Inhalable epinephrine formulations

Abstract

Provided is an inhalable epinephrine formulation comprising 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. The formulations have been demonstrated to have a surprising level of storage stability.

Description

Technical Field

[0001] The present disclosure relates to an inhalable formulation comprising a pharmaceutically acceptable salt of adrenaline or an adrenaline derivative, and a dry powder inhaler containing the inhalable formulation. Background Art

[0002] Anaphylaxis is a severe, potentially life-threatening allergic reaction. It can be caused by many triggers, including: certain foods, such as nuts, shellfish, or eggs; insect venom, such as bee or wasp stings; certain medications, such as antibiotics or aspirin; general anesthetics, and latex. As a first response to the trigger, the immune system releases a flood of chemicals that can cause the body to go into shock. Common signs and symptoms of anaphylaxis include a rapid, weak pulse; swelling of the lips, tongue, or throat; shortness of breath and difficulty breathing; rash and itching; and stomach pain, nausea, and vomiting. If the condition is not treated right away, it can be fatal.

[0003] The main treatment for allergies is the administration of epinephrine. Epinephrine (also known as adrenaline) is a hormone and neurotransmitter that stimulates the sympathetic nervous system. There are several currently known methods of using epinephrine to treat allergies. Arguably, the best known product is the EpiPen, an automatic injector for self-administration of epinephrine. The subject is asked to poke (inject) him or herself with a needle (preferably in the thigh), causing a dose of epinephrine to be released into the muscle tissue.

[0004] While the technology does have benefits, a major drawback of this product is the harshness of the treatment method. Many patients and caregivers are reluctant to inject themselves with a needle, thus wasting necessary time in the case of an urgent life-threatening reaction. In addition, the hesitation to administer epinephrine via intramuscular injection can lead to less than optimal decisions, such as 'wait and see', or treating with an oral antihistamine approach first. The use of an auto-injector device also carries the risk of accidental needle injury.

[0005] Dry powder inhalers (DPIs) in combination with respirable dry powders are used to deliver consistent doses of pharmacological agents to the airways of a patient by inhalation 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).

[0006] U.S. Patent Publication No. 2018 / 0056022 to Liu et al. discloses a positive pressure manual DPI and the use of a combination of a DPI and a wide range of traditional Chinese medicines (TCMs) for treating diseases and conditions. Although it contemplates the delivery of pharmaceutically active substances including epinephrine, it does not actually prepare or test any such pharmaceutical grade DPI formulations, and therefore does not provide guidance to those skilled in the art regarding their stability, flow properties, or overall feasibility.

[0007] DPIs present challenges in terms of a suitable formulation that has the appropriate particle size to contain the active ingredient and maintains this throughout a reasonable storage time. It is critical to achieve the necessary balance between the components of the formulation so that the active ingredient can be delivered deep into the lung to provide an appropriately rapid response time. Summary of the invention

[0008] In a first aspect, the present disclosure resides in an inhalable formulation comprising:

[0009] (i) a pharmaceutically acceptable salt of adrenaline or a derivative thereof; and

[0010] (ii) Solid support.

[0011] In embodiments, the pharmaceutically acceptable salt of adrenaline or a derivative thereof is present in about 0.01 mg to about 15.0 mg per unit dose of the formulation.

[0012] In an embodiment, the adrenaline salt or adrenaline derivative salt is selected from the group consisting of bitartrate, hydrochloride, maleate, malate, malonate, fumarate and borate, and mixtures thereof.

[0013] In an embodiment, the adrenaline derivative is selected from the group consisting of norepinephrine, dopamine, 3-methoxytyramine, synephrine, p-octopamine, and salts and mixtures thereof.

[0014] In an embodiment, the solid carrier is selected from the group consisting of: sugars and sugar alcohols, including sugars and polysaccharides, such as lactose, mannose, sucrose, mannitol, trehalose, citrate; amino acids, such as glycine, L-leucine, isoleucine, trileucine, tartrate, methionine, vitamin A, zinc citrate, trisodium citrate, zinc chloride, polyvinylpyrrolidone; phospholipids, including phosphatidylcholine diphosphate, etc.

[0015] In one embodiment, the solid carrier is selected from the group consisting of lactose monohydrate, anhydrous lactose, sucrose, mannitol and trehalose.

[0016] When the solid carrier comprises lactose, the solid carrier may be in the α-form, β-form or a mixture thereof, and may preferably be crystalline.

[0017] When the solid carrier comprises lactose, the solid carrier may be in a monohydrate or anhydrous form.

[0018] In an embodiment, the solid carrier is a powdered solid carrier.

[0019] In an embodiment, the inhalable formulation of the first aspect is a dry powder inhalable formulation.

[0020] In an embodiment of the first aspect, the inhalable formulation or dry powder inhalable formulation consists of or consists essentially of: adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative and a solid carrier.

[0021] In a preferred embodiment, the inhalable formulation does not contain any excipients other than the solid carrier. That is, the formulation contains only the adrenaline salt or adrenaline derivative salt and a single solid carrier.

[0022] In a second aspect, the present disclosure resides in a container comprising the inhalable formulation of the first aspect.

[0023] 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.

[0024] In a third aspect, the present disclosure resides in a dry powder inhaler comprising the inhalable formulation of the first aspect.

[0025] In an embodiment, 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 hereby incorporated by reference in their entirety.

[0026] In a fourth aspect, the present disclosure is a method of forming the inhalable formulation of the first aspect, the method comprising the steps of:

[0027] (a) micronizing a pharmaceutically acceptable salt of adrenaline or an adrenaline derivative, and

[0028] (b) combining micronized adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative with a solid carrier.

[0029] In a fifth aspect, the disclosure resides in the inhalable formulation of the first aspect, when produced by the method of the fourth aspect.

[0030] In a sixth aspect, the present disclosure is a method of delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject in need thereof, the method comprising the steps of:

[0031] administering the inhalable formulation of the first aspect to the subject,

[0032] The adrenaline or pharmaceutically acceptable salt of the adrenaline derivative is thereby delivered to the subject.

[0033] In an embodiment, the method of delivering the epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to the subject comprises the following steps:

[0034] providing the inhalable formulation of the first aspect to the subject; and

[0035] allowing the subject to inhale the inhalable formulation,

[0036] The adrenaline or pharmaceutically acceptable salt of the adrenaline derivative is thereby delivered to the subject.

[0037] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise providing the dry powder inhaler of the third aspect to the subject.

[0038] 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.

[0039] In an embodiment, the method of delivering the adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative to a subject further comprises the step of loading the container into the dry powder inhaler of the third aspect.

[0040] In an embodiment, the method of delivering the adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative to a subject is a method of delivering the adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative to the lungs of a subject.

[0041] In a seventh aspect, the present disclosure is a method of preventing or treating a disease, disorder or condition responsive to adrenaline in a subject in need thereof, the method comprising the steps of:

[0042] administering the inhalable formulation of the first aspect to the subject;

[0043] The disease, disorder or condition in the subject is thereby prevented or treated.

[0044] In embodiments, the disease, disorder or condition responsive to adrenaline is selected from the group consisting of allergies, cardiac arrest, glaucoma, asthma, bronchospasm, croup and respiratory distress.

[0045] In an embodiment, the method of the seventh aspect comprises the following steps:

[0046] providing the inhalable formulation of the first aspect to the subject; and

[0047] allowing the subject to inhale the inhalable formulation,

[0048] The disease or condition in the subject is thereby treated.

[0049] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise providing the dry powder inhaler of the third aspect to the subject.

[0050] 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.

[0051] Unless explicitly indicated otherwise, each aspect or embodiment as defined herein may be combined with any other aspect or embodiment. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 : SEM (scanning electron microscope) image showing the particle size distribution of micronized adrenaline bitartrate at the initial time point.

[0053] Figure 2 : SEM images showing the particle size distribution of micronized adrenaline bitartrate at the 4 week time point (2-8°C).

[0054] Figure 3 : SEM images showing the particle size distribution of micronized adrenaline bitartrate at the 4 week time point (40°C / 75% RH).

[0055] Figure 4 : SEM images showing the particle size distribution of micronized adrenaline bitartrate and magnesium stearate at the initial time point.

[0056] Figure 5 : SEM images showing the particle size distribution of micronized adrenaline bitartrate and magnesium stearate at the 4 week time point (2-8°C).

[0057] Figure 6 : SEM images showing the particle size distribution of micronized adrenaline bitartrate and magnesium stearate at the 4 week time point (40°C / 75%RH).

[0058] Figure 7 : It is shown that the epinephrine formulation with lactose monohydrate is free of loose agglomerates before and after blending.

[0059] Figure 8 : The epinephrine formulation with lactose monohydrate and magnesium stearate was shown to be free of loose agglomerates before and after blending.

[0060] Fig. 9 : is a graphical representation of the NGI testing of batch BN021 / 21 1.0 mg strength capsules which have been stored at 25°C / 60% RH for 18 months. DETAILED DESCRIPTION

[0061] It should be understood that the preparation of the present invention comprising components as described herein can be composed of those components in another embodiment or substantially composed of those components in another embodiment. In certain embodiments, the term "comprising (comprise)" refers to including the indicated components, such as epinephrine and a solid carrier, and including other components, an activating agent and a pharmaceutically or physiologically acceptable carrier, an excipient, an emollient, a stabilizer, etc., as known in industry. The term "substantially consisting of ... consisting of (consisting essentially of)" refers to a preparation, the only major component of which is the listed component, and the preparation excludes all other components that will substantially affect the basic characteristics of the preparation. However, other compounds that are not directly related to the desired characteristics of the preparation can be included. As used herein, the term "consisting of ... consisting of (consisting of)" refers to that the preparation only includes the specifically listed components.

[0062] As used herein, the term "substantially" is a broad term and will be given its ordinary and conventional meaning to one of ordinary skill in the art and refers without limitation to a large extent but not necessarily entirely to the specified meaning. Substantially can mean that something 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% of the specified thing. For example, "substantially crystalline" may mean that a substance 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.

[0063] As used herein, the term "about" refers to a range of ±10% of the specified value or the range associated with experimental error known to one of ordinary skill in the art in measuring the specified value, whichever is greater.

