WO2022169582A1 - Compositions et procédés d'administration parentérale claire concentrée d'agents thérapeutiques de dantrolène - Google Patents

Compositions et procédés d'administration parentérale claire concentrée d'agents thérapeutiques de dantrolène Download PDF

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WO2022169582A1
WO2022169582A1 PCT/US2022/012526 US2022012526W WO2022169582A1 WO 2022169582 A1 WO2022169582 A1 WO 2022169582A1 US 2022012526 W US2022012526 W US 2022012526W WO 2022169582 A1 WO2022169582 A1 WO 2022169582A1
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stable
hours
formulation
solution
lyophilized
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PCT/US2022/012526
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English (en)
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Ahmad Malkawi
George A. Digenis
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Uswm, Llc
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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
    • A61K9/14—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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61K9/0019—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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

  • MH Malignant hyperthermia
  • MH had a mortality rate of nearly 80 percent at the time it was identified in 1960.
  • Treatment consisted only of cooling the patient and treating the specific symptoms, but not the underlying cause.
  • IV intravenous
  • DS -IV dantrolene sodium
  • a rapid response to MH onset is critical because death due to MH can occur as early as 30 min from onset.
  • a co-solvent system for the formulation of a dantrolene sodium (DS) product with increased solubility for intravenous use Further disclosed are methods for the production of a clear, concentrated pharmaceutical composition of DS product made by using a novel macromolecule co-solvent system composed of a supramolecular host molecule (such as cyclodextrin, cucurbituril etc.) and an organic solvent such as tertiary butyl alcohol (TBA).
  • TSA tertiary butyl alcohol
  • the produced DS lyophilisate dry powder may be rapidly reconstituted, producing a stable clear 2X- 20X concentrated dantrolene solution for intravenous injection, minimizing the amount of Sterile Water for Injection (WFI).
  • WFI Sterile Water for Injection
  • the active pharmaceutical compound may comprise at least one compound selected from dantrolene and a pharmaceutically acceptable salt of dantrolene.
  • Dantrolene is represented by the formula:
  • the pharmaceutically acceptable salt of dantrolene is a deprotonated form of dantrolene with a cationic counter ion.
  • the counter ion include, but are not limited to, alkali metals, alkaline earth metals, ammonium, substituted ammonium, pyridinium, and substituted pyridinium.
  • alkali metals include, but are not limited to, sodium and potassium.
  • the active pharmaceutical ingredient (API) dantrolene sodium (DS) is a hemiheptahydrate salt; l-5-(4-nitro phenyl)furfurylidene aminoimidazolidine-2, 4-dione, containing 14.5-17.0% (w/w) of water and has a molecular weight of 399.
  • the anhydrous salt has a molecular weight of 336.
  • Dantrolene sodium (USP) is an orange, odorless powder with a melting point of 279- 280°C. It is completely soluble in propylene glycol, slightly soluble in ethanol and methanol, and is insoluble in H2O (15 mg/L). Higher solubility in water at pH 8.0 or greater is exhibited by dantrolene sodium. Its free acid form (dantrolene) is totally insoluble and it is a weak acid with a pKa of about 7.5. [006] Dantrolene sodium can be used as a skeletal muscle relaxant particularly in controlling the manifestations of clinical spasticity resulting from upper neuron disorders. It is also used in the prevention and treatment of malignant hyperthermia in humans.
  • Dantrolene sodium for injection comes as a dry powder that must be dissolved in sterile water prior to injection. Generally, it is supplied in small glass containers containing enough powder to give about 16 to about 20 mg of the active drug.
  • Malignant Hyperthermia Association of the United States recommends that 36 vials be stocked.
  • the insolubility of DS in water necessitates its dissolution at a considerably higher pH than its pKa value.
  • the higher pH of its formulation requirement results in: a) the alkaline hydrolysis (loss of potency) of DS, and b) susceptibility of its solution to carbon dioxide during its introduction into vials (filling of vials).
  • the atmospheric carbon dioxide (CO2) through its formation of carbonic acid appears to interact with the alkaline (e.g., NaOH) content of the filled vials resulting in the reduction of the pH of their solution resulting in a possible undesirable effect in the DS formulation.
  • the above two phenomena require that the dissolution of the DS (API) at the time of its formulation process and the subsequent introduction of its solution to vials be expedited prior to the commencement of its freeze drying.
