WO2008015695A2 - Inclusion complex of olopatadine and cyclodextrin - Google Patents

Inclusion complex of olopatadine and cyclodextrin Download PDF

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Publication number
WO2008015695A2
WO2008015695A2 PCT/IN2007/000199 IN2007000199W WO2008015695A2 WO 2008015695 A2 WO2008015695 A2 WO 2008015695A2 IN 2007000199 W IN2007000199 W IN 2007000199W WO 2008015695 A2 WO2008015695 A2 WO 2008015695A2
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Prior art keywords
solution
olopatadine
cyclodextrin
present
hydroxypropyl
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PCT/IN2007/000199
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French (fr)
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WO2008015695A3 (en
Inventor
Subhas Balaram Bhowmick
Ritu Nitin Laddha
Surekha Khopade
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Sun Pharmaceutical Industries Limited
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Publication of WO2008015695A2 publication Critical patent/WO2008015695A2/en
Publication of WO2008015695A3 publication Critical patent/WO2008015695A3/en

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    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/0043—Nose
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to inclusion complex of olopatadine in cyclodextrin and to aqueous solutions oF olopatadine or its pharmaceutically acceptable salt for topical administration and process for preparation thereof.
  • Olopaiadine hydrochloride is a carboxyl'ic acid derivative of doxepin, chemically described as (.Z)- I l -[3-(Dimethylamino) propylidene]-6, 1 1-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride [C 21 H 21 NO 3 .HCl], as disclosed in U.S. Pat Nos.4,87 1 ,865 and 4.923,892, b ⁇ lh assigned to Burroughs Wellcome. Olopatadine has antihistami e and antiasthmatic activity.
  • Olopaladine hydrochloride is commercially available in the U. S as U. 1 % and U.2% sterile ophthalmic solutions under the brand names PATANOL* and PATADAY 1 ' 1 respectively, both marketed by Alcon.
  • PATANOL ® is indicated for the treatment of signs and symptoms of allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride 0 equivalent to 0.1 % olopatadine, 0.01% benzalkonium chloride as preservative, dibasic sodium phosphate, sodium chloride, hydrochloric acid and / or sodium hydroxide (to adjust the pH) and purilled water.
  • PATADAY" 1' is indicated for the treatment " of ocular itching associated with allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride equivalent to 0.2% 5 ⁇ l ⁇ patadine, 0.01 % benzalkonium chloride as preservative, povidone, dibasic sodium phosphate, sodium chloride, edetale disodium. hydrochloric acid and / or sodium hydroxide (to adjust the p H) and purilled water. It has a pH of about 7, and osmolality ⁇ l ' ab ⁇ ut 300mOsm/kg.
  • Une obstacle for preparing olopaiadine hydrochloride aqueous solutions lor topical deliver) is0 the stability of the aqueous solutions of olopatadine hydrochloride over the storage period.
  • Olopaiadine aqueous solutions having a concentrations of 0. 17%vv/v or higher were found to be unstable over extended storage periods.
  • the olopatadine hydrochloride precipitates or crystallizes out of the solution when used in concentrations higher than U.17%w/v.
  • United Stales Patent No.6,995, 186 (Alcon Inc., 2006, the M 86 patent) discloses topically administrable solution composition for treating allergic or inflammatory disorders of the eye and nose comprising olopatadine and a polymeric ingredient, where the polymeric ingredient is a polymeric physical stability enhancing ingredient consisting essentially of polyvinylpyrrolidone or polystyrene sulfonic acid in an amount sufficient to enhance the physical stability of the solution, and wherein the composition does not contain polyvinyl alcohol, polyvinyl acrylic acid, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, xanthan gum. Polyvinyl alcohol, polyvinyl acrylic acid, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose and xanthan gum have been disclosed in the " 1 86 patent to cause physical instability of olopatadine solutions.
  • hydroxypiOpyl- ⁇ -cyclodextrin H.P ⁇ CD
  • polysorbate 20 polysorbate 80
  • propylene glycol hydroxypropyl methylcellulose 2910
  • HPMC E4M premium propylene glycol
  • polyvinylpyrrolidone K-30 polyvinylpyrrolidone K-30
  • xanthan gum sodium carboxymethylcellulose (Sodium CMC)
  • carbopol 934P polyvinyl alcohol and mixtures thereof.
  • stable aqueous topical solutions of olopatadine hydrochloride can be prepared by forming an inclusion complex with a hydroxyalkyl clodextrin, preferably hydiOxypropyl- ⁇ -cyclodextrin (HP ⁇ CD).
  • a hydroxyalkyl clodextrin preferably hydiOxypropyl- ⁇ -cyclodextrin (HP ⁇ CD).
  • HPMC hydroxypropyl methylcellulose
  • an aqueous topical solution comprising a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt: hydroxyalkyl ⁇ -cylcodextrin, preferably hydroxypropyl ⁇ -cylcodextrin and hydroxypropyl methyl cellulose in amount sufficient to enhance the physical stability of the solution.
  • the present invention provides an inclusion complex of olopatadine ⁇ r its pharmaceutically acceptable salt and hydroxyalkyl- ⁇ -cyclodextrin, particularly hydr ⁇ xypr ⁇ pyl- ⁇ -cyclodexlrin.
  • the present invention also provides an aqueous topical solution, comprising a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt; hydroxyalkyl- ⁇ - cyclodextrin, particularly hydroxypropyl- ⁇ -cyclodextrin and hydroxypropyl methylcellulose in an amount sufficient to enhance the physical stability of the solution.
  • the lerm "in an amount sufficient to enhance the physical stability of the solution”, as used herein means that the amount of hydroxyalkyl- ⁇ -cyclodextrin, particularly hydroxypropyl- ⁇ - cycl ⁇ dextrin .is sufficient to form a complex with olopatadine or its pharmaceutically acceptable salt and thus keep it in solution, i.e. Prevent its precipitation or crystallization.
  • the aqueous topical solution contains olopatadine or its pharmaceutically acceptable salts.
  • Examples of the pharmaceutically acceptable salts of olopatadine include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, fumarate, tartrate and citrate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; metal salts such as aluminum salt and zinc salt; and organic amine addition salts such as triethylamine addition salt (also known as trometh amine), morpholine addition salt and piperidine addition salt.
  • the olopatadine for use in the aqueous topical solution is a hydrochloride salt.
  • the olopatadine hydrochloride salt may be used in concentrations such that it is equivalent to the olopatadine free base in amount ranging from about 0.1 7% to about 0.62%.
  • the solution formulations intended for use in the eye contain about 0. 1 7% to about 0.25% olopatadine and the solution formulations intended for use in the nose contain about 0.35% to about 0.62% olopatadine,
  • the aqueous topical solution comprises cyclodextrin to enhance the physical stability of the solution.
  • Cyclodexlrins are a group of structurally related saccharides which are formed by enzymatic cyclization of starch by a group of amylases termed glycosyltra ⁇ sferases.
  • Cyclodextrins are cyclic oligosaccharides, consisting of (alpha- 1 ,4)-l inked alpha-D-glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface.
  • cyclodextrins form inclusion complexes with many drugs through a process in which the water molecules located in the central cavity are replaced by ' either the whole drug molecule, or more frequently, by some lipophilic portion of the drug structure.
