slide 1

Back to the List of the Granted Patents                                   Click here to download KE000277 PDF

(11)Patent Number: KE 277
(45)Date of grant: 05/02/2009
(12)PATENT
(51)Int.C1.:
(21)Application    Number: KE/P/1996/000192   
      
(22) Filing    Date:   05/1111996   

(73) Owner(s):    PANACEA BIOTEC LIMITED of 102 ASHOK PLAZA, 24 ,SCHOOL LANE,NEW    DELHI    110001,INDIA.

(72)Inventor(s)   AMRJIT    SINGH

(74) Agent/address for correspondence:   Waruinge & Waruinge Advocates,

(54) Title: A NOVEL THERAPEUTIC ANT-INFLAMMATORY ANDANALGESIC PHARMACEUTICAL COMPOSITION CONTAINING NIMISULIDE 4-NITRO, PHENOXYPHENYL METHANE SULPHONAMIDE FOR USE TRANSDERMALL Y AND PROCESS    FOR    THE    MANUFACTURE    THEREOF.

(57) Abstract: Anovel therapeutic anti-inflammatory and and analgesic pharmaceutical composition containing nimisulide for transdermally and a process for the manufacture thereof is disclosed . The nimesulide composition is used for direct application on the skin for the the treatment of inflammation through transdermal absorption at very low dose level. The composition comprises nimesulide and a percutaneous enhancing vehicle base which acts as a microcarrier preconcentrate or a microcarrier .The percutaneous enhancing vehicle base comprises a percutaneuos enhancer, surfactant, gelling agent and one or more vehicle/base.

                                                 TECHNICAL FIELD

This invention relates to novel therapeutic anti-inflammatory and analgesic pharmaceutical compositions containing Nimesulide which is N- (4 nitro, 2 phenoxyphenyl methane sulphonamide) for use transdermally and a process for the manufacture thereof.

                                             BACKGROUND OF THE INVENTION

For a drug to be absorbed transdermally, it has to travel through various layers of the skin before reaching the site of    action.

The layers of the skin are different in nature- some are hydrophilic while some are lipophilic (Montagna W. Parrakhal PF: The structure and Function of the skin , 3rd ed. Academic press, New York, 1974) .    Accordingly, any drug which is used transdermally must possess both hydrophilic and lipophillic properties. Nimesulide which is N-(4 nitro, 2 phenoxyphenyl methane sulphonamide) compound, is a highly hydrophobic drug and consequently it is considered a poor candidate for transdermal absorption. When applied to the skin, it is absorbed in very minute quantities or not absorbed at     all.

Transdermal route for administration of anti-inflammatory agents offers various advantages over the oral route such as lower dosage, less toxicity/side effects, no G I irritation, no dose dumping in the body and it is more site specific (Chien YW: Novel Drug Delivery System, Marcel Dekker, New    York,    1982).

The Literature and the market surveys show that at present, there exists no properly effective percutaneous    formulations    ofNimesulide.

In the patent for Nimesulide drug molecule (US Patent No. 3,840,597) the use of Nimesulide as an anti-inflammatory agent in the dose range of 1 mg to 500 mg per kg. body weight in the form of cream, gel, tapes and the like has been cited. According to our studies, it was observed that the drug either precipitated out in the conventional formulation or precipitated on application to human skin when applied as a conventional gel or cream in the above stated dosage and practically no percutaneous absorption occured. An over-riding difficulty is the inherent insolubility of the Nimesulide in aqueous media and hence the provision of a dosage form which can contain Nimesulide in sufficiently high concentration to permit convenient use and yet meet the required criteria in terms of bioavailability e.g. enabling effective absorption from the skin.

U S Patent 5, 446070 granted to Mantell et al. discloses a flexible finite, bioadhesive composition. The present invention however, is not a finite composition or bioadhesive composition. The present invention comprises a composition which is non-finite in other words capable of being applied to large body areas for action at site of inflammation for instance the synovial fluids     in    joints.