  • compositions and methods which may employ a novel supramolecular host molecule in combination with TBA co-solvent system to produce a highly concentrated stable and clear composition that (a) reduces freezing time of the DS-IV formulation, (b) reduces its freeze-drying time (c) shortens the reconstitution time of the DS freeze-dried product (d) formulate DS-IV at a lower pH and reduces degradation (e) significantly reduces the number of the vials needed for the MH treatment (f) provides a rapid response to MH onset (g) reduces the amount of mannitol inside each DS-IV vial, and (h) causes a considerable reduction in the fluid that is needed to be administered to the patient.
  • a faster reconstitution of the DS-IV product provides a great pharmacotherapeutic advantage in the treatment of patients exhibiting the life-threatening condition of malignant hyperthermia (MH) while undergoing surgery.
  • these patients generally require a rapid intravenous (IV) infusion of nine to ten (9-10) vials of DS-IV product, generally comprising from about 2.5 to about 10 mg/kg patient weight, and each reconstituted with about 60 ml of Sterile Water for Injection (WFI) (See, for example, Merck Manual, 18" Edition, 2006).
  • WFI Sterile Water for Injection
  • the number of DS-IV vials used ranges from about 10 to about 20 but can be even more.
  • Organic co-solvent systems encompass a wide variety of organic solvents.
  • Exemplary organic co- solvents include tert butyl alcohol, ethanol, n-propanol, n-butanol, iso-propanol, ethyl acetate, acetone, methyl acetate, methanol, carbon tetrachloride, dimethylsulfoxide, chlorobutanol, cyclohexane, and acetic acid.
  • the supramolecular host molecule may be selected from one or more of cyclodextrins (CDs), calixarenes (CXs) and cucurbiturils (CBn), including combinations thereof.
  • Cyclodextrins (CDs) are cyclic oligomers of glucose, which typically contain 6, 7, or 8 glucose monomers joined by a- 1,4 linkages.
  • Calixarenes (CXs) are macrocycle or cyclic oligomer based on a hydroxy alkylation product of a phenol and an aldehyde. Due to their superior geometric shape, calixarenes can accommodate drug molecules by forming inclusion complexes.
  • Cucurbiturils (CBn) are macrocyclic hosts featuring n glycoluril units (5-10) linked by methylene bridges.
  • Cucurbiturils (CB) are potential stabilizing, solubilizing, activating, and delivering agents for drugs. They may be water-soluble, for example at the concentrations disclosed herein, thermally as well as chemically stable, with a superior binding affinity.
  • the host guest complexes can inherit beneficial properties of the host molecules like enhancing solubility.
  • the molar ratio of dantrolene sodium to the cyclodextrin and cucurbituril compound may be from about 1 : 1 to about 1:20.
  • An additional beneficial effect of the host molecule is the great increase in the solubility of the lyophilized dry powder DS product, resulting in a substantial decrease in the number of administrated vials of the product and accompanying reduction in the amount of diluent liquid used for reconstitution of the vials. It takes 9 to 10 vials of the marketed DS product containing 20 milligram DS/vial to be administered to reach a concentration of 2.5 to 2.8 mg / kg at which the alleviation of the malignant hyperthermia MH symptoms occurs. In contrast only two vials of a DS product containing 120 mg/vial and only one vial of the 240 mg DS/ vial are needed to achieve a safe level of 3.4 mg/kg of DS. Added to this supramolecular host molecules beneficial contributions in the DS pre-lyophilized formulation, is the addition of TBA which induces the rapid reconstitution of the lyophilized DS dry powder for the fast treatment of MH.
  • the present disclosure relates generally to a macromolecule co-solvent system for formulation and production of DS with increased solubility. Also disclosed are methods of freeze-drying a DS pharmaceutical formulation.
  • DS-IV dantrolene sodium
  • this substantially complete dissolution to a clear solution is accomplished in less than about 30 seconds. In one aspect, this substantially complete dissolution is accomplished in about 10 to about 20 seconds.
  • a method for producing the DS-IV product may comprise the following:
  • the present disclosure further relates to stable clear concentrated pharmaceutical compositions of dantrolene sodium, lyophilized dantrolene sodium and its use in treatment of various disease states, especially malignant hyperthermia and other conditions involving high fever.
  • the present disclosure relates to a pharmaceutical composition of dantrolene sodium comprising trace amounts not more than about 0.5% (w/w) of organic solvent after reconstitution of a lyophilized pharmaceutical composition of dantrolene sodium as disclosed herein.
  • the present disclosure relates to a lyophilized preparation of dantrolene sodium comprising about 0.01% to about 0.65% (w/w) dantrolene sodium after reconstitution.
