Claims:WE CLAIM:

1) A process for preparing micron sized particles of diclofenac dimethylamine, comprising the steps of;
• micronization of diclofenac dimethylamine by high energy milling technology using kinetic impact;
• employing pressurized process gas imparting high velocity to particles of said diclofenac dimethylamine;
• reducing particle size of said diclofenac dimethylamine in powder form to micron-sized particles;
• separating said particles by the exhaust process gas stream; and
• collecting said micron sized particles of said diclofenac dimethylamine of size ranging between 1- 500 microns.

2) The process as claimed in Claim 1, wherein said particle size increases the dissolution rate and absorption of diclofenac dimethylamine as it dissolves faster and provides better homo-geneity in a dosage form.

3) A topical pharamcetuical formulation, consisting of:
- about 0.5 – 5% by weight of diclofenace dimethylamine (micronized form);
- pharmaceutically accepted vehicle(s);
- carrier(s);
- inactive(s); and
- excipient(s) including water, oil, alcohol or propylene glycol mixed with preserva-tives, emulsifiers, absorption promoters and fragrances.

4) The topical pharamcetuical formulation as claimed in Claim 3, wherein said formulation is in the form of gel, spray, lotion, transdermal patch and ointment.

5) The topical pharamcetuical formulation as claimed in Claim 3, wherein said formulation also comprises of Linseed Oil, Polysorbate, Disodium Edetate, Carbomer, Sodium Hydrox-ide Pellets, Menthol, Butylated Hydroxytoulene, Benzyl Alcohol, Sodium Lauryl Sulphate, Triethylamine, Diethylamine, Propylene Glycol, polyethylene glycol hexadecyl ether, cocoyl capryloccaprate, Isopropyl Alcohol, Parafin, Benzene benzoate, Macrogol Cetostearyl Ether, Oleyl alcohol, acrylic acid polymer, isopropanol, alcohol-capric acid / caprylic acid ester.

6) The topical pharamcetuical formulation as claimed in Claim 3, wherein said formulation is stable and provides an enhanced therapeutic effect.

7) The topical pharamcetuical formulation as claimed in Claim 3, wherein said formulation reduces the symptoms of inflammatory disorder i.e. Osteoarthritis.
, Description:FIELD OF THE INVENTION

[001] The invention relates generally to process of micronization and more particularly pro-cess of producing micron sized particles of the pharmaceutically acceptable salt of diclo-fenac (diclofenac dimethylamine) and a formulation thereof, comprising said micron sized particles of diclofenac dimethylamine as the active pharmaceutical ingredient.

BACKGROUND OF THE INVENTION

[002] Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs, probably due to their therapeutic properties as anti-inflammatories, analgesics, antipy-retics, and anti-thrombotic and are used to treat a variety of clinical conditions manifesting such symptoms as pain, inflammation, fever, and to treat and prevent atherosclerosis. While these drugs are highly effective, oral administration of many NSAIDs can cause serious ad-verse effects such as gastrointestinal bleeding and ulceration, liver and kidney damages, and central nervous system and cutaneous disturbances, particularly after extended use. There-fore, in an effort to minimize the adverse effects associated with oral administration, non-oral delivery of NSAIDs has been extensively investigated in recent years.

[003] Diclofenac is a non-steroidal anti-inflammatory drug ("NSAID") known chemically as as 2- [(2,6dichlorophenyl) amino] benzeneacetic acid. Owing to its excellent analgesic properties, diclofenac is widely used for treating various types of pain, including both chronic and acute painful episodes. The drug is administered for the treatment of musculo-skeletal and joint disorders such as rheumatoid arthritis, osteoarthritis, and ankylosing spon-dylitis; periarticular disorders such as bursitis and tendonitis; soft tissue disorders such as sprains and strains, and other painful conditions such as renal colic, acute gout, dysmenor-rhea, and some surgical procedures.

