The present invention relates to process for the preparation of therapeutic compositions containing nimesulide. These compositions are for administration by inhalation route. Such compositions are designed to deliver nimesulide to the respiratory tract.
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 moiety as the acidic group. (fig. 1) (Magni E, Nimesulide an overview, Drug Invest 1991; 3 Suppl. 2: 1-3).
(Figure Removed)
The therapeutic effects of NSAIDs are largely the result of their ability to inhibit prostaglandin synthesis via inhibition of cyclooxygenase. 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. Nimesulide an overview, Drug Invest 1991; 3 Suppl. 2: 1-3).
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 myeloperoxidase 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 on renal prostaglandin synthesis in rats.
Nimesulide dose dependently (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 two steps of the cell response. It is also reported to inhibit the release of histamine by 50% during immunological reaction in the perfused sensitised guinea pig lung model at 0.93 mg/L level (Berti F, et al., Arzneimittel Forschung 1990; 40: 1011-6). Further, when 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: 34-9).
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 nimesulide 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 (770%) 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 plasma 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 and patients with moderately impaired renal function [creatinine clearance 1.8 to 4.8 L/h (30 to 80 ml/min)]. 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 nimesulide 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, diclofenac, niflumic acid, fentiazac, 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.
Prior art
Nimesulide has been reported to be effective in inflammation of upper airways in conditions like rhinitis, rhinosinusitis (Ref. Bellussi, L, Pasali, D., Drugs 46 (suppl. 1): 107 -110, 1993).
US Patent No. 4,617,407 granted to Merck Frosst Canada, Inc. discloses the use of leukotriene antagonist compounds alongwith NSAIDs like Nimesulide for treatment for asthma.

US Patent No. 4,783,465 describes the combination of propionic acid NSAIDs with antihistaminic agent to treat cough, cold and flu symptoms.
In the prior art, the different dosage forms reported for nimesulide include tablets, granules, suppositories and suspensions (Drugs 48(3): 431 - 454, 1994) and lately the applicant has patented transdermal (Indian Pat. No. 186558) and intramuscular injection (Indian Pat. No. 186558) formulations. Such dosage forms are administered by oral, parenteral, rectal or topical/transdermal route.
The compositions of nimesulide for administration by inhalation route to human beings have not been reported in prior art. This route helps in administration of drugs directly to the respiratory tract resulting in increased absorption and faster response in conditions like asthma. In prior art no such compositions of nimesulide have been described. It has been found by the inventors that stable inhalation compositions of nimesulide can be provided by means of novel formulations described herein.
Accordingly the present invention provides a process for the preparation of therapeutic composition for administration through inhalation route which process comprises mixing nimesulide from 0.1% to 98% w/w in micro-particulate form, the size of the micro-particles being less than 10 micron and the convention excipients, as herein described, from 2% to 99.9% w/w.
Accordingly to a preferred embodiment of the present invention, the size of the micro-particles of nimesulide is less than 5 micron.
According to a more preferred embodiment of the present invention, the size of the micro-particles of nimesulide is less than 2 micron. Such nimesulide compositions, preferably, may be in the form of solutions, suspension or emulsions. The drug nimesulide may be present in the form of micro-particulate systems like microspheres, co-precipitates, co-agglomerates, nanoparticles, nanocrystals, nanospheres, niosomes, liposomes and pulmospheres. The particle size of such micro-particulate systems is less than 10 microns, preferably less than 5 micron and more preferably less than 2 micron. The inhalation compositions can be dispersed in the form of pressurised systems (metered dose aerosols) based on chlorofluorocarbon propellants or non-chlorofluorocarbon propellants. Other forms of inhalation products include dry powder inhalation and nebulizer. For such products, the therapeutic compositions may be in spray dried or lyophilized form.
Size reduction of nimesulide may be carried out using processes known to those skilled in the art. These processed include the use of techniques like air jet milling, ball milling, co-milling with an inert excipient, colloid milling homogenization of a suspension of nimesulide along with an inert excipient and the like.
In addition to the active ingredient i.e. nimesulide, the composition contains excipients known to persons skilled in the art like surfactants, stabilizing agents, wetting agents, solubilizers, anticaking agents, antioxidants, lipophilicity enhancers, bilayer membrane stabilizers, co-solvents, diluents and the like.