Secondly, where the Mantell patent is restricted to a solvent range of 5 to 70 wt%, the solvent concentration of the present invention is upto 99.99% since the composition of the invention is a spreading non-finite    composition.

Besides, unlike the Mantell et al Patent which requires a plasticizer, a plastizer is not required in the present invention    because of its    non utility.

As regards the presence of polysaccharide, the present invention uses it along with a non polysaccharide and the usage of a polysaccharide is at a much lower % by weight than 20% to 50% by weight as disclosed by Mantell.

Besides the polysaccharide used by Mantell in large quantities is necessary for bioadhesion which    is not    required in our     case.

Also Mantell discloses water as an non-entity whereas in the present invention water is required in the composition.

The use of Nimesulide through intra-muscular administration as an analgesic agent has not been successful because Nimesulide being practically insoluble in water and its formulations in conventional oily bases or as suspensions result in depot formation in the muscular tissues which defies the main objective of quick relief.

The market and literature survey shows that no parenteral dosage form of Nimesulide is reported. (Drugs 48 (3) 431-454, 1994)
It is an object of the present invention to provide a therapeutic composition containing Nimesulide in combination with other compounds which alter the hydrophobic property of Nimesulide, and a process for the manufacture thereof thus making it possible for the said composition to be used for direct application on the skin for the treatment of inflammation through transdermal absorption.

It is a further object of the present invention to provide a novel therapeutic composition containing Nimesulide in combination with other compounds which alter the physico-chemical property of Nimesulide, thus making it possible for the said composition to be used for direct application on the skin for the treatment of inflammation through transdermal absorption, at dose levels much lower than the dose levels according to the known art.

                                      SUMMARY OF THE INVENTION
The present invention provides a Novel Therapeutic Anti-inflammatory and Analgesic pharmaceutical composition for topical use which comprises:

1.   Nimesulide      :  0.1  % to  10  % w/w
2.   Percutaneous  absorption            :  90  % to  99.9  % w/w
      enhancing  vehicle     base   

The said Percutaneous enhancing vehicle base acts as a microcarrier preconcentrate or a microcarrier    and    comprises:

1.  Percutaneous enhancer     :  0.5    % to  60    %  w/w
     as herein described           
2.  Surfactant as herein                        :  0.0    % to  12    % w/w
   described           
3.  Gelling agent/Thickening     : 0.2    % to  19    %  w/w
   agent as herein described           
4.  One or more vehicle/base     : 5  %  to  97  % w/w.
     including water    as herein described

Preferably     the     percutaneous     enhancing     base comprises:

1.  Percutaneous   enhancer    : 6  %   to  15  %  w/w.
  as herein described.   
2.  Surfactant as herein      :0.5  %   to  12  % w/w
  described       

3.Gelling    agent/Thickening    : 0.5 % to 19 % w/w                                                                                agent    as    herein    described

4. One    or    more    vehicle/base    : 5 % to 60 % w/w.                                                                                            as    herein    described

Water is required for the composition in the range of 1% to 15% w/w,preferably 9% to 11% w/w and more preferably in the range of 9.5% to 10.5 % w/w.

Besides the above disclosed ingredients the composition for topical use also comprises a Neutralising agent/ph adjusting agent such as herein described in the range of 0.0% to 2.0%.
DETAILED     DESCRIPTION     OF     THE     INVENTION

According to the present invention, it has been found that it is possible to solubilise and deliver a highly hydrophobic drug like Nimesulide to the site of action through transdermal route. The present invention involves the process of incorporation of Nimesulide in a formulation which can solubilize the drug and transport through the skin barriers, in intact condition to the site of action.
Preferably the percutaneous enhancing base comprises:
1. Percutaneous enhancer          : 6 %        to     15%    w/w.
  as herein   described.       
2.  Surfactant   as herein           : 0.5  %    to     12%    w/w
3.  Gelling agent/Thickening          : 0.5  %    to     19%    w/w
  agent as herein described       
4.  One or more vehicle/base         : 5  %          to     60 %    w/w.
  including water as herein       
  described           

Preferably nimesulide is in the range of 1 %to 5 %w/w.
More preferably the composition for topical use also comprises a Neutralising agent/ph adjusting agent as herein described in the range of 0.0% to 2.0%.