  • the drug molecules may be dissociated through complex dilution, by replacement of the included drug by some other suitable molecule or, the drug may be transferred to the matrix for which it has the highest affinity.
  • the complexes are in dynamic equilibrium with free drug and cyclodexlrin molecules.
  • the complexes are usually prepared by addition of an excess amount of the drug to an aqueous cyclodextrin solution.
  • cyclodextrins are alpha- eyclodexlrin, ⁇ -cyclodextrin and gamma-cyclodextrin consisting of 6, 7 and 8 glucopyranose units, respectively and their ., derivatives, ⁇ -cyclodextrin appears to be the most useful pharmaceutical complexing agent due to its cavity size, availability and low cost.
  • cyelodextrin derivatives that may be used in the pharmaceutical compositions of present invention include the hydroxypropyl derivatives of alpha-, beta- and gamma-cyclodextrin, sulfoalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin, alkylated cyclodextrins such as the randomly methylated beta-cyclodextrin, and various branched cyclodextrins such as glucusyl- and maltosyl beta-cyclodextrin, and the like, and mixtures thereof.
  • sulfoalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin
  • alkylated cyclodextrins such as the randomly methylated beta-cyclodextrin
  • various branched cyclodextrins such as glucusyl-
  • the preferred cyclodextrins for use in the present invention include alky I cyclodextrins, hydroxy alkyl cyelodextrin, such as hydroxy propyl beta-cyclodextrin, carboxy alky 1 cyclodextrins and sulf ⁇ alkyl ether cyelodextrin, such as sulfo butyl ether beta-cyclodextrin.
  • Suitable cyclodextrins for use in the present invention non-exclusively include alphci-cyclodextrin; bela- cyel ⁇ dextrin; gamma-cycloclextrin; methyl alpha-cyclodextrin; methyl beta-cyclodexlrin; methyl gamma-cyclodextrin; ethyl beta-cyclodextrin; butyl alpha-cyctodextrin; butyl beta-cyclodextrin; butyl gamma-cyclodextrin; pentyl gamma-cyclodextrin; hydroxyethyl beta-cyclodextrin; hydroxyethyl gamma-cyclodextrin; 2-hydiOxypropyl alpha-cyclodextrin; 2-hydroxypropyl beta- cyclodextrin; 2-hydroxypropyl gamma-cyclodextr
  • the most preferred cyelodextrin for use in the pharmaceutical composition of the present invention is hydroxy propyl beta-cyclodextrin.
  • hydroxypropyl beta-cyclodextrin may be used in concentrations ranging from about 0.1% to about 20%w/v of the composition, and more preferably used in concentrations ranging from about 1.0% to about 10% w/v of the composition.
  • concentration of hydr ⁇ xypropyl bela-cyclodextrin is in the range from about 1.0% to about 5%; for solutions meant for nasal administration, the concentration of hydroxypropyl bela-cyclodexli ⁇ n is in the range from about 1.0% to about 10%.
  • Olopatadine or its pharmaceutically acceptable salt forms an inclusion complex with cyclodextrins, particularly hydroxyalkyl- ⁇ -cyclodextrin, more particularly hydroxypropyl- ⁇ -cyclodextrin .
  • inclusion complex refers to a combination of olopatadine or its pharmaceutically acceptable salt as defined above and a cyclodextrin wherein the olopatadine or its pharmaceutically acceptable salt or a portion thereof is associated with the cyclodextrin.
  • the olopatadine or its pharmaceutically acceptable sail ⁇ r guest molecule is included within the cavity of the cyclodextrin, or the host molecule, wherein the cavity of the cyclodextrin is the space created by the cyclodextrin torous and the cyclodextrin substiluents.
  • the ratio of olopatadine or its pharmaceutically acceptable salt to hydroxypropyl ⁇ -cylc ⁇ dextrin in the inclusion complex is from about 1 : 1 .05 to about 1 :50 b ⁇ weight.
  • the amount of hydroxypropyl ⁇ -eylcodexli ⁇ n present in the inclusion complex is sufficient to enhance the physical stability of the olopatadine solution.
  • the composition further includes hydroxypropyl methylcellulose (HPMC).
  • HPMC hydroxypropyl methylcellulose
  • HPMC hydroxypropyl methylcellulose
  • Various grades of hydroxypropyl methylcellulose may be used in the present invention. The grades commercially available are categorized depending upon the chemical substitution and hydration rates, and may be used in the compositions of the present invention.
  • Hydroxypropyl methylcellulose having a methoxy content of 19-24 % and hydroxypropyl content of 7- 12 % with a fastest relative rate of hydration is available commercially under the brand name of Methocel Grade K.
  • Hydroxypropyl methylcellulose w ith 28-30 % methoxy content and -7- 12 % of hydroxypropyl content with a faster relative hydration rale as compared to the above grade is available commercially under the brand name ⁇ f Methocel Grade E.
  • hydroxypropyl methylcellulose with 27-30 % methoxy content and 4.0 - 7.5 % of hydroxypropyl content with a slow relative hydration rate is available as Methocel F grade and that with 27.5-3 1 .5 % methoxy content and 0 % hydroxypropyl content and with slowest rate of hydration is available as Methocel Grade A.
  • hydroxypropyl methylcellulose a 2%w/v aqueous solution of which has a viscosity of 4000 cps at 20 ⁇ C, and which is commercially available as METHOCEL E4M, is used.
  • hydroxypropyl methylcellulose may be used concentrations ranging from about 0.001 % to about 5%, and more preferably in concentrations ranging from about 0.01 % to about 1 % w/v.
  • the aqueous topical solution of the present invention may include an effective amount of an antimicrobial preservative.
  • pharmaceutically acceptable preservatives that may be used in the present invention include, but are not limited to. beiizeUi ⁇ nium chloride, butylparaben, methyl paraben, ethyl paraben, propyl paraben, benzalk ⁇ nium chloride, cdyl pyridinium chloride, thimerosai, chlorobutanol, phenylethyl alcohol, benzyl alcohol, potassium sorbate, sodium benzoate, sorbic acid and the like and mixtures thereof.
  • the preferred preservative for the aqueous topical solution of the present invention is benzalkonium chloride. It may be used in an amount ranging from about 0.005% to about l %w/v.
  • the aqueous topical solution of the present invention may include an effective amount of a chelating agent.
  • Chelating agents remove trace amounts of metal ions such as iron, copper and lead and act as antioxidants, as otherwise these heavy metals catalyze oxidation reactions.
  • Presently preferred chelating agents include different salts of edetic acid. These non-e.xclusively include edetate disodium, edetate calcium disodium, edetate tetrasodium, edetate trisodium, and the like and mixtures thereof.
  • the preferred chelating agent for the aqueous topical solution of the present invention is disodium edetate. It may be present in the concentrations ranging From about 0.005% to about 0. 1 % vv/v.
  • the aqueous topical solution of the present invention may further include an effective amount ⁇ f a tonicity agent.
  • tonicity agents that may be used in the aqueous topical solution of the present invention include all pharmaceutically acceptable and pharmacologically inert water- soluble compounds referred to in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing Company, Easton, Pennsylvania (1995).
  • Preferred tonicity agent is sodium chloride, which may be added in an amount which renders the solution isoosmotic.
  • the aqueous topical solution is intended to be administered as nasal solution or eye drops.
