TREATMENT WITH POWDERED INTRANASAL EPINEPHRINE

Abstract

Disclosed is a pharmaceutical composition in dry powder form for intranasal administration, comprising an anti-anaphylactic adrenergic receptor agonist in the form of dry powder for intranasal administration, the composition comprising solid particles of the active agent in combination with at least one functional additive, and solid particles of an inert carrier.

Claims

1. A pharmaceutical composition 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, 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.

2. The pharmaceutical composition of claim 1, wherein said second type particles are of a mean particle size of about 50-200 microns.

3. The pharmaceutical composition of claim 1 or claim 2, being 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.

4. The pharmaceutical composition of any one of claims 1 to 3, wherein said active agent is any one of epinephrine, norepinephrine, dopamine or antihistamine or pharmaceutically acceptable salts or derivatives thereof.

5. The pharmaceutical composition of claim 4, wherein said active agent is epinephrine or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 4 or claim 5, wherein said active agent is epinephrine or pharmaceutically acceptable bitartrate, hydrochloride or borate salt thereof.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein said functional additive is any one of a buffering agent, glidant or lubricant.

8. The pharmaceutical composition of claim 7, wherein said buffering agent is any one of sodium di-hydrogen phosphate.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the ratio between said at least one pharmaceutically active agent and said at least one functional additive in said first type particles is predetermined.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein said carrier is any one of lactose monohydrate, lactose, a lactose functional analogue, or any mixture of at least two thereof.

11. The pharmaceutical composition of any one of claims 1 to 9, wherein said carrier is any one of dextrose, sorbitol, mannitol, maltitol and xylitol, a cellulose or cellulose derivative, or starch or starch derivative.

12. The pharmaceutical composition of any one of claims 1 to 10, wherein the weight ratio between said first type particles and said second type particle is between 1:9 to 9:1.

13. 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.

14. The epinephrine pharmaceutical composition of claim 14, wherein the molar ratio between the epinephrine bitartrate to sodium dihydrogen phosphate is 0.9:1.

15. The epinephrine pharmaceutical composition of claim 13 or 14, wherein said therapeutically effective amount of epinephrine is equivalent to about 0.3 mg or 0.5 mg epinephrine administered intramuscularly (i.m.).

16. 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.

17. A disposable dose unit form for intranasal administration to a subject of a pharmaceutical composition according to claim 13 or 14, wherein said dose unit is loaded with a predetermined single dose of the composition and provides the subject with a metered dose epinephrine.

18. A disposable dose unit form for intranasal administration to a subject of a pharmaceutical composition according to claim 15, wherein said 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 (i.m.).

19. A kit for intranasal administration of epinephrine comprising: a. at least one dose unit for intranasal administration comprising a pharmaceutical composition as defined in any one of claims 13 to 15; and b. instructions for use.

20. A method of treating anaphylactic shock in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of a composition as defined in any one of claims 1 to 12 or at least one dose unit as defined in claim 16.

21. 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 in any one of claims 13 to 15 or at least one dose unit as defined in claim 17 or 18.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0028] In order to better understand the subject matter that is disclosed herein and to exemplify how it can be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0029] FIG. 1 exemplary Unit Dose Powder Device and its components for nasal administration

[0030] FIG. 2 schematic representation of the modified spray-dryer apparatus used in the present examples, as described in Example 1

[0031] FIG. 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.

[0032] FIG. 4 shows the particle size distribution of the dry powder intranasal formulation obtained in Example 2.

DESCRIPTION OF EMBODIMENTS

[0033] Disclosed herein are novel formulations the form of dry powder, for intranasal administration of pharmaceutically active agent/s. Generally, 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.

[0034] In a first aspect, 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.

[0035] 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 (μm) 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. Therefore, the size distribution of the presently disclosed compositions, wherein the major part (about 90%) of the particles comprising the pharmaceutically active agent have a mean size of 10-30 microns, and only less than 10% of the particles are of a mean diameter of less than 5 microns their use in nasal spraying renders them beneficial for the intranasal administration.

