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US20220304995A1 - Ophthalmic compositions - Google Patents

Ophthalmic compositions Download PDF

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Publication number
US20220304995A1
US20220304995A1 US17/841,433 US202217841433A US2022304995A1 US 20220304995 A1 US20220304995 A1 US 20220304995A1 US 202217841433 A US202217841433 A US 202217841433A US 2022304995 A1 US2022304995 A1 US 2022304995A1
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US
United States
Prior art keywords
volume
weight
oxopropan
isoquinolin
ylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US17/841,433
Inventor
Cheng-Wen Lin
Casey Kopczynski
Mitchell A. deLong
Jill M. Sturdivant
Ramesh Krishnamoorthy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alcon Inc
Original Assignee
Aerie Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=59846699&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20220304995(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Aerie Pharmaceuticals Inc filed Critical Aerie Pharmaceuticals Inc
Priority to US17/841,433 priority Critical patent/US20220304995A1/en
Assigned to AERIE PHARMACEUTICALS, INC. reassignment AERIE PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DELONG, MITCHELL A., KOPCZYNSKI, CASEY, KRISHNAMOORTHY, RAMESH, LIN, CHENG-WEN, STURDIVANT, JILL M.
Priority to US17/858,889 priority patent/US11590123B2/en
Priority to US17/894,809 priority patent/US11707460B2/en
Publication of US20220304995A1 publication Critical patent/US20220304995A1/en
Assigned to ALCON INC. reassignment ALCON INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AERIE PHARMACEUTICALS, INC.
Abandoned legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Ophthalmic compositions are needed which provide sufficient solubility for the active pharmaceutical ingredient, while maintaining stability of the active pharmaceutical ingredient and reducing discomfort upon administration.
  • ophthalmic compositions are administered at or near physiological pH for both ease of dosing and reduced discomfort upon administration.
  • active pharmaceutical ingredients are sufficiently soluble at physiological pH. Therefore, a composition that both allows for sufficient solubility of the active pharmaceutical ingredient and minimizes discomfort upon administration is needed.
  • the present disclosure provides an ophthalmic composition
  • an ophthalmic composition comprising 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • the present disclosure provides an ophthalmic composition
  • an ophthalmic composition comprising 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; boric acid; and mannitol, wherein the composition has a pH from about 4.5 to about 5.2.
  • the present disclosure provides an ophthalmic composition
  • an ophthalmic composition comprising about 0.02% weight/volume of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salt; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • the present disclosure provides an ophthalmic composition, comprising 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; boric acid; mannitol; and latanoprost.
  • the present disclosure provides methods of treating an ophthalmic disease, the method comprising topically administering to the eye of a patient in need an ophthalmic composition as described herein.
  • the conjunctive term “or” includes any and all combinations of one or more listed elements associated by the conjunctive term.
  • the phrase “an apparatus comprising A or B” may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B are present.
  • the phrases “at least one of A, B, . . . and N” or “at least one of A, B, . . . N, or combinations thereof” are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, . . . and N, that is to say, any combination of one or more of the elements A, B, . . . or N including any one element alone or in combination with one or more of the other elements which may also include, in combination, additional elements not listed.
  • the modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity).
  • the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints.
  • the expression “from about 2 to about 4” also discloses the range “from 2 to 4.”
  • the term “about” may refer to plus or minus 10% of the indicated number.
  • “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1.
  • Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.
  • each intervening number there between with the same degree of precision is explicitly contemplated.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • the present disclosure provides an ophthalmic composition
  • an ophthalmic composition comprising netarsudil or its pharmaceutically acceptable salts; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • ophthalmic compositions comprising: 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • compositions comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethyl benzoate or a pharmaceutically acceptable salt thereof; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • ophthalmic compositions comprising: about 0.02% to about 0.03% weight/volume of (S)- 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • compositions comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; mannitol; and latanoprost.
  • compositions comprising; mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • ophthalmic compositions comprising: about 0.02% to about 0.03% weight/volume of a mixture of (S) 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • ophthalmic compositions comprising: a mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; mannitol; and latanoprost.
  • the pH is from about 3.5 to about 5.5.
  • the pH is from about 4.5 to about 5.2.
  • compositions further comprise a preservative.
  • the preservative comprises benzalkonium chloride.
  • compositions further comprise an emulsifying agent.
  • the emulsifying agent comprises polyoxyl 40 stearate, polyethoxylated castor oil, or a combination thereof.
  • the tonicity agent comprises mannitol.
  • the buffer comprises boric acid or its salts.
  • compositions further comprise water.
  • compositions further comprise a pH adjusting agent.
  • the 4-(3-amino-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate is a dimesylate salt.
  • the 4-(3-amino-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof.
  • compositions further comprise a second ophthalmic active compound.
  • the second ophthalmic active compound is a prostaglandin analog.
  • the prostaglandin analog is latanoprost or travoprost.
  • compositions comprise about 0.02% w/v to about 0.03% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof.
  • compositions comprise about 4.7% weight/volume of mannitol.
  • compositions comprise about 0.05% weight/volume of boric acid.
  • compositions comprise about 0.015% weight/volume of benzalkonium chloride.
  • compositions further comprise 0.005% weight/volume of latanoprost or travoprost.
  • the pharmaceutically acceptable salt is the dimesylate salt.
  • the pharmaceutically acceptable salt is the dihydrochloride salt.
  • the pharmaceutically acceptable salt is the mesylate salt.
  • the pharmaceutically acceptable salt is the hydrochloride salt.
  • 4-(3-Amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts may be present in the ophthalmic composition in an amount of about 0.01% w/v to about 0.06% w/v.