[004] Diclofenac is generally taken orally in the form of normal tablets or tablets covered with coatings resistant to gastric juices, or rectally, or by injection, or topically. Diclofenac is an effective analgesic and anti-arthritic agent. It is available, inter alia, as enteric coated tab-lets and sustained release tablets containing diclofenac sodium, and also as sugar coated tab-lets of diclofenac potassium.
[005] Diclofenac is administered through solid dosage ranges from 75 mg to 100 mg daily. In standard doses of 100 mg is taken in daily. Prescription of Diclofenac recommend that it should be taken with meals if possible. Dosage generally should not exceed 100 mg daily. It is less permeable in skin and percutaneous absorption is low, due to lower penetration from hydrophillic dermis to stratum corneum.Moreover, an oral administration of diclofenac ex-hibits poor bioavailability (40-60%), short biological half-life (2-3 h), and therefore required a large amount of drug for the treatment. Due to the relatively poor solubility of diclofenac in water, an aqueous injection solution with a reasonable volume cannot be obtained. Fur-ther, diclofenac is relatively unstable in solution.

[006] Micronization is the process of reducing the average diameter of a solid particles to micron sized particles. Traditional or convnetional techniques for micronization focus on mechanical means, such as milling and grinding. Modern techniques make use of the proper-ties of supercritical fluids and manipulate the principles of solubility. Using conventional methods of micronization, for instance air-jet milling or high-pressure homogenization, amorphous regions and/or lattice defects are introduced into the sample, which means that once the sample is micronized and isolated, it has a strong tendency to absorb environmental moisture and undergo a degree of change of physical form. This rate of change is dependant on the storage conditions employed and hence special care is required to maintain steady conditions throughout the subsequent drug product manufacturing processes.

[007] Various processes are proposed to process drugs to alter certain physicochemical properties of the drug. The aforesaid processes make use of solvents that have low pharma-cological tolerability and therefore their residual presence needs to be strictly monitored. In addition, many of these solvents are highly flammable, making larger scale commercial man-ufacture difficult. In addition, it is well known that the current state-of-the-art high energy physical processing procedures, such as air jet milling, dry powder ball-milling or high pres-sure homogenisation, result in a partial loss of drug crystallinity.

[008] Topical application of diclofenac delivers the drug to the site of inflammation and minimizes diclofenac levels in the gastrointestinal and circulatory systems. Undesirable side effects resulting from oral administration of the drug are greatly reduced and, properly ad-ministered in the manner disclosed herein, the topical application produces therapeutic bene-fits.

[009] Hence, there still remains an unmet need for alternative process for preparing mi-cronized particles and formulations of diclofenac or a pharmaceutically acceptable salt thereof having characteristics which are fundamental to topical preparations and can accom-plish the desired therapeutic effect. The challenge has been to develop an improved process and optimal formulation which will deliver the active agent to the underlying tissue in suffi-cient concentration on a long term basis, while providing a formulation that leads to and en-courages patient compliance. The present invention satisfies these and other needs.

OBJECT OF THE INVENTION

[010] The main object of the present invention is to eliminate the shortcomings of existing prior art.

[011] An object of the present invention is to provide a process for preparing micron sized particles of diclofenac dimethylamine, wherein the reduced particle size increases the disso-lution rate and absorption of diclofenac dimethylamine as it dissolves faster and provides better homogeneity in dosage form due to smaller size.

[012] Another object of the present invention is to provide a process for preparing mi-cronized particles of diclofenac dimethylamine to achieve a desired particle size of Diclo-fenac Diethylamine which is free of segregation or clumping of particles.

[013] Other objects and advantages of the present invention will become apparent from the following description taken in connection with the accompanying drawings, illusrations to disclose the aspects of the present invention.

SUMMARY OF THE INVENTION
[014] The present invention is directed to a process for preparing micron sized particles of diclofenac dimethylamine and a topical formulation, comprising said micron sized particles of diclofenac dimethylamine as the active pharmaceutical ingredient which displays greater pharmacokinetic absorption in vivo, high permeation and improved efficacy when compared to prior compositions.

