Pharmaceutical compositions for drug delivery

Abstract

According to the present invention, a pharmaceutically acceptable composition is provided, which is preferably in the form of a spray-dried powder, comprising a mixture of: (a) a pharmacologically effective dose of at least one pharmaceutically active compound; and (b) a pharmaceutically acceptable carrier material comprising a combination of a disaccharide and a polymeric material. The composition is suitable for, for example, transmucosal drug delivery, including sublingual and nasal delivery. In the case of nasal delivery, the composition can be loaded into a single-use or multiple-use nasal applicator. In this regard, preferably, a pharmaceutically acceptable carrier includes lactose or trehalose and dextrin (e.g., cyclodextrin or maltodextrin), which can be combined and spray-dried. The composition may further include one or more alkyl saccharides. Preferably, the alkyl saccharide includes a sucrose ester, such as sucrose monolaurate.

Description

[0001] The present invention relates to pharmaceutical compositions suitable for use in a variety of medical conditions. The present invention also relates to methods of making such compositions and formulating them into dosage forms. Background Art

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

[0003] Of the various well-known routes of drug delivery, oral delivery to the gastrointestinal tract is the most common and is generally considered the most popular with patients and physicians.

[0004] However, oral drug administration is known to have certain disadvantages, including the fact that the active ingredient is subject to first-pass metabolism in the liver and enzymatic degradation in the gastrointestinal tract (and beyond). This can affect the efficacy of certain drugs and, in some cases, may even completely disqualify it as a route of administration.

[0005] Oral administration to the gastrointestinal tract has the additional disadvantage that the active ingredient needs to be absorbed through the intestine as part of the digestive process, which is time consuming.In certain conditions, such as the treatment of acute disorders, a more rapid onset of pharmacological action is often highly desirable.

[0006] In such cases, the principle of administration in which the drug is immediately absorbed into the systemic circulation is more likely to result in a rapid onset of action. Although this can be accomplished by parenteral administration (e.g., subcutaneous or intravenous injection), such modes of delivery are inconvenient and are often extremely difficult and / or impossible for the patient to perform, thereby requiring time-consuming intervention by a physician to ensure compliance and avoid unnecessary or adverse effects.

[0007] Transmucosal administration of active ingredients is a viable alternative to parenteral administration. It allows for the direct delivery of drug molecules through the mucosa (e.g., rectal, sublingual, buccal, pulmonary, and intranasal) into the systemic circulation and may offer advantages such as increased patient compliance, improved drug bioavailability, more rapid onset of action, and reduced side effects.

[0008] However, transmucosal administration of drugs presents its own, quite significant, problems. Unlike the gastrointestinal tract, which is a large organ containing relatively large amounts of biological fluids, the oral and nasal cavities, for example, are relatively small spaces and contain much less body fluids, such as saliva and / or mucus. This necessarily places considerable restrictions on the amount of active ingredient that can be administered in a single dose.

[0009] Furthermore, although the gastrointestinal tract is a dynamic system, it is in the main part somewhat of a "closed" system. In contrast, the rapid clearance mechanisms occurring in both the oral and nasal cavities mean that for the already more limited amount of drug, the time available for absorption across the mucosal surfaces is often also limited.

[0010] Many formulation principles have been proposed to address this problem, including, for example, bioadhesive formulation principles, such as buccal patches for oromucosal 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)).

[0011] Transmucosal drug delivery systems in solid form can present significant advantages in allowing higher drug loads in the formulation. However, while solid drug delivery compositions are more common when administered to the rectal, buccal, sublingual, and pulmonary mucosa, the vast majority of intranasal drug delivery systems are still presented as liquid sprays, usually in the form of aqueous solutions, where drug solubility plays another limiting factor in the amount of drug available for absorption.

[0012] Such liquid sprays for intranasal delivery are almost universal because it is not easy to formulate solid drug formulations in the form of nasal powders.Unlike powders that are often used to inhale the active ingredient into the lungs, there are very few commercially available intranasal powder formulations.

[0013] When formulated as a dry powder, pulmonary drug delivery compositions are typically in the form of an "aggregate" mixture comprising micronized particles of the API on larger carrier particles. These aggregates are intended to dissociate / break down upon inhalation or actuation of the device, thereby depositing only fine particles of the active ingredient in the lungs.

[0014] However, such drug delivery systems are understood to be unable to work effectively in the context of intranasal drug delivery. This is because the presence of such fine particles results in a significant risk of lung exposure, which is not the intended site of administration. If the drug particle size is increased to avoid this problem, it will be difficult to ensure proper interaction in the heterogeneous "interaction" mixture, which depends on the substantial difference in the size of the two components to ensure interaction, thereby causing potential manufacturing problems, such as separation during filling. Attempting to compensate for this by correspondingly increasing the carrier particle size will not necessarily solve the problem, but will inevitably increase the mass of inactive excipients in the total mass of the already limited dosage form, thereby potentially causing a reduction in the dose of the active ingredient.

[0015] The difficulty of formulating dry powders for intranasal delivery is addressed in U.S. patent application US 2005 / 001411 A1. In this document, it is stipulated that powders for nasal administration need to be fine enough to be effectively transported by the airflow and effectively deposited in the nose, but also coarse enough to facilitate the introduction of the powder into a suitable powder device, which is always required for intranasal administration. US 2005 / 001411 A1 specifically addresses this problem by preparing loosely formed secondary particles (aggregates) containing the primary particles of the active ingredient. The dimensions of the aggregates are several hundred microns, and this is said to enable more efficient loading into a suitable intranasal administration device (applicator, dispenser, or insufflator). When such a device is activated and the composition is applied, the aggregates are significantly and rapidly broken down into the primary particles of the active ingredient. These primary particles are only a few microns in size, which is said to aid in their dissolution and subsequent intranasal absorption of the active ingredient.

[0016] As stated above, transmucosal (eg, intranasal) delivery of drugs intended for systemic absorption avoids first-pass metabolism, which is an inevitable part of oral administration. Drug metabolism occurs through chemical reactions with enzymes that are able to change the chemical structure of the active ingredient.

[0017] Since most drugs are organic molecules containing functional groups capable of undergoing such chemical reactions, they are often susceptible to some form of chemical breakdown when they come into contact with substances capable of interacting with those functional groups in vitro.

[0018] Such chemical transformations are generally classified as chemical "degradation" in the pharmaceutical field because they can often result in loss of efficacy, or in extreme cases, toxic byproducts, either or both of which can render the drug ineffective and / or harmful to the patient.

[0019] The rate at which such degradation may occur depends, first of all, on the degree of inherent chemical instability of the drug compound, its formulation, and its storage conditions. Typically, high temperatures and humidity can cause accelerated degradation.

[0020] This loss of chemical integrity is measurable and is the reason all drug products have a shelf life printed on their labels and / or embossed on their packaging. It is also the reason some prescription drugs contain specific printed information on the package insert regarding appropriate storage conditions.

[0021] As outlined by Kou and Zhou in Chapter 16 of the textbook Amorphous Solid Dispersions, Shah et al. (eds.), Springer (2014), if a drug is formulated in an amorphous rather than a crystalline physical state, it often exists in a higher energy state and therefore may be chemically and physically less stable, thus posing challenges to the drug formulator.

[0022] Therefore, chemical stability is often improved by presenting the drug in a crystalline state, typically through salt formation. The primary goal of salt formation is often to increase the hydrophilicity of the active ingredient to address issues of poor water solubility and dissolution rate. However, when preparing salts, other physicochemical and biological issues, such as chemical stability, are often addressed simultaneously. For example, basic drugs (e.g., those containing at least one amino group) are often presented as acid addition salts, which are generally more chemically stable than the corresponding "free" amino base.

[0023] However, while potentially providing the active ingredient in a form that can be more easily stored without chemical degradation and more effective in terms of its rate and / or extent of dissolution following administration, crystalline salts generally have slower dissolution rates and are less efficiently absorbed across mucosal membranes than if the corresponding active ingredient were present in amorphous and / or unionized form, respectively.

[0024] In general, active pharmaceutical ingredients formulated as amorphous solid dispersions generally have the advantage of greater bioavailability but often present challenges of reduced physical and chemical stability, whereas drugs formulated in crystalline and / or salt forms, while generally more stable, tend to have lower bioavailability.

[0025] The latter problem can be particularly detrimental in the case of transmucosal, e.g., intranasal or sublingual drug delivery, where, as stated above, the residence time of the drug in the relevant compartment where it needs to be absorbed into the systemic circulation is limited. This, combined with poor permeability across the mucosa at physiological pH, can result in unacceptably low and / or slow transmucosal absorption to provide adequate therapeutic effect.

[0026] Many complex formulation principles have been devised over the years to address the balance between solubility and permeability in transmucosal drug delivery systems. Such formulation principles include the addition of pH-adjusting substances to convert the ionized salt form of the active ingredient into a more permeable non-ionized state.

[0027] However, in view of all the aforementioned potential advantages they offer, there remains a need for improved solid (eg, powder-based) transmucosal and, in particular, intranasal drug delivery systems.

[0028] In particular, there remains a significant unmet clinical need in the field of transmucosal delivery for powdered drug delivery compositions that:

[0029] (i) be physically and chemically stable; and

[0030] (ii) providing the following active ingredients:

[0031] • have adequate dosage; and

[0032] • Be permeable enough to allow

[0033] The desired therapeutic effect (e.g., speed of onset) is provided at the (relatively) lower doses possible, and the shorter residence time achievable in a transmucosal environment, such as the nasal cavity.

[0034] In addition to the foregoing, in the more specific area of ​​intranasal drug delivery, there remains a significant unmet clinical need for drug delivery compositions comprising particles of appropriate size to be able to effectively:

[0035] • filling the drug delivery device; and

[0036] •Deposited in relevant cavities (e.g. nasal cavity).

[0037] Intranasal dry powder formulations are known from, inter alia, international patent applications WO 2010 / 142696 and WO 2019 / 038756, US patent application number 10,653,690 B1 and US patent application US 2018 / 0092839A.

[0038] Russo et al. (J. Pharm. Sci. 95, 2253 (2006)) disclosed spray drying of the opioid analgesic compound, morphine base, with a variety of excipients. Spray-dried formulations were also disclosed by Vengerovich et al., Bulletin of Experimental Biology and Medicine, 163, 737 (2017), in which attempts were made to microencapsulate the active ingredient (naloxone) in various substances, including 2-hydroxypropyl-β-cyclodextrin, in order to develop a sustained-release formulation based on a polymeric carrier for acute care.

[0039] We have now discovered that certain active ingredients can be formulated in the form of amorphous dry powder compositions by methods such as those disclosed below, such as spray drying those active ingredients with specific combinations of carrier materials. Such compositions can provide surprising and significant improvements in the stability of those active ingredients prior to administration. Such compositions can also provide improved bioavailability and / or accelerated absorption of those active ingredients after administration. Summary of the Invention

[0040] According to a first aspect of the present invention, there is provided a pharmaceutically acceptable composition in the form of an amorphous, single-particle powder comprising a mixture of:

[0041] (a) a pharmacologically effective amount of at least one pharmaceutically active compound; and

[0042] (b) a pharmaceutically acceptable carrier material comprising a combination of a disaccharide and a polymeric material,

[0043] The pharmaceutically acceptable compositions are hereinafter collectively referred to as "compositions of the present invention."

[0044] The composition of the present invention is in the form of an amorphous, single-particle powder. "Single particle" means that the plurality of particles forming the powdered composition of the present invention comprises a homogeneous or heterogeneous mixture in which the pharmaceutically active ingredient is encapsulated in an amorphous state within a carrier material as defined above, optionally in the presence of other ingredients. The particles of the powdered composition of the present invention thus represent an amorphous composite of the active ingredient, the aforementioned carrier material, and optionally other ingredients.

[0045] Because they are amorphous in nature, the compositions of the present invention can be completely amorphous and / or predominantly amorphous (e.g., greater than about 50% by weight, such as greater than about 75% by weight, including greater than about 80% by weight, such as greater than about 90% or 95% by weight, including greater than about 99% by weight amorphous).

[0046] As described hereinafter, despite being in an amorphous physical state, the compositions of the present invention exhibit remarkable and unexpected physical and chemical stability and can therefore be provided as pharmaceutical products that exhibit excellent shelf-life when stored under normal storage conditions.

[0047] The compositions of the present invention are produced in solid powder form by suitable techniques. Generally, suitable techniques are "solvent-based" methods, including spray drying, fluidized bed technology, coprecipitation, supercritical fluid technology, spray granulation, cryogenic techniques (including freeze drying), electrospinning, and rotary jet technology, or "fusion-based" methods, including melt granulation, melt extrusion, high shear mixing (e.g., KinetiSol®), milling, and the use of carrier technology (e.g., Meltdose®) to melt the material. Preferred methods include freeze drying, and more preferably, the compositions of the present invention are prepared by spray drying.

[0048] Such powders may be suitable for direct delivery to a patient by any pharmaceutically acceptable route of administration, or may be presented as an intermediate composition that can subsequently be formulated into a pharmaceutically acceptable dosage form intended for administration to one or more patients.

[0049] In this regard, there is provided a pharmaceutical formulation and / or a pharmaceutically acceptable dosage form intended for administration to a patient and comprising one or more compositions of the present invention.

[0050] Suitable pharmaceutical dosage forms may thus comprise liquid formulations, such as solutions, which can be prepared by dissolving the composition of the invention in a pharmaceutically acceptable solvent, such as water, for delivery to such patients, for example, by injection or by infusion.

[0051] Alternative pharmaceutical dosage forms may comprise liquid or semisolid formulations, for example liquid suspensions and / or gel compositions which may comprise a composition of the invention (e.g., particles thereof) suspended or dissolved in a suitable liquid or semisolid carrier which may be loaded into a suitable dosage form or delivered by, for example, injection or infusion or which may be formed following injection (e.g., subcutaneously or intramuscularly) to form an implant or depot formulation.

[0052] In an alternative embodiment, the composition of the present invention may be present as part of a substantially solid pharmaceutical dosage form. It will be well understood by those skilled in the art that the term "solid" includes any form of matter that retains its shape and density when not constrained, and / or in which molecules are generally packed as tightly as possible within the limits permitted by the repulsive forces between them. Thus, a substantially solid formulation 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.

[0053] In this regard, the compositions of the present invention may be provided in a multiparticulate form (e.g., as a powder, granules, pellets, and / or beads) comprising a plurality of particles that may individually and / or collectively consist essentially of and / or comprise one or more compositions of the present invention.

[0054] Thus, the composition of the present invention may be in the form of a single powder mixture, powder microparticles, coated powder microparticles, a lyophilized lipid dispersion, or a combination thereof following its preparation (eg, by spray drying).

[0055] If a pharmaceutically acceptable dosage form of the invention "consists essentially of particles of one or more compositions of the invention," this will be understood to mean that the dosage form contains only one or more compositions of the invention, as well as other features that do not substantially affect the basic properties of the dosage form. Alternatively, where a dosage form of the invention "consists essentially of one or more compositions of the invention," this will be understood to mean that the dosage form contains a total of at least about 90% by weight, such as at least about 95% by weight, including at least about 97% by weight (e.g., about 99%) of those one or more compositions of the invention.

[0056] In the alternative, a pharmaceutical dosage form comprising one or more compositions of the invention may be provided in a single unit dosage form, such as a pessary, a suppository or another form of insert, a pill, a capsule, a cake, a patch (e.g., a buccal patch), a film (e.g., an intraoral film), or a lozenge (e.g., a sublingual lozenge).

[0057] Capsules can be prepared by loading the composition of the invention in the form of a spray-dried powder directly into pharmaceutically acceptable capsules made of appropriate materials designed for sublingual or, preferably, oral delivery, or by mixing the composition with excipients prior to loading into such capsules, which may involve a granulation step as described below, followed by loading into capsules for such delivery.

[0058] In this regard, the compositions of the present invention are granulated into pellets or pills, but they can also be formulated (that is, provided for application) in the form of a dry, free-flowing powder. "Dry" includes substantially free of water and other liquid solvents, including less than about 10%, such as less than about 5%, more preferably about 3%, such as less than about 2%, such as less than about 1% of the formulation being liquid, such as water.

[0059] Suitable techniques for preparing dosage forms comprising dry powders or granules include simple dry mixing, granulation (including dry granulation, wet granulation, melt granulation, thermoplastic pelletising, spray granulation), extrusion / spheronisation or freeze drying.

[0060] Dry granulation techniques 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 slugging and roller compaction, for example as described below.

[0061] Wet granulation techniques are also well known to those skilled in the art and include any technique that involves massing a mixture of dry primary powder particles using a granulating 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 adhesive. Such techniques may involve forcing the wet mass through a screen to produce wet granules, which are then dried, preferably with a drying loss of less than about 3% by weight.

[0062] As will be known to those skilled in the art, melt granulation encompasses any technique that produces particles by adding a molten binder or a solid binder that melts during the process (the binder material may comprise a pharmaceutically acceptable carrier material for the compositions of the present invention). Following granulation, the binder solidifies at room temperature. Known thermoplastic pelletization is similar to melt granulation, but utilizes the plastic properties of the binder. In both methods, the resulting agglomerates (particles) comprise a matrix structure.

[0063] Extrusion / spheronization will be well known to those skilled in the art and includes any method involving dry mixing of the ingredients, wet combining with a binder, extrusion, spheronization of the extrudate into uniformly sized spheres, and drying.

