Title of Invention

"PROCESS FOR PREPARING OPHTHALMIC COMPOSITION EFFECTIVE AGAINST PATHOGENIC MICROBES"

Abstract

Prolonged use of ophthalmic composition containing Levofloxacin alone has been found to be associated with a number of disadvantages like over-growth of non-susceptible organism, elevation of plasma concentration of theophylline, interference with the metabolism of caffeine, transient elevations in serum creatinine, etc. The present invention aims at overcoming the aforementioned drawbacks and provides a process for preparing an ophthalmic composition comprising a fluoroquinolone derivative "Levofloxacin" hemihydrate and Hydroxypropylmethylcellulose (IP), the combination of which shows enhanced action against pathogenic microbes characterized in that the above ingredients are admixed in the form their aqueous solutions in the following amounts :

Full Text

-2 - The present invention relates to a process for preparing ophthalmic composition in solution form effective against pathogenic microbes. More particularly, this invention relates to a process for preparing an ophthalmic composition having Levofloxacin as the active ingredient for treating a wide range of bacterial infections of the eyes. Levofloxacin is a fluoroquinolone antibacterial agent and is the L-isomer of another fluoroquinolone derivative, Ofloxacin. The optically active L-isomer, Levofloxacin, has been found to posses twice the activity of the racemate, Ofloxacin, and has pronounced bactericidal activity. Levofloxacin has greater solubility in water around pH7 in comparison to Ofloxacin and hence ophthalmic solution containing this compound can be produced with a higher active concentration ( 0.5 %) compared to other fluoroquinolones like Ofloxacin (0.3 %). Levofloxacin has been in use for sometime under the brand name "QUIXIN" in concentration of 0.5 % as a sterile topical ophthalmic solution. This antibacterial active agent has been found to be effective against a broad spectrum of Gram-positive and Gram-negative ocular pathogens. US Patent No. 4,382,892 narrates the use of Levofloxacin in making ophthalmic solutions. However, prolonged use of ophthalmic composition containing Levofloxacin alone has been found to result in some cases overgrowth of non-susceptible organisms, including fungi. In some instances the systemic administration of this fluoroquinolone derivative has been shown to elevate plasma concentration of theophylline, interfere with the metabolism of caffeine, and enhance the effects of the oral anticoagulant warfarin and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving systemic cyclosporine concomitantly. SFD^DEfniE-l/PATtBT -3- The present invention aims at providing an ophthalmic composition which is substantially free from the aforementioned contra-indications and adverse physiological side effects. The principal object of this invention is to provide a process for preparing an ophthalmic composition in solution form effective against pathogenic microbodies. A further object of this invention is to provide a process for preparing an ophthalmic composition which hardly shows any adverse side effects on prolonged use, unlike the compositions containing Levofloxacin heretofore used. A still further object of this invention is to use a specific ingredient or additive which produces certain unforeseen effects in association with the optically active quinolone derivative Levofloxacin which render the composition safe and soothing. The foregoing objects are achieved by the present invention which provides a process for preparing an ophthalmic composition comprising a fluoroquinolone derivative Levofloxacin hemihydrate and Hydroxypropylmethylcellulose (IP), the combination of which shows synergistically enhanced action against pathogenic microbes. characterized in that Hydroxypropylmethylcellulose (IP) is dissolved in purified water and sterilized in an autoclave at a temperature between 115°C and 125°C for around 15 minutes and Levofloxacin hemihydrate is dissolved in purified water and mixed with Sodium Chloride of IP grade in an amount of around 0.6% w/v and the solution is sterilized, followed by