  • the osmolality may be adjusted preferably between 150 to 450 mOsm, and more preferably between 250 to 350 mOsm.
  • the aqueous topical solution of the present invention may include an effective amount of buffering agent.
  • the buffering agents are included to minimize any change in pH during shelf life of the aqueous topical solution.
  • Examples of buffering agents include, but are not limited to, lactic acid, citric acid, tartaric acid, phosphoric acid, acetic acid, hydrochloric acid, nitric acid, tr ⁇ methainine, sodium or potassium melaphosphate, sodium or potassium phosphate, dibasic sodium phosphate dodecahydrate, sodium or potassium acetate, ammonia, sodium carbonate.
  • the aqueous topical solution intended for ophthalmic administration has a pH 4 to 8, preferably pH of 6.5 to 7.5, and most preferably a pH of 6.8 to
  • the aqueous topical solution intended for nasal administration has a pH of 3.0 to 6.0, and most preferably a pH of 3.5 to 5.0.
  • the aqueous topical solution of the present invention may optionally include an effective amount of an antioxidant.
  • the antioxidant may be one or more antioxidants, reducing agents and antioxidant synergist, and may be selected from acetyl cysteine, alpha tocopherol acetate, d- alpha tocopherol, dl-alpha tocopherol, ascorbyl palmitate, butylaled hydr ⁇ xyanisole (BHAj, biilylaled hydroxytoluene (BHT), cysteine, cysteine hydrochloride, propyl gallate, ascorbic acid, calcium ascorbate, calcium bisulphate, calcium sulphite, ascorbic acid, isoascorbic acid, potassium metabisulfile, sodium ascorbate, sodium bisulphate, sodium metabisulphite.
  • the aqueous topical solution of the present invention may optionally include an effective amount of viscosity enhancer.
  • An increase in viscosity of topical solutions will result in a longer residence time in eye or nose, providing a longer time for drug absorption and effect.
  • the list of viscosity enhancers that are conventionally used for topical solutions are given in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing Company, Easton, Pennsylvania ( 1995).
  • the viscosity enhancers may be used in concentrations conventional to the pharmaceutical art.
  • the aqueous topical solution of the present invention is chemically stable.
  • the term "chemically stable" as used herein means that the aqueous topical solution when stored on the shelf for up Io two years has less than 2% total degradation products as determined by the area norinali/aliun method.
  • the chemical stability may be assessed by accelerated stability testing.
  • the aqueous topical solution of the present, invention may be stored in a closed container at 30 l 'C / 65% relative humidity or 40 u C / 75% relative humidity or 2-8 ⁇ C (refrigeration condition) and analyzed at one month duration for up to three months or six months. It is generally accepted that a product is stable on the shelf over a period of two years, if the product is stable for three months at an accelerated stability test condition of 40 l) C / 75% relative humidity.
  • the chemical stability is assessed by evaluating the percent total degradation of olopatadine aqueous topical solutions that are subjected to accelerated stability test conditions and ambient conditions using high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Buffer 6.8 gm KH2PO 4 is dissolved in 1000ml of water and the solution is adjusted to a pH of 4.5 with orthophosphoric acid.
  • Standard preparation 50/65 mg olopatadine HCI is dissolved in 100 ml with mobile phase. A sample of 5 ml is diluted to 50 ml with mobi le phase
  • Test preparation 2 ml of the olopatadine HCl solution is diluted with 200 ml of mobile phase
  • the percent total degradation products in the olopatadine aqueous topical solution is calculated by area normalization method (excluding peaks from placebo and diluent, if any) from the chr ⁇ matogram obtained by injecting 20 ⁇ l of test preparation as described above in chromatographic conditions for analyzing degradation of olopatadine.
  • area normalization method excluding peaks from placebo and diluent, if any
  • the formula for calculating the percent total degradation products in olopatadine aqueous topical solution is given below:
  • the value of percent individual degradation 5 product should not be more than 1 % and the percent total degradation products should not be more than 2%.
  • a value of percent total degradation products lesser than 2% in the aqueous topical solution of the present invention is considered to be acceptable.
  • the aqueous topical solution may be I D prepared by the following process: a. Dissolving hydiOxypropyl- ⁇ -cyclodexlrin(HP ⁇ CD) in water for injection till clear solution is formed. b. Dissolving tonicity agent, buffering agent, chelating agent and antimicrobial preservative in the bulk solution of step (a) and stirring to get clear solution.
  • the aqueous topical solution of the present invention may be Formulated to be dispensed in suitable containers as drops, sprays, metered sprays, aerosols and metered aerosols.
  • the aqueous 5 topical solution to be delivered as nasal spray may be filled in containers fitted with a spray pump with or without a metering valve.
  • the aqueous topical solution to be delivered as aerosol may be filled into canisters suitable for delivering pharmaceutical aerosols.
  • Canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle, or preferably a metal can, for example an aluminium can0 which may optionally be anodized, lacquer-coated and / or plastic-coaled, which container is closed with a metering valve.
  • the metering valves are designed to deliver a metered amount of the aqueous solution per actuation, and have a gasket to prevent leakage of propellant through the valve.
  • the aqueous topical solution is packed in opaque plastic or glass containers.
  • the container for an ophthalmic solution is an opaque, white low-density polyethylene container that has been sterilized using ethylene oxide like liipolen bottle.
  • the container for a nasal solution is a U . S. P type I amber color glass container equipped with a suitable nasal spray pump.
  • compositions shown in table 1 and table 2 below were prepared and subjected to stability studies for evaluating the physical stability.
  • the vials were studied For stability at two temperature conditions: one at room temperature (25° + 2 0 C) and the other at refrigeration temperature (2-8 11 C) condition.
  • Olopatadine hydrochloride aqueous, nasal solution comprising hydroxypiOpyl- ⁇ -eyclodextrin and hyd ⁇ xypropy ) methylcellulose, was prepared as described in table 4 below.
  • HydiOxypropyl- ⁇ -cyclodextrin (HP ⁇ CD) was dissolved in water for injection in a container.
  • Disudium edetate, sodium chloride, benzalkonium chloride solution (50%) and dibasic sodium phosphate dodecahyclrate were added to above container and stirred to get a clear solution.
  • Olopatadine hydrochloride was dissolved in water for injection and added to the above solution in the container, under stirring.
  • Olopatadine hydrochloride aqueous, solutions of example 1 were packed in vials and stored at0 3O 0 C / 65% relative humidity, 40 11 C / 75% relative humidity and 2-8 0 C (refrigeration condition) For a period up to 6 months.
  • the samples were analyzed using high performance liquid chromatography (HPLCj.
  • HPLCj high performance liquid chromatography
  • Ul ⁇ paladine hydrochloride aqueous solution (Composition B) of example 1 was packed in vials lltled with a conventional pump and actuator. These vials were subjected l ⁇ I ' reeze-thaw stabi l ity studies upt ⁇ fourteen cycles, where each cycle involved storage for one day at low temperature (i.e. - 1 0 u C to -2O 0 C), followed by storage for one day at high temperature (i.e. 40V and 75%Relative Humidity). The samples were analyzed using high performance liquid chromatography (HPLC). The percent total degradation was calculated by area normalization method and the samples were observed visually for formation of crystals and the results obtained are summarized in table 7 below.