[0064] Those skilled in the art will recognize that spray granulation encompasses any technique involving the drying of a liquid (solution, suspension, melt) while simultaneously forming particles in a fluidized bed. Thus, the term encompasses methods in which an exogenous seed (germ) is provided and particles are formed thereon, as well as methods in which an intrinsic seed (germ) forms in the fluidized bed due to abrasion and / or rupture, in addition to any conventional spray granulation techniques. The sprayed liquid coats the germ and facilitates further aggregation of the particles. This is then dried to form particles in the form of a matrix.

[0065] The term "freeze drying" includes freeze drying or cryodesiccation and any low temperature desolvation (eg, dehydration) process in which the product is frozen, the pressure is reduced, and the frozen solvent (eg, water) is removed by sublimation.

[0066] In an alternative, the compositions of the present invention are provided in the form of lozenges for oral, buccal and / or sublingual use. Such lozenges can be formed, for example, by direct compression / compacting the compositions of the present invention, optionally with one or more suitable excipients, such as diluents, disintegrants, slip agents and / or lubricants mixed together, and can be realized using the technology of those described below: such as " Pharmaceutical Dosage Forms: Tablets " volume 1, the 3rd edition, Augsburger et al. (eds.) CRC Press (2008) and the files cited therein. Suitable compacting equipment includes standard tablet making machines, such as Kilian SP300 or Korsch EKO, XP1, XL 100 and XL 200.

[0067] Suitable disintegrants that can be used in tablets (as defined, for example, in Rowe et al., Handbook of Pharmaceutical Excipients, 6th ed. (2009)) include cellulose derivatives such as hydroxypropylcellulose (HPC), low-substituted HPC, methylcellulose, ethylhydroxyethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, modified cellulose gum; starch derivatives such as appropriately cross-linked starch, modified starch, hydroxypropyl starch, and pregelatinized starch; and other disintegrants such as calcium alginate, sodium alginate, alginic acid, polyglucosamine, colloidal silicon dioxide, docusate sodium, guar gum, magnesium aluminum silicate, polacrilin potassium, and polyvinylpyrrolidone. Combinations of two or more disintegrants may be used.

[0068] Preferred disintegrants include so-called "superdisintegrants" (as defined, for example, in Mohanachandran et al., International Journal of Pharmaceutical Sciences Review and Research, 6, 105 (2011)), such as cross-linked polyvinyl pyrrolidone, sodium starch glycolate, and cross-linked sodium carboxymethylcellulose. Combinations of two or more superdisintegrants may be used.

[0069] When the disintegrant and / or superdisintegrant is used in an amount between 0.5 and 15 wt % (e.g., a total amount) based on the total weight of the composition, the preferred range is 1 to 8 wt %, e.g., about 2 wt % to about 7 wt % (e.g., about 5 wt %, e.g., about 4 wt %).

[0070] If present, the binder is preferably used in an amount between 0.5% and 20% by weight based on the total weight of the tablet formulation. The preferred range is 1 to 15% by weight, such as from about 2.0 to about 12% by weight (e.g., about 10% by weight). Suitable binders include cellulose gum and microcrystalline cellulose.

[0071] No matter in powder form or other forms, the dosage form comprising the composition of the present invention can be prepared in addition by standard techniques and using standard equipment known to those skilled in the art. In this regard, the composition of the present invention can be used in combination with the customary pharmaceutical additives and / or excipients used in this technology for relevant preparations, and standard techniques are used to be incorporated into various types of pharmaceutical preparations to prepare the dosage form of the present invention (see, for example, Lachman et al., "Industrial Pharmacy Theory and Practice (The Theory and Practice of Industrial Pharmacy)" Lea & Febiger, 3rd edition (1986); "Remington: Pharmaceutical Science and Practice (Remington: The Science and Practice of Pharmacy)" Troy (ed.), University of the Sciences in Philadelphia, 21st edition (2006); and / or "Aulton's Pharmaceutics: The Design and Manufacture of Medicines (Aulton ' s Pharmaceutics: The Design and Manufacture of Medicines)" Aulton and Taylor (ed.), Elsevier, 4th edition, 2013).

[0072] Preferably, the compositions of the present invention are adapted and / or formulated for transmucosal delivery of the active ingredient into the systemic circulation.

[0073] Those skilled in the art will understand that the term "transmucosal" means that although the composition is administered to the patient, the composition is present at the relevant mucosal surface in a form such that the active ingredient can be absorbed across the mucosal surface after its dissolution. Relevant mucosal surfaces therefore include the oral, nasal, ocular, vaginal, cervical, pulmonary and / or anorectal mucosa, more particularly the oral mucosa (including buccal and sublingual mucosa) and the nasal mucosa.

[0074] Thus, dosage forms comprising the compositions of the present invention can be administered directly to a patient's mucosal surface (including rectally, vaginally, buccally, sublingually, or intranasally) for transmucosal delivery of the active ingredient.

[0075] If administered to the sublingual mucosa, the composition of the invention may be in the form of a sublingual lozenge, for example, as described above, which may comprise a disintegrant / disintegrating agent (which may be defined as any material capable of accelerating the disintegration / dispersion of such a composition of the invention to a measurable extent), which may be achieved, for example, by a material capable of swelling and / or expanding when in contact with an aqueous medium, as described hereinafter.

[0076] Alternatively, the compositions of the invention may be administered sublingually in the form of a powder as described herein, which may be poured into the mouth and under the tongue from a suitable container (eg, a capsule or sachet).

[0077] If the composition of the present invention is suitable for and / or formulated for sublingual administration, or more notably intranasal administration, it is preferably administered in the form of a powder composition in which the dose of the active ingredient does not exceed about 100 mg. Such sublingual and / or intranasal powder compositions may comprise the composition of the present invention in admixture with other excipients, or may consist essentially of the composition of the present invention as defined above.

[0078] The compositions of the present invention suitable for and / or formulated for intranasal administration are preferably provided by means of a dosing member suitable for nasal delivery. Such dosing members may contain one spray-dried powder composition of the present invention, or they may contain two or more such compositions. In the latter case, the dosing member contains two or more doses of the compositions of the present invention, each of which contains a pharmacologically effective dose of a pharmacologically active compound (also referred to herein interchangeably as "drug," "pharmaceutical active ingredient," and / or "active ingredient").

[0079] Two or more compositions of the present invention can be administered intranasally by repeated actuation of a device comprising or communicating with the dosing member. Thus, the compositions of the present invention may be present in a suitable device (e.g., a nasal applicator or dispenser (insufflator), e.g., as described below) and / or in a container or reservoir that is part of, attached to, and / or suitable for attachment to such an applicator. Such a container or reservoir may contain one or more compositions of the present invention, each containing a pharmacologically effective dose of the active ingredient.

[0080] In this way, an appropriate dosing member and / or nasal applicator can be actuated only once to deliver a single composition of the present invention comprising an appropriate dose of the active ingredient upon actuation (that is, a single-use dosing unit), can be actuated multiple times to deliver two or more compositions of the present invention each comprising an appropriate dose of the active ingredient upon each such actuation (that is, multiple-use dosing units), and / or refilled with an alternative source of compositions of the present invention (e.g., a container or reservoir) comprising one or more such compositions to provide single and / or multiple doses and / or dosing regimens.

[0081] The composition of the invention may thus be administered in the form of a plurality of particles, which particles may individually and / or collectively consist of and / or comprise the composition of the invention.

[0082] The compositions of the present invention are prepared (initially) in the form of a solid, dry, free-flowing, multi-particulate powder. "Dry" includes being substantially free of water and other liquid solvents, including less than about 10%, such as less than about 5%, more preferably about 3%, such as less than about 2%, such as less than about 1% of the formulation being liquid, such as water.

[0083] As stated above, the compositions of the present invention are provided in the form of amorphous, single-particle powders. They do not consist of a physical association of two or more discrete, separate collections of particles of distinct components in the form of a mixture, such as an ordered or interacting mixture of smaller particles of the active ingredient combined with larger, but separate, and chemically distinct particles of a carrier material. That is, the compositions of the present invention can be provided as small particles that can then adhere to separate, larger carrier particles in the interacting mixture, and such presentation may be suitable if the dosage form is intended for inhalation (see, for example, J. Drug Delivery, Art. ID 5635010, 1-19 (2018)).

[0084] As mentioned above, the process for preparing the composition of the present invention enables the formation of a pharmaceutical product as defined herein that exhibits an excellent shelf life in terms of both physical and chemical stability when stored under normal storage conditions.

[0085] The compositions of the present invention are preferably prepared by a spray drying process. Those skilled in the art will understand that a "spray drying" process includes any method of producing a dry powder from a liquid, including a solution or suspension (including a slurry), which involves rapid drying using a hot gas to convert a liquid stream into evaporated solvent and solid particles comprising solutes previously dissolved in the solution and / or particles previously suspended in the evaporated liquid.

[0086] Suitable spray drying equipment includes some form of atomizing means, such as a nozzle, which 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 vortex nozzles, rotating disks and / or atomizing wheels, high-pressure single-fluid nozzles, two-fluid nozzles, and / or ultrasonic nozzles.

[0087] The spray dryer may be a single-effect or multiple-effect spray dryer and may comprise an integrated and / or external vibrating fluidized bed, a particle separator and / or a collecting member which may be a rotating drum or a cyclone.

[0088] According to another aspect of the present invention, there is provided a method for producing the composition of the present invention, wherein the method comprises the following steps:

[0089] i) mixing the one or more active ingredients with a pharmaceutically acceptable carrier material in a suitable volatile solvent,

[0090] ii) spray drying the mixture from step i).

[0091] Preferred volatile solvents include water or organic solvents such as lower alkyl alcohols (e.g. ethanol), hydrocarbons (e.g. C 5-10 alkanes), halogenated alkanes, dimethylformamide, dimethyl sulfoxide, ethyl acetate, acetone, etc. or mixtures thereof.

[0092] We prefer to mix the one or more active ingredients, pharmaceutically acceptable carrier materials and other optional ingredients as described herein (eg, alkyl saccharides as described below) with a solvent to provide a spray-dryable solution.

[0093] Suitable pharmaceutically acceptable carrier materials that can be used in the compositions of the present invention include relevant materials that are suitable for (and / or approved for) pharmaceutical use and / or transmucosal (e.g., sublingually or, notably, intranasal) delivery in a solid state under normal storage conditions, in appropriate combinations, and are capable of maintaining their physical and / or chemical integrity and / or do not affect the physical and / or chemical integrity of any active ingredient and / or any other ingredient that may be present in the composition (e.g., alkyl saccharide).

[0094] It is well known that significant difficulties can be encountered when attempting to obtain chemically and physically stable solid compositions (e.g., powders). If the physical form of the composition changes under normal storage conditions (e.g., from a free-flowing powder to an agglomerated mass that is difficult to discharge), irreproducible active ingredient dosages may result. This is particularly true when dispensing the composition from or through a nasal applicator as described herein, where such agglomeration may result in a complete inability to dispense the active ingredient.

[0095] Similarly, for multiple dosage units containing two or more doses of a composition, such stability is critical to ensuring reproducibility of the dose of the active ingredient over time. Any of these issues may adversely affect the health status of an individual and / or place the health of an individual at significant risk.

[0096] For certain compositions of the present invention, exposure to atmospheric water may result in a powder composition having poor solid state stability. For example, exposure to certain (e.g., higher) 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 (e.g., carrier material), or in other ways.

[0097] Therefore, the compositions of the present invention and pharmaceutical formulations and dosing components (e.g., nasal applicators) comprising the same are preferably packaged in containers that substantially prevent the ingress of atmospheric water under the storage conditions defined herein. Such containers may include packaging materials such as blister packs and heat-sealed aluminum bags and / or thermoformed plastics for tablets and capsules.

[0098] The phrase "maintaining physical and chemical integrity" essentially means chemical stability and solid-state stability.

[0099] "Chemical stability" includes that any composition of the present invention can be stored as an isolated solid under normal storage conditions when formulated into a pharmaceutical formulation or dosage form and / or when loaded into a drug administration device, such as a nasal applicator or reservoir therefor (with or without appropriate drug packaging), without significant chemical degradation or decomposition of the composition itself or the active ingredient included therein.

[0100] "Solid-state stability" includes that any composition of the present invention can be stored as an isolated solid under normal storage conditions when formulated into a pharmaceutical formulation or dosage form and / or when loaded into a drug delivery device (e.g., a nasal applicator or reservoir therefor (with or without appropriate drug packaging)), wherein the composition itself or the active ingredient included therein undergoes no significant degree of solid-state transformation (e.g., crystallization, recrystallization, loss of crystallinity, solid-state phase transition (e.g., between a glassy or rubbery state, or to a condensed state)), hydration, dehydration, solvation or desolvation.

[0101] Examples of "normal storage conditions" for the compositions of the present invention, whether in pharmaceutical formulation or dosage form, and / or when loaded into a drug delivery member, the drug delivery member being loaded into an applicator, a device, a drug reservoir (e.g., a canister or container), or otherwise, include a temperature between about -50°C and about +80°C (preferably between about -25°C and about +75°C, for example, about 50°C), and / or a pressure between about 0.1 and about 2 bar (preferably atmospheric pressure), and / or exposure to about 460 lux of UV / visible light, and / or a relative humidity between about 5 and about 95% (preferably about 10 to about 40%), for an extended period of time (that is, greater than or equal to about twelve months, for example, about six months).

[0102] Under such conditions, less than about 15% of the composition of the present invention (and / or the active ingredient contained therein) may be found to chemically degrade / decompose, and / or undergo solid-state transformation, as appropriate, more preferably less than about 10%, and especially less than about 5%. Those skilled in the art will appreciate that the above upper and lower limits for temperature and pressure represent 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).

[0103] Such chemical and, in particular, physical stability is important in solid compositions, such as powders, to ensure that an appropriate dose is delivered to the patient. This is particularly true when the composition is to be delivered intranasally.

[0104] Particularly preferred pharmaceutically acceptable carrier materials that can be used to produce the compositions of the present invention and that have the desired properties mentioned herein include disaccharide components, maltitol, trehalose, sucralose, sucrose, isomalt, maltose and in particular lactose (including β-D-lactose and α-D-lactose, in particular α-D-lactose monohydrate).

[0105] For the polymeric material component, preferred pharmaceutically acceptable carrier materials that can be used to produce the compositions of the present invention and have the desired properties mentioned herein include cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose, HPMC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), methylcellulose (MC), ethylhydroxyethylcellulose, carboxymethylcellulose (CMC), modified cellulose gum, microcrystalline cellulose and sodium carboxymethylcellulose; starches, such as rice starch, tapioca starch, wheat starch and more particularly corn starch and potato starch; starch derivatives, such as pregelatinized starch, carboxymethyl starch and moderately cross-linked starch. Examples of the present invention include: starch, modified starch, and sodium starch glycolate; polysaccharides, including dextrins, such as dextrins, cyclodextrins, and linear or branched dextrins, such as maltodextrins; powdered tragacanth; waxy excipients, such as cocoa butter and suppository waxes; polyols, such as solid polyethylene glycols; acrylic acid polymers, such as carbomers and their derivatives; polyvinylpyrrolidone (povidone, PVP); cross-linked polyvinylpyrrolidone; polyethylene oxide (PEO); polyglucosamine (poly-(D-glucosamine)); natural polymers, such as gelatin, sodium alginate, pectin; scleroglucan; sucralose; guar gum; poly-(methyl vinyl ether / maleic anhydride); and cross-linked carboxymethylcellulose (e.g., cross-linked carboxymethylcellulose sodium). Hydroxypropyl methylcellulose acetate succinate (HPMCAS), copovidone, and polyvinyl alcohol (PVA or PVOH) may also be mentioned.

[0106] More preferred polymeric materials include sodium carboxymethylcellulose, sodium starch glycolate, polyvinylpyrrolidone and, in particular, hydroxypropyl methylcellulose (e.g., hypromellose 2906, preferably hypromellose 2910 (i.e., "Type E"), and more preferably USP / NF hypromellose 2208 (i.e., "Type K")), or in particular, polysaccharides, such as dextrins, including cyclodextrins (e.g., α-, β-, and γ-cyclodextrins and derivatives thereof, such as 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether β-cyclodextrin sodium salt, randomized methylated β-cyclodextrin, branched β-cyclodextrin, and in particular 2-hydroxypropyl-β-cyclodextrin); and linear or branched dextrins, such as maltodextrins, which can be classified by dextrose equivalent (DE) between 3 and 20 (the higher the DE value, the shorter the average length of the glucose chain), in particular maltodextrins with a DE between 6 and 15, such as 8 and 12.

[0107] In any event, suitable polymers for use in the compositions of the present invention should be of sufficiently high molecular weight that, when used in combination with the disaccharide in any given amount, they form a suitable carrier material for the active ingredient.

[0108] 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.

[0109] In this regard, it may be preferred that the polymer has a relative viscosity value of no more than about 1000 (more preferably no more than about 120, such as no more than about 60, and in particular no more than about 10) mPa*s at 20°C, as measured for any of the specified and substantially the following:

[0110] (a) A water-soluble polymer, such as a 2 wt% aqueous solution of the polymer, which is prepared by the standard USP method for viscosity, i.e. <911> Method I, and / or <912> Method I; and

[0111] (b) A water-insoluble polymer, such as a 5 wt% solution of the polymer in a suitable organic solvent, such as acetone, methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, methylene chloride, toluene, and mixtures thereof, wherein the solvent system may be dry or partially aqueous, as determined by USP method <911> Method I.

[0112] One skilled in the art will understand which test is more appropriate for the polymer being tested.

[0113] Mixtures from any of the foregoing lists of disaccharides and / or polymeric materials may be used.