  • the dosage form may be about 5 to about 400 mg of dantrolene sodium, about 10 to about 30 mg of dantrolene sodium, about 10 mg to about 20 mg of dantrolene sodium, and about 20 mg of dantrolene sodium.
  • a pharmaceutical dosage form that includes a lyophilized preparation of dantrolene sodium containing not more than about 0.05% to about 1%, or about 0.6% to about 0.7%, DS-IV (w/w).
  • dosage forms can be about 5 to about 400 mg of dantrolene sodium, about 10 to about 300 mg of dantrolene sodium, about 10 to about 100 mg of dantrolene sodium, about 20 to 400 mg of dantrolene sodium, and about 12 mg to about 22 mg of dantrolene sodium per vial or pharmaceutical container.
  • the organic solvents may include one or more of ethyl, methyl, propyl, butyl alcohol.
  • the organic solvent is tertiary butanol, also known as TBA, t- butanol, tert-butyl alcohol, or tertiary butyl alcohol, alone or in combination with one or more additional solvents.
  • the dantrolene sodium product may be capable of substantial reconstitution in a carrier in less than about 60 seconds. In another aspect, the dantrolene sodium product is capable of substantial reconstitution in a carrier in about 20 seconds.
  • the lyophilized powder may be produced from the pre-lyophilization solution.
  • methods for preparing a dantrolene sodium lyophilized preparation that includes dissolving dantrolene sodium in a stabilizing concentration of an alcohol solvent of between about 1% to about 99.9% (v/v) alcohol to form a pre-lyophilization solution; and lyophilizing the pre-lyophilization solution; wherein the dantrolene sodium lyophilized preparation made from such methods may comprise mannitol and a macromolecule.
  • the concentration of organic solvent like tertiary -butanol is about 0.5% to about 30% (v/v). In another aspect, the concentration of tertiary -butanol is about 1% to about 20% (v/v). In another aspect, the concentration of tertiary -butanol is about 2% to about 10% (v/v). In one aspect, the excipients may be added before lyophilization.
  • the excipient is mannitol at a concentration of about 20 to about 100 mg/ml.
  • the pre-lyophilized concentrations of dantrolene sodium are from about 0.1 mg/ml to about 50 mg/ml.
  • lyophilizing the pre-lyophilization solution may comprise: i) cooling the pre-lyophilization solution to a temperature capable of forming a frozen solution; ii) holding the frozen solution at a temperature capable of forming a frozen solution, for a time sufficient to substantially freeze the solutions; iii) ramping the frozen solution to a primary drying temperature; iv) holding at a primary drying temperature at a temperature and for a time sufficient to form a substantially dried lyophilized product; iv) optionally ramping the dried solution to a secondary drying temperature; and v) optionally holding at the secondary drying temperature at a temperature and for a time sufficient to form a substantially dried dantrolene sodium lyophilized preparation.
  • lyophilizing the pre-lyophilization solution comprises: i) freezing the pre- lyophilization solution to a temperature below about -40 °C. for a time sufficient to substantially freeze the solution; ii) drying the frozen solution at a drying temperature between about -50 °C and about 30 °C for about 1 to about 100 hours to form a dantrolene sodium lyophilized preparation.
  • lyophilizing the pre-lyophilization solution comprises: i) freezing the pre-lyophilization solution to a temperature below about -20 °C for a time sufficient to substantially freeze the solution; ii) drying the frozen solution at a drying temperature between about -60 °C and about 30 °C to form a DS lyophilized preparation.
  • the stable and lyophilized formulation has a freeze-drying cycle of about 72 hours or less.
  • lyophilizing the pre-lyophilization solution comprises: i) freezing the pre-lyophilization solution to a temperature below about -40 °C to form a frozen solution; ii) holding the frozen solution at or below about -40 °C for at least 2 hours; iii) ramping the frozen solution to a primary drying temperature between about -40 °C and about 30 °C to form a dried solution; iv) holding for about 10 to about 70 hours; v) ramping the dried solution to a secondary drying temperature between about 20 °C and about 40 °C; and vii) holding for about 5 to about 40 hours to form a dantrolene sodium lyophilized preparation.
  • the lyophilization cycle includes starting with the pre-lyophilization solution at a shelf temperature for loading of about 0 °C to about 30 °C, about 5 °C to about 25 °C, about 5 °C to about 15 °C. [0036] In another aspect, the lyophilization cycle includes ends with unloading the lyophilized vials at about 0 °C to about 30 °C, about 5 °C to about 25 °C, about 5°C to about 15 °C.
