The present invention relates to a controlled release composition of Nimesulide. The composition is related to a once-a-day dosage forms which are very useful in treatment of chronic diseases such as arthritis.
TECHNICAL BACKGROUND OF THE INVENTION
Nimesulide is a nonsteroidal anti-inflammatory drug (NSAID) that also has antipyretic and analgesic properties. The compound is weakly acidic (pKa: = 6.5) and differs from other NSAIDs in that its chemical structure contains a sulfonanilide moeity as the acidic group, (fig. 1) (Magni E, Nimesulide an overview, Drug Invest 1991; 3 Suppl. 2: 1-3). (Figure Remove)
The therapeutic effects of NSAIDs are largely the result of their ability to inhibit prostaglandin synthesis via inhibition of cyclo-oxygenase. Unfortunately, this effect is also responsible for the inhibition of gastroprotective prostaglandins, which leads to gastrointestinal intolerance. In vitro, Nimesulide is a relatively weak inhibitor of prostaglandin synthesis
and appears to exert its effects through a variety of mechanisms. (Magni E. The effect of nimesulide on prostanoid formation. Drugs 1993; 46 Suppl. 1:10-4.) Indeed, the mechanism of action of this drug is more complex than previously thought and may involve interference with the production/action of mediators other than prostaglandins such as enzymes, toxic oxygen derivatives, cytokines, platelet-activating factor (PAF) and histamine,
The anti-inflammatory, analgesic and antipyretic activities of Nimesulide, a non-steroidal anti-inflammatory drug (NSAID) of the sulfonanilide class, have been demonstrated in a number of experimental models and in numerous clinical trials. Nimesulide has exhibited potency similar to or greater than that of indomethacin, diclofenac, piroxicam and ibuprofen in standard animal models of inflammation such as carrageenin-induced rat paw oedema and inflammation, ultraviolet light-induced erythema in guinea-pigs and adjuvant arthritis in rats. The analgesic potency in nimesulide was similar to that of ibuprofen and less than that of indomethacin in an acetic acid writhing test in rats, and acetic acid and acetycholine writhing tests in mice. Nimesulide has shown superior antipyretic potency to indomethacin, ibuprofen, aspirin and paracetamol (acetaminophen) in rats with yeast-induced fever.
Nimesulide is a relatively weak inhibitor of prostaglandin synthesis in vitro and appears to exert its effects through a variety of mechanisms including free-radical scavenging, effects on histamine release, the neutrophil mycloperoxidase pathway, bradykinin activity, tumour necrosis factor-a release, cartilage degradation, metalloprotease synthesis, phosphodiesterase
type IV inhibition, platelet aggregation and synthesis of platelet activating factor. Animal studies have suggested that Nimesulide is less ulcerogenic than aspirin, indomethacin, naproxen, piroxicam and ibuprofen. Nimesulide appears to have little effect en renal prostaglandin synthesis in rats.
Nimesulide dose dependency (0.3 to 15.4 mg/L) and at near therapeutic plasma drug concentrations affects neutrophil activity in vitro during inflammatory reactions in at least 2 steps of the cell response. It is also reported to inhibit the release of histarnine by 50% during immunological reaction in the perfused sensitised guinea pig lung model at 0.93 mg/L level (Berti F, et ai., Arzneimittel Forschung 1990; 40: 1011-6). Further, vvnen added to human articular cartilage explant in vitro, nimesulide, at a therapeutic concentration (3 mg/L), reduced the degradation of the matrix by inhibiting the synthesis of metalloproteinases such as collagenase and stromelysin (Pelletier JP, Martel-Pelletier J, Drugs 1993; 46 Suppl. 1: 34-3j.