[0114] The amount of carrier material that can be used in the compositions of the present invention is generally 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% by weight 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% to about 75% by weight, based on the total weight of the composition (whether a dose of the composition is included in an administration member or otherwise).

[0115] Preferably, the combination of support materials is such that a composition of the present invention has a glass transition temperature (Tg) of:

[0116] (a) enables production into a hard and / or brittle, "glassy," amorphous, powdery physical form that can be readily formulated into a pharmaceutical formulation or dosage form, and / or loaded into a suitable drug delivery device, such as a nasal applicator, or a drug reservoir and / or container within or adjacent to such an applicator as described herein; and

[0117] (b) sufficiently high that after such pharmaceutical formulation, dosage form, or drug delivery member, e.g., applicator or reservoir, is packaged as described herein and thereafter subjected to elevated external temperatures (e.g., up to between about 50°C and about 80°C), it remains in the glassy state, rather than converting to a more viscous or rubbery state, and / or a crystalline state.

[0118] In warm and / or sunny climates, the interior of the medium is typically subjected to such extreme external temperatures, and the medium will often be placed for a long time under sufficient sunlight, where the heat increase produced can be enormous. If the Tg of the composition of the present invention is relatively low, the composition can be converted into such a sticky / rubbery state after being exposed to such high temperatures, which will cause inefficient administration of the composition of the present invention, such as, once the administration member or applicator is actuated, the composition will be discharged from the administration member, applicator or reservoir inefficiently (and the dosage of the active ingredient is also such). In addition, too low a Tg may affect the disintegration and / or dissolution of the composition of the present invention in the form of a lozenge for sublingual or oral use.

[0119] In this regard, we prefer that the compositions of the present invention have a minimum measurable Tg of 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 at most about 35%, such as at most about 30%, including at most about 25% (e.g., at most about 20%, such as less than about 15%, such as less than about 10%). "Minimum measurable Tg" includes that the compositions of the present invention may include particles that are heterogeneous in nature. In particular, the particles may include discrete regions of the carrier material or a complex mixture thereof, and thus may have individual and separate Tg values. It will be clear to those skilled in the art that the value of the minimum measurable Tg has a strong impact on the physical stability of the composition.

[0120] We have found that compositions of the present invention comprising a combination of a disaccharide with a polymer (e.g. HPMC as defined herein) and / or in particular dextrin, are capable of producing compositions and active ingredients with suitable levels of physical and chemical stability when compared to other carrier materials used alone or in isolation.

[0121] Particularly preferred combinations of carrier materials therefore include trehalose, or more preferably lactose, such as α-D-lactose monohydrate, and dextrin, and in particular cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin, or maltodextrin, such as maltodextrin 12DE. We have found that such combinations of carrier materials can be spray-dried with the active ingredient and, if present, an appropriate proportion of alkyl saccharides to produce a composition of the invention as defined herein having both the desired physical and chemical stability under normal storage conditions.

[0122] We have found that the relative amounts of the disaccharide and polymer components in the carrier material (and particularly when the polymer is a dextrin) can be adjusted to ensure the desired level of physical and / or chemical stability of the active ingredient without lowering the Tg of the composition of the invention in a way that affects its physical stability.

[0123] We have found that a ratio of disaccharide:polymer (e.g., dextrin) by weight of between about 50:1 and about 1:50, based on the total weight of the composition, works depending on the active ingredient used. Preferred ratios of disaccharide:polymer (e.g., dextrin) by weight, based on the total weight of the composition, range from about 10:1 to about 1:40 (including up to about 1:30 or up to about 1:20), for example, between about 2:1 and about 1:10, more preferably about 1:1 to about 1:8.

[0124] Regardless of their proportions in the final mixture, the compositions of the present invention include a spray-dried carrier material comprising a combination of a disaccharide and a polymeric material (e.g., dextrin). Thus, the carrier material can be prepared by spray drying those ingredients to form a composite carrier material, which is then spray dried together with the other essential ingredients to form the composition of the present invention, or more preferably, prepared in situ by spray drying all of the essential components of the composition of the present invention together.

[0125] Active pharmaceutical ingredients useful in the compositions of the present invention include any compound having pharmaceutical activity.

[0126] Specific active pharmaceutical ingredients that may be mentioned include those suitable for transmucosal, including sublingual and especially intranasal administration, for example in a dose of less than or equal to about 100 mg.

[0127] In this regard, the compositions of the present invention may comprise an antipsychotic drug (also referred to herein simply as an "antipsychotic drug"), including first generation or second generation antipsychotic drugs.

[0128] First generation antipsychotic drugs that can be used in the compositions of the present invention include phenothiazines, such as acepromazine maleate, chlorpromazine, cyamemazine, dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine, periciazine, perphenazine, pipotiazine, prochlorperazine, promazine, promethazine, prothipendyl, thioproperazine, thioridazine, trifluoperazine or triflupromazine; thiophene; Thioxanthenes, such as chlorprothixene, clopenthixol, flupentixol, thiothixene, and zuclopenthixol; butyrophenones, such as benperidol, bromperidol, droperidol, haloperidol, moperone, pipamperone, or timiperone; indolinone derivatives, such as indolinone dihydroindolon or molindolone; dibenzepine; diphenylbutylpiperidines such as fluspirilene, penfluridol, or pimozide; dibenzothiazepines such as tianepine or metiapine; perathiepine, chlorotepine, metitepine; tricyclics carbamazepine carpipramine, clocapramine, clorotepine, clotiapine, loxapine or mosapramine; molindone or a substituted benzamide such as sulpiride, sultopride or veralipride.

[0129] Preferably, the phenothiazine has a substituent at position 10, such as chlorpromazine, mesoridazine, pipotazine, perphenazine or trifluoperazine. Preferred substituents at position 10 are aliphatic hydrocarbons, piperidine or piperidine. .

[0130] First generation antipsychotic drugs that may be used in the compositions of the present invention include substances that block D2 receptors and / or block muscarinic cholingeric receptors.

[0131] Preferred first generation antipsychotic drugs that can be used in the compositions of the present invention block D2 receptors in the mesolimbic pathway and / or block muscarinic cholinergic receptors, such as chlorpromazine, fluphenazine, haloperidol, perphenazine, thioridazine, thiothixene or trifluoperazine.

[0132] Second-generation antipsychotic drugs that can be used in the compositions of the present invention include benzamides such as amisulpride, nemonapride, remoxipride sultopride, sulpiride, or veralipride; benzisoxazoles / benzisothiazoles such as iloperidone, lurasidone, paliperidone palmitate, and valproate; palmitate), perospirone, risperidone, or ziprasidone; butyrophenones, such as melperone; phenylpiperazine / quinolinones, such as aripiprazole, brexpiprazole, or cariprazine; tricyclics, such as asenapine, clozapine, olanzapine, quetiapine, or zotepine; blonanserin, pimavanserin, or sertindole.

[0133] The second generation of antipsychotic drugs that can be used in the composition of the present invention include serotonin-dopamine antagonists; serotonin 5-HT antagonists that block or partially block the serotonin 2A and / or 5-HT 1A receptors and D2 receptors; exhibits 5-HT 2A , D2 and other system receptors, such as cholinergic, histaminergic, 5-HT 1A , 5-HT 2c Substances that have affinity for D2 and D2-like receptors; substances that block the D3 subtype of D2 and D2-like receptors.

[0134] "D2-like receptors" means a subfamily of dopamine receptors that bind the endogenous neurotransmitter dopamine, comprising a G2-like receptor coupled to i / G o The subfamily includes three G protein-coupled receptors that mediate inhibitory neurotransmission, D2, D3, and D4.

[0135] Optionally, antipsychotic drugs useful in the compositions of the present invention include partial dopamine receptor agonists comprising a partial agonist at the dopamine D2 receptor that acts as a functional antagonist in the mesolimbic dopamine pathway but exhibits functional agonist activity in the mesocortical pathway.

[0136] Naturally occurring antipsychotic drugs, such as L-photostephaniaceae, may also be used in the compositions of the present invention.

[0137] Preferably, antipsychotic drugs acting on dopamine-induced systems block only mesocortical pathways.

[0138] Substances that act as D2 antagonists can be used in the compositions of the present invention. Preferably, these substances reduce dopamine-induced neurotransmission in at least one of the four dopamine pathways. These dopamine pathways include the mesocortical, mesolimbic, nigrostriatal, and tuberoinfundibular pathways. The mesolimbic pathway is preferred.

[0139] Preferred D2 antagonists that can be used in the compositions of the present invention include 3-PPP, aceprometazine, amisulpride, aripiprazole, BL-1020, blonanserin, buspirone, testosterone, chlorprothixene, desmethoxyfallypride, doxepin, eticlopride, fallypride, flunarizine, itopride, Ketanserin, L-741,626, lumateperone, metoclopramide, ocaperidone, olanzapine, opipramol, panamersine, pimozide, pipamperone, pridopidine, raclopride, spiperone, stepholidine, tiotixene, or trimethobenzamide.

[0140] Preferred second generation antipsychotic drugs that can be used in the compositions of the present invention include aripiprazole, asenapine, clozapine, aloperidon, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, cariprazine or ziprasidone.

[0141] More preferably, the composition of the invention comprises trifluoroperazine, haloperidol, prochlorperazine, blonanserin or, more preferably, loxapine or olanzapine.

[0142] In alternative embodiments, the compositions of the present invention may include one or more anticonvulsant drugs, which may include paraldehyde, stiripentol, potassium bromide, felbamate, valproic acid, sodium valproate, divalproex sodium, vigabatrin, progabide, tiagabine, topiramate, hydantoins (e.g., ethotoin, phenytoin, mephenytoin, and fosphenytoin), paramethadione, trimethadione, ethadione, beclamide, primidone, brivarathin, dapoxetine ... acetam), etiracetam, levetiracetam, seletracetam, ethosuximide, phensuximide, mesuximide, acetazolamide, sultiame, methazolamide, zonisamide, lamotrigine, pheneturide, phenacemide, valpromide, valnoctamide, perampanel, stiripentol, pyridoxine.Preferred anticonvulsant drugs include barbiturates (e.g., amobarbital, methohexital, thiamylal, thiopental, phenobarbital, primidone, methylphenobarbital (mephobarbital), and barbexaclone), and benzodiazepines (e.g., clorazepate, diazepam, flurazepam, halazepam, prazepam, chlordiazepoxide, lormetazepam, oxazepam, temazepam, clonazepine, chlordiazepoxide, lormetazepam, oxazepam, temazepam, clonazepine, clorazepate ... zepam), flunitrazepam, nimetazepam, nitrazepam, adinazolam, alprazolam, estazolam, triazolam, climazolam, loprazolam, midazolam, bentazepam, clotiazepam, etizolam, metizolam, deschloroetizolam, and specifically lorazepam), and carboxamides (e.g., oxcarbazepine, eslicarbazepine, and specifically carbamazepine).

[0143] The compositions of the present invention may also include one or more cannabinoid drugs. The term "cannabinoid" refers to compounds that act on cannabinoid receptors in cells, thereby altering the release of neurotransmitters in the brain. Ligands for these receptor proteins include endocannabinoids (produced naturally in animals), phytocannabinoids (found in cannabis and some other plants), and synthetic cannabinoids (artificially produced cannabinoids).

[0144] The most famous cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis. There are at least 113 different cannabinoids isolated from the cannabis plant, each exhibiting a variety of effects.

[0145] In certain embodiments, the cannabinoid is cannabinoid-agonist (or cannabinoid-ergic), that is, a compound that acts on endocannabinoid neurotransmitters (e.g., a cannabinoid receptor agonist, a cannabinoid receptor antagonist, an endocannabinoid enhancer (eCBE), or an endocannabinoid reuptake inhibitor (eCBRI)).

[0146] Cannabinoids that can be used in the compositions and / or dosage forms of the present invention include phytocannabinoids (e.g., CBG, CBC, CBD, THC, CBN, CBE, isoTHC, CBL, and CBT) and endocannabinoids (e.g., AEA, 2-AG, noradrenaline ether, NAD A, OAE, and LPI). Cannabinoids can be phytocannabinoids (e.g., cannabigerol type (CBG type), cannabichromene type (CBC type), cannabidiol type (CBD type), dehydrocannabidiol type (CBND type), Δ 9 -Tetrahydrocannabinol type (Δ 9 -THC type), Δ 8 -Tetrahydrocannabinol type (Δ 8 Cannabinoids include cannabinoids of the cannabinoid type (CBT), cannabichromene (CBL), cannabitriol (CBT), or cannabichromone (CBCN). Other phytocannabinoids that may be used in the compositions and / or dosage forms of the present invention include dehydrocannabifuran, cannabifuran, cannabichromanone, 10-hydroxy-delta-6a-tetrahydrocannabinol, or cannabiripsol.

[0147] Alternatively, the cannabinoid may be a synthetic cannabinoid (e.g., nabilone, rimonabant, JWH-018, JWH-073, CP-55940, dimethylheptylpyran, HU-210, HU-331, SR144528, WIN 55,212-2, JWH-133, levonantradol / Nantrodolum, or AM-2201) and mimetics thereof.

[0148] The cannabinoids may include at least one of THC (tetrahydrocannabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabichromene), CBV (cannabinol), THCV (tetrahydrocannabinol), CBDV (cannabidiol), CBCV (cannabigerol), CBGV (cannabigerol), CBGM (cannabigerol monomethyl ether), CBE (cannabichromene), CBT (cannabidipyran), nabilone, rimonabant, JWH-018, JWH-073, CP-55940, dimethylheptylpyran, HU-210, HU-331, SR144528, WIN55,212-2, JWH-133, levonantradol / Nantrodolum, or AM-2201.

[0149] Preferred endocannabinoids are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, such as CB1, CB2, or CB3 (GPR55), and cannabinoid receptor proteins expressed throughout the vertebrate central nervous system (including the brain) and peripheral nervous system.

[0150] Preferred cannabinoids include THC (tetrahydrocannabinol, such as dronabinol), THCA (tetrahydrocannabinolic acid), CBD (cannabidiol), CBDA (cannabidiolic acid), CBN (cannabinol), CBG (cannabigerol), CBC (cannabichromene), CBL (cannabichromene), CBV (cannabinol), THCV (tetrahydrocannabinol), CBDV (cannabidiol), CBCV (cannabinoids), CBGV (cannabigerol), CBGM (cannabigerol monomethyl ether), CBE (cannabichromene) and CBT (cannabidipyranoside). A particularly preferred cannabinoid is cannabidiol.

[0151] The composition of the present invention may also contain peptides. Useful peptides include naturally occurring peptides or synthetic analogs thereof, semisynthetic peptides, synthetic peptides, and proteose.

[0152] The peptide may be a single-chain peptide or a multi-chain peptide, that is to say a peptide formed from two or more different amino acid chains, such as human insulin, or a cyclic peptide, such as cyclosporine. Preferably, the peptide is not a naturally occurring protein or a recombinant protein.

[0153] Types of naturally occurring peptides include plant peptides, bacterial / antibiotic peptides, fungal peptides, invertebrate peptides, amphibian / skin peptides, venom peptides, cancer / anticancer peptides, vaccine peptides, immune / inflammatory peptides, brain peptides, endocrine peptides, feeding peptides, gastrointestinal peptides, cardiovascular peptides, renal peptides, respiratory peptides, opioid peptides, neurotrophic peptides, blood-brain peptides, ribosomal peptides, non-ribosomal peptides, neuropeptides, lipopeptides, and peptide hormones.

[0154] "Proteose" means a mixture of peptides produced by the hydrolysis of proteins.

[0155] The peptides useful in the compositions of the present invention may be naturally occurring peptides, such as insulin, interferon beta, interferon gamma, TPA, albumin, HGH, factor VIII, erythropoietin, calcitonin, oxytocin or vasopressin, or synthetic analogs thereof, semisynthetic peptides, such as voclosporin, or synthetic peptides.

[0156] Semisynthetic peptides can be obtained by chemically treating peptides of natural origin.

[0157] The peptides that can be used in the composition of the present invention can be ribosomal peptides, which include antimicrobial peptides, such as peptides belonging to the magainin family, the bactericidal peptide family, the antimicrobial peptide family, and the defensin family; tachykinin peptides, such as substance P, kassinin, neurokinin A, eledoisin, and neurokinin B; vasoactive intestinal peptides, such as VIP (vasoactive intestinal peptide; PHM27), PACAP (pituitary adenylate cyclase activating peptide), peptide PHI 27 (peptide histidine isoleucine 27), and GHRH1-24 (growth hormone releasing hormone 1-24). Glucagon, incretin; pancreatic polypeptide-related peptides, such as NPY (neuropeptide Y), PYY (peptide YY), APP (avian pancreatic polypeptide), PPY pancreatic polypeptide; opioid peptides, such as proopiomelanocortin (POMC) peptide, endomorphin (and analogs, such as endorphin-2), enkephalin pentapeptide, dynorphin; calcitonin peptides, such as calcitonin, amylin, AGG01 or self-assembling peptides, such as amphiphilic peptides, short aromatic peptides or biomimetic peptides.

[0158] Preferably, the ribosomal peptide has hormonal activity.

[0159] Peptides useful in the compositions of the present invention include B-type natriuretic peptide (BNP) lactotripeptide, a peptide component from the traditional Chinese medicine CollaCorii Asini.

