Nasal formulations for non-invasive nasal delivery

Abstract

The present invention relates to nasal formulations for non-invasive delivery comprising a hemostatic agent and a super absorbent polymer in a powder form, and to uses of said formulations for preventing and / or treating epistaxis.

Description

NASAL FORMULATIONS FOR NON-INVASIVE NASAL DELIVERY

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to US Provisional Application 63 / 680,111 filed August 7, 2024, which is herein incorporated by reference.

[0003] FIELD

[0004] The present invention relates to nasal formulations for non-invasive delivery comprising a hemostatic agent and a super absorbent polymer in a powder form, and to uses of said formulations for preventing and / or treating epistaxis.

[0005] BACKGROUND

[0006] Nosebleeds, also known as epistaxis, are very common, occurring at some point in at least 60% of the population, yet in some patients, epistaxis is a life-threatening medical emergency. The health care burden of epistaxis is significant: it is estimated that 1 out of every 200 patients presenting to the emergency department in the US does so for epistaxis. In an audit of epistaxis cases in the UK, 14% of patients with epistaxis returned to the emergency department within 30 days of an initial nosebleed, and the 30-day all-cause mortality was 3.4% in these patients. A non-invasive means for treating epistaxis that could even be selfadministered by patients could prevent or shorten emergency department visits, thereby significantly reducing this health care burden.

[0007] However, the prevalent standard of care for the management of epistaxis necessitates inserting absorbable and / or non-absorbable packing and pledgets into the nasal cavity to apply direct pressure or medication to the bleeding site. This can be very painful and invasive for the patient during the entire period that the packs are in place, which typically ranges from 48 to 72 hours or longer. Efficacy of nasal packing is also limited, with primary rebleeding rates reported in approximately half of patients. Re-bleeding has been attributed to the inability of the nasal packing to reach the bleeding source, and to trauma caused to the fragile nasal mucosa as packing is inserted and removed. Use of such material can cause nasal complications, including septal perforation, creation of scar tissue or adhesions, mucosal dryness, and nasal abrasions, all of which can actually create a new, secondary source of nosebleed immediately or longer term, creating a vicious cycle of recurrent epistaxis. In addition, there have been reports of very serious complications of both absorbable and non-absorbable nasal packing in patients, including aspiration of packing material into the lungs causing life- threatening hypoxia, and migration of the packing material into the digestive tract causing bowelperforation. Finally, major cardiac and pulmonary complications have been reported with the use of nasal packing and pledgets, including permanent disability and death. Nevertheless, nasal packing remains the prevalent standard of care for emergency epistaxis.

[0008] Topical intranasal application of an active pharmaceutical agent for treatment of epistaxis would seem desirable. However, some intranasal medicament formulations may directly enter the central nervous system via the nose-to-brain route, carrying the risk of serious neurological complications such as seizure, stroke, disability or death. Moreover, topical administrations may suffer from poor adherence and persistence in the nasal cavity, leading to poor management of persistent or recurrent bleeding.

[0009] Clearly, there is a need for a means to manage epistaxis which is less invasive and more effective relative to existing treatment methods.

[0010] SUMMARY

[0011] The present invention relates to nasal formulations for non-invasive delivery comprising a hemostatic agent and a super absorbent polymer in a powder form, and to uses of said formulations for preventing and / or treating epistaxis.

[0012] In an embodiment, there is provided a nasal formulation for non-invasive nasal delivery, comprising: (i) a hemostatic agent; and (ii) a super absorbent polymer (SAP), wherein the nasal formulation is a powder.

[0013] In an embodiment, there is provided a nasal formulation for non-invasive nasal delivery, comprising: (i) tranexamic acid (TXA); and (ii) a cellulose-based and / or a starch-based super absorbent polymer (SAP), wherein the nasal formulation is a powder.

[0014] In an embodiment, there is provided a method of preventing and / or treating epistaxis in a subject, comprising: (i) non-invasively delivering a nasal formulation through a nostril into a nasal cavity, wherein the nasal formulation is a powder comprising a super absorbent polymer (SAP).

[0015] In an embodiment, there is provided a method of preventing and / or treating epistaxis in a subject, comprising: (i) non-invasively delivering a nasal formulation through a nostril into a nasal cavity, wherein the nasal formulation is a powder comprising tranexamic acid (TXA) and a cellulose-based and / or a starch-based super absorbent polymer (SAP).

[0016] In an embodiment, there is provided a nasal formulation for use in preventing and / or treating epistaxis in a subject, wherein the nasal formulation is for non-invasive deliverythrough a nostril into a nasal cavity, wherein the nasal formulation is a powder comprising a super absorbent polymer (SAP).

[0017] In an embodiment, there is provided a nasal formulation for use in preventing and / or treating epistaxis in a subject, wherein the nasal formulation is for non-invasive delivery through a nostril into a nasal cavity, wherein the nasal formulation is a powder comprising tranexamic acid (TXA) and a cellulose-based and / or a starch-based super absorbent polymer (SAP).

[0018] BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Embodiments will be described, by way of example only, with reference to the accompanying figures.

[0020] FIGURE 1: Measurable treatment effect immediately after application.

[0021] FIGURE 2: Measurable treatment effect 4 hours after application.

[0022] FIGURE 3: Sustained effect of active agent in (A) Anterior Septum, (B) Posterior Septum, (C) Nasopharynx, (D) Sinuses.

[0023] FIGURE 4: Sustained moisture in (A) Anterior Septum, (B) Posterior Septum, (C) Nasopharynx, (D) Sinuses.

[0024] FIGURE S: Particle size distribution of powder TXA.

[0025] FIGURE 6: Target-site deposition by formulation.

[0026] FIGURE 7: Target-site deposition and powder density by formulation.

[0027] FIGURE 8: Displacement of powder samples at clinically -relevant time points across different formulations.

[0028] FIGURE 9: Retention of powder after simulated epistaxis across different formulations, by colourimetry score.

[0029] FIGURE 10: Retention of tranexamic acid after simulated epistaxis across different formulations as demonstrated by spectrometry.

[0030] DETAILED DESCRIPTION

[0031] The present invention provides for nasal formulations that can be effectively delivered non-invasively into the nasal cavity to minimize patient discomfort and maximize easeof use, such as for an effective and non-invasive treatment of epistaxis. The present inventors have surprisingly discovered that nasal formulations comprising a super absorbent polymer in powder form can effectively reach the anterior and posterior nasal cavity, nasopharynx, and sinuses when delivered non-invasively, enhancing mucosal moisture and providing enhanced delivery and persistence of a hemostatic agent, as compared to the delivery of a hemostatic agent alone in either powder or liquid form. The present invention can thus provide for an effective, non-invasive method of preventing and / or treating epistaxis that avoids many of the disadvantages of prior treatment methods. The present inventors further have surprisingly discovered that polysaccharide SAPs (e.g. cellulose-based SAPs and starch-based SAPs) exhibit enhanced delivery, mucoadherence, and persistence compared to active agent alone, or active agent with the polymer hyaluronic acid.

[0032] Hemostatic Agents

[0033] In some embodiments, the nasal formulations of the present invention comprise at least one hemostatic agent. Hemostasis is a process that prevents, reduces, and / or stops bleeding. A hemostatic is an agent that causes hemostasis. As used herein, the term “hemostatic agent” refers to a compound (such as a small molecule, a polypeptide, a hormone, or other molecule) that prevents, reduces, and / or stops bleeding. Although super absorbent polymers as described herein may exhibit hemostatic effects, the term “hemostatic agent” as used herein refers to compounds other than a super absorbent polymer as described herein. A hemostatic agent may cause hemostasis by one or more mechanisms including, but not limited to, vasoconstriction, blood coagulation, cauterization, anti-fibrinolytic effects, and inhibition of angiogenesis. One or more hemostatic agents that cause hemostasis by one or more of these mechanisms may be included in the nasal formulations of the present invention.

[0034] Many hemostatic agents are known in the art and may be used in the nasal formulations of the present invention. Any hemostatic agent that can be provided in the form of a powder and that is active or activated upon application to the epithelium of the nasal cavity, nasopharynx, and / or sinuses is suitable for use in the nasal formulations of the present invention.

[0035] In some embodiments, the hemostatic agent is a vasoconstrictive agent. A vasoconstrictive agent causes the narrowing of blood vessels at or near the site of bleeding, causing a reduction of blood flow to the site of bleeding. Many vasoconstrictive agents are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the vasoconstrictive agent is oxymetazoline, phenylephrine, epinephrine,xylometazoline, naphazoline, tetryzoline, angiotensin II, vasopressin, felypressin, cocaine, midodrine, or a combination thereof.

[0036] In some embodiments, the hemostatic agent is an antifibrinolytic agent. An antifibrinolytic agent inhibits the process of fibrinolysis. Fibrinolysis is the process of inhibiting the formation of blood clots and / or breaking blood clots by enzymatic degradation of fibrin by the enzyme plasmin. By inhibiting fibrinolysis, an antifibrinolytic agent may promote blood coagulation. Many antifibrinolytic agents are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the antifibrinolytic agent is aprotinin, nafamostat, a lysine analog, or a combination thereof. In some embodiments, the lysine analog is tranexamic acid (TXA), aminocaproic acid (ACA), aminomethylbenzoic acid, or a combination thereof.

[0037] In some embodiments, the hemostatic agent comprises tranexamic acid (TXA).