  • the lyophilization cycle includes wherein the vacuum pressure is about 50 to about 200 microns, about 50 to about 150 microns, about 100 to about 150 microns throughout primary drying and about 50 to about 200 microns, about 50 to about 150 microns, about 100 to about 150 microns throughout secondary drying.
  • dantrolene sodium formulations for lyophilization may include an excipient and a stabilizing concentration of an organic solvent.
  • the organic solvent may further comprise an alkali.
  • the pre-lyophilization solution may comprise about 1 to about 1000 mg/ml excipient. In another aspect, the pre-lyophilization solution may comprise about 1 to about 500 mg/ml excipient. In another aspect, the pre-lyophilization solution may comprise about 10 to about 100 mg/ml excipient.
  • One formulation includes dantrolene sodium at a concentration of about 0.01 to about 15 mg/ml, mannitol at a concentration of about 1 to about 200 mg/ml, organic solvent at a concentration of about 0.5% to about 50% (v/v) and water.
  • Another formulation includes dantrolene sodium at a concentration of about 0.05 to about 5 mg/ml, mannitol at a concentration of about 8.0 mg/ml to about 100 mg/ml, tertiary-butyl alcohol at a concentration of about 1% to about 30% (v/v) and water.
  • a pharmaceutical dosage form of dantrolene is disclosed, wherein the dosage form may comprise a 65 ml vial or other pharmaceutically acceptable container.
  • Concentrations of dantrolene sodium may include about 1 to about 400 mg/container, about 5 to about 50 mg/container, about 5 mg to about 20 mg/container and about 10 mg to about 20 mg/container.
  • pre-lyophilized pharmaceutical compositions of dantrolene sodium may include dantrolene sodium, a macromolecule, mannitol, tertiary-butyl alcohol, sodium hydroxide and water.
  • An aqueous composition may be used to produce a lyophilized dry powder which may be rapidly reconstituted into an intravenously injectable active pharmaceutical compound.
  • the aqueous composition may comprise an active pharmaceutical compound, a macromolecule derivative, and organic solvent.
  • the pH of the aqueous composition is greater than 7.
  • the aqueous composition may comprise water. After the aqueous composition is formed, it is lyophilized to form the dry powder.
  • administration of the pharmaceutically active compounds and the pharmaceutical compositions includes systemic use, as by injection (especially parenterally), intravenous infusion, suppositories, and oral administration thereof, as well as topical application of the compounds and compositions. Intravenous administration is particularly preferred in the present invention.
  • ком ⁇ онент herein is meant that the components of the compositions which comprise the present invention are capable of being commingled without interacting in a manner which would substantially decrease the efficacy of the pharmaceutically active compound under ordinary use conditions.
  • the terms “effective amount” or “pharmaceutically effective amount” refer to a nontoxic but enough of the agent to provide a desired biological result. That result can be one or more of: reduction and/or alleviation of the signs, symptoms, or causes of a disease, such as neural diseases and malignant hyperthermia, or any other desired alteration of a biological system. Such amounts are described below. An appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • excipient means the substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations; in one aspect, an excipient does not lower or interfere with the primary therapeutic effect of the API. In one aspect, an excipient is therapeutically inert.
  • excipient encompasses carriers, diluents, vehicles, solubilizers, stabilizers, bulking agents, acidic or basic pH-adjusting agents and binders.
  • Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process. Excipeints are approved for or considered to be safe for human and animal administration, i.e., GRAS substances (generally regarded as safe). GRAS substances are listed by the Food and Drug Administration in the Code of Federal Regulations (CFR) at 21 CFR 182 and 21 CFR 184, incorporated herein by reference. [0051] As used herein, the terms “formulate” refers to the preparation of a drug, e.g., dantrolene, in a form suitable for administration to a mammalian patient, such as a human. Thus, “formulation’ can include the addition of pharmaceutically acceptable excipients, diluents, or carriers and pH adjusting agents.
  • lyophilized powder or “lyophilized preparation” refers to any solid material obtained by lyophilization, i.e., freeze-drying of an aqueous solution.
  • the aqueous solution may contain a non-aqueous solvent, i.e., a solution composed of aqueous and one or more non-aqueous solvent(s).
  • organic solvent means an organic material, usually a liquid, capable of dissolving other substances.
  • trace amount of an organic solvent means an amount of solvent that is equal to or below recommended levels for pharmaceutical products, for example, as recommended by ICH guidelines (International Conferences on Harmonization, Impurities — Guidelines for Residual Sol vents. Q3C. Federal Register. 1997: 62(247):67377). The lower limit is the lowest amount that can be detected.