[0064] It will be understood by those of ordinary skill in the art that adrenaline and adrenaline hormone are two recognized terms for the same active pharmaceutical ingredient (API), and references to adrenaline herein may be considered references to adrenaline hormone. That is, the terms may be used interchangeably herein. Additionally, the term adrenaline may refer to a single pure enantiomer of adrenaline, such as R-adrenaline or racemic adrenaline (containing a 1:1 ratio of R-enantiomer and S-enantiomer) or a mixture of enantiomers of adrenaline in any ratio.

[0065] The present disclosure describes how inhalable adrenaline salt formulations can be uniquely tailored to be delivered to a subject's lungs via a dry powder inhaler (DPI) to treat or prevent a condition, disorder or disease that responds to adrenaline. It has been surprisingly discovered that a simple formulation of a pharmaceutically acceptable salt of adrenaline or an adrenaline derivative with a solid carrier provides a stable composition having useful aerodynamic particle size distribution characteristics without the need for additional force control, lubrication, flow or other agents or excipients. In addition, it has been discovered that the use of a fine powder of a carrier (e.g., fine lactose powder) to assist in the deagglomeration of adrenaline bitartrate from alpha lactose monohydrate is not necessary to achieve an aerodynamic particle size distribution that can be used for inhalation delivery of adrenaline.

[0066] In a first aspect, the present disclosure resides in an inhalable formulation comprising:

[0067] (i) a pharmaceutically acceptable salt of adrenaline or an adrenaline derivative; and

[0068] (ii) Solid support.

[0069] In an embodiment, the pharmaceutically acceptable salt of adrenaline or a derivative thereof is a crystalline salt of adrenaline or a derivative thereof.

[0070] In an embodiment, the pharmaceutically acceptable salt of adrenaline or a derivative thereof is a crystalline salt of adrenaline.

[0071] In an embodiment, the pharmaceutically acceptable salt of adrenaline or a derivative thereof is present in the inhalable formulation at about 0.01 mg to about 15.0 mg of the formulation per unit dose. For example, a unit dose of the formulation of the first aspect may contain about 0.01 mg to about 14.0 mg, about 0.01 mg to about 13.0 mg, about 0.01 mg to about 12.0 mg, about 0.01 mg to about 11.0 mg, about 0.01 mg to about 10.0 mg, about 0.01 mg to about 9.0 mg, about 0.01 mg to about 8.0 mg, about 0.01 mg to about 7.0 mg, about 0.01 mg to about 6.0 mg, about 0.01 mg to about 5.0 mg, about 0.01 mg to about 4.5 mg, about 0.01 mg to about 4.0 mg, about 0.01 mg to about 3.5 mg, about 0.01 mg to about 3.0 mg or about 0.025 mg to about 15.0 mg, about 0.025 mg to about 14.0 mg, about 0.025 mg to about 13.0 mg, about 0.025 mg to about 12.0 mg, about 0.025 mg to about 11.0 mg, about 0.025 mg to about 10.0 mg, about 0.025 mg to about 9.0 mg, about 0.025 mg to about 8.0 mg, about 0.025 mg to about 7.0 mg, about 0.025 mg to about 6.0 mg, about 0.025 mg to about 5.0 mg, about 0.025 mg to about 4.5 mg, about 0.025 mg to about 4.0 mg, about 0.025 mg to about 3.5 mg, about 0.025 mg to about 3.0 mg, or about 0.05 mg to about 15.0 mg, about 0.05 mg to about 14.0 mg, about 0.05 mg to about 13.0 mg, about 0.05 mg to about 12.0 mg, about 0.05 mg to about 11.0 mg, about 0.05 mg to about 10.0 mg, about 0.05 mg to about 9.0 mg, about 0.05 mg to about 8.0 mg, about 0.05 mg to about 7.0 mg, about 0.05 mg to about 6.0 mg, about 0.05 mg to about 5.0 mg, about 0.05 mg to about 4.0 mg, about 0.05 mg to about 3.5 mg, about 0.05 mg to about 3.0 mg or about 0.1 mg to about 15.0 mg, about 0.1 mg to about 14.0 mg, about 0.1 mg to about 13.0 mg, about 0.1 mg to about 12.0 mg, about 0.1 mg to about 11.0 mg, about 0.1 mg to about 10.0 mg, about 0.1 mg to about 9.0 mg, about 0.1 mg to about 8.0 mg, about 0.1 mg to about 7.0 mg, about 0.1 mg to about 6.0 mg, about 0.1 mg to about 5.0 mg, about 0.1 mg to about 4.5 mg, about 0.1 mg to about 4.0 mg, about 0.1 mg to about 3.5 mg, about 0.1 mg to about 3.0 mg, or about 0.25mg to about 15.0mg, about 0.25mg to about 14.0mg, about 0.25mg to about 13.0mg, about 0.25mg to about 12.0mg, about 0.25mg to about 11.0mg, about 0.25mg to about 10.0mg, about 0.25mg to about 9.0mg, about 0.25mg to about 8.0mg, about 0.25mg to about 7.0mg, about 0.25mg to about 6.0mg, about 0.25mg to about 5.0mg, about 0.25 mg to about 4.5 mg, about 0.25 mg to about 4.0 mg, about 0.25 mg to about 3.5 mg, about 0.25 mg to about 3.0 mg, or about 0.3 mg to about 15.0 mg, about 0.3 mg to about 14.0 mg, about 0.3 mg to about 13.0 mg, about 0.3 mg to about 12.0 mg, about 0.3 mg to about 11.0 mg, about 0.3 mg to about 10.0 mg, about 0.3 mg to about 9.0 mg, ... g to about 8.0 mg, about 0.3 mg to about 7.0 mg, about 0.3 mg to about 6.0 mg, about 0.3 mg to about 5.0 mg, about 0.3 mg to about 4.5 mg, about 0.3 mg to about 4.0 mg, about 0.3 mg to about 3.5 mg, about 0.3 mg to about 3.0 mg, or about 0.5 mg to about 15.0 mg, about 0.5 mg to about 14.0 mg, about 0.5 mg to about 13.0 mg, about 0.5 mg to about 12.0 mg, about 0. .5 mg to about 11.0 mg, about 0.5 mg to about 10.0 mg, about 0.5 mg to about 9.0 mg, about 0.5 mg to about 8.0 mg, about 0.5 mg to about 7.0 mg, about 0.5 mg to about 6.0 mg, about 0.5 mg to about 5.0 mg, about 0.5 mg to about 4.5 mg, about 0.5 mg to about 4.0 mg, about 0.5 mg to about 3.5 mg, about 0.5 mg to about 3.0 mg of an adrenaline salt or an adrenaline derivative salt.

[0072] It will be appreciated by those skilled in the art that the unit dose of an adrenaline salt or adrenaline derivative salt will be determined by the final application. For example, in the treatment of asthma, when appropriately delivered, it may be sufficient to use the inhalable formulation of the first aspect at a dosage of about 0.05 mg to 0.1 mg of adrenaline. For use in the treatment of allergies, for some pediatric uses, the required dose may be between about 0.1 mg to 1.0 mg, or for some adult therapeutic dose ranges, the required dose may be between about 1.0 mg to 2.0 mg. These factors and typical therapeutic dose considerations (such as age, weight and general health of the subject) will be considered by a skilled formulator or physician and the dosage will be selected accordingly.

[0073] Those skilled in the art will appreciate that when treating anaphylactic shock in a patient, a much higher dose of the inhalable formulation of the first aspect may be used. The dose may be between about 1.0 mg and 15.0 mg, or between about 3.0 mg and 15.0 mg, or between about 5.0 mg and 15.0 mg. It may even be necessary to administer one or more additional doses of the inhalable formulation of the first aspect.

[0074] In an embodiment, the adrenaline salt or adrenaline derivative salt is selected from the group consisting of bitartrate, hydrochloride, maleate, malate, malate, fumarate and borate and mixtures thereof. In one embodiment, the adrenaline salt or adrenaline derivative salt is bitartrate. In a preferred embodiment, the adrenaline salt is adrenaline bitartrate.

[0075] It has been discovered that the salt form of epinephrine can provide significant advantages in the stability of the formulation compared to the free base form of epinephrine.

[0076] In an embodiment, the adrenaline derivative salt is selected from the group consisting of norepinephrine salts, dopamine salts, 3-methoxytyramine salts, synephrine salts, p-octopamine salts, and mixtures thereof.

[0077] In a preferred embodiment, the pharmaceutically acceptable salt of adrenaline or a derivative thereof is a pharmaceutically acceptable salt of adrenaline. However, it should be understood that certain derivatives of adrenaline or salts thereof may be present as impurities or even degradation products that do not negatively affect the efficacy of the inhalable formulation to any significant extent. For example, noradrenaline may be present in the formulation at less than about 2.5% w / w, or less than about 1.5% w / w, or less than about 1.0% w / w, or less than about 0.5% w / w.

[0078] In embodiments, the solid carrier is present in the inhalable formulation of the first aspect at 25% w / w to 99% w / w of the entire formulation. For example, the formulation of the first aspect may comprise 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 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 to 98% w / w, or 80% w / w to 98% w / w, or 85% w / w to 98% w / w, or 30% w / w to 97% w / w, or 35% w / w to 97% w / w, or 40% w / w to 97% w / w, or 45% w / w to 97% w / w, or 50% w / w to 97% w / w, or 55% w / w to 97% w / w 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% w / w to 96% w / w, or 80% w / w to 96% w / w, or 85% w / w to 96% w / w, or 30% w / w to 95% w / w, or 35% w / w to 95% w / w, or 40% w / w to 95% w / w, or 45% w / w to 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 of a solid carrier.

[0079] In embodiments, the solid carrier is 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% w / w to 92% w / w, or 86% w / w to 94% w / w. 7% 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 is present in the inhalable formulation of the first aspect.

[0080] In another preferred embodiment, when the inhalable formulation is intended for pediatric use, the solid carrier may be 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 99% w / w. The inhalable formulation of the first aspect may be present in the inhalable formulation of the first aspect in the range of 1% to 90% w / w, or 10% to 10% w / w, or 10% to 10% w / w, or 10% to 10% w / w. The inhalable formulation of the first aspect may be present in the range of 1% to 90% w / w, or 10% to 10% w / w, or 10% to 10% w / w, or 10% to 10% w / w.

