Pharmaceutical Compositions Containing Biopharmaceutical Compounds

Abstract

According to the present invention, there is provided a composition in the form of an amorphous monoparticulate powder comprising a mixture of: (a) at least one biopharmaceutical compound in a pharmacologically effective dosage amount; and (b) a pharmaceutically acceptable carrier material, the carrier material comprising a combination of a disaccharide and a polymeric material. Preferred pharmaceutically acceptable carriers in this regard include lactose or trehalose and dextrin (e.g., maltodextrin). The composition may further comprise one or more alkyl sugars. Preferred alkyl sugars include sucrose esters, such as sucrose monolaurate. The powder composition may be produced by combining the various components and spray drying them together.

Description

[Technical field]

[0001] The present invention relates to novel pharmaceutical compositions containing biological agents that are useful in a variety of medical conditions. The present invention also relates to methods of making such compositions and formulating them into dosage forms. [Background technology]

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

[0003] Of the various well-known drug delivery routes, oral delivery to the gastrointestinal tract is the most common and is generally considered to be the most preferred by patients and practitioners.

[0004] However, oral drug administration is known to have drawbacks, including the fact that active ingredients are inevitably subject to first-pass metabolism in the liver, enzymatic degradation in (and outside) the gastrointestinal tract, and have limited access to the blood-brain barrier (BBB) ​​for treating diseases of the central nervous system (CNS). These factors not only affect the efficacy of certain drugs, but in some cases may make oral drug delivery completely unsuitable as a route of administration.

[0005] Oral administration to the gastrointestinal tract has the additional disadvantage that the active ingredient must be absorbed through the intestine as part of the digestive process, which takes time, and often requires high doses of the active ingredient (due to low bioavailability), which entails an increased risk of numerous side effects and / or safety issues.

[0006] Finally, another limitation of oral formulations that limits their long-term use is microbial instability, which may require the use of preservatives to control, which can result in irritation and cause sensitization / allergic effects.

[0007] In the treatment of certain conditions, such as acute disorders, a more rapid onset of pharmacological effect than can be afforded by oral drug delivery is often highly desirable.

[0008] In such cases, the principle of administration, that the drug is quickly absorbed into the systemic circulation, is likely to result in a rapid onset of action. Although this can be accomplished via parenteral administration (such as subcutaneous or intravenous injection), such means of delivery are inconvenient and may be very difficult and / or impossible for patients to administer, requiring time-consuming intervention by a physician to ensure compliance and avoid unwanted or adverse effects.

[0009] Transmucosal administration of active ingredients is a viable alternative to parenteral administration, offering the possibility of delivering drug molecules directly into the systemic circulation via mucosal membranes (e.g., rectal, sublingual, buccal, pulmonary, and intranasal), potentially offering advantages such as increased patient compliance, improved drug bioavailability and therefore lower doses, more rapid onset of action, and reduced side effects.

[0010] However, transmucosal administration of drugs has its own very distinct problems. Unlike the gastrointestinal tract, which is a large organ containing a relatively large amount of fluid, spaces such as the oral and nasal cavities are relatively small and contain much less fluid, such as saliva and / or mucus. This necessarily results in a significant limitation on the amount of active ingredient that can be administered in a single dose.

[0011] Furthermore, although the gastrointestinal tract is a dynamic system, for the most part it is a somewhat "closed" system: Conversely, the rapid clearance mechanisms that occur in both the oral and nasal cavities often mean that there is also limited time available for absorption across mucosal surfaces for an already more limited amount of drug.

[0012] To address this issue, numerous formulation principles have been proposed, including bioadhesive formulation principles such as buccal patches for oral mucosal drug delivery (see, e.g., Shojaei, J. Pharm. Pharmaceutical Sci., 15, 19 (1998) and Gandhi, Advanced Drug Delivery Reviews, 43, 67 (1994)), and in situ gelling compositions for intranasal drug delivery (see, e.g., Bertan et al., Eur. J. Pharm. Sci., 27, 62 (2006)).

[0013] Solid transmucosal drug delivery systems may have considerable advantages in that they allow higher drug loading in the formulation.However, while solid drug delivery compositions are much more common when administered to the rectum, buccal, sublingual, and pulmonary mucosa, the majority of intranasal drug delivery systems remain in the form of liquid spray, typically aqueous solutions, and drug solubility is another factor that limits the amount of drug that can be absorbed.

[0014] The near ubiquity of liquid sprays for intranasal delivery is due to the lack of ease in formulating solid pharmaceutical formulations in the form of nasal powders: unlike the powders that are frequently used for inhalation of active ingredients into the lungs, there are very few intranasal powder formulations available on the market.

[0015] When formulated as dry powders, pulmonary drug delivery compositions typically take the form of "agglomerated" mixtures containing finely divided particles of the API on larger carrier particles. These agglomerates are intended to dissociate / break down upon inhalation or actuation of the device, depositing only fine particles of the active ingredient in the lungs.

[0016] However, it is understood that such drug delivery systems do not work effectively in the case of intranasal drug delivery. This is because the presence of such fine particles poses a significant risk of exposure to the lung, which is not the intended site of administration. If the particle size of the drug is increased to avoid this problem, it is likely to be difficult to ensure proper interaction in the heterogeneous "interaction" mixture, which relies on substantial differences in the size of the two components to ensure interaction, which then leads to potential manufacturing problems such as separation during filling. Attempting to counter this by increasing the particle size of the corresponding carrier does not necessarily solve the problem, and may result in an inevitable increase in the mass of inactive excipients in the already finitely limited total mass of the dosage form, resulting in a reduced dose of active ingredient.

[0017] The difficulty of formulating dry powders for intranasal delivery is addressed in US Patent Application No. 2005 / 001411A1. In this document, it is stated that powders for nasal administration must be sufficiently fine to be efficiently carried by the gas stream and efficiently deposited in the nose, and also sufficiently coarse to facilitate the introduction of the powder into a suitable powder device, which is always necessary for intranasal administration. US2005 / 001411A1 apparently solves this problem by creating loosely formed secondary particles (agglomerates) of primary particles that contain the active ingredient. The agglomerates are said to have dimensions of several hundred microns, which allows for more efficient loading into a suitable intranasal administration (applicator, dispenser, or inhaler) device. Upon actuation of such a device and administration of the composition, the agglomerates apparently rapidly break down into primary particles of the active ingredient. These primary particles are said to be only a few microns in size, facilitating dissolution and subsequent intranasal absorption of the active ingredient.

[0018] As discussed above, transmucosal (e.g., intranasal) delivery of drugs intended for systemic absorption necessarily avoids first-pass metabolism, which is a component of oral administration. Drug metabolism occurs via chemical reactions with enzymes that can alter the chemical structure, physical structure, and / or biological activity of the active ingredient.

[0019] Most drugs are organic molecules that contain functional groups capable of undergoing such chemical reactions and are therefore often susceptible to some form of chemical degradation when they come into contact with substances outside the body that can interact with those functional groups.

[0020] Such chemical transformations are typically classified in the pharmaceutical art as chemical "degradation" because they often result in a loss of efficacy or, in extreme circumstances, toxic by-products, either or both of which can result in a drug that is ineffective and / or harmful to the patient.

[0021] How quickly such degradation may occur depends on how inherently chemically unstable the drug compound is to begin with, how it is formulated, and the conditions under which it is stored. In many cases, high temperatures and humidity can result in accelerated decomposition.

[0022] Such loss of chemical integrity is measurable, which is why all pharmaceutical products have a shelf life printed on the label and / or embossed on the packaging, and why certain given medications contain specific printed information on the package insert regarding proper storage conditions.

[0023] As a rule of thumb, the more complex the active ingredient, the higher the chance of chemical or physical integrity resulting in problematic biological inactivation. In this regard, biologically active drugs / active pharmaceutical ingredients (APIs), such as vaccines, enzymes, antibodies / portions thereof, and antibody analogs and mimetics, present particular problems due to, for example, their higher-order (e.g., tertiary) structure and the interplay between proper conformation and effective function.

[0024] Furthermore, in comparison to other APIs that are small molecules, despite proving to be increasingly useful in the treatment of a wide range of diseases and disorders, certain biological agents or biologics, such as antibodies / portions thereof, may not be particularly potent and may require high doses to achieve a significant biological effect.

[0025] As summarized by Kou and Zhou in Chapter 16 of the textbook Amorphous Solid Dispersions, Shah et al (Eds.), Springer (2014), when a drug is formulated in an amorphous, as opposed to crystalline, physical state, it is typically provided in a higher energy state and is therefore likely to be more chemically and physically unstable, presenting a challenge to the pharmaceutical manufacturer.

[0026] Thus, chemical stability is often improved by providing drugs, especially small molecule ones, in a crystalline state via salt formation. However, providing large (macromolecular) biologics in such salt form is not a simple matter, and in practice is usually not an option.

[0027] Thus, considering all of the aforementioned potential advantages it offers, there remains a need for improved solid (e.g., powder-based) transmucosal, and particularly intranasal, drug delivery systems.

[0028] In particular, in the field of drug delivery, there remains a significant unmet clinical need for powdered drug delivery compositions that: (i) It is physically and chemically stable; (ii) in sufficient doses, and / or If systemic administration is intended, To provide the active ingredient in a form that is sufficiently penetrating to provide the required therapeutic effect (such as rate of onset and / or access to drug target) at the lowest possible dose (relatively speaking) and at the short residence time available in a transmucosal context, such as intranasally.

[0029] In addition to the above, in the more specific area of ​​intranasal drug delivery, there remains a significant unmet clinical need for such drug delivery compositions comprising appropriately sized particles that enable both efficient Filling of drug delivery devices, and • Deposition in associated (e.g. nasal) cavities.

[0030] Intranasal dry powder formulations are known, inter alia, from International Patent Applications Nos. 2010 / 142696 and 2019 / 038756, U.S. Pat. No. 10,653,690 (B1), and U.S. Patent Application No. 2018 / 0092839 (A).

[0031] Spray drying of biologics is disclosed, for example, in Buerki et al, Int. J. Pharm., 408, 248 (2011) and Lipiuainen et al, ibid., 543, 21 (2018).

[0032] The inventors have found that it is possible to formulate certain biologically active ingredients (i.e., biological agents or biologics) in the form of amorphous dry powder compositions, for example, by the process of spray drying these active ingredients together with a particular combination of carrier materials, as disclosed below. Such compositions may provide a surprising and substantial improvement in the stability of those active ingredients prior to administration, without significant loss of the pharmacological and / or biological activity of the associated active ingredients. Such compositions may further provide improved bioavailability and / or absorption rate of those active ingredients after administration. Summary of the Invention

[0033] According to a first aspect of the present invention there is provided a pharma- ceutically acceptable composition in the form of a solid amorphous monoparticulate powder comprising: (a) a pharmacologically effective dosage amount of at least one biopharmaceutical compound; (b) a pharma- ceutically acceptable carrier material, the carrier material comprising a combination of a disaccharide and a polymeric material; and The pharma- ceutically acceptable compositions are hereinafter jointly referred to as "the compositions of the invention."

[0034] The composition of the present invention is in the form of an amorphous monoparticle powder. By "monoparticle" is meant that the particles forming the powder composition of the present invention comprise a homogeneous or heterogeneous mixture in which the biopharmaceutical compound(s) (also referred to herein as "active ingredient(s)", "pharmacologically active ingredient(s)", "pharmacologically active compound(s)", and / or "drug(s)") are encapsulated in an amorphous state within a carrier material as defined above, optionally in the presence of other ingredients. Thus, the particles of the powder composition of the present invention are provided as an amorphous composite of the active ingredient, the carrier material, and optionally other ingredients.

[0035] Due to their amorphous nature, the compositions of the present invention may be completely amorphous and / or predominantly amorphous (e.g., more than about 50% amorphous, such as more than about 75% amorphous, including more than about 80% amorphous, such as more than about 90% amorphous or more than 95% amorphous, including more than about 99% amorphous). Alternatively, the compositions of the present invention may be less than about 50% amorphous, including less than about 25%, more preferably less than about 20%, such as less than about 10% amorphous, including less than about 5% amorphous or less than about 1% amorphous. The degree (%) of crystallinity may be determined by those skilled in the art using powder X-ray diffraction (PXRD). Other techniques such as solid-state NMR, FT-IR, Raman spectroscopy, differential scanning calorimetry (DSC) microcalorimetry, and calculation of true density may also be used.

[0036] As described below, despite being in an amorphous physical state, the compositions of the present invention exhibit surprising and unexpected physical and chemical stability and therefore may be provided in pharmaceutical forms that exhibit excellent shelf life when stored under normal storage conditions.

[0037] The composition of the present invention is produced by suitable techniques, at least initially in multiparticulate form (i.e. as powder).Generally, suitable techniques are classified into "solvent-based" methods, including spray drying, fluidized bed techniques, co-precipitation, supercritical fluid techniques, spray granulation, cryogenic techniques (including freeze drying), electrospinning and rotary jet techniques, or "fusion-based" methods, including melt granulation, melt extrusion, high shear mixing (e.g. KinetiSol®), milling and molten material on carrier techniques (e.g. Meltdose®).Preferred methods include freeze drying, and more preferably, the composition of the present invention is produced by spray drying process.

[0038] Such powders may be suitable for direct delivery to a patient via any pharma- ceutically acceptable route of administration, or may be provided as intermediate compositions that can be subsequently formulated into pharma- ceutically acceptable dosage forms for administration to one or more patients.

[0039] In this regard, pharmaceutical formulations and / or pharma- ceutically acceptable dosage forms are provided which comprise one or more compositions of the invention, and which are administered to a patient.

[0040] Suitable pharmaceutical dosage forms may therefore include liquid formulations, such as solutions, which may be prepared by dissolving (e.g., immediately prior to administration) a composition of the invention in a pharma- ceutically acceptable solvent, such as water, for delivery to such patients, for example, by injection or infusion. Such administration means may be useful where the active ingredient is an antibody, etc.

[0041] Alternative pharmaceutical dosage forms may include liquid or semi-solid formulations such as 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 semi-solid carrier which may be loaded into a suitable dosage form or may be delivered, for example, by injection or infusion, or may be formed to form an implant or depot preparation after injection (e.g., subcutaneously or intramuscularly).

[0042] Alternatively, the composition of the present invention may be provided as part of an essentially solid pharmaceutical dosage form. The term "solid" will be well understood by those skilled in the art to include any form of matter that retains its shape and density when unconfined and / or in which the molecules are generally as tightly compressed as the repulsive forces between them permit. Thus, an essentially solid formulation is one in which at least about 80% is in such a form, such as at least about 90%, including at least about 95% (or at least about 99%).

[0043] In this regard, the compositions of the present invention may be provided in any multiparticulate form comprising a plurality of particles (e.g., simple powders, granules, pellets and / or beads) which may, individually and / or collectively, consist essentially of and / or comprise one or more compositions of the present invention.

[0044] Thus, the compositions of the present invention may be provided after preparation (e.g., by spray drying) in the form of a simple powder mixture, powdered microspheres, coated powdered microspheres, lyophilized liposomal dispersions, or combinations thereof.

[0045] When a pharma- ceutically acceptable dosage form of the invention "consists essentially of" particles of one or more compositions of the invention, this is understood to mean that the dosage form contains only one or more compositions of the invention, together with other features and / or components that do not substantially affect the basic and novel property(ies) of the dosage form. Alternatively, in situations where a dosage form of the invention "consists essentially of" one or more compositions of the invention, this may be understood to mean that the dosage form contains, in total, at least about 90%, such as at least about 95%, including at least about 97% by weight (e.g., about 99%) of one or more compositions of the invention.

[0046] Alternatively, the pharmaceutical dosage form may comprise one or more compositions of the present invention, which may be provided in a single unit dosage form, such as a pessary, suppository or other form of insert, pill, capsule, cake, patch (e.g., buccal patch), film (e.g., buccal film), or tablet (e.g., sublingual tablet).

[0047] Capsules may be prepared by loading the compositions of the present invention as a spray-dried powder directly into a pharma- ceutically acceptable capsule made from suitable materials designed for sublingual or, preferably, oral delivery, or by mixing the compositions with excipients prior to loading into such capsules for such delivery, which may include a granulation step as described below. Oral delivery may be used when the active ingredient is, for example, an enzyme.

[0048] In this regard, the compositions of the present invention may be granulated into pellets or pills, but may also be formulated (i.e., provided for administration) in the form of a dry, free-flowing powder. "Dry" includes essentially free of water and other liquid solvents, including less than about 10%, such as less than about 6%, including less than about 5% or less than about 4%, more preferably less than about 3%, such as less than about 2%, e.g., less than about 1%, of the formulation is liquid, such as water.

[0049] The flowability of the powder compositions of the present invention may be measured by standard techniques known to those skilled in the art, including bulk density measurements, or measurements made with a powder flow analyzer (e.g., those sold by Stable Micro Systems or Meritics, both in the UK), including powder flow rate dependency tests, caking tests, agglomeration tests, etc. A preferred measurement of flowability is the standard angle of repose, which may be performed using a rotating cylinder, a stationary funnel, or a tilting box.

[0050] In the context of the present invention, the term "free flowing" is intended to include powders that allow the compositions of the invention to be efficiently loaded into a drug delivery device during manufacture and / or that provide sufficient shot weight when expelled from the device (see below).

