Mucosal suction patch and its use in drug delivery - Patents.com

Abstract

The present disclosure provides a mucosal suction patch comprising at least one valve containing a drug, wherein the at least one valve has elasticity, when mechanical pressure is applied to a pressure application surface, the at least one valve is deformed, and when the mechanical pressure is released while the patch sealing surface is on the target mucosa, the at least one valve at least partially recovers its expanded state, and then deforms the mucosa, which reversibly fills at least a part of the at least one valve cavity, and moves the drug into the mucosa.The use of the patch for transmucosal delivery of drugs in a subject is also provided.The patch allows non-invasive, non-injection systemic administration of drugs, particularly macromolecular drugs.

Description

[Technical field]

[0001] The present disclosure relates to mucosal suction patches and their use in non-injection drug delivery. [Background technology]

[0002] Over the past decades, advances in biotechnology and pharmaceutical sciences have led to the development and commercialization of a variety of new pharmaceuticals ranging from peptides, proteins, nucleic acids (e.g., RNA) to novel chimeric molecules such as proteolysis targeting chimeras (PROTACs). These compounds often exhibit superior properties compared to traditional low molecular weight drugs, such as target specificity and high potency. Their therapeutic indications also span a wide range of pathologies, e.g., cardiovascular and immunological diseases, hepatitis, and cancer. However, the molecular weight (typically greater than 1000 Da) and physicochemical properties (e.g., hydrophilicity, electrostatic charge) of these compounds often prevent their efficient absorption from the gastrointestinal (GI) tract, and many of these compounds may degrade prematurely in the GI tract or during first pass metabolism. As a result, these drugs are generally administered by parenteral routes, i.e., intravascular and extravascular injections, which often results in low patient compliance and high treatment costs.

[0003] Therefore, great efforts have been made to develop novel non-injectable drug delivery systems for these macromolecular drugs (M. Sam, D. Brayden. “Formulation strategies to improve the efficacy of intestinal permeation enhancers.” Adv. Drug Deliv. Rev (2021): 113925). However, there have been few successes. For example, in the case of peptides, only a few oral formulations for systemic delivery have entered clinical trials in the past 30 years, and as a result, only four of them have reached the market. Meanwhile, the oral bioavailability of the majority of these drugs remains very low (generally less than 1%). As a result, novel and more efficient non-injectable drug delivery strategies are of great interest to the pharmaceutical industry.

[0004] There is a need for non-invasive (eg, needle-free), non-injection drug administration systems to enhance systemic delivery, particularly of macromolecular drugs.

[0005] This description makes reference to several documents, the contents of which are incorporated herein by reference in their entirety. Summary of the Invention [Problem to be solved by the invention]

[0006] The present disclosure describes a drug delivery device that utilizes the low pressure generated by suction patch actuation to achieve efficient and controllable mucoadhesion and slight mucosal deformation and disruption. The patch creates a high concentration gradient at the site of mucosal patch attachment, enhancing transmucosal drug delivery and absorption by deformation of the mucosa to which it adheres. [Means for solving the problem]

[0007] The suction patch of the present disclosure has adjustable adhesion strength achieved by the pressure differential between the outside (ambient pressure) and inside of the patch valve(s) and ultimately the chemical interaction of the contact area of ​​the patch with the mucosa. The adhesion strength can be adjusted by varying one or more of the following: (a) (i) the enclosed fluid volume (i.e., at least one cavity volume) (e.g., the diameter of the opening and the depth of the cavity), (ii) the enclosed fluid volume shape (i.e., at least one cavity shape), (iii) the size of the patch area in contact with the mucosa (contact area(s)), (iv) the number of valve(s), and (v) the valve shape, including those that define the membrane thickness of the at least one valve(s) (e.g., affecting the elasticity / flexibility and strength of the valve), (b) the material of the patch (e.g., at least one valve) (e.g., affecting the elasticity / flexibility, strength, watertightness and airtightness of the patch), and (c) the final adhesive coating and / or sealer on the at least one valve(s) of the suction patch.

[0008] The suction strength generated by the low pressure and the resulting tissue deformation improves the penetration of the delivered drug by disrupting the mucosa, which improves drug diffusion, among other things, by enhancing paracellular penetration (see, e.g., Figures 4 and 8).

[0009] Mucosal suction patch Patch Shape The patch comprises at least one cavity (i.e., one (single) cavity or a plurality / array of cavities of at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or more). The portion(s) of the patch forming the cavity or plurality thereof is referred to herein as "valve(s)" (i.e., suction component(s)). Each patch comprises at least one valve (one or more valves). The patch has an exterior surface comprising a (mechanical) pressure application surface, an interior surface (consisting of the interior surface of one or more valves), and a mucosal sealing surface substantially opposite the patch pressure application surface. The patch mucosal sealing surface comprises one or more rim(s) (contact area) of the valve(s) it comprises. The patch mucosal sealing surface bounds the opening(s) of the at least one valve(s) and defines the patch base surface area. In a patch containing multiple valves / cavities, the term "total base surface area" refers to the combined surface area of ​​all valve openings. The shape of each of the one or more valves can be the same or different, e.g., cup-shaped, cone-shaped, etc. (see, e.g., Figures 2A-I). A larger valve can contain one or more smaller valves in an array or core-shell configuration (e.g., Figures 2B, 2E and 2H). Multiple valves can be connected by a backing layer, which itself can contain compartments for drug(s) and / or excipient(s).

[0010] Each cavity has a volume and is in fluid communication (e.g., air, drug formulation, sealing fluid, biological fluid) with at least one opening to the outside (e.g., cup-shaped). When the patch is in use on a mucosa, at least one opening is closed by the mucosa. In a patch that includes multiple valves / cavities, the term "total cavity volume" refers to the combined volume of all patch cavities. The total cavity volume is of sufficient size to contain the drug formulation intended for delivery and, together with other features of the patch, allows for the creation of low (negative) pressure within the patch cavity(ies).

[0011] At least one, and up to all, of the valves in the patch contain a drug formulation. When a patch contains more than one valve that contains a drug formulation, the drug formulation can be the same or different in the two or more valves.

[0012] Each drug has specific delivery requirements (e.g., smaller / larger surface area or larger / smaller mucosal deformation required). The present disclosure encompasses the use of different valve shapes to tailor different drug deliveries and / or adhesion strengths. For example, the present disclosure encompasses patches that include large valves in the center (with stronger adhesion to the mucosa) and smaller valves on the periphery (with individually weaker adhesion to the mucosa).

[0013] In specific embodiments, the patch mucosal sealing surface may also include structural elements that (a) reduce undesired detachment of the patch from the mucosa (increase adhesion of the patch to the mucosa), (b) increase shear and peel forces, reduce lateral migration, and / or (c) include a combination of (a) and (b).

[0014] The cavity / inner surface of the patch comprises structural elements that form at least one drug-loaded compartment (e.g., FIG. 3A-D). The drug-loaded compartment(s) are designed to accommodate a desired amount of drug and carrier and / or excipient(s). The structural elements that form the drug-loaded compartment(s) may be designed so as not to detrimentally reduce the adhesive strength of the patch.

[0015] The thickness of the patch valve is designed to allow for easy finger mechanical pressure and release of that pressure. In a specific embodiment, the thickness of the patch valve material is about 0.1-3 mm.

[0016] The patch pressure application surface is the surface to which mechanical pressure (e.g., finger pressure) is applied when the patch mucosal sealing surface is placed on the mucosa to create suction. More specifically, as a result of the pressure, one or more bulbs distort (collapse) and, upon release of the mechanical pressure, one or more bulbs substantially regain their original size and shape (expanded shape), creating a temporary negative pressure in one or more cavities, which in turn deforms (distorts) the mucosa, which fills at least a portion of the bulb(s).

[0017] Various non-limiting embodiments of patches of the present disclosure are shown in Figures 2A-I. Mucosal suction patches of the present disclosure are shown to include a single valve (see, e.g., Figures 1A-1C, 2A, 2C, 2D, and 2I), a plurality / array of valves (see, e.g., Figures 2F and 2G), and / or a core-shell structure with multiple valves (see, e.g., Figures 2B, 2E, and 2H). Patches can have simple or more complex structures.

[0018] When the patch includes two or more adjacent valves, the patch may include a backing layer having a lower surface and an upper surface. The two or more valves are attached by their upper surfaces (opposite their open surfaces) to the lower surface of the backing layer (e.g., FIG. 2F). The upper surface of the backing layer is the patch pressure application surface in such an embodiment. In a patch without a backing layer, the patch pressure application surface may be the upper surface of one of the at least one valve (e.g., the upper surface of a single valve, or the upper surface of a larger valve that includes at least one smaller valve).

[0019] In a specific embodiment, (i) the total cavity volume and (ii) total base surface area (all areas bounded by the valve rim(s)) of at least one valve are each less than or equal to 10 mm 3 ~3000mm 3 (10 μL and 3000 μL) (total cavity volume), and (ii) 0.8 to 1200 mm 2(total base surface area), where the patch contains multiple bulbs (two or more), or 0.8 to 400 mm2 if the patch contains a single bulb. 2 It is.

[0020] The aforementioned features are referred to herein as the patch geometry.

[0021] The shape of the patch significantly contributes to the adhesive strength of the patch, the negative pressure, and the degree of associated deformation of the mucosa, which in turn affect the permeation enhancing effect.

[0022] Valve Elasticity Elasticity is the ability of an object to resist a straining effect and return to its original size and shape when the effect or force is removed. One or more bulbs of the patch have a higher elastic modulus than that of the mucosa (e.g., buccal mucosa) to which they are intended to adhere. As a result, when the mucosal sealing surface of the patch is placed on the mucosa and the mechanical pressure (straining effect) applied to the at least one bulb is released, the at least one bulb regains at least a part of its original size and shape (expanded state), and the mucosa is then deformed (strained) and fills a part of the cavity volume of the at least one bulb. In specific embodiments, upon application of the patch to a mucosa, the total cavity volume of the patch is reduced by at least 10% (or at least 15%, or at least 20%, or at least 25%, or at least 30%, or at least 35%, or at least 40%, or at least 45%, or at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%).

