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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1611—Inorganic compounds
• • 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
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0043—Nose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • 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
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • 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

Definitions

• Intranasal delivery has a number of compelling advantages over other routes of administration, namely its non-invasiveness, rapid attainment of therapeutically relevant concentrations to the bloodstream, no first-pass metabolism, and ease of administration.
• Viable nasal delivery technologies are expected to enable the development of innovative pharmaceutical formulations and medicaments of novel as well as approved active pharmaceuticals ingredients by delivery via novel routes of administration.
• Anaphylaxis is a systemic and life-threatening allergic reaction characterized by anaphylactic shock associated with a critical decrease in blood pressure and deterioration in consciousness. The most frequent triggers of severe anaphylactic reactions are drugs, insect venoms, and foods [(1), (2)].
• Epinephrine is currently a universally recommended as the initial drug of choice for the treatment of anaphylaxis [(3), (4), (5)] providing a unique effect on body systems potentially involved in anaphylaxis. Epinephrine
• Epinephrine acts on both a- and b-adrenergic receptors. Through its action on a- adrenergic receptors, epinephrine decrease the vasodilation and increased vascular permeability that occurs during anaphylaxis, which can lead to loss of intravascular fluid volume and hypotension. Through its action on b-adrenergic receptors, epinephrine causes bronchial smooth muscle relaxation and helps alleviate bronchospasm, wheezing and dyspnea that may occur during anaphylaxis.
• Epinephrine is also known to alleviate pmritus, urticaria, and angioedema and may relieve gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxant effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder.
• epinephrine functionally antagonizes all of the important pathomechanisms of anaphylaxis by vasoconstriction, reduction of vascular permeability, bronchodilatation, edema reduction, and positive inotropy in the heart (6).
• Epinephrine is currently available for use in only an injectable dosage form, in ampules or in auto-injectors (7).
• Each auto-injector contains a single dose of epinephrine and the recommended dose is 0.3 mg/0.3 mL or 0.5 mg/ml epinephrine injection for single use. Repeat injections may be needed with severe persistent anaphylaxis.
• epinephrine When given subcutaneously or intramuscularly, epinephrine has a rapid onset and short duration of action.
• Dry powders are used in intranasal drug delivery due to the many advantages of using this dosage form including the improved stability, administration of larger doses and lack of microbial growth (no need for preservatives).
• the administration of intranasal powders may improve patient compliance, especially where the smell and taste of the delivered solution composition comprising excipients is unpleasant.
• the administration of powders can result in a prolonged contact with the nasal mucosa.
• Powder form is suitable for delivery of both small molecules and biologicals, especially peptides, hormones and antibodies.
• WO2019/038756 describes a pharmaceutical composition in a form of dry powder for intranasal administration, the composition comprising solid particles of at least one active agent and solid particles of a carrier/disaggregation agent/deagglomerating agent/diluent, the pharmaceutical composition being substantially free of excipients other than the solid diluent, the pharmaceutical composition having at least 90% of the particles of the active agent with a mean particle size of 10-30 microns and less than 10% of the particles of the active agent with a mean particle size equal to or below 5 microns, and having the particles of said disaggregation agent/diluent with a mean particle size of 50-200 microns.
• compositions comprising as active agent an anti-anaphylactic adrenergic receptor agonist in the form of dry powder for intranasal administration, said composition comprising a first type of solid particles comprising at least one active agent in combination with at least one functional additive, and a second type of solid particles comprising a pharmaceutically acceptable carrier/diluent/disaggregating/ deagglomerating agent, wherein at least about 90% of said first type particles are of a mean particle size of about 10-30 microns and less than about 10% of said first type particles are of a mean particle size equal to or below about 10 microns and said second type particles are of a mean particle size greater than that of the first type particles.
• the second type particles are of a mean particle size of about 50-200 microns.
• the pharmaceutical composition of can be substantially free of excipients other than said at least one functional additive comprised in said first type particles and said carrier comprised in said second type particles.
• the active agent can be any one of epinephrine, norepinephrine, dopamine or antihistamine or pharmaceutically acceptable salts or derivatives thereof, but is not limited thereto.
