Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

• CAIs carbonic anhydrase inhibitors
• This compound is disclosed in U.S. Pat. No. 5,378,703 (Dean, et al).
• Brinzolamide is highly specific, no-competitive, reversible and effective inhibitor of carbonic anhydrase II, able to suppress formation of aqueous humor which reduces intraocular pressure
• Brinzolamide can be used as first line medication due to fewer side effects and as monotherapy in patients unresponsive to beta-blockers or in patients in whom beta-blockers are contra-indicated, or as adjunctive therapy to beta blockers and prostaglandins.
• IOP intraocular pressure
• brinzolamide because of the poor aqueous solubility of brinzolamide, the clinical application is extremely limited.
• US Pat. No. 6,071,904 discloses ophthalmic suspensions containing brinzolamide and processes for manufacturing the suspensions.
• Azopt ® (brinzolamide) commercial preparation of Brinzolamide available in the market is an aqueous multiple use suspension composed of 1% w/v Brinzolamide.
• this formulation is associated with side effects, such as blurred vision, pain, discomfort (stinging and burning), eye discharge, blepharitis, dry eye, and taste perversion and the limitations of requirement of multiple dosing required (3 to 4 time per day) and dosing inaccuracy.
• the bioavailability of the suspension formulation is reduced because of the fact that the drug must be dissolved in order to be absorbed before being eliminated from the eye surface.
• the suspension formulation also suffer the drawback that the particulates have a potential to cause irritation, increasing the likelihood that they would be rubbed or washed from the eye.
• manufacturing of sterile suspension formulation for ophthalmic use has its own challenges like particle size reduction, degree of homogenization required and ability of the formulation to remains in to the suspended state without particle aggregation throughout the shelf life.
• in-situ gelling nanoemulsion ophthalmic compositions of brinzolamide which can deliver drug at the right dosage to the eye with the convenience of dosing just like any other ophthalmic solution.
• Entrapment of drug in oil phase of nanoemulsion can protect it from degradation, metabolism and cellular efflux during the course of drug delivery.
• Application method of in-situ gelling nanoemulsion is simple like conventional drop and also avoids the discomfort associated with the other dosage forms.
• the present invention provides a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising of oil in water type emulsion that increases the bioavailability of the drug.
• Said emulsion is stable during storage without the need of including in its composition the potentially irritating products and ones that can cause cataractogenic process.
• the invention relates to a pharmaceutical in- situ gelling nanoemulsion ophthalmic compositions comprising brinzolamide and process of preparing the same.
• the nanoemulsion ophthalmic compositions is a sterile composition.
• the corticosteroid is selected from the group consisting of prednisolone, methylprednisolone, difluprednate, prednisone acetate, prednisolone sodium phosphate, triamcinolone, fluocinolone; fluorometholone, betamethasone, medrysone, rimexolone, dexamethasone, hydrocortisone, loteprednol and a combination thereof.
• the anti-inflammatory is selected from a group consisting of a corticosteroid, a non-steroidal anti-inflammatory drug (“NS AID”), thymosin beta 4, and a combination thereof.
• the NSAID is selected from the group consisting of diclofenac, flubiprofen, ketorolac, ketorolac thromethamine, bromfenac, nepafenac, flurbiprofen, and a combination thereof.
• the beta-adrenergic receptor agonist is selected from the group consisting of dopexamine, epinephrine, isoprenaline, isoproterenol, levalbuterol, salbutamol, albuterol, and a combination thereof.
• the beta-blocker is selected from the group consisting of timolol, propranolo, sotalol, nadolol, betaxolol, levobetaxolol and a combination thereof.
• the prostaglandins analog is selected from the group consisting of latanoprost, bimatoprost, travoprost, tafluprost, and a combination thereof.
• the carbonic anhydrase inhibitor is selected from the group consisting of dorzolamide, methazolamide, dichlorphenamide, and a combination thereof.
