Sublingual epinephrine compositions containing pH-modifying excipients and penetration enhancers and methods of using same

Abstract

The present invention provides sublingual epinephrine compositions comprising epinephrine microparticles formulated with a pH-modifying excipient and a penetration enhancer. The sublingual compositions are used to control the absorption of epinephrine at the site of delivery in the oral cavity. The present invention also provides methods of therapeutic use of the sublingual compositions for the treatment of epinephrine-responsive conditions and / or to increase the sublingual bioavailability of epinephrine.

Description

[Technical field]

[0001] The present invention falls within the field of drug formulations and relates generally to modifications in drug formulations that result in improved delivery of sublingually administered drugs, particularly modifications in drug formulations that increase the permeability of the active ingredient of a sublingually administered drug, and most particularly to sublingual epinephrine compositions comprising epinephrine microparticles formulated with pH-modifying excipients and penetration enhancers that improve sublingual delivery / absorption of epinephrine. [Background technology]

[0002] Epinephrine (Epi) is the drug of choice for emergency treatment of anaphylaxis (1-4). For outpatient emergency treatment of anaphylaxis, Epi auto-injectors such as EpiPen®, EpiPen Jr® (Mylan Specialty LP, Basking Ridge, NJ, USA) are prescribed. However, self-injectable Epi is underutilized when anaphylaxis occurs (5, 6). Disadvantages of Epi auto-injectors include high cost that limits affordability and availability worldwide (6), bulkiness, limitations when repeated administration is required (7), fear and anxiety associated with the use of needles, and administration errors due to imprecise administration technique (8).

[0003] Epinephrine is extensively metabolized after oral administration by catechol-O-methyltransferase in the gastrointestinal tract and by monoamine oxidase in the gastrointestinal tract and liver (9). In aqueous solution, Epi is unstable in the presence of light, oxygen, heat, and neutral or alkaline pH values. Epi decomposes into the neurotoxic molecules, adrenochrome and adrenolutin (10).

[0004] The sublingual route of administration is a promising alternative route for the administration of Epi. Drugs that can be absorbed sublingually bypass potential metabolic transformations in the gastrointestinal tract and first-pass metabolism in the liver, and reach the systemic circulation in a pharmacologically active form (11-14). The high vascularity of the sublingual mucosa and the low molecular weight of Epi facilitate rapid absorption directly into the venous circulation.

[0005] Orally disintegrating tablets that disintegrate rapidly in a minimal volume of oral saliva are good candidates for sublingual administration of Epi. (15, 16) They are thought to release Epi instantaneously into the sublingual cavity for rapid absorption through the sublingual mucosa into the systemic circulation. (17)

[0006] The optimum pH value for the stability of Epi in aqueous solution is 3.0-3.8 (10). However, the pH of saliva under normal conditions varies between 5.8 and 7.1. Also, some pharmaceutical excipients and acidic or alkaline beverages may alter the normal salivary pH, which may affect the stability of sublingual Epi (18).

[0007] It is recommended that the administered sublingual tablet is kept under the patient's tongue until it is completely disintegrated or dissolved and can no longer be felt under the tongue. The time for complete tablet disintegration or dissolution under the patient's tongue should not exceed 2 to 5 minutes, and the patient is instructed not to eat or drink anything during this time. The required therapeutic dose of the administered drug should already be absorbed into the systemic circulation through the sublingual mucosa during this time. Although the contact time between Epi and saliva in the sublingual cavity will be short, there is no evidence in the literature that shows that Epi is stable during its sublingual administration and how variations in saliva pH may affect its stability. Therefore, it is very important to evaluate how changes in saliva pH due to various beverages and potential pharmaceutical excipients used in the tablet formulation may affect the stability of Epi during its sublingual administration. Furthermore, the stability of Epi in human saliva during its sublingual administration needs to be evaluated with respect to any potential enzymatic degradation of Epi that may occur during its sublingual administration, and the feasibility of using the sublingual route as a potential route for administration of Epi for first aid treatment of anaphylaxis needs to be evaluated.

[0008] Similarly, the permeability of drugs depends on their degree of ionization at the site of administration (19). The degree of ionization of weakly basic or acidic drugs is based on the prevailing pH. pH-modifying excipients incorporated into the dosage form may alter the absorption medium and thus affect the permeability and bioavailability of the administered drug. The choice of excipients to be used in the dosage form depends on the characteristics of the target absorption site. The addition of pH-modifying agents into tablet formulations designed for sublingual administration ensures that the pH of the saliva at the absorption site is controlled within a range that is optimal for drug absorption and reduces the variability of absorption with respect to individual salivary pH variability or with respect to any potential effects of food and beverages on salivary pH. The choice of these excipients is particularly important for Epi as a weak base. Its extent of absorption can be highly dependent on its degree of ionization, which is mainly influenced by the pH of saliva. Therefore, the evaluation of various pH-modifying excipients is very important to enhance Epi sublingual permeability and absorption and therefore its bioavailability.

[0009] Another approach to enhance drug absorption is the use of penetration enhancers. There is a wide range of enhancers that have been evaluated at various concentrations for their ability to enhance drug absorption and their safety (20). The mechanism of penetration enhancement can be utilized for hydrophilic and lipophilic drugs through paracellular diffusion, transcellular diffusion, or both. Epi has a logP of -1.37 that may make it a candidate for increasing its absorption using penetration enhancers (21). Previous in vivo studies have shown that the relative sublingual bioavailability of Epi is low when compared to intramuscular injection of Epi (22). Therefore, evaluation of different penetration enhancers to be incorporated into a sublingually administered dosage form on Epi sublingual permeation rate is necessary. A wide range of penetration enhancers can be used at various concentrations to enhance Epi permeation rate. For example, sodium dodecyl sulfate (SDS) can be used at concentrations ranging from 0.05% to 1% (23, 24), and palmitoylcarnitine chloride (PCC) can be used at concentrations ranging from 0.05 mM to 0.35 mM (25, 26) with minimal and reversible local tissue damage (27).

[0010] Without being bound by theory, it is believed that preparation of epinephrine into microparticles, including epinephrine nanoparticles or nanocrystals and epinephrine microparticles or microcrystals, and incorporation of the epinephrine microparticles into a tablet formulation along with pH modifying excipients and penetration enhancers, will significantly increase the permeation rate of epinephrine and therefore the absorption of sublingually administered epinephrine, resulting in a reduction in the required sublingual epinephrine dosage for both adults and children.

