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    • 专利摘要:
    high concentration olopatadine ophthalmic composition. the present invention is an ophthalmic composition containing a relatively high concentration of olopatadine. the composition is typically an aqueous ophthalmic solution containing relatively high concentrations of olopatadine solubilized within the solution. the composition is preferably capable of providing increased relief of ocular symptoms of allergic conjunctivitis, particularly late stage symptoms of ocular allergic conjunctivitis.
    公开号:BR112013022057B1
    申请号:R112013022057-0
    申请日:2012-05-18
    公开日:2021-09-08
    发明作者:Daniel A. Gamache；Laman Alani；Malay Ghosh；Francisco Javier Galán；Núria Perdiguer；Onkar Singh
    申请人:Novartis Ag；
    IPC主号:
    专利说明:

    Cross Reference to Related Patent Application
    [001] The present patent application claims priority based on Provisional Patent Application Serial No. US 61/487,789, filed May 19, 2011, and Provisional Patent Application Serial No. US 61/548,957, filed on October 19, 2011. Technical Field of the Invention
    [002] The present invention relates to an ophthalmic composition containing a relatively high concentration of olopatadine. More particularly, the present invention relates to an aqueous ophthalmic solution containing a relatively high concentration of solubilized olopatadine wherein the solution is capable of providing enhanced relief of symptoms of allergic ocular disorders (e.g., conjunctivitis) in the early stage, in the late phase or preferably in both phases. Background of the Invention
    [003] Individuals suffering from allergic conjunctivitis experience symptoms such as eye irritation, itching, redness and the like. These symptoms were found to be significantly reduced using topical ophthalmic solutions containing olopatadine. Such solutions are sold under the trade names PATANOL® and PA-TADAY®, both of which are commercially available from Alcon Laboratories, Inc., Fort Worth, TX.
    [004] It was generally believed that these solutions sold were without the most effective products known to deal with the symptoms of allergic conjunctivitis. Surprisingly, and as discussed further below, solutions of relatively high concentration of olopatadine have been found to provide significantly improved reduction in ocular symptoms of late stage allergic conjunctivitis in addition to relief of early stage symptoms. Even more surprisingly, such high concentrations of olopatadine have also been found to provide significantly improved reduction in first-stage redness. Furthermore, it has been found that increased relief of these early and late phase symptoms can be achieved by a once-daily dose of the relatively high concentration solution of olopatadine as opposed to higher dosing frequencies.
    [005] The found improved reduction of early and late stage symptoms is quite significant and desirable for individuals suffering from allergic conjunctivitis. Generally, these findings can provide patients with greater relief from itching and provide the best aesthetic appearance to the eye. Furthermore, avoidance of more frequent dosing is more suitable for patients and helps ensure the best compliance. Furthermore, early prevention and/or improved redness reduction is particularly desirable as patients generally have a desire to avoid as much redness of their eyes as possible.
    [006] The finding that relatively high concentration solutions of olopatadine can alleviate late-stage ocular symptoms of allergic conjunctivitis provides hope to ocular allergic conjunctivitis sufferers that a single dose of olopatadine per day can provide a substantial degree of relief for a full day of your symptoms. However, the development of a multidose ophthalmic solution that includes the high concentrations of olopatadine necessary to achieve the desired levels of efficacy is extremely difficult and complex.
    [007] Solubilizing high concentrations of olopatadine in a stable manner proved difficult in itself. Olopatadine by itself is only soluble in water (pH approximately 7.0) at room temperature to a concentration of approximately 0.18% w/v. However, it is desirable to achieve solubilization of much higher concentrations of olopatadine in an attempt to treat late-stage allergic conjunctivitis.
    [008] Solubilizing such higher concentrations of olopatadine proved difficult. As an example, excipients such as polyethylene glycol (PEG) 400 and polyvinylpyrrolidone (PVP), when used in reasonably desirable concentrations, have proven incapable, alone or in combination, to solubilize sufficient concentrations of olopatadine in compositions having approximately neutral pH. Thus, the innovation must solubilize a sufficient concentration of olopatadine.
    [009] In the process of such innovation, it was found that higher molecular weight PEGs such as PEG 6000 can significantly increase the solubility of olopatadine. However, such PEGs pose a risk of discomfort when administered to humans. It has also been found that cyclodextrins, such as hydroxypropyl-Y-cyclodextrin, hydroxypropyl-β-cyclodextrin and sulfoalkyl ether β-cyclodextrin, have the ability to solubilize significantly higher concentrations of olopatadine. However, undesirably, it has been found that the use of high concentrations of cyclodextrins reduces the efficacy of olopatadine and/or the preservation efficacy of the solutions. As such, further innovation was needed to create a desirable olopatadine formulation that not only solubilized sufficient amounts of olopatadine, but also allowed the formulation to achieve other desirable pharmaceutical characteristics.
    [0010] Thus, the present invention is directed to an ophthalmic composition that can deliver high concentrations of olo-patadine topically to the eye. Furthermore, the present invention is directed to such a composition in which olopatadine is solubilized in the solution in a stable manner, the composition exhibits consistent efficacy against symptoms of late phase allergic conjunctivitis, the composition exhibits sufficient antimicrobial activity to provide desired levels of preservation effectiveness or any combination of these. Invention Summary
    [0011] The present invention is directed to an ophthalmic composition for the treatment of allergic conjunctivitis. The composition will include a relatively high concentration of olopatadine, preferably at least 0.67% w/v olopatadine, preferably dissolved in solution. The composition will typically include a cyclodextrin, and more particularly, a Y-cyclodextrin derivative and/or a β-cyclodextrin derivative to help solubilize the olopatadine. The cyclodextrin derivative is preferably hydroxypropyl-Y-cyclodextrin (HP-Y-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), sulfo-alkyl ether β-cyclodextrin (SAE-β-CD) (for example , sulfobutyl ether β-cyclodextrin (SBE-β-CD)), or a combination thereof. The composition will typically include a lactam polymer (e.g., polyvinylpyrrolidone (PVP)) to aid in the solubilization of olopatadine. The composition will also typically include a polyether (e.g., polyethylene glycol (PEG)) to increase solubility and/or assist in achieving the desired tonicity. It is generally desirable for the composition to be disposed in a dropper, have a pH of 5.5 to 8.0, have an osmolality of 200 to 450, have a viscosity of 10 to 200 cps, or any combination thereof. The composition will also typically include a preservative to enable the composition to meet United States and/or European Pharmacopoeia preservation standards. Preferred preservatives include a polymeric quaternary ammonium compound such as polyquaternium-1 and benzalkonium chloride. The composition also typically includes borate and/or polyol to assist in achieving the desired preservation.
    The present invention also contemplates a method of treating ocular allergy symptoms. The method will include topical application of a composition having a defined combination of the characteristics described above to an eye of a human being. This step of topical application of the composition preferably includes dispensing an eye drop from a dropper. Brief Description of Drawings
    [0013] FIG. 1 is a graph of mean conjunctival redness determined by a 27-minute conjunctival allergen challenge (CAC).
    [0014] FIG. 2 is a graph of mean conjunctival redness determined by a 16-hour conjunctival allergen challenge (CAC).
    [0015] FIG. 3 is a graph of the mean total redness determined by a 24-hour conjunctival allergen challenge (CAC).
    [0016] FIG. 4 is a graph of the average ocular itching determined by a 24-hour conjunctival allergen challenge (CAC).
    [0017] FIG. 5 is a graph of mean total conjunctival redness determined by a 24-hour conjunctival allergen challenge (CAC). Detailed Description of the Invention
    [0018] The present invention is declared after providing an ophthalmic composition for the treatment of allergic conjunctivitis. The ophthalmic composition is preferably an aqueous solution. The ophthalmic composition includes a relatively high concentration of olopatadine solubilized in the aqueous solution. The ophthalmic composition also includes a unique set of excipients to solubilize olopatadine while maintaining the comfort of the composition and/or the effectiveness of the composition in treating symptoms associated with allergic conjunctivitis, particularly symptoms associated with late stage allergic conjunctivitis. Preferably, the composition exhibits improved late phase efficacy in reducing eye itching, eye redness, or both. The composition also preferably exhibits improved early stage efficacy in reducing ocular redness relative to vehicle and/or relative to lower concentrations of olopatadine. In a preferred embodiment, the ophthalmic composition is a multi-dose ophthalmic composition that also exhibits a necessary degree of preservative efficacy.
    [0019] Unless otherwise indicated, all amounts of components (i.e., concentrations) are presented in a percentage of basis weight to volume (% w/v) and all references to concentrations of olopatadine are for the olopatadine-free base.
    Olopatadine is a known compound obtainable by the methods described in U.S. Pat. No. 5,116,863, the entire contents of which are hereby incorporated by reference into this specification for all purposes. The formulation of the present invention contains at least 0.50%, more typically at least 0.55%, more typically at least 0.6% or 0.65%, even more typically at least 0.67% or 0.68% , even more typically at least 0.7%, possibly at least 0.75% and even possibly at least 0.85% but typically not greater than 1.5% more typically not greater than 1.0%, even more typically not greater than 0.8%, possibly not greater than 0.75%, and even possibly not greater than 0.72% olopatadine where olopatadine concentrations typically represent concentrations of olopatadine in the free base form if olopatadine is added to composition like a salt. These lower limits of olopatadine concentrations are particularly important as the efficacy of olopatadine in aqueous ophthalmic solutions in reducing late-phase allergy symptoms and increased reduction in early-phase redness has been found to show improvement in concentrations. greater than 0.5% w/v olopatadine and begins to show statistically significant improvements in reducing late-phase allergy symptoms at concentrations of approximately 0.7% w/v olopatadine and above (eg, at least 0, 65% w/v, at least 0.67% w/v or at least 0.68% w/v). Even more preferably, the concentration of olopatadine in the composition is 0.7% w/v.
