WO2002089765A1

WO2002089765A1 - Method of preparing antibacterial gel and cotrimoxazole gel

Info

Publication number: WO2002089765A1
Application number: PCT/IN2001/000099
Authority: WO
Inventors: Sanjay Suri; J. Dr. Singh; Ulhas Dhuppad; A. K. Dr. Bhatham; Pravin Kulhkarni
Original assignee: Morepen Laboratories Ltd
Priority date: 2001-05-04
Filing date: 2001-05-04
Publication date: 2002-11-14

Abstract

Co-trimoxazole a gel formulation of the present invention is useful for external use for the treatment of open wound to prevent and treat infection caused by susceptible micro-organisms. The gel for local application to the skin, according to the invention includes trimethoprim, sulphamethoxazole, and a carrier gel base comprising carboxy vinyl polymer, polyethylene glycol, and a trialkanolamine. An antioxident, chelating agent and other optional compounds may also be added to the formulation.

Description

riTLG: METHOD OF PREPARING ANTIBACTEP EAL GEL AND CO- TRIMOXAZOLE. GEL

The present invention relates to new type of preparation of Co--t rimoxaπol , more par icularly, novel gel preparation, which is useful for an external use, and a m i hod for the preparation of the same.

PPJUR ART π FID OP INVENTION:

It E- well now that c o- t rimov.azole , a combina ion of tr lmethoprim and su_ faniethoiia-ole in 1:5 ratio, has an excellent antibacterial property and is used orally and parentar 1 ly to treat urinary tract infe tions, acute titis media, acute exacerbations of chronic bronchitis and <=hιqe I los s due to susceptible microb al strains. Co-, πmo.taπoie IE more effective than trimethopπ and su. fa ethoxaxio le used alone. Sulfamethoxazole, i.e. N - i 5--methyl- 3-ιsoxazol yl ) su J fam la ide (molecular formulas C H N 0 G, molecular we qh : 255.28) inhibits bacterial synthesis of dihydrofolic ≤tcid, by competing w t'h para a ino benzo c ac d, which s important for bacterial synthesis of dihydrofolic acid. Tr methopr m i.e. 2 , 4-~d am no-5-( 3 ,4 , 5 tr imethoxybenzy 1 ) pyπmidme (molecular formula: C H O , molecular weights '_?^c'0.3 ) blocks the production of te rahydrofα I c and from dihydrofolic and by binding to and reversibly inhibiting dihydrofolate reductase. Thus, when c:o- tr mo.:a__ole s used, i he two consecutive steps in the __. biosynthesis of nucleic acids and proteins a.r^ blαcl-ed which are essential for growth of many bacteria. In vitro studies havp shown , that bacteria] resistance develops more slowly with co-trimoxazole than with either tr ethopr i and sulphame tho.;a__ol e alone.

Althouqh fo-lr lmoxaiolp s widely used in oral dosage form as an an bacterial, no significant attempt has been made l use it in topical dosage form s an antibacteri l for treatment of infections ύ\ <^ to susceptible organisms. In veterinary sciences co- trimo.tazole tablets ΛΓS being used for topical treatment, in which tablets are triturated and directly applied on the wound.

An h.e of the pr ent invention is to provide a new type of preparation of cα~-tr ιmo;arole which is useful for external use. Another object of the invention is to provide a gel preparation of co- trimov.ar.ole . 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 follo mq desc iption.

Accordingly to the invention, the method of preparing Ant bacte al gel comprises:

(i) dissolving antibacterial agent trimethoprim and sulfamethoxazole in polyethylene glyco3--400 with the help of mechanical stirrer, to ..et a homogenous solutio ;

( -i ) dissolving carhoxyvinyl polymer as he ein described in the solution obtained m step ( ) and stirring continuously with a mechanc al stirrer to get homogenous solution of desired visro i ty s.

(111) Adding mixture of basic substance and purilied water as herein described m the solution obtained in step (11) and continuously stirring in a closed container to get a gels

(iv) adding an agueous antiox di ng agent as herein described, to the gel obtained n step (111) by 1 ontmuously stirring.

DETAILED DESCRIPTION OF THE INVENTION

^"I he preparation of the present invention ran be prepared by dissolving trimethopπm and su I famethoxa__ole in polyethylene glycol, and admixing the solution of tr methop and sul famethoxazole n polyethylene glycol with pha maceutically acceptable carriers or diluents. Pharmaceutically acceptable and suitable polyethyl ne-' qlycols have empirical formula HUCH (CH ϋCH )m OH where m represents the average number of oxyethylene group. Suitable polyethlene qlycols include PEG 200, PEG -.00 , PEG 400 .

