Title of Invention

AN OPHTHALMIC PHARMACEUTICAL PREPARATION

Abstract

The invention consists of a stable ophthalmic pharmaceutical preparation, comprising of an anti inflammatory agent and an anti-infective agent. The anti-inflammatory agent in this invention is a corticosteroid , and the anti-infective agent is a derivative of quinolone , amino-glycoside or their pharmaceutically acceptable salts. The pharmaceutical preparation essentially comprises of i. An anti-inflammatory agent which is a corticosteroid, ii. An anti-infective agent selected from the group comprising of derivatives of quinolone, aminoglycoside and their pharmaceutically acceptable salts; iii.) a Complexation enhancing polymer; iv) a solubiliser exhibiting an inclusion phenomenon, and contained in the ratio of 1M:2M to 1M:6M of steroid to solubiliser, along with pharmaceutically acceptable excipients with a suitable carrier system, together resulting in. To

Full Text

FORM 2 THE PATENTS ACT 1970 (39 OF 1970) (Under Section 10) COMPLETE SPECIFICATION Title: An Ophthalmic Pharmaceutical preparation Applicants: FDC LIMITED , and Indian Company incorporated within the meaning of the Company's Act 1956, and having their registered address at B,8, M.I.D.C Industrial Area, Waluj, Maharashtra 431135, India The following specification particularly describes and ascertains the nature of the invention: Field of Invention: The invention relates to an Ophthalmic Pharmaceutical preparation comprising of anti- inflammatory agents in the nature of steroids and an anti- infective agent. Back ground of invention*. Anti-infective agents in the form of antibacterial agents and anti-inflammatory agents in the nature of steroids, have been used in combination for effective control of infection and inflammation. Use of such combination drugs of appropriate antibacterial agents and steroids helps in increasing patient compliance to therapy as it reduces the number of instillation of different drugs. This is specially true in the case of ophthalmic treatment, when the number of instillation of drugs requires to be minimal. Not only is a combination of steroid and antibacterial agents desirable, but it is also essential that the combination when required for ophthalmic purposes is available as a clear formulation, either as a solution or a gel. In formulations, for ophthalmic treatment, a clear formulation is highly desirable, because any formulation in suspension form causes irritation to the eye, as well as causes crust formation around the eye. The U.S. Patent No.5472954 describes a process by which the solubility of lipophilic or sparingly soluble active ingredients (drug/ cosmetic/ agrochemical) is increased by complexing with different derivatives of cyclodextrin. This patent only describes a process by which a single active ingredient can be made soluble by complexing it with cyclodextrin derivatives. In post operative ophthalmic treatment, where in a combination therapy of antibiotic or antibacterial and anti- inflammatory agent is used, a clear formulation is highly desired. Even in non-operative cases ophthalmic preparations in clear formulation is preferred to a suspension, as a preferred line of treatment, as it increases the physical and physiological acceptance of the medication. Ciprofloxacin, which is a quinolone derivative, and a broad spectrum antibacterial, and considered a 'standard' for the treatment of ocular bacterial infections is currently available in local markets in combination with the steroid dexamethasone in a suspension form. In addition U.S. Patent No: 6,284,804 describes a suspension formulation containing dexamethasone and ciprofloxacin together with a non-ionic polymer, non-ionic surfactant and an ionic tonicity agent. Though the above combination is known to be effective against most ocular pathogens, it is not preferred for use in post- operative cases, because it is currently available only in suspension form. An instillation of a drug in suspension form results in crust formation around the eye causing a foreign bodylike feeling in the eye and irritation. Steroids are generally sparingly soluble in aqueous solution which is the reason for most anti-infective agent / steroid combinations being available in suspension form. The antibiotic