    [0021] Generally, olopatadine will be added in the form of a pharmaceutically acceptable salt. 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 zinc salt and aluminum salt; and organic amine addition salts such as triethylamine addition salt (also known as tromethamine), morpholine addition salt and piperidine addition salt. The most preferred form of olopatadine for use in the solution compositions of the present invention is the hydrochloride salt of (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydro-dibenz-[b,e]oxepin acid hydrochloride -2-acetic. When olopatadine is added to the compositions of the present invention in this salt form, 0.77% olopatadine hydrochloride is equivalent to 0.7% olopatadine free base, 0.88% olopatadine hydrochloride is equivalent to 0.8 olopatadine free base %, and 0.99% olopatadine hydrochloride is equivalent to 0.9% olopatadine free base.
    [0022] Generally, it is preferred that the entire concentration of olopatadine be dissolved in the composition as a water-based or aqueous solution. However, it is contemplated that olopatadine can only be partially dissolved. For example, a portion of the olopatadine may be in solution with the remainder being in suspension.
    [0023] The composition of the present invention also preferably includes the cyclodextrin derivative and more preferably the β-cyclodextrin derivative, Y-cyclodextrin derivative or both to aid in the solubilization of olopatadine (i.e., as a solubilizer). The β-cyclodextrin derivative, Y-cyclodextrin derivative or combination thereof is typically present in the composition at a concentration that is at least 0.5% w/v, more typically at least 1.0% w/v and even possibly at least 1.3% w/v, but not typically greater than 4.0% w/v, not typically greater than 3.2% w/v, even possibly not greater than 2.8% w/v v. Preferably, the total concentration of the cyclodextrin is from 0.9% w/v to 3.2% w/v.
    The specific amount of the β-cyclodextrin derivative, Y-cyclodextrin derivative or combination thereof in a particular composition will typically depend on the type or combination of types of derivatives used. A particularly desirable β-cyclodextrin derivative is an alkyl hydroxy β-cyclodextrin such as hydroxypropyl-β-cyclodextrin (HP-β-CD). A particularly desirable Y-cyclodextrin derivative is a hydroxy alkyl Y-cyclodextrin such as hydroxypropyl-Y-cyclodextrin (HP-Y-CD). Another particularly desirable β-cyclodextrin derivative is sulfoalkyl ether β-cyclodextrin (SAE-β-CD), particularly sulfobutyl ether β-cyclodextrin (SBE-β-CD). It is contemplated that a combination of hydroxypropyl-β-cyclodextrin, hydroxypropyl-Y-cyclodextrin and/or sulfoalkyl ether derivative of β-cyclodextrin may be employed in a single composition, but it is typically desirable to use only one of the three as the sole or substantially the only derivative (i.e., at least 90% by weight of the cyclodextrin component) of cyclodextrin.
    [0025] When HP-β-CD is employed as the single or substantially single β-cyclodextrin derivative, it is typically present in the composition at a concentration that is at least 0.5% w/v, more typically at least 1, 0% w/v to more typically at least 1.3% w/v, but typically not greater than 3.0% w/v, not typically greater than 2.2% w/v and typically not greater than 1.7% in p/v. When HP-Y-CD is employed as the single or substantially single Y-cyclodextrin derivative, it is typically present in the composition at a concentration that is at least 0.5% w/v, more typically at least 1.0% by p/v to more typically at least 1.3% w/v, but typically not greater than 3.0% w/v, not typically greater than 2.2% w/v, typically not greater than 1 ,7% w/v. When SAE-β-CD is employed as the single or substantially single β-cyclodextrin derivative, it is typically present in the composition at a concentration that is at least 0.3% w/v, more typically at least 0.7% in p/v to more typically at least 0.9% w/v, but typically not greater than 2.4% w/v, not typically greater than 1.5% w/v, typically not greater than 1 .1% w/v.
    [0026] HP-β-CD is a consumer product and pharmaceutical grades of HP-β-CD can be purchased from a variety of sources, for example, from SIGMA ALDRICH, which has its corporate headquarters in St. Louis, Missouri or ASHLAND SPECIALTY INGREDIENTS based in Wayne, New Jersey. HP-Y-CD is a consumer product and pharmaceutical grades of HP-Y-CD can be purchased from a variety of sources, for example, from SIGMA ALDRICH, which is headquartered in St. Louis, Missouri or ASHLAND SPECIALTY INGREDIENTS , based in Wayne, New Jersey. SAE-β-CD can be formed based on the teachings of U.S. Patent Nos. 5,134,127 and 5,376,645, which are incorporated herein by reference for all purposes. It is generally preferred, however, to use purified SAE-β-CD. Purified SAE-β-CD is preferably formed in accordance with the teachings of U.S. Patent Nos. 6,153,746 and 7,635,773. Purified SAE-β-CD is commercially available under the tradenames CAPTISOL® from CyDex Pharmaceuticals, Inc., Lenexa, KS.
    [0027] As for the Y-cyclodextrin derivative and β-cyclodextrin derivative in the composition of the present invention, it was undesirably found that high concentrations of Y-cyclodextrin derivative and/or β-cyclodextrin derivative can significantly interfere in the preservation effectiveness of compositions, particularly when benzalkonium chloride and/or polymeric quaternary ammonium compound are employed as preservatives. Thus, lower concentrations of Y-cyclodextrin derivative and/or β-cyclodextrin derivative are typically preferred. Advantageously, it has also been found, however, that the ability of Y-cyclodextrin derivative and β-cyclodextrin derivatives to solubilize olopatadine is very strong and relatively low concentrations of the Y-cyclodextrin derivative and/or the β-cyclodextrin derivative can solubilize significant concentrations of olopatadine in aqueous solution. As such, more desirable and reasonable concentrations of additional solubilizing agent can be used to aid in solubilizing desired amounts of olopatadine.
    [0028] Furthermore, it has been found that a composition formed using a combination of solubilizing agents such as polyvinylpyrrolidone, tyloxapol, polyethylene glycol and others to solubilize relatively high concentrations of olopatadine in the absence of the Y-cyclodextrin derivative and/or the β derivative -cyclodextrin will typically require long term stability or shelf life. It has been found that such a composition will typically undesirably begin to precipitate after short periods of time. Therefore, it is important to employ the Y-cyclodextrin derivative and/or β-cyclodextrin derivative in combination with one or more additional solubilizers.
    As such, the ophthalmic composition of the present invention includes at least one solubilizing agent (i.e., solubilizer), but possibly two or more solubilizing agents, in addition to cyclodextrin. Additional solubilizing agents can include surfactants such as castor oil, polysorbate or others. Preferably, the additional solubilizing agent(s) include(s) one or more polymers. A preferred polymer to help solubilize olopatadine is the lactam polymer. Another preferred polymer to help solubilize olopatadine is polyether.
    [0030] As used in this application, the phrase "lactam polymer" refers to any polymer formed from more than one lactam monomer. The lactam polymer is typically present in the composition at a concentration that is at least 1.0% w/v, more typically at least 3.0% w/v to more typically at least 3.7% w/v , but is typically not greater than 8.0% w/v, not typically greater than 5.0% w/v, and is typically not greater than 4.3% w/v. Polyvinylpyrrolidone (PVP) is the most preferred lactam polymer and can be the only or substantially the only lactam polymer. Thus, in a preferred embodiment, the lactam polymer consists or consists essentially only of PVP. The average molecular weight of the lactam polymer, particularly when it is PVP, is at least 20,000, more typically at least 46,000 and even more typically at least 54,000 but is typically not greater than 90,000, more typically not greater than 70,000 and even more typically not greater than 70,000 greater than 62,000. A preferred PVP is sold under the tradenames PLASDONE® K29/32 or K30, which have an average molecular weight of approximately 50,000 and are commercially available from ASHLAND SPECIALTY INGREDIENTS, located in Wayne, NJ, USA.
    The polyether can aid the solubility of olopatadine in the composition and/or can provide tonicity to the composition (i.e., act as a tonicity agent). The polyether is typically present in the composition at a concentration that is at least 1.0% w/v, more typically at least 3.0% w/v, to more typically at least 3.7% w/v, but not typically greater than 8.0% w/v, not typically greater than 5.0% w/v, and typically not greater than 4.3% w/v. Polyethylene glycol (PEG) is the most preferred polyether and can be the only or substantially the only polyether polymer. Thus, in a preferred embodiment, the polyether consists or consists essentially only of PEG. The average molecular weight of the PEG will typically depend on the particular solubility and particular desired tonicity of the composition. In a preferred embodiment, the average molecular weight of the polyether, particularly when it is PEG, is at least 200, more typically at least 320 and even more typically at least 380 but typically not greater than 800, more typically not greater than 580 and still more typically no greater than 420. A preferred PEG is PEG400.
    [0032] It may also be desirable for the ophthalmic composition of the present invention to include a viscosity-increasing agent in order to increase the composition's residence time on the cornea when the composition is administered topically. Examples of the potentially suitable viscosity-increasing agent include, without limitation, carboxyvinyl polymer, galactomannan, hyaluronic acid, cellulosic polymer, any combination of these or the like. In a preferred embodiment, the ophthalmic composition includes hydroxyethylcellulose (HEC), hydroxylpropylmethylcellulose (HPMC), or both. A preferred HEC is sold under the tradename NASTROSOL® 250HX, which is commercially available from Hercules Incorporated, Aqualon Division, Argyle, TX. A preferred HPMC is sold under the tradename E4M 2910 and is commercially available from Dow Chemical, Midland, MI.
    [0033] The amounts and molecular weights of HPMC and/or HEC used in the composition will depend on the viscosity, osmolality and other attributes to be achieved by the composition. As used in this application, viscosity is measured by a Brookfield viscometer (LVDVI+, CP-42, 12 RPM and a temperature of 25°C). In a preferred embodiment, the viscosity of the composition is at least 2.0 centipoise (cps), more typically at least 15 cps, to more typically at least 21 cps and even possibly at least 27 cps, but is typically not greater than 65 cps , not typically greater than 40 cps, more typically not greater than 33 cps, and even possibly not greater than 30 cps. Advantageously, and as further discussed below, it has been found that viscosity within these ranges is more desirable to produce desired droplet sizes when the composition of the present invention is currently released from a dropper.
    The preferred average molecular weight of HEC, when used, is typically in the range of 90,000 to 1,300,000 (eg, approximately 1,000,000). The preferred average molecular weight of HPMC is typically in the range of 10,000 to 1,500,000 and more typically in the range of 189,000 to 688,000).