[0081] In a preferred embodiment, when the solid carrier of the inhalable formulation of any embodiment of the first aspect is a 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 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 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 99% w / w. 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 to 98% w / w, or 80% w / w to 98% w / w, or 85% w / w to 98% w / w, or 30% w / w to 97% w / w, or 35% w / w to 97% w / w, or 40% w / w to 97% w / w, or 45% w / w to 97% w / w, or 50% w / w to 97% w / w, or 55% w / w to 98% 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 97% w / w, or 75% w / w to 97% w / w 5% w / w to 96% w / w, or 80% w / w to 96% w / w, or 85% w / w to 96% w / w, or 30% w / w to 95% w / w, or 35% w / w to 95% w / w, or 40% w / w to 95% w / w, or 45% w / w to 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 is present in the inhalable formulation of the first aspect. In another preferred embodiment,The lactose monohydrate and / or anhydrous lactose solid carrier is 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% w / w to 92% w / 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 is present in the inhalable formulation of the first aspect. ,

[0082] In another preferred embodiment, when the inhalable formulation is intended for pediatric use, the lactose monohydrate and / or anhydrous lactose solid carrier may be present 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 is present in the inhalable formulation of the first aspect.

[0083] Aerodynamic particle size distribution is a key parameter to consider to ensure that the inhalable formulation is delivered to the deep lung. Particles with a diameter greater than 5 μm are generally deposited in the mouth, throat or upper respiratory tract, while particles with a diameter less than 0.5 μm do not settle out of the airflow but are deposited in the lungs and are then immediately exhaled. It has been advantageously found that the inhalable formulations of the present disclosure provide a useful particle size distribution for delivering adrenaline active substances to the lungs.

[0084] In an embodiment, the median particle size distribution (Dv50) of the adrenaline salt or adrenaline derivative salt by volume is between about 0.5 μm and about 5 μm. In one embodiment, the Dv50 value of the adrenaline salt or adrenaline derivative salt is between 1 μm and about 4 μm, or between 1 μm and about 3 μm, or between 2 μm and about 3 μm.

[0085] In another embodiment, the maximum particle diameter (below which 90% of the adrenaline salt or adrenaline derivative salt exists) (Dv90) is between about 2 μm and about 5 μm. In one embodiment, the Dv90 value of the adrenaline salt or adrenaline derivative salt is between 3 μm and about 4 μm.

[0086] A range of solid carriers suitable for inhalation formulations are known in the art. In an embodiment, the solid carrier may be selected from the group consisting of sugars, sugar alcohols, citrates, amino acids and peptides, vitamins and other suitable solid carriers.

[0087] When the solid carrier is a sugar or a sugar alcohol, the solid carrier may be selected from the group consisting of lactose, mannose, sucrose, mannitol and trehalose.

[0088] When the solid carrier is a citrate, the solid carrier may be selected from the group consisting of zinc citrate and trisodium citrate.

[0089] When the solid carrier is an amino acid or a peptide, the solid carrier may be selected from the group consisting of glycine, L-leucine, isoleucine, methionine and trileucine.

[0090] When the solid carrier is a vitamin, the solid carrier may be vitamin A.

[0091] Other suitable carriers may include zinc chloride, polyvinyl pyrrolidone and phosphatidylcholine diphosphate and the like.

[0092] In one embodiment, the solid carrier is selected from the group consisting of α-lactose monohydrate, β-lactose, anhydrous lactose, mannitol, sucrose and trehalose.

[0093] When the solid carrier comprises lactose, the solid carrier may be in the α-form, β-form, or a mixture thereof, and may be crystalline in either form.

[0094] It will be appreciated by those skilled in the art that the α-lactose form can exist in both a monohydrate form and an anhydrous form. In addition, the β-form generally exists only in an anhydrous form rather than a hydrate. When the solid carrier comprises lactose, the solid carrier can be in any of these forms, either a single form or any combination. For example, in the presence or absence of an anhydrous β-form, the solid carrier can comprise α-lactose in both a monohydrate form and an anhydrous form. In combination with all of these embodiments of α-lactose and / or β-lactose, lactose can be in crystalline or amorphous form. It may be preferred that any α-lactose form and / or β-lactose form is crystalline.

[0095] In an embodiment, the solid carrier is a powdered solid carrier.

[0096] The solid carrier, optionally a lactose solid carrier, may have a particle size distribution of: D10 between 20 μm and 45 μm, optionally between 25 μm and 35 μm; D50 between 50 μm and 70 μm, optionally between 55 μm and 65 μm; and D90 between 75 μm and 105 μm, optionally between 85 μm and 100 μm. In an embodiment, the solid carrier is commercially available Respitose SV003 provided by DFE Pharma, but a similar grade of lactose solid carrier will also be suitable.

[0097] In preferred embodiments of the first aspect, the solid support comprises, consists of, or consists essentially of a crystalline solid support.

[0098] In an embodiment, a majority of the solid carrier is in crystalline form. Crystalline carriers are preferred for the inhalable formulations of the present invention because they reduce processing complexity and are thermodynamically more stable than amorphous carriers. Use of a crystalline solid carrier means that a pharmaceutical spray dryer is not required, so the solid carrier is not limited to only spray-dried processable materials, stability thermodynamics may be improved in the crystalline state, and the hygroscopicity of the crystalline adrenaline salt may be lower than that of the amorphous adrenaline salt form.

[0099] In an embodiment, the inhalable formulation of the first aspect is a dry powder inhalable formulation. That is, all components of the formulation for delivery to a subject are in substantially dry powder form.

[0100] 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.

[0101] In certain embodiments, the dry powder inhalable formulation comprises, consists of, or consists essentially of:

[0102] (i) a pharmaceutically acceptable salt of adrenaline, optionally bitartrate of adrenaline; and

[0103] (ii) a solid carrier based on lactose, optionally lactose monohydrate and / or anhydrous lactose; a solid carrier based on lactose, optionally crystalline lactose monohydrate and / or crystalline anhydrous lactose.

[0104] In certain embodiments, the dry powder inhalable formulation comprises, consists of, or consists essentially of:

[0105] (i) a pharmaceutically acceptable salt of adrenaline, optionally bitartrate of adrenaline; and

[0106] (ii) a lactose-based solid carrier, optionally lactose monohydrate and / or anhydrous lactose solid carrier, 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.

[0107] The epinephrine salt and lactose carrier can be as described in any of the previous embodiments or combinations thereof.

[0108] In an embodiment of the first aspect, the inhalable formulation or dry powder inhalable formulation consists of or consists essentially of: an adrenaline salt or an adrenaline derivative salt; and a solid carrier.

[0109] Typically, many other excipients and carriers must be added to dry powder formulations to achieve desired properties, such as the desired stability of the formulation, the correct aerodynamic particle size distribution, and the necessary anti-agglomeration properties of these particles. This may be particularly true for adrenaline, which may be challenging to formulate while maintaining stability, preventing reaction with one or more formulation components in the formulation components, and avoiding significant agglomeration and caking of the formulation. It has been surprisingly found that it is not necessary to add any additional excipients other than the selected solid carrier to a pharmaceutically acceptable adrenaline salt to form the inhalable formulation of the present disclosure and achieve the described benefits. In addition, it is not necessary to add a small portion of carrier excipients to help API deagglomerate from carrier particles. Therefore, the inhalable formulation described herein does not need to be specially designed to focus on the delivery device that realizes the deagglomeration of dry powder agglomerates. Such devices may be complex, require expensive manufacturing, and may often be unsuccessful in the deagglomeration process, thereby causing the poor delivery of the active agent. The simplicity of the inhalable formulation described herein is a significant advantage of the present invention, while maintaining the described advantages.

[0110] In an embodiment of the first aspect, the inhalable formulation does not contain, other than the listed solid carriers, any pharmaceutical agent that can be considered an excipient or that actively acts as an excipient, a secondary carrier material, a flow control agent, a lubricant, a force control agent, a pH buffer, or other additives that aid in the delivery of the active adrenaline form.

[0111] In any embodiment of the present disclosure, the inhalable formulation of the first aspect does not contain a pH buffer, such as sodium dihydrogen phosphate. Although a buffer may be required for formulations to be delivered intranasally, a buffer is not required for formulations of the present invention designed for delivery to the lungs via DPI.

[0112] Thus, when the inhalable formulation of the first aspect comprises adrenaline bitartrate and lactose monohydrate, the inhalable formulation does not comprise sodium dihydrogen phosphate.

[0113] Thus, in an example, the inhalable formulation of the first aspect comprises: (i) a pharmaceutically acceptable adrenaline salt or adrenaline derivative salt, optionally adrenaline bitartrate; and (ii) a single excipient, the single excipient being a solid carrier. Optionally, the single excipient as a solid carrier is a lactose carrier, such as lactose monohydrate and / or anhydrous lactose. The lactose carrier may comprise any ratio of α-lactose form and β-lactose form, and may be crystalline, amorphous or a mixture thereof. In certain instances, the crystalline lactose form may be preferred.

[0114] In an embodiment, the inhalable formulation comprises: (i) a pharmaceutically acceptable salt of adrenaline or an adrenaline derivative, optionally adrenaline bitartrate; and (ii) lactose monohydrate and / or anhydrous lactose.

[0115] In any embodiments of the first aspect, the adrenaline salt or adrenaline derivative salt is crystalline micronized adrenaline bitartrate.

[0116] 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 at about 50% w / w to about 99% w / w of the entire formulation, and the crystalline lactose solid carrier is selected from a lactose monohydrate solid carrier and / or an anhydrous lactose solid carrier.

[0117] 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.

[0118] In an embodiment of the first aspect, the inhalable formulation comprises, consists essentially of, or consists of: (i) micronized adrenaline bitartrate having a Dv50 of between about 0.5 μm and about 5 μm and / or a Dv90 of between about 2 μm and about 5 μm; and (i) a solid carrier, optionally a lactose solid carrier, such as lactose monohydrate and / or anhydrous lactose.

[0119] 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 between about 0.5 μm and about 5 μm and a Dv90 of between about 2 μm and about 5 μm; and (i) a solid carrier, optionally a lactose solid carrier, such as lactose monohydrate and / or anhydrous lactose.

[0120] In an embodiment, Dv50 is between about 1 μm and about 5 μm, or between about 1 μm and about 4 μm, or between about 1 μm and about 3 μm, or between about 1 μm and about 2 μm, or between about 1.5 μm and about 5 μm, or between about 1.5 μm and about 4 μm, or between about 1.5 μm and about 3 μm, or between about 1.5 μm and about 2 μm, or between about 2 μm and about 5 μm, or between about 2 μm and about 4 μm, or between about 2 μm and about 3 μm.

