Novel pharmaceutical devices for use in intranasal administration - Patent Application 20070229633

Abstract

In accordance with the present invention, there is provided a needleless applicator suitable for administering a solid amorphous single particle powder composition to a body cavity of a human patient, the cavity comprising a mucosal surface, the applicator comprising: (i) an opaque reservoir containing the powder composition; (ii) an optional actuation means for generating a force upon actuation of the device by a user; and (iii) a dispensing means through which the powder composition may be dispensed following said actuation, the powder composition comprising a pharmacologically effective dosage amount of an adrenergic receptor modulator or a pharma- ceutically acceptable salt thereof encapsulated in an amorphous state together with a pharmacologically acceptable carrier material, the powder composition being chemically degraded by less than about 4% after storage of (a) at least about 3 months at 40° C. and 75% relative humidity, (b) at least about 18 months at less than about 30° C., and / or (c) at least about 18 hours in UV light greater than about 1 million lux. The composition for use in the applicator is preferably made by spray drying, and the carrier material may include a disaccharide, such as lactose or trehalose, and maltodextrin, which may be combined with the active ingredient and spray dried. The composition may further include one or more alkyl sugars. Preferred alkyl sugars include sucrose esters, such as sucrose monolaurate. Preferred adrenergic receptor modulators include epinephrine (adrenaline). Thus, the composition is particularly useful in treating allergic reactions, including anaphylaxis.

Description

[Technical field]

[0001] The present invention relates to novel medical devices and methods for their manufacture.

[0002] Prior Art and Background The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or common general knowledge.

[0003] In the treatment of acute disorders, a more rapid onset of pharmacological effect than can be achieved by oral drug delivery is often highly desirable. Administration principles that ensure that the drug is immediately available in the systemic circulation are more likely to result in a rapid onset of action.

[0004] Adrenaline, also known as epinephrine, is an endogenous hormone secreted primarily by the medulla of the adrenal gland, but also by a small number of neurons. Its main role in the body is as a stimulant of components of the sympathetic nervous system. Adrenaline is typically released during stressful situations and plays a key role in the fight-or-flight response by increasing blood flow to muscles, cardiac output, pupil dilation, and plasma glucose levels. It exerts this effect by binding to and stimulating alpha and beta adrenergic receptors.

[0005] Adrenaline was first isolated in the late 19th century and is now commonly used exogenously as a drug to treat, for example, allergic reactions (including anaphylaxis) and cardiac arrest, as well as croup and asthma.

[0006] For the treatment, particularly emergency treatment, of severe and / or acute conditions such as allergic reactions, including severe allergic reactions, anaphylaxis, and anaphylactic shock (which may be caused by insect venom from stings or bites, certain foods or drugs, and other chemicals such as latex), adrenaline is currently administered parenterally, for example by subcutaneous, intravenous, or intramuscular injection, along with other emergency medical interventions.

[0007] Individuals susceptible to such severe allergic reactions typically carry adrenaline auto-injectors to be self-administered in emergencies. Auto-injectors are typically single-use, disposable, spring-loaded syringes intended for self-administration by the patient or administration by untrained people or first responders.

[0008] The most common adrenaline auto-injector devices are sold under the brand names EpiPen® and EpiPen® Jr., but are also sold under other brand names such as Adrenaclick® and Auvi-Q®.

[0009] Injectable delivery means are often considered inconvenient: it is sometimes very difficult, if not impossible, for patients to self-administer drugs via a needle, sometimes requiring wasteful and time-consuming intervention by first responders and / or physicians to ensure compliance and avoid any unwanted or harmful effects.

[0010] Moreover, all of the above auto-injectors contain a solution of adrenaline, which is chemically very unstable. In fact, the EpiPen product label instructs that the product should be stored in its original packaging at room temperature (specifically 20°C to 25°C) and away from light and moisture. It cannot be refrigerated or frozen (e.g., to improve the stability of the product) as this would result in loss of performance of the device in an emergency (due to the need to inject a liquid solution through a thin needle).

[0011] Even under prescribed storage conditions, the shelf life of an EpiPen is only up to 24 months, and that of Epipen Jr. is only up to 19 months. Furthermore, due to storage time during distribution, this shelf life is often reduced by as much as 12 months by the time end users are prescribed or obtain their devices. Users are instructed on the product label to replace the unit before its expiration date.

[0012] Due to the instability of epinephrine solutions, common to all auto-injectors, the EpiPen also contains an inspection window, through which the user is instructed to inspect the product on the product label, specifically to visually check for particulates (precipitate) or discoloration. If such particles and / or discoloration are present, the user is instructed to replace the unit, even if this occurs before the expiration date.

[0013] These factors combine to increase the number of unused and wastefully discarded adrenaline auto-injectors, but in addition, adrenaline solutions tend to contain stabilizers (antioxidants), more specifically sulfites, to which many patients are allergic, further limiting their use (see, e.g., Roth and Shields, Anesthesia & Analgesia, 98, 1499 (2004)).

[0014] Therefore, for the reasons stated above, there is a significant unmet clinical need for drug delivery compositions comprising adrenaline that have improved stability (physically and, more importantly, chemically).

[0015] Transmucosal administration of active ingredients is a viable alternative to parenteral administration, offering the possibility of delivering drug molecules directly into the systemic circulation via mucosal membranes (e.g., rectal, sublingual, buccal, pulmonary, and intranasal), potentially offering advantages such as increased patient compliance, improved drug bioavailability and therefore lower doses, more rapid onset of action, and reduced side effects.

[0016] However, transmucosal administration of drugs has its own very distinct problems. Unlike the gastrointestinal tract, which is a large organ containing a relatively large amount of fluid, spaces such as the oral and nasal cavities are relatively small and contain much less fluid, such as saliva and / or mucus. This necessarily results in a significant limitation on the amount of active ingredient that can be administered in a single dose.

[0017] Furthermore, although the gastrointestinal tract is a dynamic system, for the most part it is a somewhat "closed" system: Conversely, the rapid clearance mechanisms that occur in both the oral and nasal cavities often mean that there is also limited time available for absorption across mucosal surfaces for an already more limited amount of drug.

[0018] To address this issue, numerous formulation principles have been proposed, including bioadhesive formulation principles such as buccal patches for oral mucosal drug delivery (see, e.g., Shojaei, J. Pharm. Pharmaceutical Sci., 15, 19 (1998) and Gandhi, Advanced Drug Delivery Reviews, 43, 67 (1994)), and in situ gelling compositions for intranasal drug delivery (see, e.g., Bertan et al., Eur. J. Pharm. Sci., 27, 62 (2006)).

[0019] Solid transmucosal drug delivery systems may have considerable advantages in that they allow higher drug loading in the formulation.However, while solid drug delivery compositions are much more common when administered to the rectum, buccal, sublingual, and pulmonary mucosa, the majority of intranasal drug delivery systems remain in the form of liquid spray, typically aqueous solutions, and drug solubility is another factor that limits the amount of drug that can be absorbed.

[0020] The near ubiquity of liquid sprays for intranasal delivery is due to the lack of ease in formulating solid pharmaceutical formulations in the form of nasal powders: unlike the powders that are frequently used for inhalation of active ingredients into the lungs, there are very few intranasal powder formulations available on the market.

[0021] When formulated as dry powders, pulmonary drug delivery compositions typically take the form of "agglomerated" mixtures containing finely divided particles of the API on larger carrier particles. These agglomerates are intended to dissociate / break down upon inhalation or actuation of the device, depositing only fine particles of the active ingredient in the lungs.

[0022] However, it is understood that such drug delivery systems do not work effectively in the case of intranasal drug delivery. This is because the presence of such fine particles poses a significant risk of exposure to the lung, which is not the intended site of administration. If the particle size of the drug is increased to avoid this problem, it is likely to be difficult to ensure proper interaction in the heterogeneous "interaction" mixture, which relies on substantial differences in the size of the two components to ensure interaction, which then leads to potential manufacturing problems such as separation during filling. Attempting to counter this by increasing the particle size of the corresponding carrier does not necessarily solve the problem, and may result in an inevitable increase in the mass of inactive excipients in the already finitely limited total mass of the dosage form, resulting in a reduced dose of active ingredient.

[0023] The difficulty of formulating dry powders for intranasal delivery is addressed in US Patent Application No. 2005 / 001411A1. In this document, it is stated that powders for nasal administration must be sufficiently fine to be efficiently carried by the gas stream and efficiently deposited in the nose, and also sufficiently coarse to facilitate the introduction of the powder into a suitable powder device, which is always necessary for intranasal administration. US2005 / 001411A1 apparently solves this problem by creating loosely formed secondary particles (agglomerates) of primary particles that contain the active ingredient. The agglomerates are said to have dimensions of several hundred microns, which allows for more efficient loading into a suitable intranasal administration (applicator, dispenser, or inhaler) device. Upon actuation of such a device and administration of the composition, the agglomerates apparently rapidly break down into primary particles of the active ingredient. These primary particles are said to be only a few microns in size, facilitating dissolution and subsequent intranasal absorption of the active ingredient.

[0024] As discussed above, transmucosal (e.g., intranasal) delivery of drugs intended for systemic absorption necessarily avoids first-pass metabolism, which is a component of oral administration. Drug metabolism occurs via chemical reactions with enzymes that can alter the chemical structure, physical structure, and / or biological activity of the active ingredient.

[0025] Most drugs are organic molecules that contain functional groups capable of undergoing such chemical reactions, and therefore are often susceptible to some form of chemical degradation when they come into contact with substances that can interact with those functional groups outside the body. As discussed above, the problem of chemical instability is particularly acute in the case of adrenaline.

[0026] As summarized by Kou and Zhou in Chapter 16 of the textbook Amorphous Solid Dispersions, Shah et al (Eds.), Springer (2014), when a drug is formulated in an amorphous, as opposed to crystalline, physical state, it is typically provided in a higher energy state and is therefore likely to be more chemically and physically unstable, presenting a challenge to the pharmaceutical manufacturer.

[0027] Therefore, chemical stability is often improved by providing drugs in a crystalline state through salt formation. The main purpose of salt formation is usually to increase the hydrophilicity of the active ingredient, addressing the problem of poor aqueous solubility and dissolution rate. However, in making salts, other physicochemical and biological concerns, such as chemical stability, can often be simultaneously addressed. For example, basic drugs (e.g., drugs that contain at least one amine group) are often provided in the form of acid addition salts, which are typically more chemically stable salts than the corresponding "free" amine bases.

[0028] However, while potentially providing the active ingredient in a form that can be more easily stored without chemical degradation and that is more efficient in terms of rate and / or extent of dissolution following administration, crystalline salts generally dissolve slower and are absorbed less efficiently across mucous membranes than when the corresponding active ingredient is provided in an amorphous and / or non-crystalline form, respectively.

[0029] Thus, active pharmaceutical ingredients formulated as amorphous solid dispersions generally offer the advantage of high bioavailability but typically present challenges in the form of reduced physical and chemical stability, whereas drugs formulated in crystalline and / or salt forms are generally more stable but tend to have lower bioavailability.

[0030] The latter problem can be particularly detrimental in the case of transmucosal drug delivery, such as intranasal or sublingual, which, as discussed above, limits the residence time of the drug in the relevant cavity necessary for absorption into the systemic circulation to occur. This, combined with poor permeability across mucosal membranes at physiological pH, can result in unacceptably low and / or slow transmucosal absorption to provide adequate therapeutic effect.

[0031] A number of sophisticated formulation principles have been devised over the years to address the balancing act between solubility and permeability in transmucosal drug delivery systems, including the addition of pH modifiers that convert the ionized salt form of the active ingredient into a more permeable non-ionized state.

[0032] However, considering all of the aforementioned potential advantages it offers, there remains a need for improved solid (e.g., powder-based) transmucosal, and particularly intranasal, drug delivery systems.

[0033] In particular, in the field of transmucosal drug delivery, there remains a significant unmet clinical need for powdered drug delivery compositions that: (i) It is physically and chemically stable; (ii) in sufficient doses, and / or ● Providing the active ingredient in a form that is sufficiently penetrating to provide the required therapeutic effect (e.g. rate of onset and / or access to drug target) at the lowest possible dose (relatively speaking) and at the short residence time available in a transmucosal context such as intranasal.

[0034] In the more specific area of ​​intranasal drug delivery, there remains a significant unmet clinical need for such drug delivery compositions that include appropriately sized particles that enable both efficient: Filling of drug delivery devices, and • Deposition in associated (e.g. nasal) cavities.

[0035] Intranasal dry powder formulations are known, inter alia, from International Patent Applications Nos. 2010 / 142696 and 2019 / 038756, U.S. Patent Application No. 10,653,690 B2 and U.S. Patent Application No. 2018 / 0092839 A. See also U.S. Patent Nos. 7,947,742 (B2), 8,415,397 (B2) and 8,747,813 (B2).

[0036] Russo et al. (J. Pharm. Sci., 95, 2253 (2006)) disclose spray drying of an opioid analgesic compound, namely morphine, with a number of excipients. Spray-dried formulations are also disclosed by Vengerovich et al., Bulletin of Experimental Biology and Medicine, 163, 737 (2017), who attempted to microencapsulate the active ingredient in various materials, including 2-hydroxypropyl-β-cyclodextrin, with a view to developing sustained-release formulations based on polymeric carriers for acute care applications.

[0037] It has now been found that it is possible to formulate an adrenergic receptor modulator, such as adrenaline, in the form of an amorphous dry powder composition, for example by a process of spray drying the active ingredient together with a carrier material, as disclosed below.Compared to currently available devices, such as EpiPen, a surprising improvement in the stability of the active ingredient during storage and before administration has been observed when loaded into an applicator device.Such compositions may further provide improved bioavailability and / or absorption rate of such active ingredient after administration. Summary of the Invention

[0038] According to a first aspect of the present invention there is provided a needleless applicator suitable for administering a solid amorphous single particle powder composition to a body cavity of a human patient, the cavity comprising a mucosal surface, the applicator comprising: (i) an opaque reservoir containing the solid, amorphous, single-particle powder composition; (ii) optional actuation means for generating a force upon actuation of the device by a user; and (iii) a dispensing means through which the powder composition may be dispensed after said actuation; The solid amorphous single particle powder composition comprises a pharmacologically effective dosage amount of an adrenoceptor modulator, or a pharma- ceutically acceptable salt thereof, encapsulated in an amorphous state together with a pharma- ceutically acceptable carrier material; The powder composition comprises: (a) at 40°C and 75% relative humidity for at least about 3 months; (b) at least about 18 months at less than about 30° C.; and / or (c) UV light of more than 1 million lux for at least 18 hours After storage, less than approximately 4% is chemically degraded.