    [0035] When HPMC is used alone, it is typically present in the composition at a concentration that is at least 0.15% w/v, more typically at least 0.3% w/v to more typically at least 0.5 % w/v, but typically not greater than 1.5% w/v, not typically greater than 1.0% w/v, and typically not greater than 0.7% w/v. When HEC is used alone, it is typically present in the composition at a concentration that is at least 0.1% w/v, more typically at least 0.25% w/v, to more typically at least 0.45% w/v. /v, but typically not greater than 1.4% w/v, not typically greater than 0.9% w/v, and typically not greater than 0.65% w/v. Advantageously, when HPMC and HEC are used together, they can produce a synergistic viscosity effect that allows the use of low concentrations of these excipients to produce the desired viscosity of the compositions. When HPMC and HEC are used in combination, HPMC is typically present in the composition at a concentration that is at least 0.05% w/v, more typically at least 0.1% w/v, to more typically at least 0. 2% w/v, but not typically greater than 1.0% w/v, not typically greater than 0.55% w/v, and typically not greater than 0.4% w/v. When HPMC and HEC are used in combination, HEC is typically present in the composition at a concentration that is at least 0.02% w/v, more typically at least 0.06% w/v, and even more typically at least 0. 09% w/v, but not typically greater than 0.6% w/v, not typically greater than 0.3% w/v, and typically not greater than 0.17% w/v. Notably, in at least some embodiments of the present invention, HPMC is a preferred viscosity-increasing agent since, as the data presented below shows, it can also aid in the solubilization of olopatadine.
    [0036] The composition may also include buffering agents and/or tonicity agents. Suitable tonicity adjusting agents and/or buffering agents include, but are not limited to, mannitol, sodium chloride, glycerin, sorbitol, phosphates, borates, acetate and the like.
    [0037] Borate is a highly preferred buffering agent and will typically be included in the composition of the present invention. As used in this application, the term "borate" shall refer to boric acid, boric acid salts, borate derivatives and other pharmaceutically acceptable borates or combinations thereof. The most suitable are: boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate and other such borate salts. Typically, when used, the borate is at least about 0.05% w/v, more typically at least about 0.18% w/v and possibly up to possibly at least about 0.27% w/v of the ophthalmic composition and is typically less than about 1.0% w/v, more typically less than about 0.75% w/v and still more typically less than about 0.4% w/v, and even possibly less than about 0.35% w/v of the ophthalmic composition.
    [0038] The composition of the present invention may also include polyol. As used in this application, the term "polyol" includes any compound that has at least one hydroxyl group on each of two adjacent carbon atoms that are not in trans configuration to each other. The polyol can be linear or cyclic, substituted or unsubstituted, or mixtures thereof, so long as the resulting complex is water-soluble and pharmaceutically acceptable. Examples of such compounds include: sugars, sugar alcohols, sugar acids and uronic acids. Preferred polyols are sugars, sugar alcohols and sugar acids, including, but not limited to: mannitol, glycerin, xylitol, sorbitol and propylene glycol. It is contemplated that the polyol can be comprised of two or more different polyols.
    When both borate and polyol are present in the composition, the borate typically interacts with polyols such as glycerol, propylene glycol, sorbitol and mannitol or any combination thereof to form borate polyol complexes. The type and proportion of such complexes depend on the number of OH groups in a polyol on adjacent carbon atoms that are not in trans configuration to each other. It should be understood that the weight/volume percentages of the polyol and borate ingredients include those amounts whether as part of a complex or not. Advantageously, borate and polyol can act as buffers and/or tonicity agents and can also aid in increasing the preservation effectiveness of the composition.
    [0040] In a preferred embodiment of the invention, the composition includes propylene glycol, glycerin or both. It has been found that Y-cyclodextrin derivatives and/or β-cyclodextrin derivatives tend to inhibit the preservation efficacy within the formulations of the present invention, however, propylene glycol in the presence of borate appears to significantly limit this inhibition. Furthermore, it has been found that glycerin often acts in a very similar way to propylene glycol when used to aid preservation. When used, propylene glycol, glycerin or a combination thereof are typically present in the composition at a concentration that is at least 0.4% w/v, more typically at least 0.65% w/v and up to possibly at least 0.85 % w/v but typically not greater than 5.0% w/v, more typically not greater than 2.2% w/v and even more typically not greater than 1.7% w/v.
    [0041] In the same preferred or alternative embodiment of the invention, the composition includes mannitol, sorbitol or both. Mannitol can also help preserve the composition of the present invention when used in the presence of borate. Furthermore, it has been found that sorbitol often acts in a very similar way to mannitol when used to aid preservation. When used, mannitol, sorbitol or a combination thereof are typically present in the composition at a concentration that is at least 0.05% w/v, more typically at least 0.2% w/v and up to possibly at least 0.4 % w/v but typically not greater than 3.0% w/v, more typically not greater than 1.0% w/v to more typically not greater than 0.5% w/v.
    [0042] The composition of the present invention typically includes a preservative. Potential preservatives include, without limitation, hydrogen peroxide, benzalkonium chloride (BAK), polymeric quaternary ammonium compound (PQAM), biguanides, sorbic acid, chlorhexidine, or others. Of these, benzalkonium chloride and a polymeric quaternary ammonium compound such as polyquaternium-1 have proven to be quite desirable.
    [0043] The polymeric quaternary ammonium compounds useful in the compositions of the present invention are those that have an antimicrobial effect and that are ophthalmically acceptable. Preferred compounds of this type are described in U.S. Pat. US 3,931,319; 4,027,020; 4,407,791; 4,525,346; 4,836,986; 5,037,647 and 5,300,287; and PCT patent application WO 91/09523 (Dziabo et al.). The most preferred polymeric ammonium compound is polyquaternium-1, otherwise known as POLYQUAD® with an average molecular weight between 2,000 and 30,000. Preferably, the average molecular weight is between 3,000 and 14,000.
    [0044] When used, the polymeric quaternary ammonium compound is generally used in the composition of the present invention in an amount that is greater than approximately 0.00001% w/v, more typically greater than approximately 0.0003% w/v. /v and even more typically greater than approximately 0.0007% w/v of the ophthalmic composition. Furthermore, the polymeric quaternary ammonium compound is generally used in the composition of the present invention in an amount which is less than approximately 0.01% w/v, more typically less than approximately 0.007% w/v, even more typically less than 0.003% w/v, even more typically less than 0.0022% w/v to possibly less than approximately 0.0015% w/v of the ophthalmic composition.
    [0045] BAK is generally used in the composition of the present invention in an amount that is greater than approximately 0.001% w/v, more typically greater than approximately 0.003% w/v and even more typically greater than approximately 0.007% w/v v of the ophthalmic composition. Furthermore, BAK is generally used in the composition of the present invention in an amount that is less than approximately 0.1% w/v, more typically less than approximately 0.03% w/v and more typically less than approximately 0.020 or 0.015% w/v of the ophthalmic composition.
    [0046] It is also contemplated that the composition of the present invention may benefit from the use of two different polyols, borate and a preservative (eg BAK or polymeric quaternary ammonium compound) to provide increased preservation effectiveness. Examples of such systems are described in U.S. Patent Publication Nos. 2009/0232763 and 2010/0324031, which are expressly incorporated in this application in their entirety for all purposes.
    [0047] Notably, it has been found that polymeric ammonium compound is particularly desirable for preserving compositions containing SAE-β-CD while BAK is particularly desirable for preserving compositions containing hydroxypropyl beta or gamma cyclodextrin derivatives. It has also been found that filtration (eg, micron filtration) of the preservative followed by aseptic addition of the preservative to the sterile composition can aid preservation effectiveness.
    [0048] It is contemplated that the composition of the present invention may include a variety of additional ingredients. Such ingredients include, without limitation, additional therapeutic agents, additional or alternative antimicrobial agents, suspending agents, surfactants, additional or alternative tonicity agents, additional or alternative buffering agents, antioxidants, additional or alternative viscosity modifying agents, chelating agents any combination of these or the like.
    The compositions of the present invention will generally be formulated as sterile aqueous solutions. The compositions of the present invention are also formulated to be compatible with the eye and/or other tissues to be treated with the compositions. Ophthalmic compositions intended for direct application to the eye will be formulated to have a pH and tonicity that is compatible with the eye. It is also contemplated that the compositions may be suspensions or other types of solutions.
    The composition of the present invention will typically have a pH in the range of 4 to 9, preferably 5.5 to 8.5, and even more preferably 5.5 to 8.0. Particularly desirable pH ranges are 6.0 to 7.8 and more specifically 6.4 to 7.2. The compositions will have an osmolality of 200 to 400 or 450 milliosmols per kilogram (mOsm/kg), more preferably 240 to 360 mOsm/kg.
    It is generally preferred that the composition of the present invention be provided in an eyedropper that is configured to dispense the composition as eye drops topically to the cornea of the eye. However, the desired size of a single eye drop (ie, droplet size) for the ophthalmic composition can be difficult to achieve. It has been found that cyclodextrin in the composition imparts a relatively high surface energy to the composition. In turn, the droplet size tends to be relatively high. It has been found, however, that by dispensing droplets through the relatively small orifice and/or keeping the composition viscosity within the ranges discussed above, the desired droplet size can be achieved. The desired droplet size is typically at least 10 μl, more typically at least 18 μl and even more typically at least 23 μl, but typically not larger than 60 μl, not typically larger than 45 μl and typically not larger than 33 μl . Advantageously, this droplet size of the composition with the concentrations of olopatadine specified in this application allows an individual to dispense one droplet per eye once a day and receive relief from ocular allergic conjunctivitis symptoms generally, but particularly to receive relief from phase symptoms late-onset allergic conjunctivitis.
    [0052] In a preferred embodiment, the composition of the present invention is a multidose ophthalmic composition that has sufficient antimicrobial activity to allow the compositions to meet USP preservative efficacy requirements, as well as other preservative efficacy standards of aqueous pharmaceutical compositions.
    [0053] The preservative efficacy standards of multidose ophthalmic solutions in the US and other countries/regions are presented in the following table: Preservative Efficacy Test Criteria ("PET") (Log-Order Reduction of Microbial Inoculum Over Time

