WO2023218472A1 - An aqueous ophthalmic solution of nsaids and fluoroquinolone antibiotic and process of preparation thereof - Google Patents
An aqueous ophthalmic solution of nsaids and fluoroquinolone antibiotic and process of preparation thereof Download PDFInfo
- Publication number
- WO2023218472A1 WO2023218472A1 PCT/IN2023/050005 IN2023050005W WO2023218472A1 WO 2023218472 A1 WO2023218472 A1 WO 2023218472A1 IN 2023050005 W IN2023050005 W IN 2023050005W WO 2023218472 A1 WO2023218472 A1 WO 2023218472A1
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- WO
- WIPO (PCT)
- Prior art keywords
- ophthalmic solution
- solution according
- present
- nepafenac
- ophthalmic
- Prior art date
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- 239000003306 quinoline derived antiinfective agent Substances 0.000 title claims abstract 4
- 239000002997 ophthalmic solution Substances 0.000 title claims description 51
- 229940054534 ophthalmic solution Drugs 0.000 title claims description 51
- 238000000034 method Methods 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title abstract description 7
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- QEFAQIPZVLVERP-UHFFFAOYSA-N nepafenac Chemical compound NC(=O)CC1=CC=CC(C(=O)C=2C=CC=CC=2)=C1N QEFAQIPZVLVERP-UHFFFAOYSA-N 0.000 claims abstract description 50
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- 230000003612 virological effect Effects 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000011576 zinc lactate Substances 0.000 description 1
- 235000000193 zinc lactate Nutrition 0.000 description 1
- 229940050168 zinc lactate Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 229960001296 zinc oxide Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
Definitions
- the present invention relates a pharmaceutical composition comprising a combination of a NSAIDs and an antibiotic for the treatment of diseases associated with multiple eye conditions.
- the present invention further relates to an ophthalmic composition comprising a combination NSAIDs and an antibiotic agent, wherein at least one of the active agents is poorly water soluble.
- Ophthalmic disorders caused by viral or bacterial infections impacts millions of people annually.
- Bacterial infections are considered to be one of the most common types of eye disorders. Such ophthalmic infections are frequently accompanied by inflammation of the infected ophthalmic tissues and sometimes the surrounding tissues. Ocular Infection and inflammation may also lead to blindness if prompt and appropriate therapy is not administered.
- External ocular infections EOIs
- EOIs External ocular infections
- Bacterial agents are known to cause different types of EOIs. The most common EOIs include conjunctivitis, blerpharitis, keratitis, dacryocystitis and canaliculitis.
- Ophthalmic surgical procedures that pose a risk of microbial infections may also cause inflammation of the affected tissues.
- Ophthalmic surgeries around 8% of all ocular surgery patients are reported to suffer from infection, including the potentially catastrophic endophthalmitis, and various negative sight threatening side effects after surgery, such as inflammatory uveitis, corneal edema, and cystid macular edema.
- antibiotics are used in ophthalmic delivery for multiples ocular diseases. Infectious disease is one of the most important public health challenges. Antibacterial therapies can be administrated in the eye by topical, subtenon, intraocular or subconjunctival administration. Tetracyclines, fluoroquinolones, aminoglycosides and penicillins are examples of antibiotics commonly used in the treatment of eye infections.
- Types of anti-inflammatory agents currently used for treating ocular inflammation are either Corticosteroids or Non-Steroidal Anti-inflammatory Drugs (NSAIDs).
- NSAIDs Non-Steroidal Anti-inflammatory Drugs
- corticosteroids have been the drug of choice and considered as gold standard for treatment of ocular inflammation after cataract surgery. Although effective, these drugs are associated with an increased incidence of adverse effects like cataract formation, a rise in IOP, increased susceptibility to herpetic infections due to a suppressed host immune response and retardation in corneal epithelial and stromal wound healing. While historically corticosteroids have held a prominent role in the treatment of ocular inflammation, the development of topical anti-inflammatory agents devoid of the detrimental effects of corticosteroid therapy represented a significant advancement in the development of ocular pharmacotherapy. (Polansky J.R., Weinreb R.N. (1984) Anti-Inflammatory Agents. In: Sears M.L. (eds) Pharmacology of the Eye. Handbook of Experimental Pharmacology (Continuation of Handbuch der experimentellen Pharmakologie), vol 69. Springer, Berlin, Heidelberg)
- NSAIDs are a heterogeneous group of compounds that have been in use for over a quarter of a century, with, except for aspirin (acetylsalicylic acid), exert anti-inflammatory activity primarily through the reversible inhibition of cyclo-oxygenase (COX) activity.
- COX is the main constituent of an enzyme system that acts on certain polyunsaturated fatty acids (primarily arachidonate) to produce the eicosanoids, namely, prostaglandins, prostacyclin and thromboxanes.
- Topical NSAIDs are classified into six groups based in their chemical composition: indoles phenylacetic acids, phenylalkanoic acids, salicylates, fenamates and pyrazolones. Salicylates, fenamtes and pyrazolones are considered too toxic to be in the eye. NSAIDs available commercially for topical ophthalmic use are considered organic acids, with the exception of nepafenac, which is a benzoylbenzeneacetamide prodrug metabolized in vivo to its corresponding acid.
- the present invention provides a fixed dose combination of an NSAIDs agent and anti-microbial agents for the treatment of ocular infections and inflammations.
- the ability to deliver two drugs through the same formulation without the need to use two separate drops will improve patient compliance and hence patient adherence to treatment.
- Topical eye drop is the most convenient and patient compliant route for ocular drug administration, especially for the treatment of anterior segment diseases. Eye drops of poorly soluble drugs are frequently formulated as suspension. Obtaining the desired bioavailability of a drug in suspension is a great challenge as compared to drug in the form of a solution. The bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid. Thus another aim of the present invention is development of novel ophthalmic solution comprising a fixed dose amount of NSAIDs and anti-microbial agent with the desired bioavailability and efficacy.
- Drug concentrations in ophthalmic eye drop solutions are usually in the range of 0.1% to 4%, but such drug concentrations in solution are difficult to reach for hydrophobic drugs, and therefore topical eye drop formulations of poorly water soluble drugs are in suspensions. Even though ophthalmic suspensions are commonly used, their biopharmaceutical properties are poorly understood, the bioavailability of a drug suspension is a great challenge.
- Another objective of the present invention is to provide a fixed dose ophthalmic solution comprising a combination of NSAIDs, wherein the NSAIDs is nepafenac and antimicrobial agent, wherein the antimicrobial agent is moxifloxacin.
- Moxifloxacin may be in the form of pharmaceutically acceptable salt, wherein moxifloxacin hydrochloride is preferred.
- Another objective of the present invention is to provide an ophthalmic solution comprising a fixed dose combination of nepafenac and moxifloxacin hydrochloride for treatment of ocular microbial infection and associated inflammation
- Another objective of the present invention is to provide an ophthalmic pharmaceutical solution comprising a fixed dose combination of nepafenac and moxifloxacin hydrochloride for the treatment of post-surgery associated ocular microbial infection and inflammation.
- the present invention provides an ophthalmic formulation comprising fixed dose combination of NSAIDs and antimicrobial agent wherein NSAIDs is nepafenac and antimicrobial agent is moxifloxacin. is preferred.
- the ophthalmic formulation of present invention is an aqueous ophthalmic solution of nepafenac and moxifloxacin used for the treatment of ocular infection and inflammations associated with post-operative ocular surgeries.
- the pharmaceutical formulation of present invention is a stable ophthalmic solution comprising nepafenac and moxifloxacin or a pharmacologically acceptable salt thereof, wherein moxifloxacin hydrochloride is being preferred and pharmaceutically acceptable excipients resulting in improved bioavailability.
- Ophthalmic solution OR “aqueous ophthalmic composition” in the present invention refers to ophthalmic solution comprising water as a vehicle.
- Optymic suspension in the present invention refers to ophthalmic liquid formulation comprising solid particles suspended in a vehicle.
- ком ⁇ онент is meant a carrier comprised of a material that is not biologically or otherwise undesirable.
- vehicle means any solvent or carrier in a pharmaceutical product that has no pharmacological role.