[0121] In one embodiment, Dv50 is between about 1.5 μm and about 3 μm.

[0122] In one embodiment, Dv50 is about 2 μm.

[0123] In embodiments, Dv90 is between about 2 μm and about 4.5 μm, or between about 2 μm and about 4 μm, or between about 2.5 μm and about 5 μm, or between about 2.5 μm and about 4.5 μm, or between about 2.5 μm and about 4 μm, between about 3 μm and about 5 μm, between about 3 μm and about 4.5 μm, or between 3 μm and about 4 μm. In embodiments, the inhalable formulation provides a fine particle fraction greater than 20%, or greater than 25%, or greater than 30%, or greater than 35%, or greater than 40%, the fine particle fraction being expressed as a percentage of the fine particle dose relative to the emitted dose.

[0124] In the embodiments, the crystalline micronized adrenaline bitartrate has not been formed by a spray drying process.

[0125] It has been found that the combination of adrenaline and lactose is particularly advantageous as an inhalable formulation. It has been found that a single adrenaline powder has a strong tendency to agglomerate. This is a major risk factor for dry powder inhaler formulations, because particle agglomeration greatly increases particle size and significantly reduces the percentage of API successfully delivered to the deep lung. In particular, it has been found that a single crystallized micronized adrenaline bitartrate will form agglomerates, and it is expected that in addition to a solid carrier, various glidants and / or anti-agglomeration agents are also required, or complex processing methods (such as spray drying) will be necessary. As described in the examples, it has been surprisingly found that when adrenaline is used in combination with a lactose carrier purely, the inhalable formulation of the present invention shows minimal signs of agglomeration. Therefore, it has been found that the inhalable formulation of the present invention is extremely stable in terms of aerodynamic particle size distribution over an extended period of time, and provides a continuous FPF for the expectation of being delivered to a subject.

[0126] As described in the examples, it has been found that the inhalable formulation comprising adrenaline salt and lactose is stable for at least 6 months at ambient temperature (25°C) and at elevated temperature (40°C). Additionally, it has been found that the formulation is stable at up to 75% relative humidity. Therefore, in an embodiment, the inhalable formulation according to the embodiment of the first aspect can be stably stored 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 an embodiment, when stored at a temperature between about ambient temperature (25°C) and about 40°C, the inhalable formulation can be stably stored 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 an embodiment, when stored at a temperature between about ambient temperature (25°C) and about 40°C and at a relative humidity between about 60% to 75%, the inhalable formulation can be stably stored 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.

[0127] 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 storage stable for 6 months at about ambient temperature (25° C.) and about 60% relative humidity.

[0128] In one embodiment, the inhalable formulation comprises, consists essentially of, or consists of: (i) micronized crystalline adrenaline bitartrate having a Dv50 of between about 1.5 μm and about 3 μm and a Dv90 of between about 2 μm and about 5 μm; and (ii) crystalline α-lactose monohydrate present at about 75% w / w to about 99% w / w of the entire formulation, wherein the dry powder inhalable formulation: (a) provides a fine particle fraction greater than 30% when manufactured, wherein the fine particle fraction is expressed as a percentage of fine particle dose relative to emitted dose; and / or (b) is storage stable for 6 months at 25°C and 60% relative humidity.

[0129] As discussed above, this stability of aerodynamic particle size distribution in the extended time period is a significant and unexpected advantage, because other processing steps or specific storage processes need not be implemented to the degree that they will reach for the inhalable formulations that tend to natural agglomeration. Additionally, the inhalable formulation of the first aspect does not need to be delivered only by a specified Diskus, which is designed to have a component or chamber for deagglomeration of agglomerate dry powder formulation purposes. When crystalline micronized adrenaline (such as adrenaline bitartrate) was proven to form significant agglomerates naturally, this situation just could not occur in the adrenaline formulation. Due to the reasons discussed further below, the challenge of avoiding or reducing adrenaline agglomeration may not yet be further expected to be solved by a single carrier and particularly by a lactose carrier.

[0130] Without wishing to be bound by theory, this unexpected effect may be due to the unexpectedly strong stabilizing effect of lactose on the adrenaline particle size distribution during long-term storage, otherwise the adrenaline (particularly adrenaline bitartrate) would tend to self-agglomerate and thus require further processing before loading or specialized equipment for delivery to a subject. This was not expected, and in fact, based on the known reactions between secondary amines (such as adrenaline) and reducing sugars (such as lactose) as discussed below, the exact opposite would be expected.

[0131] Challenges to be aware of when producing pharmaceutical formulations include undesirable side reactions, such as the Maillard reaction. The Maillard reaction is a chemical reaction between a secondary amine (such as epinephrine) and a reducing sugar (such as lactose). For example, Wirth et al. observed the Maillard reaction in all of their experiments using secondary amines and α-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, which is hereby incorporated by reference in its entirety).

[0132] As the degradation reaction proceeds, the reaction produces a noticeable browning coloration in the powder and may be problematic for adrenaline preparations. In order to prevent this reaction, additional additives such as antioxidants are usually added. In the food industry, these additives are typically sulfite compounds, such as sulfur dioxide or salts containing metabisulfite, which are known triggers for asthma, even if the amount of inhalation is very low. Therefore, it is particularly surprising that the lactose solid carrier can be used alone with adrenaline bitartrate to solve the agglomeration problem mentioned above, while not causing stability or storage difficulties based on the expected reaction between the two components. Based on the inherent problems that it is expected to bring, the combination of adrenaline salts with reducing sugars as solid carriers as the only two components of the preparation is not a naturally presented solution for a skilled formulator. The inhalable formulation of the present invention does not require or include an antioxidant.

[0133] It may therefore be particularly advantageous and surprising that the inhalable formulations of the present invention, in particular when lactose is the solid carrier, do not show any tendency to undergo side reactions. As demonstrated in the examples, the inhalable formulations have a high chemical stability even after 6 months of storage and, despite the absence of antioxidant excipients, show no signs of Maillard browning degradation. Thus, agglomeration of adrenaline alone is avoided in the claimed formulations and the expected Maillard reaction is not seen to occur even over extended storage periods.

[0134] In embodiments, the inhalable formulation consists of or consists essentially of:

[0135] (i) a pharmaceutically acceptable salt of adrenaline or an adrenaline derivative; and

[0136] (ii) lactose monohydrate and / or anhydrous lactose.

[0137] In an embodiment, the inhalable formulation consists of or consists essentially of: (i) adrenaline bitartrate; and (ii) α-lactose monohydrate and / or anhydrous α-lactose, optionally wherein the adrenaline bitartrate is crystalline adrenaline bitartrate, including micronized crystalline adrenaline bitartrate, optionally wherein the α-lactose monohydrate and / or anhydrous α-lactose is crystalline.

[0138] In an embodiment, in addition to the solid carrier, the inhalable formulation does not contain lactose fine powder. The lactose fine powder is ground and micronized lactose particles. The lactose fine powder is usually added to the dry powder inhaler formulation as a separate grade of lactose (processed by grinding, micronization, screening, grading or other methods of producing a powder with a particle size significantly smaller than that of the standard grade of lactose). Lactose fine powder is added to various drug product DPI formulations to help fine API particles deagglomerate and disperse from the solid carrier particles in the aerosol, and thus improve the delivery of API to the deep lung. Although a small amount of lactose fine powder in the inhalable formulation of the present invention may be useful or moderately beneficial, the advantage is that it is not necessary to add lactose fine powder to the adrenaline DPI formulation of the first aspect to achieve pharmaceutically useful aerodynamic particle size distribution, flowability and minimize aggregation. Surprisingly, when using conventional particle size lactose When administered in combination with aspirin, the inhalable formulations of the present invention exhibit desirable delivery properties to the deep lung.

[0139] In embodiments, when the inhalable formulation comprises lactose finely powdered, the inhalable formulation is present at 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 entire formulation.

[0140] In a preferred embodiment, the inhalable formulation does not include magnesium stearate. Magnesium stearate is a common lubricant 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 need to add magnesium stearate to show the desired properties. It is generally expected in the art that in order to achieve the appropriate aerodynamic particle size distribution of this adrenaline and solid carrier formulation, a lubricant is needed to reduce the adhesion of the powder formulation to the container and any device surface and to help the consistent processing of the encapsulation step during capsule manufacturing. The inhalable formulation of the first aspect is found not to need this additional function of magnesium stearate or any other lubricant to meet the required parameters, and in fact their absence may be beneficial.

[0141] In a second aspect, the present disclosure resides in a container comprising the inhalable formulation of the first aspect.

[0142] 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.

[0143] Such containers are well known in the art and will vary depending on the manner in which the formulation is released from the container using an appropriate delivery device during an inhalation operation. In one embodiment, the container may be a capsule adapted to be pierced by one or more actuators in the delivery device. The container may be as described in WO2020 / 257845 and / or WO2020 / 257843, but it should be understood that the present invention is not limited thereto.

[0144] In a third aspect, the present disclosure resides in a dry powder inhaler comprising the inhalable formulation of the first aspect and / or the container of the second aspect.

[0145] In an embodiment, the dry powder inhaler of the third aspect may be as described in any embodiment disclosed in WO2020 / 257845 and / or WO2020 / 257843, which are hereby incorporated by reference in their entirety.

[0146] In an embodiment, the inhalable formulation of the first aspect is provided in the form of a capsule, as described for the second aspect, which capsule is designed for use in the dry powder inhaler of the third aspect.

[0147] In a fourth aspect, the present disclosure is a method of forming the inhalable formulation of the first aspect, the method comprising the steps of:

[0148] (a) micronizing an adrenaline salt or an adrenaline derivative salt, and

[0149] (b) combining the micronized adrenaline salt or adrenaline derivative salt with the solid carrier.

[0150] In embodiments, the step of micronizing the adrenaline salt may be performed using a low temperature micronization or an ambient temperature micronization method.An advantage of the present disclosure is that low temperature micronization, while useful, is not a requirement to achieve a useful formulation.

[0151] In an embodiment, the micronized adrenaline salt or adrenaline derivative salt and the solid carrier are passed through a sieve prior to being combined.

[0152] In embodiments, the combining step is a step of dry mixing the solid carrier with the micronized adrenaline salt or adrenaline derivative salt.