The novel Therapeutic Anti-Inflammatory and Analgesic Composition for topical use according to the present invention, is prepared by the process which comprises the following steps:

(a)    0. 5% to 3 0% w/w of a percutaneous enhancer, as herein described, is mixed with 2. 5% to 30% w/w of one or more vehicle or base as herein described, in a container by stirring and to the mixture obtained 0.1% to 10% w/w of Nimesulide is added and stirred till completely dissolved.
(b)    0.5% to 12% w/w of a Surfactant, as herein described, 0.2% to 50% w/w of a Gelling agent/thickening agent, as herein described, and 2.5% to 30% w/w of one or more Vehicle/ Base, as herein described, are mixed in a homogeniser to obtain a homogenised mixture.
(c)  The mixture obtained in step (a)      is added to the homogenised

mixture obtained in step (b) under stirring without vortex formation to avoid aeration. The mixture is neutralised or its pH adjusted by addition of 0.0% to 2.0% of a neutralising agent or a pH adjusting agent to bring the pH on the acidic, as herein described, with slow stirring resulting in the    preparation of the desired Anti-inflammatory  and  Analgesic  Composition.
As Percutaneous enhancer any known Percutaneous enhancer may be used preferably a c12 -24 mono or poly-unsaturated fatty acids such as vaccenic, cis-vaccenic, Linoleic, Linolenic, elaidic, oleic, petroselinic, erucic or nervonic acid or any of their corresponding alcohols, especially oleic acid or oleyl alcohol or 1-dodecylazacycloheptane-2-one also known as azone; sulphoxides like dimethylsuphoxide, n-decyl methylsulphoxide; Amides like dimethylacetamide, dimethylformamide and N, N-diethylm-toluamide;
Pyrrolidones like 2-pyrrolidone and N-methyl-2 Pyrrolidone.
As surfactant, any pharmaceutically acceptable hydrophilic or lipophilic surfactant or mixture thereof may be used, especially suitable for this purpose are the reaction products of natural or hydrogenated vegetable oils and ethylene glycol i.e. . Polyoxyethylene glycolated natural or hydrogenated vegetable oils, e.g. polyoxyethylene glycolated natural or hydrogenated castor oils; especially various tensides available under the trade name CREMOPHOR particularly CREMOPHOR RH 40 and CREMOPHOREL. Also suitable for use are the various surfactants available under the trade name NIKKOL e.g. NIKKOL HC0-60.

Polyoxyethlene -Sorbitan fatty acid esters e.g. mono and trilauryl, palmityl, stearyl and oleyl esters e.g. those available under the trade name TWEEN preferably TWEEN 40 and TWEEN 80.
Polyoxyethylene-polyoxypropylene block copolymers e.g. especially those available under the trade name POLOXAMER preferably POLOXAMER 188.

Polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters, commercially available under the trade name MYRJ as well as polyoxyethylene fatty acid esters commercially available under the trade name CEIIOL HE;


Propylene glycol mono-and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxysterate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate;

Examples of suitable lipophilic surfactants include Transesterification products of natural Vegetable oil triglycerides and polyalkylene polyols. Preferred are products obtained by trans-estrification of 2 molar parts of natural vegetable oil triglycerides with one molar parts of polyethylene glycol (e.g. having an average molecular weight of from 200 to 800) . Various forms of such trans-estrification product are commercially available under the trade name LABRAFIL, preferably LABRAFIL M 1944 CS;

Sorbitan fatty acid esters commercially available under the trade name SPAN including Sorbitan monolauryl, monopalmityl,-monostearyl,-tristearyl.-monooleyl and -trioleyl esters;

Monoglycerides e.g. Glycerol monooleate, glycerol monopalmitate and glyceryl monostearate commercially available under the trade names MYVATEX, MYVAPIEX and MYVEROL.

