Inhalable epinephrine preparations

Abstract

An inhalable epinephrine formulation is provided that includes a pharmaceutically acceptable salt of epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative and a solid carrier, without the need for additional excipients, and that exhibits a surprising level of stability upon storage.

Description

[Technical Field]

[0001] The present disclosure relates to inhalable formulations comprising epinephrine or pharmaceutically acceptable salts of epinephrine derivatives, and dry powder inhalers comprising the inhalable formulations. [Background technology]

[0002] Anaphylaxis is a severe, potentially life-threatening allergic reaction. It can be triggered by several triggers, including certain foods such as nuts, shellfish, or eggs; insect venoms such as bee and wasp stings; certain medications such as antibiotics and aspirin; general anesthetics; and latex. As an initial response to the trigger, the immune system releases a large number of chemicals, potentially sending the body into shock. Common signs and symptoms of anaphylaxis include a rapid and weak pulse; swelling of the lips, tongue, or throat; shortness of breath and difficulty breathing; skin rash and itching; and stomach pain, nausea, and vomiting. If the condition is not treated immediately, it can be fatal.

[0003] The primary treatment for anaphylaxis is the administration of epinephrine. Epinephrine, also known as adrenaline, is a hormone and neurotransmitter that stimulates the sympathetic nervous system. Currently, several methods of treating anaphylaxis using epinephrine are known. Perhaps the best-known product is EpiPen, an autoinjector for self-administration of epinephrine. The subject must prick (inject) themselves with a needle (preferably in the thigh), and a dose of epinephrine is released into muscle tissue.

[0004] While this technology certainly has its advantages, one of the major drawbacks of this product is the harshness of the procedure. Many patients and caregivers are reluctant to stick themselves with a needle, resulting in valuable time wasted in the event of an emergency, life-threatening reaction. Furthermore, the reluctance to administer epinephrine via intramuscular injection leads to suboptimal decision-making, such as "wait and see" or treating with an oral antihistamine approach first. The use of autoinjector devices also carries the risk of accidental needle injury.

[0005] Dry powder inhalers (DPIs) combined with inhaled dry powders are used to treat diseases such as respiratory disease, cardiovascular disease, diabetes, obesity, and cancer, or symptoms associated with these and other diseases (e.g., nausea, vomiting, pain, and inflammation), by delivering consistent doses of pharmacological agents to a patient's airways via inhalation.

[0006] U.S. Patent Publication No. 2018 / 0056022 to Liu et al. discloses a positive pressure manual DPI and its use in combination with various traditional Chinese medicines (TCM) to treat diseases and disorders. It contemplates the delivery of pharmaceutically active agents, including epinephrine, but does not actually manufacture or test such pharmaceutical-grade DPI formulations and therefore does not provide guidance to those skilled in the art regarding their stability, flow characteristics, or overall feasibility.

[0007] DPIs present challenges in terms of suitable formulations that have a suitable particle size containing the active ingredient and maintain this throughout a reasonable shelf life. Achieving the necessary balance between the components of the formulation to enable delivery of the active ingredient to the deep lung to provide a suitably rapid response time is essential. Summary of the Invention

[0008] In a first aspect, the present disclosure provides an inhalable formulation comprising: (i) a pharmaceutically acceptable salt of epinephrine or a derivative thereof, and (ii) relates to inhalable formulations containing a solid carrier.

[0009] In embodiments, epinephrine or a pharmaceutically acceptable salt of a derivative thereof is present in an amount of from about 0.01 to about 15.0 mg per unit dose of the formulation.

[0010] In embodiments, the epinephrine salt or epinephrine derivative salt is selected from the group consisting of bitartrate, hydrochloride, maleate, malate, malonate, fumarate, and borate salts, and mixtures thereof.

[0011] In embodiments, the epinephrine derivative is selected from the group consisting of norepinephrine, dopamine, 3-methoxytyramine, synephrine, p-octopamine, and salts and mixtures thereof.

[0012] In embodiments, the solid support is selected from the group consisting of sugars and sugar alcohols (e.g., sugars and polysaccharides including lactose, mannose, sucrose, mannitol, trehalose), citrate, amino acids (e.g., glycine, L-leucine, isoleucine), trileucine, bitartrate, methionine, vitamin A, zinc citrate, trisodium citrate, zinc chloride, polyvinylpyrrolidone, phospholipids (including diphosphotidylcholine, etc.).

[0013] In one embodiment, the solid carrier is selected from the group consisting of lactose monohydrate, anhydrous lactose, sucrose, mannitol, and trehalose.

[0014] When the solid carrier comprises lactose, it may be in the alpha form, the beta form, or a mixture thereof, and preferably is crystalline.

[0015] If the solid carrier comprises lactose, it may be in the monohydrate or anhydrous form.

[0016] In an embodiment, the solid carrier is a powdered solid carrier.

[0017] In an embodiment, the inhalable formulation of the first aspect is a dry powder inhalable formulation.

[0018] In an embodiment of the first aspect, the inhalable formulation or dry powder inhalable formulation consists of or consists essentially of a pharmaceutically acceptable salt of epinephrine or an epinephrine derivative and a solid carrier.

[0019] In a preferred embodiment, the inhalable formulation does not contain any excipients other than the solid carrier, i.e., the formulation contains only an epinephrine salt or an epinephrine derivative salt and a single solid carrier.

[0020] In a second aspect, the present disclosure relates to a container comprising the inhalable formulation of the first aspect.

[0021] The container may be a capsule, cartridge, blister, blister strip or other suitable container which, when filled with the formulation of the first aspect, can be loaded into a dry powder inhaler.

[0022] In a third aspect, the present disclosure relates to a dry powder inhaler comprising the inhalable formulation of the first aspect.

[0023] In embodiments, the dry powder inhaler of the second aspect may be as described in any embodiment disclosed in WO2020 / 257845 and / or WO2020 / 257843 (which are incorporated by reference in their entirety).

[0024] In a fourth aspect, the present disclosure provides a process for forming the inhalable formulation of the first aspect, comprising: (a) micronizing epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative; (b) combining the micronized epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative with a solid carrier.

[0025] In a fifth aspect, the present disclosure relates to the inhalable formulation of the first aspect when produced by the process of the fourth aspect.

[0026] In a sixth aspect, the present disclosure provides a method of delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject in need thereof, the method comprising: administering to a subject an inhalable formulation of the first aspect; thereby comprising the step of delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject.

[0027] In embodiments, there is provided a method of delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject, the method comprising: providing an inhalable formulation of the first aspect to a subject; enabling a subject to inhale the inhalable formulation; thereby delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject.

[0028] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise providing the subject with a dry powder inhaler of the third aspect.

[0029] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise at least partially filling a container with the inhalable formulation.

[0030] In embodiments, the method of delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject further comprises loading a container into the dry powder inhaler of the third aspect.

[0031] In embodiments, the method of delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject is a method of delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to the lungs of a subject.

[0032] In a seventh aspect, the present disclosure provides a method of preventing or treating an epinephrine-responsive disease, disorder, or condition in a subject in need thereof, comprising: administering to a subject an inhalable formulation of the first aspect; thereby preventing or treating a disease, disorder, or condition in a subject.

[0033] In embodiments, the epinephrine-responsive disease, disorder, or condition is selected from the group consisting of anaphylaxis, cardiac arrest, glaucoma, asthma, bronchospasm, croup, and respiratory distress.

[0034] In embodiments, the method of the seventh aspect comprises: providing an inhalable formulation of the first aspect to a subject; enabling a subject to inhale the inhalable formulation; thereby treating the disease or condition in the subject.

[0035] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise providing the subject with a dry powder inhaler of the third aspect.

[0036] In an embodiment, the method of the seventh aspect further comprises the steps of (i) monitoring the patient; and (ii) optionally administering a further amount of the inhalable formulation of the first aspect.

[0037] Each aspect or embodiment defined herein can be combined with any other aspect or embodiment unless otherwise stated. [Brief explanation of the drawings]

[0038] [Figure 1] 1 shows an SEM (scanning electron microscope) image of particle size distribution of micronized epinephrine bitartrate at an initial time point. [Figure 2] 1 shows SEM images of particle size distribution of micronized epinephrine bitartrate at 4 weeks (2-8° C.). [Figure 3] 1 shows an SEM image of particle size distribution of micronized epinephrine bitartrate at 4 weeks (40° C. / 75% RH). [Figure 4] 1 shows SEM images of particle size distribution of micronized epinephrine bitartrate and magnesium stearate at initial time points. [Figure 5] 1 shows SEM images of particle size distribution of micronized epinephrine bitartrate and magnesium stearate at 4 weeks (2-8° C.). [Figure 6] 1 shows SEM images of particle size distribution of micronized epinephrine bitartrate and magnesium stearate at 4 weeks (40° C. / 75% RH). [Figure 7] 1 shows that epinephrine formulations containing lactose monohydrate are free of loose aggregates before and after blending. [Figure 8] 1 shows that epinephrine formulations containing lactose monohydrate and magnesium stearate are free of loose agglomerates before and after blending. [Figure 9] FIG. 10 is a graphical representation of NGI testing of batch BN021 / 21 1.0 mg strength capsules stored at 25° C. / 60% RH for 18 months. DETAILED DESCRIPTION OF THE INVENTION

[0039] It should be understood that formulations of the present invention containing the ingredients described herein may, in other embodiments, consist of, or, in other embodiments, consist essentially of, those ingredients. In some embodiments, the term "comprises" refers to the inclusion of the indicated ingredients, such as epinephrine and a solid carrier, as well as other ingredients, active agents, and pharmaceutically or physiologically acceptable carriers, excipients, emollients, stabilizers, and the like, as known in the art. The term "consisting essentially of" refers to a formulation in which the recited ingredients are the primary components and excludes all additional ingredients that materially affect the essential characteristics of the formulation. However, the formulation may include other compounds that are not directly involved in imparting the formulation's desired properties. The term "consisting of," as used herein, means that the formulation contains only the specifically recited components.

[0040] As used herein, the term "substantially" is a broad term and is to be given its ordinary and accustomed meaning to those of ordinary skill in the art, referring, without limitation, to most, but not necessarily all, of what is specified. Substantially can mean 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.99%, 99.999%, or 99.9999% of what is specified. For example, "substantially crystalline" can mean that the material is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, 99.99%, 99.999%, or 99.9999% crystalline.

[0041] As used herein, the term "about" refers to a range of ±10% of the particular value or the range associated with experimental error known to one of ordinary skill in the art in determining the particular value, whichever is greater.

[0042] Those skilled in the art will understand that epinephrine and adrenaline are two accepted terms that refer to the same active pharmaceutical ingredient (API), and that a reference herein to epinephrine can be considered a reference to adrenaline. That is, these terms can be used interchangeably herein. Furthermore, the term "epinephrine" can refer to a single pure enantiomer of epinephrine (e.g., R-epinephrine), or racemic epinephrine (comprising a 1:1 ratio of R- and S-enantiomers), or a mixture of epinephrine enantiomers in any ratio.