[0011] Epinephrine is an important drug in health systems worldwide for the management of life-threatening allergies, i.e., anaphylaxis, cardiac events, i.e., cardiac arrest, and respiratory distress, i.e., asthma, bronchial asthma, bronchitis, emphysema, and respiratory infections. It would be highly advantageous to have non-invasive sublingual drug delivery of epinephrine as a potential alternative patient-friendly, convenient, and cost-effective form of administration. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Kemp SF, Lockey RF, Simons FE. Epinephrine: the drug of choice for anaphylaxis. World Allergy Organization statement. Allergy. 2008;63(8):1061-70. [Non-Patent Document 2] McLean-Tooke AP, Bethune CA, Fay AC, Spikett GP. Epinephrine in the treatment of anaphylaxis: what's the evidence?. BMJ. 2003;327(7427):1332-5. [Non-Patent Document 3] Simons KJ, Simons FE. Epinephrine and its use in anaphylaxis: an update. Curr Opin Allergy Clin Immunol. 2010;10(4):354-61. [Non-Patent Document 4] Soar J, Pumphrey R, Cant A, Clarke S, Corbett A, Dawson P, et al. Emergency management of anaphylactic reactions--a guide for health care providers. Resuscitation. 2008;77(2):157-69. [Non-Patent Document 5] Simons FE. The epinephrine auto-injector: a first aid measure that remains out of reach for many during anaphylaxis threats in community settings. Ann Aller Asthma Immunol. 2009;102(5):403-9. [Non-Patent Document 6] Simons FER. Lack of worldwide availability of epinephrine auto-injectors for outpatients during anaphylaxis crisis. Ann Allergy Asthma Immunol. 2005;94(5):534-8. [Non-Patent Document 7] Korenblat P, Lundie MJ, Dankner RE, Day JH. Retrospective study of epinephrine administration for anaphylaxis: How many doses are needed? Allergy Asthma Proc. 1999;20(6):383-6. [Non-Patent Document 8] Sicherer SH, Forman JA, Noone SA. Evaluation of the use of self-administered epinephrine among food-allergic children and pediatricians. Pediatrics. 2000;105(2):359-62. [Non-Patent Document 9] Hoffman BB, Taylor P. Neurotransmission: Autonomic and Somatomotor Systems. In: Hardman JG, Limbird LE, Gilman AG, eds., Goodman & Gilman's Pharmacological Basis of Therapy. 9th ed. New York: McGraw-Hill Companies, Inc.; 2001. p. 115-53. [Non-Patent Document 10] Connors KA, Amidon GL, Stella VJ. Chemical stability of pharmaceuticals: a handbook for pharmacists. 2nd ed. New York: Wiley-Interscience Publication; 1986. 438-47pp. [Non-Patent Document 11] Bredenberg S, Duberg M, Lennernas B, Lennernas H, Pettersson A, Westerberg M et al. In vitro and in vivo evaluation of a new sublingual tablet system for rapid oral mucosal absorption using fentanyl citrate as the active substance. Eur J Pharm Sci. 2003;20(3):327-34. [Non-Patent Document 12] Glover ED, Glover PN, Franzon M, Sullivan CR, Cerullo CC, Howell RM, et al. Sublingual nicotine versus placebo for smoking cessation. Nicotine Tob Res. 2002;4(4):441-50. [Non-Patent Document 13] Guez S. Efficacy of desensitization via the sublingual route in mite allergy. Chem Immunol Allergy. 2003;82:62-76. [Non-Patent Document 14] Saxena P, Salhan S, Sarda N. Sublingual versus vaginal misoprostol for cervical indoctrination before surgical completion of first-trimester abortion. Eur J Obstet Gynecol Reprod Biol. 2006;125(1):109-13. [Non-Patent Document 15] Rawas-Qalaji MM, Simons FE, Simons KJ. Rapidly disintegrating sublingual epinephrine tablets: effect of tablet size on tablet characteristics. Drug Dev Ind Pharm. 2007;33(5):523-30. [Non-Patent Document 16] Rawas-Qalaji MM, Simons FER, Simons KJ. Rapidly disintegrating sublingual tablets: effect of epinephrine loading on tablet properties. AAPS PharmSciTech. 2006;7(2):E72-E8. [Non-Patent Document 17] Birudaraj R, Berner B, Shen S, Li X. Buccal penetration of buspirone: mechanistic studies on the delivery pathway. J Pharm Sci. 2005;94(1):70-8. [Non-Patent Document 18] Diem K, Lentner C. Scientific Tables. 7th ed. Basle, Switzerland: Ciba-Geigy Limited; 1971. [Non-Patent Document 19] Goswami T, Li X, Jasti BR. Effect of lipophilicity and drug ionization on penetration across porcine sublingual mucosa. AAPS PharmSciTech. 2017;18(1):175-81. [Non-Patent Document 20] Hassan N, Ahad A, Ali M, Ali J. Chemical penetration enhancers for transbuccal drug delivery. Expert Opin Drug Deliv. 2010;7(1):97-112. [Non-Patent Document 21] Epinephrine: Chemical and Physical Properties. Bethesda, MD, USA PubChem, National Center for Biotechnology Information, US National Library of Medicine; 2018 [https: / / pubchem.ncbi.nlm.nih.gov / compound / 5816#section=Chemical-and-Physical-Properties]. [Non-Patent Document 22] Rawas-Qalaji MM, Simons FE, Simons KJ. Sublingual epinephrine tablets versus intramuscular epinephrine injections: equivalent doses for potential treatment of anaphylaxis. J Allergy Clin Immunol. 2006;117(2):398-403. [Non-Patent Document 23] Attia MA, El-Gibaly I, Shaltout SE, Fetih GN. Transbuccal penetration, anti-inflammatory activity, and clinical efficacy of piroxicam formulated in various gels. Int J Pharm. 2004;276(1-2):11-28. [Non-Patent Document 24] Nicolazzo JA, Reed BL, Finnin BC. Evaluation of the effect of sodium dodecyl sulfate on the buccal permeability of caffeine and estradiol. J Pharm Sci. 2004;93(2):431-40. [Non-Patent Document 25] Duizer E, van der Wulp C, Versantvoort CH, Groten JP. Enhanced absorption, structural changes in tight junctions and cytotoxicity induced by palmitoylcarnitine in Caco-2 and IEC-18 cells. J Pharmacol Exp Ther. 1998;287(1):395-402. [Non-Patent Document 26] Sutton SC, LeCluyse EL, Cammack L, Fix JA. Enhancement of cefoxitin bioavailability using palmitoyl L-carnitine. I. Activity of enhancers in various intestinal regions. Pharm Res. 1992;9(2):191-4. [Non-Patent Document 27] Swenson ES, Milisen WB, Curatolo W. Intestinal permeability enhancement: efficacy, acute local toxicity, and reversibility. Pharm Res. 1994;11(8):1132-42. [Non-Patent Document 28] RHMuller et al. Eur J Pharm Biopharm 78(1):1-9 2011. Summary of the Invention [Problem to be solved by the invention]