As Gelling Agent/Thickening agent, any known such pharmaceutically acceptable agent may be used including synthetic or semi-synthetic polymeric materials, polyacrylate and polyacrylate co-polymeric resins e.g. polyacrylic acid and polyacrylic acid/methacrylic acid resins, commercially available under the trade name CARBOPOL, particularly CARBOPOL 934, 940 and 941 and EUDRAGIT, particularly EUDRAGIT  E, L, S, RL, and RS; Cellulose and cellulose derivatives including alkyl celluloses e.g.methyl-, ethyl-, and propyl-celluloses; hydroxyalkyl-celluloses e.g. hydroxypropyl cellulose, hydroxypropyl alkylcellulose such as hydroxypropyl-methyl- cellulose, acylated celluloses e.g. cellulose-acecates, cellulose acetate phthalates and salts thereof such as sodium     carboxymethyl    cellulose;

Polyvinyl resins including polyvinylacetates and alcohols as well as other polymeric materials including alginates e.g alginic acid and salts thereof e.g. sodium alginate and propylene glycol alginate.

As Neutralising/pH adjusting agent any such conventional such agent may be used including sodium bicarbonate, sodium hydroxide, potassium hydroxide, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate. Preferably polar organic amines like diethylamine, diisopropanolamine, triethylamine and triethanolamine may be used.

As  vehicles/base, the     following may be used:

Pharmaceutically acceptably lower (having c1 -5) alkanols, particularly ethanol; water soluble macrogols like polyethylene glycol having an average molecular weight from 200 to 600 : l,2 - propylene carbonate, propane-l, 2-diol and 1,2,-propylene glycol; glycerol triacetate or (1, 2, 3,) - triacetin; lower ketones, particularly acetone and 1,2,3-propanetriol may be incorporated.

Water in varying concentration may be added to provide requisite hydrophilic nature to the composition.

Pharmaceutically acceptable c1 -5 alkyl or tetra hydrofurfuryl; di or partial ether of a low molecular weight mono or polyoxy-alkanediol particularly those available under the trade names

TRANSCUTOL and COLYCOFUROL.

As base having lipophilic phase for the preparation of emulsions, may be used fatty acid triglycerides, preferably medium chain fatty acid triglycerides; vegetable oils like coconut oils, olive oil, castor oil and their derivatives; ethyl oleate.

As base, for the preparation of the said therapeutic composition in the form of an ointment, may be used fatty acids, fats, oils and waxes of animal origin like bees wax, spermacetii, wool fat, waxes of vegetable origin or mineral origin like hard, soft and liquid paraffin.

The topical dosage forms are formulated suitably such that the resultant product is easy to apply and is non-staining.                                                                                                                                    For the said therapeutic composition in the form of aerosol formulation for topical applications, as pharmaceutically acceptable propellants may be used chlorofluoro carbons e.g. the Propellant 11, Propellant 12, Propellant 114; Hydrocarbon propellants like n-butane, isobutane and propane; compressed gas propellants e.g. Nitrous oxide, carbon dioxide, and nitrogen.

The novel therapeutic composition according to the present invention may be used in the following forms:

1. Topical  aqueous gel.
2.  Oil-in-water or water-in-oil emulsion or micro-emulsion or cream.
3.  Solution for topical applications.
4.  Ointment.
5. Aerosol formulation for topical applications.

The therapeutic composition according to the present invention may be applied on the skin by utilising a physical form of energy like electrical energy or ultrasonic energy to effect better percutaneous absorption of the drug.

