FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL DOSAGE FORM"
2. APPLICANT:
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention.

Technical field:
The present invention relates to a multi-unit pharmaceutical dosage forms and process for making the same thereof.
Background & Prior Art:
Irritable Bowel Syndrome (IBS) is part of a spectrum of diseases known generally as Functional Gastrointestinal Disorders which include diseases such as non-cardiac chest pain, non-ulcer dyspepsia, and chronic constipation or diarrhoea. Ulcerative colitis is one another most common inflammatory bowel disease and it can be difficult to diagnose because its symptoms are similar to other intestinal disorders and to another type of IBD called Crohn's disease. Crohn's disease differs from ulcerative colitis because it causes inflammation deeper within the intestinal wall. Also, Crohn's disease usually occurs in the small intestine, although it can also occur in the mouth, oesophagus, stomach, duodenum, large intestine, appendix, and anus. The diseases like non-cardiac chest pain, non-ulcer dyspepsia are all characterized by chronic or recurrent gastrointestinal symptoms for which no structural or biochemical cause can be found.
There are two major types of IBS. The first type, spastic-colon type, is commonly triggered by eating, and usually produces periodic constipation and diarrhea with pain. Mucous often appears in the stool. The pain can come in bouts of continuous dull aching pain or cramps, usually in the lower abdomen. The person suffering from spastic- colon type IBS can also experience bloating, gas, nausea, headache, fatigue, depression, anxiety, and difficulty concentrating. The second type of IBS usually produces painless diarrhea or constipation. The diarrhea can begin suddenly and with extreme urgency. Often the diarrhea occurs soon after a meal and can sometimes occur immediately upon awakening. In UK alone, Irritable Bowel Syndrome is responsible for 30-50% of all gastroenterology referrals to secondary care. IBS is believed to be due to a number of
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factors such as physiological, emotional, cognitive and behavioural factors and is frequently encountered during periods of stress. Diagnosis of IBS is one of exclusion and is based on the (Observed symptoms in any given case.
Commonly accepted criteria for IBS, known as the "Rome" criteria, include at least 3 months of continuous or recurrent symptoms of:
(1) abdominal pain or discomfort that is relieved with defecation, and/or associated with a
change in the frequency of stools, and/or associated with a change in the consistency of
stool; and
(2) two or more of the following on at least a quarter of occasions: altered stool
frequency, altered stool form, altered stool passage, passage of mucus, and/or bloating or
feeling of abdominal distension.
Conventional treatment of IBS and other inflammatory bowel diseases are based on the severity and the nature of each person's symptoms and whether or not any psychological factors are involved. Treatment of IBS may include one or more of the following: lifestyle changes, pharmacological treatment and psychological treatment. However, there is no general treatment which is applicable to all cases of IBS.
Broad-spectrum antibiotics are often administered to treat the symptoms. The antibiotic metronidazole is often administered when the disease affects the large intestine or causes abscesses and fistulas around the anus. Long-term use of metronidazole, however, can damage nerves, resulting in pins-and-needles sensations in the arms and legs.
Sulfasalazine and chemically related drugs can suppress mild inflammation, especially in the large intestine. These drugs, however, are less effective in sudden, severe flare-ups.
Corticosteroids, such as prednisone, reduce fever and diarrhoea and relieve abdominal pain and tenderness.
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Corticosteroids have been the mainstay of therapy in patients with moderate to severe active inflammatory bowel disease. They have been extensively used for acute flare-ups of most forms of IBD when 5-ASA (5-acetyl salicylic acid) compounds are inadequate. However, corticosteroids are not appropriate for maintenance. IV hydrocortisone 300 mg/day or methylprednisolone 60 to 80 mg/day by continuous drip or in divided doses is used for severe disease; oral prednisone or prednisolone 40 to 60 mg once/day may be used for moderate disease. Treatment is continued until symptoms remit (usually 7 to 28 days) and then tapered by 5 to 10 mg weekly to 20 mg once/day. Treatment is then further tapered by 2.5 to 5 mg weekly while instituting maintenance therapy with 5-ASA or immunomodulators. Adverse effects of short-term & long term corticosteroid therapy in high doses include hyperglycemia, hypertension, insomnia, hyperactivity, and acute psychotic episodes, increased risk of infection, osteoporosis, water retention, and fragility of the skin.
