WO2023152642A1 - Compositions ophtalmiques et procédés associés - Google Patents

Compositions ophtalmiques et procédés associés Download PDF

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Publication number
WO2023152642A1
WO2023152642A1 PCT/IB2023/051097 IB2023051097W WO2023152642A1 WO 2023152642 A1 WO2023152642 A1 WO 2023152642A1 IB 2023051097 W IB2023051097 W IB 2023051097W WO 2023152642 A1 WO2023152642 A1 WO 2023152642A1
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WO
WIPO (PCT)
Prior art keywords
acid
ophthalmic composition
composition
ophthalmic
sodium
Prior art date
Application number
PCT/IB2023/051097
Other languages
English (en)
Inventor
Mahesh Kandula
Original Assignee
Avaca Pharma Private Limited
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
Application filed by Avaca Pharma Private Limited filed Critical Avaca Pharma Private Limited
Publication of WO2023152642A1 publication Critical patent/WO2023152642A1/fr

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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
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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

Definitions

  • Present invention provides a stable ophthalmic composition
  • a stable ophthalmic composition comprising atropine and its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, stereoisomers or derivatives thereof in combination with R-lipoic acid and its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, enantiomers, stereoisomers or derivatives thereof or nicotinamide.
  • a mixture or combination thereof in ophthalmic preparations having atropine in a pharmaceutically acceptable form in combination with nicotinamide or R-lipoic acid in a pharmaceutically salt form comprising at least one carrier, diluent, antioxidant, polymer, excipient or combination thereof in various storage stable, ready-to-use, and method of manufacturing such compositions.
  • present invention provides a sterile ophthalmic composition
  • a sterile ophthalmic composition comprising: (a) about 0.01%w/w atropine sulfate and less than about 0.1% of tropic acid formed from degradation of the atropine sulfate, (b) about 0.10%w/w nicotinamide, (c) about 1% buffer component, (d) about 0.50%w/w thickening agent, (e) about 0.01%w/w preservative, (f) about 0.13%w/w chelating agent, (g) about 0.30% tonicity adjustment agent, (h)about 0.01% pH adjustment agent, and (i) water QS, wherein the ophthalmic composition has a pH between 3.5 to 3.8.
  • the thickening agent is hypromellose.
  • the chelating agent is ethylene diamine tetra acetic acid.
  • the tonicity adjustment agent is sodium chloride.
  • the pH adjustment agent is hydrochloric acid.
  • the ophthalmic composition is acidic.
  • the ophthalmic composition is a liquid, solution, emulsion or suspension in a storage-stable ophthalmic composition comprising formula I and / or formula II or combination or mixtures thereof.
  • ophthalmic composition further comprising of one or more buffers, one or more tonicity agent, one or more viscosity modifier, one or more chelator agents, one or more polymers one or more thickening agents, one or more lubricants, one or more vehicles or a mixture thereof.
  • the amount of formula I in combination or mixture with formula II is present in a concentration of about 0.0001 wt% to about 5.0 wt % by weight of the composition.
  • the concentration of the mixture of atropine sulfate monohydrate and sodium salt of R-lipoic acid is present in about 0.0001 wt% to about 5.0 wt % by weight of the composition.
  • present invention discloses use of suitable viscosity modifier s/thickening agents selected from a group comprising hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose thereof.
  • present invention discloses use of suitable lubricants, wherein the lubricant is dextran.
  • the ophthalmic composition may include one or more polymer, wherein the polymer is a water-soluble polymer selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, Methocel and mixtures thereof.
  • the present invention provides an ophthalmic composition wherein the composition as is used for treating broad spectrum of ophthalmic diseases or ocular disorders.
  • the terms “therapeutically effective amount” and “effective amount” of an active agent in general mean an amount of an active agent sufficient to provide a therapeutic benefit in the treatment or management of a disease or disorder, or to delay or minimize one or more symptoms associated with the disease or disorder.
  • a “therapeutically effective amount” and “effective amount” of a compound/drug mean an amount of therapeutic agent, alone or in combination with one or more other agent(s), which provides a therapeutic benefit in the treatment or management of the disease or disorder.