In yeast induced febrile rats, the ED50 (producing a 5°C decrease in rectal temperature) of nimesulide is reported to be 0.21 mg/kg, indicating more potency than indomethacin (ED50 = 1.8 mg/kg), ibuprofen (ED5o = 3.7 mg/kg) and aspirin (ED50 = 25 mg/kg) [Tanaka K. et al. Arzneimittel Forschung 1992; 42: 935-44]. Using the same animal model, Ceserani et al. (Drugs 1993; 46 Suppl. 1: 48-51) observed that orally and rectally administered nimesulide (ED50 range 0.22 to 0.47 mg/kg) displayed more antipyretic potency than paracetamol (ED50 range 10 to 118 mg/kg) and maintained its potency throughout the observation period (6 to 9 hours after administration of ye;i:;t).
After oral administration of nimesulide 50 to 200 mg to healthy adult volunteers, peak serum concentrations of 1.98 to 9.85 mg/L are achieved within 1.22 to 3.17 hours. Compared with values obtained with oral drug administration, peak serum concentrations are slightly lower (2.14 to 2.32 mg/L) and are achieved more slowly (3 to 4.58 h) after rectal administration of nimesufide 100 and 200 mg. Oral drug absorption is nearly complete and concomitant administration of food may decrease the rate, but not the extent of absorption of nimesulide. The drug is extensively bound (99%) to plasma proteins and has an estimated apparent volume of distribution of 0.19 to 0.35 L/kg following oral administration.
Nimesulide is extensively metabolised (1 to 3% of a dose is excreted unchanged in the urine) to several metabolites which are excreted mainly in the urine (« 70%) or the faeces (* 20%). The drug is almost completely biotransformed into 4-hydroxy-nimesulide in both free and conjugated forms and this metabolite appears to contribute to the anti-inflammatory activity of the compound. Peak concentration of 4-hydroxy-nimesulide ranged from 0.84 to 3.03 mg/L and were attained within 2.61 to 5.33 hours after oral administration of Nimesulide 50 to 200 mg to healthy adult volunteers. The elimination half-life of 4-hydroxy-nimesulide ranges from 2.89 to 4.78 hours and is generally similar to or slightly higher than that of the parent compound (1.56 to 4.95 h).
The pharmacokinetic profile of nimesulide is not significantly altered in children, elderly volunteers and patients with moderately impaired renal function [creatinine clearance 1.8 to 4.8 L/h (30 to 80 ml/min)J. Slight accumulation of 4-hydroxy-nimesulide was noted in patients with moderate renal impairment; however, the clinical significance of this finding is unknown.
Clinical studies have established the analgesic, anti-inflammatory and antipyretic effectiveness of orally (mostly 200 mg/day) or rectally (400 mg/day) administered nimesuiide in the treatment of a variety of painful inflammatory conditions, including those associated with osteoarthritis, oncology, postoperative trauma, sports injuries, ear, nose and throat disorders, dental surgery, bursitis/tendinitis, thrombophlebitis, upper airways inflammation and gynaecological disorders. In these indications, nimesulide is more effective than placebo and is at least as effective as therapeutic dosages of other NSAIDs, including piroxicam, ketoprofen, naproxen, etodolac, mefenamic acid, didofenac, niflumic acid, fentiazae, feprazone and flurbiprofen. Nimesulide therapy was characterised by a rapid onset of analgesia and symptomatic relief in studies where as significant difference in clinical efficacy between active treatment was observed However, most of these studies evaluated small numbers of patients and were probably too small to identify any small differences in effectiveness.
In children, nimesulide suspension, granules and suppositories are more effective than placebo and are at least as effective as paracetamol. diclofenac, naproxen, lysine acetylsalicylate, mefenamic acid, ketoprofen and
dipyrone in reddcing in pain, inflammation and fever associated with respiratory tract infection, postoperative pain and musculoskeletal injury. Nimesulide has oeen well tolerated by both young and elderly adults and children in 2 large postmarketing surveillance surveys. As with other NSAIDs, the most common adverse effects are gastrointestinal disturbances (epigastralgia, heartburn, nausea, diarrhoea and vomitings 5.1 to 8.5% of patients), dermatological reactions (rash, pruritus; 0.2 to 0.6%) and central nervous system effects (dizziness, somnolence, headache; 0.3 to 0.4%). Withdrawal rates associated with short term (up to 30 days) nimesulide treatment range from 1.1 to 2.2% in adult, elderly and paediatric patients.