[0038] In some embodiments, the hemostatic agent is a coagulation factor. Blood coagulation is a process by which coagulation factors are activated to cause blood clotting that blocks blood loss at the site of bleeding. A hemostatic agent may be a coagulation factor or a compound that increases the presence or activity of a coagulation factor. As used herein, a “coagulation factor” is any molecule involved in the blood coagulation pathway, including naturally occurring coagulation factors, recombinant coagulation factors, or modified coagulation factors, either in inactive or active forms. A coagulation factor provided in a nasal formulation of the present invention may supplement or interact with coagulation factors at the site of bleeding. Many coagulation factors are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the coagulation factor is fibrinogen, fibrin, factor II, factor VII, factor Vila, factor VIII, factor IX, factor X, factor XIII, thrombin, prothrombin, vitamin K, or a combination thereof. Coagulation factors for use in the present invention may be provided from a number of sources and in different combinations. Coagulation factors may be provided as isolated factors from a blood fraction, or may be derived from a blood fraction such as autologous or allogenic plasma, platelet rich plasma, isolated platelets, or a blood fraction cryoprecipitate. In some embodiments, the coagulation factor is a modified coagulation factor including, but not limited to, a modified factor X (e.g. andexant alfa, Andexxa™). In some embodiments, the coagulation factor is provided as a mixture of coagulation factors in active and / or inactive forms including, but not limited to, a prothrombin complex concentrate comprising inactive factors II, IX, and X (e.g. Profilnine™); a prothrombin complex concentrate comprising inactive factors II, IX, X, and VII (e.g. Kcentra™); or an anti-inhibitor coagulant complex comprising active factor VII, and inactive factors II, IX, and X (e.g. FEIBA™).

[0039] In some embodiments, the hemostatic agent is a hemostatic hormone or an analog thereof. Some hormones are known to exhibit hemostatic effects and are suitable for use in the present invention. As used herein, an “analog” of a hormone includes both a structural analog of a hormone that exhibits similar or selective effects of the original hormone or that is an inhibitor of the original hormone, or a structurally dissimilar molecule that interacts with the hormone receptor to provide an agonist or an antagonist effect. Many hemostatic hormones and analogs thereof are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the hemostatic hormone or an analog thereof is desmopressin, estriol, a selective estrogen modulator, or a combination thereof.

[0040] In some embodiments, the hemostatic agent is an angiogenesis inhibitor. An angiogenesis inhibitor is a compound that inhibits the process of angiogenesis. Angiogenesis is the process by which new blood vessels form in a tissue by the local migration, growth, and differentiation of endothelial cells. Many angiogenesis inhibitors are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the angiogenesis inhibitor is thalidomide.

[0041] In some embodiments, the hemostatic agent is a hemostatic antibody. Hemostatic antibodies may exhibit effects including, but not limited to, binding to inhibitors of blood coagulation or binding to angiogenic factors. Many hemostatic antibodies are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the hemostatic antibody is idarucizumab, bevacizumab, or a combination thereof.

[0042] In some embodiments, the hemostatic agent is a cauterization agent. Cauterization is a process that induces local tissue damage to seal off the site of bleeding. Many cauterization agents are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the cauterization agent is silver nitrate, chromic acid, trichloroacetic acid, or a combination thereof.

[0043] Super Absorbent Polymers

[0044] The nasal formulations of the present invention comprise at least one super absorbent polymer (SAP). As used herein, a “super absorbent polymer” is a polymer that is capable of absorbing many times its own weight of aqueous liquid and / or has the ability to swell, retain liquid without dissolving, and form a gel-like substance when exposed to aqueous liquids.SAPs are derived from hydrophilic polymers, or polymers comprising hydrophilic monomers, that are cross-linked, naturally and / or synthetically, to provide a three-dimensional structure that swells in an aqueous environment to absorb and trap aqueous liquid. In some embodiments, an SAP is a polymer that absorbs up to 10, 50, 100, 200, 300, 400, 500, 1000 or more of its own dry weight of aqueous liquid. As used herein, a “polymer” is meant to encompass polymers comprising a single type of monomer and copolymers comprising more than one type of monomer. SAPs may be provided as a powder that swells and absorbs an aqueous liquid upon contact. Any SAP that can be provided in the form of a powder and that is biocompatible may be suitable for use in the present invention. A biocompatible polymer is a polymer that causes minimal or no adverse effects such as irritation or toxicity.

[0045] In some embodiments, the SAP comprises a biodegradable polymer. As used herein, a “biodegradable polymer” is a polymer that is capable of being broken down by an organism and / or that is degraded over time after application to a subject. In some embodiments, the SAP comprises a non-biodegradable polymer that may be removed by subsequent irrigation or by the production of mucus and the action of ciliated cells.

[0046] In some embodiments, the SAP comprises a synthetic polymer. Many synthetic SAPs are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the synthetic polymer comprises polyacrylic acid, polyacrylate (e.g. sodium polyacrylate), polyacrylamide, polyacrylonitrile, polyvinyl alcohol, or a copolymer thereof.

[0047] In some embodiments, the SAP comprises a polymer or copolymer of polyglycolide (PGA), poly(lactic acid) (PLA), or poly(lactic-co-glycolic) acid (PLGA). In some embodiments, the SAP comprises a polymer based on poly(N-isopropyl acrylamide) (PNIPAAm), PNIPAAm-poly ethylene glycol (PNIPAAm-PEG), poly(N,N’- dimethylacrylamide-co-N-phenylacrylamide), poly(glycidyl methacrylate-co-N- isopropylacrylamide), poly(ethylene oxide)-b-poly(propylene oxide-b-poly(ethylene oxide), poly(ethylene glycolj-polyester copolymer, or amphiphilic block copolymers. In some embodiments, the SAP comprises a copolymer of PNIPAAm with an acrylate monomer including alkyl acrylate (e.g. methyl acrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate), an acrylamide, or an acrylic acid or salt (e.g. 2-ethylacrylic acid, 2-propylacrylic acid, N-acryloxysuccinimide); and / or with a methacrylate monomer including a methacrylate (e.g. 2- hydroxymethacrylate, hydroxyethyl methacrylate, butyl methacrylate, methyl ether methacrylate, or methyl methacrylate), a methacrylamide, or a methacrylic acid or salt. In some embodiments, the SAP comprises an NIPAAm-based polymer conjugated with MMP-susceptible peptide,gelatin, collagen, hyualuronic acid, and / or dextran. In some embodiments, the SAP comprises N- vinyl-2-pyrrolidone.

[0048] In some embodiments, the SAP comprises a natural polymer. Many natural SAPs are known in the art and may be used in the nasal formulations of the present invention. In some embodiments, the natural polymer comprises a polysaccharide, a polypeptide, or a copolymer thereof.

[0049] In some embodiments, the natural polymer comprises a polysaccharide. In some embodiments, the natural polymer comprises cellulose or modified cellulose including, but not limited to, oxidized regenerated cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. In some embodiments, the natural polymer comprises starch or modified starch including, but not limited to, potato starch, sago starch, and com starch. In some embodiments, the natural polymer comprises chitosan or modified chitosan including, but not limited to, carboxymethyl chitosan, quaternary ammonium salt chitosan, chitosan glutamate, and chitosan hydroglutamate. In some embodiments, the natural polymer comprises alginate (e.g. sodium alginate) or a derivative of alginate. In some embodiments, the natural polymer comprises hyaluronic acid. In some embodiments, the natural polymer comprises dextran.

[0050] In some embodiments, the polysaccharide SAP comprises a cellulose-based SAP. As used herein, “cellulose-based” refers to an SAP that comprises cellulose and / or a modified cellulose and / or a cellulose derivative. Cellulose is a polymer of glucose linked by Beta(l-4) glycosidic bonds. Numerous modified celluloses or cellulose derivatives are known in the art and may be used in the present invention including, but not limited to, oxidized regenerated cellulose (ORC, also known as oxidized cellulose (CAS number 9032-53-5)), methyl cellulose (CAS number 9004-67-5), hydroxypropyl cellulose (CAS number 9004-64-2), hydroxypropylmethyl cellulose (HPMC, also known as Hypromellose (INN), e.g. HPMC400, HPMC4000 (CAS number 9004-65-3)), carboxymethyl cellulose (CAS number 9004-32-4), hydroxyethyl cellulose (CAS number 9004-62-0), and microcrystalline cellulose (also known as colloidal microcrystalline cellulose (CAS number 9004-34-6)). In some embodiments, the SAP is a cellulose-based SAP. In some embodiments, the cellulose-based SAP comprises, by way of nonlimiting example, cellulose, oxidized regenerated cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, colloidal microcrystalline cellulose, or a combination thereof. In someembodiments, the SAP comprises one or more cellulose-based SAPs and does not comprise hyaluronic acid.

[0051] In some embodiments, the polysaccharide SAP comprises a starch-based SAP. As used herein, “starch-based” refers to an SAP that comprises starch and / or a modified starch and / or a starch derivative. Starch is a polymer of glucose linked by alpha(l-4) glycosidic bonds, in some cases with branching linked by alpha(l-6) glycosidic bonds. Numerous forms of starch or starch derivatives are known in the art and may be used in the present invention including, but not limited to, starch, potato starch, sago starch, com starch, amylose, amylopectin, microporous starch microspheres, cyclodextrin, and hydroxypropyl-Beta-cyclodextrin. In some embodiments, the SAP is a starch-based SAP. In some embodiments, the starch-based SAP comprises, by way of non-limiting example, starch, potato starch, sago starch, com starch, amylose, amylopectin, microporous starch microspheres, cyclodextrin, hydroxypropyl-Beta-cyclodextrin, or a combination thereof. In some embodiments, the SAP comprises one or more starch-based SAPs and does not comprise hyaluronic acid.

