The present invention relates to new type of preparation of Co-trimoxazole, more particularly, novel gel preparation, which is useful for an external use, and a method for the preparation of the same,
PRIOR ART/FIELD OF INVENTION:
It is well known that Co-trimoxazole, a combination of trimethopr.im and sulfamethoxazole in 1:5 ratio, has an excellent antibacterial property and is used orally and parentarally to treat urinary tract infections, acute otitis media, acute exacerbations of chronic. bronchitis and shigellosis due to susceptible microbial strains. Co-trimoxazole is more effective than trimethoprim and sulfamethoxazole used alone. Sulfamethoxazole, i.e. N -(5-methy1-3-isoxazoly1) sulfanilamide (molecular formula: C H NO S, molecular weight:253.23) inhibits bacterial synthesis of dihydrofolic acid, by competing with para amino benzoic acid, which is important for bacterial synthesis of dihydrofolic acid) Trimethoprim i.e. 2,4-diamino~5-(3,4,5 trimethoxybenzy1) pyrimidine (molecular formula: C H NO, molecular weight: 290.3) blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting dihydrofolate reductase. Thus, when co-trimoxazole is used, the two consecutive steps in the
biosynthesis of nucleic acids and proteins are blocked which are essential for gropwth of many bacteria. In vitro studies have shown, that bacterial resistance develops more slowly with co-trimoxazole than with either trimethoprim and sulphamethoxazole alone.
Although co-trimoxazole is widely used in oral dosage form as an antibacterial, no significant attempt has been made to use it in topical dosage form as an antibacterial for treatment of infections due to susceptible organisms. In veterinary sciences co— trimoxazol. e tablets are being used for topical treatment, in which tablets are triturated and directly applied on the wound.
An Object, of the present invention is to provide a new type of preparation of co-trimoxazole which is useful for external use. Another object, of the invention is to provide a gel preparation of co-trimoxazole. Still further object of the invention is to provide a process for preparing the preparation as set forth above. These and other object of the invention will be apparent. from the following description.
Accordingly to the invention, the method of preparing Antibacterial gel comprises:
(i) dissolving antibacterial agent. trimethoprim and sulfamethoxaxole in polyethylene glycol-400 with
the help of mechanical stirrer, to get. a homogenous solution ;
(ii) dissolving carboxyvinyl polymer as herein described in the solution obtained in step (i) and stirring continuously with a mechanical stirrer to get. homogenous solution of desired
viscocity ;
(iii) adding mixture of basic substance and purified
water as herein described in the solution
obtained in step (ii) and continuously stirring
in a closed container to get a
(iv) adding an aqueous ant.iox.idi zing agent as herein described, to the gel obtained in step (iii) by continuously stirring .
DETAILED DESCRIPTION OF THE INVENTION
The preparation of the present invention can be prepared by dissolving trimethoprim and sulfamethoxazole in polyethylene glycol , and admixing the solution of trimethoprim and sulfamethoxazole in polyethylene glycol with pharmaceutically acceptable carriers or diluents. Pharmaceutically acceptable and suitable polyethylene glycols have empirical formula HOCH (CH OCH )m OH where m represents the average number of oxyethylene group. Suitable polyethlene glycols include PEG 200,
PEG 300, PEG 400.
The gel preparation for topical application is a
transparent, preparation having pH of 6 to 10 and a
viscosity of 2,000 to 1000,000 cps at 200C, which is
prepared by admixing a solution of trimethoprim and sulfamethoxazole in polyethylene glycol with carboxyvinyl polymer under stirring, and thereto adding with stirring a basic substance. In the gel preparation, polyethylene glycol is contained in an amount 25 to 35 % by weight based on the total amount of the preparation. Carboxyvinyl polymer is added to the preparation in order to give a suitable viscosity to the preparation. The carboxyvinyl polymer is a hydrophillic vinyl polymer with active? carboxyl groups, which is prepared by polymerization of monomers comprising predominantly acrylic, acid. All commercially available carboxyvinyl polymers can be used in the present invention. Suitable examples are Carbopol 934, Carbopol 940, and Carbopol 941, which are tradename® of the products of 8.F. Goodrich. The carboxyvinyl polymer has free carboxyl groups and aqueous solution is acidic. When the carboxyvinyl polymer is neutrall ized with a basic substance, a sticky gel is formed.
The basic substance to be used for neutral li.2at.ion of carboxyvinyl polymer includes organic amines, such as a trialkanolamine having 1 to 4 carbon atoms in each alkanol moiety (e.g. trimethanolamine, triethanolamine,
or tripropano.lam.ine)., and also includes inorganic bases such as an aqueous solution of alkali metal hydroxides (e.g. sodium hydroxide or potassium hydroxide). All these basic substances can give a gel having a similar viscosity when the aqueous solution of carboxyvinyl polymer is neutrallised with basic substances.