[015] According to an embodiment of the present invention, the process for preparing mi-cron sized particles of diclofenac dimethylamine, comprises the steps of; micronization of diclofenac dimethylamine by high energy milling technology using kinetic impact ; employ-ing pressurized process gas imparting high velocity to particles of diclofenac dimethylamine; reducing particle size of said diclofenac dimethylamine in a powder form to micron sized particles; separating said particles from the exhaust process gas stream; and collecting the micron sized particles ranging between 1- 500 microns.

[016] According to an embodiment of the present invention, the topical formulation com-prises of therapeutically effective amount of diclofenac dimethylamine (micronized form) in the range of about 0.5 –5% by weight in combination with one or more pharmaceutically ac-cepted vehicles, carriers, inactives and excipients including water, oil, alcohol or propylene glycol mixed with preservatives, emulsifiers, absorption promoters and fragrances.

BRIEF DESCRIPTION OF THE DRAWINGS

[017] The present invention will be better understood after reading the following detailed description of the presently preferred aspects thereof with reference to the appended draw-ing, in which:

Figure 1 illustrates graphical représentation between area/volume and side length of a cube.

DETAILED DESCRIPTION OF THE INVENTION

[018] The following detailed description discloses specific and/or preferred variants of the individual features of the invention. The present invention also contemplates as encompass-ing, as particularly preferred embodiments of the invention, those embodiments which are obtained by combining two or more of the specific and/or preferred variants described for two or more of the features of the present invention.
[019] Unless expressly specified otherwise, all indications of relative amounts in the pre-sent application are made on a weight/weight basis. Indications of relative amounts of a component characterized by a generic term are intended to refer to the total amount of all specific variants or members covered by said generic term. If a certain component defined by a generic term is specified to be present in a certain relative amount or range of amount, and if an embodiment of the invention further characterizes this component as comprising a specific variant or member covered by the generic term, it is intended that other variants or members covered by the generic term may be present only in an amount such that the total relative amount of all components covered by the generic term does not exceed the speci-fied relative amount. Preferably, in such case, no other variants or members covered by the generic term are present at all.

[020] Generally, when referring to a formulation comprising "x% wt" of an ingredient, such formulation should be understood to allow for a pharmaceutically acceptable variation in the % wt of said ingredient of ± 10%. For example, when referring to a formulation com-prising "3% wt of diclofenac", such formulation should be understood to allow for a phar-maceutically acceptable variation in the % wt of diclofenac of ± 10%, i.e. from 2.7% wt to 3.3% wt.

[021] The term 'Diclofenac' is in context of the invention includes its polymorphic forms, the pharmaceutically acceptable salts, including salts esters and pother chemical derivatives or intermediates etc.

[022] The term 'micronization' as used herein refers to the process of reducing the average diameter of a solid material's particles. Usually, the term micronization is used when the par-ticles that are produced are only a few micrometres in diameter. Traditional micronization techniques are based on the use of friction to reduce particle size. Such methods include milling and grinding. Reduction in particle size may also take place as a result of collision and impact.

[023] The term “topical formulation” is used herein to generally include a formulation that can be applied to skin or a mucosa. Topical formulations may, for example, be used to con-fer therapeutic benefit to a patient or cosmetic benefits to a consumer. Topical formulations can be used for both topical and transdermal administration of substances.
[024] When referring to diclofenac, it should be understood to refer to any one or more of the NSAID named 2-(2,6-dichloranilino) phenylacetic acid (CAS Registry Number 15307- 86-5), its sodium salt, its potassium salt, its epolamine salt, its diethylamine salt, and/or any other pharmaceutically acceptable salt thereof. A pharmaceutically acceptable salt of diclo-fenac is e.g. diclofenac dimethylamine, diclofenac sodium, diclofenac potassium, diclofenac diethylammonium or diclofenac epolamine. In particular preferred is diclofenac dimethyla-mine

[025] Diclofenac Dimethylamine is sparingly soluble in water. A therapeutic formula-tion/composition and a process is provided which is stable, has higher absorption and per-meation and thus improved efficacy leading to increased patient compliance and conven-ience.