[0013] Epinephrine (Epi) is life-saving in the treatment of anaphylaxis. In the community setting, emergency doses of epinephrine in amounts of 0.1 mg, 0.15 mg, or 0.3 mg are injected into the mid-lateral thigh by the patient or caregiver using an auto-injector such as EpiPen® (epinephrine auto-injector 0.3 or 0.15 mg, Mylan Inc., Basking Ridge, NJ) or Aubi-Q® (epinephrine auto-injector 0.1, 0.3, or 0.15 mg, kaleo, Inc., Richmond, VA). Epi auto-injectors are underutilized due to needle phobia, bulky size, and high cost, in addition to only having two or three fixed doses and a shelf life of only 12-18 months, which can lead to unintended injection and injury. [Means for solving the problem]

[0014] The present invention avoids the above-mentioned problems by providing a rapidly disintegrating epinephrine tablet formulation for the treatment of anaphylaxis, which, although designed for anaphylaxis, is equally effective and is believed to be for use in the treatment of any condition that responds to epinephrine, such as cardiac events, i.e., cardiac arrest, and respiratory distress, i.e., asthma, bronchial asthma, bronchitis, emphysema, and respiratory infections.

[0015] In a validated rabbit model, this rapidly disintegrating epinephrine tablet formulation produced plasma epinephrine concentrations similar to those achieved after intramuscular injection of 0.3 mg epinephrine.(22) Moreover, epinephrine was stable in these rapidly disintegrating tablets for at least 7 years.

[0016] The inventors hypothesized that adjusting the pH of the sublingual microenvironment surrounding the Epi tablet using an alkalizing excipient can modify the pH of the saliva in that area (the diffusion layer or stagnant unstirred layer of the tablet that forms around the tablet and contains Epi dissolved from the tablet) and reduce Epi ionization without affecting its stability, which will increase Epi permeation rate. Similarly, incorporating a penetration enhancer into the sublingual tablet formulation can increase Epi permeation rate as well. Some of the experiments that led to the composition of the present invention are described herein: 1) evaluating the stability of Epi in various media, 2) evaluating the effect of modifying the pH of the diffusion medium on enhancing Epi sublingual permeation rate, 3) evaluating the ability of pH-modifying excipients to change the pH of the microenvironment of the absorption medium of the Epi tablet, and 4) evaluating the effect of using different penetration enhancers on enhancing Epi sublingual permeation rate.

[0017] One of the most common approaches to enhance the rate of drug dissolution and absorption is to significantly reduce its particle size to the micro- or nano-size range. Drug nanocrystals (NCs) or microcrystals (MCs) are advantageous due to the minimal excipients required, and nearly 100% of the pure drug is generated during the manufacturing process (28). Similarly, the collected dry drug NCs or MCs can be formulated into various dosage forms.

[0018] The phrase "epinephrine microparticles" refers to epinephrine particles with a size of about 2.5 μm or less to about 500 nm-100 nm, and includes epinephrine nanoparticles or nanocrystals, and epinephrine microparticles or microcrystals.

[0019] In one aspect, the invention provides epinephrine microparticles.

[0020] In one aspect, the invention provides epinephrine nanoparticles. The epinephrine can be either epinephrine base, epinephric acid tartrate or other effective epinephrine salts, or a prodrug of epinephrine.

[0021] In another aspect, the present invention provides epinephrine nanocrystals. Nanocrystals are nanoparticles having a crystalline structure. The term "nanocrystal" is a more specific term to describe nanoparticles. Drug nanocrystals contain nearly 100% pure drug, i.e., epinephrine nanocrystals contain nearly 100% pure epinephrine. Drug nanoparticles can include nanocrystals or drug encapsulated in polymers at different ratios. One example is epinephrine nanoparticles containing chitosan and triphosphate (TPP) as described in previously filed related application U.S. Provisional Patent Application No. 61 / 550,359, filed October 21, 2011.

[0022] The term "about" as used in this application refers to an amount at or near a defined amount that will still allow for the desired function.

[0023] In yet another aspect, the present invention provides improved delivery of sublingually administered drugs, particularly but not limited to enhanced permeation rate of active ingredients of sublingually administered drugs.

[0024] In an embodiment, the present invention provides a sublingual epinephrine composition comprising epinephrine microparticles formulated with a pH-modifying excipient and a penetration enhancer.

[0025] In one aspect of this embodiment, the present invention encompasses a sublingual composition formulated as a rapidly disintegrating tablet. The composition includes epinephrine microparticles, such as, but not limited to, epinephrine tartrate microparticles, and one or both of a pH-modifying excipient and a penetration enhancer. A preferred non-limiting epinephrine is about 20 mg or less of epinephrine, 15 mg or less of epinephrine, or epinephrine tartrate equivalent to a range of about 20 mg to about 1 mg epinephrine. Non-limiting examples of pH-modifying excipients are the alkalizing agents, sodium carbonate, sodium bicarbonate, and calcium citrate. These alkalizing agents can be added to the compositions of the present invention in any effective percentage, such as, but not limited to, sodium bicarbonate added in a percentage of 0.75% w / v or 10% w / v of the tablet weight. A non-limiting example of a penetration enhancer is sodium dodecyl sulfate (SDS) or palmitoylcarnitine chloride (PCC). These penetration enhancers can be added to the compositions of the present invention in any effective percentage, such as, but not limited to, SDS added at 0.075% w / v or 1% w / w of the API used and PCC added at 1.2% w / v or 16% w / w of the API used.