[0023] In a specific embodiment, at least one valve of the patch has an elasticity of about 0.01 MPa to about 1000 MPa (about 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 6, 7, 10, 15, 20, 30, 40, 50, 75 MPa to about 50, 100, 200, 300, 400, 500, 600, 700, 800, or 900 MPa) at a temperature of about 20° C. to about 55° C. In a patch that includes two or more valves, the valves may have substantially the same or different elasticities. In a specific embodiment, they have substantially the same elasticity.

[0024] Patch Size The size of the patch is small enough to be comfortably placed on a mucosa (e.g., oral (e.g., buccal) or vaginal mucosa) and large enough to contain a desired amount of drug formulation and encapsulate a sufficient amount of fluid to allow deformation and adherence of the mucosa. Without being so limited, its external volume is 50 μL to 5000 μL. Its total cavity volume is 10 μL to 3000 μL. In specific embodiments, the diameter of its total base surface area (including the mucosal sealing surface that bounds the opening(s)) is about 1000 μm to about 40 mm if the patch includes multiple valves, and about 1000 μm to about 22.5 mm if the patch includes a single valve. In a specific embodiment, the height of the patch (when measured from its base to its apex) is from about 1 to about 20 mm (or from about 2 to about 20 mm, from about 3 to about 20 mm, from about 4 to about 20 mm, from about 5 to about 20 mm, from about 6 to about 20 mm, from about 7 to about 20 mm, from about 8 to about 20 mm, from about 9 to about 20 mm, from about 10 to about 20 mm, from about 1 to about 19 mm, from about 2 to about 19 mm, from about 3 to about 19 mm, from about 4 to about 19 mm, from about 5 to about 19 mm, from about 6 to about 19 mm, from about 7 to about 19 mm, from about 8 to about 19 mm, from about 9 to about 19 mm, from about 10 to about 19 mm, from about 1 to about 18 mm, from about 2 to about 18 mm, from about 3 to about 1 8 mm, about 4 to about 18 mm, about 5 to about 18 mm, about 6 to about 18 mm, about 7 to about 18 mm, about 8 to about 18 mm, about 9 to about 18 mm, about 10 to about 18 mm, about 1 to about 15 mm, about 2 to about 15 mm, about 3 to about 15 mm, about 4 to about 15 mm, about 5 to about 15 mm, about 6 to about 15 mm, about 7 to about 15 mm, about 8 to about 15 mm, about 9 to about 15 mm, about 10 to about 15 mm, about 1 to about 10 mm, about 2 to about 10 mm, about 3 to about 10 mm, about 4 to about 10 mm, about 5 to about 10 mm, about 6 to about 10 mm, about 7 to about 10 mm, about 8 to about 10 mm, about 9 to about 10 mm, etc.

[0025] The dimensions of the patch can be easily adjusted depending on the drug dose and the patient's needs. The dimensions of each feature can be adjusted within a range. For example, when using a single valve / cavity patch as shown in Figure 1A, the potential size ranges for each part shown are as follows: Part 1: 0.1-3 mm, Part 2: 0.5-10 mm, Part 3: 1-25 mm, Part 4: 0.1-4 mm, Part 5: 0-7 mm, Part 6: 0.1-3 mm, Part 7: 1-30 mm, Part 8: 2-30 mm, Part 9: 1-30 mm, Part 10: 0-5 mm, Part 11: 2-30 mm, Part 12: 0.1-3 mm.

[0026] When using patches containing multiple bulbs, the possible size ranges for each part are as follows: number of bulbs per patch: 2-20, distance between the centers of two adjacent individual bulbs: 3-20 mm, diameter of the patch containing multiple bulbs: 6-40 mm.

[0027] Patch material / valve material The material of at least one valve of the patch is medicamentously acceptable, flexible / elastic enough to allow easy mechanical compression thereof using a finger, watertight and airtight (i.e., sufficient to create and maintain a negative pressure inside the patch and retain the drug). The material of at least one valve comprises or consists of an elastomer. The valve material is such that it provides the one or more valves with an elasticity of about 0.01 MPa to about 1000 MPa. Materials encompassed by the present disclosure include, but are not limited to, elastomers such as poly(ε-caprolactone), poly(glycolide), poly(lactide), poly(hydroxyalkanoates), poly(4-hydroxybutyrate), poly(dioxanone), poly(1,3-trimethylene carbonate), poly(ethylene succinate), polybutylene terephthalate, and copolymers thereof, polyether-based elastomers such as poly(ethylene glycol), poly(tetramethylene) glycol, poly(propylene oxide), poly(p-phenylene oxide), polyarylate ketone, poly(phenylene oxide), ... Polyetherketones, polyphenylethers, polytetrahydrofurans, and copolymers thereof, polyamide-based elastomers, polyurethane-based elastomers, poly(ester)-based elastomers, polysaccharide-based elastomers, poly(β-aminoester)-based elastomers, poly(β-thioester)-based elastomers, polyidaityloxirane (PDMS)-based elastomers, polyacrylic acid-based elastomers, synthetic and natural rubbers such as polybutadiene, copolymers (block, diblock, or triblock) of at least two of them, or mixtures of at least two of these materials. In specific embodiments, the materials are non-biodegradable (e.g., polyether-based elastomers, polydimethylsiloxane (PDMS)-based elastomers, polyacrylate-based elastomers, synthetic and natural rubbers such as polybutadiene). In other specific embodiments, the material is biodegradable (e.g., polyester-based elastomers, polyamide-based elastomers, polyurethane-based elastomers, poly(ester amide)-based elastomers, polysaccharide-based elastomers, poly(β-amino ester)-based elastomers, poly(β-thioether ester)-based elastomers).In a specific embodiment, at least one valve is an elastomer that is a polyester-based elastomer, a polyether-based elastomer, a polyamide-based elastomer, a polyurethane-based elastomer, a poly(ester amide)-based elastomer, a polysaccharide-based elastomer, a poly(β-amino ester)-based elastomer, a poly(β-thioether)-based elastomer, a polydimethylsiloxane (PDMS)-based elastomer, a polyacrylate-based elastomer, a synthetic rubber, a natural rubber, a copolymer of at least two thereof, or a mixture of at least two thereof.

[0028] The patch can be made of a single material (i.e., the material of at least one valve) or multiple materials, e.g., a first material for at least one valve and a second material for a backing layer, different materials for different valves, different materials for a single valve, etc. The patch material(s) can be biodegradable or non-biodegradable. The patch material is medicamentously acceptable.

[0029] The optional biodegradability of the patch within the gastrointestinal tract avoids the risks associated with accidental swallowing of the patch.

[0030] In a specific embodiment, the suction patch may be manufactured by 3D printing and molding.

[0031] Patch Coating / Sealer In specific embodiments, the patch mucosal sealing surface can be coated with a pharma- ceutically acceptable mucoadhesive compound or composition (mucoadhesive coating) to further modulate (e.g., increase) patch adhesion strength. Without being so limited, such compounds and compositions include mucoadhesive polymers such as carbomers, polysaccharides such as chitosan and cellulose derivatives, poly(acrylic acid)-based polymers, lectins, thiomers, proteins / glycoproteins such as polydopamine, poly(vinyl alcohol) (PVA), alginates, poly(methacrylic acid)-based polymers, various gums, poly(N-vinylpyrrolidone), and copolymers thereof.

[0032] In other specific embodiments, a sealer can be added onto the patch to cover its mucosal sealing surface immediately prior to its use. The sealer is pharma- ceutically acceptable or food grade. In specific embodiments, the sealer has a viscosity of about 0.98 mPa·s to about 1000 Pa·s. In a non-limiting specific embodiment, the sealer is water. In other embodiments, the mucosal patch is placed onto the mucosa without the addition of a sealer.

[0033] Such mucoadhesive coatings and / or sealers can further increase adhesion of the patch to the mucosa by (a) improving the shear or peel resistance of the patch, (b) reducing air / liquid leakage, and / or (c) a combination of (a) and (b).

[0034] Adhesion strength As used herein, adhesive strength is meant to refer to the force required to peel the patch from its substrate, e.g., a mucosa such as the oral (e.g., buccal) mucosa, normalized by the surface area of ​​the inner rim (opening) of at least one valve or the total base surface area of ​​the inner rims (openings) of two or more or all valves. The strength must be high enough to ensure patch adherence on the mucosa for a sufficient time for the drug to be released, yet low enough to avoid bleeding or ulceration of the mucosa.

[0035] The patch of the present disclosure has a pressure resistance of about 0.5 kPa to about 200 kPa (i.e., about 0.05 N / cm 2 ~20N / cm 2) of adhesive strength. Such strength stems at least in part from the negative pressure achieved within the patch (e.g., up to about 100 kPa) and ultimately from the patch adhesive coating and / or sealer, which can increase adhesive strength (e.g., up to about 150 kPa). Without being limited thereto, various patch designs of the present disclosure tested ex vivo on porcine buccal tissue reproducibly achieved suction strengths of about 50 kPa (e.g., patches having a diameter of 0.5 cm at the contact area and a design similar to that shown in FIG. 1). In specific embodiments, the adhesive strength is about 5 kPa to about 150 kPa, about 10 kPa to about 150 kPa, about 15 kPa to about 150 kPa, about 20 kPa to about 150 kPa, about 5 kPa to about 120 kPa, about 10 kPa to about 120 kPa, about 15 kPa to about 120 kPa, about 20 kPa to about 120 kPa, about 5 kPa to about 110 kPa, about 10 kPa to about 110 kPa, about 15 kPa to about 110 kPa, about 20 kPa to about 110 kPa, about 5 kPa to about 100 kPa, about 10 kPa to about 100 kPa, about 15 kPa to about 100 kPa, or about 20 kPa to about 100 kPa.