[0043] The present disclosure describes how inhalable epinephrine salt formulations can be uniquely tailored for delivery to a subject's lungs via a dry powder inhaler (DPI) to treat or prevent epinephrine-responsive conditions, disorders, or diseases. Surprisingly, it has been discovered that a simple formulation of a pharmaceutically acceptable salt of epinephrine or an epinephrine derivative with a solid carrier provides a stable composition with useful aerodynamic particle size distribution characteristics without the need for additional force control, lubrication, flow, or other agents or excipients. Furthermore, it has been discovered that the use of carrier microparticles (e.g., lactose microparticles) to aid in the deagglomeration of epinephrine bitartrate from alpha-lactose monohydrate is not necessary to achieve a useful aerodynamic particle size distribution for inhalation delivery of epinephrine.

[0044] In a first aspect, the present disclosure provides an inhalable formulation comprising: (i) a pharmaceutically acceptable salt of epinephrine or an epinephrine derivative, and (ii) relates to inhalable formulations containing a solid carrier.

[0045] In embodiments, the pharmaceutically acceptable salt of epinephrine or a derivative thereof is a crystalline salt of epinephrine or a derivative thereof.

[0046] In embodiments, the pharmaceutically acceptable salt of epinephrine or a derivative thereof is a crystalline salt of epinephrine.

[0047] In embodiments, epinephrine or a pharmaceutically acceptable salt of a derivative thereof is present in the inhalable formulation from about 0.01 to about 15.0 mg per unit dose of the formulation. For example, the unit dose of the formulation of the first embodiment is about 0.01 to about 14.0 mg, about 0.01 to about 13.0 mg, about 0.01 to about 12.0 mg, about 0.01 to about 11.0 mg, about 0.01 to about 10.0 mg, about 0.01 to about 9.0 mg, about 0.01 to about 8.0 mg, about 0.01 to about 7.0 mg, about 0.01 to about 6.0 mg, about 0.01 to about 5.0 mg, about 0.01 to about 4.5 mg, about 0.01 to about 4.0 mg, about 0.01 to about 3.5 mg, about 0.01 to about 3.0 mg, or about 0.025 to about 15.0 mg, about 0.025 to about 16.0 mg, about 0.025 to about 18.0 mg, about 0.01 to about 20.0 mg, about 0.01 to about 24.0 mg, about 0.01 to about 26.0 mg, about 0.01 to about 28.0 mg, about 0.01 to about 30.0 mg, about 0.01 to about 31.0 mg, about 0.01 to about 32.0 mg, about 0.01 to about 35.0 mg, about 0.01 to about 36.0 mg, about 0.01 to about 37.0 mg, about 0.01 to about 38.0 mg, about 0.01 to about 39.0 mg, about 0.01 to about 40.0 mg, about 0.01 to about 41.0 mg, about 0.01 to about 42.0 mg, about 0.01 to about 43.0 mg, about 0.01 to about 14.0 mg, about 0.025 to about 13.0 mg, about 0.025 to about 12.0 mg, about 0.025 to about 11.0 mg, about 0.025 to about 10.0 mg, about 0.025 to about 9.0 mg, about 0.025 to about 8.0 mg, about 0.025 to about 7.0 mg, about 0.025 to about 6.0 mg, about 0.025 to about 5.0 mg, about 0.025 to about 4.5 mg, about 0.025 to about 4.0 mg, about 0.025 to about 3.5 mg, about 0.025 to about 3.0 mg, or about 0.05 to about 15.0 mg, about 0.05 to about 14.0 mg, about 0.05 to about 13.0 mg, about 0.05 to about 12.0 mg, about 0.05 to about 11.0 mg, about 0.05 to about 10.0 mg, about 0.05 to about 9.0 mg, about 0.05 to about 8.0 mg, about 0.05 to about 7.0 mg, about 0.05 to about 6.0 mg, about 0.05 to about 5.0 mg, about 0.05 to about 4.5 mg, about 0.05 to about 4.0 mg, about 0.05 to about 3.5 mg, about 0.05 to about 3.0 mg, or about 0.1 to about 15.0 mg, about 0.1 to about 14.0 mg, about 0.1 to about 13.0 mg, about 0.1 to about 12.0 mg, about 0.1 to about 11.0 mg g, about 0.1 to about 10.0 mg, about 0.1 to about 9.0 mg, about 0.1 to about 8.0 mg, about 0.1 to about 7.0 mg, about 0.1 to about 6.0 mg, about 0.1 to about 5.0 mg, about 0.1 to about 4.5 mg, about 0.1 to about 4.0 mg, about 0.1 to about 3.5 mg, about 0.1 to about 3.0 mg, or about 0.25 to about 15.0 mg, about 0.25 to about 14.0 mg, about 0.25 to about 13.0 mg, about 0.25 to about 12.0 mg, about 0.25 to about 11.0 mg, about 0.25 to about 10.0 mg, about 0.25 to about 9.0 mg, about 0.25 to about 8.0 mg, about 0.25 to about 7.0 mg, about 0.25 to about 6.0 mg, about 0.25 to about 5.0 mg, about 0.25 to about 4.5 mg, about 0.25 to about 4.0 mg, about 0.25 to about 3.5 mg, about 0.25 to about 3.0 mg, or about 0.3 to about 15.0 mg, about 0.3 to about 14.0 mg, about 0.3 to about 13.0 mg, about 0.3 to about 12.0 mg, about 0.3 to about 11.0 mg, about 0.3 to about 10.0 mg, about 0.3 to about 9.0 mg, about 0.3 to about 8.0 mg, about 0.3 to about 7.0 mg, about 0.3 to about 6.0 mg, about 0.3 to about 5.0 mg, about 0.3 to about 4.5 mg, about The epinephrine salt or epinephrine derivative salt may contain 0.3 to about 4.0 mg, about 0.3 to about 3.5 mg, about 0.3 to about 3.0 mg, or about 0.5 to about 15.0 mg, about 0.5 to about 14.0 mg, about 0.5 to about 13.0 mg, about 0.5 to about 12.0 mg, about 0.5 to about 11.0 mg, about 0.5 to about 10.0 mg, about 0.5 to about 9.0 mg, about 0.5 to about 8.0 mg, about 0.5 to about 7.0 mg, about 0.5 to about 6.0 mg, about 0.5 to about 5.0 mg, about 0.5 to about 4.5 mg, about 0.5 to about 4.0 mg, about 0.5 to about 3.5 mg, or about 0.5 to about 3.0 mg.

[0048] Those skilled in the art will understand that the unit dose of epinephrine salt or epinephrine derivative salt will be determined by the end use. For example, in the treatment of asthma, using an inhalable formulation of the first embodiment at a dose of epinephrine of about 0.05 to 0.1 mg may be sufficient if properly delivered. For use in the treatment of anaphylaxis, the required dose may be about 0.1 to 1.0 mg for some pediatric uses, or about 1.0 to 2.0 mg for some adult therapeutic dosage ranges. These factors, along with typical therapeutic administration considerations such as the subject's age, weight, and general health, will be considered by a skilled formulator or physician, and the dose will be selected accordingly.

[0049] Those skilled in the art will appreciate that much higher doses of the inhalable formulation of the first aspect may be used when treating anaphylactic shock in a patient. The dose may be about 1.0 to 15.0 mg, or about 3.0 to 15.0 mg, or about 5.0 to 15.0 mg. It may also be necessary to administer one or more additional doses of the inhalable formulation of the first aspect.

[0050] In embodiments, the epinephrine salt or epinephrine derivative salt is selected from the group consisting of bitartrate, hydrochloride, maleate, malate, malonate, fumarate, and borate salts, and mixtures thereof. In one embodiment, the epinephrine salt or epinephrine derivative salt is bitartrate. In a preferred embodiment, the epinephrine salt is epinephrine bitartrate.

[0051] It has been discovered that salt forms of epinephrine can provide significant advantages in formulation stability over the free base form of epinephrine.

[0052] In embodiments, the epinephrine derivative salt is selected from the group consisting of norepinephrine salts, dopamine salts, 3-methoxytyramine salts, synephrine salts, p-octopamine salts, and mixtures thereof.

[0053] In a preferred embodiment, the pharmaceutically acceptable salt of epinephrine or a derivative thereof is a pharmaceutically acceptable salt of epinephrine. However, it will be understood that certain derivatives of epinephrine or salts thereof may be present as impurities or even degradation products that will not adversely affect the efficacy of the inhalable formulation to a significant extent. For example, norepinephrine may be present in the formulation at less than about 2.5 wt. %, or less than about 1.5 wt. %, or less than about 1.0 wt. %, or less than about 0.5 wt. %.

[0054] In an embodiment, the solid carrier is present in the inhalable formulation of the first aspect in an amount of from 25% w / w to 99% w / w of the total formulation.For example, the formulation of the first aspect may be 30% w / w to 99% w / w, or 35% w / w to 99% w / w, or 40% w / w to 99% w / w, or 45% w / w to 99% w / w, or 50% w / w to 99% w / w, or 55% w / w to 99% w / w, 60% w / w to 99% w / w, or 65% w / w to 99% w / w, or 70% w / w to 99% w / w, or 75% w / w to 99% w / w, or 80% w / w to 99% w / w, or 85% w / w to 99% w / w, or 30% w / w to 98% w / w, or 35% w / w to 98% w / w, or 40% w / w to 98% w / w. %w / w, or 45%w / w~98%w / w, or 50%w / w~98%w / w, or 55%w / w~98%w / w, or 60%w / w~98%w / w, or 65%w / w~98%w / w, or 70%w / w~98%w / w, or 75%w / w~98%w / w, or 80%w / w~98%w / w, or 85%w / w~98%w / w, or 30%w / w~97%w / w, or 35%w / w~97%w / w, or 40%w / w~97%w / w, or 45%w / w~97%w / w, or 50%w / w~97%w / w, or 55%w / w~97%w / w, or 60% w / w to 97% w / w, or 65% w / w to 97% w / w, or 70% w / w to 97% w / w, or 75% w / w to 97% w / w, or 80% w / w to 97% w / w, or 85% w / w to 97% w / w, or 30% w / w to 96% w / w, or 35% w / w to 96% w / w, or 40% w / w to 96% w / w, or 45% w / w to 96% w / w, or 50% w / w to 96% w / w, or 55% w / w to 96% w / w, or 60% w / w to 96% w / w, or 65% w / w to 96% w / w, or 70% w / w to 96% w / w, or 75% The solid carrier may be comprised of from 96% w / w to 96% w / w, or from 80% w / w to 96% w / w, or from 85% w / w to 96% w / w, or from 30% w / w to 95% w / w, or from 35% w / w to 95% w / w, or from 40% w / w to 95% w / w, or from 45% w / w to 95% w / w, or from 50% w / w to 95% w / w, or from 55% w / w to 95% w / w, or from 60% w / w to 95% w / w, or from 65% w / w to 95% w / w, or from 70% w / w to 95% w / w, or from 75% w / w to 95% w / w, or from 80% w / w to 95% w / w, or from 85% w / w to 95% w / w.