[0153] In embodiments, after micronization, the median particle size distribution (Dv50) of the adrenaline salt or adrenaline derivative salt is between about 0.5 μm and about 5 μm, or between about 1 μm and about 5 μm, or between about 1 μm and about 4 μm, or between about 1 μm and about 3 μm, or between about 1 μm and about 2 μm, or between about 1.5 μm and about 5 μm, or between about 1.5 μm and about 4 μm, or between about 1.5 μm and about 3 μm, or between about 1.5 μm and about 2 μm, or between about 2 μm and about 5 μm, or between about 2 μm and about 4 μm, or between about 2 μm and about 3 μm.

[0154] In one embodiment, the median particle size distribution (Dv50) of the adrenaline salt or adrenaline derivative salt is between about 1.5 μm and about 3 μm. In an embodiment, the median particle size distribution (Dv50) of the adrenaline salt or adrenaline derivative salt is about 2.0 μm. It has been advantageously found that the particle size distribution can be stably maintained in storage for a period of at least one month.

[0155] In an embodiment, the inhalable formulation of the first aspect can be blended by low shear or high shear blending technology. The advantage of the formulation of the first aspect is that the requirements for strict processing control of any key process parameters in terms of intensity or time of blending are very low. This provides a robust method that can be more easily scaled up than methods with more process parameter criticality or sensitivity in terms of how API and solid carriers are blended. For example, the method of the fourth aspect does not require a spray drying step.

[0156] In embodiments, the method of the fourth aspect further comprises the step of packaging the inhalable formulation in a suitable container of the second aspect for use in the dry powder inhaler of the third aspect.

[0157] In a fifth aspect, the present disclosure resides in the inhalable formulation of the first aspect, when produced by the method of the fourth aspect.

[0158] In a sixth aspect, the present disclosure is a method of delivering an adrenaline salt or an adrenaline derivative salt to a subject in need thereof, the method comprising the steps of:

[0159] administering the inhalable formulation of the first aspect to the subject,

[0160] The adrenaline salt or adrenaline derivative salt is thereby delivered to the subject.

[0161] In an embodiment, the method of delivering the adrenaline salt or adrenaline derivative salt to the subject comprises the following steps:

[0162] providing the inhalable formulation of the first aspect to the subject; and

[0163] allowing the subject to inhale the inhalable formulation,

[0164] The adrenaline salt or adrenaline derivative salt is thereby delivered to the subject.

[0165] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise providing the dry powder inhaler of the third aspect to the subject.

[0166] 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.

[0167] In embodiments, the method of delivering the adrenaline salt or adrenaline derivative salt to a subject further comprises the step of loading the container into the dry powder inhaler of the third aspect.

[0168] In embodiments, the method of delivering epinephrine to a subject is a method of delivering epinephrine to the respiratory tract and in particular to the lungs of a subject.

[0169] It may be particularly advantageous to treat a subject with the inhalable formulation of the first aspect. The unique properties of the inhalable formulation (such as anti-agglomeration properties and aerodynamic particle size distribution) allow the adrenaline salt or adrenaline derivative salt to travel to the deep lungs by inhalation without being deposited in the upper respiratory tract and throat.

[0170] In an embodiment, the method of delivering adrenaline to a subject is by self-administering the inhalable formulation to the respiratory tract using the dry powder inhaler of the third aspect.

[0171] In a seventh aspect, the present disclosure is a method of treating or preventing a disease, disorder or condition responsive to adrenaline in a subject in need thereof, the method comprising the steps of:

[0172] administering the inhalable formulation of the first aspect to the subject;

[0173] The disease, disorder or condition in the subject is thereby treated or prevented.

[0174] The unique properties of inhalable formulations allow adrenaline salts or adrenaline derivative salts to reach the deep lung without delay, and therefore, the method of the seventh aspect is a rapid and convenient way to treat a disease, disorder or condition responsive to adrenaline.

[0175] In embodiments, the disease, disorder or condition responsive to adrenaline is selected from the group consisting of allergies, cardiac arrest, glaucoma, asthma, bronchospasm, croup and respiratory distress.

[0176] In an embodiment, the method of the seventh aspect comprises the following steps:

[0177] providing the inhalable formulation of the first aspect to the subject; and

[0178] allowing the subject to inhale the inhalable formulation,

[0179] The disease, disorder or condition in the subject is thereby treated or prevented.

[0180] In embodiments, the step of providing the inhalable formulation of the first aspect may comprise providing the dry powder inhaler of the third aspect to the subject.

[0181] In embodiments, said step of allowing said subject to inhale said inhalable formulation comprises a significant proportion of said inhalable formulation reaching the lungs of said subject as a result of inhalation.

[0182] 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.

[0183] Those skilled in the art will appreciate that various changes and / or modifications may be made to the above-described embodiments without departing from the broad general scope of the present disclosure. Therefore, the embodiments of the present invention should be considered in all aspects as illustrative and not restrictive.

[0184] Itemized list of embodiments:

[0185] 1. An inhalable formulation comprising, consisting of, or consisting essentially of:

[0186] (i) a pharmaceutically acceptable salt of adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative; and

[0187] (ii) Solid support.

[0188] 2. An inhalable formulation according to clause 1, wherein the adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative is present in an amount of about 0.01 mg to about 5.0 mg per unit dose of the formulation.

[0189] 3. An inhalable formulation according to clause 1 or clause 2, wherein the pharmaceutically acceptable salt of adrenaline or an adrenaline derivative is a salt selected from the group consisting of bitartrate, hydrochloride, maleate, malate, malonate, borate and fumarate.

[0190] 4. An inhalable formulation according to any of the preceding clauses, wherein the adrenaline derivative is selected from the group consisting of noradrenaline, dopamine, 3-methoxytyramine, synephrine, p-octopamine.

[0191] 5. An inhalable formulation according to any of the preceding clauses, wherein the solid carrier is selected from the group consisting of α-lactose monohydrate, β-lactose, anhydrous lactose, mannitol, sucrose and trehalose.

[0192] 6. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation does not comprise any other excipients than the solid carrier.

[0193] 7. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation does not comprise a pH buffer.

[0194] 8. An inhalable formulation according to any of the preceding clauses, wherein the solid carrier is a crystalline solid carrier.

[0195] 9. An inhalable formulation according to any of the preceding clauses, wherein the adrenaline or adrenaline derivative salt is crystalline.

[0196] 10. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of a crystalline adrenaline salt and a crystalline lactose solid carrier.

[0197] 11. An inhalable formulation according to any of the preceding clauses, wherein the solid carrier is present in the inhalable formulation at about 50% w / w to 99% w / w of the whole formulation, optionally at about 75% w / w to 99% w / w of the whole formulation.

[0198] 12. An inhalable formulation according to any of the preceding clauses, wherein the pharmaceutically acceptable salt of adrenaline or an adrenaline derivative is a micronized crystalline pharmaceutically acceptable salt of adrenaline or an adrenaline derivative.

[0199] 13. An inhalable formulation according to any of the preceding clauses, wherein the pharmaceutically acceptable salt of adrenaline or an adrenaline derivative is adrenaline bitartrate.

[0200] 14. An inhalable formulation according to any of the preceding clauses, wherein the pharmaceutically acceptable salt of adrenaline or an adrenaline derivative is crystalline adrenaline bitartrate.

[0201] 15. An inhalable formulation according to any of the preceding clauses, wherein the pharmaceutically acceptable salt of adrenaline or an adrenaline derivative is micronized crystalline adrenaline bitartrate.

[0202] 16. An inhalable formulation according to any of the preceding clauses, wherein the solid carrier is selected from the group consisting of alpha-lactose monohydrate and anhydrous lactose.

[0203] 17. An inhalable formulation according to any of the preceding clauses, wherein the solid carrier is selected from the group consisting of crystalline alpha-lactose monohydrate and crystalline anhydrous lactose.

[0204] 18. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of epinephrine bitartrate and a solid carrier.

[0205] 19. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of crystalline adrenaline bitartrate and a solid carrier.

[0206] 20. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of crystalline adrenaline bitartrate and a crystalline solid carrier.

[0207] 21. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of crystalline adrenaline bitartrate and a crystalline lactose solid carrier.

[0208] 22. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of micronized crystalline adrenaline bitartrate and a crystalline lactose solid carrier.

[0209] 23. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of: (i) crystalline adrenaline bitartrate; and (ii) a crystalline lactose solid carrier present in an amount of about 50% w / w to about 99% w / w of the entire formulation.

[0210] 24. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of: crystalline adrenaline bitartrate and a crystalline lactose solid carrier selected from the group consisting of crystalline α-lactose monohydrate and crystalline anhydrous lactose.

[0211] 25. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of micronized crystalline adrenaline bitartrate and a crystalline lactose solid carrier selected from the group consisting of crystalline α-lactose monohydrate and crystalline anhydrous lactose.

[0212] 26. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of: crystalline adrenaline bitartrate and a crystalline lactose solid carrier, the crystalline lactose solid carrier being selected from the group consisting of crystalline α-lactose monohydrate and crystalline anhydrous lactose, the crystalline lactose solid carrier being present at about 50% w / w to about 99% w / w of the entire formulation, optionally about 75% w / w to about 99% w / w of the entire formulation.

[0213] 27. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation consists of or consists essentially of micronized crystalline adrenaline bitartrate and a crystalline lactose solid carrier, the crystalline lactose solid carrier being selected from the group consisting of crystalline α-lactose monohydrate and crystalline anhydrous lactose, the crystalline lactose solid carrier being present at about 50% w / w to about 99% w / w of the entire formulation, optionally about 75% w / w to about 99% w / w of the entire formulation.

[0214] 28. An inhalable formulation according to any of the preceding clauses, wherein the pharmaceutically acceptable salt of adrenaline or an adrenaline derivative, such as adrenaline bitartrate, has a Dv50 of between about 1.5 μm and about 3 μm and a Dv90 of between about 2 μm and about 5 μm.

[0215] 29. An inhalable formulation according to any of the preceding clauses, wherein the adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative, such as adrenaline bitartrate, has a fine particle fraction greater than 30%, the fine particle fraction being expressed as a percentage of the fine particle dose relative to the emitted dose.

[0216] 30. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation remains substantially unchanged after storage at 25°C and 60% relative humidity for 6 months, or 12 months, or 18 months, optionally wherein "substantially unchanged" means maintaining at least 90%, 91%, 92%, 93%, 94% or 95% purity as determined at these time points.