[0036] The patches of the present disclosure can remain firmly attached (adhered) to the oral (e.g., buccal) mucosa for at least 1 minute and up to 10 hours. In specific embodiments, they remain attached to the oral (e.g., buccal) mucosa for 1-5 minutes, 1-10 minutes, 1-15 minutes, 1-30 minutes, 5-10 minutes, 5-15 minutes, 5-30 minutes, 10-30 minutes, 10-60 minutes, 15-30 minutes, 15-45 minutes, 15-60 minutes, 15-180 minutes, 30-60 minutes, 30-180 minutes, 1-180 minutes, 2-5 hours, 2-10 hours, and 5-10 hours. They can be easily removed without causing tissue damage by controlled air leakage (see, e.g., Figures 10A-C).

[0037] Drugs As used herein, the term "drug(s)" refers to any pharmacologically active molecule or mixture of molecules, including unapproved active pharmaceutical ingredients (APIs). As used herein, a mixture of molecules exhibits pharmacological activity. Biological extracts, such as, but not limited to, plant or animal extracts, are encompassed by the term mixture of molecules and thereby by the term drug. Drugs that may be incorporated into the patch of the present disclosure may be low molecular weight active drug components (<1000 Da) or large molecular weight active drug components (>1000 Da), such as polysaccharides, peptides, proteins, nucleic acids, dendrimers, polymer-drug conjugates, proteolysis targeting chimeras (PROTACs), lysosomal targeting chimeras (LYTACs), antibody-based PROTACs (AbTACs), antibody-drug conjugates, lipid or polymer nanoparticles, exosomes, and vaccine antigens (see, e.g., Figures 7 and 11-14). The patch is most advantageously used to deliver drugs of high molecular weight (e.g., but not limited to, 1 kDa to 50 kDa, e.g., about 1 to about 45 kDa) or size (e.g., but not limited to, 0.5 nm to 10 nm, or about 0.5 nm to 6 nm) as such drugs typically exhibit poor oral absorption and require injection, although there is no lower size limit to the drugs that can be used in the patch of the present disclosure. The patch of the present disclosure will also be advantageously used for drugs that include drugs less than 1 kDa and exhibit poor oral bioavailability associated with degradation in the GI tract and / or poor diffusivity across mucosa (malabsorption), including, for example, cannabis oil containing cannabidiol and / or cannabigerol and / or tetrahydrocannabinol.

[0038] Drugs that would particularly benefit from the delivery device of the present disclosure include: (1) Semaglutide, an anti-diabetic and anti-obesity drug that acts like human glucagon-like peptide-1. This drug has a molecular weight of 4113 Da with oral bioavailability of about 1% even in the presence of large amounts of permeation enhancers as excipients. The recently approved oral tablet (Novo Nordisk's (Rybelsus) for diabetes) also requires the drug to be taken at a specific time each day before breakfast, as absorption is affected by food in the stomach. (2) Octreotride, which has an oral bioavailability of 0.5-1% even in the presence of permeation enhancers. (3) Human growth hormone, a drug for treating childhood growth disorders and adult growth hormone deficiency. As is typical of high molecular weight (22 kDa) protein drugs that are susceptible to degradation in the GI tract, there are currently no oral formulations of this drug on the market. (4) Insulin is currently only available for injection or pulmonary administration. (5) TNF-alpha inhibitors are antibodies that require injections. Other peptide and protein (macromolecular drugs) drugs with low oral bioavailability and high susceptibility to degradation in the GI tract: (6) PROTACs are a new type of drug molecule that can degrade target pathogenic proteins and regulate related signaling pathways. With similar molecular weights as peptide-based drugs, PROTACs often have low oral bioavailability. This patch can avoid some modifications to achieve stability and absorption through the GI tract; (7) Vaccines: Since injected vaccines only trigger systemic immunity, mucosal immunity can also or alternatively be stimulated via the mucosal route.

[0039] Given the size limitations of the patch, and the resulting limited size of the drug compartment(s), the patch may be used to deliver drugs that can be usefully administered at doses of less than about 100 mg (or less than about 50 mg).

[0040] Drug Formulations The drug(s) can be loaded into the patch with at least one excipient (one or more excipients) and / or at least one carrier / solvent (one or more carriers or one or more solvents) to form one or more drug formulations with or without additional separately loaded drug-free formulations containing at least one excipient (one or more excipients) such as carriers and solvents (one or more carriers or one or more solvents) (in a cavity / compartment separate from the one in which the drug is loaded). Each of these drug formulations and excipient / carrier / solvent formulations can independently be in a solid, organogel, hydrogel, suspension, paste, or liquid / solution state. The one or more formulations can be released simultaneously or sequentially. The one or more formulations can be loaded as a mixture, in a layered structure, or in separate compartments (Figures 3A-D).

[0041] A variety of dispersion systems (carriers and / or excipients) can be used to load the drug inside the patch, including but not limited to PVA, glycerol, hydrogels, poly(ethylene glycol), fatty acids, (poly)saccharides (e.g., cyclodextrins), waxes, etc. Without being limited thereto, such carriers and / or excipients can be used to create bulk volume and help control the release rate.

[0042] Excipients, such as, but not limited to, permeation enhancers, can be loaded into one or more compartments (cavities / valves) of the patch. The combination of chemical disruption produced by the permeation enhancers and mechanical stretching (mucosal deformation) caused by mechanical suction can further enhance the diffusion of drugs (e.g., hydrophilic macromolecules) (see, e.g., Figures 6-8, 11-14).

[0043] As used herein, permeation enhancers that can be used in the patch include, but are not limited to, fatty acids and derivatives such as sodium salcaprozate (SNAC), sodium caprate, sodium caprylate, and palmitoyl carnitine, bile salts and other steroid detergents such as deoxycholate, sodium taurocholate (NaTaC), glycocholate, and saponin, natural and synthetic surfactants such as phospholipids, sodium lauryl sulfate, sodium sulfococcinate, and their derivatives, chelators such as EDTA, citric acid / citric acid, and positively charged polymers such as polyacrylates, chitosan, cyclodextrins, and derivatives, laurocapram and derivatives, thiomenthofol and derivatives, and polysorbates and derivatives. In a specific embodiment, the permeation enhancer is NaTaC. Without being limited thereto, about 0.5 mg to 50 mg of permeation enhancer can be included in the mucosal suction patch.

[0044] Excipients such as, but not limited to, adjuvants can be loaded inside one or more compartments (cavities / valves) of the patch, such as, but not limited to, squalene and vitamin E (α-tocopherol).

[0045] The number of valves in a patch containing a drug formulation can range from 1 to 100%. When a patch contains more than one valve containing a drug formulation, the two or more drug formulations can be the same or different.

[0046] How to use The present disclosure provides for the use of a mucosal suction patch as described herein for the non-injection systemic delivery of a drug in a subject in need thereof, the patch being placed on the mucosa for a time sufficient to ensure drug delivery. In specific embodiments, the time is from about 1 minute to about 10 hours (or from about 2, 3, 4, 5, 6, 7, 10, 15, 20 minutes to 1, 2, 3, 4, 5, 6, 7, 8, or 9 hours, e.g., 1-5 minutes, 1-10 minutes, 1-15 minutes, 1-30 minutes, 1-2 hours, 1 minute to 3 hours, 5-10 minutes, 5-15 minutes, 5-30 minutes, 5-60 minutes, 5-2 hours, 10-30 minutes, 10-60 minutes, 15-30 minutes, 15-45 minutes, 15-60 minutes, 15-180 minutes, 30-60 minutes, 30 minutes to 2 hours, 30 minutes to 3 hours, 1 hour to 2 hours, 1 hour to 3 hours, 2-5 hours, 2-10 hours, and 5-10 hours, etc.). In other specific embodiments, the time range is from 5 minutes to 3 hours.

[0047] Because the drugs and excipients are encapsulated within the patch, they are not or are not significantly diluted throughout the application time, and therefore a steep drug concentration gradient can be established and maintained to achieve better drug permeation.

[0048] Delivery of the drug from the patch through the mucosa of the subject to the blood vessels of the subject occurs by passive movement of the drug, facilitated by distortion of the mucosa due to suction, and finally by the permeation enhancer. According to the present disclosure, suction and drug delivery occur simultaneously, i.e., as a single step. According to the present disclosure, the patch is stationary (i.e., once placed on the mucosa, it does not move during drug delivery). This delivery method advantageously allows the drug to pass through the mucosal epithelium, which is a barrier for absorption, typically having a thickness of 150 μm to 800 μm in humans. Thereby, the drug reaches the systemic circulation via lymphatics and / or blood vessels. This is advantageously a needle-free, electricity-free delivery that does not involve physical puncture of the mucosa.

[0049] Combination therapy The mucosal suction patch of the present disclosure can be applied as the sole delivery vehicle for drugs or in combination with other drug delivery strategies, such as permeation enhancers (e.g., NaTaC). Heat treatment can also enhance the permeation of drugs through mucous membranes. Heat generation segments on the inside or outside of the patch can further increase drug permeability.

[0050] route The mucosal suction patch can be placed on any target mucosa to deliver drugs. In a preferred embodiment, it is placed on an easily accessible (non-invasive) mucosa in a location that does not interfere with breathing or food / drink intake. Without being limited thereto, the mucosa is the oral cavity (e.g., buccal, palate, labial, or sublingual mucosa) or vaginal mucosa.

[0051] subject As used herein, the term "subject" is meant to refer to any animal, such as a mammal, including a human, dog, cat, pig, cow, monkey, cattle, horse, etc. In certain embodiments, it refers to a human.