- Anti-microbial agents OR “anti-bacterial agents” OR “antibiotics” in the present invention refers to the drugs which act by killing or inhibiting the growth of the microorganisms causing ocular infections or inflammation during or after ophthalmic surgeries.
- these agents include gentamycin, kanamycin, amikacin, sisomicin and tobramycin; quinolones such as norfloxacin, Moxifloxacin, ofloxacin, cinoxacin, ciprofloxacin, delafloxacin, gemifloxacin, levofloxacin, norfloxacin and a pharmaceutically acceptable salt thereof.
- NS AID in the present invention refers to non-steroidal anti-inflammatory drugs which are used as to relief pain and manage inflammations associated with ophthalmic surgeries or procedures by inhibiting cyclooxygenase (COX-1 & COX-2) enzymes.
- COX-1 & COX-2 cyclooxygenase
- examples include nepafenac, meloxicam, diclofenac, bendazac, ketorolac, oxyphenbutazone, bromfenac, flurbiprofen, pranoprofen, surprofen, or indomethacin, and a pharmaceutically acceptable salt thereof.
- Fixed dose composition OR “Fixed dose ophthalmic composition” in the present invention refers to a formulation of two or more medications or active ingredients combined in a single unit dosage form, and available in certain fixed doses.
- CQA in the present invention refers to Critical Quality Attributes. As per FDA guidelines CQA refers to any “physical, chemical, biological, or microbiological property or characteristic” that must be within a limit or range to ensure the pharmaceutical product meets the required quality standard.
- Solubility in the present invention refers to maximum amount of active agents (or drugs) dissolved in a vehicle at specific temperature.
- “Stability” in the present invention refers to the extent at which ophthalmic solution retains its physiochemical, microbiological, biological and toxicological properties within specified range when used or stored. The stability of various composition in the present invention is tested in a number of ways for a specified time period and include pH, physical stability, osmolarity, microbial limit test, Related substance determination by UV. [0036] “Osmolarity” in the present invention refer to the term which is used to determine the concentration of osmotic active solute present in a per litre of the vehicle. The osmolarity of ophthalmic formulation affects the ocular surfaces. Hyperosmolarity causes discomfort, inflammation or drying of eyes so it is desirable to maintain the osmolarity within a normal physiological range preferably 200-400 mOsmol/L.
- Bioavailability in the present invention refers to rate and extent at which drug (or active moiety) becomes available to the target tissue after administration.
- bioavailability according to the present invention means that administration of composition to eye will results in improved bioavailability as compared to drug in suspension or administration of the active substances in two different dosage form. In particular, it is desired to obtain quicker and larger and/or more complete uptake of the active compound, and thereby provide for a reduction of the administered dosages or for a reduction in the number of daily administrations.
- Drug concentrations in ophthalmic eye drop solutions are usually in the range of 0.1% to 4%, but such drug concentrations in solution are difficult to reach for hydrophobic drugs, and therefore topical eye drop formulations of poorly water soluble drugs are in suspensions. Even though ophthalmic suspensions are commonly used, their biopharmaceutical properties are poorly understood.
- Nepafenac is sparingly soluble in water; it is usually formulated as a highly viscous 0.1% to 0.3% w/v ophthalmic suspension to be administered in multiple doses a day. Nepafenac is stable in the solid state but different degradation compounds have been reported to be formed in water/organic solvent (CH3CN or MeOH) mixtures under different stress conditions and the structural identification of the impurities has been carried out by LC-MS analyses aided by the comparison with reference samples. Due to this reason it is only formulated as highly viscous ophthalmic suspension in the concentration of 0.1 to 0.3% w/v. But the bioavailability of a drug suspension is a great challenge as compared to drug in a solution.
- Nepafenac has four types of known impurities, which are Impurity A (Formula I), Impurity B (Formula II), Impurity C (Formula III), Impurity D (Formula IV) and Impurity E (Formula V).
- the impurities are formed due to degradation of nepafenac.
- the impurity levels of A, B, C and D has to be below 1.0%.
- the inventors of the present invention surprisingly found that a synergistic combination of selected excipients from the group of preservative, surfactant, osmotic agent and solubilizer leads to the desired solubility and impurity profile of nepafenac.
- the inventors of the present invention were able to keep the level of the known impurities not only below 1.0% but even below detectable limits.
- the present invention provides a stable ophthalmic composition
- a stable ophthalmic composition comprising a fixed dose combination of an NSAID and anti-microbial agent wherein the level of nepafenac known impurities A, B, C, D and E are less than 1.0% and/or below detectable limit.
- the present invention also provides a stable ophthalmic composition
- a stable ophthalmic composition comprising nepafenac and moxifloxacin wherein moxifloxacin impurity A, B, C, D, E are either less than 1.0% or below detectable label
- moxifloxacin impurity A is l- cyclopropyl-6,8-difluoro-7-((4aS,7aS)-hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-oxo- 1.4-dihydroquinoline-3-carboxylic acid
- moxifloxacin impurity B is 1-Cyclopropyl-
- the present invention provides an ophthalmic pharmaceutical composition comprising a fixed dose combination of nepafenac and moxifloxacin hydrochloride, wherein the composition is in aqueous solution form and wherein the nepafenac impurities are less than 1.0% or below detectable limits.
- the present invention provides an ophthalmic pharmaceutical composition comprising a fixed dose composition of nepafenac and moxifloxacin hydrochloride, wherein the composition comprises a synergistic combination of one or more excipients selected from group of preservative, surfactant, osmotic agent and solubilizer.
- Another embodiment of the present invention is to provide an ophthalmic pharmaceutical composition
- an ophthalmic pharmaceutical composition comprising a fixed dose combination of nepafenac and moxifloxacin hydrochloride, wherein the composition is in aqueous solution form, wherein the composition comprises a synergistic combination of two or more excipient selected from the group of preservative, surfactant, osmotic agent and solubilizers, wherein nepafenac impurity in the finished formulation is less than 1.0% or below detectable limit.
- an ophthalmic solution of the present invention provides a synergistic combination of preservative, solubiliser, surfactant and osmotic agent present in the ratio of 0.001:4:0.1:0.5 to 1.0: 12:1:2.
- an ophthalmic solution of the present invention provides a synergistic combination of preservative, solubiliser, surfactant and osmotic agent present in the ratio of 0.01:9:0.5: 1.
- Another embodiment of the present invention is the development of an ophthalmic formulation comprising a combination of active agents wherein at least one of the active agent of the combination is a poorly or sparingly water soluble, wherein the formulation has null degradation and related substances under stress stability conditions and facilitates patient comfort and ease of use by getting relief in a single administration.
- the ophthalmic solution of the present invention showed improved bioavailability on combining nepafenac and moxifloxacin hydrochloride and also reduces unwanted side effects such an irritation, itching or watering of eyes upon instillation and provide enhanced patient compliance.
- Another embodiment of the present invention is to provide an ophthalmic solution comprising a combination of nepafenac and moxifloxacin hydrochloride with reduced side effects such as irritation, itching or watering of eyes upon instillation and provide enhanced patient compliance.
- the present invention provides an ophthalmic solution comprising pharmaceutically acceptable excipients selected from but not limited to surfactants, preservatives, osmotic/tonicity-adjusting agents, solubilizer, soothing agent, astringent, pH adjusting agent and chelating agent.
- pharmaceutically acceptable excipients selected from but not limited to surfactants, preservatives, osmotic/tonicity-adjusting agents, solubilizer, soothing agent, astringent, pH adjusting agent and chelating agent.
- the present invention provides a stable topical ophthalmic solution comprising combination of nepafenac and moxifloxacin and pharmaceutical excipients for the treatment of post-surgery associated ocular microbial infection and inflammation.
- the aqueous ophthalmic composition comprising the concentrations with an amount of about 0.05 to 1 % w/v of nepafenac more preferably 0.05 to 0.5% w/v and moxifloxacin hydrochloride in an amount ranging from 0.1 to 2% w/v more preferably 0.1 to 1% w/v.
- Another embodiment of the invention is to develop a stable, ophthalmic solution comprising nepafenac and moxifloxacin or a pharmacologically acceptable salt thereof and pharmaceutically acceptable excipients for the treatment of pain and inflammation after cataract surgery without causing discomfort and irritation to the eyes.