The invention will now be described with reference to the foregoing examples:

Example 1

Preparation  of  topical gel dosage form
-------------------------------------------------------------------------------------------------------------------
S1. No.         Component            Quantity
 1.                    Nimesulide                 2.0    g
 2.                Dimethylacetamide          22.0    g
 3.             Ethyl     Alcohol                 40.0    g
 4.              Acetone                       10.0    g
 5.              Cremophor       RH   40        4.0    g
 6.              Propylene glycol           38.0    g
 7.             Polyethylene glycol 400       48.8    g
 8.             Carbopol    934              4.0    g
 9.             Water                        30.0 g
 10.            Diethylamine                                       1.2              g
  -------------------------------------------------------------------------------------------------------------------                            
                                Total                                 200.0   g
---------------------------------------------------------------------------------------------------------------------

Step (a)         Dimethylacetamide is mixed with ethyl alcohol and acetone at 30°C in a container with stirring. To the mixture obtained Nimesulide is added and stirred till completely dissolved.

Step (b)         Propylene glycol, polyethylene glycol 400 and water are mixed in homogenizer. To the homogenised mixture obtained, 1.5% w/w of carbopol 934 is added in small amounts at a time at room temperature and the speed of the homogenizer is kept at approximaterly 1500-2000 rpm.

Step (c)          The mixture obtained in step (a) is added to the mixture obtained in step (b) under stirring without vortex formation to avoid aeration preferably under vacuum (25 mm of Hg) . The mixture obtained is neutralised by slow addition of Diethylamine with slow stirring at a temperature and under vacuum (25mm    of    Hg) to affect gel formation.

Example 2

Preparation of     emulsion     type     topical     dosage form.
------------------------------------------------------------------------------------------------------------
Sl. No.         Component                                      Quantity
------------------------------------------------------------------------------------------------------------
1.             Nimesulide                                               l.0g
2.                  Transcutol                                            35.0     g  
3.             Water                                                10.0     g
4.             Disodium hydrogen phosphate                        0.1    g            
5.            Cremophor    RH 40                           5.0    g
6.             Labrafil    M 1944 CS                           10.0     g
7.             Glyceryl  monostearate                           8.0    g
8.             Stearic acid                                     13.0    g
9.            Ethyl  oleate                                          2.9    g
10.            Dimethyl    sulphoxide                           15.0    g
-------------------------------------------------------------------------------------------------------------------                 Total                                    100.0  g
------------------------------------------------------------------------------------------------------------------

Dissolve Nimesulide in a mixture of (6), (7), (8), (9) and (10) with warming. Separately mix (2), (3), (4) and 5 and slowly add the Nimesulide mixture to it with stirring.

Example 3

Preparation of a solution type dosage form for topical application.
-------------------------------------------------------------------------------------------------------------------
S1. No.         Component                   Quantity
--------------------------------------------------------------------------------------------------------------------
1.             Nimesulide                                 1.0 g   
2.             Dimethyl  formamide                                10.0 g   
3.             Poloxamer 188                                               2.0 g   
4.             Ethyl alcohol                                                20.0 g   
5.              Propylene glycol                                           25.0 g   
6.             Polyethylene    glycol 400                                42.0 g   
7.            Hydroxypropylmethyl-cellulose                      1.0g
8.             Triethanolamine                                      0.2 g   
9.                          Water                                                      1.0 g
 ------------------------------------------------------------------------------------------------------------------                                                                                        Total                                                                                    100.0 g
---------------------------------------------------------------------------------------------------------------------
Nimesulide is dissolved in   (2)   with stirring and    (3) 1        (4) 1    (5) 1

(6),    (7)    and   (8)    are   added   to   obtain   a   clear   solution   with

stirring. 
            
