WO2003015752A1

WO2003015752A1 - The process for preparing isotonic topical antibiotic ophthalmic formulation with improved therapeutic effect

Info

Publication number: WO2003015752A1
Application number: PCT/IB2001/001455
Authority: WO
Inventors: Bakulesh Mafatlal Khamar
Original assignee: Bakulesh Mafatlal Khamar
Priority date: 2001-08-14
Filing date: 2001-08-14
Publication date: 2003-02-27

Abstract

Eye infections are responsible for ocular morbidity and mortality if not treated in time adequately. In country like India, infections account for majority of corneal blindness. Because of this reason, there is constantly a search going on for better antibiotics to be available for ophthalmic use. The preferred antibiotic should have broad spectrum of action. It should achieve therapeutic concentration when applied topically. It is also preferable to maintain therapeutic concentration for as long as period as possible necessitating fewer application of the drug and improved compliance. The present invention relates to process of preparation of isotonic topical ophthalmic antibiotic formulation of Sparfloxacin in such a way that it is stable at room temperature, achieves higher concentration, It also has low MIC against pathogen and so achieves higher therapeutic index. This antibiotic formulation also achieves better therapeutic results.

Description

1 . THE PROCESS FOR PREPARING ISOTONIC TOPICAL ANTIBIOTIC OPHTHALMIC FORMULATION WITH IMPROVED THERAPEUTIC EFFECT.

2. Dr. Bakulesh Mafatlal Khamar, residing at 201 "Ashadha", Vasundhara Colony, Gulbai Tekra, Ellisbridge, Ahmedabad 380 006, Gujarat, India, Nationality: Indian

3. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

FIELD OF INVENTION

The objective of the present invention is to prepare isotonic topical antibiotic ophthalmic formulation for treating eye infections, with improved therapeutic effect.

The further objective of present invention is to prepare isotonic topical antibiotic ophthalmic formulation in such a way that it is stable at room temperature for more than two years and maintains therapeutic concentrations in aqueous humor for more than 6 hours.

BACKGROUND OF THE INVENTION

Eye infections are responsible for ocular morbidity and mortality if not treated in time adequately. In country like India, infections account for majority of corneal blindness. Because of this reason, there is constantly a search going on for better antibiotics to be available for ophthalmic use. The preferred antibiotic should have broad spectrum of action. It should achieve therapeutic concentration when applied topically. It is also preferable to maintain therapeutic concentration for as long as period as possible necessitating fewer application of the drug and improved compliance.

Sparfloxacin is a newer fluoroquinolone with activity against a broad range of both gm +ve as well as gm -ve organisms, atypical pathogens like Chlamydia tracomatis. It is indicated for the treatment of lower respiratory tract infections as well as acute exacerbations of COPD. Oral Sparfloxacin is a good therapeutic option in the treatment of respiratory tract infections, on account of its efficacy, once daily dosage, lack of side effects and no significant drug interactions. Sparfloxacin acts on susceptible organisms by inhibiting the enzyme, DNA gyrase. Like other quinolones, it displays a postantibiotic effect in vitro. Sparfloxacin is bactericidal at concentrations similar to or twice that of the MICs for susceptible pathogens.

Sparfloxacin provides good coverage against common bacterial pathogens responsible for external ocular infections e.g. conjunctivitis and corneal ulcer. It is active against Staph. aureus, Ps aeruginosa, N. gonorrhoeae, H. influenzae, M. catarrhalis, Staph. epidermidis, Strept. pneumoniae, Strept. viridians and Chlamydia species. The MIC₉₀ of Sparfloxacin for these organisms is in the range of 0.02 to 1.0 mcg/ml.

The penetration of Sparfloxacin into the acute humor after oral administration found to be 0.840 μg/mL.

It is desirable to have topical Sparfloxacin eye drops, since it does not achieve therapeutic concentration in aqueous following systemic administration. The preparation of Sparfloxacin for topical use is currently not available in the world. This may be due to problems associated with its formulation.

REFERENCES :

1. Comparison of topical 0.3% ofloxacin with fortified tobramycin plus cefazolin in the treatment of bacterial keratitis.

Eye 1999 Dec; 13 (Pt 6):744-7.

2. Fluoroquinolones in the treatment of bacterial keratitis. Am J Ophthalmol 1996 Jun; 121(6):712-5.

3. Topical ciprofloxacin for bacterial corneal ulcer. J Med Assoc. Thai 2000 Jul;83(7):776-82. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramcin-cefazolin in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis Study Group. Ophthalmology 1996 Nov;103(11):1854-62; discussion 1862-3.