and the steroid in the form of their salts are individually available as a clear solution, but the combination, does not give a stable clear solution. On standing turbidity appears in the mixture of antibiotic steroid solution. Further a mere admixture of antibacterial agent in clear solution and the steroid in clear solution, usually results in the crystallization of the antibacterial because of the higher pH used to dissolve the steroid, and the steroid itself degrades in a short time when mixed with the antibacterial. The present invention describes for the first time an Ophthalmic pharmaceutical preparation of a steroid and antibacterial, where in the activity and bio efficacy of the antibacterial and steroid are not in anyway hampered or affected. The invention also provides for the preparation of the combination drug in a clear solution or clear gel form, and is particularly ideal for ophthalmic treatment. The clear solution or clear gels of antibacterial and steroid, would be specially suitable as a preferred form of drug administration in post operative ophthalmic cases. SUMMARY: In its main aspect the invention consists of a stable preparation of an Ophthalmic pharmaceutical preparation, comprising of an anti inflammatory agent and an anti-infective agent. The anti-inflammatory agent in this invention is a corticosteroid , and the anti-infective agent is a derivative of quinolone , amino-glycoside or their pharmaceutically acceptable salts. The combination drug essentially comprises of i.)An anti-inflammatory agent which is a corticosteroid, ii) An anti-infective agent selected from the group comprising of derivatives of quinolone, aminoglycoside and their pharmaceutically acceptable salts; iii.) a Complexation enhancing polymer; iv) a solubiliser exhibiting an inclusion phenomenon, along with pharmaceutically acceptable excipients with a suitable carrier system. In a more important aspect of this invention, the steroid and solubiliser are in the ratio of 1M:2M (O.lg/lOOml: 0.5675g/100ml corresponding to 0.00025: 0.00050 moles the ratio being 1M:2M.) to 1M:6M (0.1 g/100 ml: 1.7025g/100ml corresponding to 0.00025 : 0.0015 moles the ratio being 1M:6M) In another aspect, this invention consists of a stable pharmaceutical preparation, which is a combination drug of a corticosteroid from the group consisting of fluorometholone, dexamethasone, Beta-methasone, corticosterone, prednisolone, and their derivatives essentially having a common nuclear structure Pregna -1, 4 - diene -3,20 dione. The anti-infective agents are selected from the group consisting of ciprofloxacin, norfloxacin, ofloxacin, sparfloxacin, tobramycin, gentamicin and their pharmaceutically acceptable derivatives and salts. In a further aspect of this invention, the solubiliser is selected from the group consisting of cyclodextrin and its derivatives preferably Beta cyclodextrin, and the complexation enhancing polymer used is selected from the group consisting of non-ionic polymers like polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose or HPMC (hydroxy propyl methyl cellulose) or hydroxy ethyl cellulose. DESCRIPTION A. brief description of the invention is as follows: In its main embodiment, the invention consists of an Ophthalmic pharmaceutical preparation, comprising of i. Anti-inflammatory agents which are corticosteroids; ii.Anti-infective agents from the group consisting of quinolone derivatives, aminoglycoside derivatives and their pharmaceutically acceptable salts; iii. A complexation enhancing polymer; and iv) a solubiliser exhibiting an inclusion phenomenon, v) phannaceutically acceptable excipients in a carrier system. The above together gives a clear stable solution.. The process of manufacturing this ophthalmic pharmaceutical preparation consists of the following steps: i. Including the steroid within a solubiliser which exhibits an inclusion phenomena, to form a solubiliser steroid blend. The steroid and solubiliser are taken in desired amounts and mixed thoroughly in a polybag to form a blend. The ratio in which the steroid and solubilizer are taken depends on the steroid and the anti-infective agent used. The steroid and solubiliser are usually taken in the in the ratio of 1M:2M (O.lg/lOOml: 0.5675/l00ml corresponding to 