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WO2024246786A1 - Formulations de guanfacine injectables et procédés - Google Patents

Formulations de guanfacine injectables et procédés Download PDF

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Publication number
WO2024246786A1
WO2024246786A1 PCT/IB2024/055236 IB2024055236W WO2024246786A1 WO 2024246786 A1 WO2024246786 A1 WO 2024246786A1 IB 2024055236 W IB2024055236 W IB 2024055236W WO 2024246786 A1 WO2024246786 A1 WO 2024246786A1
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WIPO (PCT)
Prior art keywords
guanfacine
sterile
formulation
freeze
dried
Prior art date
Application number
PCT/IB2024/055236
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English (en)
Inventor
Leo Pavliv
Andrew Vila
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Cumberland Pharmaceuticals Inc.
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Publication of WO2024246786A1 publication Critical patent/WO2024246786A1/fr

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    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the embodiments disclosed herein relate to stable freeze-dried formulations comprising guanfacine, or a pharmaceutically acceptable salt thereof, methods for preparing the above formulations, and methods for employing the above formulations for use in preventing or treating patients suffering from delirium.
  • Delirium is a syndrome, or group of symptoms, caused by a disturbance in the normal functioning of the brain. Delirium denotes an acute and debilitating decline in attention, focus, perception, and cognition that produces an altered form of semi-consciousness. Delirium manifests as an acute disturbance of consciousness and cognition that usually fluctuates overtime. There are generally three different subtypes of delirium based on psychomotor behavior: hypoactive, hyperactive and mixed-type delirium.
  • Delirium affects at least one in 10 hospitalized patients, 1 in 2 elderly hospitalized patients, and up to 85% of critically ill patients.
  • Post-operative delirium substantially lengthens Intensive Care Unit (ICU) and hospital stays and increases medical care costs by as much as $ 1.2 billion annually.
  • ICU Intensive Care Unit
  • delirious patients are more likely to consume more hospital staff time and precious life-support resources, stay longer, and develop in-hospital complications. In addition, such patients are more likely discharged to a facility, and may be readmitted to the hospital.
  • sterile guanfacine injectable formulations which comprise guanfacine or a pharmaceutically acceptable salt thereof; a vehicle, said vehicle comprising one or more bulking agents and one or more buffering agents and optionally one or more pH adjusting agents to adjust pH from 3.0 to 8.0; and a pharmaceutically acceptable diluent.
  • methods of treating delirium comprising intravenously administering to a patient in need of treatment a therapeutically effective amount of a sterile guanfacine injectable formulation.
  • stable freeze-dried sterile guanfacine formulations comprising guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle, wherein the formulation upon reconstitution with a pharmaceutically acceptable diluent forms a sterile injectable formulation.
  • Also disclosed are methods of preparing a stable freeze-dried sterile guanfacine formulation comprising combining guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle to form a sterile solution; and freeze drying said sterile solution to form the stable freeze-dried sterile guanfacine formulation.
  • Consists essentially of means that the guanfacine, or a pharmaceutically acceptable salt thereof, is the only active ingredient in the formulation, e.g., the only ingredient that is therapeutically effective, while other inactive ingredients may be present as, for instance, vehicles or mediums for administration or stabilization such as water and/or a pH-adjusting agent.
  • an injectable formulation comprising an effective amount, e.g., a therapeutically effective amount, of guanfacine as described herein or salt form thereof, and a vehicle, wherein the formulation is effective for preventing or treating delirium or symptoms of delirium thereof in the subject or patient.
  • a “therapeutically effective amount” or “effective amount” is that amount of guanfacine to achieve a pharmacological effect that treats delirium in a patient.
  • the term “therapeutically effective amount” includes, for example, a prophylactically effective amount, that is an amount effective to significantly reduce the probability of occurrence of delirium in a patient.
  • An “effective amount” is an amount needed to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. The effective amount will be selected by those skilled in the art depending on the particular patient.
  • an effective amount or “a therapeutically effective amount” can vary from patient to patient, due to variation in metabolism of guanfacine, age, weight, general condition of the subject, the severity of the condition being treated, and the judgment of the prescribing physician.
  • treat refers to any action providing a benefit to a patient for which the disclosed injectable formulations may be administered, including the treatment of any physiological state or mental condition (e.g., delirium) that is modulated or otherwise susceptible to modulation by the injectable formulations.