[026] The present invention relates to a process for preparing micron sized particles of di-clofenac dimethylamine and a topical formulation, comprising said micron sized particles of diclofenac dimethylamine as the active ingredient that displays greater pharmacokinetic ab-sorption in vivo, high permeation and improved efficacy.

[027] The process for preparing micron sized particles of diclofenac dimethylamine, com-prises the steps of;
• micronization of diclofenac dimethylamine by high energy milling technology using kinetic impact;
• employing pressurized process gas imparting high velocity to particles of diclofenac dimethylamine;
• reducing particle size of said diclofenac dimethylamine in powder form to micron size particles;
• separating said particles from the exhaust process gas stream; and
• collecting micron sized particles of diclofenac dimethylamine of size ranging between 1- 500 microns.

[028] Figure 1 illustrates a graphical représentation between area/volume and side length of a cube, wherein the graph shows that volume remains constant while the surface area of the particles of a drug increases drammatically.

[029] The topical formulation comprises of therapeutically effective amount of micron sized particles of diclofenac dimethylamine as the active pharmaceutical ingredient (0.5 – 5% w/w) in combination with one or more pharmaceutically acceptable excipients and carri-ers.

[030] The composition comprises of pharmaceutically accepted vehicles, carriers, inactives and excipients including water, oil, alcohol or propylene glycol mixed with preservatives, emulsifiers, absorption promoters and fragrances.

[031] The other ingredients which can be used to form formulations are Linseed Oil, Poly-sorbate, Disodium Edetate, Carbomer, Sodium Hydroxide Pellets, Menthol, Butylated Hy-droxytoulene, Benzyl Alcohol, Sodium Lauryl Sulphate, Triethylamine, Diethylamine, Pro-pylene Glycol, polyethylene glycol hexadecyl ether, cocoyl capryloccaprate, Isopropyl Al-cohol, Parafin, benzene benzoate, Macrogol Cetostearyl Ether, Oleyl alcohol, acrylic acid polymer, isopropanol, alcohol-capric acid / caprylic acid ester.

[032] The formulations of this invention can be topically applied to affected areas of the skin in any convenient form, e.g. gel, cream, ointment, lotion, spray, etc.

[033] The topical formulations used in the present invention are particularly suitable for formulations as topical preparations. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of where treatment is required. Examples of liquid and semi-liquid preparations include, but are not limited to, topical solutions, liniments, lotions, creams, ointment or paste, gel, and emugel. Other topical ingredients used in the topical formulation are in general those com-monly used and generally recognized by person skilled in the art of topical formulation.

[034] The topical formulation results in lower drug volume intake in body and avoids sys-temic toxicity due to lower application, while providing local action for a prolonged period of time.

[035] Hereafter, the embodiments of this disclosure are described in detail with reference to examples. The following comparative examples are not restrictive but are illustrative.

Example 1- Gel Formulation

[036] In one experiment the topical formulation was prepared in the form of a gel contain-ing 1-3% w/w of 2-[2-(2,6-dichloroanilino) phenyl]acetic acid; N-ethylethanamine (Diclo-fenac Diethylamine) with pharmaceuticals ingredients as Linseed Oil (Oleum Lini), Poly-sorbate 80, Disodium Edetate, Carbomer-940, Purified Water, Methyl Salicylate, Menthol, Hydroxy Propyl Methycellulose, Benzyl Alcohol, Triethylamine, Propylene Glycol.

[037] Although the embodiments herein are described with various specific embodiments, it will be obvious for a person skilled in the art to practice the invention with modifications. However, all such modifications are deemed to be within the scope of the invention.