5. Treatment of acute bacterial conjunctivitis with topical lomefloxacin 0.3% compared to topical ofloxacin 0.3%.

Eur J Ophthalmol 1999 Oct-Dec; 9(4):269-75.

6. Ciprofloxacin eye drops. Ciprofloxacin for topical therapy. Eur J Ophthalmol 1995 Apr-Jun;5(2):82-7.

7. Comparison of ciprofloxacin and tobramycin in bacterial conjunctivitis in children. Clin Pediatr 1997 Aug; 36(8):435-44

8. Ciprofloxacin ophthalmic solution in the treatment of conjunctivitis and blepharitis: a comparison with fusidic acid. Eur J Ophthalmol 1996 Oct-Dec;6(4):368-74

9. Topical ciprofloxacin in the treatment of blepharitis and blepharoconjunctivitis. Eur J Ophthalmol 1994 Jan-Mar;4(1 ):6-12

10. Evaluation of efficacy and safety of ciprofloxacin ophthalmic solution versus chloramphenicol. Eur J Ophthalmol 1993 Apr-Jun;3(2):77-82

11. Antibacterial effectiveness of ciprofloxacin 0.3% ophthalmic solution in the treatment of bacterial conjunctivitis.

Am J Ophthalmol 1991 Oct;112(4 Suppl):29S-33S

12. Topically administered norfloxacin compared with topically administered gentamicin for the treatment of external ocular bacterial infections. The Worldwide Norfloxacin Ophthalmic Study Group. Am J Ophthalmol 1992 Jun 15;113(6):638-44 13. The safety and efficacy of topical norfloxacin compared with placebo in the treatment of acute, bacterial conjunctivitis. The Norfloxacin-Placebo Ocular Study Group.

Eur J Ophthalmol 1992 Apr-Jun;2(2):58-66

14. The safety and efficacy of topical norfloxacin compared with chloramphenicol for the treatment of external ocular bacterial infections. The Norfloxacin-Chloramphenicol Ophthalmic Study Group.

Eye 1992;6 ( Pt 1):111-4

15. Treatment of adult gonococcal keratoconjunctivitis with oral norfloxacin. Am J Ophthalmol 1989 Nov 15;108(5):516-23

16. Safety and efficacy of topical norfloxacin versus tobramycin in the treatment of external ocular infections. Antimicrob Agents Chemother 1988 Dec;32(12): 1820-4

17. The safety and efficacy of topical norfloxacin compared with placebo in the treatment of acute, bacterial conjunctivitis. The Norfloxacin-Placebo Ocular Study Group. Eur J Ophthalmol 1992 Apr-Jun;2(2):58-66

18. Safety and efficacy of topical norfloxacin versus tobramycin in the treatment of external ocular infections. Antimicrob Agents Chemother 1988 Dec;32(12): 1820-4

19. Treatment of acute bacterial conjunctivitis with topical lomefloxacin 0.3% compared to topical ofloxacin 0.3%. Eur J Ophthalmol 1999 Oct-Dec;9(4):269-75

20. The penetration of ofloxacin into human aqueous humor given by various routes. Eur J Ophthalmol 1998 Jan-Mar;8(1):33-6

21. Twice-a-day versus four-times-a-day ofloxacin treatment of external ocular infection. CLAO J 1998 Jan;24(1):48-51 22. Topical ofloxacin compared with gentamicin in the treatment of external ocular infection. Ofloxacin Study Group. Br J Ophthalmol 1992 Dec;76(12):714-8

23. Topical 0.3% ciprofloxacin, norfloxacin, and ofloxacin in treatment of bacterial keratitis: a new method for comparative evaluation of ocular drug penetration. Br J Ophthalmol 1995 Jun;79(6):606-9

24. Treatment of acute bacterial conjunctivitis with topical lomefloxacin 0.3% compared to topical ofloxacin 0.3%. Eur J Ophthalmol 1999 Oct-Dec;9(4) : 269-75.

25. The ocular penetration of oral Sparfloxacin in humans. Am J Ophthalmol 1994 Mar 15;117(3):332-7

Results:

26. Penetration of topically applied ciprofloxacin, norfloxacin, and ofloxacin into the aqueous humor.

Ophthalmology 1994 May;101 (5); 902-5.

