WO2024256956A1 - Formulations stables de bilastine pour utilisation nasale et ophtalmique - Google Patents

Formulations stables de bilastine pour utilisation nasale et ophtalmique Download PDF

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Publication number
WO2024256956A1
WO2024256956A1 PCT/IB2024/055686 IB2024055686W WO2024256956A1 WO 2024256956 A1 WO2024256956 A1 WO 2024256956A1 IB 2024055686 W IB2024055686 W IB 2024055686W WO 2024256956 A1 WO2024256956 A1 WO 2024256956A1
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WO
WIPO (PCT)
Prior art keywords
bilastine
formulation
formulations
nasal
concentration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/055686
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English (en)
Inventor
Chandrashekhar Kocherlakota
Nagaraju Banda
Anji Reddy KESHIREDDY
Naga Udaya Sankar PULLAGURA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leiutis Pharmaceutials LLP
Original Assignee
Leiutis Pharmaceutials LLP
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 Leiutis Pharmaceutials LLP filed Critical Leiutis Pharmaceutials LLP
Publication of WO2024256956A1 publication Critical patent/WO2024256956A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention deals with stable pharmaceutical formulations of bilastine and the method of preparing such formulations for nasal and ophthalmic use.
  • the formulations may be used to treat different allergies and the associated conditions.
  • Nasal allergic symptoms such as sneezing, itchy nose, runny nose and blocked nose are observed in conditions like allergic rhinoconjunctivitis, allergic rhinitis, inflammation, nasal congestion and bronchial constriction causes difficulty in breathing. These may lead to headache, irritability, loss of sleep and inability to concentrate and ultimately compromising the patient’s quality of life.
  • Immune mediated reactions affect eyes resulting in redness, itching, burning, tearing and inflammation of eye. These symptoms contribute to various ocular allergies such as seasonal or perennial allergic conjunctivitis, vernal keratoconjunctivitis, atopic keratoconjunctivitis, contact allergic conjunctivitis and giant papillary conjunctivitis. These allergic conditions worsen when left untreated and may even progress to cause serious secondary infections. Site- specific administration of drug is effective than systemic administration to treat these nasal and ophthalmic conditions as it has localized effect and provides rapid relief of symptoms.
  • the first line of treatment includes antihistamines which exert their biological effects by acting on Hl receptors, reducing allergic inflammation by directly interfering with histamine actions. Based on the current international guidelines, non- sedating second-generation antihistamines are recommended as first- line treatment for treating allergic conditions.
  • Bilastine is a potent non-sedative, a second-generation medication used in treating allergic rhinitis and urticaria, and various other diseases caused by allergens. It works by inhibiting histamine related immune system reactions. Bilastine was approved in Europe for treating allergic rhinitis and urticaria. Bilastine in its approved tablet form is instructed not to be given along with food but taken at least before 1 hour or after 2 hours of food intake, as the bioavailability of bilastine is reduced to 30 % when taken with food (such as grapefruit juice).
  • U.S Patent Application No. US20210128544 to FAES FARMA discloses to ophthalmic formulations comprising at least 0.4% of bilastine in combination with hydroxypropyl-P-cyclodextrin specifically and at least one water soluble gelling agents, at least one viscosity agent and tonicity agent. Further it was concluded that the increase in the concentration of bilastine did not entail a notable improvement in terms of effectiveness and duration of the effect even in preclinical trials.
  • U.S Patent Publication No. US20180319766 to FAES FARMA discloses method for increasing the solubility of bilastine by forming co-crystals using glutaric acid, adipic acid, sorbic acid, succinic acid, benzoic acid, 4-aminobenzoic acid, L-malic acid, resorcinol, methyl 4-hydroxy benzoate and N-(4-hydroxyphenyl) acetamide.
  • U.S Patent Publication No. US2022339414 to James et al. discloses methods of treating nasal and/or ophthalmic diseases, symptoms, or disorders by administering formulations comprising a corticosteroid and an antihistamine.
  • bilastine Prior published literature on bilastine discloses formulations as combinations with various medications using different excipients such as alcohols, oils, lipophilic components, and preservatives.
  • excipients such as alcohols, oils, lipophilic components, and preservatives.
  • HPBCD is used as an excipient.
  • HPBCD is not a safe excipient due to its documented potential to compromise the blood-labyrinth barrier, leading to ototoxicity and hearing impairment.
  • the inventors of the current invention developed a pharmaceutical formulation of bilastine that improves drug release and addresses the drawbacks of earlier methods.
  • One aspect of the present invention is to provide stable formulations of bilastine for nasal and ophthalmic administration.
  • Another aspect of the present invention is to provide a bilastine composition formulated for nasal and ophthalmic administration free of gelling agents.
  • Another aspect of the present invention is to provide stable formulations of bilastine comprising bilastine, SBECD and other pharmaceutical excipients.
  • Another aspect of the present invention is to formulate nasal and ophthalmic compositions of bilastine comprising bilastine, SBECD and an acid selected from the group comprising carboxylic acids and amino acids, wherein the formulation is free of gelling agents.
  • the present invention relates to stable nasal and ophthalmic formulations of bilastine and processes to prepare the said formulations.
  • the invention further relates to a method of using such stable formulations of bilastine for treating symptoms related to nasal and ophthalmic allergic conditions.
  • bilastine is intended to include any of the alternative forms in which bilastine can be administered such as salts, esters, anhydrous, hydrates such as monohydrate or dihydrate, solvates, crystalline or amorphous polymorphs, racemic mixtures, enantiomeric isomers and so on.
  • “Stable” means that bilastine composition has physical and chemical stability and can be stored for commercially significant periods, such as at least 3 months, 6 months, 1 year, or 2 years or 3 years, at 2-8°C or at ambient conditions (e.g., 25° or 30°C) or elevated temperatures (e.g., 40°C). Stable means that there is no significant physical instability and chemical degradation. The degradation in the product may be determined by analyzing for impurities by suitable analytical method.
  • composition or formulation in the context of present invention refers to combination of bilastine along with at least one pharmaceutically acceptable excipient. Any excipient that is considered to be safe and non-toxic may be used.
  • Formulations of present invention contain bilastine ranging from 0.2 to 1.2% (w/v) of the total weight of the formulation. Preferred range is from 0.5 to 1% (w/v).
  • SBECD sulfobutylether beta cyclodextrin
  • compositions of present invention contain SBECD ranging from 2% to 20% (w/v) of the total weight of the formulation.
  • the permeating agents or enhancers in the present invention refers to the agents that promote the penetration of drugs through membranes. These include but not limited to sodium carbonate, sodium caprate, sodium caprylate, poloxamer-188, poloxamer-407, PEG-PE, PEG-400, Kolliphor EL and Kolliphor RH40 ranging from 0.1% to 1% of the total weight of the formulation. Using these enhancers in the formulations improve the bioavailability thereby increasing therapeutic response of ophthalmic and nasal preparations.
  • the chelating agents in the present invention refers to but not limited to (1,4,7,10- tetraazacyclododecane-l,4,7,10-tetraacetic acid), DTPA (diethylene triamine- N,N,N',N",N"-pentaacetate)/pentetic acid, EDTA (ethylene diamine tetra acetic acid), calcium disodium edetate or their salts.
  • the concentration of chelating agent if present, may vary from 0 to 0.5 % by weight of the formulation.
  • the amino acids and carboxylic acids may be selected from the group comprising L-arginine, aspartic acid, meglumine, asparagine, citrulline, glycine, histidine, lysine, sodium acetate, acetic acid, citric acid, boric acid, tartaric acid and lactic acid.
  • the formulations may additionally contain Tris (tromethamine), sodium carbonate and sodium bicarbonate.
  • concentration of amino acids and carboxylic acids may range from 0.01 to 1 % by weight of the formulation.
  • the present invention formulations do not contain any gelling agents. Use of gelling agents often causes nasal and ocular irritation thereby compromising patient compliance.
  • the present invention formulations are administered in the form of solutions, suspensions, emulsions and so on. These formulations are supplied in single use or multi use component system that can be in the form of a container or vial, drop bottle, spray container, and squeeze bottles made of robust and inert materials to ensure the stability of the formulation throughout the shelf life.
  • the formulations of present invention are intended to be administered nasally. In another embodiment, the formulations of present invention are intended to be administered ophthalmically.
  • the pH of the composition of the present invention is between 4.5 and 7.5.
  • the compositions comprise bilastine, SBECD and other pharmaceutical excipients and may have pH between 5.0 and 6.5.
  • the formulations of bilastine for nasal and/ ophthalmic administration comprise:
  • formulations of bilastine for nasal and/ ophthalmic administration comprise:
  • formulations of bilastine for nasal and/ ophthalmic administration comprise:
  • an amino acid selected from L-arginine, aspartic acid, meglumine, asparagine, citrulline, glycine, histidine, and lysine. wherein the formulation is free of gelling agents.
  • formulations of bilastine for nasal and/ ophthalmic administration comprise:
  • an amino acid selected from L-arginine, aspartic acid, meglumine, asparagine, citrulline, glycine, histidine, and lysine. wherein the formulation is free of gelling agents.
  • the formulations of present invention are subjected to accelerated stability. These formulations have not more than 0.5% of known individual impurities and not more than 0.2% of unknown individual impurities. The total impurities are not more than 5%.
  • Duration of the drug release is considered for 12 hours or till at least 50 % of the drug should be dissolved through the screened formulations for comparable evaluation.
  • the release rate constant of drug was measured for all the formulations with the respect to time intervals and percentage drug release from the linearity.
  • permeating agent sodium caprylate and sodium caprate