Hydrocortisone enemas or foam may be used for proctitis and left-sided colon disease; as an enema, 100 mg in 60 ml of isotonic solution is given once/day or bid. The enema should be retained in the bowel as long as possible; instillation at night, with the patient lying on the left side with hips elevated, may prolong retention and extend distribution. Treatment, if effective, should be continued daily for about 2 to 4 wk, then every other day for 1 to 2 wk, and then discontinued gradually over 1 to 2 wk.
Administration & thus, the management of the therapy become cumbersome which may voluntarily or involuntarily affect patient compliance.
CA2291796 disclose pharmaceutical composition for treatment of irritable bowel syndrome which composition is provided with a vanilloid compound and a carrier vehicle.
US2007264314 discloses a process for treating irritable bowel syndrome comprising ingestion of antispasmodic compound, fiber compound and pecan-derived food supplement.
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Among the different routes of drug administration, the oral route has achieved the most attention, partly due to the ease of administration and the important flexibility in dosage-form design. Unfortunately, in most cases, the important variability of gastrointestinal tract's physiology and of its transit time leads to an unpredictable bioavailability and non reproducible therapeutic effects. An orally administrated drug delivery system is exposed to a wide range of highly variable conditions as pH, agitation, intensity and gastric emptying times.
The convenience of administering a single dose of medication which releases an active medicament over an extended period of time as opposed to the administration of a number of singles doses at regular intervals has long been recognized in pharmaceutical field. A prolongation of gastric residence time (GRT) of a rate-controlled oral drug delivery system reduces the inter-subject variability, reduces the so called "peak and valley" effect and leads to a more predictable and a bioavailability increase of the dosage form, especially for molecules with a narrow absorption window.
WO2005074895 discloses an extended release once daily pharmaceutical composition comprising venlafaxine hydrochloride and pharmaceutically acceptable excipients.
EP1852111 discloses a multi-particulate controlled release SSRI formulation for once or twice oral administration comprising two or more population blends of particles, pellets or minitablets.
US5643602 discloses a targeted slow release oral pharmaceutical composition in the treatment of inflammatory bowel disease.
However there still remains a constant need for development of specific delivery of actives which are required to modify/sustain the dosage regimen at the site of action for prophylaxis and/or treatment of inflammatory bowel disease and related disorders.
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Object of the invention:
An object of the present invention is to provide a pharmaceutical dosage form comprising
modified release multiparticulate formulation.
Another object of the present invention to provide a pharmaceutical dosage form comprising modified release multiparticulate formulation with ease of manufacture designed for target specific delivery.
Yet another object of the present invention to provide a pharmaceutical dosage form comprising modified release multiparticulate formulation designed for target specific delivery.
Still another object of the present invention to provide a pharmaceutical dosage form comprising modified release multiparticulate formulation suitable for once daily administration.
Summary of the invention:
According to one aspect, there is provided a pharmaceutical composition comprising modified release multiparticulates along with one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a multiparticulate modified release composition comprising corticosteroids for administration no more frequently, on an average, than atleast 24 hour intervals.
According to yet another aspect, there is provided a process of manufacturing the said pharmaceutical dosage form comprising the said modified release multiparticulate formulation.
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An oral dosage form comprising, a therapeutically effective amount of corticosteroids which impart relief from the symptoms of inflammatory bowel disease upon administration of said dosage form, wherein said corticosteroid is in the form of multiparticulates individually coated with one or more polymer thereby enabling its release in GI tract.
A multiparticulate drug delivery system for gastrointestinal deposition, comprising a modified release composition of corticosteroid selected from the group of budesonide, testosterone, progesterone, estrogen, flunisolide, triamcinolone acetonide, beclomethasone, betamethasone 17-valerate; dexamethasone, fluticasone, methylprednisolone, prednisone, hydrocortisone, ciclesonide, mometasone, desonide, tixocortol or its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
A multiparticulate formulation comprising plurality of microgranules or microtablets that are coated with one or more modified release polymer thereby exhibiting an in-vitro dissolution profile suitable for once-a-day administration
Detailed description of the invention:
As discussed above, the present invention relates to a pharmaceutical composition comprising modified release multiparticulates The inventors have surprisingly found that a target specific delivery comprising corticosteroids, exhibited marked therapeutic efficacy where the orally administered in multiparticulates surpassed first-pass liver metabolism of the active, thus maintaining long term remission of symptoms of bowel disorders (like Crohn's disease).