[0052] Patch design and manufacturing method The patch of the present disclosure can be designed using common computer-aided design (CAD) software such as AutoCAD™, Solidworks™, etc. The patch can be manufactured using any known method, including but not limited to 3D printing, by techniques such as digital light processing (DLP), engraving, molding (e.g., compression molding, die casting, and injection molding), that allows for rapid prototyping, optimization, and mass production. Without being limited thereto, the mold can be manufactured from stainless steel and aluminum, or 3D printed materials and other materials.

[0053] Drug Loading Any known drug loading method can be used, including but not limited to film formation (e.g., drug dispersion in lipid or polymer matrix), paste injection, mini-tablet loading, etc. In the film formation method, the drug and excipients are dissolved or dispersed in a suitable solvent, which is then evaporated, leaving a solid matrix inside the patch. When film formation is performed by drug dispersion in lipid matrix, the lipid matrix can be heated, deposited into the patch, and cooled. In the paste injection method, a semi-solid solution or dispersion of drug and excipients is deposited into the patch by extrusion.

[0054] Drug Delivery When a drug-loaded patch is attached to the mucosa and the mucosa is deformed to partially fill the cavity of the patch due to negative pressure (suction effect), the drug diffuses into the medium inside the patch (e.g., drug formulation, sealing fluid, biological fluid, or a combination of at least two thereof) until it reaches the mucosa. In non-limiting examples presented herein, the negative pressure created by the patch allows the drug to reach a depth of about 500-4500 μm ex vivo in the animal tissue, thereby passing through the mucosal epithelium (about 150-800 μm thick in humans). The drug passes through the mucosal layer and reaches the blood and / or lymphatics (systemic circulation).

[0055] Non-Comprehensive Benefits Non-invasive technique. In vivo experiments in beagle dogs demonstrated the minimally invasive nature of the method (Figure 10A-C). The reversible deformation of the mucosa does not significantly compromise the structural integrity of the mucosal surface, in contrast to techniques such as microneedles that penetrate the mucosa. Non-invasiveness is supported by ex vivo investigations that show the integrity of the mucosal layer (Figure 4A-B).

[0056] Patient-friendly and reduced medical costs. In addition to being non-invasive, patch application is simple and user-friendly since it does not require special training or other devices. Thus, drugs that typically must be administered via injection can be painlessly self-administered by patients, which is most likely to increase patient acceptance and therefore compliance, especially for children or subjects with aversion to needles. The fact that the device is self-administerable also allows for home administration of drugs, which not only further increases patient comfort but also reduces the cost and requirements of medical staff.

[0057] Higher bioavailability. The bioavailability of most oral formulations of peptides is very low, i.e., 1% or less. The patch bypasses the first-pass metabolism of the liver and the mild chemical and enzymatic environment. The strong low pressure of the patch of the present disclosure extended the retention time of the drug in the vicinity of the epithelium, but also disrupted the integrity of the mucosal barrier, facilitating the permeation of the drug molecules. In vivo studies on beagle dogs demonstrated herein that the mucosal suction patch can achieve 35% higher bioavailability than the commercial tablet for the model peptide drug desmopressin (>1100 Da) after 3 hours of application time (Figure 11). When combined with a permeation enhancer, the suction patch device can achieve more than 10 times higher oral bioavailability than the commercial tablet (Figures 12 and 14). A continuous increase in plasma drug concentration was observed during and even after suction patch application.

[0058] Versatility. The patch can be used to deliver various types of drugs and excipients. The size and shape of the patch of the present disclosure can be easily adapted to the needs of the patient, for example, to a small size for children. The patch can be used with several different dosage forms (e.g., solid or paste), several excipients that allow the drug to tailor its release kinetics, and several drugs without major adaptations.

[0059] Strong and robust mucoadhesion without chemical interactions (i.e., no mucoadhesive coating required). In principle, atmospheric pressure can be used to achieve a 10 5 Adhesion strengths of up to 100 kPa (approximately 100 kPa) can be achieved, which is approximately two orders of magnitude stronger than existing mucoadhesive materials.

[0060] Scalability and cost. The simple and scalable manufacturing process by molding allows existing manufacturing plants to be used with small adjustments. Furthermore, the drug loading process, for example by film formation or paste injection, is a well-established process and can be easily adapted. As a result, the simple manufacturing, low-cost materials, and easy implementation in existing manufacturing plants make the technology easily accessible to small and large companies. A die casting process with 3D printing casting molds that allows the production of several patches at once has been established. Similar casting molds with more patches per plate can be produced by aluminum, which is typically used by industry. As a result, the scalability of the manufacturing process can be established with FDA-approved materials, which greatly simplifies the industrial translation compared to other technologies, for example, microneedles or ultrasound.

[0061] Compared to specific technologies in clinical trials, the patch of the present disclosure presents the following advantages: Compared to microneedle-based oral capsules (e.g., developed by Rani Therapeutics), the patch is a much simpler technology with low production costs using simple manufacturing. The patch is a more robust drug delivery process with lower variability compared to that obtained in the GI tract with Rani microneedle-based oral capsules due to their complex actuation mechanism. The patch has less risk of pathogen exposure due to its non-invasive nature compared to that presented by needle puncture in the GI tract. Compared to the aerosol spray-based system developed by Generex Biotechnology, which utilizes mechanical pressure to deliver drug compounds through the oral (e.g., oral) mucosa, the patch can be worn for continuous periods, allowing for steady penetration of the drug compound while the pressure generated by the aerosol spray is transient. By providing adjustable drug compartment(s) and various loading strategies, the patch offers better control over drug dosage and versatility in terms of drug as a drug and drug formulation. Compared to biochemical modification with permeable carriers developed by Applied Molecular Transport Inc., no chemical modification of the drug is required with the patch and no new chemical substances are generated, thereby simplifying the drug development and approval process. Finally, since the device (patch) can be envisaged without using protein carriers in the formulation, there is also a reduced risk of causing immune reactions and related side effects.

[0062] More specifically, the present disclosure provides the following:

[0063] Item 1. A mucosal suction patch having an external volume of 50 μL to 5000 μL, comprising at least one valve forming at least one cavity, each of the at least one cavity being in fluid communication with at least one opening, and at least one of the at least one cavity enclosing a drug; a mucosal sealing surface defining said at least one opening; a pressure application surface opposite the mucosal sealing surface; A mucosal suction patch, wherein the at least one valve is elastic, and when the at least one valve is in an expanded state and mechanical pressure is applied to the pressure application surface, the at least one valve is deformed, and when the mechanical pressure is released while the mucosal sealing surface is on a target mucosa, the at least one valve at least partially recovers its expanded state, generating a temporary negative pressure inside the at least one cavity and deforming the mucosa, which reversibly fills at least a portion of the at least one valve cavity and moves the drug into the mucosa.

[0064] Item 2. The mucosal suction patch according to Item 1, wherein the elasticity of the at least one valve is about 0.01 MPa to about 1000 MPa.

[0065] Item 3. The mucosal suction patch according to any one of Items 1 to 2, wherein the drug is in a formulation further comprising at least one excipient.

[0066] Item 4. The mucosal suction patch according to item 3, wherein the at least one excipient comprises a permeation enhancer.

[0067] Item 5. The mucosal suction patch according to any one of items 1 to 4, comprising a single valve.

[0068] Item 6. The mucosal suction patch according to any one of Items 1 to 5, further comprising a sealer.

[0069] Item 7. The mucosal suction patch according to any one of items 1 to 6, wherein the drug has a molecular weight of about 1 kDa to about 50 kDa.

[0070] Item 8. The mucosal suction patch according to any one of items 1 to 7, for transmucosally administering the drug to a subject.

[0071] Item 9. Use of a mucosal suction patch for transmucosal delivery of a drug to a subject, comprising: applying mechanical pressure to the drug-containing mucosal suction patch prior to or during placement of a mucosal sealing surface of the mucosal suction patch on a mucosa of the subject; Releasing the mechanical pressure on the mucosal suction patch to cause suction and deformation of the mucosa; A use whereby the drug migrates across the mucosal epithelium and enters the subject's systemic circulation.

[0072] Item 10. The use according to Item 9, wherein the mucosal suction patch adheres to the mucosa with a strength of about 0.5 kPa to about 200 kPa.

[0073] Item 11. The patch, at least one valve forming at least one cavity, each of the at least one cavity being in fluid communication with at least one opening, one or more of the at least one cavity enclosing the drug; the mucosal sealing surface defining the at least one opening; a pressure application surface opposite the mucosal sealing surface; 11. The use according to item 9 or 10, whereby the at least one valve is elastic, such that when the at least one valve is in an expanded state and the mechanical pressure is applied to the pressure-application surface, the at least one valve deforms and when the mechanical pressure is released, the at least one valve at least partially regains its expanded state.

[0074] Item 12. The use according to any one of Items 9 to 11, wherein the mucosal suction patch is applied to the mucosa for about 1 minute to 10 hours, preferably 5 minutes to 30 minutes.

[0075] Item 13. The use according to any one of items 9 to 12, wherein the drug is in a formulation further comprising at least one excipient.

[0076] Item 14. The use of item 13, wherein the at least one excipient comprises a permeation enhancer.

[0077] Item 15. The mucosal suction patch according to any one of items 1 to 6 or the use according to any one of items 9 to 14, wherein the mucosa is an oral mucosa or a vaginal mucosa.

[0078] Item 16. The mucosal suction patch according to any one of items 1 to 6 or the use according to any one of items 9 to 14, wherein the mucosa is an oral mucosa.

[0079] Item 17. The mucosal suction patch according to any one of items 1 to 6, or the use according to any one of items 9 to 16, wherein the drug has a molecular weight of about 1 kDa to about 50 kDa.