  • HPLC high performance liquid chromatography
  • Ol ⁇ paladine hydrochloride aqueous solution comprising olopaUidine hydrochloride and hydroxypropyl-ji-cyclodextrin was prepared as described in table 8 below.
  • I Iyclroxypropyl- ⁇ -cycloclextrin (HP ⁇ CD) was dissolved in water for injection in a container.
  • Olopatadine hydrochloride was dissolved in water for injection and added to the above solution in the container, under stirring.
  • the pH of the solution was adjusted such that it is between 3.5-5.0, using 5.0% v/v hydrochloric acid or 2% w/v sodium hydroxide.
  • Ol ⁇ patacline hydrochloride aqueous solution of example 4 was packed in vials and stored at 30"C 5 / 05% relative humidity, 40 u C / 75% relative humidity and 2-8 u C (refrigeration condition) for a period up to 6 months.
  • the samples were analyzed using high performance liquid chromatography (HPLC). The percent total degradation was calculated by area normalization method and the results obtained are summarized in table 9 below.
  • ⁇ lopatacline hydrochloride aqueous solution of example 4 was packed in vials and stored at 30 11 C / 65% relative humidity, 40 u C / 75% relative humidity and 2-8 u C (refrigeration cond ition) for a 5 period up to 6 months.
  • the saniples were observed visually for a period up to 6 months and the solution was found to be clear, without any crystallization or precipitation of olopatadine.
  • Table 10 summarized in table 10 below.
  • Olopatadine hydrochloride aqueous solution was prepared as described in table 1 1 below.
  • HydroxypiOpyl- ⁇ -cyclodextrin HP ⁇ CD was dissolved in water for injection in a container.
  • Disodium edetate, sodium chloride, benzalkonium chloride solution (50%) and dibasic sodium phosphate anhydrous were added to the above container and stirred Io get a clear solution.
  • the solution was filtered through 2.0 ⁇ m prefilter and 0.2 ⁇ m nylon 66 membrane filter, and transferred to 5 ml sterile lupolen bottle. This solution is suitable for administration to the ocular mucosa.
  • Olopatadine hydrochloride aqueous solution of example 7 was packed in vials and sl ⁇ rod at 25"C / 6U% relative humidity, 3O 0 C / 65% relative humidity, 40 u C / 75% relative humidity and 2- 8"C (refrigeration condition) for a period up to 6 months.
  • the samples were analyzed using high performance liquid chromatography (HPLC). The percent total degradation was calculated by area normalization method and the results obtained are summarized in table 12 below. Table 12
  • Ulupatadine hydrochloride aqueous solution of example 7 were packed in vials and stored at 25 1 V / 60% relative humidity, 30"C / 65% relative humidity, 40 1 V / 75% relative humidity and 2-8'V (refrigeration condition) for a period up to 6 months.
  • the samples were observed visual ly I U lor a period up to 6 months and the solution was found to be clear without any crystallization or precipitation of olopatadine.
  • Table 13 summarized in table 13 below

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Abstract

The invention relates to an inclusion complex of olopatadine or its pharmaceutically acceptable salt and hydroxyalkyl-ß-cylcodextrin, preferably hydroxypropyl-ß-cylcodextrin. The present invention also relates to an aqueous topical solution comprising a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt; hydroxyalkyl-ß-cylcodextrin, preferably hydroxypropyl-ß-cylcodextrin and hydroxypropyl methylcellulose in an amount sufficient to enhance the physical stability of the solution.

Description

INCLUSION COMPLEX
FIELD OF THE INVENTION
5 The present invention relates to inclusion complex of olopatadine in cyclodextrin and to aqueous solutions oF olopatadine or its pharmaceutically acceptable salt for topical administration and process for preparation thereof.'
BACKGROUND OF THE INVENTION
I U
Olopaiadine hydrochloride is a carboxyl'ic acid derivative of doxepin, chemically described as (.Z)- I l -[3-(Dimethylamino) propylidene]-6, 1 1-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride [C21 H21 NO3 .HCl], as disclosed in U.S. Pat Nos.4,87 1 ,865 and 4.923,892, bυlh assigned to Burroughs Wellcome. Olopatadine has antihistami e and antiasthmatic activity.
15
Olopaladine hydrochloride is commercially available in the U. S as U. 1 % and U.2% sterile ophthalmic solutions under the brand names PATANOL* and PATADAY 1'1 respectively, both marketed by Alcon. PATANOL® is indicated for the treatment of signs and symptoms of allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride 0 equivalent to 0.1 % olopatadine, 0.01% benzalkonium chloride as preservative, dibasic sodium phosphate, sodium chloride, hydrochloric acid and / or sodium hydroxide (to adjust the pH) and purilled water. It has a pH of about 7, and osmolality of about 300mOsm/kg. PATADAY"1' is indicated for the treatment "of ocular itching associated with allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride equivalent to 0.2% 5 υlυpatadine, 0.01 % benzalkonium chloride as preservative, povidone, dibasic sodium phosphate, sodium chloride, edetale disodium. hydrochloric acid and / or sodium hydroxide (to adjust the p H) and purilled water. It has a pH of about 7, and osmolality υl' abυut 300mOsm/kg.
Une obstacle for preparing olopaiadine hydrochloride aqueous solutions lor topical deliver) is0 the stability of the aqueous solutions of olopatadine hydrochloride over the storage period.
Olopaiadine aqueous solutions having a concentrations of 0. 17%vv/v or higher were found to be unstable over extended storage periods. The olopatadine hydrochloride precipitates or crystallizes out of the solution when used in concentrations higher than U.17%w/v. Hence, there is a need for preparing aqueous solutions of olopatadine hydrochloride containing olopatadine in concentrations of about 0.17%w/v or greater, which are stable when stored over the shelf life of the product.
United Stales Patent No.6,995, 186 (Alcon Inc., 2006, the M 86 patent) discloses topically administrable solution composition for treating allergic or inflammatory disorders of the eye and nose comprising olopatadine and a polymeric ingredient, where the polymeric ingredient is a polymeric physical stability enhancing ingredient consisting essentially of polyvinylpyrrolidone or polystyrene sulfonic acid in an amount sufficient to enhance the physical stability of the solution, and wherein the composition does not contain polyvinyl alcohol, polyvinyl acrylic acid, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, xanthan gum. Polyvinyl alcohol, polyvinyl acrylic acid, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose and xanthan gum have been disclosed in the " 1 86 patent to cause physical instability of olopatadine solutions.
In order to overcome the physical stability problems associated with olopatadine aqueous solutions, we have tried various ingredients selected from hydroxypiOpyl-β-cyclodextrin (H.PβCD), polysorbate 20, polysorbate 80, propylene glycol, hydroxypropyl methylcellulose 2910 (HPMC E4M premium), polyvinylpyrrolidone K-30, xanthan gum, sodium carboxymethylcellulose (Sodium CMC), carbopol 934P, polyvinyl alcohol and mixtures thereof.
We have now surprisingly found that stable aqueous topical solutions of olopatadine hydrochloride can be prepared by forming an inclusion complex with a hydroxyalkyl clodextrin, preferably hydiOxypropyl-β-cyclodextrin (HPβCD). Optionally, hydroxypropyl methylcellulose (HPMC) may be used to stabilize the inclusion complex in the pharmaceutical composition. SUMMARY OF THE INVENTION
In one aspect of the invention, there is provided an inclusion complex of olopatadine or its pharmaceutically acceptable salt and a hydroxyalkyl cyclodextrin, preferably hydroxypropyl-β- cyclodextrin.