[0051] The term may also include that the powder exhibits an angle of repose of about 50° or less, such as about 45° or less, including about 40° or less, for example about 35° or less, more particularly about 30° or less, a bulk density of about 0.3 g / mL or more, for example about 0.4 g / mL or more, such as about 0.5 g / mL or more, more particularly about 0.6 g / mL or more, and / or a tap density of about 0.5 g / mL or more, such as about 0.6 g / mL or more, for example about 0.7 g / mL or more, particularly about 0.8 g / mL or more.

[0052] Suitable techniques for making dosage forms comprising dry powders or granules include simple dry blending, granulation (including dry granulation, wet granulation, melt granulation, thermoplastic pelletizing, spray granulation), extrusion / spheronization, or more preferably freeze-drying or spray drying (see below).

[0053] Dry granulation methods are also well known to those skilled in the art and include any technique in which primary powder particles are aggregated under high pressure, including, for example, slugging and roller compaction, as described below.

[0054] Wet granulation is well known to those skilled in the art and involves any technique involving agglomeration of a mixture of dry primary powder particles with a granulation fluid comprising a volatile inert solvent such as water, ethanol or isopropanol, alone or in combination, and optionally in the presence of a binder or binding agent. This technique may include passing the wet mass through a sieve to produce wet granules, which are then dried, preferably to a loss on drying of less than about 3% by weight.

[0055] Melt granulation is known to those skilled in the art to include any technique in which granules are obtained through the addition of a molten binder or a solid binder that melts during the process (these binder materials may include the pharma- ceutically acceptable carrier material of the composition of the present invention). After granulation, the binder is solidified at room temperature. Thermoplastic pelletization is known to be similar to melt granulation, but the plastic properties of the binder are used. In both processes, the resulting aggregates (granules) contain a matrix structure.

[0056] Extrusion / spheronization is well known to those skilled in the art to include any process involving dry mixing of the ingredients, wet massing with a binder, extrusion, spheronization of the extrudate into uniformly sized spheroids, and drying.

[0057] Spray granulation is known to those skilled in the art to include any technique that involves drying a liquid (solution, suspension, melt) and simultaneously accumulating granulation in a fluidized bed. Thus, in addition to generally including any spray coating granulation technique, this term includes the process in which foreign seeds (bacteria) are provided and granules are accumulated on them, as well as the process in which indigenous seeds (bacteria) are formed in the fluidized bed by abrasion and / or crushing. The sprayed liquid covers the bacteria and helps further agglomeration of the particles. It is then dried to form granules in the form of a matrix.

[0058] The term "lyophilization" includes lyophilization or cryodesication, and any low-temperature desolvation (e.g., dehydration) process in which the product is frozen, the pressure is reduced, and the frozen solvent (e.g., water) is removed by sublimation.

[0059] Alternatively, the compositions of the present invention may be provided in the form of tablets for oral, buccal and / or sublingual use. Such tablets may be formed, for example, by direct compression / compaction of the compositions of the present invention, optionally mixed with one or more suitable excipients, such as diluents, disintegrants, glidants and / or lubricants, as described, for example, in Pharmaceutical Dosage Forms: Tablets. Volume 1, 3 rd This can be achieved using techniques such as those described in "The Compression Press: A Novel Tablet Press," 1999 Edition, Augsburger et al. (eds.), CRC Press (2008) and documents cited therein. Suitable compression equipment includes standard tablet presses such as the Kilian SP300 or Korsch EKO, XP1, XL100, and XL200.

[0060] Suitable disintegrants that may be used for tablets (see, for example, Rowe et al, Handbook of Pharmaceutical Excipients, 6 th Disintegrants, as defined in ed. (2009), include cellulose derivatives such as hydroxypropylcellulose (HPC), low substituted HPC, methylcellulose, ethylhydroxyethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, modified cellulose gums; starch derivatives such as medium crosslinked starch, modified starch, hydroxypropyl starch, pregelatinized starch; and other disintegrants such as calcium alginate, sodium alginate, alginic acid, chitosan, colloidal silicon dioxide, docusate sodium, guar gum, magnesium aluminum silicate, polacrilin potassium, and polyvinylpyrrolidone. Combinations of two or more disintegrants may be used.

[0061] Preferred disintegrants include so-called "super disintegrants" (as defined, for example, in Mohanachandran et al, International Journal of Pharmaceutical Sciences Review and Research, 6, 105 (2011)), such as cross-linked polyvinylpyrrolidone, sodium starch glycolate, and sodium croscarmellose. Combinations of two or more super disintegrants can be used.

[0062] When disintegrants and / or superdisintegrants are used in tablets, they may be used in an amount (e.g., total) of 0.5 to 15% by weight based on the total weight of the composition, with a preferred range being 1 to 8% by weight, such as about 2 to about 7% by weight (e.g., about 5% by weight, such as about 4% by weight).

[0063] When present, binders are preferably used in an amount of 0.5 to 20% by weight based on the total weight of the tablet formulation. A preferred range is 1.0 to 15% by weight, such as about 2.0 to about 12% by weight (e.g., about 10% by weight). Suitable binding agents include cellulose gum and microcrystalline cellulose.

[0064] As described herein, the compositions of the present invention are preferably made by the process of spray drying.

[0065] Furthermore, whether in powder form or not, dosage forms containing the compositions of the present invention can be prepared using standard equipment by otherwise standard techniques known to those skilled in the art. In this regard, the compositions of the present invention can be combined with conventional pharmaceutical additives and / or excipients used in the art for the relevant preparations and incorporated into various types of pharmaceutical preparations using standard techniques to produce dosage forms containing the compositions of the present invention (see, for example, Lachman et al, 'The Theory and Practice of Industrial Pharmacy', CBS, 4 th edition (2015), 'Remington: The Science and Practice of Pharmacy', Troy (ed.), Elsevier, 23 rd edition(2020), and / or 'Aulton's Pharmaceutics: The Design and Manufacture of Medicines', Taylor and Aulton(eds.), Elsevier, 5 th (See the International Journal of Clinical Chemistry, 2017 edition).

[0066] Regardless of how they are prepared, the compositions of the invention are preferably suitable and / or formulated for transmucosal delivery of an active ingredient to the systemic circulation (and, e.g., in the case of a vaccine, generating a systemic immune response) or, further, for generating an immune response in the local microenvironment, e.g., in the case of a vaccine.

[0067] Those skilled in the art will appreciate that the term "transmucosal" means that, however administered to a patient, the composition is provided to the relevant mucosal surface in a form such that the active ingredient(s) can be absorbed across that mucosal surface after dissolution. Thus, relevant mucosal surfaces include the oral, nasal, ocular, vaginal, cervical, pulmonary and / or anorectal mucosa, more particularly the oral mucosa (including the buccal and sublingual mucosa) and nasal mucosa.

[0068] Thus, dosage forms containing the compositions of the present invention may be administered directly to a mucosal surface of a patient, including pulmonary, rectal, vaginal, buccal, sublingual, or intranasal, for transmucosal delivery of the active ingredient. Pulmonary, and especially intranasal, administration is particularly useful when the active ingredient is a vaccine, in which case transmucosal absorption may not be necessary to induce an immune response to the antigen.

[0069] When administered to the sublingual mucosa, the compositions of the invention may for example be in the form of a sublingual tablet as described above, which may contain disintegrants or disintegrating agents, which are defined as any material capable of accelerating the disintegration / dispersion of such compositions of the invention to a measurable extent, which may be achieved for example by materials capable of swelling and / or expanding when contacted with an aqueous medium, as described below.

[0070] Alternatively, the compositions of the invention may be administered sublingually in the form of a powder, as described herein, which may be dispensed into the mouth and under the tongue from a suitable container, such as a capsule or sachet.

[0071] When the compositions of the invention are suitable and / or formulated for sublingual or, in particular, intranasal administration, they therefore preferably contain a dosage of about 100 mg or less of active ingredient(s), or 10 9 It is administered in the form of a powder composition that is less than or equal to International Units (IU). Such sublingual and / or nasal powder compositions may comprise the composition of the invention mixed with other excipients or may consist essentially of the composition of the invention as defined above.

[0072] The compositions of the invention suitable and / or formulated for intranasal administration are preferably provided by a dosage means suitable for nasal delivery. Such a dosage means may contain one spray-dried powder composition of the invention or may contain two or more such compositions. In the latter case, the dosage means contains two or more dosages of the composition of the invention, each of which contains a pharmacologically effective dose of the active ingredient(s).

[0073] Two or more compositions of the present invention can be administered intranasally, either by repeated actuation of any device that contains or communicates with the administration means. Thus, the compositions of the present invention can be provided in a suitable device (e.g., a nasal applicator or dispenser (inhaler), such as those described below), and / or in a container or reservoir that is part of, is attached to, and / or is suitable for placement in association with such an applicator. Such a container or reservoir can contain one or more compositions of the present invention, each containing a pharmacologically effective dosage of the active ingredient.

[0074] In this manner, a suitable dosing means and / or nasal applicator may be actuated only once to deliver a single composition of the invention containing an appropriate dose of active ingredient following that actuation (i.e., a single-use dosage unit), may be actuated two or more times to deliver two or more compositions of the invention each containing an appropriate dose of active ingredient with each such actuation (i.e., a multi-use dosage unit), and / or may be refilled with a replacement source (e.g., a container or reservoir) of composition(s) of the invention containing one or more such compositions to provide single and / or multiple doses and / or dosing regimens.

[0075] Thus, the compositions of the present invention may be administered in the form of a plurality of particles, which particles may individually and / or collectively be composed of and / or comprise the compositions of the present invention.

[0076] Thus, the compositions of the present invention are prepared (initially) in the form of a solid, dry, free-flowing multiparticulate powder, as described above.

[0077] As mentioned above, the compositions of the present invention are provided in the form of amorphous monoparticle powders. They are not composed of a physical association of two or more separate, separate sets of particles of different components in the form of a mixture, such as an ordered or interactive mixture of smaller particles of active ingredient(s) associated with larger, but separate, particles of chemically different carrier material. Nevertheless, the compositions of the present invention can be provided as small particles that can then be attached to separate larger carrier particles in the interactive mixture, such provision being useful in the case of dosage forms intended for inhalation, e.g., the lungs (see, for example, J.Drug Delivery,Art.ID 5635010,1-19(2018)).

[0078] As mentioned above, the process of making the compositions of the present invention allows for the formation of pharmaceutical products that exhibit excellent shelf life in terms of both physical and chemical stability when stored under normal storage conditions as defined herein.

[0079] The compositions of the present invention are preferably prepared by the process of spray drying, which will be understood by those skilled in the art to include any method of producing dry powders from liquids, including solutions or suspensions (including slurries), involving the use of hot gas to rapidly dry and convert a liquid stream into solid particles, including vaporized solvent, and solutes previously dissolved in solution, and / or particles previously suspended in the evaporated liquid.

[0080] Suitable spray drying equipment includes some form of atomization means, such as a spray nozzle, that disperses the liquid into a spray having a relatively uniform droplet size. Such means may include any means capable of producing a dry, free-flowing powder, and may include high pressure swirl nozzles, spinning disks and / or atomizer wheels, high pressure single-fluid nozzles, two-fluid nozzles and / or ultrasonic nozzles.

[0081] The spray dryer may be a single effect or a multiple effect spray dryer and may include an integrated and / or external vibrating fluidized bed, a particle separator, and / or a collection means which may be a drum or a cyclone.

[0082] According to a further aspect of the present invention there is provided a process for producing the composition of the present invention, the process comprising the steps of: i) mixing together one or more active ingredients and a pharma- ceutically acceptable carrier material in a suitable volatile solvent; ii) spray drying the mixture from step i).

[0083] Preferred volatile solvents include water, or lower alkyl alcohols (e.g., methanol, isopropanol, or, more particularly, ethanol), hydrocarbons (e.g., C 5-10 Examples of suitable solvents include organic solvents such as alkane, haloalkane (eg, dichloromethane), dimethylformamide, dimethylsulfoxide, ethyl acetate, acetone, and the like, or mixtures thereof.

[0084] Preferably, one or more active ingredients, a pharma- ceutically acceptable carrier material(s) as defined herein, and other optional ingredients as described herein (e.g., alkyl sugars as described below) are mixed together with a solvent to obtain a solution that can be spray dried.

[0085] Suitable pharma- ceutically acceptable carrier materials which may be used in the compositions of the invention include related materials which are solid under normal storage conditions, and which, in suitable combinations, are suitable (and / or approved) for pharmaceutical use and / or transmucosal (e.g. sublingual or especially intranasal) delivery, and which 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 (such as alkyl sugars) which is or may be present in the composition.

[0086] It is well known that obtaining a solid composition such as a powder that is both chemically and physically stable can present significant difficulties. If the physical form of the composition changes under normal storage conditions (e.g., from a free-flowing powder to agglomerates that are difficult to expel), the dose of the active ingredient can become unreproducible. This is particularly true when dispensing the composition from or through the nasal applicator described herein, where such agglomeration can make it completely impossible to dispense the active ingredient.

[0087] The compositions of the present invention may have a minimum shot weight as measured by an individual powder shot weight of about 80% of the target weight, such as about 85% (e.g., about 90%) up to about 120% (e.g., about 115%, such as about 110%), and / or an average powder shot weight of about 90% (e.g., about 95%) up to about 115% (e.g., about 110%, such as about 105%).

[0088] Similarly, in the case of multiple dose units containing two or more doses of the composition, such stability is important to ensure reproducibility of the dose of the active ingredient over time. Any of these issues may have adverse effects on the subject's health and / or may place the subject's well-being at serious risk.

[0089] For certain compositions of the present invention, exposure to atmospheric water may result in a powder composition with poor solid-state stability. For example, exposure to certain (e.g., relatively high) relative humidities may affect the physical form of the composition, for example, by deliquescence and / or by lowering the glass transition temperature of the composition and / or individual components of the composition, such as the carrier material, or in another way.

[0090] Thus, the compositions of the present invention, as well as pharmaceutical formulations and dispensing means (such as nasal applicators) containing them, 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 for tablets and capsules, as well as heat-sealed aluminum pouches and / or thermoformed plastics. Such containers may also include desiccants, such as silica gel and / or suitable molecular sieves, for example with a pore size of 3 Å or 4 Å.

[0091] The phrase "maintaining physical and chemical integrity" essentially means chemical stability and solid state stability.

[0092] "Chemical stability" includes that any composition of the present invention, when formulated into a pharmaceutical preparation or dosage form and / or loaded into a pharmaceutical dispensing device such as a nasal applicator or reservoir therefor (with or without appropriate pharmaceutical packaging), or otherwise capable of being stored in isolated solid form under normal storage conditions with only a minor degree of chemical degradation or decomposition of either the composition itself or any of the active ingredients contained therein.

[0093] The term "chemical stability" may also include "stereochemical" and / or "conformational" stability, which refers to resistance to stereochemical transformation, such as racemization, at one or more chiral centers within a Biopharmaceutical Compound molecule.

[0094] "Physical stability" or "solid state stability" includes that any composition of the present invention, when formulated into a pharmaceutical formulation or dosage form and / or loaded into a pharmaceutical dispensing means such as a nasal applicator or reservoir therefor (with or without appropriate pharmaceutical packaging), or otherwise may be stored in isolated solid form under normal storage conditions, with only minor degrees of solid state change (e.g., crystallization, recrystallization, loss of crystallinity, solid state phase transition (e.g., between a glassy or rubbery state, or to an aggregated form), hydration, dehydration, solvation, or desolvation) of either the composition itself or any of the active ingredients contained therein. "Physical stability" also includes retention of the correct conformation of a folded protein and / or retention of biological activity as defined below.

[0095] Examples of "normal storage conditions" for the compositions of the invention, whether in the form of a pharmaceutical formulation or dosage form, and / or when loaded into an applicator, device, drug reservoir (such as a canister or container), or otherwise, include temperatures of about -50°C to about +80°C (preferably -85°C (such as about -25°C) to about +75°C, such as about 50°C), and / or pressures of about 0.1 to about 2 bar (preferably atmospheric pressure), and / or exposure to at least about 460 lux of UV / visible light, and / or a relative humidity of about 5 to about 95% (preferably about 10 to about 40%) for an extended period of time (i.e., for about 12 months or more, such as about 6 months).

[0096] Under such conditions, the compositions of the invention (and / or the active ingredients contained therein), whether or not contained in a pharmaceutical dispensing device such as a nasal applicator or its reservoir (with or without appropriate pharmaceutical packaging), or otherwise, as appropriate, may be found to be chemically degraded / decomposed and / or solid state converted to less than about 15%, more preferably less than about 10%, especially less than about 5%.Those skilled in the art will appreciate that the above upper and lower limits of temperature and pressure represent the extremes of normal storage conditions, and that certain combinations of these extremes will not be experienced during normal storage (e.g., a temperature of 50°C and a pressure of 0.1 bar).