[0055] In an embodiment, the solid carrier is present in the inhalable formulation of the first aspect in an amount of 85% w / w to 95% w / w, or 85% w / w to 94% w / w, or 85% w / w to 93% w / w, or 85% w / w to 92% w / w, or 86% w / w to 95% w / w, or 86% w / w to 94% w / w, or 86% w / w to 93% w / w, or 86% It is present in an amount of from 87% w / w to 92% w / w, or from 87% w / w to 95% w / w, or from 87% w / w to 94% w / w, or from 87% w / w to 93% w / w, or from 87% w / w to 92% w / w, or from 88% w / w to 95% w / w, or from 88% w / w to 94% w / w, or from 88% w / w to 93% w / w, or from 88% w / w to 92% w / w.

[0056] In another preferred embodiment, when the inhalable formulation is intended for pediatric use, the solid carrier is present in the inhalable formulation of the first aspect in an amount of 90% w / w to 99% w / w, or 90% w / w to 98% w / w, or 90% w / w to 97% w / w, or 90% w / w to 96% w / w, or 91% w / w to 99% w / w, or 91% w / w to 98% w / w, or 91% w / w to 97% w / w, or 91% w / w to 96% w / w, or 92% w / w It may be present in up to 99% w / w, or 92% w / w to 98% w / w, or 92% w / w to 97% w / w, or 92% w / w to 96% w / w, or 93% w / w to 99% w / w, or 93% w / w to 98% w / w, or 93% w / w to 97% w / w, or 93% w / w to 96% w / w, or 94% w / w to 99% w / w, or 94% w / w to 98% w / w, or 94% w / w to 97% w / w, or 94% w / w to 96% w / w.

[0057] In a preferred embodiment, when the solid carrier of the inhalable formulation of any embodiment of the first aspect is lactose monohydrate and / or anhydrous lactose solid carrier, optionally crystalline lactose monohydrate and / or crystalline anhydrous lactose, the lactose monohydrate and / or anhydrous lactose solid carrier is present in the inhalable formulation of the first aspect in an amount of 25% w / w to 99% w / w, or 30% w / w to 99% w / w, or 35% w / w to 99% w / w, or 40% w / w to 99% w / w, or 45% w / w to 99% w / w, or 50% w / w to 99% w / w, or is 55% w / w to 99% w / w, or 60% w / w to 99% w / w, or 65% w / w to 99% w / w, or 70% w / w to 99% w / w, or 75% w / w to 99% w / w, or 80% w / w to 99% w / w, or 85% w / w to 99% w / w, or 30% w / w to 98% w / w, or 35% w / w to 98% w / w, or 40% w / w to 98% w / w, or 45% w / w to 98% w / w, or 50% w / w to 98% w / w, or 55% w / w to 98% w / w, or 60% w / w to 98% w / w, or 65% w / w to 98% w / w, or 70% w / w to 98% %w / w, or 75%w / w~98%w / w, or 80%w / w~98%w / w, or 85%w / w~98%w / w, or 30%w / w~97%w / w, or 35%w / w~97%w / w, or 40%w / w~97%w / w, or 45%w / w~97%w / w, or 50%w / w~97%w / w, or 55%w / w~97%w / w, or 60%w / w~97%w / w, or 65%w / w~97%w / w, or 70%w / w~97%w / w, or 75%w / w~97%w / w, or 80%w / w~97%w / w, or 85%w / w~97%w / w, or 30% w / w~96%w / w, or 35%w / w~96%w / w, or 40%w / w~96%w / w, or 45%w / w~96%w / w, or 50%w / w~96%w / w, or 55%w / w~96%w / w, or 60%w / w~96%w / w, or 65%w / w~96%w / w, or 70%w / w~96%w / w, or 75%w / w~96%w / w, or 80%w / w~96%w / w, or 85%w / w~96%w / w, or 30%w / w~95%w / w, or 35%w / w~95%w / w, or 40%w / w~95%w / w, or 45%w / w~95%w / w,or 50% w / w to 95% w / w, or 55% w / w to 95% w / w, or 60% w / w to 95% w / w, or 65% w / w to 95% w / w, or 70% w / w to 95% w / w, or 75% w / w to 95% w / w, or 80% w / w to 95% w / w, or 85% w / w to 95% w / w. In another preferred embodiment, the lactose monohydrate and / or anhydrous lactose solid carrier is present in the inhalable formulation of the first aspect in an amount of 85% w / w to 95% w / w, or 85% w / w to 94% w / w, or 85% w / w to 93% w / w, or 85% w / w to 92% w / w, or 86% w / w to 95% w / w, or 86% w / w to 94% w / w, or 86% w / w to 95% w / w. It is present in an amount of 86% w / w to 92% w / w, or 87% w / w to 95% w / w, or 87% w / w to 94% w / w, or 87% w / w to 93% w / w, or 87% w / w to 92% w / w, or 88% w / w to 95% w / w, or 88% w / w to 94% w / w, or 88% w / w to 93% w / w, or 88% w / w to 92% w / w.

[0058] In another preferred embodiment, when the inhalable formulation is intended for pediatric use, the lactose monohydrate and / or anhydrous lactose solid carrier is present in the inhalable formulation of the first aspect in an amount of 90% w / w to 99% w / w, or 90% w / w to 98% w / w, or 90% w / w to 97% w / w, or 90% w / w to 96% w / w, or 91% w / w to 99% w / w, or 91% w / w to 98% w / w, or 91% w / w to 97% w / w, or 91% w / w to 96% w / w. or 92% w / w to 99% w / w, or 92% w / w to 98% w / w, or 92% w / w to 97% w / w, or 92% w / w to 96% w / w, or 93% w / w to 99% w / w, or 93% w / w to 98% w / w, or 93% w / w to 97% w / w, or 93% w / w to 96% w / w, or 94% w / w to 99% w / w, or 94% w / w to 98% w / w, or 94% w / w to 97% w / w, or 94% w / w to 96% w / w.

[0059] Aerodynamic particle size distribution is an important parameter to consider in order to ensure that an inhalable formulation is delivered to the deep lung. Particles with a diameter greater than 5 μm typically deposit in the mouth, throat, or upper respiratory tract, while particles with a diameter less than 0.5 μm fall out of the airstream and are not deposited in the lungs, but are then quickly exhaled. Advantageously, the inhalable formulations of the present disclosure have been found to provide a useful particle size profile for delivering epinephrine active agents to the lungs.

[0060] In one embodiment, the epinephrine salt or epinephrine derivative salt has a particle size distribution median by volume (Dv50) of about 0.5 μm to about 5 μm. In another embodiment, the epinephrine salt or epinephrine derivative salt has a Dv50 value of 1 μm to about 4 μm, or 1 μm to about 3 μm, or 2 μm to about 3 μm.

[0061] In another embodiment, the maximum particle size (Dv90) at which less than 90% of the epinephrine salt or epinephrine derivative salt exists is about 2 μm to about 5 μm. In one embodiment, the Dv90 value of the epinephrine salt or epinephrine derivative salt is 3 μm to about 4 μm.

[0062] A range of solid carriers suitable for inhalable formulations are known in the art, in embodiments the solid carrier may be selected from the group consisting of sugars, sugar alcohols, citrate salts, amino acids and peptides, vitamins, and other suitable solid carriers.

[0063] When the solid carrier is a sugar or sugar alcohol, it may be selected from the group consisting of lactose, mannose, sucrose, mannitol, and trehalose.

[0064] When the solid carrier is a citrate salt, it may be selected from the group consisting of zinc citrate and trisodium citrate.

[0065] When the solid support is an amino acid or peptide, it may be selected from the group consisting of glycine, L-leucine, isoleucine, methionine, and trileucine.

[0066] When the solid carrier is a vitamin, it can be vitamin A.

[0067] Other suitable carriers may include zinc chloride, polyvinylpyrrolidone, and diphosphotidylcholine.

[0068] In one embodiment, the solid carrier is selected from the group consisting of alpha-lactose monohydrate, beta-lactose, anhydrous lactose, mannitol, sucrose, and trehalose.

[0069] If the solid carrier comprises lactose, it may be in the alpha form, beta form, or a mixture thereof, and may be crystalline in either form.

[0070] Those skilled in the art will understand that alpha-lactose forms can exist as both monohydrate and anhydrous forms. Furthermore, the β-form generally exists only as anhydrous forms, not as a hydrate. When the solid carrier contains lactose, it may be in any of these forms (alone or in any combination). For example, the solid carrier may contain alpha-lactose in both monohydrate and anhydrous forms, regardless of whether anhydrous β-form is present. In combination with all of these embodiments of alpha- and / or β-lactose, the lactose may be in crystalline or amorphous form. It may be preferred that any alpha- and / or β-lactose form is crystalline.

[0071] In an embodiment, the solid carrier is a powdered solid carrier.

[0072] The solid carrier, optionally a lactose solid carrier, may have a particle size distribution as follows: D10 of 20-45 μm, optionally 25-35 μm; D50 of 50-70 μm, optionally 55-65 μm; and D90 of 75-105 μm, optionally 85-100 μm. In an embodiment, the solid carrier is commercially available Respitose SV003 provided by DFE Pharma, although lactose solid carriers of similar grades would also be suitable.

[0073] In a preferred embodiment of the first aspect, the solid support comprises, consists of, or consists essentially of a crystalline solid support.

[0074] In embodiments, the majority of the solid carrier is in crystalline form. Crystalline carriers are preferred for the present inhalable formulations because they reduce processing complexity and are more thermodynamically stable than amorphous carriers. The use of crystalline solid carriers means that a pharmaceutical spray dryer is not required, and therefore the solid carrier is not limited to spray-dryable materials only; the thermodynamics of stability may be improved in the crystalline state; and crystalline epinephrine salts may be less hygroscopic than amorphous epinephrine salt forms.

[0075] In embodiments, the inhalable formulation of the first aspect is a dry powder inhalable formulation, i.e., all components of the formulation for delivery to a subject are substantially in dry powder form.

[0076] In an embodiment of the first aspect, the solid carrier consists of or consists essentially of lactose monohydrate and / or anhydrous lactose, optionally crystalline lactose monohydrate and / or crystalline anhydrous lactose.

[0077] In certain instances, the dry powder inhalable formulation comprises: (i) a pharmaceutically acceptable salt of epinephrine, optionally a bitartrate salt of epinephrine, and (ii) a lactose-based solid carrier, optionally comprising, consisting of, or consisting essentially of lactose monohydrate and / or anhydrous lactose solid carrier, optionally crystalline lactose monohydrate and / or crystalline anhydrous lactose.