    1There are two standards of preservative efficacy in the European Pharmacopoeia '"A" and "B".
    [0054] The standards identified above for USP 27 are substantially identical to the requirements set forth in previous editions of USP, particularly USP 24, USP 25 and USP 26. Advantages and Problems Overcome
    The olopatadine ophthalmic composition of the present invention can provide multiple advantages over olopatadine compositions that came before it. The composition described in this application provides an aqueous ophthalmic composition having a relatively high concentration of olopatadine that provides increased relief from the late stage of allergic conjunctivitis and the early stage of allergic conjunctivitis. Surprisingly and advantageously, preferred compositions of the present invention, as shown in FIGs. 1 to 5 and tables K to O, showed improved reduction in early-stage redness, late-stage redness, and late-stage itching. It is surprising that the increased concentration of olopatadine would show such a significant reduction in late phase symptoms. It is even more surprising that the increased concentration of olopatadine showed increased reduction in first phase redness since it was generally believed that itching and redness would show similar responses at different concentrations of olopatadine.
    [0056] Furthermore, the composition can solubilize the relatively high concentration of olopatadine in the form of a suitable solution as an eye drop where other formulations have failed. Furthermore, the composition can solubilize higher concentrations of olopatadine while maintaining efficacy in treating the symptoms of allergic conjunctivitis where other efforts to develop such a solution have failed. Furthermore, the compositions, when in multidose form, may pass preservation efficacy standards where other compositions have failed.
    [0057] As an additional advantage, it was found that, for the particular composition of the present invention, it was unexpectedly found that the composition containing HP-Y-CD is more susceptible to preservation. It has also been unexpectedly found to have similar solubility characteristics to another beta cyclodextrin derivative discussed in this application. This finding was particularly advantageous in providing a composition that is capable of solubilizing relatively high concentrations of olopatadine, capable of being stable for extended periods of time, and capable of robust preservation as far as European and US preservation efficacy standards are concerned.
    It is still further advantageous that cyclodextrin does not appear to interfere with the efficacy of olopatadine. In particular, it has been found that cyclodextrins capture other drugs in a way that does not allow those drugs to release late and show efficacy. However, this was not the case for olopatadine and particularly not the case for HP-Y-CD.
    [0059] Applicants specifically incorporate the entire contents of all references cited in this disclosure. Furthermore, when an amount, concentration, or other value or parameter is given as a range, preferred range or a list of higher preferred values and lower preferred values, this is to be understood as specifically describing all the formed ranges of any pair of any range limit or upper preferred value and any range limit or lower preferred value, even if the ranges are separately described. Where a range of numerical values is cited in this application, unless otherwise stated, the range is intended to include their endpoints, and all whole numbers and fractions within the range. The scope of the invention is not intended to be limited to the specific values cited when defining a range.
    [0060] Other embodiments of the present invention will be apparent to those skilled in the art from examination of this descriptive report and practice of the present invention described in this application. It is understood that the present descriptive report and examples are considered to be exemplary only with the true scope and spirit of the invention being indicated by the following claims and their equivalents.
    [0061] Table A below provides a listing of exemplary ingredients suitable for an exemplary preferred formulation of the ophthalmic composition of the present invention and a desired weight/volume percentage of those ingredients. It should be understood that the following Table A is exemplary and that certain ingredients may be added to or removed from the Table and concentrations of certain ingredients may be modified while the formulation may remain within the scope of the present invention, unless otherwise noted. specifically stated. TABLE A