[0097] Notwithstanding the above definition of "normal storage conditions," the composition of the present invention (and / or the active ingredient contained therein) may be (a) at 0° C. or room temperature (e.g., about 20° C. or about 25° C.) or about −85° C., including −25° C., such as about 40° C., and 75% relative humidity, for at least about 3 months, including at least about 6 months or at least about 12 months; (b) at 0° C. or room temperature (e.g., about 20° C. or about 25° C.) or below about −85° C., including −25° C., such as about 30° C. (e.g., at about 65% relative humidity, including about 60%), for at least about 18 months, such as at least about 24 months, including about 36 months; and / or (c) UV light exceeding approximately 1 million lux for at least approximately 18 hours may be chemically (and / or stereochemically) degraded after storage by less than about 5%, such as less than about 4% (including less than about 3%, such as less than about 2.5% (e.g., less than about 2%), including less than about 1.5%, and / or even less than about 1%. Such chemical stability, and especially physical stability, is important in solid compositions such as powders to ensure that an appropriate dose is delivered to the patient.

[0098] Thus, the compositions of the present invention may be stored within a dosage form such as an applicator or its reservoir (with or without appropriate pharmaceutical packaging) or otherwise at any temperature (e.g., as low as about -85°C, such as -25°C, including 0°C or 20°C) up to about 25°C (e.g., up to about 30°C), preferably with fluctuations up to about 40°C or even up to about 50°C.

[0099] Particularly preferred pharma- ceutically acceptable carrier materials which may be used to produce the compositions of the present invention and which have the desirable properties described herein include the disaccharide components maltitol, sucralose, sucrose, isomalt, maltose, lactose, and especially trehalose.

[0100] For the polymeric material component, preferred pharma- ceutically acceptable carrier materials that may be used to produce the compositions of the invention and that have the desirable properties described herein include cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate, hydroxypropyl methylcellulose (hypromellose, HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), ethylhydroxyethylcellulose, carboxymethylcellulose (CMC), modified cellulose gums, microcrystalline cellulose, and sodium carboxymethylcellulose; starches, such as rice starch, tapioca starch, wheat starch, and more particularly corn starch and potato starch; pregelatinized starch, carboxymethyl starch, and moderately crosslinked starches, modified These include starch and starch derivatives such as sodium starch glycolate; polysaccharides including dextrins such as dextran, pullulan, inulin, and linear or branched dextrins such as dextrin, cyclodextrin, and maltodextrin; powdered tragacanth; waxy excipients such as cocoa butter and suppository wax; polyols such as solid polyethylene glycols; acrylic polymers such as carbomer and its derivatives; polyvinylpyrrolidone (povidone, PVP); cross-linked polyvinylpyrrolidone; polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; poly co-(methyl vinyl ether / maleic anhydride); and croscarmellose (e.g. croscarmellose sodium). Mention may also be made of hypromellose succinate (HPMCAS), copovidone, and polyvinyl alcohol (PVA, or PVOH).

[0101] More preferred polymeric materials include polysaccharides such as sodium carboxymethylcellulose, sodium starch glycolate, polyvinylpyrrolidone, and in particular hydroxypropyl methylcellulose (such as hypromellose 2906, preferably hypromellose 2910 (i.e., type "E"), and more preferably USP / NF hypromellose 2208 (i.e., type "K")), or dextrins, including, in particular, cyclodextrins (e.g., α-, β-, and γ-cyclodextrins and derivatives thereof, such as 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether β-cyclodextrin sodium salt, randomly methylated β-cyclodextrin, branched β-cyclodextrins, in particular 2-hydroxypropyl-β-cyclodextrin), and linear or branched dextrins, such as maltodextrin.

[0102] In any event, suitable polymers for use in the compositions of the present invention should have a sufficiently high molecular weight such that when used in any given amount in combination with the disaccharide, it can form a suitable carrier material for the active ingredient.

[0103] 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.

[0104] In this regard, it may be preferred for any given essential case below that the polymer has a relative viscosity value at 20°C of about 1000 mPa*s or less (more preferably about 120 or less, such as about 60 or less, especially about 10 or less), as measured. (a) The standard USP method for viscosity, i.e. <911> Method I and / or <912> a water-soluble polymer as a 2% solution of the polymer in water according to method I; and (b) USP method <911> By Method I, the water insoluble polymer as a 5% by weight solution of the polymer in a suitable organic solvent such as acetone, methanol, ethanol, isopropyl alcohol, ethyl acetate, acetonitrile, dichloromethane, toluene, and mixtures thereof, where the solvent system can be dry or partially aqueous.

[0105] One skilled in the art will understand which test is more suitable for the polymer being tested.

[0106] It is preferred that the carrier material is capable of causing the composition of the present invention to have a glass transition temperature (Tg) of: (a) is capable of being readily formulated into a pharmaceutical formulation or dosage form and / or its production in a hard and / or brittle, "glassy," amorphous, powdered physical form that can be readily loaded into a suitable dispensing means, such as a nasal applicator as described herein, or a drug reservoir and / or container within or associated with such an applicator; and (b) sufficiently high that after such pharmaceutical formulation, dosage form, or dispensing means, such as such applicator or reservoir, is packaged as described herein and thereafter subjected to an elevated external temperature (e.g., up to about 50° C. to about 80° C.), the composition remains in its glassy state rather than converting to a more viscous or rubbery state, and / or a crystalline state.

[0107] Such extreme external temperatures are often experienced inside vehicles in warm and / or sunny climates, where such vehicles are frequently parked under the hot sun for long periods of time, and the resulting heat can be enormous. If the Tg of the (e.g., powder) composition of the present invention is low, the composition may transform into such a viscous / rubbery state after being exposed to such high temperatures, which may result in inefficient dosing of the composition of the present invention, such as inefficient release of the composition (and also the dose(s) of active ingredient) from the dosing means, such as an applicator or a reservoir therefor, when the dosing means or applicator is actuated. Furthermore, a Tg that is too low may affect the disintegration and / or dissolution of the composition of the present invention in the form of a tablet for sublingual or oral use.

[0108] In this regard, the lowest measurable Tg of the composition of the present invention is preferably at least 10°C, such as at least about 15°C, such as at least about 20°C, including at least about 25°C, such as at least about 35°C, including at least about 40°C, such as at least about 50°C, including at least about 55°C, including at least about 60°C, when measured at a relative humidity of up to about 35%, such as up to about 30%, including up to about 25% (e.g., up to about 20%, such as less than about 15%, e.g., less than about 10%). By "lowest measurable Tg" we include that the composition of the present invention may include particles that are heterogeneous in nature. In particular, the particles may include distinct regions of carrier materials, or a composite mixture thereof, and thus may have individual and distinct Tg values. It will be apparent to those skilled in the art that the lowest measurable Tg value will have a strong impact on the physical stability of the composition.

[0109] The inventors have found that the compositions of the invention, particularly those comprising a combination of a disaccharide with a polymer (e.g. HPMC as defined herein) and / or especially a dextrin, when used alone or in isolation, can provide an appropriate level of physical and chemical stability of the composition and active ingredient compared to other carrier materials.

[0110] Thus, a particularly preferred combination of carrier materials includes lactose, such as α-D-lactose monohydrate, or more preferably trehalose, and a dextrin, in particular a cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin, or a maltodextrin having a DE greater than 11, such as maltodextrin 12DE, or a DE greater than 15, such as maltodextrin 19DE. The inventors have found that such combinations of carrier materials can be spray dried in appropriate ratios together with the active ingredient and alkyl sugars, if present, to produce compositions of the invention that have both the desired physical and chemical stability under normal storage conditions as defined herein.

[0111] The inventors have found that the relative amounts of disaccharide and polymeric components in the carrier material (particularly when the polymer is a dextrin) can be adjusted to ensure a desired level of physical and / or chemical stability of the active ingredient while at the same time not lowering the Tg of the compositions of the present invention in a manner that affects physical stability.

[0112] Depending on the active ingredient used, it has been found that disaccharide:polymer (e.g., dextrin) ratios of about 50:1 to about 1:50 by weight based on the total weight of the composition can work. Preferred ratios are in the range of about 10:1 to about 1:40 (including up to about 1:30 or up to about 1:20), for example, about 7:1 to about 1:5, including about 5:1, such as about 4:1, about 3:1, or about 2:1, for example, about 1:10, such as about 1:8, including 1:3 or 1:2, more preferably about 8:1 (e.g., about 7:1, about 3:1, about 2:1, or about 1:1) to about 1:8 (e.g., about 1:3 or about 1:2) disaccharide:polymer (e.g., dextrin) based on the total weight of the composition.

[0113] Thus, particularly preferred combinations of carrier materials include trehalose or lactose, such as α-D-lactose monohydrate, and a dextrin, in particular a cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin, or, more preferably, maltodextrin.

[0114] Maltodextrins are classified by their DE (dextrose equivalent); the higher the DE value, the shorter the average length of the glucose chains.

[0115] Preferred maltodextrins include those having a DE of 6 to 15, such as 8 to 12, or greater than 15, for example up to 47, such as 38, 39, preferably 23, 24, 25 or 26, or more preferably 16, 17, 18, 20, 21 or 22, and especially a DE of 19. Those skilled in the art will appreciate that maltodextrins with a DE of greater than 20 are referred to as "glucose syrups".

[0116] Maltodextrins with a DE above 15 have a lower average molecular weight than those with a DE below 15. All maltodextrins are mixtures of polysaccharides with different chain lengths, and maltodextrins with a DE above 15 have fewer higher molecular weight sugar units.

[0117] It has been found that maltodextrins with lower DE, such as maltodextrins with a DE of 12 or less, contain longer polysaccharide chains (e.g., having about 24 glucose units or more) and can form aggregates when present in aqueous solution with other ingredients, such as active ingredients like sucrose esters and / or surfactants, and have a tendency to form helical structures that result in a cloudy solution prior to spray drying. This cloudiness can cause stability and / or processability problems during manufacturing, necessitating the use of an in-line filter.

[0118] It has been found that the aforementioned haze problem can be alleviated to some extent by reducing the relative amount of maltodextrin included in the compositions of the present invention, although this can be achieved by increasing the amount of other ingredients such as other carrier materials (e.g., disaccharides), active ingredients, or certain additives such as sucrose esters; the higher the molecular weight of the maltodextrin, the less needs to be included and the more, e.g., disaccharides or sucrose esters, needs to be added to alleviate the haze.

[0119] When adding more sucrose esters to reduce this haze, more may need to be added than is necessary to provide the appropriate (e.g., physical, chemical and / or biological) effect, including absorption-enhancing effects, as described herein. Conversely, increasing the amount of disaccharide relative to maltodextrin in the carrier material may have a negative impact on the Tg and therefore the solid state stability of the compositions described herein.

[0120] It has been found that such problems can be reduced, and perhaps avoided altogether, by using an entirely different maltodextrin, i.e., one having a higher DE, such as one having a DE greater than 15, e.g., a DE of 18, 20, or more preferably a DE of 19.

[0121] Notwithstanding the above, polymers, including maltodextrin, suitable for use in the powder compositions described herein should nevertheless have a sufficiently high molecular weight such that when used in any given amount (in combination with disaccharides) they can form a suitable carrier material for the active ingredient, including providing an adequate degree of physical stability.

[0122] Mixtures from any of the foregoing lists of disaccharide and / or polymeric materials (including maltodextrin) may be used.

[0123] The amount of carrier material that may be employed in the compositions of the present invention (whether a unit dose of the composition is included in a dosage form or otherwise) is typically in the range of about 5% to about 99.9% by weight, including about 50% to about 75% by weight (e.g., about 25% by weight, including about 35% by weight) to about 85% by weight, including up to about 99% by weight (e.g., up to about 95% by weight or about 90% by weight), based on the total weight of the composition.

[0124] Regardless of their ratio in any final mixture, the composition of the present invention comprises a spray-dried carrier material comprising a combination of disaccharides and polymeric materials (e.g., dextrins). Thus, the carrier material can be prepared by spray-drying the relevant components to form a composite carrier material before either spray-drying the carrier material together with other essential components to form the composition of the present invention, or more preferably, made in situ by spray-drying all of the essential components of the composition of the present invention together. The composition of the present invention can be prepared by spray-drying in the presence of a processing aid such as L-leucine, isoleucine, trileucine, L-tyrosine, or L-arginine.

[0125] The compositions of the invention may contain at least one biopharmaceutical compound. By "biopharmaceutical compound," this definition includes biological agents or biologics that are produced from or contain components of a living organism or its products.

[0126] Biopharmaceutical compounds include proteins and / or oligo- or polypeptides, enzymes, antibodies / portions thereof, vaccines, nucleotides etc., or antibody analogs, antibody mimetics, immunoglobulins, immunomodulators, or combinations thereof. Biopharmaceutical compounds also include any of the following: blood (e.g., blood cells suspended in blood), blood components (e.g., human blood components), cells, allergens (e.g., pollen, house dust mites, animal dander, mold, drugs, insect venom, and various foods), genes, viruses (e.g., animal viruses, plant viruses, bacterial viruses, bacteriophages, archaeal viruses, helper viruses, mycoviruses, neurotropic viruses, novel viruses, emergent viruses, oncoviruses, orphan viruses, passenger viruses, proviruses, retroviruses, slow viruses, DNA viruses, dsDNA viruses, dsDNA-RT viruses, dsRNA viruses, nucleocytoplasmic large DNA viruses (NCLDVs), negative sense ssRNA viruses, RNA viruses, ssDNA viruses, ssRNA viruses, satellite viruses (single-stranded RNA satellite viruses, double-stranded DNA satellite viruses, and single-stranded RNA viruses) The biological agent or biologic may include a nucleic acid molecule, ...

[0127] It is to be understood that such proteins and / or oligo- or polypeptides that may be used include those occurring naturally as well as their synthetic analogs, semi-synthetic, synthetic, proteolytic, etc. Preferably, such proteins and / or oligo- or polypeptides are naturally occurring or recombinant proteins and / or peptides. More preferably, such proteins, oligo- and / or polypeptides have a molecular weight of more than 5 kDa, e.g. more than 10 kDa, e.g. more than 20 kDa, including more than 30 kDa.

[0128] Types of naturally occurring proteins, oligopeptides and / or polypeptides include cytoskeletal proteins such as actin, Arp2 / 3, Arp2 / 3, coronin, dystrophin, formin, FtsZ, gloverin, keratin, myosin, tubulin; extracellular matrix proteins such as collagen, elastin, F-spondin, pikachurin, fibronectin; globular proteins such as plasma proteins (e.g., serum amyloid P component), coagulation factors such as complement proteins (e.g., C1 inhibitor, C3 convertase), factor X protein (Fc1, Fc2, Fc3, Fc4, Fc5, Fc6, Fc7, Fc8, Fc9, Fc9, Fc10, Fc11, Fc12, Fc13, Fc14, Fc15, Fc16, Fc17, Fc18, Fc19, Fc20, Fc21, Fc22, Fc31, Fc32, Fc33, Fc34, Fc35, Fc36, Fc37, Fc38, Fc39, Fc44, Fc39, Fc45, Fc46, Fc47, Fc48, Fc49 ... Factor III, protein C, protein S, protein Z, protein Z-related protease inhibitor, thrombin, von Willebrand factor, acute phase proteins (e.g., C-reactive protein); hemoproteins (e.g., hemoglobin), cell adhesion proteins (e.g., cadarin, ependymin, integrins, NCAM, selexin), transmembrane transport proteins (e.g., CFTR, glycophorin D, scramblase), ion channels (e.g., potassium channels, calcium channels, sodium channels, glucose transporters), ho monocytes and growth factors (e.g., colony stimulating factors (CSF), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), transforming growth factor (TGF), vascular endothelial growth factor (VEGF)), transmembrane receptors (e.g., rhodopsin), intracellular receptors (e.g., estrogen receptor), DNA binding proteins (e.g., histones, protamines), transcription and regulatory proteins (e.g., CI proteins, C-myc, FOXP2, FOXP3, MyoD, p53), RNA binding proteins (e.g., SRRT), immune system proteins proteins (e.g. immunoglobulins, major histocompatibility antigens, T cell receptors), nutrient storage and / or transport proteins (e.g. ferritin), chaperone proteins (e.g. GroEL), cytokines and analogs (including recombinant cytokines), such as IL-1 receptor antagonists, anakinra, IL-4, IL-6, IL-10, IL-12, IL-17, IL-23, IL-27, IL-33, IL-35 or, more particularly, IL-2, IL-7, IL-15 or IL-21, TNF-alpha, IFN-alpha, pifonakin, movenakin,Adargileukin alfa, aldesleukin, celmoleukin, denileukin diftitox, pegaldesleukin, teceleukin, tucotuzumab Cytokines (e.g., bone morphogenetic proteins (BMPs), granulocyte colony-stimulating factor (G-CSF), interferon alpha, IL-11), enzymes (e.g., oxidoreductases, transferases, hydrolases, lyases, isomerases, ligases), proenzymes (e.g., angiotensinogen, trypsinogen, chymotrypsinogen, pepsinogen, prothrombin, plasminogen, procaspase), cytokines (e.g., cytokines ... digestive enzyme mixtures including α-glucosidase, α-D-galactosidase, β-glucocerebrosidase, idronate-2-sulfatase, n-acetylgalactosamine-6-sulfatase, n-acetylgalactosamine-4-sulfatase, pancreatic enzyme products (PEP), pancrelipase, lipases, proteases and amylases; alteplase, reteplase, and tenecteplase; dornase alfa, pegloticase, rasburicase, L-asparaginase, collagenase, pegademase (bovine), glucarpidase, ocriplasmin; and lactase (asperillus oryzae, Aspergillus niger, Kluyveromyces fragilis, Kluyveromyces lactis or E. coli); human peptide hormones such as anti-Muellerian hormone, adiponectin, adrenocorticotropic hormone, angiotensinogen, angiotensin, antidiuretic hormone, atrial natriuretic peptide, cholecystokinin, corticotropin releasing hormone, cortistatin, endothelin, follicle stimulating hormone, galanin, gastrin,Glucagon-like peptide-1, glucagon and glucagon-like peptide-1 analogs, dasiglucagon, gonadotropin-releasing hormone, growth hormone-releasing hormone, hepcidin, human chorionic gonadotropin, human placental lactogen, growth hormone, inhibin, leptin, lipotropin, luteinizing hormone, melanocyte-stimulating hormone, motilin, orexin, osteocalcin, pancreatic polypeptide, prolactin, prolactin-releasing hormone, relaxin, renin, growth hormone-inhibiting hormone, growth hormone-releasing ... long-term hormone release inhibiting hormone, somatotropin release inhibiting factor, somatotropin release inhibiting hormone, thrombopoietin, thyrotropin, thyrotropin releasing hormone, guanylin uroguanylin, tetracosactide, mecasermin, somapsitan, pegvisomant, desemopressin, terlipressin, lypressin, ornipressin, argipressin, demoxitocin, carbetocin, octreotide, vapreotide, elcatonin, or combinations thereof.