[0080] Item 18. A method for transmucosal delivery of a drug to a subject, comprising: applying mechanical pressure to the drug-containing mucosal suction patch prior to or during placement of a mucosal sealing surface of the mucosal suction patch on a mucosa of the subject; Releasing the mechanical pressure to cause suction and deformation of the mucosa; whereby the drug migrates across the mucosal epithelium and enters the subject's systemic circulation.

[0081] Item 19. The method of item 18, wherein the drug migrates to a depth of at least 150 μm.

[0082] Item 20. The method according to Item 18 or 19, wherein the mucosal suction patch adheres to the mucosa with a strength of about 0.5 kPa to about 200 kPa.

[0083] Item 21. The patch, at least one valve forming at least one cavity, each of the at least one cavity being in fluid communication with at least one opening, one or more of the at least one cavity enclosing the drug; the mucosal sealing surface defining the at least one opening; a pressure application surface opposite the mucosal sealing surface; whereby application of said mechanical pressure to said pressure application surface causes the at least one bulb to deform, and when said mechanical pressure is released, said at least one bulb at least partially regains its expanded state. The method according to any one of Items 18 to 20.

[0084] Item 22. The method according to any one of Items 18 to 21, wherein the mucosa is an oral mucosa.

[0085] Other objects, advantages and features of the present disclosure will become more apparent upon reading the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings in which: [Brief description of the drawings]

[0086] [Figure 1A] Exemplary designs of mucosal suction patch-based drug delivery systems according to the present disclosure. Examples of 2D structures of mucosal suction patches (Type 1, Examples 4 and 6-14), including the dimensions used in the in vivo assays presented herein. [Figure 1B] Exemplary designs of mucosal suction patch-based drug delivery systems according to the present disclosure: Figure 1 shows a cross-sectional view of a mucosal suction patch structure loaded with a drug formulation. [Figure 1C] Exemplary designs of mucosal suction patch-based drug delivery systems according to the present disclosure. Final 3D printed poly(β-thioether ester) mucosal suction patches used in ex vivo and in vivo Examples 4 and 6-14 compared to nickels. [Figure 2A]Illustrative sketches of different types of mucosal suction patch structures that can be utilized for drug delivery according to the present disclosure: A simple disc-shaped mucosal suction patch with drug compartments / valves (mucosal sealing surface side shown). [Figure 2B] Exemplary sketches of different types of mucosal suction patch structures that can be utilized for drug delivery according to the present disclosure: A hierarchical mucosal suction patch structure with an embedded array of valves / cavities, where drugs can be loaded within and / or between the patch layers. [Figure 2C] 13A-13C are exemplary sketches of different types of mucosal suction patch structures that can be utilized for drug delivery according to the present disclosure: A bio-inspired mucosal suction patch with large valve / drug compartments, bottleneck structures, and patterns in the contact area on the mucosal sealing surface. [Figure 2D] 2C-C are exemplary sketches of different types of mucosal suction patch structures that may be utilized for drug delivery according to the present disclosure. [Figure 2E] 1 is an exemplary sketch of different types of mucosal suction patch structures that may be utilized for drug delivery according to the present disclosure. An example of a multi-layer mucosal suction patch structure with the possibility of incorporating different functionalities, for example, heating between the single layers. [Figure 2F]

[0023] Figure 1 shows exemplary sketches of different types of mucosal suction patch structures that can be utilized for drug delivery according to the present disclosure. An example of a mucosal suction patch comprising an array of valves and a solid backing layer. The valves are connected by the backing layer, which itself contains drug compartments between the valves. [Figure 2G] 1 is an exemplary sketch of different types of mucosal suction patch structures that can be utilized for drug delivery according to the present disclosure. An example of a 3D printed mucosal suction patch with seven individual valves and a backing layer manufactured using a biodegradable polymer, namely poly(β-thioether ester), and compared to a one-cent coin. [Figure 2H]1 is an exemplary sketch of different types of mucosal suction patch structures that can be utilized for drug delivery according to the present disclosure. An example of a hierarchical mucosal suction patch with embedded arrays produced by 3D printing with a biodegradable polymer, namely poly(β-thioether ester). [Figure 2I] Exemplary sketches of different types of mucosal suction patch structures that can be utilized for drug delivery according to the present disclosure: Type 1' suction patch A, which is structurally close to Type 1 (FIGS. 1A / 1C), but has a cylinder on top, allowing the insertion of floss (Example 1), which is manufactured by molding with food-grade polydimethylsiloxane (PDMS). [Figure 3A] Examples of suction patch loading methods for different drug formulations presented by vertical cross-sections. Multi-layer coating: first layer containing the drug / active pharmaceutical ingredient (API) (black dots) and a matrix of polymers and other excipients (white), second layer of other polymers and excipients (grey, striped). [Figure 3B] Examples of inhalation patch loading methods for different drug formulations presented by vertical cross-sections: matrix of polymer and other excipients (light grey) and single layer coating with drug / API (black dots). [Figure 3C] Example of suction patch loading method of different drug formulations presented by vertical cross-section. Multiple compartments: several sealed and separated compartments. For example, one side may contain a matrix of polymers and other excipients (white) with drug / API (black dots) and the other side may contain a liquid, hydrogel, or organogel. The separation barrier breaks during application and compression, allowing the two components to mix. [Figure 3D] Examples of suction patch loading methods for different drug formulations presented by vertical cross-sections. Single compartment with non-solid loading: drug / API (black dots) can be dissolved or dispersed inside a liquid or semi-solid matrix (gray waves on white background) containing solvents and other excipients. After loading, the formulation is sealed inside the patch by a polymeric film (black stripes on gray background). [Figure 4A]Tissue integrity and histology. Fluorescent images of 20 μm cryopreserved tissue slices after 3 h of application of a mucosal suction patch (Type 1, Figure 1A / C) loaded with 54 μg of model surrogate, the dye Cy5, and 1.2 mg of PVA. Tissues were stained with iFluor™ 488-conjugated phalloidin (F-Actin stain) and Hoechst 33342 (Nucleus stain) and imaged with a widefield microscope (40x). Small single images were acquired from three channels (Ex: 340-380, 460-500, and 590-650 nm; Em: 450-490, 512-542, 662-738 nm, respectively) and merged overlaid. [Figure 4B] Tissue integrity and histology. Hematoxylin and eosin (H&E) stained tissue slices from the same specimen. [Diagram 5] Adhesion force of different 3D printed suction patch designs (Type 1' and Type 2) made of the non-degradable polymer poly(β-thioether-ester) and tested on porcine mucosa at different angles (0°, 45°, 90°, and 135°) and artificial surfaces. Error bars indicate standard deviation of n=9 measurements with m=3 patches (each measured in triplicate). [Figure 6A] Effect of permeation enhancers in combination with mucosal suction patches (type 1, Figure 1A / Figure 1C). Ex vivo evaluation of drug permeation through porcine oral mucosa. Penetration depth profile of a model surrogate (Cy5) (normalized to maximum fluorescence intensity). Mucosal suction patches were loaded with 40 μL of a solution containing 2 mM Cy5 (54 μg), 3% PVA (1.2 mg), and 265 mM of various types of permeation enhancers, namely, sodium taurocholate (NaTaC) (5.7 mg), sodium caprate (C10) (2.1 mg), and sodium salcaprozate (SNAC) (3.2 mg). Data are presented as mean (n=3 samples) + standard deviation (n=15 measurements). [Figure 6B] Effect of permeation enhancers in combination with mucosal suction patch (Type 1, Figure 1A / Figure 1C). Ex vivo evaluation of drug permeation through porcine oral mucosa. Fluorescence images of buccal mucosa slices after 3 hours of application of a mucosal suction patch formulation containing Cy5 and PVA. [Figure 6C] Effect of permeation enhancers in combination with mucosal suction patch (Type 1, FIG. 1A / FIG. 1C). Ex vivo evaluation of drug permeation through porcine oral mucosa. Fluorescence images of buccal mucosa slices after 3 hours of application of mucosal suction patch formulations containing Cy5, PVA and SNAC. [Figure 6D] Effect of permeation enhancers in combination with mucosal suction patch (Type 1, Figure 1A / Figure 1C). Ex vivo evaluation of drug permeation through porcine oral mucosa. Fluorescence images of buccal mucosa slices after 3 hours of application of a mucosal suction patch formulation containing Cy5, PVA, and C10. [Figure 6E] Effect of permeation enhancers in combination with mucosal suction patch (Type 1, Figure 1A / Figure 1C). Ex vivo evaluation of drug permeation through porcine oral mucosa. Fluorescence images of buccal mucosa slices after 3 hours of application of a mucosal suction patch formulation containing Cy5, PVA, and NaTaC. [Figure 7] Ex vivo evaluation of surrogate permeation through porcine oral mucosa at different molecular weights administered with a mucosal suction patch. Mucosal suction patches were loaded with (a) 160 μg of 2k-PEG-Cy5 (approximately 2 kDa, stars), 207 μg of 20k-PEG-Cy5 (approximately 20 kDa, squares), or 304 μg of Alexa647-ovalbumin conjugate (approximately 45 kDa, circles), (b) 5.7 mg of NaTaC, and (c) 1.2 mg of PVA, as illustrated in FIG. 6, and applied to porcine oral tissue for 3 hours. Specimens were processed as described in Example 6. The penetration depth profiles of the surrogates were plotted against the fluorescence intensity (normalized to the maximum exposure) on a logarithmic scale. Data are presented as the mean (n=3 samples) + standard deviation (n=15 measurements). The graph shows that molecules of different molecular weights, greater than 1 kDa, can penetrate greater than 500 μm and therefore cross the mucosal permeability barrier. [Figure 8]Effect of low pressure on the diffusion of marker molecules. Ex vivo evaluation of drug permeation through porcine oral mucosa under controlled pressure. Mucosal suction patches (type 1, Fig. 1A / 1C) were loaded with 54 μg Cy5, 2.1 mg C10, and 1.2 mg PVA and applied to porcine oral tissue for 1 or 3 hours. Specimens were processed as described in Example 6. Cy5 penetration depth profiles were plotted against fluorescence intensity (linearly normalized to exposure time and gain) on a logarithmic scale. Data are presented as mean (n=3 samples) + standard deviation (n=15 measurements). [Figure 9A] In vitro release of desmopressin from mucosal suction patch formulations. Mucosal suction patches (type 1, Fig. 1A / 1C) were loaded with 1.2 mg desmopressin, 1.2 mg PVA, and one of various permeation enhancers: 5.7 mg NaTaC (n=3), 2.1 mg C10 (n=5), and 3.2 mg SNAC (n=3). Data are presented as mean ± standard deviation. [Figure 9B] In vitro release of semaglutide from mucosal suction patch formulations. Mucosal suction patches were loaded with 3 mg semaglutide, 1.2 mg PVA and one of various permeation enhancers: 3.9 mg NaTaC (n=3), 1.4 mg C10 (n=5) and 2.2 mg SNAC (n=3). Data are presented as mean ± standard deviation. [Figure 10A] In vivo application of mucosal suction patch and risk assessment. In vivo application of mucosal suction patch (Type 1, Figure 1A / 1C) formulation to the buccal mucosa of a beagle dog. Adhesion of the mucosal suction patch to the dog's buccal mucosa immediately after application. [Figure 10B] In vivo application of mucosal suction patch and risk assessment. In vivo application of mucosal suction patch (Type 1, Figure 1A / 1C) formulation to the buccal mucosa of a beagle dog. Application site of mucosal suction patch immediately after removal (patch applied for 3 hours). [Figure 10C] In vivo application of mucosal suction patch and risk assessment. In vivo application of mucosal suction patch (Type 1, Fig. 1A / 1C) formulation to the buccal mucosa of a beagle dog. The same location 3 hours after removal. [Figure 11]Pharmacokinetic study of mucosal suction patch compared with oral tablet. Plasma concentrations of desmopressin after oral administration of tablet or after application of formulations of desmopressin (1.2 mg) with suction (mucosal suction patch (type 1, Fig. 1A / 1C) (1.2 mg PVA) 3 h) and without suction (clamp (1.2 mg PVA + 5.7 mg NaTaC) 0.5 h) to beagle dogs. Data are presented as mean ± standard deviation (n=3). [Figure 12] Pharmacokinetic studies with desmopressin and different permeation enhancers and different application times. Plasma concentrations after application of mucosal suction patches (type 1, Fig. 1A / 1C) containing desmopressin (1.2 mg), sodium caprate (C10) (2.1 mg), or sodium taurocholate (NaTaC) (5.7 mg), and 1.2 mg PVA to beagle dogs. Mucosal suction patches were removed for either 3 or 0.5 hours. Data are presented as mean ± standard deviation (n=3). [Figure 13] Pharmacokinetic study with semaglutide (4 kDa). Plasma concentrations after application of a mucosal suction patch (type 1, Fig. 1A / 1C) containing 9 mg semaglutide, 11.7 mg sodium taurocholate (NaTaC) and 1.2 mg PVA in beagle dogs. The mucosal suction patch was removed at 3 hours. Nested graphs present an expansion of the first 6 hours of the study. Data are presented as mean ± standard deviation (n=3). [Figure 14] Pharmacokinetic study of desmopressin with sodium taurocholate (NaTaC) and PVA. Plasma concentrations after application of a mucosal suction patch (type 1, Fig. 1A / 1C) containing desmopressin (1.2 mg), 5.7 mg sodium taurocholate (NaTaC), and 1.2 mg PVA to beagle dogs. The mucosal suction patch was removed in 10 min. Data are presented as mean ± standard deviation (n=3). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0087] The present disclosure is illustrated in further detail by the following non-limiting examples.