[0052] In some embodiments, the natural polymer comprises a polypeptide. In some embodiments, the polypeptide comprises polyaspartic acid or polyglutamic acid. In some embodiments, the polypeptide comprises a gelatin or a modified gelatin including, but not limited to, a hemostatic gelatin thrombin matrix and purified porcine gelatin.

[0053] In some embodiments, the SAP comprises a natural polymer that is modified by cross-linking and / or copolymerization with another natural polymer and / or with a synthetic polymer. In some embodiments, the SAP comprises a synthetic polymer that is modified by cross-linking and / or copolymerization with another synthetic polymer and / or with a natural polymer.

[0054] Further to the cross-linked structure of SAPs, SAPs may be provided in preformed three dimensional structures. In some embodiments, the SAP is formed into a microsphere. In some embodiments, the microsphere is porous. In some embodiments, the porous microsphere comprises a starch. In some embodiments, the microspheres have an average diameter of 50-70 pm, such as about 65 pm. In some embodiments, the SAP is provided in the form of microporous starch microspheres derived from a potato starch (e.g. Arista™).

[0055] In some embodiments of the present invention, epistaxis is prevented and / or treated by non-invasive application of a nasal formulation comprising an SAP into the nasal cavity. Without being bound by theory, SAP in powder form may function as a mechanical hemostatic, acting as a molecular sieve through contact with the site of bleeding and promotingplatelet aggregation. Further, without being bound by theory, the SAP may impact mucociliary clearance and may enhance the adherence and / or penetration of a hemostatic agent to an epithelial surface. Without being bound by theory, SAP in powder form may provide hemostatic effects by swelling when exposed to liquid and thereby tamponading the source of the bleeding.

[0056] Other Agents and Excipients

[0057] In some embodiments, nasal formulations of the present invention may further comprise other agents to provide secondary therapeutic effects. In some embodiments, the nasal formulation further comprises an antibiotic or an antiseptic to prevent and / or treat infection. In some embodiments, the antibiotic or antiseptic is bacitracin, clindamycin, erythromycin, fusidic acid, gentamycin, metronidazole, mupirocin, neomycin, ozenoxacin, retapamulin, tetracyclines, dapsone, or polymyxin B; local anti-infectives including alcohol, isopropyl alcohol, benzalkonium, boric acid, chlorhexidine, hexachlorophene, iodine, iodoquinol, mafenide, selenium sulfide, silver sulfadiazine, sodium hypochlorite, or sulfacetamide sodium; or a combination thereof. In some embodiments, the nasal formulation further comprises a topical anesthetic to prevent and / or reduce pain or irritation. In some embodiments, the topical anaesthetic is lidocaine, tetracaine, bupivacaine, procaine, mepivacaine, benzocaine, cocaine, or a combination thereof.

[0058] In some embodiments, nasal formulations of the present invention may comprise one or more excipients including, but not limited to, fillers (e.g. sucrose, lactose, mannitol, sorbitol, trehalose, raffinose, glycine, histidine, calcium carbonate, talc, barium sulfate), cryoprotectants (e.g. sucrose, lactose, trehalose, mannitol, sorbitol, glucose, raffinose, maltose, maltodextrin, pullulan, inulin, ficoll, amino acids, polyethylene glycol, albumin), buffering agents (e.g. citrate, sodium citrate, phosphate, sodium phosphate, potassium phosphate, sodium hydroxide, Tris (Tris(hydroxymethyl)aminomethane, Tris-acetate, Tris-HCl, HEPES, acetate, sodium acetate, zinc acetate, zinc carbonate, threonine, succinate, sodium succinate, histidine, lysine, carbonate, sodium carbonate, sodium bicarbonate), a tonicity agent (e.g. dextrose, glycerol, glycerin, mannitol, sodium chloride, potassium chloride), a preservative (e.g. EDTA), antioxidants (e.g. histidine, arginine, adipic acid, leucine, glutamic acid, phenylalanine, succinic acid, succinate, acetic acid, acetate, citric acid, citrate, lactic acid, ascorbic acid, tocopherol) or absorption enhancers (e.g. surfactants, bile salts, fatty acids, phospholidpids, glycyrrhetinic acid derivatives, chelating agents, cyclodextrins, cationic compounds).

[0059] Powder Formulations

[0060] The nasal formulations of the present invention are provided in the form of a powder. As used herein with respect to nasal formulations, a “powder” is a solid dosage form comprised of fine particles of polymers, agents, and / or excipients. A powder dosage form may flow freely when agitated and may form an aerosol or aerial suspension when dispersed into the air by the application of a force. A powder dosage form is dry with a moisture content by weight or by volume of less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, or no measurable water content.

[0061] Without being bound by theory, powder dosage forms delivered nasally may offer several advantages over other formulations, including superior drug stability, less need for drug preservatives, and greater ability of powders to stick to the moist surface of nasal epithelia and mucosa than liquid formulations. In addition, powders may demonstrate better diffusion and absorption across mucosa, and permit delivery of larger medication doses, when indicated.

[0062] SAPs, hemostatic agents, secondary agents, and excipients provided in the nasal formulations of the present invention are provided in a powder form. SAPs, agents, and / or excipients for use in the present invention may be dried to provide a powder form by numerous techniques known in the art including, but not limited to, lyophilization, freeze drying, spray drying, spray freeze drying, supercritical fluid assisted spray drying, thin-film freeze drying, and vacuum freeze drying.

[0063] Powder forms for use in the present invention may be in a suitable powder form following drying or may be further processed using any suitable method of granulation known in the art to obtain a suitable particle size and / or morphology and / or homogeneity of the SAPs, agents, and / or excipients. Many granulation techniques are known in the art including, but not limited to, dry granulation, pneumatic dry granulation, wet granulation, reverse wet granulation, steam granulation, moisture-activated dry granulation, thermal adhesion granulation, freeze granulation, and agglomeration of micronized powders. Powders for use in the present invention may also be manufactured using any suitable method. Many powder manufacturing techniques are known in the art, including but not limited to freeze drying, spray drying, emulsification and evaporation, precipitation, supercritical fluid-assisted spray drying, and spray freeze drying.

[0064] In some embodiments, the average particle size in the powder of the nasal formulation is about 300 pm, 250 pm, 200 pm, 190 pm, 180 pm, 170 pm, 160 pm, 150 pm, 140 pm, 130 pm, 120 pm, 110 pm, 100 pm, 90 pm, 80 pm, 70 pm, 65 pm, 60 pm, 50 pm, 40 pm,30 pm, 20 pm, or 10 pm. In some embodiments, the median particle size in the powder of the nasal formulation is about 300 pm, 250 pm, 200 pm, 190 pm, 180 pm, 170 pm, 160 pm, 150 pm, 140 pm, 130 pm, 120 pm, 110 pm, 100 pm, 90 pm, 80 pm, 70 pm, 65 pm, 60 pm, 50 pm, 40 pm, 30 pm, 20 pm, or 10 pm. In some embodiments, the particle size in the powder of the nasal formulation is about 10-300 pm, 10-250 pm, 20-250 pm, 10-200 pm, 20-200 pm, 10-150 pm, 20-150 pm, 10-100 pm, 20-100 pm, 10-50 pm, 20-50 pm, 30-50 pm, 40-50 pm, 20-40 pm, 30-40 pm, , 10-20 pm, 10-30 pm, or 10-40 pm. In some embodiments, the minimum particle size in the powder of the nasal formulation is 10 pm, 20 pm, 30 pm, 40 pm, 50 pm, 60 pm, 70 pm, 80 pm, 90 pm, or 100 pm.

[0065] In some embodiments, the average particle size of the hemostatic agent in the nasal formulation is about 300 pm, 250 pm, 200 pm, 190 pm, 180 pm, 170 pm, 160 pm, 150 pm, 140 pm, 130 pm, 120 pm, 110 pm, 100 pm, 90 pm, 80 pm, 70 pm, 65 pm, 60 pm, 50 pm, 40 pm, 30 pm, 20 pm, or 10 pm. In some embodiments, the median particle size of the hemostatic agent in the nasal formulation is about 300 pm, 250 pm, 200 pm, 190 pm, 180 pm, 170 pm, 160 pm, 150 pm, 140 pm, 130 pm, 120 pm, 110 pm, 100 pm, 90 pm, 80 pm, 70 pm, 65 pm, 60 pm, 50 pm, 40 pm, 30 pm, 20 pm, or 10 pm. In some embodiments, the particle size of the hemostatic agent in the nasal formulation is about 10-300 pm, 10-250 pm, 20-250 pm, 10- 200 pm, 20-200 pm, 10-150 pm, 20-150 pm, 10-100 pm, 20-100 pm, 10-50 pm, 20-50 pm, SOSO pm, 40-50 pm, 20-40 pm, 30-40 pm, , 10-20 pm, 10-30 pm, or 10-40 pm. In some embodiments, the minimum particle size of the hemostatic agent in the nasal formulation is 10 pm, 20 pm, 30 pm, 40 pm, 50 pm, 60 pm, 70 pm, 80 pm, 90 pm, or 100 pm.