It has also been found useful to add an antioxidant to the composition. A prefered embodiment uses sodium metabisulfite as an antioxidant to provide stability to the gel preparation. Moreover, a small amount of sodium edetate (i.e. sodium ethylenediamine tetraacetate) may be added to the preparation to enhance its stabi1ity.
In preparation of the gel co-trimoxazole is firstly dissolved in polyethylene glycol at room temperature, to the resulting solution, carboxyvinyl polymer is added with constant stirring. To the mixture so obtained a basic substance is added with constant stirring. By the addition of the basic substance, and purified water carboxyvinyl polymer is neutrallized to increase the viscocity of the mixture, and there is obtained a transparent gel preparation wherein the components are all uniformly dispersed. To the resulting gel, aqueous solution of an antioxidant, sodium metabisulfite is added with stirring. Further purified water is added to make .100 % in total. The gel preparation thus obtained has a viscosity of 200(3 to 100,00 cps.
Wherein the carboxyvinyl polymer is contained in an amount. of 0.1 to 3.0 % by weight, preferably .1.0 to 2.® 7, by weight, based upon the total weight of the preparation. Moreover, the gel preparation is regulated to a pH of 7 to 10, preferably 8 to 9, by controlling the amount of basic substance. The gel preparation contains usually 0.5 to 4.0 7. by weight of c:o-trimoxazole (containing trimethoprim and sulfamethoxazole in 1:5 ratio) and sodium metabisulfite, usually 0.05 to 0.5 7. by weight, preferably 0.05 to 0.15 7.. The new type of preparation of co-trimoxazole of the present invention is stable and no precipitation of any crystal occurs during storage thereof or when applied to the skin. It. can be applied to the skin in a conventional manner. For instance, a gel preparation having comparatively low viscosity can directly be applied to the skin from a vessel, and the gel preparation which have a comparatively higher viscocity can be applied with fingers. Application of the gel preparation on the skin, leads to its contact with salts such as sodium chloride contained in a very small amount in the perspiration or are present on the surface of the skin, causes the viscosity of the preparation to rapidly decrease, and the preparation is liquified and thereby leading to excellent spreadabi1ity on to the skin. Furthermore a film of carboxyvinyl polymer is formed on the skin, the film of carboxyvinyl polymer thus formed is readily dried when it comes in contact with air. Hence the skin surface, to which the preparation is
applied., does not become greasy, sticky and messy. Thus the shortcomings, of ointments such as greasyness, stickiness and soiling of clothes are eliminated.
The present invention is illustrated by the following examples, but is not limited thereto. In the examples purified water was prepared by purifying water with an
ion exchange resin, and the viscosity was measured
700C by a Brook field iscometer.
Example 1
Co-trimoxazole (3 g) was dissolved in polyethylene glycol 400 (30 g), and thereto was added carbopo.1 934 (1.5 g) with stirring well, and thereto was gradually added triethanolamine (12 g), and further was added 10 7. aqueous solution of sodium metabisulfite (1 g) with stirring well, and further was added purified water to make 100 g in total. After stirring well, the mixture gave a transparent gel preparation and a pH of 8.2.
Example 2.
Co-trimoxazole (2 g) was dissolved in polyethylene glycol 400 (20 g), and thereto was added carbopo.1 934 (1.5 g) with stirring well, and thereto was gradually added triethanolamine (f3 g), and further was added 10% aqueous solution of sodium metabisulfite (1 g) with stirring well, and further was added purified water to make 100 g in total. After stirring well, the mixture
gave a transparent gel preparation and a pH of 8.4.
Example 3
Co—t.r imoxazole (3 g) was dissolved in polyethylene g.lyco.1 400 < 30 g), and thereto was added carbopol 934 (1.0 g) with '.stirring well, and threto was gradually added triethanolamine (10 g), and further was added 10 7. aqueous solution of sodium trietgabisulfite (.1 g) with stirring well, and further was added purified water to make 100 g in total. After stirring well, the mixture gave a transparent gel preparation and a pH of 8.2.
Example? 4
Co-trimoxazole (3 g) was dissolved in polyethylene g.lyco.1 400 (30 g), and thereto was added carbopol 934 (1.5 g) with stirring well, and thereto was gradually added triethanolamine (12 g), and further was added 10 % aqueous solution of sodium metabisulfite (1 g) with stirring well and 10 %, aqueous solution of sodium edetate (0.1 g) with stirring well, and further was added purified water to make 100 g in total. After stirring well, the mixture gave a transparent gel preparation and a pH of 8.3.
Example 5
Co-trimoxaxole (3 g) was dissolved in polyethylene g.lyco.1 400 (30 g), and thereto was added carbopol 934 (1.5 g) with stirring well, and thereto was gradually added aqueous solution of triethanolamine (12 g), and
further was added purified water to make 100 g in total.