[0039] The term "needle-free" refers to a device for administering a pharmaceutical active ingredient that does not include an injection means further comprising a means for piercing, for example, the skin or a mucosal surface, to inject said active ingredient into the body, for example subcutaneously or intramuscularly (as the adrenaline auto-injector described above does). Such needle-free applicators as defined above are hereinafter collectively referred to as "the applicator of the present invention".

[0040] Adrenergic receptors that may be mentioned (α 1A , α 1b , α 1c , α 1d , α 2a , α 2b , α 2c , α 2dModulators (also known as "stimulants" or "agonists") of the stimulants (including β1, β2 and β3 subreceptors) include phenylephrine, oxymetazoline, methyldopa, clonidine, dexmedetomidine, lofexidine, dobutamine, mirabegron, dopamine, albuterol (salbutamol), formoterol, levalbuterol, olodaterol, salmeterol, pirbuterol, terbutaline, fenoterol, rimiterol, hexoprenaline, tretoquinol, carbuterol, tulobuterol, clenbuterol, procaterol, bitolterol, indacaterol, corterol, pseudoephedrine, ephedrine, more preferably norepinephrine, isoprenaline, and especially epinephrine (hereinafter referred to as "adrenaline" for consistency).

[0041] The compositions contained and / or for inclusion in the reservoir of the applicator of the present invention are in the form of amorphous mono-particle powders. By "mono-particle" it is meant that the particles forming these powder compositions comprise a homogeneous or heterogeneous mixture, in which the adrenoceptor modulator or its salt is encapsulated in an amorphous state within a carrier material as defined above, optionally in the presence of other ingredients. Thus, the particles of the powder composition for inclusion in the reservoir of the applicator of the present invention are provided as an amorphous composite of the adrenoceptor modulator or its pharma- ceutically acceptable salt (hereinafter referred to as "active ingredient"), the carrier material, and, optionally, other ingredients.

[0042] Due to their amorphous nature, such powder compositions can be completely amorphous and / or predominantly amorphous (e.g., more than about 50% amorphous, such as more than about 75% amorphous, including more than about 80% amorphous, such as more than about 90% amorphous or more than 95% amorphous, including more than about 99% amorphous). Alternatively, the powder compositions can be less than about 50% amorphous, including less than about 25%, more preferably less than about 20%, such as less than about 10% amorphous, including less than about 5% or less than about 1% crystalline. The degree (%) of crystallinity can be determined by those skilled in the art using powder X-ray diffraction (PXRD). Other techniques such as solid state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) microcalorimetry, and calculation of true density can also be used.

[0043] As described below, despite being in an amorphous physical state, the compositions that may be contained in the reservoir of the present applicator exhibit surprising and unexpected physical and chemical stability and, therefore, may be provided in pharmaceutical forms that exhibit excellent shelf life when stored under normal storage conditions.

[0044] The stability of the powder compositions described herein is excellent both prior to loading into the reservoir of the applicator of the invention, and once the powder composition is loaded into the reservoir. In the latter situation, stability is maintained (if not improved). In any event, compositions that may be included in the applicators of the invention may be stored without significant chemical degradation, either within such applicators or as bulk powders under the conditions described herein.

[0045] The composition that can be used in the applicator of the present invention is provided as a powder (i.e., in a multiparticulate form) by a suitable technique. Generally, suitable techniques are classified as "solvent-based" methods, including spray drying, fluidized bed techniques, co-precipitation, supercritical fluid techniques, spray granulation, cryogenic techniques (including freeze drying), electrospinning and rotary jet techniques, or "fusion-based" methods, including melt granulation, melt extrusion, high shear mixing (e.g., KinetiSol®), milling and molten material on carrier techniques (e.g., Meltdose®). Preferred methods include freeze drying, and more preferably, the composition used in the applicator of the present invention is made by a spray drying process.

[0046] Compositions for inclusion in the reservoir of the applicator of the present invention may be provided in a multiparticulate form comprising a plurality of particles (e.g., simple powders, granules, pellets and / or beads) which, individually and / or collectively, may consist essentially of and / or comprise one or more such compositions.

[0047] Thus, such compositions may be provided after preparation (e.g., by spray drying) in the form of a simple powder mixture, powdered microspheres, coated powdered microspheres, lyophilized liposomal dispersions, or combinations thereof.

[0048] When a powder composition for inclusion in an applicator of the invention "consists essentially of" these particles, this is understood to mean that the reservoir of the applicator contains only one or more such compositions, together with other features and / or components that do not substantially affect the basic and novel feature(s) of the applicator of the invention or the compositions contained therein. Alternatively, in the situation where a dosage form of the invention "consists essentially of" one or more compositions of the invention, this can be understood to mean that the dosage form contains, in total, at least about 90%, such as at least about 95%, including at least about 97% by weight (e.g., about 99%) of one or more composition(s) of the invention. An applicator of the invention may alternatively contain two or more such composition(s).

[0049] Suitable techniques for making dry powders or multiparticulates, including granules, include simple dry blending, granulation (including dry granulation, wet granulation, melt granulation, thermoplastic pelletizing, spray granulation), extrusion / spheronization, or more preferably freeze-drying or spray drying (see below).

[0050] Dry granulation methods are also well known to those skilled in the art and include any technique in which primary powder particles are aggregated under high pressure, including, for example, slugging and roller compaction, as described below.

[0051] Wet granulation is well known to those skilled in the art and involves any technique involving agglomeration of a mixture of dry primary powder particles with a granulation fluid comprising a volatile inert solvent such as water, ethanol or isopropanol, alone or in combination, and optionally in the presence of a binder or binding agent. This technique may include passing the wet mass through a sieve to produce wet granules, which are then dried, preferably to a loss on drying of less than about 3% by weight.

[0052] Melt granulation is known to those skilled in the art to include any technique in which granules are obtained through the addition of a molten binder or a solid binder that melts during the process (these binder materials may include the pharma- ceutically acceptable carrier material of the composition used in the applicator of the present invention). After granulation, the binder is solidified at room temperature. Thermoplastic pelletization is known to be similar to melt granulation, but the plastic properties of the binder are used. In both processes, the resulting aggregates (granules) contain a matrix structure.

[0053] Extrusion / spheronization is well known to those skilled in the art to include any process involving dry mixing of the ingredients, wet massing with a binder, extrusion, spheronization of the extrudate into uniformly sized spheroids, and drying.

[0054] Spray granulation is known to those skilled in the art to include any technique that involves drying a liquid (solution, suspension, melt) and simultaneously accumulating granulation in a fluidized bed. Thus, in addition to generally including any spray coating granulation technique, this term includes the process in which foreign seeds (bacteria) are provided and granules are accumulated on them, as well as the process in which indigenous seeds (bacteria) are formed in the fluidized bed by abrasion and / or crushing. The sprayed liquid covers the bacteria and helps further agglomeration of the particles. It is then dried to form granules in the form of a matrix.

[0055] The term "lyophilization" includes lyophilization or cryodesication, and any low-temperature desolvation (e.g., dehydration) process in which the product is frozen, the pressure is reduced, and the frozen solvent (e.g., water) is removed by sublimation.

[0056] As described herein, compositions that may be used in the applicators of the present invention are preferably made by the process of spray drying.

[0057] Compositions for inclusion in the applicators of the present invention may otherwise be prepared by standard techniques and using standard equipment known to those skilled in the art. In this regard, compositions for inclusion in the reservoirs of the applicators of the present invention may be combined with conventional pharmaceutical additives and / or excipients used in the art for the relevant preparations and incorporated into various types of pharmaceutical preparations using standard techniques to produce the applicators of the present invention (see, for example, Lachman et al, 'The Theory and Practice of Industrial Pharmacy', CBS, 4 th edition (2015), 'Remington: The Science and Practice of Pharmacy', Troy (ed.), Elsevier, 23 rdedition(2020), and / or 'Aulton's Pharmaceutics: The Design and Manufacture of Medicines', Taylor and Aulton(eds.), Elsevier, 5 th (See the International Journal of Clinical Chemistry, 2017 edition).

[0058] Regardless of the method of manufacture, the compositions contained in the applicators of the present invention are preferably suitable and / or formulated for transmucosal delivery of active ingredients to the systemic circulation.

[0059] Those skilled in the art will appreciate that the term "transmucosal" means that however it is administered to a patient, the composition is provided to the relevant mucosal surface in a form such that the active ingredient(s) can be absorbed across that mucosal surface after dissolution. Thus, relevant mucosal surfaces include the oral, nasal, ocular, vaginal, cervical, pulmonary and / or anorectal mucosa, more particularly the oral mucosa (including the buccal and sublingual mucosa) and nasal mucosa.

[0060] In this regard, the applicator of the present invention may be used to deliver the powder composition contained therein directly to a patient's body cavities, including mucosal surfaces (including pulmonary, rectal, vaginal, oral, sublingual, or intranasal), for transmucosal delivery of the active ingredient.

[0061] Thus, such compositions may be administered sublingually by expelling the powder composition described herein from an applicator of the present invention into the mouth and under the tongue.

[0062] When the compositions for inclusion in the reservoir of an applicator of the invention are suitable and / or formulated for sublingual or, especially, intranasal administration, they are preferably administered in the form of a powder having a dosage of active ingredient of about 100 mg or less. Such sublingual and / or nasal powder compositions may comprise or consist essentially of a composition for inclusion in the reservoir of an applicator of the invention as defined herein in admixture with other excipients.

[0063] An applicator of the invention suitable for intranasal administration may contain one spray-dried powder composition in its reservoir, or may contain two or more such compositions, in which case the applicator may contain two or more dosages of the powder composition, each dosage containing a pharmacologically effective dose of the active ingredient(s).

[0064] Two or more such compositions may be administered intranasally by repeated actuation of a suitable applicator of the invention. Suitable devices (e.g., nasal applicators or dispensers (inhalers)) are described below. Compositions for inclusion in the reservoir of the applicator of the invention may be provided in such a reservoir that is part of, associated with, and / or suitable for placement on the applicator to form the applicator of the invention. Such a container or reservoir may contain one or more powder compositions, each housing a pharmacologically effective dosage of the active ingredient.

[0065] Thus, a suitable dosing means and / or nasal applicator may be actuated only once to deliver a single powder composition containing an appropriate dose of active ingredient following such actuation (i.e., a single-use dosage unit), may be actuated two or more times to deliver two or more such powder compositions each containing an appropriate dose of active ingredient upon each such actuation (i.e., a multi-use dosage unit), and / or may be refilled with a replacement source of such composition (e.g., a container or reservoir) containing one or more such powder compositions to provide single and / or multiple doses and / or dosing regimens.

[0066] Thus, the composition contained in the applicator of the present invention is administered in the form of a plurality of particles, which particles may individually and / or collectively be composed of and / or comprise a powder composition as defined herein.

[0067] Such compositions are prepared in the form of a solid, dry, free-flowing, multiparticulate powder.

[0068] "Dry" includes essentially free of water and other liquid solvents, including less than about 10%, such as less than about 6%, including less than about 5% or less than about 4%, more preferably less than about 3%, such as less than about 2%, e.g., less than about 1%, of the formulation is liquid such as water.

[0069] It will be appreciated by those skilled in the art that the term "solid" includes any form of matter that retains its shape and density when unconfined and / or in which the molecules are generally as tightly packed as the repulsive forces between them will permit. Thus, an essentially solid composition is one that is at least about 80%, such as at least about 90%, including at least about 95% (or at least about 99%) in such a form.

[0070] The flowability of the powder compositions of the present invention may be measured by standard techniques known to those skilled in the art, including bulk density measurements, or measurements made with a powder flow analyzer (e.g., those sold by Stable Micro Systems or Meritics, both in the UK), including powder flow rate dependency tests, caking tests, agglomeration tests, etc. A preferred measurement of flowability is the standard angle of repose, which may be performed using a rotating cylinder, a stationary funnel, or a tilting box.

[0071] In the context of the present invention, the term "free flowing" is intended to include powders that allow the composition to be efficiently loaded into the applicator (i.e., drug delivery device) of the present invention during manufacture and / or provide a sufficient shot weight when expelled from the device (see below).

[0072] The term may also include that the powder exhibits an angle of repose of about 50° or less, such as about 45° or less, including about 40° or less, for example about 35° or less, more particularly about 30° or less, a bulk density of about 0.3 g / mL or more, for example about 0.4 g / mL or more, such as about 0.5 g / mL or more, more particularly about 0.6 g / mL or more, and / or a tap density of about 0.5 g / mL or more, such as about 0.6 g / mL or more, for example about 0.7 g / mL or more, particularly about 0.8 g / mL or more.

[0073] Being in the form of an amorphous monoparticulate powder, the composition for inclusion in the applicator of the invention does not consist of a physical association of two or more separate, separate sets of particles of different components in the form of a mixture, such as an ordered or interactive mixture of smaller particles of the active ingredient in association with larger, but separate, particles of a chemically distinct carrier material. Nevertheless, the powder compositions described herein can be provided as small particles that can then be attached to separate larger carrier particles in the interactive mixture, such provision being useful in the case of dosage forms intended for inhalation, e.g., the lungs (see, e.g., J. Drug Delivery, Art. ID 5635010, 1-19 (2018)).

[0074] As mentioned above, the process of making the compositions for inclusion in the applicators of the present invention allows for the formation of pharmaceutical products that exhibit excellent shelf life in terms of both physical and chemical stability when stored under normal storage conditions as defined herein.

[0075] Compositions for inclusion in the applicator of the present invention are preferably prepared by the process of spray drying, which will be understood by those skilled in the art to include any method of producing a dry powder from a liquid, including a solution or suspension (including a slurry), that involves the use of hot gas to rapidly dry and convert the liquid stream into solid particles, including vaporized solvent, and solutes previously dissolved in the solution, and / or particles previously suspended in the evaporated liquid.

[0076] Suitable spray drying equipment includes some form of atomization means, such as a spray nozzle, that disperses the liquid into a spray having a relatively uniform droplet size. Such means may include any means capable of producing a dry, free-flowing powder, and may include high pressure swirl nozzles, spinning disks and / or atomizer wheels, high pressure single-fluid nozzles, two-fluid nozzles and / or ultrasonic nozzles.

[0077] The spray dryer may be a single effect or a multiple effect spray dryer and may include an integrated and / or external vibrating fluidized bed, a particle separator, and / or a collection means which may be a drum or a cyclone.

[0078] According to a further aspect of the present invention there is provided a process for manufacturing an applicator of the present invention comprising the steps of: i) mixing an adrenoceptor modulator or a pharma- ceutically acceptable salt thereof together with a pharma- ceutically acceptable carrier material in a suitable volatile solvent; ii) spray drying the mixture from step i); iii) loading the product from step ii) into a reservoir of an applicator of the present invention.