The gel preparation for topical application is a transparent preparation having pH of 6 to 10 and a o viscosity of 2,000 to 1000,000 cps at 20 C, which is prepared by admixing a solution of t π methopπm and sulfamethoxazo] e m polyethylene glycol with carboxyvmyl pol mer under stirring, and thereto adding w th stirring a basic substance. In the qel prepa tion, polyethylene qJycoi is contained in an amount 25 to _>5 /_ by weiqht based on the total amount of the preparation. Car boxyvmy 1 polymer is added to the preparation in order to give a suitable viscosity to the preparation. The carboxyvmyl polymer ι<:- a hydrophi 31 c vinyl polymer w th active carbαxyl groups, which is prepared by polymeri rat ion of monomers comprising predominantly acrylic acid. All commercially available carho yvinyl polymers can be used n the present invention. Suitable examples are Carbopol '-? ..4 „ Carbopol ^4 , and Carbopol ^41, which r re trade-names of the products of B.F. Goodrich. The carboxyvmyl polymer- has free carboxyl groups and aqueous solution is acidic. When h³ carboxy/my] polymer s neutral I ized with a basic substance, a sticly gel s formed.

The basic substance to be used for neutral 11 zation of carboxyvmyl polymer includes organic amines, such as a trial . anol mi ne havmq 1 to 4 carbon atoms in each

Λ Hanoi moiety (e.g. tr l e t hanol amme , tπet hanolam ne , or triprαpanolam ) , and also includes morqan c bases such as an aqueous solution of all all metal hydroxides (e»q. sodium hydro;; de or potassium hydroxide). All these basic substan s ran c.. e a qol having a sim lar vis osity when the aqueous solution of carboxyvmyl pol mer is neu al 1 i ed with basic substances.

Tt has also been found useful to .d an antio ant t the cornposit ion . A prefered embodiment uses sodium metab sul f te as an antioxidant to provide stability to th gel preparation. Mo eover, a sm ll amount of sodium edetate (i.e. sodium ethy lenediamine t et r aaretat€? ) may be added t o the preparation to enhance its stabil ty. In preparation if the gel co- 1 r imoxazole is firstly dissolved in polyethylene glycol at room temperatur , to the resulting solu ion, rboxyvmyl polymer is added w th constant- stirring. To the mixture so obtained a basic sub tance is added with constant stirring. By the add ion of the basic: substance, and purified water carboxyvmyl polymer is neutral lired to increase the v cocity of the mixture, and there is obtained a transpart-nt cjel preparation wherein the components ^r^ alt uniformly dispersed. To the resul ing gel, aqueous solution of an antioxidant, sodium me abisul f ite s added w th stirring. Further purified water is added to male .1 0 "/. . total. The gel preparation thus obtained has a viscosity of 2000 to 100,00 cps. Wherein the carboxyvmyl polymer s contained n an amount of 0.1 t o .s . ifl V. by weight, preferably 1.0 to 2.0 "<• by weight, based upon the total weight of the preparation. Moreover, the gel preparation s regulated to a pH of 7 to 1 „ preferably 8 to 9, by controlling the amount of basic substance. The gel preparation contains usually 0.5 to 4.0 "/. by weight of co-- t ι moxarol e (containing tr methoprim and su I f methoxarol in 1:5 ratio) and sodium metab ul f I t , usually 0.05 to 0.5 ° by weight , preferably 0.05 to 0.15 "/. „ The new type of preparation of cα™trιmoxazo3 e of the present invention is stable and no prec p tati or. of any crystal occurs during storage thereof or when applied to the si ι n . It n be appl led to the si n m a convent onal manner. For instance, a q.?l preparation having comparal^~ vel v low viscosi y can directly be applied to the si n from a vessel , and the gel preparation which have a comparatively higher vjscosity can be applied w th fingers. Application of the gel preparation on the si in, leads to its contact with salts such as sociium chloride contained m a very sm ll amount- in the perspi rat ion or arc? present on the surface of he si in, causes the viscosity of the preparation to api ly decrease, and the preparation is liquified and thereby leading to excellent spreadabi I ity on to the πhn. Furthermore a f lm of carboxyvmyl polymer is formed on the si- in, the f lm of carboxyvmyl polymer thus formed is readily dried when it comes n contact with air. Hence the εlin surface, to which the preparation s applied, does not become qreasy, sticky and messy. Thus the shortcomings of ointments such as qreasyness, stickiness and soiling of clothes e,re eliminated.