Example 4.               
Preparation of ointment type dosage form topical application.
---------------------------------------------------------------------------------------------------------------------Sl. No.           Component        Quantity
---------------------------------------------------------------------------------------------------------------------1.                  Nimesulide                                 2.0  g
2.                  Dimethylsulphoxide                                                 21.0  g
3.                     Glycerylmonostearate                                                             16.0    g
4.                          Mineral oil                                             62.0    g
5.                   White petrolatum                                                                 97.0    g
6.                    Water                                                         2.0    g
--------------------------------------------------------------------------------------------------------------------                     Total                                                       200.0    g
-------------------------------------------------------------------------------------------------------------------
Warm (3), (4)    and   (5)    and   add    with    stirring   a    solution   of
Nimesulide in dimethyl sulphoxide.
Example 5.               
Preparation of an aerosol dosage form for topical use.   
Sl. No.                  Component        Quantity
1.               Nimesulide                                   1.0    g
2.                      Dimethylacetamide                             10.0    g
3.               Ethyl alcohol                                 10.0    g
4.                Cremophor RH 40                             10.0    g
5.                Propellant  114                              29.0    g
6.                Propellant  12                               39.0    g
7.                Water                               l.0 g
---------------------------------------------------------------------------------------------------------------------                                 Total                                                                                    100.0  g
The analgesic activity of the therapeutic composition, prepared according to the present invention, was found to be dose dependent and passed the tests of subacute toxicity and undue toxicity.

The dose levels of the novel Anti-inflammatory and Analgesic composition, according to the present invention, are comparatively much lower than the dose levels of the Conventional Nimesulide formulations for equally effective results.

The various forms of the therapeutic composition prepared according to the present invention were subjected to in-vitro drug release studies using modified USP dissolution apparatus attached with enhancer cell (Pharm Tech. Jan. 1995, 52-58). The dissolution media used was phosphate buffer pH 7.4. The results indicated that the cumulative drug release and permeation flux were proportional to the drug load.

The said compositions were also subjected to standard pharmacological test methods to measure anti-inflammatory activity such as rat paw oedema and quinea pig erythema. These tests showed significant activity when compared to placebo.

The said Therapeutic compositions were also tested on sixty healthy human volunteers for irritation or other undue side effects. No incidence of irritation/side effects was reported.

Since    many   apparently   different   embodiments   of   the   present invention    could   be   made   without   departing   from   the   spirit   and scope thereof, it is intended that the description of the invention herein be interpreted as being illustrative only and not limiting in any manner whatsoever.
We Claim

1. A Novel Therapeutic Anti-inflammatory and Analgesic pharmaceutical composition for topical    use which    comprises:

1.      Nimesulide                     :    0.1  % to  10    % w/w
2.     Percutaneous absorption               :     90  %  to   99. 9  % w/w
     enhancing vehicle base       

2. A pharmaceutical Composition for topical use as claimed in claim 1 wherein the said Percutaneous enhancing vehicle base acts as a microcarrier preconcentrate or a microcarrier and

    comprises:   
1.      Percutaneous enhancer           :  0.5  % to  60  % w/w
      as herein described   
2.      Surfactant as herein               : 0.0  % to  12  % w/w
      described   
3.      Gelling agent/Thickening           :  0.2  % to  19  % w/w
       agent as herein described   
4.        One or more vehicle/base           :  5  % to  97  % w/w.
       including water   
      as herein described   

3.    A   pharmaceutical   composition   as   claimed   in   claim   2   which
          comprises           
1.      Percutaneous enhancer       :     6  % to  15  % w/w.
      as herein described.       
2.      Surfactant as herein         :     0.5    % to  12  % w/w
3.      Gelling agent/Thickening     :    0.5    % to  19  % w/w
           agent as herein described

4. One or more vehicle/base      : 5 % to 60 % w/w. including water as herein described

4. A pharmaceutical composition as claimed in claim 1 which comprises a neutralising agent/ ph adjusting agent in the range of 0.0% w/w to 2.0% w/w.

