The technical field of the present invention relates to a process of preparing oral solid dosage form of NSAID (Non steroidal anti-inflammatory drug).
Pain management requires fast absorption of drugs into the circulating blood. Therefore, for oral dosage forms it is important to have the drug dissolved, completely or partly, already when present in the gastric fluid. Thus, in the event where the drug is not absorbed from the gastric mucosa, it should be ready for being absorbed when entering the upper intestinal tract, such as duodenum, because it has a limited amount of liquid that would result in slow dissolution of the drug.
Several approaches have been reported for the manufacturing and formulation of oral solid dosage forms of drugs that are substantially water-insoluble so as to achieve quick in-vitro dissolution in gastric media which would result in faster in-vivo absorption.
For example, PCT application WO 9532737 relates to an inclusion complex of an NSAID, such as lornoxicam and a cyclodextrin. WO 9614839 relates to an inclusion complex of an anti-inflammatory drug and an alkaline substance.
WO 06000228 relates to a pharmaceutical composition, and a process to manufacture thereof, which utilizes a minimum amount of liquid, preferably without utilizing liquid at all. It involves intensive mixing in the form of co-milling of drug and an alkaline substance so as to provide close physical contact between them.
WO 0015195 relates to a quick release pharmaceutical composition of lornoxicam. It follows a process of mixing drug and alkaline substance in a planetary mixer and granulation of the blend by spray granulation method for a better contact between the two and for a control over the granulate particle size.
The prior art discloses complex and expensive processes involving multiple steps for the preparation of lornoxicam and other NSAIDs oral dosage forms. Therefore, there is a need for providing oral solid dosage forms, which may be prepared by a simplified
process, still possessing a fast disintegration and dissolution in gastric environment, while at the same time exhibiting good stability and robustness.
The invention is directed to a simplified process for preparing oral solid dosage form of NSAID.
In one aspect, the present invention relates to a process of preparing oral solid dosage form of NSAID comprising the steps of:
a) mixing NSAID with one or more alkaline substances to form a blend,
b) mixing the blend of step a) with one or more intragranular pharmaceutically acceptable excipients,
c) granulating the blend of step b) using granulating fluid,
d) drying and sizing the granules,
e) mixing the granules with one or more extragranular pharmaceutically acceptable excipients, and
f) processing into oral solid dosage form.
In another aspect, the present invention relates to a process of preparing oral solid dosage form of lornoxicam comprising the steps of:
a) mixing lornoxicam with one or more alkaline substances to form a blend,
b) mixing the blend of step a) with one or more intragranular pharmaceutically acceptable excipients,
c) granulating the blend of step b) using granulating fluid,
d) drying and sizing the granules,
e) mixing the granules with one or more extragranular pharmaceutically acceptable excipients, and
t) processing into oral solid dosage form.
In another aspect, the present invention relates to a process of preparing oral solid dosage form of lornoxicam comprising the steps of:
a) mixing lornoxicam with sodium bicarbonate to form a blend,
b) mixing the blend of step a) with one or more intragranular pharmaceutically acceptable excipients,
c) granulating the blend of step b) using granulating fluid,
d) drying and sizing the granules,
e) mixing the granules with one or more extragranular pharmaceutically acceptable excipients, and
0 processing into oral solid dosage form.
In another aspect, the present invention relates to a process of preparing oral solid dosage form of lornoxicam comprising the steps of:
a) mixing lornoxicam with sodium bicarbonate to form a blend,
b) mixing the blend of step a) with one or more intragranular pharmaceutically acceptable excipients,
c) granulating the blend of step b) with a mixture of water and organic solvent,
d) drying and sizing the granules,
e) mixing the granules with one or more extragranular pharmaceutically acceptable excipients, and
f) processing into oral solid dosage form.
In another aspect, the present invention relates to a process of preparing oral lornoxicam tablet comprising the steps of:
a) mixing lornoxicam with sodium bicarbonate to form a blend,
b) mixing the blend of step a) with one or more intragranular pharmaceutically acceptable excipients,
c) granulating the blend of step b) with a mixture of water and organic solvent,
d) drying and sizing the granules,
e) mixing the granules with one or more extragranular pharmaceutically acceptable excipients, and
f) compressing into tablet.