The range of such excipients is between 2% to 99.9%. Suitable example of such ingredients include :
Stabilizing/matrix forming agents: These may be natural, semi-synthetic, synthetic or man-modified. Suitable materials include cellulose and cellulose derivatives like microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate phthalate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, cellulose acetate trimellitate, cellulose carboxymethyl ethers and their salts, hydroxypropylmethyl cellulose phthalate, hydroxypropyl methylcellulose acetate succinate.
Sorbitan trioleate, Oligo lactic acid, Lecithin & Oleic acid, Poloxamer 188
Polyethylene; Polyquaternium-1; Polyvinyl acetate (homopolymer); Polyvinyl acetate
phthalate; Propylene glycol alginate; PVM/MA copolymer; PVP/
dimethiconylacrylate/polycarbamyl/polyglycolester; PVP/dimethylamino ethyl
methacrylate copolymer; PVP/dimethylaminoethylmethacrylate /polycarbamyl polyglycol ester; PVP/polycarbamyl polyglycol ester; PVP/ VA copolymer; polylactic acid, polyglycolic acid, poly (lactic co-glycolic acid) polymers.
Lanolin and lanolin derivatives, glyceryl monostearate, stearic acid, paraffins,
beeswax, carnauba wax, Tribehenin, Polyalkylene polyols like polyethylene glycols, Gelatin and gelatin derivatives, Alginates, Carbomers,
Polycarbophils, Methacrylic acid copolymers, Carrageenans, pectins, chitosans, cyclodextrins, lecithins. Natural and synthetic gums containing galactomannans like xanthan gum, tragacanth, acacia, agar, guargum, etc.
Surfactants : Sorbitan esters, Polyoxyethylene sorbitan fatty acid esters, Lecithin, Phosphatidyl cholines, Reaction products of natural and hydrogenated vegetable oils and
ethylene glycol 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®.
Dioctyl sodium sulfosuccinate, 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.
Plasticizers : Polyethylene glycols, propylene glycol, triacetin, diacetin, diethyl phthalate, dibutyl phthalate, castor oil, triethyl citrate and dibutyl sebacate.
pH adjusting agents : Sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium citrate, citric acid, hydrochloric acid, lactic acid, tartaric acid and malic acid.
Propellants: Propellant 11 (trichloromonofluoromethane), Propellant 12 (dichlorodifluoromethane), Propellant 114 (dichlorotetrafluoroethane), Butane, Isobutane, Propane, Difluoroethane Hydrofluoro alkane (P134a) and Hydrofluoro alkane (227).
Cosolvents : Ethanol, Myristyl alcohol, oleyl alcohol & Propylene glycol. Diluents/Dry carriers : D-Mannitol, Lactose and Sodium Chloride.
Antioxidants : Vitamin E, Vitamin E acetate, Sodium EDTA and Vitamin E TPGS
Lipophilicity Enhancers : Cholesterol
Bilayer membrane stabilizer: Sorbitan trioleate, Polyethylene (5) sorbitan mono oleate and phosphatidyl ethanolamine, phosphatidyl choline, dioleyl phosphatidyl ethanolamine
Cryoprotectants : Trehalose, Sucrose, Mannitol, Glucose, Glycerol, Sorbitol, Sodium chloride, polyethylene glycol
Poreformers : Perfluoro octylethane, Perfluoro decaline and Perfluoro octyl bromide Co-precipitants : Lactose, Calcium chloride dihydrate
Solvents : Dichloromethane, Methanol, Ethanol, Dimethyl acetamide, Isopropyl acetate, Isopropyl alcohol.
In another embodiment of the present invention nimesulide may be combined with other suitable active pharmaceutical ingredients like antiasthamatics, antihistaminics, steroids, and smooth muscle relaxants for administration in inhalation form.
The invention is further described with reference to the following examples of various compositions.
Example - I Chlorofluorocarbon based pressurized delivery
%w/w
1. Nimesulide 0.10
2. Sorbitan Trioleate 0.50
3. Oleyl Alcohol 6.80
4. Myristyl Alcohol 6.80
5. Propellant11 33.30
6. Propellant12 q.s. to 100
i. Blend 1 and 2 and disperse in a mixture of 3 and 4.
ii. Fill the concentrate of step - i into suitable containers and seal with a suitable valve.
iii. Fill 5 and 6 to container of step - ii using pressure burette
Example - II Non-Chlorofluorocarbon based pressurized delivery
%w/w
1. Nimesulide 0.10
2. Sorbitan Trioleate 0.50
3. Oleyl Alcohol 18.70
4. Myristyl Alcohol 23.30
5 1,1,1,2-tetrafluroethane (HFC - 134a) q.s. to 100
i. Blend 1 with 2 and disperse in a mixture of 3 and 4.