    [0062] The following examples are presented to further illustrate selected embodiments of the present invention. The formulations shown in the examples were prepared using procedures that are well known to those of ordinary skill in the field of ophthalmic pharmaceutical compositions. EXAMPLES Preparatory Example 1
    [0063] In a suitable clean and tared glass bottle, add and dissolve HPMC with an amount of purified water equivalent to 90-95°C at approximately 15% of the required batch size. Mix by shaking until homogenized. Bring to 35% final weight with purified water and mix by stirring with propeller until complete dispersion. Add HEC and mix by shaking until homogenized. Sterilize the solution with steam (122°C/20 min) and then cool it down (Part A). In a separate vessel with a movement bar, add an amount of purified water equivalent to approximately 40% of the batch size required. Add and dissolve weighed batch amounts of PEG400, PVP, HP-β-CD, Olopatadine HCl, Boric acid, Mannitol, EDTA and BAC, allowing each component to dissolve before adding the next component. Check pH and adjust to 7.0 ± 0.1 with required amount of 2N NaOH (Part B). In a laminar flow hood (sterile conditions), filter the Part B solution into the glass bottle containing the autoclaved fraction (Part A), using the GV PVDF membrane, 0.22 μm filter unit and shake until homogenized. Mix by stirring with propeller for 15 min. Check pH and adjust to 7.0 ± 0.1 with the required amount of 1N NaOH/1N HCl if necessary. Bring to final weight with sterile purified water and shake until homogenized. Preparatory Example 2