In one aspect of the present invention the inventors have been able to develop the dosage form, by way of, modified release delivery of the active to the target site i.e. GI tract,
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preferably lower GI tract, by oral administration of multiparticulates comprising drug-polymer matrix along with one or more pharmaceutically acceptable excipients.
The term "modified release" used in the present context is defined as the composition from which the delivery or release of the active at the target site differs from that of a conventional dosage form. The release rate is in other words controlled and it is possible to manipulate the release rate by e.g. changing the formulation parameters. The term "modified" is often used in the sense of prolonged, but the term is not restricted to an extended or prolonged effect; the term "modified" may as well cover the situation where the release rate is manipulated in such a manner that a quicker release than normally expected is obtained. Thus, in the present context, the terms "quick", "fast" and "enhanced" release as well as "controlled", "delayed", "sustained", "prolonged", "extended" and other synonyms well known to a person skilled in the art are covered by the term "modified".
Accordingly, in one embodiment of the present invention the modified release multiparticulates may comprise a core comprising a drug-polymer matrix followed by coating the core with one or more pharmaceutically acceptable film forming polymer/polysaccharide which includes, but are not limited to pharmaceutically acceptable film-forming water swellable polymers, water insoluble polymers, water soluble polymers, natural/synthetic gums or mixtures thereof.
The term drug as used in the specification and corresponding claims refers to the drug per se as well as their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
In another embodiment of the present invention the modified release multiparticulates may comprise core comprising polymer/ polysaccharide treated drug(s) or pharmaceutically acceptable salts, pharmaceutically acceptable solvates,
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pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs. The polymer/polysaccharide may be selected from the class which includes, but are not limited to pharmaceutically acceptable film-forming water swellable polymers, water insoluble polymers, water soluble polymers, natural/synthetic gums or mixtures thereof.
It will be well acknowledged to a person skilled in the art that the context of the present invention may be extended to other therapeutic agents such as orally administrable steroids including but not limited to androgens, estrogens, progestogens, glucocorticoids, mineralocorticoids, anabolic steroids, phytosterols, anti-inflammatory steroids, ergosterols or their synthetic analogues, derivatives and enantiomers thereof.
The pharmaceutical dosage form, according to the present invention, comprises one or
more drugs selected from the class of corticosteroids like e.g. budesonide, ciclesonide,
fluticasone, betamethasone, beclomethasone, tixocortol, formocortal, rimexolone,
triamcinolone; anti-inflammatory drugs like e. g. ibuprofen, indomethacin, naproxen,
nalophine; anti-Parkinsonism agents like e. g. bromocriptine, biperidin, benzhexol,
benztropine; antidepressants like e. g. imipramine, nortriptyline, pritiptyline; antibiotics
like e. g. clindamycin, erythomycin, fusidic acid, gentamicin, mupirocine, amfomycin,
neomycin, metronidazole, sulphamethizole, bacitracin, framycetin, polymyxin-B,
acitromycin; antifungal agents like e. g. miconazole, ketoconazole, clotrimazole,
amphotericin B, nystatin, mepyramine, econazole, fluconazole, flucytocine, griseofulvin,
bifonazole, amorofine, mycostatin, itraconazole, terbenafine, terconazole, tolnaftate;
antimicrobial agents like e. g. metronidazole, tetracyclines, oxytetracylines, penicillins;
antiemetics like e. g. metoclopramide, droperidol, haloperidol, promethazine;
antihistamines like e. g. chlorpheniramine, terfenadine, triprolidine; antimigraine agents
like e. g. dihydroergotamine, ergotamine, pizofylline; coronary, cerebral or peripheral
vasodilators like e. g. nifedipine, diltiazem; antianginals such as, e. g., glyceryl nitrate,
isosorbide dinitrate, molsidomine; calcium channel blockers like e. g. verapamil,
nifedipine, diltiazem, nicardipine; hormonal agents like e. g. estradiol, estriol,
polyestradiol, polyestriol, dienestrol, diethylstilbestrol, progesterone,
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dihydroprogesterone, cyprosterone, danazol, testosterone; contraceptive agents like e. g. ethinyl estradiol, lynestrenol, ethynodiol, norethisterone, mestranol, norgestrel, levonorgestrel, desodestrel, medroxyprogesterone; antithrombotic agents like e. g. heparin, warfarin; diuretics like e. g. hydrochlorothiazide, flunarizine, minoxidil; antihypertensive agents like e. g. propranolol, metoprolol, clonidine, pindolol or their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.