  • 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts may be present in an amount of about 0.02% w/v to about 0.03% w/v, depending on the particular salt form.
  • 0.0285% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate provides 0.02% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate free base; and 0.0233% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate diHCl provides 0.02% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate free base.
  • 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate may be an enantiomerically enriched isomer of a stereoisomer.
  • the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate may have an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the (S)- or the (R)-enantiomer.
  • Enantiomer when used herein, refers to either of a pair of chemical compounds whose molecular structures have a mirror-image relationship to each other.
  • a preparation of a compound disclosed herein is enriched for an isomer of the compound having a selected stereochemistry, e.g., R or S, corresponding to a selected stereocenter.
  • the compound has a purity corresponding to a compound having a selected stereochemistry of a selected stereocenter of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • pharmaceutically acceptable salt includes salts of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate that are prepared with relatively nontoxic acids.
  • Neutral forms of the compounds may be regenerated by contacting the salt with a base and isolating the parent compound in a conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as molecular weight and solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure. Examples of pharmaceutically acceptable salts are discussed in Berge et al, 1977, “Pharmaceutically Acceptable Salts.” J. Pharm. Sci. Vol. 66, pp. 1-19.
  • the compound is present in mono-salt form.
  • the compound is present in di-salt form.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, ethanesulfonic acid, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, p-toluenesulf
  • the ophthalmic compositions may comprise a buffer.
  • the buffer may serve to minimize pH drift of the composition and help to stabilize the composition.
  • Suitable buffers include, but are not limited to, acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, the pharmaceutically acceptable salts thereof, tromethamine, and combinations thereof.
  • the buffer may be present in the ophthalmic composition in an amount of from about 0.01% weight/volume to about 1% weight/volume or about 0.1% w/v to about 0.9% w/v, or about 0.3% w/v to about 0.8% w/v, or about 0.4% w/v to about 0.6% w/v.
  • the buffer may be present in at least 0.01% w/v, at least 0.05% w/v, at least 0.1% w/v, at least 0.3% w/v, or at least 0.5% w/v.
  • the buffer may be present in an amount of no more than 1.0% w/v, no more than 0.8% w/v, or no more than 0.6% w/v.
  • the buffer may be present in the ophthalmic composition in an amount of about 0.03% w/v, about 0.04% w/v, about 0.05% w/v, about 0.06% w/v, or about 0.07% w/v.
  • the buffer may suitably be boric acid.
  • the tonicity, or osmolality, of the composition can be adjusted to hypotonicity, isotonicity, or hypertonicity relative to normal tears by use of conventional materials known in the art.
  • Tonicity agents are typically nonionic compounds. Examples of tonicity agents include, but are not limited to, sodium chloride, potassium chloride, mannitol, dextrose, glycerine, and propylene glycol.
  • the tonicity agent may be present in the ophthalmic composition in an amount of from about 0.01% weight/volume to about 10% weight/volume or about 1% w/v to about 10% w/v, or about 2.5% w/v to about 7.5% w/v, or about 4% w/v to about 6% w/v.
  • the tonicity agent may be present in at least 0.01% w/v, at least 0.05% w/v, at least 1% w/v, at least 2.5% w/v, at least 4% w/v, or at least 5% w/v.
  • the tonicity agent may be present in an amount of no more than 10% w/v, no more than 7.5% w/v, no more than 6% w/v, or no more than 5% w/v.
  • the tonicity agent may be present in the ophthalmic composition in an amount of about 4.5% w/v, about 4.6% w/v, about 4.7% w/v, about 4.8% w/v, or about 4.9 w/v %.
  • the tonicity agent may suitably be mannitol.
  • the composition may also contain pH adjusting agents in an amount sufficient to adjust the pH of the composition to between about 3.5 and about 5.5.
  • the ophthalmic composition may have a pH of about 4.5 to about 5.2 or about 4.5 to about 5.1.
  • the ophthalmic composition has a pH of about 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, or a range bounded by any two of these values.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide.
  • the composition may also contain an emulsifying agent.
  • Suitable emulsifying agents include, but are not limited to, polyoxyl 40 stearate, polyethoxylated castor oil, and combinations thereof, and other agents known to one skilled in the art.
  • the emulsifying agent may be present in the ophthalmic composition in an amount of from about 0.01% weight/volume to about 1% weight/volume or about 0.1% w/v to about 0.9% w/v, or about 0.3% w/v to about 0.8% w/v, or about 0.4% w/v to about 0.6% w/v.
  • the emulsifying agent may be present in at least 0.01% w/v, at least 0.05% w/v, at least 0.1% w/v, at least 0.3% w/v, or at least 0.5% w/v.
  • the emulsifying agent may be present in an amount of no more than 1.0% w/v, no more than 0.8% w/v, or no more than 0.6% w/v.
  • the emulsifying agent may be present in the ophthalmic composition in an amount of about 0.2% w/v, about 0.25% w/v, about 0.3% w/v, about 0.5% w/v, or about 0.75% w/v.
  • Ophthalmic compositions are typically packaged in unit dose or multidose form.
  • Preservatives may be present to prevent or inhibit microbial contamination. Suitable preservatives include, but are not limited to, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, boric acid, sorbic acid, or other agents known to one skilled in the art. If present, the preservative may be present in the ophthalmic composition in an amount of about 0.001% w/v to about 1.0% w/v, or about 0.01% w/v to about 1.0% w/v, or about 0.1% w/v to about 1.0% w/v.
  • the preservative may be present in at least 0.001% w/v, at least 0.005% w/v, at least 0.01% w/v, at least 0.05% w/v, at least 0.1% w/v, or at least 0.5% w/v.
