WO2023052974A1 - Compositions oculaires et méthodes pour le traitement de maladies et de troubles ophtalmiques - Google Patents

Compositions oculaires et méthodes pour le traitement de maladies et de troubles ophtalmiques Download PDF

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Publication number
WO2023052974A1
WO2023052974A1 PCT/IB2022/059155 IB2022059155W WO2023052974A1 WO 2023052974 A1 WO2023052974 A1 WO 2023052974A1 IB 2022059155 W IB2022059155 W IB 2022059155W WO 2023052974 A1 WO2023052974 A1 WO 2023052974A1
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Prior art keywords
solvent
composition
ophthalmic composition
phase
pilocarpine
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PCT/IB2022/059155
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English (en)
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Mahesh Kandula
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Avaca Pharma Private Limited
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Publication of WO2023052974A1 publication Critical patent/WO2023052974A1/fr

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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

Definitions

  • the present invention generally relates to pharmaceutical compositions and more specifically relates to an ocular composition or formulation comprising pilocarpine-(R)-lipoate or pharmaceutical acceptable hydrate or solvate or crystal or co-crystal or enantiomer or stereoisomer or polymorph or mixtures or combinations thereof and a pharmaceutically acceptable excipient and uses thereof for treating ophthalmic diseases and disorders.
  • BACKGROUND OF THE INVENTION [0002]
  • the eye is a complex sensory organ with a specified function.
  • Eye diseases/disorder include those that effect the whole of the eye and those that affect the different types involved in vision process.
  • the most common forms of vision impairment are errors of refraction while other vision problems can be related to optic nerve disorder, retinal disorder, cataracts, age related macular degeneration eye disorder due to diabetic conditions and glaucoma. These problems can lead to defective vision.
  • treatment options can be restoring the lost vision completely/partially, preserving the remaining vision by halting the progression of the conditions and delaying vision loss.
  • Most of the eye diseases can be treated if diagnosed correctly on time.
  • Age-related Macular Degeneration AMD
  • cataract cataract
  • diabetic retinopathy glaucoma
  • presbyopia are major reasons for the increase in blindness in elderly/aging population.
  • Age-related macular degeneration AMD
  • Glaucoma is a progressive condition that causes damage to optic nerve due to buildup of pressure inside the eye.
  • Presbyopia is an age-related condition due to gradual thickening and loss of flexibility of the natural lens inside your eye.
  • Cataract is a clouding of the lens in the eye which leads to a decrease in vision.
  • Diabetic retinopathy is a medical condition with damaged retina due to diabetes mellitus gradually leading blindness.
  • Major treatment options for the correction of vision and related problems include various ocular therapeutics and surgeries.
  • a major hurdle faced in ophthalmic drug delivery system is the attainment of an optimal concentration at the target site. Bioavailability of the ophthalmic formulation depends on various physiological and anatomical ocular barriers such as tear production, pre-corneal fluid dynamics, systemic drug absorption, drug related factor such as solubility, molecular weight & size, drug metabolism etc., making it difficult to deliver the drug to the site of action. [0007] Worldwide patent application no.
  • WO2019/097318 relates to Pilocarpine-(R)-Lipoate and its use in treatment of eye disorders.
  • the application in its entirety is incorporated by way of reference.
  • WO2019/097318 does not disclose suitable formulations with the stability data suitable for ocular administration and human use.
  • the instant invention discloses ocular compositions and formulations with improved stability of R-lipoic acid, delivery and formulation compositions to administer as a topical eye drop for the treatment of an eye disease or disorder.
  • the ocular formulations of the present application improves is targeted to improve safety and tolerability profile and to minimize unwanted side effects.
  • the present invention relates to pharmaceutical ocular compositions, more particularly an ophthalmic solution formulation comprising of Pilocarpine-(R)-Lipoate or pharmaceutical acceptable hydrate or solvate or crystal or co-crystal or enantiomer or stereoisomer or polymorph or mixtures or combinations thereof and pharmaceutical acceptable excipients suitable for ocular formulations.
  • Pilocarpine-(R)-Lipoate and its use in the treatment of eye disorder are disclosed in the Worldwide Application WO2019/097318.
  • pilocarpine-(R)-lipoate formulations are in the need for the treatment of ocular/eye disorders such as glaucoma, presbyopia and other age-related ocular disorders.
  • the pharmaceutical ocular compositions of the present invention stabilizes the R-lipoic acid in the formulation of Pilocarpine-R-Lipoic acid and, enhances its therapeutic utility by improving the residence time in the ocular tissue by releasing under conditions present in the tissue during the diseased state.
  • the invention provides for a pharmaceutical ocular compositions comprising a therapeutically effective amount of pilocarpine-(R)-lipoate or derivatives or mixtures or combinations thereof and with at least one pharmaceutical acceptable excipient suited for ocular use.
  • the pharmaceutical acceptable excipient(s) used in the ocular formulation regulates the osmolality, pH, viscosity, drug stability, drug delivery and the drug penetration of the formulation and contribute to the product attributes, biopharmaceutical profile and shelf life.
  • the ocular compositions will have additional substances which increase viscosity to improve the bioavailability of composition which do not diffuse through biological membranes.
  • the ocular composition will have additional substances such as antimicrobial agents and/or antioxidants and/or a preservative. In some embodiments, the ocular composition will be free of antimicrobial agents and/or antioxidants and/or preservative. [0014] In some embodiments, ocular composition may further include addition of surfactants. In some embodiments, ocular composition is free of surfactants. [0015] In certain embodiments, the ocular composition is free of a buffer agent. In certain embodiments, the ocular composition in a solution comprises a buffer agent.
  • exemplary excipients include one or more or a combination of, but are not limited to, permeation enhancer substance, buffering agent, tonicity agents, viscosity enhancer/ viscosity modifier or thickening agent, emulsifiers, solubilizer, chelating agent, stabilizer, lubricants (hydrophilic and or hydrophobic), polymers, solvents/diluent, co-solvents, salt, antioxidant, antimicrobial agent/preservatives and other known excipients in the art for ocular pharmaceutical formulations.
  • dosage form of the ocular formulation is a liquid which can selected from a solution or suspension or emulsion.
  • Ocular formulations for the treatment of eye disease are usually performed using a dropper or dropper nozzle, tube nozzle, or any drug delivery device known in in the art for administration of ocular formulation.
  • Ocular formulations are a sterile and pyrogen free.
  • the solubility of pilocarpine-(R)-lipoate in co-solvent is found to be more than 200 mg/mL in propylene glycol and Transcutol.
  • the pharmaceutical ocular composition comprises a therapeutically effective amount of pilocarpine-(R)-lipoate and excipient, mixed in an aqueous solution having a pH within range suitable for ocular formulation and known in the art, wherein at least 98% of the pilocarpine-(R)-lipoate is present in the pharmaceutical ocular composition, following storage at 40°C, at accelerated stability ICH conditions (21 to 30 days).
  • ocular formulation of pilocarpine-R-lipoate solution was stable ( ⁇ 99%) at 2 to 8°C and 25 °C after 4 weeks of storage.
  • the formulation was found to be stable in citrate-borate buffer pH 4.0 to 5.0.
  • the preservative is benzalkonium chloride, SOC or other well- known ocular formulation preservatives known in the art.
  • the invention provides an ocular formulation comprising the non- aqueous composition mixed in an aqueous solution.
  • the aqueous solution comprises a buffer.
  • the ocular formulation has a pH of 3.3 to 7.4.
  • the ocular formulation comprises at least one ingredient selected from the group consisting of permeation enhancer substance, buffers, tonicity agents, viscosity enhancer or viscosity modifier, thickener, chelating agent, emulsifiers, solubilizer, stabilizer, lubricants (hydrophilic and or hydrophobic), polymers, solvents or diluents, co-solvents, salt, antioxidant, antimicrobial agent or preservatives.
  • biochemical/biomolecules or amino acids can be used in the pharmaceutical/ocular composition/formulation.