[0088] Example 1: Preparation of mucosal patches Mucosal patch design The mucosal suction patch was designed with the 3D computer-aided design (CAD) software SolidWorks™. The exemplary design of the mucosal suction patch used in the in vivo test has an outer diameter of 5 mm to 3 cm and a height of 1 mm to 1 cm. The dimensions of the device can be easily adjusted depending on the drug dose, formulation, and physiological characteristics of the patient.

[0089] 3D printing To fabricate the mucosal suction patches (types 1, 1' and 2) used in Examples 4-14, poly(β-thioether ester) polymer (14 g), initiator phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (BAPO) (0.75 wt%), light absorber Sudan I (0.04 wt%), dilution solvent N-vinylpyrrolidone (NVP) (11 wt%), and UV inhibitor vitamin E (0.3 wt%) were mixed and sonicated at 80 °C until a homogenous resin was obtained. To build the 3D objects, a commercial DLP 3D printer (Asiga PICO2, Sydney, Australia) was employed. The printer was equipped with a 405 nm LED light source and a customized tray with a heating system that allowed printing at various temperatures, e.g., 75 °C. After printing, the resin residue was removed with isopropanol and ethanol. The mucosal suction patches were then cured under 405 nm UV light for 15 min. Please refer to Figures 1A-C.

[0090] molding The Type 1 suction patch structure was modified in the CAD software SolidWorks™ by adding a small cylinder (φ3 mm, height 2 mm) on top of the dome of the patch to allow for the insertion of floss, thus designing the Type 1' patch (Figure 2I). The design was inverted and split in half to prepare a negative mold with multiple entities to allow for high-scale production. The mold consists of two parts (i.e., the body and the insert).

[0091] To fabricate the suction patch, food-grade polydimethylsiloxane (PDMS) (Bluesil RTV 3428, Elkem) base and curing agent were mixed in a 10:1 ratio (w / w), followed by vacuum degassing for 5 min to remove all air bubbles. Next, the PDMS prepolymer was poured onto the mold and vacuum degassed for another 5–10 min. After that, the insert was placed on the body, and the combined plate was placed in a holder to apply pressure uniformly during PDMS curing. Specifically, the PDMS was cured overnight at room temperature. This process was always performed using two molds simultaneously. Afterwards, the inserts and excess material were removed. Two similar clean body molds were coated with a thin layer of freshly prepared, degassed PDMS prepolymer and merged. As in the previous step, the combined molds were placed in the holder, closed, and cured overnight. Finally, the combined molds were opened, the suction patch was demolished, and excess material was removed.

[0092] Example 2: Various 3D structures of mucosal suction patches Mucosal suction patch drug delivery devices can have a variety of 3D shapes, including but not limited to single valve patches with adjustable drug compartment size, multiple valves with a backing layer (e.g., FIG. 2F), multiple valves / arrays of valves nested within a larger valve (e.g., FIG. 2B), mucosal suction patches with patterned mucosal sealing surfaces (e.g., FIG. 2C), multi-layer patch structures that can incorporate heat generating materials / devices (e.g., FIG. 2E). Designs can be directly produced by a variety of manufacturing methods such as 3D printing and molding. See FIG. 2A-I.

[0093] Example 3: Mucosal suction patch drug and surrogate / fluorescent dye loading Drug surrogates / fluorescent dyes A stock buffer was prepared by first dissolving 15k PVA in deionized (DI) water to a final concentration of 3% w / v.

[0094] The drug surrogates Cy5 (54 μg / 2 mM Cy5 in Examples 4, 6 and 8, 160 μg / 2 mM 2k-PEG-Cy5 in Example 7, and 207 μg / 258 μM 20k-PEG-Cy5 in Example 7) or Alexa647 (304 μg / 168 μM Alexa647-ovalbumin conjugate in Example 7) were added to the stock solution along with a permeation enhancer (5.7 mg / 265 mM NaTaC in Examples 6 or 7, 2.1 mg / 265 mM C10 in Examples 6 and 8, or 3.2 mg / 265 mM SNAC in Example 6) to form a clear solution.

[0095] Mucosal suction patches (Type 1, Figure 1A / Figure 1C) were loaded by drop-casting 40 μL of fresh clear solution inside the mucosal suction patch cavity, which was then dried overnight at ambient conditions and subsequently dried under vacuum for 2-4 h (loading is shown diagrammatically in Figure 3B). Thus, each mucosal suction patch was loaded with the surrogate and 1.2 mg of PVA (loading is shown diagrammatically in Figure 3B).

[0096] Desmopressin A stock buffer was prepared by first dissolving 15k PVA in DI water to a final concentration of 3% w / v.

[0097] Desmopressin (26.56 mM (Examples 9-12, and 14)) was added to the stock solution along with a permeation enhancer having a concentration of 265 mM (5.7 mg of NaTaC in Examples 9, 11-12, and 14, or 2.1 mg of C10 in Examples 9-10, and 12) to form a clear solution.

[0098] Mucosal suction patches (Type 1, Figure 1A / Figure 1C) were loaded by drop-casting 40 μL of fresh clear solution inside the mucosal suction patch cavity, which was then dried overnight at ambient conditions and subsequently dried under vacuum for 2-4 h. Thus, each mucosal suction patch was loaded with 1.2 mg of desmopressin and 1.2 mg of PVA (loading is shown diagrammatically in Figure 3B).

[0099] Semaglutide A stock buffer was prepared by first dissolving 15k PVA in Tris buffer to a final concentration of 3% w / v for Example 9, or 1.5% w / v for Example 13.

[0100] Semaglutide (18.23 mM (Example 9), 27.35 mM (Example 13)) was added to the stock solution along with a permeation enhancer having a concentration of 182.3 mM (3.9 mg NaTaC, 1.4 mg C10 or 2.2 mg SNAC in Example 9) or 273.5 mM (11.7 mg NaTaC in Example 13) to form a clear solution.