  • the preservative may be present in an amount of no more than 1.0% w/v, no more than 0.9% w/v, no more than 0.5% w/v, or no more than 0.1% w/v.
  • the preservative may be present in the ophthalmic composition in an amount of about 0.005% w/v, about 0.010% w/v, about 0.015% w/v, about 0.020% w/v, about 0.025% w/v, or about 0.030% w/v.
  • the preservative may suitably be benzalkonium chloride.
  • the composition may comprise a second active pharmaceutical ingredient.
  • the second active pharmaceutical ingredient may be a prostaglandin, such as latanoprost or travoprost. If present, the second active pharmaceutical ingredient may be present in an amount of about 0.001% w/v to about 1.0% w/v, or about 0.01% w/v to about 1.0% w/v, or about 0.1% w/v to about 1.0% w/v.
  • the second active pharmaceutical ingredient may be present in at least 0.001% w/v, at least 0.005% w/v at least 0.01% w/v, at least 0.05% w/v, at least 0.1% w/v, or at least 0.5% w/v, at least 5% w/v.
  • the second active pharmaceutical ingredient may be present in an amount of no more than 1,0% w/v, no more than 0.9% w/v, no more than 0.5% w/v, or no more than 0.1% w/v.
  • ophthalmic compositions such as surfactants, comfort-enhancing agents, solubilizing agents, antioxidants, and stabilizing agents, may also be present.
  • the buffer and tonicity agent are mixed with or without the preservative.
  • 4-(3-Amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate is then added to the mixture and stirred. Water is then added to bring the composition to 100%. The pH is then adjusted by adding pH adjusting agents.
  • the ophthalmic formulations of the present disclosure may be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, and gels.
  • the compositions are suitably aqueous.
  • treat or “treating” as used herein refers to administering a regimen to the subject, e.g., the administration a compound or composition described herein, such that the disorder or at least one symptom of the disorder is healed, alleviated, relieved, altered, remedied, ameliorated, and/or improved. Treating includes administering an amount effective to alleviate, relieve, alter, remedy, ameliorate, improve and/or affect the disorder or the symptoms of the disorder.
  • the treatment may inhibit deterioration or worsening of a symptom of a disorder.
  • the methods comprise topically applying to the affected eye(s) of the patient a therapeutically effective amount of a composition according to the present disclosure.
  • the frequency and amount of dosage can be readily determined by one of skill in the art based on various clinical factors.
  • the methods typically comprise topical application to the eye of one or two drops once or twice a day.
  • provided herein are methods of treating an ophthalmic disease in a subject in need thereof, the method comprising topically administering to an eye of a patient a composition provided herein.
  • the ophthalmic disease is glaucoma.
  • provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • ophthalmic composition comprising: about 0.02% to about 0.03% weight/volume of (S)-4-(3-amino-1-(isoquinolin-S-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethyl benzoate or a pharmaceutically acceptable salt thereof; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; mannitol; and latanoprost.
  • provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • ophthalmic composition comprising: about 0.02% to about 0.03% weight/volume of a mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: a mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; mannitol; and latanoprost.
  • Embodiment 1 An ophthalmic composition, comprising: 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • Embodiment 2 The composition of embodiment 1, wherein the pH is from about 3.5 to about 5.5.
  • Embodiment 3 The composition of embodiments 1 or 2, wherein the pH is from about 4.5 to about 5.2.
  • Embodiment 4 The composition of any one of embodiments 1-3, further comprising a preservative.
  • Embodiment 5 The composition of embodiment 4, wherein the preservative comprises benzalkonium chloride.
  • Embodiment 6 The composition of any one of embodiments 1-5, further comprising an emulsifying agent.
  • Embodiment 7 The composition of embodiment 6, wherein the emulsifying agent comprises polyoxyl 40 stearate, polyethoxylated castor oil, or a combination thereof.
  • Embodiment 8 The composition of any one of embodiments 1-7, wherein the tonicity agent comprises mannitol.
  • Embodiment 9 The composition of any one of embodiments 1-8, wherein the buffer comprises boric acid or its salts.
  • Embodiment 10 The composition of any one of embodiments 1-9, further comprising water.
  • Embodiment 11 The composition of any one of embodiments 1-10, further comprising a pH adjusting agent.
  • Embodiment 12 The composition of any one of embodiments 1-11, wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethyl benzoate is a dimesylate salt.
  • Embodiment 13 The composition of any one of embodiments 1-12, wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts.
  • Embodiment 14 The composition of any one of embodiments 1-13, further comprising a second ophthalmic active compound.
  • Embodiment 15 The composition of embodiment 14, wherein the second ophthalmic active compound is a prostaglandin analog.
  • Embodiment 16 The composition of embodiment 15, wherein the prostaglandin analog is latanoprost or travoprost.
  • Embodiment 17 The composition of any one of embodiments 1-16, comprising about 0.02% w/v to about 0.03% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or it pharmaceutically acceptable salts.
  • Embodiment 18 The composition of any one of embodiments 1-17, comprising about 4.7% weight/volume of mannitol.
  • Embodiment 19 The composition of any one of embodiments 1-18, comprising about 0.05% weight/volume of boric acid.
  • Embodiment 20 The composition of any one of embodiments 1-19, comprising about 0.015% weight/volume of benzalkonium chloride.
  • Embodiment 21 The composition of embodiment 16, further comprising 0.005% weight/volume of latanoprost or travoprost.
  • Embodiment 22 An ophthalmic composition, comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • Embodiment 23 An ophthalmic composition comprising: about 0.02% to about 0.03% weight/volume of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • Embodiment 24 An ophthalmic composition, comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; boric acid; mannitol; and latanoprost.