[0160] Peptides that can be used also include peptides that act as GnRH agonists, such as buserelin, gonarelin, goserelin, histrelin, leuprorelin, nafarelin, triptorelin, and GnRH antagonists, such as abarelix, cetrorelix, degarelix, ganirelix, elagolix, relugolix, and teverelix; peptides that act as vasopressin receptor 2 (AVPR2) agonists, such as desmopressin, or as GLP-1 receptor agonists, such as liraglutide, exenatide, lixisenatide, albiglutide, dulaglutide, or semaglutide.

[0161] Peptides may include those that act as SRIF agonists, such as somatostatin and analogs such as octreotide, pasireotide, or lanreotide.

[0162] Peptides useful in the compositions of the present invention further include peptides useful for treating osteoporosis, such as teriparatide, a recombinant protein form of parathyroid hormone.

[0163] Other peptides that may be used include immunosuppressive peptides such as cyclosporine, which may be used to treat rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, and / or prevent tissue / organ transplant rejection.

[0164] Preferably, the composition of the invention comprises a peptide comprising one or more of buserelin, gonadorelin, goserelin, histrelin, leuprorelin, nafarelin, triptorelin, abarelix, cetrorelix, degarelix, ganirelix, elagolix, relugolix, teverelix, leuprolide, liraglutide, octreotide and desmopressin.

[0165] The compositions of the present invention may comprise a bisphosphonate, such as alendronate, clodronate, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, and zoledronate.

[0166] The compositions of the present invention may contain a general anesthetic and / or a sedative. General anesthetics and / or sedatives that can be used in the compositions of the present invention include those typically administered intravenously, such as barbiturates (e.g., amobarbital, methohexital, thiamobarbital, and thiopental); benzodiazepines (e.g., any of those mentioned above under the heading of anticonvulsants, and in particular diazepam, lorazepam, and midazolam); and other drugs, such as etomidate, propofol, and in particular ketamine.

[0167] Other sedatives include muscle relaxants such as succinylcholine, decamethonium, mivacurium, rapacuronium, atracurium, cisatracurium, rocuronium, vecuronium, alcuronium, doxacurium, gallamine, metocurine, pancuronium, pipecuronium, and tubocurarine.

[0168] The compositions of the present invention may include an analgesic agent, which includes a nonsteroidal anti-inflammatory drug, such as aspirin, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, bromfenac, nabumetone, piroxicam, and dapoxetine. m), meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, phenylbutazone (bute), mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide, clonixin, and licofelone; and synthetic opioid analgesics, such as tramadol, alfentanil, fentanyl, remifentanil, and sufentanil. Preferred analgesics include aspirin, as well as ketorolac and diclofenac, plus piroxicam, meloxicam, tenoxicam, droxaxicam, lornoxicam and isoxicam.

[0169] The compositions of the present invention may comprise an antidepressant, which includes a selective serotonin reuptake inhibitor (SSRI), such as fluoxetine, sertraline, doxepin, citalopram, escitalopram oxalate, fluvoxamine, paroxetine; a serotonin-norepinephrine reuptake inhibitor (SNRI), such as desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine; and a serotonin modulator and stimulator (SMS), such as vilazodil and vortioxetine. statins; serotonin antagonists and reuptake inhibitors (SARIs), such as nefazodone and trazodone; norepinephrine reuptake inhibitors (NRIs), such as atomoxetine, reboxetine, teniloxazine, and viloxazine; norepinephrine-dopamine reuptake inhibitors (NDRIs), such as bupropion; tricyclic antidepressants, such as amitriptyline, amitriptyline oxytocin, clomipramine, and desipramine. amine), diphenhydramine, dimethoprim, dosulpiride, doxepin, imipramine, lofepramine, melitracen, nitroxazepine, nortriptyline, noxiptiline, opipramol, pipofiazine, protriptyline, and trimipramine; tetracyclic antidepressants, such as amoxapine, maprotiline, and diphenhydramine.

[0170] The compositions of the present invention may comprise an antihistamine (i.e., an H1 antagonist / inverse agonist) such as crivastine, azatadine, azelastine, bilastine, bromodiphenhydramine, brompheniramine, buclizine, carbinoxamine, cetirizine, chlorodiphenhydramine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, Diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocabastine, levocetirizine, loratadine, meclizine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupatadine, alergoliber, tripelennamine, and triprolidine.

[0171] The compositions of the present invention may comprise modulators of neurotransmitter receptors (in addition to those already mentioned above or below), including modulators of adrenergic receptors (including α 1A , α 1b , α 1c , α 1d , α2a , α 2b , α 2c , α 2d , β1, β2, β3 subreceptors), GABA-stimulated receptors (including GABA A , GABA B1a , GABA B1δ , GABA B2 , GABA C sub-receptors), dopamine receptors (including D1, D2, D3, D4 and D5 sub-receptors), glutamate agonist receptors (including NMDA, AMPA, kainate, mGluR1, mGluR2, mGluR3, mGluR4, mGluR5, mGluR6, mGluR7), cholinergic receptors (including muscarinic (M1, M2, M3, M4 and / or M5) receptors, nicotinic receptors, muscle receptors and neuronal (α-toxin-insensitive and α-toxin-sensitive) receptors), serotonin agonist receptors (including 5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 1E , 5-HT 1F , 5-HT 2A , 5-HT 2B , 5-HT 2C , 5-HT3, 5-HT4, 5-HT5, 5-HT6, 5-HT7 sub-receptors) and glycinergic receptors.

[0172] Glutamate receptor modulators that may be mentioned and are not mentioned above or below include selfotel, aspartame, amantadine, agmatine, dextromethorphan, eliprodil, remacemide, gabapentin, etc. GABA receptor modulators that may be mentioned include short-acting hypnotics such as zaleplon, zolpidem, eszopiclone, or zopiclone. Adrenaline receptor modulators that may be mentioned include norepinephrine, isoproterenol, and more specifically epinephrine (adrenaline). Modulators of dopamine-stimulated receptors that may be mentioned and not mentioned above or below include cabergoline, bromocriptine, pramipexole, pergolide, ropinirole, rotigotine, and in particular apomorphine. Modulators of serotonin-stimulated receptors that may be mentioned and not mentioned above include triptans (e.g. almotriptan, eletriptan, or alternatively dilizatriptan, zolmitriptan, sumatriptan, frovatriptan and naratriptan).

[0173] Other antimigraine compounds that may be mentioned include diltiazem, lisuride, verapamil, ergotamine, dihydroergotamine, caffeine, and the like.

[0174] Other active ingredients that may be used in the compositions of the present invention include cardiovascular drugs, including the following:

[0175] • Anticoagulants, such as factor Xa inhibitors (including apixaban, dabigatran etexilat, edoxaban, and rivaroxaban); and platelet inhibitors (including cropituitar, telopiidine, aspirin, dipyridamole, epoprostenol, iloprost, abciximab, eptifibatid, tirofiban, treprostinil, prasugrel, cilostazol, ticagrelor, cangrelor, vorapaxar, and sepsipaq);

[0176] • α- and β-adrenergic receptor antagonists (also known as α- and β-blockers), which are used to treat a variety of cardiovascular conditions (e.g., hypertension, high blood pressure, etc.). Alpha-blockers include prazosin and doxazosin; beta-blockers include atenolol, pindolol, propranolol, metoprolol, as well as timolol, sotalol, nadolol, carteolol, penbutolol, acebutolol, betaxolol, bisoprolol, esmolol, nebivolol, and randiolol; and combined α- and β-blockers include labetalol and carvedilol;

[0177] • Angiotensin-converting enzyme (ACE) inhibitors, such as captopril, enalapril, lisinopril, perindopril, ramipril, benazepril, fosinopril, trandolapril, spirapril, and moexipril;

[0178] • Angiotensin II receptor antagonists, such as losartan, eprosartan, valsartan, irbesartan, candesartan, telmisartan, olmesartan medoxomil, azilsartan, and medoxomil;

[0179] • neprilysin inhibitors, such as sacubitril;

[0180] • Calcium channel blockers, such as amlodipine, felodipine, isradipine, nifedipine, nimodipine, nisoldipine, clevidipine, verapamil, diltiazem, and bepridil;

[0181] • Diuretics, such as bendroflumethiazide, hydrochlorothiazide, hydroflumetiazide, chlorothiazide, polythiazide, chlorthalidone, metolazone, indapamide, furosemide, bumetanide, torsemide, spironolactone, eplerenone, amiloride, triamterene, tolvaptan, and conivaptan;

[0182] • HMG-CoA reductase inhibitors (cholesterol-lowering drugs), such as simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin;

[0183] •Vasodilators, such as nitroglycerin, isosorbide, and isosorbide mononitrate;

[0184] •Endothelin receptor antagonists, such as bosentan, ambrisentan, sitaxentan, macitentan, and riociguat.

[0185] • digitalis preparations, that is, preparations containing cardiac glycosides, such as digoxin; and

[0186] •Other high blood pressure treatments, such as hydralazine, veratrum, pargyline, etc.

[0187] Other active ingredients that can be used in the compositions of the present invention include antiviral agents for, for example, hepatitis C (e.g., ribavirin, sofosbuvir, dasabuvir, elbasvir, grazoprevir, ledipasvir, ombitasvir, paritaprevir, ritonavir, velpatasvir, voxilaprev, ir), glecaprevir, and pibrentasvir; more specifically, drugs for the treatment of erectile dysfunction, such as avanafil, sildenafil, tadalafil, and vardenafil; muscle relaxants, such as quinine and chlorzoxaone; stimulants, such as ephedrine, fenfluramine, and caffeine; e), amphetamine, methamphetamine, dexamphetamine, methcathinone, etc.; antiemetics, such as dolasetron, granisetron, metoclopramide, meclizine, cyclizine, ondansetron, palonosetron ), dimenhydrinate, diphenhydramine, scopolamine, promethazine, etc.; and other drugs, including chlordiazepoxide, betahistine, clonidine, hyoscyamine, and sex hormones (such as testosterone, estrogen, estradiol, etc.).

[0188] Those skilled in the art will appreciate that one or more of the aforementioned active ingredients may have one or more of the aforementioned medical functions. For example, ketamine may have biological activities including analgesia, sedation, and antidepressant functions.

[0189] Preferred active ingredients that can be used in the compositions of the present invention include those (listed above or otherwise) that comprise a molecular structure comprising at least one nitrogen atom in the form of an amine moiety. The amine moiety may be a quaternary amine, or more preferably, may be a primary, secondary or tertiary amine.

[0190] Such amine moieties may be aromatic in nature, in other words, wherein one or more carbon atoms are bonded to at least one nitrogen atom within the molecular structure of the active ingredient via an sp2 arrangement (that is, comprising one or more "aryl" groups). However, more preferably, such amine moieties may be aliphatic in nature, in other words, wherein one or more carbon atoms are bonded to at least one nitrogen atom within the molecular structure of the active ingredient via an sp3 arrangement (that is, comprising one or more "alkyl" groups).

[0191] Drugs containing an amino group include many of those mentioned herein, such as those that mimic or interfere with the action of natural amine neurotransmitters, for example, chlorpheniramine, chlorpromazine, ephedrine, phenylephrine, amitriptyline, imipramine, lofepramine, clomipramine, nortriptyline, desipramine, amoxapine, and especially loxapine, ketamine, apomorphine, epinephrine, olanzapine, aripiprazole, haloperidol, ziprasidone, asenapine, risperidone, and any of the aforementioned triptans.

[0192] Additionally and / or in the alternative, preferred active ingredients useful in the compositions of the present invention include those (whether listed above (e.g., in the list of amine drugs) or otherwise) having a pKa of at least about 0, such as at least about 2, including at least about 4, more particularly at least about 6, such as at least about 7.5, such as at least about 8, and especially at least about 8.5; and no more than about 14, such as no more than about 12.5, including no more than about 12, preferably no more than about 11.5, such as no more than about 11, including no more than about 10.5, and especially no more than about 10.

[0193] Still additionally and / or in the alternative, preferred active ingredients useful in the compositions of the present invention include those (listed above or otherwise) having a water solubility at room temperature and atmospheric pressure of at least about 10 mg / mL, such as at least about 1 mg / mL, including at least about 100 μg / mL, such as at least about 10 μg / mL, for example at least about 1 μg / mL, and in particular at least about 0.5 μg / mL. "Water-soluble" is understood to include not only solubility in pure water, but also solubility in relevant physiological fluids, and particularly those found in the nose (which can also be simulated based on isotonicity and pH).

[0194] Preferably, the active ingredient of the composition of the present invention is not an opioid antagonist. In particular, when the composition of the present invention is formulated for (and / or suitable for) intranasal administration, it is preferred that the active ingredient used therein is not an opioid antagonist.

[0195] According to another aspect of the present invention, there is provided a composition of the present invention, which is suitable for and / or formulated to include the one or more pharmaceutically active ingredients therein:

[0196] •Oral delivery to the gastrointestinal tract;

[0197] •Topical delivery to the eye, vagina, cervix, and / or anorectal mucosa;

[0198] •Sublingual delivery (e.g. as a lozenge or in powder form);

[0199] •buccal delivery (e.g., as a buccal lozenge or patch);

[0200] •delivered by injection or by infusion (e.g. as a suspension in an infusion); or

[0201] • Intranasal delivery (in powder form),

[0202] This is with the proviso that in the latter (intranasal) case, one or more of the pharmaceutically active ingredients is not an opioid antagonist.

[0203] Additionally, provided are methods of treating a patient comprising administering a composition of the invention by a route of administration comprising:

[0204] •Oral delivery to the gastrointestinal tract;

[0205] •Topical delivery to the eye, vagina, cervix, and / or anorectal mucosa;

[0206] •Sublingual delivery (e.g. as a lozenge or in powder form);

[0207] •buccal delivery (e.g., as a buccal lozenge or patch);

[0208] •delivered by injection or by infusion (e.g. as a suspension in an infusion); or

[0209] • Intranasal delivery (in powder form),

[0210] The composition comprises one or more pharmaceutically active ingredients suitable for and / or intended for delivery via one or more of the routes of administration mentioned above, with the proviso that, in the latter case (intranasal), one or more of the pharmaceutically active ingredients is not an opioid antagonist.

[0211] The term "opioid antagonist" includes any agent that has little or no opioid activity but is capable of displacing opioid agonists from opioid receptors, thereby reversing or preventing the pharmacological effects of opioid agonists, whether such effects are intended (euphoria, sedation, and / or decreased craving) or unintended (unconsciousness, decreased heart rate, decreased lung function, hypoxia, etc.). Therefore, opioid antagonists have potential use in the treatment of overdose of substances (e.g., opioids, including opiates). In this regard, the term "opioid agonist" includes exogenous opioid receptor ligands (i.e., those mentioned above) and endogenous opioid receptor ligands (e.g., endorphins). Thus, opioid antagonists include naloxone, nalmefene, and naltrexone, or pharmacologically acceptable salts thereof, such as their hydrochloride salts. In the context of the present application, the term "opioid antagonist" also includes active pharmaceutical ingredients known to be partial antagonists of opioid receptors, such as buprenorphine, and active pharmaceutical ingredients otherwise known to be useful in treating opioid withdrawal symptoms, such as lofexidine.

[0212] Preferred active ingredients that can be used in the compositions of the present invention include one or more of the GnRH agonists or one or more of the GnRH antagonists mentioned above, plus lurasidone, blonanserin, olanzapine, carbamazepine, lorazepam and cannabidiol, in particular aspirin, and more in particular ketorolac, as well as aripiprazole, haloperidol ... Ziprasidone, asenapine, loxapine, ketamine, apomorphine, epinephrine, almotriptan, or eletriptan, or alternatively rizatriptan, zolmitriptan, sumatriptan, frovatriptan, and naratriptan.

[0213] Combinations of one or more of the foregoing active ingredients of the same or different classes may be employed.

[0214] The active ingredients mentioned above may be provided in the form of (e.g., pharmaceutically acceptable) salts, including any such salts known in the art and described for the drugs discussed in the medical literature, for example, Martindale - The Complete Drug Reference, 38th edition, Pharmaceutical Press, London (2014) and documents mentioned therein (the relevant disclosures of all documents being incorporated herein by reference).

[0215] In addition, pharmaceutically acceptable salts include acid addition salts and base addition salts, which can be formed in a conventional manner, for example, by reacting a compound of the invention in free acid or free base form with one or more equivalents of an 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 (e.g., in vacuo, by freeze drying or by filtration). Salts can also be prepared using techniques known to those skilled in the art, for example, by exchanging the counterion of a compound of the invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0216] Specific acid addition salts that may be mentioned include carboxylates, such as succinate, tartrate, formates, acetates, benzoates, oxalates, fumarates, maleates, and the like, sulfonates, such as methanesulfonates, ethanesulfonates, toluenesulfonates, and the like, halides, such as hydrochlorides, hydrobromides, and the like, sulfates and phosphates, such as sulfate or phosphate, and the like.

[0217] Specific base addition salts that may be mentioned include salts formed with alkali metals (e.g., Li, Na, and K salts), alkaline earth metals (e.g., Mg and Ca salts), or other metals (e.g., Al and Zn salts), amine bases (e.g., amines, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine). More particularly, base addition salts that may be mentioned include Mg salts, Ca salts, and most particularly, K salts and Na salts.

[0218] When the composition of the present invention is prepared by a solvent-based method as described above (including a method by spray drying), this may cause the active ingredient to no longer be in the form of a crystalline salt, because it is freely dispersed in the carrier material in an amorphous form and encapsulated by the carrier material. However, despite not being in the form of a crystalline salt, the composition of the present invention can generally provide little or no loss of chemical stability of the active ingredient under the normal storage conditions mentioned herein, as is typical for solid mixtures and / or powder compositions.