- the surfactants are selected from group consisted of, but are not limited to nonionic surfactant and include polysorbate80, polysorbate 60, poloxamers polysorbate, 40, polysorbate 20, cremophors, tyloxapols, poloxamers, benzalkonium chloride, benzethonium chloride, cetyl alcohol, carbomer, cholesterol, cocamidopropyl betaine, glyceryl monostearate, lanolin alcohols, lauralkonium chlorides, n lauroylsarcosine, nonoxynol 9, octoxynol 40, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, sorbitan monolaurate, sorbitan monooleate, or a combination thereof.
- nonionic surfactant is present in an amount preferably from about 0.005 to about 0.2% (w/v).
- the nonionic surfactant is selected from octoxynol-40, poloxamers or combination thereof present in amount preferably from about 0.005 to about 0.2% (w/v) most preferably about 0.02-0.1 % w/v.
- ophthalmic solution further comprises one or more preservative and are selected from group consisted of, but are not limited to quaternary ammonium compounds such as benzalkonium chloride (BAK), benzethonium chloride, benzyl alcohol, busan, cetrimide, chlorhexidine, chlorobutanol, mercurial preservatives, or phenylmercuric nitrate, phenylmercuric acetate, thimerosal, phenylethyl alcohol and or a combination thereof.
- preservative is present in an amount preferably from about 0.001 % to 0.05 % w/v.
- preservative is selected from phenylmercuric nitrate, benzalkonium chloride (BAK) or combination thereof in an amount ranging from about 0.001 % to 0.05 % w/v, preferably about 0.005 % to 0.01% w/v.
- BAK benzalkonium chloride
- ophthalmic solution further comprises osmotic/tonicity-adjusting agents which is required to maintain isotonicity of the composition with respect to the ophthalmic fluids present in the human eye and adjust osmolarity between 200 to 400 mOsmol/L.
- osmotic/tonicity-adjusting agents are selected from group consisted of, but are not limited to sodium chloride, potassium chloride, calcium chloride, sodium bromide, sodium phosphate sodium sulfate, mannitol, glycerol, sorbitol, propylene glycol, dextrose, sucrose, polyethylene glycols (PEG) or combinations thereof.
- osmotic/tonicity-adjusting agents present in an amount preferably 0.5 to 5 %w/v.
- osmotic/tonicity-adjusting agent is mannitol in an amount ranging from about 0.5-2 %w/v.
- ophthalmic solution further comprises solubilizer.
- Cyclodextrins are well-known pharmaceutical excipient which are used to [0064] enhance the solubility of poorly or insoluble drugs.
- cyclodextrins derivatives are selected as a solubilizer and are selected from group consisted of, but are not limited to hydroxypropyl-beta-cyclodextrin (HP-P-CD), sulfobutylether-P-cyclodextrin, P-cyclodextrin, alpha Cyclodextrin, Gamma Cyclodextrin or combinations thereof presents in an amount ranging from about 2% w/v to 15% w/v.
- solubilizer is hydroxypropyl-beta-cyclodextrin present in an amount ranging from about 5% w/v to 12% w/v.
- ophthalmic solution further comprises soothing agents which are used sooth and lubricate the eyes and reduces dryness and irritation.
- Soothing agent are selected from group consisted of, but are not limited to from carboxymethylcellulose sodium, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, boric acid, cellulose derivatives, dextran, gelatin, polysorbate 80, polyvinyl alcohol, povidone, glycerin, propylene glycol, glycerol, di propylene glycol or combinations thereof.
- soothing agents presents in an amount ranging from about 0.1-5% w/v.
- soothing agent is selected from propylene glycol, boric acid or combination thereof in an amount ranging from 0.1-2% w/v
- ophthalmic solution further comprises astringent and are selected from group consisted of, but are not limited to silver sulfate, zinc sulfate, zinc lactate, silver nitrate, zinc oxide, potassium aluminum sulfate, aluminum chloride, aluminum allantoin, zinc chloride or combinations thereof presents in an amount ranging from 0.001-0.005 % w/v.
- astringent is zinc chloride presents in an amount ranging from 0.001-0.005 % w/v.
- ophthalmic solution further comprises chelating agent and are selected from group consisted of, but are not limited to ethylene diamine tetraacetic acid (EDTA) or salts thereof, ethylenediamine, nitrilotriacetic acid, n- hydroxyethylethylenediaminetriacetic acid or combinations thereof presents in an amount ranging from 0.02-1 % w/v.
- EDTA ethylene diamine tetraacetic acid
- chelating agent is Disodium EDTA presents in an amount ranging from 0.05-0.5 % w/v.
- ophthalmic solution further comprises pH-adjusting agents selected from hydrochloric acid, Sulfuric acid, acetic acid, potassium hydroxide, sodium borate, sodium hydroxide, Sodium bicarbonate, sodium carbonate or combinations thereof presents in an amount ranging from 0.01-1 % w/v.
- pH-adjusting agent is sodium hydroxide presents in an amount ranging from 0.01-0.5 % w/v.
- the pH of the composition of the present invention may be between 3-8, preferably within the range of 4-8, most preferably within the range of 5-8.
- the pharmaceutical composition of the present invention can be obtained by known conventional methods.
- Formulation A and Formulation B were prepared by using a selected combination of phenylmercuric nitrate as preservative, hyrdoxypropyl beta cyclodextrin as solubilizer, Octoxynol-40 as surfactant, Mannitol as osmotic agent and with additional pharmaceutically acceptable excipient.
- Fomulation C and Formulation D were prepared by using a selected combination of benzalkonium chloride as preservative, hyrdoxypropyl beta cyclodextrin as solubilizer, poloxamine (Tetronic 1304) as surfactant, Mannitol as osmotic agent and with additional pharmaceutically acceptable excipient.
- Formulation E, F, G and H were prepared by using benzalkonium chloride as preservative, hydroxyproply beta cyclodextrin as solubiliser, octoxynol-40 as surfactant and Mannitol as osmotic agent, with additional pharmaceutically acceptable excipients.
- octoxynol 40 as the surfactant in combination with benzalkonium chloride as preservative was used than an increase in concentration of the solubiliser was required to obtain a stable formulation in terms of the assay, pH and osmolarity.
- Example 4-Process for preparing ophthalmic formulation [0084] The steps involved in the process are as follows:
- Disodium Edetate was dissolved in water of injection in a tank and was stirred at temperature 60-70°C for 10 minutes at 250 RPM. The bulk solution was than cool down up to 55-60°C. After cooling, boric acid was dissolved in the bulk solution at temperature 55-60°C for 10 minute at 250 rpm. Propylene glycol was added to the solution and stirred for 5 minutes at 250 rpm.
- Mannitol was added to the resultant solution at temperature 55-60°C for 5 minutes at 250 rpm, the solution was cooled down to 50-55°C. After cooling the solution zinc chloride was added at temperature 50-55 °C was added and stirred for 5 minutes at 250 rpm. After stirring, hydroxyl propyl betacyclodextrin was added and dissolved in the solution for 5 minutes at 250 rpm. The solution was than cooled upto 30-35°C.
- Step-3 Mixing the solution obtained in Step- 1 and step-2 to obtain ophthalmic solution
- nepafenac colloidal solution obtained in step-2 was added to the moxifloxacin HCL bulk solution and stirred for 60 minutes at 300 rpm to obtain a clear solution. The solution was than checked for clarity test and if any solid particles were visible the solution again stirred for 30 minutes or until a clear solution was obtained. Initial pH of the solution was checked and if required pH was adjusted between 6.50 to 7.50 by using 10% w/v sodium hydroxide solution.
- the resultant solution was volume make up to 95% with water for injection at temperature 25-30°C.
- the solution was than checked for pH and if required, the pH was adjusted between 6.50 to 7.50 by using 10% w/v sodium hydroxide solution and the solution was stirred for 15 minutes.