[0078] In certain instances, the dry powder inhalable formulation comprises: (i) a pharmaceutically acceptable salt of epinephrine, optionally a bitartrate salt of epinephrine, and (ii) a lactose-based solid carrier, optionally comprising, consisting of, or consisting essentially of lactose monohydrate and / or anhydrous lactose, optionally crystalline lactose monohydrate and / or crystalline anhydrous lactose, wherein the lactose-based solid carrier is present at about 50% w / w to about 99% w / w.

[0079] The epinephrine salt and lactose carrier can be those described in any of the previous embodiments, or combinations thereof.

[0080] In an embodiment of the first aspect, the inhalable formulation or dry powder inhalable formulation consists of or consists essentially of an epinephrine salt or an epinephrine derivative salt and a solid carrier.

[0081] Typically, several other excipients and carriers must be added to dry powder formulations to achieve desired properties, such as the desired stability of the formulation, the appropriate aerodynamic particle size distribution, and the necessary anti-agglomeration properties of the particles. This can be particularly true for epinephrine, which can be difficult to formulate while maintaining stability, preventing reaction with one or more of the formulation components, and avoiding significant agglomeration and clumping of the formulation. Surprisingly, it was discovered that no additional excipients other than the selected solid carrier were required to add to pharmaceutically acceptable epinephrine salts to form the inhalable formulations of the present disclosure and achieve the described advantages. Furthermore, it was not necessary to add fine particle fractions of the carrier excipients to aid in the deagglomeration of the API from the carrier particles. Thus, the inhalable formulations described herein do not require delivery devices specifically designed to achieve deagglomeration of the dry powder clumps. Such devices can be complex, require expensive manufacturing, and often suffer from a poor deagglomeration process, which can result in insufficient delivery of the active agent. The simplicity of the inhalable formulations described herein, while maintaining the advantages described, is a significant advantage of the present invention.

[0082] In an embodiment of the first aspect, the inhalable formulation does not include any agent that can be considered or plays an active role as an excipient, second carrier material, flow control agent, lubricant, force control agent, pH buffer, or other additive that aids in the delivery of the active epinephrine form other than the recited solid carriers.

[0083] In any embodiment of the present disclosure, the inhalable formulation of the first aspect does not include a pH buffering agent, such as sodium dihydrogen phosphate, which may be required for the formulation to be delivered intranasally, but is not required for the present formulation, which is designed to be delivered to the lung via a DPI.

[0084] Thus, when the inhalable formulation of the first aspect includes epinephrine bitartrate and lactose monohydrate, it does not include sodium dihydrogen phosphate.

[0085] Thus, in an embodiment, the inhalable formulation of the first aspect comprises (i) a pharmaceutically acceptable epinephrine salt or epinephrine derivative salt, optionally epinephrine bitartrate, and (ii) a single excipient that is a solid carrier. Optionally, the single excipient that is a solid carrier is a lactose carrier, such as lactose monohydrate and / or anhydrous lactose. The lactose carrier may contain any ratio of α- and β-lactose forms, and may be crystalline, amorphous, or a mixture thereof. Crystalline lactose forms may be preferred in certain instances.

[0086] In embodiments, the inhalable formulation comprises (i) epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative, optionally epinephrine bitartrate, and (ii) lactose monohydrate and / or anhydrous lactose.

[0087] In any embodiment of the first aspect, the epinephrine salt or epinephrine derivative salt is crystalline micronized epinephrine bitartrate.

[0088] In an embodiment of the first aspect, the inhalable formulation comprises, consists essentially of, or consists of (i) micronized epinephrine bitartrate, and (ii) a crystalline lactose solid carrier present in about 50% w / w to about 99% w / w of the total formulation and selected from lactose monohydrate solid carrier and / or anhydrous lactose solid carrier.

[0089] In embodiments, the crystalline lactose solid carrier is present at 55% w / w to 99% w / w, or 60% w / w to 99% w / w, or 65% w / w to 99% w / w, or 70% w / w to 99% w / w, or 75% w / w to 99% w / w, or 80% w / w to 99% w / w, or 85% w / w to 99% w / w.

[0090] In an embodiment of the first aspect, the inhalable formulation comprises, consists essentially of, or consists of (i) micronized epinephrine bitartrate having a Dv50 of about 0.5 μm to about 5 μm and / or a Dv90 of about 2 μm to about 5 μm, and (i) a solid carrier, optionally a lactose solid carrier such as lactose monohydrate and / or anhydrous lactose.

[0091] In an embodiment of the first aspect, the inhalable formulation comprises, consists essentially of, or consists of (i) micronized epinephrine bitartrate having a Dv50 of about 0.5 μm to about 5 μm and a Dv90 of about 2 μm to about 5 μm, and (i) a solid carrier, optionally a lactose solid carrier (e.g., lactose monohydrate and / or anhydrous lactose).

[0092] In an embodiment, the Dv50 is from about 1 μm to about 5 μm, or from about 1 μm to about 4 μm, or from about 1 μm to about 3 μm, or from about 1 μm to about 2 μm, or from about 1.5 μm to about 5 μm, or from about 1.5 μm to about 4 μm, or from about 1.5 μm to about 3 μm, or from about 1.5 μm to about 2 μm, or from about 2 μm to about 5 μm, or from about 2 μm to about 4 μm, or from about 2 μm to about 3 μm.

[0093] In one embodiment, the Dv50 is from about 1.5 μm to about 3 μm.

[0094] In one embodiment, the Dv50 is about 2 μm.

[0095] In embodiments, the Dv90 is from about 2 μm to about 4.5 μm, or from about 2 μm to about 4 μm, or from about 2.5 μm to about 5 μm, or from about 2.5 μm to about 4.5 μm, or from about 2.5 μm to about 4 μm, or from about 3 μm to about 5 μm, or from about 3 μm to about 4.5 μm, or from 3 μm to about 4 μm. In embodiments, the inhalable formulation provides a fine particle fraction, expressed as the ratio of fine particle dose to emitted dose, of greater than 20%, or greater than 25%, or greater than 30%, or greater than 35%, or greater than 40%.

[0096] In embodiments, the crystalline micronized epinephrine bitartrate is not formed by a spray drying process.

[0097] The combination of epinephrine and lactose has been found to be particularly advantageous for inhalable formulations. Epinephrine powder alone has been found to have a strong tendency to aggregate. This is a major risk factor for dry powder inhaler formulations, as particle aggregation significantly increases particle size and significantly reduces the percentage of API successfully delivered to the deep lung. In particular, crystalline micronized epinephrine bitartrate alone was found to form aggregates, predicting the need for various glidants and / or anti-agglomerating agents in addition to the solid carrier, or complex processing approaches such as spray drying. As described in the Examples, surprisingly, the inhalable formulations of the present invention were found to exhibit minimal signs of aggregation when epinephrine was used purely in combination with a lactose carrier. Thus, the inhalable formulations of the present invention were found to have highly stable aerodynamic particle size distributions over extended periods of time, providing the desired sustained FPF for delivery to subjects.

[0098] As described in the Examples, inhalable formulations comprising epinephrine salts and lactose have been found to be stable for at least 6 months at ambient temperature (25°C) and elevated temperature (40°C). Additionally, the formulations have been found to be stable at relative humidity up to 75%. Thus, in embodiments, inhalable formulations according to embodiments of the first aspect are stable upon storage for at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months. In embodiments, the inhalable formulations are stable upon storage for at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months when stored at temperatures between about ambient temperature (25°C) and about 40°C. In embodiments, the inhalable formulation is stable upon storage for at least 3 months, or at least 4 months, or at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months when stored at a temperature of about ambient temperature (25°C) to about 40°C and a relative humidity of about 60% to 75%.

[0099] In one embodiment, the inhalable formulation comprises, consists essentially of, or consists of (i) micronized epinephrine bitartrate and (ii) a lactose solid carrier, wherein the inhalable formulation is stable for six months of storage at about ambient temperature (25° C.) and about 60% relative humidity.

[0100] In one embodiment, an inhalable formulation comprises, consists essentially of, or consists of (i) micronized crystalline epinephrine bitartrate having a Dv50 of about 1.5 μm to about 3 μm and a Dv90 of about 2 μm to about 5 μm, and (ii) crystalline alpha-lactose monohydrate present at about 75% w / w to about 99% w / w of the total formulation, wherein the dry powder inhalable formulation (a) upon manufacture provides a fine particle fraction, expressed as a ratio of fine particle dose to emitted dose, of greater than 30%; and / or (b) is stable for 6 months of storage at 25° C. and 60% relative humidity.

[0101] As discussed above, the stability of the aerodynamic particle size distribution over time is an important and unexpected advantage in that it eliminates the need to implement additional processing steps or specific storage processes as is the case with inhalable formulations that tend to naturally aggregate. Additionally, the inhalable formulation of the first embodiment does not require delivery solely through a specific dry powder inhaler designed with components or chambers intended to deagglomerate the agglomerated dry powder formulation. This was unexpected for epinephrine formulations, given that crystalline micronized epinephrine, such as epinephrine bitartrate, has been demonstrated to spontaneously form significant aggregates. Furthermore, the problem of avoiding or reducing epinephrine aggregation was unexpectedly solved by a single carrier, particularly a lactose carrier, for reasons discussed further below.

[0102] Without wishing to be bound by theory, this unexpected effect may be due to lactose having an unexpectedly strong stabilizing effect on epinephrine particle size distribution during long-term storage; otherwise, epinephrine (especially epinephrine bitartrate) would readily self-aggregate, requiring further processing prior to filling or specialized equipment for delivery to a subject. This was unexpected; in fact, the exact opposite would have been expected based on the known reaction between secondary amines such as epinephrine and reducing sugars such as lactose, as discussed below.

[0103] Issues that should be taken into consideration when producing pharmaceutical formulations include undesirable side reactions such as the Maillard reaction. The Maillard reaction is a chemical reaction between a secondary amine (e.g., epinephrine) and a reducing sugar (e.g., lactose). For example, Wirth et al. observed the Maillard reaction in all experiments conducted using a secondary amine and alpha-lactose monohydrate or anhydrous lactose (Wirth et al., "Maillard Reaction of Lactose and Fluoxetine Hydrochloride, a Secondary Amine", Journal of Pharmaceutical Sciences, Vol. 87(1):31-39, January 1998, incorporated herein by reference in its entirety).

[0104] This reaction, which results in a distinct brown coloration of the powder as the degradation reaction progresses, can be problematic in epinephrine formulations. To prevent this reaction, additional additives, such as antioxidants, are typically added. In the food industry, these additives are typically sulfite compounds, such as sulfur dioxide or metabisulfite-containing salts, which are known to be asthma triggers even when inhaled at low levels. Therefore, it is particularly surprising that the use of a lactose solid carrier alone with epinephrine bitartrate can solve the aggregation problem described above without creating stability or storage issues due to the anticipated reaction between the two components. The combination of an epinephrine salt and a reducing sugar, as a solid carrier and the only two components of a formulation, would not be a solution that a skilled formulator would naturally encounter due to the inherent problems it would be expected to pose. The inhalable formulations of the present invention do not require or contain antioxidants.