  • the ocular composition comprises a concentration of the Pilocarpine-(R)-Lipoate compounds or pharmaceutical acceptable hydrate or solvate or crystal or co-crystal or enantiomer or stereoisomer or polymorph or prodrug or derivatives or mixtures or combinations thereof from 0.1 to 20% by weight of the formulation; and 90 to 99.9 % of one or more excipient(s) by weight of the formulation.
  • the excipients can be any of those known in the art.
  • the ophthalmic acceptable excipients are selected from a group consisting of hydroxypropyl- ⁇ -cyclodextrin, mannitol, Methocel E4M, Kolliphor EL, Kolliphor RH 40, Tween 80, Tween 80-A, Povidone (Kollidon 12 PF), Myrj S-40, PEG-400, PEG 6000, glycerin, sodium ascorbate, trisodium citrate, boric acid, EDTA, propylene glycol, polysorbate 80, methyl paraben, propyl paraben, HPMC, arginine, lysine, sodium carbonate, sodium chloride, isoascorbic acid, ethanol, methyl cellulose, buffers, hydroxyl propyl methyl cellulose, benzalkonium chloride, SOC, Captisol, ascorbic acid, purified water, xanthan gum, sodium CMC, Carbopol, polyoxyethylene-40
  • the ocular composition is ophthalmic solution.
  • the ocular composition comprises of two phases: powder phase and solvent or buffer phase, wherein the two phases are stored separately and reconstituted before administration.
  • the powder phase includes the active agent and one or more excipients in a blended mixture; and the solvent or buffer phase includes one or more excipients.
  • ophthalmic composition comprising the powder phase consists of pilocarpine-(R)-lipoate and a mannitol mixed into a blended mixture.
  • the solvent or the buffer phase consists of: a thickening agent, a buffer component, a solubilizer, a chelating agent, a preservative, and a solvent.
  • the ophthalmic composition is stored into a container having separate chambers for storing the powder and solvent phase separately or commercially available containers or known in the art having the provision for filling the powder phase into the first chamber and solvent phase in another or second chamber.
  • the two chambers are separated by semipermeable membrane. This membrane can be raptured using external pressure.
  • the powder phase and solvent phase are packed separately to improve the stability of the ophthalmic composition or formulation and increase the shelf life of the drug product.
  • the method of preparing the ophthalmic solution comprises of two main steps: step 1-powder blend preparation; step 2- solvent preparation. This two components are packed into a suitable container or packaging system having provisional to store the two components separately without mixing until reconstitution of the ophthalmic formulation at the time of administration.
  • the pharmaceutical ocular formulation or ophthalmic composition is characterized by one or more of: a) having a concentration of the Pilocarpine-(R)-Lipoate or derivatives or mixture or combination thereof from 0.5% to 20% by weight of the formulation; b) having a concentration of a preservative 0.005% to 1% by weight of the formulation; c) having a pH of 3.3 to 7.4, preferably the pH is 6 to 7; d) having other ophthalmic acceptable excipient(s) suitable for ocular administration in the formulation; and e) having a shelf-life stability.
  • the ocular formulation or ophthalmic composition is characterized by one or more of: a) having a concentration of the Pilocarpine-(R)-Lipoate or derivatives or mixture or combination thereof from 0.5% to 20% by weight of the formulation with an excipient in a blended mixture, constituting the powder phase of the composition which is the first component of the compositions; b) having one or more excipient(s) suitable for ocular formulation constituting the solvent/buffer phase of the composition which is the second component of the compositions; c) having a pH of 3.3 to 7.4, preferably the pH is 6 to 7; d) each component of the composition is stored separately in a single packing system/container having provisions to hold the each components of the composition separately.
  • the ophthalmic composition for topical application comprises about 0.1 to 20 %w/w of pilocarpine-R- lipoate, 0.1 to 0.8 % w/w of thickening agent, 0.1 to 1% w/w of buffering agent, 0.1 to 0.5 %w/w of diluent, 0.13 % of chelating agent, 0.001 to 0.05% of preservative, 0.1 to 2% of solubilizer and sterile water.
  • the thickening agent is MethocelTM, HPMC, sodium CMC, xanthan gum, Carbopol, methyl cellulose, preferably Methocel E4M.
  • the buffering agent is boric acid, citric acid, sodium carbonate, trisodium citrate, preferably boric acid and trisodium citrate.
  • the solubilizer is Kolliphor RH 40 or hydroxypropyl- ⁇ -cyclodextrin or polysorbate 80, preferably Kolliphor RH 40 or hydroxypropyl- ⁇ -cyclodextrin.
  • the chelating agent is EDTA.
  • the preservative is benzalkonium chloride, potassium sorbate, SOC, propyl paraben or methyl paraben, preferably benzalkonium chloride.
  • the ophthalmic composition for topical application comprising a powder phase; and a solvent or buffer phase.
  • the powder phase consists of pilocarpine-(R)-lipoate mixed with a diluent as a blended mixture.
  • the diluent is mannitol.
  • the solvent/buffer phase comprises of one or more excipients. The excipients are selected from a group consisting of a thickening agent, a buffering agent, a solubilizer, a chelating agent, a preservative, and a solvent.
  • the excipients in the solvent phase are Methocel E4M, boric acid, trisodium citrate, Kolliphor RH 40, Polysorborate 80, HP-Gama- cyclodextrin, EDTA, benzalkonium chloride, potassium sorbate, methyl paraben, propyl paraben and purified water or a mixture thereof.
  • the powder phase of the ophthalmic composition consists of: 0.1 to 20 %w/w of pilocarpine-R- lipoate, mixed with 1.7% w/w of mannitol, as a blended mixture; and the solvent or the buffer phase comprises of: 0.5 % w/w of Methocel E4M, 1% w/w of boric acid, 0.45% w/w of trisodium citrate, 1% of kolliphor RH 40, 0.13 % of EDTA, 0.01 % w/w of benzalkonium chloride and water.
  • the powder phase and the solvent phase are packed into a single packaging system having two separate chambers, and the chambers are separated by semipermeable polymer.
  • the semipermeable polymer between the two chamber prevent the powder phase and the solvent phase contact.
  • the semipermeable polymer separating the two chambers holding the powder phase and the solvent phase is raptured by applying of externally pressure.
  • the rapturing of the semipermeable polymer allows the powder phase and the solvent phase to mix and form the final clear ophthalmic solution for use.
  • the composition is an ophthalmic solution with a pH of 3.5 to 7.
  • the method of treating an ocular disease comprises administering the ophthalmic composition to a subject or patient.
  • the ophthalmic composition is administered topically.
  • the ocular disease is glaucoma and presbyopia.
  • the ophthalmic composition is administered through single use or multi use droppers bottles.
  • the dropper bottles are selected from low density polyethylene (LDPE) dropper bottle, high density polyethylene (HDPE) dropper bottle, polypropylene (PP) bottle, polyester (PET) dropper bottle or Ethylene vinyl alcohol copolymer (EVOH) dropper bottle.
  • LDPE low density polyethylene
  • HDPE high density polyethylene
  • PP polypropylene
  • PET polyester
  • the process of preparing the ophthalmic composition comprises of two steps: step (1) preparing a powder blend to form a powder phase, step (2) preparing a solvent solution to form a solvent /buffer phase for reconstitution of the powder blend for administration, wherein, the process of preparing the powder blend comprises (a).
  • the process of preparing the solvent solution comprises: (i) mixing the pharmaceutically acceptable excipients with 80% of batch quantity of serial water; (ii) mixing benzalkonium chloride and sterile water and transferring to step (i) solution; add the required volume to make up the solution using sterile water; iii)sterilize the solution; and iv) cool the final solution; further the powder obtained from step 1 and the solvent obtained from step 2 are packed into a single container having first chamber and second chamber separate by semipermeable polymer or a membrane or a thin foil.
  • the osmolality of the ocular composition is about 200 to800 Osm/Kg, without marked discomfort to the eye.
  • the ocular composition may be packed into container or packing system suitable for single use and multi-use.
  • the invention also includes methods of treating patients having an ophthalmic disease and disorder, utilizing the ocular pharmaceutical compositions or formulations thereof for the treatment of presbyopia, intraocular hypertension of eye and glaucoma.