  • the terms “therapeutically effective amount” and “effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.
  • active agents means formula I such as atropine, its pharmaceutically acceptable salts forms, free base salt forms, mixtures or a combination thereof.
  • atropine salt form is atropine sulfate monohydrate.
  • active agents means formula II such as R-lipoic acid, its pharmaceutically acceptable salts forms, prodrugs, free base salt forms, mixtures or a combination thereof.
  • R-lipoic acid salt form is sodium salt of R-lipoic acid.
  • the active agents used in the preparation of ophthalmic composition for ophthalmic applications which includes treating ophthalmic diseases and disorders as an mydriatic in eye examinations, refractive errors, myopia and eye related diseases.
  • ophthalmic diseases or disorders refer to myopia, axial myopia, refractive myopia, cycloplegia, amblyopia, refractive errors, eye examination in different ocular conditions requiring dilation of the pupil.
  • the term “effective amount” in specific refers to an amount of active agent as defined above used to treat, ameliorate, prevent, or eliminate the identified ophthalmic condition (e.g., disease or disorder), or to exhibit a detectable therapeutic or preventative effect.
  • the effect can be detected by, for example, chemical markers, antigen levels, or time to a measurable event, such as morbidity or mortality.
  • the precise effective amount for a subject will depend upon the subject's body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • atropine derivatives includes any and all possible isomer, stereoisomer, enantiomer, diastereomer, tautomer, pharmaceutically acceptable salts, hydrate, solvates, and prodrugs of the formula I described herein above paragraphs.
  • pharmaceutically acceptable salt include mineral salts and organic salts.
  • the present invention discloses an ophthalmic composition comprises compounds of formula I or compounds of formula II or a mixture of compound of formula I and II as the active ingredients along with one or more pharmaceutically acceptable carriers or excipients or diluent.
  • the present invention discloses an ophthalmic composition
  • an ophthalmic composition comprises the compounds of formula I wherein, the compound is atropine or pharmaceutically acceptable salts of atropine and compounds of formula II is R-Lipoic acid or pharmaceutically acceptable salt form of R- Lipoic acid.
  • the ophthalmic composition comprises mixture of atropine sulfate monohydrate and sodium salt of R-lipoic acid.
  • the present invention discloses an ophthalmic composition
  • an ophthalmic composition comprises the compound of formula I wherein, the compound is atropine or its pharmaceutically acceptable salts of atropine preferably atropine sulfate monohydrate in combination with nicotinamide.
  • Nicotinamide is a vitamin that may have a prophylactic use in the reduction of IOP in glaucoma. Nicotinamide composition may also ameliorate energy deficiency and improves the retinal function.
  • the present invention discloses ophthalmic composition the amount of formula I in combination with formula II is present in a concentration of about 0.0001 wt % to about 5.0 wt % by weight of the composition.
  • present invention discloses a sterile ophthalmic composition
  • a sterile ophthalmic composition comprising: (a) a compound of formula I or a pharmaceutically acceptable salt from 0.0001 % w/w to about 5.0 % w/w; (b) a compound of formula II or a pharmaceutically acceptable salt from 0.0001 % w/w to about 5.0 % w/w; and at least one pharmaceutically acceptable excipients, wherein the ophthalmic composition has a pH between 3.5 to 6.5; and wherein the composition after storage over at least three months at 25° C. and 40% relative humidity contains equal or less than 0.045 % level of tropic acid formed from degradation of the compound of formula I or the pharmaceutically acceptable salt.
  • the ophthalmic composition comprises of compound of formula II, wherein, the formula II is sodium R lipoate.
  • Lipoic acid is an antioxidant and it is metabolized by oxidoreductases to the active species, dihydrolipoic acid (DHLA), thereby protecting the protein components of lens of the eye.
  • DHLA dihydrolipoic acid
  • present invention discloses a sterile ophthalmic composition