Available data indicate that the gastrointestinal tolerability of nimesulide in adults and children is similar to that of other NSAIDs. The rate of endoscopically verified gastroduodenal irritation with nimesulide appears to be similar to that with placebo and diclofenac ana less than that with indomethacin. The drug is well tolerated by most patients intolerant of aspirin and/or other NSAIDs and by patients with asthma
The literature surveys shows that different dosage forms reported for nimesulide are tablets, granules, suppository ?md suspension (Drugs 48 (3): 431-454, 1994) and lately our group has patented transdermal (US Pat. No. 5688829) and intramuscular injection (US Pat No. 5716609) formulations The reported dosage forms have to be administered twice-a-day based on biological half life of nimesulide. The usual orsi/rectal dosage of nimesuiiae in
adults is 100 to 200 mg twice daily whereas, in children it is 5 mg/kg/day divided into 2 or 3 daily doses.
Thus, it is desirable to have once-a-day dosage form for nimesulide particularly for treatment of chronic diseases like arthritis. The once-a-day dosage form is expected to significantly increase the dosing convenience and patient compliance. However, controlled release once-a-day dosage form of nimesulide have not been reported so far. By expenditure of considerable intellectual effort and careful experimentation we have found out that nimesulide can be formulated into a controlled release once-a-day dosage form.
SUMMARY OF THE INVENTION
A controlled release composition of nimesulide is disclosed in the invention.
The composition in accordance with present invention comprises a controlled release pharmaceutical composition of Nimesulide which comprises nimesulide as an active drug from 5% to 95% w/w of the composition, one or more sustaining materials from 2% to 95% w/w of the composition and pharmaceutical excipients from 0% to 90% w/w of the composition.
Preferably the composition tn accordance with the present invention comprises nimesulide an active drug from 20% to 70% w/vv of the composition, one or more sustaining materials from 5% to 65% w/w of the
composition and pharmaceutical excipients from 10% to 70% w/w of the
composition.
More preferably the composition in accordance with the present invention comprises nimesulide as an active drug from 40% to 60% w/w of the composition, one or more sustaining materials from 8% to 20% w/w of the composition and pharmaceutical excipients from 30% to 60% w/w of the composition.
DETAILED DESCRIPTION OF INVENTION
In accordance with the present invention there is disclosed a controlled release composition of Nimesulide.
The composition in accordance with present invention comprises a controlled release pharmaceutical composition of Nimesulide which comprises nimesulide as an active drug from 5% to 95% w/w of the composition, one or more sustaining materials from 2% to 95% w/w of the composition and pharmaceutical excipients from 0% to 90% w/w of the composition.
Preferably the composition in accordance with the present invention comprises nimesulide as an active drug from 20% to 70% w/w of the composition, one or more sustaining materials from 5% to 65% w/w of the composition and pharmaceutical excipients from 10% to 70% w/w of the composition.
More preferably the composition in accordance with the present invention comprises nimesulide as an active drug from 40% to 60% w/w cf the composition, one or more sustaining materials from 8% to 20% w/w of the composition and pharmaceutical excipients from 30% to 60% w/w of the composition.
The sustaining materials are selected from the group cellulose and cellulose derivatives, waxes, carbomers, polyalkylene polyols, polycarbophils, methacrylate acid derivatives, gelatins, gums, polyethylene oxides.
The sustaining materials comprise materials which are non-toxic and pharmaceutically acceptable. These may be natural, semi-synthetic, synthetic or man-modified. Suitable materials include cellulose and cellulose derivatives like microcrystalline cellulose, methyl cellulose, ethyl cellubse, hydroxypropyimethyi cellulose, hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate trimellitate, cellulose carboxymethyl ethers and their salts, hydroxypropyl methylceliulose phthalate , hydroxypropyl methylcellulose acetate succinate.
