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Back to the List of the Granted Patents                                      Click here to download KE000106 PDF(11) Patent Number: KE 106
(45) Date of grant: 10/03/2005

(12) PATENT
(51) Int.Cl.6: A 61K 31/8
(21) Application Number: 1999/ 000265
(22) Filing Date: 01/02/1999

(30) Priority data:628/B0M/97 21/01/1999 IN
 
(74) Agent/address for correspondence: T.S. Viswannathan, P.o.Box 79642 Nairobi
 
(54) Title: THE PROCESS FOR MANFACTURING TOPICAL FORMULATION OF NIMESULIDE.
(57) Abstract:The invention relates to a new formulation of nimesulide gel formulated with polytylene glycol and polysorbate 80. It is formulated into the gel form of carbopol in alcohol.
 
The present invention relates to a process of manufacturing a formulation of Nimesulide for topical application to alleviate inflammation and pain.
The present invention is directed to a process of manufacturing of a topical formulation of Nimesulide in such a way to achieve tissue concentration faster and for longer duration.
Nimesulide is a new class of non-steroidal anti-inflammatory drug. It reduces pain and inflammation like any other non-steroidal anti-inflammatory drug. However, it is devoid of action on Cox-1 enzymes which imparts gastric protection. This results in absence of side effects.

Nimesulide when taken orally is found to be effective. However; because of its rate limiting absorptiostion it is not possible to achieve higher tissue concentration. The increase in strength of Nimesulide from 200 mg to 400 mg for oral use is not associated with any significant advantage.
It is also known that long term systemic use may be associated with hepatic toxicity. Thus it is desirable to have a topical preparation which provide higher tissue concentration locally and negligible concentration elsewhere to have better analgesic anti-inflammatory effect but minimizing side effects.
The other side effects seen with oral Nimesulide include gastrointestinal disturbances, C.N.S. side effects.
 
The objective of present invention is to provide topical formulation of Nimesulide. The furtherobjective of present invention is to provide a topical formulation of Nimesulide which achieves higher tissue concentration and better effect compared to oral preparation.
The further objective of present invention is to provide formulation of Nimesulide which is fast acting.
The further objective of present invention is to provide topical formulation of Nimesulide which is non-staining and non-irritant.
The further objective of present invention is to provide topical formulation of Nimesulide which is effective for long duration.
The further objective of present invention is to increase compliance by elimination of side effects of oral Nimesulide.
The further object of present invention is to provide a stable topical formulation.
The following specification particular describes and ascertain the nature of this invention and manner in which it is to be performed.
The process comprises of following steps:
A. Preparation of Nimesulide solution.
B. Preparation of gel base
C. Mixing of Nimesulide solution and gel base
D. Addition of stabilizer
E. Adjustment of pH of gel
 
A. Preparation of Nimesulide Solution
1. The dear solution of Nimesulide is prepared in polyethylene Glycol-400.Ensure that total drug has gone into solution and there are no residue on the sides or corners of the container.
2. Filter the resultant solution and add polysorbate 80. Stir the solution for further 15 minutes to get clear solution.
B. Preparation of Gel base
1. In a separate stainless steel vessel take filtered ethyl alcohol.
2. Add Carbopol 940 slowly under continuous stirring and stir well till homogenous gel is formed.
3. After completion of stirring, transfer the gel completely in mixer and stir further for 30 minutes.
C. Mixing of drug solution and gel base
1. Start mixer at low speed which contains non-aqueous gel gel base.
2. Transfer slowly the drug solution A with continuous mixing.
3. Continue mixing at slow speed till a uniform gel is formed.
D. Addition of stabilizer
1. Add filtered propylene glycol- with continuous mixing
2. After complete addition, mix at slow speed for 30 minutes till homogenous mass is obtained.
E. Adjustment of the pH of gel
1. Dissolve sodium hydroxide in purified water and add ethyl alcohol with
mixing in a separate vessel (alcoholic NaOH solution).
2. Check the initial pH of the-gel after completion of step C.
 
3. Adjust the pH of the gel with alcoholic NaOH solution to pH 4.0 to 4.5.
4. Addition of alcoholic NaOH solution should be slow with continuous stirring. After each addition stir well.
5. After adjustment of pH, transfer the gel in stainless steel container which is ready for packing.
Nimesulide 0.5% to 5% gel can reduce inflammation and pain. It was optimized at Nimesulide 1% w/w gel.

Carbopol can be Carbopol-940, 932, 970 which forms gel in solution. The concentration of Carbopol in final formulation can be 0.5% to 5%.
The concentration of Polyethylene Glycol can be 5% to 25%.
The stabilizer can be Propylene Glycol. The concentration of. Propylene Glycol can be 5% to 25% pH is usually acidic and needs to be adjusted with alcoholic Sodiumhydroxide solution,
The concentration of ethyl alcohol can be 10% to 90%.
 A typical example of formulation
Nimesulide              1.0 gm.
Polyethylene glycol    15.0 gm.
Polysorbate 80 -   8.0 gm.
Carbopol 940    2.0 gm.
Ethyl alcohol    60.0 gm.
Propylene glycol      13.5 gm.
Alcoholic NaOH solution Q.S. to make 100 gm. (To adjust pH 4.0 to 4.5).
The pharmaceutical composition so manufactured is evaluated for stability and accuracy.  
The pharmaceutical composition so manufactured is evaluated at different standard test conditions of temperature and humidity.
 