[0129] Other types of proteins, oligopeptides, and / or polypeptides may include viral or bacterial proteins. The term "viral or bacterial proteins" includes both components and products of viruses or bacteria, preferably proteins encoded by the genome of viruses or bacteria. Preferably, the viral proteins are components of the capsid or envelope of the virus. The viral proteins may be the spike (S) protein of coronavirus or a portion or variant thereof, the hemagglutinin (H) or neuraminidase (N) protein of influenza virus or a portion or variant thereof, the L3 protein of adenovirus or a portion or variant thereof, the fusion protein of respiratory syncytial virus (RSV) or a portion or variant thereof.

[0130] The protein, oligopeptide or polypeptide may be human insulin, cyclosporine, insulin, interferon beta, interferon gamma, TPA, albumin, HGH, factor VIII, erythropoietin, calcitonin, oxytocin, vasopressin, voclosporin, substance P, kassinin, neurokinin A, eledosin, neurokinin B, VIP (vasoactive intestinal peptide, PHM27), PACAP (pituitary adenylate cyclase activating peptide), peptide PHI27 (peptide Histidine Isoleucine 27), GHRH1-24 (Growth Hormone Releasing Hormone 1-24), Glucagon, Secretin, NPY (Neuropeptide Y), PYY (Peptide YY), APP (Avian Pancreatic Polypeptide), PPY Pancreatic Polypeptide, Proopiomelanocortin (POMC) Peptide, Endomorphin, Enkephalin Pentapeptide, Prodynorphin Peptide, Calcitonin, Amylin, AGG01, B-type Natriuretic Peptide (BNP) Lactotripeptide, Traditional Chinese Medicine Colla Corii Asini-derived peptide components, buserelin, gonadorelin, goserelin, histrelin, leuprorelin, nafarelin, triptorelin, abarelix, cetrorelix, degarelix, ganirelix, elagolix, relugolix, teverelix, desmopressin, liraglutide, exenatide, lixisenatide, albiglutide, dulaglutide, semaglutide, somatostatin and similar The drug is not a peptide that contains one or more of the following: octreotide, pasireotide, lanreotide, teriparatide, or buserelin, gonadorelin, goserelin, histrelin, leuprorelin, nafarelin, triptorelin, abarelix, cetrorelix, degarelix, ganirelix, elagolix, relugolix, teverelix, leuprolide, liraglutide, octreotide, or desmopressin.

[0131] Biopharmaceutical compounds that may be used in the compositions of the present invention also include antibodies. The term "antibody" will be understood to include polyclonal and monoclonal antibodies. The term also includes all isotypes of antibodies, such as: IgG, IgA, IgM, IgD, and IgE. The antibody may be a polyclonal antibody, or preferably a monoclonal antibody.

[0132] In some circumstances, particularly when the antibody is to be administered repeatedly to a human patient, it is preferred if the monoclonal antibody is a human monoclonal antibody or a humanized monoclonal antibody. Suitable monoclonal antibodies can be prepared by known techniques, such as those described in 'Monoclonal Antibodies Meeting the Challenges in Manufacturing, Formulation, Delivery and Stability of Final Drug Product' Steven Shire, (Woodhead Publishing, 2015), Current Trends in Monoclonal Antibody Development and Manufacturing', Shire et al. (Springer New York, 2010), 'Therapeutic Monoclonal Antibodies: From Bench to Clinic', Zhiqiang An (Wiley 2009), 'Monoclonal Antibodies; A manual of techniques', H Zola (CRC Press, 1988) and 'Monoclonal Hybridoma Antibodies: Techniques and Application', SGR Hurrell (CRC Press, 1982), the relevant disclosures of which are incorporated herein by reference. Polyclonal antibodies can be generated which are multispecific or monospecific.

[0133] In one embodiment, the antibody may be a murine, human (including humanized), or chimeric antibody. Chimeric antibodies are discussed by Neuberger et al (1998, 8th International Biotechnology Symposium Part 2, 792-799), the relevant disclosure of which is incorporated herein by reference. Suitably prepared non-human antibodies may be "humanized" in known manner, for example, by inserting the complementarity determining regions (CDRs) of a murine antibody into the framework of a human antibody. The antibodies may be human antibodies, in the sense that they have the amino acid sequence of a human antibody with specificity for a desired antigen or epitope, but they may be prepared using methods known in the art that do not require human immunization. For example, transgenic mice containing essentially human immunoglobulin genes are available (see Vaughan et al (1998) Nature Biotechnol. 16, 535-539), the relevant disclosure of which is incorporated herein by reference.

[0134] Non-limiting examples of (monoclonal) antibodies that may be used according to the invention are edrecolomab (L01XC01), tositumomab (V10XA53), rituximab (L01XC02), basiliximab (LO4AC02), infliximab (L04AB02), adalimumab (L04AB04), ibritumomab (V10XX02), vedolizumab (L04AA33), trastuzumab (L01XC03), gemtuzumab ozogamicin (L01XC05), cetuximab (L01XC06), bevacizumab (L01XC07), panitumumab (L01XC08), erythrocyte serine monocytogenes (ECN) and erythrocyte serine monocytogenes (ECN). C08), denosumab (M05BX04), evolocumab (C10AX13), brodalumab (L04AC12), erenumab (N02CD01), catumaxomab (L01XC09), ofatumumab (L01XC10), ipilimumab (L01XC11), erenumab-aooe, brentuximab vedotin (L01XC12), pertuzumab (L01XC13), trastuzumab emtansine (L01XC14), obinutuzumab (L01XC15), dinutuximab beta (L01XC16), nivolumab (L01X C17), natalizumab (L04AA23), ixekizumab (L04AC13), reslizumab (R03DX08), dupilumab (D11AH05), pembrolizumab (L01XC18), blinatumomab (L01XC19), ramucirumab (L01XC21), necitumumab (L01XC22), elotuzumab (L01XC23), daratumumab (L01XC24), mogamulizumab (L01XC25), inotuzumab ozogamicin (L01XC26), olaratumab (L01XC27), durvalumab (L01XC28), bermekimab ( L01XC29), avelumab (L01XC31), atezolizumab (L01XC32), cemiplimab (L01XC33), moxetumomab passudotox (L01XC34), tafasitamab (L01XC35), enfortumab vedotin (L01XC36), polatuzumab vedotin (L01XC37), isatuximab (L01XC38), belantamab mafodotin (L01XC39), dostarlimab (L01XC40), trastuzumab deruxtecan (L01XC41), bispecific T-cell engagers (BiTEs, blinatumab, etc.),solitomab, AMG330, MT112, MT111, BAY2010112, MEDI-565, fremanezumab, galcanezumab-gnlm, eptinezumab-jjmr, ustekinumab, eculizumab, omalizumab, or a combination thereof.

[0135] Other non-limiting examples of antibodies that may be used in accordance with the present invention include etanercept, tocilizumab, siltuximab, sarilumab, olokizumab, sirukumab, tildrakizumab, guselkumab, BI-655066, LY3074828, secukinumab, CNTO6785, bimekizumab, SCH-900117, MLDL1278A, bococizumab, briakinumab, muromonab, abciximab, alemtuzumab, certolizumab, canakinumab, belimumab, idarucizumab, mepolizumab. , alirocumab, ocrelizumab, emicizumab, benralizumab, burosumab, lanadelumab, emapalumab, ibalizumab, ravulizumab, romosozumab, risankizumab, brolucizumab, crizanlizumab, sacituzumab, efalizumab, nebacumab, daclizumab, omalizumab, ustekinumab, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan, satralizumab, inebilizumab, teprotumumab, evinacumab, amivantamab, tralokinumab, anifrolumab , loncastuximab tesirin, atortivimab, maftivimab, odesivimab-ebgn, margetuximab-cmkb, ansuvimab-zykl, aducanumab, aducanumab-avwa, regdanvimab, sotrovimab, tisotumab vedotin, tisotumab vedotin-tftv, tezepelumab, tezepelumab-ekko, teventafsp, teventafsp-tebn, faricimab, faricimab-svoa, stimlimab, stimlimab-jome, leratolimab, tixagevimab, silgavi mab, casirivimab, imdevimab, tislelizumab, omburtamab, spesolimab, nirsevimab, teclistamab, ublituximab, mosunetuzumab, tremelimumab, penprimab, lekanemab, inolimomb, teplizumab, donanemab, mirvetuximab soravtansine, toripalimab, sintilimab, retifanlimab, oportuzumab monatox, narsoplimab, or combinations thereof.

[0136] Biopharmaceutical compounds that may be used in the compositions of the invention also include antibody mimetics. Non-limiting examples of antibody mimetics that may be used include affibody molecules (such as ABY-025), affilins (such as SPVF2801), affimers, affitins, alphabodies (such as CMPX-1023), anticalins, avimers, designed ankyrin repeat proteins (DARPins such as MP0112), finomers, Kunitz domain peptides (such as Ecallantide (Kalbitor)), adnectins and monobodies (such as Pegdinetanib (Angiocept)), nanoCLAMPs, single domain antibodies such as camelid antibodies, and V-antibody derived from IgNARs. NAR These include fragments, cartilaginous fish derived (immunoglobulin neoantigen receptors), bivalent single domain antibodies (such as caplacizumab (Cablivi)), and armadillo repeat proteins engineered below armadillo repeat proteins, peptide aptamers, and knottins, or combinations thereof.

[0137] In the alternative, the compositions of the invention include antibody fragments (F(ab), e.g., ranibizumab (S01LA04), bivalent antibody fragments (F(ab') 2 ), and related molecules such as variable fragments (Fv) and other fragments which retain their antigen-binding sites, single chain variable fragments (scFv), (which may be bivalent (e.g., diabodies) or trivalent), single domain antibodies (dAbs), or combinations thereof. By "bivalent" it is meant that antibodies, antibody mimetics, antibody derived molecules, and related molecules have two antigen-binding sites. In contrast, monovalent molecules have only one antigen-binding site. A general review of the techniques involved in the synthesis of antibody-derived molecules which retain their specific binding sites can be found in Winter & Milstein (1991) Nature 349, 293-299.

[0138] "ScFv molecule" means a V H and V LThese include molecules in which partner domains are linked via flexible oligopeptides. There are several fold advantages to using antibody derived molecules rather than whole antibodies. The smaller size of the fragments may result in improved pharmacological properties such as better penetration to target sites. Effector functions of whole antibodies such as complement binding are removed. Fab, Fv, ScFv and dAb antibody derived molecules can all be expressed in and secreted from antibody derived molecules, thus allowing for the facile production of large amounts of the molecules.

[0139] It is understood that such antibodies, antibody mimetics, antibody derived molecules, and related molecules may be monospecific, bispecific, or multispecific, or a combination thereof, where bispecific or multispecific includes the meaning that they bind to two or more different targets.

[0140] The term "antibody" also includes antibody-like molecules that can be screened and selected using both in vivo and in vitro based selection methods, including yeast surface display, prokaryotic or bacterial surface display, mammalian surface display, ribosome display, mRNA display, cDNA display, CIS display, covalent antibody display (CAD), in vitro compartmentalization (IVC), and phage display techniques, or other random selection techniques for molecules.

[0141] Biopharmaceutical compounds that may be used in the compositions of the invention also include the following antibodies / immunoglobulins: Immunoglobulin, normal human, for extravascular administration (J06BA01), Immunoglobulin, normal human, for intravascular administration (J06BA02), Anti-D(rh) immunoglobulin (J06BB01), Tetanus immunoglobulin (J06BB02), Chickenpox / Zoster immunoglobulin (J06BB03), Hepatitis B immunoglobulin (J06BB04), Rabies immunoglobulin (J06BB05), Rubella immunoglobulin (J06BB06), Vaccinia immunoglobulin (J06BB07), Staphylococcus aureus immunoglobulin (J06BB08), Cytomegalovirus immunoglobulin (J06BB09), rovirus immune globulin (J06BB09), diphtheria immune globulin (J06BB10), hepatitis A immune globulin (J06BB11), encephalitis, tick-borne immune globulin (J06BB12), pertussis immune globulin (J06BB13), measles immune globulin (J06BB14), parotitis immune globulin (J06BB15), palivizumab (J06BB16), motavizumab (J06BB17), raxibacumab (J06BB18), bezloxumab (J06BB21), obiltoxaximab (J06BB22), anthrax immune globulin (J06BB19), combinations (J06BB30), or combinations thereof.

[0142] The compositions of the invention are particularly useful where the biopharmaceutical compound comprises one or more vaccines.

[0143] Cost is an important factor when considering improvements in vaccination programs in developing countries. One way to reduce vaccine costs is to generate more stable vaccine compositions, which do not require a cold chain, for example, making them cheaper and easier to ship and store. Furthermore, loss of vaccine activity under suboptimal storage conditions is thought to contribute significantly to ineffective vaccination programs (Brandau et al, 2003). The World Health Organisation (WHO) requires a minimum titer of vaccine preparations after one week of storage at 37°C. However, many vaccines can lose more than 50% of their potency when stored at room temperature for just one hour (Plotkin & Orenstein, 2004).

[0144] In one embodiment, the vaccine can be a live or active vaccine, an attenuated vaccine, a live attenuated vaccine (e.g., measles, mumps, and rubella (MMR) vaccine, varicella (chickenpox) vaccine), an inactivated vaccine, or a killed vaccine (e.g., polio vaccine, influenza vaccine).

[0145] In one embodiment, the vaccine may be a whole pathogen vaccine, a subunit vaccine, or a nucleic acid vaccine, such as, for example, a live attenuated vaccine, an inactivated vaccine, a subunit vaccine, a recombinant vaccine, a polysaccharide vaccine, a conjugate vaccine, a toxoid vaccine, a viral vector vaccine, and / or a messenger RNA (mRNA) vaccine.

[0146] In another embodiment, the vaccine is a subunit vaccine (e.g., Hepatitis B, acellular pertussis vaccine, influenza, HIV, HPV, malaria, gonorrhea, polio, Zika, smallpox, monkeypox, various types of cancer (such as cancers expressing and / or overexpressing HER2 (human epidermal growth factor receptor 2), EGFR (epidermal growth factor receptor), CD-20, VEGF (vascular endothelial growth factor), VEGFR (vascular endothelial growth factor receptor), CEA (carcinoembryonic antigen), CA-125 (cancer antigen 125), MUC-1 (mucin 1), or MAGE (melanoma associated antigen)), more particularly acute respiratory distress syndrome (ARDS) and / or severe acute respiratory syndrome (SA). The vaccine may be a protein subunit vaccine, e.g. a recombinant vaccine or a virus-like particle (VLP) vaccine (including capsid virus-like particles, virus-like particles derived from viral capsids) against acute respiratory diseases caused by respiratory syncytial viruses (RSV) such as RSV (RSV) or coronaviruses (including any variants), in particular COVID-19, where for example the protein is the spike (S) protein or a part thereof; a polysaccharide vaccine, e.g. a pneumococcal polysaccharide vaccine, a meningococcal vaccine; or a conjugate vaccine, e.g. a pneumococcal conjugate vaccine, a haemophilus influenza type B conjugate, a meningococcal conjugate vaccine, MenACWY, etc. The subunit vaccine may be produced in different systems, e.g. an E. coli system, a yeast cell system, an insect cell system, a plant system, or a mammalian cell system.

[0147] In yet another embodiment, the vaccine can be a nucleic acid vaccine (such as a DNA vaccine or an RNA vaccine, preferably where the RNA is messenger RNA (mRNA)). Examples of such vaccines include DNA vaccines against cancer, DNA vaccines against tuberculosis, DNA vaccines against Edwardsiella tarda, DNA vaccines against HIV, DNA vaccines against anthrax, DNA vaccines against influenza, DNA vaccines against dengue fever, DNA vaccines against typhoid fever, DNA vaccines against various antigens (e.g., p CE6 , p CE18, S iniae DNA vaccines in the form of plasmids pSia10, pIDSia10, pIDOmpU, pSiVa1, etc.), prophylactic DNA vaccines, non-replicating mRNA vaccines, in vivo self-replicating mRNA vaccines, in vitro dendritic cell non-replicating mRNA vaccines, dendritic cell vaccines, personalized cancer vaccines (e.g., where an RNA sequence within the vaccine is designed to code for a cancer-specific antigenic molecule), RNA vaccines against SARS diseases (such as those caused by the coronavirus SARS-CoV-2, i.e., coronavirus 2019, or COVID-19).