• the active agent is epinephrine or a pharmaceutically acceptable salt thereof, which can be any one of pharmaceutically acceptable bitartrate, hydrochloride or borate salt thereof, as well as hydrates and anhydrates thereof.
• the functional additive comprised in said first type particles can be any one of a buffering agent, glidant or lubricant.
• the buffering agent comprised in said first type particles can be sodium di-hydrogen phosphate, but is not limited thereto.
• the ratio between the at least one pharmaceutically active agent and the at least one functional additive in the first type particles is predetermined, according to chemical and other properties of the specific constituents.
• the carrier/diluent/ disaggregating/deagglomerating agent can be any one of lactose monohydrate, lactose, a lactose functional analogue, or any mixture of at least two thereof.
• the carrier/diluent/disaggregating/ deagglomerating agent can be any one of dextrose, sorbitol, mannitol, maltitol and xylitol, a cellulose or cellulose derivative, or starch or starch derivative.
• the weight ratio between said first type particles and said second type particle can be between 1:9 to 9:1, for example 1:9, 2:8, 3:7, 4:6, 5:5, 6:6, 7:3, 8:2 or 9:1, and any mid-ratios therebetween.
• the present disclosure provides an epinephrine pharmaceutical composition in the form of dry powder for intranasal administration, comprising as active agent epinephrine or a pharmaceutically acceptable salt thereof, said composition comprising a first type of solid particles comprising epinephrine or a pharmaceutically acceptable salt thereof in combination with a physiologically acceptable buffering agent, and a second type of solid particles comprising lactose monohydrate as carrier, wherein at least about 90% of said first type particles are of a mean particle size of about 10-30 microns and less than about 10% of said first type particles are of a mean particle size equal to or below about 10 microns and said second type particles are of a mean particle size greater than that of the first type particles, providing a metered therapeutically effective nominal dose of said epinephrine or pharmaceutically acceptable salt thereof.
• epinephrine pharmaceutical composition the molar ratio between the epinephrine bitartrate to sodium dihydrogen phosphate can be 0.9:1.
• the therapeutically effective amount of epinephrine in this epinephrine pharmaceutical composition is essentially equivalent to about 0.3 mg or 0.5 mg epinephrine administered i.m. (intra-muscularly, also referred to as IM).
• IM intra-muscularly, also referred to as IM.
• a disposable dose unit form for intranasal administration to a subject of a pharmaceutical composition according to any one of claims 1 to 12, wherein said dose unit is loaded with a predetermined single dose of the composition and provides the subject with a metered dose the pharmaceutically active adrenergic receptor agonist.
• the disposable dose unit form can be loaded with a predetermined single dose of the composition and provides the subject with a metered dose epinephrine.
• the dose unit is loaded with a predetermined single dose of the composition and provides the subject with a metered dose epinephrine being equivalent to about 0.3 mg or 0.5 mg epinephrine administered intramuscularly a.
• a kit for intranasal administration of epinephrine comprising at least one dose unit for intranasal administration comprising a pharmaceutical composition as disclosed herein and instructions for use.
• a method of treating anaphylactic shock in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a composition as disclosed herein or at least one dose unit as disclosed herein.
• the present disclosure provides a method of treating anaphylactic shock in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of an epinephrine composition as defined herein or at least one epinephrine dose unit as disclosed herein.
• Figure 3 SEM images of lactose monohydrate (large irregular particles) and epinephrine bitartrate/ sodium di-hydrogen phosphate particles (small spherical particles) of the dry powder intranasal formulation obtained in Example 2.
• Figure 4 shows the particle size distribution of the dry powder intranasal formulation obtained in Example 2.
• a formulation according to the present disclosure comprises two types of solid particles, a first type of essentially spherical particles comprising the pharmaceutically active agent in combination with a functional additive, and a second type of irregularly shaped particles comprising an essentially inert carrier/diluent/disaggregating/deagglomerating agent.
• the present disclosure relates to a pharmaceutical composition in the form of dry powder for intranasal administration, comprising a first type of solid particles comprising at least one pharmaceutically active agent in combination at least one functional additive, and a second type of solid particles comprising a pharmaceutically acceptable carrier/diluent/disaggregating/deagglomerating agent, in which at least about 90% of said first type particles are of a mean particle size of about 10-30 microns and less than about 10% of said first type particles are of a mean particle size equal to or below about 10 microns and said second type particles are of a mean particle size greater than that of the first type particles, such as a mean particle size of about 50-200 microns.