[0079] Preferred volatile solvents include water, or lower alkyl alcohols (e.g., methanol, isopropanol, or, more particularly, ethanol), hydrocarbons (e.g., C 5-10 Examples of suitable solvents include organic solvents such as alkane, haloalkane (eg, dichloromethane), dimethylformamide, dimethylsulfoxide, ethyl acetate, acetone, and the like, or mixtures thereof.

[0080] Preferably, one or more active ingredients, a pharma- ceutically acceptable carrier material(s) as defined herein, and other optional ingredients as described herein (e.g., alkyl sugars as described below) are mixed together with a solvent to obtain a solution that can be spray dried.

[0081] Pharmaceutically acceptable carrier materials used in compositions for inclusion in the applicators of the invention should be solid under normal storage conditions, suitable (and / or approved) for pharmaceutical use and / or transmucosal (e.g. sublingual or especially intranasal) delivery, be able to maintain their physical and / or chemical integrity, and / or not affect the physical and / or chemical integrity of the active ingredient and / or any other ingredients (such as alkyl sugars) that are or may be present in the composition.

[0082] It is well known that obtaining a solid composition such as a powder that is both chemically and physically stable can present significant difficulties. If the physical form of the composition changes under normal storage conditions (e.g., from a free-flowing powder to agglomerates that are difficult to expel), the dose of the active ingredient can become unreproducible. This is particularly true when dispensing the composition from or through the nasal applicator described herein, where such agglomeration can result in a complete inability to dispense the active ingredient, which can be fatal in an emergency.

[0083] The compositions included in the applicators of the present invention may have a minimum shot weight as measured by an individual powder shot weight of about 80% of the target weight, such as about 85% (e.g., about 90%) up to about 120% (e.g., about 115%, such as about 110%), and / or an average powder shot weight of about 90% (e.g., about 95%) up to about 115% (e.g., about 110%, such as about 105%).

[0084] Similarly, in the case of multiple dose units containing two or more doses of the composition, such stability is important to ensure reproducibility of the dose of the active ingredient over time. Any of these issues may have adverse effects on the subject's health and / or may place the subject's well-being at serious risk.

[0085] For certain compositions contained in the applicator of the present invention, exposure to atmospheric water may result in a powder composition with poor solid state stability. For example, exposure to certain (e.g., relatively high) relative humidities may affect the physical form of the composition, for example, by deliquescence and / or by lowering the glass transition temperature of the composition and / or individual components of the composition, such as the carrier material, or in another manner.

[0086] Thus, compositions for inclusion in the reservoir of the applicator of the invention, and the applicators of the invention containing them, are preferably packaged in containers that substantially prevent the ingress of atmospheric water under storage conditions defined herein. Such containers may include packaging materials such as blister packs, heat-sealed aluminum pouches and / or thermoformed plastics. Such containers may also include a desiccant, such as, for example, silica gel and / or suitable molecular sieves having a pore size of 3 Å or 4 Å.

[0087] The phrase "maintaining physical and chemical integrity" essentially means chemical stability and solid state stability.

[0088] "Chemical stability" includes that any powder composition described herein, when formulated in an applicator of the present invention or in a reservoir thereof (with or without appropriate pharmaceutical packaging) or otherwise under normal storage conditions, may be stored in an isolated solid form with only minor degrees of chemical degradation or decomposition of either the composition itself or any active ingredient contained therein.

[0089] The term "chemical stability" also includes "stereochemical" and / or "constitutional" stability, which refers to the resistance to stereochemical transformation, such as racemization, at one or more chiral centers within the molecule of an active ingredient. This is particularly important in the case of adrenaline, where the R enantiomer (i.e., L-(-)-epinephrine) is the active enantiomer and the S enantiomer (i.e., D-(+)-epinephrine) is less active and therefore may be considered an impurity.

[0090] "Physical stability" or "solid state stability" includes that any powder composition described herein, when formulated into an applicator of the present invention or a reservoir thereof (with or without appropriate pharmaceutical packaging) or otherwise under normal storage conditions, may be stored in an isolated solid form with only minor degrees of solid state change (e.g., crystallization, recrystallization, loss of crystallinity, solid state phase transition (e.g., between a glassy or rubbery state, or to an aggregated form)), hydration, dehydration, solvation, or desolvation of either the composition itself or any of the active ingredients contained therein.

[0091] Examples of "normal storage conditions" for applicators of the present invention include temperatures of about -50°C to about +80°C (preferably about -25°C to about +75°C, such as about 50°C) for extended periods of time (i.e., about 12 months or more, such as about 6 months), and / or pressures of about 0.1 to about 2 bar (preferably atmospheric pressure), and / or exposure to at least about 460 lux of UV / visible light, and / or relative humidity of about 5 to about 95% (preferably about 10 to about 40%).

[0092] Under such conditions, the composition contained in the applicator of the present invention (and / or the active ingredient contained therein) may be found to be chemically degraded / decomposed and / or solid state converted, optionally to less than about 15%, more preferably less than about 10%, especially less than about 5%.Those skilled in the art will appreciate that the above upper and lower limits of temperature and pressure represent the extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g., a temperature of 50°C and a pressure of 0.1 bar).

[0093] Such chemical stability, and especially physical stability, is important in solid compositions such as powders to ensure that an appropriate dose is delivered to the patient.

[0094] Notwithstanding the above definition of "normal storage conditions," the composition for inclusion in the reservoir of the applicator of the present invention (and / or the active ingredient contained therein) should be stored under the following conditions: (a) at 40° C. and 75% relative humidity for at least about 3 months, including at least about 6 months or at least about 12 months; (b) at less than about 30° C., such as about 30° C. or about 25° C., and / or at a relative humidity of, for example, about 65%, such as about 60%, for at least about 18 months, such as at least about 24 months, including at least about 36 months; and / or (c) UV light exceeding approximately 1 million lux for at least approximately 18 hours may be chemically and / or stereochemically degraded after storage by less than about 5%, such as less than about 4% (including less than about 3%, such as less than about 2.5% (e.g., less than about 2%), including less than about 1.5%, and / or even less than about 1%.

[0095] Thus, the applicator of the present invention may be stored at any temperature (e.g., as low as about -20°C) up to about 25°C (e.g., up to about 30°C), preferably with fluctuations up to about 40°C or even up to about 50°C.

[0096] Particularly preferred pharma- ceutically acceptable carrier materials that may be used to produce compositions for use in the applicators of the present invention and that have the desirable properties described herein include disaccharide and polymeric material components, especially when used in combination.

[0097] Preferred disaccharide building blocks include maltitol, sucralose, sucrose, isomalt, maltose, preferably lactose (including β-D-lactose and α-D-lactose, especially α-D-lactose monohydrate), more preferably trehalose.

[0098] Suitable polymeric material components which may be used as pharma- ceutically acceptable carrier materials in powder compositions for use in the applicator of the invention and which have the desirable properties described herein include cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose (hypromellose, HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylhydroxyethylcellulose, carboxymethylcellulose (CMC), modified cellulose gums, microcrystalline cellulose, and sodium carboxymethylcellulose; starches, such as rice starch, tapioca starch, wheat starch, and more particularly corn starch and potato starch; pregelatinized starch, carboxymethyl starch, and moderately crosslinked starches. starch derivatives such as starch, modified starches and sodium starch glycolate; polysaccharides including dextran, pullulan, inulin, and dextrins such as linear or branched dextrins such as dextrin, cyclodextrin, and maltodextrin; powdered tragacanth; waxy excipients such as cocoa butter and suppository wax; polyols such as solid polyethylene glycol; acrylic polymers such as carbomer and its derivatives; polyvinylpyrrolidone (povidone, PVP); cross-linked polyvinylpyrrolidone; polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; poly co-(methyl vinyl ether / maleic anhydride); and croscarmellose (e.g., croscarmellose sodium). Mention may also be made of hypromellose succinate (HPMCAS), copovidone and polyvinyl alcohol (PVA, or PVOH).

[0099] More preferred polymeric materials include polysaccharides such as sodium carboxymethylcellulose, sodium starch glycolate, polyvinylpyrrolidone, and in particular hydroxypropyl methylcellulose (such as hypromellose 2906, preferably hypromellose 2910 (i.e., type "E"), and more preferably USP / NF hypromellose 2208 (i.e., type "K")), or dextrins, including, in particular, cyclodextrins (e.g., α-, β-, and γ-cyclodextrins and derivatives thereof, such as 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether β-cyclodextrin sodium salt, randomly methylated β-cyclodextrin, branched β-cyclodextrins, in particular 2-hydroxypropyl-β-cyclodextrin), and linear or branched dextrins, such as maltodextrin.

[0100] In any event, polymers suitable for use in the compositions employed in the applicators of the present invention should have a sufficiently high molecular weight so that, in any given amount, when used in combination with, for example, a disaccharide, they can form a suitable carrier material for the active ingredient.

[0101] For any given polymer, the polymer chain length (and therefore molecular weight) is directly proportional to its viscosity. In other words, the viscosity of a solution of that polymer is proportional to the molecular weight or chain length of the particular polymer.

[0102] In this regard, it may be preferred for any given essential case below that the polymer has a relative viscosity value at 20°C of about 1000 mPa*s or less (more preferably about 120 or less, such as about 60 or less, especially about 10 or less), as measured. (a) The standard USP method for viscosity, i.e. <911> Method I and / or <912> a water-soluble polymer as a 2% solution of the polymer in water according to method I; and (b) USP method <911> By Method I, the water insoluble polymer as a 5% by weight solution of the polymer in a suitable organic solvent such as acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, acetonitrile, dichloromethane, toluene, and mixtures thereof, where the solvent system can be dry or partially aqueous.

[0103] One skilled in the art will understand which test is more suitable for the polymer being tested.

[0104] The amount of carrier material that may be used in a composition for inclusion in an applicator of the present invention (whether a unit dose of the composition is included in a dosage device or otherwise) is typically in the range of about 5% to about 99.9% by weight, including up to about 99% by weight (e.g., up to about 95% or about 90% by weight), such as about 10% by weight (e.g., about 25% by weight, including about 35% by weight) to about 85% by weight, including about 50% by weight to about 75% by weight, based on the total weight of the composition.

[0105] Whether provided as a combination of materials or otherwise, the carrier material is preferably capable of resulting in a composition for inclusion in the applicator of the present invention having a glass transition temperature (Tg) of: (a) is capable of being readily formulated into a pharmaceutical formulation or dosage form and then produced in a hard and / or brittle, "glassy," amorphous, powdered physical form that can be readily loaded into an applicator of the invention, such as a nasal applicator as described herein, or a drug reservoir and / or container within or associated with such an applicator; and (b) such that after such an applicator or reservoir is packaged as described herein and then exposed to high external temperatures (e.g., up to about 50° C. to about 80° C.), the composition remains in the exemplary glassy state instead of transforming into a more viscous or rubbery state, and / or a crystalline state.

[0106] Such extreme external temperatures are often experienced inside vehicles (e.g., first responders') in warm and / or sunny climates, where such vehicles are frequently parked under the hot sun for extended periods of time, and the resulting heat can be enormous. If the Tg of the powder composition is low, the composition may transform into such a viscous / rubbery state after exposure to such high temperatures, which results in inefficient dosing of the composition, e.g., inefficient ejection of the composition (and also the dose(s) of active ingredient) from the applicator of the present invention or a reservoir contained therein, when the applicator is actuated.

[0107] In this regard, the lowest measurable Tg of a composition for inclusion in an applicator of the present invention is preferably at least about 35°C, including at least about 40°C, such as at least about 50°C, such as at least about 55°C, including at least about 60°C, when measured at a relative humidity of up to about 35%, such as up to about 30%, including up to about 25% (e.g., up to about 20%, such as less than about 15%, e.g., less than about 10%). By "lowest measurable Tg" we include that the subject powder composition may include particles that are heterogeneous in nature. In particular, the particles may include distinct regions of carrier materials, or composite mixtures thereof, and thus may have individual and distinct Tg values. It will be apparent to one skilled in the art that the lowest measurable Tg value will have a strong impact on the physical stability of the composition.

[0108] The inventors have found that the relative amounts of disaccharide and polymeric components in the carrier material (particularly when the polymer is a dextrin) can be adjusted to ensure a desired level of physical and / or chemical stability of the active ingredient while at the same time not lowering the Tg of the composition for inclusion in the applicator of the present invention in a manner that affects physical stability.

[0109] Depending on the active ingredient used, it has been found that disaccharide:polymer (e.g., dextrin) ratios of about 50:1 to about 1:50 by weight based on the total weight of the composition can work. Preferred ratios are in the range of about 10:1 to about 1:40 (including up to about 1:30 or up to about 1:20), for example, about 7:1 to about 1:5, including about 5:1, such as about 4:1, about 3:1, or about 2:1, for example, about 1:10, such as about 1:8, including 1:3 or 1:2, more preferably about 8:1 (e.g., about 7:1, about 3:1, about 2:1, or about 1:1) to about 1:8 (e.g., about 1:3 or about 1:2) disaccharide:polymer (e.g., dextrin) based on the total weight of the composition.

[0110] Thus, particularly preferred combinations of carrier materials include trehalose or lactose, such as α-D-lactose monohydrate, and a dextrin, in particular a cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin, or, more preferably, maltodextrin.

[0111] Maltodextrins are classified by DE (dextrose equivalent), the higher the DE value, the shorter the average length of the glucose chains. Preferred maltodextrins include those having a DE of 6 to 15, such as 8 to 12, or more than 15, for example up to 47, such as 38, 39, preferably 23, 24, 25, or 26, or more preferably 16, 17, 18, 20, 21, or 22, and especially a DE of 19. Those skilled in the art will appreciate that maltodextrins with a DE of more than 20 are referred to as "glucose syrups".

[0112] Maltodextrins with a DE above 15 have a lower average molecular weight than those with a DE below 15. All maltodextrins are mixtures of polysaccharides with different chain lengths, and maltodextrins with a DE above 15 have fewer higher molecular weight sugar units.

[0113] It has been found that maltodextrins with lower DE, such as maltodextrins with a DE of 12 or less, contain longer polysaccharide chains (e.g., having about 24 glucose units or more) and can form aggregates when present in aqueous solution with other ingredients, such as active ingredients like sucrose esters and / or surfactants, and have a tendency to form helical structures that result in a cloudy solution prior to spray drying. This cloudiness can cause stability and / or processability problems during manufacturing, necessitating the use of an in-line filter.

[0114] It has been found that the aforementioned haze problem can be alleviated to some extent by reducing the relative amount of maltodextrin included in the compositions described herein, although this can be achieved by increasing the amount of other ingredients such as other carrier materials (e.g., disaccharides), active ingredients, or certain additives such as sucrose esters; the higher the molecular weight of the maltodextrin, the less needs to be included and the more, e.g., disaccharides or sucrose esters, needs to be added to alleviate the haze.

