FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Provisional Specification
(See section 10 and rule 13)
NOVEL PROCESSING OF NIMESULIDE
PANACEA BIOTEC LIMITED
A company incorporated under the laws of India having their office at 104, SAMARPAN COMPLEX, NEW-LINK ROAD, CHAKALA, ANDHERI (E), MUMBAI 400099,
MAHARASHTRA, INDIA
The following specification describes the invention
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FIELD OF THE INVENTION:
The invention relates to processing of Nimesulide to obtain amorphous/micronized Nimesulide which provides enhanced aqueous solubility and/or dissolution and/or absorption. The present invention is also useful for the manufacturing of compositions comprising the said Nimesulide with desired improved bioavailability.
BACKGROUND OF THE INVENTION:
Nimesulide (4-nitro-2phenoxymethane sulfonamide) is a potent non-steroidal antiinflammatory drug (NSAID) which causes several actions, including the following: (a) inhibition of prostaglandin synthesis, (b) inhibition of toxic oxygen metabolite formation, (c) inhibition of cytokine release, (d) inhibition of histamine release, and (e) inhibition of cartilage degradation. In accord with these actions, Nimesulide exerts anti-inflammatory, analgesic and anti-pyretic activities, and therefore effectively treats a wide range of disorders. Nimesulide has a molecular weight of 308.31 g/mol and is practically insoluble in water, having a half-life of about 4 hours. It operates by selectively inhibiting cyclooxygenase-2 (COX-2).
Nimesulide has been marketed under numerous trade names, including Ainex®, Aulin®, Donulide®, Edrigyl®, Eskaflam®, Fansidol®, Flogovital®, Guaxan®, Heugan®, Mesulid®, Nemil®, Nexen®, Nide®, Nidol®, Nimed®, Nimedex®, Nisulid®, Plarium®, Scaflam®, Scaflan®, and Sulidene®. Conventional solid oral dose of Nimesulide is available as 100 mg, administered as twice daily and extended release products are developed using 200 mg Nimesulide as once daily.
Nimesulide is a hydrophobic substance and practically insoluble in water. Due to its poor aqueous solubility and regio-specific absorption behavior, it has lower oral bioavailability. Many techniques have been used to improve its dissolution and/or bioavailability e.g. micronization, nanoparticulate composition, complexation with cyclodextrin and/or other polymeric material, making of its L-lysine salt, making of its micronized salt with metal and spray drying of aqueous complexes. United State Patent No. 5,756,546 to Pirotte et al. discloses a water-soluble salt formed from equimolar amounts of Nimesulide and L-lysine.
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But variation from the 1:1 molar ratio may lead to contamination with excess L- lysine or insoluble Nimesulide. United State Patent No. 5,744,165 to Geczy et al. relates to alkali and alkaline earth salts of Nimesulide that, when combined with a cyclodextrin to form inclusion complexes, can be dissolved in water. However, compositions of this type can deliver unwanted amounts of cyclodextrin and sodium ion to a patient.
As mentioned above micronization is a technique to improve the solubility of a molecule. Micronized Nimesulide has been utilized in the art. These micronized Nimesulide have been obtained by milling or grinding (e.g. ball milling, hammer milling, air jet milling), use of supercritical fluid technique and spray drying of Nimesulide in presence of polymeric material and/or other pharmaceutically acceptable carrier. But each technique has its own drawback. Milling or grinding method is subjected to loss of active principle during processing and thus provides a very low yield. And also, the micronized form of Nimesulide obtained by milling or grinding is very difficult to handle due to the presence of static charge on the particle of Nimesulide. Use of supercritical fluid technique is a complex and expensive process, which requires using sophisticated technology and method and spray drying in presence of cyclodextrin or other polymeric material encompasses use of other unwanted additional excipients.
PCT application WOO 166090 relates to production of micronized form of Nimesulide characterized by amorphous or semi-crystalline particles of micrometric and sub-micrometric dimensions by the action of supercritical fluid. Although micronized form of Nimesulide is known by this invention but the process of making micronized form of Nimesulide by spray drying is not described. Also, super critical fluid technique is very expensive and requires specific solvents to obtain the Nimesulide in micronized form.