0.00025: 0.00050 moles the ratio being 1M:2M.) to 1M:6M (0.1 g/100 ml: 1.7025g/100ml corresponding to 0.00025 : 0.0015 moles the ratio being 1M:6M ). The solubiliser used is cyclodextrin or its derivatives, preferably Beta cyclodextrin. The use of Beta cyclodextrin makes this process cost effective. ii. Dispersing or dissolving the anti-infective agent in a suitable solvent preferably water. The solvent and anti-infective agent are stirred to form a slurry. The complexation enhancing polymer solution is added to the slurry and sufficient water is further added and stirred for 10 to 30 minutes to form a clear anti-infective agent polymer solution. Dispersion is usually carried out at a temperature between 20° to 50° C, preferably ambient temperature. The solution is maintained at a pH range between 4 to 7. iii. Controlled addition of anti-infective agent polymer solution to steroid solubiliser blend with constant stirring to form a water soluble complex of anti-infective agent-steroid -polymer and solubiliser. The addition can even be done at room temperature. The clarity of the final solution is dependant on the crucial ratio of the anti-infective agent polymer solution to the steroid-solubiliser blend. The ratio depends upon the type of anti-infective agent and anti-inflammatory agent used. If the ratio is disturbed the clarity of the final solution is affected. The complexation usually occurs within 30 minutes. The complex formed is stable up to a temperature of 50°C. iv. Incorporating the complex in a carrier system. The complex may be incorporated together with suitable excipients, in water , ointment base or a gel, depending upon the final purpose of its use. The complex when dissolved in water or gel, along with excipients, forms a clear stable solution and clear stable gel respectively, which is very suitable for ocular treatment. The excipients used are benzalkonium chloride as preservative, disodium EDTA as chelating agent, mono or dibasic sodium phosphate as a buffering agent, and sodium chloride as tonicity adjustor. In respect of gel preparations sorbitol is used as tonicity adjustor. In its preferred embodiment the steroids used are selected from the group having a general nuclear structure Pregna - 1, 4 - diene - 3, 20 dione which could be dexamethasone, fluorometholone, Betamethasone, corticosterone, prednisolone and such others . The anti-infective agents are selected from the group consisting of derivatives of Ciprofloxacin, , Ofloxacin, sparfloxacin, Norfloxacin, Tobramycin sulphate, gentamicin sulphate and their pharmceutically acceptable salts. The following examples specifically describe the various combination drugs and the process for the different combinations of steroids and anti-infective agents used in the various carrier systems. MANUFACTURING PROCESS OF THE EYE DROF'S: Example : 1 Steroid - Dexamethasone Anti-infective agent - Ciprofloxacin Hydrochloride 1. 0.1 % of Dexamethasone and 1 % of Betacyclodextrin are accurately weighed. 2. Betacyclodextrin and Dexamethasone are blended thoroughly for 5 minutes. 3. 0.35% of Ciprofloxacin Hydrochloride is dispersed in water and stirred for 5 minutes to form a slurry 4. 1 % of Polyvinyl alcohol solution is slowly added as a complexation enhancing agent. Sufficient water is added and stirred for 10-30 minutes to form a clear solution. 5. Blend of solubiTized Dexamethasone and Betacyclodextrin are gradually added to Step No. 4 by stirring it for 10-30 minutes. 6. 0.0005% of Sodium Phosphate is added to Step 5 as a buffering agent and stirred for 5 minutes. 7. 0.1% of Disodium Edetate is added to Step No. 6 as a chelating agent. 8. 0.01% of Benzalkonium Chloride is added as a preservative to Step No. 7. 9. 0.8% of Sodium Chloride is added to Step No. 8 as a tonicity adjustor. 10. The solution is stirred for 10 minutes and pH of the solution is checked. Sodium Hydroxide solution is used to adjust the pH of solution between 4.5 and 5.0. * All the steps from 1 to 9 are carried out in class 100 area. 11. The solution is filtered through 0.2 n filter to get a sterile ophthalmic solution. The solution is filled in a suitable container. Example : 2 Steroid - Dexamethasone Anti-infective agent - Tobramycin Sulphate 1. 0.1% of Dexamethasone and 1% of Betacyclodextnn are accurately weighed. 