- Example-5 Stability, impurity and solubility study under accelerated conditions
- the prepared ophthalmic solution of 0.1% w/v nepafenac and moxifloxacin hydrochloride was subjected for stability studies under Temperature. 40° ⁇ 2°C & Relative Humidity 25% a) Nepafenac Impurity test (by HPLC) under accelerated conditions b) Moxifloxacin hydrochloride impurity profile (by HPLC) under accelerated conditions c) Solubility profile under accelerated conditions
- Example 6 Stability, impurity and solubility study under intermediate conditions
- Example 7- stability, impurity and solubility study under long term conditions [0093] The prepared ophthalmic solution of 0.1% w/v nepafenac and moxifloxacin hydrochloride was subjected for stability studies under temp.25° ⁇ 2°C & relative humidity 40% ⁇ 5%. a) Nepafenac impurity profile (by HPLC) under long term conditions b) Moxifloxacin hydrochloride impurity profile (by HPLC) under long term conditions c) Solubility profile under long term conditions
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Abstract
The invention relates to an ophthalmic composition comprising fixed dose combination of NSAIDs and fluoroquinolone antibiotic for the treatment of ocular disorders and process of preparation thereof. In particular, an ophthalmic formulation of present invention is an aqueous solution of nepafenac and moxifloxacin hydrochloride used in treatment of post-surgery associated ocular microbial infections and inflammations.
Description
AN AQUEOUS OPHTHALMIC SOLUTION OF NSAIDS AND ELUOROQUINOLONE
ANTIBIOTIC AND PROCESS OF PREPARATION THEREOF
Field of Invention
[001] The present invention relates a pharmaceutical composition comprising a combination of a NSAIDs and an antibiotic for the treatment of diseases associated with multiple eye conditions. The present invention further relates to an ophthalmic composition comprising a combination NSAIDs and an antibiotic agent, wherein at least one of the active agents is poorly water soluble. of Invention
[002] Ophthalmic disorders caused by viral or bacterial infections, impacts millions of people annually. Bacterial infections are considered to be one of the most common types of eye disorders. Such ophthalmic infections are frequently accompanied by inflammation of the infected ophthalmic tissues and sometimes the surrounding tissues. Ocular Infection and inflammation may also lead to blindness if prompt and appropriate therapy is not administered. External ocular infections (EOIs) frequently involve the eye lid, conjunctiva and cornea. Bacterial agents are known to cause different types of EOIs. The most common EOIs include conjunctivitis, blerpharitis, keratitis, dacryocystitis and canaliculitis. (Teweldemedhin, M., Gebreyesus, H., Atsbaha, A.H. et al. Bacterial profile of ocular infections: a systematic review. BMC Ophthalmol 17, 212 (2017)). Generally, eye is rigid and protected by the continuous flow of tear containing antibacterial compounds. However, beyond its defence mechanisms, if inflammation and scarring occurs it necessitates immediate management and mitigation. (KrishnanNair Geetha Deepthi, Solai Ramatchandirane Prabagaran, Ocular bacterial infections: Pathogenesis and diagnosis, Microbial Pathogenesis, Volume 145, 2020)
[003] Ophthalmic surgical procedures that pose a risk of microbial infections may also cause inflammation of the affected tissues. For example, in case of ophthalmic surgeries around 8% of all ocular surgery patients are reported to suffer from infection, including the potentially
catastrophic endophthalmitis, and various negative sight threatening side effects after surgery, such as inflammatory uveitis, corneal edema, and cystid macular edema.
[004] To prevent ocular microbial infection, the current standard of care includes antibiotics. Antibiotics are used in ophthalmic delivery for multiples ocular diseases. Infectious disease is one of the most important public health challenges. Antibacterial therapies can be administrated in the eye by topical, subtenon, intraocular or subconjunctival administration. Tetracyclines, fluoroquinolones, aminoglycosides and penicillins are examples of antibiotics commonly used in the treatment of eye infections.
[005] Types of anti-inflammatory agents currently used for treating ocular inflammation are either Corticosteroids or Non-Steroidal Anti-inflammatory Drugs (NSAIDs). In Sabari S. H. et al, a study wherein an ophthalmic emulgel for delivery of a betamethasone sodium phosphate (BSP) a corticosteroids and levofloxacin an antibacterial agent, was disclosed. The study concluded that the emulgel composition allow simultaneous and extended release of the two drugs. (Sabry, H. S., Al-Shohani, A., & Mahmood, S. Z. (2021) Formulation and Evaluation of Levofloxacin and Betamethasone Ophthalmic Emulgel. Journal of pharmacy & bioallied sciences, 13(2), 205-211)
[006] In Stern G.A. et al, a study on the use of corticosteroid in combination with an antibacterial agent has been disclosed. The study analysed the risk of using a corticosteroid, use of which is considered to be controversial in eye disease, with an antimicrobial agent. The study reported that Corticosteroids are contraindicated in the treatment of fungal keratitis, and relatively contraindicated in the treatment of Acanthamoeba bacterial keratitis. (George A. Stern, Melanie Buttress, Use of Corticosteroids in Combination with Antimicrobial Drugs in the Treatment of Infectious Corneal Disease, Ophthalmology, Volume 98, Issue 6, 1991, Pages 847-853)
[007] In Blair J. et al, a comparative study of antibiotic -only vs antibiotic-steroid combination treatment in corneal ulcer patients were studied. Patients were randomized before enrolment; 15 were treated with gatifloxacin and masked dexamethasone 0.1% (Maxidex). No benefit was demonstrated in the primary outcome for using steroids in combination with antibiotic treatment of corneal ulcers. (Blair, J. et al., Comparison of antibiotic-only and antibiotic-steroid
combination treatment in corneal ulcer patients: double -blinded randomized clinical trial, Canadian Journal of Ophthalmology, 46-1, 2011, 40-45)
[008] Historically corticosteroids have been the drug of choice and considered as gold standard for treatment of ocular inflammation after cataract surgery. Although effective, these drugs are associated with an increased incidence of adverse effects like cataract formation, a rise in IOP, increased susceptibility to herpetic infections due to a suppressed host immune response and retardation in corneal epithelial and stromal wound healing. While historically corticosteroids have held a prominent role in the treatment of ocular inflammation, the development of topical anti-inflammatory agents devoid of the detrimental effects of corticosteroid therapy represented a significant advancement in the development of ocular pharmacotherapy. (Polansky J.R., Weinreb R.N. (1984) Anti-Inflammatory Agents. In: Sears M.L. (eds) Pharmacology of the Eye. Handbook of Experimental Pharmacology (Continuation of Handbuch der experimentellen Pharmakologie), vol 69. Springer, Berlin, Heidelberg)
[009] NSAIDs are a heterogeneous group of compounds that have been in use for over a quarter of a century, with, except for aspirin (acetylsalicylic acid), exert anti-inflammatory activity primarily through the reversible inhibition of cyclo-oxygenase (COX) activity. COX is the main constituent of an enzyme system that acts on certain polyunsaturated fatty acids (primarily arachidonate) to produce the eicosanoids, namely, prostaglandins, prostacyclin and thromboxanes. ((Koay P, The emerging roles of topical non-steroidal anti-inflammatory agents in ophthalmology. British Journal of Ophthalmology 1996; 80:480-485.)
[0010] The main advantage of topical NSAIDs is that the undesirable effects of topical corticosteroids are avoided. Topical NSAIDs are classified into six groups based in their chemical composition: indoles phenylacetic acids, phenylalkanoic acids, salicylates, fenamates and pyrazolones. Salicylates, fenamtes and pyrazolones are considered too toxic to be in the eye. NSAIDs available commercially for topical ophthalmic use are considered organic acids, with the exception of nepafenac, which is a benzoylbenzeneacetamide prodrug metabolized in vivo to its corresponding acid.
[0011] Presently to treat microbial infection and associated inflammation a dual therapy of an antimicrobial agent and anti-inflammatory agents are used. But the use of dual therapy with two
separate medicaments adds to the cost of the treatment, assigned the correct use, and carries a risk of certain per se not therapeutic monitoring which can cause a decrease in the expected therapeutic efficacy of the treatment.
[0012] Thus there is a need in the art of fixed dose drug composition which targets and treats both causes i.e. microbial infection and inflammation, especially after post ophthalmic surgeries. The present invention provides a fixed dose combination of an NSAIDs agent and anti-microbial agents for the treatment of ocular infections and inflammations. The ability to deliver two drugs through the same formulation without the need to use two separate drops will improve patient compliance and hence patient adherence to treatment.