[0148] In yet another embodiment, the vaccine may be a toxoid vaccine (e.g., a tetanus toxoid (TT) vaccine, a diphtheria vaccine, a diphtheria, pertussis, and tetanus (DPT) vaccine, or a botulinum toxoid vaccine). For the avoidance of doubt, toxoid vaccines include, for example, those that use a toxin made by a disease-causing bacterium.

[0149] In yet another embodiment, the vaccine can be a viral vector vaccine. The viral vector can be a poxvirus (e.g., vaccinia virus, modified vaccinia Ankara (MVA), avipox, fowlpox), retrovirus (e.g., lentivirus), vesicular stomatitis virus (VSV), measles virus, adenovirus, adeno-associated virus, cytomegalovirus, Sendai virus, herpes simplex virus, or combinations thereof. The viral vector can be a live or active viral vaccine, an attenuated viral vaccine, a live attenuated viral vaccine, an inactive or killed viral vaccine.

[0150] In yet another embodiment, the vaccine may be a bacterial vector vaccine. The bacterial vector may be Mycobacterium bovis BCG, Lactococcus lactis, Salmonella, Salmonella spp, Bacillus subtilis, Pseudomonas aeruginosa, Shigella, Shigella spp, Vibrio Cholera, Vibrio anguillarum, Corynebacterium pseudotuberculosis, Bordetella pertussis, Streptococcus, Listeria Monocytogenes, Escherichia coli, Yersinia enterocolitica, Mycobacterium smegmatis, Lactobacillus, or combinations thereof.

[0151] In yet another embodiment, the vaccine may be a conjugate vaccine, for example against pneumococcal bacterial infection.

[0152] In yet another embodiment, the vaccine may be a recombinant vector vaccine.

[0153] In yet another embodiment, the vaccine may be a nanoparticle-based vaccine (e.g., a mesoporous silica nanoparticle (MSN)-based vaccine or a solid lipid nanoparticle (sLNP)-based vaccine), or a virus-like particle (VLP) vaccine (e.g., a capsid VLP vaccine or a VLP vaccine derived from a viral capsid), each of which vaccines may be used to treat influenza, HIV, HPV, malaria, gonorrhea, polio, Zika, smallpox, monkeypox, bacterial infections (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, or Mycobacterium tuberculosis, or various types of cancer (such as cancers expressing and / or overexpressing HER2 (human epidermal growth factor receptor 2), EGFR (epidermal growth factor receptor), CD-20, VEGF (vascular endothelial growth factor), VEGFR (vascular endothelial growth factor receptor), CEA (carcinoembryonic antigen), CA-125 (cancer antigen 125), MUC-1 (mucin 1), or MAGE (melanoma associated antigen), colorectal cancer, breast cancer, prostate cancer, lung cancer, cervical cancer, and ovarian cancer), more particularly acute respiratory diseases caused by viruses such as respiratory syncytial virus (RSV) or coronaviruses (including any variants), such as acute respiratory distress syndrome (ARDS) and / or severe acute respiratory syndrome (SARS), in particular COVID-19. Nanoparticle or VLP-based vaccines may also carry and / or deliver proteins or portions thereof (e.g., viral, bacterial, mammalian, fungal, or parasitic proteins, which may be membrane proteins, surface proteins, fusion proteins, envelope proteins, structural proteins, spike proteins, nucleocapsid or capsid proteins, or combinations thereof), DNA, lipids, polysaccharides, toxins, (such as bacterial toxins), mRNA, RNA, or viral vaccines (such as live or active viral vaccines, attenuated viral vaccines, live attenuated viral vaccines, inactivated or killed viral vaccines, etc.).Nanoparticle or VLP-based vaccines may also further carry and / or deliver adjuvants and immune stimulatory molecules such as TLR agonists and cytokines.

[0154] Optionally, the composition of the present invention in the form of a vaccine composition may contain an adjuvant. The term "adjuvant" is intended to mean any compound added to a formulation to increase the biological effect of one or more products of the present invention in the formulation. The adjuvant may be one or more of zinc, copper, or silver salts with different anions, such as, but not limited to, fluoride, chloride, bromide, iodide, thiocyanate, sulfite, hydroxide, phosphate, carbonate, lactate, glycolate, citrate, borate, tartrate, and acetate with different acyl composition. Adjuvants can also be organic polycations (e.g., polyethyleneimine (PEI)), cationic polymers such as cationic cellulose ethers, cationic cellulose esters, deacetylated hyaluronic acid, chitosan, cationic dendrimers, cationic synthetic polymers such as poly(vinylimidazole), and cationic polypeptides such as polyhistidine, polylysine, polyarginine, and peptides containing these amino acids, cationic (N3) or anionic (L3) lipid adjuvants. Depending on the host species, various adjuvants can be used to increase the immunological response.Such adjuvants include toxoid adjuvants, cytokines, natural killer T cell (NKT) ligands (e.g., alpha-galactosylceramide (alphaGalCer) and analogs), C-type lectin receptor (CLR) ligands, toll-like receptor (TLR) agonists (e.g., CpG, CpG ODN, poly I:C, glucopyranosyl lipid A (GLA), monophosphoryl lipid A (MPL), resiquimod (R848), flagellin, imidazoquinolines (e.g., imiquimod)), STING ligands (e.g., STING agonist: bis-(3',5')-cyclic dimeric guanosine monophosphate (c-di-GMP or cdGMP)), muramyl dipeptide, the "Iscoms" of EP 109942, EP 180564, and EP 231039, lysorcytin, and the like. Any surfactant, polyion, peptide, limpet hemocyanin (KLH), aluminum salts, alum, Alhydrogel, aluminum hydroxide, aluminum phosphate, saponin-based adjuvants (e.g., Matrix M1), delta inulin microparticle adjuvants (e.g., Advax), DEAE-dextran, neutral oils (e.g., Miglyol), vegetable oils (e.g., peanut oil), squalene (e.g., shark squalene (shark squalene)), glycerol, glycerol-based adjuvants (e.g., glycerol-based adjuvants), ... squalene) emulsions (e.g., MF59, AS03, Freund's complete or incomplete adjuvant, Montanide ISA51, Montanide ISA720), liposomes (e.g., DOPE (1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine):DDA (dimethyldioctadecylammonium bromide salt) multilamellar liposomes, N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP) liposomes), lipid nanoparticles, poly(lactic-co-glycolic acid) (PLGA) nanoparticles, Pluronic polyols or Ribi adjuvant systems, nucleic acids (e.g., single-stranded RNA), Hiltonol, or combinations thereof. "Pluronic", "Alhydrogel", "Hiltonol", and "Montanide" are registered trademarks.

[0155] Such vaccines would be suitable for use in vaccinating against, reducing the risk of, preventing, or combating diseases, disorders, and / or conditions. The diseases, disorders, and / or conditions may be caused, for example, by viral, bacterial, and / or parasitic infections. Alternatively, the diseases, disorders, and / or conditions may have an intrinsic and / or genetic / environmental etiology, including autoimmune diseases, cardiovascular diseases, inflammatory diseases, metabolic diseases, and / or cancer.

[0156] In a preferred embodiment, the virus causing the disease, disorder and / or condition is an orthomyxovirus (e.g., influenza virus such as influenza A(H1N1), A(H3N2), A(H7N7), A(H3N8), isavirus, or thogotovirus), parvovirus (e.g., adeno-associated virus, canine parvovirus (CPV), feline panleukopenia virus (FPV), mink enteritis virus (MEV)), adenovirus, pneumovirus, (e.g. respiratory syncytial virus (RSV)), herpesviruses (e.g. herpes simplex virus (HSV), feline herpesvirus type 1 (FHV-1), equine herpesvirus (EHV), varicella zoster virus), matonaviruses (e.g. rubella virus), rhabdoviruses (rabies virus), retroviruses (e.g. lentivirus, human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV)), poxviruses (e.g. , vaccinia virus, smallpox virus, monkeypox), paramyxovirus (e.g., measles virus, Newcastle disease virus, mumps virus, canine distemper virus (CDV), canine parainfluenza virus (CPi)), papillomavirus (e.g., human papillomavirus (HPV)), reovirus (e.g., rotavirus), picornavirus (e.g., poliovirus, hepatitis A virus, hepatitis B virus), calivirus (e.g., viruses such as Norwalk virus, Sapovirus, feline calicivirus (FCV)), norovirus, flavavirus (e.g., West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus, Japanese encephalitis virus), togavirus (e.g., alphavirus), or coronavirus (e.g., severe acute respiratory syndrome coronavirus such as SARS-CoV-1 or SARS-CoV-2).

[0157] In a preferred embodiment, the bacteria is a coccus bacterium (e.g., Chlamydia trachomatis, Neisseria gonorrhoeae, Neisseria meningitidis, Staphylococcus aureus, Staphylococcus haemolyticus, Streptococcus agalactiae, Streptococcus bovis, Streptococcus equi, Streptococcus pyogenes), a bacillus bacterium (e.g., Bacillus anthracis, Bordetella pertussis, Bordetella bronchiseptica, Chlamydophila pneumoniae, Clostridium tetani, Corynebacterium diphtheriae, Legionella pneumophila, Mycobacterium leprae, Mycobacterium tuberculosis, Vibrio cholerae, Rickettsia), a spiral (spirochete or spirilla) bacterium (e.g., Borrelia burgdorferi, Leptospira, Leptospira interrogans, Treponema pallidum, Treponema denticola), Neorickettsia risticii, or mycoplasma (e.g., Mycoplasma gallisepticum, Mycoplasma hyopneumoniae).

[0158] In preferred embodiments, the parasite may be a protozoan (eg, Giardia, Plasmodium), a helminthic parasite (eg, flatworms, nematodes), or an ectoparasite (eg, ticks, fleas, lice, mites).

[0159] In preferred embodiments, the autoimmune disease may be uveitis, atopic dermatitis, hidradenitis supporativa, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type 1 diabetes, myasthenia gravis, Guillain-Barre syndrome, osteoarthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, paroxysmal nocturnal hemoglobinuria, neuromyelitis optica, chronic idiopathic urticaria, migraine, or cystic fibrosis.

[0160] In one embodiment, the cancer may be a carcinoma, sarcoma, lymphoma, leukemia, germ cell cancer, or blastoma. Preferably, the cancer is bone and muscle cancer, brain and nervous system cancer (e.g., glioblastoma, glioma, neuroblastoma, chordoma), breast cancer (e.g., breast cancer, medullary carcinoma, phyllodes tumor), endocrine system cancer (e.g., thyroid cancer, multiple endocrine neoplasia syndrome, adrenal cortical carcinoma), eye cancer (e.g., uveal melanoma, retinoblastoma, optic nerve glioma), gastrointestinal cancer (e.g., gastric (stomach) cancer, colon cancer, rectal cancer, colorectal cancer, pancreatic cancer, liver cancer, gallbladder cancer), reproductive and gynecological cancer (e.g., bladder cancer, foetal cancer, ovarian ... The cancer may be cervical cancer, ovarian cancer, renal cell carcinoma, prostate cancer, nephroblastoma, urothelial bladder cancer), head and neck cancer (e.g., head and neck cancer, esophageal cancer, pharyngeal cancer, oral cancer), hematopoietic cancer (Hodgkin's lymphoma, AIDS-related lymphoma, acute myeloid leukemia, acute lymphocytic leukemia, non-Hodgkin's lymphoma), skin cancer (e.g., melanoma), basal cell carcinoma, squamous cell skin cancer, keratoacanthoma), thoracic and respiratory cancer (e.g., small cell lung cancer, non-small cell lung cancer, pleuropulmonary blastoma), virus-related cancer (e.g., HIV / AIDS-related cancer).

[0161] In another embodiment, the cancer may express and / or overexpress one or more tumor associated antigens, such as HER2 (human epidermal growth factor receptor 2), EGFR (epidermal growth factor receptor), CD-20, VEGF (vascular endothelial growth factor), VEGFR (vascular endothelial growth factor receptor), CEA (carcinoembryonic antigen), CA-125 (cancer antigen 125), MUC-1 (mucin 1), MAGE (melanoma associated antigen).

[0162] Thus, exemplary vaccines include, but are not limited to, injectable polio vaccines (Sak vaccines), hepatitis A vaccines, rabies vaccines (e.g., canine, feline or human rabies vaccines), influenza vaccines (e.g., equine influenza vaccines), tick-borne encephalitis vaccines, Eastern and Western Equine Encephalomyelitis vaccines (EEE / WEE), coronavirus (e.g., SARS coronavirus) vaccines (including BBIBP-CorV, CoronaVac, Covaxin, QazVac, TURKOVAC, CoviVac), injectable typhoid vaccines, cholera vaccines, petasis vaccines, whooping cough vaccines, anthrax vaccines, cholera vaccines, plague vaccines, Salmonella vaccines, tuberculosis vaccines, typhoid vaccines, enterotoxigenic Escherichia coli ... coli vaccines, live attenuated influenza vaccines (LAIV) such as FLUMIST, Japanese encephalitis vaccines, measles vaccines, mumps vaccines, measles and rubella (MR) vaccines, measles, mumps, rubella, and varicella (MMR) vaccines, measles, mumps, rubella, and chickenpox (MMRV) vaccines, polio vaccines, rotavirus vaccines, rubella vaccines, smallpox vaccines, chickenpox vaccines, yellow fever vaccines, zoster / shingles vaccines, tick-borne encephalitis vaccines, COVID-19), mRNA vaccines, toxoid vaccines (e.g., tetanus toxoid, diphtheria toxoid, botulinum toxoid), viral vector vaccines, DNA vaccines, recombinant vector vaccines, subunit vaccines (protein subunits, e.g., Hepatitis B, acellular pertussis vaccines, polysaccharides, e.g., pneumococcal polysaccharide vaccines, meningococcal vaccines, or conjugates, e.g., pneumococcal conjugate vaccines, Haemophilus influenzae type B conjugate vaccines, meningococcal conjugate vaccines, etc.), recombinant vaccines, conjugate vaccines, as well as vaccine adjuvants, or combinations thereof.

[0163] Other examples of vaccines include Ebola vaccines, Zika vaccines, poxvirus vaccines (e.g., monkeypox vaccines), RSV vaccines, HIV vaccines, feline rhinotracheitis (FVR) vaccines, equine West Nile virus vaccines, Potomac horse fever (PHF) vaccines, equine herpesvirus vaccines, and malaria vaccines (e.g., RTS, S / A S01 or Mosquirix®) or vaccines against cancer (e.g., HEPLISAV-B®, Gardasil®, Cervarix®, T-VEC (Imlygic®), Sipuleucel-T, PROSTVAC®, CVAC-301 (PANVAC®), CV9104, MVA.5T4, MVA-BN®-HER2, TroVax®, DCVax-L, TAEK-VAC-HerBy, ChAdOx1-MAGEA3-NYESO, Rindopepimut, and vaccines against HER2 and brachyury-expressing cancers.

[0164] In some embodiments, the vaccine may be administered to the subject only once. In other embodiments, the vaccine may be administered to the subject two or more times. For example, in embodiments where the vaccine is an inactivated vaccine, a subunit vaccine, a recombinant vaccine, a polysaccharide vaccine, a conjugate vaccine, or a toxoid vaccine, it may be appropriate to administer a primary dose and one or more subsequent booster doses separately to the subject.

[0165] In some embodiments, the vaccine may be administered to a subject in combination with another type of biopharmaceutical compound (e.g., an antibody). Thus, immunization may include active and / or passive immunization components. Active immunization induces active immunity following exposure to an antigen, whereas passive immunization passively provides immunity, for example, via preformed antibodies that are exogenously generated (e.g., from another host).

[0166] Immunotherapy, optionally the immunotherapy is oncolytic virotherapy. Oncolytic virotherapy (OV) refers to a form of immunotherapy that uses a replication-competent virus to infect and destroy cancer cells. Preferably, the replication-competent virus specifically attacks tumor cells but not healthy cells.

[0167] The composition of the present invention also comprises Antigens, including exogenous antigens, endogenous antigens, and autoantigens, or combinations thereof; and / or - May include viral vectors including retroviruses (e.g., lentiviruses), poxviruses, adenoviruses, and adeno-associated viruses (AAV), or combinations thereof.