Preferably, according to the one aspect of the present invention, the pharmaceutical dosage form comprise corticosteroid-polymer matrix dispersed with one or more pharmaceutically acceptable excipients for oral administration thereby exhibiting modified release of the active in the GI tract. Alternatively, the said dosage form may comprise individual drug particles coated with suitable one or more polymers to form a core matrix dispersed with one or more pharmaceutically acceptable excipients for oral administration.
According to yet another aspect of the present invention, the modified release multiparticulate formulation is in the form of minitablets; which may comprise a core of a drug-polymer matrix followed by coating the core with one or more pharmaceutically acceptable film forming polymr/polysaccharide which includes, but are not limited to pharmaceutically acceptable film-forming water swellable polymers, water insoluble polymers, water soluble polymers, natural/synthetic gums or mixtures thereof.
According to another aspect of the present invention, the drug-polymer matrix comprises one or more polymers which include, but are not limited to, pharmaceutically acceptable film-forming water swellable polymers, water insoluble polymers, water soluble polymers, polysaccharides/synthetic polysaccharides and mixtures thereof to attain the said modified release which effectively permits the drug to release over a period of, not less than about 24 hours following oral administration.
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The pharmaceutical composition, according to the present invention, comprise drug-polymer matrix dispersed with one or more phrmaceutically acceptable excipients in the form of multiparticulates i.e. a multiplicity of the individual units contained in a formulation in such a form that individual units are made available from the formulation in the gastrointestinal tract that may be administered directly in the form of powder admixture, extrudates, granulates, pellets, beadlets, sugar/salt spheres, minitablets or may be administered in capsules, sachets or other carrier forms. These multiple unit dosage forms possess a large surface area, which advantageously promotes complete and uniform absorption, minimizes peak plasma fluctuations and thus reduces the potential for systemic side effects. A further advantage of these dosage forms is that a high local concentration of the active substance in the GI system is avoided as a consequence of the units being distributed freely throughout the tract.
According to one embodiment, the microparticulate dosage form, according to the present invention, may be in the form of minitablets of dimension ranging from about 1000 to 6000 micrometers.
According to the present invention, the pharmaceutical dosage form may comprise one or more excipients which includes, but are not limited to, diluents, binders, disintegrants, alkalinizing agents, plasticizers, lubricants, glidants, and optionally colourants (e.g. ready colour mix systems).
As discussed above, the pharmaceutically acceptable excipients comprising diluents or fillers which includes, but are not limited to, microcrystalline cellulose, powdered cellulose, sugar compressible, lactose, fructose, lactitol, saccharose, sorbitol, mannitol, dextrates, dextrins, dextrose, maltodextrin, croscarmllose sodium, starch, pregelatinised starch and mixtures thereof.
Examples of binders or binding agents, according to the present invention, which includes, but are not limited to cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxylpropyl cellulose (HPC), hydroxylpropyl methyl cellulose (HPMC);
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polyvinyl pyrrolidone (PVP), gelatin, gum arabic, polyvinyl alcohol, tragacanth, sodium alginate and equivalents thereof. Additionally, suitable organic solvents may be incorporated as binder solvents which include, but are not limited to, water; aliphatic alcohols such as ethanol, methanol, isopropyl alcohol; ketones such as acetone and others.
Examples of the disintegrants, according to the present invention, which includes, but are not limited to hydroxylpropyl cellulose (HPC), low density HPC, carboxymthylcellulose (CMC), sodium CMC, calcium CMC, croscarmellose sodium, starch, crystalline cellulose, sodium starch glycollate, hydroxylpropyl starch and equivalents thereof.
