[go: up one dir, main page]

WO2023076477A2 - Comprimé à désintégration orale pour formulations de promédicament d'épinéphrine - Google Patents

Comprimé à désintégration orale pour formulations de promédicament d'épinéphrine Download PDF

Info

Publication number
WO2023076477A2
WO2023076477A2 PCT/US2022/048024 US2022048024W WO2023076477A2 WO 2023076477 A2 WO2023076477 A2 WO 2023076477A2 US 2022048024 W US2022048024 W US 2022048024W WO 2023076477 A2 WO2023076477 A2 WO 2023076477A2
Authority
WO
WIPO (PCT)
Prior art keywords
epinephrine
odt
prodrug
dipivefrin
tablet
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.)
Ceased
Application number
PCT/US2022/048024
Other languages
English (en)
Other versions
WO2023076477A3 (fr
Inventor
Mingbao Zhang
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.)
Insignis Therapeutics Inc
Original Assignee
Insignis Therapeutics Inc
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 Insignis Therapeutics Inc filed Critical Insignis Therapeutics Inc
Publication of WO2023076477A2 publication Critical patent/WO2023076477A2/fr
Publication of WO2023076477A3 publication Critical patent/WO2023076477A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2063—Proteins, e.g. gelatin
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • This disclosure provides epinephrine prodrug orally disintegrating tablet formulations.
  • the disclosure also provides a method of treating a patient who has a condition responsive to epinephrine such as a cardiac event, asthma, croup, cancer, a microbial infection, Addison's disease, or an allergic reaction, particularly anaphylaxis by administering an orally disintegrating dipivefrin tablet formulations to the patient.
  • Epinephrine is used to treat a number of conditions including anaphylaxis, cardiac arrest, and superficial bleeding, asthma and croup. Injectable epinephrine has also been shown to be efficacious for preventing and treating cancer.
  • U.S. Patent No. 5,925,682 discloses that injecting a mammal with an effective amount of epinephrine results in the significant reduction of tumorous growth. Epinephrine may also be efficacious in treating microbial infections.
  • Epinephrine, delivered via intramuscular or subcutaneous injection is a drag of choice for emergency treatment of anaphylaxis. It is commercially available in injectable form delivered by autoinjectors or pre-filled syringes.
  • An epinephrine prodrag can provide an alternative for the delivery of epinephrine.
  • US patent application Pub No US 2019 / 0076378 Al discloses using epinephrine prodrug dipivefrin, including L-dipivefrin, for systemic delivery of epinephrine.
  • US patent application Pub No US 2020/0276114 Al discloses dipivefrin, including L- dipivefrin hydrochloride, orally dissolving tablet formulations
  • a number of other epinephrine prodrugs are known in the art..
  • a prodrug can present improved hydrophobicity, better permeation, dose reduction, reduced side effects, enhanced speed of absorption and better metabolic stability. It can also provide alternative compositions with unique stability profiles.
  • Other prodrugs could have similar stability and/or be designed based on the desired stability profile exhibited with certain additives.
  • the current disclosure provides an effective, convenient, an easy to use formulation capable of quickly delivering a therapeutic level of epinephrine to a patient's bloodstream and provides additional advantages.
  • This disclosure is directed to an epinephrine prodrug orally disintegrating tablet (ODT), comprising an epinephrine prodrug, or its pharmaceutically acceptable salt, a binder, a disintegrator and/or matrix former, and a taste masking agent and optionally a permeation enhancer.
  • ODT epinephrine prodrug orally disintegrating tablet
  • the epinephrine prodrug disclosed in the instant application is not dipivefrin, L-dipivefrin or its pharmaceutically acceptable salts.
  • the epinephrine prodrug is a compound of the formula or a pharmaceutically acceptable salt thereof wherein
  • R 1 , R 2 , R 3 , and R 4 are independently chosen from H, C 1 -C 12 alkylcarbonyl, mono or di-C 1 -C 12 alkylaminocarbonyl, C 1 -C 12 alkoxycarbonyl, (C 3 -C 6 cycloalkyl)C 0 -C 4 alkylcarbonyl, phenylC 0 -C 4 alkylcarbonyl, (C 0 -C 12 alkyl)sulfate, and (C 0 -C 12 alkyl)phosphate;
  • each alkyl or alkoxy in the definition of R 3 optionally contains one or more double or triple bonds, has one or more CH? groups replaced by O, S, NH, or NR 5 where R 5 is C1-C6alkyl, and is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, amino, oxo, or cyano;
  • R 1 alkyl or alkoxy may be joined to the R 2 alkyl or alkoxy to form a 5 to 7-membered ring or the R 3 alkyl or alkoxy may be joined to the R 4 alkyl or alkoxy to form a 5- to 7-membered ring;
  • the ODT comprises about 0.01 mg, to about 60 mg the epinephrine prodrug or 0.5mg, 1.0 mg, 2.5 mg, 5 mg, 10 mg, or 20 mg epinephrine prodrug.
  • the epinephrine prodrug ODT of the disclosure can have a total tablet weight of less than 100 mg.
  • the epinephrine prodrug ODT of the disclosure can comprise 10 to 70% binder (wt%), 5 to 50% matrix former and/ or disintegrat'd (wt%), and 1 to 20%' taste masking agent (wt%).
  • the binder can comprise gelatin and/ or povidone.
  • the matrix former can be glycine or mannitol.
  • the taste masking agent can include citric acid and/or a sweetener such as sucralose and sodium saccharin.
  • the epinephrine prodrug ODT composition can optionally contain a chelating agent.
  • the epinephrine prodrug ODT composition can optionally contain an antioxidant.
  • the epinephrine prodrug ODT composition can optionally contain a permeation enhancer.
  • the epinephrine prodrug ODT composition can optionally contain a flavoring agent.
  • the epinephrine prodrug ODT composition can optionally contain a colorant.
  • the epinephrine prodrug ODT composition of the present disclosure can optionally contain a pH modifier.
  • the epinephrine prodrug ODT of this disclosure is suitable for treating conditions in a subject such as anaphylaxis in which epinephrine is urgently needed in the subject's systemic circulation.
  • the disclosure include epinephrine prodrug ODTs capable of providing an epinephrine T max of less than 60 min, less than 45 minutes from administration to the subject and an epinephrine plasma C max of 0.1 to 50 ng/mL when administered to a subject.
  • the epinephrine prodrug ODT contains not more than 10 mg of epinephrine prodrug hydrochloride and provides a plasma level of epinephrine at 20 minutes after administration that is equal or greater than a plasma level of epinephrine provided by a US FDA-approved 0.3 mg injectable epinephrine dosage form.
  • the US FDA- approved injectable epinephrine dosage form can be a 0.5mg, 0.3 mg, 0.15 mg, or 0.1 mg epinephrine dosage form for intramuscular administration.
  • the US FDA-approved injectable epinephrine dosage form can be a 0.5 mg, 0.3 mg, 0.15 mg, or 0.1 mg epinephrine dosage form for subcutaneous administration.
  • the disclosure includes a method of treating a subject suffering from a condition responsive to epinephrine by administering a epinephrine prodrug ODT of the disclosure.
  • the condition responsive to epinephrine can be a breathing difficulty, such as a breathing difficulty is associated with anaphylaxis, asthma, bronchitis, emphysema, croup, or a respiratory infection.
  • the condition responsive to epinephrine is anaphylaxis.