• Active agents for intranasal administration in dry powder form are usually produced by milling techniques. As a result, their particle size distribution is broad and the particles are usually non-spherical and non-uniform. The presence of active agent particles of less than 5 microns (pm) should however be avoided. Such very small particles may reach the lung mucosa by nasal spraying or by inhaling, which completely unacceptable for intranasal administration from the safety point of view.
• the pharmaceutically active agent can be an adrenergic receptor agonist, for example, but not limited to any one of epinephrine, norepinephrine, dopamine or antihistamine or pharmaceutically acceptable salts or derivatives thereof.
• a specific pharmaceutically active agent is, but not limited to, epinephrine or a pharmaceutically acceptable salt thereof, such as, but not limited to any one of bitartrate, hydrochloride or borate salts of epinephrine.
• the said functional additive can be any one of a buffering agent, glidant or lubricant and others.
• a buffering agent can be but is not limited to sodium di-hydrogen phosphate, potassium di-hydrogen phosphate, Tris-buffer, or any other physiologically and pharmaceutically acceptable buffer which can elevate pH.
• the functional additive is compatible with the active agent.
• the inert carrier/diluent/disaggregating/deagglomerating agent can be any one of lactose monohydrate, lactose, a lactose functional analogue, or any mixture of at least two thereof.
• a lactose functional analogue can be but is not limited to dextrose, sorbitol, mannitol, maltitol and xylitol, or a cellulose or cellulose derivative or starch or starch derivative.
• lactose powder is used as a carrier in nasal drugs and has no effect on drug absorption or the nasal epithelium in short and long term follow up [(10), (11), (12)].
• the present pharmaceutical composition is substantially free of excipients other than the at least one functional additive comprised in said first type particles and the inert carrier/diluent/disaggregating/deagglomerating agent comprised in said second type particles.
• the pharmaceutical composition according to the present disclosure can be contained in disposable dose units for intranasal administration, providing predetermined metered dose of epinephrine.
• disposable dose units for intranasal administration providing predetermined metered dose of epinephrine.
• An example of such dose unit is illustrated in Figure 1 , which shows Unitdose Powder Device (UDS), manufactured by Aptar Pharma.
• UDS Unitdose Powder Device
• Devices of this type for powder spraying are user friendly and designed to enable systemic delivery of small and accurately metered doses of drug formulations by patients or caregivers who are not healthcare professionals or medically trained.
• the present disclosure relates to a dose unit form, specifically a disposable dose unit form, for intranasal administration to a subject of a pharmaceutical composition according to all aspects and embodiments of the present disclosure, wherein the dose unit is loaded with a predetermined dose of the composition and provides the subject with a metered dose the pharmaceutically active ingredient comprised in the composition.
• the dose unit device loaded with epinephrine -buffer combination exhibits good product stability under normal and accelerated storage conditions.
• Bi-dose and multi-dose intranasal administration devices can be used.
• Such powder delivery devices generally have a disposable drug containing member and a reusable device body that can be packaged along with a number of drug-containing members.
• the disposable drug containing member contains the powdered drug within standard size inhalation capsules. Each capsule content equals to one dose.
• syringe-driven and pump-driven spraying atomizers used for delivery of a variety of nasal medications can be used for the delivery of the present pharmaceutical composition.
• the pharmaceutically active ingredient is epinephrine.
• epinephrine microspheres powder for intranasal administration is also referred to as FMXIN002.
• this formulation comprises solid essentially spherical particles of epinephrine bitartrate as the pharmaceutically active ingredient and sodium di-hydrogen phosphate as the pH-adjusting functional additive (first type of particles) and solid irregularly shaped particles of lactose monohydrate as a carrier/diluent/disaggregating/deagglomerating agent (second type of particles).
• the first type smaller particles contained not only the epinephrine, but also the sodium di-hydrogen phosphate, which was unexpected and is of major advantage reducing any effects of local irritation by epinephrine, as herein discussed.
• FMXIN002 can be administered intranasally by intranasal delivery devices, for example a disposable intranasal device as described above.