  • Embodiment 25 The compositions of any one of embodiments 22-24 wherein the salt is the dimesylate salt.
  • Embodiment 26 A method of treating an ophthalmic disease, the method comprising topically administering to the eye of a patient in need a composition of any one of claims 1 - 24 .
  • Embodiment 27 The method of embodiments 26, wherein the ophthalmic disease is glaucoma.
  • the present disclosure has multiple aspects, illustrated by the following non-limiting examples.
  • the below materials and characterization techniques have been used.
  • Table 1 shows the composition of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate formulations.
  • Formulations N, O, and P were prepared by adding boric acid, d-mannitol, and with or without 0.015% benzalkonium chloride in a labeled 150 -milliliter (mL) plastic storage container.
  • Table 2 shows the formulations of fixed-dose combination of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate and latanoprost.
  • Formulations R and S were prepared by adding boric acid and d-mannitol in a labeled 150-milliliter (mL) plastic storage container.
  • 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate and benzalkonium chloride/latanoprost stock solution (100 ⁇ ) were then added and dissolved by stirring the solution for another 10 minutes.
  • Table 3 shows the formulations of preservative-free, fixed-dose combination of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate and latanoprost.
  • Table 4 shows compositions of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate formulations as its dimesylate and diHCl salts.
  • Formulations N4 and O4 were prepared by adding boric acid, d-mannitol, and with or without 0.015% benzalkonium chloride in a labeled 150-milliliter (mL) plastic storage container.
  • Formulation P4 may be prepared according to the process described herein.

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Abstract

The present disclosure provides an ophthalmic composition comprising 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.

Description

    RELATED APPLICATIONS
  • This application is a continuation of U.S. patent application Ser. No. 15/691,607, filed Aug. 30, 2017, which claims priority of U.S. Provisional Patent Application No. 62/382,237, filed Aug. 31, 2016, the entire content of each of which is incorporated herein by reference.
    • INTRODUCTION
  • Ophthalmic compositions are needed which provide sufficient solubility for the active pharmaceutical ingredient, while maintaining stability of the active pharmaceutical ingredient and reducing discomfort upon administration. Typically ophthalmic compositions are administered at or near physiological pH for both ease of dosing and reduced discomfort upon administration. However, not all active pharmaceutical ingredients are sufficiently soluble at physiological pH. Therefore, a composition that both allows for sufficient solubility of the active pharmaceutical ingredient and minimizes discomfort upon administration is needed.
    • DETAILED DESCRIPTION
  • In an aspect, the present disclosure provides an ophthalmic composition comprising 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • In another aspect, the present disclosure provides an ophthalmic composition comprising 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; boric acid; and mannitol, wherein the composition has a pH from about 4.5 to about 5.2.
  • In another aspect, the present disclosure provides an ophthalmic composition comprising about 0.02% weight/volume of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salt; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • In another aspect, the present disclosure provides an ophthalmic composition, comprising 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; boric acid; mannitol; and latanoprost.
  • In another aspect, the present disclosure provides methods of treating an ophthalmic disease, the method comprising topically administering to the eye of a patient in need an ophthalmic composition as described herein.
    • 1. Definitions
  • Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.
  • The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.
  • The conjunctive term “or” includes any and all combinations of one or more listed elements associated by the conjunctive term. For example, the phrase “an apparatus comprising A or B” may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B are present. The phrases “at least one of A, B, . . . and N” or “at least one of A, B, . . . N, or combinations thereof” are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, . . . and N, that is to say, any combination of one or more of the elements A, B, . . . or N including any one element alone or in combination with one or more of the other elements which may also include, in combination, additional elements not listed.
  • The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.
  • For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
    • 2. Compositions
  • In an aspect, the present disclosure provides an ophthalmic composition comprising netarsudil or its pharmaceutically acceptable salts; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
    • a. 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate
  • In another aspect, provided herein are ophthalmic compositions, comprising: 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • In another aspect, provided herein are ophthalmic compositions, comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethyl benzoate or a pharmaceutically acceptable salt thereof; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • In another aspect, provided herein are ophthalmic compositions, comprising: about 0.02% to about 0.03% weight/volume of (S)- 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • In another aspect, provided herein are ophthalmic compositions, comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; mannitol; and latanoprost.
  • In another aspect, provided herein are ophthalmic compositions, comprising; mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • In another aspect, provided herein are ophthalmic compositions, comprising: about 0.02% to about 0.03% weight/volume of a mixture of (S) 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • In another aspect, provided herein are ophthalmic compositions, comprising: a mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; mannitol; and latanoprost.
  • In some embodiments of the compositions provided herein, the pH is from about 3.5 to about 5.5.
  • In some embodiments of the compositions provided herein, the pH is from about 4.5 to about 5.2.
  • In some embodiments, the compositions further comprise a preservative.
  • In some embodiments, the preservative comprises benzalkonium chloride.
  • In some embodiments, the compositions further comprise an emulsifying agent.
  • In some embodiments, the emulsifying agent comprises polyoxyl 40 stearate, polyethoxylated castor oil, or a combination thereof.
  • In some embodiments, the tonicity agent comprises mannitol.
  • In some embodiments, the buffer comprises boric acid or its salts.
  • In some embodiments, the compositions further comprise water.
  • In some embodiments, the compositions further comprise a pH adjusting agent.
  • In some embodiments, the 4-(3-amino-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate is a dimesylate salt.
  • In some embodiments, the 4-(3-amino-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the compositions further comprise a second ophthalmic active compound.
  • In some embodiments, the second ophthalmic active compound is a prostaglandin analog.
  • In some embodiments, the prostaglandin analog is latanoprost or travoprost.