  • a sterile ophthalmic composition comprising: (a) a compound of formula I or a pharmaceutically acceptable salt from 0.0001 % w/w to about 5.0 % w/w; in combination with (b) a compound of formula II or a pharmaceutically acceptable salt from 0.0001 % w/w to about 5.0 % w/w; and at least one pharmaceutically acceptable excipients, wherein the ophthalmic composition has a pH between 3.5 to 6.5; and wherein the composition after storage over at least three months at 25° C/ 40% relative humidity contains equal or less than 0.1 % level of tropic acid formed from degradation of the compound of formula I or the pharmaceutically acceptable salt.
  • present invention discloses a sterile ophthalmic composition
  • a sterile ophthalmic composition comprising: (a) a compound of formula I or a pharmaceutically acceptable salt from 0.0001 % w/w to about 5.0 % w/w; in combination with 0.01 %w/w to 10 w/w nicotinamide; and at least one pharmaceutically acceptable excipients, wherein the ophthalmic composition has a pH between 3.5 to 6.5; and wherein the composition after storage over at least three months at 25° C/ 40% relative humidity contains equal or less than 0.1 % level of tropic acid formed from degradation of the compound of formula I or the pharmaceutically acceptable salt.
  • the frequency of administration of pharmaceutical formulation may be administered once or multiple times, at predetermined intervals of time. It is understood in the art that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined using known protocols from in vivo or in vitro test. It is further understood that for any individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the physician administering or supervising the administration of the formulations.
  • semisolid ophthalmic composition is in situ gel, eye ointments, thereof.
  • the non-limiting example of solid ophthalmic composition is contact lenses coated with drugs, ocular inserts, soluble ophthalmic drug inserts, minidiscs/ocular therapeutic system, mini tablets.
  • pharmaceutically acceptable carriers or excipients or diluent is selected from a group consisting of buffer, tonicity agent, viscosity modifier, penetration enhancer, thickening agents, lubricants, vehicles such as purified water, chelator, polymers, preservatives or mixtures thereof.
  • the buffer is selected from a buffer system comprising an acid and a salt of the acid, a first and a second salt, and amphoteric buffer molecules.
  • buffer include citric acid/sodium citrate buffers, ethanoic acid/sodium ethanoate buffers, dibasic sodium phosphate hydrate, sodium dihydrogen phosphate, sodium dihydrogen phosphate monohydrate, Di sodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate dihydrate, potassium dihydrogen phosphate, sodium monohydrogen phosphate heptahydrate, trisodium phosphate, and dipotassium phosphate, carbonic acid, sodium bicarbonate, sodium carbonate, ammonium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, and magnesium carbonate, acetic acid, ammonium acetate, potassium acetate, calcium acetate, and sodium acetate, sodium tartrate and potassium tartrate, boric acid, trisodium Citrate, sodium boric acid, trisodium Citrate, sodium
  • the non-limiting examples of viscosity modifier to adjust the viscosity of the composition includes various polymers, glycerol, and polysaccharidic polymers, cellulosic viscosity modifiers include modified and unmodified hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose (all of which are contemplated herein).
  • the exact quantity of the viscosity modifier may vary depending on the type of modifier used and desired final viscosity. The person of ordinary skill will be readily able to adjust the viscosity to a desired measure using viscometers well known in the art.
  • dextran in the composition is used to impart lubricant action & increase the ocular contact time, thereby decreasing the drainage rate and increasing drug bioavailability.
  • the non-limiting examples of a preservatives include boric acid, benzalkonium chloride, cetrimide or cetrimonium chloride or bromide, benzododecinium bromide, miramine, cetylpyridinium chloride, polidronium chloride or polyquaternium- 1 , polyquaternium-42, sepazonium chloride; mercurial derivatives such as the phenylmercury salts (acetate, borate or nitrate), mercuriothiolate sodium (otherwise called thiomersal or thimerosal) and mercurobutol; amidines such as chlorhexidine digluconate or polyhexamethylene biguanide (PHMB); alcohols such as chlorobutanol or phenylethanol or benzyl alcohol or phenol or m-cresol or phenoxyethanol; parabens or esters such as parahydroxybenzoic acid, methylparaben, and propylparab
  • Examples of dosing modes or strategies include clinical scenarios where these can be employed include chronic disease, disease exacerbation, need for suppression treatment, need for recurrence treatment, or state of treatment like medicament tolerance.