[0013] Topical eye drop is the most convenient and patient compliant route for ocular drug administration, especially for the treatment of anterior segment diseases. Eye drops of poorly soluble drugs are frequently formulated as suspension. Obtaining the desired bioavailability of a drug in suspension is a great challenge as compared to drug in the form of a solution. The bioavailability of suspended drug depends on the retention and dissolution of drug particles in the tear fluid. Thus another aim of the present invention is development of novel ophthalmic solution comprising a fixed dose amount of NSAIDs and anti-microbial agent with the desired bioavailability and efficacy.
[0014] Drug concentrations in ophthalmic eye drop solutions are usually in the range of 0.1% to 4%, but such drug concentrations in solution are difficult to reach for hydrophobic drugs, and therefore topical eye drop formulations of poorly water soluble drugs are in suspensions. Even though ophthalmic suspensions are commonly used, their biopharmaceutical properties are poorly understood, the bioavailability of a drug suspension is a great challenge.
[0015] Addition of an additional drug into a suspension will directly affect the stability and bioavailability of the formulation creating additional hurdles for formulators. Thus preparation of an ophthalmic suspension comprising a combination of drugs and wherein one of the drug is a sparingly water soluble drug was not found to be industrially and commercially viable. Thus there is a need in the art for ophthalmic composition comprising a combination drug which treats both infection and inflammation, and is safe, stable and efficacious, and are able to overcome the problems present in prior art
Objectives
[0016] To provide a fixed dose pharmaceutical composition comprising an anti-inflammatory agent and antimicrobial agent for the treatment of ocular disorders.
[0017] To provide a fixed dose pharmaceutical ophthalmic solution comprising an antiinflammatory agent and anti-microbial agent, wherein at-least one of the active agent is poorly water soluble.
[0018] To provide a fixed dose ophthalmic solution comprising NSAIDs and an antimicrobial agent for the treatment of ocular infections and associated inflammation.
[0019] Another objective of the present invention is to provide a fixed dose ophthalmic solution comprising a combination of NSAIDs, wherein the NSAIDs is nepafenac and antimicrobial agent, wherein the antimicrobial agent is moxifloxacin. Moxifloxacin may be in the form of pharmaceutically acceptable salt, wherein moxifloxacin hydrochloride is preferred.
[0020] Another objective of the present invention is to provide an ophthalmic solution comprising a fixed dose combination of nepafenac and moxifloxacin hydrochloride for treatment of ocular microbial infection and associated inflammation
[0021] Another objective of the present invention is to provide an ophthalmic pharmaceutical solution comprising a fixed dose combination of nepafenac and moxifloxacin hydrochloride for the treatment of post-surgery associated ocular microbial infection and inflammation.
Summary of the invention-
[0022] The present invention provides an ophthalmic formulation comprising fixed dose combination of NSAIDs and antimicrobial agent wherein NSAIDs is nepafenac and antimicrobial agent is moxifloxacin. is preferred. The ophthalmic formulation of present invention is an aqueous ophthalmic solution of nepafenac and moxifloxacin used for the treatment of ocular infection and inflammations associated with post-operative ocular surgeries. The pharmaceutical formulation of present invention is a stable ophthalmic solution comprising nepafenac and moxifloxacin or a pharmacologically acceptable salt thereof, wherein
moxifloxacin hydrochloride is being preferred and pharmaceutically acceptable excipients resulting in improved bioavailability.
Detailed description of invention
[0023] Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
[0024] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
[0025] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
[0026] “Ophthalmic solution” OR “aqueous ophthalmic composition” in the present invention refers to ophthalmic solution comprising water as a vehicle.
[0027] “Ophthalmic suspension” in the present invention refers to ophthalmic liquid formulation comprising solid particles suspended in a vehicle.
[0028] The term "pharmaceutically acceptable" is meant a carrier comprised of a material that is not biologically or otherwise undesirable.
[0029] As used herein, the term "vehicle" means any solvent or carrier in a pharmaceutical product that has no pharmacological role.
[0030] “Anti-microbial agents” OR “anti-bacterial agents” OR “antibiotics” in the present invention refers to the drugs which act by killing or inhibiting the growth of the microorganisms causing ocular infections or inflammation during or after ophthalmic surgeries. Examples of these agents include gentamycin, kanamycin, amikacin, sisomicin and tobramycin; quinolones such as norfloxacin, Moxifloxacin, ofloxacin, cinoxacin, ciprofloxacin, delafloxacin, gemifloxacin, levofloxacin, norfloxacin and a pharmaceutically acceptable salt thereof.
[0031] “NS AID” in the present invention refers to non-steroidal anti-inflammatory drugs which are used as to relief pain and manage inflammations associated with ophthalmic surgeries or procedures by inhibiting cyclooxygenase (COX-1 & COX-2) enzymes. Examples include nepafenac, meloxicam, diclofenac, bendazac, ketorolac, oxyphenbutazone, bromfenac, flurbiprofen, pranoprofen, surprofen, or indomethacin, and a pharmaceutically acceptable salt thereof.
[0032] “Fixed dose composition” OR “Fixed dose ophthalmic composition” in the present invention refers to a formulation of two or more medications or active ingredients combined in a single unit dosage form, and available in certain fixed doses.
[0033] “CQA” in the present invention refers to Critical Quality Attributes. As per FDA guidelines CQA refers to any “physical, chemical, biological, or microbiological property or characteristic” that must be within a limit or range to ensure the pharmaceutical product meets the required quality standard.
[0034] “Solubility” in the present invention refers to maximum amount of active agents (or drugs) dissolved in a vehicle at specific temperature.
[0035] “Stability” in the present invention refers to the extent at which ophthalmic solution retains its physiochemical, microbiological, biological and toxicological properties within specified range when used or stored. The stability of various composition in the present invention is tested in a number of ways for a specified time period and include pH, physical stability, osmolarity, microbial limit test, Related substance determination by UV.
[0036] “Osmolarity” in the present invention refer to the term which is used to determine the concentration of osmotic active solute present in a per litre of the vehicle. The osmolarity of ophthalmic formulation affects the ocular surfaces. Hyperosmolarity causes discomfort, inflammation or drying of eyes so it is desirable to maintain the osmolarity within a normal physiological range preferably 200-400 mOsmol/L.
[0037] “Bioavailability” in the present invention refers to rate and extent at which drug (or active moiety) becomes available to the target tissue after administration. The term “bioavailability” according to the present invention means that administration of composition to eye will results in improved bioavailability as compared to drug in suspension or administration of the active substances in two different dosage form. In particular, it is desired to obtain quicker and larger and/or more complete uptake of the active compound, and thereby provide for a reduction of the administered dosages or for a reduction in the number of daily administrations.
Existing issues in formulating Ophthalmic Eye Drop solutions
[0038] Drug concentrations in ophthalmic eye drop solutions are usually in the range of 0.1% to 4%, but such drug concentrations in solution are difficult to reach for hydrophobic drugs, and therefore topical eye drop formulations of poorly water soluble drugs are in suspensions. Even though ophthalmic suspensions are commonly used, their biopharmaceutical properties are poorly understood.
[0039] Nepafenac is sparingly soluble in water; it is usually formulated as a highly viscous 0.1% to 0.3% w/v ophthalmic suspension to be administered in multiple doses a day. Nepafenac is stable in the solid state but different degradation compounds have been reported to be formed in water/organic solvent (CH3CN or MeOH) mixtures under different stress conditions and the structural identification of the impurities has been carried out by LC-MS analyses aided by the comparison with reference samples. Due to this reason it is only formulated as highly viscous ophthalmic suspension in the concentration of 0.1 to 0.3% w/v. But the bioavailability of a drug suspension is a great challenge as compared to drug in a solution.
[0040] Addition of an additional drug into a suspension will directly affect the stability and bioavailability of the formulation creating additional hurdles for formulators. Thus preparation
of an ophthalmic suspension comprising a combination of drugs and wherein one of the drug is a sparingly water soluble drug was not found to be industrially and commercially viable. To overcome the problems, associate in preparation of stable and efficacious combination the inventors of the present invention formulated the combination in the form of an aqueous solution. But the problems faced in formulating combination as an aqueous solution was in the solubilizing a poorly water soluble drug in an aqueous solution. Extensive studies and experimentation were required to overcome instability of nepafenac in the aqueous solution.