• the alpha 2 adrenergic receptor agonists include, but are not limited to, brimonidine, 4-NEMD, 7-Me-marsanidine, agmatine, apraclonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, marsanidine, medetomidine, methamphetamine, mivazerol, rilmenidine, romifidine, talipexole, tizanidine, tolonidine, xylazine, xylometazoline, and the like including pharmaceutically acceptable salts thereof.
• antibiotics and/or antibacterial includes besifloxacin, neomycin; polymyxin b, tobramycin, sulfacetamide sodium, gentamicin, oxytetracycline, natamycin, chloramphenicol, tetracycline, gatifloxacin, moxifloxacin and a combination thereof.
• the antihistamine/mast cell stabiliser include, but are not limited to, levocabastine, alcaftadine, azelastine, bepotastine, emedastine, epinastine, ketotifen, olopatadine and a combination thereof.
• the concentration of the brinzolamide present in the pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions according to the present invention is in the range of about 0.02% to 5% w/v of composition; preferably 0.01, 0.5, 0.75, 1, 2, 3, 4 or 5% w/v of composition or intermediate fraction thereof.
• An emulsion refers to a liquid-liquid dispersion system in which at least one liquid is dispersed in another liquid with which it is immiscible, and the emulsion generally has a size distribution ranging from 0.1 to several tens of micrometers.
• the water is continuous phase and an oil is dispersed phase i.e. oil globules dispersed in the water.
• Nanoemulsion are oil-in-water emulsions, the oil globules of which have a very fine particle size, i.e. a mean globule size of 50 nm to 250 nm.
• the globule size were measured by using DelsaTM Nano C, Beckman Coulter connected with DelsaTM Nano UI software version 3.73.
• “In-situ gel emulsion” is an emulsion that undergoes gelation in situ (at physiological site of application), to form a gel within 30 seconds of administration.
• the viscosity of gel formed in-situ is at least twice of the initial formulation.
• viscosity of gel formed in-situ is increased at least 3 to 9 times of the initial formulation.
• viscosity of gel formed in-situ is increased at least 5-7 times of initial formulation.
• the oil soluble or partly oil soluble drugs such as brinzolamide are included in an oil in water type emulsion to be administered in the eye thus increasing the bioavailability of the same with regard to other compositions.
• Said vehicle comprises an oil and a non-ionic surfactant, as well as enough preservative to meet the requirements of the pharmacopeia.
• the present invention can also be formulated as preservative free pharmaceutical composition when stored in specialized containers which prevent microbial ingress into the container and retains the sterility of the content during its shelf life and in-use period.
• NOVELIA® manufactured by Nemera.
• the oil that forms part of the emulsion may be a vegetable oil, an animal oil, a mineral oil, fatty acids, a medium chain triglyceride, fatty alcohols or any combination of these oils and/or oily substances that are well tolerated at the eye level.
• the preferred oils are medium chain triglycerides, vegetable oils, olive oil, sunflower seed oil, sesame seed oil with an acid value less than 0.5, castor oil, mineral oil and glyceryl monostearate (GMS) or combination thereof.
• the more preferred oils are castor oil, mineral oil and glyceryl monostearate (GMS) or combination thereof.
• the oil phase contains the brinzolamide totally or partially solubilized in the oil.
• oil is present in concentration preferably between 0.1% and 25% w/v of composition. In a preferred embodiment the oil present in 2% w/v to 20% w/v of composition. In most preferred embodiment oil component is present in 5% w/v to 10% w/v of composition.
• the surfactant may be primary or secondary surfactant.
• primary surfactant is surfactant used in to increase solubility of brinzolamide in oil.
• secondary surfactant is used as emulsifier in aqueous phase of emulsion.
• primary surfactant and secondary surfactant are selected from the group consisting of, but not limited to, sorbitan esters (such as Span or Arlacel), glycerol esters (such as glycerin mono stearate), polyethylene glycol esters (such as polyethylene glycol stearate), block polymers (such as poloxamers (Pluronics®)), acrylic polymers (such as Pemulen®), ethoxylated fatty esters (such as polyoxyl 35 castor oil ,Cremophor® RH-40), ethoxylated alcohols (such as Brij®), ethoxylated fatty acids (such as polysorbate 80, Tween or Tween 20), monoglycerides, silicon based surfactants alone or in combination.