[0036] In all embodiments of all aspects of the present disclosure, 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.

[0037] In all embodiments of all aspects of the present disclosure, 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.

[0038] In all embodiments of all aspects of the present disclosure, 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. For example, 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)].

[0039] In all aspects and embodiments of the present disclosure 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.

[0040] The pharmaceutical composition according to the present disclosure can be contained in disposable dose units for intranasal administration, providing predetermined metered dose of epinephrine. An example of such dose unit is illustrated in FIG. 1, which shows Unitdose Powder Device (UDS), manufactured by Aptar Pharma. 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.

[0041] Thus, in a further aspect 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. As shown in the following Examples, the dose unit device loaded with epinephrine-buffer combination exhibits good product stability under normal and accelerated storage conditions.

[0042] 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.

[0043] In addition, 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.

[0044] In specific embodiments of all aspects of the present disclosure, the pharmaceutically active ingredient is epinephrine.

[0045] One specific formulation of epinephrine microspheres powder for intranasal administration disclosed herein is also referred to as FMXIN002. Generally, 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). Surprisingly, as shown in FIG. 3 and Example 2, 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. In more detail, 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 μm, and less than about 10%, 9%, 8%, 7%, 6% or 5% of drug particles have a mean diameter of less than about 5 μm, preventing lung inhalation. The lactose monohydrate particles are larger, and ranges between about 50 to about 200 μm. An in vitro study has demonstrated that immediately after deposition of the powder in the nasal cavity, epinephrine dissolves in the nasal fluid and is rapidly absorbed through the nasal epithelia due to the spherical and small particle size, and high-water solubility (Error! Bookmark not defined.). In specific embodiments, the molar ratio between the epinephrine bitartrate to sodium dihydrogen phosphate is 0.9:1 (weight ratio of 1.67/1).

[0046] As mentioned, 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. In other embodiments, 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. As mentioned, 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.

[0047] The pH-adjusting agent (buffering 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.

[0048] 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:

[0049] 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;

[0050] 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

[0051] 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 presently disclosed pharmaceutical composition in dry powder form. The 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.

[0052] 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 μm, depending on a particular nozzle used. In the present embodiments, 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.

[0053] At the laboratory scale, the stiffing 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. At industrial scale, the stiffing 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. In contrast, 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.

[0054] Generally, the preparation of presently disclosed pharmaceutical composition by use of the described apparatus comprises the following steps:

[0055] 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.

[0056] B. Filling the receiving chamber with a canier/diluent/disaggregating/deagglomerating agnet and continuously stifling the canier/diluent/disaggregating/deagglomerating agent in the receiving chamber;

[0057] 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;

[0058] D. Separating the particles from the moist air or gas through vortex separation in the cyclone separator, exhausting the air or gas and transferring the separated particles to the receiving chamber through a bag filter;

[0059] E. 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

[0060] F. Optionally, additional mixing of the pharmaceutical composition obtained in (E) with an additional amount of the canier/diluent/disaggregating/deagglomerating agent to achieve the desired active agent-to-carrier ratio in said pharmaceutical composition.

[0061] In a further aspect, 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. In specific embodiments, 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. Treatment begins with administration of a single dose. If the patient is not stabilized within few minutes, additional doses can be repeatedly administered within 5-15 minutes, and patient is transferred to hospital for further observation. Patients prone to anaphylactic shock or caregiver should be routinely equipped with 2 device packages. Intranasal administration can be to one or both nostrils, as instructed.

[0062] Further provided herein is a kit for the treatment of anaphylaxis. The kit comprises at least one dose unit, preferably two dose units of epinephrine as disclosed herein and instructions for use.

[0063] In the following description, various aspects of the present application will be described. For purposes of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the present application. However, it will also be apparent to one skilled in the art that the present application may be practiced without the specific details presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the present application.