[0041] Issues with bioavailability are a major concern when formulating poorly water soluble drug in an aqueous solution. Solubility is fundamental parameters that control rate and extent of drug absorption and its bioavailability. The number of insoluble drug candidates has increased in recent years, with almost 70% of new drug candidates showing poor water solubility. For these drug candidates, poor aqueous solubility and poor permeability is a limiting factor to the in vivo bioavailability
[0042] Nepafenac has four types of known impurities, which are Impurity A (Formula I), Impurity B (Formula II), Impurity C (Formula III), Impurity D (Formula IV) and Impurity E (Formula V). The impurities are formed due to degradation of nepafenac. For a composition to meet the safety criteria the impurity levels of A, B, C and D has to be below 1.0%. Extensive studies and experimentation were required to overcome instability of nepafenac in the aqueous solution, which is poorly water soluble and forms degradation compounds
[0043] To overcome the problems associated with degradation product of nepafenac and to obtain the required solubility, the inventors of the present invention surprisingly found that a synergistic combination of selected excipients from the group of preservative, surfactant, osmotic agent and solubilizer leads to the desired solubility and impurity profile of nepafenac. The inventors of the present invention were able to keep the level of the known impurities not only below 1.0% but even below detectable limits.
Formula III Formula IV
[0044] Thus in another embodiment, the present invention provides a stable ophthalmic composition comprising a fixed dose combination of an NSAID and anti-microbial agent wherein the level of nepafenac known impurities A, B, C, D and E are less than 1.0% and/or below detectable limit. [0045] In another embodiment the present invention also provides a stable ophthalmic composition comprising nepafenac and moxifloxacin wherein moxifloxacin impurity A, B, C, D, E are either less than 1.0% or below detectable label, wherein moxifloxacin impurity A is l- cyclopropyl-6,8-difluoro-7-((4aS,7aS)-hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-oxo-
1.4-dihydroquinoline-3-carboxylic acid, wherein moxifloxacin impurity B is 1-Cyclopropyl-
1.4-dihydro-6,8-dimethoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3- quinolinecarboxylic acid hydrochloride, wherein moxifloxacin impurity C is 1-cyclopropyl- 8-ethoxy-6-fluoro-7-((4aS,7aS)-hexahydro-lH-pyrrolo[3,4-b]pyridin-6(2H)-yl)-4-oxo-l,4- dihydroquinoline-3-carboxylic acid hydrochloride, wherein moxifloxacin Impurity D is 1- Cyclopropyl-8-fluoro-l,4-dihydro-6-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4 b] pyridine-6-yl]-4-oxo-3-quinolinecarboxylic acid dihydrochloride and wherein moxifloxacin Impurity E is l-cyclopropyl-6-fluoro-7-((4aS,7aS)-hexahydro-lH-pyrrolo[3,4-b]pyridin- 6(2H)-yl)-8-hydroxy-4-oxo- 1 ,4-dihydroquinoline-3-carboxylic acid.
[0046] Thus in an embodiment, the present invention provides an ophthalmic pharmaceutical composition comprising a fixed dose combination of nepafenac and moxifloxacin hydrochloride, wherein the composition is in aqueous solution form and wherein the nepafenac impurities are less than 1.0% or below detectable limits. In another embodiment the present invention provides an ophthalmic pharmaceutical composition comprising a fixed dose composition of nepafenac and moxifloxacin hydrochloride, wherein the composition comprises a synergistic combination of one or more excipients selected from group of preservative, surfactant, osmotic agent and solubilizer.
[0047] Another embodiment of the present invention is to provide an ophthalmic pharmaceutical composition comprising a fixed dose combination of nepafenac and moxifloxacin hydrochloride, wherein the composition is in aqueous solution form, wherein the composition comprises a synergistic combination of two or more excipient selected from the group of preservative, surfactant, osmotic agent and solubilizers, wherein nepafenac impurity in the finished formulation is less than 1.0% or below detectable limit.
[0048] In an embodiment an ophthalmic solution of the present invention provides a synergistic combination of preservative, solubiliser, surfactant and osmotic agent present in the ratio of 0.001:4:0.1:0.5 to 1.0: 12:1:2.
[0049] In most preferred embodiment an ophthalmic solution of the present invention provides a synergistic combination of preservative, solubiliser, surfactant and osmotic agent present in the ratio of 0.01:9:0.5: 1.
[0050] Another embodiment of the present invention is the development of an ophthalmic formulation comprising a combination of active agents wherein at least one of the active agent of the combination is a poorly or sparingly water soluble, wherein the formulation has null degradation and related substances under stress stability conditions and facilitates patient comfort and ease of use by getting relief in a single administration.
[0051] It was surprisingly found that the ophthalmic solution of the present invention showed improved bioavailability on combining nepafenac and moxifloxacin hydrochloride and also reduces unwanted side effects such an irritation, itching or watering of eyes upon instillation and provide enhanced patient compliance.
[0052] Thus another embodiment of the present invention is to provide an ophthalmic solution comprising a combination of nepafenac and moxifloxacin hydrochloride with reduced side effects such as irritation, itching or watering of eyes upon instillation and provide enhanced patient compliance.
[0053] In an embodiment the present invention provides an ophthalmic solution comprising pharmaceutically acceptable excipients selected from but not limited to surfactants, preservatives, osmotic/tonicity-adjusting agents, solubilizer, soothing agent, astringent, pH adjusting agent and chelating agent.
[0054] The present invention provides a stable topical ophthalmic solution comprising combination of nepafenac and moxifloxacin and pharmaceutical excipients for the treatment of post-surgery associated ocular microbial infection and inflammation.
[0055] In the present invention the aqueous ophthalmic composition comprising the concentrations with an amount of about 0.05 to 1 % w/v of nepafenac more preferably 0.05 to 0.5% w/v and moxifloxacin hydrochloride in an amount ranging from 0.1 to 2% w/v more preferably 0.1 to 1% w/v.
[0056] Another embodiment of the invention is to develop a stable, ophthalmic solution comprising nepafenac and moxifloxacin or a pharmacologically acceptable salt thereof and pharmaceutically acceptable excipients for the treatment of pain and inflammation after cataract surgery without causing discomfort and irritation to the eyes.
[0057] In one embodiment the surfactants are selected from group consisted of, but are not limited to nonionic surfactant and include polysorbate80, polysorbate 60, poloxamers polysorbate, 40, polysorbate 20, cremophors, tyloxapols, poloxamers, benzalkonium chloride, benzethonium chloride, cetyl alcohol, carbomer, cholesterol, cocamidopropyl betaine, glyceryl monostearate, lanolin alcohols, lauralkonium chlorides, n lauroylsarcosine, nonoxynol 9, octoxynol 40, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, sorbitan monolaurate, sorbitan monooleate, or a combination thereof. In an embodiment nonionic surfactant is present in an amount preferably from about 0.005 to about 0.2% (w/v).
[0058] In a preferred embodiment the nonionic surfactant is selected from octoxynol-40, poloxamers or combination thereof present in amount preferably from about 0.005 to about 0.2% (w/v) most preferably about 0.02-0.1 % w/v.
[0059] In one embodiment ophthalmic solution further comprises one or more preservative and are selected from group consisted of, but are not limited to quaternary ammonium compounds such as benzalkonium chloride (BAK), benzethonium chloride, benzyl alcohol, busan, cetrimide, chlorhexidine, chlorobutanol, mercurial preservatives, or phenylmercuric nitrate, phenylmercuric acetate, thimerosal, phenylethyl alcohol and or a combination thereof. In an embodiment preservative is present in an amount preferably from about 0.001 % to 0.05 % w/v.
[0060] In a preferred embodiment preservative is selected from phenylmercuric nitrate, benzalkonium chloride (BAK) or combination thereof in an amount ranging from about 0.001 % to 0.05 % w/v, preferably about 0.005 % to 0.01% w/v.