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • a “pharmaceutically acceptable carrier” is a material that is nontoxic and generally inert and does not affect the functionality of the active ingredients adversely.
  • pharmaceutically acceptable carriers are well known, and they are sometimes referred to as diluents, vehicles, or excipients.
  • the carriers may be organic or inorganic in nature.
  • pharmaceutically acceptable carriers that may be present in the present lyophilized formulations may be gelatin, lactose, starch, cocoa butter, dextrose, sucrose, sorbitol, mannitol,
  • PVP polyvinylpyrrolidone
  • physiological pH or a “pH” in the physiological range” is meant a pH in the range of approximately 7.2 to 8.0 inclusive, more typically in the range of approximately 7.2 to 7.6 inclusive.
  • composition as used herein shall mean a composition that is made under conditions such that it is suitable for administration to humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients, e.g., without limitation, stabilizers, pH adjusting agents such as NaOH, bulking agents, buffers, carriers, diluents, vehicles, solubilizers, and binders.
  • pharmaceutical composition includes but is not limited to a pre-lyophilization solution or dispersion as well as a liquid form ready for injection or infusion after reconstitution of a lyophilized preparation.
  • a “pharmaceutical dosage form” as used herein means the pharmaceutical compositions disclosed herein being in a container and in an amount suitable for reconstitution and administration of one or more doses.
  • stable pharmaceutical composition is meant any pharmaceutical composition having sufficient stability to have utility as a pharmaceutical product.
  • the shelf-life or expiration can be that amount of time where the active ingredient degrades to a point below 90% purity.
  • stable pharmaceutical composition includes reference to pharmaceutical compositions with specific ranges of impurities as described herein.
  • the term “subject” encompasses mammals and non-mammals.
  • mammals include, but are not limited to, any member of the mammalia class: humans, nonhuman primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like.
  • treating or “treatment of a disease include preventing the disease, i.e., preventing clinical symptoms of the disease in a subject that may be exposed to, or predisposed to, the disease, but does not yet experience or display symptoms of the disease.
  • vial refers to any walled container, whether rigid or flexible.
  • compositions prepared from an active pharmaceutical agent are stable, clear, pharmaceutically acceptable compositions prepared from an active pharmaceutical agent.
  • compositions prepared from dantrolene prepared from dantrolene.
  • a highly concentrated, stable, and clear formulations for the lyophilization of dantrolene sodium is disclosed.
  • the lyophilized powder obtained from such formulations may be from about 2x to about 20x, or from about 5x to about 15x, or from about lOx to about 12x concentrated and more easily reconstituted than the presently available lyophilized powder of dantrolene.
  • formulations of dantrolene that may be useful for treating various disease states, especially neural diseases, and malignant hyperthermia.
  • a lyophilized formulation of dantrolene sodium may be achieved following removal of an organic solvent in water.
  • organic solvents can be used, for example, ethanol, n-propanol, n-butanol, isoproponal, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, acetone, 1 -pentanol, methyl acetate, methanol, carbon tetrachloride, dim ethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl Sulfone, acetic acid, cyclohexane.
  • solvents may be used individually or in combination.
  • Useful solvents must form stable solutions with dantrolene sodium and must not react chemically or appreciably degrade or deactivate the API.
  • the insolubility of DS in water necessitates its dissolution at a considerably higher pH than its pKa value.
  • the higher pH of its formulation requirement results in: a) the alkaline hydrolysis (loss of potency) of DS, and b) susceptibility of its solution to carbon dioxide during its introduction into vials (filling of vials).
  • the atmospheric carbon dioxide (CO2) appears to interact with the alkaline (e.g., NaOH) content of the filled vials resulting in the reduction of the pH of their solution resulting in a possible undesirable effect in the DS formulation.
  • the above two phenomena require that the dissolution of the DS (API) at the time of its formulation process and the subsequent introduction of its solution to vials be expedited prior to the commencement of its freeze-drying.
  • the DS formulation described herein has greater stability which will allow more time during the manufacturing process.
  • DANTRIUM® (dantrolene sodium) for injection comes as a dry powder that must be dissolved in sterile water prior to injection. It is currently supplied in small glass containers containing enough powder to give about 16 to about 20 mg of the active drug. RY ANODEX®
  • the described aqueous composition and lyophilized dry powder provide several improvements.
  • the solubility of the active pharmaceutical is increased and is more stable.
  • the dry powder can be reconstituted quickly as a clear solution.