  • physiological state or mental condition e.g., delirium
  • Guanfacine is a central alpha-2 adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. It is also indicated in the management of hypertension, either alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.
  • ADHD Attention Deficit Hyperactivity Disorder
  • guanfacine hydrochloride N-amidino-2-(2,6- dichlorophenyl) acetamide monohydrochloride.
  • U.S. Patent Number 3,632,645 discloses guanfacine and its pharmaceutically acceptable acid addition salts specifically.
  • the freeze-dried and injectable formulations disclosed herein comprise guanfacine or a pharmaceutically acceptable salt thereof.
  • the chemical structure of guanfacine is:
  • the guanfacine useful in the formulations disclosed herein may be formulated with a pharmaceutically acceptable salt.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical art.
  • salts include salts of inorganic or organic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, benzoate, tartrate, bitartrate, succinate, maleate, formate, fumarate, gluconate, saccharate, benzoate, sulfamate, methane sulfonate, ethanesulfonate, benzenesulfonate, mesylate, p-toluenesulfonate, pamoate [i.e., 1,1’- methylene-bis-(2 -hydroxy-3 naphthoate)], camsylate, isethionate, edisylate, closylate salts, and the like.
  • the guanfacine formulations comprise guanfacine hydrochloride.
  • Pharmaceutically acceptable base addition salts may also be used to produce pharmaceutically acceptable salt forms.
  • the chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of guanfacine that are acidic in nature are those that form non-toxic base salts with such compounds.
  • Such non-toxic base salts include, but are not limited to, benzathine, choline, diethanolamine, aluminum, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium, lithium, and sodium) and alkaline earth metal cations (e.g., calcium, zinc and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines, among others.
  • alkali metal cations e.g., potassium, lithium, and sodium
  • alkaline earth metal cations e.g., calcium, zinc and magnesium
  • ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine)
  • the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines among others.
  • the guanfacine injectable formulations may contain from 0.01 to 50.0 mg/mL guanfacine.
  • the guanfacine injectable formulation contains from 0.05 to 29.0 mg/mL, from 0.10 to 10.0 mg/mL, from 0.20 to 5.00 mg/mL, or from 0.50 to 1.50 mg/mL guanfacine.
  • the guanfacine injectable formulation contains 0.50, 0.60, 0.70, 0.80, 0.90, 1.00, 1.10, 1.20, 1.30, 1.40, or 1.50 mg/mL guanfacine.
  • the guanfacine injectable formulations may be administered by any pharmaceutically effective parenteral route.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the guanfacine injectable formulations are administered as an intravenous injection.
  • the intravenous injection may be continuous or a bolus injection. Any known device useful for parenteral injection or infusion of drug formulations can be used to effect such administration.
  • the sterile guanfacine injectable formulations may comprise: (a) guanfacine or a pharmaceutically acceptable salt thereof; (b) a vehicle; and (c) a pharmaceutically acceptable diluent, wherein the vehicle may comprise (i) one or more bulking agents and (ii) one or more buffering agents and optionally one or more pH adjusting agents to adjust pH from 3.0 to 8.0.
  • the one or more bulking agents may be present in an amount from 0.10 mg to 100 mg, from 1.0 mg to 100 mg, from 10 mg to 50 mg, or from 20 mg to 40 mg per one milliliter of the sterile guanfacine injectable formulation.
  • bulking agents suitable for use herein include, but are not limited to, mannitol, sucrose, lactose, glycine, trehalose, maltose, xylitol, glucose, starches, sorbitol, erythritol, maltitol, dextran, dextrose, lactitol, or a combination thereof.
  • the sterile guanfacine injectable formulations comprise mannitol as the bulking agent.
  • One or more buffering agents and optionally one or more pH adjusting agents may be employed in an amount to adjust pH of an aqueous solution of the guanfacine formulation from 3.0 to 9.0.
  • the pH may be adjusted to from 3.0 to 8.0, from 3.0 to less than 7.0, from 3.0 to 5.0, or from 3.0 to 4.0.
  • the pH may be 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, or 9.0.
  • the buffer may be employed in an amount from 5 to 100 pmol per one milliliter of the sterile guanfacine injectable formulation or from 5.00 mM to 100 mM.
