2 99.1 100.4 92.8 92.6
The tablets prepared according to present invention do not begin the release of prednisone for about 2 hours. There is a rapid release of prednisone at 5 hours and within approximately 7 hours, above 90% of the prednisone is released from the formulation.
Methacrylate polymers significantly retarded the drug release rate and that drug release was varied according to the amount of plasticizer used.
While various embodiments in accordance with the present invention have been shown and described, it is understood the invention is not limited thereto, and is

susceptible to numerous changes and modifications as known to those skilled in the art. Therefore, this invention is not limited to the details shown and described herein, and includes all such changes and modifications as encompassed by the scope of the claims.

WE CLAIM:
1. A delayed release oral dosage form comprising
a) a core comprising prednisone or its pharmaceutically acceptable salts;
b) delayed release coating comprising a polymeric material;
c) citric acid derivatives;
along with one or more pharmaceutically acceptable excipient(s);
wherein the dosage form provides a dissolution rate (measured by USP. paddle method in 500 ml water at 37 °C) of not more than about 25% after 3 hours and not less than 70% after 7 hours.
2. The delayed release oral dosage form of claim 1, wherein the polymeric material is selected from hypromellose (HPMC), high and low molecular weight cross linked polyacrylic acid polymers and various grades of copolymer of ethyl acrylate, methyl acrylate and low content of methacrylic acid ester with quaternary ammonium groups; wherein the polymeric material is used in the range of about 1% to 40% w/w.
3. The delayed release oral dosage form of claim 2, wherein the polymeric material is ammonio methacrylate copolymer dispersion of Type A (Eudragit RL 30D) or Type B (Eudragit RS 30D) or mixtures thereof.
4. The delayed release oral dosage form of claim 1, wherein the citric acid derivative is sodium citrate.
5. The delayed release oral dosage form of claim 1, wherein the citric acid derivative is used in the range of about 0.1% to 50% w/w.
6. The delayed release oral dosage form of claim 1, wherein the dosage form provides a dissolution rate (measured by USP. paddle method in 500 ml water at 37 °C) of not more than about 15% after 3 hours and not less than 90% after 7 hours.
7. The delayed release oral dosage form of claim 1, wherein the pharmaceutically acceptable excipient is selected from diluents, binder, disintegrant, surfactant, glidant and lubricant.

8. The delayed release oral dosage form of claim 1, wherein Prednisone is used in the range of 0.1 to 5% w/w.
9. The delayed release oral dosage form of claim 1, wherein the dosage form comprises:

a) the core comprising prednisone in the range about 0.1 to 5% w/w,
b) delayed release coating comprising the ammonio methacrylate copolymer dispersion of Type A (Eudragit RL 30D) or Type B (Eudragit RS 30D) or mixtures thereof in the range about 1% to 40% w/w; and
c) citric acid derivative in the range about 0.1% to 50% w/w.
10. A delayed release oral dosage form comprising
a) a core comprising prednisone in the range about 0.1 to 5% w/w,
b) inner layer coated around the core, wherein the inner layer comprises a hydrophilic polymer in the range about 1 to 10% w/w;
c) outer layer disposed around the inner layer, wherein the outer layer comprises a polymeric material in the range about 1% to 40% w/w; and
d) citric acid derivatives in the range about 0.1% to 50% w/w.