[0105] Therefore, it may be particularly advantageous and surprising that the inhalable formulations of the present invention do not exhibit any tendency to undergo side reactions, especially when lactose is the solid carrier.As shown in the examples, the inhalable formulations have high chemical stability even after 6 months of storage and do not show signs of Maillard browning degradation, despite the absence of antioxidant excipients.Therefore, the claimed formulations avoid aggregation of epinephrine alone, and the expected Maillard reaction is unlikely to occur even over long storage periods.

[0106] In embodiments, the inhalable formulation comprises: (i) a pharmaceutically acceptable salt of epinephrine or an epinephrine derivative, and (ii) consisting of, or consisting essentially of, lactose monohydrate and / or anhydrous lactose.

[0107] In embodiments, the inhalable formulation consists of or consists essentially of (i) epinephrine bitartrate and (ii) α-lactose monohydrate and / or anhydrous α-lactose, optionally where the epinephrine bitartrate is crystalline epinephrine bitartrate, including micronized crystalline epinephrine bitartrate, and optionally where the α-lactose monohydrate and / or anhydrous α-lactose is crystalline.

[0108] In embodiments, the inhalable formulation does not contain lactose microparticles in addition to the solid carrier. Lactose microparticles are milled, micronized lactose particles. They are typically added to dry powder inhaler formulations as a separate grade of lactose (processed via milling, micronization, sieving, classification, or other means that produce a powder with a particle size substantially smaller than standard grades of lactose). Lactose microparticles are added to various pharmaceutical DPI formulations to aid in the deagglomeration and dispersion of particulate API particles from solid carrier particles in the aerosol, thus improving deep lung delivery of the API. While small amounts of lactose microparticles in the inhalable formulations of the present disclosure may be useful or moderately beneficial, it is advantageous that the addition of lactose microparticles to the epinephrine DPI formulation of the first aspect is not necessary to achieve a pharmaceutically useful aerodynamic particle size distribution, flowability, and minimize agglomeration. Surprisingly, the inhalable formulations of the present invention exhibit the desired deep lung delivery characteristics when using regular particle size lactose (Respitose®).

[0109] In embodiments, when the inhalable formulation contains lactose microparticles, they are present in less than 20% w / w, or less than 15% w / w, or less than 10% w / w, or less than 5% w / w, or less than 3% w / w, or less than 1.5% w / w of the total formulation.

[0110] In a preferred embodiment, the inhalable formulation does not contain magnesium stearate. Magnesium stearate is a common lubricating excipient added to dry powder formulations to improve aerosol performance and moisture resistance. It may be particularly advantageous that the inhalable formulation of the present invention does not require the addition of magnesium stearate to exhibit desired properties. To achieve a suitable aerodynamic particle size distribution of such epinephrine and solid carrier formulations, it is generally expected in the art that a lubricant is required to reduce adhesion of the powder formulation to the container and any device surfaces, and to facilitate consistent processing of the encapsulation step during capsule manufacturing. It has been found that the inhalable formulation of the first aspect does not require this additional function of magnesium stearate or any other lubricant to meet the required parameters, and in fact can benefit from their absence.

[0111] In a second aspect, the present disclosure relates to a container comprising the inhalable formulation of the first aspect.

[0112] The container may be a capsule, cartridge, blister, blister strip or other suitable container which, when filled with the formulation of the first aspect, can be loaded into a dry powder inhaler.

[0113] Such containers are well known in the art and will vary depending on the manner in which the formulation is released from the container during inhalation using a suitable delivery device. In one embodiment, the container may be a capsule suitable for being pierced by one or more actuators in the delivery device. The container may be one of those described in WO2020 / 257845 and / or WO2020 / 257843, although it will be understood that the present invention is not limited thereto.

[0114] In a third aspect, the present disclosure relates to a dry powder inhaler comprising the inhalable formulation of the first aspect and / or the container of the second aspect.

[0115] In embodiments, the dry powder inhaler of the third aspect may be as described in any of the embodiments disclosed in WO2020 / 257845 and / or WO2020 / 257843 (which are incorporated herein by reference in their entireties).

[0116] In embodiments, the inhalable formulation of the first aspect is provided in a capsule designed for use in a dry powder inhaler of the third aspect, as described for the second aspect.

[0117] In a fourth aspect, the present disclosure provides a process for forming the inhalable formulation of the first aspect, comprising: (a) micronizing an epinephrine salt or an epinephrine derivative salt; (b) combining the micronized epinephrine salt or epinephrine derivative salt with a solid carrier.

[0118] In embodiments, the step of micronizing the epinephrine salt can be performed using a low temperature micronization or an ambient temperature micronization approach. One advantage of the present disclosure is that low temperature micronization, while useful, is not a requirement to achieve a useful formulation.

[0119] In embodiments, the micronized epinephrine salt or epinephrine derivative salt and the solid carrier are passed through a sieve before being combined.

[0120] In embodiments, the combining step is a step of dry blending the solid carrier with the micronized epinephrine salt or epinephrine derivative salt.

[0121] In an embodiment, the median particle size distribution (Dv50) of the epinephrine salt or epinephrine derivative salt after micronization is about 0.5 μm to about 5 μm, or about 1 μm to about 5 μm, or about 1 μm to about 4 μm, or about 1 μm to about 3 μm, or about 1 μm to about 2 μm, or about 1.5 μm to about 5 μm, or about 1.5 μm to about 4 μm, or about 1.5 μm to about 3 μm, or about 1.5 μm to about 2 μm, or about 2 μm to about 5 μm, or about 2 μm to about 4 μm, or about 2 μm to about 3 μm.

[0122] In one embodiment, the epinephrine salt or epinephrine derivative salt has a median particle size distribution (Dv50) of about 1.5 μm to about 3 μm. In an embodiment, the epinephrine salt or epinephrine derivative salt has a median particle size distribution (Dv50) of about 2.0 μm. Advantageously, it has been found that this particle size distribution can be maintained stable during storage for at least one month.

[0123] In embodiments, the inhalable formulation of the first aspect can be blended using either low-shear or high-shear blending techniques. An advantage of the formulation of the first aspect is that it has very low requirements in terms of the need for strict processing control of any critical process parameters, such as blending intensity or time. This provides a robust process that can be more easily scaled up compared to processes that may have more process parameter sensitivity or importance to how the API and solid carrier are blended. For example, the process of the fourth aspect does not require a spray-drying step.

[0124] In an embodiment, the process of the fourth aspect further comprises the step of filling the inhalable formulation into a suitable container of the second aspect for use in the dry powder inhaler of the third aspect.

[0125] In a fifth aspect, the present disclosure relates to the inhalable formulation of the first aspect when produced by the process of the fourth aspect.

[0126] In a sixth aspect, the present disclosure provides a method of delivering an epinephrine salt or an epinephrine derivative salt to a subject in need thereof, comprising: administering to a subject an inhalable formulation of the first aspect; This relates to a method for delivering an epinephrine salt or an epinephrine derivative salt to a subject.

[0127] In embodiments, a method of delivering an epinephrine salt or an epinephrine derivative salt to a subject comprises: providing an inhalable formulation of the first aspect to a subject; enabling a subject to inhale the inhalable formulation; thereby delivering an epinephrine salt or an epinephrine derivative salt to the subject.

[0128] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise providing the subject with a dry powder inhaler of the third aspect.

[0129] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise at least partially filling a container with the inhalable formulation.

[0130] In embodiments, the method of delivering an epinephrine salt or an epinephrine derivative salt to a subject further comprises loading a container into the dry powder inhaler of the third aspect.

[0131] In embodiments, the method of delivering epinephrine to a subject is a method of delivering epinephrine to the respiratory tract, particularly the lungs of a subject.

[0132] Treating a subject with the inhalable formulation of the first aspect can be particularly advantageous. The unique properties of the inhalable formulation, such as anti-aggregation properties and aerodynamic particle size distribution, allow the epinephrine salt or epinephrine derivative salt to travel to the deep lung via inhalation without deposition in the upper respiratory tract and throat.

[0133] In embodiments, the method of delivering epinephrine to a subject is a method of self-administering an inhalable formulation to the airways by using the dry powder inhaler of the third aspect.

[0134] In a seventh aspect, the present disclosure provides a method of treating or preventing an epinephrine-responsive disease, disorder, or condition in a subject in need thereof, comprising: administering to a subject an inhalable formulation of the first aspect; thereby treating or preventing a disease, disorder, or condition in a subject.

[0135] The unique properties of the inhalable formulation allow the epinephrine salt or epinephrine derivative salt to reach the deep lung without delay, and therefore the method of the seventh aspect is a rapid and convenient method for treating epinephrine-responsive diseases, disorders, or conditions.

[0136] In embodiments, the epinephrine-responsive disease, disorder, or condition is selected from the group consisting of anaphylaxis, cardiac arrest, glaucoma, asthma, bronchospasm, croup, and respiratory distress.

[0137] In embodiments, the method of the seventh aspect comprises: providing an inhalable formulation of the first aspect to a subject; enabling a subject to inhale the inhalable formulation; thereby treating or preventing a disease, disorder, or condition in a subject.

[0138] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise providing the subject with a dry powder inhaler of the third aspect.

[0139] In embodiments, the step of allowing the subject to inhale the inhalable formulation comprises a substantial proportion of the inhalable formulation reaching the subject's lungs as a result of inhalation.

[0140] In an embodiment, the method of the seventh aspect further comprises the steps of (i) monitoring the patient; and (ii) optionally administering a further amount of the inhalable formulation of the first aspect.