  • the disclosure includes a method of reducing the severity of an allergic reaction or anaphylaxis or inhibiting the onset of an allergic reaction or anaphy laxis in a subject, comprising administering a epinephrine prodrug ODT of the disclosure to the subject following exposure of the subject to an allergen.
  • the epinephrine prodrug ODT of the disclosure can be the only pharmaceutical agent administered to a subject or can be administered together with another pharmaceutical agent such as an antihistamine, for example diphenhydramine.
  • the disclosure includes a method for treating a condition responsive to epinephrine in a subject, in which tire subject has a deficiency of epinephrine.
  • the deficiency can be short term or chronic.
  • Such conditions include Addison's disease, adrenal hyperplasia, hypoglycemia, or chronic active hepatitis.
  • FIGURE 2 Mean plasma epinephrine concentration vs time profiles after single oral dose of epinephrine prodrug (dipivefrin) HC1 orally disintegrating tablet 5 mg and
  • FIGURE 3 Mean plasma epinephrine concentration vs time profiles after single oral dose of epinephrine prodrug (dipivefrin) HC1 orally disintegrating tablet 1.0 mg,
  • epinephrine prodrug orally disintegrating tablet or “epinephrine prodrug orally dissolving tablet” or “epinephrine prodrug ODT' refers to an orally disintegrating tablet comprising epinephrine prodrug (freebase), or a pharmaceutically acceptable salt, solvate, or polymorph of dipivefrin.
  • a preferred epinephrine prodrug ODT comprises epinephrine prodrug hydrochloride or L-epinephrine prodrug hydrochloride.
  • R 1 -R 4 carries the definitions set forth above.
  • R 1 , R 2 , R 3 , and R 4 are independently chosen from H, C 1 -C 6 alkylcarbonyl, mono or di-C 1 - C 16 alkylaminocarbonyl, C 1 -C 6 alkoxycarbonyl, phenylC 0 -C 2 alkylcarbonyl, (C 0 - C 6 alkyl)sulfate, and (C 0 -C 6 alkyl) phosphate;
  • each alkyl or alkoxy in the definition of R 3 optionally contains one or more double or triple bonds, has one or more CH 2 groups replaced by O, S, NH, or NR 3 where R 5 is C 1 -C 6 alkyl, and is optionally substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, amino, oxo or cyano. .
  • R 1 , R 2 , R 3 , and R 4 are independently selected from any of H, CH 3 C(O)-, CH 3 CH 2 C(O)-, CH 3 CH 2 OC(O)-, CH 3 (CH 2 ) 2 C(O)-, CH 3 (CH 2 ) 3 C(O)-, CH 3 (CH 2 ) 5 C(O)-, (CH 3 ) 2 CHC(O)-, CH 3 (CH 2 ) 3 OC(O)-, (CH 3 )CC( O).
  • R 1 and R 2 are the same.
  • R 3 and R 2 are both not hydrogen.
  • R 3 and R 4 are both hydrogen.
  • R 1 , R 2 , and R 3 are the same and are not hydrogen, R 4 is hydrogen.
  • the term "pharmaceutically acceptable salt” is a salt formed from, for example, an acid and a basic group of an epinephrine prodrug composition.
  • Illustrative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, acid chloride, bromide, iodide, nitrate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannnate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinante, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamo
  • pharmaceutically acceptable salt also refers to a salt prepared from a composition having an acidic functional group, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base and also to a salt prepared from a composition having a basic functional group, such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.
  • a "pharmaceutical agent” means a compound (including for example, an epinephrine prodrug or epinephrine), element, or mixture that when administered to a subject, alone or in combination with another compound, element, or mixture, confers, directly or indirectly , a physiological effect on the subject.
  • the indirect physiological effect may occur via a metabolite or other indirect mechanism.
  • administer refers to any manner of providing a pharmaceutical agent (such as epinephri ne prodrug or a pharmaceutically acceptable salt thereof) to a subject or patient.
  • routes of administration can be accomplished through any means known by those skilled in the art. Such means include oral, buccal, intravenous, subcutaneous, intramuscular, transdermal, and inhalation, sublingual, intranasal. Oral administration is a preferred route of epinephrine prodrug administration.
  • oral administration refers to a manner of providing a pharmaceutical agent to a subject or patient by the mouth through the gastrointestinal tract (digestive tract, digestional tract, GI tract, GIT, gut, or alimentary canal) and/or through the oral mucosa and are used interchangeably .
  • the gastrointestinal tract is tut organ system within humans and other animals which takes in food, digests it to extract and absorb energy and nutrients, and expels the remaining waste as feces.
  • the mouth, esophagus, stomach and intestines are part of the gastrointestinal tract.
  • a "dosage form” means a unit of administration of a pharmaceutical agent.
  • the dosage forms are orally disintegrating tablets.
  • An “orally disintegrating (or dissolving) tablet” is a solid dosage form that disintegrates or dissolves rapidly, usually within a matter of seconds, when placed in the mouth. Orally disintegrating dosage forms are designed to disintegrate or dissolve rapidly on contact with saliva, thus eliminating the need for chewing, swallowing, or taking the solid dosage with water.
  • An orally disintegrating dosage can promote pregastric absorption of the active ingredients through buccal, sublingual, oropharyngeal and esophageal membranes. As a result, an orally dissolving dosage can provide faster onset of action and higher bioavailability than a conventional solid dosage form.
  • a "pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the present application includes both one and more than one such excipient.
  • a "subject” is a human or non-human mammal, such as a companion animal, e.g. cat or dog.
  • a subject can be a human or non-human patient in need of medical treatment.
  • a “therapeutically effective amount” or “effective amount” is that amount of a pharmaceutical agent to achieve a pharmacological effect.
  • 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 a disorder in a patient at risk for the disorder.
  • An “effective amount” of epinephrine prodrug is an amount needed to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. The effective amount of epinephrine prodrug will be selected by those skilled in the art depending on the particular patient and the type of conditions being treated.
  • an effective amount or “a therapeutically effective amount” can vary from patient to patient, due to variation in general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician.
  • an effective amount includes an amount effective to have a statistically significant and favorable effect on the rate of the patient's cancer proliferation over time or on a level of biological marker for the cancer.
  • treating and “treatment” mean implementation of therapy with the intention of reducing in severity or frequency symptoms, elimination of symptoms or underlying cause, prevention of the occurrence of symptoms or their underlying cause, or the improvement or remediation of damage due to a disorder or disease.
  • treatment includes prophylactic treatment, which includes administering an amount of epinephrine prodrug effective to significantly reduce the proliferation of cancerous tissue, reduce the chance of infection of a patient by a microbial pathogen.
  • treatment includes inhibiting the onset of anaphylaxis or reducing the severity of allergy symptoms in a subject exposed to an allergen.