• FMXIN002 epinephrine microspheres powder is composed of two populations of particles: most of the epinephrine bitartrate and buffer (pH adjusting agent) particles (drug particles), namely at least about 80%, 85%, 90% of the particles or more, have an optimal mean diameter of 10-30 pm, and less than about 10%, 9%, 8%, 7%, 6% or 5% of drug particles have a mean diameter of less than about 5 pm, preventing lung inhalation.
• the lactose monohydrate particles are larger, and ranges between about 50 to about 200 mih.
• the molar ratio between the epinephrine bitartrate to sodium dihydrogen phosphate is 0.9:1 (weight ratio of 1.67/1).
• the first type particles comprise both the active drug and the functional additive, for example epinephrine or salt thereof and a buffering agent such as sodium di-hydrogen phosphate.
• buffer materials can be added to epinephrine microsphere to provide pharmaceutical acceptable pH.
• Some epinephrine salts such as epinephrine bitartrate have acidic pH below 3.5.
• the administration of microspheres comprising only these salts can cause irritation and discomfort to nasal mucosa. In such cases adjusting the pH in the nasal cavity is recommended, for example by the addition of pH elevating buffers, as described and exemplified herein.
• the pH-adjusting agent for example small amounts of physiological phosphate buffer (sodium di-hydrogen phosphate), provides for maintaining an adequate pH of the epinephrine solution after its dissolution in the nasal mucus, and prevent local irritation or any other discomfort to the patient.
• physiological phosphate buffer sodium di-hydrogen phosphate
• the disclosed pharmaceutical composition can be prepared by a modified spray drying method, as described for example in WO2019/038756.
• An apparatus for the preparation of the disclosed pharmaceutical composition in the dry powder form essentially comprises the following components: a) A spray -drying chamber capable of spray -drying a clear and homogeneous solution of the active agent and the functional additive to obtain dry powder particles of said first type, specifically wherein said solution is free of other excipients; b) A cyclone separator capable of receiving the dry powder particles and the moist air stream from the spray-drying chamber, separating said particles from the moist air through vortex separation, exhausting the air and transferring the separated particles to a receiving chamber through a bag filter; and c) A receiving chamber pre-filled with a carrier/diluent/disaggregating/deagglomerating agent and adapted for receiving the separated dry powder particles from the cyclone separator, stirring and homogenising said particles with the carrier/diluent/disaggregating/deagglomerating agent to obtain
• the spray-drying chamber is equipped with nozzles, used to produce droplets of the active agent solution, to control the droplet and powder particle size and to maximise heat transfer and the rate of solvent vaporisation.
• the droplet size may range from 20 to 180 pm, depending on a particular nozzle used.
• the sprayed solution of the active agent is free of any carrier/diluent/disaggregating/deagglomerating agent.
• the nozzles are designed to spray the solution of the active agent into a hot air flow, thereby achieving a thorough mixing and uniform distribution of the hot air flow and sprayed solution in the spray -drying chamber to allow for substantially complete evaporation of liquids and drying of solid particles of the active agent from the mixture throughout said chamber.
• the stirring and homogenisation is achieved by using a magnetic stirrer and a magnetic bar of appropriate size, in addition to the rotation of the receiving chamber.
• the stirring and homogenisation may be achieved by using a mechanical stirrer of appropriate size and form, or moving, rotation and vibration of the whole receiving chamber.
• a conventional spray-drying apparatus contains the empty receiving chamber collecting the dry powder particles of an active agent. This receiver is emptied from time to time in order to ensure the continuous process.
• the present application discloses the receiving chamber pre-filled with a continuously stirred carrier/diluent/disaggregating/deagglomerating agent for preventing aggregation of the dry powder particles and preserving their original size and shape.
• A Preparing a clear and homogeneous solution of at least epinephrine bitartrate or other pharmaceutically acceptable salt thereof or another active epinephrine analogue and a pH- adjusting agent (buffering agent, for example sodium di-hydrogen phosphate) in an organic solvent (for example acetone) or solvent mixture, in a solvent-water or water-miscible solvent mixture, or in water.