The samples of formulation were taken for study. These were found to be stable with no blistering or gas formation.
This formulation of Nimesulide gel 1% made as described (new formulation) was evaluated for its anti-inflammatory and analgesic effects in animal models.
The new formulation is also evaluated for topical absorption in human volunteers.
In Carragenan paw edema model in rat’s new formulation found to reduce edema by 72.2%.
In deatran paw edema model in rat’s new formulation found to reduce edema by 46.21%.
Similarly, in acetic acid induced righting model in mice new formulation relieved' the analgesia and the effect is persisted for more than 6hrs (the study period).
Thus, improved efficacy with longer duration of effect of new formulation is established in different animal models of inflammation and analgesia.
In the In Vitro release study through synthetic lipid membrane and rat skin using the Venkel enhancer cell, new formulation showed slow but sustained release of drug from both the membranes.

This also confirms the longer duration of effect of new formulation observed in animal models.

200 mg accurately weighed new formulation were applied locally to human volunteers. After different time interval of the application of Nimesulide gel, the gel retained on the skin was recovered into the phosphate buffer and analyzed for Nimesulide content. The difference between applied amount and recovered amount, gives the amount disappeared and eventually the amount diffused across the epidermis. It was observed that the major portion of drug is absorbed within 15 minutes, which is in accordance with clinical observation that pain relief is attained within 15 minutes. With the oral Nimesulide formulation, the effect observed only after 1.2 hours. Thus faster action, of new formulation is established in healthy volunteers.
The topical preparation of Nimesulide is available in the market (Nimulide gel). This topical formulation is found to have gas formation which is undesirable in terms of stability and efficacy point of view. It also causes skin coloration. The effect of which in a controlled trial is found to be less effective in Carragenan paw edema and Acetic acid induce wrighting response.
The 1% formulation made according to the present invention provides 72.2% reduction in carrageenan paw edema model in rats at 3 hours compared to 3034% with that of Nimulide gel.
 
In acetic acid induced wrighting model in mice, the inhibition seen with 19 formulation made according to current invention is 56.67% and 43.48% at 4 & 5 hour respectively compared to 33.86% and 27.95% seen with Nimulide.
The In Vitro (synthetic lipid membrane model) drug release with the 1% formulation made by present invention results in drug release for more than 12 hours compared to Nimulide 1% which drug release up to 6 hours only.
In human volunteer 1% formulation made by present invention pain relief obtained for around 24 hours compared to 12 hours or less with Nimulide.
Nimulide gel is formed to have viscosity is than 20000 cps, It also does not contain alcohol, polyethylene glycol and propylene glycol.
The use of these compounds and higher viscosity obtained by claimed process responsible for better stability, penetration, longer duration of effect and better relied of inflammation
 
CLAIM
1. The process of manufacturing a topical stable, non-irritating, non-staining formulation of Nimesulide which is to provide longer duration of action, which comprises of the steps.
i. a. making solution of Nimesulide in a propylene glycol
b. making a gel base
ii. adding solution of Nimesulide to gel.
iii. adding stabilizer
iv. adjusting pH
2. A process as in claim 1 wherein concentration of Nimesulide can be 0.5% to 5%
preferably between 0.75% and 1.25%.
3. A process as in claim 1&2 wherein Nimesulide solution is prepared by dissolving
Nimesulide in polyethylene glycol.
4. A process as in claim 1 to 3 wherein concentration of polyethylene glycol can be 5% to 25%, preferably between 12% and 17%.
5. A process as in claim 1 to 4 wherein Nimesulide solution contains surfactant.
6. A process as in claim 1 to 5 wherein surfactant can be Tween 80.
7. A process as in claim 1 to 6 wherein concentration of Tween 80 can be 4% to 16%, preferably between 6% and 10%.
8. A process as in claim 1 to 7 wherein get forming agent is Carbopol.
9. A process as in claim 1 to 8 wherein concentration of Carbopol can be 0.5% to 5%, preferably between 1% and 3°/0, so as to give viscosity more than 30,000 cps.
 
10. A process as in claim 1 to 9 wherein get base is prepared by dissolving Carbopol into alcohol.
11. A process as in claim 1 to 10 wherein concentration of alcohol can be 10% to 90%, preferably between 50% and 75%.
12. A process as in claim to 11 wherein stabilizer used can be propylene glycol.
13. A process as in claim 1 to 12 wherein concentration of propylene glycol can be 5% to 25%, preferably between 10% and 15%.
14. A process as in claim 1 to 13 wherein pH is adjusted between .3.75 and 4.75, preferably between 3.95 and 4.25.
 
ABSTRACT
Nimesulide is a new class of non-steroidal anti-inflammatory drug. It reduces pain and inflammation like any other non-steroidal anti-inflammatory drug. However, it is devoid of action on Cox-1 enzymes which imparts gastric protection. This results in absence of side effects.
Nimesulide when taken orally is found to the effective. However, because of its rate limiting absorption it is not possible to achieve higher tissue concentration. The increase in strength of Nimesulide from 200 mg to 400 mg for oral use is not associated with any significant advantage.
It is also known that long term systemic use may be associated with hepatic toxicity. Thus it is desirable to have a topical preparation which provide higher tissue concentration locally and negligible concentration elsewhere to have better analgesic anti-inflammatory effect but minimizing side effects.
The other side effects seen with oral Nimesulide include gastrointestinal disturbances, C.N.S. side effects.
According to present invention new formulation of Nimesulide gel formulated with polyethylene glycol and polysorbate 80. It is formulated into the gel form of carbopol in alcohol. To the gel so prepared, a non-aqueous solution of Nimesulide is gradually added while stirring so that Nimesulide is uniformly distributed into gel. Then propylene glycol is added to provide a stable formulation. Its pH is adjusted with alcoholic NaOH solution to 4.0 to 4.5.
The new formulation of Nimesulide gel is found stable, more efficacious and have a longer duration of action. It is also a non-sticking, non-irritant and does not leave any residue after drying.

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