[0066] In some embodiments, the average particle size of the SAP in the nasal formulation is about 300 pm, 250 pm, 200 pm, 190 pm, 180 pm, 170 pm, 160 pm, 150 pm, 140 pm, 130 pm, 120 pm, 110 pm, 100 pm, 90 pm, 80 pm, 70 pm, 65 pm, 60 pm, 50 pm, 40 pm, 30 pm, 20 pm, or 10 pm. In some embodiments, the median particle size of the SAP in the nasal formulation is about 300 pm, 250 pm, 200 pm, 190 pm, 180 pm, 170 pm, 160 pm, 150 pm, 140 pm, 130 pm, 120 pm, 110 pm, 100 pm, 90 pm, 80 pm, 70 pm, 65 pm, 60 pm, 50 pm, 40 pm, 30 pm, 20 pm, or 10 pm. In some embodiments, the particle size of the SAP in the nasal formulation is about 10-300 pm, 10-250 pm, 20-250 pm, 10-200 pm, 20-200 pm, 10-150 pm, 20-150 pm, 10-100 pm, 20-100 pm, 10-50 pm, 20-50 pm, 30-50 pm, 40-50 pm, 20-40 pm, 30- 40 pm, , 10-20 pm, 10-30 pm, or 10-40 pm. In some embodiments, the minimum particle size of the SAP in the nasal formulation is 10 pm, 20 pm, 30 pm, 40 pm, 50 pm, 60 pm, 70 pm, 80 pm, 90 pm, or 100 pm.

[0067] Non-invasive Delivery

[0068] The present invention relates to nasal formulations for non-invasive delivery and to methods and uses comprising a non-invasive application of a nasal formulation through a nostril and into a nasal cavity. As used herein, “non-invasive” delivery or application into the nasal cavity refers to an application or delivery whereby the physical means (i.e. delivery device) by which the nasal formulation is delivered or applied to the nasal cavity has a limited maximum penetration into the nasal cavity; the physical means does not penetrate into the sinuses; and / or the physical device does not involve any puncturing or cutting of tissue. The “non-invasive” delivery or application of the present invention minimizes patient discomfort and maximizes ease of use. As used herein, “non-invasive” delivery or application excludes the surgically- delivered application of a nasal formulation, the injection of a nasal formulation into a tissue by a needle, the injection of a nasal formulation onto a tissue or into a cavity by penetrating a tissue with a needle, and packing of the nasal cavity (e.g. with cotton pledgets). It is understood by persons skilled in the art that the size of the nasal cavity varies between patients. Persons skilled in the art will be able to determine a maximum degree of non-invasive penetration into the nasal cavity for a given patient based on the size of the patient’s nasal cavity. In some embodiments, a non-invasive delivery or application comprises the insertion of a physical means (i.e. delivery device) no more than a maximum of about 0.5-50 mm, preferably 0.5-30 mm, into the nasal cavity. In some embodiments, a non-invasive delivery or application comprises the insertion of a physical means (i.e. delivery device) no more than a maximum of about 50 mm, 49 mm, 48 mm, 47 mm, 46 mm, 45 mm, 44 mm, 43 mm, 42 mm, 41 mm, 40 mm, 39 mm, 38 mm, 37 mm, 36 mm, 35 mm, 34 mm, 33 mm, 32 mm, 31 mm, 30 mm, 29 mm, 28 mm, 27 mm, 26 mm, 25 mm, 24 mm, 23 mm, 22 mm, 21 mm, 20 mm, 19 mm, 18 mm, 17 mm, 16 mm, 15 mm, 14 mm, 13 mm, 12 mm, 11 mm, 10 mm, 9 mm, 8 mm, 7 mm, 6 mm, 5 mm, 4 mm, 3 mm, 2 mm, 1 mm, or 0.5 mm into the nasal cavity. Although nasal formulations according to the present invention are non-invasively delivered into the nasal cavity, the delivered nasal formulation may reach the nasopharynx and / or the sinuses.

[0069] In some embodiments, the nasal formulation is comprised in a non-invasive delivery device for delivery or application into the nasal cavity. Many non-invasive delivery devices capable of expelling or insufflating a powder into a nasal cavity are known in the art and may be used in the present invention for non-invasive delivery or application.

[0070] In some embodiments, the non-invasive nasal delivery device comprises a nosepiece for insertion into a nostril. The nosepiece may either contain the nasal formulation ormay be operably connected to another portion of the device that contains the nasal formulation. In either case, actuation of the non-invasive nasal delivery device expels the nasal formulation through the nosepiece and into the nasal cavity.

[0071] Non-invasive nasal delivery devices may be actuated by a number of mechanisms known in the art. In some embodiments, the non-invasive nasal delivery device comprises a pressurized compartment and the device is actuated by releasing pressure from the pressurized compartment to expel the nasal formulation. In some embodiments, the pressure is released by pressing upon a portion of the device to open a seal, valve, or nozzle to release the pressure. In some embodiments, the nasal formulation is comprised inside of the pressurized compartment. In some embodiments, the nasal formulation is comprised in a portion of the device operably connected to the pressurized compartment.

[0072] In some embodiments, the non-invasive nasal delivery device is actuated pressing upon a portion of the device to create a pressure that expels the nasal formulation. In some embodiments, the nasal formulation is comprised in a pressurizable compartment (e.g. a syringe) or in a compartment operably connected to a pressurizable compartment. In such devices, a plunger is pressed into the pressurizable compartment to create a pressure that expels the nasal formulation. In some embodiments, the nasal formulation is comprised in a deformable compartment (e.g. a bulb or a squeeze bottle) or in a compartment operably connected to a deformable compartment. In such devices, the deformable compartment is squeezed to create a pressure that expels the nasal formulation.

[0073] In some embodiments, the non-invasive nasal delivery device is actuated by the patient blowing into the device (i.e. a breath-actuated device). In such devices, the device comprises a mouthpiece into which the patient blows to create a pressure. The mouthpiece is operably connected to a compartment comprising the nasal formulation such that the pressure created by blowing into the mouthpiece expels the nasal formulation. Exhalation into a device by a subject causes the soft palate to automatically elevate, which separates the oral cavity and nasal passages, thereby preventing inhalation of the drug into the lungs during drug delivery. This phenomenon also ensures the drug is delivered to and retained at the target sites, including the septum, nasopharynx, and sinus tissue.

[0074] In some embodiments, the non-invasive nasal delivery device is a patient- operated delivery device. As used herein, a “patient-operated delivery device” is a device that is capable of being operated by the patient for self-delivery of a medication or formulation, but that may also be operated by another individual such as a care provider or a medical practitioner. Apatient-operated delivery device may be used by the patient to non-invasively deliver or apply nasal formulation into the nasal cavity without the aid of another individual such as a medical practitioner.

[0075] In some embodiments, the nasal formulation is pre-loaded into the non-invasive nasal delivery device. In some embodiments, the nasal formulation is comprised in a cartridge or blister that is inserted into the non-invasive nasal delivery device.

[0076] Many non-invasive delivery devices are known in the art and suitable for use in the present invention. In some non-limiting embodiments, the non-invasive delivery device is a pharmaceutically acceptable carrier, container, kit or device. In some embodiments, the non- invasive delivery device is Monopowder™ (Valois Dispray SA; Aptar), Pfeiffer™ system (Pfeiffer), Unidose-DP™ (Bespak), a multi-dose breath actuated metering device (e.g. as used in Rhinocort™ Turbuhaler™), Prohaler™ (Aptar), Unit Dose System™ (UDS; Aptar), Bi Dose System™ (BDS; Aptar), Puvlizer™, Optinose™ Bi-Directional™ Exhalation Delivery System (EDS), pco™ System, NetiRinse™ bottle or NeilMed™ bottle.

[0077] Epistaxis

[0078] The present invention relates to the prevention and / or treatment of epistaxis. “Treating” or “treatment of’, or “preventing” or “prevention of’, as used herein, refers to an approach for obtaining beneficial or desired results. Beneficial or desired results can include, but are not limited to, prevention, alleviation, amelioration, or arrest of bleeding. “Treating” may be distinguished from “preventing” in that “treating” typically occurs in a subject who already has epistaxis, whereas “preventing” typically occurs in a subject who does not yet have epistaxis. As will be appreciated, there may be overlap in treatment and prevention. For example, it is possible to be “treating” epistaxis in a subject, while at same time “preventing” continuance or worsening of epistaxis in said subject.

[0079] In understanding the scope of the present disclosure, the term “comprising” and its derivatives, as used herein, are intended to be open ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives. The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The term “consisting essentially of’, asused herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and / or steps.

[0080] As used herein, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. In embodiments comprising an “additional” or “second” component, the second component as used herein is different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0081] The present invention will now be described by way of non-limiting examples having regard to the appended drawings.

[0082] EXAMPLES

[0083] Example 1

[0084] Nasal product development studies using 3D-printed nasal model casts permit rigorous testing of the efficiency of nasal products and have become standard in the nasal product development industry. An exemplary nasal formulation according to the present invention comprising an SAP and a hemostatic agent in a powder dosage form was tested using a 3-D printed nasal model (PJW-N1-V2, Fusetec™, Australia) to assess efficacy of non-invasive delivery and maintenance of nasal powder formulations.

[0085] The tested nasal formulation comprised microporous starch microspheres (MPS) as an exemplary SAP and tranexamic acid (TXA) as an exemplary hemostatic agent, both combined in a dry powder dosage form. TXA is a hemostatic agent which stabilizes blood clots by competitively inhibiting the binding of plasminogen to fibrin to prevent fibrinolysis, or dissolution of the clot. TXA is most commonly delivered to bleeding patients in intravenous, oral tablet, or topical liquid form. To date, topical TXA in powder form has not been described for use in control of epistaxis. The tested nasal formulation was formed by mixing 500 mg of TXA with 500 mg of microporous starch microspheres (MPS).