  • ODT over-the-counter
  • ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed whole.
  • the ODT serves as an alternative dosage form for patients who experience dysphagia (difficulty in swallowing) or for patients for whom compliance is a known issue and need an easier to swallow dosage form to ensure that medication is taken.
  • Dysphagia is common among all age groups. It is observed in about 20% of the general population, 33% of hospital patients, and in up to 40%' of patients in long-term care facilities.
  • ODT dosages forms are also an option for pediatric patients too young to swallow pills.
  • ODTs also have a faster onset of action than tablets or capsules due to pregastric absorption (absorption from the mouth, pharynx and esophagus as the saliva passes down into the stomach), and can be conveniently taken without water.
  • ODTs are particularly suitable for delivering epinephrine for emergency treatment of anaphylaxis given their unique advantages as patient-friendly and convenient pharmaceutical dosage forms that can be taken anytime, anywhere and by anyone without water and the need to swallow a whole tablet.
  • epinephrine is not absorbed when taken orally, precluding the development of epinephrine ODTs for anaphylaxi s.
  • the inventor has developed new orally disintegrating epinephrine prodrug tablets, suitable for commercial use.
  • the ODTs of this disclosure are stable at temperatures of from less than 0 °C to at least 60 °C and thus provide a significant advantage over epinephrine auto-injectors because they do not need to be stored within a narrow temperature range. Stability of the epinephrine prodrug ODTs of this disclosure can be further enhanced by excluding moisture and oxygen during their manufacture and storage.
  • the epinephrine prodrug ODTs of this disclosure contain from about 0.01 to about 60 mg epinephrine prodrug or an epinephrine prodrug salt such as epinephrine prodrug hydrochloride.
  • This disclosure includes ODTs containing 0.1 mg, 0.5 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 7.0 mg. 7.5 mg, 10 mg, 12 mg, 15 mg, or 20 mg or 30 mg epinephrine prodrug or epinephrine prodrug HC1.
  • this disclosure includes ODTs comprising 0.01 to about 60 mg, about 0.01 to about 50 mg, about 0.01 to about 40 mg, about 0.01 to about 30 mg, about 0.01 to about 30 mg, about 0.01 to about 15 mg, about 0.01 to about 12 mg, about 0.01 to about 10 mg, about 0.01 to about 7.5 mg, about 0.01 to about 5.0 mg, about 0.01 to about 1.0 mg, 0.1 to about 60 mg, about 0.1 to about 50 mg, about 0.1 to about 40 mg, about 0.1 to about 30 mg, about 0.1 to about 20 mg, about 0.1 to about 15 mg, about 0.1 to about 12 mg, about 0.1 to about 10 mg, about 0.1 to about 7.5 mg, about 0.1 to about 5.0 mg, about 0.1 to about 1.0 mg, 1.0 to about 60 mg, about 1.0 to about 50 mg, about 1.0 to about 40 mg, about 1.0 to about 30 mg, about 1 .0 to about 20 mg, about 1.0 to about 15 mg, about 1.0 to about 12 mg, about
  • the orally disintegrating epinephrine prodrug tablet of the present disclosure includes one or more excipients.
  • the orally disintegrating epinephrine prodrug tablet of the present disclosure includes: (a) one or more fillers, (b) one or more binders, (c) one or more glidants, (d) one or more disintegrants, (e) one or more sweeteners or taste-masking agent, (f) one of more flavors or taste-masking agent, (g) one or more colorants, (h) one or more lubricants, (i) one or more matrix formers, (j ) one or more diluents, or (k) a combination thereof.
  • the epinephrine prodrug ODTs of this disclosure contain a binder.
  • suitable binders include water-soluble, alcohol-soluble or acetone/water soluble binders, e.g. gelatin, dextran, alginates, gum Arabic, modified starch, polyvinylpyrrolidone (PVP, also povidone) including PVP K30, Cas. Reg. No.
  • corn starch polyethylene oxide, polyethylene glycol, hydroxypropyl methylcellulose (HPMC), methylcellulose, cellulose derivatives, crystalline cellulose, hyprodroxypropyl methylcellulose, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, ethylcellulose, microcrystalline dextrose, a sugar, sucrose, D-mannitol, mannitol, glucose, dextrose, molasses, sorbitol, xylitol, lactose, dextrin, sodium alginate, alginic acid and salts thereof, pektines, polyvinyl acetate, povidone, copovidone, crospovidone, polyvinylpyrrolidone, xanthan gum, polyvinyl alcohol, starch, pregelatinized starch, gum tragacanth, a natural or synthetic gum, acacia,
  • the amount of binder in the epinephrine prodrug ODT ranges from 10% to 70% (wt%), including 10%' to 65%, 10 % to 60%, 10% to 50%, 10% to 40%, 10% to 35%', 20% to 70 %, 20% to 65%, 20 % to 60%, 20% to 50%, 20% to 40%, 20% to 35%, 25% to 70 %, 25% to 65%, 25 % to 60%, 25% to 50%, 25% to 40%, 25% to 35%, 30% to 70 %, 30% to 65%, 30% to 60%, 30% to 50%, 30% to 40%, 30% to 35%, 35% to 70 %, 35% to 65%, 35% to 60%, 35% to 50%, 40% to 70 %, 40% to 65%, 40% to 60%, 40% to 50%, 45% to 70 %, 45% to 60%, 50% to 70 %, and 50% to 60% (wt%).
  • the epinephrine prodrug ODTs of this disclosure optionally contain a disintegrant.
  • a distintegrant is typically present.
  • the disintegrant may be any disintegrani suitable for orally disintegrating tablets, for example the disintegrant may be a sugar alcohol such as sorbitol, mannitol, xylitol, isomalt, and hydrogenated starch hydrolysates, or an amino acid such as glycine, the disintegrant may also be crospovidone (crosslinked PVP), sodium starch glycolate, crosslinked sodium carboxy methyl cellulose, low substituted hydroxypropylcellulose, agar-agar, calcium carbonate, potato starch, tapioca starch, alginic acid, certain silicates, sodium carboxymethyl cellulose, starch, pregelatinized starch or mixture thereof.
  • crospovidone crosslinked PVP
  • sodium starch glycolate crosslinked sodium carboxy methyl cellulose
  • low substituted hydroxypropylcellulose a
  • the disintegrant is mannitol, glycine, or a combination thereof.
  • the amount of disintegrant in the ODTs can be from 1% to 50%' (wt%), including, e.g., 10% to 50%, 10% to 40%, 10% to
  • Epinephrine prodrug ODTs of this disclosure optionally contain a matrix former.
  • Epinephrine prodrug ODTs of this disclosure prepared by lyophilization contain a matrix former and optionally contain a disintegrant.
  • the matrix former is preferably a crystalline material that remains crystalline upon lyophilization but dissolves readily in saliva.
  • Matrix formers include gelatins, dextrans, alginates, glycine, crystalline sugars such as mannitol (including D-mannitol), sorbitol, erythritol, and xylitol, microcrystalline cellulose, maltodextran, crystalline cellulose, and mixtures thereof.
  • the amount of matrix former in the ODTs can be from 5% to 50% (wt%), including, e.g., 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 15% to 50%, 15% to 40%, 15% to 30%, 15% to 25%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 50%, 25% to 40%, 25%' to 35%, 30% to 50%', 30% to 40%, or 40% to 50%.
  • 5% to 50% e.g., 5% to 50%, 5% to 40%, 5% to 30%, 5% to 20%, 5% to 15%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 15% to 50%, 15% to 40%, 15% to 30%, 15% to 25%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 50%, 25% to 40%, 25%' to 35%, 30% to 50%', 30% to 40%, or 40% to 50%.
  • the epinephrine prodrug ODTs of this disclosure include a taste masking agent.