  • In some embodiments, the compositions comprise about 0.02% w/v to about 0.03% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof.
  • In some embodiments, the compositions comprise about 4.7% weight/volume of mannitol.
  • In some embodiments, the compositions comprise about 0.05% weight/volume of boric acid.
  • In some embodiments, the compositions comprise about 0.015% weight/volume of benzalkonium chloride.
  • In some embodiments, the compositions further comprise 0.005% weight/volume of latanoprost or travoprost.
  • In some embodiments, the pharmaceutically acceptable salt is the dimesylate salt.
  • In some embodiments, the pharmaceutically acceptable salt is the dihydrochloride salt.
  • In some embodiments, the pharmaceutically acceptable salt is the mesylate salt.
  • In some embodiments, the pharmaceutically acceptable salt is the hydrochloride salt.
  • 4-(3-Amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts may be present in the ophthalmic composition in an amount of about 0.01% w/v to about 0.06% w/v. Suitably, 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts may be present in an amount of about 0.02% w/v to about 0.03% w/v, depending on the particular salt form. For example, 0.0285% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate provides 0.02% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate free base; and 0.0233% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate diHCl provides 0.02% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate free base. (S)-4-(3-Amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate is also known as netarsudil mesylate.
  • In an embodiment, 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate may be an enantiomerically enriched isomer of a stereoisomer. For example, the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate may have an enantiomeric excess of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the (S)- or the (R)-enantiomer. Enantiomer, when used herein, refers to either of a pair of chemical compounds whose molecular structures have a mirror-image relationship to each other. In an embodiment, a preparation of a compound disclosed herein is enriched for an isomer of the compound having a selected stereochemistry, e.g., R or S, corresponding to a selected stereocenter. For example, the compound has a purity corresponding to a compound having a selected stereochemistry of a selected stereocenter of at least about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%.
  • The term “pharmaceutically acceptable salt” includes salts of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate that are prepared with relatively nontoxic acids. Neutral forms of the compounds may be regenerated by contacting the salt with a base and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as molecular weight and solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of this disclosure. Examples of pharmaceutically acceptable salts are discussed in Berge et al, 1977, “Pharmaceutically Acceptable Salts.” J. Pharm. Sci. Vol. 66, pp. 1-19. In an embodiment, the compound is present in mono-salt form. In embodiments, the compound is present in di-salt form.
  • Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, ethanesulfonic acid, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, p-toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids; tannic acid, carboxymethyl cellulose.
    • b. Buffers
  • The ophthalmic compositions may comprise a buffer. The buffer may serve to minimize pH drift of the composition and help to stabilize the composition. Suitable buffers include, but are not limited to, acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, the pharmaceutically acceptable salts thereof, tromethamine, and combinations thereof. The buffer may be present in the ophthalmic composition in an amount of from about 0.01% weight/volume to about 1% weight/volume or about 0.1% w/v to about 0.9% w/v, or about 0.3% w/v to about 0.8% w/v, or about 0.4% w/v to about 0.6% w/v. Suitably, the buffer may be present in at least 0.01% w/v, at least 0.05% w/v, at least 0.1% w/v, at least 0.3% w/v, or at least 0.5% w/v. Suitably, the buffer may be present in an amount of no more than 1.0% w/v, no more than 0.8% w/v, or no more than 0.6% w/v. In embodiments, the buffer may be present in the ophthalmic composition in an amount of about 0.03% w/v, about 0.04% w/v, about 0.05% w/v, about 0.06% w/v, or about 0.07% w/v. The buffer may suitably be boric acid.
    • c. Tonicity Agents
  • The tonicity, or osmolality, of the composition can be adjusted to hypotonicity, isotonicity, or hypertonicity relative to normal tears by use of conventional materials known in the art. Tonicity agents are typically nonionic compounds. Examples of tonicity agents include, but are not limited to, sodium chloride, potassium chloride, mannitol, dextrose, glycerine, and propylene glycol. Suitably, the tonicity agent may be present in the ophthalmic composition in an amount of from about 0.01% weight/volume to about 10% weight/volume or about 1% w/v to about 10% w/v, or about 2.5% w/v to about 7.5% w/v, or about 4% w/v to about 6% w/v. Suitably, the tonicity agent may be present in at least 0.01% w/v, at least 0.05% w/v, at least 1% w/v, at least 2.5% w/v, at least 4% w/v, or at least 5% w/v. Suitably, the tonicity agent may be present in an amount of no more than 10% w/v, no more than 7.5% w/v, no more than 6% w/v, or no more than 5% w/v. In embodiments, the tonicity agent may be present in the ophthalmic composition in an amount of about 4.5% w/v, about 4.6% w/v, about 4.7% w/v, about 4.8% w/v, or about 4.9 w/v %. The tonicity agent may suitably be mannitol.
    • d. Other Components
  • In embodiments, the composition may also contain pH adjusting agents in an amount sufficient to adjust the pH of the composition to between about 3.5 and about 5.5. Suitably, the ophthalmic composition may have a pH of about 4.5 to about 5.2 or about 4.5 to about 5.1. In some embodiments, the ophthalmic composition has a pH of about 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, or a range bounded by any two of these values. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide.