• a pH- adjusting agent buffering agent, for example sodium di-hydrogen phosphate
• organic solvent for example acetone
• solvent-water or water-miscible solvent mixture or in water.
• step (C) Streaming the solution prepared in step (A) together with hot air or gas to the spray- draying chamber, spray-drying the solution in the spray-drying chamber to obtain dry powder particles of said at least one active agent in a moist air or gas, and transferring the obtained dry powder particles and the moist air or gas stream to the cyclone separator;
• step (D) Stirring and homogenising said particles obtained in step (D) with the carrier/diluent/disaggregating/deagglomerating agent in the receiving chamber to obtain the presently disclosed pharmaceutical composition in dry powder form; wherein said carrier/diluent/disaggregating/deagglomerating agent is capable of colliding and continuously in-situ blending with the particles during the stirring in the receiving chamber, thereby preventing their aggregation and preserving their original size and shape; and
• the present disclosure provides method for treating and/or alleviating a medical condition responsive to an adrenergic receptor agonist, as defined herein, for example by not limited to epinephrine and pharmaceutically acceptable salt thereof.
• the method of treatment according to the present invention comprises intranasal administration to a subject in need a therapeutically effective amount of an adrenergic receptor agonist pharmaceutical composition as disclosed herein, optionally where loaded in a dose form unit as disclosed herein.
• the adrenergic receptor agonist is epinephrine, more specifically epinephrine bitartrate, at a therapeutically effective amount of IN dose of from about 1.6 mg to about 3.2 mg.
• kits for the treatment of anaphylaxis comprises at least one dose unit, preferably two dose units of epinephrine as disclosed herein and instructions for use.
• drug refers to a pharmaceutically active substance that provides a therapeutic/physiological effect to a patient, and can also refer to a mixture of at least two thereof.
• formulation comprising an adrenergic receptor agonist, such as but not limited to epinephrine or a pharmaceutically active salt thereof for use in therapy/medicine.
• adrenergic receptor agonist such as but not limited to epinephrine or a pharmaceutically active salt thereof for use in therapy/medicine.
• inert refers to components of the pharmaceutical composition, or used in the preparation thereof, that do not instantly react with the active ingredient or adversely affect its properties, or cause any biological effect upon administration to a subject when administered at reasonable amounts to a subject.
• inert refers to components of the pharmaceutical composition, or used in the preparation thereof, that do not instantly react with the active ingredient or adversely affect its properties, or cause any biological effect upon administration to a subject when administered at reasonable amounts to a subject.
• the general examples of these components are described in "The Handbook of Pharmaceutical Excipients", 4 th Edition, by Rowe, Sheskey and Weller, Pharmaceutical press, 2003. Additional exemplary list is Inactive Ingredients Guide of the Food and Drug Administration, USA.
• Carrier used herein interchangeably, and refer to an inert ingredient added to the pharmaceutical composition.
• the drug is an adrenergic receptor agonist as herein described
• the " patient “ or " subject” is a human, suffering from a medical condition responsive to such agonist. Such conditions may be cardiac arrest and other heart problems, patients prone to anaphylactic shock including all Type 1 allergy patients, asthmatic patients and others.
• "An adrenergic receptor agonist” as used herein is to be taken to mean an agent that stimulates a response from adrenergic receptors.
• An examples of such agonists are epinephrine (adrenaline) and its pharmaceutically acceptable salts.
• Epinephrine as used herein also refers to pharmaceutically active salts thereof.
• pH adjusting agent adjusting agent
• buffer buffer
• compositions or substances "substantially free of excipients" is to be taken to mean that it does contain more than 5% of such excipient/s.
• the terms “treat”, or forms thereof, and the term “ alleviate ” and the like are to be taken to mean at least partially ameliorate or cure or totally eliminate the patient's condition as defined herein.
• intranasal administration as used herein is to be taken to mean nasal application in one or both nostrils of the subject.
• “About” as used herein generally refers to approximate values. When referred to a dose of drug, or size of particles and the like, “about” should be understood as including the range of a value ⁇ 15 %. When referred to other values, the term should be understood as including the range of a value ⁇ 15%, for example ⁇ 15%, ⁇ 12%, ⁇ 10%, ⁇ 8%, ⁇ 5%, ⁇ 2% or ⁇ 1%. Other similar terms, such as “substantially”, “generally”, “up to” and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skilled in the art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given experiment, technique or an instrument used to measure a value.