  • the ocular compositions or formulations can be used for the treatment of ophthalmic diseases and disorders to restore the normal conditions and prevent further progress of the conditions or prevent the diseases in patients who are under risk.
  • the invention also provides a kit comprising the ocular compositions or formulations and instruction leaflet on how to use or apply the pharmaceutical/ocular compositions or formulation to the patient’s eyes.
  • a “patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.
  • the term “active agent”, “drug” and “therapeutic agent” are used interchangeably herein and refer to any substance used to treat an ophthalmic disease or disorders.
  • compositions or “pharmaceutical formulation” or “Ocular composition” or “ocular formulation” or “ophthalmic formulation” or “drug product” are used interchangeably herein and refer to active agent used to treat ophthalmic disease/disorders along with pharmaceutically acceptable excipients.
  • an effective amount means the amount of active agent, or its derivative or its mixture or in combination required to treat or to prevent the occurrence of, or eradicate, an ophthalmic disorder/diseases.
  • treating is means administering the ocular composition/formulation for prophylactic and/or therapeutic purposes.
  • preventing refers to precluding a patient from getting a disorder, causing a patient to remain free of a disorder for a longer period of time, or halting the progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art.
  • administering is meant a method of giving one or more unit doses of an ocular composition or formulation to patient.
  • viscosity modifier or “viscosity enhancer” is well known in the art and mean an agent used for increasing or decreasing the viscosity of the pharmaceutical/ocular composition or formulation.
  • compositions or formulations and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • excipient refers to pharmaceutically acceptable excipient.
  • phrases “pharmaceutically acceptable excipient” or “ophthalmically acceptable excipient” or “excipient” or “carrier” is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent, buffer, solubilizer, chelating agent, thickener, preservative or encapsulating material involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient.
  • a pharmaceutically acceptable carrier is non-pyrogenic.
  • materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, (3) cellulose, and its derivatives, (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, (10) glycols, (11) polyols, (12) esters, (13) agar; (14) buffering agents, (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations specifically for ocular administration .
  • the pharmaceutically acceptable carrier for ocular administration is water, or acceptable organic solvent, or combination of both known in the art.
  • tonicity of the formulation is maintained by used substance known in the art such as sodium chloride, potassium chloride, glycerol, mannitol, sorbitol, sodium borate, sodium acetate or the like.
  • ocular/pharmaceutical solutions are “liquid preparations that contain one or more active agent/substances dissolved in a suitable solvent or mixture of mutually miscible solvents” (aqueous or non –aqueous).
  • the term “Pilocarpine-(R)-Lipoate” is understood to have the following chemical structure: Formula I and its pharmaceutical acceptable hydrate or solvate or crystal or co-crystal or enantiomer or stereoisomer or polymorph or prodrug or derivatives or mixtures or combinations thereof.
  • a “derivative” is a compound that can be synthesized from a parent compound by replacement of one atom with another atom or group of atoms.
  • the term “derivative” of Pilocarpine- (R)-Lipoate is understood as any compound or a mixture of compounds, excluding Pilocarpine-(R)- Lipoate, formed from the interaction of lipoic acid with a non-aqueous or aqueous pharmaceutical excipient used in the pharmaceutical composition and, Pilocarpine derivative that is formed as an ionic interaction with any excipient in the solution composition.
  • the derivative is a product formed by non-ionic or ionic reaction or interaction of lipoic acid with propylene glycol.
  • the derivative is a product formed by interaction of lipoic acid with glycerol.
  • the R-lipoic acid used in the present invention is a highly unstable substance having a thiol and therefore is sensitive to temperature, pH, humidity, light and moisture.
  • Ikuta International Journal of Molecular Sciences (2013) 14, 3639-3655
  • Ikuta teaches that R-(+)-lipoic acid is not stable when exposed to low pH or heat and is therefore difficult to use as a pharmaceutical.
  • the instability and limited water solubility of R- Lipoic acid is continued to be known as a problem to persons of skill in the art. (Celebioglu et al., Journal of Agricultural Food Chemistry 2019, 67, 13093 ⁇ 13107 (Celebioglu).
  • Celebioglu teaches that R-lipoic acid has limited water solubility, and poor thermal and oxidative stability.
  • the solution form of Pilocarpine-(R)-Lipoate of the ophthalmic formulation is found to be unstable.
  • an ophthalmic composition comprising e separate components/phases: a solvent or buffer phase and a powder phase, and this two phases are packed separately into a single container with dual chambers or similar dual chamber container known in the art.
  • the active ingredient, pilocarpine (R) lipoate is included in the powder phase with at least one excipients as a mixture in a freely flowing phase.
  • the composition is stored in a container having dual chamber or packing materials known in the art wherein the solvent and powder phase are packed separately into a single pack container and, can be easily reconstituted by the patient before topical administration to the eyes.
  • the ophthalmic composition comprising solvent phase (buffer phase) as one component and powder phase (active ingredient phase) as another component, is packed into separate chambers of the commercially available dual chamber container, such that the two components are not mixed together until the subject or patient decides to administer to the eyes.
  • solvent phase buffer phase
  • powder phase active ingredient phase
  • stored ophthalmic solution is found to be stable up to 6 months to 12 months at accelerated stability study conditions and 12 months at long term stability study conditions (stability data refer tables 43 to 46 and 48 to 51).
  • ophthalmic composition or “ophthalmic formulation” or “ocular composition” or “ocular formulation” or “ophthalmic solution” are used interchangeably herein and refers to a composition/formulation intended for application to the eye/ocular tissue or its related or surrounding tissues such as, for example, the eyelid or onto the cornea.
  • the term also includes compositions intended to therapeutically treat conditions of the eye itself or the tissues surrounding the eye.
  • the ophthalmic composition can be applied topically or by other techniques, as known to or appreciated by persons skilled in the pertinent art, such as injection to the eye.
  • suitable topical administration to the eye examples include administration in form of eye drops in the form of suspension, solution and by spray formulations. A further suitable topical administration route is by subconjunctival injection.
  • the compositions can also be provided to the eye periocularly or retro- orbitally.
  • the ocular formula may include one or more buffers to adjust or maintain the pH of the formulation (pH 3.3-7.4).
  • the pH is near physiological pH (pH of tears is about 7).
  • the pH of the formulation can be about 6 to about 8, about 6.5 to about 7.5, about 6.8 to about 7.2, about 7.1 to about 7.5, or about 7.
  • the pH is about 5.5.
  • the pH of the formulation can be about 4 to about 7, about 4.5 to about 6, about 4.5 to about 5.5, about 5.5 to about 6.5, about 5 to about 6, about 5.25 to about 5.75, or about 5.5.
  • exemplary buffers include, but are not limited to, phosphate buffers (e.g., sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous), borate buffers, and HBSS (Hank's Balanced Salt Solution).
  • the buffer is a phosphate buffer.
  • the buffer is sodium phosphate monobasic monohydrate and/or sodium phosphate dibasic anhydrous.
  • the ocular compositions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment.
  • the desired amount of the composition to be administered to a patient will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the active agent (e.g., Pilocarpine-(R)-Lipoate) from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated.
  • a method of treating an eye disorder or diseases or complications thereof in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the ocular formulation comprising of Pilocarpine-(R)-Lipoate, or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer, stereoisomer, polymorph or prodrug or a derivative or mixture or a combination or thereof.
  • the therapeutically effective amount for treating or preventing glaucoma and presbyopia can be determined by measuring clinical outcomes including, but not limited to, the IOP in eye, elasticity, stiffness, viscosity, density, or opacity of a lens.
  • the eye disorder or eye diseases that can be treated by the method disclosed herein can include macular degeneration, cataract, glaucoma, diabetic retinopathy, dry eye, ocular neuritis, retinitis pigmentosa presbyopia and other age related eye disorders.
  • Pilocarpine-(R)-Lipoate, or a derivative or mixture or a combination thereof can be administered to said subject in combination with a pharmaceutically acceptable excipient preferably excipient suitable for ocular tissue administration.