[0141] Those skilled in the art will appreciate that numerous variations and / or modifications may be made to the above-described embodiments without departing from the broad general scope of the present disclosure, and the present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0142] List of items in the embodiment: 1. An inhalable formulation comprising: (i) a pharmaceutically acceptable salt of epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative, and (ii) Inhalable formulations comprising, consisting of, or consisting essentially of a solid carrier. 2. The inhalable formulation according to item 1, wherein the epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative is present in an amount of about 0.01 to about 5.0 mg per unit dose of the formulation. 3. The inhalable formulation according to item 1 or 2, wherein the pharmaceutically acceptable salt of epinephrine or an epinephrine derivative is a salt selected from the group consisting of bitartrate, hydrochloride, maleate, malate, malonate, borate, and fumarate. 4. The inhalable formulation of any one of the preceding items, wherein the epinephrine derivative is selected from the group consisting of norepinephrine, dopamine, 3-methoxytyramine, synephrine, and p-octopamine. 5. The inhalable formulation of any one of the preceding items, wherein the solid carrier is selected from the group consisting of alpha-lactose monohydrate, beta-lactose, anhydrous lactose, mannitol, sucrose, and trehalose. 6. An inhalable formulation according to any one of the preceding items, wherein the inhalable formulation does not contain any other excipients other than the solid carrier. 7. The inhalable formulation of any one of the preceding items, wherein the inhalable formulation does not contain a pH buffering agent. 8. An inhalable formulation according to any one of the preceding items, wherein the solid carrier is a crystalline solid carrier. 9. The inhalable formulation of any one of the preceding items, wherein the epinephrine or epinephrine derivative salt is crystalline. 10. The inhalable formulation of any one of the preceding paragraphs, wherein the inhalable formulation consists of or consists essentially of a crystalline epinephrine salt and a crystalline lactose solid carrier. 11. An inhalable formulation according to any one of the preceding items, wherein the solid carrier is present in the inhalable formulation in an amount of from about 50% w / w to 99% w / w of the total formulation, optionally from about 75% w / w to 99% w / w of the total formulation. 12. The inhalable formulation of any one of the preceding items, wherein the pharmaceutically acceptable salt of epinephrine or an epinephrine derivative is a micronized, crystalline pharmaceutically acceptable salt of epinephrine or an epinephrine derivative. 13. The inhalable formulation of any one of the preceding items, wherein the epinephrine or pharmaceutically acceptable salt of an epinephrine derivative is epinephrine bitartrate. 14. The inhalable formulation of any one of the preceding items, wherein the epinephrine or pharmaceutically acceptable salt of an epinephrine derivative is crystalline epinephrine bitartrate. 15. The inhalable formulation of any one of the preceding items, wherein the epinephrine or pharmaceutically acceptable salt of an epinephrine derivative is micronized crystalline epinephrine bitartrate. 16. The inhalable formulation of any one of the preceding items, wherein the solid carrier is selected from the group consisting of alpha-lactose monohydrate and anhydrous lactose. 17. The inhalable formulation of any one of the preceding items, wherein the solid carrier is selected from the group consisting of crystalline alpha-lactose monohydrate and crystalline anhydrous lactose. 18. The inhalable formulation of any one of the preceding items, wherein the inhalable formulation consists of or consists essentially of epinephrine bitartrate and a solid carrier. 19. The inhalable formulation of any one of the preceding paragraphs, wherein the inhalable formulation consists of or consists essentially of crystalline epinephrine bitartrate and a solid carrier. 20. The inhalable formulation of any one of the preceding paragraphs, wherein the inhalable formulation consists of or consists essentially of crystalline epinephrine bitartrate and a crystalline solid carrier. 21. The inhalable formulation of any one of the preceding paragraphs, wherein the inhalable formulation consists of or consists essentially of crystalline epinephrine bitartrate and a crystalline lactose solid carrier. 22. The inhalable formulation of any one of the preceding paragraphs, wherein the inhalable formulation consists of, or consists essentially of, micronized crystalline epinephrine bitartrate and a crystalline lactose solid carrier. 23. The inhalable formulation of any one of the preceding paragraphs, wherein the inhalable formulation consists of, or consists essentially of, (i) crystalline epinephrine bitartrate, and (ii) a crystalline lactose solid carrier present in an amount of from about 50% w / w to about 99% w / w of the total formulation. 24. The inhalable formulation of any one of the preceding items, wherein the inhalable formulation consists of, or consists essentially of, crystalline epinephrine bitartrate and a crystalline lactose solid carrier selected from the group consisting of crystalline alpha-lactose monohydrate and crystalline anhydrous lactose. 25. The inhalable formulation of any one of the preceding items, wherein the inhalable formulation consists of, or consists essentially of, micronized crystalline epinephrine bitartrate and a crystalline lactose solid carrier selected from the group consisting of crystalline alpha-lactose monohydrate and crystalline anhydrous lactose. 26. The inhalable formulation of any one of the preceding items, wherein the inhalable formulation consists of, or consists essentially of, crystalline epinephrine bitartrate and a crystalline lactose solid carrier selected from the group consisting of crystalline alpha-lactose monohydrate and crystalline anhydrous lactose, wherein the crystalline lactose solid carrier is present in an amount of from about 50% w / w to about 99% w / w of the total formulation, optionally from about 75% w / w to about 99% w / w of the total formulation. 27. The inhalable formulation of any one of the preceding items, wherein the inhalable formulation consists of, or consists essentially of, crystalline micronized epinephrine, crystalline epinephrine bitartrate, and a crystalline lactose solid carrier selected from the group consisting of crystalline alpha-lactose monohydrate and crystalline anhydrous lactose, wherein the crystalline lactose solid carrier is present in an amount of from about 50% w / w to about 99% w / w of the total formulation, optionally from about 75% w / w to about 99% w / w of the total formulation. 28. The inhalable formulation of any one of the preceding items, wherein the epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative (e.g., epinephrine bitartrate) has a Dv50 of about 1.5 μm to about 3 μm, and a Dv90 of about 2 μm to about 5 μm. 29. The inhalable formulation of any one of the preceding items, wherein the epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative (e.g., epinephrine bitartrate) has a fine particle fraction (expressed as the ratio of fine particle dose to emitted dose) of greater than 30%. 30. The inhalable formulation of any one of the preceding paragraphs, wherein the inhalable formulation is substantially unchanged after storage at 25°C and 60% relative humidity for 6 months, 12 months, or 18 months, optionally "substantially unchanged" meaning that the inhalable formulation maintains a purity by assay of at least 90%, 91%, 92%, 93%, 94%, or 95% at these time points. 31. (i) micronized crystalline epinephrine bitartrate having a Dv50 of about 1.5 μm to about 3 μm and a Dv90 of about 2 μm to about 5 μm, and (ii) crystalline α-lactose monohydrate or crystalline anhydrous lactose present in an amount of about 75% w / w to about 99% w / w of the total formulation; 10. The inhalable formulation of any one of the preceding items, wherein the inhalable formulation (a) provides a fine particle fraction, expressed as a ratio of fine particle dose to emitted dose, of greater than 30% upon manufacture, and / or (b) is stable to storage for 6 months at 25°C and 60% relative humidity. 32. An inhalable formulation according to any one of the preceding items, having a mass mean aerodynamic diameter (MMAD) of less than 5 microns after storage at 25°C and 60% relative humidity for 6 months, or 12 months, or 18 months. 33. An inhalable formulation according to any one of the preceding paragraphs, wherein the inhalable formulation provides a fine particle fraction, expressed as the ratio of fine particle dose to emitted dose, of greater than 30%, or greater than 35%, or greater than 40%, after storage at 25°C and 60% relative humidity for 6 months, or 12 months, or 18 months. 34. An inhalable formulation according to any one of the preceding items, wherein the inhalable formulation is a dry powder inhalable formulation. 35. A dry powder inhaler comprising an inhalable formulation according to any one of the preceding paragraphs. 36. A process for forming an inhalable formulation according to any one of items 1 to 34, comprising: (a) micronizing epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative; (b) combining micronized epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative with a solid carrier. 37. The inhalable formulation of any one of items 1 to 34 when produced by the process of item 36. 38. A method for delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject in need thereof, comprising: administering to a subject the inhalable formulation according to any one of items 1 to 34, thereby delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject. 39. A method of treating an epinephrine-responsive disease, disorder, or condition in a subject in need thereof, comprising: administering to a subject the inhalable formulation according to any one of items 1 to 34, thereby treating a disease, disorder, or condition in a subject. 40. The method of claim 39, wherein the epinephrine-responsive disease, disorder, or condition is selected from the group consisting of anaphylaxis, cardiac arrest, glaucoma, asthma, bronchospasm, croup, and respiratory distress. 41. The method of administration is providing a subject with an inhalable formulation according to any one of items 1 to 34; enabling a subject to inhale the inhalable formulation; thereby treating the disease, disorder, or condition in the subject. 42. The method of any one of items 39 to 41, wherein the step of providing an inhalable formulation comprises providing the subject with the dry powder inhaler of item 35. 43. The method of any one of items 39 to 42, further comprising (i) monitoring the patient, and (ii) optionally administering a further amount of the inhalable formulation of any one of items 1 to 34.

[0143] experiment Example 1: Composition of an inhalable epinephrine formulation containing lactose monohydrate as a carrier Table 1 shows six epinephrine formulations, each blended using a Turbula mixer (a low shear mixer), each containing crystalline micronized epinephrine bitartrate and alpha-lactose monohydrate (Respitose SV003). [Table 1]

[0144] Blends 1A, 1B, 1C, 1D, and 1E were filled into size 3 HPMC capsules containing 25 mg of each blend, with the 1.2%, 4%, 6%, and 12% blends corresponding to capsule strengths of 0.3 mg, 1.0 mg, 1.5 mg, and 3.0 mg epinephrine, respectively.

[0145] Example 2: Composition of an inhalable epinephrine formulation containing mannitol as a carrier Tables 2 and 3 show theoretical and actual inhalable formulations of crystalline epinephrine bitartrate with mannitol as a carrier. [Table 2] [Table 3]

[0146] Once an acceptable blend was achieved, the formulation was further processed by filling into glass vials for stability testing. No issues were encountered in performing the powder processing transfer from the bulk blend to the filled vials.

[0147] Example 3: Composition of an inhalable epinephrine formulation containing trehalose as a carrier Tables 4 and 5 show examples of theoretical and actual inhalable epinephrine compositions that include trehalose as a carrier. [Table 4] [Table 5]

[0148] Once an acceptable blend was achieved, the formulation was further processed by filling into glass vials for stability testing. No issues were encountered in performing the powder processing transfer from the bulk blend to the filled vials.

[0149] Example 4: Manufacturing Process Step 1: Micronization of API (epinephrine bitartrate) Epinephrine bitartrate active pharmaceutical ingredient (API) was sourced from Transo-Pharm Handels-GmbH (Siek, Germany). Micronization of epinephrine bitartrate (API) was performed using an air jet micronizer (MC Jetmill Type 50) and a drug feeder (K-Tron T20) to deliver epinephrine bitartrate at a controlled flow rate to the feed chute.

[0150] The API was micronized using the following milling process parameters and scale to achieve the listed yields shown in Table 6. [Table 6]

[0151] Cryogenic micronization, using a temperature-controlled variable feed system delivering a liquid nitrogen co-feed to the jet mill, was used to micronize the API of batch E80-18002M1, providing a similarly useful milling process and subsequent formulated inhalable epinephrine blend. Cryogenic micronization was found to be a suitable alternative processing mode for operating the jet mill. Nevertheless, a conventional jet mill configuration at ambient room temperature (RT) without a cryogenic feed system was also found to be a suitable process and a simpler processing configuration for producing inhalable crystalline micronized epinephrine bitartrate. Powders from both processing configurations yielded material that exhibited clear X-ray powder diffraction peaks characteristic of epinephrine bitartrate and showed virtually no evidence of amorphization (loss of crystallinity). Thus, the micronization process is surprisingly versatile, capable of delivering crystalline powders after milling, regardless of whether the temperature during milling was uncontrolled, ambient, or controlled at cryogenic, low-temperature conditions. Because some API materials undergo a significant degree of amorphization during air-jet milling (micronization), cryogenic milling, sometimes a more complex processing setup, is essential to produce an inhalable drug substance powder without compromising crystallinity. Surprisingly, epinephrine bitartrate was found not to necessarily require this, offering a versatile, simpler process option that operates at ambient or lower temperatures as needed.