[0064] The terminology used herein is for describing particular embodiments only and is not intended to be limiting of the invention. The term “comprising” and “comprises”, used in the claims, should not be interpreted as being restricted to the components and steps listed thereafter; they do not exclude other components or steps. They need to be interpreted as specifying the presence of the stated features, integers, steps and/or components as referred to, but does not preclude the presence and/or addition of one or more other features, integers, steps or components, or groups thereof. Thus, the scope of the expression “a composition comprising A and B” should not be limited to compositions consisting only of components A and B. Also, the scope of the expression “a method comprising the steps X and Z” should not be limited to methods consisting exclusively of those steps.

Definitions

[0065] The terms “drug”, “active substance”, “API” (Active Pharmaceutical Ingredient) or “active principle” or “active ingredient”, “pharmaceutically active agent”, “pharmaceutically active ingredient”, “active substance”, “active molecule”, “active compound” and the like used herein interchangeably, refer 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.

[0066] The terms “formulation”, “pharmaceutical formulation”, “composition” and “pharmaceutical composition” may be used herein interchangeably, and are to be taken to mean a formulation comprising an adrenergic receptor agonist, such as but not limited to epinephrine or a pharmaceutically active salt thereof for use in therapy/medicine.

[0067] The terms “inert” or “inactive” or “inactive ingredient” or “inert ingredient”, as used interchangeably herein refer 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.sup.th Edition, by Rowe, Sheskey and Weller, Pharmaceutical press, 2003. Additional exemplary list is Inactive Ingredients Guide of the Food and Drug Administration, USA.

[0068] “Carrier”, “diluent”, “disaggregating agent” and “deagglomerating agent” are used herein interchangeably, and refer to an inert ingredient added to the pharmaceutical composition.

[0069] A “patient” or “subject” that may be administered with the pharmaceutical composition and/or dose units loaded therewith according to the presently disclosed subject matter. In general, where 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.

[0070] “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.

[0071] “pH adjusting agent”, “buffering agent” and “buffer” as used herein interchangeably are to be taken to mean any chemical agent that affects the pH of its immediate environment.

[0072] The term a composition or substance “substantially free of excipients” is to be taken to mean that it does contain more than 5% of such excipient/s.

[0073] 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.

[0074] The term “intranasal administration” as used herein is to be taken to mean nasal application in one or both nostrils of the subject.

[0075] The term “suitable” as used herein is to be taken to mean having the properties that enable providing the defined result.

[0076] “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.

[0077] As used herein, the term “and/or” includes any combinations of one or more of the associated listed items. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity.

[0078] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealised or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity.

[0079] As used in the specification and claims, the forms “a”, “an” and “the” include singular as well as plural references unless the context clearly dictates.

[0080] Throughout this specification and the Examples and claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0081] The presently disclosed subject matter is further illustrated by the following examples, which are illustrative only and are not to be construed as limiting the scope of the invention. Variations and equivalents of these examples will be apparent to those skilled in the art in light of the present disclosure, the drawings and the claims herein.

[0082] It is appreciated that certain features of the presently disclosed subject matter which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the presently disclosed subject matter, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination.

[0083] Although the presently disclosed subject matter has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0084] All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent and patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as relevant prior art to the presently disclosed subject matter.

DESCRIPTION OF NON-LIMITING EXAMPLES

Materials

[0085] Epinephrine bitartrate (TransoPharma); Sodium Phosphate Dibasic Dihydrate (Merck), lactose monohydrate (Meggle Pharma); acetone (BioLab).