27. Penetration of ofloxacin and ciprofloxacin in aqueous humor after topical administration.

Ophthalmic Surg Lasers 1999 Jun;30(6):465-8

28. Bactericidal kinetics and postantibiotic effect of Sparfloxacin against selected species of respiratory pathogens. J Chemother 1995 Dec; 7(6):530-4.

29. Relationship between the sensitivity of Pseudomonas aeruginosa and the post- antibiotic effect of sparfloxacin and ciprofloxacin Rev Esp Quimioter 1998 Dec;11(4):333-8

Results :

The MIC of sparfloxacin and ciprofloxacin ranged from 0.25-256 mg/ml and from 0. 25- 128 mg/ml, respectively. PAE values ranged from 46 8.71 to 59.6 2.51 min and from 46.33 15.2 to 62.6 3.70 min, respectively.

DESCRIPTION OF THE INVENTION

According to present invention is described a method of preparing isotonic topical antibiotic formulation with improved therapeutic effect.

The objective of the present invention is to provide a broad spectrum antibiotic formulation for topical use with improved therapeutic effect.

The further objective of the present invention is to provide a topical antibiotic formulation which penetrates the cornea.

Another objective of the present invention is to provide an antibiotic formulation which achieves tissue concentration much more above MIC for majority of organisms.

Another objective of the present invention is to provide a topical formulation which maintains therapeutic concentrations for a longer period of time.

As per the present invention it is found that Sparfloxacin drops made as per the description meet the requirement. As per the present invention it is observed that Sparfloxacin drops made as per the present invention achieves therapeutic concentration in the aqueous humor for more than 6 hours.

As per the present invention it is observed that preparation made as per the present invention achieves significantly higher tissue concentration compared to MIC. It is known that Sparfloxacin has effect on organism which is concentration dependent i.e. increasing tissue concentration is advantageous in killing of organisms.

It is also known that Sparfloxacin has significantly more post-antibiotic effect which prolongs the duration of action (pharmacodynamic effect).

It is also known that Sparfloxacin is not readily soluble.

As per the present invention it is found that: sparfloxacin eye drops has a better therapeutic effect due to low MIC, higher Cmax resulting into higher therapeutic index. As per the present invention it is found that:

1. Sparfloxacin is soluble in lactic acid, ascorbic acid and lactobionic acid.

2. Amber coloured glass container is suitable for storage of Sparfloxacin.

3. The container is not to be stored in deep freeze.

4. The three reagents mentioned (lactic acid, ascorbic acid and lactobionic acid) can be used for solubilisation of Sparfloxacin.

5. Sparfloxacin is incompatable with potassium chloride and sodium chloride.

6. Propylene glycol and beta-cyclodextrin are to be used for formation of complex with sparfloxacin.

7. Mannitoi and dextrose can be used for adjusting isotonicity.

The follwing is one of the examples for preparing Sparfloxacin isotonic topical ophthalmic formulation with improved therapeutic effect as per the present invention: EXAMPLE 1 :

1. gterile environment is maintained throughout the process. Exposure to light is avoided during the process.

2. The weight of all the ingredients are checked as per the formulation sheet.

3. Sparfloxacin is micronized.

4. Uniform suspension of Sparfloxacin is maintained in sufficient amount of water for injection.

5. Lactic acid is added in drops to get a clear solution.

6. The above solution is checked for pH.

7. HPMC, disodium EDTA and beta-cyclodextrin are added separately and dissolved in water for injection.

8. Mannitoi is added to make solution isotonic. The formulation, prepared as per the present invention, is a light yellow coloured clear solution, with pH between 3.5 to 5.5.

The formulation so prepared is isotonic and well tolerated in animal studies.

The formulation is also stable over a period of more than 2 years.

The formulation prepared as per the present invention was subjected to pharmacokinetic studies.

Ocular penetration of the formulation has been studied following instillation of 1 drops of 0.3% eye drops in the conjunctival sac over a period of 6- hours. After 15 minutes, Sparfloxacin levels in aqueous humor was found to be 1.4 meg / ml. Maximum concentrations of 3.7 meg / ml was found at 1 hour and the levels were maintained above 1 meg / ml for upto 4-hours. Elimination half-life of the drug in the aqueous humor was 1.84 hours (see figure).

The topical ophthalmic antibiotic formulation made as per the present invention, has better ocular penetration. Cmax of sparfloxacin is 3.7 mcg/ml which is 2.51 times than ofloxacin, 10.57 times than ciprofloxacin. Such a high Cmax of sparfloxacin due to better ocular penetration gives it an advantage over other quinolones.