[0115] When adding more sucrose esters to reduce this haze, more may need to be added than is necessary to provide the appropriate (e.g., physical, chemical and / or biological) effect, including absorption-enhancing effects, as described herein. Conversely, increasing the amount of disaccharide relative to maltodextrin in the carrier material may have a negative impact on the Tg and therefore the solid state stability of the compositions described herein.

[0116] It has been found that such problems can be reduced, and perhaps avoided altogether, by using an entirely different maltodextrin, i.e., one having a higher DE, such as one having a DE greater than 15, e.g., a DE of 18, 20, or more preferably a DE of 19.

[0117] Notwithstanding the above, maltodextrins suitable for use in the powder compositions described herein should nevertheless have a sufficiently high molecular weight such that when used in any given amount (in combination with disaccharides or otherwise) they can form a suitable carrier material for the active ingredient, including providing an appropriate degree of physical stability.

[0118] Mixtures from any of the foregoing lists of disaccharide and / or polymeric materials (including maltodextrin) may be used.

[0119] Whatever their proportions in the final mixture, compositions for inclusion in the applicators of the present invention include spray-dried carrier materials, which may be prepared by spray-drying the relevant components to form a composite carrier material prior to either spray-drying the carrier material together with the other essential ingredients to form a powder composition as described herein, or, more preferably, made in situ by spray-drying all of the essential components of the composition together.

[0120] In particular, it has been found that compositions that may be included in the applicator of the present invention, including a combination of disaccharides and polymers (e.g., HPMC as defined herein) and / or preferably dextrins, especially maltodextrins, can provide an adequate level of physical and chemical stability of the composition and active ingredients (especially adrenaline and its salts). Indeed, as described below, the degree of chemical stability in particular is comparatively significant when compared to currently available products that include adrenaline for the treatment of allergic reactions, such as EpiPen.

[0121] Thus, a particularly preferred combination of carrier materials includes trehalose and a maltodextrin having a DE greater than 11, such as maltodextrin 12 DE, or greater than 15, such as maltodextrin 19 DE. The inventors have found that such combinations of carrier materials can be spray dried in appropriate ratios together with the active ingredient and, if present, alkyl sugars to produce a powder composition having both the desired physical and chemical stability under normal storage conditions as defined herein.

[0122] Combinations of adrenoceptor modulators or salts thereof may be used in compositions for inclusion in the applicators of the present invention.

[0123] Salts of adrenergic receptor modulators are known in the art and are described in Martindale-The Complete Drug Reference, 40 th Edition, Pharmaceutical Press, London (2020) and the documents cited therein, the relevant disclosures of all of which are incorporated herein by reference.

[0124] Otherwise, pharma- ceutically acceptable salts include acid addition salts and base addition salts, which may be formed by conventional means, for example, by reacting the relevant active ingredient in free acid or free base form with one or more equivalents of the appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (for example, by vacuum, lyophilization, or filtration).Salts may also be prepared using techniques known to those skilled in the art, such as, for example, by exchanging a counterion of a compound of the present invention in the form of a salt with another counterion using a suitable ion exchange resin.

[0125] Particular acid addition salts which may be mentioned include carboxylates, such as succinates, tartrates, formates, acetates, benzoates, oxalates, fumarates, maleates, xinafoate, etc.; sulfonates, such as methanesulfonates, ethanesulfonates, toluenesulfonates, etc.; halide salts, such as hydrochlorides, hydrobromides, etc.; sulfates and phosphates, such as sulfates or phosphates.

[0126] Particular salts of adrenaline that may be mentioned include the bitartrate salt.

[0127] When the composition for inclusion in the applicator of the present invention is made by the aforementioned solvent-based process, including by the process of spray drying, this may result in the presence of the active ingredient in a form that is no longer in the form of a crystalline salt, since it is freely dispersed and encapsulated within the amorphous carrier material. However, despite not being in the form of a crystalline salt, as is typically present in the case of typical solid mixtures and / or powder compositions, the powder compositions described herein may lose little to no chemical stability of their active ingredients under the storage conditions mentioned herein.

[0128] The amount of active ingredient that can be used in a single dose of the composition contained in the applicator of the present invention should be sufficient to exert its pharmacological effect. For compositions administered mucosally (e.g., sublingually, bucally, and especially intranasally), the amount should not exceed about 100 mg in a single dose. The actual dosages of the relevant active ingredients mentioned above are known in the art and are described in Martindale-The Complete Drug Reference, 40 thThe drugs in question have been described in the medical literature, such as The Journal of Clinical Chemistry, Vol. 13, No. 1, 1999, 1999 Edition, Pharmaceutical Press, London (2020) and documents cited therein, the relevant disclosures of all of which are incorporated herein by reference. However, the compositions contained in the applicator of the present invention may be found to exhibit better bioavailability and / or rapid absorption, resulting in a more rapid onset of action and / or higher plasma concentrations, compared to prior art compositions containing the same active ingredient.

[0129] In this respect, the pharmacologically appropriate amount of the active ingredient in the composition contained in the applicator of the present invention may be less than that mentioned in the literature (see above). Nevertheless, such amount can be determined by a person skilled in the art and may vary depending on the type and severity of the condition being treated and what is most suitable for an individual patient. This is also likely to vary depending on the nature of the formulation and the type and severity of the condition being treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient being treated.

[0130] Depending on the potency of the active ingredient and the final formulation that may be used, the total amount of active ingredient that may be used in a composition for inclusion in an applicator of the present invention may range from about 0.0002% by weight, such as about 0.01% by weight, including about 0.1% by weight (e.g., about 1%, about 2% or about 5% by weight), about 0.001% by weight, such as about 10% by weight (e.g., about 20% by weight), up to about 95% by weight, such as about 75% by weight, for example about 50% by weight, for example about 40% by weight, based on the total weight of the composition. This is regardless of the number of separate doses (which must be the same) of the composition initially present in the applicator of the present invention.

[0131] For transmucosal administration, including pulmonary, buccal, sublingual, or preferably intranasal, suitable doses of active ingredient (calculated as free acid / base) per kg of body weight range from about 1 μg / kg, such as about 2 μg / kg, including about 3 μg / kg, about 5 μg / kg, or about 6 μg / kg, up to about 15 μg / kg, such as about 13 μg / kg, including about 12 μg / kg, such as about 10 μg / kg or about 8 μg / kg.

[0132] Alternatively, a suitable dose of active ingredient (calculated as free acid / base) per unit dosage is in the range of about 1 μg (e.g., about 10 μg, such as about 250 μg) to about 100 mg (e.g., about 80 mg), such as about 1 mg to about 60 mg (e.g., about 3 mg to about 50 mg, such as about 10 mg), depending on the active ingredient used.

[0133] When administered sublingually, or preferably intranasally, specific doses of adrenaline range from about 0.1 mg (e.g., about 0.5 mg) to up to about 10 mg, such as up to about 5 mg, including up to about 3 mg or up to about 2 mg (e.g., about 1.2 mg, about 1 mg, or about 1.5 mg, including about 0.8 mg).

[0134] As mentioned above, the composition contained in the applicator of the present invention may also contain or be administered together with one or more alkyl sugars. In this regard, it may be found that the composition contained in the applicator of the present invention exhibits surprisingly good bioavailability and absorption rate, for example, compared to a corresponding composition that does not contain an alkyl sugar and / or contains a different excipient known to act as a surfactant.

[0135] Alkyl sugars that can be used include alkyl glycosides, which are 7-18Alkyl glycosides can be defined as any sugar attached by a linkage to an alkyl group, such as alkyl glycosides. Thus, alkyl glycosides can include alkyl maltosides (such as dodecyl maltoside), alkyl glucosides, alkyl sucrosides, alkyl thiomaltosides, alkyl thioglucosides, alkyl thiosucrose, and alkyl maltotriosides. However, it is preferred that the alkyl sugars are sugar esters.

[0136] Sugar esters that may be used in the powder compositions described herein include trisaccharide esters such as raffinose esters, monosaccharide esters such as glucose esters, galactose esters and fructose esters, and / or preferably disaccharide esters such as maltose esters, lactose esters, trehalose esters, and especially one or more sucrose esters.

[0137] Sucrose esters that may be used in compositions for inclusion in the applicator of the present invention may have a hydrophilic-lipophilic balance value of 6 to 20. The term "hydrophilic-lipophilic balance" (HLB) is a term of art that will be well understood by those skilled in the art (see, for example, 'The HLB System: A Time-Saving Guide to Emulsifier Selection' published 1976 (revised 1980) by ICI Americas Inc, chapter 7 (pages 20-21) of the document provides a method for determining the HLB value). The longer the fatty acid chain of the sucrose ester and the higher the degree of esterification, the lower the HLB value. The preferred HLB value is 10 to 20, more preferably 12 to 20.

[0138] Therefore, sucrose esters have the C 8-22 Saturated or unsaturated fatty acid esters, preferably saturated fatty acid esters, preferably C 10-18 Fatty acid esters, most preferably C 12Fatty acid esters are included. Particularly suitable fatty acids from which such sucrose esters can be formed include erucic acid, behenic acid, oleic acid, stearic acid, palmitic acid, myristic acid and lauric acid. A particularly preferred such fatty acid is lauric acid. Commercially available sucrose esters include those sold under the trademarks Surfhope® and Ryoto® (Mitsubishi-Kagaku Foods Corporation, Japan).

[0139] The sucrose ester may be a diester or monoester of a fatty acid, preferably a monoester such as sucrose monolaurate. Those skilled in the art will understand that the term "monolaurate" refers to a monoester of lauric acid, and that the terms "lauric acid ester" and "laurate" have the same meaning and can therefore be used interchangeably. Commercially available sucrose monolaurate products are sometimes referred to as "sucrose laurate". Commercially available sucrose monolaurate (or sucrose laurate) products, such as Surfhope® D-1216 (Mitsubishi-Kagaku Foods Corporation, Japan), may contain small amounts of diesters and / or higher sucrose esters, as well as small amounts of other sucrose esters and free sucrose, and are suitable for use in the present invention. Those skilled in the art will understand that any reference herein to a particular sucrose ester includes commercially available products that contain that sucrose ester as a major component.

[0140] Preferred sucrose esters contain only one sucrose ester, which means that a single sucrose ester (e.g., a commercially available sucrose ester product) contains a single sucrose ester as the main component (commercial products may contain impurities, e.g., a monoester product may contain small amounts of diesters and / or higher esters, and the product may be considered to "contain only one sucrose ester" in the context of the present invention). As used herein, the term "main component" will be understood to refer to the major component (e.g., more than about 50%, such as about 70% w / w or vol / vol) in a mixture of sucrose esters, such as a common commercially available surfactant product, which is typically sold with a certain range of ester compositions.

[0141] A particularly preferred sucrose ester is sucrose monolaurate.

[0142] When included in a composition for inclusion in the applicator of the present invention or when included in the applicator of the present invention, the amount of alkyl sugar that may be used may be in the range of about 0.5% to about 5% by weight, preferably about 0.1% to about 10% by weight, such as about 0.75% to about 3% by weight (e.g., up to about 2% by weight, such as about 1% by weight), based on the total weight of the composition.

[0143] Furthermore, optional additional excipients may be used within the composition for inclusion in the applicator of the invention or may be administered together with the composition of the invention, including one or more (further) surfactants. Surfactants that may be mentioned include polyoxyl 8 stearate (Myrj™ S8), polyoxyl 32 stearate (Gelucire™ 48 / 16), polyoxyl 40 stearate (Myrj™ S40), polyoxyl 100 stearate (Myrj™ S100), and polyoxyl 15 hydroxystearate (Kolliphor™ HS Polyoxyethylene alkyl ethers (e.g., Brij™) including polyoxyl cetostearyl ethers (e.g., Brij™ CS12, CS20, and CS25), polyoxyl lauryl ethers (e.g., Brij™ L9 and L23), and polyoxyl stearyl ethers (e.g., Brij™ S10 and S20); polyoxyglycerides (e.g., Gelucire™) including lauroyl polyoxyglyceride (Gelucire™ 44 / 14) and stearoyl polyoxyglyceride (Gelucire™ 50 / 13); sorbitan esters (e.g., Myrj™) including sorbitan monopalmitate (Span™ 40) and sorbitan monostearate (Span™ 60) (e.g., Myrj™); , Span™), polysorbates (Tweens™), including polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), and sodium lauryl sulfate; and monoacylglycerols (monoglycerides) such as 2-oleoylglycerol, 2-arachidonoylglycerol, monolaurin, glycerol monomyristate, glycerol monopalmitate, glyceryl hydroxystearate, and preferably, glycerol monostearate, glycerol monooleate (e.g., Cithrol™), and glycerol monocaprylate (e.g., Capmul™).Other surfactants may include dipalmitoyl phosphatidylcholine (DPPC), lauryl lactate, and poloxamer.

[0144] Other optional additional components (excipients) that may be included in or administered with a composition for inclusion in an applicator of the invention include isotonic and / or osmotic agents (e.g., sodium chloride), sterols (or steroid alcohols) such as cholesterol and phytosterols (e.g., campesterol, sitosterol, and stigmasterol); antioxidants (e.g., sodium metabisulfite, or in addition, alpha-tocopherol, ascorbic acid, potassium ascorbate, ascorbic acid esters, etc.); sodium, ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, dodecyl gallate, octyl gallate, propyl gallate, ethyl oleate, monothioglycerol, vitamin E polyethylene glycol succinate, or thymol; chelating (complexing) agents (e.g., edetic acid (EDTA), citric acid, tartaric acid, malic acid, maltol, and galactose, including salt forms of any of these agents); preservatives (e.g., benzalkonium chloride, or in addition, benzyl alcohol, boric acid, parabens, propionic acid , phenol, cresol, or xylitol); viscosity modifiers or gelling agents (such as cellulose derivatives including hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, etc., starch and modified starches, colloidal silicon dioxide, aluminum metasilicate, polycarbophil (e.g., Noveon®), carbomer (e.g., Carbopol®), and polyvinylpyrrolidone); mucoadhesive polymers such as carboxymethyl cellulose, modified cellulose gum, and sodium carboxymethyl cellulose (NaCMC); starch derivatives such as moderately crosslinked starches, modified starches, and sodium starch glycolate; acrylic polymers such as crosslinked polyvinylpyrrolidone, carbomer and its derivatives (polycarbophil, Carbopol®, etc.); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride);and croscarmellose (e.g., croscarmellose sodium); pH buffers (e.g., citric acid, maleic acid, malic acid, or glycine or their corresponding salts such as sodium citrate); colorants; penetration enhancers (e.g., isopropyl myristate, isopropyl palmitate, pyrrolidone, or tricaprylin); other lipids (neutral and polar); aromatic carboxylic acids such as benzoic acid, e.g., toluic acid or salicylic acid, optionally substituted with one or more groups selected from methyl, hydroxyl, amino, and / or nitro; optionally, flavors (e.g., lemon, peppermint powder, or preferably menthol), sweeteners (e.g., neohesperidin, acesulfame K, or sucralose), and dyes. Other excipients may include trisaccharides (e.g., raffinose) and mannitol, and pH adjusters (e.g., hydrochloric acid and sodium hydroxide).