European Patent application No. 1258241, relates to a method of making Nimesulide more bioavailable by adsorption on a polymeric carrier, with use of the solubilization technique in an organic solvent or by co-grinding in a high- energy mill, with formation of an inclusion complex [Nimesulide: polymeric carrier] of improved bio-pharmaceutical qualities.
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PCT application WO 9947172 teaches oral rapid release composition comprising an active ingredient forming an inclusion complex with polymeric material such as cyclodextrin, polyvinyl pyrrolidone and others. These inclusion complexes can be prepared by co-grinding, lyophilization, granulation and spray-drying. Thus according to this invention, such formulations are useful in increasing the bioavailability of water insoluble or slightly soluble active ingredients.
European Patent application 0937709 relates to Nimesulide soluble salts in micronized form. Micronization can be carried out, according to the invention, by spray-drying Nimesulide sodium salt or by grinding the precipitated salt in vibrational mills. In an embodiment, alkaline solution of Nimesulide is either precipitated or spray dried to obtain the sodium salt of Nimesulide. As known in prior arts, salts of Nimesulide have disadvantages like color of the matter, pH, etc making it difficult to be utilized in formulating it into acceptable dosage forms.
United State Patent Application 20040156872 provides nanoparticulate Nimesulide compositions. The compositions preferably comprise Nimesulide and at least one surface stabilizer adsorbed on or associated with the surface of the Nimesulide particles. Such composition require specific solvent in which Nimesulide is poorly soluble and surface stabilizer to reduce the particle size of Nimesulide. Nanoparticulate Nimesulide compositions can be made using any suitable method such as, for example, milling, homogenization, or precipitation techniques. Such formulations are very expensive, cumbersome and require sophisticated technologies and method of production.
As observed in all the above cited prior arts, the active ingredient has either been processed in its salt form or has been derivatized using polymeric materials in order to obtain a composition with improved bioavailability. But there is still a need to develop a simple, useful and very effective method of processing Nimesulide without derivatization or salification to obtain an amorphous/micronized Nimesulide which has substantially improved solubility/dissolution/absorption and hence improved bioavailability as compared to the
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conventional unprocessed Nimesulide as well to other known Nimesulide forms. A suitable formulation developed using this easily made amorphous/micronized Nimesulide would be such that it can reduce the effective dose and hence the dose-related side effects, improve clinical efficacy, and potentially reduce the cost of therapy.
SUMMARY OF THE INVENTION:
The present invention provides a process of preparing substantially amorphous/micronized Nimesulide by spray drying method without use of any pharmaceutically acceptable carrier(s).
The present invention thus provides a process of preparing substantially amorphous/micronized Nimesulide without derivatization or salification by dissolving Nimesulide in suitable organic solvent(s) and removing the solvent(s) from the resulting solution by spray drying. The thus obtained spray-dried Nimesulide has substantially higher solubility and/or dissolution and/or absorption when compared to pure Nimesulide and Nimesulide treated with other techniques.
The present invention further provides pharmaceutical composition comprising the said spray-dried Nimesulide and pharmaceutically acceptable excipient (s), which provides desired improved dissolution and/or bioavailability.
The present invention further provides pharmaceutical composition comprising the said spray-dried Nimesulide and other active ingredient(s) whose concurrent administration may be useful for the treatment of one or more pathological conditions.
The present invention further provides pharmaceutical composition comprising mixture of the said spray-dried Nimesulide and crystalline Nimesulide in different ratio(s) to show different dissolution/bioavailability profile.
The present invention provides pharmaceutical composition comprising the said spray-dried Nimesulide and pharmaceutically acceptable excipient(s), which provides desired
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improved dissolution and/or bioavailability, wherein the pharmaceutical composition may be immediate release, controlled release, delayed release, timed pulse release and the like.
It is an object of the present invention to provide use of the said spray-dried Nimesulide and use of pharmaceutical composition comprising the said spray-dried Nimesulide for the treatment of NSAID's indicated disorders.
It is also an object of the present invention to provide low dose composition comprising the said spray-dried Nimesulide. Such low dose compositions are designed to exhibit a bioavailability which is effective in the treatment of NSAID's indicated disorders. Such compositions are designed to reduce the cost of therapy in diseases like arthritis which require long term treatment and reduce dose related side-effects associated with use of composition comprising conventional Nimesulide or its salt/derivatives.