5. A pharmaceutical composition as claimed in claim 2 wherein said percutaneous enchancer is selected from    the group comprising:

a C12-24 mono or poly-unsaturated fatty acids such as vaccenic, cis-vaccenic, Linoleic, Linolenic, elaidic, oleic, petroselinic, erucic or nervonic acid or any of their corresponding alcohols, especially oleic acid or oleyl alcohol or 1-dodecylazacycloheptane-2-one,; sulphoxides such as dimethylsuphoxide, n-decyl methylsulphoxide; Amides such as dimethylacetamide, dimethylformamide and N, N-diethylm-toluamide; Pyrrolidones such as 2-pyrrolidone and N-methyl-2 Pyrrolidone.
6.    A pharmaceutical composition as claimed in claim 5 wherein the surfactant is dimethylacetamide.

7.    A pharmaceutical composition as claimed in claim 2 wherein the said surfactant is selected from the group comprising; any pharmaceutically acceptable hydrophilic or lipophilic surfactant or mixture thereof, the reaction products of natural or hydrogenated vegetable oils and ethylene glycol such as polyoxyethylene glycolated natural or hydrogenated vegetable oils such as polyoxyethylene glycolated natural or hydrogenated  castor oils; Polyoxyethlene -Sorbitan fatty acid esters e.g. mono and trilauryl, palmityl, stearyl and oleyl esters, Polyoxyethylene-polyoxypropylene block copolymers, Polyoxyethylene fatty acid esters,Propylene glycol mono-and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxysterate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate, propylene glycol stearate; lipophilic surfactants such as transesterification products of natural Vegetable oil triglycerides and polyalkylene polyols, Sorbitan fatty acid esters, Monoglycerides such as Glycerol monooleate, glycerol monopalmitate and glyceryl monostearate.
8. A pharmaceutical composition as claimed in claim 2 wherein said gelling/thickening agent is selected from    the group    comprising:

synthetic or semi-synthetic polymeric materials, polyacrylate and polyacrylate co-polymeric resins such as polyacrylic acid and polyacrylic acid/methacrylic acid resins, Cellulose and cellulose derivatives including alkyl celluloses such as. methyl-, ethyl-, and propyl-celluloses; hydroxyalkyl-celluloses such as hydroxypropyl cellulose, hydroxypropyl alkylcellulose such as hydroxypropyl-methyl-cellulose, acylated celluloses such as cellulose-acetates, cellulose acetate phthalates and salts thereof such as sodium carboxymethyl cellulose; Polyvinyl resins including
polyvinylacetates    and   alcohols   as   well   as   other   polymeric materials including alginates such as alginic acid and salts thereof such as sodium alginate and propylene glycol alginate.

9. A pharmaceutical composition as claimed in claim 2 wherein water is present in the range 1 % to 15%    w/w.

l0. A pharmaceutical composition as claimed in claim 9 wherein water is present in the range of 9 % to 11 % w/w more preferably in the range of 9.5 %to 10.5% w/w.

11. A pharmaceutical composition as claimed in claim 4 wherein the said neutralising agent is selected from the group comprising:

sodium bicarbonate, sodium hydroxide, potassium hydroxide, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate, polar organic amines such as diethylamine, diisopropanolamine, triethylamine and triethanolamine.

12. A pharmaceutical composition as claimed in claim 2 wherein the said vehicle/base is selected from the group comprising: Pharmaceutically acceptably lower (having C1 - 5) alkanols, particularly ethanol; water soluble macrogols like polyethylene glycol having an average molecular weight from 200 to 600 : 1,2-propylene carbonate, propane-1, 2-diol and 1,2,-propylene glycol; glycerol triacetate or ( 1, 2, 3,) - triacetin; lower ketones, particularly acetone and 1,2,3-propanetriol may be incorporated, pharmaceutically acceptable c1 -5 alkyl or tetra hydrofurfuryl; di or partial ether of a low molecular weight mono or polyoxy-alkanediol; as base- fatty acid triglycerides, preferably medium chain fatty acid triglycerides; vegetable oils like coconut oils, olive oil, castor oil and their derivatives; ethyl oleate, oils and waxes of animal origin like bees wax, spermacetii, wool fat, waxes of vegetable origin or mineral origin like hard, soft and liquid paraffin.
13. A pharmaceutical Composition as claimed in Claim 1 which is in the Form of a Topical aqueous gel.