ii. Fill the concentrate of step - i into suitable containers and seal with a suitable valve.
iii. Fill 5 to the container of step - ii using pressure burette
Example - III Non-Chlorofluorocarbon based pressurized delivery
% w/w
1. Nimesulide 0.10
2. Oligo Lactic Acid 0.80
3. Oleyl Alcohol 5.93
4. Myristyl Alcohol 7.52
5. 1,1,1,2-tetrafluroethane (HFC- 134a) q.s. to 100
i. Blend 1 with 2 and disperse in a mixture of 3 and 4
ii. Fill the concentrate of step - i into suitable canisters and seal with a suitable valve.
iii. Fill 5 to the container of step - ii using pressure burette.
Example - IV Dry powder inhalation
% w/w
1. Nimesulide 7.3
2. Lactose q.s. to 100
i. Dissolve 2 in water and suspend 1 in the solution
ii. Pass through colloid mill to obtain a particle size in the range 2-10
iii. Spray dry the suspension to prepare co-precipitates.
iv. Fill into hard gelatin capsules or unit dose blister.
Example-V Dry powder inhalation
%w/w
1. Nimesulide 24.85
2. Zafirlukast 38.92
3. D-Mannitol 9.45
4. Sodium Chloride 6.23
5. Lactose q.s. to 100
i. Co-mill 1, 2 with 4 using ball mill to obtain average particle size less than 10
1.
ii. Blend with the milled mass of step - i with 3 and 5. iii. Fill into hard gelatin capsules or unit dose blister.
Example - VI Dry powder inhalation
% w/w
1. Nimesulide 32.65
2. Sodium Cromoglycate 27.95
3. D-Mannitol 13.47
4. Sodium Chloride 7.95
5. Lactose q.s. to 100
i. Co-mill 1,2,3 and 4 using ball mill to obtain on particle size in the range of 2 - 5 µ.
ii. Blend with the milled mass of step - i with 5.
iii. Fill into hard gelatin capsules or unit dose blister.
Example - VII Pulmospheres
% w/w
Solution A
1. Perfluro Octyl Ethane 9.74
2. Distearoyl Phosphatidyl Choline (DSPC) 0.45
3. Water q.s. to 100
Solution B
4. Nimesulide 0.50
5. Dichloromethane 3.25
6. Egg Phosphatidyl Choline 10.20
7. Poloxamer188 2.00
8. Water q.s. to 100
Solution C
9. Calcium Chloride Dihydrate 2.56
10. Lactose Monohydrate 4.89
11. Water q.s. to 100
Propellant
12. 1,1,1,2-tetrafluroethane(HFC-134a) q.s.
i. Mix 1, 2 and 3 to prepare Solution A. Separately mix 4, 5, 6, 7, and 8 to prepare Solution B. In a third vessel mix 9, 10 and 11 to prepare Solution C.
ii. An aqueous feed solution was prepared by mixing the solutions A, B and C in an optimized ratio, immediately prior to spray drying. Spray dried particles were filled into canisters and the canister filled with 12 by pressure burette through valve stem.
iii. The pulmospheres were dispersed in 12 by sonication followed by wrist-action shaking.
Example - VIM Dry powder inhalation
%w/w
1. Nimesulide 0.20
2. Beclomethasone dipropionate 0.10
3. Sorbitol 12.5
4. Lactose q.s. to 100
i. Co-mill 1, 2 and 3 using air jet milling.
ii. Blend the milled mass of step - i with 4 and fill into hard gelatin capsules or unit dose blister packs.
Example - IX Liposomal dispersion for nebulization
%w/w
1. Nimesulide 0.10
2. Dipalmitoyl Phosphatidyl Choline 0.23
3. Phosphatidyl Ethanolamine 0.81
4. Egg Phosphatidyl Choline 13.54
5. Cholesterol 6.15
6. Vitamin E Acetate 0.018
7. Sodium EDTA 0.032
8. Trehalose 11.92
9. Sucrose 9.54
10. Sodium Chloride 2.62
11. Phosphate Buffer Saline (pH 7.4) q. s. to 100
i. Dissolve 1, 2, 3, 4, 5 and 6 in a 1: 3 mixture of chloroform: methanol, and prepare a
film using rotating flask evaporator.
ii. Dissolve 7, 8, 9 and 10 in 11 and hydrate the film of step - i. iii. Fill the prepared liposomal dispersion into suitable containers, iv. Freeze dry the dispersion.