[0145] The total amount of such "additional" excipients (including non-alkyl sugar surfactants that may be present) that may be included within the powder compositions described herein themselves may be up to about 15% by weight, such as up to about 5% by weight (e.g., about 10% by weight), based on the total weight of the composition.

[0146] The total amount of such "additional" excipients that may be included within the applicators of the present invention, including one or more powder compositions for inclusion in the applicators of the present invention, may be up to about 99.99%, for example, up to about 99%, such as up to about 99.9%, including up to about 90%.

[0147] Those skilled in the art will appreciate that if any additional optional ingredients are included in a composition for inclusion in an applicator of the present invention, the nature of those ingredients and / or the amount of those ingredients included should not adversely affect the Tg of the powder composition for the reasons discussed above. In this regard, such optional ingredients may be incorporated into the spray drying process (i.e., mixed together with the active ingredient and carrier material in a suitable volatile solvent and then spray dried) or may be included separately in the spray dried plurality of particles.

[0148] In particular, taking into account the improved chemical stability of the compositions for inclusion in the applicator of the present invention resulting in highly unstable active ingredients such as adrenaline, and the fact that those compositions are primarily intended for use in the treatment of patients who are susceptible to allergic reactions (and therefore may be sensitized to certain chemicals), it is preferred that the relevant compositions are essentially free of such "additional" excipients, in particular the above-mentioned antioxidants and / or preservatives such as benzalkonium chloride, more in particular sulfites, and / or chelating agents such as EDTA.

[0149] In this regard, a composition for inclusion in an applicator of the present invention may consist essentially of a pharmacologically effective dosage of an adrenergic receptor modulator or salt thereof, a pharma- ceutically acceptable carrier material as defined herein, and (optionally) an alkyl saccharide material as defined herein. When such a composition "consists essentially" of the above components, this will be understood to mean that the composition includes only those components, together with other features and / or components that do not substantially affect the basic and novel characteristic(s) of the composition. Alternatively, in the situation where a composition for inclusion in an applicator of the present invention "consists essentially" of those components of the present invention, this may be understood to mean that the composition includes, in total, at least about 90% by weight of those components, such as at least about 95% by weight, including at least about 97% by weight (e.g., about 99% by weight).

[0150] According to a further aspect of the present invention, there is provided an applicator of the present invention for use in medicine (human and veterinary medicine), thus in the treatment of a patient in need of medical treatment of a condition that the associated active ingredient is known to treat.

[0151] "Treatment" of such conditions includes curative, symptomatic and palliative treatment as well as prophylaxis / prevention or diagnosis of such conditions.

[0152] Thus, the applicators of the present invention are useful in the treatment of a variety of disorders, depending on the active ingredient(s) contained in such compositions.

[0153] The applicator of the present invention containing dopamine may be used in the correction of hemodynamic imbalances present in shock syndromes resulting from myocardial infarction, trauma, endotoxin sepsis, open heart surgery, renal failure, and chronic heart failure (congestive failure), the applicator of the present invention containing oxymetazoline may be used as a decongestant, the applicator of the present invention containing dobutamine may be used, for example, in the treatment of heart failure, the applicator of the present invention containing mirabegron may be used in the treatment of overactive bladder syndrome, and the applicator of the present invention containing a bronchodilator such as albuterol (salbutamol), formoterol, levalbuterol, olodaterol, salmeterol, and terbutaline may be used in the treatment of asthma (exercise-induced bronchospasm (EIB)) and / or chronic obstructive pulmonary disease (COPD, including associated bronchospasm). The applicator of the present invention containing terbutaline may also be used in the treatment of preterm labor.

[0154] The applicators of the invention containing norepinephrine may be used in blood pressure control (and / or cardiac arrest) induced in certain acute hypotensive conditions including sympathectomy, poliomyelitis, pheochromocytectomy, spinal anesthesia, myocardial infarction, sepsis, blood transfusion, or drug reactions. The applicators of the invention containing isoprenaline may be used in the treatment of bradycardia, heart block, and possibly asthma.

[0155] In particular, the applicator of the present invention containing adrenaline is useful in treating allergic reactions, including, for example, heart failure (e.g., heart attack) and / or more particularly, extreme or severe allergic reactions, anaphylaxis, and / or anaphylactic shock, characterized by, for example, a severe drop in blood pressure, as a result of, for example, insect stings / bites, reactions to foods, drugs, and / or other substances. Extreme and / or severe allergic reactions can further include sepsis and / or septic shock, which can be, for example, a reaction to infection by fungi, bacteria, and / or viruses. Anaphylaxis and sepsis can further result in organ dysfunction, including organ failure and / or eventual death.

[0156] The applicators of the invention containing adrenaline may also be used in the treatment of allergic reactions to, for example, any type 1 hypersensitivity reaction, particularly allergic asthma, allergic conjunctivitis, allergic rhinitis, anaphylaxis (including idiopathic or exercise-induced anaphylaxis), angioedema, urticaria, eosinophilia, drug allergies (including antibiotic allergies), food allergies, animal sera, insect bites and stings, diagnostic test substances, and other allergens; treatment of acute asthma attacks to relieve bronchospasm; treatment of systemic toxic responses (anaphylactoid reactions); paroxysmal changes in the heartbeat mechanism; are useful in the treatment and prevention of episodes of transient atrioventricular block with cardiac arrest and / or fainting, including transient loss of consciousness due to a sudden but significant decrease in cardiac output caused by changes in blood pressure (Stokes-Adams syndrome); inducing an increase in mean arterial blood pressure in adult patients with hypotension associated with septic shock; inducing and maintaining pupillary dilation during intraocular surgery; in the treatment of gastrointestinal and / or renal bleeding; in the treatment of superficial bleeding, premature labor, hypoemia, and cardiogenic, hemorrhagic, and traumatic shock; and / or in the treatment of croup (an infection of the upper respiratory tract that obstructs breathing and causes a characteristic barking cough).

[0157] The applicators of the invention containing adrenaline are particularly useful in the treatment and / or prevention (prophylaxis) of severe reactions, including anaphylaxis and sepsis and / or anaphylactic and septic shock, as described above. Prevention and / or prophylaxis of these severe reactions may be achieved by administration (including self-administration) of one or more compositions from the applicators of the invention to a patient at risk of such reactions following exposure (or suspected exposure) to the relevant substances described above, to which the patient is sensitive and / or sensitized.

[0158] According to three further aspects of the invention there is provided: an applicator of the invention comprising adrenaline for use in treating an allergic reaction (e.g., by transmucosal, such as intranasal, administration of a composition contained therein); Use of a composition as described herein, comprising adrenaline, for the manufacture of an applicator for treating an allergic reaction by transmucosal, such as intranasal, administration of said composition via the applicator of the invention; and - A method for treating an allergic reaction, the method comprising transmucosal, such as intranasal, administration of a composition via an applicator of the present invention containing adrenaline to a patient suffering from or susceptible to the condition.

[0159] 1. A method of treating (e.g., severe) allergic reactions, including anaphylaxis, in a human patient, comprising: (a) identifying a human patient having or at acute risk of having such an allergic reaction; (b) administering from the applicator of the present invention a dosage amount of adrenaline or a pharma- ceutically acceptable salt thereof in the form of a solid, amorphous, monoparticulate powder as defined herein, suitable for treating the allergic reaction, and dispensing said dosage amount of adrenaline or a salt thereof into a body cavity of the patient comprising a mucosal surface, thereby providing said powder comprising said adrenaline or a salt thereof to said mucosal surface to facilitate absorption of said adrenaline across said mucosal surface, and thus treating or preventing said severe allergic reaction.

[0160] The compositions contained in the applicator of the present invention are preferably administered intranasally. In this regard, the applicator is preferably a suitable nasal applicator or dispenser means capable of administering a suitable dose of the active ingredient in the form of one or more powder compositions described herein to the nasal cavity.

[0161] A suitable nasal applicator of the present invention should therefore be capable of containing and storing one or more doses of the relevant composition itself, or be capable of being attached to a reservoir / container that contains and stores one or more doses of said composition and prevents significant loss of the physical and chemical integrity of the composition, including through ingress of water. In this way, the composition is ready for use as soon as the applicator device is actuated by the end user (whether this is for single or multi-dose use), and the applicator then delivers a composition (e.g., a powder) having an appropriate dose of the active ingredient as defined herein to the nasal mucosa of the subject.

[0162] Suitable applicator means are described in the prior art. When used in the context of the present invention, the composition may be loaded into a reservoir attached to or forming part of such an applicator of the present invention, and is contained therein until the applicator means, or dispenser, is actuated. Hereinafter, the terms "applicator", "dispensing means", "applicator device", "dispensing device" and "inhaler" may be used interchangeably and may mean the same thing.

[0163] An essential requirement of the applicator of the present invention is that the reservoir that contains the solid amorphous single particle powder composition is opaque. Due to the unexpected stability of the composition contained in the applicator of the present invention, there is no need to inspect the contents of the reservoir (i.e., the powder composition) prior to administration or use. This is in contrast to commercially available devices such as EpiPen, whose product labels include the need to check the integrity of the contents prior to dispensing for very good reasons, including the instability of the liquid solution composition contained therein to heat, cold, and light.

[0164] With this in mind, the reservoirs housing the powder compositions described herein may be opaque, which will be understood by those of skill in the art to include "not transparent or translucent, not allowing light to pass through and / or not allowing light to pass through."

[0165] Thus, the applicators of the present invention do not have (and do not require) an inspection window through which the contents of the applicator's reservoir can be observed, and in this regard, they may be completely opaque in nature, i.e., at least about 98%, such as at least about 99%, particularly about 99.9% opaque, and / or about 2% or less, such as about 1% or less, particularly about 0.1%, transparent, translucent, and / or light transmissible, allowing inspection of the contents of the reservoir.

[0166] Such applicator means may therefore also include a mechanism for expelling the powder composition described herein from the reservoir via an outlet (or dispensing) means, including a suitably shaped nozzle or the like, any size sized for placement in a human body cavity, such as a nostril.

[0167] Thus, the mechanism for expelling the powder may include means for actuating the device, which may include breath-actuated actuation, or may include actuation means for generating a force upon actuation of the device by a user.

[0168] Therefore, the applicator needs to be able to provide a reproducible and sufficient amount of the powder formulation in a single administration step that provides a therapeutic dose of the active ingredient (and in a manner that does not require "priming" the device).

[0169] Moreover, due to the unexpected stability of the compositions contained in the applicators of the present invention, and the lack of need to test the contents of the reservoir (i.e., powder composition) prior to use for administration, the applicators of the present invention may be used to administer an adrenergic receptor modulator (e.g., adrenaline) or a pharma- ceutically acceptable salt thereof to a mucosal surface to treat or prevent said severe allergic reaction as soon as a patient is identified as having or at acute risk of having an allergic reaction. Thus, the administration steps identified above may be performed immediately following the steps identified above, without any delay, which delay may be (i) inspecting a composition contained within a reservoir of an applicator of the present invention; and (ii) A period of time sufficient to determine whether a formulation containing the relevant adrenoceptor modulator (e.g., adrenaline) can be safely administered to a patient to effectively treat the allergic reaction in question.

[0170] Nasal applicators / inhalation devices that may be used to administer the powder compositions described herein include multi-dose applications such as metered dose inhalers (MDIs), dry powder inhalers (DPIs, including low, medium and high resistance DPIs) and soft mist inhalation devices (SMIs), which can be adapted based on techniques known in the art for delivery of active ingredients to the lungs.

[0171] In an MDI, the powder composition must be capable of forming a stable suspension when suspended in a solvent typically used therein, such as a propellant, which has sufficient vapor pressure to form an aerosol upon actuation of the delivery device (e.g., a hydrocarbon, a fluorocarbon, a hydrogen-containing fluorocarbon, or a mixture thereof).

[0172] However, if the nasal applicator is a single-dose applicator in which the composition is dispensed after actuation and discarded after use, suitable applicator means or devices for delivering a single dose of the active ingredient include breath-assisted and blow-assisted designs (such as Optinose®), as well as those described in US 6,398,074, US 6,938,798, or US 9,724,713, the relevant disclosures of all documents being incorporated herein by reference. Figures 1 and 2 of the present application are based on Figures 1 and 2 of US 6,398,074, respectively, and Figures 3-7 are based on Figures 19-23 of US 9,724,713, respectively. Both are diagrams of applicators that can be used to administer powder compositions intranasally.

[0173] In Figure 1, the device comprises a body top / dispenser head 1 incorporating an outlet channel 40 (i.e. part of the "outlet means" mentioned above) and a gripping means 60 enabling the user to actuate the device. On the inside of the body top / dispenser head 1 is attached an element, the assembly of which is designated by the reference number 2, which incorporates a reservoir 10 and an air chamber 22 for the air blast 20. This element 2 can be produced integrally with the body 1. A body bottom 3 is also provided to be able to slide relative to the body top 1 and relative to the element 2, on which the user exerts a pressure force to actuate the device.

[0174] The reservoir 10 contains a single dose of the composition described herein. The reservoir 10 has an air inlet 11 and a product outlet 15. A product retention device 12, including an air permeable grid, is positioned within the air inlet 11 to retain the product within the reservoir 10 until the composition is dispensed. The product outlet 15 is blocked, preferably in a sealing manner, by a closure ball 16, which is removed from its blocked position by the flow of air when the applicator is actuated and the product is dispensed.

[0175] When the user actuates the device, pressure is applied to the plunger 25 such that the piston 21 compresses the air 20 contained in the chamber 22. As the grid 12 is permeable to air, the compression of the air in the chamber 22 creates an air blast which is transmitted to the reservoir 10 and thus to the closing ball 16 blocking the product outlet 15.

[0176] The dimensions of the closure ball 16 and its fixation at the reservoir product outlet 15 are such that when a minimum predetermined pressure is created through the reservoir 10 by a blast of air 20, the ball 16 is removed from its blocking position.

[0177] The pre-compression created by the closing ball 16 ensures that when the ball is removed from its blocking position, the energy stored in the user's hand is such that the piston 21, integral with the plunger 25, is propelled within the chamber 22, thereby generating a powerful blast of air 20, i.e. an airflow suitable for finely atomizing a dose of powder composition.

[0178] Once this minimum pressure is reached, the ball moves rapidly towards the outlet channel 40 of the device and the flow of air 20 created by the blast expels substantially all of the dose of composition contained within the reservoir 10.