In another aspect of the invention, there is provided an aqueous topical solution comprising a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt: hydroxyalkyl β-cylcodextrin, preferably hydroxypropyl β-cylcodextrin and hydroxypropyl methyl cellulose in amount sufficient to enhance the physical stability of the solution.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an inclusion complex of olopatadine υr its pharmaceutically acceptable salt and hydroxyalkyl-β-cyclodextrin, particularly hydrυxyprυpyl-β-cyclodexlrin. The present invention also provides an aqueous topical solution, comprising a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt; hydroxyalkyl-β- cyclodextrin, particularly hydroxypropyl-β-cyclodextrin and hydroxypropyl methylcellulose in an amount sufficient to enhance the physical stability of the solution.
Unless indicated otherwise, all component concentrations are presented on a %(w/v) basis and all reference to olopatadine are to olopatadine free base.
The lerm "in an amount sufficient to enhance the physical stability of the solution", as used herein means that the amount of hydroxyalkyl-β-cyclodextrin, particularly hydroxypropyl-β- cyclυdextrin .is sufficient to form a complex with olopatadine or its pharmaceutically acceptable salt and thus keep it in solution, i.e. Prevent its precipitation or crystallization. According to one embodiment of the present invention, the aqueous topical solution contains olopatadine or its pharmaceutically acceptable salts. Examples of the pharmaceutically acceptable salts of olopatadine include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, fumarate, tartrate and citrate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; metal salts such as aluminum salt and zinc salt; and organic amine addition salts such as triethylamine addition salt (also known as trometh amine), morpholine addition salt and piperidine addition salt. In a preferred embodiment of the present invention, the olopatadine for use in the aqueous topical solution is a hydrochloride salt. In a most preferred embodiment of the present invention, the olopatadine hydrochloride salt may be used in concentrations such that it is equivalent to the olopatadine free base in amount ranging from about 0.1 7% to about 0.62%. Preferably, the solution formulations intended for use in the eye contain about 0. 1 7% to about 0.25% olopatadine and the solution formulations intended for use in the nose contain about 0.35% to about 0.62% olopatadine,
According to one embodiment of the present invention, the aqueous topical solution comprises cyclodextrin to enhance the physical stability of the solution. Cyclodexlrins are a group of structurally related saccharides which are formed by enzymatic cyclization of starch by a group of amylases termed glycosyltraηsferases. Cyclodextrins are cyclic oligosaccharides, consisting of (alpha- 1 ,4)-l inked alpha-D-glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface. In aqueous solutions, cyclodextrins form inclusion complexes with many drugs through a process in which the water molecules located in the central cavity are replaced by ' either the whole drug molecule, or more frequently, by some lipophilic portion of the drug structure. Once included in the cyclodextrin cavity, the drug molecules may be dissociated through complex dilution, by replacement of the included drug by some other suitable molecule or, the drug may be transferred to the matrix for which it has the highest affinity. Importantly, since no covalenl bonds are formed or broken during the drug-cyclodextrin complex formation, the complexes are in dynamic equilibrium with free drug and cyclodexlrin molecules. In solution, the complexes are usually prepared by addition of an excess amount of the drug to an aqueous cyclodextrin solution. The most common naturally occurring cyclodextrins are alpha- eyclodexlrin, β-cyclodextrin and gamma-cyclodextrin consisting of 6, 7 and 8 glucopyranose units, respectively and their ., derivatives, β-cyclodextrin appears to be the most useful pharmaceutical complexing agent due to its cavity size, availability and low cost. Examples of cyelodextrin derivatives that may be used in the pharmaceutical compositions of present invention include the hydroxypropyl derivatives of alpha-, beta- and gamma-cyclodextrin, sulfoalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin, alkylated cyclodextrins such as the randomly methylated beta-cyclodextrin, and various branched cyclodextrins such as glucusyl- and maltosyl beta-cyclodextrin, and the like, and mixtures thereof.
The preferred cyclodextrins for use in the present invention include alky I cyclodextrins, hydroxy alkyl cyelodextrin, such as hydroxy propyl beta-cyclodextrin, carboxy alky 1 cyclodextrins and sulfυalkyl ether cyelodextrin, such as sulfo butyl ether beta-cyclodextrin. Examples of suitable cyclodextrins for use in the present invention non-exclusively include alphci-cyclodextrin; bela- cyelυdextrin; gamma-cycloclextrin; methyl alpha-cyclodextrin; methyl beta-cyclodexlrin; methyl gamma-cyclodextrin; ethyl beta-cyclodextrin; butyl alpha-cyctodextrin; butyl beta-cyclodextrin; butyl gamma-cyclodextrin; pentyl gamma-cyclodextrin; hydroxyethyl beta-cyclodextrin; hydroxyethyl gamma-cyclodextrin; 2-hydiOxypropyl alpha-cyclodextrin; 2-hydroxypropyl beta- cyclodextrin; 2-hydroxypropyl gamma-cyclodextrin; 2-hydroxybutyl beta-cyclodextrin; acetyl alpha-eyclυdextrin; acetyl beta-cyclodextrin; acetyl gamma-cyclodextrin; propionyl bela- cyelodextrin; butyryl beta-cyclodextrin; succinyl alpha-cyclodextrin: succinyl beta-cyclodextrin; succinyl gamma-cyclodexlrin; benzoyl beta-cyclodextrin; palmityl beta-cyclodextrin; toluenesulfonyl beta-cyclodextrin; acetyl methyl beta-cyclodextrin; acetyl butyl beta- cyclodextrin; glucosyl alpha-cyclodextrin; glucosyl beta-cyclodextrin; glucosyl gamma- cyclodextrin; maltosyl alpha-cyclodextrin; maltosyl beta-cyclodextrin; maltosyl gamma- cyelodextrin; alpha-cyclodextrin carboxymethylether; bela-cyclodextrin carbυxymetliylelher; gamma-cycloclextrin carboxymethylether; carboxymethylethyl bela-cyclodcxlrin; phosphate ester alpha-cyclodextrin; phosphate ester beta-cyclodextrin; phosphate ester gamma-cycloclextrin; 3- lrimethylammonium-2-hydiOxypropyl beta-cyclodextrin; sulfobutyl ether beta-cyclodextrin; carboxymethyl alpha-cyclodextrin; carboxymethyl beta-cyclodextrin; carboxymethyl gamma- cyelodextrin, and combinations thereof. The most preferred cyelodextrin for use in the pharmaceutical composition of the present invention is hydroxy propyl beta-cyclodextrin. In a preferred embodiment of the present invention, hydroxypropyl beta-cyclodextrin may be used in concentrations ranging from about 0.1% to about 20%w/v of the composition, and more preferably used in concentrations ranging from about 1.0% to about 10% w/v of the composition. Generally, for solutions meant for ophthalmic administration preferable concentration of hydrυxypropyl bela-cyclodextrin is in the range from about 1.0% to about 5%; for solutions meant for nasal administration, the concentration of hydroxypropyl bela-cyclodexliϊn is in the range from about 1.0% to about 10%.