Examples of suitable glidants and lubricants, according to the present invention, which includes, but are not limited to stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, colloidal silicon dioxide and equivalents thereof.
Additionally, as described above, the polymers that may be incorporated in the pharmaceutical dosage form are selected from the group consisting of pharmceutically acceptable film-forming water swellable polymers, water insoluble polymers (water insoluble acrylic or water insoluble cellulosic or both), water soluble polymers, natural/synthetic gums, waxes or mixtures thereof.
According to the invention, fim forming water swellable polymers may be selected from gum arabic, Carrageenan, Guar gum, Gum tragacanth, Agar, Sodium Carboxymethyl cellulose, Hydroxyethyl cellulose (HEC), Hydroxypropylmthylcellulose (HPMC), sodium alginate, Chitosan, Xanthan gum, Sodium croscarmellose, pectin and combinations thereof.
According to the invention, film forming water soluble polymers may be selected from hompolymers and co-polymers of N-vinyllacamsespecially homopolymers and co¬polymers of N-vinyl pyrrolidone e.g. polyvinylpyrrolidone (PVP), co-polymers of PVP
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and vinyl acetate, co-polymers of N-vinyl pyrroiidone and vinyl acetate or vinyl propionate, dextrins such as grades of maltodextrin, cellulose derivatives such as cellulose esters and cellulose ethers, high molecular polyalkylene oxides such as polyethylene oxide and polypropylene oxide and co-polymers of ethylene oxide and propylene oxide.
According to the invention, film forming water insoluble polymers may be selected from acrylic copolymers e.g. Eudragit El00 or Eudragit EPO; Eudragit L30D-55, Eudragit FS30D, Eudragit RL (e.g. Eudragit RL30D), Eudragit RS (e.g. Eudragit RS30D), Eudragit NE30D, Acryl-Eze (Colorcon Co.); polyvinylacetate, for example, Kollicoat SR 30D (BASF Co.); cellulose derivatives such as ethylcellulose, cellulose acetate e.g. Surelease (Colorcon Co.), Aquacoat ECD and Aquacoat CPD (FMC Co.).
Plasticizers can be incorporated depending on the polymer and the process requirement. Examples of plasticizers which can be used in the present invention, include, but are not limited to, Spans such as sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monoisostearate & polysorbates such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate; citrate ester type plasticizers like triethyl citrate, citrate phthalate; propylene glycol; glycerin; low molecular weight & high molecular weight polyethylene glycol (PEG's); triacetin; dibutyl sebacate, tributyl sebacate; dibutyl tartrate, dibutyl phthalate.
Suitable alkalinizing agents may be incorporated based on the polymers used in the formulation. Examples of alkalinizing agents which can be used in the present invention, include, but are not limited to, sodium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium hydroxide and magnesium oxide.
Alternatively, the pharmaceutical dosage form comprising (i) core of drug-polymer matrix with one or more pharmaceutically acceptable excipients; or
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(ii) core comprising one or more drug coated with one or more pharmaceutically acceptable film forming polymers wherein the polymers may be selected from the group of water soluble polymers or water insoluble polymers or water swellable polymers or natural/synthetic gums or waxes or mixtures thereof to form homogeneous matrix may, further, be coated with specific polymers which are so designed for active release at high pH (e.g. 4.0 to 7.5) found in the lower GI tract e.g. small intestine. The polymers may be selected from the group of anionic carboxylic polymers comprising cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate and acrylic acid polymers e.g. partly esterified methacrylic acid polymers such as Eudragit L, Eudragit LI00-55 and Eudragit S. The dosage form is so designed for administration to formulate in the form of multiparticulates i.e. a multiplicity of the individual units contained in a formulation in such a form that individual units are made available from the formulation in the gastrointestinal tract that may be administered directly in the form of powder admixture, extrudates, granulates, pellets, beadlets, sugar/salt spheres, minitablets or may be administered in capsules, sachets or other carrier forms.