DESCRIPTION OF THE INVENTION:
The present invention provides a method of achieving substantially higher solubility and/or dissolution and/or absorption for Nimesulide by a process of dissolving the Nimesulide in suitable organic solvent(s) and removing the solvent(s) from the resulting solution by spray drying technique to obtain substantially amorphous/micronized Nimesulide.
The present invention provides such a method for preparing substantially amorphous/micronized Nimesulide by dissolving the Nimesulide in suitable organic solvent(s) preferably without the addition of any pharmaceutically acceptable carrier and removing the solvent(s) from the resulting solution by spray drying technique to obtain an amorphous/micronized Nimesulide without any derivatization or salification.
It should be understood that the Nimesulide can be processed to obtain a spray-dried Nimesulide of the present invention either by spray-drying commercially available Nimesulide as described above or by spray-drying the mother liquor obtained during the chemical process of synthesizing Nimesulide at the final stage.
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The thus obtained spray-dried Nimesulide of the present invention is porous, round agglomerates or particles, which are uniform in size, stable and consistent in properties having substantially higher solubility and hence higher dissolution and absorption. The process of the present invention is simple, cheaper and easily up scalable, which requires less sophisticated technology and methods as compared to other techniques. This process provides a Nimesulide active ingredient, which would comply with ICH and other pharmacopoeial requirements.
Organic solvent which may be suitably used in the present invention includes ketones such as acetone, alcohols such as methanol, isopropyl alcohol, ethanol, nitrites such as acetonitrile, ethers such as tetrahydrofurane and dioxane, esters such as methyl or ethyl acetate, chlorinated solvents such as methylene chloride or chloroform and a mixture thereof, and the likes in which Nimesulide is soluble, preferably acetone; preferably used in concentration of 10% w/v.
In spray drying, an inert gas such as argon, nitrogen, carbon dioxide or air may be used as a drying gas. Inlet and outlet temperatures thereof may be dependent on the boiling point of the solvent used. For example, the inlet temperature may range 50 to 140° C, preferably 60 to 125° C and the outlet temperature may range 45 to 100° C, preferably 50 to 80° C. By employing appropriate spray drying conditions, a product having a uniform particle size may be formed.
Amorphous/micronized Nimesulide prepared by the said spray drying techniques as described herein has wide range of advantages over the prior arts (1) easy to prepare, cheaper process and higher yield (2) no use of pharmaceutical acceptable carrier i.e. complex with cyclodextrin, and/or other polymeric material (3) easy to handle due to absence of static charge on the particles (4) faster onset of action; (5) a potential decrease in the frequency of dosing; (6) smaller doses of drug required to obtain the same pharmacological effect; (7) increased solubility (8) an increased rate of dissolution; (9) increased bioavailability; (10) high redispersibility of the spray-dried Nimesulide particles present in the compositions of the invention following administration; (11) improved performance characteristics for oral, intravenous, subcutaneous, or intramuscular injection,
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such as higher dose loading; (12) improved pharmacokinetic profiles, such as improved T max, Cmax, and AUC profiles; (13) substantially similar or bioequivalent pharmacokinetic profiles of the spray-dried Nimesulide compositions when administered in the fed versus the fasted state; (14) the spray-dried Nimesulide compositions can be used in conjunction with other active agents; (15) the spray-dried Nimesulide containing compositions are suitable for parenteral administration; and (16) the spray-dried Nimesulide containing compositions do not require additional organic solvents or pH extremes during manufacturing the composition.
In an embodiment, the solubility, the dissolution and hence the absorption of the said spray-dried Nimesulide is substantially higher than the conventionally available Nimesulide active ingredient.