  • In embodiments, the composition may also contain an emulsifying agent. Suitable emulsifying agents include, but are not limited to, polyoxyl 40 stearate, polyethoxylated castor oil, and combinations thereof, and other agents known to one skilled in the art. The emulsifying agent may be present in the ophthalmic composition in an amount of from about 0.01% weight/volume to about 1% weight/volume or about 0.1% w/v to about 0.9% w/v, or about 0.3% w/v to about 0.8% w/v, or about 0.4% w/v to about 0.6% w/v. Suitably, the emulsifying agent may be present in at least 0.01% w/v, at least 0.05% w/v, at least 0.1% w/v, at least 0.3% w/v, or at least 0.5% w/v. Suitably, the emulsifying agent may be present in an amount of no more than 1.0% w/v, no more than 0.8% w/v, or no more than 0.6% w/v. In embodiments, the emulsifying agent may be present in the ophthalmic composition in an amount of about 0.2% w/v, about 0.25% w/v, about 0.3% w/v, about 0.5% w/v, or about 0.75% w/v.
  • Ophthalmic compositions are typically packaged in unit dose or multidose form. Preservatives may be present to prevent or inhibit microbial contamination. Suitable preservatives include, but are not limited to, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, boric acid, sorbic acid, or other agents known to one skilled in the art. If present, the preservative may be present in the ophthalmic composition in an amount of about 0.001% w/v to about 1.0% w/v, or about 0.01% w/v to about 1.0% w/v, or about 0.1% w/v to about 1.0% w/v. Suitably, the preservative may be present in at least 0.001% w/v, at least 0.005% w/v, at least 0.01% w/v, at least 0.05% w/v, at least 0.1% w/v, or at least 0.5% w/v. Suitably, the preservative may be present in an amount of no more than 1.0% w/v, no more than 0.9% w/v, no more than 0.5% w/v, or no more than 0.1% w/v. In some embodiments, the preservative may be present in the ophthalmic composition in an amount of about 0.005% w/v, about 0.010% w/v, about 0.015% w/v, about 0.020% w/v, about 0.025% w/v, or about 0.030% w/v. The preservative may suitably be benzalkonium chloride.
  • In embodiments, the composition may comprise a second active pharmaceutical ingredient. The second active pharmaceutical ingredient may be a prostaglandin, such as latanoprost or travoprost. If present, the second active pharmaceutical ingredient may be present in an amount of about 0.001% w/v to about 1.0% w/v, or about 0.01% w/v to about 1.0% w/v, or about 0.1% w/v to about 1.0% w/v. Suitably, the second active pharmaceutical ingredient may be present in at least 0.001% w/v, at least 0.005% w/v at least 0.01% w/v, at least 0.05% w/v, at least 0.1% w/v, or at least 0.5% w/v, at least 5% w/v. Suitably, the second active pharmaceutical ingredient may be present in an amount of no more than 1,0% w/v, no more than 0.9% w/v, no more than 0.5% w/v, or no more than 0.1% w/v.
  • Other components commonly used in ophthalmic compositions, such as surfactants, comfort-enhancing agents, solubilizing agents, antioxidants, and stabilizing agents, may also be present.
  • Typically, the buffer and tonicity agent are mixed with or without the preservative. 4-(3-Amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate is then added to the mixture and stirred. Water is then added to bring the composition to 100%. The pH is then adjusted by adding pH adjusting agents.
    • 3. Formulations and Methods of Use
  • The ophthalmic formulations of the present disclosure may be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, and gels. The compositions are suitably aqueous.
  • The present disclosure is also directed to methods of treating glaucoma and other ophthalmic diseases. As used herein, “treat” or “treating” as used herein refers to administering a regimen to the subject, e.g., the administration a compound or composition described herein, such that the disorder or at least one symptom of the disorder is healed, alleviated, relieved, altered, remedied, ameliorated, and/or improved. Treating includes administering an amount effective to alleviate, relieve, alter, remedy, ameliorate, improve and/or affect the disorder or the symptoms of the disorder. The treatment may inhibit deterioration or worsening of a symptom of a disorder.
  • The methods comprise topically applying to the affected eye(s) of the patient a therapeutically effective amount of a composition according to the present disclosure. The frequency and amount of dosage can be readily determined by one of skill in the art based on various clinical factors. The methods typically comprise topical application to the eye of one or two drops once or twice a day.
  • Thus, in one aspect, provided herein are methods of treating an ophthalmic disease in a subject in need thereof, the method comprising topically administering to an eye of a patient a composition provided herein. In some embodiments, the ophthalmic disease is glaucoma.
  • In some embodiments, provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • In some embodiments, provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • In some embodiments, provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: about 0.02% to about 0.03% weight/volume of (S)-4-(3-amino-1-(isoquinolin-S-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethyl benzoate or a pharmaceutically acceptable salt thereof; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • In some embodiments, provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; mannitol; and latanoprost.
  • In some embodiments, provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • In some embodiments, provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: about 0.02% to about 0.03% weight/volume of a mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • In some embodiments, provided herein are methods of treating glaucoma in a subject in need thereof, the method comprising topically administering to an eye of a patient an ophthalmic composition comprising: a mixture of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof and (R)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or a pharmaceutically acceptable salt thereof; boric acid; mannitol; and latanoprost.
    • 4. Embodiments
  • Embodiment 1. An ophthalmic composition, comprising: 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; about 0.01% weight/volume to about 1.0% weight/volume of a buffer; and about 0.01% weight/volume to about 10% weight/volume of a tonicity agent.
  • Embodiment 2. The composition of embodiment 1, wherein the pH is from about 3.5 to about 5.5.
  • Embodiment 3. The composition of embodiments 1 or 2, wherein the pH is from about 4.5 to about 5.2.
  • Embodiment 4. The composition of any one of embodiments 1-3, further comprising a preservative.
  • Embodiment 5. The composition of embodiment 4, wherein the preservative comprises benzalkonium chloride.
  • Embodiment 6. The composition of any one of embodiments 1-5, further comprising an emulsifying agent.