[0152] The powders before and after micronization were analyzed for particle size using a laser diffraction system in dry powder sample preparation mode (Sympatec Helos, Clausthal-Zellerfeld, Germany). From the particle size analysis, data for the volume-based mean particle size (Dv50), the cumulative 90% of the volume size (Dv90), and the total volume of particles less than 5 μm in size are summarized in Table 7. [Table 7]

[0153] Crystalline epinephrine bitartrate was found to micronize well at scales ranging from 50 g to 300 g. It is generally accepted that a fraction of particles in the 0.5-5 μm size range is particularly suitable for deep lung impact deposition. Larger diameter particles may impact the throat or upper airway, while finer particles may be exhaled to some extent. Thus, particle size analysis data demonstrates that micronization using conventional ambient (RT) or cryogenic grinding conditions is useful for converting sourced epinephrine bitartrate from a state that is essentially untouchable via the lungs to bulk epinephrine bitartrate drug substance (essentially less than 5 μm, with an average size within the desired 0.5-5 μm size range). Micronization is therefore useful for processing epinephrine for inhaled drug delivery without compromising crystallinity.

[0154] Step 2: Low shear mixing of epinephrine bitartrate and lactose monohydrate Prior to blending, the micronized epinephrine bitartrate was passed through a 250 μm mesh sieve to remove any level of agglomeration, if present.

[0155] The first blending step involved mixing epinephrine bitartrate with an equal amount of lactose monohydrate, and the mixture was blended in a Turbula mixer at about 34 rpm for about 30 minutes.

[0156] The remaining lactose monohydrate required for the formulation was divided into three equal portions.

[0157] Three additional blending steps were performed by mixing the remaining one-third of the lactose monohydrate into the powder bulk, followed by blending in a Turbula mixer at about 34 rpm for about 30 minutes.

[0158] After settling, the final formulation was passed twice through a 250 μm mesh sieve before being returned to the blending vessel. The formulation was manually swirled before sampling.

[0159] The blend uniformity test results for the 1.2% (Blend Code 1B) and 6% (Blend Code 1D) formulations are summarized in Table 8. [Table 8]

[0160] The formulation blends demonstrated a high degree of blend uniformity and expected assay potency. The bulk powder was further processed via accurate weight-based filling into capsules and packaged in sealed glass bottles without desiccant. Sample capsules from each lot containing 25 mg of the blend were loaded into a Plastiape RS01 dry powder inhaler device equipped with a shortened mouthpiece and tested using a Next Generation Impactor (NGI). The aerosols were characterized for aerodynamic particle size distribution (APSD) and are summarized in Table 9. [Table 9]

[0161] This APSD data demonstrates that the blend performed surprisingly well in the RS01 device. The mass mean aerodynamic diameter (MMAD) was found to be well within the desired 0.5-5 μm range. The fine particle fraction (FPF) was observed to be significantly higher than the typical range of approximately 25-30% often observed with DPI devices. This suggests that the crystalline micronized epinephrine bitartrate particles were efficiently deaggregated from the carrier lactose particles during aerosolization. Therefore, a useful fine particle dose (FPD) was observed, demonstrating that a significant amount of the capsule drug content was delivered to the deep lung of patients requiring epinephrine. For reference, intramuscular administration of epinephrine via an autoinjector to adult anaphylactic patients is prescribed at 0.3 mg per injection. Therefore, the blend prepared in this example achieved an inhalation-delivered fine particle dose (FPD) via NGI testing that bracketed this useful therapeutic dose level (0.11-0.43 mg epinephrine).

[0162] The 6-month study was conducted on an epinephrine bitartrate and lactose monohydrate formulation (blend code 8B) with an epinephrine potency of 12% w / w. The results of the next-generation impactor testing at each time point after holding at 25°C / 60% RH are summarized in Table 10. [Table 10]

[0163] Results from the next-generation impactor testing over a six-month storage period indicate that consistent key parameters of inhalation delivery, including the desired MMAD range and FPD levels, are higher than the expected minimum required to treat patients in need via inhalation without the use of intramuscular injections.

[0164] or Step 2: High shear mixing of epinephrine bitartrate and lactose monohydrate Epinephrine bitartrate was passed through a 250 μm mesh sieve to remove any level of aggregation (if present).

[0165] Epinephrine bitartrate in an amount equivalent to 5.2 w / w epinephrine was added to a Diosna P1-6 (Germany) high shear mixer bowl containing alpha-lactose monohydrate, and the active ingredient was layered between equal amounts of lactose.

[0166] The manufacturing and sampling parameters listed in Table 11 were used sequentially to blend the remaining blends from each previous run. [Table 11]

[0167] After mixing, powder samples were taken representatively from various locations within the mixing bowl and tested by HPLC for blend uniformity. Additional blend uniformity tests were performed after settling periods of 4 and 7 days. The uniformity results are summarized in Table 12. [Table 12]

[0168] The formulation blends from Runs 1 and 3 were further processed by accurately filling capsules with a fill mass target of 25 mg, then loaded into a Plastiape RS01 dry powder inhaler device equipped with a shortened mouthpiece and tested using a next generation impactor. The results are summarized in Table 13. [Table 13]

[0169] Results from next-generation impactor testing with impeller speeds ranging from 150 RPM to 600 RPM demonstrated consistent key parameters for inhalation delivery with MMAD in the desired 1-5 μm range for deep lung delivery, with a fine particle dose slightly higher than 0.3 mg, very close to the prescribed dose for intramuscular delivery by autoinjector of epinephrine to patients suffering from anaphylaxis and requiring epinephrine.

[0170] This data also demonstrates that crystalline micronized epinephrine bitartrate formulated with lactose can be efficiently mixed by either low-shear or high-shear blending methods (e.g., using the Turbula and Diosna equipment described herein, or other similar mixer brands and types). In some cases, high-shear mixing processes can be more easily scaled up to larger batch sizes, while in other cases, small-scale lots are more conveniently blended via low-shear methods. Surprisingly, the data show that crystalline micronized epinephrine bitartrate can be blended in a robust processing regime regardless of the type of mixing equipment (level of shear). Furthermore, the APSD data verify that useful MMAD and FPD performance characteristics were observed regardless of the type of mixing technology applied.

[0171] Example 5: Aggregation experiments with epinephrine bitartrate and magnesium stearate The particle size distribution for micronized epinephrine bitartrate alone was analyzed at different time points. The results comparing the first test time point to the 4 week time point are summarized in Table 14. [Table 14]

[0172] Figures 1-3 show scanning electron microscope images corresponding to the three time points in Table 14.

[0173] Based on the significant increase in all particle size parameters and the decrease in the proportion of particles less than 10 μm, it is clear that crystalline micronized epinephrine bitartrate alone, without the addition of lactose monohydrate as a carrier, is prone to spontaneous aggregation. This degree of aggregation is excessively high for a DPI product, as aggregation would significantly reduce the proportion of available drug delivered to the deep lung, potentially below therapeutic dosage levels.

[0174] Magnesium stearate (MgSt) was added to analyze particle size distribution for crystalline micronized epinephrine bitartrate at different time points. The results comparing the first test time point to the 4-week time point are summarized in Table 15. [Table 15]

[0175] Figures 4-6 show scanning electron microscope images corresponding to the three time points in Table 15.

[0176] Magnesium stearate is commonly used as a lubricating excipient or force control agent in DPI formulations, helping to break up interparticle and particle / surface attractive forces, allowing for better dispersion of fine drug particles. From the results in Table 15, it is clear that formulations containing magnesium stearate are still prone to aggregation, even though magnesium stearate might be expected in the art to be a useful functional excipient for avoiding or minimizing aggregation.

[0177] Example 6: Flocculation experiments with the addition of lactose monohydrate [Table 16]

[0178] The formulation was manufactured using alpha-lactose monohydrate in 10% w / w API loaded with micronized crystalline epinephrine bitartrate material. Prior to blending, the API was passed through a 250 μm sieve using a palette knife with moderate manual force to help the powder pass through the screen. After sieving, no large particles remained on the sieve mesh. The API, excipient carriers, and magnesium stearate (if applicable) were then layered in a glass vial and blended in a Turbula at approximately 34 rpm for approximately 30 minutes to produce a blend.

[0179] Figures 7 (A. Epinephrine formulation before blending, B. Epinephrine formulation after blending) and 8 (A. Epinephrine formulation + MgSt before blending, B. Epinephrine formulation + MgSt after blending) show that both formulations in Table 16 are free of loose aggregates before and immediately after blending.

[0180] Example 7a: High chemical and physical stability of the formulation An extended stability study was conducted at 6 months on an epinephrine bitartrate and lactose monohydrate formulation (blend code 8B) with an epinephrine potency of 12% w / w. The results of the stability study at each time point after holding at 25°C / 60% RH are summarized in Table 17A. Note that with a blend fill weight target of 25 mg per capsule, this corresponds to an epinephrine strength of 3.0 mg per capsule.

[0181] Blend 1E was tested for stability up to 18 months at 25°C / 60% RH and the results are listed in Table 17b. [Table 17] [Table 18]

[0182] Example 7a demonstrated that a representative blend of epinephrine bitartrate blended with alpha-lactose monohydrate exhibited high chemical stability over storage and testing periods of 6 and 18 months at 25°C and 60% relative humidity (storage conditions used to simulate pharmaceutical products stored at controlled room temperature). The assay showed no significant change from the initial 3.0 mg / capsule state. The impurity profile, assessed by HPLC analysis with a 0.05% limit of quantification, showed no significant increase in impurities over the 18-month storage period, with impurity A remaining at similar levels over the 18-month period and not showing any significant increase over storage. Impurity B was detected near the limit of quantification at 3 months and again at 0.03% at 6 months, although its trace levels were below the limit of quantification. The water content did not change significantly over 6 months, with the majority of the quantified water mass corresponding to the weight of monohydrate water in the lactose excipient. This suggests that there was no significant absorption or loss of moisture in the blend over the 6-month storage period. Similar observations can be made from Table 17b over the longer 18-month testing period. Thus, the encapsulated blend of crystalline micronized epinephrine bitartrate and alpha-lactose monohydrate exhibited highly stable chemical properties over the 18-month stable storage period, supporting a drug product stored at convenient room temperature. Furthermore, Example 7a demonstrated that a representative blend of epinephrine bitartrate blended with alpha-lactose monohydrate exhibited high physical stability over the 18-month storage and testing period at 25°C and 60% room humidity (storage conditions used to simulate drug products stored at controlled room temperature).