[0217] 31. An inhalable formulation according to any of the preceding clauses, consisting of:

[0218] (i) micronized crystalline adrenaline bitartrate, the micronized crystalline adrenaline bitartrate having a Dv50 of between about 1.5 μm and about 3 μm and a Dv90 of between about 2 μm and about 5 μm; and

[0219] (ii) crystalline alpha-lactose monohydrate or crystalline anhydrous lactose present in an amount of about 75% w / w to about 99% w / w of the entire formulation,

[0220] The inhalable formulation: (a) provides a fine particle fraction greater than 30% when manufactured, wherein the fine particle fraction is expressed as a percentage of the fine particle dose relative to the emitted dose; and / or (b) is storage stable for 6 months at 25°C and 60% relative humidity.

[0221] 32. An inhalable formulation according to any of the preceding clauses, wherein the mass mean aerodynamic diameter (MMAD) is less than 5 microns after storage at 25°C and 60% relative humidity for 6 months, or 12 months, or 18 months.

[0222] 33. An inhalable formulation according to any of the preceding clauses, wherein after storage at 25°C and 60% relative humidity for 6 months, or 12 months, or 18 months, the inhalable formulation provides a fine particle fraction of greater than 30%, or greater than 35%, or greater than 40%, expressed as a percentage of the fine particle dose relative to the emitted dose.

[0223] 34. An inhalable formulation according to any of the preceding clauses, wherein the inhalable formulation is a dry powder inhalable formulation.

[0224] 35. A dry powder inhaler comprising an inhalable formulation according to any of the preceding clauses.

[0225] 36. A method of forming an inhalable formulation according to any one of clauses 1 to 34, the method comprising the steps of:

[0226] (a) micronizing a pharmaceutically acceptable salt of adrenaline or an adrenaline derivative, and

[0227] (b) combining micronized adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative with the solid carrier.

[0228] 37. An inhalable formulation according to any one of clauses 1 to 34, when produced by a method according to clause 36.

[0229] 38. A method of delivering epinephrine or a pharmaceutically acceptable salt of an epinephrine derivative to a subject in need thereof, the method comprising the steps of:

[0230] administering to the subject an inhalable formulation according to any one of clauses 1 to 34,

[0231] The adrenaline or pharmaceutically acceptable salt of the adrenaline derivative is thereby delivered to the subject.

[0232] 39. A method of treating a disease, disorder or condition responsive to epinephrine in a subject in need thereof, the method comprising the steps of:

[0233] administering to the subject an inhalable formulation according to any one of clauses 1 to 34;

[0234] The disease, disorder or condition in the subject is thereby treated.

[0235] 40. The method of clause 39, wherein the disease, disorder or condition responsive to adrenaline is selected from the group consisting of allergies, cardiac arrest, glaucoma, asthma, bronchospasm, croup and respiratory distress.

[0236] 41. The method according to clause 39 or clause 40, wherein the method of applying comprises the following steps:

[0237] providing the subject with an inhalable formulation according to any one of clauses 1 to 34; and

[0238] allowing the subject to inhale the inhalable formulation,

[0239] The disease, disorder or condition in the subject is thereby treated.

[0240] 42. The method according to any one of clauses 39 to 41, wherein the step of providing the inhalable formulation comprises providing the subject with a dry powder inhaler according to clause 35.

[0241] 43. A method according to any one of clauses 39 to 42, wherein the method further comprises the steps of: (i) monitoring the patient; and (ii) optionally administering a further amount of the inhalable formulation according to any one of clauses 1 to 34.

[0242] experiment

[0243] Example 1: Composition of an inhalable epinephrine preparation using lactose monohydrate as a carrier

[0244] Table 1 shows six epinephrine formulations, each blended using a Turbula mixer (low shear type mixer). Each formulation contained crystalline micronized epinephrine bitartrate and α-lactose monohydrate (Respitose SV003).

[0245] Table 1: Epinephrine blend compositions.

[0246]

[0247] Blends 1A, 1B, 1C, 1D and 1E were filled into size 3 HPMC capsules containing 25 mg of blend each. The 1.2%, 4%, 6% and 12% blends corresponded to capsule strengths of 0.3 mg, 1.0 mg, 1.5 mg and 3.0 mg epinephrine, respectively.

[0248] Example 2: Composition of an inhalable adrenaline preparation using mannitol as a carrier

[0249] Tables 2 and 3 show the theoretical and actual inhalable formulations of crystalline adrenaline bitartrate with mannitol as carrier.

[0250] Table 2: Theoretical inhalable epinephrine compositions with mannitol as carrier.

[0251]

[0252] Table 3: Actual inhalable epinephrine compositions with mannitol as carrier.

[0253]

[0254] *The target API mass of 2.838 g was adjusted to 2.85 g to account for the epinephrine potency of the specific batch of epinephrine bitartrate API used in the experiment.

[0255] After achieving acceptable blending, the formulation was further processed by filling into glass vials for stability testing. No problems were encountered in the powder handling transfer from bulk blend to filled vials.

[0256] Example 3: Composition of an inhalable adrenaline preparation using trehalose as a carrier

[0257] Tables 4 and 5 show examples of theoretical and actual inhalable adrenaline compositions using trehalose as a carrier.

[0258] Table 4: Theoretical inhalable adrenaline compositions using trehalose as carrier.

[0259]

[0260] Table 5: Actual inhalable adrenaline composition with trehalose as carrier.

[0261]

[0262] *The target API mass of 2.838 g was adjusted to 2.85 g to account for the epinephrine potency of the specific batch of epinephrine bitartrate API used in the experiment.

[0263] After achieving acceptable blending, the formulation was further processed by filling into glass vials for stability testing. No problems were encountered in the powder handling transfer from bulk blend to filled vials.

[0264] Example 4: Manufacturing process

[0265] Step 1: Micronization of API (epinephrine bitartrate)

[0266] Epinephrine bitartrate API was obtained from Transo-Pharm Handels-GmbH (Siek, Germany). Epinephrine bitartrate (API) was micronized using a jet micronizer (MC Jetmill 50 model) and a quantitative feeder (K-Tron T20) to deliver the API to the feed chute at a controlled flow rate.

[0267] The following milling process parameters and scale were used to micronize the API and achieve the listed yields as shown in Table 6:

[0268] Table 6: Micronization process parameters, scale and output yields.

[0269]

[0270] Low temperature micronization using a temperature-controlled variable feed system that delivers liquid nitrogen co-feed to a jet mill is used to micronize the API in batch E80-18002M1, and provides a similar useful grinding process and a subsequently formulated inhalable adrenaline blend. It was found that low temperature micronization is a suitable alternative processing mode for operating a jet mill. Nevertheless, it was also found that ambient room temperature (RT) conventional jet milling configuration (without a low temperature feed system) is a method and a simpler process configuration suitable for producing inhalable crystalline micronized adrenaline bitartrate. The material produced from the powder of any processing configuration shows a distinct X-ray powder diffraction peak unique to adrenaline bitartrate, and there is no obvious sign of amorphization (loss of crystallinity). Therefore, surprisingly, the micronization method is versatile, capable of delivering crystalline powders after grinding, regardless of whether the temperature during grinding is an uncontrolled ambient temperature, or whether the temperature is controlled to a cryogenic condition. Since some API materials undergo a significant degree of amorphization during air jet milling (micronization), cryogenic milling is sometimes a substantially more complex processing configuration for producing an inhalable API powder without loss of crystallinity. It was surprisingly discovered that adrenaline bitartrate does not necessarily require this process, giving a simpler process option with the versatility of operating at ambient or colder temperatures when desired.

[0271] The particle size of the powders before and after micronization was analyzed using a laser diffraction system in dry powder sample preparation mode (Sympatec Helos, Clausthal-Zellerfeld, Germany). Based on the particle size analysis, the data of the volume-based average particle size (Dv50), the cumulative 90% volume size (Dv90) and the total volume of particles with a size less than 5 μm are summarized in Table 7.

[0272] Table 7: Micronization results.

[0273]

[0274] It was found that crystalline adrenaline bitartrate micronized in a robust manner in a scale ranging from 50g to 300g. For powders that impact and deposit in the deep lung, the particle fraction in the 0.5–5μm size range is generally considered to be particularly suitable for this. Larger diameter particles may affect the throat or upper respiratory tract, and finer particles may be exhaled to some extent. Therefore, the particle size analysis data indicate that micronization by conventional ambient (RT) or cryogenic grinding conditions can be used to convert the obtained adrenaline bitartrate from a substantially non-deliverable state through the lungs into an adrenaline bitartrate bulk drug substance that is substantially less than 5μm, and where the average size is within the desired 0.5–5μm size range. Therefore, micronization can be used to process adrenaline for inhaled drug delivery without losing crystallinity.

[0275] Step 2: Low shear mixing of epinephrine bitartrate and lactose monohydrate

[0276] Prior to blending, the micronized adrenaline bitartrate was passed through a 250 μm mesh screen to eliminate any level of agglomeration, if present.

[0277] The first blending step involved mixing epinephrine bitartrate with an equal amount of lactose monohydrate and blending the mixture in a Turbula mixer at approximately 34 rpm for approximately 30 minutes.

[0278] The remainder of the lactose monohydrate required for the formulation was divided into three equal amounts.

[0279] Three additional blending steps were performed by mixing one third of the remaining lactose monohydrate into the powder bulk, followed by blending in a Turbula mixer at approximately 34 rpm for approximately 30 minutes.

[0280] After standing, the final formulation was passed through a 250 μm mesh screen twice and returned to the blending vessel. The formulation was manually spun before sampling.

[0281] The blend uniformity test results for the 1.2% (Blend Code 1B) and 6% (Blend Code 1D) formulations are summarized in Table 8.

[0282] Table 8: Crystallized micronized blended epinephrine blend homogeneity testing results by representative sampling and HPLC analysis testing (n=10).

[0283]

[0284] The formulation blends showed a high degree of blend uniformity and expected assay (efficacy). The bulk powder was further processed into capsules by accurate weight-based filling and packaged into sealed glass jars without desiccant. Each batch of sample capsules containing 25 mg of the blend was loaded into a Plastiape RS01 dry powder inhaler device with a shortened interface and tested using a next generation impactor (NGI). The aerosol was characterized by the aerodynamic particle size distribution (APSD) summarized in Table 9.

[0285] Table 9: Aerodynamic particle size data for crystallized micronized lactose blended epinephrine bitartrate (NGI results).

