THERAPEUTIC ANTI-INFLAMMATORY AND ANALGESIC COMPOSITION CONTAINING SELECTIVE COX-2 INHIBITOR DRUGS FOR USE TRANSDERMALLY AND A PROCESS FOR THE MANUFACTURE
THEREOF
TECHNICAL FIELD
This invention relates to novel therapeutic anti-inflammatory and analgesic pharmaceutical compositions containing Selective COX- 2 inhibitors drugs 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. COX- 2 inhibitor drugs such as Celecoxib and Rofecoxib are a 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 a3 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 anti-inflammatory drugs (NSAIDs.) COX-1 activity appears to be related to
"constitutive" or "house-keeping" functions in the gastric mucαsa, kindney and platelets.
COX-2 activity is "indυcible" 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 NSA1D3 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 characteristics; 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:-
Celecoxib
Celecoxib:- p[5-p-Tolyl-3-(trifluoromethyl) pyrazol-1-yl) benzenesulfonamide.
Rofecoxib
Rofecoxib:- 4-[4-(methyl sulphonyl) phenyl]-3-phenyl-2(5H)-furanone.
In the Patent Application PCT Publication 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 invention in combination with other compounds which alter the physico-chemical property of COX-2.
SUMMARY 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 enhancer 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 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% 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%.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, it has been found that it is possible to deliver a 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% 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%.
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 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, a3 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% 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 neutralised or its pH adjusted by addition of 0.0% to 5.0% of neutralizing agent or a pH adjusting agent to being 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, 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, volatile oils like oil of citrata, mentha, winter green.
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
CREMOPHOR EL. Also suitable for use are the various surfactants available under the trade name NIKKOL e.g. NIKKOL HCO-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, pripylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleater, propylene glycol stearate;
Examples of suitable lipophilic surfactants include trans-esterification products of natural vegetable oil triglycerides and polyalkylene polyols. Preferred are products obtained by trans-esterification 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-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 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. 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-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 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, trithylamine and triethanolamine may be used, acidifying agents including hydrochloric acid, lactic acid, malic acid, tartaric acid
and the like may also be used.
As vehicles base, the following may be used :
Pharmaceutically acceptably lower (having Cι<s) alkanols, particularly ethanol; water soluble macrogels like polyethylene glycol having an average molecular weight from 200 to 600: 1 , 2-propylene carbonate, proρane-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. Water in varying concentration may be added to
provide the requisite hydrophilic nature to the composition.
Pharmaceutically acceptable Ci 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 oil3, 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, pharmaceutically 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-irv-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 gg| dosaαo form
SI. No. Component Quantity
1. Celecoxib 2.00 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
T o t a l 200.0 g
Step (a) Dimethylacetamide is mixed with ethyl alcohol and acetone at 30βC. in a container with stirring. To the mixture obtained Celecoxib 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
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 25β - 30βC and under vacuum (25 mm of Hg) to affect
gel formation.
EXAMPLE 2
Preparation of toolcal oβl dosaαβ form
SI.No. Component Quantity
1. Rofecoxib 2.00 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 T o t a l 200.0 g
Step (a) Dimethylacetamide is mixed with ethyl alcohol and acetone at 30βC. 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 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
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) to affect
gel formation.