14. A pharmaceutical Composition as Claimed- in claim 1 which is in the Form of an oil-in-water or water-in-oil emulsion or micro-emulsion or cream.

15. A pharmaceutical Composition as claimed in Claim 1 which is in the Form of a Solution for topical    application.

16.  A pharmaceutical  Composition  as  claimed  in  claim  1  which  is
in  the     Form  of  an  ointment.   
17. A pharmaceutical Composition as claimed in Claim 1 which is in the form of an Aerosol formulation.

18. A Novel Therapeutic. Anti-inflammatory and Analgesic pharmaceutical composition for topical use which comprises:

1.      Nimesulide                : 0.1    % to    10    % w/w
2.        Percutaneous    enhancer      :  0.5    % to    60    % w/w
       as herein described
3.     Surfactant as herein         :   0.0  % to    12  % w/w
           described       
4.    Gelling agent/Thickening       :  0.2  % to    19  % w/w
           agent as herein described       
5.    One or more vehicle/base      :  5  % to  97  % w/w.
           including water
           as herein described
 

19. A Novel Therapeutic Anti-inflammatory and Analgesic pharmaceutical composition for topical    use    which    comprises:

1.      Nimesulide               :     0.1            %    to  10  % w/w
2.      Percutaneous enhancer       :     0.5    % to  60  % w/w
      as herein described       
3.      Surfactant as herein          :      0.0    % to  12  % w/w
      described       
4.      Gelling agent/Thickening      :          0.2              %        to  19  % w/w
      agent as herein described       
5.       One or more vehicle/base      :  5  % to  97   % w/w.
     including water       
      as herein described       
6.      A neutralising agent/ph      :  0.0%  w/w  to  2.0%  w/w.
      adjusting agent       
20.  A   process   for   the   production   of   a   therapeutic   anti -
inflammatory  and  analgesic  pharmaceutical  composition  for  topical

use  which  comprises  the  following  steps:

a)    mixing  0.5%  w/w  to  30%  w/w  of  a  percutaneous  enhancer  with
2.5%  to  30%  w/w   of  one  or  more  vehicle  or  base;

b)    adding to the mixture oE step a) 0.1% w/w to 10% w/w of Nimesulide followed by stirring the mixture until completely dissolved;

c)    mixing  separately  0.5%  w(w  to  12  % w/w  of  a  surfactant,   0.2%
w/w to 50% w/w of a Gelling agent/thickening agent and 2.5% w/w to 30% w/w of one or more vehicle or base and mixing the entire mixture in a homhgeniser to obtain a homogenised mixture;

d) adding the mixture obtained in step b) to the homogenised mixture obtained in step c) under stirring to obtain the desired composition for analgesic use.

21. A process as claimed in claim 20 wherein a neutralising agent or a ph adjusting agent is added to the composition in step

d)  to neutralise or adjust the ph of the mixture.

22. A process as claimed in claim 21 wherein the said neutralising agent/ ph adjusting agent is added in the range of 0.0%w/w to 2.0% w/w.
23.    A process as claimed in claim 20 wherein a neutralising agent or a ph adjusting agent is added to the composition in step

d)  to neutralise or adjust the ph of the mixture.

24.    A   process   as   claimed   in   claim   20    wherein   the   said  neutralising  agent/  ph  adjusting    agent  is  added  in  the  range  of
0.0%w/w  to  2.0%  w/w.

Newsletter

Join our newsletter for CIPIT news through subscriptions!

SEND

Social Media

    

Contact Us

TEL : (254) 703 034 612