[0168] Biopharmaceutical compounds that may be used in the compositions of the invention also include oligonucleotides, including aptamers (including DNA, RNA, XNA, or peptide aptamers), morpholinos, CpG oligodeoxynucleotides, polypurine reverse Hoogsteen hairpins, or combinations thereof, as well as nucleotides (e.g., adenosine monophosphate (AMP), guanosine monophosphate (GMP), cytidine monophosphate (CMP), uridine monophosphate (UMP), cyclic adenosine monophosphate (cAMP), Cyclic guanosine monophosphate (cGMP), cyclic cytidine monophosphate (cCMP), cyclic uridine monophosphate (cUMP), deoxyadenosine monophosphate (dAMP), deoxyguanosine monophosphate (dGMP), deoxycytidine monophosphate (dCMP), (deoxy)thymidine monophosphate (dTMP), adenosine diphosphate (ADP), guanosine diphosphate (GDP), cytidine diphosphate (CDP), uridine diphosphate (UDP), deoxyadenosine diphosphate (dADP), deoxyguanosine diphosphate (dGDP), deoxycytidine diphosphate (dCDP), (deoxy)thymidine diphosphate (dTDP), adenosine triphosphate (ATP), guanosine triphosphate (GTP), cytidine triphosphate (CTP), uridine triphosphate (UTP), deoxyadenosine triphosphate (dATP), deoxyguanosine triphosphate (dGTP), deoxycytidine triphosphate (dCTP), (deoxy)thymidine triphosphate (dTTP)), nucleosides and the corresponding nucleic acid bases (e.g., adenine, adenosine, Antisense elements (e.g., antisense oligonucleotides, antisense RNA), siRNA therapeutics (e.g., ONPATTRO® (patisiran) and GIVLAARI™ (givosiran)), mRNA therapeutics, DNA therapeutics, or combinations thereof.

[0169] Biopharmaceutical compounds that may be used in the compositions of the invention also include immunomodulatory agents such as interleukins (e.g., IL-2, IL-7, IL-12, IL-27, IL-4, IL-10, IL-35, IL-33), cytokines (e.g., interferons, G-CSF), chemokines (e.g., CCL3, CCL26, CXCL7), cytosine phosphate-guanosine, oligodeoxynucleotides, glucans, or combinations thereof.

[0170] Additionally and / or alternatively, preferred biopharmaceutical compounds that may be used in the compositions of the invention include those (listed above or otherwise) that have an aqueous solubility at room temperature and atmospheric pressure of at least about 10 mg / mL, such as at least about 1 mg / mL, for example at least about 1 μg / mL, including at least about 100 μg / mL, such as at least about 10 μg / mL, in particular at least about 0.5 μg / mL, for example at least about 0.1 μg / mL, such as at least about 0.05 μg / mL, in particular at least about 0.01 μg / mL. It will be understood that "aqueous" solubility includes not only solubility in pure water, but also solubility in relevant physiological fluids, in particular those found in the nose (which may also be simulated in terms of isotonicity and pH).

[0171] Preferred active ingredients that may be used in the compositions of the invention include the fusion protein abatacept and the following antibodies: pembrolizumab, adalimumab, ustekinumab, trastuzumab, bevacizumab, rituximab, nivolumab, infliximab, eculizumab, omalizumab, cetuximab and panitumumab, fremanezumab, galcanezumab-gnlm, and eptinezumab-jjmr; the following enzymes: alteplase, reteplase, tenecteplase, dornase alfa, pegloticase, rasburicase and and L-asparaginase; and the following vaccines: typhloid vaccine, whooping cough vaccine, cholera vaccine, tuberculosis vaccine, typhoid vaccine, measles, mumps and / or rubella (including MMR) vaccine, polio vaccine, yellow fever vaccine, zoster / shingles vaccine, tetanus toxoid, diphtheria toxoid and botulinum toxoid vaccines, especially influenza vaccines and SARS coronavirus (e.g., SARS-CoV-2) vaccines.

[0172] Other active ingredients that may be used in the compositions of the present invention include carcinoembryonic antigen (CEA), cancer-associated tumor markers (such as cancer antigen 125 (CA-125)), mucin 1 (MUC-1), melanoma-associated antigen (MAGE), and the like.

[0173] Combinations of one or more of the above active ingredients of the same or different classes may be used.

[0174] When the composition of the present invention is made by the above-mentioned solvent-based process, including by the process of spray drying, this may result in the presence of the active ingredient in a form that is no longer in the form of a crystalline salt, since it is freely dispersed and encapsulated within the amorphous carrier material.The composition of the present invention may provide chemical stability with little or no loss of its active ingredient under normal storage conditions as described herein.

[0175] Moreover, when so prepared, the biopharmaceutical compound present in the composition of the invention may have essentially the same biological activity when compared to the biopharmaceutical compound in isolated form prior to manufacture of the relevant composition. "Essentially the same biological activity" includes, for example, less than about 95%, such as less than about 90%, including less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 20%, less than about 25%, less than about 20%, or less than about 15%, loss of biological activity (which may include pharmacological effects such as potency, binding activity, and / or immune response, depending on the biopharmaceutical compound used), as may be measured by a suitable assay for the subject biopharmaceutical compound as described below.

[0176] Furthermore, the compositions of the invention, when in isolated solid form, formulated into a pharmaceutical preparation or dosage form, and / or loaded into a pharmaceutical dispensing means such as a nasal applicator or reservoir therefor (with or without appropriate pharmaceutical packaging), or otherwise under normal storage conditions as defined above, may be stored with only a minor degree of loss of the biological activity of the biopharmaceutical compound (e.g., less than about 95%, such as less than about 90%, including less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 20%, less than about 25%, less than about 20%, or less than about 15%, in particular less than about 10% loss of the biological activity of the biopharmaceutical compound), which may be measured by an appropriate assay for the subject biopharmaceutical compound as described below.

[0177] The amount of active ingredient that can be used in a single dose of the composition of the present invention should be sufficient to exert its pharmacological effect. For the composition of the present invention that is administered mucosally (e.g., sublingually, bucally, and especially intranasally), the amount should not exceed about 100 mg in a single dose. The actual dose of the above related biopharmaceutical compounds is known in the art and can be found in Martindale-The Complete Drug Reference, 40 th The subject active ingredients may be described in medical literature, such as The Journal of Clinical Chemistry, Vol. 13, No. 1, 2011, pp. 1171-1175, 2012 Edition, Pharmaceutical Press, London (2020) and documents cited therein, the relevant disclosures of all of which are incorporated herein by reference. However, the compositions of the present invention may be found to exhibit better bioavailability and / or rapid absorption, resulting in a more rapid onset of action and / or higher plasma concentrations, as compared to prior art compositions containing the same active ingredients.

[0178] In this respect, the pharmacologically appropriate amount of the active ingredient in the composition of the present invention may be less than the amount mentioned in the literature (see above).Nevertheless, such amount can be determined by a person skilled in the art and may vary depending on the type and severity of the condition being treated and what is most suitable for an individual patient.This is also likely to vary depending on the nature of the formulation and the type and severity of the condition being treated, as well as the age, weight, sex, renal function, hepatic function and response of the particular patient being treated.

[0179] Depending on the potency of the biopharmaceutical compound and the final dosage form used, the total amount of active ingredient that may be used in the compositions of the present invention may range from about 0.0001% by weight or about 0.0002% by weight, such as about 0.01% by weight, including about 0.1% by weight (e.g., about 1% by weight, about 2% by weight or about 5% by weight), such as about 10% by weight (e.g., about 20% by weight), up to about 95% by weight, such as about 75% by weight, for example about 50% by weight, for example about 40% by weight, based on the total weight of the composition. This is independent of the number of separate doses (which must be the same) of the composition initially present in the dosage means according to the present invention.

[0180] For transmucosal administration, including pulmonary, buccal, sublingual, or preferably intranasal, suitable doses of active ingredient (calculated as the free acid / base) per unit dosage are in the range of about 0.01 μg (e.g. about 10 μg, such as about 250 μg) to a maximum of about 100 mg (e.g. about 80 mg), such as about 0.1 μg, including about 1 μg, such as about 1 mg to about 60 mg (e.g. about 3 mg to about 50 mg, such as about 10 mg), depending on the active ingredient used.

[0181] For other forms of administration (e.g., by injection or oral administration), suitable doses of active ingredient (calculated as the free acid / base) per unit dosage are in the range of about 1 mg to about 300 mg (e.g., about 3 mg, such as about 10 mg to about 200 mg), about 1,000 mg, such as about 1 μg to about 500 mg (e.g., about 400 mg), depending on the active ingredient used.

[0182] Alternatively, appropriate doses of active ingredients can be based on the biological activity or effect (rather than the mass of the biopharmaceutical compound) of various biological agents (i.e., proteins, oligopeptides, polypeptides, enzymes, antibodies and portions thereof, vaccines, nucleotides, etc., antibody analogs, antibody mimetics, immunoglobulins, immunomodulators, blood, blood components, cells, allergens, genes, viruses, toxins, poisons, or combinations thereof). Appropriate doses are about 10 -9 International Unit (IU) ~ approx. 1 x 10 9 The amount of IU may range from 100 mg to 100 mg / kg. International Units (IU) refers to the amount of active ingredient that produces a specific effect when tested according to an internationally accepted standardized biological procedure (see World Health Organization (WHO) International Standards). Methods for calculating the appropriate IU for various biopharmaceutical compounds will be known to those skilled in the art.

[0183] According to three further aspects of the invention there is provided: A composition of the invention for use in the treatment of a condition in which at least one biopharmaceutical compound contained therein is useful (e.g., by transmucosal, such as intranasal, administration of the composition); Use of a composition of the invention for the manufacture of a medicament (e.g., transmucosal, such as intranasal) for the treatment of a condition in which at least one biopharmaceutical compound contained therein is useful; and - A method for the treatment of a condition for which at least one biopharmaceutical compound contained within the composition of the invention is useful, comprising administration of the composition of the invention (e.g. transmucosally, such as intranasally) to a patient suffering from or susceptible to the condition.

[0184] Depending on the nature of the active ingredient(s) contained in such compositions, the compositions of the present invention are useful for the treatment of a wide range of clinical conditions including rheumatoid arthritis, psoriasis, ankylosing spondylitis, Crohn's disease, multiple sclerosis, diabetic retinopathy, age-related macular degeneration, diabetes, diabetes insipidus, cancer, as well as psoriatic arthritis and chronic obstructive pulmonary disease (COPD).

[0185] For example, compositions of the invention comprising vatacept and adalimumab (anti-TNF(alpha) agents) may be used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis, hidradenitis suppurativa, uveitis, and juvenile idiopathic arthritis; compositions of the invention comprising ranibizumab and aflibercept may be used to treat diabetic retinopathy and age-related macular degeneration; compositions of the invention comprising adalimumab may be used to treat psoriasis and ankylosing spondylitis; compositions of the invention comprising cetuximab and panitumumab may be used to treat psoriasis and ankylosing spondylitis. , EGFR-expressing metastatic colorectal cancer, compositions of the invention comprising pembrolizumab (anti-PD-1 agent) may be used to treat melanoma, non-small cell lung cancer, head and neck cancer, Hodgkin's lymphoma, gastric cancer, cervical cancer, urothelial cancer, colorectal cancer, renal cell carcinoma, and breast cancer, compositions of the invention comprising ustekinumab (anti-interleukin (IL)-12 / 23 agent) may be used to treat psoriasis, compositions of the invention comprising trastuzumab (anti-HER2 agent) may be used to treat breast cancer, and bevacizumab (anti-VEGF agent) may be used to treat psoriasis. The present invention, which includes rituximab (an anti-CD20 agent) can be used to treat colon cancer, the present invention, which includes nivolumab (an anti-PD1 agent) can be used to treat non-Hodgkin's lymphoma, the present invention, which includes infliximab (an anti-TNF(alpha) agent) can be used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and psoriasis, and the present invention, which includes eculizumab (an anti-complement component C5 agent) can be used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and psoriasis. Compositions of the invention comprising omalizumab (an anti-IgE agent) may be used to treat asthma and chronic idiopathic urticaria; compositions of the invention comprising cetuximab and panitumumab (anti-EGFR agents) may be used to treat colorectal cancer; compositions of the invention comprising fremanezumab (e.g., fremanezumab-vfrm), galcanezumab (e.g., galcanezumab-gnlm), and eptinezumab (e.g.,Compositions of the invention containing eptinezumab-jjmr) (a calcitonin gene-related peptide (CGRP) inhibitor) can be used to treat migraine headaches.

[0186] The compositions of the invention containing the relevant enzymes are useful in treating glycogen storage disorders (α-glucosidase), lipid storage disorders (α-D-galactosidase A and β-glucocerebrosidase), mucopolysaccharidoses (α-L-iduronidase and iduronate-2-sulfatase), mucopolysaccharidoses (N-acetylgalactosamine-6-sulfatase and N-acetylgalactosamine-4-sulfatase), various pancreatic diseases, cystic fibrosis, Shwachman-Diamond syndrome, chronic pancreatitis, pancreatic tumors, or removal of all or part of the pancreas (PEP), acute myocardial infarction (alteplase, reteplase, and tenecteplase), cystic fibrosis (dr It may be used for a variety of conditions such as collagen-based diseases such as lunase alfa), chronic gout (peglotticase), tumor lysis syndrome (rasburicase), leukemia (L-asparaginase), Dupuytren's contracture (collagenase), severe combined immunodeficiency (pegademase, bovine), methotrexate detoxification (glucarpidase), vitreomacular adhesions (ocriplasmin), acute myocardial infarction (alteplase, reteplase, and tenecteplase), cystic fibrosis (dornase alfa), chronic gout (pegloticase), tumor lysis syndrome (rasburicase) and L-leukemia (asparaginase).

[0187] The compositions of the invention, including vaccines, may be used to treat relevant conditions for which an immune response is intended to be elicited, including any of those mentioned above.

[0188] As mentioned above, the composition of the present invention can also contain or be administered together with one or more alkyl sugars.The composition of the present invention that contains alkyl sugars can be found to show surprisingly good bioavailability and absorption rate, for example, compared with the corresponding composition that does not contain alkyl sugars and / or contains a different excipient that is known to act as a surfactant.

[0189] Alkyl sugars that can be used include alkyl glycosides, which are 7-18 Alkyl glycosides can be defined as any sugar attached by a linkage to an alkyl group, such as alkyl glycosides. Thus, alkyl glycosides can include alkyl maltosides (such as dodecyl maltoside), alkyl glucosides, alkyl sucrosides, alkyl thiomaltosides, alkyl thioglucosides, alkyl thiosucrose, and alkyl maltotriosides. However, it is preferred that the alkyl sugars are sugar esters.

[0190] Sugar esters that can be used 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 especially one or more sucrose esters.

[0191] The sucrose esters used in the compositions of the present invention may have a hydrophilic-lipophilic balance value of 6 to 20. The term "hydrophilic-lipophilic balance" (HLB) is a term of art that will be well understood by those skilled in the art (see, for example, 'The HLB System: A Time-Saving Guide to Emulsifier Selection' published in 1976 (revised in 1980) by ICI Americas Inc, chapter 7 (pages 20-21) of the document provides a method for determining the HLB value). The longer the fatty acid chain of the sucrose ester and the higher the degree of esterification, the lower the HLB value. The preferred HLB value is 10 to 20, more preferably 12 to 20.

[0192] Therefore, sucrose esters have the C 8-22 Saturated or unsaturated fatty acid esters, preferably saturated fatty acid esters, preferably C 10-18 Fatty acid esters, most preferably C 12Fatty acid esters are included. Particularly suitable fatty acids from which such sucrose esters can be formed include erucic acid, behenic acid, oleic acid, stearic acid, palmitic acid, myristic acid and lauric acid. A particularly preferred such fatty acid is lauric acid. Commercially available sucrose esters include those sold under the trademarks Surfhope® and Ryoto® (Mitsubishi-Kagaku Foods Corporation, Japan).

[0193] The sucrose ester may be a diester or monoester of a fatty acid, preferably a monoester such as sucrose monolaurate. Those skilled in the art will understand that the term "monolaurate" refers to a monoester of lauric acid, and that the terms "lauric acid ester" and "laurate" have the same meaning and can therefore be used interchangeably. Commercially available sucrose monolaurate products are sometimes referred to as "sucrose laurate". Commercially available sucrose monolaurate (or sucrose laurate) products, such as Surfhope® D-1216 (Mitsubishi-Kagaku Foods Corporation, Japan), may contain small amounts of diesters and / or higher sucrose esters, as well as small amounts of other sucrose esters and free sucrose, and are suitable for use in the present invention. Those skilled in the art will understand that any reference herein to a particular sucrose ester includes commercially available products that contain that sucrose ester as a major component.

[0194] Preferred sucrose esters contain only one sucrose ester, which means that a single sucrose ester (e.g., a commercially available sucrose ester product) contains a single sucrose ester as the main component (commercial products may contain impurities, e.g., a monoester product may contain small amounts of diesters and / or higher esters, and such products may be considered to "contain only one sucrose ester" in the context of the present invention). As used herein, the term "main component" will be understood to refer to the major component (e.g., more than about 50% by weight or volume, such as about 70% by weight / weight or volume / volume) in a mixture of sucrose esters, such as a common commercially available surfactant product, which is typically sold with a certain range of ester compositions.

[0195] A particularly preferred sucrose ester is sucrose monolaurate.

[0196] The amount of alkyl sugars that may be used, whether included within a composition of the invention or in a final dosage form comprising one or more compositions of the invention, may range from about 0.5% to about 5% by weight, preferably from about 0.1% to about 10% by weight, such as from about 0.75% to about 3% by weight (e.g., up to about 2% by weight, such as about 1% by weight), based on the total weight of the composition.