Example - X Niosomal formulation for nebulization
% w/w
1. Nimesulide 0.10
2. Sorbitan Monooleate 8.70
3. Sorbitan Trioleate 0.87
4. Polyoxyethylene 20 Sorbitan Monooleate 2.10
5. Polyoxyethylene (5) Sorbitan Monooleate 0.42
6. Cholesterol 6.80
7. Phosphate Buffer Saline (pH 7.4) q. s. to 100
i. Dissolve 1, 2, 3, 4, 5 and 6 in a mixture of dichloromethane: ethanol, and prepare a
film using rotating flask evaporator, ii. Hydrate the film of step - i with 7. iii. Fill the prepared niosomal dispersion into suitable dispensers and freeze dry.
Alternatively the dispersion may be spray dried.
Example XI Nimesulide in combination with anti-histaminic agent
%w/w
1. Nimesulide 0.10
2. Cetirizine Dihydrochloride 0.01
3. Oligo Lactic Acid 0.87
4. Ethyl Alcohol 15.00
5. 1,1,1,2-tetrafluoroethane(HFC-134a) q.s. to 100
i. Disperse 1 and 2 in mixture of 3 and 4.
ii. Fill in aerosol canisters. Seal with metered dose inhalation valve.
iii. Fill 5 to the container of step - ii using pressure burette
Example XII
%w/w
1. Nimesulide 0.10
2. Ethyl Alcohol 15.00
3. 1,1,1,2-tetrafluoroethane (HFC-134a) q.s. to 100
i. Dissove 1 in 2.
ii. Fill in aerosol canisters. Seal with metered dose inhalation valve.
iii. Fill 3 to the container of step - ii using pressure burette
Example XIII Micropheres for inhalation
%w/w
1. Poly (lactic co-glycolic acid) polymer 15.0
2. Nimesulide 10.0
3. Dichloromethane 25.0
4. Water 47.0
5. Polyvinyl acetate 3.0
i. Dissolve 1 in 3, add 2 and stir.
ii. Dissolve 5 in 4.
iii. Add the solution of step i to the solution of step ii and stir for about 30 minutes.
iv. Heat the emulsion to about 40 °C to remove 3. Filter and dry the microspheres.
Wash to remove adhering solvents and dry. v. Fill the dried material into hard gelatin capsules/unit dose blisters.
Example XIV Nanospheres for inhalation
% w/w
1. Albumin 10.0
2. Nimesulide 7.5
3. Water 20.0
4. Hydrogenated castor oil 2.5
5. Glutaraldehyde 3.0
6. Lactose q.s. to 100
i. Dissolve 1 in 3, add 2 and 4. Stir for 5 to 10 min.
ii. Add the mixture of step i to light paraffin liquid and homogenize to prepare an
emulsion.
iii. Slowly add 5 to the mixture of step ii. Stir continuously for 30 minutes,
iv. Filter to separate the microspheres, wash with suitable solvent, and dry.
v. Mix with 6 and fill into hard gelatin capsules or unit dose blisters Example XV Microparticles for nebulisation
% w/w
1. Nimesulide 10.0
2. Polyoxyethylene sorbitan monooleate 2.0
3. Sorbitan monooleate 3.0
4. Glycerin 15.0
5. Water q.s. to 100
i. Disperse 1 in 2, 3 and 4.
ii. Add 5 and pass through a colloid mill.

iii. Fill into suitable containers for dispensing

We claim:
1. A therapeutic composition for administration through inhalation route comprising
nimesulide from 0.1% to 98% w/w in micro-particulate form, along with one or
more excipients selected from the group comprising propellant, surfactant,
stabilizing agent, wetting agent, solubilizer, anticaking agent, antioxidant,
lipophilicity enhancer, bilayer membrane stabilizer, co-solvent, diluent from 2% to
99.9% w/w; optionally containing other active pharmaceutical ingredients as
herein described characterized in that the size of micro-particles is less than 10
micron.
2. The composition as claimed in claim 1, wherein the size of the micro-particles of
nimesulide is less than 5 micron.
3. The composition as claimed in claim 1, wherein the size of the micro-particles of
nimesulide is less than 2 micron.