  • Suitable taste masking agents include, but are not limited to, artificial and natural flavorants, citric acid, and sweeteners, including artificial sweeteners, nutritive sweeteners, and sugar alcohols.
  • sweeteners useful as taste masking agents include saccharin, aspartame, acesulfame K, neotame, sodium saccharin, sucralose, trehalose, tagatose, mannitol, sorbitol, xylitol, erythritol, maltitol, sucrose, fructose, acacia syrup, alitame, sodium chloride, neohesperidine dihydrocbalcone, magnesium chloride, disodium inosinate, sodium L-glutamate, honey, cyclamate, cylamate, dextrose, calcium citrate, glycyrrhizin, sucrose, sugar, monosaccharides, oligosaccharides, aldose, ketose, maltose, lactose, xylitol, D-sorbitol, pentitol, hexitol, malitol, sodium cyclamate,
  • Suitable flavorants include, but are not limited to, essential oils, peppermint oil, menthol, spearmint oil, citrus oil, cinnamon oil, strawberry flavor, cherry flavor, raspberry flavor, orange oil, apple, pear, peach, banana, Bavarian cream, caramel, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cool cherry, camphor, cool citrus, eucalyptus, fruit punch, ginger, spearmint, spearmint cream, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, lemon, lemon cream, honey-lemon, lemon-lime, lemon-mint, lime, root beer, tutti frutti, walnut, watermelon, rum, anise, black currant, butterscotch, orange, cola, Swiss cream, mandarine, tangerine, grapefruit, vanilla, berry, mixed berry, raspberry, strawberry cream, wild cherry, maple, marshmallow, mint cream, Wintergreen, peppermint flavors, pepper
  • Additional suitable taste-masking agent include, but are not limited to, cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate (, ethylcellulose, hypromellose phthalate, hypromellose acetate succinate , poly(butyl methacrylic, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) 1:2:1, poly(ethyl acrylate, methyl methacrylate) 2:1, poly(methacrylic acid, methylmethacrylate) 1:1, poly (methacrylic acid, ethyl acrylate) 1:1, poly (methacrylic acid, methyl methacrylate) 1:2, poly(methyl acrylate, methyl methacrylate, methacrylic acid) 7:3:1, poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) l:2:0.2, polytethyl acrylate,
  • the amount of taste-masking agent in the epinephrine prodrug ODTs of this disclosure can be from 0.1% to 25% (wt%), 0.5% to 25%, 1% to 25%, 2% to 25%, 5% to 25%, 10% to 25%, 0.1% to 20% (wt%), 0.5% to 20%, 1% to 20%, 2% to 20%, 5% to 20%, 10% to 20%, 0.1% to 10% (wt%), 0.5% to 10%, 1% to 10%, 2% to 10%, 5or 5% to 10%.
  • the taste masking agent is citric acid, sucralose, or saccharin, or a combination thereof.
  • the epinephrine prodrug ODT composition can optionally contain a chelating agent.
  • Suitable chelating agents for the epinephrine prodrug ODTs of this disclosure include, but are not limited to, EDTA, a salt of EDTA, desferrioxamine B, deferoxamine, dithiocarb sodium, penicillamine, pentetate calcium, a sodium salt of pentetic acid, succimer, trientine, nitrilotriacetic acid, trans diaminocyclohexanetetraacetic acid (DCTA), diethylenetriaminepentaacetic acid, bis(aminoethyl)glycolether-N,N,N', N'- tetraacetic acid, iminodiacetic acid, citric acid, tartaric acid, fumaric acid, or a salt thereof.
  • DCTA trans diaminocyclohexanetetraacetic acid
  • the amount of chelating agent in the epinephrine prodrug ODTs of this disclosure can be from 0.1% to 25% (wt%), including, e.g., 0.1% to 25%, 0.5% to 25%, 1% to 25%, 2% to 25%, 5% to 25%, 10% to 25%, 0.1% to 20%, 0.5% to 20%, 1% to 20%, 2% to 20%, 5% to 20%, 10% to 20%, 0.1% to 10%, 0.5% to 10%, 1% to 10%, 2% to 10%, or 5% to 10%.
  • the epinephrine prodrug ODT composition can optionally contain an antioxidant.
  • Antioxidants suitable for the epinephrine prodrug ODTs of the present disclosure include, but are not limited to, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, methionine, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, alpha tocopherol (vitamin E), cysteine hydrochloride and combinations thereof.
  • the epinephrine prodrug ODT composition of the present disclosure can optionally contain a permeation enhancer.
  • Permeation enhancers suitable for tire present disclosure include, but are not limited to, caprylic acid, oleic acid, polysorbate 80, menthol, EDTA, sodium edetate, cetylpyridinium chloride, benzylkonium chloride, essentials such as peppermint oi, clove oil, sodium lauryl sulfate, citric acid, sodium desoxycholate, sodium deoxyglycolate, glyceryl oleate, L - lysine, and combinations thereof.
  • the epinephrine prodrug ODT composi tion of the present disclosure can optionally contain a pH modifier.
  • pH modifiers suitable for the present invention include, but tire not limited to, hydrochloric acid, citric acid, fumaric acid, lactic acid, sodium hydroxide, mono or dibasic sodium phosphate, amino acids, sodium citrate, sodium bicarbonate, sodium carbonate, ammonium carbonate and combinations of any of the foregoing.
  • the epinephrine prodrug ODT composition of this disclosure has a pH of from 1 - 7, in some embodiments a pH of from 1-5, and in some embodiments a pH of from 2.5 - 3.5.
  • the epinephrine prodrug ODTs can optionally contain a pharmaceutically acceptable colorant.
  • Colorants suitable for the epinephrine prodrug ODTs of the present disclosure include, but tire not limited to, yellow, orange, red, green, and blue, colorants, or mixtures thereof.
  • the epinephrine prodrug ODTs of this disclosure can optionally contain a coating, such as an immediate release coating.
  • the epinephrine prodrug ODTs can optionally contain a pharmaceutically acceptable filler.
  • Fillers suitable for the epinephrine prodrug ODTs of the present disclosure include, but are not limited to, micro-crystalline cellulose, starches, lactose, sucrose, glucose, mannitol, sorbitol, xylitol, glucose, sugar, sugar derivates, calcium hydrogen phosphates, dicalcium phosphate, and mixtures thereof.
  • the amount of filler in the ODTs can be from 1%' to 50% (wt%), including, e.g., 10% to 50%, 10% to 40%, 10% to 30%, 10%' to 20%, 15%' to 50%, 15% to 40%, 15% to 30%, 15% to 25%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 50%, 25%' to 40%, 25% to 35%', 30% to 50%, 30% to 40%, or 40% to 50%.
  • the epinephrine prodrug ODTs can optionally contain a pharmaceutically acceptable glidant.
  • Glidants suitable for the epinephrine prodrug ODTs of the present disclosure include, but are not limited to, sterotes, magnesium stearate, calcium stearate, a hydrocarbon, mineral oil, hydrogenated castor oil, hydrogenated vegetable oil, hydrogenated soybean oil, silicone oil, a surfactant, stearic acid, sodium stearyl fumarate, macrogol, talc, sugar alcohols, solid polyethylene glycols, polyethylene glycol, methoxypolyethylene glycol magnesium or sodium lauryl sulfate, colloidal silica, sodium oleate, sodium benzoate, glyceryl behenate, glycerol, waxes, calcium hydroxide, silicon dioxide, starch, corn starch, colloidal silicon dioxide, and mixtures thereof.
  • the amount of glidant in the ODTs can be from 1 % to 50% (wt%), including, e.g., 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 15% to 50%, 15% to 40%, 15%' to 30%, 15% to 25%', 20% to 50%, 20% to 40%, 20% to 30%, 25% to 50%, 25% to 40%, 25% to 35%, 30% to 50%, 30% to 40%, or 40% to 50%.
  • the epinephrine prodrug ODTs can optionally contain a pharmaceutically acceptable lubricant.