[0197] Furthermore, optional additional excipients may be used within or administered with the compositions of the invention, including one or more (further) surfactants. Surfactants that may be mentioned include polyoxyl 8 stearate (Myrj™ S8), polyoxyl 32 stearate (Gelucire® 48 / 16), polyoxyl 40 stearate (Myrj™ S40), polyoxyl 100 stearate (Myrj™ S100), and polyoxyl 15 hydroxystearate (Kolliphor® HS Polyoxyethylene alkyl ethers (e.g., Brij™) including polyoxyl cetostearyl ethers (e.g., Brij™ CS12, CS20, and CS25), polyoxyl lauryl ethers (e.g., Brij™ L9 and L23), and polyoxyl stearyl ethers (e.g., Brij™ S10 and S20); polyoxyglycerides (e.g., Gelucire™) including lauroyl polyoxyglyceride (Gelucire™ 44 / 14) and stearoyl polyoxyglyceride (Gelucire™ 50 / 13); sorbitan esters (e.g., Myrj™) including sorbitan monopalmitate (Span™ 40) and sorbitan monostearate (Span™ 60) (e.g., Myrj™); , Span™), polysorbates (Tweens™), including polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), and polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), and sodium lauryl sulfate; and monoacylglycerols (monoglycerides) such as 2-oleoylglycerol, 2-arachidonoylglycerol, monolaurin, glycerol monomyristate, glycerol monopalmitate, glyceryl hydroxystearate, and preferably, glycerol monostearate, glycerol monooleate (e.g., Cithrol™), and glycerol monocaprylate (e.g., Capmul™).Other surfactants may include lauryl lactate, dipalmitoyl phosphatidylcholine (DPPC), and poloxamer.

[0198] Other optional additional components (excipients) that may be included in or administered with the compositions of the invention include isotonicity and / or osmolarity agents (e.g., sodium chloride), sterols (or steroid alcohols) such as cholesterol and phytosterols (e.g., campesterol, sitosterol, and stigmasterol); antioxidants (e.g., sodium metabisulfite, or in addition, alpha-tocopherol, ascorbic acid, potassium ascorbate, sodium ascorbate, ascorbyl palmitate, butylated hydrochloride, etc.); xytoluene, butylated hydroxyanisole, dodecyl gallate, octyl gallate, propyl gallate, ethyl oleate, monothioglycerol, vitamin E polyethylene glycol succinate, or thymol; chelating (complexing) agents (e.g., edetic acid (EDTA), citric acid, tartaric acid, malic acid, maltol, and galactose, including salt forms of any of these agents); preservatives (e.g., benzalkonium chloride, or in addition, benzyl alcohol, boric acid, parabens, propionic acid, phenol, cresol, or xylitol); viscosity modifiers. or gelling agents (such as cellulose derivatives including hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, etc., starch and modified starches, colloidal silicon dioxide, aluminum metasilicate, polycarbophil (e.g., Noveon®), carbomer (e.g., Carbopol®), and polyvinylpyrrolidone); mucoadhesive polymers such as carboxymethylcellulose, modified cellulose gum, and sodium carboxymethylcellulose (NaCMC); starch derivatives such as moderately crosslinked starches, modified starches, and sodium starch glycolate; acrylic polymers such as crosslinked polyvinylpyrrolidone, carbomer and its derivatives (polycarbophil, Carbopol®, etc.); polyethylene oxide (PEO); chitosan (poly-(D-glucosamine)); natural polymers such as gelatin, sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; polyco-(methyl vinyl ether / maleic anhydride); and croscarmellose (e.g., croscarmellose sodium);pH buffers (e.g., citric acid, maleic acid, malic acid, or glycine or their corresponding salts such as sodium citrate); colorants; penetration enhancers (e.g., isopropyl myristate, isopropyl palmitate, pyrrolidone, or tricaprylin); other lipids (neutral and polar); aromatic carboxylic acids such as benzoic acid, e.g., toluic acid or salicylic acid, optionally substituted with one or more groups selected from methyl, hydroxyl, amino, and / or nitro; optionally, flavors (e.g., lemon, peppermint powder, or preferably menthol), sweeteners (e.g., neohesperidin, acesulfame K, or sucralose), and dyes. Other excipients may include trisaccharides (e.g., raffinose) and mannitol, and pH adjusters (e.g., hydrochloric acid and sodium hydroxide);

[0199] The total amount of such "additional" excipients (including non-alkyl sugar surfactants that may be present in the compositions of the invention) that may be included with the compositions of the invention themselves (regardless of the form in which they are included) may be up to about 15% by weight, such as up to about 5% by weight (e.g., about 10% by weight), based on the total weight of the composition.

[0200] The total amount of such "additional" excipients that may be included in a final dosage form comprising one or more compositions of the present invention may be up to about 99%, such as up to about 99.99%, including up to about 90%, for example, when the one or more additional excipients are fillers or carriers for tablets, films, etc.

[0201] Those skilled in the art will understand that if any additional optional ingredients are included in the composition of the present invention, the nature of those ingredients and / or the amount of those ingredients included must not adversely affect the Tg of the composition for the reasons mentioned above. In this regard, such optional ingredients can be incorporated into the spray drying process (i.e., mixed together with the active ingredient and carrier material in a suitable volatile solvent and then spray dried) or can be included separately in the spray-dried particles.

[0202] According to a further aspect of the present invention there is provided a composition of the invention for use in medicine (human and veterinary medicine), thus for use in the treatment of a patient in need of medical treatment of a condition which the associated active ingredient is known to treat.

[0203] "Treatment" of such conditions includes curative, symptomatic and palliative treatment as well as the prevention or diagnosis of such conditions.

[0204] The compositions of the present invention may be administered by any suitable dosing means known to those skilled in the art. The compositions of the present invention may be administered transmucosally, in particular intranasally, by means of a suitable nasal applicator or dispenser, which is capable of administering a suitable dose of the active ingredient in the form of one or more compositions of the present invention to the nasal cavity.

[0205] Thus, a suitable nasal dosing means and / or applicator may contain and store one or more doses of the composition of the invention itself, or may be attached to a reservoir / container that contains and stores one or more doses of the composition of the invention and prevents significant loss of the physical and chemical integrity of the composition, including through ingress of water. In this way, the composition is ready for use as soon as the applicator device is actuated by the end user (whether this is for single or multi-dose use), whereupon the applicator delivers a composition (e.g., a powder) having an appropriate dose of the active ingredient as defined herein to the nasal mucosa of the subject.

[0206] Suitable applicator means have been described in the prior art. When used with the compositions of the present invention, such compositions may be loaded into a reservoir attached to or forming part of such applicator means and are contained therein until the applicator means, or dispenser, is actuated. Hereinafter, the terms "applicator", "dispensing device", "device", "applicator means", "dispensing means", "applicator device", "dispensing device" and "inhaler" may be used interchangeably and may mean the same thing.

[0207] The reservoir containing the solid multiparticulate powder composition of the present invention may be opaque. Due to the stability of the compositions of the present invention, it is not necessary to inspect the contents of the reservoir (i.e., the powder composition) prior to administration or use.

[0208] The term "opaque" will be understood by those skilled in the art to include "not transparent or translucent, not transmitting light and / or not allowing light to pass through."

[0209] Thus, an applicator comprising a composition of the present invention does not include (or require) an inspection window through which the contents of the applicator's reservoir can be observed, and in this regard, may be completely opaque in character, i.e., at least about 98%, such as at least about 99%, particularly about 99.9% opaque, and / or about 2% or less, such as about 1% or less, particularly about 0.1%, transparent, translucent, and / or light transmissible, allowing inspection of the contents of the reservoir.

[0210] Such applicator means may therefore also include a mechanism for expelling the powder composition described herein from the reservoir via an outlet means, which may include a suitably shaped nozzle or the like, any size sized for placement in a human body cavity, such as a nostril.

[0211] Thus, the mechanism for expelling the powder may include means for actuating the device, which may include breath-actuated actuation, or actuation means for generating a force upon actuation of the device by a user.

[0212] Therefore, the applicator needs to be able to provide a reproducible and sufficient amount of the powder formulation in a single administration step that provides a therapeutic dose of the active ingredient (and in a manner that does not require "priming" the device).

[0213] Nasal applicators / inhalation devices that may be used to administer the compositions of the present invention in the form of a powder may include metered dose inhalers (MDIs), dry powder inhalers (DPIs; including low, medium, and high resistance DPIs) and multi-dose applications such as soft mist inhalation devices (SMIs), which may be adapted based on techniques known in the art of delivery of active ingredients to the lungs.

[0214] In an MDI, the compositions of the present invention can form a stable suspension when suspended in a solvent, such as a propellant typically used therein, which must have sufficient vapor pressure to form an aerosol upon actuation of the delivery device (e.g., a hydrocarbon, a fluorocarbon, a hydrogen-containing fluorocarbon, or a mixture thereof).

[0215] However, when the nasal applicator is a single-dose applicator in which the composition is dispensed after actuation and discarded after use, suitable applicator means or devices for delivering a single dose of the active ingredient include breath-assisted and blow-assisted designs (such as Optinose®), as well as those described in US 6,398,074, US 6,938,798, or US 9,724,713, the relevant disclosures of all documents are incorporated herein by reference. Figures 1 and 2 of the present application are based on Figures 1 and 2 of US 6,398,074, respectively, and Figures 3-7 are based on Figures 19-23 of US 9,724,713, respectively. Both are diagrams of applicators that can be used to intranasally administer the composition of the present invention.

[0216] In Figure 1, the device comprises a body top / dispenser head 1 incorporating an outlet channel 40 (i.e. part of the "outlet means" mentioned above) and a gripping means 60 enabling the user to actuate the device. On the inside of the body top / dispenser head 1 is attached an element, the assembly of which is designated by the reference number 2, which incorporates a reservoir 10 and an air chamber 22 for the air blast 20. This element 2 can be produced integrally with the body 1. A body bottom 3 is also provided to be able to slide relative to the body top 1 and relative to the element 2, on which the user exerts a pressure force to actuate the device.

[0217] The reservoir 10 contains a single dose of the composition of the invention. The reservoir 10 has an air inlet 11 and a product outlet 15. A product retention device 12, including an air permeable grid, is positioned within the air inlet 11 for retaining the product within the reservoir 10 until the composition is dispensed. The product outlet 15 is blocked, preferably in a sealing manner, by a closure ball 16, which is removed from its blocking position by the flow of air when the applicator is actuated and the product is dispensed.

[0218] When the user actuates the device, pressure is applied to the plunger 25 such that the piston 21 compresses the air 20 contained in the chamber 22. As the grid 12 is permeable to air, the compression of the air in the chamber 22 creates an air blast which is transmitted to the reservoir 10 and thus to the closing ball 16 blocking the product outlet 15.

[0219] The dimensions of the closure ball 16 and its fixation at the reservoir product outlet 15 are such that when a minimum predetermined pressure is created through the reservoir 10 by a blast of air 20, the ball 16 is removed from its blocking position.

[0220] The pre-compression created by the closing ball 16 ensures that when the ball is removed from its blocking position, the energy stored in the user's hand is such that the piston 21, integral with the plunger 25, is propelled within the chamber 22, thereby generating a powerful blast of air 20, i.e. an airflow suitable for finely atomizing a dose of the composition of the invention.

[0221] Once this minimum pressure is reached, the ball moves rapidly towards the outlet channel 40 of the device and the flow of air 20 created by the blast expels substantially all of the dose of the composition of the present invention contained within the reservoir 10.

[0222] Preferably, the outlet channel 40 has a diameter larger than that of the closing ball 16, to allow the dose of product to be discharged through the outlet channel 40 by flowing around the ball 16. As shown in Figure 2, which represents the same device after actuation, the channel 40 is provided with means 41 for stopping or fixing the ball 16, to prevent the discharge of the ball from the device when the product is being discharged.

[0223] Further embodiments that can be used to administer the compositions of the invention intranasally are provided in column 7, line 50 to column 8, line 61 and Figures 19 to 23 of US 9,724,713, which are reproduced as Figures 3 to 7 in the present application.

[0224] In this embodiment, the reservoir 10 is fixed within a body top / dispenser head 1 which includes a dispenser outlet channel 40 (i.e., part of the "outlet means" previously discussed) having a gripping means or finger rest 60 which allows a user to actuate the device. A radial shoulder 37 (see Figure 5) of the body top / dispenser head 1 advantageously defines an assembly location for the reservoir 10 within the body top / dispenser head 1.

[0225] The mechanical opening system comprises a set of rods 61, 62, and when the device is actuated, a second rod portion 62 is pushed against said first rod portion 61. At the end of their actuation stroke, i.e. in the dispensing position, the set of rods 61, 62 cooperate with the closure element 16, which is spherical, in particular a ball as in the first embodiment discussed above, and mechanically eject it from the closed position.

[0226] In this embodiment, the piston 21 is separate from the first rod portion 61 and slides against both the air chamber 22 and a cylindrical surface 614 fixed to the first rod portion 61. Figure 7 is a perspective view of the air expeller of the device of Figures 3-6 in a rest position.

[0227] The air chamber 22 may thus be cylindrical and in a rest position communicate with the surrounding air by means of flutings or grooves 615 formed in said cylindrical surface 614 and cooperating with the piston 21 in particular in the rest position. The piston 21 thus comprises an inner lip 215 which slides in an airtight manner on the cylindrical wall 614 during actuation and which cooperating with said flutings 615 in the rest position. The piston 21 also comprises an axial extension 216 which cooperating with an upper edge 251 of a pusher element 25 (called "plunger" in the first embodiment) which moves said piston 21 in the air chamber 22 during actuation.

[0228] The retaining member 42 is extended downwardly by an axial extension 43 which contacts an upper axial end 610 of the first rod portion 61 during actuation.

[0229] Additionally, in this embodiment, there is no outer body, only a cover 27 assembled onto the lower axial edge of the air chamber 22 .

[0230] A spring 80 is provided between the radial flange 225 of the air chamber 22 and the first rod portion 61 and the portion forming the cylindrical surface 614 so that the air expeller automatically returns to its rest position after actuation.

[0231] The principle of operation is as follows: In the rest position of Fig. 3, the reservoir 10 is sealed closed by the retaining member 42 and the closure element / ball 16. The air expeller is open to the atmosphere by cooperation between the inner lip 215 of the piston 21 and the flutings 615 of the cylindrical surface 614.

[0232] When it is desired to actuate the device, the user pushes the pusher element 25. During this first stroke, the inner lip 215 of the piston leaves the flutings 615 and comes into air-tight cooperation with the cylindrical surface 614, thereby closing the air chamber 22. At the same time, the upper edge 251 of the pusher element 25 comes into contact with the axial extension 216 of the piston 21 and the upper axial end 610 of the first rod portion 61 comes into contact with the axial extension 43 of the retaining member 42.

[0233] However, as can be seen in FIG. 4, the upper axial end 621 of the second rod portion 62 is still not in contact with the rounded surface 55 of the closure element / ball 16 .

[0234] Continued actuation therefore simultaneously moves the piston 21 within the air chamber, thereby compressing the air contained therein and moving the retaining member 42 away from the position that closes the reservoir 10. When the second rod portion 62 contacts the rounded surface 55 of the closure element / ball 16, said closure element / ball is mechanically expelled from its closed position so that the composition can be expelled under the influence of the air compressed by the air expeller.

[0235] The dispensing position is shown in Figure 5. As can be seen in Figure 5, the retaining member 42 can move away from the first rod part 61 while the composition is being expelled under the effect of compressed air provided by the air expeller. In this position, the closure element / ball 16 is expelled from the reservoir 10 so that fluid or powder can be dispensed under the effect of compressed air. The closure element / ball 16 is thus jammed in the spline 3 of the top body / dispenser head 1, which in particular prevents any risk of the closure element / ball 16 being expelled from the top body / dispenser head 1.

[0236] As shown in FIG. 6, when the user releases the device, the spring 80, which was compressed during actuation, returns the first rod portion 61 towards its rest position. This creates a suction force that draws the closure element 16 and the retaining member 42 towards or near their closed position. This therefore blocks a new suction path, with the empty reservoir remaining assembled on the air expeller so that it does not get dirty during its automatic return to the rest position. However, the piston 21 remains in its dispensing position as a result of friction with the air chamber 22 and the suction force created in the reservoir 30, such that the cylindrical surface 614 slides on the inner lip 215 until said inner lip once again cooperates with the flutings 615. At this point, the air chamber 22 is again in communication with the surrounding air and the suction force by returning to the rest position is no longer created. The piston 21 is therefore also retracted towards its rest position. This allows the reservoir to be closed after use.

[0237] Optionally, the unit formed by the body top / dispenser head 1 and the empty reservoir 10 can be removed from the air expeller and replaced with a new unit containing a full reservoir.

[0238] Suitable applicator devices that can be used include those available from Aptar Pharma, France (UDS Monopowder). See, for example, International Patent Applications Nos. 2022 / 208014 and 2021 / 005311. Other examples of applicator devices that can be used in combination with the compositions of the present invention (especially those in the form of powders) include those described in U.S. Patent Application Nos. 2011 / 0045088, 7,722,566 (see, for example, Figures 1 and 7) and 5,702,362, and International Patent Application No. 2014 / 004400, the relevant disclosures of which are incorporated herein by reference.

[0239] According to a further aspect of the present invention, there is provided a process for manufacturing an applicator device comprising a composition of the present invention, the process comprising the step of loading the composition into a reservoir within or associated with the applicator device.

[0240] According to a further aspect of the present invention there is provided a needleless applicator suitable for administering a solid amorphous single particle powder composition of the present invention to a body cavity of a human patient, the cavity comprising a mucosal surface, the applicator comprising: (i) a reservoir (optionally opaque) within or associated with said applicator that contains a composition of the present invention; (ii) optional actuation means for generating a force upon actuation of the device by a user; and (iii) a dispensing means through which the powder composition may be dispensed after said actuation.