[0179] Preferably, the outlet channel 40 has a diameter larger than that of the closing ball 16, to allow the dose of product to be discharged through the outlet channel 40 by flowing around the ball 16. As shown in Figure 2, which represents the same device after actuation, the channel 40 is provided with means 41 for stopping or fixing the ball 16, to prevent the discharge of the ball from the device when the product is being discharged.

[0180] Further embodiments that may be used to intranasally administer the powder compositions described herein are provided in column 7, line 50 to column 8, line 61 and Figures 19-23 of US 9,724,713, reproduced as Figures 3-7 of the present application.

[0181] In this embodiment, the reservoir 10 is fixed within a body top / dispenser head 1 which includes a dispenser outlet channel 40 (i.e., part of the "outlet means" previously discussed) having a gripping means or finger rest 60 which allows a user to actuate the device. A radial shoulder 37 (see Figure 5) of the body top / dispenser head 1 advantageously defines an assembly location for the reservoir 10 within the body top / dispenser head 1.

[0182] The mechanical opening system comprises a set of rods 61, 62, and when the device is actuated, a second rod portion 62 is pushed against said first rod portion 61. At the end of their actuation stroke, i.e. in the dispensing position, the set of rods 61, 62 cooperate with the closure element 16, which is spherical, in particular a ball as in the first embodiment discussed above, and mechanically eject it from the closed position.

[0183] In this embodiment, the piston 21 is separate from the first rod portion 61 and slides against both the air chamber 22 and a cylindrical surface 614 fixed to the first rod portion 61. Figure 7 is a perspective view of the air expeller of the device of Figures 3-6 in a rest position.

[0184] The air chamber 22 may thus be cylindrical and in a rest position communicate with the surrounding air by means of flutings or grooves 615 formed in said cylindrical surface 614 and cooperating with the piston 21 in particular in the rest position. The piston 21 thus comprises an inner lip 215 which slides in an airtight manner on the cylindrical wall 614 during actuation and which cooperating with said flutings 615 in the rest position. The piston 21 also comprises an axial extension 216 which cooperating with an upper edge 251 of a pusher element 25 (called "plunger" in the first embodiment) which moves said piston 21 in the air chamber 22 during actuation.

[0185] The retaining member 42 is extended downwardly by an axial extension 43 which contacts an upper axial end 610 of the first rod portion 61 during actuation.

[0186] Additionally, in this embodiment, there is no outer body, only a cover 27 assembled onto the lower axial edge of the air chamber 22 .

[0187] A spring 80 is provided between the radial flange 225 of the air chamber 22 and the first rod portion 61 and the portion forming the cylindrical surface 614 so that the air expeller automatically returns to its rest position after actuation.

[0188] The principle of operation is as follows: In the rest position of Fig. 3, the reservoir 10 is sealed closed by the retaining member 42 and the closure element / ball 16. The air expeller is open to the atmosphere by cooperation between the inner lip 215 of the piston 21 and the flutings 615 of the cylindrical surface 614.

[0189] When it is desired to actuate the device, the user pushes the pusher element 25. During this first stroke, the inner lip 215 of the piston leaves the flutings 615 and comes into air-tight cooperation with the cylindrical surface 614, thereby closing the air chamber 22. At the same time, the upper edge 251 of the pusher element 25 comes into contact with the axial extension 216 of the piston 21 and the upper axial end 610 of the first rod portion 61 comes into contact with the axial extension 43 of the retaining member 42.

[0190] However, as can be seen in FIG. 4, the upper axial end 621 of the second rod portion 62 is still not in contact with the rounded surface 55 of the closure element / ball 16 .

[0191] Continued actuation therefore simultaneously moves the piston 21 within the air chamber, thereby compressing the air contained therein and moving the retaining member 42 away from the position that closes the reservoir 10. When the second rod portion 62 contacts the rounded surface 55 of the closure element / ball 16, said closure element / ball is mechanically expelled from its closed position so that the composition can be expelled under the influence of the air compressed by the air expeller.

[0192] The dispensing position is shown in Figure 5. As can be seen in Figure 5, the retaining member 42 can move away from the first rod part 61 while the composition is being expelled under the effect of compressed air provided by the air expeller. In this position, the closure element / ball 16 is expelled from the reservoir 10 so that fluid or powder can be dispensed under the effect of compressed air. The closure element / ball 16 is thus jammed in the spline 3 of the top body / dispenser head 1, which in particular prevents any risk of the closure element / ball 16 being expelled from the top body / dispenser head 1.

[0193] As shown in FIG. 6, when the user releases the device, the spring 80, which was compressed during actuation, returns the first rod portion 61 towards its rest position. This creates a suction force that draws the closure element 16 and the retaining member 42 towards or near their closed position. This therefore blocks a new suction path, with the empty reservoir remaining assembled on the air expeller so that it does not get dirty during its automatic return to the rest position. However, the piston 21 remains in its dispensing position as a result of friction with the air chamber 22 and the suction force created in the reservoir 30, such that the cylindrical surface 614 slides on the inner lip 215 until said inner lip once again cooperates with the flutings 615. At this point, the air chamber 22 is again in communication with the surrounding air and the suction force by returning to the rest position is no longer created. The piston 21 is therefore also retracted towards its rest position. This allows the reservoir to be closed after use.

[0194] Optionally, the unit formed by the body top / dispenser head 1 and the empty reservoir 10 can be removed from the air expeller and replaced with a new unit containing a full reservoir.

[0195] Suitable applicator devices that can be used include those available from Aptar Pharma, France (UDS Monopowder). See, for example, International Patent Applications Nos. 2022 / 208014 and 2021 / 005311. Other examples of applicator devices that can be used in combination with the powder compositions according to the present invention include those described in U.S. Patent Application Nos. 2011 / 0045088, 7,722,566 (see, for example, Figures 1 and 7) and 5,702,362, and International Patent Application No. 2014 / 004400, the relevant disclosures of which are incorporated herein by reference.

[0196] According to a further aspect of the present invention there is provided a process for manufacturing an applicator of the present invention, the process comprising the step of loading the composition defined herein into a reservoir within or associated with the applicator.

[0197] According to another aspect, there is provided an applicator of the invention comprising one or more compositions according to the invention, which can be actuated one or more times to deliver the one or more compositions, each containing an appropriate dose of active ingredient at each such actuation, the applicator comprising: an outlet through which at least one composition is dispensed; means for generating an external force (e.g., airflow) upon actuation of the applicator device by a user; at least one (optionally replaceable, optionally opaque) reservoir containing said one or more compositions, which is in, or can be arranged to be in, direct or indirect communication with the dispenser outlet; a replaceable, optionally reversible, sealing means on the applicator and / or reservoir to retain one or more compositions within the reservoir until the composition is dispensed; a mechanical opening system that cooperates with said sealing means such that the single dose composition is mechanically expelled by the force application means when the applicator is actuated; and Optionally, a mechanism for resealing the device and / or the reservoir to retain the additional composition within the reservoir until the additional composition is dispensed.

[0198] According to a still further aspect of the present invention there is provided an applicator of the present invention containing a single dose of a composition according to the present invention and suitable for dispensing said composition, said applicator comprising: Dispenser outlet, an air expeller for generating an air flow while the device is actuated, the air expeller including a piston that slides within the air chamber between a rest position and a dispensing position; The piston slides in an airtight manner within the air chamber; at least one (e.g., opaque) reservoir containing a dose of the composition according to the invention, the reservoir comprising an air inlet connected to the air expeller; a composition outlet connected to the dispenser outlet; said air inlet including a displaceable sealing means (e.g., a retaining member) for retaining the composition within the reservoir until the composition is dispensed; a composition outlet of the reservoir, said composition outlet being closed by a closure element fitted to said composition outlet; the applicator further including a mechanical opening system cooperating with the closure element to mechanically eject the closure element from the closed position during actuation of the applicator; and The piston of the air expeller cooperates in a non-airtight manner with the air chamber when in a rest position.

[0199] In the latter aspect of the invention, it is preferred that: (i) the air chamber into which the piston slides in an airtight manner is substantially cylindrical; (ii) the closure element is press-fitted onto the composition outlet of the reservoir; (iii) the air chamber is in communication with the atmosphere in a stationary position; and / or (iv) the piston includes an inner lip adapted to cooperate with a cylindrical surface, the cylindrical surface including fluting that cooperates in a non-sealing manner with the inner lip of the piston in a rest position.

[0200] Such nasal applicators or dispensing devices can provide a suitable and reproducible powder spray pattern and / or geometric plume shape that allows efficient delivery of the powder to the nasal cavity (e.g., nostrils).

[0201] In the compositions used in the applicator of the present invention, the average particle size can be provided as the average diameter by weight, number, or volume. As used herein, the term "average diameter by weight" is understood by those skilled in the art to include the average particle size being characterized and defined from the particle size distribution by weight, i.e., the existing fraction (relative amount) in each size class is defined as the weight fraction obtained, for example, by sieving (e.g., wet sieving). The term "average diameter by volume" is similar in meaning to the average diameter by weight, but is understood by those skilled in the art to include the average particle size being characterized and defined from the particle size distribution by volume, i.e., the existing fraction (relative amount) in each size class is defined as the volume fraction measured, for example, by laser diffraction. As used herein, the term "average diameter by number" is understood by those skilled in the art to include the average particle size being characterized and defined from the particle size distribution by number, i.e., the existing fraction (relative amount) in each size class is defined as the number fraction measured, for example, by microscopy. Other instruments known in the art may be used to measure particle size, such as, for example, instruments sold by Malvern Instruments, Ltd (Worcestershire, UK), Sympatec GmbH (Clausthal-Zellerfeld, Germany), and Shimadzu (Kyoto, Japan).

[0202] Powder compositions for use in the applicators of the present invention typically have a volumetric mean diameter (VMD) in the range of about 0.2 μm, such as about 0.5 μm (e.g., about 1 μm), up to about 1,000 μm (e.g., up to about 500 μm, such as about 400 μm or about 500 μm), and appropriate particle size ranges may be selected based on the dosage form intended to contain such compositions.

[0203] However, one of ordinary skill in the art will appreciate that to allow for effective intranasal administration, the powder will typically have a volumetric mean diameter (VMD) in the range of about 5 μm up to about 300 μm (e.g., up to about 200 μm). Depending on the applicator device used, the VMD may range from about 10 μm to about 100 μm, such as from about 20 μm to about 60 μm.

[0204] Preferred particle size distributions for intranasal drug delivery may also include those with D10 greater than about 3 μm, such as greater than about 10 μm, and less than about 75 μm (e.g., up to about 50 μm), and D90 between about 80 μm and about 1,000 μm, such as less than about 100 μm (e.g., about 500 μm). One of ordinary skill in the art will appreciate that the parameter "D10" (or "Dv(10)") refers to the size (or diameter) in the particle size distribution below which 10% of the total volume of the material in the sample falls. Similarly, "D90" (or "Dv(90)") refers to the size below which 90% of the material falls.

[0205] Powders having a particle size distribution and VMD within the above ranges include the bulk VMD and / or the emitted VMD, i.e., the particle size distribution when initially loaded into and / or expelled from the device, respectively.

[0206] Particle size can be measured by standard equipment such as dry (or wet) particle size measurement techniques, including dry dispersion techniques available from manufacturers such as Sympatec and Malvern.

[0207] Preferred particle shapes include spherical or substantially spherical, meaning that the particles have an aspect ratio of less than about 20, more preferably less than about 10, such as less than about 4, and especially less than about 2, and / or may have a variation in radius (measured from the center of gravity to the particle surface) of less than about 50% of the mean value, such as less than about 30% of the mean value, for example less than about 20% of that value, in at least about 90% of the particles.

[0208] Nevertheless, the particles may be of any shape, including irregularly shaped (e.g., "raisin" shaped), needle-shaped, disk-shaped, or rectangular shaped particles. For non-spherical particles, the size may be given as the size of a corresponding spherical particle of, for example, the same weight, volume, or surface area.

[0209] The spray angle of a powder composition emitted (dispensed) from a nasal applicator according to the present invention should preferably be less than about 90°.

[0210] When the word "about" is used herein in the context of quantities, such as absolute amounts, e.g., doses, weights, volumes, sizes, diameters, aspect ratios, angles, or relative amounts (e.g., percentages) of individual components in a composition or of a component of a composition (including concentrations and ratios), time frames, and parameters such as temperature, pressure, relative humidity, etc., it will be understood that such variables are approximate and thus may vary by ±10%, e.g., ±5%, and preferably ±2% (e.g., ±1%) from the actual numerical values ​​specified herein. This is true even when such numbers are first presented as percentages (e.g., "about 10%" may mean ±10% for the number 10, which is anywhere from 9% to 11%).

[0211] The composition of the present invention and the composition contained therein have the advantage that they can be stored over a wide range of temperatures and / or relative humidity.Accordingly, the applicator of the present invention can be subjected to low temperatures (e.g., below freezing) without affecting the amount of active ingredient administered to a subject.Furthermore, the applicator of the present invention can have the advantage that the powder composition contained therein is more physically and chemically stable at all (higher) temperatures than related prior art devices such as EpiPen.

[0212] The applicators of the present invention may further have the advantage of providing a higher bioavailability of the active ingredient as compared to prior art applicators or compositions, such as those containing adrenaline. The compositions contained in the applicators of the present invention may provide this higher bioavailability along with more rapid absorption, which is likely to result in a more rapid onset of action than such prior art and / or commercially available compositions, thus fulfilling an important medical need.

[0213] The applicators, compositions, uses, and methods described herein may also have the advantage that they may be more convenient for first responders, physicians, and / or patients, may be more effective, may have less toxicity, may have a broad spectrum of activity, may be more potent, may produce fewer side effects, may have less inter-patient variability, or may have other useful pharmacological properties over similar formulations or methods (treatments) known in the prior art, whether for use in treating a condition for which the associated active ingredient is known, by transmucosal administration, such as intranasally, or otherwise, in treating said condition.

[0214] The invention is illustrated by the following examples, but is in no way limited, with reference to the drawings in which Figs. 1-7 represent drawings of an actuator device that may be used to dispense the powder composition, and Fig. 8 shows epinephrine plasma concentrations versus time (linear scale, arithmetic mean) by treatment obtained in a Phase I clinical study. [Brief description of the drawings]

[0215] [Figure 1] FIG. 1 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Diagram 2] FIG. 2 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Diagram 3] FIG. 3 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Figure 4] FIG. 4 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Diagram 5] FIG. 5 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Figure 6] FIG. 6 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Figure 7] FIG. 7 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Figure 8] FIG. 8 shows epinephrine plasma concentrations versus time (linear scale, arithmetic mean) by treatment obtained in a Phase I clinical study.