[0219] The amount of active ingredient in a single dose of the composition of the present invention must be sufficient to exert its pharmacological effect. For compositions of the present invention administered through mucosa (e.g., sublingually, buccally, and particularly intranasally), the amount must not exceed about 100 mg in a single dose. The actual dosage of the relevant active ingredients mentioned above includes those dosages known in the art and described for drugs discussed in, for example, Martindale - The Complete Drug Reference, 38th edition, Pharmaceutical Press, London (2014) and the literature mentioned therein (all relevant disclosures in the literature are incorporated herein by reference). However, compared to prior art compositions comprising the same active ingredient, it can be found that the compositions of the present invention exhibit good bioavailability and / or rapid absorption, thereby causing a faster onset and / or higher plasma concentration.

[0220] It was found that the compositions of the present invention may in this respect exhibit unexpectedly good bioavailability and absorption rate compared to corresponding compositions not comprising eg alkyl saccharides and / or comprising different excipients known to act as surfactants.

[0221] In this regard, the pharmacologically appropriate amount of the active ingredient in the composition of the present invention may be lower than those mentioned in the literature (see above). Nevertheless, such amounts can be determined by those skilled in the art and may vary depending on the type and severity of the condition to be treated and the amount most suitable for an individual patient. This may also vary depending on the nature of the formulation and the type and severity of the condition to be treated, as well as the age, weight, sex, renal function, liver function and response of the specific patient to be treated.

[0222] Depending on the efficacy of the active ingredient, and according to the final dosage form intended to be used, the total amount of the active ingredient that can be used in the composition of the present invention can be in the range of about 0.0002 wt %, for example, about 0.001 wt %, for example, about 0.01 wt %, including about 0.1 wt % (for example, about 1 wt %, about 2 wt % or about 5 wt %), for example, about 10 wt % (for example, about 20 wt %) up to about 95 wt %, for example, about 75 wt %, for example, about 50 wt %, for example, about 40 wt %, based on the gross weight of the composition. This is independent of the number of the respective doses (which should be the same) of the composition initially present in the drug delivery member of the present invention.

[0223] For transmucosal, including buccal, sublingual, or preferably intranasal, administration, suitable dosages of the active ingredient (calculated as free acid / base) per unit dose are in the range of about 1 μg to about 100 mg (e.g., about 80 mg), for example, between about 1 mg and about 60 mg (e.g., about 3 mg, e.g., about 10 mg to about 50 mg), depending on the active ingredient used.

[0224] For certain specific active ingredients mentioned above, specific dosages useful in the compositions of the present invention when administered transmucosally, including buccally, sublingually, or preferably intranasally (calculated in each case as the free (acid / base) compound) include: for lurasidone, about 10 to about 100 mg; for blonanserin, about 2 to about 10 mg; for olanzapine, about 5 to about 20 mg; for carbamazepine, about 10 to about 100 mg; for lorazepam, about 0.5 to about 4 mg; for cannabidiol, about 10 to about 100 mg; for loxapine, about 5 mg to about 50 mg (e.g., about 7 to about 12 mg, e.g., about 10 mg); for apomorphine, about 1 mg to about 10 mg; for ketorolac, about 10 mg to about 40 mg; for aripiprazole, about 1 mg to about 30 mg; for haloperidol, about 1 mg to about 10 mg (e.g., about 2 mg to about 5 mg); for ziprasidone, about 10 to about 100 mg; for asenapine, about 2.5 mg to about 20 mg (e.g., about 5 and about 10 mg); for epinephrine, about 0.1 mg to about 5 mg (e.g., about 1 mg); for almotriptan, about 5 mg to about 15 mg; for eletriptan, about 10 mg to about 40 mg; for sumatriptan, about 5 mg to about 15 mg (e.g., about 11 mg); and for zolmitriptan, about 1 mg to about 10 mg, for example, about 2 mg to about 7.5 mg (e.g., about 2.5 mg and about 5 mg). In addition, for aspirin, suitable specific transmucosal (e.g., buccal, sublingual, or preferably intranasal) doses (calculated as the free acid compound) that can be used in the compositions of the present invention are in the range of about 5 to about 100 mg.

[0225] For other forms of administration (e.g. by injection or oral administration), appropriate dosages of the active ingredient per unit dose (calculated as free acid / base) are in the range of about 1 μg to about 500 mg (e.g. about 400 mg), e.g. between about 1 mg and about 300 mg (e.g. about 3 mg, e.g. about 10 mg to about 200 mg), depending on the active ingredient used.

[0226] For the active ingredients mentioned above, specific dosages useful in the compositions of the present invention when administered by a route other than transmucosal administration (in each case calculated as the free (acid / base) compound) include: for lurasidone, about 10 to about 100 mg; for blonanserin, about 2 to about 10 mg; for olanzapine, about 5 to about 20 mg; for carbamazepine, about 10 to about 100 mg; for lorazepam, about 0.5 to about 4 mg; for cannabidiol, about 10 to about 100 mg; for loxapine, about 5 mg to about 50 mg (e.g., about 7 to about 12 mg, e.g., about 10 mg); for apomorphine, about 1 mg to about 10 mg; for ketorolac, about 10 mg to about 40 mg; for aripiprazole, about 1 mg to about 30 mg; for haloperidol, about 1 mg to about 10 mg (e.g., about 2 mg to about 5 mg); for ziprasidone, about 10 to about 100 mg. for asenapine, about 2.5 mg to about 20 mg (e.g., about 5 and about 10 mg); for epinephrine, about 0.1 mg to about 5 mg (e.g., about 1 mg); for almotriptan, about 10 mg to about 50 mg (e.g., about 12.5 mg to about 40 mg); for eletriptan, about (oral dose 30 mg to about 60 mg (e.g., about 40 mg); for sumatriptan, about 5 mg to about 15 mg (e.g., about 11 mg); for zolmitriptan, about 1 mg to about 10 mg, e.g., about 2 mg to about 7.5 mg (e.g., about 2.5 mg and about 5 mg); and for aspirin, about 5 to about 500 mg, e.g., about 10 mg to about 300 mg.

[0227] According to three other aspects of the present invention, there are provided:

[0228] • a composition of the invention suitable for treating a condition for which the at least one pharmaceutically active compound comprised in the composition is useful (e.g. by transmucosal, e.g. intranasal, administration of the composition);

[0229] • use of a composition of the invention for the manufacture of a medicament (e.g. transmucosal, e.g. intranasal) for the treatment of a condition for which the at least one pharmaceutically active compound comprised in the composition is useful; and

[0230] •A method of treating a condition for which the at least one pharmaceutically active compound included in the composition of the invention is useful, the method comprising administering the composition of the invention to a patient suffering from or susceptible to the condition (e.g., transmucosal, e.g., intranasal).

[0231] In this regard, the compositions of the invention comprising an antipsychotic drug, such as those mentioned above, are suitable for the treatment of psychosis.There is therefore provided a composition of the invention comprising at least one antipsychotic drug suitable for the treatment of psychosis.

[0232] Psychosis should be understood to include a broad range of clinical psychiatric conditions, including mood disorders such as schizophrenia; schizoaffective disorder; bipolar disorder; agitation associated with schizophrenia and / or bipolar disorder; depression (e.g., major depressive disorder) and / or anxiety disorders; obsessive-compulsive disorder (OCD) and / or attention deficit hyperactivity disorder (ADHD); physical problems such as continuous hiccups, balance problems, and nausea; or agitation and psychotic experiences in dementia. Preferred conditions include schizophrenia and schizoaffective disorder and their symptoms (e.g., delusions and hallucinations), bipolar disorder and its symptoms (e.g., depression and mania), and OCD / ADHD.

[0233] Antipsychotic drugs suitable for treating schizophrenia and schizoaffective disorder include first-generation antipsychotics, such as chlorpromazine, fluphenazine, haloperidol, perphenazine, thioridazine, thiothixenethioxanthene, or trifluoperazine; and second-generation antipsychotics, such as aripiprazole, asenapine, cariprazine, clozapine, olanzapine, paliperidone, paliperidone palmitate, quetiapine, risperidone, ziprasidone, blonanserin, lurasidone, and specifically loxepin. Thus, the present invention provides a composition of the present invention comprising one or more of the aforementioned antipsychotics suitable for treating schizophrenia, and specifically blonanserin, lurasidone, olanzapine, and more specifically loxepin. Carbamazepine can also be used to treat schizophrenia.

[0234] Antipsychotic drugs suitable for treating bipolar disorder include aripiprazole, asenapine, cariprazine, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, and specifically lurasidone. Carbamazepine can also be used to treat bipolar disorder.

[0235] Antipsychotic drugs suitable for treating ADHD include quetiapine, risperidone, and in particular olanzapine. Accordingly, the present invention provides a composition of the invention comprising one or more of quetiapine, risperidone, and in particular olanzapine, suitable for treating ADHD.

[0236] Antipsychotic drugs suitable for treating agitation associated with schizophrenia and / or bipolar disorder include loxapine, olanzapine, aripiprazole, haloperidol, ziprasidone, and asenapine.

[0237] Anticonvulsant drugs, such as any of the benzodiazepines (e.g., lorazepam) and carboxamides (e.g., carbamazepine) mentioned above, and certain cannabinoid drugs (e.g., cannabidiol) can be used to treat epileptic disorders, including epilepsy, epileptic seizure disorder, and the like.

[0238] Benzodiazepines (eg, lorazepam) may also be useful as sedatives and / or for treating anxiety disorders.

[0239] Compositions of the invention comprising peptides such as those mentioned above are useful, depending on the peptide included in such compositions, for treating a wide range of clinical conditions, including diabetes, diabetes insipidus, obesity, bedwetting, hemophilia A, von Willebrand disease, high blood urea levels, nocturnal urination, bleeding disorders, prostate cancer, breast cancer, polycystic disease, hypotension, diarrhea, endometriosis, or uterine fibroids.

[0240] Examples of polycystic diseases include polycystic kidney disease, polycystic liver disease, or polycystic ovary syndrome. Hypotension includes orthostatic hypotension and postprandial hypotension. Diarrhea may include intractable diarrhea, also known as refractory diarrhea. Diarrhea may also be secretory diarrhea, which may be chronic; may be caused by dumping syndrome, short bowel syndrome, chemotherapy, radiation therapy, HIV / AIDS, and / or neuroendocrine tumors (e.g., carcinoid or vasoactive intestinal peptide (VIP)-secreting adenomas), or due to graft-versus-host disease, irritable bowel syndrome (IBS), inflammatory bowel disease (which includes conditions that cause inflammation of the intestine, such as Crohn's disease and ulcerative colitis), celiac disease (also known as celiac sprue), chronic pancreatitis, diverticular disease, endocrine disorders, vasculitis, postoperative diarrhea, carbohydrate malabsorption syndrome, amyloidosis, lactose intolerance, small intestinal bacterial overgrowth, hepatobiliary disorders, luminal bile acid deficiency, bile acid malabsorption, dysregulated gastric emptying, pancreatic exocrine insufficiency or neoplasia (e.g., intestinal cancer), or may be due to traumatic infectious diseases and / or bacterial endotoxins (e.g., cholera).

[0241] Peptides useful in the compositions of the present invention that are suitable for treating hormone-responsive cancers, such as prostate cancer or breast cancer, and estrogen-dependent conditions, such as endometriosis or uterine fibroids, include leuprolide / leuprorelin. Peptides useful in the compositions of the present invention that are suitable for treating type 2 diabetes are amylin and fragments, exendin and fragments, insulin-like growth factor and fragments, gastric inhibitory polypeptide and fragments, chromogranin A, pancreatic inhibin, insulin C-peptide, glucagon and glucagon-like peptides or gastric hormone peptides, preferably GLP-1 receptor agonists, including semaglutide, liraglutide, albiglutide, or dulaglutide. Peptides useful in the compositions of the present invention that are suitable for treating obesity are peptides that act as melanocortin receptor modulators or as GLP-1 receptor agonists. Peptides that can be used in the composition of the present invention and are suitable for treating endometriosis or uterine fibroids are peptides that act as GnRH agonists, including buserelin, gonarelin, goserelin, histrelin, leuprorelin, nafarelin or triptorelin, and peptides that act as GnRH antagonists, such as abarelix, cetrorelix, degarelix, ganirelix, elagolix, relagolix and teverelix. Peptides that can be used in the composition of the present invention and are suitable for treating polycystic disease or hypotension or intractable diarrhea or neuroendocrine tumors or carcinoid syndrome are peptides that act as SRIF agonists, such as octreotide, pasireotide or lanreotide.

[0242] In particular, peptides useful in the compositions of the invention that are suitable for treating urological disorders are peptides that selectively bind to the V-2 receptor, such as desmopressin. Accordingly, the present invention provides a composition of the invention comprising desmopressin that is suitable for treating urological disorders.

[0243] Compositions of the invention comprising bisphosphonates such as alendronate, clodronate, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate and zoledronate may be useful in treating osteoporosis, including postmenopausal osteoporosis, in order to reduce the risk of fractures.

[0244] Compositions of the present invention comprising an anesthetic and / or sedative, such as those mentioned above, are suitable for anesthesia and / or sedation. Thus, the present invention provides a composition of the present invention comprising an anesthetic suitable for anesthetizing a subject and / or treating pain; and a composition of the present invention comprising a sedative suitable for sedating a subject and / or treating pain or anxiety. In particular, a composition of the present invention comprising ketamine suitable for sedating a subject and / or treating pain or anxiety is provided.

[0245] Compositions of the invention comprising an antidepressant, such as those mentioned above, and in particular allopregnanolone (postpartum depression), esketamine and ketamine, are suitable for the treatment of depression. The present invention therefore provides a composition of the invention comprising an antidepressant suitable for the treatment of depression or a depressive disorder.

[0246] The composition of the invention comprising an antihistamine, such as those mentioned above, is suitable for treating inflammation and / or allergy. Accordingly, the present invention provides a composition of the invention comprising an antihistamine, which is suitable for treating inflammation and / or allergy.

[0247] Compositions of the invention comprising analgesics, such as those mentioned above, are useful in the treatment of pain. In particular, compounds useful in the compositions of the invention for such treatment include nonsteroidal anti-inflammatory drugs, such as ketorolac.

[0248] Compositions of the present invention comprising adrenergic receptor modulators, such as those mentioned above, are suitable for treating a variety of conditions, depending on the compound included in such compositions. In particular, compositions of the present invention comprising epinephrine (adrenaline) are suitable for treating, for example, allergic reactions, including extreme allergic reactions, such as anaphylactic shock, to, for example, insect stings / bites, foods, drugs, and / or other substances. Thus, the present invention provides a composition of the present invention comprising epinephrine that is suitable for treating allergic reactions, such as anaphylactic shock.

[0249] Compositions of the invention comprising dopamine-stimulating receptors, such as those mentioned above, are suitable for treating a variety of conditions, depending on the compound included in such compositions. In particular, compositions of the invention comprising apomorphine are suitable for treating, for example, Parkinson's disease, and in particular, for treating so-called "wearing-off" events (that is, motor fluctuations, such as muscle stiffness, loss of muscle control, etc.) in patients with advanced Parkinson's disease and / or receiving levodopa therapy. Thus, the present invention provides a composition of the invention comprising apomorphine that is suitable for treating Parkinson's disease, for example, for treating muscle stiffness and / or loss of muscle control in patients with Parkinson's disease.

[0250] Compositions of the invention comprising serotonin-stimulating receptors, such as those mentioned above, are suitable for treating a variety of conditions, depending on the compound included in such compositions. In particular, compositions of the invention comprising any of the triptans mentioned above are suitable for treating migraine. Thus, the present invention provides a composition of the invention comprising a triptan (e.g., almotriptan, eletriptan, or alternatively, dilizatriptan, zolmitriptan, sumatriptan, frovatriptan, or naratriptan) suitable for treating migraine.

[0251] The composition of the present invention comprises one or more of the cardiovascular drugs mentioned above, wherein the cardiovascular drugs include one or more of the following:

[0252] • Anticoagulants (Factor Xa inhibitors or platelet inhibitors);

[0253] • alpha- and beta-blockers, ACE inhibitors, angiotensin II receptor antagonists, neprilysin inhibitors, calcium channel blockers; diuretics, vasodilators, endothelin receptor antagonists, digitalis preparations, and other hypertension treatments; and

[0254] • HMG-CoA reductase inhibitors,

[0255] The composition of the present invention is suitable for preventing or treating various cardiovascular diseases, and comprises:

[0256] • Conditions characterized by blood clots (including stroke, transient ischemic attack, cardiac arrest, deep vein thrombosis, pulmonary embolism, etc.),

[0257] • Conditions characterized by high blood pressure (including hypertension, angina, congestive heart failure, etc.); and

[0258] • Coronary heart disease (including high levels of cholesterol and other lipids such as low-density lipoprotein and triglycerides, atherosclerosis, etc.

[0259] According to a further aspect of the present invention, there is provided a composition of the present invention comprising:

[0260] • one or more of the antiviral agents mentioned above, the composition being suitable for treating viral (e.g. hepatitis C) infection;

[0261] • One or more of the above-mentioned erectile dysfunction drugs, the composition is suitable for treating female sexual dysfunction, such as erectile dysfunction, in men.

[0262] The compositions of the present invention may also include, or may be administered with, one or more alkyl sugars. Alkyl sugars that may be used include alkyl glycosides, which may be defined as any sugar linked by a bond to an alkyl group, such as C 7-18Alkyl glycosides. Thus, the alkyl glycosides may include alkyl maltosides (e.g., dodecyl maltoside), alkyl glucosides, alkyl sucrosides, alkyl thiomaltosides, alkyl thioglucosides, alkyl thiosucroses, and alkyl maltotriosides. However, we prefer that the alkyl sugar be a sugar ester.