    [0064] In a clean and tared suitable glass bottle, add and dissolve HPMC with an amount of purified water equivalent to 90-95°C at approximately 15% of the required batch size. Mix by shaking until homogenized. Bring to 30% final weight with purified water and mix by stirring with propeller until complete dispersion. Add HEC and mix by shaking until homogenized (Part A). In a clean beaker with the movement bar, weigh an amount of purified water equivalent to approximately 40% of the required batch size. Heat and keep this water around 70-75°C. Add 1N NaOH and mix by gentle agitation. Add PVP and dissolve under stirring for 20 minutes. Add 1N HCl, mix and quickly cool to 30-40°C. Add and dissolve batch amounts of PEG400, HP-β-CD, Olopatadine HCl, Boric acid, EDTA and BAC, allowing each component to dissolve before adding the next component. Check the pH of the solution and adjust to 6.8 ± 0.1 with the required amount of 2N NaOH (Part B). Transfer Part B to Part A and shake the batch until smooth. Bring to 85% of the final weight with purified water and shake until homogenized. Sterilize the solution with steam (122°C/20 min) and cool later. In a laminar flow hood (sterile conditions), check the pH and adjust to 7.0 ± 0.1 with the required amount of 1N NaOH/1N HCl, if necessary. Bring to final weight with sterile purified water and shake until homogenized. Examples of forms A through I in table B below
    [0065] Examples of forms A through I show the solubility of daolopatadine in different formulations.