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Epidemiology (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)
  • Otolaryngology (AREA)
  • Inorganic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne les formulations pharmaceutiques de bilastine et les procédés de préparation de telles formulations pour une utilisation nasale et ophtalmique. Les formulations de la présente invention sont stables et comprennent de la bilastine et d'autres excipients pharmaceutiquement acceptables. Ces compositions peuvent être utilisées dans le traitement de différentes allergies et des affections associées.
PCT/IB2024/055686 2023-06-13 2024-06-11 Formulations stables de bilastine pour utilisation nasale et ophtalmique Pending WO2024256956A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN202341040180 2023-06-13
IN202341040180 2023-06-13

Publications (1)

Publication Number Publication Date
WO2024256956A1 true WO2024256956A1 (fr) 2024-12-19

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ID=93851481

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/055686 Pending WO2024256956A1 (fr) 2023-06-13 2024-06-11 Formulations stables de bilastine pour utilisation nasale et ophtalmique

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019141563A1 (fr) * 2018-01-18 2019-07-25 Faes Farma, S.A. Compositions ophtalmiques comprenant de la bilastine, une bêta-cyclodextrine et au moins un agent gélifiant
EP3725298A1 (fr) * 2019-04-16 2020-10-21 Faes Farma, S.A. Compositions pharmaceutiques stables et préservées de bilastine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019141563A1 (fr) * 2018-01-18 2019-07-25 Faes Farma, S.A. Compositions ophtalmiques comprenant de la bilastine, une bêta-cyclodextrine et au moins un agent gélifiant
EP3725298A1 (fr) * 2019-04-16 2020-10-21 Faes Farma, S.A. Compositions pharmaceutiques stables et préservées de bilastine

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