  • Lubricants suitable for the epinephrine prodrug ODTs of the present disclosure include, but are not limited to, sterotes, magnesium stearate, calcium stearate, a hydrocarbon, mineral oil, hydrogenated castor oil, hydrogenated vegetable oil, hydrogenated soybean oil, silicone oil, a surfactant, stearic acid, sodium stearyl fumarate, macrogol, talc, sugar alcohols, solid polyethylene glycols, polyethylene glycol, methoxypolyethylene glycol magnesium or sodium lauryl sulfate, colloidal silica, sodium oleate, sodium benzoate, glyceryl behenate, glycerol, waxes, calcium hydroxide, silicon dioxide, starch, corn starch, colloidal silicon dioxide, and mixtures thereof.
  • the amount of lubricant in the ODTs can be from 1% to 50% (wt%), including, e.g., 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 15% to 50%, 15% to 40%, 15% to 30%, 15% to 25%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 50%, 25% to 40%, 25% to 35%, 30% to 50%, 30% to 40%, or 40% to 50%.
  • the epinephrine prodrug GDI's can optionally contain a pharmaceutically acceptable diluent.
  • Diluents suitable for the epinephrine prodrug ODTs of the present disclosure include, but are not limited to, lactose, starch, mannitol, sorbitol, dextrose, tricalcium phosphate, calcium phosphate, anhydrous lactose, spray-dried lactose, pregelatinized starch, compressible sugar, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, calcium lactate trihydrate, dextrates, hydrolyzed cereal solids, amylose, powdered cellulose, calcium carbonate, glycine, kaolin, sodium chloride, and mixtures thereof.
  • the amount of diluent in the ODTs can be from 1% to 50% (wt%), including, e.g., 10%' to 50%, 10% to 40%', 10% to 30%, 10% to 20%, 15% to 50%, 15% to 40%, 15% to 30%, 15% to 25%, 20% to 50%, 20% to 40%, 20% to 30%, 25% to 50%, 25% to 40%, 25% to 35%, 30% to 50%, 30% to 40%, or 40% to 50%.
  • the epinephrine prodrug ODTs are freeze dried tablets containing a binder, optionally a disintegrate, at least one matrix forming agent, also known as matrix former, and at least one taste masking agent.
  • the taste masking agent can include a sweetener.
  • Typical packaging of the freeze-dried epinephrine prodrug ODTs include aluminum blister packs.
  • the blister pack comprises a multi-layered (e.g. 5 layers) laminated blister film and a lidding foil.
  • the lidding foil is peelable such that the lidding foil over each tablet may be removed to reach the tablet.
  • the epinephrine prodrug ODTs can be manufactured by any of the manufacturing processes known in the art for preparing ODTs.
  • the epinephrine prodrug ODTs of this disclosure can be manufactured using conventional tableting process such as direct compression.
  • the epinephrine prodrug ODTs can also be manufactured by wet granulation followed by drying the granules and compressing the granules into tablets.
  • the epinephrine prodrug ODTs of the disclosure can be manufactured by a tablet molding process using water soluble excipients such as saccharides. Direct compression tablets of this disclosure typically contain a disintegrate.
  • the total weight of the ODT is less than 100 mg, less than 70 mg, less than 50 mg, less than 40 mg, less than 30 mg, less than 20 mg, or less than 10 mg.
  • the epinephrine prodrug orally disintegrating tablet dissolves completely in simulated saliva at 37 °C in less than 30 seconds, or less than 10 seconds or in less than 5 seconds.
  • the epinephrine prodrug orally disintegrating tablet dissolves completely in water at ambient temperature in less than 30 seconds, or less than 10 seconds or in less than 5 seconds.
  • An aspect of the present disclosure relates to an epinephrine prodrug orally disintegrating tablet (ODT), comprising epinephrine prodrug, or a pharmaceutically acceptable salt thereof, a binder, a matrix former, and a taste masking agent, wherein tire tablet produces no detectable epinephrine when dissolved in fresh human saliva at 37° C. for 3 minutes, as determined by HPLC.
  • ODT epinephrine prodrug orally disintegrating tablet
  • the percent epinephrine is determined by HPLC, using the following conditions: C18 column, 3 ⁇ m, 100 mm x 4.6 mm, temperature 30° C, 254 nm detection, 1.0 mL/minute flow rate, 10 microliter injection volume, elution gradient:
  • Solvent A is 0.1% Trifluoroacetic acid (TFA) in H 2 O,
  • Solvent B is 0.1 % TFA in acetonitrile, and the gradient from 0 to 12 minutes
  • the ODT comprises 0.01 mg to 20 mg epinephrine prodrug, or a pharmaceutically acceptable salt thereof, such as epinephrine prodrag hydrochloride.
  • the ODT comprises 0.5 mg, 1.0 mg, 2.5 mg, or 5 mg epinephrine prodrug or a pharmaceutically acceptable salt thereof, such as epinephrine prodrug hydrochloride.
  • the total weight of tire ODT is less than 50 mg.
  • the ODT comprises 10 to 70% binder (wt%), 5 to 50% matrix former (wt %), and 1 to 20% taste masking agent (wt%).
  • An further aspect of the present disclosure relates to an epinephrine prodrag orally disintegrating tablet (ODT), comprising not more than 63.5 mg epinephrine prodrug, or a pharmaceutically acceptable salt thereof (such as, epinephrine prodrug hydrochloride), a binder, a matrix former, and a taste masking agent, wherein the ODT provides an epinephrine T max of less than 45 minutes and a plasma epinephrine C max of 0.1 to 50 ng/mL, when administered to a dog or human.
  • ODT epinephrine prodrag orally disintegrating tablet
  • the ODT contains not more than 5 mg of epinephrin prodrag or pharmaceutically acceptable salt thereof (e.g., epinephrin prodrug hydrochloride) and provides a plasma level of epinephrine at 20 minutes after administration that is equal or greater than a plasma level of epinephrine provided by a US FDA-approved injectable epinephrine dosage form, comprising 0.5 mg, epinephrine 0.3 mg epinephrine, 0.15 mg epinephrine, or 0.1 mg epinephrine.
  • epinephrin prodrag or pharmaceutically acceptable salt thereof e.g., epinephrin prodrug hydrochloride
  • the US FDA-approved injectable epinephrine dosage form is approved for intramuscular administration.
  • the US FDA-approved injectable epinephrine dosage form is approved for subcutaneous administration.
  • An additional aspect of the present disclosure relates to an epinephrine prodrug orally disintegrating tablet (ODT), comprising epinephrine prodrug, or a pharmaceutically acceptable salt thereof (such as, epinephrine prodrug hydrochloride), and 9- 53% gelatin (wt%), 20-40% glycine (wt%), 10-20% PVP K30 (wt%), 5-10% citric acid (wt%), and 5-10% saccharin sodium (wt%).
  • ODT epinephrine prodrug orally disintegrating tablet
  • the ODT further comprises a permeation enhancer.
  • the permeation enhancer includes or is caprylic acid, oleic acid, polysorbate 80 (Polyethylene glycol sorbitan monooleate), menthol, ethylenedi aminetetraaceti c acid (EDTA), sodium edetate, cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium desoxycholate, sodium deoxy glycolate, glyceryl oleate, L-lysine, or a mixture thereof.
  • the permeation enhancer includes or is caprylic acid, oleic acid, polysorbate 80 (Polyethylene glycol sorbitan monooleate), menthol, ethylenedi aminetetraaceti c acid (EDTA), sodium edetate, cetylpyridinium chloride, sodium lauryl sulfate, citric acid, sodium desoxycholate, sodium deoxy glycolate, glyceryl o
  • Yet another aspect of the disclosure relates to an epinephrine prodrag orally disintegrating tablet (ODT), comprising epinephrine prodrug, or a pharmaceutically acceptable salt thereof (such as, epinephrine prodrug hydrochloride), a binder, a matrix former, a taste masking agent, and a penetration enhancer, wherein the tablet produces not more than 13 percent epinephrine when dissolved in fresh human saliva at 37° C for 11 minutes, as determined by HPLC.