  • buffers suitable for use herein include, but are not limited to, phosphate buffers (e.g., sodium phosphate, potassium phosphate), borate buffers, citrate buffers (e.g., sodium citrate dihydrate, citric acid), tricine, TRIS, acetate buffers, sodium carbonate, sodium bicarbonate, arginine, histidine, cysteine, glycine, diethanolamine, tartrate, ascorbate, benzoate, lactate, malate, maleate, succinate, or a combination thereof.
  • phosphate buffers e.g., sodium phosphate, potassium phosphate
  • borate buffers e.g., sodium citrate dihydrate, citric acid
  • citrate buffers e.g., sodium citrate dihydrate, citric acid
  • TRIS a
  • the sterile guanfacine injectable formulations comprise sodium citrate dihydrate and citric acid as buffering agents. In one embodiment, from 0.15 to 10.6 mg of sodium citrate dihydrate, from 0.62 to 17.3 mg of citric acid, or a combination thereof are used as buffers per milliliter of the sterile guanfacine injectable formulation. In another embodiment, from 0.15 to 0.53 mg of sodium citrate dihydrate, from 0.62 to 0.86 mg of citric acid, or a combination thereof are used as buffers per milliliter of the sterile guanfacine injectable formulation.
  • pH adjusting agents may also be employed in the aqueous solution of the freeze-dried guanfacine formulation.
  • an acidic pH adjusting agent such as hydrochloric acid, citric acid, malic acid, maleic acid, succinic acid, phosphoric acid, lactic acid, ascorbic acid, sulfuric acid, methane sulfonic acid, aspartic acid, glutamic acid, or a combination thereof may be employed.
  • a basic pH adjusting agent may be employed such as sodium hydroxide, potassium hydroxide, calcium carbonate, citrate, malate, maleate, succinate, dibasic phosphate, tribasic phosphate, lactate, ascorbate, tromethamine, tricine, bicarbonate, carbonate, lysine, arginine, ornithine, histidine, diethanolamine, triethanolamine, ethyl diamine, ammonium hydroxide, or a combination thereof.
  • the sterile guanfacine injectable formulation comprises hydrochloric acid, sodium hydroxide, or a combination thereof as the pH-adjusting agent.
  • Guanfacine formulations disclosed herein may optionally further comprise a pharmaceutical excipient, such as a solvent, preservative, antioxidant, solubilizer, or a combination thereof.
  • a pharmaceutical excipient such as a solvent, preservative, antioxidant, solubilizer, or a combination thereof.
  • the solvent include isotonic saline, 5% dextrose, alcohol, propylene glycol, macrogol, glycerin, and the like.
  • the preservative include a parahydroxybenzoate, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid, methyl paraben, propyl paraben, phenol, thiomersal, and the like.
  • antioxidants examples include a sulfite, ascorbic acid, a-tocopherol, a reductant such as cysteine, glutathione, and N-acetyl cysteine, a metal ion chelator such as ethylene diaminetetraacetic acid, and the like.
  • solubilizer examples include a complexing agent such as a cyclodextrin (e.g., hydropropylbetacyclodextrin, sulfobutyl ether cyclodextrin), a surfactant (e.g., a polysorbate, a chremophor, solutol, D-a-tocopheryl polethylene glycol succinate (vitamin E TPGS), lecithin, a phospholipid, a negatively charged phospholipid), a hydrotropic agent (e.g., niacinamide, salicylate, urea, propyl paraben, methyl paraben), and the like.
  • a complexing agent such as a cyclodextrin (e.g., hydropropylbetacyclodextrin, sulfobutyl ether cyclodextrin), a surfactant (e.g., a polysorbate, a chre
  • Exemplary guanfacine formulations may be prepared using the following components:
  • Guanfacine, or a pharmaceutically acceptable salt thereof may also be formulated with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as an anesthetically-effective compound.
  • anesthetics include articaine, bupivacaine, levobupivacaine, ropivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), etidocaine, lidocaine, mepivacaine, prilocaine, trimecaine, and combinations thereof.
  • the guanfacine formulations comprise guanfacine and ropivacaine as active materials.
  • the guanfacine formulations comprise guanfacine and lidocaine as active materials.
  • the guanfacine, or a pharmaceutically acceptable salt thereof, and a vehicle are combined to form a solution and the solution is freeze-dried in a manner to form a freeze- dried powder or cake.
  • the components of the stable freeze-dried sterile guanfacine formulation may be combined in any order.
  • the one or more buffering agents may be added to water for injection, forming a solution.
  • Guanfacine, or a pharmaceutically acceptable salt thereof may be added to the solution.