  • the amount of active pharmaceutical that can be solubilized from the dry powder is increased which allows fewer vials to be used for rapid treatment of MH.
  • less of the excipient, mannitol is needed.
  • the active pharmaceutical compound is more resistant to hydrolysis.
  • the solubility of dantrolene sodium in the selected solvent must be high enough to form commercially useful concentrations of the drug in solvent. Additionally, the solvent should be capable of being removed easily from an aqueous dispersion or solution of the drug product, e.g., through lyophilization or vacuum drying. In one aspect, a solution having a concentration of about from about 1 to about 80 mg/ml is used; in another aspect, a solution of about from about 0.05 to about 10 mg/ml is used, in another aspect, a solution of about from about 0.1 to about 3.5 mg/ml is used.
  • a pharmaceutically acceptable lyophilization excipient can be dissolved in the aqueous phase during the formulation process. Mannitol is one such excipient. Other excipients that may be used if desired include cyclodextrins and or cucurbiturils and pH adjusting agents.
  • An exemplary formulation and lyophilization cycle is provided below. Lyophilization can be carried out using standard equipment as used for lyophilization or vacuum drying. The cycle may be varied depending upon the equipment and facilities used for the fill/finish.
  • an aqueous pre-lyophilization solution or dispersion may first be formulated in a pharmaceutically acceptable compounding vessel.
  • the solution may be aseptically filtered into a sterile container, filled into an appropriately sized vial, partially stoppered and loaded into the lyophilizer.
  • the solution may be lyophilized until moisture content in the range of from about 0.01 to about 1.0 % may be achieved.
  • the resulting lyophilization powder can be readily reconstituted with Sterile Water for Injection, or other suitable carrier, to provide clear liquid formulations of dantrolene sodium, suitable for internal administration e.g., by parenteral injection.
  • the product is placed in a lyophilization chamber under a range of temperatures and then subjected to temperatures well below the products freezing point, generally for several hours.
  • the product is chilled below the freezing point of the solution to about -5 °C, or to about -10 °C or lower, or also to about -20 °C or lower.
  • the temperature will be at or below about -40 °C for at least 2 hours.
  • the chamber and the condenser are evacuated through vacuum pumps, the condenser surface having been previously chilled by circulating refrigerant. Typically, the condenser will have been chilled below the freezing point of the solution generally to about -40 °C.
  • the condenser will have been chilled to about -45 °C or lower, in another aspect to about -60 °C or lower. Additionally, evacuation of the chamber should continue until a pressure of from about 10 to about 600 mTorr, or from about 50 to about 150 mTorr is obtained.
  • the product composition is then warmed under vacuum in the chamber and condenser. This usually will be carried out by warming the shelves within the lyophilizer on which the product rests during the lyophilization process at a pressure ranging from about 10 to about 600 mTorr.
  • the warming process will optimally take place very gradually. In one aspect, the warming process will take place over the course of several hours.
  • the product temperature is initially increased from about -40 °C to about 20 °C and maintained for about 10 to about 70 hours. In another aspect, the product temperature is initially increased from about -46 °C to about 20 °C and maintained for about 20 to about 40 hours.
  • the product temperature can be increased to a temperature to about 25 °C to about 40 °C over a period of 0 to about 20 hours.
  • the pressure in the chamber can be slowly released to atmospheric pressure (or slightly below) with sterile, dry-nitrogen gas (or equivalent gas). If the product composition has been lyophilized in containers such as vials, the vials can be stoppered and sealed. Several representative samples can be removed for purposes of performing various physical, chemical, and microbiological tests to analyze the quality of the product. [0084] After lyophilization, the dantrolene lyophilization powder may be filled into containers, such as 65 ml capacity vials, or alternatively the pre-lyophilization solution can be filled into such vials and lyophilized therein, resulting in vials which directly contain the lyophilized dantrolene formulation.
  • Such vials are, after filling or lyophilization of the solution therein, sealed, as with a stopper, to provide a sealed, sterile, pharmaceutical dosage form.
  • a vial will contain a lyophilized powder including about 10-400 mg/vial, 20-400 mg/vial, and about 100 mg/vial, dantrolene sodium and from about 5 mg to about 3.0 g/vial, and about 1 to about 3 gram per vial mannitol, or 1.5 g/vial, mannitol.
  • the lyophilized formulations may be reconstituted with water, such as Sterile Water for Injection, or other substantially sterile fluid such as co-solvents, to provide an appropriate solution of dantrolene sodium for intravenous administration.
