TECHNICAL FIELD
"This invention relates to a novel therapeutic anti-inflammatory and analgesic pharmaceutical compositions for topical / transdermal use containing selective COX-2 inhibitors drugs 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 lipophilic properties COX-2 inhibitor drugs such as Celecoxib and Rofecoxib are highly hydrophobic drugs and consequently they are considered poor candidate for transdermal absorption When applied to the skin, these are absorbed in very minute quantities or not absorbed at all
A 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 identification of two cyclooxygenase (COX) enzymes has been a tremendous advance in understanding the role of prostaglandins in inflammation and the actions of nonsteroidal antiinflammatory drugs (NSAIDs) COX-1 activity appears to be related to "Constitutive" or "house-keeping" functions in the gastric mucosa, kidney and platelets COX-2 activity is "inducible" and generally occurs in response to a specific stimulus to enhance inflammatory actions Current NSAIDs inhibit both COX-1 and COX-2, although the clinical benefit of NSAIDs appears to be associated with inhibition of COX-2 activity The inhibition of COX-1 activity by NSAIDs is related to adverse side effects in general, particularly gastrointestinal toxicity Recently COX-2 selective inhibitors have been developed Current data would suggest that by inhibiting COX-2 action, these agents may have efficacy similar to that of standard NSAIDs and that by not inhibiting COX-1 activity, they may have less toxicity than standard NSAIDs Thus, these actions indicate that COX-2 selective inhibitors will have similar clinical efficacy to the traditional NSAIDs with fewer adverse side effects Celecoxib is a known selective COX-2 inhibitor having analgesic and anti-inflammatory activity, but which has the drawback of having unfavourable chemical-physical characteristic, the main obstacle to the use of celecoxib in topical formulation is in fact its insolubility in water and, on the other hand, its poor solubility in the solvents/raw materials usually employed in such formulation
The chemical structure of Celecoxib and Rofecoxib are given hereinbelow alongwith their
chemical names
(Formula Removed)
Celecoxib - p[5-p-Tolyl-3-(tnfluoromethyl) pyrazol-1-yl] benzenesulfonamide
(Formula Removed)