Methods

[0086] The spray-drying process was carried out using the Mini Spray Dryer B-290 of Büchi 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. The accelerating voltage of 20 kV was applied to provide magnification from 250 to 10,000 times. In addition, an X-ray Element Analysis Detector (Link ISIS, Oxford Instruments, England) was used to determine particles morphology and chemical composition and their distribution throughout Dry Powder Inhaler (DPI). Particle size was measured using the Malvern Mastersizer 3000 series based on the Light Diffraction method. Epinephrine assay in the compositions was determined using Dionex HPLC-PDA instrument equipped with Chromeleon software; Column & packing: Thermo ODS, 3 μ100×4.6 mm Cat No: 30103-104630 or equivalent Mobile phase A: Buffer:Acetonitrile (95:5, v/v) Mobile phase B: Buffer:Acetonitrile (55:45, v/v) Flow rate: 1.2 mL/min

Gradient Table for sample:

TABLE-US-00002 Time, min % A % B 0.0 95 5 20 50 50 21 50 50 23 95 5 30 95 5
Gradient Table for standard:

TABLE-US-00003 Time, min % A % B 0.0 95 5 10 72.5 27.5 10.5 95 5 15 95 5

[0087] Injection volume: 20 μL Detector PDA: UV, 210 nm; 200-400 nm for identification. Column temperature: 50° C. Auto sampler temperature: ambient Run time 30 min Diluent: Mobile Phase A RT of epinephrine peak: 5-7 min

Example 1: Modification of the Commercial Büchi Labortechnik AG Spray-Dryer

[0088] FIG. 2 schematically shows a modified spray dryer used in the present examples. A Mini Spray-Dryer B-290 of Büchi Labortechnik AG was modified by:

[0089] 1. Addition of a magnetic bar into the glass receiver and placing a magnetic stirrer under the continuously rotating glass receiver of the spray-dryer.

[0090] 2. Selection of a suitable two-fluids spraying nozzle for spraying the solution containing only the active agent epinephrine (without canier/diluent/disaggregating/deagglomerating agent) into fine droplets suitable for the preparation of 10-30 μm dry powder particles of the active agent. One of the fluids is the clear and homogeneous solution of the active agent, and the second fluid is the drying gas.

[0091] 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

[0092] 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 stiffing at 300 rpm. An appropriate size magnetic bar was placed in the receiver and lactose monohydrate (3.0 g) was added thereto, with the stiffing rate set at 150 rpm. A clear and homogeneous solution of the drug was obtained, and spray-dried using the modified Büchi Mini Spray-Dryer with inlet nitrogen temperature of 130° C. and outlet temperature of 80° C., thereby obtaining a dry powder of epinephrine bitartrate/sodium di-hydrogen phosphate, which was further blended in-situ with lactose monohydrate in the receiver. Stiffing was maintained in the receiver during the entire process. The loading of epinephrine bitartrate/sodium di-hydrogen phosphate in the composition was about 8.7% w/w.

[0093] The SEM images presented in FIG. 3 show that the small spherical particles of epinephrine bitartrate/sodium di-hydrogen phosphate have a narrow size distribution of 5-30 μm, and are dispersed between large irregular particles of lactose ranging between 40 □m to 240 μm.

[0094] The obtained epinephrine bitartrate/sodium di-hydrogen phosphate composition was subjected to particle size analysis using a Malvern Laser Diffraction instrument. As shown in FIG. 4, the following particle size distribution was obtained: D=21.4 μm, D (50) =82.0 μm and D (90)=133 μm. The amount of the obtained particles having the size less than 10 μm was about 3.7% v/v. 5 μm was about 2.8% v/v. The particle size distribution of epinephrine microspheres thus meets powder Bulk Drug Product specification and safety requirements (11, 13)

Example 3: Epinephrine bitartrate Drug-Device Combination Product Preparation

[0095] 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 bitartrate.

Example 4: Stability Data of Epinephrine Drug-Device Combination Product Under Accelerated Aging Conditions

[0096] The epinephrine bitartrate combination products prepared in Example 3 were subjected to accelerated aging conditions at 40° C.±2° C. and 75% RH±5% RH. Three months stability data are presented in Table 2.