The oral solid dosage form according to the present invention is required for use in those cases where a fast onset of a therapeutic effect is desired, e.g. in connection with acute or mild to moderate pain. The oral solid dosage form, intended for oral administration, is designed in such a manner so that the drug release is very fast in gastric environment, whereby the drug will become dissolved and hence available for absorption immediately upon entrance into the small intestine.
In contrast to the complex processes as described in prior art, the process involved in the invention follows simple conventional wet granulation steps. Hence, the dosage form may be prepared by an economical and faster way while exhibiting good stability and robustness as desired.
The term "NSAID" relates to the class of drugs which are used to treat pain, inflammation and other related conditions. Specific examples of NSAID include lornoxicam, diclofenac, nimesulide, ibuprofen, piroxicam, naproxen, ketoprofen, tenoxicam, tolfenamic acid, aceclofenac, indometacin, nabumetone, acemetacin, morniflumate, meloxicam, flurbiprofen, tiaprofenic acid, proglumetacin, mefenamic, acid, fenbufen, etodolac, sulindac, phenylbutezone, fenoprofen, tolmetin, acetylsalicylic acid, dexibuprofen and the like. It also include pharmaceutically acceptable salts. complexes, enantiomers and/or prodrugs and mixtures thereof. In particular, the NSAID is lornoxicam. The amount of the NSAID in the oral solid dosage form may vary from about 0.5% to about 25 % w/w, in particular 1 to 10 % w/w. The NSAID used in the dosage form may be used as such or milled so that the resulting drug powder has a D90 value not more than 15 µm, in particular not more than 10 µm.
The term "alkaline substance" relates to substances that provide an alkaline pH in the range of 8-14, when being dissolved in water at room temperature in an amount of about 10 mg/ml. Specific examples of alkaline substances include sodium carbonate, sodium bicarbonate, calcium carbonate, trisodium phosphate, di-sodium hydrogen phosphate, dicalcium phosphate and tribasic calcium phosphate or mixtures thereof. In particular the alkaline substance is sodium bicarbonate. The amount of the alkaline substance in the
oral solid dosage form may vary from about 2 % to about 50 % w/w, in particular 10 to
35 % w/w.
The term "pharmaceutically acceptable inert excipients" as used herein includes all physiologically inert excipients used in the pharmaceutical art of dispensing. The term "intragranular excipients" includes, the excipients added prior to the drying of the granules. The term "extragranular excipients" includes, the excipients added after the drying of the granules. Examples include diluents, disintegrants, lubricants/glidants, binders, granulating fluids, plasticizers, coloring agents, opacifiers and the like.
Specific examples of diluents include calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, cellulose, microcrystalline cellulose, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar confectioners, and the like.
Specific examples of disintegrants include low-substituted hydroxypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, microcrystalline cellulose, hydroxypropyl starch, partly pregelatinized starch, and the like.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Specific examples of solvents used as granulating fluid or for preparing a solution/dispersion of the coating composition include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, chloroform, ether, water, and the like.
Specific examples of plasticizers include triethylcitrate, acetylated triacetin, tributylcitrate, glyceroltributyrate, monoglyceride. rape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, and the like.
Coloring agents include any FDA approved color for oral use.
Specific examples of opacifiers includes talc, calcium carbonate, kaolin, titanium dioxide, iron oxide and the like
The term "oral solid dosage form" as used herein includes solid dosage forms such as granule, pellet, tablet, capsule and the like.
In one of the embodiment the lornoxicam tablets may be prepared by:
a) mixing lornoxicam with sodium bicarbonate to form a blend,
b) mixing the blend of step a) with one or more intragranular diluent, disintegrant, and binder,
c) granulating the blend of step b) using a mixture of water and ethanol,
d) drying the granules in fluidized bed drier and sizing the granules using suitable sieves,
e) mixing the granules with one or more extragranular disintegrant, glidant/lubricant; and
t) compressing into tablet using suitable toolings.
The tablets of the present invention may be further coated with one or more nonfunctional coating layers comprising one or more film forming polymers and pharmaceutically acceptable excipients.
Example of film forming polymers include ethylcellulose, hydroxypropyl ethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethyl-cellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; waxes such as polyethylene glycol; methacrylic acid polymers and co-polymers and the like. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry* may also be used for coating.
The coating may be applied as solution or dispersion of one or more film forming polymers with pharmaceutically acceptable excipients in suitable solvents.