Rofecoxib - 4-[4-(methyl sulphonyl) phenyl]-3-phenyl-2(5H)-furanone
In the PCT Patent Application No PCT/US94/12720 Celecoxib is disclosed However,
no transdermal composition of this Drug is disclosed
It is an object of the present invention to provide a therapeutic composition containing COX-2 inhibitor 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 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 COX-2 inhibitor in combination with other compounds which alter the physico-chemical property of COX-2
SUMMAY OF THE INVENTION
The present invention provides a Novel Therapeutic Anti-inflammatory and Analgesic
Pharmaceutical composition for topical use which comprises
1 Selective Cox-2 inhibitor drugs 0 1 % to 40% w/w
2. Percutaneous absorption 60% to 99.9% w/w
enhancing vehicle/base. The said Percutaneous enhancing vehicle/base comprises
1 Percutaneous enhance 0 5% to 60% w/w
2 Surfactant 0 0% to 20% w/w
3 Gelling agent/Thickening agent 0 0% to 60% w/w
4 One or more vehicle/base 2% to 98% w/w
Preferably the percutaneous base comprises
1 Percutaneous enhancer 6%to15%w/w
2. Surfactant 0 5%to12%w/w
3 Gelling agent/Thickening agent 0 5%to19%w/w
4 One or more vehicle/base 5% to 60% w/w
One or more percutaneous enhancers can be used in compositions according to this invention One or more surfactants can be used in compositions according to this invention One or more gelling agents/thickening agents can be used in compositions according to this invention
Besides the above disclosed ingredients the composition for topical use also comprises a neutralizing agent/pH adjusting agent such as herein described in the range of 0 0% to 5 0% w/w
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, it has been found that it is possible to deliver highly hydrophobic drugs such as COX-2 inhibitor drugs to the site of action through a transdermal route The present invention involves the process of incorporation of COX- 2 inhibitor drugs in a formulation which can transport the drug 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
2 Surfactant 0 5% to 12% w/w
3 Gelling agent/Thickening agent 0 5% to 19% w/w
4 One or more vehicle/base 5 0% to 60% w/w
Preferably the COX-2 inhibitor drugs are in the range of 0 2% to 20% 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% w/w
Statement of Invention
According to the present invention a novel Therapeutic Anti-inflammatory and Analgesic Composition for topical/transdermal use comprises a selective COX-2 inhibitor drug from 0 1% to 40% w/w and percutaneous absorption enhancing vehicle/base from 60% to 99 9% w/w, wherein the said percutaneous absorption enhancing vehicle/base comprises percutaneous enhancer from 0 5% to 60% w/w, one or more vehicle/base from 2 0% to 98%
w/w, gelling agent/thickening agent from 0 0% to 60% w/w and surfactant from 0 0% to 20%w/w and optionally a neutralizing agent/pH adjusting agent
The said composition according to the present invention is prepared by the process which comprises the following steps
(a) 0 5% to 60% w/w of a Percutaneous enhancer, as herein described, is mixed with 2 0% to 98% 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 40% w/w of COX-2 inhibitor drugs are added and stirred till completely dissolved
(b) 0 0% to 20 % w/w of a Surfactant, as herein described, 0 2% to 60% w/w of a Gelling agent/thickening agent, as herein described, and 0 5% to 60% 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 neutralized or its pH adjusted by addition of 0 0% to 5 0% w/w of neutralizing agent or a pH adjusting agent to shift the pH of the product on the acidic side, as herein described, with slow stirring resulting in the preparation of the desired Anti-inflammatory and Analgesic Composition
As Percutaneous enhancer any chemical can be used which interacts with the stratum corneum layer of the mammalian skin causing reversible change in its barrier properties
Preferably, 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, Lmolenic, 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 dimetylacetamide, dimethylformamide, N, N-diethylm-toluamide, Pyrrolidones like 2-pyrrohdone and N-methyl-2 Pyrrolidone, volatile oils like oil of citrata, mentha, winter green
As surfactant, any pharmaceutical^ 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 CREMOPHOR® EL Also suitable for use are the various surfactants available under the trade name NIKKOL e g NIKKOL® HCO-60
Polyoxyethylene-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 CETIOL® HE,
Propylene glycol mono-and di-fatty acid esters such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxystearate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ncinoleate, propylene glycol stearate,
Examples of suitable lipophilic surfactants include trans-estenfication products of natural vegetable oil triglycerides and polyalkylene polyols Preferred are products obtained by trans-estenfication of 2 molar parts of natural vegetable oil triglycerides with one molar part of polyethylene glycol (e g having an average molecular weight of from 200 to 800) Various forms of such trans-estenfication 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 -tnoeyl esters, Monoglycendes e g Glycerol monooleate, glycerol monopalmitate and glycerol 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 polyacryhc acid and polyacryhc 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 methylcellulose, acylated celluloses e g 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 e g alginic acid and salts thereof e g sodium alginate and propylene glycol alginate
As neutrahsing/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, dnsopropanolamine, triethylamine and tnethanolamine may be used, acidifying agents including hydrochloric acid, lactic acid, malic acid, tartaric acid and the like may be used
As vehicles/base, the following may be used
Pharmaceutically acceptable lower (having C1-5) alkanols, particularly ethanol, water soluble
macrogels 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)-tnacetin, lower ketones, particularly acetone and 1,2,3 - propanetnol may be
incorporated Water in varying concentration may be added to provide the requisite
hydrophilic nature to the composition
Pharmaceutically acceptable C-1-5 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 GLYCOFUROL®
As the base having lipophilic properties for the preparation of emulsions, fatty acid triglycerides, preferably medium chain fatty acid triglycerides, vegetable oils like coconut oil, olive oil, castor oil and their derivatives, and ethyl oleate may be used
As base, for the preparation of the said therapeutic composition in the form of an ointment, 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 may be used The topical dosage forms are formulated suitably such that the resultant product is easy to apply and is non-staining
For the therapeutic composition in form of an aerosol formulation for topical applications, pharmaceutical^ acceptable propellants may be used such as 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 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 utilizing 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
(Table Removed)
Step (a) Dimethylacetamide is mixed with ethyl alcohol and acetone at 30°C in a container
with stirring To the mixture obtained, Celecoxib, Cremophor® RH 40 is added and stirred till
completely dissolved
Step (b) Propylene glycol, polyethylene glycol 400 and water are mixed in homogenizer To
the homogenized mixture obtained, Carbopol® 934 is added in small amount at a time at
room temperature and the speed of the homogenizer is kept at approximately 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 of 25° - 30°C and under vacuum (25 mm of Hg) to affect gel formation
EXAMPLE 2
(Table Removed)

Step (a) Dimethylacetamide is mixed with ethyl alcohol and acetone at 30°C in a container with stirring To the mixture obtained Rofecoxib is added and stirred till completely dissolved Step (b) Propylene glycol, polyethylene glycol 400 and water are mixed in homogenizer To the homogenized mixture obtained, carbopol 934 is added in small amount at a time at
room temperature and the speed of the homogenizer is kept at approximately 1500 - 2000
rpm
Step © 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 of 25° - 30°C and under vacuum (25 mm of Hg) of affect gel formation
EXAMPLE 3
(Table Removed)