The present invention is illustrated by he following examples, but is not limited thereto. In the examples purified water was prepared by purifying water with an ion exchanqe resin, and the viscosity was measured o 20 C by a Brook field v sco eter.

Exampl 1 t o -tr imoxarole (^".' g) was dissolved in polyethylene glycol 400 (30 g), and thereto was added carbopol S4

(1.5 g) wi h s irring weJ 1 , and thereto was gradually added tri ethanolamine (12 g), and further was added 10 "/. aqueous- solution of so ium me t abi sul f i te (1 g) w th stirring well, and further was added purified water to mal 100 g in total. After stirring we , the mixture? gave a transparent qel preparation and a pH of 8.2.

f_ -.am le 2

Co- tr imoxarole (2 q ) was dissolved in polyethylene glycol 400 (20 q ) , and thereto was added carbopol 9.'.4 (.1.5 ςi ) with stirring well, and thereto was gradually added tri ethanol mine (8 g), and further was added 10 "/» aqueous solution of sodium metab ul fite (1 g) w th 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.

Exam l

Co-trimoxarole (3 g) was> dissolved in polyethylene glycol 400 (30 g), and thereto was added carbopol 954 (1,0 cι ) with stirring well, and thereto was gradually added tr lethanolamine (10 g), and further was added 10 "/. aqueous solution of sodium met abisul f i te (1 c. ) w th stirring well, and further was added purified water to mal 1 0 c. in total. After stirring well, the mixture gave a transpar nt q l preparation and c. pH of 8.2.

E^: ample 4

Co-t r ιmoxa.:ole (3 g) was dissolved n polyethylene glycol 40ø (30 g), and thereto was added carbopol 954 (1.5 g) with st rr nq well, and thereto was gradually added tr lethanol amme (12 g), and further was added 10 7. aqueous solution of sodium metabi sul fite (.1 g) w th stirring well ami 10 7. aqueous solution of sodium edetat ( ..1 g) with stirring we I I, and further was- added purified water to make 100 q in total. After stirring well, the mixture gave a transparent gel preparation and a pH of 8.3.

Fx m l. 5

Co- tr i moxa_:o] e ( s g) was dissolved in polyethylene glycol 400 (30 g), and thereto was added carbopol 934 (1.5 q ) w th stirring well, and thereto was gradually added aqueous solution of tr lethanol amme (12 q), and further was added purified water to male IΘ0 q in total.

After stirring well, the mixture qave a transparent gel prepa tion and a pH of 8.4.

E TAB 111TY TESTING Of I HE E OKMUl AT I ON

5 Formulation described above; were tested under decele ate ag ng conditions? for the stability of the compo i tion .

Table I.

Stability testing at 40 L'

Time Criteria Example 1 E- .-.ample 2 Example 3 Example 4 Example in

Mon t h<~

Appear transparent transparent transparent transparent transparen ancp colourl ss colourless colourless colou less colourless ^"(rime- 101.42 "/. 79.86 "/. 100.34 7. 99.93 7. 100.04 7. ho r i m

Su I fame - tho role 99.89 V. 99.89 7. 1 .. 7. .4 7. 100.02 7, Appear- transparent transparent transparent transparent t ansparent. ance colourless colourless¹- colourless colourless yellowish

Tri e 101.22 V. 100.01 7. 99.89 7. 99.72 7. 98.84 7. hoprim

Sul fame- tho zole 99.08 7. i00.09 7. 100.00 7. 99.42 7. 98.83 7. 5 Appea- transparen transparent transparent: transparent transparent aance colourless colourless colourless colourless yellowish lπme- 101.24 7. 100.11 7. 97.8/ 7. 79.99 7. 98.82 7, thopri

Sul fame - t h xa-ole 99.86 7. 100.19 7. .1 ø .02 7. 99.41 . 98.76 7. It is very clear from the data in table I, all compos tions were stable?, with respect to active ingredient content. Composition of example 5, which do not contain antioxidant, shows discoloration.