2. Betacyclodextrin and Dexamethasone are blended thoroughly for 5 minutes. 3. 0.3% of Tobramycin Sulphate is dispersed in water and stirred for 5 minutes to form a slurry 4. 1% of Polyvinyl alcohol solution is slowly added as a co-compiexing agent. Sufficient water is added and stirred for 10-30 minutes to form a clear solution. 5. Blended solublized steriod of Dexamethasone and Betacyclodextrin are gradually added to Step No. 4 by stirring it for 10-30 minutes. 6. 0.0005% of Sodium Phosphate is added to Step 5 as a buffering agent. 7. 0.1% of Disodium Edetate is added to Step No. 6 as a chelating agent. 8. 0.01% of Benzalkonium Chloride is added as a preservative to Step No. 7. 9. 0.8% of Sodium Chloride is added to Step No. 8 as a tonicity adjustor. 10. The solution is stirred for 10 minutes and pH of the solution is checked. Sodium Hydroxide solution is used to adjust the pH of solution between 7.0 and 7.5. * All the steps from 1 to 9 are carried out in class 100 area. 11. The solution is filtered through 0.2 x filter to get a sterile ophthalmic solution. The solution is filled in a suitable container. Example : 3 Steroid - Dexamethasone Anti-infective agent - Ofloxacin 1. 0.1% of Dexamethasone and 1% of Betacyclodextrin are accurately weighed. 2. Betacyclodextrin and Dexamethasone are blended thoroughly for 5 minutes. 3. 0.3% of Ofloxacin is dispersed in water and stirred for 5 minutes to form a slurry 4. 1% of Polyvinyl alcohol solution is slowly added as a co-complexing agent. Sufficient water is added and stirred for 10-30 minutes to form a clear solution. 5. Blend of solublized Dexamethasone and Betacyclodextrin is gradually added to Step No. 4 by stirring it for 10-30 minutes. 6. 0.0005%) of Sodium Phosphate is added to Step 5 as a buffering agent and stirred for 5 minutes. 7. 0.1% of Disodium Edetate is added to Step No. 6 as a chelating agent. 8. 0.01%) of Benzalkonium Chloride is added as a preservative to Step No. 7. 9. 0.8%) of Sodium Chloride is added to Step No. 8 as a tonicity adjustor. 10. The solution is stirred for 10 minutes and pH of the solution is checked. Sodium Hydroxide solution is used to adjust the pH of solution between 6.5 and 7. * All the steps from 1 to 9 are carried out in class 100 area. 11. The solution is filtered through 0.2 x filter to get a sterile ophthalmic solution. The solution is filled in a suitable container. Example : 4 MANUFACTURING PROCESS OF EYE DROPS Steroid - Dexamethasone Anti-infective agent - Sparfloxacin 1. 0.1% of Dexamethasone and 1% of Betacyclodextnn are accurately weighed. 2. Betacyclodextrin and Dexamethasone are blended thoroughly for 5 minutes. 3. 0.3% of Sparfloxacin is dispersed in water and stirred for 5 minutes to form a slurry 4. 1% of Polyvinyl alcohol solution is slowly added as a complexing agent Sufficient water is added and stirred for 10-30 minutes to form a clear solution. 5. Blended solubilized steriod of Dexamethasone and Betacyclodextrin are gradually added to Step No. 4 by stirring it for 10-30 minutes. 6. 0.0005% of Sodium Phosphate is added to Step 5 as a buffering agent and stirred for 5 minutes. 7. 0.1% of Disodium Edetate is added to Step No. 6 as a chelating agent. 8. 0.01% of Benzalkonium Chloride is added as a preservative to Step No. 7. 9. 0.8% of Sodium Chloride is added to Step No. 8 as a tonicity adjustor. 10. The solution is stirred for 10 minutes and pH of the solution is checked. Sodium Hydroxide solution is used to adjust the pH ; * All the steps from 1 to 9 are carried out in class 100 area. 11. The solution is filtered through 0.2 n filter to get a sterile ophthalmic solution. The solution is filled in a suitable container. Example: 5 MANUFACTURING PROCESS OF EYE DROPS Steroid - Dexamethasone Anti-infective agent - Gentamicin Sulphate 1. 0.1 % of Dexamethasone and 1 % of Betacyclodextrin are accurately weighed. 2. Betacyclodextrin and Dexamethasone are blended thoroughly for 5 minutes. 3. 0.3% of Gentamicin Sulphate is dispersed in water and stirred for 5 minutes to form a slurry 4. 1% of Polyvinyl alcohol solution is slowly added as a co-complexing agent. Sufficient water is added and stirred for 10-30 minutes to form a clear solution. 5. Blend of solublized Dexamethasone and Betacyclodextrin is gradually added to Step No. 4 by stirring it for 10-30 minutes. 