[0241] 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, which applicator or device may be actuated one or more times to deliver one or more compositions of the present invention, each containing an appropriate dose of active ingredient on each such actuation, the applicator / dispenser device comprising: an outlet through which at least one composition is dispensed; a means for generating an external force (e.g., airflow) upon actuation of the device by a user; At least one (optionally replaceable) reservoir containing one or more compositions of the present invention, which is in, or can be arranged to be in, direct or indirect communication with the dispenser outlet; a replaceable, optionally reversible, sealing means in the device and / or reservoir to retain one or more compositions within the reservoir until the composition is dispensed; a mechanical opening system which cooperates with said sealing means such that the unitary composition of the present invention is mechanically expelled by the force application means when the device is actuated; Optionally, a mechanism for resealing the device and / or the reservoir to retain the further composition within the reservoir until the further composition is dispensed.

[0242] According to a still further aspect of the present invention there is provided an applicator and / or dispenser device comprising and suitable for dispensing a single dose of the composition of the present invention, the applicator / dispenser device comprising: Dispenser outlet, an air expeller for generating an air flow while the device is actuated, the air expeller including a piston that slides within the air chamber between a rest position and a dispensing position; The piston slides in an airtight manner within the air chamber; at least one reservoir containing a dose of the composition of the present invention, the reservoir comprising an air inlet connected to said air expeller; a composition outlet connected to the dispenser outlet; said air inlet including a displaceable sealing means (e.g., a retaining member) for retaining the composition within the reservoir until the composition is dispensed; a composition outlet of the reservoir, said composition outlet being closed by a closure element fitted to said composition outlet; the device further comprising a mechanical opening system cooperating with the closure element to mechanically eject the closure element from the closed position during actuation of the device; and The piston of the air expeller cooperates in a non-airtight manner with the air chamber when in a rest position.

[0243] In the latter aspect of the invention, it is preferred that: (i) the air chamber into which the piston slides in an airtight manner is substantially cylindrical; (ii) the closure element is press-fitted onto the composition outlet of the reservoir; (iii) the air chamber is in communication with the atmosphere in a stationary position; and / or (iv) the piston includes an inner lip adapted to cooperate with a cylindrical surface, the cylindrical surface including fluting that cooperates in a non-sealing manner with the inner lip of the piston in a rest position.

[0244] Such nasal applicators or dispensing devices can provide a suitable and reproducible powder spray pattern and / or geometric plume shape that allows efficient delivery of the powder to the nasal cavity (e.g., nostrils).

[0245] In the composition of the present invention, the average particle size can be presented as the average diameter by weight, number, or volume. As used herein, the term "average diameter by weight" is understood by those skilled in the art to include that the average particle size is characterized and defined from the particle size distribution by weight, i.e., the existing fraction (relative amount) in each size class is defined as the weight fraction obtained, for example, by sieving (e.g., wet sieving). The term "average diameter by volume" is similar in meaning to the average diameter by weight, but is understood by those skilled in the art to include that the average particle size is characterized and defined from the particle size distribution by volume, i.e., the existing fraction (relative amount) in each size class is defined as the volume fraction measured, for example, by laser diffraction. As used herein, the term "average diameter by number" is understood by those skilled in the art to include that the average particle size is characterized and defined from the particle size distribution by number, i.e., the existing fraction (relative amount) in each size class is defined as the number fraction measured, for example, by microscopy. Other instruments known in the art may be used to measure particle size, such as, for example, instruments sold by Malvern Instruments, Ltd (Worcestershire, UK), Sympatec GmbH (Clausthal-Zellerfeld, Germany), and Shimadzu (Kyoto, Japan).

[0246] Where the compositions of the invention are formulated, for example, for administration orally, topically, to the buccal, ocular or other mucous membrane, or by injection or infusion, particle size is not (or may not even be) critical, but powder compositions of the invention typically have a volumetric mean diameter (VMD) within the range of about 0.2 μm, such as about 0.5 μm (e.g., about 1 μm), up to about 1,000 μm (e.g., up to about 500 μm, such as about 400 μm or about 500 μm), and appropriate particle size ranges may be selected based on the dosage form intended to contain such compositions.

[0247] However, one of ordinary skill in the art will appreciate that to allow for effective intranasal administration, the powder will typically have a volumetric mean diameter (VMD) in the range of about 5 μm up to about 300 μm (e.g., up to about 200 μm). Depending on the applicator device used, the VMD may range from about 10 μm to about 100 μm, such as from about 20 μm to about 60 μm.

[0248] Preferred particle size distributions for intranasal drug delivery may also include those with D10 greater than about 3 μm, such as greater than about 10 μm, and less than about 75 μm (e.g., up to about 50 μm), and D90 between about 80 μm and about 1,000 μm, such as less than about 100 μm (e.g., about 500 μm). One of ordinary skill in the art will appreciate that the parameter "D10" (or "Dv(10)") refers to the size (or diameter) in the particle size distribution below which 10% of the total volume of the material in the sample falls. Similarly, "D90" (or "Dv(90)") refers to the size below which 90% of the material falls.

[0249] One of ordinary skill in the art will appreciate that to allow for effective pulmonary administration, the powder will typically have a VMD within the range of about 0.2 μm up to about 10 μm.

[0250] Powders having a particle size distribution and VMD within the above ranges include the bulk VMD and / or the emitted VMD, i.e., the particle size distribution when initially loaded into and / or expelled from the device, respectively.

[0251] 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.

[0252] Preferred particle shapes include spherical or substantially spherical, meaning that the particles have an aspect ratio of less than about 20, more preferably less than about 10, such as less than about 4, and especially less than about 2, and / or may have a variation in radius (measured from the center of gravity to the particle surface) of less than about 50% of the mean value, such as less than about 30% of the mean value, for example less than about 20% of that value, in at least about 90% of the particles.

[0253] Nevertheless, the particles may be of any shape, including irregularly shaped (e.g., "raisin" shaped), needle-shaped, disk-shaped, or rectangular shaped particles. For non-spherical particles, the size may be given as the size of a corresponding spherical particle of, for example, the same weight, volume, or surface area.

[0254] The spray angle of the powder compositions of the present invention upon emission (dispensing) from a nasal applicator and / or dispenser device should preferably be less than about 90°.

[0255] When the word "about" is used herein in the context of quantities, such as absolute amounts, e.g., doses, weights, volumes, sizes, diameters, aspect ratios, angles, or relative amounts (e.g., percentages) of individual components in a composition or of a component of a composition (including concentrations and ratios), time frames, and parameters such as temperature, pressure, relative humidity, etc., it will be understood that such variables are approximate and thus may vary by ±10%, e.g., ±5%, and preferably ±2% (e.g., ±1%) from the actual numerical values ​​specified herein. This is true even when such numbers are first presented as percentages (e.g., "about 10%" may mean ±10% for the number 10, which is anywhere from 9% to 11%).

[0256] The compositions of the present invention have the advantage that they can be prepared and subsequently stored over a wide range of temperatures and / or relative humidity without significant loss of biological activity.Thus, the compositions of the present invention can be subjected to low temperatures (e.g., below freezing) without affecting the amount of active ingredient administered to a subject.Furthermore, the compositions of the present invention can have the advantage that they are more physically and chemically stable at high temperatures than related prior art compositions.

[0257] The compositions of the present invention may further have the advantage of providing a higher bioavailability of the active ingredient as compared to prior art compositions. The compositions of the present invention may provide this higher bioavailability along with more rapid absorption, which is likely to result in a more rapid onset of action than such prior art and / or commercially available compositions, thus fulfilling an important medical need.

[0258] The compositions, pharmaceutical formulations, uses, and methods described herein may also have the advantage that they may be more convenient for first responders, physicians, and / or patients, may be more effective, may have less toxicity, may have a broad spectrum of activity, may be more potent, may produce fewer side effects, may have less inter-patient variability, or may have other useful pharmacological properties over similar formulations or methods (treatments) known in the prior art, whether for use in treating a condition for which the relevant active ingredient is known, by transmucosal administration, such as intranasally, or otherwise, in the treatment of said condition.

[0259] The invention is illustrated by the following examples, but is in no way limited, with reference to the figures in which Figures 1-7 represent drawings of an actuator device that may be used to dispense powder compositions, and Figures 8 and 9 show the retained activity under various conditions of SARS-CoV-2 RBD spike protein after formation of a spray dried powder versus the activity of the same protein relative to the initial solution before spray drying. [Brief description of the drawings]

[0260] [Figure 1] FIG. 1 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Diagram 2] FIG. 2 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Diagram 3] FIG. 3 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Figure 4] FIG. 4 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Diagram 5] FIG. 5 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Figure 6] FIG. 6 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Figure 7] FIG. 7 depicts a diagram of an actuator device that may be used to dispense a powder composition. [Figure 8] FIG. 8 shows the retained activity under various conditions of the SARS-CoV-2 RBD spike protein after formation of a spray-dried powder versus the activity of the same protein relative to the initial solution before spray drying. [Figure 9] FIG. 9 shows the retained activity under various conditions of the SARS-CoV-2 RBD spike protein after formation of a spray-dried powder versus the activity of the same protein relative to the initial solution before spray drying.

[0261] Example 1 Composition I of the Invention Six formulations, approximately 2 g of powder each, were prepared by adding the required amount of lyophilized β-galactosidase (lactase enzyme, 5000 units per mg, Merck / Sigma Aldrich Germany) and the following excipients: trehalose (Merck / Sigma Aldrich, Germany), maltodextrins (MD) IT12 and IT19 (Roquette, France), sucrose laurate D1216 (SL, Mitsubishi Chemicals, Japan), and HPMC K3 (Dupont, USA) to a 30 mL glass vial. The compositions are shown in Table 1 below (individual components in % by weight). [Table 1]

[0262] The vials were then placed in a freezer maintained at −20° C. Prior to shipping, the vials were placed in an aluminum bag containing a desiccant (molecular sieves) and placed in an insulated box containing wet ice.

[0263] Spray drying was carried out at Xedev (Belgium) using a ProCepT spray dryer equipped with an expansion column. From the six formulations prepared, a total of 12 samples were generated by varying the nozzle type and process conditions. An overview of the spray drying process is shown in Table 2 below.

[0264] Prior to spray drying, the six prepared formulations were dissolved in water such that the resulting solid loading (w / w%, water:solid) ranged from 5-10%. From these solutions, 0.5 mL was extracted from each vial into separate LC vials and placed in a freezer prior to shipping. These were the reference solutions used to determine the activity of the enzyme prior to spray drying.

[0265] The solution feed rate was set at 4 g / min, resulting in processing times between 1 and 5 min for the samples shown in Table 2. An ice bath was used to cool the collection vessel during some runs to reduce the potential for heat exposure during processing. [Table 2]

[0266] After spray drying, the samples were placed in a freezer until shipping. Samples were shipped under the same conditions as above, i.e., with desiccant and wet ice.

[0267] Enzyme activity assays were performed using 2-nitrophenyl β-D-galactopyranoside (ONPG, Merck / Sigma Aldrich, Germany) as the enzyme substrate.

[0268] Prior to analysis, 100 mg of each spray-dried material was transferred to a separate LC vial and diluted to the same concentration as the reference solution (see above).

[0269] The enzyme solutions, references and spray-dried powders were diluted with PBS (pH 7.4) and then 5 mM ONPG was added in excess. The UV / vis absorbance of the mixtures was measured at 420 nm at 0.5, 1, 2, 3, 4 and 5 min in duplicate.

[0270] The absorbance of the spray dried solutions was compared to the corresponding reference solutions using linear regression. The reference solutions were designated as having 100% activity, while the slope division quotient was used to determine the retained activity of the spray dried solutions. The results are shown in Table 3 below. (Note - results for samples 001 and 002 were excluded as there was some uncertainty regarding the integrity of the reference samples.) [Table 3]

[0271] The results show that there is minimal loss of enzyme activity following the spray drying process according to the present invention.

[0272] Example 2 Composition II of the Invention Twelve formulations, each containing approximately 2.5-2.6 g of powder, were prepared by adding the required amount of lyophilized SARS-CoV-2 RBD spike protein (L452R), His Tag ("S protein", SPD-C52He, ACRO Biosystems, US), and the following excipients: trehalose dihydrate (Pfanstiel, US), maltodextrin (MD) IT19 (Roquette, France), sucrose laurate D1216 (SL, Mitsubishi Chemicals, Japan), phosphate buffered saline (PBS), and pure deionized water (5% solids fill) to a 100 mL glass flask. The formulations had the composition a shown in Table 4 below (individual components in % by weight). [Table 4]

[0273] Spray drying was carried out using a ProCepT spray dryer equipped with an extended column using both ultrasonic and two-fluid nozzles. A summary of the spray drying process is shown in Table 5 below.

[0274] Prior to spray drying, 0.8 mL of solution was extracted from each vial into a separate LC vial and placed in a freezer (-20°C). These were the reference solutions used to determine the initial activity of the protein prior to spray drying.

[0275] The solution feed rate was set at 4 g / min, resulting in a processing time of approximately 13 minutes for the samples shown in Table 5. [Table 5]

[0276] After spray drying, samples were placed into sealed aluminum pouches containing desiccant and stored at -20°C until analysis. Additional powders were packaged in the same manner and stored at four different temperatures for up to four weeks: -20°C, -5°C, 20°C, and 40°C.

[0277] Protein activity was analyzed using the SARS-CoV-2 Spike Protein Titer Assay Kit, ELISA (RAS-A020-96TEST, ACRO Biosystems, US). Prior to analysis, the spray-dried material and the initial solution were diluted to a target concentration of approximately 0.2 ng / mL, and all samples were analyzed in duplicate.

[0278] As shown in Figure 8, the retained activity measured after spray drying of the powder relative to the initial solution ranged from 30% (acceptable loss) to 100% (minimal loss).

[0279] A second assay was performed after 4 weeks of storage. As shown in Figure 9, it was apparent that activity was retained in all samples stored at all temperatures, with some variation both between and within assays noted, including higher activity upon storage and variation between duplicates.

Claims

1. A pharmaceutically acceptable composition, the composition comprising: (a) a pharmacologically effective dosage of at least one biopharmaceutical compound; (b) a pharmaceutically acceptable composition in the form of a solid amorphous single particle powder composition comprising a mixture of a pharmaceutically acceptable carrier material, the carrier material comprising a combination of a disaccharide and a polymeric material.

2. The composition of claim 1 , wherein the polymeric material comprises maltodextrin.

3. 3. The composition of claim 1, wherein the disaccharide is selected from the group consisting of maltitol, trehalose, sucralose, sucrose, isomalt, maltose, and lactose.

4. The composition of claim 3 , wherein the disaccharide comprises lactose or trehalose.

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

6. 3. The composition of claim 1, wherein the weight ratio of disaccharide to polymer, based on the total weight of the composition, is in the range of about 10:1 to about 1:

10.

7. 7. The composition of claim 6, wherein the ratio of disaccharide to polymer ranges from about 2:1 to about 1:

8.

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

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

10. The composition of claim 9 , wherein the sucrose ester comprises sucrose monolaurate.

11. 3. The composition of claim 1 or claim 2, wherein the pharmacologically effective dosage of the at least one biopharmaceutical compound is about 100 mg or less.

12. 3. The composition of claim 1 or claim 2, wherein the at least one biopharmaceutical compound is selected from the group of proteins, oligopeptides, polypeptides, enzymes, antibodies, vaccines, and nucleotides.

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

14. 14. The composition of claim 13, wherein the particle size distribution of the powder comprises a D10 greater than about 3 μm.

15. 14. The composition of claim 13, wherein the powder has a particle size distribution comprising a volume-based mean diameter in the range of about 10 μm to about 100 μm.

16. The composition of claim 13 , wherein the biopharmaceutical compound is a vaccine.

17. 3. The composition of claim 1 or claim 2, which is suitable and / or adapted for oral delivery.

18. 18. The composition of claim 17, wherein the biopharmaceutical compound is an enzyme.

19. 3. The composition of claim 1 or claim 2, dissolved in a pharmaceutically acceptable solvent for delivery by injection or infusion.

20. 20. The composition of claim 19, wherein the biopharmaceutical compound is an antibody.

21. A process for the production of the composition of claim 1 or claim 2, said process comprising: (i) mixing together one or more biopharmaceutical compounds and a pharmaceutically acceptable carrier material in a suitable volatile solvent; (ii) spray drying the mixture from step i).

22. 22. A composition obtainable by the process of claim 21.

23. A nasal applicator device suitable and / or adapted for delivering a composition according to claim 1 or claim 2 to the nose, the nasal applicator device comprising or being associated with and / or attached to a reservoir, the composition being contained within the reservoir.

24. 24. A process for manufacturing an applicator device as described in claim 23, comprising the process described in claim 21, followed by loading the composition so formed into a reservoir within, attached to, or attached to the applicator device.

25. 3. The composition of claim 1 or claim 2 for use in the treatment of a condition for which the at least one biopharmaceutical compound contained in the composition is useful.

26. 10. Use of the composition of claim 1 or claim 2 for the manufacture of a medicament for the treatment of a condition for which the at least one biopharmaceutical compound contained in the composition is useful.

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