• Epinephrine bitartrate TransoPharma
• Sodium Phosphate Dibasic Dihydrate Merck
• lactose monohydrate Meggle Pharma
• acetone BioLab
• the spray-drying process was carried out using the Mini Spray Dryer B-290 of Btichi Labortechnik AG.
• a magnetic stirrer (Fried Electric) was placed under the receiver (receiving chamber), a magnetic bar of appropriate size was inserted into the receiver, and then the carrier/diluent/disaggregating/deagglomerating agent was added.
• the liquid feed containing at least one active agent was prepared by dissolving at least one active compound in the selected solvent or mixture of solvents. Quantification was performed using HPLC and a Dionex HPLC instrument.
• a FEI Quanta-200 Scanning Electron Microscope (SEM) equipped with an Everhart-Thornley Detector was used to obtain the images of the spray- dried powder.
• Detector PDA UV, 210 nm; 200 - 400 nm for identification.
• Example 1 Modification of the commercial Biichi Labortechnik AG spray-dryer [0073]
• Fig. 2 schematically shows a modified spray dryer used in the present examples.
• a Mini Spray -Dryer B-290 of Biichi Labortechnik AG was modified by:
• the modified spray dryer is suitable for the particles engineering and prevention of agglomeration according to the present disclosure.
• Example 2 Epinephrine bitartrate/sodium di-hydrogen phosphate composition with lactose monohydrate
• Epinephrine bitartrate (2.5 g) and sodium di-hydrogen phosphate (1.5 g) were dissolved for 20 min in 15 g of acetone and 20 g water mixture under nitrogen and stirring at 300 rpm.
• An appropriate size magnetic bar was placed in the receiver and lactose monohydrate (3.0 g) was added thereto, with the stirring rate set at 150 rpm.
• Example 3 Epinephrine bitartrate Drug-Device Combination Product Preparation
• Aptar Unit-Dose Powder disposable devices assembled according to the manufacturer's guidelines, were filled with the epinephrine bitartrate / sodium di-hydrogen phosphate composition prepared in Example 2. Each device contained 35 mg of powder including 1.6 mg of epinephrine bi tartrate.
• Example 4 Stability Data of Epinephrine Drug-Device Combination Product under accelerated aging conditions
• the powdered epinephrine formulation of the present invention showed good stability after 3 months at 40°C and 75% relative humidity (RH). It contained 0.8% of the total impurities and similar assay of API. All results meet drug device combination products stability specifications.
• intranasal administration of epinephrine requires a higher dose.
• the clinical use of IN epinephrine in humans ranges from 1 mg up to 12 mg for different indications and in different formulations, with no serious adverse events (Error! Bookmark not defined.) ⁇
• Prior studies using IN (intranasal) epinephrine showed 5 or 6 mg IN dose as equivalent to IM injection of 0.3 mg.
• a starting IN dose of 1.6 mg is estimated to be equivalent to an IM dose of 0.1 mg.
• a starting dose of IN epinephrine 1.6 mg represents a low dose that may be increased to 3.2 mg based on the safety and PK data.
• IN dose of 3.2 mg is estimated to be equivalent to IM dose of 0.2 mg, which is still below the range of approved IM dosage for anaphylaxis of 0.3-0.5 mg.
• PK study is conducted in a stepwise manner with a starting lower dose, which may be increased if there are no serious adverse events (SAEs) and low exposure while constant and careful monitoring are maintained throughout the study by experienced clinical team including an allergy expert.
• SAEs serious adverse events
• FMXIN002 is investigated in a single administration.
• the safety and tolerability of FMXIN002 can be based on the evidence from published literature and animal studies.
• Epinephrine for nasal administration (Adrenaline) is already approved for multiple administrations and available at higher doses as OTC product as well as for use in surgery.
• the safety of IN epinephrine in adults with seasonal allergies, has also been demonstrated in other studies where the administered dose of epinephrine was higher than the suggested dose in the current investigation of FMXIN002.
• Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products — Chemistry, Manufacturing, and Controls Documentation; Guidance for Industry; CDER, July 2002

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