[0061] In one embodiment ophthalmic solution further comprises osmotic/tonicity-adjusting agents which is required to maintain isotonicity of the composition with respect to the ophthalmic fluids present in the human eye and adjust osmolarity between 200 to 400 mOsmol/L. osmotic/tonicity-adjusting agents are selected from group consisted of, but are not limited to sodium chloride, potassium chloride, calcium chloride, sodium bromide, sodium phosphate sodium sulfate, mannitol, glycerol, sorbitol, propylene glycol, dextrose, sucrose, polyethylene glycols (PEG) or combinations thereof. In an embodiment osmotic/tonicity- adjusting agents present in an amount preferably 0.5 to 5 %w/v.
[0062] In a preferred embodiment osmotic/tonicity-adjusting agent is mannitol in an amount ranging from about 0.5-2 %w/v.
[0063] In one embodiment ophthalmic solution further comprises solubilizer. Cyclodextrins are well-known pharmaceutical excipient which are used to [0064] enhance the solubility of poorly or insoluble drugs. In an embodiment cyclodextrins derivatives are selected as a solubilizer and are selected from group consisted of, but are not limited to hydroxypropyl-beta-cyclodextrin (HP-P-CD), sulfobutylether-P-cyclodextrin, P-cyclodextrin, alpha Cyclodextrin, Gamma Cyclodextrin or combinations thereof presents in an amount ranging from about 2% w/v to 15% w/v.
[0065] In a preferred embodiment solubilizer is hydroxypropyl-beta-cyclodextrin present in an amount ranging from about 5% w/v to 12% w/v.
[0066] In one embodiment ophthalmic solution further comprises soothing agents which are used sooth and lubricate the eyes and reduces dryness and irritation. In an embodiment Soothing agent are selected from group consisted of, but are not limited to from carboxymethylcellulose sodium, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, boric acid, cellulose derivatives, dextran, gelatin, polysorbate 80, polyvinyl alcohol, povidone, glycerin, propylene glycol, glycerol, di propylene glycol or combinations thereof. In an embodiment soothing agents presents in an amount ranging from about 0.1-5% w/v.
[0067] In a preferred embodiment soothing agent is selected from propylene glycol, boric acid or combination thereof in an amount ranging from 0.1-2% w/v
[0068] In one embodiment ophthalmic solution further comprises astringent and are selected from group consisted of, but are not limited to silver sulfate, zinc sulfate, zinc lactate, silver nitrate, zinc oxide, potassium aluminum sulfate, aluminum chloride, aluminum allantoin, zinc chloride or combinations thereof presents in an amount ranging from 0.001-0.005 % w/v.
[0069] In preferred embodiment astringent is zinc chloride presents in an amount ranging from 0.001-0.005 % w/v.
[0070] In an embodiment ophthalmic solution further comprises chelating agent and are selected from group consisted of, but are not limited to ethylene diamine tetraacetic acid (EDTA) or salts thereof, ethylenediamine, nitrilotriacetic acid, n- hydroxyethylethylenediaminetriacetic acid or combinations thereof presents in an amount ranging from 0.02-1 % w/v.
[0071] In preferred embodiment chelating agent is Disodium EDTA presents in an amount ranging from 0.05-0.5 % w/v.
[0072] In an embodiment ophthalmic solution further comprises pH-adjusting agents selected from hydrochloric acid, Sulfuric acid, acetic acid, potassium hydroxide, sodium borate, sodium hydroxide, Sodium bicarbonate, sodium carbonate or combinations thereof presents in an amount ranging from 0.01-1 % w/v.
[0073] In preferred embodiment pH-adjusting agent is sodium hydroxide presents in an amount ranging from 0.01-0.5 % w/v.
[0074] The pH of the composition of the present invention may be between 3-8, preferably within the range of 4-8, most preferably within the range of 5-8.
[0075] In an embodiment the pharmaceutical composition of the present invention can be obtained by known conventional methods.
[0076] The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.
Examples 1-
[0077] Formulation A and Formulation B were prepared by using a selected combination of phenylmercuric nitrate as preservative, hyrdoxypropyl beta cyclodextrin as solubilizer,
Octoxynol-40 as surfactant, Mannitol as osmotic agent and with additional pharmaceutically acceptable excipient.
Table 1 - Formula A & B for ophthalmic solution comprising Nepafenac & Moxifloxacin
Table 2 - CQA: Formulation- A & B:
[0078] From the comparative analysis against the drug product CQA, it was observed that Formulation B was superior to formulation A in terms of solubility but both formulations were found to fail in microbial attributes like microbial limit test. The results are tabulated in Table 2. Hydroxy propyl beta cyclodextrin when used as a solubiliser in combination with Octoxynol-
40 as surfactant and mannitol as the osmotic agent was found to solubilize the combination of nepafenac and moxifloxacin, specifically when the ratio of solubiliser:surfactant:osmotic agent is 7:0.04:1.
Table 3- Formula C & D for ophthalmic solution comprising nepafenac & moxifloxacin
Table 4: CQA: Formulation- C & D:
[0079] Fomulation C and Formulation D were prepared by using a selected combination of benzalkonium chloride as preservative, hyrdoxypropyl beta cyclodextrin as solubilizer, poloxamine (Tetronic 1304) as surfactant, Mannitol as osmotic agent and with additional pharmaceutically acceptable excipient.
[0080] The observation of the comparative analysis against the drug product CQA is provided in Table 4. A different category of surfactant and preservative were used in C and D. Although both formulation achieve the required solubility level but only formulation D was able to achieve the microbial limit test. Thus it was observed that a synergistic combination of hydroxypropyl beta cyclodextrin as solubiliser, poloxamine as surfactant, mannitol as osmotic agent is required to get the targeted solubility and benzalkonium chloride in the concentration of 0.008% is required to meet the Microbial test limit. The ratio of the solubilizing ingredients and Preservative required was found to be
0.008(Preservative):9(Solubilizer):0.05(Surfactant): l(osmotic agent). Example 2-
Table 5: - Formula for E, F, G & H for ophthalmic solution comprising nepafenac & moxifloxacin
Table 6: CQA: Formulation- E, F, G & H:
[0081] Formulation E, F, G and H were prepared by using benzalkonium chloride as preservative, hydroxyproply beta cyclodextrin as solubiliser, octoxynol-40 as surfactant and Mannitol as osmotic agent, with additional pharmaceutically acceptable excipients.
[0082] When octoxynol 40 as the surfactant in combination with benzalkonium chloride as preservative was used than an increase in concentration of the solubiliser was required to obtain a stable formulation in terms of the assay, pH and osmolarity. It was further observed that the chelating agent and an astringent in the concentration of 0.08 to 0.1 and 0.002 in combination with the ratio of 0.01 (Preservative):9(solubilizer):0.05(Surfactant): l(osmotic agent) was required to obtain the targeted stability.
Example 3
[0083] The below given formulation was prepared with nepafenac concentration of 0.1 %, 0.2%. 0.3%, 0.4% and compared against the pre-optimized formulation H. It was observed that as nepafenac concentration changes from 0.1 to 0.3% it doesn’t have any impact on product chemical and physical properties. Results are tabulated in Table 8.
Table 7: - Formula for I for ophthalmic solution comprising nepafenac & moxifloxacin
Table 8: CQA: Formulation- 1
Example 4-Process for preparing ophthalmic formulation [0084] The steps involved in the process are as follows:
[0085] Predetermined amount of Disodium Edetate was dissolved in water of injection in a tank and was stirred at temperature 60-70°C for 10 minutes at 250 RPM. The bulk solution was than
cool down up to 55-60°C. After cooling, boric acid was dissolved in the bulk solution at temperature 55-60°C for 10 minute at 250 rpm. Propylene glycol was added to the solution and stirred for 5 minutes at 250 rpm.
[0086] Mannitol was added to the resultant solution at temperature 55-60°C for 5 minutes at 250 rpm, the solution was cooled down to 50-55°C. After cooling the solution zinc chloride was added at temperature 50-55 °C was added and stirred for 5 minutes at 250 rpm. After stirring, hydroxyl propyl betacyclodextrin was added and dissolved in the solution for 5 minutes at 250 rpm. The solution was than cooled upto 30-35°C.