CN-VπfiO ANTIMICROBIAL EFFECTS:

EFFΓCTIVFNFSB TESTING

The antimicrobial effectiveness of example I was tested by the "/one of inhibition" technigue and compared with other ant microbi l preparations as Betadine (Povidone Iodine) 5 7. ointment. Silver sul fadiazine 1 7. cream, and Furacin ( i trofur a zone 0.2 7. ) cream. The procedure for the test is described below.

i. Nutrient agar cups were prepared petri dishes.

2. Each petri dish was seeded with a given target microorganism, and in this example, S. Aureus, P. Aerυgmosa, S. Typhi and E. Coll. These &re the standard mi r oorgamsms epresenting both gram positive and qram nega11 ve .

3>. Approx a ely 0.2 gm of each solution was added to individual agar cups. o

4. Each petri dish was incubated at 37 C for 48 hours.

5. The dishes were removed and the rone of inhibition was

from the edge of the cup to the? nearest area of microbia. qrowth. All results were measured m i 31 ete s.

The results of the zones of inhibition tests are shown below in table 2

5 Table 2

Zone of Inh mti n in mm

i r roorqan is E am 1e I Betadme cream Si Iver Furac n cream (5 "<_) suifadiazine (ø.2 7.) cream .1 7.)

S. Aureus 42.44 19.29 no inhibi ion 20.79

P. Λeruq inosa ^"3.54 no inhibition 19.06 no inhibition

S.Ty hi 23.08 no inhibition 13.10 14.9/

E. Coll 54.24 19.07 10.33 11.20

As can be seen, the qel composition of example 1, found to be most- effective against common

tested above.

Topical treatment regimens according . to the practice of tins invention involve applying the composition herein directly to the si- in at the site at infection. The rate of application and duration of treatment will depend upon the severity and nature of the condition, the response of par+tcular patient, and related factors within the sound medical judgement or an attending physician or the patient. In general, qel formulation is applied at least daily, preferably twice or three times daily, until 1 the eradication of the infection.

Claims

WE CLA IM :

1. A method of preparing Antibac er al gel compr ι se _

i) dissolving an iba te ial agent trimethoprim and 5 sul famet.hoxa.7ole in polyethylene g3ycol-40ø with the help of mechanical stirrer , to get a homogenous solution;

(ι.ι) dissolving carboxyvmyl polvmer as herein described in the solution obtained m step (l)

.1 and stirring continuously with a mechancial stirrer to get homogenous solution of desired viscocity ;

(m) Adding mixture of basic substance and purified water as herein described in the solution i ^ obtained in step (ii) and continuously stirring in a closed container to get a gel;

(iv) Lidding an aqueous ant OX idi zing agent as herein described, to the gel obtained in step (in) by c nt nuously stirring.

20 2. A method of preparing antibacterial gel as claimed in claim 1 wherein trimethoprim and sulfamethoxazole lias w/w ratio of 1;5 and thereby mal g w/w ratio o1 co--t r i moraπole in qe-1 as ø .5-4 7..

7^ 3. A method of preparing antibacterial qel as claimed in claim 2 wherein tr im t h iprim sul famethoxa;:ole and polyethylene glycol <:<v& dissolved at room temper ture .

4. A method of p paring an iba te al qel as. claimed claim 1 wherein viscocity adjusting agent c_re selee: ted from carbopol 9 _■4 , carbopol 940 and c bopol 941 in W/W . o1 1-2.

5. A method of preparmq antibacterial gel as claimed n claim 1 and 4 wherein viscoc y of the lø gel is the range of 2000- tøø ,000 CF'S.

6. Λ method o1 preparing antibacterial gel as claimed in claim L wherein preferred basic: substance, t π et hano3 amince is _.n the range of 6-

14 (W/W

7.), preferably .2.0.

5 /. A me hod of preparing antibacterial gel as claimed in earlier claims wherein PH of the gel s requlated at 7-10, preferably 8-9.

8. A method of preparing antibacterial gel a<=- laimed in preceeding claim wherein preferred

20 antioxidi g aqent is sodium metabisulpi te the range of .05-0.5 (W/W 7.), preferably 0.05-

0.15.

9. A method of preparing antibacterial qel as c 1 ai ed in c 1 ai m 1 heroin t lie voh c: 1e s purified water m the range of 40-- /ø (W/W v.).

10. Co-t imoxazole qel iompos.it on substantially at herein described with reference to examples as fe c n bed he e in .

11. A method of prepa ing antiba terial co- tπmo;:_Λ_.o3 e qel sub an ially as herein described with referen e to examples as described herei n .