[0216] Comparative Example 1 Spray-dried epinephrine (adrenaline) formulation Adrenaline bitartrate (0.729 g; Fisher Scientific, Sweden) was dispensed into a glass flask (total 2.50 g) together with α-D-lactose monohydrate (0.500 g; DFE Pharma, Germany), maltodextrin (Glucidex IT 12DE, 1.247 g, Roquette, France), and sucrose monolaurate D-1216 (0.025 g, Mitsubishi-Kagaku Foods Corporation, Japan) and dissolved in MQ water (47.50 g) by stirring at room temperature.

[0217] The resulting mixture was fed into a spray dryer (ProCepT, Belgium) equipped with an ultrasonic nozzle operating at 25 kHz. The feed rate of the spray dryer was set at 3.0 g / min, the inlet temperature was set at 180° C., the gas flow rate was set at 300 L / min, and the cyclone gas was set at 1.5 bar.

[0218] The resulting spray dried powder was collected fine, dry, free-flowing, with a nominal dosage of 4 mg adrenaline free base in 25 mg powder.

[0219] Powders were analysed for particle size distribution (PSD) by dry powder laser diffraction. Samples were dispersed in an Aero S dry dispersion unit (using 0.5 bar compressed air) before sizing with a Mastersizer3000 laser diffraction sensor (both from Malvern Panalytical, UK) as shown in Table 1 below. [Table 1]

[0220] The PSD of the adrenaline formulation was well within a range of distribution suitable for intranasal administration.

[0221] The assay and purity of the spray dried adrenaline formulation was determined by HPLC / UV analysis: the assay was 99.7% and the percentage of total related substances (RS%) (i.e., impurities and degradation products) was less than 0.29%.

[0222] Comparative Example 2 Chemical stability of spray-dried powders Amounts of 105-115 mg of the spray-dried powder from Comparative Example 1 above were dispensed into 1.5 mL glass vials closed with screw caps. Two vials were placed in a climate cabinet at 40° C. and 75% relative humidity (40 / 75) and two vials were placed in a climate cabinet at 25° C. and 60% relative humidity (25 / 60). For each storage condition, one vial was left in the cabinet as is and one vial was packaged in a heat-sealed aluminum pouch.

[0223] The chemical stability of the drug substance after up to 18 months is summarized for different compositions and packages in Table 2 below, along with the total amount of impurities and degradation products expressed as RS%, where NA means "not analyzed". [Table 2]

[0224] Comparative Example 3 Pharmacokinetic study of adrenaline in dogs after intranasal and intramuscular administration. The objective of this study was to obtain and evaluate the baseline pharmacokinetic profile following intranasal administration of the composition of Comparative Example 1 and following intramuscular administration of adrenaline in aqueous solution.

[0225] The study was conducted on six beagle dogs, three males and three females, approximately 15-18 months of age. The dogs were dosed in a crossover dosing regimen to compensate for potential sequential effects. Dosing was always performed in the morning, and the dogs were fasted overnight (minimum 8 hours). Water was available ad libitum, and food was offered 4 hours after dosing.

[0226] Each dog was administered intranasally the composition of Comparative Example 1 at a dose of 4 mg / animal (IN 4 mg) and adrenaline in aqueous solution (1 mg / mL) at a dose of 0.3 mg / animal (IM 0.3 mg). The composition of Comparative Example 1 was administered intranasally by a specific intranasal device from Aptar Pharma, France (UDS Monopowder).

[0227] Aqueous solutions of adrenaline were administered intramuscularly into the left hind leg musculature (quadriceps muscle), with a washout period of 48 hours between each administration.

[0228] The in vivo part of the study was carried out in accordance with the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (ETS No. 123).

[0229] Blood samples were collected under conventional sterile conditions from all dogs at the designated time points via the cephalic or saphenous vein. A volume of 1 mL was collected in a plastic Vacuette® tube containing K3EDTA. Blood samples were kept on ice before being centrifuged at 3500 rpm for 10 minutes at +4°C.

[0230] Plasma was extracted and transferred to pre-labeled cryovials containing sodium metabisulfite as an antioxidant and stored at -80°C until transport for bioanalysis. Scheduled sampling time points were as follows: -5 (pre-dose), 2.5, 5, 10, 15, 20, 30, 45, 60, and 90 min post-dose.

[0231] Frozen plasma samples were shipped to Recipharm OT, Uppsala, Sweden for bioanalysis. Plasma concentrations of adrenaline were determined using HPLC-MS-MS analysis, which allows measuring the concentration of adrenaline in dog plasma in the range of 0.05-100 ng / mL, using adrenaline-D6 as a deuterated internal standard. Analytes were extracted from sample plasma using protein precipitation with TCA. After centrifugation, the supernatant was used for analysis.

[0232] All samples were analyzed by first separating the analytes using an Acquity HSS T3 column (2.1mm*100mm, 1.7μm) and then detecting them using positive electrospray ionization and multiple reaction monitoring (MRM). Quantification was performed in the range of 0.05-100ng / mL.

[0233] Pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin (v8.0) and are shown in Table 3 below. AUC last is the area under the plasma concentration versus time curve up to the maximum last sampling point, and C max is the maximum measurable concentration after administration, and t max is the time to maximum measurable concentration. Values ​​shown in Table 3 are the average of N=6. [Table 3]

[0234] Example 1 Epinephrine (adrenaline) preparations produced by spray drying in air. Eight aqueous solutions (50 g each, formulations A to I respectively) containing dry matter compositions each having 0.364 g adrenaline bitartrate and having the respective amounts of excipients lactose monohydrate, maltodextrin (Glucidex IT 12DE), HPMC (Methocel K3), sucrose monolaurate (D-1216), sodium metabisulfite (Merck Chemical & Lifescience AB, Sweden), and / or disodium EDTA (Titriplex® III, Merck Chemical & Lifescience AB, Sweden) shown in Table 4 below in grams were spray dried according to the general procedure described in Comparative Example 1 above to produce a fine, dry, free-flowing powder with a nominal dose of 1.0 mg adrenaline free base in 25 mg powder. [Table 4]

[0235] The PSD of the resulting powder was determined as described in Comparative Example 1 and is shown in Table 5 below, and was well within a distribution suitable for nasal administration. [Table 5]

[0236] The initial assay and purity (expressed as RS%) as determined by HPLC / UV analysis are shown in Table 6 below. [Table 6]

[0237] Chemical stability experiments were performed essentially as described in Comparative Example 2 above by packaging vials containing various adrenaline formulations in heat-sealed aluminum pouches with 4 Å molecular sieve desiccant and storing them in a 40 / 75 climate cabinet.

[0238] The chemical stability after up to 12 months is summarized for the various compositions in Table 7 below, along with the total amount of impurities and decomposition products expressed as RS%. [Table 7]

[0239] The observed change in RS% for the readily degraded adrenaline indicates surprisingly good chemical stability of the drug substance when formulated in the manner described herein.

[0240] One or more of formulations AI are loaded into specific intranasal devices from Aptar Pharma, France (UDS Monopowder) for administration to human patients, as described in Comparative Example 3 above.

[0241] Example 2 Epinephrine (adrenaline) formulations produced by spray drying under nitrogen. Five aqueous solutions (50 g each, Formulations J-N respectively) containing dry matter compositions each having 0.218 g adrenaline bitartrate and having the respective amounts of excipients lactose monohydrate, maltodextrin (Glucidex IT 12DE), HPMC (Methocel K3), sucrose monolaurate (D-1216), and / or sodium metabisulfite as shown in Table 8 below in grams were spray dried by the general procedure described in Comparative Example 1 above, except that nitrogen was used instead of air as the drying gas, to produce a fine, dry, free-flowing powder having a nominal dose of 1.0 mg adrenaline free base in 25 mg powder. [Table 8]

[0242] The initial assay and purity (expressed as RS%) as determined by HPLC / UV analysis are shown in Table 9 below. [Table 9]

[0243] Chemical stability experiments were performed essentially as described in Comparative Example 2 above by packaging vials containing various adrenaline formulations in heat-sealed aluminum pouches with 4 Å molecular sieve desiccant and storing them in a 40 / 75 climate cabinet.

[0244] The chemical stability after up to 12 months is summarized for the various compositions in Table 10 below, along with the total amount of impurities and decomposition products expressed as RS%. [Table 10]

[0245] One or more of formulations JN are loaded into specific intranasal devices from Aptar Pharma, France (UDS Monopowder) for administration to human patients, as described in Comparative Example 3 above.

[0246] Example 3 Evaluation of various disaccharides and maltodextrins. Nine aqueous solutions (50 g each, formulations O to W respectively) containing dry matter compositions each having 0.364 g adrenaline bitartrate (Transo Pharm, Taiwan) and having the respective amounts of disaccharides (lactose monohydrate (LT), trehalose (TH, Sigma-Aldrich (Merck), Sweden), sucrose (SU), and maltose (MT) (both Merck, Germany), maltodextrins (Glucidex IT 6DE, Glucidex IT 12 DE or Glucidex IT 19 DE, all Roquette, France), and sucrose monolaurate (D-1216, SM) shown in Table 11 below in grams were spray dried according to the general procedure described in Comparative Example 1 above to produce a fine, dry, free-flowing powder with a nominal dose of 1.0 mg adrenaline free base in 25 mg powder. [Table 11]

[0247] Chemical stability experiments were performed essentially as described in Comparative Example 2 above by packaging vials containing various adrenaline formulations in heat-sealed aluminum pouches with 4 Å molecular sieve desiccant and storing them in a climatic cabinet at 40 / 75 and in a conventional oven at 50° C. and ambient RH.

[0248] The chemical stability after up to 1 month (40 / 70) and up to 4 weeks (50° C.) is summarized for the various compositions in Table 12 below, along with the total amount of impurities and decomposition products expressed as RS%. [Table 12]

[0249] One or more of formulations O-W are loaded into specific intranasal devices from Aptar Pharma, France (UDS Monopowder) for administration to human patients, as described in Comparative Example 3 above.

[0250] Example 4 Storage stability Commercially available EpiPens (Meda Pharma GmbH & Co. KG, Germany), which had a shelf life of approximately 9–12 months remaining upon arrival at the analytical laboratory, were purchased from a pharmacy.

[0251] Chemical stability experiments were performed essentially as described in Comparative Example 2, storing the EpiPens in a climate cabinet at 40 / 75. Chemical stability after up to 3 months is summarized for various compositions in Table 13 below, along with the total amount of impurities and decomposition products expressed as RS%. [Table 13]

[0252] In a separate experiment, three Epipen auto-injectors, one in its original packaging (control), one with the outer box removed (original), and one stripped from its plastic protective packaging leaving only the glass syringe containing the product (syringe only), were placed in a light box and exposed to 1.2 million lux of UV light for 18 hours. Formulation S (see Example 1 above), and Formulation W 1 (having the same composition as Formulation W in Example 1 above, but prepared on a larger scale) was also subjected to the same direct light exposure. Chemical stability is summarized for the various compositions in Table 14 below, along with the total amount of impurities and decomposition products expressed as RS %. [Table 14]

[0253] The anti-meric purity of the samples (Epipen, formulation A from Example 1 above, and formulation W 1(see above)) was also determined by chiral HPLC after storage for up to 6 months at 40 / 75 according to standard USP-based methods.

[0254] The antimerical stability, expressed as (% of S-adrenergic), is summarized for the various compositions in Table 15 below. [Table 15]

[0255] Example 5 Evaluation of different doses of adrenaline using trehalose and different maltodextrins. Four aqueous solutions (50 g each, Formulations X through AA, respectively), each containing a dry matter composition having the respective amounts of adrenaline bitartrate (Transo Pharm, Taiwan), trehalose, maltodextrin (Glucidex IT 12 DE or Glucidex IT 19 DE), and sucrose monolaurate (D-1216) shown in Table 16 below in grams, were spray dried by the general procedure described in Comparative Example 1 above to produce a fine, dry, free-flowing powder having a nominal dose of 1.0 mg or 3.0 mg of adrenaline free base in 25 mg of powder. [Table 16]

[0256] Chemical stability experiments were performed essentially as described in Comparative Example 2 above by packaging vials containing various adrenaline formulations in heat-sealed aluminum pouches with 4 Å molecular sieve desiccant and storing them in a 40 / 75 climate cabinet.

[0257] The chemical stability after one month is summarized for the various compositions in Table 17 below, along with the total amount of impurities and decomposition products expressed as RS%. [Table 17]

[0258] One or more of formulations X-AA are loaded into specific intranasal devices from Aptar Pharma, France (UDS Monopowder) for administration to human patients, as described in Comparative Example 3 above.

[0259] All formulations disclosed in Examples 1, 2, 3, and 5 above containing maltodextrins with a DE of less than 15 (e.g., 6 or 12) were found to be slightly cloudy when observed visually unless 40% disaccharide was used, which clarified the solution.

[0260] All formulations disclosed above in Examples 3 and 5 in which the maltodextrin had a DE greater than 15 (eg, 19) were found to be non-turbid upon visual observation.

[0261] Example 6 The lowest measurable Tg value Approximately 6-9 mg samples of the various formulations identified in Table 18 below were weighed into individual Differential Scanning Calorimetry (DSC) crucibles and equilibrated in open vials at 0%, 11%, 22%, 33%, and 43% RH conditions as follows:

[0262] For the 0% RH condition, a silica gel / molecular sieve desiccant was used, and for the other four RH conditions, saturated salt solutions were used as humidifiers as follows: 11% RH-LiCl, 22% RH-CH3COOK, 33% RH-MgCl2, and 43% RH-K2CO3.

[0263] Each sample was then capped and analyzed using modulated DSC to determine the apparent glass transition temperature (Tg).

[0264] DSC was performed using a Netzsch DSC 204F1 instrument. The glass transition temperature (Tg value) for each of the investigated formulations was determined using a sealed ampoule or a perforated lid (0% RH). A hermetic lid was fitted and crimped onto the hermetic pan of all samples stored with a saturated salt solution.

[0265] For 0% RH conditions, a conventional DSC pan with a lid that had a 0.3 mm hole drilled in the lid by the instrument was used. This was done to promote completely dry conditions during the experiment, when the sample was surrounded by nitrogen in the instrument and any moisture potentially absorbed during the heating phase would be released.

[0266] For the remaining samples, the DSC lid was airtight throughout the entire DSC run. Because the gas space around the sample in the cup was very small, strictly limiting the amount of water present in the gas phase at equilibrium, and because the experimental time was very short, it can be inferred that equilibrium water was maintained in the sample throughout the experiment, despite the increased temperature for all Tg values ​​in the lower temperature range.

[0267] Each sample was analyzed using a modulated temperature profile with an average heating rate of 5 K / min, a modulation period of 20 seconds, and an amplitude of ±0.5 K. The starting minimum temperature was 0° C. and the maximum temperature was 200° C. Before heating, the temperature was held at 0° C. for 15 minutes.