[0086] Control nasal formulations comprising (1) only TXA powder (500 mg) without an SAP or (2) TXA in a liquid formulation (500 mg of TXA in 5 mL solution, final concentration 100 mg / mL) were tested alongside the tested nasal formulation according to the present invention. The control formulation comprising only TXA powder was delivered via an exemplary breath actuated device as described below. The control formulation comprising liquid TXA was delivered topically by a standard of care method, with 5 mL of a 100 mg / mL TXAsolution applied to a cotton pledget nasal pack and the cotton pledget nasal packing inserted into the nasal cavity.

[0087] The tested nasal formulation and the control nasal formulation comprising only TXA powder were delivered via an exemplary breath actuated device comprising a nasal pillow attached to the end of a syringe comprising the nasal formulation, the syringe operably linked to a mouthpiece with a 1-way valve via tubing. The nasal pillow was non-invasively inserted into the nostril of the sinonasal model and the nasal formulation was delivered into the nasal cavity of the sinonasal model by breath-actuation of the device.

[0088] After delivery, the treatment effect of TXA was measured by pH. TXA in pure form has a pH of 8. Th pH of sites in the sinonasal model in the absence of TXA is 6. A higher local pH reading indicates a higher quantity of TXA at that site.

[0089] Immediately after application, greater quantities of hemostatic agent (TXA) was measurable when delivered with the exemplary breath-actuated device in powder form than when delivered as a liquid by the standard method (cotton pledget). A greater treatment was measurable with a nasal formulation consisting of powder TXA alone, as well as the tested nasal formulation according to the present invention consisting of powder TXA+microporous starch microspheres (MPS) (Figure 1). Moreover, delivery in powder dosage form was more effective than standard method in delivering higher measurable levels of the hemostatic agent to not only the anterior septum, but also the deeper tissue, including the posterior septum, nasopharynx, and sinus cavities (Figure 1).

[0090] In epistaxis patients, recurrence of bleeding after packing often occurs in the first 4 hours. Delivery of a powder dosage form exhibited the best measurable treatment effect 4 hours after treatment application relative to standard method (cotton pledget) for application of liquid TXA. This finding was demonstrated for all sites, including the anterior septum, posterior septum, nasopharynx, and sinuses. The greatest treatment effect was also obtained with the tested nasal formulation according to the present invention consisting of powder TXA and SAP (MPS), relative to powder TXA or liquid TXA alone (Figure 2).

[0091] Evaluation of the combination of hemostatic agent (TXA) and SAP (MPS) in dry powder dosage form demonstrated sustained, unexpected, and superior results. Delivery of the TXA+MPS nasal formulation according to the present invention exhibited a longer treatment effect measured over 48 hours in each of the sampled sites, including anterior septum, posterior septum, nasopharynx, and sinuses, when compared to TXA powder alone or liquid TXA (Figure 3A-D).

[0092] Dryness of nasal or paranasal mucosa not only causes epistaxis, but also exacerbates the risk of repeat epistaxis in the future. The tested nasal formulation according to the present invention demonstrated sustained, unexpected, and superior results over standard treatment in maintaining tissue moisture. Immediately after application, moisture was maintained when treatment consisted of powder TXA+MPS according to the present invention, but declined substantially when treatment consisted of either powder TXA or liquid TXA alone (Figure 4A- D). This superior outcome of tissue moisture was measurable across all locations, including anterior septum, posterior septum, nasopharynx, and sinuses.

[0093] The tested nasal formulation according to the present invention demonstrated unexpected and superior results over standard treatment with respect to rebound treatment effect. Some degree of progressive tissue dryness was demonstrated across all treatments and all tissue sites over the span of 48 hours. However, when saline mist was applied 48 hours after treatment, the treatment effect of TXA+MPS according to the present invention was significantly greater than standard treatment using liquid TXA applied by nasal packing (Figures 3A-D, “48h Moisture”).

[0094] Example 2

[0095] Nasal product development studies using 3D-printed nasal model casts permit rigorous testing of the efficiency of nasal products and have become standard in the nasal product development industry. Exemplary nasal formulations were evaluated using yet another standard 3-D printed nasal model (PJW-N4-V2, Fusetec™, Australia) to assess efficacy of non- invasive delivery and maintenance of nasal powder formulations.

[0096] The intravenous formulation of tranexamic acid (TXA) has widely been used off- label for emergency treatment of epistaxis by applying it as an intranasal topical liquid, commonly in doses of 500 mg to 1,000 mg. There are known serious adverse events associated with the use of TXA given intravenously, the most common of which is seizures, related to the fact that TXA does cross the blood-brain barrier. There are also several reported cases of unintended intrathecal administration of TXA to the cerebral spinal fluid in doses ranging from 50 mg to 500 mg, which have caused seizure, permanent disability, and death. Nose-to-brain delivery route, which occurs by transport along the olfactory nerve endings deep within the nasal cavity, is preferable for some medications. This delivery route is facilitated by formulations of consisting of small particles, typically less than 100 nanometers in diameter, yet it is blocked by formulations with larger particles.

[0097] Surprisingly and concemingly, the inventors discovered that liquid TXA, a solution with very small particles, typically less than 1 nanometer in diameter, reaches the olfactory zone within the 3-D printed nasal model, whereby TXA could enter the cerebral spinal fluid along the olfactory nerve, facilitating delivery of TXA to the central nervous system and further exacerbating risk of seizures. However, in an exemplary nasal formulation of the present invention comprising TXA nasal powder, the particle size was greater than 10 micrometers, or 10,000 times too large for nose-to-brain delivery. See Figure 5.

[0098] Example 3

[0099] Medication must be delivered to the target site in order to exert a treatment effect. Nasal deposition of powder medication can be affected by many factors, including formulation and delivery mechanism. Nasal formulations of the present invention were tested, comprising TXA as an exemplary hemostatic agent with several different exemplary SAPs. Six powder nasal formulations were prepared: TXA plus hydroxypropylmethyl cellulose (HPMC); TXA plus carboxymethyl cellulose (CMC); TXA plus microporous starch microspheres (MPS); TXA plus hyaluronic acid (HA), and TXA alone.

[0100] Using standard methodology for nasal powder formulation development studies, synthetic mucus was prepared in a standard method using ethanol and glycerol (75:25) and then brushed onto silicone sheeting using a dry paintbrush. The coated silicone sheets were weighed and then used to line the anterior nasal septum and the posterior nasal septum of the 3-D printed nasal cast. Each powder nasal formulation was applied to the nasal cast model using a standard class I nasal product delivery device. The silicone sheets were then removed from the nasal cast and reweighed. The amount of nasal product which reached the anterior and posterior septum was calculated.

[0101] Next, the distribution and density of the nasal powders were analyzed. Using standard methodology for nasal powder formulation development studies, photos were taken of the silicone sheeting in front of a black background at a fixed camera location. Photosensitivity was set to 1600 ISO at shutter speed 1 / 750 with ultrawide angle to ensure consistency of the photo parameters. The photos were imported into ImageJ software (version 1.54p, National Institutes of Health, USA). The colour selection threshold was used to evaluate the powder distribution.

[0102] Surprisingly and unexpectedly, nasal formulations comprising powder TXA with cellulose-based SAPs (HPMC, CMC, oxidized regenerated cellulose) or with a starch-based SAP (microporous starch microspheres; MPS), all demonstrated superior and exemplary delivery tothe most common sites of epistaxis, the anterior nasal septum and the posterior nasal septum, relative to formulations with hyaluronic acid (HA) or with no excipient at all. See Figures 6 and 7.

[0103] Example 4

[0104] Once delivered to the targeted site in the nose and sinonasal regions, medication must adhere to the nasal mucosa in order to exert a therapeutic effect. As such, nasal formulations which enhance mucoadherence and avoid nasal dripping are advantageous. When dry powder contacts mucosa, mucoadhesiveness is the property whereby the powder hydrates and sticks to the nasal mucosa, which influences residence time and absorption of active ingredients. Using standard methodology for powder nasal formulation development studies, the mucoadhesive potential of eight different nasal formulations was evaluated across 3 trials: TXA plus hydroxypropylmethyl cellulose (HPMC); TXA plus carboxymethyl cellulose (CMC); TXA plus hydroxyethyl cellulose (HEC); TXA plus oxidized regenerated cellulose (ORC), TXA plus microporous starch microspheres (MPS), TXA plus hyaluronic acid (HA), TXA powder alone, and TXA liquid alone. A hot solution of 1.5% agar (pH 6.4) was cast on a petri dish and left refrigerated for gelation for 12 hours, then stored at 36°C for 1 hour. Twenty-five mg of each formulation was placed on top of the agar gel in a spot with approximately 10 mm diameter in triplicate. The dish was placed in an upright position and the displacement of the medicament samples was measured as a function of time.

[0105] Liquid TXA did not demonstrate any degree of mucoadherence, as it was immediately displaced the entire length of the gel (80 mm). Surprisingly and unexpectedly, the formulation containing TXA plus hyaluronic acid (HA) also demonstrated no evidence of mucoadherence, immediately running more than 80 mm, which is beyond the entire length of entire nasal septum, the anterior nasal septum and posterior nasal septum combined. Inclusion of cellulose-based SAPs (HPMC, HEC, OxCell (oxidized regenerated cellulose)) or a starch-based SAP (MPS) in the formulation, however, enhanced the mucoadherence of TXA, relative to TXA+HA or to TXA powder alone. Surprisingly and unexpectedly, the cellulose-based SAPs and the starch-based SAP enhanced mucoadherence, extending nasal residence time beyond important physiologic time points, including initiation of the coagulation cascade (35 seconds) the mucociliary clearance time (15 minutes), and a common rebleed timepoint in epistaxis cases (180 minutes). See Figure 8.