  • One or more bulking agents may then be added to the solution.
  • one or more buffering agents may be added to water for injection, followed by addition of one or more bulking agents to the solution, followed by addition of guanfacine, or a pharmaceutically acceptable salt thereof to the solution.
  • PH adjustment using one or more pH-adjusting agents may occur prior to and/or after the addition of guanfacine, or a pharmaceutically acceptable salt thereof, prior to and/or after addition of one or more buffering agents, and/or prior to and/or after addition of one or more bulking agents.
  • an anti-oxidant, preservative, or both may be added before the addition of guanfacine, or a pharmaceutically acceptable salt thereof, to the solution with pH adjustment using one of more pH adjusting agents prior to and/or after addition.
  • the solution may be subjected to sterilization by, for instance, filtration, autoclaving, and/or radiation sterilization.
  • the resulting final solution may be aseptically filled into sterile containers and aseptically loaded into a sterilized freeze drier.
  • the container may be flash frozen.
  • the freeze drying may be carried out by any suitable process.
  • the freeze drying cycle may be carried out by cooling of the sterile final solution to about -45°C at a suitable cooling rate.
  • the drying may be performed at a temperature below around 40°C and a suitable vacuum and duration to form the stable freeze-dried sterile guanfacine formulation.
  • the freeze drying step is carried out in at least three phases: (1) a freezing phase which includes cooling of the sterile final solution to about -45 °C at a suitable cooling rate, (2) a primary drying phase which is performed at about -45°C or higher and a suitable vacuum and duration, and (3) a secondary drying phase which is performed at about -20°C or higher and a suitable vacuum and duration, to form the stable freeze-dried sterile guanfacine formulation.
  • the secondary drying phase may be performed up to 40°C.
  • the containers with the resulting stable freeze-dried sterile guanfacine formulation may be aseptically stoppered under atmospheric pressure or partial vacuum and sealed.
  • the headspace of the container may be purged with an inert headspace gas (e.g., nitrogen or argon) just prior to stoppering.
  • the formulations may be presented in unitdose or multi-dose containers, for example vials, disposable syringes, pens, IV bags, or multiple dose vials made of glass or plastic.
  • the freeze-dried guanfacine formulation may be reconstituted in a pharmaceutically acceptable diluent in an amount sufficient to deliver to a patient a therapeutically effective amount.
  • the pharmaceutically acceptable diluent may be water for injection, normal saline, half normal saline, 5% dextrose, lactated ringers, or a combination thereof.
  • the freeze-dried guanfacine formulation may be reconstituted with water for injection.
  • a suitable dosage of guanfacine may be from 0. 1 mg to 5.0 mg or from 0.5 to 4.0 mg per day. In one embodiment, a dosage of 0.1, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg may be administered daily. The dosage may be administered as a single daily dose or in multiple doses per day. For instance, the reconstituted guanfacine formulations may be administered twice daily. In one embodiment, the dose may be 0.5, 1.0, or 2.0 mg guanfacine administered twice a day. [0041] The disclosed guanfacine formulations are useful in the prevention or treatment of delirium in a subject.
  • a guanfacine formulation comprising intravenously administering to a patient in need of treatment a therapeutically effective amount of a guanfacine formulation.
  • the terms “subject”, “individual” or “patient” are used interchangeably herein and refer to a vertebrate, such as a mammal. Mammals include, but are not limited to, murines, rodents, simians, humans, farm animals, sport animals and pets.
  • the human patient is at least 60 years old.
  • the human patient has at least one comorbidity selected from the group consisting of hypertension, cardiac disease, pulmonary disease, diabetes, kidney disease, cancer, and combinations thereof.
  • the human patient is on mechanical ventilation, on non-invasive positive pressure ventilation (NIPPV), being treated for shock (e.g., with vasopressors), or a combination thereof.
  • NIPPV non-invasive positive pressure ventilation
  • the term “delirium” is defined herein as acute cognitive impairment associated with a medical problem. Delirium may be precipitated by various factors, including but not limited to, surgical trauma, withdrawal from drugs or alcohol, metabolic disturbances, and/or sepsis. Symptoms of delirium may include hallucinations, delusions, psychosis, disorientation, confusion, anxiety, attention deficit, memory impairment, personality changes, depression, immobility, sleep disturbance, language disturbance, sensory deficits, or a combination thereof.