6. 0.0005% of Sodium Phosphate is added to Step 5 as a buffering agent and stirred for 5 minutes. 7. 0.1% of Disodium Edetate is added to Step No. 6 as a chelating agent. 8. 0.01% of Benzalkonium Chloride is added as a preservative to Step No. 7. 9. 0.8% of Sodium Chloride is added to Step No. 8 as a tonicity adjustor. 10. The solution is stirred for 10 minutes and pH of the solution is checked. Sodium Hydroxide solution is used to adjust the pH of solution between 4.5 and 5.0. * All the steps from 1 to 9 are carried out in class 100 area. 11. The solution is filtered through 0.2 x filter to get a sterile ophthalmic solution. The solution is filled in a suitable container. Example 6: MANUFACTURING PROCESS OF EYE DROPS Steroid : Dexamethasone Anti-infective Agent: Norfloxacin 1. Accurately weigh 0.1% of Dexamethasone and 1% of Betacyclodextrin . 2. Blend thoroughly Betacyclodextrin and Dexamethasone for 5 minutes. 3. Disperse 0.3% of Norfloxacin in water to form a slurry and stir for 5 minutes. 4. Add 1% of Polyvinyl alcohol solution as a complexing agent slowly. Add sufficient water and stir for 10 - 30 minutes to form a clear solution. 5. Add solubilized steroid blend of Dexamethasone and Betacyclodextrin to Step No. 4 gradually under stirring for 10 - 30 minutes. 6. Add 0.0005% Sodium Phosphate as a buffering agent to Step No. 5 and stir for 5 minutes, 7. Add 0.1% of Disodium Edetate in Step No. 6 as chelating agent. 8. Add 0.01% of Benzalkonium Chloride as preservative in Step No. 7. 9. Add 0.8% of Sodium Chloride in Step No. 8 as a tonicity adjustor. 10. Stir the solution for 10 minutes and check pH of the solution. Adjust the pH of solution between 4.5 to 5.0 using Sodium Hydroxide solution. * Carry out all the steps 1 to 9 in class 100 area. 11. Filter the solution through 0.2 x filter to get a sterile ophthalmic solution. Fill the solution in suitable container. Example 7: MANUFACTURING PROCESS OF EYE DROPS Steroid; Dexamethasone Anti-infective Agent: Ciprofloxacin Polymer: Polyvinyl Pyrollidone (PVP) 1. Accurately weigh . 1 % of Dexamethasone and 1 % of Betacyclodextrin. 2. Blend thoroughly Betacyclodextrin and Dexamethasone for 5 minutes. 3. Disperse 0.35% of Ciprofloxacin Hydrochloride in water to form a slurry and stir for 5 minutes. Add 1% of Polyvinyl Pyrollidone (PVP) solutions as a co-complexing agent slowly. Add sufficient water and stir for 10-30 minutes to form a clear solution. 5. Add solubilized blend of Dexamethasone and Betacyclodextrin to Step No.4 gradually under stirring for 10-30 minutes. 6. Add 0.0005% Sodium Phosphate as a buffering agent to Step No.5 and stir for 5 minutes. 7. Add 0.1% of Disodium Edetate in Step No.6 as chelating agent. 8. Add 0.01% of Benzalkonium Chloride as preservative in Step No.7 9. Add 0.8% of Sodium Chloride in Step No.8 as a tonicity adjustor. 10. Stir the solution for 10 minutes and check pH of the solution. Adjust the pH of solution between 4.5 to 5.0 using Sodium Hydroxide solution. • Carry out all the steps 1 to 9 in class 100 area. 11. Filter the solution through 0.2 u filter to get a sterile ophthalmic solution. Fill the solution in suitable container. MANUFACTURING PROCESS OF OPHTHALMIC GEL: Example : 8 Steroid - Dexamethasone Anti-infective agent - Ciprofloxacin Hydrochloride 1. 0.1% of Dexamethasone and 1% of Betacyclodextrin are accurately weighed. 2. Betacyclodextrin and Dexamethasone are blended thoroughly for 5 minutes. 3. 0.3% of Ciprofloxacin Hydrochloride is dispersed in water to form a solution and stirred for 5 minutes. 4. Blend of solublized Dexamethasone and Betacyclodextrin is gradually added by stirring it for 10-30 minutes. 5. 0.01% of Benzalkonium Chloride is dissolved as a preservative in hot water and added to Step No. 4. 6. The solution of step 5 is filtered through 0.2 u membrane filter and given a wash with water. 7. HPMC 2% is dispersed as viscofying agent in hot water with continuous stirring till a uniform gel without any lumps formatioa 8. 12% of sorbitol is added to Step 6 as tonicity adjuster / Humactant under constant stirring. 9. The gel is autoclaved at 121° C for about 15 minutes. 