• sorbitan esters such as Span or Arlacel
• glycerol esters such as glycerin mono stearate
• polyethylene glycol esters such as polyethylene glycol stearate
• the primary surfactant and secondary surfactant is polyoxyl 35 castor oil and polysorbate 80 used alone or in combination.
• primary surfactant is polyoxyl 35 castor oil and secondary surfactant is polysorbate 80.
• the primary surfactant is ethoxylated fatty esters (polyoxyl 35 castor oil) and the secondary surfactant is ethoxylated fatty acids (polysorbate 80).
• the ratio of primary surfactant to secondary surfactant is 1:2, 1: 1.5, 1: 1, 1.5: 1, 2: 1, 2.5: 1, 3: 1 or fractions in between. In more preferred embodiment the ratio of primary to secondary surfactant is 1.5: 1.
• the thickener is a polymer material having an ion-sensitive characteristics.
• ionic strength dependent in-situ gel polymers are polymers that undergo a sol-gel transition upon contact with physiological ions (Na + , K + , Ca ++ , Mg ++ etc.) in the site of application or site of action.
• Example of ionic strength in-situ gel polymers include various types of sodium alginate, gellan gum, guar gum, pectin and sodium hyaluronate.
• the thickener is gellan gum.
• ionic strength in-situ gel polymer may be used alone or in combination.
• in-situ gel polymer can be combined with other thickening polymers like one or more of hypromellose (HPMC), methyl cellulose (MC), polyvinyl pyrrolidone (PVP), polyvinylalcohol (PVA), and Poly(acrylic acid) polymers such as carbomers, and the like can also be added.
• HPMC hypromellose
• MC methyl cellulose
• PVP polyvinyl pyrrolidone
• PVA polyvinylalcohol
• Poly(acrylic acid) polymers such as carbomers, and the like can also be added.
• thickener is present in concentration preferably about 0.10% w/v to 0.50%w/v of the composition. In a preferred embodiment thickener is present in about 0.15% to 0.30% w/v of the composition. In most preferred embodiment thickener is present in about 0.20% to 0.25%w/v of the composition. In one of the most preferred embodiments the present invention comprises gellan gum as a thickener in concentration about 0.20% to 0.25% w/v of the composition.
• the composition may optionally further comprise of one or more of the following components; isotonizing agents, stabilizers, buffers, preservatives and/or antioxidants.
• the composition of the present invention may include an isotonizing agent such as mannitol, glycerin, glycerol, sorbitol, glucose or combination thereof.
• the isotonizing agent is glycerin, glycerol or combination thereof.
• composition of present invention may contain stabilizers such as sodium edatate, citric acid or combination thereof; buffers such as tris(hydroxymethyl)aminomethane, sodium phosphate and potassium phosphate, sodium citrate, sodium carbonate and sodium bicarbonate or combination thereof; preservatives such as quaternary ammonium compound like benzalkonium chloride, chlorobutanol, sodium perborate or combination thereof.
• preservative used is benzalkonium chloride.
• compositions of the present invention may be sterilized by filtration or they may be obtained by sterilization of the aqueous phase and the oily phase and subsequently mixing and emulsifying in aspectic conditions.
• an embodiment discloses a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising;
• Another embodiment disclose a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising;
• oil phase includes oil globules having a mean globule size of less than 250 nm.