  • the delirium treated or prevented by the guanfacine formulations disclosed herein is associated with a severe acute respiratory syndrome (SARS) coronavirus 2 infection.
  • the delirium is associated with surgery, for instance postoperative delirium following a surgical procedure.
  • the delirium is associated with a critically ill patient, i.e., a patient with a state of poor health with life-threatening injuries and illnesses or at risk of developing them (e.g., those patients that would generally be admitted to an Intensive Care Unit (ICU) of a hospital).
  • ICU Intensive Care Unit
  • the concentration of Guanfacine freebase in the WFI control was 0.10 mg/mL and 1.05 mg/mL, as determined by HPLC.
  • the compatibility solutions were not able to be analyzed by the HPLC assay for Guanfacine because Guanfacine and Ropivacaine have very similar elution times and only the Ropivacaine peak could be seen on the chromatogram.
  • Guanfacine HC1 (Laxai Avanti, Lot CPL-01-2013-014-033) was dissolved in WFI to a final concentration of 1. 14 mg/mL.
  • One milliliter of the 1.14 mg/mL guanfacine solution was added to the 30 mL vial of 1% Lidocaine (Hospira Inc. Lot#81-434-DK) and mixed (final guanfacine concentration ⁇ 31 pg/mL).
  • Six milliliters of the Guanfacine-Lidocaine mixture were removed into 10 mL syringes. The mixture in the syringes was stored at room temperature overnight (up to ⁇ I7 hours).
  • the mixture was analyzed using HPLC at 1, 3, 5, and 6 hour time points and after overnight according to the USP monograph for Guanfacine- Hydrochloride Assay.
  • Guanfacine -HC1 was dissolved in WFI to a concentration of 1.0 mg/mL and then serially diluted down to 0.025 mg/mL.
  • the concentrations for the standards in mg/mL were 1.0, 0.50, 0.05, and 0.025.
  • the guanfacine main peak eluted at RT 5.9 min.
  • the mixture was found to be physically compatible after overnight storage at room temperature. For chemical stability there was a slight increase in a guanfacine-related degradation product after 3 hours, which then reached levels of 1.0% after overnight storage ( ⁇ 17 hours) (Table 2, below).
  • the 1.0% degradation product would represent a maximum of 2.5 ig per injection, which is below the identification threshold for maximum daily doses ⁇ 1 mg, according to ICH guideline Q3B(R2), Impurities in New Drug Substances.
  • WFI at a concentration of 0.5 mg/mL passed through a 0.22 pm PVDF membrane in a biosafety cabinet, and then filled into 20 mb glass vials (particle free), or 150 ml polyolefin IV bags.
  • the vials and IV bags were stored at room temperature conditions.
  • the Guanfacine solutions in the vials and IV bags were at pH 5.7 and 5.0, respectively. After 72 hours at room temperature the Guanfacine solution in the vials formed a degradation product at 0.23% and the Guanfacine solution in the IV bags formed a degradation product at 0.16%.
  • Guanfacine HC1 (Laxai Avanti, Lot CPL-01-2013-014-033) was dissolved in WFI to a final concentration of 1. 14 mg/mL, pH 4.5, passed through a 0.22 pm
  • Guanfacine solutions could be enhanced by lowering the pH. Solutions of 1 mg/mL Guanfacine were made at pH levels ranging from 3.0 to 6.0 for stability testing. For the pH
  • Another sample solution was also made at 20 mM sodium acetate, pH 5.0, except the solvent was sparged with nitrogen and the head space of the vial was purged with nitrogen just prior to stoppering in order to remove air from the sample.
  • pH 6.0 sample a stock solution with 1,840 pL of 0.5 M sodium phosphate monobasic and 160 pL of 0.5 M sodium phosphate dibasic was made that was then diluted to 10 mM sodium phosphate by adding 1.0 mb to a final of 50 grams of solution. The solution was then completed as described previously. It was found that at pH 7.0, 1 mg/mL of guanfacine did not completely dissolve and so this solution was further examined, as described in more detail below.
  • pH 8.0 sample a stock solution of 0.028 mL of 0.5 M sodium phosphate monobasic and 0.372 mLs of 0.5 M sodium phosphate dibasic was added to a glass tube followed by -8.0 mLs of WFI and 11.48 mg of Guanfacine-HCl. The solution was then adjusted to pH 8.0 with a solution of 0.2 N NaOH and adjusted to a volume of 10 mLs with WFI. Both samples were cloudy and contained precipitate after 1 hour of sonication. After 1 hour of sonication both samples were then filtered through a 0.22 pm PVDF filter and analyzed by HPLC.