[0286]

[0287] a is expressed as the fine particle fraction (FPF) expressed as a percentage of the fine particle dose relative to the ejected dose.

[0288] The APSD data show that the blend performs surprisingly well in the RS01 device. The mass mean aerodynamic diameter (MMAD) was found to be well within the desired range of 0.5-5 μm. The fine particle fraction (FPF) was observed to be significantly higher than the typical range of approximately 25–30% often observed for DPI devices, indicating that the crystalline micronized adrenaline bitartrate particles were effectively deagglomerated from the carrier lactose particles during atomization. Therefore, a useful fine particle dose (FPD) was observed, indicating that a significant amount of the capsule drug contents would be delivered to the deep lungs of patients who need adrenaline. For reference, the prescribed dose of adrenaline administered intramuscularly to adult allergy patients via an automatic injector is 0.3 mg per injection. Therefore, the blend prepared in this example achieved an inhaled delivery fine particle dose (FPD) that included this useful therapeutic drug dose level (0.11–0.43 mg adrenaline) in the range through the NGI test.

[0289] A 6 month time point study was conducted on an epinephrine bitartrate and lactose monohydrate formulation (blend code 8B) at an epinephrine potency of 12% w / w. The Next Generation Impactor test results at each time point after holding at 25°C / 60% RH are summarized in Table 10.

[0290] Table 10: Next Generation Impactor Results for 12% w / w Epinephrine Blend (Blend Code 8B).

[0291]

[0292]

[0293] Next Generation Impactor testing results over 6 months of storage showed consistent key parameters for inhalation delivery, including the desired MMAD range and FPD levels above the expected minimum required to treat patients in need by inhalation without the use of intramuscular injection.

[0294] Alternatively, step 2: high shear mixing of adrenaline bitartrate and lactose monohydrate

[0295] The epinephrine bitartrate was passed through a 250 μm mesh screen to eliminate any level of agglomeration, if present.

[0296] Epinephrine bitartrate in an amount equivalent to 5.2% w / w epinephrine was added to the bowl of a Diosna P1-6 (Germany) high shear mixer with alpha-lactose monohydrate, layering the active ingredient between equal parts of lactose.

[0297] The manufacturing and sampling parameters listed in Table 11 were used in a continuous manner to blend the remaining blends from the corresponding previous runs.

[0298] Table 11: Manufacturing and sampling parameters for high shear blending of crystalline epinephrine bitartrate with alpha-lactose monohydrate.

[0299]

[0300] After mixing, powder samples were representatively taken from various locations in the mixing bowl and tested for blend uniformity by HPLC. Additional blend uniformity testing was performed after a 4-day and 7-day rest period. The uniformity results are summarized in Table 12.

[0301] Table 12: Homogeneity test results of epinephrine blends after high shear mixing

[0302]

[0303]

[0304] The formulation blends from Runs 1 and 3 were further processed by accurately filling into capsules at a 25 mg fill mass target and then loaded into a Plastiape RS01 dry powder inhaler device with a shortened interface and tested using a Next Generation Impactor. The results are summarized in Table 13.

[0305] Table 13: Next generation impactor results.

[0306] run MMAD(μm) FPD<5μm(mg) <![CDATA[FPF a (%)]]> 1 2.65 0.38 41.84 3 2.66 0.39 44.77

[0307] a Fine particle fraction (FPF) expressed as a percentage of the fine particle dose relative to the emitted dose.

[0308] Results from the next generation impactor testing with impeller speeds ranging from 150 RPM to 600 RPM showed the key parameters of consistent inhalation delivery, with the MMAD within the desired 1-5 μm range for delivery to the deep lung, and with the fine particle dose very close to and slightly above the 0.3 mg prescription dose for autoinjector intramuscular delivery of epinephrine to patients with allergies who require epinephrine.

[0309] The data also demonstrates that crystallized micronized adrenaline bitartrate formulated with lactose can be effectively mixed by low shear or high shear blending methods (e.g., using Turbula and Diosna equipment, or other similar brands and types of mixing machines herein). In some cases, high shear mixing processes can be more easily scaled up to larger batch sizes, and in other cases, small-scale batches are more convenient to blend by low shear methods. The data surprisingly show that crystallized micronized adrenaline bitartrate can be blended in a robust processing manner, regardless of the type of mixing equipment (shear force level). In addition, the APSD data confirms that useful MMAD and FPD performance characteristics are observed, regardless of the type of mixing technology applied.

[0310] Example 5: Agglomeration experiment of adrenaline bitartrate and magnesium stearate

[0311] The particle size distribution of micronized adrenaline bitartrate alone was analyzed at different time points. The results comparing the initial test time point with the 4 week time point are summarized in Table 14.

[0312] Table 14: Particle size distribution of micronized adrenaline bitartrate.

[0313]

[0314]

[0315] Figures 1 to 3 Scanning electron microscope images corresponding to the three time points in Table 14 are shown.

[0316] Based on the significant increase in all particle size parameters and the decrease in the proportion of particles less than 10 μm, it is apparent that crystalline micronized epinephrine bitartrate alone, without the addition of lactose monohydrate as a carrier, naturally tends to agglomerate. This degree of agglomeration is too high for a DPI product, as the proportion of drug available for delivery to the deep lung would be substantially reduced to potentially subtherapeutic dosing levels due to agglomeration.

[0317] The particle size distribution of crystallized micronized adrenaline bitartrate was analyzed at different time points with the addition of magnesium stearate (MgSt). The results comparing the initial test time point with the 4 week time point are summarized in Table 15.

[0318] Table 15: Particle size distribution of micronized adrenaline bitartrate and MgSt.

[0319] Time Dv10(μm) Dv50(μm) Dv90(μm) Volume less than 10μm(%) initial 0.265 1.15 4.2 94.88 4 weeks (2-8℃) 0.952 95.1 524 33.78 4 weeks (40℃ / 75%RH) 8.07 181 434 10.82

[0320] Figures 4 to 6 Scanning electron microscope images corresponding to the three time points in Table 15 are shown.

[0321] Magnesium stearate is often used as a lubricant excipient or force control agent in DPI formulations to help break up inter-particle and particle / surface attractions, allowing fine drug particles to disperse better. It is clear from the results in Table 15 that formulations with magnesium stearate still tend to agglomerate, even though it might be expected in the art that magnesium stearate would be a useful functional excipient for avoiding or minimizing agglomeration.

[0322] Example 6: Agglomeration experiment with addition of lactose monohydrate

[0323] Table 16: Crystalline micronized adrenaline bitartrate formulation with alpha-lactose monohydrate as carrier.

[0324] preparation Drug amount (g) Carrier Magnesium stearate content (g) Scale(g) 1 0.2 Lactose Monohydrate - 2 2 0.2 Lactose Monohydrate 0.04 2

[0325] The formulation was prepared with 10% w / w API loading of alpha-lactose monohydrate and micronized crystalline adrenaline bitartrate material. Prior to blending, the API was passed through a 250 μm sieve using a tray knife with moderate manual force to help the powder pass through the sieve. No large particles remained on the sieve after sieving. The blend was then produced by layering the API with the excipient carrier and magnesium stearate (where appropriate) in a glass vial and mixing by Turbula at approximately 34 rpm for approximately 30 minutes.

[0326] Figure 7 (A. epinephrine formulation, before blending; B. epinephrine formulation, after blending) and 8 (A. epinephrine formulation, before blending, +MgSt; B. epinephrine formulation, after blending, +MgSt) show that both formulations of Table 16 contained no loose agglomerates both before and immediately after mixing.

[0327] Example 7a: High chemical and physical stability of the formulation

[0328] A 6 month duration stability study was conducted on an epinephrine bitartrate and lactose monohydrate formulation (blend code 8B) at a potency of 12% w / w of an epinephrine blend. The results of the stability testing at each time point after holding at 25°C / 60% RH are summarized in Table 17a. Note that at a 25 mg / capsule blend fill weight target, this corresponds to a 3.0 mg epinephrine strength / capsule.

[0329] The stability of Blend IE was tested at 25°C / 60% RH for up to 18 months and the results are described in Table 17b.

[0330] Table 17a: Summary of 6 month chemical and physical stability data for epinephrine bitartrate and lactose monohydrate formulations (blend code 8B) stored at 25°C / 60% RH.

[0331]

[0332] RT – retention time on the HPLC chromatograph used for the analysis of impurities, FPD – fine particle dose, FPF – fine particle fraction, MMAD – mass median aerodynamic diameter, GSD – geometric standard deviation; the limit of quantification of related substance impurities is 0.05%; the test was performed with a Plastiape RS01 modified with a shortened interface.

[0333] Table 17b: Summary of 18 month chemical and physical stability data for epinephrine bitartrate and lactose monohydrate formulations (blend code IE / batch BN022 / 21 3.0 mg concentration) stored at 25°C / 60% RH.

[0334]

[0335]

[0336] Example 7a demonstrates that a representative blend of adrenaline bitartrate blended with alpha-lactose monohydrate exhibits high chemical stability during storage and testing for 6 and 18 months at 25°C and 60% relative humidity as storage conditions for drug products simulating controlled room temperature storage. No significant changes were observed in the assay relative to the initial state of 3.0 mg / capsule. The impurity profile evaluated by HPLC analysis with a limit of quantification of 0.05% showed that no impurities increased significantly even within 18 months of storage, with impurity A remaining at a similar level within 18 months without any significant increase over time during storage. At 3 months, impurity B was detected near the limit of quantification, and at the 6-month time point, impurity B was detected again at a value of 0.03%, but at the trace level, the amount was below the limit of quantification. The water content did not show significant changes over a 6-month period, and most of the quantified water mass corresponded to the weight of monohydrate water in the lactose excipient. This indicates that the blend had no significant moisture absorption or loss over a 6-month storage period. Similar observations can be made from Table 17b even over the extended 18 month testing period. Thus, the encapsulated blend of crystallized micronized adrenaline bitartrate and alpha-lactose monohydrate exhibits highly stable chemical properties over 18 months of stability storage and supports a convenient room temperature storage drug product. In addition, Example 7a demonstrates that a representative blend of adrenaline bitartrate and alpha-lactose monohydrate exhibits high physical stability over an 18 month period of storage and testing at 25°C and 60% room humidity, which are storage conditions for drug products that simulate controlled room temperature storage.