[0026] In yet another aspect, the present invention provides a method of controlling the microenvironment at the site of drug delivery in the oral cavity. For example, the present invention provides a method of controlling the pH of saliva within an optimal range, preferably, but not limited to, within a range of about 6.8 and about 8 for absorption at the site of sublingual administration in a subject in need thereof. In another similar aspect, the present invention provides a method of modifying the ionization of epinephrine at the site of sublingual administration of epinephrine in a subject in need thereof. Both methods include providing a composition comprising epinephrine microparticles and at least one of a pH-modifying excipient and a penetration enhancer, and administering the composition to the subject. Controlling the pH of saliva preferably includes increasing the pH.

[0027] In another aspect, the present invention provides compositions comprising epinephrine nanoparticles or nanocrystals that can enhance the sublingual bioavailability of epinephrine for the emergency treatment of anaphylaxis and / or other conditions responsive to epinephrine.

[0028] In another aspect, the present invention provides an "orally disintegrating tablet (ODT)" comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals.

[0029] As described herein, buccal or sublingual orally disintegrating tablets (ODTs) are distinguished from traditional sublingual tablets, troches, or buccal tablets by the ability of the ODT to completely dissolve or disintegrate in the mouth in less than about 1 minute.

[0030] The present invention also provides pharmaceutical compositions comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals in ODT form.

[0031] The present invention also provides a pharmaceutical composition comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals and a pharma- ceutically acceptable carrier for buccal or sublingual administration.

[0032] The phrase "pharmaceutical acceptable carrier" refers to an inert and non-toxic material used in conjunction with an active material, i.e., epinephrine, particularly to aid in the application of the active material. Non-limiting examples of pharmaceutical acceptable carriers are diluents, binders, disintegrants, flavorings, fillers, and lubricants. A pharmaceutical acceptable carrier can have more than one function, i.e., a filler can also be a disintegrant. In addition, a pharmaceutical acceptable carrier may also be referred to as a non-medicinal ingredient (NMI).

[0033] The present invention also provides a pharmaceutical composition for buccal or sublingual administration comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals and at least one of a pharma- ceutically acceptable carrier, a surfactant, a penetration enhancer, a pH-modifying excipient, and a mucoadhesive. The pharmaceutical composition may further comprise at least one of a taste enhancer and a sweetener and a mouthfeel enhancer. A non-limiting example of a taste enhancer is citric acid. Citric acid masks the bitter taste of epinephrine. A non-limiting example of a sweetener and a mouthfeel enhancer is mannitol. The pharmaceutical composition may further comprise at least one of a filler, a lubricant, and a disintegrant. Non-limiting examples include microcrystalline cellulose (filler), magnesium stearate (lubricant), and low hydroxypropyl ether of cellulose (disintegrant).

[0034] Additionally, the present invention provides pharmaceutical compositions comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals, whereby the bitter taste of epinephrine is masked by a taste enhancer, a non-limiting example of which is citric acid.

[0035] In another aspect, the present invention provides a method for increasing the sublingual bioavailability of epinephrine in a subject in need thereof, comprising providing a composition comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals and at least one pharma- ceutically acceptable carrier, and administering the composition to the subject. The above-mentioned rapidly disintegrating epinephrine tablet increases the bioavailability of epinephrine by releasing epinephrine within 60 seconds of administration. The term "subject" includes any human or animal that can benefit from the compositions and methods of the present invention. The term "patient" is also used herein to refer to a subject.

[0036] In another aspect, the present invention provides a method for treating an epinephrine-responsive condition in a subject in need thereof, comprising providing a composition comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals and at least one pharma- ceutically acceptable carrier, and administering the composition to the subject. An epinephrine-responsive condition is responsive to the administration of epinephrine. Non-limiting examples of epinephrine-responsive conditions include cardiac events, i.e., cardiac arrest, or allergic reactions, i.e., anaphylaxis, asthma, or bronchial asthma.

[0037] The phrase "effective amount" refers to the amount of a composition necessary to achieve its intended function.

[0038] The phrase "pharmaceutical effective dose" refers to the amount of a composition required to achieve a desired therapeutic effect. It is often desirable to use the lowest effective dose of a drug. An example of a dosage range for the epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals described above is about 1 mg to 40 mg epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals.

[0039] The phrase "therapeutically effective amount" refers to the amount of a composition required to achieve a desired function, i.e., treatment of a medical condition that responds to epinephrine.

[0040] In another aspect, the present invention provides a method of treating dyspnea in a subject in need thereof comprising providing a composition comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals and at least one pharma- ceutically acceptable carrier and administering the composition to the subject.Dyspnea responsive to epinephrine includes, but is not limited to, dyspnea associated with anaphylaxis, asthma, bronchial asthma, bronchitis, emphysema, and respiratory infections.

[0041] The invention additionally provides a method of treating an allergic emergency condition in a subject diagnosed or suspected of having an allergic emergency condition comprising providing a composition comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals and at least one pharma- ceutically acceptable carrier, and administering the composition to the subject. Non-limiting examples of allergic emergency conditions are anaphylaxis, asthma, and bronchial asthma.

[0042] In an additional aspect, the present invention provides a method of treating a cardiac event in a subject diagnosed or suspected of having a cardiac event comprising providing a composition comprising epinephrine nanoparticles or nanocrystals or epinephrine microparticles or microcrystals and at least one pharma- ceutically acceptable carrier and administering the composition to the subject. A non-limiting example of a cardiac event is cardiac arrest.

[0043] Any of the epinephrine microparticles (including epinephrine nanoparticles or nanocrystals and epinephrine microparticles or microcrystals), compositions, and pharmaceutical compositions described above, particularly the epinephrine microparticles (including epinephrine nanoparticles or nanocrystals and epinephrine microparticles or microcrystals), compositions, and pharmaceutical compositions intended for use in emergency situations, can be formulated for buccal or sublingual administration.

[0044] In another aspect, any of the epinephrine microparticles described above (including epinephrine nanoparticles or nanocrystals and epinephrine microparticles or microcrystals) can be used in the manufacture of any of the compositions and pharmaceutical compositions described above.

[0045] Other objects and advantages of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings which set forth by way of example examples and certain embodiments of the invention, the drawings being incorporated in and constituting a part of this specification, including exemplary embodiments of the invention and illustrating various objects and features thereof.