[0263] Sugar esters useful in the compositions of the present invention 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 in particular one or more sucrose esters.

[0264] Sucrose esters useful in the compositions of the present invention have a hydrophilic-lipophilic balance (HLB) value between 6 and 20. The term "hydrophilic-lipophilic balance" is a technical term well understood by those skilled in the art (see, for example, "The HLB System: A Time-Saving Guide to Emulsifier Selection," published by ICI Americas Inc. in 1976 (revised in 1980), which provides methods for determining HLB values ​​in Chapter 7 (pp. 20-21). The longer the fatty acid chain and the higher the degree of esterification in the sucrose ester, the lower the HLB value. Preferably, the HLB value is between 10 and 20, and more preferably between 12 and 20.

[0265] Sucrose esters therefore include C 8-22 Saturated or unsaturated fatty acid esters, preferably saturated fatty acid esters, and preferably C 10-18 Fatty acid esters, and most preferably C 12 Fatty acid esters. 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 fatty acid of this type is lauric acid. Commercially available sucrose esters include those sold under the trademarks Surfhope® and Ryoto® (Mitsubishi-Kagaku Foods Co., Ltd., Japan).

[0266] Sucrose esters can be diesters or monoesters of fatty acids, preferably monoesters, such as sucrose monolaurate. Those skilled in the art will understand that the term "monolaurate" refers to the monoester of lauric acid, and the terms "lauric acid ester" and "laurate" have the same meaning and can therefore be used interchangeably. Commercially available sucrose monolaurate products are sometimes also referred to as "sucrose laurate." Commercially available sucrose monolaurate (or sucrose laurate) products that may contain small amounts of diesters and / or higher sucrose esters, and slight amounts of other sucrose esters and free sucrose, such as Surfhope® D-1216 (Mitsubishi-Kagaku Foods Co., Ltd., Japan), are suitable for use in the present invention. Those skilled in the art will understand that any reference to a particular sucrose ester herein includes commercially available products comprising the sucrose ester as a major component.

[0267] Preferably, the sucrose ester contains only one sucrose ester, meaning that the single sucrose ester (e.g., a commercially available sucrose ester product) contains a single sucrose ester as the major component (commercially available products may contain impurities, e.g., a monoester product may contain small amounts of diesters and / or higher esters, such products may be considered to "contain only one sucrose ester" in the context of the present invention). As used herein, the term "major component" is understood to refer to the major component (e.g., greater than about 50%, e.g., about 70% weight / weight or volume / volume) of a mixture of sucrose esters, such as a typical commercially available surfactant product, which is typically sold with a range of ester compositions.

[0268] An especially preferred sucrose ester is sucrose monolaurate.

[0269] Whether included in the composition of the present invention or included in the final dosage form of one or more compositions of the present invention, the amount of alkyl saccharide that can be used can be in the range of about 0.1 wt % to about 10 wt %, such as about 0.5 wt % to about 5 wt %, preferably about 0.75 wt % to about 3 wt % (e.g. to about 2 wt %, such as about 1 wt %), based on the total weight of the composition.

[0270] Furthermore, optionally additional excipients may be used in or administered together with the compositions of the present invention comprising one or more (other) surfactants. Surfactants that may be mentioned include polyethylene oxide (e.g. Myr TM ), including polyethylene glycol 8 stearate (Myrj TM S8), polyethylene glycol 32 stearate (Gelucire® 48 / 16), polyethylene glycol 40 stearate (Myrj TM S40), polyethylene glycol 100 stearate (Myrj TMS100) and polyethylene glycol 15 hydroxystearate (Kolliphor® HS 15), polyoxyethylene alkyl ethers (such as Brij TM ), including polyethylene glycol hexadecyl ether (e.g. Brij TM CS12, CS20 and CS25), polyethylene glycol lauryl ether (such as Brij TM L9 and L23) and polyethylene glycol stearyl ether (e.g. Brij TM S10 and S20) and polyoxyglycerol esters (e.g., Gelucire®), including lauroyl polyoxyglycerol (Gelucire® 44 / 14) and stearyl polyoxyglycerol (Gelucire® 50 / 13), sorbitan esters (e.g., Span™), including sorbitan monopalmitate (Span™ 40) and sorbitan monostearate (Span™ 60), polysorbates (Tweens TM ), 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-olein, 2-arachidonin, glyceryl monolaurate, glyceryl monomyristate, glyceryl monopalmitate, glyceryl hydroxystearate, and preferably glycerol monostearate, glycerol monooleate (e.g., Cithrol®) and glycerol monocaprylate (e.g., Capmul®).

[0271] Other optional additional ingredients (excipients) that can be included in or administered with the compositions of the present invention include isotonic and / or osmotic agents (e.g., sodium chloride), sterols (or steroids), such as cholesterol and plant sterols (e.g., campesterol, sitosterol, and stigmasterol); antioxidants (e.g., sodium metabisulfite, or alternatively, α-tocopherol, ascorbic acid, potassium ascorbate, sodium ascorbate, ascorbyl palmitate, butylated hydroxytoluene, butylated hydroxyanisole, lauryl gallate, octyl gallate, propyl gallate, ethyl oleate, monothioglycerol, vitamin E polyethylene glycol succinate, or vinyl alcohol); chelating agents. (Complexing) agents (e.g., edetic acid (EDTA), citric acid, tartaric acid, malic acid, maltitol, and galactose, including salt forms of any of these agents); preservatives (e.g., benzalkonium chloride, or alternatively, benzyl alcohol, boric acid, parabens, propionic acid, phenol, cresol, or xylitol); viscosity modifiers or gelling agents (e.g., cellulose derivatives, including hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and the like, starches and modified starches, colloidal silicon dioxide, aluminum metasilicate, polycarbophils (e.g., Noveon®), carbomers (e.g., Carbopol®), and polyvinylpyrrolidone); mucosal Adhesive polymers such as carboxymethylcellulose, modified cellulose gum, and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately cross-linked starch, modified starch, and sodium starch glycolate; cross-linked polyvinylpyrrolidone, acrylic acid polymers such as carbomer and its derivatives (Polycarbophyl, Carbopol®, etc.); polyethylene oxide (PEO); polyglucosamine (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; tannin gum; guar gum; poly-(methyl vinyl ether / maleic anhydride); and cross-linked carboxymethylcellulose (e.g., cross-linked sodium bicarboxymethyl cellulose); pH buffers (e.g. citric acid, maleic acid, malic acid or glycine or their corresponding salts, e.g. sodium citrate); colorants; penetration enhancers (e.g. isopropyl myristate, isopropyl palmitate, pyrrolidone or tricaprylin); other lipids (neutral and polar); aromatic carboxylic acids, e.g. benzoic acid optionally substituted with one or more groups selected from the group consisting of methyl, hydroxyl, amino and / or nitro groups, e.g. toluic acid or salicylic acid; and, if appropriate, flavorings (e.g. lemon, peppermint powder, or preferably menthol), sweeteners (e.g. neohesperidin, acesulfame K, or preferably sucrose) and dyes.

[0272] The total amount of such "additional" excipients (including surfactants which are not alkyl saccharides present in the composition of the invention) which may themselves comprise the composition of the invention (regardless of the dosage form in which it is comprised) may also be up to about 15% by weight (e.g. about 10% by weight), for example up to about 5% by weight, based on the total weight of the composition.

[0273] For example, if one or more additional excipients are fillers or carriers in a tablet, film, or the like, the total amount of such "additional" excipients that can be included in a final dosage form comprising one or more compositions of the invention can be up to about 99.99%, such as up to about 99.9%, including up to about 99%, such as up to about 90%.

[0274] Those skilled in the art will appreciate that if any additional optional ingredients are included in the compositions of the present invention, the nature of those ingredients and / or the amounts in which those ingredients are included should not have an adverse effect on the Tg of the composition, for the reasons described above. In this regard, such optional ingredients may be incorporated into the spray drying process (that is, mixed 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.

[0275] According to another aspect of the present invention, there is provided a composition of the invention suitable for use in medicine (human and veterinary medicine), and therefore suitable for use in the treatment of a patient in need of medical treatment for a condition for which a relevant active ingredient is known to be useful for treatment.

[0276] "Treatment of such conditions" includes prevention or diagnosis of such conditions, as well as therapeutic, symptomatic and palliative treatment.

[0277] The compositions of the present invention may be administered by any suitable administration means known to those skilled in the art. The compositions of the present invention may be administered transmucosally, and in particular intranasally, with the aid of a suitable transnasal applicator or dispenser means capable of administering to the nasal cavity a suitable dose of the active ingredient in the form of one or more compositions of the present invention.

[0278] Thus, suitable nasal administration means and / or applicators should be capable of containing and storing one or more doses of the composition of the present invention itself, or be capable of being connected to a reservoir / container that contains and stores one or more doses of the composition of the present invention, without causing significant loss of the physical and chemical integrity of the composition, including, for example, the ingress of water. In this way, once the applicator device is actuated by the end user (whether this is for single or multiple dose use), the composition will be available, at which point the applicator will deliver the composition (e.g., powder) having the appropriate dose of the active ingredient as defined herein to the individual's nasal mucosa.

[0279] Suitable application members have been described in the prior art. When used with the composition of the present invention, such composition may be loaded into a reservoir attached to or forming part of such an application member, where the composition is held until the application member or dispenser is actuated. Hereinafter, the terms "applicator," "dispenser," "device," "application member," "dispensing member," "applicator," "dispensing device," and "insufflator" are used interchangeably and mean the same thing.

[0280] Such an application member may therefore also comprise a mechanism for expelling the powder formulation from the reservoir through an outlet member comprising any kind of object sized to be placed in a human nostril, such as a nozzle of appropriate shape.

[0281] Thus, the applicator should be able to provide a reproducible and sufficient amount of the powder formulation in a single administration step (and in such a way that no "priming" of the device is required) so that a therapeutic dose of the active ingredient will be provided.

[0282] Nasal administration / inhalation devices that can be used to administer the compositions of the present invention in powder form may include multi-dose administration devices that can be adjusted based on techniques known in the art of delivering active ingredients to the lungs, such as metered dose inhalers (MDIs), dry powder inhalers (DPIs; including lower, medium and higher resistance DPIs) and soft mist inhalers (SMIs).

[0283] In an MDI, the composition of the present invention should be capable of forming a stable suspension when suspended in a solvent typically used therein, such as a propellant having sufficient vapor pressure to form an aerosol upon actuation of the delivery device (e.g., a hydrocarbon, fluorocarbon, hydrofluorocarbon, or mixtures thereof).

[0284] However, if the nasal applicator is a single-dose applicator from which the composition is dispensed after actuation and then discarded after use, suitable administration members or devices for delivering a single dose of the active ingredient include those described in US 6,398,074, US 6,938,798 or US 9,724,713, the relevant disclosures of which are incorporated herein by reference. Figure 1 and Figure 2 are based on US 6,398,074 Figure 1 and Figure 2 ,and Figures 3 to 7 19 to 23 of US 9,724,713. Both are diagrams of applicators that can be used for intranasal administration of the composition of the present invention.

[0285] exist Figure 1In the embodiment of the present invention, the device comprises an upper body / dispenser head 1, which incorporates an outlet channel 40 (that is, part of the "outlet member" as described above) and a gripping member 60 that allows the user to actuate the device. Mounted within the upper body / dispenser head 1 is an assembly, designated by reference numeral 2, which incorporates a reservoir 10 and an air chamber 22 for air 20. This assembly 2 may be produced integrally with the upper body / dispenser head 1. A lower body 3 is also provided so as to be able to slide relative to the upper body / dispenser head 1 and relative to the assembly 2, with the user applying a pushing force on the lower body to actuate the device.

[0286] The reservoir 10 contains a single dose of the composition of the present invention. The reservoir 10 has an air inlet 11 and a product outlet 15. A product retaining device 12 comprising an air-permeable mesh is positioned in the air inlet 11 to retain the product in the reservoir 10 until the composition is dispensed. The product outlet 15 is preferably sealed by a blocking member / ball 16 that is displaced from its blocking position by air flow when the applicator is actuated and the product is dispensed.

[0287] When the user activates the device, pressure is exerted on the push assembly / plunger 25 in such a way that the piston 21 compresses the air 20 contained in the air chamber 22. Since the product holding device 12, which comprises a gas-permeable mesh, is gas-permeable, the compression of the air in the air chamber 22 generates a jet of air that is transferred to the reservoir 10 and thereby applied to the blocking assembly / ball 16 for blocking the product outlet 15.

[0288] The blocking assembly / ball 16 is sized and secured to the reservoir product outlet 15 so that it moves from its blocking position when a minimum predetermined pressure is generated through the reservoir 10 by blasting air 20 .

[0289] The pre-compression generated by the blocking member / ball 16 ensures that when the blocking ball moves from its blocking position, the energy accumulated in the user's hand causes the piston 21 integral with the pushing member / plunger 25 to be pushed in the air chamber 22, thereby generating a powerful jet of air 20, that is, an air flow suitable for finely spraying a dose of the composition of the present invention.

[0290] When this minimum pressure is reached, the ball moves rapidly towards the outlet channel 40 of the device and the air flow generated by the air jet expels substantially the entire dose of the composition of the invention contained in the reservoir 10 .

[0291] Preferably, the diameter of the outlet passage 40 is larger than the diameter of the barrier assembly / ball 16 so as to allow the dose of product to be discharged through the outlet passage 40 by flowing around the barrier assembly / ball 16. Figure 2, which shows the same device after braking, the outlet passage 40 includes means 41 for blocking or securing the blocking assembly / ball 16 to prevent the ball from being ejected from the device as the product is discharged.

[0292] Another example of a composition useful for intranasal administration of the present invention is provided in US 9,724,713 at column 7, line 50 to column 8, line 61 and Figures 19 to 23, which are reproduced herein. Figures 3 to 7 .

[0293] In this embodiment, the reservoir 10 is secured in an upper body / dispenser head 1 comprising a dispenser outlet passage 40 (that is to say part of the "outlet member" as described above), said upper body / dispenser head having a gripping member 60 which allows the user to actuate the device. The radial shoulder 7 (see Figure 4 ) advantageously defines the assembled position of the reservoir 10 in said upper body / dispenser head 1 .

[0294] The mechanical opening system comprises a set of rods, a first rod part 61 and a second rod part 62, wherein when the device is actuated, the second rod part 62 is pushed by the first rod part 61. At the end of their braking stroke, that is to say in the dispensing position, the first and second rod parts 61, 62 cooperate with the blocking member / ball 16, which is spherical, in particular as in the first embodiment described above, to be mechanically ejected from its blocking position.

[0295] In this embodiment, the piston 21 is separate from the first rod portion 61 and slides both relative to the air chamber 22 and relative to the cylindrical surface 614 fastened to the first rod portion 61 . Figure 7 for Figures 3 to 6 A diagrammatic perspective view of an air expeller of the device in its rest position.

[0296] The air cavity 22 can thus be cylindrical and, in its rest position, communicate with the ambient air at a groove or recess 615 formed in the cylindrical surface 614 and cooperating with the piston 21, in particular in its rest position. The piston 21 thus comprises an inner lip 215 which slides in an airtight manner on the cylindrical surface 614 during braking and which, in its rest position, cooperates with the groove or recess 615. The piston 21 also comprises an axial extension 216 cooperating with the top edge 251 of the push member / plunger 25 which moves the piston 21 in the air cavity 22 during braking.

[0297] The retainer member 42 is extended downwardly by an axial extension 43 which comes into contact with the top axial end 610 of the first rod portion 61 during braking.

[0298] Furthermore, in this embodiment, there is no outer body, but only a cover 27 assembled on the bottom axial edge of the air cavity 22 .

[0299] A spring 80 is provided between the radial flange 225 of the air cavity 22 and the components forming the first rod portion 61 and the cylindrical surface 614 in order to automatically return the air expeller to its rest position after braking.

[0300] The operating principle is as follows. Figure 3 In the rest position in , the reservoir 10 is closed in a sealed manner by the retainer member 42 and by the blocking assembly / ball 16. The air expeller is in contact with the atmosphere by cooperating between the inner lip 215 of the piston 21 and the groove or recess 615 of the cylindrical surface 614.

[0301] When it is desired to actuate the device, the user depresses the push assembly / plunger 25. During this initial stroke, the inner lip 215 of the piston leaves the groove or recess 615 to cooperate in an airtight manner with the cylindrical surface 614, thereby closing the air chamber 22. At the same time, the top edge 251 of the push assembly / plunger 25 comes into contact with the axial extension 216 of the piston 21, and the top axial end 610 of the first rod portion 61 comes into contact with the axial extension 43 of the retainer member 42.

[0302] However, the top axial end 621 of the second rod portion 62 is still not in contact with the circular surface 55 of the blocking assembly / ball 16, as shown in FIG. Figure 4 Visible in.

[0303] Continuous braking thus simultaneously moves the piston 21 in the air chamber, thereby compressing the air contained therein, and moves the retaining member 42 away from the position closing the reservoir 10. When the second rod portion 62 contacts the circular surface 55 of the blocking assembly / ball 16, the blocking assembly / ball is mechanically expelled from its closed position, so as to enable the composition to be expelled under the action of the air compressed by the air expeller.