Polyethylene; Polyquaternium-1; Polyvinyl acetate (homopolymer); Polyvinyl acetate phthalate; Propylene glycol alginate; PVM/MA copolymer; PVP/ dimethiconylacrylate/polycarbamyl/polyglycolester;PVP/dimethylaminoetnylm ethacrylate copolymer; PVP/dimethylaminoethylmethacrylate/polycarbamyl polyglycol ester; PVP/polycarbamyl polyglycol ester; PVP/ VA copolymer
Lanolin and lanolin derivatives, glyceryl monostearate, stearic acid, paraffins, beeswax, carnauba wax, Tribehenin.
Polyalkylene polyols like polyethylene glycols.
Gelatin and gelatin derivatives.
Alginates. Carborners. Polycarbophils.
Methacrylic acid copolymers.
Carrageenans, pectins, chitosans, cyclodextrins, lecithins.
Natural- and synthetic gums containing galactomannans like xanthan gum, tragacanth, acacia, agar, guar gum, etc.
Pharmaceutical excipients as used in the composition are selected from the group of excipients generally used by persons skilled in the art e.g. fillers, bulking agent, colourants, stabilizers, preservatives, lubricants, glidants, chelating agents and the like.
Preferably the composition also comprises release modifiers. Such release modifiers are selected from the groups wetting agents, solubilizers, surfactants, plasticizers, solvents, pore formers, pH modifiers and tonicity adjusting agents.
Suitable example of such ingredients include :
Reaction products of natural and hydrogenated vegetable oils and ethylene gtycol e.g. polyoxyethylene glycolated natural or hydrogenated castor oil such as those available under the trade name Cremophor.
Other suitable products include polyoxyethylene sorbitan fatty acid esters e.g.
of the type available under the trade name TWEEN.
Polyoxyethylene fatty acid esters e.g. MYRJ and CETIOL HE.
Polyoxyethylene polyoxypropylene copolymers e.g. PLURONIC and
Polyoxyethylene polyoxypropylene block copolymers e.g. POLOXAMER.
Dioctylsodiumsulfosuccinate, sodium lauryl sulphate.
Propylene glycol mono- and di- fatty acid esters e.g. MIGLYOL 840.
Bile salts e.g alkali metals salts e.g. sodium taurocholate.
Polyethylene glycols, propylene glycol, triacetin, diacetin, diethyl phthalate,
dibutyl phthalate, castor oil.
Sodium chloride, potassium chloride, lactose, mannitol, sucrose, sorbitol.
Sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium citrate,
citric acid, hydrochloric acid, lactic acid, tartaric acid, malic acid.
The calculation of dose of nimesulide for once-a-day controlled release dosage form was done on the basis of its pharmacokinetic parameters ik.ing the following equation :
Dose - CP x Vd x K,i x T
CP = Effective plasma concentration, 3.0 mg/L
Vd = Apparent Volume of distribution, 15.6 L
K«i = Elimination Rate constant, 0.166 h"1
T = Desired Duration of action, 24 hrs
Based on the above equation the dose was calculated to be 207.0 mg.
Further, the theoretical drug release profile for such a once-a-day contrcl'ed release dosage form was calculated using a computer software named MINSQ developed at Micromath Scientific Software, Salt Lake City, Utah (USA).
The calculations are based on the following parameters :
A = Immediate release dose (Value = 0)
dose
B = Initial dissolution rate = = 22.657 mcj/h
Duration x 0.3678
C = Sustained dissolution rate = 1/T = 0.04166
The equation used for calculating the release profile is
F = B T exp -CT The results of the simulated release profile are given below
. Time (hours) % release
(Table Remove)The graphical representation of the above data is given in fig. 2.