[0101] Mucosal suction patches (Type 1, Figure 1A / 1C) were loaded by drop-casting 40 μL (Example 9) or 80 μL (Example 13) of fresh clear solution inside the mucosal suction patch cavity, which was then dried overnight at ambient conditions and subsequently dried under vacuum for 2-4 hours. Thus, each mucosal suction patch was loaded with 3 mg semaglutide (Example 9) or 9 mg semaglutide (Example 13) and 1.2 mg PVA (loading is shown diagrammatically in Figure 3B).

[0102] Example 4: Ex vivo evaluation of surrogate (fluorescent dye) loaded mucosal suction patch devices on fresh porcine oral mucosa Ex vivo evaluation of the surrogate (fluorescent dye)-loaded mucosal suction patch device (Type 1, Figure 1A / C) was performed on fresh porcine oral mucosal tissue obtained from a local slaughterhouse. Whole cheeks were harvested and placed immediately after slaughter in a buffer solution, e.g., DMEM / F-12 (Dulbecco's Modified Eagle Medium / Nutrient Mixture F-12), HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid), without phenol red, pH 7.4, 1 v / v% antimycotic (10,000 units penicillin, 10 mg streptomycin, and 25 μg amphotericin B per mL).

[0103] The tissues were transported on ice to the laboratory, where the underlying tissue was removed with a scalpel and surgical scissors at a thickness of approximately 1–2 cm. After sectioning, the tissues were washed with PBS, placed in a 6-well plate with fresh buffer, and incubated at 37 °C for 20 min. For application of the mucosal suction patch, the tissue specimens were removed from the buffer for up to 3 min. Then, 80 μL of deionized water was added within the prepared mucosal suction patch and applied to the buccal mucosa by hand within 2 min. The specimens were then incubated in an oven at 37 ± 2 °C for 3 h before removing the mucosal suction patch. The tissues were then washed with PBS to remove excess marker molecules, followed by snap-frozen for 30 s using liquid nitrogen-cooled isopentane. Afterwards, excess tissue was removed with a razor blade, and 20 μm-thick slices on glass slides were obtained using a cryotome at -20 °C. After warming to room temperature for 30 min, the glass slides were fixed in methanol-free paraformaldehyde PBS solution (pH 7.4) for 5 min and washed for 3 min.

[0104] The sample for fluorescence imaging is shown in FIG. 4A. The specimen was permeabilized with 0.5% Trition™X100 in PBS buffer for 15 min, washed in PBS for 3 min, and incubated with 0.1% iFluor™ 488-conjugated phalloidin (F-Actin stain) and 0.1% Hoechst 33342 (nuclear stain) in PBS buffer for 30 min. Finally, the slide was washed in PBS for 3 min and mounted with ProLong™ Diamond (Thermo Fisher) mounting medium and coverslip. In contrast, samples for quantification, as described in Examples 6-8, were fixed as described above and mounted directly after washing in PBS for 3 min.

[0105] Finally, H&E staining (Figure 4B) was performed by an automated H&E stainer, with 90 seconds of staining and 3 seconds of dropping at each step. The slides were washed with 100% ethanol (EtOH), 100% EtOH, 95% EtOH, 70% EtOH, DI-H 2 HO, Mayer's hematoxylin, Mayer's hematoxylin, tap water, HCl-EtOH (70% EtOH, 29.9% ddHO) 2HO, 0.1% hydrochloric acid (37%), tap water, dd H 2 The sections were then immersed in 95% EtOH, eosin Y, eosin Y, 95% EtOH, 100% EtOH, 100% EtOH, xylene, and finally mounted with a coverslip and Entellan for imaging with a wide-field microscope. The integrity of the mucosal structure was maintained during physical deformation (stretching). The results are shown in Figure 4A-B.

[0106] Example 5: Evaluation of the adhesive properties of the patch The adhesive properties of the mucosal suction patches (types 1' and 2) were evaluated using a texture analyzer (TA.XT+ texture analyzer, 50 kg load cell, Stable Micro Systems, Godalming (UK)). Adhesion tests were performed by adhering porcine mucosal tissue, soft silicone or glass substrates (artificial surfaces) to a rigid 3D printing platform with different angles attached with standard clamps. The suction patch was compressed onto the test surface and pulled vertically until the clamps were released (rupture). During pulling at a constant speed, the force and pulling distance were measured and recorded. The adhesive strength was calculated by dividing the measured adhesive force by the inner diameter (contact area). The results are shown in Figure 5, where the mucosal suction patch exhibited a 1 N / cm adhesive strength under various pulling conditions. 2 ~20N / cm 2 It indicates that it provides [approximately 10 kPa to approximately 200 kPa].

[0107] Example 6: Ex vivo evaluation of mucosal suction patches for drug permeation using Cy5 as a surrogate through porcine oral mucosa Fluorescence images were acquired using a wide-field microscope (Leica DMI 6000) at 20x magnification in tile scanning mode and merged into a single image. Specimens were excited at 590-650 nm and emission was filtered from 662-738 nm. To assess the penetration depth of the surrogates, images were processed as grayscale in Fiji-ImageJ™ software. Grayscale intensity line profiles were obtained by drawing multiple straight lines perpendicular to the surface of the mucosal lining. The resulting intensity-distance profiles were transferred to Microsoft Excel™ and MatLab™ for further processing. Autofluorescence was first corrected by subtracting the mean baseline intensity multiplied by three times its standard deviation obtained from lower producing areas of the tissue. Drug distribution profiles were normalized by setting the maximum intensity to 100% and the corresponding distance values ​​to zero. As a result, the penetration depth profiles of the surrogates could be plotted and compared between different conditions or formulations. The results are presented in Figures 6A-E and show the performance of the permeation enhancer in response to the drug.

[0108] Example 7: Ex vivo evaluation of the permeation of surrogates of different molecular weights (approximately 2-45 kDa) through mucosa when administered with a mucosal suction patch The molecular weight range of administrable drugs was evaluated ex vivo on porcine buccal mucosa tissue by applying drug surrogates with different molecular weights. Samples were prepared as described in Example 3 and processed as described in Example 6 with n=15 measurements using n=3 samples. The following surrogates and formulations were used: 2k-PEG-Cy5 and 20k-PEG-Cy5 are Cy5 dyes attached to PEG with a molecular weight of polyethylene glycol (PEG) of 2 kDa or 20 kDa, respectively. Alexa647-Ovalbumin is an Alexa647 dye attached to ovalbumin (approximately 5.5 nm, 45 kDa). Amounts deposited on mucosa: 2k=160 μg, 20k-PEG-Cy5=207 μg, Alexa647-Ovalbumin=304 μg. The formulation was a drug surrogate with 1.2 mg PVA and 5.7 mg NaTaC. The results are shown in Figure 7 and show that all drug surrogates are able to diffuse at least 500 μm deep into the tissue, thus crossing the mucosal epithelium (2k-PEG-Cy5 and 20k-PEG-Cy5) or reaching the deep interior of the mucosal epithelium (Alexa647-Ovalbumin). This indicates that molecules up to 45 kDa (>5 nm) or potentially larger can be administered with the mucosal suction patch and reach the systemic circulation. As a result, large biopharmaceuticals such as recombinant human growth hormone (22.1 kDa) can be administered with the mucosal suction patch.

[0109] Example 8: Ex vivo evaluation of low pressure on the diffusion of marker molecules in porcine oral mucosa via a mucosal suction patch To evaluate the effect of low pressure on drug permeability, a small electric vacuum pump system was connected to the mucosal suction patch via a tube that connects through a puncture on the top of the patch. The device can continuously monitor and control the pressure in the patch up to a constant value, e.g., 30 kPa. For this application, buccal tissue was prepared as described above and placed in a 6-well plate filled with DMEM buffer. According to Example 3, a mucosal suction patch preloaded with 54 μg Cy5, 2.1 mg C10 and 1.2 mg PVA was filled with 80 μL deionized water and placed on the tissue. The pressure was then set to 30 kPa by the pressure reducing valve and left in a 37°C incubator for 3 hours. The vacuum pump was then turned off and the mucosal suction patch was removed. The tissue specimen was processed as described before for fluorescence imaging. To allow comparability, the intensity of each image was converted to the equivalent of a 150 ms exposure time. When plotting the fluorescence intensity-distance profiles, absolute intensity was utilized instead of normalization to compare the pressure-related permeation enhancement effect between different samples. The results are presented in FIG. 8 and show that negative pressure and the associated deformation of the mucosa effectively promoted drug permeation.

[0110] Example 9: In vitro release of desmopressin and semaglutide from mucosal suction patch formulations In vitro release tests were performed in 50 mL Falcon tubes with 3D printed inlets to avoid subsidence of the mucosal suction patch in the tip. A mucosal suction patch (type 1 shown in Figure 1A / Figure 1C) containing a formulation of 1.2 mg desmopressin mixed with the permeation enhancers NaTac (5.7 mg), C10 (2.1 mg) or SNAC (3.2 mg) and 1.2 mg PVA (Figure 9A), or a formulation of 3 mg semaglutide mixed with the permeation enhancers NaTac (3.9 mg), C10 (1.4 mg) or SNAC (2.2 mg) and 1.2 mg PVA was used. The mucosal suction patch was first drug-loaded as described in Example 3 and placed in 40 mL of PBS aqueous buffer (pH 7.4) for desmopressin or 15 ml of Tris aqueous buffer (pH 7.4) for semaglutide.