[0304] Allocation location shown in Figure 5 In. Figure 5 As can be seen in FIG, when the composition is expelled under the action of compressed air provided by the air expeller, the retainer member 42 may be separated from the first rod portion 61. In this position, the blocking assembly / ball is expelled from the reservoir 10 to enable the fluid or powder to be dispensed under the action of compressed air. As a result, the blocking assembly / ball 16 is trapped in the spline 33 of the upper body / dispenser head 1, which specifically prevents any risk of the blocking assembly / ball 16 being expelled from the upper body dispenser head 1.

[0305] When the user releases the device, Figure 6 As shown in , the compressed spring 80 during braking returns the first rod portion 61 to its resting position. This generates suction, thereby sucking the blocking assembly / ball 16 and the retainer component 42 back to their closed position, or close to their closed position. This therefore blocks the path of new suction to avoid contaminating the air expeller when it automatically returns to its resting position while the empty reservoir is still assembled on the air expeller. However, the piston 21 remains in its dispensing position due to friction with the air chamber 22 and the suction generated in the reservoir 10, causing the cylindrical surface 614 to slide on the inner lip 215 of the piston until the inner lip again cooperates with the groove or recess 615. At this point, the air chamber 22 is once again connected to the ambient air and no longer generates suction due to returning to the resting position. Therefore, the piston 21 is also brought to its resting position. This makes it possible to close the reservoir after use.

[0306] Optionally, the unit formed by the upper body / dispenser head 1 and the empty reservoir 10 can be removed from the air expeller and replaced by a new unit comprising a full reservoir.

[0307] Suitable applicator devices that can be used include those available from Aptar Pharma, France (UDS Monopowder). Other examples of applicator devices that can be used in conjunction with the compositions of the present invention (particularly those in powder form) include U.S. Patent Application No. US 2011 / 0045088A, U.S. Patent No. US 7,722,566 (see, e.g., Figure 1 and 7 ) and those described in US 5,702,362 and international patent application WO 2014 / 004400, the relevant disclosures of which are incorporated herein by reference.

[0308] According to another aspect of the present invention, there is provided a method for manufacturing an applicator device comprising a composition of the present invention, wherein the method comprises the step of loading the composition into a reservoir within or attached to the applicator device.

[0309] According to another aspect of the present invention, there is provided an applicator and / or dispenser device comprising one or more compositions of the present invention in powder form, said applicator or device being actuable one or more times to deliver, on each such actuation, one or more compositions of the present invention, each comprising an appropriate dose of the active ingredient, said applicator / dispenser device comprising:

[0310] an outlet through which at least one composition is dispensed;

[0311] means for externally generating a force (e.g., air flow) when a user brakes the device;

[0312] at least one (optionally replaceable) reservoir containing said one or more compositions of the invention, said reservoir being placed or capable of being placed in direct or indirect communication with the dispenser outlet;

[0313] a removable, optionally reversible, sealing member in the device and / or reservoir for retaining the one or more compositions within the reservoir until the composition is dispensed;

[0314] a mechanical opening system cooperating with the sealing member so that when the device is actuated, the single composition of the invention is mechanically expelled by the drive member; and

[0315] Optionally, a mechanism for resealing the device and / or reservoir to retain more composition within the reservoir until more composition is dispensed.

[0316] According to yet another aspect of the present invention, there is provided an applicator and / or dispenser device comprising a single dose of a composition of the present invention, suitable for dispensing said composition, said applicator / dispenser device comprising:

[0317] Distributor outlet;

[0318] an air expeller for generating an air flow when the device is actuated, the air expeller comprising a piston sliding in an air cavity between a rest position and a dispensing position;

[0319] the piston sliding in the air chamber in an airtight manner;

[0320] at least one reservoir containing a dose of a composition of the invention, said reservoir comprising an air inlet connected to said air expeller;

[0321] a composition outlet connected to the dispenser outlet;

[0322] the air inlet, which includes a movable sealing member (e.g., a retainer component) for retaining the composition in the reservoir until the composition is dispensed;

[0323] a composition outlet closed by a blocking member mounted in the composition outlet of the reservoir;

[0324] said device further comprising a mechanical opening system cooperating with said blocking assembly to mechanically eject said device from its closed position when said device is actuated; and

[0325] The piston of the air expeller, when in the rest position, cooperates with the air chamber in a non-airtight manner.

[0326] In the following aspect of the present invention, preferably:

[0327] (i) the air chamber within which the piston slides in an airtight manner is substantially cylindrical;

[0328] (ii) the barrier assembly is forcibly installed in the composition outlet of the reservoir;

[0329] (iii) the air cavity is in communication with the atmosphere in the rest position; and / or

[0330] (iv) The piston comprises an inner lip adapted to cooperate with a cylindrical surface, the cylindrical surface comprising a groove cooperating in a non-gas-tight manner with the inner lip of the piston in the rest position.

[0331] Such nasal applicators or dispensing devices are capable of providing an appropriate and reproducible powder spray pattern and / or plume geometry, thereby enabling effective delivery of the powder to the nasal cavity (eg, nostrils).

[0332] In the compositions of the present invention, the average particle size can be expressed as a mean diameter based on weight, number, or volume. As used herein, those skilled in the art will understand that the term "mean diameter based on weight" includes the average particle size being characterized and defined by a particle size distribution by weight, that is, wherein the existing fraction (relative amount) in each size class is defined as a weight fraction as obtained by, for example, sieving (e.g., wet sieving). The term "mean diameter based on volume" is similar in meaning to the mean diameter based on weight, but those skilled in the art will understand that it includes the average particle size being characterized and defined by a particle size distribution by volume, that is, wherein the existing fraction (relative amount) in each size class is defined as a volume fraction as measured by, for example, laser diffraction. As used herein, those skilled in the art will understand that the term "mean diameter based on number" includes the average particle size being characterized and defined by a particle size distribution by number, that is, wherein the existing fraction (relative amount) in each size class is defined as a number fraction as measured by, for example, microscopy. Other instruments well known in the art may be used to measure particle size, such as equipment sold by, for example, Malvern Instruments Ltd. (Worcestershire, UK), Sympatec GmbH (Clausthal-Zellerfeld, Germany), and Shimadzu (Kyoto, Japan).

[0333] Although particle size is not (or rather may not be) critical when the compositions of the invention are formulated for administration, e.g., orally, topically, to the mouth, eye, or other mucous membranes, or by injection or infusion, the volume-based mean diameter (VMD) of the powder compositions of the invention will typically be in the range of about 0.2 μm, e.g., about 0.5 μm (e.g., about 1 μm) up to about 1,000 μm (e.g., up to about 500 μm, e.g., about 400 nm or about 500 nm), and an appropriate particle size range can be selected based on the dosage form intended to include such a composition.

[0334] However, those skilled in the art will appreciate that to allow for effective intranasal administration, the volume-based mean diameter (VMD) of the powder will typically be in the range of about 5 μm to about 300 μm (e.g., up to about 200 μm). Depending on the applicator device used, the VMD may be in the range of about 10 μm to about 100 μm, for example, about 20 μm to about 60 μm.

[0335] Preferred particle size distributions for intranasal drug delivery may also include those wherein D10 is greater than about 3 μm and less than about 75 μm (e.g., up to about 50 μm), such as greater than about 10 μm, and D90 is between about 80 μm and about 1,000 μm (e.g., about 500 μm), such as less than about 100 μm. One skilled in the art will understand that the parameter "D10" (or "Dv(10)") means the size (or diameter) in the particle size distribution that comprises less than 10% of the total volume of the material in the sample. Similarly, "D90" (or "Dv(90)") means the size that comprises less than 90% of the material.

[0336] The powder having a particle size distribution and VMD within the above ranges includes the bulk VMD and / or the emitted VMD, that is to say the particle size distribution when initially loaded into the device and / or when discharged therefrom, respectively.

[0337] 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.

[0338] Preferred particle shapes include spherical or substantially spherical, by which we mean 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 radius variation (measured from the center of gravity to the particle surface) of no more than about 50% of the average value, such as no more than about 30% of the value, such as no more than about 20% of the value in at least about 90% of the particles.

[0339] However, the particles can be of any shape, including irregular shapes (e.g., "raisin" shapes), needle-shaped, disc-shaped, or dice-shaped particles. For non-spherical particles, the size can be indicated as the size of a corresponding spherical particle having, for example, the same weight, volume, or surface area.

[0340] The spray angle of the powder composition of the present invention emitted (dispensed) from the nasal applicator and / or dispenser device should preferably be less than about 90°.

[0341] When the word "about" is used herein in the context of quantities, e.g., absolute quantities, such as doses, weights, volumes, sizes, diameters, aspect ratios, angles, etc., or relative quantities (e.g., percentages) of individual ingredients in a composition or component thereof (including concentrations and ratios), time frames, and parameters such as temperature, pressure, relative humidity, etc., it is understood that such variables are approximate and, therefore, may vary from the actual numerical values ​​specified herein by ±10%, e.g., ±5%, and preferably ±2% (e.g., ±1%). This is true even if such numerical values ​​are first expressed as a percentage (e.g., "about 10%" may mean approximately the numerical value 10 ± 10%, i.e., any value between 9% and 11%).

[0342] The compositions of the present invention have the advantage of being able to be stored over a wide range of temperatures. Thus, the compositions of the present invention can withstand low temperatures (e.g., below freezing) without affecting the amount of active ingredient that can be administered to an individual. Furthermore, the compositions of the present invention may have the advantage of being physically and chemically more stable at higher temperatures than related prior art compositions.

[0343] The compositions of the present invention may also have the further advantage that they provide a higher bioavailability of the active ingredient compared to prior art compositions. The compositions of the present invention may provide this higher bioavailability and faster absorption than such prior art and / or commercially available compositions, which will likely result in a faster onset of action and thus meet a significant medical need.

[0344] The compositions, pharmaceutical formulations, uses and methods described herein may also have the following advantages: in treating conditions where the relevant active ingredients are known, they may be more convenient, more effective, less toxic, have a broader spectrum of activity, be more potent, produce fewer side effects, have less inter-patient variability, or may have other useful pharmacological properties compared to similar formulations or methods (therapies) known in the prior art, whether administered transmucosally, e.g., intranasally, or otherwise suitable for treating those conditions.

[0345] The present invention is described below by way of example with reference to the accompanying drawings, but is in no way limiting thereof: Figures 1 to 7A diagram showing an actuator device that can be used to dispense the composition of the present invention, and Figures 8 to 11 Presented are plasma concentration-time profiles from a pharmacokinetic study conducted in dogs in which intranasally administered compositions of the invention comprising different active ingredients were compared to the plasma concentration-time profiles of the same active ingredients delivered by a different route of administration.

[0346] Example 1

[0347] Spray-dried epinephrine (Adrenaline) formulation

[0348] Epinephrine tartrate (0.729 g; Fisher Scientific, Sweden) as well as α-D-lactose monohydrate (0.500 g; DFE Pharma, Germany), maltodextrin (Glucidex IT 12 DE; 1.247 g; Roquette, France), and sucrose monolaurate D-1216 (0.025 g; Mitsubishi-Kagaku Foods Corporation, Japan) were dispensed (2.50 g in total) into a glass flask and dissolved in MQ-water (47.50 g) by stirring at room temperature.

[0349] The resulting mixture was fed into a spray dryer (ProCepT, Belgium) equipped with an ultrasonic nozzle operating at 25 kHz. The spray dryer feed rate was set to 3.0 g / min, the inlet temperature was set to 180°C, the gas flow rate was set to 300 L / min, and the cyclone gas was set to 1.5 bar.

[0350] The resulting spray-dried powder was collected as a fine, dry, free-flowing powder with a nominal dose of 4 mg of epinephrine free base in 25 mg of powder.

[0351] The particle size distribution (PSD) of the powders was analyzed by dry powder laser diffraction. The samples were dispersed using an Aero S dry dispersion unit (compressed air at 0.5 bar) (both Malvern Panalytical, UK) before sizing using a Particle Size Analyzer 3000 laser diffraction sensor, as shown in Table 1 below.

[0352] Table 1

[0353]

[0354] The PSD of the epinephrine formulation is well within a profile suitable for nasal administration.

[0355] The assay and purity of the spray-dried epinephrine formulation were determined by HPLC / UV analysis. The assay was 99.7% and the percentage of total related substances (i.e., impurities and degradation products) (RS%) was less than 0.29%.

[0356] Example 2

[0357] Spray-dried apomorphine formulation

[0358] Using the general procedure described in Example 1 above, an aqueous solution (50.00 g) containing apomorphine hydrochloride (0.114 g; Johnson Matthey, UK), α-D-lactose monohydrate (0.500 g), maltodextrin (Glucidex IT 12 DE; 1.861 g), and sucrose monolaurate D-1216 (0.025 g) was spray dried to give a fine, dry, free-flowing powder with a nominal dose of 1 mg apomorphine free base in 25 mg powder.

[0359] Analysis of the PSD of the powder described in Example 1 above by dry powder laser diffraction is shown in Table 2 below and was determined to be well within a distribution suitable for nasal administration.

[0360] Table 2

[0361]

[0362] Assay and purity were 103.7% as determined by HPLC / UV analysis, and RS% was less than 0.38%.

[0363] Example 3

[0364] Spray-dried roxapine formulation

[0365] An aqueous solution (62.50 g) containing roxapine succinate (0.205 g; Tiefenbacher, Germany), along with α-D-lactose monohydrate (0.500 g), maltodextrin (Glucidex IT 12 DE; 1.771 g), and sucrose monolaurate D-1216 (0.025 g) was spray dried using the general procedure described in Example 1 above to produce a fine, dry, free-flowing powder with a nominal dose of 1.5 mg of roxapine free base in 25 mg of powder.

[0366] The PSD of the resulting powder was determined as described in Example 1 and is shown below in Table 3. It is well within the distribution suitable for nasal administration.

[0367] Table 3

[0368]

[0369] Assay and purity were 100.2% as determined by HPLC / UV analysis, and RS% was less than 0.05%.

[0370] Example 4

[0371] Spray-dried ketorolac formulations

[0372] An aqueous solution (50.02 g) containing ketorolactromethamine (0.737 g; Uquifa, ES), α-D-lactose monohydrate (0.500 g), maltodextrin (Glucidex IT 12 DE; 1.771 g), and sucrose monolaurate D-1216 (0.025 g) was spray dried using the general procedure described in Example 1 above to produce a fine, dry, free-flowing powder with a nominal dose of 5 mg ketorolac free acid in 25 mg powder.

[0373] The PSD of the resulting powder was determined as described in Example 1 and shown in Table 4 below, and was again well within a distribution suitable for nasal administration.

[0374] Table 4

[0375]

[0376] Assay and purity were 103.0% as determined by HPLC / UV analysis, and RS% was less than 0.22%.

[0377] Example 5

[0378] Chemical stability of spray-dried powders

[0379] Amounts of between 105 and 115 mg of the spray-dried powder from Examples 1 to 4 above were dispensed into 1.5 mL glass vials sealed with screw caps. Two vials of each powder were placed inside a climate chamber at 40°C and 75% relative humidity (40 / 75). One vial was placed into the chamber as is, and one vial was further packaged in a heat-sealed aluminum sachet.

[0380] The chemical stability of three drug substances (epinephrine, apomorphine and loxetine) after 6 months and ketorolac after 2 months for different compositions and encapsulations is summarized in Table 5 below, where the total amount of impurities and degradation products is expressed as RS %.

[0381] Table 5

[0382]

[0383]

[0384] The observed changes in RS % for these sensitive active ingredients primarily relative to Example 3, and in particular relative to Example 2, show that the chemical stability of the drug substance is unexpectedly good when formulated in the composition of the present invention.

[0385] Example 6

[0386] Pharmacokinetic studies in dogs following nasal and intramuscular administration of epinephrine

[0387] The purpose of the study was to obtain and evaluate the basic pharmacokinetic profile of epinephrine following nasal administration of the composition of Example 1 and following intramuscular administration of an aqueous solution.

[0388] The study was conducted in six Beagle dogs, three males and three females, approximately 15-18 months of age. The dogs were dosed in a staggered dosing schedule to compensate for potential sequential effects. Dosing was always performed in the morning, and the dogs had fasted overnight (minimum 8 hours). Water was provided ad libitum and food was fed 4 hours after administration.

[0389] Each dog was intranasally administered with the composition of Example 1 at a dose of 4 mg / animal (IN 4 mg), and epinephrine (1 mg / mL) was administered at a dose of 0.3 mg / animal (IM 0.3 mg). The composition of Example 1 was administered intranasally using a specific intranasal device from Aptar Pharma, France (UDS Monopowder).

[0390] An aqueous solution of epinephrine was administered intramuscularly into the left hind leg musculature (quadriceps femoris) with a 48-hour washout period between each administration.

[0391] The in vivo part of the studies was conducted in compliance with the European Convention for the Protection of Vertebrate Animals for Experimental and Other Scientific Purposes (ETS No. 123).

[0392] Blood samples were collected from the cephalic vein (V. cephalica antebrachic) ​​or saphenous vein (V. saphena) of the forearm of all dogs by venipuncture at designated time points under customary aseptic conditions. A 1 mL volume was collected into a plastic Vacuette® catheter containing K3EDTA. Blood samples were kept on ice and then centrifuged at 3500 rpm for 10 minutes at +4°C.

[0393] Plasma was extracted and transferred to pre-labeled cryovials containing sodium metabisulfite as an antioxidant and stored at -80°C prior to bioanalysis. Scheduled sampling time points were -5 (pre-dose), 2.5, 5, 10, 15, 20, 30, 45, 60, and 90 minutes after administration.