  • the therapeutically effective amount of Pilocarpine-(R)-Lipoate, or a derivative or mixture or a combination thereof that can be administered to said subject can range from 0.001mg to 100mg.
  • the Pilocarpine-(R)-Lipoate, or a derivative or mixture or a combination thereof can be administered topically to at least one eye of a subject in need of treatment for eye disease and disorder or complications resulting from the manifestation of such eye condition and other associated complication therewith.
  • the term “shelf-stability” or “shelf stable” is understood as a character of or to characterize a composition or Pilocarpine-(R)-Lipoate or derivatives or mixture or combination thereof that is substantially unchanged upon storing under various conditions.
  • the storage conditions are25° C , 40% relative humidity (RH) or 30° C, 65% relative humidity (RH) or 40° C, 25% relative humidity (RH) or 2°- 8° C for a period of time (e.g., 6 months, 12 months).
  • shelf-stability can be measured by HPLC to determine the percentage of the composition or active ingredient (e.g., Pilocarpine-(R)-Lipoate) that remains or has been degraded in a formulation following storing the formulation for a certain period of time.
  • shelf stable ocular composition can refer to a composition, which after being stored at 25° C.
  • shelf stable ocular composition can also refer to a composition, which after being stored at 25° C. under 40% RH for 3 months, has 5% or less (e.g., less than 4%, less than 3%, less than 2%, less than 1%, or less than 0.5%) of the active ingredient (e.g., pilocarpine and lipoic acid) being degraded as measured by HPLC.
  • the invention provides a pharmaceutical/ ocular composition/formulation comprising a therapeutically effective amount of Pilocarpine-(R)-Lipoate or derivatives or mixture or combination thereof.
  • the pharmaceutical/ocular composition/formulation comprises a lyophilized powder comprising a therapeutically effective amount of Pilocarpine-(R)-Lipoate or derivatives or mixture or combination thereof.
  • the lyophilized powder also includes a non-aqueous excipient.
  • the lyophilized powder is obtained by lyophilizing any of the pharmaceutical compositions described herein.
  • the pharmaceutical/ocular composition/formulation comprises a therapeutically effective amount of Pilocarpine-(R)-Lipoate, or derivatives or mixture or combination thereof and an aqueous and/or non-aqueous excipients for treatment eye/ophthalmic diseases and disorders.
  • the therapeutically effective amount of Pilocarpine- (R)-Lipoate, and the aqueous and or non-aqueous excipient are having a pH of 3.3 to 7.4.
  • the pH is near physiological pH (pH of tears is about 7).
  • the ocular formulation is purged with nitrogen /or any inert gas to remove oxygen.
  • the ocular aqueous solution is substantially oxygen free.
  • the ophthalmically acceptable excipients are selected from a group consisting of hydroxypropyl- ⁇ -cyclodextrin, mannitol, methocel E4M, Kolliphor EL, Kolliphor RH 40, Tween 80, Tween 80-A, Povidone (Kollidon 12 PF), Myrj S-40, PEG-400, PEG 6000, glycerin, sodium ascorbate, trisodium citrate, boric acid, EDTA, propylene glycol, hydroxyl propyl methyl cellulose, Benzalkonium Chloride, SOC, polysorbate 80, methyl paraben, propyl paraben, HPMC, arginine, lysine, sodium carbonate, sodium chloride, isoascorbic acid, ethanol, methyl cellulose, buffers, Captisol, ascorbic acid, purified water, xanthan gum, sodium CMC, Carbopol, polyoxy
  • the ocular formulation is ophthalmic solution and wherein the ophthalmic solution comprises of two phases: powder phase and solvent or buffer phase.
  • the powder phase includes the active agent and a diluent; and the solvent phase includes one or more excipients.
  • ophthalmic composition comprising the powder phase consists of pilocarpine-(R)-lipoate and mannitol.
  • the solvent /buffer phase includes thickening agent, buffer component, solubilizer, chelating agent, preservative and solvent.
  • the ophthalmic composition can be packed into a commercially available sterile dual chamber containers or bottles, or any suitable containers known in the art having provisions or means for storing the powder and solvent phase separately as well as for filling the power phase and solvent phase separately to improve the stability of the composition in a sterile condition.
  • the active agent pilocarpine –R-lipoate, wherein R-lipoic acid in the solution phase is unstable at higher temperature and humidity conditions for prolonged periods of time, in order to improve the stability of the drug it is stored in a commercially available dual chamber container.
  • the dual chamber container has the provision to store powder phase and solvent phase separately in two different chambers in a single pack wherein the two chambers are separated by a thin or semipermeable polymer that can be easily pierced or punctured by the applying of slight pressure thereby the powder phase will be pushed to the solvent or buffer phase containing chamber and reconstitution will be done through shaking of the container to mix for a clear homogenous solution in few seconds to three to five minutes of shaking and is ready for use by the patient as an eye drop.
  • method of preparing the ophthalmic solution mainly comprises of powder blend preparation, solvent preparation and reconstitution of solution.
  • the powder blend preparation step comprises: dispensing the required weight of pilocarpine-(R)-Lipoate and mannitol for the powder phase, sifting the pilocarpine-(R)- lipoate and mannitol through ASTM sieve and transferred to a blender and mixed for 10 min at 15 rpm and the mixture is resifted using ASTM sieve and blended again in a blender for 10 min at 15 rpm and obtained mixed powder blend is filled into the portion of the dual chamber container for loading the powder phase.
  • the solvent phase preparation includes: Step 1: - dispensing the required weights of the raw materials for preparing the solvent phase.
  • Step 2 dispense batch quantity of benzalkonium chloride using calibrated weighing balance into glass vial and add sterile WFI mix this solution in the glass vial for 15 minutes and transfer this to step 1 solution and make up the volume to required quantity using sterile WFI.
  • the ophthalmic solution is packed into commercially available dual chamber container until reconstitution and use.
  • the commercially available sterile, gas impermeable, dual chambers or containers are used for storing or packing the ophthalmic composition of the present invention.
  • any commercially available dual chamber container or bottles having two separate chambers or units suitable for filling or storing each component of the composition, separately without mixing until reconstitution and use is preferred.
  • the commercially available dual chambers will include a bottom container or a chamber or reservoir or a bottle suitable for holding the solvent which constitute the solvent phase, and a reservoir or a chamber for storing the powder phase, which can be proximally fitted over the bottle holding the solvent phase.
  • the chambers/units holding the solvent and powder phase are separated using a thin membrane or seal, which can be torn, punctured using light pressure by the individual before reconstitution and mixing of the two components.
  • a perforator extending throughout the length of the reservoir with a tapering end at one end for puncturing/breaking the membrane/seal is provided. When the seal is broken the powder from the reservoir flow through into the solvent, which is mixed by shaking and thus reconstituted ophthalmic solution is ready for administration/use.
  • the non-aqueous excipient can be an ophthalmic formulation acceptable excipient.
  • the non-aqueous excipient is non-hydrolytic.
  • the non-aqueous excipient is substantially miscible with water.
  • the non-aqueous excipient forms an emulsion upon mixing with water.
  • Emulsion can be oil in water or water in oil preferably oil in water.
  • micro-emulsions and nano-emulsions formulation can also be prepared with Pilocarpine-(R)-Lipoate or derivate, mixture or a combination thereof.
  • the non-aqueous excipient is an ionic liquid.
  • suspension formulation can also be prepared.
  • the non-aqueous excipient that is substantially miscible with water is an alcohol (e.g., ethanol, sorbitol, propylene glycol, polyethylene glycol, glycerol, or a mixture thereof).
  • the alcohol is a polyol (e.g., propylene glycol, glycerol, ethylene glycol, diethylene glycol, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, pentaerythritol, or sucrose).
  • a polyol e.g., propylene glycol, glycerol, ethylene glycol, diethylene glycol, erythritol, lactitol, maltitol, mannitol, sorbitol, xylitol, pentaerythritol, or sucrose.
  • Concentrations of the non-aqueous excipient (e.g., glycerol) in the pharmaceutical composition can be from 0.1% to 10% (e.g., 0.1%, 0.2, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, or any ranges based on these specified numeric values) by weight of the composition.