[0183] The aerosol performance characteristics tested demonstrated adequate mean total dose of epinephrine across a wide range of inspiratory flow rates (tested with the Next Generation Impactor, NGI, and RS01 Plastiape DPI high-resistance modified device). The mass mean aerodynamic diameter (MMAD) was significantly below the 5-micron threshold with consistently low variability (GSD), supporting deep lung delivery of crystalline micronized epinephrine bitartrate from the lactose blend throughout the storage test period. Figure 9 shows a graphical representation of NGI testing of batch BN021 / 21 1.0 mg strength capsules stored at 25°C / 60% RH for 18 months. The graph demonstrates optimal distribution of epinephrine across stages 3-5, representing deep lung delivery. Thus, the encapsulated blend of crystalline micronized epinephrine bitartrate and alpha-lactose monohydrate demonstrated highly stable physical properties over an unexpected 18-month shelf life, supporting a dry powder inhalation-delivered pharmaceutical product stored at convenient room temperature.

[0184] Example 7b: High chemical and physical stability of the formulation Blend code 1C was processed as in Example 7a and then accurately filled into size 3 HPMC capsules in a manner equivalent to step 2 of Example 4. The capsules were packaged in HDPE bottles containing desiccant and stored at 25°C / 60% RH and 40°C / 75% RH for 6 months.

[0185] The results of the stability studies at each time point after holding at 25°C / 60% RH are summarized in Table 18. Note that with a blend fill weight target of 25 mg per capsule, this corresponds to an epinephrine strength of 1.0 mg per capsule. [Table 19]

[0186] The results of the stability testing at each time point after holding at 40°C / 75% RH are summarized in Table 19. Note that with a blend fill weight target of 25 mg per capsule, this corresponds to an epinephrine strength of 1.0 mg per capsule. [Table 20]

[0187] Example 7b shows similarly useful stability results for the 1.0 mg strength capsules. Additional packaging in HDPE bottles with desiccant corresponded to superior stability characteristics in real-time and accelerated storage conditions.

[0188] Example 8: Addition of lactose microparticles During the 6-month stability study in Example 7, additional formulations were blended to evaluate how the inclusion of fine alpha-lactose monohydrate carrier particles affected the stability and performance of the formulations stored at 25°C / 60% RH.

[0189] Respitose SV003 was used as the coarse lactose carrier, and Lactohale LH300 was used as the fine lactose carrier particles. Both the fine and coarse lactose materials were alpha-lactose monohydrate. As summarized in Table 20, different ratios of lactose microparticles were mixed with either standard crystalline epinephrine bitartrate or cold-micronized epinephrine bitartrate. [Table 21]

[0190] Assay results were as expected and consistent with previous time points for all formulations, verifying that product potency was stable over the storage period regardless of the presence of lactose fines or the ratio of fine to coarse lactose material in the blend.

[0191] The MMAD for all formulations plateaued after the 1-month time point, except for Formulation B, which increased slightly. For Formulation A, the FPD remained relatively consistent after the 3-month time point, and the %FPF appeared stable at the 1-month time point. For Formulation B, the FPD and %FPF decreased at each subsequent time point. For Formulation C, the FPD at 6 months was consistent with the previous time point. The %FPF increased slightly from the 3-month time point. For Formulation E, the FPD increased from the 3-month time point and was higher than at the initial time point. The %FPF remained relatively consistent across all time points.

[0192] Formulation A showed the highest percentage of deposition from 0-3 μm particles, a distribution indicative of deep lung delivery.

[0193] The delivered dose results for all formulations at 6 months were consistent with the initial time points. The water content was approximately 4% for all formulations, which was consistent with the previous time points. The %RSD was low for all formulations.

[0194] Example 9: Stability of epinephrine bitartrate + α-lactose monohydrate and epinephrine bitartrate + α-lactose monohydrate + magnesium stearate formulations Only the epinephrine bitartrate + α-lactose monohydrate composition demonstrated significantly better chemical stability than the epinephrine bitartrate + α-lactose monohydrate + magnesium stearate formulation, as shown in Tables 21 and 22 below. This is surprising, as the addition of magnesium stearate was expected to be necessary to achieve the necessary stability during storage based on the lack of stability and significant aggregation observed with epinephrine bitartrate alone. The epinephrine bitartrate + α-lactose monohydrate formulation showed a minimal increase in total related substances over the one-month stressed storage period. Meanwhile, the epinephrine bitartrate + α-lactose monohydrate + magnesium stearate formulation showed a dramatic increase in related substances, most of which were degradation products (RRT approximately 3.07). This data demonstrates a surprising level of chemical incompatibility with magnesium stearate. Total impurities increased from 0.19% at T = 0 to 2.88% at T = 1 month in the presence of magnesium stearate, whereas in the lactose blend without magnesium stearate, they increased from 0.17% at T = 0 to 0.35% at T = 1 month.

[0195] Thus, good chemical compatibility was observed in the absence of magnesium stearate, a common formulation, and with a simpler formulation of lactose monohydrate carrier only. In contrast to the typical functional effects of lactose and magnesium stearate excipients, magnesium stearate was ineffective in preventing epinephrine bitartrate aggregation and actually caused problems. On the other hand, the carrier excipient lactose was surprisingly effective in reducing the tendency of epinephrine bitartrate to self-aggregate, enabling a useful inhalable formulation with improved chemical and physical stability compared to those containing magnesium stearate. [Table 22] [Table 23]

[0196] The data table clearly shows that a surprising level of chemical stability is achieved with epinephrine bitartrate blended with lactose alone, rather than with the further addition of magnesium stearate to the epinephrine / lactose blend. This is surprising, given that magnesium stearate is one of the most widely used excipients in pharmaceuticals, and it is unusual to see this level of chemical incompatibility with magnesium stearate. Furthermore, it is surprising that a lubricant (or force control agent), such as magnesium stearate, most commonly found in DPI products, was not required at all to mitigate the strong tendency of micronized crystalline epinephrine bitartrate to self-aggregate. A simple blend with lactose monohydrate was found to be more chemically stable than when magnesium stearate was also added, and the tendency of the API to self-aggregate was no longer observed when simply blended with lactose monohydrate. It was unexpected and beneficial that a simpler formulation of an API containing lactose could have such a positive impact on chemical and physical stability.

[0197] The more complex process of spray drying, which converts crystalline solids into essentially amorphous solids, is commonly used in DPI products and has been reported by others for epinephrine. Spray drying requires dedicated, expensive processing equipment and facilities. It is a processing technique that is less readily available in contract manufacturing sites. The process requires the use of organic solvents, which can leave residues in the powder product. It also requires specific site licenses and abatement systems to allow processing with such solvents. Furthermore, the process yield of spray drying is generally lower than that of conventional micronization, and amorphous spray-dried products are thermodynamically less stable than crystalline products. For all these reasons, micronization and lactose blending are preferred and simpler processing techniques than spray drying. The simple formulation and process devised herein—micronizing crystalline epinephrine bitartrate, blending with lactose, filling capsules, and loading into dry powder inhalers—have been found to provide a highly useful process and product for pharmaceutical purposes, delivering epinephrine via a DPI to patients in need thereof.

Claims

1. 1. An inhalable formulation comprising: (i) a pharmaceutically acceptable salt of epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative, and (ii) Inhalable formulations comprising a solid carrier.

2. 10. The inhalable formulation of claim 1, wherein the pharmaceutically acceptable salt of epinephrine or the pharmaceutically acceptable salt of an epinephrine derivative is present in an amount of from about 0.01 to about 5.0 mg per unit dose of the formulation.

3. 3. The inhalable formulation of claim 1, wherein the pharmaceutically acceptable salt of epinephrine or the pharmaceutically acceptable salt of an epinephrine derivative is a salt selected from the group consisting of bitartrate, hydrochloride, maleate, malate, malonate, borate, and fumarate salts, and mixtures thereof.

4. 10. An inhalable formulation according to any one of the preceding claims, wherein the epinephrine derivative is selected from the group consisting of norepinephrine, dopamine, 3-methoxytyramine, synephrine, p-octopamine, and / or salts and mixtures thereof.

5. 10. An inhalable formulation according to any one of the preceding claims, wherein the solid carrier is selected from the group consisting of alpha-lactose monohydrate, beta-lactose, anhydrous lactose, mannitol, sucrose, and trehalose.

6. 10. An inhalable formulation according to any one of the preceding claims, wherein the inhalable formulation consists essentially of the pharmaceutically acceptable salt of epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative and a solid carrier.

7. 10. An inhalable formulation according to any one of the preceding claims, wherein the inhalable formulation does not contain any other excipients other than the solid carrier.

8. 10. An inhalable formulation according to any one of the preceding claims, wherein the inhalable formulation does not contain a pH buffering agent.

9. 10. An inhalable formulation according to any one of the preceding claims, wherein the inhalable formulation consists or consists essentially of epinephrine bitartrate and a solid carrier, preferably crystalline epinephrine bitartrate and a solid carrier.

10. 10. An inhalable formulation according to any one of the preceding claims, wherein the inhalable formulation consists of or consists essentially of epinephrine bitartrate and a lactose solid carrier, optionally an alpha-lactose monohydrate solid carrier.

11. 10. An inhalable formulation according to any one of the preceding claims, wherein the solid carrier is present in the inhalable formulation in an amount of from about 50% w / w to 99% w / w of the total formulation.

12. A dry powder inhaler comprising an inhalable formulation according to any one of the preceding claims.

13. A process for forming an inhalable formulation according to any one of claims 1 to 11, comprising the steps of: (a) micronizing the pharmaceutically acceptable salt of epinephrine or the pharmaceutically acceptable salt of an epinephrine derivative; (b) combining the micronized pharmaceutically acceptable salt of epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative with the solid carrier.

14. An inhalable formulation according to any one of claims 1 to 11 when produced by a process according to claim 13.

15. 1. A method for delivering epinephrine to a subject in need thereof, comprising: administering to the subject an inhalable formulation according to any one of claims 1 to 11; thereby delivering said epinephrine to said subject.

16. 1. A method of treating an epinephrine-responsive disease, disorder, or condition in a subject in need thereof, comprising: administering to the subject an inhalable formulation according to any one of claims 1 to 11; thereby treating said disease, disorder, or condition in said subject.

17. 17. The method of claim 16, wherein the disease, disorder, or condition is selected from the group consisting of anaphylaxis, cardiac arrest, glaucoma, asthma, bronchospasm, croup, and respiratory distress.

18. The method of administration is Providing to the subject an inhalable formulation according to any one of claims 1 to 11; allowing the subject to inhale the inhalable formulation; and b. treating said disease or condition in said subject.

19. 19. The method of any one of claims 16 to 18, wherein the step of providing the inhalable formulation comprises providing the subject with a dry powder inhaler according to claim 12.

20. 20. The method of any one of claims 16 to 19, further comprising the steps of: (i) monitoring the patient; and (ii) optionally administering a further amount of the inhalable formulation of any one of claims 1 to 11.

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