Example of granulation fluid and solvent for preparing coating solution/dispersion include one or more of water, organic solvents such as methylene chloride, isopropyl alcohol, acetone, methanol, ethanol and the like.
The invention is further illustrated by the following examples, which are for illustrative purpose only and should not be construed as limiting the scope of the invention in any
way.
Examples I. Composition
Table 1. Composition of lornoxicam tablets

(Table Removed)
Procedure:
1) Lornoxicam and sodium bicarbonate were sifted through 60# BSS mesh sieve and mixed in geometrically.
2) Calcium hydrogen phosphate, hydroxypropyl cellulose and MCC were sifted through 60# BSS mesh sieve and mixed with blend of step 1.
3) The blend of step 2 was granulated using mixture of purified water and ethanol in Rapid mixer granulator.
4) The granular mass was dried in fluidized bed drier at 60°C.
5) The semi dried granular mass was passed through multimill using 5.0 mm sieve followed by drying.
6) The dried granules were sized using 22# BSS mesh sieve after passing through multimill using 1.0 mm sieve.
7) L-HPC was sifted through 60# BSS mesh sieve and mixed with blend of step 6,
8) Calcium stearate (60# BSS mesh sieve) was mixed with blend of step 7 in double cone blender for 5 minutes.
9) The final blend was compressed using 10.0 mm punch.
10) The compressed tablets were then coated using a dispersion of Opadry® white in water in the Ganscoater®.
II. In vitro dissolution and assay for drug content
Tablets prepared as per the composition of Example 1 were stored at 40°C/75%RH. In-vitro dissolution and assay for drug content of the tablets were carried out, at regular intervals, over a period of 3 months. The dissolution was carried out in IP (Indian pharmacopoeia) I-Paddle dissolution apparatus at a temperature of 37±0.5°C, in 900 ml of 0.1 N HCI media at a paddle speed of 50 rpm. The tablets were analyzed for the drug content using validated in house HPLC method. The results of the dissolution and assay for drug content are given in Table 2 and 3 respectively.
Table 2. In-vitro release of lornoxicam

(Table Removed)
III. Assay
Table 3. Assay of lornoxicam tablets for the drug content
(Table Removed)

WE CLAIM:
1. A process of preparing an oral solid dosage form of NSAID comprising the steps
of:
a) mixing NSAID with one or more alkaline substances to form a blend,
b) mixing the blend of step a) with one or more intragranular pharmaceutically acceptable excipients,
c) granulating the blend of step b) using granulating fluid,
d) drying and sizing the granules,
e) mixing the granules with one or more extragranular pharmaceutically acceptable excipients, and
f) processing into oral solid dosage form.

2. The process according to claim 1 wherein the NSAID is one or more of lornoxicam, diclofenac, nimesulide, ibuprofen, piroxicam, naproxen, ketoprofen. tenoxicam, tolfenamic acid, aceclofenac, indometacin, nabumetone, acemetacin, morniflumate, meloxicam, flurbiprofen, tiaprofenic acid, proglumetacin, mefenamic, acid, fenbufen, etodolac. sulindac, phenylbutezone, fenoprofen, tolmetin, acetylsalicylic acid and dexibuprofen.
3. The process according to claim 2 wherein the amount of NSAID in the dosage form may vary from 0.5% to 25 % w/w.
4. The process according to claim 1 wherein the alkaline substance is one or more of sodium carbonate, sodium bicarbonate, calcium carbonate, trisodium phosphate, di-sodium hydrogen phosphate, dicalcium phosphate and tribasic calcium phosphate.
5. The process according to claim 4 wherein the amount of alkaline substance in the dosage form may vary from 2 % to 50 % w/w.
6. The process according to claim 1 wherein the granulating fluid is one or more of water and organic solvents such as methylene chloride, isopropyl alcohol, acetone, methanol and ethanol.
7. The process according to claim 1 wherein the dosage form is granule, pellet, tablet or capsule.
8. The process according to claim 1 wherein the dosage form may be coated with one or more non-functional coating layers comprising one or more film forming polymers and pharmaceutically acceptable excipients.
9. The process according to claim 1 or 8 wherein pharmaceutically acceptable inert excipients are one or more of diluents, disintegrants, lubricants/glidants, binders, granulating fluids, plasticizers, coloring agents and opacifiers.
10. A process of preparing an oral solid dosage form of NSAID as described and illustrated in the examples herein.