  • Embodiment 7. The composition of embodiment 6, wherein the emulsifying agent comprises polyoxyl 40 stearate, polyethoxylated castor oil, or a combination thereof.
  • Embodiment 8. The composition of any one of embodiments 1-7, wherein the tonicity agent comprises mannitol.
  • Embodiment 9. The composition of any one of embodiments 1-8, wherein the buffer comprises boric acid or its salts.
  • Embodiment 10. The composition of any one of embodiments 1-9, further comprising water.
  • Embodiment 11. The composition of any one of embodiments 1-10, further comprising a pH adjusting agent.
  • Embodiment 12. The composition of any one of embodiments 1-11, wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethyl benzoate is a dimesylate salt.
  • Embodiment 13. The composition of any one of embodiments 1-12, wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts.
  • Embodiment 14. The composition of any one of embodiments 1-13, further comprising a second ophthalmic active compound.
  • Embodiment 15. The composition of embodiment 14, wherein the second ophthalmic active compound is a prostaglandin analog.
  • Embodiment 16. The composition of embodiment 15, wherein the prostaglandin analog is latanoprost or travoprost.
  • Embodiment 17. The composition of any one of embodiments 1-16, comprising about 0.02% w/v to about 0.03% w/v of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or it pharmaceutically acceptable salts.
  • Embodiment 18. The composition of any one of embodiments 1-17, comprising about 4.7% weight/volume of mannitol.
  • Embodiment 19. The composition of any one of embodiments 1-18, comprising about 0.05% weight/volume of boric acid.
  • Embodiment 20. The composition of any one of embodiments 1-19, comprising about 0.015% weight/volume of benzalkonium chloride.
  • Embodiment 21. The composition of embodiment 16, further comprising 0.005% weight/volume of latanoprost or travoprost.
  • Embodiment 22. An ophthalmic composition, comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; boric acid; and mannitol; wherein the composition has a pH from about 4.5 to about 5.2.
  • Embodiment 23. An ophthalmic composition comprising: about 0.02% to about 0.03% weight/volume of (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; about 4.7% weight/volume of mannitol; about 0.05% weight/volume of boric acid; and about 0.015% weight/volume of benzalkonium chloride; wherein the composition has a pH from about 4.5 to about 5.2.
  • Embodiment 24. An ophthalmic composition, comprising: (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate or its pharmaceutically acceptable salts; boric acid; mannitol; and latanoprost.
  • Embodiment 25. The compositions of any one of embodiments 22-24 wherein the salt is the dimesylate salt.
  • Embodiment 26. A method of treating an ophthalmic disease, the method comprising topically administering to the eye of a patient in need a composition of any one of claims 1-24.
  • Embodiment 27. The method of embodiments 26, wherein the ophthalmic disease is glaucoma.
    • 5. Examples
  • The present disclosure has multiple aspects, illustrated by the following non-limiting examples. In the various examples, the below materials and characterization techniques have been used.
    • Example 1. Formulations of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate
  • Table 1 shows the composition of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate formulations. Formulations N, O, and P were prepared by adding boric acid, d-mannitol, and with or without 0.015% benzalkonium chloride in a labeled 150 -milliliter (mL) plastic storage container. 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate, with or without 5% benzalkonium chloride stock solution, was then added and dissolved by stirring the solution for another 10 minutes. 100 milliliter (mL) of purified water was then added to bring the solution almost to 100%, and the pH was adjusted to approximately 5.0. Sufficient 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate (CAS number: #1422144-42-0) (0.0285% w/v) was added to have 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate free base (CAS number; #1254032-66-0) present at 0.02% w/v.
  • TABLE 1
    Formulation (% weight/volume)
    Ingredient N O P
    4-(3-amino-1-(isoquinolin-6- 0.02 0.02 0.04
    ylamino)-1-oxopropan-2-
    yl)benzyl 2,4-
    dimethylbenzoate free base
    Boric acid 0.05 0.05 0.05
    D-mannitol 4.7 4.7 4.7
    Benzalkonium chloride — 0.015 0.015
    Purified water q.s. q.s. q.s.
    pH 5.0 5.0 5.0
    • Example 2. Formulations of Fixed-Dose Combination of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethyl Benzoate and Latanoprost
  • Table 2 shows the formulations of fixed-dose combination of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate and latanoprost. Formulations R and S were prepared by adding boric acid and d-mannitol in a labeled 150-milliliter (mL) plastic storage container. 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate and benzalkonium chloride/latanoprost stock solution (100×) were then added and dissolved by stirring the solution for another 10 minutes. 100 milliliter (mL) of purified water was then added to bring the solution almost to 100%, and the pH was adjusted to approximately 5.0. Sufficient 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate dimesylate (CAS number: #1422144-42-0) (0.0285% w/v) was added to have 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate free base (CAS number: #1254032-66-0) present at 0.02% w/v.
  • TABLE 2
    Formulation (% weight/volume)
    Ingredient R S
    4-(3-amino-1-(isoquinolin-6- 0.02 0.02
    ylamino)-1-oxopropan-2-
    yl)benzyl 2,4-
    dimethylbenzoate free base
    Latanoprost 0.005 0.005
    Boric acid 0.05 0.05
    D-mannitol 4.7 4.7
    Benzalkonium chloride 0.015 0.02
    Purified water q.s. q.s.
    pH 5.0 5.0
    • Example 3. Preservative-Free, Fixed-Dose Combination 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate and Latanoprost
  • Additional formulations may be prepared according to the method in Example 1. Table 3 shows the formulations of preservative-free, fixed-dose combination of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate and latanoprost.