  • the non-aqueous excipient is glycerol
  • the concentration of glycerol is in the range of 0.1% to 5% (e.g., 0.1%, 0.2%, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
  • the concentration of glycerol is 0.1%, 0.4%, 1.3%, or 2.7% by weight of the composition.
  • the ocular composition may include other excipients.
  • Non-limiting examples of such excipients are selected from the group consisting of permeation enhancer, viscosity modifier (is used to either increases/ decreases the viscosity), complexing agent, thickening agent, solvent/diluent, pH modifier, chelating agent, a tonicity agent, buffering agent, suspending agent, preservative, emulsifiers, solubilizer, stabilizer, salts, co-solvents, a surfactant, an antimicrobial agent and an antioxidant.
  • the co-solvents means as water-miscible organic solvents that is used in solution formulations to increase the solubility of poorly water-soluble substances or to enhance the chemical stability of a drug.
  • co-solvents examples include glycine, propylene glycol, PEG400, glycerol, Transcutol and others well known in the art of ocular formulation.
  • solvents include water, ethanol, mannitol, PEG 400, PEG 6000 and others well known in the art of ocular formulation.
  • solubilizer/solubilizing agents, emulsifiers and suspending agents/ dispersing agents are used for formulations in suspension when the active ingredient is poorly soluble.
  • Examples of such products are polysorbate, Kolliphor, Captisol, HP- ⁇ -CD, xanthan gum, sodium lauryl sulphate and sorbitan monoleate, Kolliphor RH40, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, polysorbate 80, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • amino acids or biochemical/biomolecules can also be used in the preparation of ocular formulation.
  • amino acids include alanine, glycine, valine, leucine, isoleucine, 2-oxoglutarate, glutamate, and glutamine, etc.
  • biochemical or biomolecules includes a sugar or metabolites thereof (e.g., glucose, glucose-6-phosphate (G6P)), pyruvate (e.g., ethyl pyruvate), lactose, lactate, a lipid (e.g., a fatty acid or derivatives thereof such as mono-, di-, and tri-glycerides and phospholipids), and others (e.g., NADH).
  • G6P glucose-6-phosphate
  • pyruvate e.g., ethyl pyruvate
  • lactose lactate
  • a lipid e.g., a fatty acid or derivatives thereof such as mono-, di-
  • the pharmaceutical composition includes one or more preservatives to minimize microbial contamination or enhance shelf stability.
  • preservatives include, but are not limited to, benzalkonium chloride (BAK), cetrimonium, chlorobutanol, edetate disodium (EDTA), polyquaternium-1 (Polyquad®), polyhexamethylene biguanide (PHMB), phenylmercuric acetate, pheylmercuric nitrate, propyl paraben, methyl parsben, methyl 4-hydroxybenzoate, potassium sorbate, stabilized oxychloro complex/SOC (PURITE®), stabilized chlorite peroxide, sodium perborate, chlorohexidine acetate and SofZia®.
  • BAK benzalkonium chloride
  • EDTA edetate disodium
  • Polyquad® polyquaternium-1
  • PHMB polyhexamethylene biguanide
  • PURITE® stabilized oxychloro complex
  • the preservative amount may be, e.g., less than about 0.02%, about 0.004% or less, or about 0.005% to about 0.01%.
  • Suitable amount of a preservative in the pharmaceutical composition can be in the range of 0.005% to 0.10% (e.g., 0.005, 0.01, 0.02%, 0.05%, 0.1%, 0.5% or any ranges based on these specified numeric values) by weight of the composition.
  • the preservative is benzalkonium chloride.
  • the benzalkonium chloride is in the amount of 0.005% to 0.10% (e.g., 0.005, 0.01, 0.02%, 0.05%, 0.1%, 0.5% or any ranges based on these specified numeric values) by weight of the composition. In some embodiments, the benzalkonium chloride is in the amount of 0.01% by weight of the composition. In any of the embodiments described herein, the preservative is in an amount that is ophthalmically acceptable. In some embodiments, the pharmaceutical composition is free of a preservative. [0111] In some embodiments, suitable buffering agent can be any of those known in the art that can achieve a desired pH (e.g., described herein) for the pharmaceutical composition.
  • Non-limiting examples include phosphate buffers (e.g., sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, sodium carbonate), trisodium citrate, acetate buffer, citrate buffer, borate buffers, and HBSS (Hank's Balanced Salt Solution).
  • phosphate buffers e.g., sodium phosphate monobasic monohydrate, sodium phosphate dibasic anhydrous, sodium carbonate
  • trisodium citrate acetate buffer, citrate buffer, borate buffers, and HBSS (Hank's Balanced Salt Solution).
  • HBSS Hors Balanced Salt Solution
  • Suitable amount of a buffer agent can be readily calculated based on a desired pH.
  • the buffer agent is in an amount that is acceptable for ophthalmic formulation.
  • the ophthalmic composition does not include a buffer agent.
  • the pH of the aqueous solution or the final pharmaceutical composition is adjusted with an acid (e.g., hydrochloride acid) or a base (e.g., sodium hydroxide) to the desired pH range (e.g., as described herein).
  • an acid e.g., hydrochloride acid
  • a base e.g., sodium hydroxide
  • suitable tonicity agent can be any of those known in the art.
  • Non- limiting examples include glycerol, sodium chloride, potassium chloride, mannitol, dextrose, glycerin, propylene glycol, trehalose dehydrate, D-(-)-mannitol, magnesium chloride and mixtures thereof.
  • Suitable amount of tonicity agent in the pharmaceutical composition is any amount that can achieve an osmolality of 200-460 mOsm (e.g., 260-360 mOsm, or 260-320 mOsm).
  • the pharmaceutical composition is an isotonic composition.
  • the amount of a tonicity agent e.g., sodium chloride, potassium chloride
  • a tonicity agent e.g., sodium chloride, potassium chloride
  • the tonicity agent is in an amount that is ophthalmic formulation acceptable.
  • suitable surfactant including ionic surfactants and nonionic surfactants.
  • Non-limiting ionic surfactants include ammonium lauryl sulfate, sodium lauryl sulfate, sodium laureth sulfate, sodium myreth sulfate, dioctyl sodium sulfosuccinate, perfluorooctanesulfonate, perfluorobutanesulfonate, linear alkylbenzene sulfonates, sodium lauroyl sarcosinate, perfluorononanoate, perfluorooctanoate, octenidine dihydrochloride, cetyl trimethylammonium bromide, cetyl trimethylammonium chloride, cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, cetrimonium bromide, dioctadecyldimethylammonium bromide
  • Non-limiting examples of useful nonionic surfactants include polyoxyethylene fatty esters (e.g., polysorbate 80 [poly(oxyethylene)sorbitanmonooleate], polysorbate 60 [poly(oxyethylene)sorbitanmonostearate], polysorbate 40 [poly(oxyethylene)sorbitanmonopalmitate], poly(oxyethylene) sorbitan monolaurate, poly(oxyethylene)sorbitan trioleate, or polysorbate 65 [poly(oxyethylene)sorbitan tristearate]), polyoxyethylene hydrogenated castor oils (e.g.,polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, or polyoxyethylene hydrogenated castor oil 60), polyoxyethylene polyoxypropylene glycols (e.g., polyoxyethylene (160) polyoxypropylene (30) glycol [Pluronic F681], polyoxyethylene (42) polyoxypropylene (67) glycol [Pluronic P123], polyoxyethylene (5
  • the surfactant is polysorbate 80.
  • Suitable amount of surfactant in the pharmaceutical composition can be in the range of 0.01% to 5% (e.g., 0.05, 0.1, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
  • the surfactant is polysorbate 80, and the amount of polysorbate 80 is in the range of 0.05% to 5% (e.g., 0.05, 0.1, 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
  • the amount of polysorbate 80 is 0.5% by weight of the composition.
  • the surfactant is in an amount that is acceptable for ophthalmic formulation.
  • the pharmaceutical composition is free of a surfactant.
  • a surfactant may act as a solubility enhancing agents, stabilizer and/or an emulsifier.