    [0066] As can be seen, cyclodextrin can significantly increase the solubility of olopatadine in the aqueous solution. Furthermore, it will be appreciated that lower solubility formulations, particularly those without cyclodextrin, will also typically exhibit poorer solubility characteristics over time and will tend to form precipitates. Example form J to M in table C below
    [0067] Examples of forms J to M show the preservation efficacy of olopatadine containing formulations both with and without β-cyclodextrin.


    [0068] As can be seen, cyclodextrin derivatives can significantly inhibit the ability of a preservative to provide the desired preservation to an aqueous formulation.
    [0069] As an added advantage, it has also been found that HPMC can aid in solubilization of olopatadine. This effect is shown in Table D below.

    [0070] Table E below presents several formulations (N to Q) that can solubilize a high concentration of olopatadine using PVP in combination with a relatively low amount of HP-β-CD and that show desirable preservation using a combination of BAK and Acid Boric. Notably, it is also believed that PEG and HPMC are aiding in the solubility of olopatadine. TABLE AND


    [0071] Tables F and G below show the difficulty associated with preserving formulations (R to X) containing SBE-β-CD.TABLE F

    TABLE G


    [0072] Tables H and I show the achievement of significantly improved preservation of formulations (Y to II), which also contain SBE-β-CD.TABLE H

    TABLE I


    [0073] Table J illustrates that formula preservation can best be achieved using HP-Y-CD. In particular, Formulas JJ to TT in Table J exhibit robust preservation to both European and US preservation standards. This is particularly surprising when the data in Table J are compared with the data in Tables A, B, and E since there is no readily identifiable reason that formulations containing HP-Y-CD should exhibit greater preservation efficacy than to formulations containing HP-β-CD.TABLE J

    TABLE ALREADY CONTINUED


    [0074] Tables K to O below corresponding to the graphs in FIGS. 1 to 5 provide results from a conjunctival allergen challenge (CAC) study of a high concentration olopatadine composition as compared to a lower concentration olopatadine composition sold (sold as PATADAY® by Alcon Laboratories, Inc., Novartis Company). The CAC study was performed according to a standard CAC model that instills allergen to the eye (challenge) and then makes determinations of ocular redness and ocular itchiness at time points (determination times) after challenge. The CAC study was performed by ORA, Inc., Andover, Massachusetts, United States, 01810, which uses a model accepted by the Food and Drug Administration (FDA). It was noted that in tables K to O and in FIGs. 1 to 5, references for olopatadine 0.77% are references for olopatadine HCL and in fact represent olopatadine 0.7% as the base and references for olopatadine 0.2% are references for olopatadine HCl 0.22% and olopatadine 0.2% as a base.
    [0075] In the CAC model, each patient is dosed with drug or vehicle and exposed to the allergen at specific times of challenge. Study challenge times were 27 minutes, 16 hours and 24 hours after dosing. Thereafter, itching is determined at determination times of 3, 5 and 7 minutes after challenge times and redness is determined at determination times of 7, 15 and 20 minutes after challenge times. Therefore, patients received three doses of drug or vehicle and each dose was followed by an allergen challenge and then determinations of itching and redness are made as discussed. Results of determination times are given in Tables K by O and the graphs of FIGS. 1 to 5.
    [0076] Redness scores are determined on a scale of 0 to 4 by visual observation and the patient is asked to rate their eye itching on a scale of 0 to 4 to achieve the itching scores and for each score 0 is less than 4 it's bigger. The results of those determinations at those time points are given in Tables K to O and the graphs of FIGS. 1 to 5. Each of Tables K to O provides a mean score (Mean), a standard deviation (Std) for that score, the number (N) of patients, a minimum score (Min) determined for any one of the patients, a maximum score (Max) determined for any of the patients and p-values for indications of statistical significance with a p-value of less than 0.05 indicating statistical significance.
    [0077] Table K below provides the data for mean conjunctival redness as determined by the 27 minute post-challenge conjunctival allergen challenge (CAC) study and that data is provided as a graph in FIG 1. TABLE K

    [0078] Treatment by time interaction value p=0.0036
    [0079] As can be seen in Table K and FIG. 1, olopatadine at a concentration of 0.7% (note that 0.77% above is for olopatadine HCl and represents 0.7%) olopatadine provides statistically significant relief (ie, p<0.05) of redness at onset of action for both vehicle and 0.2% olopatadine. In addition, olopatadine at a concentration of 0.7% provides more than a 1.0 unit difference to vehicle in relieving redness. Olopatadine at this concentration is believed to be the first antihistamine/mast cell stabilizer to provide such a difference. These data are particularly surprising since, prior to this CAC study, there was no indication that a composition of olopatadine at high concentrations would provide any further reduction in redness at onset of action.
    The IC50 value of olopatadine or half maximal inhibitory concentration (IC50) for inhibition of human conjunctival mast cell degranulation is in the range of 500 to 600 μM. The binding affinity value of olopatadine (Ki) for histamine binding to the H1 receptor is in the range of 30 to 50 nM. The molar concentration of olopatadine in a 0.1% solution of olopatadine is approximately 2.5 mM. These values suggest that a 0.1% solution of olopatadine should have more than a sufficient amount of olopatadine to provide maximal inhibition of human conjunctival mast cell degranulation and maximal total histamine binding.
    [0081] In particular, for the inhibition of mast cell degranulation, these values indicate that when a 0.1% solution of olopatadine is dosed into the eye, there is exposure to 5 times the IC50 value for mast cell degranulation (500 µM against 2.5 mM). When a 0.2% olopatadine solution is dosed into the eye, exposure increases from approximately 2.5 mM (for a 0.1% solution) to 5 mM or approximately 10-fold excess drug for inhibition of mast cell degranulation. As olopatadine has no vasoconstrictive effect, which would typically reduce redness, it is believed that this inhibition of redness results from inhibition of the release of mast cell mediators brought about by mast cell degranulation. As such, a 0.1% or 0.2% solution of olopatadine should provide complete inhibition of redness at onset of action since both of these solutions provide excess olopatadine to inhibit mast cell degranulation.
    [0082] Surprisingly, however, the data in Table K and FIG. 1 show that a 0.7% solution of olopatadine prevents redness even better than a 0.2% solution of olopatadine at onset of action. Even more surprising, it provides a statistically significant difference in redness inhibition relative to the 0.2% solution at onset of action.
    [0083] In contrast to this surprising finding for redness, a similar finding was not made for itching (see Table KK below), which is believed to be avoided through histamine binding.