4. The composition as claimed in claim 1, wherein the propellant is selected from the
group comprising Propellant 11 (trichloromonofluoromethane), Propellant 12
(dichlorodifluoromethane), Propellant 114 (dichlorotetrafluoroethane), Butane,
Isobutane, Propane, Difluoroethane Hydrofluoro alkane (P134a) and Hydrofluoro
alkane (227) and mixtures thereof.
5. The composition as claimed in claim 1, wherein the surfactant is selected from the
group comprising sorbitan esters, polyoxyethylene sorbitan fatty acid esters,
lecithin, phosphatidyl cholines, reaction products of natural and hydrogenated
vegetable oils and ethylene glycol, polyoxyethylene fatty acid esters,
polyoxyethylene polyoxypropylene copolymers, polyoxyethylene polyoxypropylene
block copolymers, dioctyl sodium sulfosuccinate, sodium lauryl sulphate,
propylene glycol mono and di fatty acid esters, and mixtures thereof.
6. The composition as claimed in claim 1, wherein the stabilizing agent is selected
from the group comprising cellulose derivatives, sorbitan trioleate, oligo lactic acid,
lecithin, oleic acid, polaxamer 188, polyethylene, polyquaternium-1, polyvinyl
acetate (homopolymer), polyvinyl acetate phthalate, propylene glycol alginate,
PVM/MA copolymer, PVP/ dimethiconylacrylate/polycarbamyl/polyglycolester,
PVP/dimethylaminoethyl methacrylate copolymer, PVP/dimethyl aminoethyl methacrylate/polycarbamyl polyglycol ester, PVP/polycarbamyl polyglycol ester, PVP/VA copolymer, polylactic acid, polyglycolic acid, poly (lactic co-glycolic acid) polymers, lanolin and lanolin derivatives, glyceryl monostearate, stearic acid, paraffins, beeswax, carnauba wax, tribehenin, polyalkylene polyols, gelatin and gelatin derivatives, alginates, carbomers, polycarbophils, methacrylic acid copolymers, carrageenans, pectins, chitosans, cyclodextrins, lecithins, natural and synthetic gums, and mixtures thereof.
7. The composition as claimed in claim 1, wherein the lipophilicity enhancer is
cholesterol.
8. The composition as claimed in claim 1, wherein the bilayer membrane stabilizer is
selected from the group comprising sorbitan trioleate, polyethylene sorbitan
monooleate, phosphatidyl ethanolamine, phosphatidyl choline, dioleyl
phosphatidyl ethanolamine and mixtures thereof.
9. The composition as claimed in claim 1, wherein the antioxidant is selected from
the group comprising vitamin E, vitamin E acetate, sodium EDTA, vitamin E TPGS
and mixtures thereof.
10. The composition as claimed in claim 1, wherein the co-solvent is selected from
the group comprising ethanol, myristyl alcohol, oleyl alcohol, propylene glycol and
mixtures thereof.
11. The composition as claimed in claim 1, wherein the diluent is selected from the
group comprising D-mannitol, lactose, sodium chloride and mixtures thereof.
12. The composition as claimed in claim 1, wherein the micro-particulate form of
nimesulide include microspheres, nanoparticles, nanocrystals, niosomes,
liposomes, micronized powders, pulmospheres, co-agglomerates or co-
precipitates.
13. The composition as claimed in claim 1, wherein the active pharmaceutical
ingredients are antiasthamatics, antihistaminics, steroids, and smooth muscle
relaxants selected from the group comprising zafirlukast, beclomethasone dipropionate, cetirizine dihydrochloride, albumin and sodium cromoglycate.
14. A process for the preparation of therapeutic composition as claimed in claim 1,
which process comprises the following steps:
a. reducing the size of nimesulide to form micro-particles having a size less
than 10 micron,
b. mixing the micro-particles of nimesulide from 0.1% to 98% w/w along with
one or more excipients selected from the group comprising propellant,
surfactant, stabilizing agent, wetting agent, solubilizer, anticaking agent,
antioxidant, lipophilicity enhancer, bilayer membrane stabilizer, co-solvent,
diluent and the like, from 2% to 99.9% w/w,
c. formulating the mixture into a suitable dosage form.
15. The therapeutic composition for administration through inhalation route
substantially as herein described and exemplified by the examples herein.
16. The process for the preparation of therapeutic composition for administration
through inhalation route substantially as herein described and exemplified by the
examples herein.