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

Celecoxib is dissolved in (2) with stirring and (3), (4), (5), (6), (7) and (8) are added to obtain a clear solution with stirring
EXAMPLE 6
(Table Removed)
Rofecoxib is dissolved in (2) with stirring and (3), (4), (5), (6), (7) and (8) are added obtain a clear solution with stirring
EXAMPLE 7
(Table Removed)
Warm (3), (4) and (5) and add with stirring a solution of Rofecoxib in dimethyl sulphoxide EXAMPLE 8
(Table Removed)

Warm (3), (4) and (5) and add with stirring a solution of Celecoxib in dimethyl sulphoxide
EXAMPLE 9
(Table Removed)

EXAMPLE 10
I(Table Removed)
EXAMPLE 11
(Table Removed)
EXAMPLE 12
(Table Removed)
EXAMPLE 13
(Table Removed)
EXAMPLE 14
(Table Removed)

Process
Step 1 Mix 1 and 2 in a jacketed vessel
Step 2 Mix ingredients 3 to 11 separately at 40 - 60°C
Step 3 Mix phases of step 1 and 2 using a homogenizer
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 therapeutic anti-inflammatory and analgesic pharmaceutical composition for topical/transdermal use consisting of a selective COX-2 inhibitor drug from 0.1% to 40% w/w and percutaneous absorption enhancing vehicle/base from 60% to 99.9% w/w, wherein the said percutaneous absorption enhancing vehicle/base comprises percutaneous enhancer from 0.5% to 60% w/w, one or more vehicle/base from 2.0% to 98% w/w, gelling agent/thickening agent from 0.0% to 60% w/w and surfactant from 0.0% to 20%w/w and optionally a neutralizing agent/pH adjusting agent.
2. A composition as claimed in claim 1, wherein the percutaneous enhancer is selected from the group comprising sulphoxides, amides or pyrrolidones, laurocapram essential oils, or C12-24 mono or poly-unsaturated fatty acids or any of their corresponding alcohols.
3. A composition as claimed in claim 2, wherein the percutaneous enhancer is dimethylacetamide.
4. A composition as claimed in claim 1, wherein the surfactant is a pharmaceutically acceptable hydrophilic or lipophilic surfactant or mixture thereof.
5. A composition as claimed in claim 4, wherein the surfactant is selected from the group comprising polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene-polyoxypropylene block copolymers, polyoxyethylene fatty acid esters, propylene glycol mono- and di-fatty acid esters; lipophilic surfactant selected from the group comprising sorbitan fatty acid esters, monoglycerides, sugar esters and, transesterification products of natural vegetable oil triglycerides and alkylene polyols.
6. A composition as claimed in claim 1, wherein said gelling agent/thickening agent is selected from the group comprising natural, synthetic or semi-synthetic polymeric materials, polyacrylate and polyacrylate co-polymeric resins, cellulose and cellulose derivatives and polyvinyl resins.
7. A composition as claimed in claims 1, wherein the composition comprises a neutralizing agent/pH adjusting agent in an amount from 0.0% to 5.0%w/w.
8. A composition as claimed in claim 1, wherein the neutralizing agent/pH adjusting agent is selected from the group comprising polar organic amines, acidifying agents, sodium bicarbonate, sodium hydroxide, potassium hydroxide, borax, disodium hydrogen phosphate and sodium dihydrogen phosphate.
9. A composition as claimed in claim 8, wherein the polar organic amine is diethylamine, diisopropanolamine, triethylamine or triethanolamine.
10. A composition as claimed in claim 8, wherein the acidifying agent is hydrochloric acid, lactic acid, malic acid or tartaric acid.
11. A composition as claimed in claim 1, wherein the vehicle/base is selected from the group comprising pharmaceutically acceptable lower (C1-5) alkanols; water soluble macrogols; 1,2-propylene carbonate, butylene glycol, polypropylene glycol, 1,2-propylene glycol, glycerol triacetate, glycerol, lower ketones, chlorofluorocarbons, hydrofluorocarbons and water.
12. A composition as claimed in claim 1, wherein the selective COX-2 inhibitor drug is selected from a group comprising Celecoxib and Rofecoxib.
13. A process for the preparation of a therapeutic anti-inflammatory and analgesic pharmaceutical composition for topical/transdermal use as claimed in claim 1, which comprises:

a) mixing 0.5% to 60% w/w of a percutaneous enhancer with 2.0% to 98% w/w of one or more vehicle or bases;
b) adding to the mixture of step (a) 0.1% to 40% w/w of selective COX-2 inhibitor followed by stirring the mixture until completely dissolved;
c) mixing separately 0.0% to 20% w/w of a surfactant, 0.0% to 60% w/w of a gelling agent/thickening agent and 2.0% to 98% w/w of one or more vehicles or bases and mixing; and
d) adding the mixture obtained in step (b) to the mixture obtained in step (c) under stirring to obtain the composition.
14. A therapeutic anti-inflammatory and analgesic pharmaceutical composition and
process for topical/transdermal use substantially as herein described with reference to
the foregoing description and the accompanying examples.