Example 1 Sustained release matrix tablet type
(i) Nimesulide - 200 mg
(ii) Lactose - 73 mg
(iii) Hydroxypropylmethyl Cellulose - 70 mg
(iv) Magnesium Stearate - 3.5 mg
(v) Purified Talc - 3.5 mg
Blend (i), (ii), (iii), (iv) and (v) after sifting through mesh no. 30 (BBS). Compress into tablets,
The results of Dissolution Release Profile of Nimesulide SR Tablets based on example 1 are given below : (Table Remove)
The graphical representation of the release profile is given in fig. 3. It is observed that the released profile compares suitably with the simulatedrelease profile as shown in fig 2. The dissolution profile as given in fig. 3 of the nimesulide sustained release tablet should not be construed to limit the scope of the invention. Variations to the dissolution profile can be possible depending upon the dosage requirements without departing from the spirit of the invention,
Example 2 Extended release membrane diffusion controlled tablet type
(i) Nimesulide - 200 mg
(ii) Microcrystalline Cellulose - 60 mg
(iii) Lactose - 60 mg
(iv) Maize Starch - 10mg
(v) Purified Talc - 3.5 mg
(vi) Ethyl Cellulose - 10mg
(vii) Polyethylene Glycol - 3.5 mg
Blend (i), (ii) and (iii) and granulate with starch paste and dry the granules. Sift through mesh no. 22 (BSS). Lubricate with Magnesium Stearate and Talc. Compress into tablets. Coat the tablets with Ethyl Cellulose using Polyethylene Glycol as a channel former.
Example 3 Sustained release bead type
(i) Non - Pareil Beads - 347 mg
(ii) Nimesulide - 200 mg
(iii) Mannitol - 30 mg
(iv) Lactose - 30 mg
(v) Polyvinyl Pyrrolidone - 20 mg
(vi) Purified Talc - 15mg
(vii) Ethyl Cellulose - 7 mg
(viii) Diethyl Phthalate - 1.4mg
Coat the non-pareil beads with blend of (ii), (iii) and (iv) using (v) as a binder in a conventional or fluidized bed coater. Talc may be dusted onto the beads. Final coating is given with Ethyl Cellulose using (viii) as plasticizer.
Example 4 Osmotically controlled constant release type device Upper Layer
(i) Nimesulide - 200 mg
(ii) Sodium Hydroxide - 15mg
(iii) Lactose - 34 mg
(iv) Sodium Chloride - 30 mg
(v) Polyvinyl Pyrrolidone - 6 mg
(vi) Polyethylene Oxide - 1.5 mg
Lower Layer
(vii) Polyethylene Oxide - 22 mg
(viii) Carbomer 934P - 1.2 mg
(ix) Hydroxypropylmethyl Cellulose - 1.8mg
(x) Sodium Chloride - 20 mg
(xi) Alcohol - q.s (Lost in processing)
Semi-permeable Coat
(xii) Cellulose Acetate - 30 mg
(xiii)Triacetin - 1 mg
(xiv) Acetone - q.s (Lost in procesing)
(xv) Water - q.s (Lost in processing)
Blend finely powdered (i), (ii), (iii), (iv) and (vi). Granulate with aqueous solution of (v). Granulate the blend of (vii), (ix) and (x) with dispersion of (viii) in alcohol. Compress the two granulates into bilayer tablets and coat with the dispersion of (xii) and (xiii) in aqueous acetone. Finally, drill a hole in the drug layer (Upper layer) through which the drug is released in a controlled fashion due to osmotic pressure.
Example 5 Coated capsule type
(i) Nimesulide - 200 mg
(ii) Microcrystalline Cellulose - 88.4 mg
(iii) Lactose - 70 mg
(iv) Polyvinyl Pyrrolidone - 7 mg
(v) Magnesium Stearate - 3.9 mg
(vi) Ethyl Cellulose - 20 mg
(vii) Polyethylene Glycoi - 0.7 mg
(viii) Alcohol ; Dichloromethane (1 : 2) (ix) Empty Gelatin Capsule (Size '1')
q.s (Lost in processing)
Blend (i), (ii), (iii), (iv) and (v) and fill into empty gelatin capsule size '1'. Coat the capsules with dispersion of (vi) and (vii) in (viii).