[0046] A more complete understanding of the present invention can be obtained by reference to the accompanying drawings when considered in conjunction with the following detailed description, in which: The embodiments shown in the drawings are intended to be illustrative of the present invention only and should not be construed as limiting the present invention to the illustrated embodiments. [Brief description of the drawings]

[0047] [Figure 1] 1 is a graph showing % epinephrine recovery at various pH levels, mean ± SD (n=3). [Diagram 2] 1 is a graph showing epinephrine recovery (%) in human saliva, mean ± SD (n=3). [Diagram 3] FIG. 1 is a graph showing the cumulative epinephrine permeated and percentage across porcine sublingual mucosa over time at various pH, mean±SD (n=4). [Figure 4] 1 is a graph showing the AUC0-90 of epinephrine permeation across porcine sublingual mucosa at various pH, mean ± SD (n=4). [Diagram 5] FIG. 1 is a graph showing epinephrine influx and permeability across porcine sublingual mucosa at various pH, mean±SD (n=4). [Figure 6] FIG. 1 is a graph showing cumulative epinephrine permeation and percentage across porcine sublingual mucosa over time with various penetration / penetration enhancers, mean±SD (n=4). [Figure 7] FIG. 1 is a graph showing the cumulative epinephrine permeation and percentage across porcine sublingual mucosa over time with various formulations, mean±SD (n=4). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] For purposes of facilitating an understanding of the principles of the invention, reference will now be made below to the embodiments exemplified herein, and specific language will be used below to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is intended thereby. It is contemplated that any alternatives and further modifications in the above-mentioned compositions, formulations, epinephrine microparticles, methods, procedures, and techniques described herein, together with any further applications of the principles of the invention as described herein, would normally occur to one skilled in the art to which the invention pertains.

[0049] As stated above, the experiments described herein had a defined objective which led to the development of the compositions of the present invention.

[0050] First, the short-term stability of epinephrine (Epi) over a wide range of pH was evaluated. Modification of the pH of the absorption microenvironment can alter the degree of drug ionization and therefore its permeability. Altering the salivary pH (5.5-7.2) to enhance the sublingual absorption of Epi and reduce its absorption variability may, on the other hand, adversely affect its stability. It was believed that altering Epi ionization by modifying the pH of the absorption medium without adversely affecting Epi stability could enhance Epi permeability and optimize sublingual Epi delivery as an alternative route for the treatment of anaphylaxis and other conditions responsive to Epi.

[0051] Epi has been found to be relatively stable at saliva pH and over the period required for its sublingual administration up to pH 8. Altering the pH of the absorption microenvironment to enhance the sublingual delivery of Epi and reduce its absorption variability up to pH 8 should not affect its stability.

[0052] Next, the effect of modifying pH on the sublingual permeation rate of epinephrine (Epi) to alter its degree of ionization was evaluated. It was believed that altering Epi ionization by modifying the pH of the absorption medium could enhance Epi permeation rate and optimize sublingual Epi delivery as an alternative route for the treatment of anaphylaxis and other Epi-responsive conditions.

[0053] It has been found that increasing the pH of the diffusion medium and the subsequent decrease in Epi ionization can result in a significant increase in sublingual penetration of Epi.

[0054] Finally, the effect of different penetration enhancers on the sublingual permeation rate of epinephrine (Epi) was evaluated. It was believed that the incorporation of a penetration enhancer could further increase the sublingual permeation rate of Epi as a potential alternative route of administration for the treatment of anaphylaxis and other conditions responsive to Epi.

[0055] It was found that the penetration enhancer could increase the sublingual permeation rate of Epi. Sodium dodecyl sulfate (SDS) was superior to palmitoylcarnitine chloride (PCC) in enhancing the sublingual permeation of Epi. The incorporation of a penetration enhancer into the Epi formulation can significantly increase the Epi permeation rate and potentially the sublingual absorption as a potential alternative route of administration for the treatment of anaphylaxis and other conditions responsive to Epi. EXAMPLES

[0056] Example 1: Stability of epinephrine (Epi) in various media

[0057] The optimal stability of Epi in aqueous solutions is in the pH range of 3.0-3.8 (10). However, the normal salivary pH is between 5.8-7.1, which can also be modified by excipients used in food, beverage, or sublingual dosage forms. pH-modifying excipients can be used in sublingual formulations to modify the degree of drug ionization and therefore its permeability. However, modifying the salivary pH using pH-modifying excipients to enhance the sublingual absorption of Epi and / or reduce its absorption variability by food or beverages may, on the other hand, adversely affect its stability. Therefore, the short-term stability of Epi (20-30 min) was evaluated in various media to test the feasibility of administering Epi subcutaneously at various pH values ​​for the treatment of anaphylaxis and other pathologies responsive to Epi.

[0058] Epinephrine stability at various pH levels

[0059] Epinephrine tartrate (EpiBit) equivalent to 20 mg Epi was dissolved in 2 mL of MacVillian buffer (n=3) (acetate phosphate buffer) at specific pH including pH 1.2, 3.5, 4.5, 5, 5.5, 6, 6.8, 7.4, and 8. Aliquot samples were removed at specific intervals including 2 (maximum expected time for sublingual administration), 4, 6, 10, 15, and 30 min. Removed samples were immediately diluted with a stabilizing solution containing 0.1 M perchloric acid and 0.1 mM sodium metabisulfite to stabilize and stop any potential epi degradation. Collected samples were frozen for further analysis by HPLC for Epi content using the USP method for Epi injection. % Epi recovery at T0 was used as a positive control for each sample. The mean ± SD of Epi recovery (%) at each pH during different time periods was calculated and statistically compared using repeated measures ANOVA and Tukey-Kramer test (p<0.05).

[0060] The mean ± SD (n = 3) Epi recoveries (%) at different time intervals at various pHs tested are shown in Table 1. The mean ± SD (n = 3) Epi recoveries (%) were not significantly different (p > 0.05) from the original concentration (positive control T0) at different sampling time intervals in the pH ranges of 1.2-3.5 and 5.5-8 (Figure 1). At pH 4, 4.5, and 5, Epi recoveries (%) were significantly decreased (p < 0.05).

[0061] (Table 1) TIFF0007657457000001.tif24369

[0062] Epi was stable over a wide range of pH values ​​over a sufficient time period to allow sublingual drug administration, except between pH 4 and 5, which resulted in 10-17% Epi loss in the first 2 minutes. Sublingual Epi administration should be feasible due to the incorporation of pH-modifying excipients into the tablet formulation or due to human consumption of a variety of beverages with a wide range of acidity and alkalinity (except between pH 4 and 5) without adjusting the pH, and degradation is expected to be minimal or nonexistent.