[0337] The tested aerosol performance properties indicated an adequate average total delivered dose of epinephrine across a wide range of inhalation flow rates (tested by the Next Generation Impactor NGI and with the RS01 Plastiape DPI High Resistance Modified Device). The mass mean aerodynamic diameter (MMAD) remained significantly below the 5 micron threshold and had a consistently low variability (GSD) throughout the storage test period, supporting deep lung delivery of micronized epinephrine bitartrate from the crystals of the lactose blend. Fig. 9 is a graphical representation of NGI testing of batch BN021 / 21 1.0 mg strength capsules that have been stored at 25°C / 60% RH for 18 months. The graph shows the best distribution of epinephrine across stages 3 to 5, indicating delivery to the deep lung. Thus, the encapsulated blend of crystalline micronized epinephrine bitartrate and alpha-lactose monohydrate exhibits highly stable physical properties over an unexpected 18-month stability storage and supports a convenient room temperature stored dry powder inhalation delivered drug product.

[0338] Example 7b: High chemical and physical stability of the formulation

[0339] Blend Code 1C was processed similar to Example 7a and then filled into size 3 HPMC capsules exactly in a manner equivalent to Example 4, step 2. The capsules were packaged into HDPE bottles with desiccant and stored at 25°C / 60% RH and 40°C / 75% RH for 6 months.

[0340] The results of the stability testing at each time point after holding at 25°C / 60% RH are summarized in Table 18. Note that at the 25 mg / capsule blend fill weight target, this corresponds to a 1.0 mg epinephrine strength / capsule.

[0341] Table 18: Summary of 18 month chemical and physical stability data for epinephrine bitartrate and lactose monohydrate formulations (blend code 1C) stored at 25°C / 60% RH.

[0342]

[0343] FPD – fine particle dose, FPF – fine particle fraction expressed as a percentage of fine particle dose relative to the ejected dose, MMAD – mass median aerodynamic diameter, The limit of quantification of related substance impurities is 0.05%, The following related substances are within the specified acceptance criteria: Impurity A – <0.3, Impurity C – <0.2, Impurity D – <0.1, Impurity E – <0.1, Each unspecified impurity – <0.5; Impurity B is the only impurity detected and quantified across the tested time points; Tested with Plastiape RS01 modified with a shortened interface.

[0344] The results of the stability testing at each time point after holding at 40°C / 75% RH are summarized in Table 19. Note that at the 25 mg / capsule blend fill weight target, this corresponds to a 1.0 mg epinephrine strength / capsule.

[0345] Table 19: Summary of 6 month chemical and physical stability data for epinephrine bitartrate and lactose monohydrate formulations (blend code 1C) stored at 40°C / 75% RH.

[0346]

[0347]

[0348] FPD – fine particle dose, FPF – fine particle fraction expressed as a percentage of fine particle dose relative to the ejected dose, MMAD – mass median aerodynamic diameter, The limit of quantification of related substance impurities is 0.05%, The following related substances are within the specified acceptance criteria: Impurity A – <0.3, Impurity C – <0.2, Impurity D – <0.1, Impurity E – <0.1, Each unspecified impurity – <0.5; Impurity B is the only impurity detected and quantified across the tested time points; Tested with Plastiape RS01 modified with a shortened interface.

[0349] Example 7b demonstrates similar useful stability results for 1.0 mg strength capsules.Additional packaging in HDPE bottles with desiccant corresponds to excellent stability properties under both immediate and accelerated storage conditions.

[0350] Example 8: Adding lactose powder

[0351] 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 would affect the stability and performance of the formulations stored at 25°C / 60% RH.

[0352] Respitose SV003 was used as a coarse lactose carrier and Lactohale LH300 was used as a fine lactose carrier particle. Both the fine lactose material and the coarse lactose material were α-lactose monohydrate. Different ratios of lactose fine powder were mixed with standard crystallized micronized adrenaline bitartrate or low temperature micronized adrenaline bitartrate as summarized in Table 20.

[0353] Table 20: Formulations with crude lactose and fine lactose powder.

[0354]

[0355] *Purity and salt / base conversion adjusted to achieve 12% w / w epinephrine blend potency

[0356] The assay results for all formulations were as expected and consistent with previous time points, demonstrating that the product potency was stable over the storage period regardless of the presence of lactose fines or the ratio of fines to coarse lactose material in the blend.

[0357] The MMAD for all formulations plateaued after the one month time point, with the exception of Formulation B which increased slightly. For Formulation A, the FPD remained relatively consistent after the 3 month time point, and the %FPF appeared to have stabilized at the 1 month time point. For Formulation B, the FPD and %FPF decreased with each subsequent time point. For Formulation C, the FPD at the 6 month time point was consistent with the previous time point. The %FPF increased slightly since the 3 month time point. For Formulation E, the FPD has increased since the 3 month time point and is higher than the initial time point. The %FPF remained relatively consistent across all time points.

[0358] Formulation A showed the highest deposition ratio of particles in the range of 0-3 μm, a distribution indicative of deep lung delivery.

[0359] The delivered dose results for all formulations at the 6 month time point were consistent with the initial time point. The water content for all formulations was approximately 4%, which was consistent with the previous time point. The RSD% was low for all formulations.

[0360] Example 9: Stability of epinephrine bitartrate + α-lactose monohydrate formulation vs. epinephrine bitartrate + α-lactose monohydrate + magnesium stearate formulation

[0361] As demonstrated in Tables 21 and 22 below, only the composition of bitartrate adrenaline + alpha-lactose monohydrate shows a chemical stability significantly superior to bitartrate adrenaline + alpha-lactose monohydrate + magnesium stearate formulations. This is surprising, because based on the lack of stability observed in the case of separate bitartrate adrenaline and significant agglomeration, it is expected that magnesium stearate will need to be added to achieve the stability required for storage. The sum of related substances produced in the pressure storage of 1 month period shows that the increase of bitartrate adrenaline + alpha-lactose monohydrate is minimal. At the same time, for bitartrate adrenaline + alpha-lactose monohydrate + magnesium stearate formulations, related substances increase significantly, most of which are degradation products with RRT of about 3.07. The data show that there is a surprising level of chemical incompatibility with magnesium stearate. In the presence of magnesium stearate, total impurities increased from 0.19% at T=0 to 2.88% at T=1 month, but in the lactose blend without magnesium stearate, total impurities increased from 0.17% at T=0 to 0.35% at T=1 month.

[0362] Thus, good chemical compatibility is observed in the absence of magnesium stearate, a commonly used formulation agent, and in the case of a simpler composition with only lactose monohydrate carrier. In contrast to the typical functional effects of lactose and magnesium stearate excipients, magnesium stearate is not effective in preventing agglomeration of adrenaline bitartrate and in fact causes difficulties. At the same time, lactose, a carrier excipient, is surprisingly effective in reducing the tendency of adrenaline bitartrate to self-agglomerate and allows useful inhalable formulations with improved chemical and physical stability compared to inhalable formulations containing magnesium stearate.

[0363] Table 21: Results from related substances testing of 10% micronized epinephrine bitartrate + lactose monohydrate.

[0364]

[0365] ND – Not Detected

[0366] Table 22: Results from related substance testing of 10% micronized epinephrine bitartrate + lactose monohydrate + magnesium stearate.

[0367]

[0368] ND – Not Detected

[0369] The data table clearly shows that surprising chemical stability levels are achieved by blending epinephrine bitartrate with lactose alone, but not by further adding magnesium stearate to the epinephrine / lactose blend. This is surprising considering that magnesium stearate is one of the most widely used excipients in pharmaceutical products, and it is unusual to see this level of chemical incompatibility with magnesium stearate. In addition, surprisingly, no lubricant (or force control agent) (most commonly as magnesium stearate in DPI products) is needed at all to mitigate the strong tendency of micronized crystalline epinephrine bitartrate to self-agglomerate. It is found that simple blending with lactose monohydrate is also more stable chemically than simple blending with added magnesium stearate, and once simply blended with lactose monohydrate, the self-agglomeration tendency of the API can no longer be seen. Unexpectedly and usefully, the simpler composition of API with lactose has such a positive effect on chemical and physical stability.

[0370] More complex spray drying processing methods (converting the crystalline solid state into a substantially amorphous solid state) are commonly used for DPI products and reported by others for epinephrine. Spray drying requires specialized expensive processing equipment and facilities. The spray drying is a processing technology that is not very suitable for contract manufacturing sites. The spray drying requires the use of organic solvents in the processing, which may leave residues in the powdered product, and also requires specific site permits and emission reduction systems to allow the use of such solvents for processing. In addition, the process yield of spray drying is generally less than conventional micronization, and the amorphous spray-dried product is thermodynamically more unstable than the crystalline product. For all these reasons, micronization and lactose blending are preferred and are simpler processing techniques than spray drying. It is found that the simple formulation and processing of micronizing crystalline bitartrate epinephrine and blending it with lactose, filling it into capsules and loading it into a dry powder inhaler, which is contemplated here, realizes a highly useful method and product for the purpose of delivering epinephrine to patients in need through a DPI.

Claims

1. An inhalable formulation comprising: (i) a pharmaceutically acceptable salt of adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative; and (ii) Solid support.

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

3. An inhalable formulation according to claim 1 or claim 2, wherein the pharmaceutically acceptable salt of adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative is a salt selected from the group consisting of bitartrate, hydrochloride, maleate, malate, malonate, borate and fumarate, and mixtures thereof.

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

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

6. An inhalable formulation according to any one of the preceding claims, wherein the inhalable formulation consists essentially of: A pharmaceutically acceptable salt of adrenaline or a pharmaceutically acceptable salt of an adrenaline derivative; and a solid support.

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

8. An inhalable formulation according to any one of the preceding claims, wherein the inhalable formulation does not comprise a pH buffer.

9. 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 solid carrier, preferably crystalline epinephrine bitartrate and a solid carrier.

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. An inhalable formulation according to any one of the preceding claims, wherein the solid carrier is present in the inhalable formulation at about 50% w / w to 99% w / w of the entire formulation.

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

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

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

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

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

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

18. The method according to claim 16 or claim 17, wherein the administration method comprises the following steps: providing the subject with an inhalable formulation according to any one of claims 1 to 11; and allowing the subject to inhale the inhalable formulation, The disease or condition in the subject is thereby treated.

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. The method according to any one of claims 16 to 19, wherein the method further comprises the following steps: (i) monitoring the patient; and (ii) optionally administering an additional amount of An inhalable formulation according to any one of claims 1 to 11.

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