mixing with the sterlie solution of Hydroxypropylmethylcellulose (IP) under asceptic condition, wherein the above ingredients are present in the final composition in the undernoted amounts : i) Levofloxacin hemihydrate - 0.5% w/v and ii) Hydroxypropylmethylcellulose (IP) - 0.25% w/v. ERWDS^nLE-U MTEITr _4 - Levofloxacin in the form of its hemihydrate is then separately dissolved in purified water and mixed with Sodium Chloride (IP) in an amount of around 0.6% w/v and the solution is sterized to give rise to (B). Sterile solutions (A) and (B) are mixed together under asceptic conditions to produce the desired ophthalmic composition. To obtain protection against UV light and also to enhance shelf-like it has found to be advantageous to include Benzalkonium Chloride in the composition in an amount varying between 0.01% - 0.02% w/v. Such inclusion is done in the solution of Levofloxacin hemihydrate and Sodium Chloride prior to sterilization and admixing with sterile solution of Hydroxypropylmethylcellulose. After mixing of the stelized solutions (a) and (b) under asceptic conditions, the PH of the final solution is adjusted to.a,yalue_between 6 and 7, preferably at around 6.7, by addition of 10% aqueous solution of acid, or alkali, followed by filtration asceptically through 1.2 u cartridge filter. The ingredient referred to above is hydroxypropyl methylcellulose (HPMC) or 'Hypromellose' which is a protective colloid that is useful as a dispersing and/ or thickening agent since its mucillages have greater clarity and usually contain fewer undispersed fibres. Ophthalmic composition prepared according to this invention using *HPMC have been found to posses lubricating and demulcent actions that provide relief from discomforts due to dry eye syndromes, exposure to wind or sun and other irritants, besides reducing redness and reflex lacrimation due to irritations. Hypromellose also ensures sustained medicameiht contacts and prolongs the actions of Levofloxacin. -5- The composition prepared by the subject process may optionally include a stabilizer like Benzalkonium Chloride. The invention will now be described by means of a working example which is given by way of illustration and not by way of limitation. Example. INGREDIENTS REQUIRED FOR 100 UTS CHARGE VOLUME : Levofloxacin Hemihydrate - 572 gms. (considering 10 % overage and water content) Sodium Chloride I.P. - 600 gms. Benzalkonium Chloride Solution I.P. - 20 ml. Hydroxypropylmethylcellulose I.P. (4000) - 250 gms. Purified water q.s. to make 100 lits. 1. In 20 Its purified water, 250 gms. of Hydroxypropylmethylcellulose (4000) is dissolved and sterilized in an autoclave at a temp, of arround 121°C for 15 minutes. The sterilised solution of HPML is then kept in a refrigerator for at least 24 hours at a temperature not exceeding 8°C. 2. In 65 Its purified water, 600 gms. Sodium Chloride and 572 gms. Levofloxacin Hemihydrate and 20 ml. Benzalkonium Chloride solution are dissolved by stirring with a mechanical stirrer. The solution is then sterilised by filtration through a 0.2 \i membrane filter. 3. No. (1) and No. (2) are mixed aseptically. 4. The volume is made upto 100 Its by adding purified water. 5. pH is adjusted to between 6 and 7, preferably at 6.7, by adding 10 % solution of Hydrochloric Acid or 10 % solution of Sodium Hydroxide. -6- 6. No. (5) is then filtered through a 1.2 micron cartridge filter aseptically. 7. The solution is then to be filled and sealed aseptically in preseterilised containers. 8. The filled quantity in each container will be 5.2 ml. and as such the theoretical filling quantity in each batch will be 19,230. approximately. 9. The filled containers are kept in quarantine for necessary testing i.e. chemical analysis and sterility test. 10. After getting the O.K. reports in respect of the above tests the vials/bottles are checked visually to ensure the absence of any particulate matter. 11. Checked vials/bottles are then labeled in an Automatic Sticker labelling Machine. 