In further embodiment, the bioavailability and plasma concentration of the said spray-dried amorphous/micronized Nimesulide of the present invention present in a composition is sufficiently effective to produce desired pharmacological effects such as analgesic and/or anti-inflammatory and/or antipyretic effects and the like at low dose. Particularly the low dose composition comprising spray dried amorphous/micronized Nimesulide of the present invention is very useful in mammals, more particularly in humans, for the treatment of preferably the NSAID's indicated disorders such as acute painful conditions like lower back pain, early morning pathologies, post-operative trauma, pain associated with cancer, postoperative pain, sports injuries, dysmenorrhoea, migraine headache, neurological pain and pain associated with sciatica and spondylitis, arthritis, idiopathic pain, myofascial pain, osteoarthitis, neuropathic pain, fibromyalgia and inflammatory pain states such as rheumatoid arthritis and osteoarthritis. Neuropathic pain includes pain such as pain secondary to injury to nerves and includes postherpetic neuralgia, diabetic neuropathy, postamputation pain, mono- and polyneuropathies, radiculopathy, central pain, shingles, trigeminal neuralgia, temporomandibular joint disorder; cancer pain; chronic pain; sympathetically mediated pain, Raynaud's disease, CPS (Chronic Pain Syndrome); tension and migraine headache, stump pain, polyarteritis nodosa, osteomyelitis, bums involving nerve damage, AIDS related pain syndromes, and connective tissue disorders, such as
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systemic lupus erythematosis, systemic sclerosis, polymyositis, and dermatomyositis, other degenerative joint disorders, or any other disorders mediated by particularly the cyclooxygenase enzyme, and the like, or a combination of several disorders or any other associated disorder. Also, the low dose compositions comprising spray-dried amorphous/micronized Nimesulide are useful as an antioxidant or a platelet aggregation inhibitor or as an anticancer agent.
So it is an object of the present invention to provide a low dose pharmaceutical composition comprising spray-dried Nimesulide which reduces the cost of therapy in disease like arthritis which requires long term treatment and reduces the dose-related side effects associated with conventional recommended dose of untreated Nimesulide-containing composition.
The spray-dried Nimesulide of the present invention can be easily formulated into desired pharmaceutical compositions by conventional methods, comprising the said spray-dried Nimesulide and pharmaceutically acceptable excipients. These formulations can be administered orally, parenterally, topically, transdermally, rectally or by any other route of administration. In a further embodiment, the composition of the present invention is preferably in the form of oral dosage forms such as powder, granules, tablets, capsules, pellets, suspensions, solutions, emulsions, or the like, more preferably as a solid oral dosage form such as tablets or capsules. The oral dosage forms can be immediate release, controlled release, timed pulse release and/or the like. In another embodiment, the pharmaceutical composition may contain other pharmacologically active ingredient(s) whose concurrent administration may be useful.
The pharmaceutically acceptable excipients of the present invention are selected from but not limited to a group comprising disintegrants, binders, mucoadhesive agents, fillers, bulking agents, anti-adherants, rate-controlling agents, anti-oxidants, buffering agents, colorants, flavoring agents, coating agents, plasticizers, stabilizers, preservatives, lubricants, glidants, chelating agents, and the like or any other pharmaceutically acceptable excipient known to the art, used either alone or in combination thereof. It will be
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appreciated that certain excipients used in the present composition can serve more than one purpose.
The present invention also provides a method for treating several cyclooxygenase enzyme inhibition mediated and NSAID's indicated disorders in mammals which comprises administrating thereto an effective amount of the amorphous/micronized Nimesulide wherein micronization of Nimesulide is carried out by spray drying method without using pharmaceutically acceptable carrier.
The present invention will be described in further detail with reference to Examples. However, it should be understood that the present is not restricted by the specific Examples.
EXAMPLE 1 Table 1:

S.No. Components % w/v
1 Nimesulide 10%
2 Acetone Quantity sufficient
10 mg Nimesulide is dissolved in 100 ml acetone and this resulting solution is subjected to spray-drying at an inlet temperature of 70-110 °C and outlet temperature 50-90 °C which produces Nimesulide in amorphous, micronized, porous and agglomerate stage.
Dissolution studies were carried out in 0.001 N HC1 with 1% sodium lauryl sulfate, 1000 ml, paddle method, 75 rpm.
The dissolution data of spray dried Nimesulide of the present invention is compared with untreated Nimesulide and Nimesulide spray-dried in presence of polyvinyl pyrrolidone and sodium lauryl sulfate is depicted in Table 2.
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Table 2:

Time (Min) % dissolved
Nimesulide (untreated) Nimesulide + PVP + SLS (spray-dried) Nimesulide +Acetone(spray-dried)
0 0.0 0.0 0.0
5 16.60 82.96 73.36
15 30.12 84.46 99.16
30 44.50 84.00 93.27
60 61.92 84.20 94.12
90 73.86 84.54 94.95
120 81.18 84.48 95.79
Dated this 31st of Aug 2006
FOR PANACEA BIOTEC LIMITED (Dr. MAHALAXMI ANDHERIA)
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