[0087] After the above solution was cooled, moxifloxacin hydrochloride was stirred for 10 minutes at 250 rpm. Benzalkonium chloride solution was stirred for 5 minutes at 250 rpm, after addition of benzalkonium chloride pH was adjusted between 6.50 to 7.50 with 10% w/v sodium hydroxide solution.
Step-2 Preparation of Nepafenac colloidal solution
[0088] Water for injection was taken separately in S.S. container and octoxynol-40 was added, mixed and stirred for 10 minutes at 250 rpm. Appropriate amount of nepafenac was added in the solution and stirred for 30 minutes at 300 rpm at temperature 25-27°C to form a colloidal solution.
Step-3 Mixing the solution obtained in Step- 1 and step-2 to obtain ophthalmic solution
[0089] The nepafenac colloidal solution obtained in step-2 was added to the moxifloxacin HCL bulk solution and stirred for 60 minutes at 300 rpm to obtain a clear solution. The solution was than checked for clarity test and if any solid particles were visible the solution again stirred for 30 minutes or until a clear solution was obtained. Initial pH of the solution was checked and if required pH was adjusted between 6.50 to 7.50 by using 10% w/v sodium hydroxide solution.
[0090] The resultant solution was volume make up to 95% with water for injection at temperature 25-30°C. The solution was than checked for pH and if required, the pH was adjusted between 6.50 to 7.50 by using 10% w/v sodium hydroxide solution and the solution was stirred for 15 minutes.
Example-5 Stability, impurity and solubility study under accelerated conditions
[0091] The prepared ophthalmic solution of 0.1% w/v nepafenac and moxifloxacin hydrochloride was subjected for stability studies under Temperature. 40°±2°C & Relative Humidity 25%
a) Nepafenac Impurity test (by HPLC) under accelerated conditions
b) Moxifloxacin hydrochloride impurity profile (by HPLC) under accelerated conditions
c) Solubility profile under accelerated conditions
Example 6 - Stability, impurity and solubility study under intermediate conditions
[0092] The prepared ophthalmic solution of 0.1 % w/v nepafenac and moxifloxacin hydrochloride was subjected for stability studies under temperature 30°±2°C & relative humidity 35%±5%
a) Nepafenac impurity test (by HPLC) under intermediate conditions
b) Moxifloxacin hydrochloride impurity profile (by HPLC) under intermediate conditions
c) Solubility profile under intermediate conditions
Example 7- stability, impurity and solubility study under long term conditions [0093] The prepared ophthalmic solution of 0.1% w/v nepafenac and moxifloxacin hydrochloride was subjected for stability studies under temp.25°±2°C & relative humidity 40%±5%.
a) Nepafenac impurity profile (by HPLC) under long term conditions
b) Moxifloxacin hydrochloride impurity profile (by HPLC) under long term conditions
c) Solubility profile under long term conditions
Claims
We Claim,
1. An ophthalmic solution comprising a combination of non-steroidal anti-inflammatory drugs (NSAIDs) and fluoroquinolone antibiotic, and pharmaceutically acceptable excipients.
2. The ophthalmic solution according to claim 1, wherein NSAIDs is nepafenac or a pharmaceutically acceptable salt thereof and fluoroquinolone antibiotic is moxifloxacin or a pharmaceutically acceptable salt.
3. The ophthalmic solution according to claim 1 and 2, wherein the combination further comprises a synergistic combination of pharmaceutically acceptable excipients selected from preservative, surfactant, osmotic agent and a solubiliser.
4. The ophthalmic solution according to claim 3, wherein the synergistic combination of preservative, solubiliser, surfactant and osmotic agent are present in the ratio of 0.001:4:0.1:0.5 to 1.0: 12:1:2.
5. The ophthalmic solution according to claim 3 and 4, wherein the synergistic combination of preservative, solubiliser, surfactant and osmotic agent are present in the ratio of 0.01:9:0.5:1
6. The ophthalmic solution according to claim 3-5, wherein the preservative is present in the range of 0.001 % to 0.05 % w/v, the solubiliser is present in the range of 5% w/v to 12% w/v, surfactant is present in the range of 0.005 to about 0.2% (w/v), and the osmotic agent is present in the range of 0.5-2 % (w/v).
7. The ophthalmic solution according to claim 3-6, wherein the composition further comprises pharmaceutically acceptable excipient selected from chelating agent, astringent, soothing agent and pH adjusting agent.
8. The ophthalmic solution according to any of the above claims, wherein the nepafenac is present in an amount ranging from 0.05 to 1 % w/v and Moxifloxacin hydrochloride present in an amount ranging from 0.1 to 2% w/v. . The ophthalmic solution according to any of the above claim wherein the nepafenac impurity A, B, C, D and E levels are less than 1% or below detectable limit
10. The ophthalmic solution according to any of the above claim wherein the moxifloxacin impurity A, B, C, D and E levels are less than 1% or below detectable limit
11. The ophthalmic solution according to any of the above claim wherein Nepafenac has null degradation.
12. An ophthalmic solution according to claim 1, wherein the solution comprises: i. Nepafenac present in an amount ranging from 0.05 to 1% w/v. ii. Moxifloxacin hydrochloride present in an amount ranging from 0.1 to 2% w/v. iii. Surfactant presents in an amount ranging from 0.005 to about 0.2% (w/v) iv. Preservatives present in an amount ranging from about 0.001 % to 0.05 % w/v. v. Solubilizer presents in an amount ranging from about 5% w/v to 12%. vi. Osmotic/tonicity-adjusting agents presents in an amount ranging from about 0.5-2 %w/v.
13. An ophthalmic solution according to claim 13, wherein the surfactant is a non-ionic surfactant selected from the group consisting of polysorbate 80, polysorbate 60, poloxamers polysorbate, 40, polysorbate 20, cremophors, tyloxapols, poloxamers, benzalkonium chloride, benzethonium chloride, cetyl alcohol, carbomer, cholesterol, cocamidopropyl betaine, glyceryl monostearate, lanolin alcohols, lauralkonium chlorides, n lauroylsarcosine, nonoxynol 9, octoxynol 40, polyoxyl 35 castor oil, polyoxyl 40
hydrogenated castor oil, polyoxyl 40 stearate, sorbitan monolaurate, sorbitan monooleate, or a combination thereof. An ophthalmic solution according to claim 13, wherein preservative selected from the group consisting of benzalkonium chloride (BAK), benzethonium chloride, benzyl alcohol, busan, cetrimide, chlorhexidine, chlorobutanol, mercurial preservatives, or phenylmercuric nitrate, phenylmercuric acetate, thimerosal, phenylethyl alcohol and or a combination thereof. An ophthalmic solution according to claim 13, wherein the solubilizer is cyclodextrins derivatives selected from the group consisting of hydroxypropyl-beta-cyclodextrin (HP-P- CD), sulfobutylether-P-cyclodextrin, P-cyclodextrin, alpha Cyclodextrin, Gamma
Cyclodextrin or combination thereof. An ophthalmic solution according to claim 13, wherein the Osmotic/tonicity-adjusting agent is selected from the group consisting of sodium chloride, potassium chloride, calcium chloride, sodium bromide, sodium phosphate sodium sulfate, mannitol, glycerol, sorbitol, propylene glycol, dextrose, sucrose, polyethylene glycols (PEG) or combinations thereof. An ophthalmic solution according to claim 1, wherein the solution is used for the treatment of post-surgery associated ocular microbial infection and inflammation.
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| US20210077299A1 (en) * | 2015-07-22 | 2021-03-18 | Incept, Llc | Coated implants |
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| US20210077299A1 (en) * | 2015-07-22 | 2021-03-18 | Incept, Llc | Coated implants |
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| Title |
|---|
| SARKAR SANDIP, BARDOLOI NARAYAN, DEB AMIT KUMAR: "Comparison between 0.1% Nepafenac and 1% Prednisolone Eye Drop in Postoperative Management Following Micro-incisional Cataract Surgery", KOREAN JOURNAL OF OPHTHALMOLOGY, KOREAN OPHTHALMOLOGICAL SOCIETY, KR, vol. 35, no. 3, 5 June 2021 (2021-06-05), KR , pages 188 - 197, XP093110148, ISSN: 1011-8942, DOI: 10.3341/kjo.2020.0135 * |
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