  • TABLE 3
    Formulation (% weight/volume)
    Ingredient T U V
    4-(3-amino-1-(isoquinolin-6- 0.02 0.02 0.02
    ylamino)-1-oxopropan-2-
    yl)benzyl 2,4-
    dimethylbenzoate free base
    Latanoprost 0.005 0.005 0.005
    Boric acid 0.05 0.05 0.05
    D-mannitol 4.7 4.7 4.7
    Polyoxyl 40 stearate 0.5 — —
    (Myrj-52)
    Cremophr RH 40 — 0.25 0.5
    Benzalkonium chloride — — —
    Purified water q.s. q.s. q.s.
    pH 5.5 5.5 5.5
    • Example 4. Formulations of 4-(3-amino-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate
  • Table 4 shows compositions of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate formulations as its dimesylate and diHCl salts. Formulations N4 and O4 were prepared by adding boric acid, d-mannitol, and with or without 0.015% benzalkonium chloride in a labeled 150-milliliter (mL) plastic storage container. The disalts 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate mesylate (CAS number: #1422144-42-0), or 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate chloride (CAS number: #1253952-02-1), with or without 5% benzalkonium chloride stock solution, was then added and dissolved by stirring the solution for another 10 minutes. 100 milliliter (mL) of purified water was then added to bring the solution almost to 100%, and the pH was adjusted to approximately 5.0.
  • Formulation P4 may be prepared according to the process described herein.
  • TABLE 4
    Formulation (% weight/volume)
    Ingredient N4 O4 P4
    4-(3-amino-1-(isoquinolin-6- 0.0285 0.000 0.0143
    ylamino)-1-oxopropan-2-
    yl)benzyl 2,4-
    dimethylbenzoate mesylate
    (disalt)
    4-(3-amino-1-(isoquinolin-6- 0.000 0.0233 0.0116
    ylamino)-1-oxopropan-2-
    yl)benzyl 2,4-
    dimethylbenzoate HCl
    (disalt)
    Boric acid 0.05 0.05 0.05
    D-mannitol 4.7 4.7 4.7
    Benzalkonium chloride 0.015 0.015 0.008
    Purified water q.s. q.s. q.s.
    pH 5.0 4.8 4.9
  • It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the disclosure, which is defined solely by the appended claims and their equivalents.

Claims (32)

1. An ophthalmic formulation, consisting essentially of:
A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.02 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.8; or
F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.008 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.9.
2. The ophthalmic formulation of claim 1, wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate.
3. The ophthalmic formulation of claim 1, wherein the mannitol is D-mannitol.
4. The ophthalmic formulation of claim 1, wherein the polyoxyl 40 stearate is Myrj-52.
5. The ophthalmic formulation of claim 1, wherein the polyethoxylated castor oil is Cremophor RH 40.
6. The ophthalmic formulation of claim 1, which is a topical ophthalmic formulation.
7. The ophthalmic formulation of claim 1, which is packaged in a unit dose form.
8. The ophthalmic formulation of claim 1, which is packaged in a multidose form.
9. The ophthalmic formulation of claim 1, which is in a plastic storage container.
10. The ophthalmic formulation of claim 1, consisting of:
A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.02 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.8; or
F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.008 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.9.
11. A method of treating an ophthalmic disease in a subject in need thereof, comprising topically administering to an eye of the subject an ophthalmic formulation consisting essentially of:
A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.02 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.8; or
F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.008 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.9.
12-24. (canceled)
25. The method of claim 11, wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate.
26. The method of claim 11, wherein the mannitol is D-mannitol.
27. The method of claim 11, wherein the polyoxyl 40 stearate is myrj-52.
28. The method of claim 11, wherein the polyethoxylated castor oil is cremophor RH
40.
29. The method of claim 11, wherein the ophthalmic formulation is a topical ophthalmic formulation.
30. The method of claim 11, wherein the ophthalmic formulation is packaged in a unit dose form.
31. The method of claim 11, wherein the ophthalmic formulation is packaged in a multidose form.
32. The method of claim 11, wherein the ophthalmic formulation is in a plastic storage container.
33. The method of claim 11, wherein the ophthalmic formulation consists of:
A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.02 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.8; or
F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.008 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.9.
34. A method of treating glaucoma in a subject in need thereof, comprising topically administering to an eye of the subject an ophthalmic formulation consisting essentially of:
A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.02 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.8; or
F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.008 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.9.
35. The method of claim 34, wherein the 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate is (S)-4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate.
36. The method of claim 34, wherein the mannitol is D-mannitol.
37. The method of claim 34, wherein the polyoxyl 40 stearate is myrj-52.
38. The method of claim 34, wherein the polyethoxylated castor oil is cremophor RH 40.
39. The method of claim 34, wherein the ophthalmic formulation is a topical ophthalmic formulation.
40. The method of claim 34, wherein the ophthalmic formulation is packaged in a unit dose form.
41. The method of claim 34, wherein the ophthalmic formulation is packaged in a multidose form.
42. The method of claim 34, wherein the ophthalmic formulation is in a plastic storage container.
43. The method of claim 34, wherein the ophthalmic formulation consists of:
A) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
B) 0.057 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
C) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
D) 0.0285 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.005 weight/volume % of latanoprost,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.02 weight/volume % of benzalkonium chloride,
water, and
a pH of 5;
E) 0.0233 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.015 weight/volume % of benzalkonium chloride, water, and
a pH of 4.8; or
F) 0.0143 weight/volume % of a dimesylate salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.0116 weight/volume % of a dihydrochloride salt of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate,
0.05 weight/volume % of boric acid,
4.7 weight/volume % of mannitol,
0.008 weight/volume % of benzalkonium chloride,
water, and
a pH of 4.9.
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