10. The autoclaved gel is aseptically mixed (at room temperature) with the solution from Step 6 under continuous stirring till clear gel forms. MANUFACTURING PROCESS OF OPHTHALMIC GEL: Example: 9 Steroid - Dexamethasone Anti-infective agent - Tobramycin Sulphate 1. 0.1% of Dexamethasone and 1% of Betacyclodextrin are accurately weighed. 2. Betacyclodextrin and Dexamethasone are blended thoroughly for 5 minutes. 3. 0.3% of Tobramycin Sulphate is dispersed in water to form a solution and stirred for 5 minutes. 4. Blend of solublized Dexamethasone and Betacyclodextrin is gradually added by stirring it for 10-30 minutes. 5. 0.01% of Benzalkonium Chloride is dissolved as a preservative in hot water and added to Step No. 4. 6. The solution of step 5 is filtered through 0.2 \x membrane filter and given a wash with water. 7. HPMC 2% is dispersed as viscofying agent in hot water with continuous stirring till a uniform gel without any lumps formation. 8. 12% of sorbitol is added to Step 6 as tonicity adjuster / Humactant under constant stirring. 9. The gel is autoclaved at 121° C for about 15 minutes. 10. The autoclaved gel is aseptically mixed (at room temperature) with the solution from Step 6 under continuous stirring till clear gel forms. WE CLAIM: 1. An ophthalmic pharmaceutical preparation, comprising amongst others of: (i) An anti-infective agent, selected from the group consisting of quinolone derivatives, amino-glycoside derivatives and their pharmaceutically acceptable salts; (ii) An ant-inflammatory agent which is a corticosteroid; (iii) A complexation enhancing polymer ; (iv) A solubilizer exhibiting an inclusion phenomena, and added in the ratio of 1M:2M to 1M;6M of steroid is to solubiliser; (v) pharmaceutically acceptable excipients within a suitable carrier system; together resulting in a clear stable non-turbid solution. 2. A preparation as claimed in claim 1, where in the steroid has a common nuclear structure Pregna-1, 4-diene-3, 20 dione. 3. A preparation as claimed in claim 2, where in the anti-inflammatory agent is a corticosteroid selected from the group consisting of fluorometholone, Beta Methasone, prednisolone, dexamethasone and their derivatives; 4. A preparation as claimed in claim 3 where in the anti-infective agent is a quinolone derivative selected from the group consisting of ciprofloxacin, norfloxacin, ofloxacin, sparfloxacin and their pharmaceutically acceptable salts. 5. A preparation as claimed in claim 4, where in the anti-infective agent is a aminoglycoside derivative selected amongst tobramycin, gentamicin and its pharmaceutically acceptable salts, preferably sulphates. 6. A preparation as claimed in claim 5, where in the polymer solution is polyvinyl alcohol , polyvinyl pyrrolidone, methyl cellulose, hydroxyethyl cellulose or HPMC (hydroxy propyl methyl cellulose). 7. A preparation as claimed in claim 6, where in the solubiliser is cyclodextrin or its derivatives preferably Beta cyclodextrin. 8. A preparation as claimed in claim 7, where in the preparation is incorporated in a carrier system consisting of water and excipients resulting in a clear stable solution for ocular treatment 9. A preparation as claimed in claim 7 where in the preparation is incorporated in a carrier having gelling polymer, and excipients resulting in a clear stable gel. 10. A preparation as claimed in claim 7 where in the preparation is incorporated in a carrier consisting of hydrophobic ointment base and excipients 11. A preparation as claimed in claim 8, 9and 10 where the excepients used are a buffering agent, chelating agent, preservative and a tonicity adjuster. 12. A preparation as claimed in claim 11, where in the excipients are benzalkonium choride as preservatives, Edetate disodium (EDTA) as chelating agent, mono or dibasic sodium phosphate as a buffering agent and sodium chloride as tonicity adjuster, all in pharmaceutically acceptable concentrations. 13. A preparation as claimed in claim 12 , where in the carrier system is water and the sodium chloride is in amounts sufficient to cause the composition to have an osmolality of about 270 -320 mOSM. 14. A preparation as claimed in claim 13 , where in the concentrations of the anti-infective agent ranges from 0.3% to 0.5% wt by volume and steriod ranges from 0.1% to 0.3% wt by volume in the final preparation. Dated this 2nd day of November 2001