After stirring well, the mixture gave a transparent gel preparation and a PH of 8.4.
STABILITY TESTING OF THE FORMULATION
Formulation described above were tested under accelerated aging conditions for the stability of the composition.
Table 1. (Table Removed)
It is very clear from the data in table 1, all compositions were stable, with respect to active
ingredient content. Composition of example 5, which do not contain antioxidant, shows discoloration.
IN-VITRO ANTIMICROBIAL EFFECTS s EFFECT IVENESS TEST ING
The antimicrobial effectiveness of example 1 was tested by the "Zone of inhibition" technique and compared with other antimicrobial preparations as Betadine (Povidone Iodine) 5 % ointment. Silver sul f adiazine t %. cream, and Furacin (Nitrofurazone 0.2 %) cream. The procedure for the? test is described below.
1. Nutrient agar cups were prepared in petri dishes.
2. Each petri dish was seeded with a given target
microorganism, and in this example, S. Aureus, P.
Aeruginosa, S. Typhi and E. Coli. These are the
standard microorganisms representing both gram positive
and gram negative.
3. Approximately 0.2 gm of each solution was added to
individual agar cups.

4. Each petridish was incubated at 370C for 48 hours.
5. The dishes were removed and the zone of inhibition
was measured from the edge of the cup to the nearest

area of microbial growth. All results were measured in mil 1.1 meters,.
The results of the zones of inhibition tests are shown below in table 2.
Table 2
(Table Removed)As can be seen, the gel composition of example 1, found to be most effective against common microorganisms tested above.
Topical treatment regimens according to the practice of this invention involve applying the composition herein directly to the skin at the site of infection. The rate of application and duration of treatment will depend upon the severity and nature of the condition, the response of particular patient, and related factors within the sound medical judgement of an attending physician or the patient. In general, gel formulation is applied at least, daily, preferably twice or three times daily, until 1 the eradication of the infection.

1. An antibacterial gel composition comprising
cot.rimoxazo.le comprising tr.imethopr.im and
multamethoxazol in the rario .1: 5 and Sodium
metapisulphite 0.05 to 0.5 % by w/w.
2. An anti bacterial gel composition a© claimed in
12 wherein Sodium metasulphite is preferably
0.005 to 0.15 % by weight.
3. An anti bacterial gel composition as according
to claim 12 wherein the viscocity of the gel
is in the range of 2000-1,00 ,000 CPS and PH is
7-10.
4. A method of preparing Antibacterial gel
comprising the steps of: —
(i) dissolving antibacterial agent trimethoprim and sulf amethoxazole in polyethylene glycol-400 with the help of mechanical atirrer, to obtain a homogenous soution;
(ii) dissolving car boxyvinyl polymer in the solution obtained in step (i) and stirring continuously with a mechanical stirrer to get homogenous solution of viscocity:
(iii) adding mixture of basic substance and purified water in the solution obtained in step (ii) and continuously stirring in a closed container to get a gel;
(iv) adding an aqueous antioxidizing agent to the gel obtained in step (iii) by continuously stirring.
5. A method of preparing antibacterial gel according
to claim t wherein trimethoprim and
sulfamethoxazole has w/w ratio of .1:5 and thereby
making w/w ratio of co-trimoxazole in gel as
0.5 4 %.
6. A method of preparing antibacterial gel as claimed
in claim 2 wherein trimethiprim sulfamethoxazole
and polyethulene glycol are dissolved at room
t em p e r a t u r e .
7. A method of preparing antibacterial gel as claimed
in claim 1 wherein viscocity adjusting agent are
selected from carbopol 934, carbopol 940 and
carbopol 941 in W/W %. of 1-2.
8. A method of preparing antibacterial gel as claimed
in claim .1 and 4 wherein viscocity of the gel is
in the range of 2000™.1.00,000 CPS.
9. A method of preparing antibacterial gel as claimed
in claim 1 wherein preferred basic substance,
triethanolamine .is in the range of 6-14 (W/W %) , poreferably 12. (9.
10. A method of preparing antibacterial gel as claimed in earlier claims wherein PH of the gel is regulated at 7-10, preferably 8-9.
11. A method of preparing antibacterial gel as claimed in proceeding claim wherein preferred antioxidizing agent is sodium metafoisulpite in the range of .05-0.5 (W/W "%), preferably 0.05-0..15.
12. A method of preparing antibacterial gel as claimed in claim 1 wherein the vehicle is purified water in the range of 40-70 (W/W "/.).
13. Co-trimoxazole gel composition substantially as
herein described with reference to examples as
described herein.
14. A method of preparing antibacterial co-trimoxazole
gel substantially as herein described with
reference to examples as described herein.