  • ODT epinephrine prodrag orally disintegrating tablet
  • the ODT comprises 0.01 mg to 20 mg epinephrine prodrug, or a pharmaceutically acceptable salt thereof (such as, epinephrine prodrug hydrochloride).
  • the ODT comprises 0.5 mg, 1.0 mg, 2.5 mg, or 5 mg epinephrine prodrug, or a pharmaceutically acceptable salt thereof (such as, epinephrine prodrag hydrochloride), wherein the total weight of the tablet is less than 50 mg.
  • the epinephrin prodrug is dipivefrin or L-dipivefrin.
  • the epinephrin prodrug salt is dipivefrin hydrochloride or L-dipivefrin hydrochloride.
  • the epinepbrin prodrug is not dipivefrin or L-dipivefrin.
  • the epinephrin prodrug salt is not dipivefrin hydrochloride or L-dipivefrin hydrochloride.
  • the disclosure includes methods of treating a subject for a condition responsive to epinephrine by administering a epinephrine prodrug ODT of this disclosure to the subject.
  • Conditions responsive to epinephrine includes breathing difficulty, including breathing difficulties associated with anaphylaxis, asthma, bronchitis, emphysema, croup, or a respiratory infection.
  • Conditions responsive to epinephrine also include allergic attack, severe allergic symptoms, and anaphylaxis.
  • Methods of treatment include administering a epinephrine prodrug ODT of this disclosure to a subject suffering from an allergic attack, severe allergies, or anaphylaxis.
  • Methods of treatment of this disclosure also include administering a epinephrine prodrug ODT of this disclosure to a subject after the subject has been exposed to a known allergen, and thereby decreasing the risk of an allergic attack, severe allergies, or anaphylaxis or lessening the severity of from an allergic attack, severe allergies, or anaphylaxis.
  • the epinephrine prodrug ODT can be administered as the only pharmaceutical agent or can optionally be administered together with another pharmaceutical agent such as an antihistamine or steroid.
  • antihistamines include diphenhydramine, brompheniramine, cetirizine, chlorpheniramine, clemastine, fexofenadine, and loratidine.
  • Method of treatment includes administering an epinephrine prodrug ODT of the disclosure to a subject having insufficient epinephrine.
  • a condition can be a chronic condition or an acute condition. Examples include Addison's disease, adrenal hyperplasia, hypoglycemia, and chronic active hepatitis.
  • the condition responsive to epinephrine can be cancer.
  • the cancer can be skin cancer, brain cancer, a glioma, a sarcoma, breast cancer, lung cancer, non-small-cell lung cancer, mesothelioma, appendicular cancer, a genitourinary cancer, a renal cell carcinoma, prostate cancer, bladder cancer, testicular cancer, penile cancer, cervical cancer, ovarian cancer, von Hippel Lindau disease, a head and neck cancer, a gastrointestinal cancer, a hepatocellular carcinoma, gallbladder cancer, esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, a neuroendocrine tumor, a thyroid tumor, a pituitary tumor, an adrenal tumor, a hematological malignancy, a lymphoma, a leukemia, or a combination thereof.
  • the condition can be skin cancer, and the skin cancer is a melanoma.
  • the condition responsive to epinephrine can be a microbial infection.
  • the microbial infection can be a bacterial, viral, fungal, or parasitic infection.
  • the microbial infection can be a viral infection, such as an influenza infection.
  • the microbial infection can be a bacterial infection, such as a methicillin-resistant Staphylococcus aureus (MRS A) infection.
  • Epinephrine prodrug or its pharmaceutically acceptable salt can be an adjunctive antimicrobial agent and the method further comprises the use of at least one additional antimicrobial agent for treating infection in the subject.
  • the additional antimicrobial agent can be an antibiotic.
  • the additional antimicrobial agent can be an antiviral agent.
  • the condition responsive to epinephrine can be an autoimmune disorder.
  • the autoimmune disorder can be rheumatoid arthritis, systemic lupus erythematosus (lupus), multiple sclerosis (MS), Type 1 diabetes mellitus, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, psoriasis, Graves' disease, Hashimoto's thyroiditis. Myasthenia gravis, vasculitis, and inflammatory bowel disease (IBD). Ulcerative colitis and Crohn's disease are the two major forms of IBD.
  • Epinephrine prodrug or its pharmaceutically acceptable salt can be an adjunctive agent and the method further comprises the use of at least one additional pharmaceutical agent for treating an autoimmune disease in the subject.
  • the additional pharmaceutical agent can include a steroid, immune-suppressing medicines, pyridostigmine, insulin or synthetic thyroid hormone.
  • Examples of the conditions responsive to epinephrine include croup, superficial bleeding, cardiac arrests, hypotension.
  • Table A provides the composition of simulated saliva used for in vitro evaluation of epinephrine prodrug ODTs.
  • IN HC1 is used to adjust simulated saliva pH to 6.8.
  • HPLC sample preparation For epinephrine prodrug HC1 ODT 5.0 mg, 5.00 g of the simulated saliva was accurately weighed into a 20 mL glass scintillation vial. For epinephrine prodrug HC1 ODT 2.5 mg, 2.50 g of simulated saliva was used. The vials were placed in an oil bath set at 37 °C for 5 min. One tablet was placed in the appropriate vial which was gently swirled by hand until complete dissolution is achieved. The dissolution time was recorded. The dissolution samples were immediately analyzed by HPLC for purity and assay.
  • Diluent solution pre-lyo solution minus epinephrine prodrug ODT
  • Table 1.1 To make a epinephrine prodrug ODT of a desired strength, the desired amount of epinephrine prodrug is dissolved in an appropriate amount of the diluent to obtain the epinephrine prodrug lyo solution. An aliquot of the lyo solution is then dispensed into blister pack pockets. The filled blister pack was then frozen on dry ice for at least one hour and freeze dried to obtain the epinephrine prodrug ODTs.
  • gelatin is first dissolved in deionized water at about
  • Dipivefrin HC1 (25 mg) was dissolved in 5.30 g of the diluent solution to obtain a lyo solution.
  • the lyo solution (535 ⁇ l) was then dispensed into each pocket of a blister pack with a diameter of 13 mm and a depth of 3 mm resulting in a dose of 2.5 mg per tablet.
  • the tablet blister pack was then placed on top of dry ice for one hour.
  • the frozen tablets were freeze dried for 24 h using a VirTis Sentry 2.0 (SP Scientific) Freeze Dryer with a condenser temperature of -90 °C and a pressure of 50 mTorr.
  • the lyophilized tablets were white, smooth, elegant and had sufficient strength for manual handling.
  • Dipivefrin HC1 (50 mg) was dissolved in 5.30 g of the diluent solution to obtain a lyo solution.
  • the lyo solution (535 ⁇ l) was then dispensed into each pocket of a blister pack with a diameter of 13 mm and a depth of 3 mm resulting in a dose of 2.5 mg per tablet.
  • the tablet blister pack was then placed on top of dry ice for one hour.
  • the frozen tablets were freeze dried for 24 h using a VirTis Sentry 2.0 (SP Scientific) Freeze Dryer with a condenser temperature of -90 °C and a pressure of 50 mTorr.
  • Dipivefrin HC1 assay by HPLC 96.7%.
  • Dipivefrin HC1 (66.4 mg) was dissolved in 7.00 g of the diluent solution to obtain the lyo solution.