[0063] Stability of epinephrine in human saliva.

[0064] Saliva samples were collected from human volunteers. The volunteers were asked not to eat or drink any acidic, alkaline, or spicy foods or drinks and to rinse their mouths before saliva collection. The saliva was collected in an ice bath beaker, then degassed to remove air bubbles, and then filtered through a 0.45 μm membrane.

[0065] EpiBit equivalent to 2 mg Epi was dissolved in 400 μL (equivalent to 10 mg Epi in 2 mL) of saliva (n=3) that was immersed in a 37°C water bath for 30 minutes prior to the start of the study. Aliquot samples were removed at specific intervals including 2, 4, 6, 10, 15, and 30 minutes. Removed samples were immediately diluted with Epi stabilizing solution containing 0.1 M perchloric acid and 0.1 mM sodium metabisulfite to stabilize and stop any potential epi degradation. Collected samples were frozen for further analysis by HPLC for Epi content using the USP method for Epi injection. Mean ± SD of Epi recovery (%) was calculated.

[0066] The mean ± SD (n=3) Epi recovery (%) in human saliva at different time intervals is presented in Table 2 and FIG.

[0067] (Table 2) TIFF0007657457000002.tif58158

[0068] Epi was stable in human saliva (at saliva pH and up to pH 8) for a sufficient time to allow sublingual drug administration. Epi concentrations were only significantly lower than the initial concentrations in human saliva after 15 and 30 minutes (92±0.2% and 84±0.0%, respectively). Epi is suitable for sublingual administration due to the pH and composition of human saliva, and is believed to have minimal or no significant degradation. Changing the pH of the absorption microenvironment to pH 8, enhancing the sublingual delivery of Epi and reducing its absorption variability, should not affect stability. EXAMPLES

[0069] Example 2: Epinephrine sublingual permeation rate at various pH

[0070] Modification of the pH of the absorption microenvironment due to food, beverages, or individual saliva variability can cause variability in drug permeability and absorption due to altering the degree of drug ionization. Similarly, pH-modifying excipients can be incorporated into sublingual formulations to reduce drug ionization and thus enhance its permeability and absorption. Therefore, Epi sublingual permeability over a wide range of pH was evaluated to determine the pH value at which Epi permeability is optimal.

[0071] Removal and preparation of porcine sublingual mucosa

[0072] Frozen pig heads were obtained from a local slaughterhouse. They were then thawed at room temperature. Pig mucosa was excised by dissecting the sublingual mucosa with a scalpel and fine forceps using established surgical techniques and removing the underlying connective tissue. The excised mucosa was frozen on aluminum foil at -20°C until use (<4 weeks).

[0073] Epinephrine permeability studies A static vertical jacketed Franz cell (PermeGear Inc., Hellertown, PA, USA) with an OD of 20 mm and a reservoir volume of 20 ± 1 mL was used to measure Epi permeability at various pHs. Sublingual mucosa (floor of the mouth) isolated from a pig was used as the diffusion membrane. MacVillian buffer at various pHs was used as the diffusion medium for the donor cells.

[0074] Before each experiment, the mucosa was thawed at room temperature and mounted between the donor and receptor chambers, clamped using a metal clamp. The receptor chamber with magnetic stirrer was filled with diffusion medium before mounting the membrane, and air bubbles were removed after mounting the membrane and before the experiment. The water bath was set at 37°C with circulating water in a jacketed Franz cell. The mounted membrane was equilibrated with diffusion medium for 30 min on both sides before the experiment and checked for any leaks.

[0075] EpiBit equivalent to 20 mg Epi was dissolved in 2 mL of MacVillian buffer at specific pHs including pH 5, 6, 6.8, 7.4, and 8 (n=4).

[0076] Aliquots were removed from the receptor chamber using a 6-inch needle (Popper & Sons, Inc., New Hyde Park, NY, USA) and a 1 mL syringe at 5, 10, 15, 20, 30, 45, 60, 75, and 90 min. The removed volume was replaced with fresh medium.

[0077] Samples were transferred to HPLC vials for HPLC analysis according to USP methods.

[0078] The cumulative amount of Epi infiltrated over time (AUC 0-90分 , μg / cm 2 / min), inflow (J, μg / cm 2 / min), and permeability coefficient (P, cm / min) were calculated and statistically compared using ANOVA and Tukey-Kramer test.

[0079] The mean ± SD (n=4) cumulative diffusion Epi per area at different pH are presented in Table 3 and Figure 3. The mean percentage of diffusion Epi per area at different pH are presented in Table 4 and Figure 3.

[0080] Average (±SD) Epi AUC 0-90分 , J, and P are presented in Table 5. Similarly, Epi AUC at each pH 0-90分 , influx (J), and permeability (P) are presented in Figures 4 and 5. AUC at various pH 0-90 , J, and P were significantly different from each other (p<0.05) except for pH 5 and 6, which were not significantly different from each other. 0-90分 increased linearly as the pH increased from 6 to 8 (R 2 At pH 8, Epi sublingual permeation was increased approximately 11-fold compared to pH 6.8, the average pH of human saliva.

[0081] pH had a significant effect on Epi sublingual permeation rate: as pH increased, the degree of ionization decreased, resulting in increased sublingual permeation of Epi.

[0082] Increasing and then decreasing the pH of the diffusion medium upon Epi ionization can result in a significant increase in the sublingual penetration of Epi.

[0083] (Table 3) TIFF0007657457000003.tif66165

[0084] (Table 4) TIFF0007657457000004.tif65165

[0085] (Table 5) TIFF0007657457000005.tif35153 EXAMPLES

[0086] Altering the microenvironmental pH of absorption media using pH-modifying excipients

[0087] Alkalizing (pH-modifying) excipients were selected and evaluated based on the desired pH values ​​that yielded optimal Epi stability and permeability from Examples 1 and 2 above.

[0088] Three pH modifiers, sodium bicarbonate, calcium citrate, and sodium carbonate, were selected and used in various percentages to determine in vitro the amount required to modify the pH of 2 mL of water with or without EpiBit equivalent to 20 mg Epi as diffusion medium (n=3). The mean ± SD of medium pH was calculated.

[0089] The mean (±SD) pH readings using various pH-modifying excipients with and without EpiBit equivalent to 20 mg Epi are presented in Table 6. Sodium carbonate produced the highest mean (±SD) pH, 8.6±0.2 and 11.7±0.0, at the lowest required percentage (0.75% w / v), with and without Epi.