'max OF VARIOUS F UROQUINOLONES

Therapeutic efficacy of antibiotic depends on its therapeutic index along with other factors. Sparfloxacin has therapeutic index which is more than 20 times for Staph. aureus compared to other quinolones. Staphylococcus is the commonest pathogen for external ocular disease. The comparison also reveals that sparfloxacin has therapeutic index which is higher (significantly) than any other antibiotic.

Cm_ax /MIC (Therapeutic Index)

Thus, the topical preparation of Sparfloxacin made as per the present invention provides preparation with better therapeutic efficacy.

CLINICAL EVALUATION OF PRESENT INVENTION:

Topical ophthalmic antibiotic made as per the present invention, was clinically evaluated in patients with corneal ulcers, keratitis and conjunctivitis.

CONJUCTIVITIS:

Total No. of Eyes with bacterial Conjunctivitis : 76 eyes, 50 patients

Bilateral : 26

Unilateral : 24

Bacteriological Profile : Of 76 eyes 66 grew staphylococci, 8 grew pneumococci, and 2 had diplococci. Clinical Response: Out of 76 eyes (50 patients), 75 (49 patients) (98.6%) responded to Sparfloxacin therapy and were cured clinically as well as microbiologically. One patient did not show any signs of improvement after ten days therapy and was shifted over to other therapy. The organism isolated was Staphylococcus. It was found resistant to all antibiotics tested like Cephalexin, Penicillin, Bactrim, Cefotaxime, Ampicillin, Cefadroxil, Amoxicillin, Lincomycin and Cloxacilin.

KERATITIS : (Total - 17 Patients)

Biological Profile : Of 17 eyes 12 grew staphylococci, 3 grew pneumococci and 2 had mixed infection.

Clinical Response :

One Patient withdrawn due to allergic reaction on 1 St day of therapy.

All 16 patients (100%) (excluding the patient who discontinued ) who completed the trial responded to the therapy and got cured. The Mean Cure Period was found to be 2.84 days.

CORNEAL ULCER : (Total - 46 Patients)

Biological Profile : Of 46 patients with corneal ulcer 33 grew staphylococci, 2 grew pneumococci, 3 had mixed infection and 8 grew no organism.

Clinical Response :

All 46 patients (100%) (excluding the^" patient who diagnosed as fungal ulcer) who completed the trial responded to the therapy. The Mean Cure Period was found to be 7.12 days.

Comparative Efficacy of various fluoroquinolones :

The 98.68% cure rate with the present invention compares favourably with other antibiotics and is better than cure rate obtained with other quinolones (Table above).

Keratitis:

The cure rate of 100% is a much desirable and was achieved in this trial of Sparfloxacin. This is much better than those obtained with other quinolones (Table above).

Corneal ulcer:

The bacteriological profile comprised mainly Staph. aureus. The 100% cure rate is a much desired outcome and is much better than success rate with other quinolones e.g. 70-92% for ciprofloxacin, 80-80% for norfloxacin and 85-93% for ofloxacin (Table above).

Such a high success rate (better therapeutic effect) seen with Sparfloxacin eye drops as per the present invention is desirable but has not been described for any other topical ophthalmic antibiotic.

Claims

I claim:

1. The process for preparing isotonic topical antibiotic ophthalmic formulation, with improved therapeutic effect, comprising steps of: a) making uniform suspension of the antibiotic in sufficient amount of water, b) adding solvent to get a clear solution, c) checking the pH of the above solution, d) adding the excipients, e) adding tonicity agent to adjust the tonicity of the solution, f) filtering the bulk through 0.2 μm membrane filter.

2. The process as claimed in claim 1 wherein the antibiotic is Sparfloxacin.

3. The process as claimed in claims 1 to 2 wherein the solvent used can be lactic acid, ascorbic acid, lactobionic acid and the like.

4. The process as claimed in claims 1 to 3 wherein the solvent is lactic acid.

5. The process as claimed in claim 1 whrein the excipients are HPMC, disodium EDTA and Beta-cyclodextrin.

6. The process as claimed in claims 1 to 4 wherein the pH of the solution is between 3.5-5.5.

7. The process as claimed in claim 1 to 6 wherein the tonicity agent is mannitoi or dextrose.

8. The process as claimed in claim 1 and herein described in example 1.