[0106] Example 5

[0107] For treatment of epistaxis, the therapeutic agent must not only reach the target site and adhere to the mucosa; the medication must remain at the target site during active bleeding and not simply be washed away by blood. Normally, the coagulation cascade begins almost instantly after blood vessel injury and culminates within 35 seconds in the formation of fibrin, a protein that forms a mesh-like structure to facilitate clotting and cessation of bleeding. TXA exerts its hemostatic effect by reversibly binding to plasminogen, thereby preventing the binding of plasminogen to fibrin and the subsequent degradation of fibrin, thereby protecting the clot.

[0108] As an extension of the experiments described to assess medication delivery to the target site, epistaxis simulation experiments were undertaken. Briefly, the sphenopalatine artery passes through the sphenopalatine foramen on the lateral nasal wall, terminating in the nasal septal artery and the posterior lateral nasal artery. The diameter of the nasal septal artery is 1.30 + / - 0.30 mm, while the diameter of the posterior lateral nasal artery is 1.80+ / - 0.20 mm; nasal bleeding from these arteries causes severe and potentially life-threatening hemorrhage. To simulate severe epistaxis, an angiocatheter with external diameter of 1.7 mm (16 gauge) was positioned in the sphenopalatine foramen of the nasal model. Blood mimicking fluid was prepared using a standard composition of glycerol and saline (47.5%:52.5%). Nasal powder formulations [TXA plus hydroxypropylmethyl cellulose (HPMC); TXA plus carboxymethyl cellulose (CMC); TXA plus oxidized regenerated cellulose (ORC), TXA plus microporous starch microspheres (MPS), TXA plus hyaluronic acid (HA), and TXA powder alone] were sprayed into the 3-D nasal cast model. Blood mimicking fluid was delivered to the nasal cast model through the angiocatheter at a rate of 1 mL / second, which was connected to an IV bag and tubing containing the blood mimicking fluid. Then, the silicone sheeting was removed from the nasal cast. Photos of the silicone sheeting were taken and analyzed using ImageJ software in the method described herein to determine the amount of powder retained on the anterior nasal septum and posterior nasal septum after simulated epistaxis.

[0109] Surprisingly and unexpectedly, the addition of a cellulose-based SAP or a starch- based SAP greatly enhanced the retention of nasal powder medication on both the anterior and posterior nasal septum overall, relative to nasal powder containing TXA and hyaluronic acid or nasal powder consisting of TXA alone. See Figure 9.

[0110] Trials were also undertaken to determine if liquid TXA persists after topical delivery in the nasal cavity, or if it is washed away by blood. Again, silicone sheeting was coated with artificial mucous and used to line the anterior nasal septum and posterior nasal septum of the 3-D nasal cast model. Then, liquid TXA was delivered to the model in the method commonlyused in emergency treatment of epistaxis, by insertion of nasal pledgets soaked with liquid TXA for 4 minutes. Next, epistaxis was simulated. The silicone sheeting was then placed in a Fourier Transform Infrared (FTIR) Spectrometer and assessed for presence of TXA. Infrared spectrometry was also used to measure presence of TXA after epistaxis for two other formulations: TXA plus hydroxypropylmethyl cellulose (HPMC), and TXA plus carboxymethyl cellulose (CMC). Infrared spectrometry was used to compare the formulations to controls, and to TXA alone. Results demonstrate that TXA was detectable after simulated epistaxis in powder formulations containing cellulose-based SAPs. However, TXA was not detectable after simulated epistaxis trials with liquid TXA. See Figure 10.

Claims

CLAIMS:

1. A nasal formulation for non-invasive nasal delivery, comprising:(i) a hemostatic agent; and(ii) a super absorbent polymer (SAP), wherein the nasal formulation is a powder.

2. The nasal formulation of claim 1, wherein the nasal formulation is comprised in a non- invasive nasal delivery device.

3. The nasal formulation of claim 2, wherein the non-invasive nasal delivery device is a breath-actuated delivery device.

4. The nasal formulation of claim 2 or 3, wherein the non-invasive nasal delivery device is a patient-operated delivery device.

5. The nasal formulation of any one of claims 2 to 4, wherein the non-invasive nasal delivery device comprises a nosepiece for insertion through a nostril, wherein actuation of the non-invasive nasal delivery device expels the nasal formulation through the nosepiece into a nasal cavity.

6. The nasal formulation of any one of claims 1 to 5, wherein the non-invasive delivery is expulsion of the nasal formulation through a nostril into a nasal cavity.

7. The nasal formulation of any one of claims 1 to 6, wherein the hemostatic agent comprises a vasoconstrictive agent, an antifibrinolytic agent, a coagulation factor, a hemostatic hormone or an analog thereof, an angiogenesis inhibitor, a hemostatic antibody, a cauterization agent, or a combination thereof.

8. The nasal formulation of claim 7, wherein the vasoconstrictive agent comprises oxymetazoline, phenylephrine, epinephrine, xylometazoline, naphazoline, tetryzoline, angiotensin II, vasopressin, felypressin, cocaine, midodrine, or a combination thereof.

9. The nasal formulation of claim 7, wherein the antifibrinolytic agent comprises aprotinin, nafamostat, a lysine analog, or a combination thereof.

10. The nasal formulation of claim 9, wherein the lysine analog comprises tranexamic acid (TXA), aminocaproic acid (ACA), aminomethylbenzoic acid, or a combination thereof.

11. The nasal formulation of any one of claims 1 to 7, wherein the hemostatic agent comprises tranexamic acid (TXA).

12. The nasal formulation of claim 7, wherein the coagulation factor comprises fibrinogen, fibrin, factor II, factor VII, factor Vila, factor VIII, factor IX, factor X, factor XIII, thrombin, prothrombin, vitamin K, or a combination thereof.

13. The nasal formulation of claim 7, wherein the hemostatic hormone or an analog thereof comprises desmopressin, estriol, a selective estrogen modulator, or a combination thereof.

14. The nasal formulation of claim 7, wherein the angiogenesis inhibitor comprises thalidomide.

15. The nasal formulation of claim 7, wherein the hemostatic antibody comprises idarucizumab, bevacizumab, or a combination thereof.

16. The nasal formulation of claim 7, wherein the cauterization agent comprises silver nitrate, chromic acid, trichloroacetic acid, or a combination thereof.

17. The nasal formulation of any one of claims 1 to 16, wherein the SAP comprises a biodegradable polymer.

18. The nasal formulation of any one of claims 1 to 17, wherein the SAP comprises a natural polymer, a synthetic polymer, or a combination thereof.

19. The nasal formulation of claim 18, wherein the natural polymer comprises a polysaccharide, a polypeptide, or a combination thereof.

20. The nasal formulation of any one of claims 1 to 16, wherein the SAP comprises polyacrylic acid, polyacrylate (e.g. sodium polyacrylate), polyacrylamide, polyacrylonitrile, polyvinyl alcohol, or a copolymer thereof; polyglycolide (PGA), poly(lactic acid) (PLA), or poly(lactic-co-glycolic acid) (PLGA); a polymer based on poly(N-isopropyl acrylamide) (PNIPAAm), PNIPAAm-poly ethylene glycol (PNIPAAm- PEG), poly(N,N’-dimethylacrylamide-co-N-phenylacrylamide), poly(glycidyl methacrylate-co-N-isopropylacrylamide), poly(ethylene oxide)-b-poly(propylene oxide- b-poly(ethylene oxide), poly(ethylene glycol)-polyester copolymer, or amphiphilic block copolymers; a copolymer of PNIPAAm with an acrylate monomer including alkyl acrylate (e.g. methyl acrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate), an acrylamide, of an acrylic acid or salt (e.g. 2-ethylacrylic acid, 2-propylacrylic acid, N-acryloxysuccinimide); a copolymer of PNIPAAm with a methacrylate monomer including a methacrylate (e.g. 2-hydroxymethacrylate, hydroxy ethyl methacrylate, butyl methacrylate, methyl ether methacrylate, or methyl methacrylate), a methacrylamide, or a methacrylic acid or salt; an NIPAAm-based polymer conjugated with MMP-susceptible peptide, gelatin, collagen, hyualuronic acid, and / or dextran; N-vinyl-2-pyrrolidone; cellulose, oxidized regenerated cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose; starch, potato starch, sago starch, or com starch; chitosan, carboxymethyl chitosan, quaternary ammonium salt chitosan, chitosan glutamate, or chitosan hydroglutamate; alginate or sodium alginate; hyaluronic acid; dextran; polyaspartic acid or polyglutamic acid; and / or gelatin, hemostatic gelatin thrombin matrix, or purified porcine gelatin.

21. The nasal formulation of any one of claims 1 to 19, wherein the SAP comprises a polysaccharide.

22. The nasal formulation of claim 21, wherein the SAP comprises a starch-based SAP.

23. The nasal formulation of claim 22, wherein the starch-based SAP comprises starch, potato starch, sago starch, com starch, amylose, amylopectin, microporous starch microspheres, cyclodextrin, and hydroxypropyl-Beta-cyclodextrin, or a combination thereof.