  • suitable viscosity modifier or thickener without limitation for examples include Carbopol gels, cellulosic agents (e.g., hydroxy ethylcellulose, hydroxypropyl methylcellulose(HPMC)), methyl cellulose, polycarbophil, polyvinyl alcohol, dextran, gelatin glycerin, polyethylene glycol, glycerol, xanthum gum, sodium carboxy methylcellulose (sodium CMC), other cellulose derivatives, poloxamer 407, polyvinyl alcohol and polyvinyl pyrrolidone/povidone and mixtures thereof.
  • Carbopol gels e.g., hydroxy ethylcellulose, hydroxypropyl methylcellulose(HPMC)
  • methyl cellulose polycarbophil
  • polyvinyl alcohol dextran
  • gelatin glycerin polyethylene glycol
  • glycerol polyethylene glycol
  • xanthum gum sodium carboxy methylcellulose (sodium CMC)
  • Suitable amount of viscosity modifying agent can be in the range of 0.1% to 5% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition.
  • the viscosity modifying agent is in an amount that is acceptable for ophthalmic formulation.
  • the pharmaceutical composition is free of a viscosity modifying agent (e.g., a polymeric viscosity modifying agent such as hydroxypropyl methylcellulose) and any of those known in the art.
  • suitable antioxidant can be any of those known in the art.
  • non-limiting examples of antioxidant include ascorbic acid, L-ascorbic acid stearate, isoascorbic acid, acetylcysteine, sodium bisulfite, sodium metabisulfite, alphathioglycerin, ethylenediaminetetraacetic acid, erythorbic acid, cysteine hydrochloride, N-acetylcysteine, L- carnitine, citric acid, tocopherol acetate, potassium dichloroisocyanurate, dibutylhydroxytoluene, 2,6-di-t-butyl-4-methylphenol, soybean lecithin, sodium thioglycollate, sodium thiomalate, natural vitamin E, tocopherol, ascorbyl pasthyminate, sodium pyrosulfite, DHLA, butylhydroxyanisole, 1,3-butylene glycol, pentaerythtyl tetrakis[3-(3,5-diol,
  • Suitable amount of antioxidant can be in the range of 0.1% to 5% (e.g., 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, or any ranges based on these specified numeric values) by weight of the composition. In any of the embodiments described herein, the antioxidant is in an amount that is acceptable for an ophthalmic formulation.
  • suitable complexing agents can be any of those known in the art. In some embodiments, non-limiting examples of complexing agent include cyclodextrins, hydroxypropyl—cyclodextrin, 2-hydroxypropyl--cyclodextrin, HP- ⁇ -CD, sulfobutyl ether- ⁇ -CD or a mixture thereof.
  • penetration enhancer such as EDTA are used.
  • EDTA, edetic acid and edetate salts are used in ophthalmic pharmaceutical formulations as chelating agents.
  • pH modifiers include boric acid, citric acid anhydrous, citric acid monohydrate, ethanolamine, HCL, ortho-phosphoric acid, potassium acetate and others.
  • the pharmaceutical/ ocular composition comprises of Pilocarpine- (R)-Lipoate, kolliphor EL, Tween 80, Ascorbic acid, Citrate buffer and SOC.
  • the ocular composition comprises of Pilocarpine-(R)-Lipoate, HP-gama-CD, water and buffer. [0120] In some embodiments, the ocular composition may comprise of Pilocarpine-(R)-Lipoate, HP-gama-CD, kolliphorEL, Myrjs-40/Tween80 and buffer.
  • the pharmaceutical/ocular formulation/composition comprises of: Pilocarpine-(R)-Lipoate from 0.1% to 20% (e.g., 0.1%, 0.5%, 1%, 1.7%, 3.4%, 6.8%, 7%, 8%, 9%, 10%, 10.5, 11, 12, 12.5, 15, 15.5, 16, 16.5, 18, 18.5, 20 and 20.5) or any ranges between the specified numeric values) by weight of the composition; preservative (e.g., benzalkonium chloride, SOC) of 0.001% to 1% by weight of the composition; and other excipient(s) suitable for ocular administration comprises the remaining weight of the composition.
  • preservative e.g., benzalkonium chloride, SOC
  • the ophthalmic formulation can include one or more ingredients selected from the group consisting of a permeation enhancer substance, buffers, tonicity agents, viscosity enhancer/ viscosity modifier, emulsifiers, solubilizer, stabilizer, lubricants (hydrophilic and or hydrophobic), polymers, solvents, co-solvents, salt, antioxidant, antimicrobial agent/preservatives [0123]
  • the ophthalmic composition is characterized by one or more of: (a) Pilocarpine (R) Lipoate or derivatives or mixture or combination thereof from 0.1 to 20% (e.g., 0.5%, 1%, 1.7%, 3.4%, 6.8%, 7%, 9%, 10%, 11, 15, 16, 19, 20 or any ranges based on the therapeutic outcome in the treatment of a specific disease condition of the eye) by weight of the formulation; (b) a preservative (e.g., benzalkonium chloride, SOC) 0.005 to 1%, by weight
  • the ophthalmic composition comprises: (i) a powder phase (ii) a solvent or buffer phase: a.
  • the powder phase of the composition comprises Pilocarpine (R) Lipoate or derivatives or mixture or combination thereof from 0.1 to 20% w/w (e.g., 0.5%, 1%, 1.7%, 3.4%, 6.8%, 7%, 9%, 10%, 11, 12, 13, 14, 15, 16, 18, 20 or any ranges based on the therapeutic outcome in the treatment of a specific disease condition of the eye ) along with 0.01 to 2% w/w diluent in a blended mixture.
  • the preferred diluent is mannitol; b.
  • the solvent phase of the composition comprises of benzalkonium chloride (preservative) 0.001 to 1%, w/w of the formulation; c. the solvent phase further include methocel E4M, boric acid, trisodium citrate, kolliphor RH 40, EDTA, and purified water; d. pH of 3.3 to 7.4, preferably the pH is 4.5 to 7.0; and e. having a shelf-life stability of 6 to 12 months to 24 months or more up to 5 years.
  • the ophthalmic composition comprises: (i) powder phase (ii) solvent or buffer phase: a.
  • the powder phase of the composition comprises Pilocarpine (R) Lipoate or derivatives or mixture or combination thereof from 0.1 to 20% w/w (e.g., 0.5%, 1%, 1.7%, 3.4%, 6.8%, 7%, 9%, 10%, 11%, 15%, 18%, 20%or any ranges based on the therapeutic outcome in the treatment of a specific disease condition of the eye) along with 0.01 to 2% w/w diluent in a blended mixture.
  • the preferred diluent is mannitol
  • the solvent phase of the composition comprises of benzalkonium chloride (preservative) 0.001 to 1%, w/w of the formulation; c.
  • the solvent phase further include methocel E4M, boric acid, trisodium citrate, hydroxypropyl- ⁇ - cyclodextrin, polysorbate 80, EDTA, and purified water; d. pH of 3.3 to 7.4, preferably the pH is 4.5 to 7.0; and e. having a shelf-life stability of 12 months to 24 months or more up to 5 years.
  • the ophthalmic composition comprises: (i) powder phase (ii) solvent or buffer phase: a.
  • the powder phase of the composition comprises Pilocarpine (R) Lipoate or derivatives or mixture or combination thereof from 0.1 to 20% w/w (e.g., 0.5%, 1%, 1.7%, 3.4%, 6.8%, 7%, 9%, 10%, 11, 15, 12, 18, 20 or any ranges based on the therapeutic outcome in the treatment of a specific disease condition of the eye) along with 0.01 to 2% w/w diluent in a blended mixture.
  • the preferred diluent is mannitol
  • the solvent phase of the composition comprises of potassium sorbate (preservative) 0.001 to 0.10%, w/w of the formulation; c.
  • the solvent phase further include methocel E4M, boric acid, trisodium citrate, hydroxypropyl- ⁇ - cyclodextrin, polysorbate 80, EDTA, and purified water; d. pH of 3.3 to 7.4, preferably the pH is 4.5 to 7.0; and e. having a shelf-life stability of 12 months to 24 months or more up to 5 years.