[0090] (Table 6) TIFF0007657457000006.tif72160 EXAMPLES

[0091] Effect of penetration enhancers on sublingual epinephrine permeation rates.

[0092] The objective was to evaluate the effect of different penetration enhancers on Epi sublingual permeation rate. Different penetration enhancers at different concentrations have been investigated to enhance drug permeation through the buccal and sublingual routes (20). The effect of sodium dodecyl sulfate (SDS) and palmitoylcarnitine chloride (PCC) as penetration enhancers on Epi sublingual permeation rate was evaluated. EpiBit (n=4) equivalent to 20 mg Epi and SDS (0.075% w / v) or PCC (1.2% w / v) were dissolved in 2 mL of phosphate buffer at pH 6.8 (mean saliva pH). Epi permeation rate without penetration enhancer was used as control. Isolated porcine sublingual membranes were used as described above in Example 2 to evaluate the permeation of Epi through a static vertical Franz diffusion cell at a controlled temperature of 37°C as described above in Example 2. EpiBit solutions with or without penetration enhancers were added to the donor chamber, and phosphate buffer at pH 7.4 (pH of blood) was used for the receiver chamber. Aliquots of 200 μL were removed from the receiver chamber at several time intervals. The removed volume was replenished with fresh phosphate buffer, and the collected samples were transferred into HPLC vials for HPLC analysis using a UV detector. The cumulative amount of EpiBit that penetrated over time (AUC 0-90分 , μg / cm 2 / min), inflow (J, μg / cm 2 / min), and permeability coefficient (P, cm / min) were calculated and statistically compared using ANOVA and Tukey-Kramer test.

[0093] The mean ± SD (n=4) cumulative diffusion Epi per area with different penetration enhancers is presented in Table 8 and Figure 6. The mean percentage of diffusion Epi per area with different penetration enhancers is presented in Table 9 and Figure 6.

[0094] (Table 8) TIFF0007657457000007.tif71167

[0095] (Table 9) TIFF0007657457000008.tif66165

[0096] Mean (±SD) AUC of infiltrated Epi with 0.075% SDS and 0.75% PCC 0-90分 , J, and P were statistically higher than the control (p<0.05). Permeation Epi AUC with SDS enhancer 0-90分 , J, and P were significantly higher than those with PCC enhancer (p<0.05) (Table 10). The addition of SDS 0.075% achieved the highest enhancement of Epi sublingual permeation rate, increasing Epi permeation rate by approximately 10-fold compared to the control.

[0097] (Table 10) TIFF0007657457000009.tif46165

[0098] The penetration enhancer could increase the Epi sublingual permeation rate. SDS was superior to PCC in increasing the Epi sublingual permeation rate. The incorporation of a penetration enhancer into the Epi formulation could significantly increase the Epi permeation rate and potentially the sublingual absorption as an alternative route of administration for the treatment of anaphylaxis and other conditions responsive to Epi. EXAMPLES

[0099] Combined effects of penetration enhancers on sublingual epinephrine permeation rates.

[0100] The combined effect of an alkalizing agent that could produce the pH value that produced the optimal Epi sublingual permeability from previous Examples 2 and 3 with a permeation enhancer that produced the optimal Epi sublingual permeability from previous Example 4 on the overall sublingual Epi permeability was evaluated. EpiBit equivalent to 20 mg Epi with 0.75% w / v sodium carbonate (Na Carb) as the alkalizing agent and 0.075% w / v SDS as the permeation enhancer was dissolved in 2 mL of deionized water based on the results obtained from previous Examples. Epi permeability from phosphate buffer at pH 6.8 without permeation enhancer and without alkalizing agent from previous Examples was used as a control. Excised porcine sublingual mucosa was used as described above in Example 2 and the permeation of Epi was evaluated through a static vertical Franz diffusion cell at a controlled temperature of 37° C. as described above in Example 2. EpiBit solution with permeation enhancer and alkalizing agent was added to the donor chamber. Phosphate buffer at pH 7.4 (pH of blood) was used in the receiver chamber. Aliquots of 200 μL were removed from the receiver chamber at several time intervals. The removed volume was replenished with fresh phosphate buffer and the collected samples were transferred into HPLC vials for HPLC analysis using a UV detector. The cumulative amount of Epi permeated over time (AUC 0-90分 , μg / cm 2 / min), inflow (J, μg / cm 2 Permeability (P, cm / min) and permeability coefficient (P, cm / min) were calculated and statistically compared to Epi permeability at pH 8 from Example 2, Epi permeability with 0.075% w / v SDS only from Example 4, and control data using ANOVA and Tukey-Kramer test.

[0101] The mean ± SD (n=4) cumulative diffused Epi per area at pH 8, Epi with SDS only, and with alkalinizer and penetration enhancer compared to control are presented in Table 11 and Figure 7. The mean percentage of diffused Epi per area at pH 8, Epi with SDS only, and with alkalinizer and penetration enhancer compared to control are presented in Table 12 and Figure 7.

[0102] (Table 11) TIFF0007657457000010.tif69165

[0103] (Table 12) TIFF0007657457000011.tif69165

[0104] Mean (±SD) AUC of permeated Epi with sodium carbonate (0.75% w / v) and SDS (0.075% w / v) 0-90分 , J, and P were statistically higher than all (p<0.05). The J and P of permeated Epi at pH 8 with only SDS enhancer were significantly higher than the control (p<0.05) but not significantly different from each other (p>0.05) (Table 13). The combined effect of adding sodium carbonate (0.75% w / v) with SDS 0.075% on Epi permeability enhancement was significantly higher than either alone, increasing Epi permeability by approximately 25-fold compared to the control.

[0105] (Table 13) TIFF0007657457000012.tif38157 EXAMPLES

[0106] Formulation of Epinephrine Sublingual Compositions

[0107] Epinephrine 15 mg pediatric dose and 20 mg-40 mg adult dose using epinephrine tartrate can be formulated as micronized or non-micronized particles with a particle size distribution ranging between 500 nm and 2.5 μm in a sublingual tablet formulation with or without a pH modifier (alkalinizer), with or without a permeation enhancer, with or without a flavor, and / or with or without a taste masking agent.