[0268] Formulations prepared according to Examples 3 and 5 above were analyzed and the Tg measurements are shown in Table 18 below. [Table 18]

[0269] In comparison, Formulation D, prepared according to Comparative Example 4 above, exhibited a Tg of 78° C. at 0% RH, 64° C. at 11% TH, and 59° C. at 33% RH.

[0270] All of the above values ​​are considered acceptable.

[0271] Example 7 Intranasally administered epinephrine - a pharmacokinetic study (healthy volunteers) Four 1 mg epinephrine nasal powder formulations (Formulations 1-4) were made essentially as described in Comparative Example 1 above (except the spray dryer feed rate was set at 4.0 g / min), but with varying amounts of trehalose and maltodextrin, as shown in Table 19 below. [Table 19]

[0272] A Phase I clinical study was conducted with the primary objective of determining the bioavailability of four epinephrine nasal powders versus the reference commercial product, EpiPen® ("Reference", Epinephrine, Intramuscular Injection, 0.3 mg, Meda AB, Solna, Sweden).

[0273] Secondary objectives were to characterize additional PK parameters, compare pharmacodynamic (PD) effects on systolic / diastolic blood pressure (SBP / DBP), mean arterial blood pressure (MAP), and heart rate (HR) between treatments, and evaluate the safety and tolerability of the investigational formulation.

[0274] This study was a randomized sequence, single-center, open-label, five-period crossover study to evaluate the comparative bioavailability of four powder formulations for intramuscular epinephrine injection in healthy subjects.Each subject received each of formulations 1-4, as well as Ref, consecutively according to a pre-established randomization schedule, separated by a 24-h washout period.

[0275] Subjects were randomized immediately prior to administration of the first dose of the relevant investigational medicinal product (IMP) or reference (if used). A computer-generated randomization schedule was used to assign subject numbers to one of 10 treatment sequences.

[0276] Approximately 65 subjects were screened for inclusion in the study within 28 days prior to maximum dosing. Forty eligible subjects (healthy, non-pregnant, non-lactating, males or females, aged 18-55 years, with a body mass index of 18.5-30.0 kg / m2) were recruited. 2 subjects) were admitted to the clinical unit the night before IMP administration (day −1) and remained on-site until discharge 24 h after their final dose (after receiving all five treatments).

[0277] Formulations 1-4 were administered intranasally by a specific intranasal device from Aptar Pharma, France (UDS Monopowder). Subjects received an IMP or a referral on the mornings of days 1, 2, 3, 4, and 5 with appropriate intersubject intervals (approximately 10 min) based on logistical requirements. On each dosing day, an IMP was administered in alternate nostrils. A follow-up phone call was conducted 3-5 days after the final dose to ensure the subjects' continuing well-being.

[0278] Of the 40 subjects enrolled, 37-39 underwent all IMPs and referrals. For analysis purposes, 37-39 subjects were included in the safety population, safety analysis dataset, and PK population.

[0279] Plasma concentrations of epinephrine were analyzed using non-compartmental methods to obtain estimates of standard PK parameters, as follows: [Table 20]

[0280] The following parameters were used to analyze the PD effect: [Table 21]

[0281] Evaluation of safety parameters consisted of analysis of adverse events (AEs), local tolerability, laboratory evaluations, vital signs, electrocardiograms (ECGs), and physical examination findings.

[0282] Log-transformed exposure parameters (AUC and Cmax) were compared with standard methods to assess relative bioavailability. A single mixed-effects model was fitted to each parameter to obtain estimates of geometric mean ratios (GMRs) and corresponding confidence intervals (CIs) for all treatment comparisons of interest. The model included terms for treatment actually received, study day (i.e., period), and design sequence fitted as fixed effects and subjects within sequence fitted as random effects. Results were back-transformed to a linear scale and presented. The following comparisons were of interest: Relative bioavailability compared to the reference: IMP of AUC(0~t), AUC(0~inf), and Cmax: reference GMR was determined Partial AUCs compared to the reference:IMP:reference GMRs for AUC(0–10), AUC(0–20), AUC(0–30), AUC(0–45), and AUC(0–60 min) were determined.

[0283] For PD parameters, comparisons were made using arithmetic mean differences and corresponding 90% confidence intervals.

[0284] result The arithmetic mean epinephrine plasma concentrations versus time (linear scale) by treatment are shown in Figure 8. The geometric mean epinephrine plasma concentrations versus time (semi-log scale) by treatment are listed in Table 20 below. [Table 22]

[0285] An analysis of relative bioavailability (GMR, CI90%) is shown in Table 21 below. [Table 23]

[0286] All IMP formulations demonstrated higher overall plasma exposure and similar or higher peak plasma exposure of epinephrine compared to the reference.

[0287] Table 22 below shows descriptive statistics for epinephrine partial AUC (as geometric mean, geometric CV%) by treatment. Table 23 shows the partial AUC for Formulations 1-4 compared to the reference (GMR, 90% CI). [Table 24] [Table 25]

[0288] All IMP formulations demonstrated plasma epinephrine exposures equal to or higher than the reference in the first 20 minutes after dosing.

[0289] The effects of all IMP formulations and the reference on systolic (Table 24) and diastolic (Table 25) blood pressure are shown below. [Table 26] [Table 27]

[0290] The effects of all IMP formulations and the reference on mean arterial blood pressure are shown below in Table 26 and the effects on heart rate are shown in Table 27, respectively. [Table 28] [Table 29]

[0291] Tables 28-31 show the PD parameters of formulations 1-4 compared to the reference (arithmetic mean difference, 90% CI). Table 28 shows the comparison of systolic blood pressure (SBP), Table 29 for diastolic blood pressure (DBP), Table 30 for mean arterial blood pressure (MAP) and Table 31 for heart rate (HR). [Table 30] [Table 31] [Table 32] [Table 33]

[0292] For SPB, DBP, and MAP (Tables 28-30), AUEC parameters and Emax were significantly higher (90%CI>0) for all IMPs compared to the reference. For HR (Table 31), most IMPs had higher AUEC parameters and tended to have higher Emax compared to the reference.

[0293] All epinephrine nasal powder formulations (1-4) had higher total epinephrine exposure (AUC(t)) than the reference and similar or higher Cmax compared to the reference. Tmax was slightly lower than the reference for formulations 1-4, but after 20 minutes, all four epinephrine nasal powder formulations had similar or higher epinephrine exposure than the reference, as shown in Table 23.

[0294] Intranasal epinephrine nasal powder was deemed safe, and no serious adverse events (AEs) were reported in this study. The most commonly reported AEs were nasal discomfort, nasal pain, headache, and palpitations.

Claims

1. 1. A needleless applicator suitable for administering a solid amorphous single particle powder composition to a body cavity of a human patient, the cavity comprising a mucosal surface, the applicator comprising: (i) an opaque reservoir containing the powder composition; (ii) a dispensing means through which, upon actuation, the powder composition may be dispensed; the powder composition comprises a pharmacologically effective dosage of epinephrine (adrenaline) or a pharmaceutically acceptable salt thereof encapsulated in an amorphous state together with a pharmaceutically acceptable carrier material; The powder composition (a) at 40°C and 75% relative humidity for at least about 3 months; (b) at least about 18 months at less than about 30°C; and / or (c) A needleless applicator that is chemically degraded by less than about 4% after storage in UV light greater than about 1 million lux for at least about 18 hours.

2. An applicator as described in claim 1, comprising an actuation means for generating a force when the device is actuated by a user, and when actuated, the powder composition is dispensed.

3. 3. The applicator of claim 1 or claim 2, wherein the pharmaceutically acceptable carrier material of the composition comprises maltodextrin.

4. The applicator of claim 3 , wherein the maltodextrin comprises maltodextrin 19DE.

5. 3. The applicator of claim 1 or 2, wherein the pharmaceutically acceptable carrier material of the composition comprises a disaccharide selected from the group consisting of maltitol, trehalose, sucralose, sucrose, isomalt, maltose, and lactose.

6. The applicator of claim 5 , wherein the disaccharide comprises lactose and / or trehalose.

7. 3. The applicator of claim 1 or 2, wherein the carrier material of the composition comprises a combination of trehalose and maltodextrin 19DE.

8. An applicator as described in claim 5, wherein the weight ratio of disaccharide:maltodextrin is in the range of about 10:1 to about 1:

20.

9. An applicator as described in claim 5, wherein the weight ratio of disaccharide:maltodextrin is in the range of about 3:1 to about 1:

8.

10. 3. The applicator of claim 1 or 2, wherein the lowest measurable glass transition temperature of the composition is at least about 35°C when measured at a relative humidity of up to about 35%.

11. The applicator of claim 1 or 2, wherein the composition further comprises a sucrose ester.

12. The applicator of claim 11 , wherein the sucrose ester comprises sucrose monolaurate.

13. An applicator as described in claim 12, wherein the composition contains from about 0.75% to about 3% by weight of sucrose monolaurate.

14. 3. The applicator of claim 1 or 2, which is suitable and / or adapted for nasal delivery of the composition.

15. 15. The applicator of claim 14, wherein the particle size distribution of the composition comprises a D10 greater than about 3 μm.

16. 15. The applicator of claim 14, wherein the powder composition has a particle size distribution comprising a volume-based mean diameter in the range of about 10 μm to about 100 μm.

17. The particle size distribution of the powder: (a) comprises a D10 greater than about 10 μm; and / or 3. The applicator of claim 1 or 2, comprising: (b) a D90 of less than about 500 μm.

18. An applicator as described in claim 1 or 2, wherein the particles of the powder have a D90 of less than about 100 μm.

19. An applicator as described in claim 1 or 2, wherein the pharmacologically effective dosage of epinephrine or a pharmaceutically acceptable salt thereof, calculated as a free base, is from about 0.1 mg to about 10 mg.

20. An applicator as described in claim 19, wherein the dosage calculated as the free base is from about 0.5 mg to about 3 mg.

21. An applicator as described in claim 20, wherein the composition essentially consists of the pharmacologically effective dosage of epinephrine or a pharmaceutically acceptable salt thereof.

22. An applicator as described in claim 1 or 2, wherein the composition is essentially free of water.

23. An applicator as described in claim 22, wherein the composition contains less than about 5% water.

24. 3. The applicator of claim 1 or 2, comprising actuation means for generating a force upon actuation of the device by a user, wherein upon actuation, the powder composition is dispensed to deliver a pharmacologically effective dose of epinephrine or a salt thereof to the nasal mucosa.

25. An applicator suitable for delivering a pharmacologically effective dose of epinephrine or a salt thereof to a nasal mucosa, comprising: the powder composition contained in the reservoir is in the form of a spray-dried powder; (1) about 0.5 mg to about 3 mg of epinephrine, calculated as the free base, or a pharmaceutically acceptable salt thereof; (2) a pharmaceutically acceptable carrier material comprising a combination of trehalose and maltodextrin 19DE in a weight ratio of about 3:1 to 1:3; (3) about 0.75% to about 3% by weight of sucrose monolaurate; and (4) Less than about 5% water 3. The applicator of claim 1 or 2, comprising:

26. An applicator as described in claim 1 or 2 packaged in a container that substantially prevents the ingress of atmospheric water.

27. ​​An applicator as described in claim 26, wherein the container contains a material selected from the group consisting of heat-sealed aluminum pouches and thermoformed plastics and / or a desiccant selected from the group consisting of silica gel and molecular sieves having a pore size of 3 Å or 4 Å.

28. A container that substantially prevents the intrusion of atmospheric water by containing thermoformed plastic and / or molecular sieves having a pore size of 3 Å or 4 Å, the container including an applicator as described in claim 26.

29. A process for manufacturing an applicator according to claim 1 or 2, said process comprising: i) mixing the adrenoceptor modulator or a pharmaceutically acceptable salt thereof with the pharmaceutically acceptable carrier material together in a suitable volatile solvent; ii) spray drying the mixture from step i); iii) loading the product from step ii) into the reservoir of the applicator.

30. 30. An applicator obtainable by the process of claim 29.

31. 3. An applicator according to claim 1 or 2 for use in the treatment of an allergic reaction.

32. Use of a composition according to claim 1 or 2 for the manufacture of a medicament for the treatment of an allergic reaction via an applicator according to claim 1 or 2.

33. An applicator for use as described in claim 31, wherein the reaction includes anaphylaxis.

34. 34. An applicator for use according to claim 33, wherein the allergic reaction is an allergic reaction to an insect sting or bite, a food, a drug, and / or another chemical.

35. An applicator for use as described in claim 31, wherein the treatment comprises: (A) identifying a human patient having or at acute risk of having an allergic reaction; (B) administering from the applicator of claim 1 or 2 a dosage of epinephrine (adrenaline) or a pharmaceutically acceptable salt thereof in the form of a powder according to claim 1 or 2 suitable for treating the allergic reaction, by actuating the applicator to dispense the dosage of an adrenoceptor modulator or salt thereof into a body cavity of the patient comprising a mucosal surface, thus delivering the powder comprising the adrenoceptor modulator or salt thereof to the mucosal surface to promote absorption of the adrenoceptor modulator across the mucosal surface, thereby treating or preventing the allergic reaction. Applicator.

36. 36. An applicator for use according to claim 35, wherein the administering step is carried out immediately after the particular step.

37. The administration step: (i) inspecting the composition contained within the reservoir of the applicator; 36. An applicator for use as described in claim 35, performed without (ii) confirming whether the relevant composition can be safely administered to the patient to effectively treat the allergic reaction.

38. 32. An applicator for use according to claim 31, wherein the composition is administered nasally.

39. The use of claim 32, wherein the reaction includes anaphylaxis.

40. The use of claim 39, wherein the allergic reaction is an allergic reaction to an insect sting or bite, food, a drug, and / or another chemical.

41. The use of claim 32, wherein the treatment comprises: (A) identifying a human patient having or at acute risk of having an allergic reaction; (B) administering from the applicator of claim 1 or 2 a dosage of epinephrine (adrenaline) or a pharmaceutically acceptable salt thereof in the form of a powder according to claim 1 or 2 suitable for treating the allergic reaction, by actuating the applicator to dispense the dosage of an adrenoceptor modulator or salt thereof into a body cavity of the patient comprising a mucosal surface, thus delivering the powder comprising the adrenoceptor modulator or salt thereof to the mucosal surface to promote absorption of the adrenoceptor modulator across the mucosal surface, thereby treating or preventing the allergic reaction. use.

42. The use described in claim 41, wherein the administration step is performed immediately after the specified step.

43. The administration step: (i) inspecting the composition contained within the reservoir of the applicator; 42. The use of claim 41, carried out without (ii) determining whether the relevant composition can be safely administered to the patient to effectively treat the allergic reaction.

44. The use of claim 32, wherein the composition is administered nasally.

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