  • the ophthalmic solution comprises: (i) powder phase (ii) solvent or buffer phase: a.
  • the powder phase of the composition comprises Pilocarpine (R) Lipoate or derivatives or mixture or combination thereof from 0.1 to 20% w/w (e.g., 0.5%, 1%, 1.7%, 3.4%, 6.8%, 7%, 9%, 10%, 11, 12, 11.5, 12.5, 15, 15.5, 16, 16.5, 18, 18.5, 20 or any ranges based on the therapeutic outcome in the treatment of a specific disease condition of the eye) along with 0.01 to 20% w/w diluent.
  • the preferred diluent is mannitol
  • the solvent phase of the composition comprises of propyl paraben and methyl paraben(preservatives) 0.001 to 1%, w/w of the formulation; c.
  • the solvent phase further include methocel E4M, boric acid, trisodium citrate, hydroxypropyl- ⁇ - cyclodextrin, polysorbate 80, EDTA, and purified water; d. pH of 3.3 to 7.4, preferably the pH is 4.5 to 7.0; and e. having a shelf-life stability of 12 months to 24 months or more up to 5 years.
  • the method of preparing the ophthalmic solution comprises of step 1 preparing the power blend for the powder phase and step 2 preparing the solvent of the solvent phase.
  • the powder phase consists of active ingredient and diluent.
  • the active ingredient is pilocarpine -R-lipoate and the diluent is mannitol.
  • the solvent phase comprises of one or more ophthalmic formulation acceptable excipients, and in a specific embodiment the solvent phase comprises of one or more thickening agents, one or more buffer components, one or more solubilizer, one or more chelating agents, and one or more preservatives along with sterile water.
  • powder blend preparing step involves dispensing and sifting the required batch quantity of active ingredient and diluent (for e.g of active ingredient is pilocarpine - R-lipoate and the diluent is mannitol) and adding to a blender and mixing both in the blender for 10 minutes at 15 rpm. The mixture is resifted and again added to a blender for blending before filled into a packing system of the reservoir of the commercially available sterile dual chamber container as powder phase.
  • active ingredient for e.g of active ingredient is pilocarpine - R-lipoate and the diluent is mannitol
  • preparation of the solvent phase for reconstitution of the powder blend for administration in general comprises: (i) dispensing and mixing the required batch quantity of thickening agent, buffer components, solubilizer, and chelating agents along with 80% of batch quantity of sterile water for injection (WFI) (ii) In a separate glass vial dispense required batch quantity of preservatives along with sterile WFI and mix for 15 minutes.
  • WFI sterile water for injection
  • the packing device or packing system is a single container or bag or unit made of suitable material having two separate chambers or units namely chamber one and chamber two. The chamber one and chamber two are separated by semipermeable polymer to avoid mixing of the stored components of the composition.
  • the powder blend prepared according to the above method is filled into chamber one and the solvent obtained according to the process of preparing the solvent is filled into chamber two.
  • the powder and solvent phase of the composition can be packed into commercially available dual chamber container or packing system.
  • Such dual chamber packing of powder and solvent separately is found to increase the shelf-life of pilocarpine-R-lipoate which otherwise was found to be unstable in the solution after few weeks at room temperature conditions.
  • the composition is reconstituted before use by removing the tamper evidence seal/TE- ring and applying slight pressure on the cap. Pressing downward on the cap helps in tearing or piercing the membrane separating the powder phase from solvent phase thereafter dispensing and the powder into the solvent or buffer and mixing, by shaking the container for minimum 3 minutes before administration.
  • the ocular compositions comprising Pilocarpine-(R)-Lipoate or derivatives or mixture or combination thereof (e.g., as described herein) can be employed in a method for treating or preventing ocular or ophthalmic disease or disorders.
  • the invention provides a method of treating an eye disease in a subject in need thereof, comprising administering to a lens or an eye of the subject a therapeutically effective amount of any of the ocular compositions/formulation described herein.
  • the eye diseases are glaucoma, Aniridic Glaucoma, Congenital Glaucoma, Juvenile Glaucoma, Lens-Induced Glaucoma, Neovascular Glaucoma, Post-Traumatic Glaucoma, Steroid- Induced Glaucoma, Sturge-Weber Syndrome Glaucoma, and Uveitis-Induced Glaucoma, diabetic retinopathy, macular degeneration, choroidal neovascularization, vascular occlusion, vascular leak, retinal edema, uveitis, retinal vascular disease such diabetic retinopathy, cataracts, Optic nerve disorders, retinal disorders, macular degeneration, diabetic ocular problems, conjunctivitis, Dry eye, and Uveitis.
  • the eye disease is glaucoma and presbyopia.
  • suitable amount of ocular compositions/formulation for the methods of treating or preventing an eye disease herein can be any therapeutically effective amount of drug ocular formulation required to ameliorate the condition of the patient.
  • the method comprises administering the ocular composition to the eye of the subject.
  • the method of treating an ocular disease comprises administering to a subject the ophthalmic composition as disclosed in the embodiments of the disclosure.
  • the ophthalmic composition is administered topically.
  • the ocular or eye diseases are glaucoma, aniridic glaucoma, congenital glaucoma, juvenile glaucoma, lens-induced glaucoma, neovascular glaucoma, post- traumatic glaucoma, steroid-induced glaucoma, sturge-weber syndrome glaucoma, and uveitis- induced glaucoma, diabetic retinopathy, macular degeneration, choroidal neovascularization, vascular occlusion, vascular leak, retinal edema, uveitis, retinal vascular disease such diabetic retinopathy, cataracts, optic nerve disorders, retinal disorders, macular degeneration, diabetic ocular problems, conjunctivitis, dry eye, and uveitis.
  • the eye disease is glaucoma and presbyopia.
  • the ophthalmic composition is administered through single use or multiuse dropper bottles.
  • the dosing device may be a single-dose disposable device, a single- dose reusable device, a disposable device for multiple doses and reusable device mediated eye drops are administered as prescribed by the physician for the treatment of a disease.
  • the dropper bottles used for packing the composition are selected from low density polyethylene (LDPE) dropper bottle, high density polyethylene (HDPE) dropper bottle, polypropylene (PP) dropper bottle, polyester (PET) dropper bottle or high barrier ethylene vinyl alcohol copolymer (EVOH) dropper bottle.
  • LDPE low density polyethylene
  • HDPE high density polyethylene
  • PP polypropylene
  • PET polyester
  • EVOH high barrier ethylene vinyl alcohol copolymer
  • Pilocarpine-(R)-Lipoate is dissolved using magnetic stirrer. The solution should be completely clear at this time. If required, sonicate it for few minutes. 4. A required quantity of SOC is added to the above solution. 5. Citrate buffer pH 3.4 is added slowly to make-up the volume with continuous stirring. 6. The solution is filtered using 0.45 ⁇ L syringe filter and purged with Nitrogen to attain the dissolved oxygen concentration around 5 PPM. 7. The pH and osmolality was measured. Table1: shows the detailed composition of the T71 formulation: [0147] Formulation C-3 1. Dry mix HP-gama-CD and Pilocarpine-(R)-Lipoate. Dampen the mix with 0.1 mL of water.
  • composition of Citrate Buffer pH 3.4 Citric acid (15.3 mg/mL) and Sodium Citrate (7.93 mg/mL).
  • Composition of Citrate Buffer pH 4.0 Citric acid (12.3 mg/mL) and Sodium Citrate (12 mg/mL).
  • [0153] Physical observation of Pilocarpine-(R)-Lipoate solubilized in buffer with different excipients: [0154] It is found that 2.5-3.0 mg/mL of Pilocarpine-(R)-Lipoate is soluble in citrate buffer pH 3.4. Physical changes are observed after addition of excipient in the buffer containing 2.5 mg of Pilocarpine (R) Lipoate.
  • Table 6 [0155] Formulations with Ascorbic acid and Solubilizers: Table 7: [0156] Formulations with Nitrogen Purging Table 8:
  • Blending Transfer the resifted material into suitable blender, mix for 10 minutes at 15 RPM.
  • f. Filling Fill the mixed material into Dual Chamber pack.