  • water such as Sterile Water for Injection, or other substantially sterile fluid such as co-solvents, to provide an appropriate solution of dantrolene sodium for intravenous administration.
  • the reconstituted product is administered as a rapid infusion to patients exhibiting the life-threatening condition of thermal hyperthermia during surgery.
  • a stable and lyophilized formulation of dantrolene sodium made by a process comprising: a) dissolving dantrolene sodium in an alkaline solution comprising a compound selected from cyclodextrins, cucurbiturils, and an organic solvent to form a clear concentrated pre-lyophilization solution; and b) lyophilizing the clear pre-lyophilization solution to form a powder; wherein said lyophilizing comprises: starting with a shelf temperature of from about 15 to about 25 °C for loading; cooling the mixture to freezing at a temperature of from about -40 to about -50 °C for about 2 to about 4 hours to form a frozen solution; holding the frozen solution at a temperature of about -45 °C for about 2 to about 3 hours; warming the frozen solution to about -20 °C for about 2 to about 3 hours; reducing the temperature to -50 °C for about 2 to about 3 hours; increasing the temperature to about 20 °C, for about 3 to about 5 hours;
  • This stable lyophilized formulation is added to a glass vial or other pharmaceutically acceptable container, and is reconstituted with a volume of water to provide an injectable clear solution of dantrolene sodium in a range of 20 to about 400 mg.
  • This formulation may also comprise mannitol.
  • the clear pre-lyophilization solution comprises dantrolene sodium at a concentration of about 0.1 to about 10 mg/ml, mannitol at a concentration of about 20 to about 100 mg/ml, organic solvent at a concentration of about 7 to about 700 mg/ml, a cyclodextrin/cucurbituril at a concentration of about 0.2 to about 300 mg/ml and an amount of sodium hydroxide adequate to adjust the pH to a range of from about 7.5 to about 10.5.
  • the cyclodextrin compound comprises at least one compound selected from hydroxypropyl derivatives of 0- and y-cyclodextrin, a randomly methylated 0-cyclodextrin, sulfobutylether 0-cyclodextrin, and glucosyl-0- cyclodextrins.
  • the molar ratio of dantrolene sodium to the cyclodextrin and cucurbituril compound is from about 1:1 to about 1:20.
  • the organic solvent is a water-miscible solvent, such as tertiary butanol, TBA.
  • the vial or other pharmaceutically acceptable container contains about 20 to about 400 mg of dantrolene sodium, and the formulation is reconstituted to a clear solution in about 20 to about 60 seconds, wherein the residual concentration of an organic co-solvent is less than about 0.5% (w/w).
  • the concentration of dantrolene sodium in the final lyophilized product is less than about 8% (w/w).
  • the concentration of mannitol is about 1 to about 3 gram per vial or about 1.5 gram per vial. Vial capacity is approximately 65ml.
  • the formulation is packaged in a vial or other pharmaceutically acceptable container and the formulation solution is about 96% by weight or greater dantrolene sodium and has a freeze-dry cycle of 72 hours or less.
  • This clear injectable formulation of dantrolene sodium formed by reconstituting a lyophilized dantrolene sodium powder with a diluent is suitable for intravenous administration and is useful for the treatment of malignant hyperthermia.
  • a pre-lyophilization solution is formulated in a pharmaceutically acceptable container as follow: 1) adding an excipient, such as mannitol (about 0 to about 500 mg/ml) with mixing to water at ambient temperature. 2) adding a supramolecular compound, such as cyclodextrin or cucurbituril with mixing at about 20-35 °C. 3) adding an organic solvent (0.5- 99.9% v/v), such as TBA to the aqueous solution with mixing at about 20-35 °C. 4) adding dantrolene sodium to the desired concentration with mixing. 5) adding water to achieve the final volume, and 6) cooling the solution to a temperature of from about 10 °C to about 30 °C, and about 25 °C. Quantities can be prepared on a weight basis also.
  • Example 2 The method for lyophilizing the pre lyophilization solution comprises:
  • a freeze-drying cycle to form the dry powder may be produced with 5-10% (w/w) cyclodextrin, 1-10% (w/w) cucurbituril and about 1-5% (v/v) TBA aqueous co-solvent system, as follows:
  • the vacuum pressure is about 70 to about 130 microns throughout primary drying cycle, or the pressure is about 80 to about 120 microns throughout primary drying, or from about 90 to about 110 microns throughout primary drying. In another aspect, the vacuum pressure is about 90 to about 150 microns throughout secondary drying cycle, or the pressure is about 100 to about 140 microns throughout secondary drying, or from about 110 to about 130 microns throughout secondary drying. The vacuum pressure is about 90-110 microns throughout primary drying and 210-230 microns throughout secondary drying.