[0111] The temperature was set at 37°C and the tubes were shaken at 200 rpm. After soaking the mucosal suction patch in the solution, 1 mL aliquots were taken at 5, 15, 30, 45, 60, 90, 120, 150, and 180 min. The taken volumes were replaced with the same fresh PBS buffer for desmopressin or the same Tris buffer for semaglutide. Quantification was performed by HPLC (VWR Hitachi Chromaster™ system, 5160 pump, 5260 autosampler, 5310 column oven and 5430 diode array detector, VWR International, Radnor, PA) with the UV wavelength set at 220 or 280 nm. A C18 column (XBridge™, 5 μm, 250 × 4.6 mm, Waters, Milford, MA) was used for separation, and a mixture of 75% deionized water (0.1% v / v trifluoroacetic acid) and 25% acetonitrile was used as the mobile phase. The release test of semaglutide was carried out in Tris buffer, but the rest of the settings were the same as those of desmopressin. A mixture of 57% deionized water (0.1% v / v orthophosphoric acid) and 43% acetonitrile was used as the mobile phase to elute semaglutide. The results are shown in Figures 9A-B and show that the drug release kinetics from mucosal suction patches depends on the solubility of the drug and its combination with permeation enhancers and other excipients. By adjusting the permeation enhancers, polymers and other excipients, it is possible to adjust the complete drug release from 1 minute to 10 hours.

[0112] Example 10: In vivo application and risk assessment of mucosal suction patches In vivo experiments were performed at the Institute national de la recherche scientifique (INRS) (CNBE, Laval, QC, Canada) and approved by the ethical committee. Mucosal suction patches were prepared as described in Example 3 and loaded with 1.2 mg desmopressin (D), 2.1 mg sodium caprate (C10), and 1.2 mg PVA. Three beagle dogs weighing approximately 10 kg were used in the study. Images were taken at different time points during the entire mucosal suction patch application, i.e., 0 h, 3 h, and 24 h. The results are shown in Figures 10A-C and show that the mucosal suction patch reversibly deforms the mucosa.

[0113] Example 11: Pharmacokinetic study comparing mucosal suction patch with oral tablet In vivo experiments were performed on mucosal suction patches (Type 1, FIG. 1A / FIG. 1C) containing 1.2 mg desmopressin and 1.2 mg PVA (without any permeation enhancer) as described in Example 3. As a control formulation, enteric-coated (Eudragit L100-55, Essen, Germany) capsules containing commercially available Minirin drug tablets (6 tablets containing a total of 1.2 mg desmopressin) were orally administered to dogs.

[0114] To evaluate the effect of adhesion strength on drug permeation, a control study was performed without compressing the mucosal suction patch. A 3D printed clamp containing a cavity for a suction patch containing 1.2 mg desmopressin, 1.2 mg PVA, and 5.7 mg NaTaC was attached to the mucosa of a dog, ensuring similar conditions as the applied suction patch (i.e., closed environment, close contact to the mucosa, same sample preparation and loading), but without the use of a permeation enhancer and without negative pressure and the resulting tissue deformation.

[0115] The dogs were anesthetized for the duration of the experiment (3 hours). The suction remained firmly in place for 3 hours and blood samples were taken at predetermined time points, i.e., 0, 15, 30, 60, 90, 150, 240, and 360 minutes. 2Blood samples were collected in EDTA tubes and immediately followed by centrifugation at 1700G for 10 min at 4°C. Plasma was then stored in clear polypropylene vials at -80°C until further analysis. Drug plasma concentrations were assessed using an LC-MS / MS method. Briefly, aliquots of 900 μL of dog plasma samples were mixed with 10 μL of internal standard (Goserelin, 25 ng / mL) and 300 μL of 4% H 3 PO 4 Acid water was mixed in a 1.5 mL Eppendorf tube. Plasma samples were then extracted using an Oasis™ WAX solid-phase extraction cartridge. After extraction, the solution was evaporated under low vacuum, reconstituted in 120 μL of 11:11:78 acetonitrile / methanol / deionized water, and injected into a Xevo™ G2-XS accurate mass spectrometer. Samples were analyzed in TOF-MRM mode with a quantification limit of less than 15 pg / mL. The results are shown in Figure 11 and show that a bioavailability comparable to that of commercial oral tablets can be achieved with a mucosal suction patch alone (i.e., without the addition of a permeation enhancer). Similar bioavailability can also be achieved with permeation alone and without negative pressure.

[0116] Example 12: Pharmacokinetic study of mucosal suction patch with permeation enhancer in dogs In vivo experiments were performed on mucosal suction patch formulations (Type 1, Fig. 1A / Fig. 1C) containing 1.2 mg desmopressin, 1.2 mg PVA, and 2.1 mg sodium caprate (C10) or 5.7 mg sodium taurocholate (NaTaC) as described in Example 3. The patches were applied for 0.5 or 3 hours. Blood sampling time points and analytical procedures were the same as those described in Example 11. The results are presented in Fig. 12 and show that the combination of permeation enhancer and mucosal suction patch significantly increased the bioavailability of the drug, i.e., on the order of 10-fold, compared to that achieved with the desmopressin tablet in Fig. 11.

[0117] Example 13: Pharmacokinetic study comparing semaglutide mucosal suction patch In vivo experiments were performed on a mucosal suction patch (Type 1, FIG. 1A / FIG. 1C) formulation containing 9 mg semaglutide, 1.2 mg PVA, and 11.7 mg NaTaC, prepared as described in Example 3. Dogs were anesthetized for the duration of the experiment (30 min). The suction remained firmly in place for 30 min and blood samples were taken over the designated time points, i.e., 0, 15, 30, 60, 90, 150, 240, 360, 1440 (24 h), and 4320 (72 h) min. 2 Blood samples were collected in EDTA tubes and immediately followed by centrifugation at 1700G for 10 minutes at 4°C. Plasma was then stored in clear polypropylene vials at -80°C until further analysis. Drug plasma concentrations were assessed using the LC-MS / MS method described in Example 11. The results are presented in Figure 13 and demonstrate that the mucosal suction patch and permeation enhancer achieved therapeutically relevant plasma concentrations of semaglutide (4kDa).

[0118] Example 14: Pharmacokinetic study of mucosal suction patch with permeation enhancer in dogs In vivo experiments were performed on a mucosal suction patch formulation (Type 1, FIG. 1A / FIG. 1C) containing 1.2 mg desmopressin, 1.2 mg PVA, and 5.7 mg sodium taurocholate (NaTaC) as described in Example 3. The patch was applied for 10 minutes. Blood sampling time points and analytical procedures were the same as those described in Example 11. The results are presented in FIG. 14 and show that the combination of the permeation enhancer and the mucosal suction patch significantly increased the bioavailability of the drug, i.e., on the order of 25-fold, compared to that achieved with the desmopressin tablet of FIG. 11.

[0119] The above results indicate that the mucosal suction patch can be used as a platform for various drugs.

[0120] The scope of the claims should not be limited by the embodiments set forth in the examples, but should be accorded the broadest interpretation consistent with the description as a whole. [Explanation of symbols]

[0121] 1: Part 1 Part 2 Part 3 Part 4 Part 5 Part 6 Part 7 Part 8 Part 9 10: Part 10 11: Part 11 12: Part 12

Claims

1. A mucosal suction patch having an external volume of 50 μL to 5000 μL, at least one valve forming at least one cavity, each of the at least one cavity being in fluid communication with at least one opening, one or more of the at least one cavity enclosing a drug; a mucosal sealing surface that bounds the at least one opening; a pressure application surface opposite the mucosal sealing surface; A mucosal suction patch, wherein the at least one valve is elastic, and when mechanical pressure is applied to the pressure-applying surface while the at least one valve is in an expanded state, the at least one valve is deformed, and when the mechanical pressure is released while the mucosal sealing surface is on the target mucosa, the at least one valve at least partially recovers its expanded state, generating a temporary negative pressure inside the at least one cavity and deforming the mucosa, which reversibly fills at least a portion of the at least one valve cavity and moves the drug into the mucosa.

2. The mucosal suction patch according to claim 1, wherein the elasticity of the at least one valve is from about 0.01 MPa to about 1000 MPa.

3. The mucosal suction patch according to claim 1 , comprising a single valve.

4. The mucosal suction patch according to claim 1 , further comprising a sealer.

5. The mucosal suction patch according to claim 1, which is for transmucosally administering the drug to a subject.

6. 1. A mucosal suction patch for transmucosal delivery of a drug in a subject, comprising: The transmucosal delivery applying mechanical pressure to the drug-containing mucosal suction patch before or during placement of the mucosal sealing surface of the mucosal suction patch on the mucosa of the subject; Releasing the mechanical pressure on the mucosal suction patch to cause suction and deformation of the mucosa; A mucosal suction patch whereby the drug migrates through the mucosal epithelium and enters the subject's systemic circulation.

7. A mucosal suction patch as described in claim 6, which adheres to the mucosa with a strength of approximately 0.5 kPa to approximately 200 kPa.

8. At least one valve forming at least one cavity, each of said at least one cavity being in fluid communication with at least one opening, and one or more of said at least one cavity enclosing said drug; the mucosal sealing surface defining the at least one opening; a pressure application surface opposite the mucosal sealing surface; The mucosal suction patch according to claim 6, wherein the at least one valve is elastic, and when the at least one valve is in an expanded state and the mechanical pressure is applied to the pressure-applying surface, the at least one valve is deformed, and when the mechanical pressure is released, the at least one valve at least partially recovers its expanded state.

9. A mucosal suction patch as described in claim 6, which is attached to the mucosa for approximately 1 minute to 10 hours, preferably 5 minutes to 30 minutes.

10. The mucosal suction patch according to any one of claims 1 to 9, wherein the drug is in a formulation further comprising at least one excipient.

11. The mucosal suction patch according to claim 10, wherein the at least one excipient comprises a permeation enhancer.

12. The mucosal suction patch according to any one of claims 1 to 9, wherein the mucosa is an oral mucosa or a vaginal mucosa.

13. The mucosal suction patch according to any one of claims 1 to 9, wherein the mucous membrane is an oral mucous membrane.

14. The mucosal suction patch according to any one of claims 1 to 9, wherein the drug has a molecular weight of about 1 kDa to about 50 kDa.

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