Olopatadine or its pharmaceutically acceptable salt, according to the present invention, forms an inclusion complex with cyclodextrins, particularly hydroxyalkyl-β-cyclodextrin, more particularly hydroxypropyl-β-cyclodextrin . The term "inclusion complex" as used herein refers to a combination of olopatadine or its pharmaceutically acceptable salt as defined above and a cyclodextrin wherein the olopatadine or its pharmaceutically acceptable salt or a portion thereof is associated with the cyclodextrin. Typically, the olopatadine or its pharmaceutically acceptable sail υr guest molecule, is included within the cavity of the cyclodextrin, or the host molecule, wherein the cavity of the cyclodextrin is the space created by the cyclodextrin torous and the cyclodextrin substiluents. The ratio of olopatadine or its pharmaceutically acceptable salt to hydroxypropyl β-cylcυdextrin in the inclusion complex is from about 1 : 1 .05 to about 1 :50 b\ weight. The amount of hydroxypropyl β-eylcodexliϊn present in the inclusion complex is sufficient to enhance the physical stability of the olopatadine solution.
According to one embodiment of the present invention, the composition further includes hydroxypropyl methylcellulose (HPMC). The hydroxypropyl methylcellulose (HPMC) used in the composition acts as a stabilizer for the inclusion complex of hydroxypropyl beta-cyclodextrin and olopatadine or its pharmaceutically acceptable salt. Various grades of hydroxypropyl methylcellulose (available from Dow Chemical, LJ. S. A under the METl-lOCEL trademark) may be used in the present invention. The grades commercially available are categorized depending upon the chemical substitution and hydration rates, and may be used in the compositions of the present invention. Hydroxypropyl methylcellulose having a methoxy content of 19-24 % and hydroxypropyl content of 7- 12 % with a fastest relative rate of hydration is available commercially under the brand name of Methocel Grade K. Hydroxypropyl methylcellulose w ith 28-30 % methoxy content and -7- 12 % of hydroxypropyl content with a faster relative hydration rale as compared to the above grade is available commercially under the brand name υf Methocel Grade E. Hydroxypropyl methylcellulose with 27-30 % methoxy content and 4.0 - 7.5 % of hydroxypropyl content with a slow relative hydration rate is available as Methocel F grade and that with 27.5-3 1 .5 % methoxy content and 0 % hydroxypropyl content and with slowest rate of hydration is available as Methocel Grade A. In a preferred embodiment of the present invention, hydroxypropyl methylcellulose, a 2%w/v aqueous solution of which has a viscosity of 4000 cps at 20υC, and which is commercially available as METHOCEL E4M, is used. In preferred embodiments of the present invention, hydroxypropyl methylcellulose may be used concentrations ranging from about 0.001 % to about 5%, and more preferably in concentrations ranging from about 0.01 % to about 1 % w/v.
The aqueous topical solution of the present invention may include an effective amount of an antimicrobial preservative. Examples of pharmaceutically acceptable preservatives that may be used in the present invention include, but are not limited to. beiizeUiυnium chloride, butylparaben, methyl paraben, ethyl paraben, propyl paraben, benzalkυnium chloride, cdyl pyridinium chloride, thimerosai, chlorobutanol, phenylethyl alcohol, benzyl alcohol, potassium sorbate, sodium benzoate, sorbic acid and the like and mixtures thereof. The preferred preservative for the aqueous topical solution of the present invention is benzalkonium chloride. It may be used in an amount ranging from about 0.005% to about l %w/v.
The aqueous topical solution of the present invention may include an effective amount of a chelating agent. Chelating agents remove trace amounts of metal ions such as iron, copper and lead and act as antioxidants, as otherwise these heavy metals catalyze oxidation reactions. Presently preferred chelating agents include different salts of edetic acid. These non-e.xclusively include edetate disodium, edetate calcium disodium, edetate tetrasodium, edetate trisodium, and the like and mixtures thereof. The preferred chelating agent for the aqueous topical solution of the present invention is disodium edetate. It may be present in the concentrations ranging From about 0.005% to about 0. 1 % vv/v.
The aqueous topical solution of the present invention may further include an effective amount υf a tonicity agent. Examples of tonicity agents that may be used in the aqueous topical solution of the present invention include all pharmaceutically acceptable and pharmacologically inert water- soluble compounds referred to in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing Company, Easton, Pennsylvania (1995). Preferred tonicity agent is sodium chloride, which may be added in an amount which renders the solution isoosmotic. The aqueous topical solution is intended to be administered as nasal solution or eye drops. The osmolality may be adjusted preferably between 150 to 450 mOsm, and more preferably between 250 to 350 mOsm.
The aqueous topical solution of the present invention may include an effective amount of buffering agent. The buffering agents are included to minimize any change in pH during shelf life of the aqueous topical solution. Examples of buffering agents include, but are not limited to, lactic acid, citric acid, tartaric acid, phosphoric acid, acetic acid, hydrochloric acid, nitric acid, trυmethainine, sodium or potassium melaphosphate, sodium or potassium phosphate, dibasic sodium phosphate dodecahydrate, sodium or potassium acetate, ammonia, sodium carbonate. sodium or potassium hydroxide, dibasic sodium phosphate, sodium borate, and the like and mixtures thereof. Strong mineral acids like hydrochloric acid or strong bases such as. sodium hydroxide may be used for adjusting pH. The aqueous topical solution intended for ophthalmic administration has a pH 4 to 8, preferably pH of 6.5 to 7.5, and most preferably a pH of 6.8 to
7.2. The aqueous topical solution intended for nasal administration has a pH of 3.0 to 6.0, and most preferably a pH of 3.5 to 5.0.
The aqueous topical solution of the present invention may optionally include an effective amount of an antioxidant. The antioxidant may be one or more antioxidants, reducing agents and antioxidant synergist, and may be selected from acetyl cysteine, alpha tocopherol acetate, d- alpha tocopherol, dl-alpha tocopherol, ascorbyl palmitate, butylaled hydrυxyanisole (BHAj, biilylaled hydroxytoluene (BHT), cysteine, cysteine hydrochloride, propyl gallate, ascorbic acid, calcium ascorbate, calcium bisulphate, calcium sulphite, ascorbic acid, isoascorbic acid, potassium metabisulfile, sodium ascorbate, sodium bisulphate, sodium metabisulphite. sodium sulphite, sodium thiosulphate, thioglycerol, citric acid , edelic aeid(KDT'A) and its sails. liydiOxyquinoline sulphate, phosphoric acid, sodium citrate and tartaric acid. The antioxidants may be used in amounts conventional to the pharmaceutical art.
The aqueous topical solution of the present invention may optionally include an effective amount of viscosity enhancer. An increase in viscosity of topical solutions will result in a longer residence time in eye or nose, providing a longer time for drug absorption and effect. The list of viscosity enhancers that are conventionally used for topical solutions are given in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing Company, Easton, Pennsylvania ( 1995). The viscosity enhancers may be used in concentrations conventional to the pharmaceutical art.
The aqueous topical solution of the present invention is chemically stable. The term "chemically stable" as used herein means that the aqueous topical solution when stored on the shelf for up Io two years has less than 2% total degradation products as determined by the area norinali/aliun method. The chemical stability may be assessed by accelerated stability testing. The aqueous topical solution of the present, invention may be stored in a closed container at 30l'C / 65% relative humidity or 40uC / 75% relative humidity or 2-8ϋC (refrigeration condition) and analyzed at one month duration for up to three months or six months. It is generally accepted that a product is stable on the shelf over a period of two years, if the product is stable for three months at an accelerated stability test condition of 40l)C / 75% relative humidity.