24. The nasal formulation of any one of claims 21 to 23, wherein the SAP comprises a cellulose-based SAP.

25. The nasal formulation of claim 24, wherein the cellulose-based SAP comprises cellulose, oxidized regenerated cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, colloidal microcrystalline cellulose, or a combination thereof.

26. The nasal formulation of any one of claims 1 to 25, wherein the nasal formulation further comprises an antibiotic or antiseptic.

27. The nasal formulation of claim 26, wherein the antibiotic or antiseptic comprises bacitracin, clindamycin, erythromycin, fusidic acid, gentamycin, metronidazole, mupirocin, neomycin, ozenoxacin, retapamulin, tetracyclines, dapsone, polymyxin B, alcohol, isopropyl alcohol, benzalkonium, boric acid, chlorhexidine, hexachlorophene, iodine, iodoquinol, mafenide, selenium sulfide, silver sulfadiazine, sodium hypochlorite, sulfacetamide sodium, or a combination thereof.

28. The nasal formulation of any one of claims 1 to 27, wherein the nasal formulation further comprises a topical anesthetic.

29. The nasal formulation of claim 28, wherein the topical anesthetic comprises lidocaine, tetracaine, bupivacaine, procaine, mepivacaine, benzocaine, cocaine, or a combination thereof.

30. A nasal formulation for non-invasive nasal delivery, comprising:(i) tranexamic acid (TXA); and(ii) a cellulose-based and / or a starch-based super absorbent polymer (SAP), wherein the nasal formulation is a powder.

31. The nasal formulation of claim 30, wherein the cellulose-based SAP comprises cellulose, oxidized regenerated cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, colloidal microcrystalline cellulose, or a combination thereof.

32. The nasal formulation of claim 30 or 31, wherein the starch-based SAP comprises starch, potato starch, sago starch, com starch, amylose, amylopectin, microporous starch microspheres, cyclodextrin, and hydroxypropyl-Beta-cyclodextrin, or a combination thereof.

33. The nasal formulation of any one of claims 1 to 32, wherein the nasal formulation is a powder with an average particle size of 10 pm to 300 pm.

34. The nasal formulation of any one of claims 1 to 33, wherein the average particle size of the hemostatic agent is 10 pm to 300 pm.

35. The nasal formulation of any one of claims 1 to 34, wherein the average particle size of the SAP is 10 pm to 300 pm.

36. The nasal formulation of any one of claims 1 to 35, wherein the nasal formulation is a powder with a minimum particle size of 10 pm.

37. The nasal formulation of any one of claims 1 to 36, wherein the minimum particle size of the hemostatic agent is 10 pm.

38. The nasal formulation of any one of claims 1 to 37, wherein the minimum particle size of the SAP is 10 pm.

39. A method of preventing and / or treating epistaxis in a subject, comprising:(i) non-invasively delivering a nasal formulation through a nostril into a nasal cavity, wherein the nasal formulation is a powder comprising a super absorbent polymer (SAP).

40. The method of claim 39, wherein the nasal formulation is comprised in a non-invasive nasal delivery device.

41. The method of claim 40, wherein the non-invasive nasal delivery device is a breath- actuated delivery device.

42. The method of claim 40 or 41, wherein the non-invasive nasal delivery device is a patient-operated delivery device.

43. The method of any one of claims 40 to 42, wherein the non-invasive nasal delivery device comprises a nosepiece for insertion into a nostril, wherein actuation of the non- invasive nasal delivery device expels the nasal formulation through the nosepiece into a nasal cavity.

44. The method of any one of claims 39 to 43, wherein the nasal formulation further comprises a hemostatic agent.

45. The method of claim 44, wherein the hemostatic agent comprises a vasoconstrictive agent, an antifibrinolytic agent, a coagulation factor, a hemostatic hormone or an analog thereof, an angiogenesis inhibitor, a hemostatic antibody, a cauterization agent, or a combination thereof.

46. The method of claim 45, wherein the vasoconstrictive agent comprises oxymetazoline, phenylephrine, epinephrine, xylometazoline, naphazoline, tetryzoline, angiotensin II, vasopressin, felypressin, cocaine, midodrine, or a combination thereof.

47. The method of claim 45, wherein the antifibrinolytic agent comprises aprotinin, nafamostat, a lysine analog, or a combination thereof.

48. The method of claim 47, wherein the lysine analog comprises tranexamic acid (TXA), aminocaproic acid (ACA), aminomethylbenzoic acid, or a combination thereof.

49. The method of claim 44 or 45, wherein the hemostatic agent comprises tranexamic acid (TXA).

50. The method of claim 45, wherein the coagulation factor comprises fibrinogen, fibrin, factor II, factor VII, factor Vila, factor VIII, factor IX, factor X, factor XIII, thrombin, prothrombin, vitamin K, or a combination thereof.

51. The method of claim 45, wherein the hemostatic hormone or an analog thereof comprises desmopressin, estriol, a selective estrogen modulator, or a combination thereof.

52. The method of claim 45, wherein the angiogenesis inhibitor comprises thalidomide.

53. The method of claim 45, wherein the hemostatic antibody comprises idarucizumab, bevacizumab, or a combination thereof.

54. The method of claim 45, wherein the cauterization agent comprises silver nitrate, chromic acid, trichloroacetic acid, or a combination thereof.

55. The method of any one of claims 39 to 54, wherein the SAP comprises a biodegradable polymer.

56. The method of any one of claims 39 to 55, wherein the SAP comprises a natural polymer, a synthetic polymer, or a combination thereof.

57. The method of any one of claims 39 to 54, wherein the SAP comprises polyacrylic acid, polyacrylate (e.g. sodium polyacrylate), polyacrylamide, polyacrylonitrile, polyvinyl alcohol, or a copolymer thereof; polyglycolide (PGA), poly(lactic acid) (PLA), or poly(lactic-co-gly colic acid) (PLGA); a polymer based on poly(N-isopropyl acrylamide) (PNIPAAm), PNIPAAm-polyethylene glycol (PNIPAAm-PEG), poly(N,N’- dimethylacrylamide-co-N-phenylacrylamide), poly(glycidyl methacrylate-co-N- isopropylacrylamide), poly(ethylene oxide)-b-poly(propylene oxide-b-poly(ethylene oxide), poly(ethylene glycol)-polyester copolymer, or amphiphilic block copolymers; a copolymer of PNIPAAm with an acrylate monomer including alkyl acrylate (e.g. methyl acrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate), an acrylamide, of an acrylic acid or salt (e.g. 2-ethylacrylic acid, 2-propylacrylic acid, N- acryloxysuccinimide); a copolymer of PNIPAAm with a methacrylate monomer including a methacrylate (e.g. 2-hydroxymethacrylate, hydroxy ethyl methacrylate, butyl methacrylate, methyl ether methacrylate, or methyl methacrylate), a methacrylamide, or a methacrylic acid or salt; an NIPAAm-based polymer conjugated with MMP-susceptible peptide, gelatin, collagen, hyualuronic acid, and / or dextran; N-vinyl-2-pyrrolidone; cellulose, oxidized regenerated cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose; starch, potato starch, sagostarch, or com starch; chitosan, carboxymethyl chitosan, quaternary ammonium salt chitosan, chitosan glutamate, or chitosan hydroglutamate; alginate or sodium alginate; hyaluronic acid; dextran; polyaspartic acid or polyglutamic acid; and / or gelatin, hemostatic gelatin thrombin matrix, or purified porcine gelatin.

58. The method of any one of claims 39 to 56, wherein the SAP comprises a polysaccharide.

59. The method of claim 58, wherein the SAP comprises a starch-based SAP.

60. The method of claim 59, wherein the starch-based SAP comprises starch, potato starch, sago starch, com starch, amylose, amylopectin, microporous starch microspheres, cyclodextrin, and hydroxypropyl-Beta-cyclodextrin, or a combination thereof.

61. The method of any one of claims 58 to 60, wherein the SAP comprises a cellulose-based SAP.

62. The method of claim 61, wherein the cellulose-based SAP comprises cellulose, oxidized regenerated cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, colloidal microcrystalline cellulose, or a combination thereof.

63. The method of any one of claims 39 to 62, wherein the nasal formulation further comprises an antibiotic or antiseptic.

64. The method of claim 63, wherein the antibiotic or antiseptic comprises bacitracin, clindamycin, erythromycin, fusidic acid, gentamycin, metronidazole, mupirocin, neomycin, ozenoxacin, retapamulin, tetracyclines, dapsone, polymyxin B, alcohol, isopropyl alcohol, benzalkonium, boric acid, chlorhexidine, hexachlorophene, iodine, iodoquinol, mafenide, selenium sulfide, silver sulfadiazine, sodium hypochlorite, sulfacetamide sodium, or a combination thereof.

65. The method of any one of claims 39 to 64, wherein the nasal formulation further comprises a topical anesthetic.

66. The method of claim 65, wherein the topical anesthetic comprises lidocaine, tetracaine, bupivacaine, procaine, mepivacaine, benzocaine, cocaine, or a combination thereof.

67. A method of preventing and / or treating epistaxis in a subject, comprising:(i) non-invasively delivering a nasal formulation through a nostril into a nasal cavity,wherein the nasal formulation is a powder comprising tranexamic acid (TXA) and a cellulose-based and / or a starch-based super absorbent polymer (SAP).

68. The method of claim 67, wherein the cellulose-based SAP comprises cellulose, oxidized regenerated cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, colloidal microcrystalline cellulose, or a combination thereof.