Documents:

1077-mum-2001-abstract(10-1-2006).doc

1077-mum-2001-abstract(10-1-2006).pdf

1077-mum-2001-abstract(9-11-2001).pdf

1077-mum-2001-abstract(amended)-(10-1-2006).pdf

1077-mum-2001-abstract(granted)-(24-4-2007).pdf

1077-mum-2001-abstract.doc

1077-mum-2001-abstract.pdf

1077-mum-2001-cancelled pages(10-1-2006).pdf

1077-mum-2001-claims(9-11-2001).pdf

1077-mum-2001-claims(granted)-(10-1-2006).doc

1077-mum-2001-claims(granted)-(10-1-2006).pdf

1077-mum-2001-claims(granted)-(24-4-2007).pdf

1077-mum-2001-claims.doc

1077-mum-2001-claims.pdf

1077-mum-2001-correspondence(10-1-2006).pdf

1077-mum-2001-correspondence(ipo)-(28-6-2007).pdf

1077-mum-2001-correspondence(ipo)-(30-8-2005).pdf

1077-mum-2001-correspondence(ipo).pdf

1077-mum-2001-correspondence.pdf

1077-mum-2001-description(complete)-(9-11-2001).pdf

1077-MUM-2001-DESCRIPTION(GRANTED)-(24-4-2007).pdf

1077-mum-2001-description(granted).doc

1077-mum-2001-description(granted).pdf

1077-mum-2001-esp document.pdf

1077-mum-2001-form 1.pdf

1077-mum-2001-form 18.pdf

1077-mum-2001-form 2(cancelled)-2-nov-2001.pdf

1077-mum-2001-form 2(complete)-(9-11-2001).pdf

1077-mum-2001-form 2(granted)-(10-1-2006).doc

1077-mum-2001-form 2(granted)-(10-1-2006).pdf

1077-MUM-2001-FORM 2(GRANTED)-(24-4-2007).pdf

1077-mum-2001-form 2(granted).doc

1077-mum-2001-form 2(granted).pdf

1077-mum-2001-form 2(title page)-(9-11-2001).pdf

1077-mum-2001-form 2(title page)-(granted)-(24-4-2007).pdf

1077-mum-2001-form 2(title page).pdf

1077-mum-2001-form 26.pdf

1077-mum-2001-form 3(10-1-2006).pdf

1077-mum-2001-form 3(2-11-2001).pdf

1077-mum-2001-form 3.pdf

1077-mum-2001-form 5(10-1-2006).pdf

1077-mum-2001-form 5.pdf

1077-mum-2001-specification(amended)-(10-1-2006).pdf