[0108] TIFF0007657457000013.tif75166

[0109] TIFF0007657457000014.tif74165

[0110] TIFF0007657457000015.tif74162

[0111] TIFF0007657457000016.tif74163

[0112] TIFF0007657457000017.tif75166

[0113] Summary of the Examples Epinephrine is believed to be suitable for sublingual administration due to the pH and composition of human saliva with minimal or no significant degradation. Similarly, the incorporation of pH-modifying excipients into the tablet formulation does not impair the stability of Epi (except between pH 4 and 5). These can be useful to adjust for the variability in pH of human saliva resulting from consumption of various beverages with a wide range of acidity and alkalinity. The incorporation of an alkalizing agent into the Epi sublingual tablet formulation to maintain the pH of the diffusion medium at about 8 using a permeation enhancer such as SDS can increase the Epi sublingual permeation rate by about 25-fold compared to the approximately 10-11-fold increase for each alone.

[0114] conclusion Epinephrine is an important drug in health systems worldwide for the management of life-threatening allergies, i.e., anaphylaxis, cardiac events, i.e., cardiac arrest, and respiratory distress, i.e., asthma, bronchial asthma, bronchitis, emphysema, and respiratory infections. The invention described and illustrated herein represents a new non-invasive sublingual drug delivery for epinephrine as a potentially alternative patient-friendly, convenient, and cost-effective administration form to standard epi auto-injectors.

[0115] All patents and publications cited herein are indicative of the level of skill of those skilled in the art to which this invention pertains. All patents and publications are incorporated herein by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. It should be understood that, although certain forms of the invention have been illustrated, it is not intended to limit it to the specific forms or arrangements described and illustrated herein. The invention should not be considered as limited to those shown and described herein, as it will be apparent to those skilled in the art that various modifications can be made without departing from the scope of the invention. Those skilled in the art will readily appreciate that the invention is well adapted to carry out the objects and obtain the aims and advantages illustrated, as well as those inherent therein. The compositions, formulations, dosages, epinephrine microparticles, methods, procedures, and techniques described herein represent presently preferred embodiments, are intended to be illustrative, and are not intended to be limiting in scope. Modifications therein and other uses will occur to those skilled in the art that are within the spirit of the invention. Although the invention has been described in connection with certain preferred embodiments, it should be understood that the invention ultimately claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the present invention.

Claims

1. 1. A sublingual composition formulated as a rapidly disintegrating tablet, comprising: Epinephrine microparticles, A pH-modifying excipient; and A penetration promoter; Including, The penetration enhancer is sodium dodecyl sulfate (SDS) or palmitoylcarnitine chloride (PCC); 13. The sublingual composition, wherein the pH-modifying excipient is an alkalizing excipient for increasing the pH at the administration site of the sublingual composition, the alkalizing excipient being sodium carbonate, sodium bicarbonate or calcium citrate.

2. 2. The sublingual composition of claim 1, wherein the epinephrine microparticles have a particle size distribution ranging from about 500 nm to about 2.5 μm.

3. 2. The sublingual composition of claim 1, wherein the epinephrine is epinephrine tartrate.

4. 4. The sublingual composition of claim 3, wherein the epinephric acid tartrate is equivalent to a range of about 15 mg epinephrine to about 20 mg epinephrine.

5. 4. The sublingual composition of claim 3, wherein the epinephrine tartrate is equivalent to about 15 mg epinephrine.

6. 4. The sublingual composition of claim 3, wherein the epinephrine tartrate is equivalent to about 20 mg epinephrine.

7. 2. The sublingual composition of claim 1, wherein the epinephrine microparticles are epinephrine microparticles, epinephrine microcrystals, epinephrine nanoparticles, or epinephrine nanocrystals.

8. 2. The sublingual composition of claim 1, wherein the alkalizing excipient is sodium carbonate added at 0.75% w / v.

9. 2. The sublingual composition of claim 1, wherein the penetration enhancer is sodium dodecyl sulfate (SDS) added at 0.075% w / v.

10. 2. The sublingual composition of claim 1, wherein the penetration enhancer is palmitoylcarnitine chloride (PCC) added at 1.2% w / v.

11. 10. The sublingual composition of claim 1, further comprising at least one of a filler, a flavoring agent, a sweetener, a disintegrant, a taste masking agent, and a lubricant.

12. 1. A sublingual composition formulated as a rapidly disintegrating tablet, comprising: epinephrine tartrate microparticles; Sodium carbonate, Sodium dodecyl sulfate (SDS), A sublingual composition comprising:

13. 13. The sublingual composition of claim 12, wherein the epinephric tartrate microparticles are epinephric tartrate microparticles, epinephric tartrate microcrystals, epinephric tartrate nanoparticles, or epinephric tartrate nanocrystals.

14. 13. The sublingual composition of claim 12, wherein the epinephrine tartrate is equivalent to about 20 mg epinephrine, sodium carbonate is added at 0.75% w / v, and sodium dodecyl sulfate (SDS) is added at 0.075% w / v.

15. 13. The sublingual composition of claim 12, wherein the epinephrine tartrate is equivalent to about 15 mg epinephrine, sodium carbonate is added at 0.75% w / v, and sodium dodecyl sulfate (SDS) is added at 0.075% w / v.

16. 13. The sublingual composition of claim 12, further comprising at least one of a filler, a flavoring agent, a sweetener, a disintegrant, a taste masking agent, and a lubricant.

17. 13. The sublingual composition of claim 12, wherein the epinephrine tartrate microparticles have a particle size distribution ranging from about 500 nm to about 2.5 μm.

18. A composition for sublingual administration comprising epinephrine tartrate microparticles, sodium carbonate, and sodium dodecyl sulfate (SDS) suitable for controlling the pH of saliva within an optimal range for absorption at the sublingual administration site of a subject.

19. A composition for sublingual administration as described in claim 18, characterized in that the optimal range for absorption is in the range of about 6.8 to about 8.

0.

20. 20. A composition for sublingual administration as described in claim 18, characterized in that controlling the pH of the saliva comprises increasing the pH of the saliva.

21. A composition for sublingual administration comprising epinephrine tartrate microparticles, sodium carbonate, and sodium dodecyl sulfate (SDS), suitable for altering the ionization of epinephrine at the site of sublingual administration of the epinephrine to a subject.

22. A composition for sublingual administration comprising epinephrine tartrate microparticles, sodium carbonate, and sodium dodecyl sulfate (SDS), suitable for increasing the sublingual bioavailability of epinephrine in a subject.

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