EXAMPLE 3
Preparation of emultlon type topical dosaoo form
SI. No. Component Quantity
1. Rofecoxib 1.0 g
2. Transcutol 35.0 g
3. Water 10.0 g
4. Disodium Hydrogen 0.1 g Phosphate
5. Cremophor RH 40 5.0 g
6. Labrafιl M 194 CS 10.0 g
7. Glyceryl monostearate 8.0 g
8. Stearic acid 13.0 g
9. Ethyl oleate 2.9 g
10. Diethyl Sulphoxide 15.0 g
T o t a l 100.0 g
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
Preparation of emultloπ tvoo topical dosa β form
SI.No. Component Quantity
1. Celecoxib 1.0 g
2. Transcutol 35.0 g
3. Water 10.0 g
4. Disodium Hydrogen 0.1 g Phosphate
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. Diethyl Sulphoxide 15.0 g
T o t a l 100.0 g
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
Preparation of tolutlon tvp» do»ao» form for topical application
SI.No. Component Quantity
1. Celecoxib 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 1.0 g cellulose
8. Triθthanolamine 0.2 g 9. Water 1.0 g
T o t a l 100.0 g
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
Preparation of solution type dotaoβ form for topical application
SI.No. Component Quantity
1. Rofecoxib 1.0 g
2. Dimethyl formamide 10.0 g
3. Poloxa er 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 1.0 g cellulose
8. Triethanolamine 0.2 g
9. Water 1.0 g
T o t a 100.0 g
Rofecoxib is dissolved in (2) with stirring and (3), (4), (5), (6), (7) and (8) are added to
obtain a clear solution with stirring.
EXAMPLE 7
Preparation of olntmaηt tvpo dosage form topical application
SI.No. Component Quantity
1. Rofecoxib 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
T o t a 200.0 g
Warm (3), (4) and (5) and add with stirring a solution of Rofecoxib in dimethyl sulphoxide.
EXAMPLE 8
Preparation of ointment type dosaoo form topical application SI.No. Component Quantity
1. Celecoxib 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
T o t a 200.0 g
Warm (3), (4) and (5) and add with stirring a solution of Celecoxib in dimethyl sulphoxide.
EXAMPLE 9
Preparation of an aerosol dotage form for topical u«e. SI.No. Component Quantity
1. Celecoxib 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 1.0 g
T o t a 100.0 g
EXAMPLE 10
Preparation of an aerosol dosage form for topical use. SI.No. Component Quantity
1. Rofecoxib 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 1.0 g
T o t a 100.0 g
EXAMPLE 11
Preparation of an aerosol dosage form .
SI.No. Component Quantity
1. Celecoxib 1%
2. Methyl Salicylate 20% 3. Eucalyptus 6%
4. Clove oil 1%
5. Menthol 4%
6. Camphor 10% 7. Cinnamon oil 0.5%
8. Terpentine oil 10% 9. Solvent q.s to 100%
EXAMPLE 12
preparation of an aerosol dosage form .
SI.No. Component Quantity
1. Rofecoxib 1 %
2. Methyl Salicylate 20%
3. Eucalyptus 6%
4. Clove oil 1 %
5. Menthol 4%
6. Camphor 10%
7. Cinnamon oil 0.5%
8. Terpentine oil 10%
9. Solvent q.s to 100%
EXAMPLE 13
Topical Preparation
1. Purified Water q.s. 100 g
2. Glycerin 3.00 g
3. Cetostearyl alcohol 5.00 g
4. Cetyl alcohol 2.00 g
5. Oil of wintergreen 2.00 g
6. Caprylic and capric 1.80 g triglyceride
7. Rofecoxib 0.5 g
8. Citrata oil 3.0 g
9. Parabens 1.0 g
10. Tocopherol-Ascorbyl 0.01 g palmitate soy lecithin
11. Citric acid 0.02 q
Process:
Step 1. Mix 1 and 2 is a jacketted vessel.
Step 2. Mix ingredients 3 to 11 separately at 40 - 60°C
Step 3. Mix phases of step 1 and 2 using a homegenizer
EXAMPLE 14
Topical Preparation
1. Purified Water q.s. 100 g
2. Glycerin 3.00 g
3. Cetostearyl alcohol 5.00 g
4. Cetyl alcohol 2.00 g
5. Oil of wintergreen 2.00 g
6. Caprylic and capric 1.80 g triglyceride
7. Celecoxib 0.5 g
8. Citrata oil 3.0 g
9. Parabens 1.0 g
10. Tocopherol-Ascorbyl 0.01 g palmitate soy lecithin
11. Citric acid 0.02 g
Process:
Step 1. Mix 1 and 2 is a jacketted vessel.
Step 2. Mix ingredients 3 to 11 separately at 40 - 60°C
Step 3. Mix phases of s tep 1 and 2 using a homegenizer
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.