  • the lyo solution (535 ⁇ l) was then dispensed into each pocket of a blister pack with a diameter of 13 mm and a depth of 3 mm resulting in a dose of 5.0 mg per tablet.
  • the tablet blister pack was then placed on top of dry ice for one hour.
  • the frozen tablets were freeze dried for 24 hr at ambient and 60 °C for 20h using a VirTis Sentry 2.0 (SP Scientific) Freeze Dryer with a condenser temperature of -90 °C and a pressure of 50 mTorr.
  • the lyophilized tablets were white, smooth, and elegant and had sufficient strength for manual handling.
  • Dipivefrin HC1 (33.0 mg) was dissolved in 7.00 g of the diluent solution to obtain the lyo solution.
  • the lyo solution (535 ⁇ l) was then dispensed into each pocket of a blister pack with a diameter of 13 mm and a depth of 3 mm resulting in a dose of 5.0 mg per tablet.
  • the tablet blister pack was then placed on top of dry ice for one hour.
  • the frozen tablets were freeze dried for 24 hr at ambient and 60 °C for 20 hr using a VirTis Sentry 2.0 (SP Scientific) Freeze Dryer with a condenser temperature of -90 °C and a pressure of 50 mTorr.
  • the lyophilized tablets were white, smooth, and elegant and had sufficient strength for manual handling.
  • the blister pack was then transferred to a vacuum oven connected to the freeze drier and dried at 60 °C for 1 week at a pressure of 86 mTorr.
  • One tablet was removed and tested for appearance, in vitro dissolution, HPLC purity and HPLC assay (T 1 week at 60 °C).
  • the remaining tablets were kept in the blister pack in a sealed plastic bag containing a 10g silica gel packet designed to protect an area of 91.5 cubic inch from moisture.
  • the bags are stored both at ambient and 60 °C for long term stability testing. Dipivefrin HC1 ODT 2.5mg
  • the blister pack was then transferred to a vacuum oven connected to the freeze drier and dried at 60 °C for 1 week at a pressure of 86 mTorr.
  • One tablet was removed and tested for appearance, in vitro dissolution, HPLC purity and HPLC assay (T 1 week at 60 °C).
  • the remaining tablets were kept in the blister pack in a sealed plastic bag containing a 10g silica gel packet designed to protect an area of 91.5 cubic inch from moisture.
  • the bags are stored both at ambient and 60 °C for stability testing.
  • dipivefrin HCI formulated as orally disintegrating tablets does not undergo significant hydrolysis in the oral cavity, in the short period of time which is typical for the administration of orally disintegrating tablets.
  • dipivefrin HC1 lyo solution having a composition listed in Table 6.1 below was lyophilized in a blister pack (0.560 ml/pocket) to obtain dipivefrin HCI ODT 25 mg strength as described in Example 3.
  • the tablets were elegant with good strength for manual handling and in vitro dissolution time of 26 seconds in simulated saliva at 37 °C.
  • dipivefrin HC1 lyo solution having a composition listed in Table 7.1 below was lyophilized in a blister pack (0.594 mi/pocket) to obtain dipivefrin HC1 ODT 63.5 mg as described in Example 1.
  • EXAMPLE 8 PREPARATION OF DIPIVEFRIN HCL ODT 7.0 MG FOR PHARMACOKINETICS STUDY
  • dipivefrin HC1 lyo solution having a composition listed in Table 8.1 below was lyophilized in a blister pack (0.535 ml/pocket) to obtain dipivefrin HC1 ODT 5.0 mg as described in Example 1 .
  • In vitro dissolution time in simulated saliva at 37
  • Dogs were housed one per cage and identified by ear tags and cage labels. The animals were healthy at the start of the study. Primary enclosures were as specified in the USDA Animal Welfare Act (9 CFR, Parts 1 , 2, and 3) and as described in the Guide for Care and Use of Laboratory Animals (ILAR publication, 2011, National Academy Press). Animals were fasted for a minimum of 12 hours prior to dosing and returned 4 hours post dose; Water was supplied ad libitum to the animals.
  • T max maximum plasma concentration (mean +SEM of individual dog Cmax values); Tmax: time at which maximum plasma epinephrine concentration was achieved (mean +SEM of individual dog Tmax values); AUCO-last: area under the plasma concentration versus time curve (mean +SEM of individual dog AUG values).
  • T max is the time at which the highest peak epinephrine concentration occurred in each individual dog. T max is limited by experimental design because it is a discrete variable based on defined times of blood sampling.
  • dipivefrin HC1 orally disintegrating tablet After administration of dipivefrin HC1 orally disintegrating tablet to beagle dogs, plasma epinephrine concentration rises rapidly.
  • the dipivefrin HC1 orally disintegrating 5 mg tablet dose provided 2 times of C max and AUC last compared to the epinephrine standard IM 0.3 mg injection with comparable T max .
  • Dipivefrin HC1 63.6 mg produced significantly higher levels of epinephrine when compared to either the 5mg dipivefrin HC1 orally disintegrating tablet (p ⁇ 0.05 for C max and p ⁇ 0.01 for AUC) or the standard epinephrine IM 0.3 mg (p ⁇ 0.01 for both C max and AUC).
  • Dogs were housed one per cage and identified by ear tags and cage labels. The animals were healthy at the start of the study. Primary enclosures were as specified in the USDA Animal Welfare Act (9 CFR, Parts 1, 2, and 3) and as described in the Guide for Care and U se of Laboratory Animal s (1LAR publication, 2011 , National Academy Press). Animals were fasted for a minimum of 12 hours prior to dosing and returned 4 hours post dose; Water was supplied ad libitum to the animals.
  • Tmax time at which maximum plasma epinephrine concentration was achieved (mean + SD of individual dog Tmax values); AUCO-last: area under the plasma concentration versus time curve (mean + SD of individual dog AUG values).
  • T max is the time at which the highest peak epinephrine concentration occurred in each individual dog. T max is limited by experimental design because it is a discrete variable based on defined times of blood sampling.
  • the purpose of this example is to illustrate the flexibility of the subject invention with regards to tablet size at the same strength.
  • smaller tablets can be conveniently made by simply increasing the amount of API while keeping the amount of inactive ingredients the same in the solution mix prior to lyophilization; higher API content requires smaller dose weight per blister pocket producing smaller tablets after freeze drying.
  • the amount of each inactive ingredient can also be easily adjusted (Table 11.1).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Zoology (AREA)
  • Pulmonology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un comprimé de Promédicament d'épinéphrine à désintégration orale (ODT) qui comprend un promédicament d'épinéphrine, un sel pharmaceutiquement acceptable de celui-ci, un liant, un agent de formation de matrice et un agent de masquage de goût. L'ODT de l'invention fournit rapidement de l'épinéphrine à un patient lorsqu'il est administré. L'invention concerne également un procédé de traitement d'un patient qui a un état sensible à l'épinéphrine, tel qu'un événement cardiaque, l'asthme, le croup, le Cancer, une infection microbienne, la maladie d'Addison, ou une réaction allergique, en particulier l'anaphylaxie par l'administration d'un comprimé de promédicament d'épinéphrine à désintégration orale au patient.
PCT/US2022/048024 2021-10-27 2022-10-27 Comprimé à désintégration orale pour formulations de promédicament d'épinéphrine Ceased WO2023076477A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202163272520P 2021-10-27 2021-10-27
US63/272,520 2021-10-27