    [0084] Main treatment effect p value =<0.0001
    [0085] Treatment by time interaction p value = 0.4025
    [0086] Similarity in itch values for 0.7% olopatadine and 0.2% olopatadine for early action itch should be expected since both 0.2% olopatadine and 0.7% olopatadine provide enough olopatadine to provide maximum inhibition of itching at onset of action. Thus, the finding discussed above regarding redness at the beginning of the action is quite unique.
    [0087] Table L below provides data for mean conjunctival redness determined by the CAC study 16 hours after challenge and those data are provided as a graph in FIG 2. TABLE L

    [0088] Main effect of treatment p value =0.0004
    [0089] Treatment by time interaction value p=0.0077
    [0090] As can be seen in Table L and FIG. 2, olopatadine at a concentration of 0.7% provides statistically significant relief from redness in 16 hours as much as vehicle or 2% olopatadine.
    [0091] Table M below provides data for the mean total redness determined by the CAC study 24 hours after challenge and those data are provided as a graph in FIG 3. Mean total redness is a sum of three redness determinations: i) conjunctiva ; ii) episclera; and iii) ciliary, each using a scale from 1 to 4. TABLE M

    [0092] Main treatment effect p value =<.0003
    [0093] Treatment by time interaction value p=0.0136
    [0094] As can be seen in Table M and FIG. 3, olopatadine at a concentration of 0.7% provides statistically significant relief from total redness at 24 hours for both vehicle and 2% olopatadine.
    [0095] Table N below provides data regarding eye itchiness determined by the CAC study 24 hours after challenge and those data are provided as a graph in FIG 4.TABLE N

    [0096] Main treatment effect p value =<0.0001
    [0097] Treatment by time interaction value p=0.3221
    [0098] As can be seen in Table N and FIG. 4, olopatadine at a concentration of 0.7% provides statistically significant relief from ocular itching at 24 hours for both vehicle and 2% olopatadine.
    [0099] Table O below provides the data regarding ocular itchiness determined by the CAC study 24 hours after challenge and those data are provided as a graph in FIG 5.TABLE O


    [00100] Main treatment effect p value =0.0002
    [00101] Treatment by time interaction value p=0.1540
    [00102] As can be seen in Table O and FIG. %, olopatadine at a concentration of 0.7% provides statistically significant relief of conjunctival redness within 24 hours for both vehicle and 2% olopatadine.
    权利要求:
    Claims (9)
    [0001]
    1. Ophthalmic solution for the treatment of allergic ocular conjunctivitis, characterized by the fact that it comprises: at least 0.67% w/v, but not greater than 1.0% w/v of olopatadine in the solution; hydroxypropyl-cyclodextrin in the solution at a concentration of at least 0.5% w/v, but not greater than 2.0% w/v PEG with a molecular weight of 300 to 500, the concentration of PEG in the solution being 2.0% w/v 6.0% w/v; polyvinylpyrrolidone having a molecular weight of at least 20,000, the concentration of polyvinylpyrrolidone in the solution being 2.0% w/v to 6.0% w/v; a preservative; and a borate, a polyol or both; the solution has a pH of 5.5 to 8.0, and an osmolality of 200 to 450 mOsm/kg.
    [0002]
    2. Solution according to claim 1, characterized in that the concentration of olopatadine is at least 0.7% w/v and is dissolved in the solution.
    [0003]
    3. Solution, according to claim 1 or 2, characterized by the fact that it is arranged in an eyedropper.
    [0004]
    4. Solution according to claim 1, characterized in that it comprises a preservative selected from a polymeric compound of quaternary ammonia and benzalkonium chloride.
    [0005]
    5. Solution according to claim 4, characterized in that the preservative is benzalkonium chloride.
    [0006]
    6. Solution according to claim 1, characterized in that it comprises borate at a concentration of at least 0.18% w/v, but less than 0.5% w/v.
    [0007]
    7. Solution according to claim 6, characterized in that the polyol includes polyethylene glycol at a concentration of at least 0.4% w/v, but not greater than 2.2% w/v.
    [0008]
    8. Solution according to any one of claims 1 to 7, characterized in that it is for the treatment of ocular allergy symptoms.
    [0009]
    9. Solution according to claim 8, characterized in that said treatment comprises the distribution of an eye drop from a dropper.
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    同族专利:
    公开号 | 公开日
    RU2613715C2|2017-03-21|
    CA2826725C|2016-11-01|
    US9533053B2|2017-01-03|
    EP3045172A1|2016-07-20|
    US20140296328A1|2014-10-02|
    WO2012159064A1|2012-11-22|
    UY34074A|2012-11-30|
    MX2013010039A|2013-11-04|
    RU2013140423A|2015-03-10|
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    HK1194971A1|2014-10-31|
    KR20180008868A|2018-01-24|
    KR20140009332A|2014-01-22|
    CO6801738A2|2013-11-29|
    CA2826725A1|2012-11-22|
    BR112013022057A2|2017-08-01|
    UA114597C2|2017-07-10|
    US8791154B2|2014-07-29|
    TWI544922B|2016-08-11|
    AU2012255046A1|2013-08-22|
    JP5940146B2|2016-06-29|
    US20120295967A1|2012-11-22|
    CN105534970B|2019-04-02|
    KR20200053635A|2020-05-18|
    CN103458894A|2013-12-18|
    US20170071895A1|2017-03-16|
    EP2709610B1|2016-05-18|
    AU2012255046B2|2017-06-15|
    TW201249437A|2012-12-16|
    JP2014515355A|2014-06-30|
    KR101821518B1|2018-01-23|
    KR20160144507A|2016-12-16|
    AR086490A1|2013-12-18|
    CN105534970A|2016-05-04|
    KR101689924B1|2016-12-26|
    ZA201305870B|2014-12-23|
    ES2587869T3|2016-10-27|
    CL2013002467A1|2014-05-16|
    EP2709610A1|2014-03-26|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-03-26| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-05-21| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|
    2019-12-31| B25A| Requested transfer of rights approved|Owner name: ALCON RESEARCH, LLC (US) |
    2020-01-21| B25A| Requested transfer of rights approved|Owner name: NOVARTIS AG (CH) |
    2021-07-20| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-09-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 18/05/2012, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201161487789P| true| 2011-05-19|2011-05-19|
    US61/487,789|2011-05-19|
    US201161548957P| true| 2011-10-19|2011-10-19|
    US61/548,957|2011-10-19|
    PCT/US2012/038663|WO2012159064A1|2011-05-19|2012-05-18|High concentration olopatadine ophthalmic composition|
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