  • the ophthalmic composition is administered as long as it can sufficiently provide a desired efficacy, which can be administered in eyedrops, at a frequency of 1 to 5 times a day in an amount of 1 to 2 drops each time, more preferably at a frequency of 214 times a day in an amount of 1 to 2 drops each time, and the most preferably once a day, before bedtime in an amount of 1 to 2 drops.
  • the ophthalmic composition according to the present invention is enclosed in a unit-dose container or multiple dose containers.
  • the present inventors have found that the ophthalmic composition as described herein comprising the polyaphron dispersion(s) may be autoclaved under suitable conditions to form a composition suitable for administration to the human and/or animal eye.
  • suitable autoclaving conditions are known to the person skilled in the art. Typically, autoclaving is carried out at approximately 121° C.
  • the ophthalmic formulations described herein are packaged in eye drop bottles and administered as drops.
  • a single administration (i.e. a single dose) of an ophthalmic formulation includes a single drop, two drops, three drops or more into the eyes of the patient.
  • one dose of the ophthalmic formulation described herein is one drop of the composition from the eye drop bottle.
  • the present aqueous composition is preferably used to inhibit or prevent the progression of myopia, to prevent myopia, and/or to treat myopia, used to treat cycloplegia and amblyopia and to inhibit or prevent the progression of childhood myopia.
  • composition 4 R-Lipoate in the composition:
  • composition 5 Atropine Ophthalmic Solution:
  • composition 4 concentration of atropine sulphate is low therefore, two thickening agents are added in the composition to increase the ocular contact time, thereby decreasing the drainage rate and increasing drug bioavailability. Further, dextran in the composition imparts lubricant action and increases the ocular contact time, thereby decreasing the drainage rate and increasing drug bioavailability.
  • composition 6 Atropine Ophthalmic Solution:
  • composition 7 Atropine Ophthalmic Solution:
  • Manufacturing Procedure 1. Dispense all the required raw materials using a calibrated weighing balance.
  • Composition 8 Atropine Ophthalmic Solution: 123] Manufacturing Procedure:
  • Composition 9 Atropine Ophthalmic Solution: 124] Manufacturing Procedure:
  • Manufacturing Procedure 1. Dispense all the required raw materials using a calibrated weighing balance.
  • composition 11 Atropine Ophthalmic Solution:
  • sterilization sterile the hypromellose solution using autoclave for 30 minutes. Cool the solution down to room temperature.
  • Step 2 Take 40% of batch quantity of WFI in a suitable glass beaker and add boric Acid to it. Stir till clear solution is obtained.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Ophthalmology & Optometry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une formulation pharmaceutique de formule I en combinaison avec des dérivés de formule II ou un sel, un solvate ou un hydrate de ceux-ci, ou du nicotinamide pour une administration oculaire, la formulation étant une administration topique de gouttes oculaires ayant une stabilité, une conformité, une sécurité et une biodisponibilité améliorées. L'invention concerne en outre un procédé de préparation, une composition, des procédés d'administration, des dosages de la formulation et leur utilisation pour traiter des maladies, des troubles, des erreurs de réfraction et leurs complications associées.
PCT/IB2023/051097 2022-02-08 2023-02-08 Compositions ophtalmiques et procédés associés WO2023152642A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202241006766 2022-02-08
IN202241006766 2022-02-08

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WO2023152642A1 true WO2023152642A1 (fr) 2023-08-17

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018209051A1 (fr) * 2017-05-11 2018-11-15 Nevakar Inc. Compositions pharmaceutiques d'atropine
WO2020227578A1 (fr) * 2019-05-07 2020-11-12 Aciont Inc. Formulations d'acide lipoïque

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018209051A1 (fr) * 2017-05-11 2018-11-15 Nevakar Inc. Compositions pharmaceutiques d'atropine
WO2020227578A1 (fr) * 2019-05-07 2020-11-12 Aciont Inc. Formulations d'acide lipoïque

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GARCÍA DEL VALLE INES, ALVAREZ-LORENZO CARMEN: "Atropine in topical formulations for the management of anterior and posterior segment ocular diseases", EXPERT OPINION ON DRUG DELIVERY, INFORMA HEALTHCARE, GB, vol. 18, no. 9, 2 September 2021 (2021-09-02), GB , pages 1245 - 1260, XP093085917, ISSN: 1742-5247, DOI: 10.1080/17425247.2021.1909568 *

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