  • an aqueous composition is used to produce the lyophilized dry powder.
  • the aqueous composition may comprise an active pharmaceutical compound, a cyclodextrin derivative or a cucurbituril derivative and a co-solvent.
  • the active pharmaceutical compound may comprise at least one compound selected from dantrolene and a pharmaceutically acceptable salt of dantrolene.
  • the cyclodextrin compound may comprise at least one compound selected from cyclodextrins and cyclodextrin derivatives.
  • the co-solvent may comprise at least one compound selected from tertiary butanol, n-propanol, n-butanol, and isopropanol.
  • the pH of the aqueous composition is greater than 7.
  • the aqueous composition may comprise water. After the aqueous composition is formed, it is lyophilized to form the dry powder.
  • the concentration of the co-solvent is from about 0.5% to about 20% (v/v), such as about 2% to about 10% (v/v) and about 1% to about 5% (v/v).
  • the molar ratio of the active pharmaceutical to the macromolecule compound is from about 1:1 to about 1:30.
  • the amount can vary, such as from about 1:3 to about 1:30 and about 1:5 to about 1:18.
  • the pH can vary to improve solubility.
  • the aqueous composition has a pH from about 7.5 to about 10, such as from about 8.0 to about 9.5 and about 8.5 to about 9.5.
  • the aqueous composition is formed by mixing the active pharmaceutical with enough NaOH in sterile water to bring the pH into the range of about 9.5 to about 10.5 at about 40°-50°C for a period of about 10-20 minutes. The remaining ingredients are then added.
  • the dry powder is a lyophilized (freeze-dried) powder comprising approximately 200 mg of anhydrous dantrolene sodium (API) (DS) (equivalent to 240 mg of hydrous DS containing 15.5% to 16% (w/w) of moisture), 1.5 g of mannitol, less than 3 grams of cyclodextrin or cucurbituril and enough NaOH to achieve a pH value of approximately 9.5 upon reconstitution with 60 ml of water for injection (WFI) per vial.
  • the concentration of dantrolene sodium in the final lyophilized product is less than about 8% by weight.
  • the method for treating MH in a patient involves administering a therapeutically effective amount of the active pharmaceutical ingredient.

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Abstract

L'invention concerne des procédés d'amélioration de la solubilité et de la stabilité de dantrolène sodique (DS) comprenant la formation d'un complexe ou d'un mélange d'un composé à l'aide d'un nouveau système supramoléculaire (cyclodextrine [CD], cucurbiturile [C], etc.) et co-solvant de fabrication d'une formulation de DS stable, claire et concentrée pour une utilisation intraveineuse (DS IV) ainsi que des procédés de diminution de la quantité de mannitol dans le DS IV et de réduction de l'alcalinité de la solution de formulation de DS conduisant à la réduction de la destruction chimique alcaline de DS. La solution reconstituée stable, claire et concentrée de DS IV permet de réduire le volume de diluant et de diminuer sensiblement le nombre de flacons reconstitués administrés. Cette propriété constitue une amélioration significative de la pharmacothérapie chez des patients subissant une hyperthermie maligne pendant une intervention chirurgicale.
PCT/US2022/012526 2021-02-05 2022-01-14 Compositions et procédés d'administration parentérale claire concentrée d'agents thérapeutiques de dantrolène WO2022169582A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093531A1 (en) * 2007-10-09 2009-04-09 Ahmad Malkawi Co-Solvent Compositions and Methods for Improved Delivery of Dantrolene Therapeutic Agents
WO2017067980A1 (fr) * 2015-10-20 2017-04-27 B. Braun Melsungen Ag Composition aqueuse comprenant du dantrolène

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093531A1 (en) * 2007-10-09 2009-04-09 Ahmad Malkawi Co-Solvent Compositions and Methods for Improved Delivery of Dantrolene Therapeutic Agents
WO2017067980A1 (fr) * 2015-10-20 2017-04-27 B. Braun Melsungen Ag Composition aqueuse comprenant du dantrolène

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MA YAN-LONG ET AL: "Biomimetic Recognition of Organic Drug Molecules in Water by Amide Naphthotubes", CCS CHEMISTRY, vol. 3, no. 4, 17 July 2020 (2020-07-17), pages 1078 - 1092, XP055911589, ISSN: 2096-5745, DOI: 10.31635/ccschem.020.202000288 *

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