According to another embodiment, the present invention further provides a process for manufacturing the said multiparticulate pharmaceutical dosage form. It will be well appreciated by a person skilled in the art that the said pharmaceutical dosage form, according to the present invention, may be processed by dry/wet granulation, melt granulation, melt extrusion, spheronization, melt congeal technique, spray drying.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.
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FORMULA 1: -

Sr. No. Ingredients Qty / cap (mg)
Dry mix
1. Budesonide 3.00
2. Microcrystalline cellulose 44.00
3. Hypromellose(KlOOM) 100.00
4. Colloidal silicon dioxide 1.5
Extragranular
5. Magnesium stearate 1.5
Total 150.00
Enteric coating
6. Methacrylic acid co-polymer Type C (Eudragit L10055) 20.00
7. Talc 2.00
8. Polyethylene glycol 6000 2.00
9. Sodium hydroxide 0.25
10. Polysorbate 80 0.75
11. Purified water q. s.
Total 180.00
Manufacturing process:
1. Budesonide, Microcrystalline cellulose, Hypromellose and Colloidal silicon dioxide were sifted, mixed and allowed to form a premix.
2. The above premix was blended with magnesium stearate and compressed into minitablets.
3. An enteric coat suspension was prepared by dispersing Methacrylic acid co polymer, take,polyethylene glycol, polysorbate 80 and sodium hydroxide in purified water for coating the tablets obtained in step (2).
4. Enteric coated tablets were then finally filled into empty hard gelatin capsules.
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FORMULA 2: -

Sr. No. Ingredients Qty / cap (mg)
Dry mix
1. Budesonide 3.00
2. Microcrystalline cellulose 40.50
3. Sodium alginate 100.00
Binder
4. Povidone 5.00
5. Purified water q. s.
Extragranular
6. Magnesium stearate 1.5
Total 150.00
Enteric coating
7. Methacrylic acid co-polymer Type C (Eudragit L10055) 20.00
8. Talc 2.00
9. Polyethylene glycol 6000 2.00
10. Sodium hydroxide 0.25
11. Polysorbate 80 (Tween 80) 0.75
12. Purified water q. s.
Total 180.00
Manufacturing process:
1. Budesonide, Microcrystalline cellulose and sodium alginate were sifted, mixed and allowed to form a premix.
2. Binder solution was prepared dissolution of povidone in purified water to granulate the above premix which was then dried and blended with magnesium stearate and compressed into minitablets.
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3. An enteric coat suspension was prepared by dispersing Methacrylic acid co polymer, talc, polyethylene glycol, polysorbate 80 and sodium hydroxide in purified water for coating the tablets obtained in step (2).
4. Enteric coated tablets were then finally filled into empty hard gelatin capsules.
FORMULA 3: -

SrNo. Ingredients Qty / cap (mg)
Dry mix
1. Budesonide 3.00
2. Microcrystalline cellulose 85.25
3. Methacrylates co-polymers (Eudragit RS) 48.25
4. Methacrylates co-polymers (Eudragit RL) 12.00
Binder
5. Ethanol q. s.
Extragranular
6. Magnesium stearate 1.5
Total 150.00
Enteric coating
7. Methacrylic acid co-polymer Type C (Eudragit L10055) 20.00
8. Talc 2.00
9. Polyethylene glycol 6000 2.00
10. Sodium hydroxide 0.25
11. Polysorbate 80 0.75
12. Purified water q. s.
Total 180.00
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Manufacturing process:
1. Budesonide, Microcrystalline cellulose, Eudragit RS and Eudragit RL were sifted, mixed and allowed to form a premix which was granulated with ethanol.
2. The above granulate was then dried and blended with magnesium stearate and compressed into minitablets.
3. An enteric coat suspension was prepared by dispersing Methacrylic acid co polymer, talc, polyethylene glycol, polysorbate 80 and sodium hydroxide in purified water for coating the tablets obtained in step (2).
4. Enteric coated tablets were then finally filled into empty hard gelatin capsules.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and Variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a polymer" includes a single polymer as well as two or more different polymers; reference to a "plasticizer" refers to a single plasticizer or to combinations of two or more plasticizer, and the like.
Dated this 8th day of May, 2008
Dr. P. Aruna Sree
Agent for the Applicant
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