TABLE-US-00004 TABLE 2 Stability data Testing interval, Assay Impurities/related Water Item months Appearance (HPLC) substances content pH Specifications Disposable 1.6 ± 0.32 A. ≤0.3% NMT 7% 5-7 plastic device; mg/device B. ≤0.2% white color; (80.0-120.0%) C. ≤0.2% no visible D. ≤0.10% damage E. ≤0.10% Test result initial Disposable 1.69 mg/device A. −0.29 5.3% 6.2 plastic device; (105.6%) B. ≤ND.sup.2 white color; C. ≤ND no visible D. ≤ND damage E. ≤ND Unspecified impurities: BRL.sup.1 Total Impurities: 0.3% Test result 1 No change 1.47 mg/device A. −0.19% 5.2% 6.2 (91.9%) B. ≤ND C. ≤ BRL.sup.1 D. ≤ND E. ≤ND Unspecified impurities: ND Total Impurities: 0.2% Test result 3 No change 1.36 mg/device A. −0.21% NA.sup.2 NA.sup.2 (84.7%) B. ≤ND C. ≤ND D. ≤ND E. ≤ND Unspecified impurities: (RRT 1.4)- 0.05% (RRT 1.6)- 0.07% (RRT 2.9)- 0.09% Total Impurities: 0.42% .sup.1below reporting limit (0.05%) .sup.2Not Detected

[0097] Conclusions: 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.

Example 5: in vivo study of FMXIN002

[0098] In order to mimic PK achieved by intramuscular administration (IM) 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.

[0099] Based on clinical evidence, a starting IN dose of 1.6 mg is estimated to be equivalent to an IM dose of 0.1 mg. Hence 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.

[0100] 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.

[0101] 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. In the study conducted by Chen et al. (9), the most common (≥5% overall) treatment-emergent adverse events (TEAEs) in the epinephrine nasal spray groups were nasal discomfort, tremor, headache, nasal congestion, rhinorrhea, dermatitis contact, and presyncope. In another clinical study of IN epinephrine in saline formulation in healthy adults, transient tremor was observed in one subject and palpitation in two subjects. Increase in heart rate, and diastolic and systolic blood pressures occurred at T.sub.max. in most subjects but no correlation was found between these symptoms and the plasma concentrations of epinephrine. No serious adverse effects were observed in the subjects after IN epinephrine administration. Therefore, a good safety profile of FMXIN002 use is expected.

[0102] Comparative bioavailability between the test and reference products and also within treatment comparisons of the test product with and without allergen challenge will be determined by a statistical comparison of the AUC.sub.t, AUC.sub.inf, and C.sub.max. parameters for epinephrine.

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[0105] 3. Kemp, S. F., Lockey, R. F., Simons, F. E. and World Allergy Organization ad hoc Committee on Epinephrine in, A. Epinephrine: the drug of choice for anaphylaxis—a statement of the world allergy organization. World Allergy Organ J. 2008; 1(7 Suppl): S18-26.

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[0109] 7. Mylan Inc., Highlights of Prescribing Information. EPIPEN® (epinephrine injection, USP). USA: FDA; Revised: August, 2018. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed [Aug. 6, 2019].

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[0112] 10. Cady R K, McAllister P J, Spierings E L, et al. A randomized, double-blind, placebo-controlled study of breath powered nasal delivery of sumatriptan powder (AVP-825) in the treatment of acute migraine (The TARGET Study). Headache. 2015;55(1):88-100. doi:10.1111/head.12472

[0113] 11. Orgel H A, Meltzer E O, Bierman C W, Bronsky E, Connell J T, Lieberman P L, Nathan R, Pearlman D S, Pence H L, Slavin R G, et al. J Allergy Clin Immunol. 1991 Aug;88(2):257-64

[0114] 12. Food and Drug Administration. FYs 2013-2017 Regulatory Science Report: Locally-Acting Orally Inhaled and Nasal Drug Products. OGD FY13-FY17 Regulatory Science Research Report—1; February 2018. https://www.fda.gov/drugs/generic-drugs/fys-2013-2017-regulatory-science-report-locally-acting-orally-inhaled-and-nasal-drug-products. Accessed [Nov. 20, 2019]

[0115] 13. Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products—Chemistry, Manufacturing, and Controls Documentation; Guidance for Industry; CDER, July 2002