[0394] Frozen plasma samples were transferred to Recipharm OT in Uppsala, Sweden, for bioanalysis. Plasma concentrations of epinephrine were determined using HPLC-MS-MS analysis, capable of measuring epinephrine concentrations in dog plasma within a range of 0.05 to 100, using epinephrine-D6 as a deuterated internal standard. Analytes were extracted from the sample plasma using protein precipitation with TCA. After centrifugation, the supernatant was used for analysis.

[0395] All samples were analyzed by first separating the analytes using an Acquity HSS T3 column (2.1 mm x 100 mm, 1.7 µm) and then detecting them using positive electrospray ionization and multiple reaction monitoring (MRM). Quantification was performed in the range of 0.05 to 100 ng / ml.

[0396] Pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin (version 8.0) and are provided in Tables 6 and Figure 8 Among them, AUC 最后 is the area under the curve of plasma concentration versus time until the last sampling point; C max is the highest measurable concentration after administration and t max The time to reach the highest measurable concentration. All values ​​presented in Tables 6-9 are average values ​​of N=6.

[0397] Table 6

[0398]

[0399] Example 7

[0400] Pharmacokinetic studies in dogs following nasal and intramuscular administration of apomorphine

[0401] Essentially the same procedure as described above in Example 6 was performed, wherein each dog was administered the composition of Example 2 intranasally (IN 1 mg) at a dose of 1 mg / animal and injected (IM 1 mg) with an aqueous solution of apomorphine (5 mg / ml) at a dose of 1 mg / animal.

[0402] Scheduled sampling time points were 0 (pre-dose), 2.5, 5, 10, 20, 30, 45, 60, 90, 120, and 240 minutes after administration.

[0403] Apomorphine plasma concentrations were determined by measuring apomorphine in dog plasma using apomorphine-D5 as a deuterated internal standard. Quantitation was performed over a range of 0.10 to 300 ng / ml.

[0404] The pharmacokinetic parameters are provided in Tables 7 and Figure 9 middle.

[0405] Table 7

[0406]

[0407] Example 8

[0408] Pharmacokinetic studies in dogs following nasal and intramuscular administration of loxepin

[0409] Essentially the same procedure as described in Example 6 above was performed, wherein each dog was administered the composition of Example 3 intranasally at a dose of 1.5 mg / animal (IN 1.5 mg) and injected (IM 1.5 mg) with an aqueous solution of roxapine (3 mg / ml) at a dose of 1.5 mg / animal.

[0410] Plasma was extracted and transferred to pre-labeled Eppendorf tubes and stored at -20°C or below before being sent for bioanalysis. Scheduled sampling time points were 0 (pre-dose), 2.5, 5, 10, 20, 30, 45, 60, 120, 240, and 480 minutes after administration.

[0411] Plasma concentrations of loxepin were determined using loxepin-D8 as a deuterated internal standard. Quantification was performed over a range of 0.3 to 300 ng / mL.

[0412] The pharmacokinetic parameters are provided in Table 8 and Figure 10 middle.

[0413] Table 8

[0414]

[0415] Example 9

[0416] Pharmacokinetic studies in dogs following nasal and oral administration of ketorolac

[0417] Essentially the same procedure as described in Example 6 above was performed, wherein each dog was administered intranasally (IN 5 mg) the composition of Example 4 at a dose of 5 mg / animal and administered (PO 5 mg) ketorolac oral lozenge at a dose of 5 mg / animal. The ketorolac lozenge was administered orally via syringe with approximately 3 mL of water to ensure that the lozenge was properly swallowed and completely cleared from the esophagus.

[0418] Plasma was extracted and transferred to pre-labeled Eppendorf tubes and stored at -20°C or below before being sent for bioanalysis. Scheduled sampling time points were 0 (pre-dose), 2.5, 5, 10, 20, 30, 45, 60, 90, 150, and 300 minutes after administration.

[0419] Plasma concentrations of R-ketorolac and S-ketorolac were determined by enantioselective HPLC-MS-MS analysis capable of measuring R-ketorolac and S-ketorolac concentrations in dog plasma using ketorolac-D3 as a deuterated internal standard.

[0420] All samples were analyzed by first separating the analytes using a LUX Amylose-1 palm-shaped column (2.0 mm x 50 mm, 3.0 µm) and then detecting them using positive electrospray ionization and multiple reaction monitoring (MRM). Quantification was performed over a range of 0.50 to 5000 ng / ml.

[0421] The pharmacokinetic parameters are provided in Table 9 and Figure 11 (A; R-enantiomer and B; S-enantiomer).

[0422] Table 9

[0423]

[0424] Example 10

[0425] Chemical stability of spray-dried apomorphine formulations

[0426] A procedure equivalent to that described in Example 2 above was performed to produce a powder with an assay and purity of 105.6% and RS% below 0.01% as determined by HPLC / UV analysis.

[0427] Chemical stability experiments were conducted essentially as described in Example 5 above by packaging bottles containing apomorphine formulations along with a desiccant in heat-sealed aluminum sachets.

[0428] The chemical stability of apomorphine after 1 and 3 months storage for different compositions and packaging is summarized in Table 10 below, where the total amount of impurities and degradation products is expressed as RS %.

[0429] Table 10

[0430]

[0431] The observed changes in RS% for the sensitive active ingredient apomorphine show that the chemical stability of the drug substance is unexpectedly good when formulated in the composition of the present invention.

[0432] Example 11

[0433] Chemical stability of different spray-dried roxapine formulations

[0434] The general procedure described in Example 1 above was used to prepare a mixture containing roxapine succinate (0.204 g) and α-D-lactose monohydrate (0.500 g) and

[0435] • maltodextrin (Glucidex IT 12 DE; 1.771 g) and sucrose monolaurate D-1216 (0.025 g) (Example A);

[0436] • maltodextrin (Glucidex IT 12 DE; 1.696 g) and sucrose monolaurate D-1216 (0.100 g) (Example B); and

[0437] • Different aqueous solutions (62.50 g) of HPMC (Methocel K3; 1.771 g; IMCD Nordic, Sweden) and sucrose monolaurate D-1216 (0.025 g) were spray-dried.

[0438] A fine, dry and free-flowing powder was produced in each case, with the nominal dose being 1.5 mg of roxapine free base in 25 mg of powder.

[0439] Initial assay and purity as determined by HPLC / UV analysis were:

[0440] • 102.0% for Example A, where RS% was less than 0.06%;

[0441] • 101.4% for Example B, where RS% was less than 0.06%; and

[0442] • 101.9% for Case C, where RS% is less than 0.09%.

[0443] Chemical stability experiments were performed essentially as described in Example 5 above by packaging bottles containing different loxetamine formulations together with a desiccant in heat-sealed aluminum sachets.

[0444] The chemical stability for the different compositions after 1, 3 and 6 months is summarized in Table 11 below, where the total amount of impurities and degradation products is expressed as RS %.

[0445] Table 11

[0446]

[0447] The observed RS% changes for this sensitive active ingredient demonstrate that the chemical stability of the drug substance is unexpectedly good when formulated in the composition of the present invention.

[0448] Example 12

[0449] Different epinephrine / adrenaline formulations produced by spray drying in air

[0450] Eight aqueous solutions (50 g each; Examples D to L, respectively) containing dry matter compositions each having 0.364 g of epinephrine tartrate and having respective amounts of the excipients lactose monohydrate, maltodextrin (Glucidex IT 12 DE), HPMC (hydroxypropyl methylcellulose K3), sucrose monolaurate (D-1216), sodium metabisulfite (Merck Chemical & Lifescience AB, Sweden), and / or disodium EDTA (Titriplex® III; Merck Chemical & Lifescience AB, Sweden), as shown in grams in Table 12 below, were spray dried by the general procedure described in Example 1 above to produce a fine, dry, free-flowing powder with a nominal dose of 1.0 mg of epinephrine free base in 25 mg of powder.

[0451] Table 12

[0452]

[0453] The PSD of the resulting powder was determined as described in Example 1 and shown below in Table 13, and was again well within the distribution suitable for nasal administration (NA means "Not Analyzed").

[0454] Table 13

[0455]

[0456] Initial assays and purity (expressed as % RS) as determined by HPLC / UV analysis are provided in Table 14 below.

[0457] Table 14

[0458]

[0459] Chemical stability experiments were conducted essentially as described in Example 5 above by packaging bottles containing different epinephrine formulations together with a desiccant in heat-sealed aluminum sachets and storing them in a climate chamber at 40 / 75.

[0460] The chemical stability for the different compositions after 1 month is summarized in Table 15 below, where the total amount of impurities and degradation products is expressed as RS %.

[0461] Table 15

[0462]

[0463] The observed changes in the RS% of the easily degradable epinephrine indicate that the chemical stability of the drug substance is unexpectedly good when formulated in the composition of the present invention.

[0464] Example 13

[0465] Different epinephrine / adrenaline formulations produced by spray drying under nitrogen

[0466] Five aqueous solutions (50 g each; Examples M to Q, respectively) containing dry matter compositions each having 0.218 g of epinephrine tartrate and having respective amounts of the excipients lactose monohydrate, maltodextrin (Glucidex IT 12 DE), HPMC (hydroxypropyl methylcellulose K3), sucrose monolaurate (D-1216), and / or sodium metabisulfite, as shown in grams in Table 16 below, were spray dried by the general procedure described in Example 1 above, except that nitrogen was used as the drying gas instead of air, to produce a fine, dry, free-flowing powder with a nominal dose of 1.0 mg of epinephrine free base in 25 mg of powder.

[0467] Table 16

[0468]

[0469] Initial assays and purity (expressed as % RS) as determined by HPLC / UV analysis are provided in Table 17 below.

[0470] Table 17

[0471]

[0472] Example 14

[0473] Different eletriptan formulations produced by spray drying under nitrogen

[0474] Five ethanol / water solutions (80 g each; Examples R to V, respectively) were prepared by dissolving the relevant excipients (listed below) in 20 g of water and dissolving eletriptan hydrobromide in 60 g of ethanol 70% v / v, respectively, and then adding the aqueous solution containing the dissolved excipients to the ethanolic solution containing the active ingredient. Dry matter compositions, each containing 0.727 g of eletriptan hydrobromide (Tieffenbacher, Germany) and having respective amounts of excipients lactose monohydrate, maltodextrin (Glucidex IT 12 DE), HPMC (hydroxypropyl methylcellulose K3), sucrose monolaurate (D-1216), and / or sodium metabisulfite, as shown in grams in Table 18 below, were spray-dried using the general procedure described in Example 1 above, except that nitrogen was used as the drying gas instead of air, to produce a fine, dry, free-flowing powder with a nominal dose of 5.0 mg of eletriptan free base in 25 mg of powder.

[0475] Table 18

[0476]

[0477] Assay and purity were confirmed by HPLC / UV analysis, and the PSD of the resulting powder was determined as described in Example 1 and was within a distribution suitable for nasal administration.

[0478] Example 15

[0479] Spray-dried formulations comprising opioid antagonists

[0480] Five aqueous solutions (50 g each; Examples W to AA, respectively) as set forth in Table 19 below, having respective amounts of the active ingredient (naltrexone hydrochloride (0.443 g; Mallinckrodt, UK) or nalmefene hydrochloride (1.91 g; Mallinckrodt, UK) as shown in grams and excipients lactose monohydrate, maltodextrin (Glucidex IT 12 DE), HPMC (hydroxypropylmethylcellulose K3), and / or sucrose monolaurate (D-1216)) were spray dried by the general procedure described in Example 1 above to produce a fine, dry, free-flowing powder with a nominal dose of 4 mg naltrexone in 25 mg powder and 1.5 mg nalmefene in 22.5 mg powder.

[0481] Table 19

[0482]

[0483] Initial assays and purity (expressed as % RS) as determined by HPLC / UV analysis are provided in Table 20 below.

[0484] Table 20

[0485]

[0486] Chemical stability experiments were performed essentially as described in Example 5 above by packaging bottles containing the different formulations together with a desiccant in heat-sealed aluminum sachets.

[0487] The chemical stability for the different compositions after 1, 3 and 6 months is summarized in Table 21 below, where the total amount of impurities and degradation products is expressed as RS %.

[0488] Table 21

[0489]

[0490] The observed changes in RS% of these active ingredients show that the chemical stability of the drug substance is unexpectedly good when formulated according to the present invention.

[0491] Example 16

[0492] Spray-dried desmopressin formulations

[0493] An aqueous solution (125 g) containing desmopressin acetate trihydrate (0.0025 g; Bachem, Switzerland), α-D-lactose monohydrate (5.000 g), maltodextrin (Glucidex IT 12 DE; 7.123 g), and sucrose monolaurate D-1216 (0.375 g) was spray dried using the general procedure described in Example 1 above to produce a fine, dry, free-flowing powder with a nominal dose of 5 µg desmopressin in 25 mg powder.

[0494] Assay and purity were confirmed by HPLC / UV analysis and the PSD of the resulting powder was determined as described in Example 1 and was well within a distribution suitable for nasal administration.

[0495] Example 17

[0496] Spray-dried olanzapine formulations

[0497] An ethanol / water solution (80 g) was prepared by dissolving the excipients α-D-lactose monohydrate (1.000 g), maltodextrin (Glucidex IT 12 DE; 1.100 g), HPMC (Methocel K3; 0.125 g), and sucrose monolaurate D-1216 (0.075 g) in 20 g of water, and separately dissolving olanzapine (0.200 g; Tiefenbacher, Germany) in 60 g of ethanol 70% v / v, and then adding the aqueous solution containing the dissolved excipients to the ethanol 70% v / v solution containing the dissolved olanzapine. The ethanol / water solution (80 g) was spray-dried using the general procedure described in Example 1 above, resulting in a fine, dry, free-flowing powder with a nominal dose of 2 mg of olanzapine free base in 25 mg of powder.

[0498] Assay and purity were confirmed by HPLC / UV analysis and the PSD of the resulting powder was determined as described in Example 1 and was well within a distribution suitable for nasal administration.

Claims

1. A pharmaceutically acceptable composition in the form of an amorphous powder, comprising a mixture of: (a) a pharmacologically effective dose of epinephrine or a pharmaceutically acceptable salt thereof; (b) a pharmaceutically acceptable carrier material comprising a combination of a disaccharide and a polymeric material; and (c) sucrose esters; in: (a) the polymeric material comprises dextrin and / or hydroxypropyl methylcellulose; and (b) the disaccharide is selected from the group consisting of maltitol, trehalose, sucralose, sucrose, isomalt, maltose and lactose; The particles of the powder comprise an amorphous complex of epinephrine or a pharmaceutically acceptable salt thereof and a carrier material.

2. The composition according to claim 1, wherein (a) the disaccharide comprises lactose and / or trehalose; and / or (b) The dextrin comprises cyclodextrin or maltodextrin.

3. The composition of claim 2, wherein the carrier material comprises a combination of trehalose and maltodextrin.

4. The composition of claim 1 , wherein the weight ratio of disaccharide:polymeric material is in the range of 10:1 to 1:

20.

5. A composition according to claim 4, wherein the weight ratio of disaccharide:polymeric material is in the range of 2:1 to 1:

8.

6. The composition of claim 1, wherein the composition has a lowest measurable glass transition temperature of at least 40°C when measured at a relative humidity of at most 35%.

7. The composition of claim 1, wherein the sucrose ester comprises sucrose monolaurate.

8. The composition of claim 1, wherein the pharmacologically effective dose of epinephrine is between 0.1 mg and 5 mg when calculated as the free base compound.

9. The composition of claim 1, wherein the pharmacologically effective dose of epinephrine or a pharmaceutically acceptable salt thereof is the only active ingredient in the composition.

10. The composition of claim 1, which is suitable for nasal delivery.

11. The composition of claim 1 , wherein the powder has a particle size distribution comprising: (a) D10 above 3 µm; and / or (b) Volume-based average diameter in the range of 10 μm and 100 μm.

12. The composition of claim 1, wherein the powder has a particle size of: (a) D10 greater than 10 µm; and / or (b) D90 below 500 μm.

13. The composition according to claim 12, wherein the particles of the powder have a D90 below 100 μm.

14. The composition of claim 1, wherein the composition comprises less than 10% water.

15. A method for producing a composition as claimed in any one of claims 1 to 14, wherein the method comprises the following steps: (i) mixing epinephrine or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier material and a sucrose ester in a suitable volatile solvent, (ii) spray drying the mixture from step (i).

16. A nasal administration device suitable for delivering the composition according to any one of claims 1 to 14 to the nose, the nasal administration device comprising, or being attached to or connected to a reservoir, the reservoir containing the composition and being configured such that the device, when actuated, is capable of depositing an effective dose of epinephrine or a pharmaceutically acceptable salt thereof to the nasal mucosa.

17. The nasal administration device of claim 16, packaged in a container constructed of a material that prevents the ingress of atmospheric water.

18. The nasal administration device of claim 17, wherein the container comprises a material selected from the group consisting of a heat-sealed aluminum bag and a thermoformed plastic.

19. A method for manufacturing the applicator of claim 16, the method comprising: The method of claim 15, wherein the composition thus formed is then loaded into a reservoir within the applicator, or a reservoir attached to or connected to the applicator.

20. Use of a composition according to any one of claims 1 to 14 in the preparation of a medicament for the treatment of allergic reactions.

21. The use according to claim 20, wherein the allergic reaction is an anaphylactic reaction.

22. The use according to claim 21, wherein the extreme allergic reaction comprises anaphylactic shock.

23. The use according to claim 20, wherein the reaction is a reaction to an insect bite, food or medicine.

24. The use according to claim 20, wherein the composition is administered to the nose with the aid of a nasal administration device as defined in claim 16.

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