The term "physical stability" as used herein means that when aqueous topical solution of the present invention are stored in a closed container crystals of olopatadine do not appear.
The chemical stability is assessed by evaluating the percent total degradation of olopatadine aqueous topical solutions that are subjected to accelerated stability test conditions and ambient conditions using high performance liquid chromatography (HPLC). The chromatographic conditions for analyzing the degradation of olopatadine and the procedure for calculating the percent total degradation products in olopatadine aqueous topical solution is given below:
Column : Hypersil BDS Cs (250 X 4.6) Flow rate : 1 .0 ml/min
Temperature : Ambient
Detection : 210 inn
Concentration : 50/65 ppm
Injection volume : 20μl Run time : 40 min
Mobile Phase : Buffer : Acetonitrile (720 : 280)
Buffer : 6.8 gm KH2PO4 is dissolved in 1000ml of water and the solution is adjusted to a pH of 4.5 with orthophosphoric acid.
Retention time : 10.5 min Diluent : Mobile phase
Standard preparation : 50/65 mg olopatadine HCI is dissolved in 100 ml with mobile phase. A sample of 5 ml is diluted to 50 ml with mobi le phase
Test preparation : 2 ml of the olopatadine HCl solution is diluted with 200 ml of mobile phase
The percent total degradation products in the olopatadine aqueous topical solution is calculated by area normalization method (excluding peaks from placebo and diluent, if any) from the chrυmatogram obtained by injecting 20μl of test preparation as described above in chromatographic conditions for analyzing degradation of olopatadine. The formula for calculating the percent total degradation products in olopatadine aqueous topical solution is given below:
Peak area of individual degradation product % Individual degradation product = X 100 Total area of all the peaks % Total degradation products = Sum of all % individual degradation products
For finished dosage forms (for example - solutions) the value of percent individual degradation 5 product should not be more than 1 % and the percent total degradation products should not be more than 2%. A value of percent total degradation products lesser than 2% in the aqueous topical solution of the present invention is considered to be acceptable.
According to one embodiment of the present invention, the aqueous topical solution may be I D prepared by the Following process: a. Dissolving hydiOxypropyl-β-cyclodexlrin(HPβCD) in water for injection till clear solution is formed. b. Dissolving tonicity agent, buffering agent, chelating agent and antimicrobial preservative in the bulk solution of step (a) and stirring to get clear solution.
1 5 c. Dissolving olopatadine hydrochloride in water for injection and adding to the solution of step (a). d. Adjusting pH of the solution between 3.5-5.0 for nasal solution, and between 6.8-7.2 for ophthalmic solution with 0. 1 N hydrochloric acid and 0.1 N sodium hydroxide. e. Final adjustment of volume with water for injection and measuring pH. 0 F. Filtering of the solution through 2μm prefilter and then through ϋ.2μm nylon 66 membrane Filter, and transferring the solutions to sterile containers.
The aqueous topical solution of the present invention may be Formulated to be dispensed in suitable containers as drops, sprays, metered sprays, aerosols and metered aerosols. The aqueous 5 topical solution to be delivered as nasal spray may be filled in containers fitted with a spray pump with or without a metering valve. The aqueous topical solution to be delivered as aerosol may be filled into canisters suitable for delivering pharmaceutical aerosols. Canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle, or preferably a metal can, for example an aluminium can0 which may optionally be anodized, lacquer-coated and / or plastic-coaled, which container is closed with a metering valve. The metering valves are designed to deliver a metered amount of the aqueous solution per actuation, and have a gasket to prevent leakage of propellant through the valve. In a preferred embodiment of the present invention, the aqueous topical solution is packed in opaque plastic or glass containers. In a more preferred embodiment of the present invention, the container for an ophthalmic solution is an opaque, white low-density polyethylene container that has been sterilized using ethylene oxide like liipolen bottle. In another preferred embodiment of the present invention, the container for a nasal solution is a U . S. P type I amber color glass container equipped with a suitable nasal spray pump.
It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.
COMPARATIVE EXAMPLES A-M
The compositions shown in table 1 and table 2 below were prepared and subjected to stability studies for evaluating the physical stability. The vials were studied For stability at two temperature conditions: one at room temperature (25° + 20C) and the other at refrigeration temperature (2-811C) condition.
Table 1
Figure imgf000014_0001
Table 2
Figure imgf000015_0001
15 The compositions of comparative examples A-M shown in table 1 and table 2 were visually inspected at the end of 14 days For evaluating physical stability. The solutions were Found to have crystals, or the solutions were not clear at the end oF 14 days. The results obtained are summarized in the table 3 below.
Table 3
Figure imgf000016_0001
EXAMPLE 1
Olopatadine hydrochloride aqueous, nasal solution comprising hydroxypiOpyl-β-eyclodextrin and hydυxypropy) methylcellulose, was prepared as described in table 4 below.
Table 4
Figure imgf000017_0001
*0.527% Olopaladine hydrochloride is equivalent to 0.5% olopatadine free base Manufacturing procedure: Stage A
1 . Hydroxypropyl methylcellulose was dissolved in water For injection (WFI ) lill clear solution was formed. Stage B
1 HydiOxypropyl-β-cyclodextrin (HPβCD) was dissolved in water for injection in a container.
2 Disudium edetate, sodium chloride, benzalkonium chloride solution (50%) and dibasic sodium phosphate dodecahyclrate were added to above container and stirred to get a clear solution.
3 Olopatadine hydrochloride was dissolved in water for injection and added to the above solution in the container, under stirring.
Stage C
1 . Solution obtained from stage B was added to solution of stage A. 2. The pH of the solution was adjusted such that it is between 3.5-5.0, using 5.0% v/v hydrochloric acid or 2% vv/v sodium hydroxide.
3. Final volume was made up with water For injection.
4. The .solution was Filtered through 2.0μm prefilter and 0.2μm nylon 66 membrane Filter 5 and transferred into U. S. P. type 1 amber glass containers.
EXAMPLE 2
Olopatadine hydrochloride aqueous, solutions of example 1 , were packed in vials and stored at0 3O0C / 65% relative humidity, 4011C / 75% relative humidity and 2-80C (refrigeration condition) For a period up to 6 months. The samples were analyzed using high performance liquid chromatography (HPLCj. The percent total degradation was calculated by area normalization method and the results obtained are summarized in table 5 below.
Table 5
Figure imgf000018_0001
The samples were observed visually for a period of 6 months and the solution was found to be clear without any crystallization or precipitation of olopatadine. The results are summarized in(J table b below. Table 6
Figure imgf000019_0001
EXAMPLE 3
Ulυpaladine hydrochloride aqueous solution (Composition B) of example 1 was packed in vials lltled with a conventional pump and actuator. These vials were subjected lυ I'reeze-thaw stabi l ity studies uptυ fourteen cycles, where each cycle involved storage for one day at low temperature (i.e. - 1 0uC to -2O0C), followed by storage for one day at high temperature (i.e. 40V and 75%Relative Humidity). The samples were analyzed using high performance liquid chromatography (HPLC). The percent total degradation was calculated by area normalization method and the samples were observed visually for formation of crystals and the results obtained are summarized in table 7 below.