  • the concentration of the filtered pH 7.0 sample was -0.35 mg/mL and the concentration of the filtered pH 8.0 sample was -0.12 mg/mL. Therefore Guanfacine-HCl was less soluble at pH 7.0 and 8.0 compared to pH levels of 6.0 and lower.
  • Guanfacine-HCl solutions (1 mg/ml) with 2% mannitol or sucrose, 4% mannitol or sucrose, and with no bulking agent were made.
  • pH 3.0 solutions 4.5 mL of a 1 M citric acid solution and 0.5 mL of a 1 M sodium citrate dihydrate solution were added into a glass tube and mixed until uniform. 3.125 mLs of the buffer mixture was added into 400 grams of water and 0.7175 g of Guanfacine-HCl was added. The solution was adjusted to a final pH of 3.00 ⁇ 0.05 using IN NaOH and q.s. to 500 grams using WFI.
  • 80 mLs of the pH- adjusted solution was added to a 300 mL beaker and either 20 mLs of a 20% mannitol solution (4% mannitol), 10 mLs of a 20% mannitol solution (2% mannitol), 8.62 mLs of a 46.4% sucrose solution (4% sucrose), 4.31 mLs of a 46.4% sucrose solution (2% sucrose), or nothing (no bulking agent) was added.
  • WFI was added to q.s. to 100 grams and the pH was adjusted to 3.00 ⁇ 0.05 with either HC1 or NaOH. The solutions were then filtered through a 0.22 pm PVDF filter.
  • 80 mLs of the pH-adjusted solution was added to a 300 mb beaker and either 20 mLs of a 20% mannitol solution (4% mannitol), 10 mLs of a 20% mannitol solution (2% mannitol), 8.62 mLs of a 46.4% sucrose solution (4% sucrose), 4.31 mLs of a 46.4% sucrose solution (2% sucrose), or nothing (no bulking agent) was added. Subsequently, WFI was added to q.s. to 100 grams and the pH was adjusted to 4.00 ⁇ 0.05 with either HC1 or NaOH. The solutions were then filtered through a 0.22 pm PVDF filter.
  • Table 8 24, 30, and 36 Month visual analysis of the samples stored at 25 and 40 °C.
  • Table 8 (cont). 24, 30, and 36 Month visual analysis of the samples stored at 25 and 40 °C.
  • Table 9 36 Month HPLC content and purity at 25°C.

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Abstract

L'invention concerne des formulations lyophilisées stables contenant de la guanfacine, représentées par la formule (I) : ou un sel pharmaceutiquement acceptable de celle-ci. L'invention concerne également des procédés de fabrication et d'utilisation de formulations lyophilisées de guanfacine stables.
PCT/IB2024/055236 2023-05-31 2024-05-30 Formulations de guanfacine injectables et procédés WO2024246786A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4404226A (en) * 1981-07-09 1983-09-13 Sandoz Ltd. Use of guanfacine in treating schizophrenia
US4847300A (en) * 1986-11-07 1989-07-11 Yale University Use of alpha-2I selective adrenergic receptor agonists in memory enhancement
US20070116729A1 (en) * 2005-11-18 2007-05-24 Palepu Nageswara R Lyophilization process and products obtained thereby
US20110275597A1 (en) * 2009-01-09 2011-11-10 Sun Pharma Advanced Research Company Limited Pharmaceutical composition
US20160022591A1 (en) * 2013-03-15 2016-01-28 Mylan Inc. Extended release pharmaceutical solid dosage formulations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4404226A (en) * 1981-07-09 1983-09-13 Sandoz Ltd. Use of guanfacine in treating schizophrenia
US4847300A (en) * 1986-11-07 1989-07-11 Yale University Use of alpha-2I selective adrenergic receptor agonists in memory enhancement
US20070116729A1 (en) * 2005-11-18 2007-05-24 Palepu Nageswara R Lyophilization process and products obtained thereby
US20110275597A1 (en) * 2009-01-09 2011-11-10 Sun Pharma Advanced Research Company Limited Pharmaceutical composition
US20160022591A1 (en) * 2013-03-15 2016-01-28 Mylan Inc. Extended release pharmaceutical solid dosage formulations

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