Publications (2)

Publication Number Publication Date
WO2023076477A2 true WO2023076477A2 (fr) 2023-05-04
WO2023076477A3 WO2023076477A3 (fr) 2023-07-13

Family

ID=84364008

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2022/048024 Ceased WO2023076477A2 (fr) 2021-10-27 2022-10-27 Comprimé à désintégration orale pour formulations de promédicament d'épinéphrine

Country Status (1)

Country Link
WO (1) WO2023076477A2 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925682A (en) 1995-11-20 1999-07-20 Immunotech Inc. Epinephrine as inhibitor of cancerous tumors
US10039710B2 (en) 2015-09-18 2018-08-07 Insys Development Company, Inc. Epinephrine spray formulations
US20190076378A1 (en) 2017-09-08 2019-03-14 Insignis Therapeutics, Inc. Methods of using dipivefrin
US20200276114A1 (en) 2019-03-01 2020-09-03 Insignis Therapeutics, Inc. Dipivefrin orally disintegrating tablet formulations

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160045457A1 (en) * 2005-09-09 2016-02-18 Ousama Rachid Epinephrine fine particles and methods for use thereof for treatment of conditions responsive to epinephrine
CA3116730A1 (fr) * 2018-10-19 2020-04-23 Nova Southeastern University Compositions d'epinephrine sublinguales comprenant des excipients modifiant le ph et des amplificateurs de la penetration et leurs methodes d'utilisation
AU2020373100A1 (en) * 2019-11-01 2022-05-19 Aquestive Therapeutics, Inc. Prodrug compositions and methods of treatment

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5925682A (en) 1995-11-20 1999-07-20 Immunotech Inc. Epinephrine as inhibitor of cancerous tumors
US10039710B2 (en) 2015-09-18 2018-08-07 Insys Development Company, Inc. Epinephrine spray formulations
US20190076378A1 (en) 2017-09-08 2019-03-14 Insignis Therapeutics, Inc. Methods of using dipivefrin
US20200276114A1 (en) 2019-03-01 2020-09-03 Insignis Therapeutics, Inc. Dipivefrin orally disintegrating tablet formulations

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Guide for Care and Use of Laboratory Animals", 2011, ACADEMY PRESS
ELLMAN, G. L. ET AL., BIOCHEMICAL PHARMACOLOGY, vol. 7, 1961, pages 88 - 95

Also Published As

Publication number Publication date
WO2023076477A3 (fr) 2023-07-13

Similar Documents

Publication Publication Date Title
US20240066024A1 (en) Transmucosal delivery device with enhanced uptake
US11213484B2 (en) Dipivefrin orally disintegrating tablet formulations
NO344546B1 (no) Legemiddelformuleringer med forbedrede farmakokinetiske egenskaper inneholdende vardenafil
WO2013058496A1 (fr) Composition pharmaceutique au goût masqué pour une administration orale et son procédé de préparation
EP3641759B1 (fr) Formulation de mélatonine à dissolution orale avec agent acidifiant qui rend la mélatonine soluble dans la salive
JP2010138125A (ja) 速溶性ニコチン含有フィルム製剤
EP3524247A1 (fr) Formulations à désintégration rapide et procédés d'utilisation
CN101460144A (zh) AchE-NMDA组合物干胶片
ES2671926T3 (es) Comprimido recubierto en seco que contiene tegafur, gimeracilo y oteracilo potásico
US20230218532A1 (en) LYOPHILIZED ORALLY DISINTEGRATING TABLET FORMULATIONS OF d-LYSERGIC ACID DIETHYLAMIDE FOR THERAPEUTIC APPLICATIONS
EP3915547A1 (fr) Formes posologiques transmucosales du remdésivir
WO2023076477A2 (fr) Comprimé à désintégration orale pour formulations de promédicament d'épinéphrine
US11648240B2 (en) Pharmaceutical composition comprising famotidine, lidocaine and melatonin
KR20210154964A (ko) 글리코피롤레이트를 포함하는 구강 붕해 정제 및 생체이용성을 증가시키기 위한 방법
CN114788817A (zh) 苯海拉明药物组合物
CN100387226C (zh) 一种千金藤素口腔崩解片及其制备方法
EP3727352B1 (fr) Formulation de feuille à usage oral
JPH10338634A (ja) 医薬組成物
WO2022153334A1 (fr) Formes galéniques transmucosales du foscarnet
KR20130025851A (ko) 메게스트롤 속붕해정 및 이의 제조 방법
WO2022157564A1 (fr) Composition pharmaceutique comprenant de la famotidine, de la lidocaïne et de la mélatonine
US20220233504A1 (en) Pharmaceutical composition comprising lidocaine and melatonin

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22813805

Country of ref document: EP

Kind code of ref document: A2