Table 7
Figure imgf000019_0002
EXAMPLE 4
Olυpaladine hydrochloride aqueous solution comprising olopaUidine hydrochloride and hydroxypropyl-ji-cyclodextrin was prepared as described in table 8 below.
Table 8
Figure imgf000020_0001
*0.527% Olopatadine hydrochloride is equivalent to 0.5% oiopatadine free base Manufacturing procedure: U Stage A
1 . I Iyclroxypropyl-β-cycloclextrin (HPβCD) was dissolved in water for injection in a container.
2. Edetate disodium, sodium chloride, benzalkonium chloride solution (50%) and dibasic sodium phosphate dodecahydrate were added to the above container and stirred to get a5 . clear solution.
3. Olopatadine hydrochloride was dissolved in water for injection and added to the above solution in the container, under stirring.
Stage B
1 . The pH of the solution was adjusted such that it is between 3.5-5.0, using 5.0% v/v hydrochloric acid or 2% w/v sodium hydroxide.
2. Final volume was made up with water for injection.
3. The solution was filtered through 2.0μm prefilter and 0.2 μm nylon 66 membrane filter and transferred into U.S'.P. type I amber glass containers. EXAMPLE 5
Olυpatacline hydrochloride aqueous solution of example 4 was packed in vials and stored at 30"C 5 / 05% relative humidity, 40uC / 75% relative humidity and 2-8uC (refrigeration condition) for a period up to 6 months. The samples were analyzed using high performance liquid chromatography (HPLC). The percent total degradation was calculated by area normalization method and the results obtained are summarized in table 9 below.
Table 9
Figure imgf000021_0001
EXAMPLE 6
ϋlopatacline hydrochloride aqueous solution of example 4 was packed in vials and stored at 3011C / 65% relative humidity, 40uC / 75% relative humidity and 2-8uC (refrigeration cond ition) for a 5 period up to 6 months. The saniples were observed visually for a period up to 6 months and the solution was found to be clear, without any crystallization or precipitation of olopatadine. The results are summarized in table 10 below.
U Table 10
Figure imgf000022_0001
EXAMPLE 7
Olopatadine hydrochloride aqueous solution was prepared as described in table 1 1 below.
Table 11
Figure imgf000022_0002
*0.22% Olopatadine hydrochloride is equivalent to 0.2% olopatadine free base Manufacturing procedure: Stage A
I . Hydroxypropyl methylcellulose was dissolved in water for injection (WFi) till clear solution is formed. Stage B
1. HydroxypiOpyl-β-cyclodextrin (HPβCD) was dissolved in water for injection in a container.
2. Disodium edetate, sodium chloride, benzalkonium chloride solution (50%) and dibasic sodium phosphate anhydrous were added to the above container and stirred Io get a clear solution.
. 3. Olopatadine hydrochloride was dissolved in water for injection and added Io the above solution in the container, under stirring. Stage C
1 . Solution obtained from stage B was added to solution of stage A. 2. The pH of the solution was adjusted such that it is between 6.8-7.2, using 5.0% v/v hydrochloric acid or 2% w/v sodium hydroxide.
3. Final volume was made up with water for injection.
4. The solution was filtered through 2.0μm prefilter and 0.2μm nylon 66 membrane filter, and transferred to 5 ml sterile lupolen bottle. This solution is suitable for administration to the ocular mucosa.
EXAMPLE 8
Olopatadine hydrochloride aqueous solution of example 7 was packed in vials and slυrod at 25"C / 6U% relative humidity, 3O0C / 65% relative humidity, 40uC / 75% relative humidity and 2- 8"C (refrigeration condition) for a period up to 6 months. The samples were analyzed using high performance liquid chromatography (HPLC). The percent total degradation was calculated by area normalization method and the results obtained are summarized in table 12 below. Table 12
Figure imgf000024_0001
Ulupatadine hydrochloride aqueous solution of example 7, were packed in vials and stored at 251V / 60% relative humidity, 30"C / 65% relative humidity, 401V / 75% relative humidity and 2-8'V (refrigeration condition) for a period up to 6 months. The samples were observed visual ly I U lor a period up to 6 months and the solution was found to be clear without any crystallization or precipitation of olopatadine. The results are summarized in table 13 below
Table 13
Figure imgf000025_0001
The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can be made or may be learned by practice of the invention, w ithout departing from ihe spirit and scope of the invention as defined by the following claims.

Claims

We claim:
1 . An inclusion complex of olopaladine or its pharmaceutically acceptable salt and hydroxyalkyl-β-cylcodextrin.
2. An inclusion complex, of claim 1 , wherein hydroxyalkyl-β-cylcodextrin is 5 hycliOxypropyl-β-cylcoclextrin and the ratio of olopatadine or its pharmaceutically acceptable salt to hydroxypropyl β-eylcodextrin is 'from about 1 : 1 .65 to about 1 :50 by weight.
3. A topical solution comprising an inclusion complex of olopatad ine or its pharmaceutically acceptable salt and hydroxypropyl β-cylcodextrin. l ϋ
4. A topical solution as claimed in claim 3, wherein the olopatad ine or its pharmaceutical !) acceptable salt is present in a concentration ranging from about ϋ. 1 7% to about 0.62%w/v of the solution.
5. A topical solution as claimed in claim 3, wherein the hydroxypropyl β-cyleodexlrin is present in a concentration ranging from about 1 .0% to about 10% w/v of the solution. 1 5
6. A stable aqueous topical solution of olopatadine or its pharmaceutically acceptable salt, comprising: (a) therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt;
(b) hydroxypropyl β-cylcodextrin; and 0 (C) hydroxypropyl methylcellulose.
7. A stable aqueous topical solution as claimed in claim 6, wherein the olopatadine or its pharmaceutically acceptable salt is present in a concentration ranging from about 0 1 7% Io about 0.62%w/v of the solution.
8. A stable aqueous topical solution as claimed in claim 7, wherein the olopaladine or its 5 pharmaceutically acceptable salt is present in a concentration ranging IVo m about 0. 1 7% to about 0.25%w/v of the solution and wherein the solution is suitable for administration to the eye of a patient in need thereof.
9. A stable aqueous topical solution as claimed in claim 7, wherein the olopatadine or its pharmaceutically acceptable salt is present in a concentration ranging from about U.35% Io about 0.62%w/v of the solution and wherein the solution is suitable for admin istration to the nasal mucosa of a patient in need thereof. 0. A stable aqueous topical solution as claimed -in claim 6, wherein hydroxypropyl methylcellulose is present in amount ranging from about 0.01 % to about l %w/v of the solution and hydroxypropyl β-cylcodextrin is present in a concentration ranging from about 1 .0% to about 1 0% w/v of the solution.
PCT/IN2007/000199 2006-05-15 2007-05-15 Inclusion complex of olopatadine and cyclodextrin WO2008015695A2 (en)

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CN104168885A (en) * 2012-02-10 2014-11-26 爱尔康研究有限公司 Aqueous pharmaceutical composition with enhanced stability
US10925829B2 (en) 2015-01-20 2021-02-23 Handa Neuroscience, Llc Stable solid fingolimod dosage forms
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