• Another embodiment disclose a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising; brinzolamide;
• oil phase dispersed in an aqueous phase, wherein the an oil phase selected from the group comprising of castor oil, mineral oil, glyceryl monostearate or combination thereof;
• a primary and/or a secondary surfactant selected from the group comprising of polyoxyl 35 castor oil, polysorabte 80 alone or combination thereof;
• a thickener which is gellan gum
• oil phase includes oil globules having a mean globule size of less than 250 nm;
• Another embodiment disclose a pharmaceutical in-situ gelling nanoemulsion ophthalmic compositions comprising;
• oil phase dispersed in an aqueous phase, wherein the an oil phase selected from the group comprising of castor oil, mineral oil, glyceryl monostearate or combination thereof;
• a primary and/or a secondary surfactant selected from the group comprising of polyoxyl 35 castor oil, polysorabte 80 alone or combination thereof;
• a thickener which is gellan gum
• oil phase includes oil globules having a mean globule size of less than 250 nm;
• brinzolamide is dispersed in the oil phase with one or more primary surfactant
• Another embodiment disclose a pharmaceutical preservative free in-situ gelling nanoemulsion ophthalmic compositions comprising;
• Viscosity of the nanoemulsion was determined by Rheocalc T 1.2.19 (Brookfield Engineering Labs Inc) using spindly SC4-18 at 25.0 ⁇ 0.5°C. The rotation speed was 50 rpm and the viscosity was determined in centipoise from rheogram plotted using shear stress (dyn/cm 2 ) and shear rate (1/s).
• the viscosity of the present invention is 5cps to 200cps. In preferred embodiment of the present invention, viscosity is 1Ocps to 100 cps. In preferred embodiment of present invention, the viscosity is 25cps to 75cps.
• the viscosity of gel formed in- situ is at least twice of the initial formulation. In a preferred embodiment viscosity of gel formed in-situ is increased at least 3 to 9 times of the initial formulation. In most preferred embodiment viscosity of gel formed in-situ is increased at least 5-7 times of initial solution.
• In-situ gelling of the present invention was determined by in-vitro study by placing 4mL of brinzloamide formulation of present invention in a vial containing about 2mLof pH 7.4 stimulated tear fluid (STF). Viscosity of in-situ nanoemulsion gel was determined by Rheocalc T 1.2.19 (Brookfield Engineering Labs Inc) using spindly SC4-18 at 25.0 ⁇ 0.5°C. The rotation speed was 50 rpm and the viscosity was determined in centipoise from rheogram plotted using shear stress (dyn/cm 2 ) and shear rate (1/s).
• In situ gelling time was determined by placing a drop of brinzolamide formulation of present invention in a vial containing about 2 mL of pH 7.4 stimulated tear fluid (STF).
• the AUC (DIOP vs.t) of DIOP vs. time curve calculated using trapezoid rule and the AUC Rel was calculated using the following equation;
• a pharmaceutical in- situ gelling nanoemulsion ophthalmic composition shows a decrease in elevated IOP in glaucomatous rabbits for a longer period of time as compared to reference formulation.
• the AUC (DIOP vs. t) of the present nanoemulsion was about 2-8 times higher than that of reference product.
• In-situ gelling nanoemulsion was prepared by using combination of high speed and high pressure homogenization technique.
• the drug solution phase (oil phase) was prepared by dissolving brinzolamide in mixture of castor oil and polyoxyl 35 castor oil preheated at 70-80°C under stirring using magnetic stirrer.
• Tris buffer tris(hydroxymethyl)aminomethane
• the aqueous phase was then heated at 70-80°C and Polysorbate 80, Gellan gum, Glycerol and Benzalkonium chloride were added under stirring.
• Drug solution phase was added drop wise in aqueous phase under homogenization at 12000 to 16000 RPM and homogenization continued for 45 minutes.
• This micro emulsion then passed through high pressure homogenizer at 1000-1200 bar pressure for 30 minutes.
• the pharmacodynamic studied conducted with optimized formulations of brinzolamide in-situ gelling nanoemulsion showed decrease in elevated IOP in glaucomatous rabbits for a longer period of time as compared to reference formulation.
• the AUC (DIOP vs. t) for the selected nanoemulsions were about 3-5 times higher than that of reference product.
• In-situ gelling nanoemulsion was prepared by using the method as disclosed in example 1. The result of this study is shown in Table 2 and Fig 2.
• Imax/ Dose is DIOR (mm Hg) normalized to dose, t max time taken for DIOR (h).
• AUC Rei ratio of AUC (DIOP vs. t) test (designed formulations) to AUC (DIOP vs. t) reference (marketed eyedrops).
• In-situ gelling nanoemulsion of example 3 and 4 were prepared by using the method as disclosed in example 1.

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