12. The individual labeled vials bottles are put in cartons alongwith the packing insert (leafelt, dropper, etc) if any. Levofloxacin opthalmic solution (0.5 %) is well tolerated and its concentration in tears remained above the minimum inhibitory concentration for most suspected opthalmic pathogens for at least 6 hours and in some cases upto 24 hours. With an active concentration of 0.5 % and powerful bactericidal properties the present opthalmic solution provides a new option for treating common eye infections caused by a wide range of Gram-positive bacteria including the most common pathogens, Staphyloccus aureus, Streptococcus aureus, Strepococcus pneumoniae and also Gram-negetive bacteria, such as Hemophilus influenzae. The composition is safe and efficacious in treating conjunctivitis even in paedriatic patients, and has a broad spectrum of in vitro activity against Gram-positive and Gram-negetive baGteria, as well as certain other pathogens such as Mycoplasma, Chlamydia, Legionella and Mycobacteria spp. - 7 - While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing or deviating from the spirit and scope of the invention. Thus the disclosure contained herein includes within its ambit the obvious equivalents and substitutes as well. Having described and illustrated the invention as hereinabove, it will now be more particularly defined by means of claims appended hereafter. SRD/DS/F1U 1/PATEKT -8- I claim : A process for preparing an ophthalmic composition comprising a fluoroquinolone derivative Levofloxacin hemihydrate and Hydroxypropylmethylcellulose (IP), the combination of which shows synergisticaUy enhanced action against pathogenic microbes, characterized in that Hydroxypropylmethylcellulose (IP) is dissolved in purified water and sterilized in an autoclave at a temperature between 115°C and 125°C for around 15 minutes and Levofloxacin hemihydrate is dissolved in purified water and mixed with Sodium Chloride of IP grade in an amount of around 0.6% w/v and the solution is sterilized, followed by mixing with the sterlie solution of Hydroxypropylmethylcellulose (IP) under asceptic condition, wherein the above ingredients are present in the final composition in the undernoted amounts : i) Levofloxacin hemihydrate - 0.5% w/v and ii) Hydroxypropylmethylcellulose (IP) - 0.25% w/v. 2. A process as claimed in Claim 1 wherein Benzalkonium Chloride solution (IP) is added to the solution of Levofloxacin hemihydrate and Sodium Chloride in an amount varying between 0.01% - 0.02% w/v prior to admixing with sterile solution of Hydroxypropylmethylcellulose (HPMC). 3. A process as claimed in Claims 1 and 2, wherein, pH0f the final solution is adjusted to a value between 6 and 7, preferably at around 6.7, by addition of 10% aqueous solution of acid or alkali, followed by filtration asceptically through 1.2 n cartridge filter. SRD/DS/Fli.B-1/PATENT -9- 4. A process for preparing an ophthalmic composition comprising a fluoroquinolone derivative Levofloxacin hemihydrate and Hydroxypropylmethylcellulose (IP), the combination of which shows enhanced action against pathogenic microbes substantially as hereinbefore described with particular reference to the appended Example. Prolonged use of ophthalmic composition containing Levofloxacin alone has been found to be associated with a number of disadvantages like over-growth of non-susceptible organism, elevation of plasma concentration of theophylline, interference with the metabolism of caffeine, transient elevations in serum creatinine, etc. The present invention aims at overcoming the aforementioned drawbacks and provides a process for preparing an ophthalmic composition comprising a fluoroquinolone derivative "Levofloxacin" hemihydrate and Hydroxypropylmethylcellulose (IP), the combination of which shows enhanced action against pathogenic microbes characterized in that the above ingredients are admixed in the form their aqueous solutions in the following amounts :

Documents:

00242-kol-2003-abstract.pdf

00242-kol-2003-claims.pdf

00242-kol-2003-correspondence.pdf

00242-kol-2003-description(complete).pdf

00242-kol-2003-description(provisional).pdf

00242-kol-2003-form-1.pdf

00242-kol-2003-form-18.pdf

00242-kol-2003-form-2.pdf

00242-kol-2003-form-3.pdf

00242-kol-2003-form-5.pdf

00242-kol-2003-letters patent.pdf