Example 6 pH dependent delayed release type (i) Nimesulide
(ii) Microcrystalline Cellulose (iii) Lactose
(iv) Polyoxyl 40 Hydrogenated Castor Oil -(y) Polyvinyl Pyrrolidone (vi) Magnesium Stearate (vii) Purified Talc (viii) Cellulose Acetate Phthalate (ix) Diethyl Phthalate (x) Water (xi) Alcohol Dichloromethane (1:2)
100mg
150mg
76 mg
7 mg
10mg
3.5 mg
3.5 mg
28 mg
2mg
q.s (Lost in processing)
q.s (Lost in processing)
Granulate the blend of (i), (ii), (iii) and (iv) with solution of (v) and (vi) in water. Compress into tablets. Coat with tne dispersion of (viii) and (ix) in (xi).
Example 7 Timed release bead type
(i) Nimesulide 100mg 100mg 10Cmg
(ii) Microcrystalline Cellulose 200 mg 200 mg 200 mg
(iii) Lactose 50 mg 42 mg 35mg
(iv) Polyvinyl Pyrrolidone 10mg 10mg 10mg
(v) Water q.s q.s q.s
(vi) Ammonio Methacrylate
Copolymer Type B 10 mg 18 mg 25 mg
(Eudragit RS)
(vii) Diacetin 0.5 mg 0.5 mg 0.5 mg
(viii) Water: Acetone (1:9) q.s q.s q.s
In this composition 3 types of beads are prepared which are coated with different amounts of (vi) to give a timed release profile of the drug. Beads are prepared by blending and spheronizing (i), (ii) and (iii) using aqueous solution of (iv). The dried beads are coated with dispersion of (vi) and (vii) in (viii). The 3 different beads are blended together in a fixed ratio to obtain the required release profile.
The foregoing examples are illustrative embodiments of the invention and are merely examplary A person skilled in the art may make variations and modifications without departing from the spirit and scope of the invention. All such modifications and variations are intended to be included within the scope of the invention as discuss in this specifications and the appended claims.

We claim :
A controlled release pharmaceutical composition of Nimesulide which
comprises nirnesulide as an active drug from 5% to 95% w/w of the
composition, one or more sustaining materials from 2% to 95% w/w of the
composition and pharmaceutical excipients from 0% to 90% w/w of the
composition.
A controlled release pharmaceutical composition of nimesulidB as
claimed in claim 1 which comprises nirnesulide as an active drug from 2C>% to
70% w/w of the composition, one or more sustaining materials from 5% to
65% w/w of the composition and pharmaceutical excipients from 10% to ~/0%
w/w of the composition.

A controlled release pharmaceutical composition of nimesulids as
claimed in claim 1 which comprises nirnesulide as an active drug from 40fl'o to
60% w/w of the composition, one or more sustaining materials from 8% to
20% w/w of the composition and pharmaceutical excipients from 30% to 00%
w/w of the composition.
A controlled release pharmaceutical composition of nimesulide as
claimed in claim 1 to 3 wherein the sustaining materials are selected from the
group cellulose and cellulose derivatives, waxes, carbomers, polyalklene
polyofs, polycarbophils, methacrylate acid derivatives, gelatins, claims,
polyethylene oxides
The composition as claimed in claim 1 which further comprises release modifiers.

A process for the manufacture of controlled release composition of nimesulide which comprises maxing together under conventional conditions of temperature and pressure-nimesulide as on active drug from -5% to 95% w/w of the composition one or more sustaining material home to percent to 95% w/w of the composition and pharmaceutical recipients 0% to 90% w/w of the composition

A controlled release pharmaceutical composition of nimesulide substantially
as herein describe with reference to foregoing description and the accompanying examples and figure

A process for the manufacture of controlled release composition of nimesulide
Substantially as herein described with reference to foregoing description and the accompanying figure and example.