  • WFI sterile water for injection
  • Step - 2 Rinse the vial used for stirring the benzalkonium chloride solution with WFI and transfer to step - 2 solution. e. Make up the volume to required batch quantity using sterile WFI. f. Sterilization: Sterilize the clear solution obtained using autoclave for 30 minutes. Cool the solution down to Room temperature. g. Filling: Fill the solvent into respective chamber of Dual Chamber Pack and label the container. Step – 3: Reconstitution of Solution: Reconstitution shall be done in following steps; a. Tap the bottle for 30 seconds to loosen the powder blend. b. Remove the seal provided on the cap. c. Push the cap down till it is fully pressed. d. The cap pushes the perforator down thereby cutting open the membrane holding the powder blend.
  • Container Closure System The product is stored in commercially available dual pack chamber which has a provision for filling the powder blend (with API) and solvent separately in a bottle (equivalent to 10 mL size).
  • dual chamber or the container closure system is a 4-piece pack with following parts: I. A bottle: The solvent equivalent to 10mL shall be filled in bottle. II. Reservoir: The powder phase shall be stored in the holder having plastic membrane at its bottom, which can be punctured/pierced open with slightly application of pressure on the cap. The powder phase holder fits exactly on the polypropylene bottle. III.
  • Perforator The perforator is provided which extends throughout the length of powder phase holder with a tapering end that can cut open the plastic membrane holding the powder phase enabling the powder to flow through into the solvent.
  • Cap The cap is provided with a seal to close the nozzle.
  • Stability Stability studies have been initiated for the Pilocarpine (R) Lipoate ophthalmic solution batch AC156C0125111A as per ICH guidelines. The samples were evaluated for Assay and Related substances in four storage conditions 40 ⁇ 2°C/75 ⁇ 5%RH, 30 ⁇ 2°C/65 ⁇ 5%RH, 25 ⁇ 2°C/60 ⁇ 5%RH and 2 – 8°C.
  • Table 46 Chemical Parameters of Ophthalmic Solution Stored at 2 – 8 °C, Batch No. AC156C0125111A NOTE: # The stability samples at 3 Months and 6 Months are powder for Reconstitution with Powder + Solvent filled in dual chamber pack. The sample will be reconstituted and loaded back to stability in 25°C/40% RH condition for 21 days and analyzed.
  • Table 47 Batch Formula of Pilocarpine (R)-Lipoate Ophthalmic Solution [0212] Manufacturing process and reconstitution step was prepared following the same method as described above for batch AC156C0125111A.
  • Stability Table 48 Chemical Parameters of Ophthalmic Solution Stored at 25°C/40% RH, Batch No. AC156C0125113A
  • Table 49 Chemical Parameters of Ophthalmic Solution Stored at 30°C/65% RH, Batch No. AC156C0125113A
  • Table 50 Chemical Parameters of Ophthalmic Solution Stored at 40°C/25% RH, Batch No. AC156C0125113A
  • Table 51 Chemical Parameters of Ophthalmic Solution Stored at 2-8°C, Batch No. AC156C0125113A
  • the stability samples at 3 Months and 6 Months are powder for Reconstitution with Powder + Solvent filled in dual chamber pack. The sample will be reconstituted and loaded back to stability in 25°C/40% RH condition for 21 days and analyzed.
  • Step – 2 Solvent Preparation: a. Dispensing: Dispense all the required raw materials using a calibrated weighing balance. b. Mixing: Dispense 80% of batch quantity of WFI in a suitable glass beaker and add batch quantities of Methocel E4M, Boric Acid, Trisodium Citrate, Polysorbate 80, EDTA and HP Gamma Cyclodextrin. c. Dispense batch quantity of benzalkonium chloride using calibrated weighing balance into glass vial and add sterile water for injection (WFI) to it. Mix for 15 minutes and add to step - 2 solution. d.
  • WFI sterile water for injection
  • Dispensing Dispense all the required raw materials using a calibrated weighing balance. 2. Sifting: Sift the batch quantities of Pilocarpine (R)-Lipoate and Mannitol through #40 ASTM sieve. 3. Blending: Transfer the sifted raw materials into suitable blender and mix for 10 minutes at 15 RPM. 4. Resifting: Resift the mixed materials through #40 ASTM sieve. 5. Blending: Transfer the resifted material into suitable blender, mix for 10 minutes at 15 RPM. 6. Filling: Fill the mixed material into Dual Chamber pack. Step – 2: Solvent Preparation: 1. Dispensing: Dispense all the required raw materials using a calibrated weighing balance. 2.
  • WFI Sterile Water for Injection
  • Step – 1 Powder Blend preparation 1.
  • Dispensing Dispense all the required raw materials using a calibrated weighing balance. 2.
  • Sifting Sift the batch quantities of Pilocarpine (R)-Lipoate and Mannitol through #40 ASTM sieve.
  • Blending Transfer the sifted raw materials into suitable blender and mix for 10 minutes at 15 RPM. 4. Resifting: Resift the mixed materials through #40 ASTM sieve. 5.
  • Blending Transfer the resifted material into suitable blender, mix for 10 minutes at 15 RPM. 6. Filling: Fill the mixed material into Dual Chamber pack.
  • Step – 2 Solvent Preparation: 1.
  • Dispensing Dispense all the required raw materials using a calibrated weighing balance. 2.
  • Step – 3 Reconstitution of Solution: : reconstitution step is same as described above for batch AC156C0125111A [0216] Batch No:AC156C0125105A Table 15: Batch Formula of Pilocarpine (R)-Lipoate Ophthalmic Solution
  • Step – 1 Powder Blend preparation 1.
  • Dispensing Dispense all the required raw materials using a calibrated weighing balance. 2.
  • Sifting Sift the batch quantities of Pilocarpine (R)-Lipoate and Mannitol through #40 ASTM sieve.
  • Blending Transfer the sifted raw materials into suitable blender and mix for 10 minutes at 15 RPM. 4. Resifting: Resift the mixed materials through #40 ASTM sieve. 5.
  • Blending Transfer the resifted material into suitable blender, mix for 10 minutes at 15 RPM. 6. Filling: Fill the mixed material into Dual Chamber pack.
  • Step – 2 Solvent Preparation: 1.
  • Dispensing Dispense all the required raw materials using a calibrated weighing balance. 2.
  • Step – 3 Reconstitution of Solution: reconstitution step is same as described above for batch AC156C0125111A. [0217] The release and stability specification for Pilocarpine-(R)-Lipoate Ophthalmic Solution is provided in Error! Reference source not found.Tables A below, Table A: Finished Product Specifications

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Abstract

La présente invention concerne des formulations oculaires comprenant une quantité thérapeutiquement efficace de Pilocarpine-(R)-Lipoate ou d'un mélange ou d'une combinaison de celle-ci pour traiter un trouble et des maladies oculaires. La présente invention concerne également le procédé de préparation de la formulation de solution et de son stockage à l'aide d'un compte-gouttes à usage unique ou multiusage stérile et d'un récipient à double chambre stérile disponible dans le commerce pour prolonger la stabilité et la durée de conservation de la formulation et son utilisation pour le traitement de troubles et de maladies ophtalmiques.
PCT/IB2022/059155 2021-09-29 2022-09-27 Compositions oculaires et méthodes pour le traitement de maladies et de troubles ophtalmiques WO2023052974A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019097318A1 (fr) * 2017-11-17 2019-05-23 Cellix Bio Private Limited Compositions et méthodes de traitement de troubles oculaires
WO2019150341A1 (fr) * 2018-02-05 2019-08-08 Cellixbio Private Limited Combinaison d'un agent antimuscarinique ou d'un agent anticholinergique et d'acide lipoïque et ses utilisations

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019097318A1 (fr) * 2017-11-17 2019-05-23 Cellix Bio Private Limited Compositions et méthodes de traitement de troubles oculaires
WO2019150341A1 (fr) * 2018-02-05 2019-08-08 Cellixbio Private Limited Combinaison d'un agent antimuscarinique ou d'un agent anticholinergique et d'acide lipoïque et ses utilisations

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