69. The method of claim 67 or 68, wherein the starch-based SAP comprises starch, potato starch, sago starch, com starch, amylose, amylopectin, microporous starch microspheres, cyclodextrin, and hydroxypropyl-Beta-cyclodextrin, or a combination thereof.

70. The method of any one of claims 39 to 69, wherein the nasal formulation is a powder with an average particle size of 10 pm to 300 pm.

71. The method of any one of claims 44 to 70, wherein the average particle size of the hemostatic agent is 10 pm to 300 pm.

72. The nasal formulation of any one of claims 39 to 71, wherein the average particle size of the SAP is 10 pm to 300 pm.

73. The nasal formulation of any one of claims 39 to 72, wherein the nasal formulation is a powder with a minimum particle size of 10 pm.

74. The nasal formulation of any one of claims 44 to 73, wherein the minimum particle size of the hemostatic agent is 10 pm.

75. The nasal formulation of any one of claims 39 to 74, wherein the minimum particle size of the SAP is 10 pm.

76. A nasal formulation for use in preventing and / or treating epistaxis in a subject, wherein the nasal formulation is for non-invasive delivery through a nostril into a nasal cavity, wherein the nasal formulation is a powder comprising a super absorbent polymer (SAP).

77. The nasal formulation for use of claim 76, wherein the nasal formulation is comprised in a non-invasive nasal delivery device.

78. The nasal formulation for use of claim 77, wherein the non-invasive nasal delivery device is a breath-actuated delivery device.

79. The nasal formulation for use of claim 77 or 78, wherein the non-invasive nasal delivery device is a patient-operated delivery device.

80. The nasal formulation for use of any one of claims 77 to 79, wherein the non-invasive nasal delivery device comprises a nosepiece for insertion into a nostril, wherein actuation of the non-invasive nasal delivery device expels the nasal formulation through the nosepiece into a nasal cavity.

81. The nasal formulation for use of any one of claims 76 to 80, wherein the nasal formulation further comprises a hemostatic agent.

82. The nasal formulation for use of claim 81, wherein the hemostatic agent comprises a vasoconstrictive agent, an antifibrinolytic agent, a coagulation factor, a hemostatic hormone or an analog thereof, an angiogenesis inhibitor, a hemostatic antibody, a cauterization agent, or a combination thereof.

83. The nasal formulation for use of claim 82, wherein the vasoconstrictive agent comprises oxymetazoline, phenylephrine, epinephrine, xylometazoline, naphazoline, tetryzoline, angiotensin II, vasopressin, felypressin, cocaine, midodrine, or a combination thereof.

84. The nasal formulation for use of claim 82, wherein the antifibrinolytic agent comprises aprotinin, nafamostat, a lysine analog, or a combination thereof.

85. The nasal formulation for use of claim 84, wherein the lysine analog comprises tranexamic acid (TXA), aminocaproic acid (ACA), aminomethylbenzoic acid, or a combination thereof.

86. The nasal formulation for use of claim 81 or 82, wherein the hemostatic agent comprises tranexamic acid (TXA).

87. The nasal formulation for use of claim 82, wherein the coagulation factor comprises fibrinogen, fibrin, factor II, factor VII, factor Vila, factor VIII, factor IX, factor X, factor XIII, thrombin, prothrombin, vitamin K, or a combination thereof.

88. The nasal formulation for use of claim 82, wherein the hemostatic hormone or an analog thereof comprises desmopressin, estriol, a selective estrogen modulator, or a combination thereof.

89. The nasal formulation for use of claim 82, wherein the angiogenesis inhibitor comprises thalidomide.

90. The nasal formulation for use of claim 82, wherein the hemostatic antibody comprises idarucizumab, bevacizumab, or a combination thereof.

91. The nasal formulation for use of claim 82, wherein the cauterization agent comprises silver nitrate, chromic acid, trichloroacetic acid, or a combination thereof.

92. The nasal formulation for use of any one of claims 76 to 91, wherein the SAP comprises a biodegradable polymer.

93. The nasal formulation for use of any one of claims 76 to 92, wherein the SAP comprises a natural polymer, a synthetic polymer, or a combination thereof.

94. The nasal formulation for use of any one of claims 76 to 92, wherein the SAP comprises polyacrylic acid, polyacrylate (e.g. sodium polyacrylate), polyacrylamide, polyacrylonitrile, polyvinyl alcohol, or a copolymer thereof; polyglycolide (PGA), poly(lactic acid) (PLA), or poly(lactic-co-glycolic acid) (PLGA); a polymer based on poly(N-isopropyl acrylamide) (PNIPAAm), PNIPAAm-poly ethylene glycol (PNIPAAm- PEG), poly(N,N’-dimethylacrylamide-co-N-phenylacrylamide), poly(glycidyl methacrylate-co-N-isopropylacrylamide), poly(ethylene oxide)-b-poly(propylene oxide- b-poly(ethylene oxide), poly(ethylene glycol)-polyester copolymer, or amphiphilic block copolymers; a copolymer of PNIPAAm with an acrylate monomer including alkyl acrylate (e.g. methyl acrylate, ethyl acrylate, butyl acrylate, 2-ethylhexyl acrylate), an acrylamide, of an acrylic acid or salt (e.g. 2-ethylacrylic acid, 2-propylacrylic acid, N- acryloxysuccinimide); a copolymer of PNIPAAm with a methacrylate monomer including a methacrylate (e.g. 2-hydroxymethacrylate, hydroxy ethyl methacrylate, butyl methacrylate, methyl ether methacrylate, or methyl methacrylate), a methacrylamide, or a methacrylic acid or salt; an NIPAAm-based polymer conjugated with MMP-susceptible peptide, gelatin, collagen, hyualuronic acid, and / or dextran; N-vinyl-2-pyrrolidone; cellulose, oxidized regenerated cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, or hydroxypropylmethylcellulose; starch, potato starch, sago starch, or com starch; chitosan, carboxymethyl chitosan, quaternary ammonium salt chitosan, chitosan glutamate, or chitosan hydroglutamate; alginate or sodium alginate; hyaluronic acid; dextran; polyaspartic acid or polyglutamic acid; and / or gelatin, hemostatic gelatin thrombin matrix, or purified porcine gelatin.

95. The nasal formulation for use of any one of claims 76 to 92, wherein the SAP comprises a polysaccharide.

96. The nasal formulation for use of claim 95, wherein the SAP comprises a starch-based SAP.

97. The nasal formulation for use of claim 96, wherein the starch-based SAP comprises starch, potato starch, sago starch, com starch, amylose, amylopectin, microporous starch microspheres, cyclodextrin, and hydroxypropyl-Beta-cyclodextrin, or a combination thereof.

98. The nasal formulation for use of any one of claims 95 to 97, wherein the SAP comprises a cellulose-based SAP.

99. The nasal formulation for use of claim 98, wherein the cellulose-based SAP comprises cellulose, oxidized regenerated cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, colloidal microcrystalline cellulose, or a combination thereof.

100. The nasal formulation for use of any one of claims 76 to 99, wherein the nasal formulation further comprises an antibiotic or antiseptic.

101. The nasal formulation for use of claim 100, wherein the antibiotic or antiseptic comprises bacitracin, clindamycin, erythromycin, fusidic acid, gentamycin, metronidazole, mupirocin, neomycin, ozenoxacin, retapamulin, tetracyclines, dapsone, polymyxin B, alcohol, isopropyl alcohol, benzalkonium, boric acid, chlorhexidine, hexachlorophene, iodine, iodoquinol, mafenide, selenium sulfide, silver sulfadiazine, sodium hypochlorite, sulfacetamide sodium, or a combination thereof.

102. The nasal formulation for use of any one of claims 76 to 101, wherein the nasal formulation further comprises a topical anesthetic.

103. The nasal formulation for use of claim 102, wherein the topical anesthetic comprises lidocaine, tetracaine, bupivacaine, procaine, mepivacaine, benzocaine, cocaine, or a combination thereof.

104. A nasal formulation for use in preventing and / or treating epistaxis in a subject, wherein the nasal formulation is for non-invasive delivery through a nostril into a nasal cavity, wherein the nasal formulation is a powder comprising tranexamic acid (TXA) and a cellulose-based and / or a starch-based super absorbent polymer (SAP).

105. The nasal formulation for use of claim 104, wherein the cellulose-based SAP comprises cellulose, oxidized regenerated cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, microcrystalline cellulose, colloidal microcrystalline cellulose, or a combination thereof.

106. The nasal formulation for use of claim 104 or 105, wherein the starch-based SAP comprises starch, potato starch, sago starch, com starch, amylose, amylopectin, microporous starch microspheres, cyclodextrin, and hydroxypropyl-Beta-cyclodextrin, or a combination thereof.

107. The nasal formulation for use of any one of claims 76 to 106, wherein the nasal formulation is a powder with an average particle size of 10 pm to 300 pm.

108. The nasal formulation for use of any one of claims 81 to 107, wherein the average particle size of the hemostatic agent is 10 pm to 300 pm.

109. The nasal formulation for use of any one of claims 76 to 108, wherein the average particle size of the SAP is 10 pm to 300 pm.

110. The nasal formulation for use of any one of claims 76 to 109, wherein the nasal formulation is a powder with a minimum particle size of 10 pm.

111. The nasal formulation for use of any one of claims 80 to 110, wherein the minimum particle size of the hemostatic agent is 10 pm.

112. The nasal formulation for use of any one of claims 76 to 111, wherein the minimum particle size of the SAP is 10 pm.

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