WO2020163425A1

WO2020163425A1 - Azlocillin and disulfiram-based formulations and methods of use

Info

Publication number: WO2020163425A1
Application number: PCT/US2020/016708
Authority: WO
Inventors: Jayakumar Rajadas; Mohammed INAYATHULLAH NAZIR AHMED; Venkata Raveendra Pothineni; Matthew Charles TINDALL; Vijaya BALAKRISHNAN
Original assignee: Flightpath Biosciences, Inc.; SURYA KUMAR POTULA, Hari Hara
Priority date: 2019-02-05
Filing date: 2020-02-05
Publication date: 2020-08-13

Abstract

Disclosed herein are pharmaceutical formulations which include disulfiram and/or azlocillin for the treatment of diseases such as Lyme disease and Lyme disease related disorders including post- treatment Lyme disease syndrome (PTLDS), chronic Lyme disease (CLD) and/or inflammation.

Description

AZLOCILLIN AND DISULFIRAM-BASED FORMULATIONS AND METHODS OF

USE CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to priority to 62/801,256 filed on February 5, 2019 entitled Thiuram Disulfide Analogs for the Treatment of Lyme Disease, 62/801,258 filed on February 5, 2019 entitled Pectin Based Formulation for Azlocillin and Other Penicillin

Derivatives, 62/907,596 filed on September 28, 2019 entitled Azlocillin and Disulfiram-based Formulations and Methods of Use, 62/913,656 filed on October 10, 2019 entitled Azlocillin and Disulfiram-based Formulations and Methods of Use, and 62/923,517 filed on October 19, 2019 entitled Azlocillin and Disulfiram-Based Formulations and Methods of Use, the contents of each of which are herein incorporated by reference in their entirety.

FIELD OF THE DISCLOSURE

The present disclosure relates to formulations and methods of treating disease using the formulations. Specifically provided are formulations containing therapeutic agents such as disulfiram and azlocillin.

BACKGROUND OF THE DISCLOSURE

Lyme disease is the most common zoonotic bacterial disease in North America. Over 427,000 people are newly diagnosed with Lyme disease in the United States each year according to the Center for Disease Control. The disease is caused by the spirochetes of genus Borrelia, collectively known as B. burgdorferi sensu lato (Bsl). Among the members of the genus, B. burgdorferi sensu stricto (Bss) is the single major causative agent of the disease in the United States. Oxher members of the genus include but are not limited to, B. duttonii, B. garinii, B. afzelii, B. miyamotoi, B. valaisiana, B. spielmanii, B. lusitaniae, B. babesiosis, B. bissettii, B. andersoni, and B. erlichiosis. Clinical presentations of Lyme disease in humans include erythema migrans, fatigue, fever, chills, muscle pain and joint pain.

The majority of patients with Lyme disease can be cured with the antibiotics doxycycline or amoxicillin used for 2-4 weeks, especially during the early phase of the disease.

In the absence of antibiotic therapy, B. burgdorferi (Bb) can affect

immunocompetent hosts and can establish long-term infections lasting years to lifelong in mice and humans that are its natural and incidental hosts respectively. A subset of patients experience persistent symptoms despite antibiotic therapy including neurocognitive difficulties, arthralgias, sleep disruption, headache, muscle and joint pain, generalized fatigue and musculoskeletal pains. When symptoms last longer than 6 months after antibiotic treatment, the condition is proposed to be post-treatment Lyme disease syndrome (PTLDS) or chronic Lyme disease (CLD). There remains a need to identify therapeutic agents that may be useful in the treatment of PTLDS and/or therapeutic agents that may be useful in the treatment of the early phase of the disease thereby preventing the onset of PTLDS.

SUMMARY OF THE DISCLOSURE

The present disclosure provides therapeutic agents and pharmaceutical formulations of the therapeutic agents for treating diseases such as, but not limited to, Lyme disease. In some embodiments, the therapeutic agent may be but is not limited to disulfiram, azlocillin, penicillin, thiuram, and/or any derivatives thereof.

In some embodiments, pharmaceutical formulations of the present disclosure include at least one therapeutic agent described herein and an excipient. The excipient may include one or more of a phospholipid, a pectin, a polymer, and/or an inorganic salt.

In some embodiments, the excipient may include a phospholipid. The phospholipid may be a synthetic phospholipid such as, but not limited to, dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylcholine (DMPC), dioleoyl phosphatidylcholine (DOPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), dioleoyl phosphatidylglycerol (DOPG), distearoyl

phosphatidylglycerol (DSPG), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), dioleoyl phosphatidylethanolamine (DOPE), dimyristoyl phosphatidylserine (DMPS), dipalmitoyl phosphatidylserine (DPPS),

diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC),

ditricosanoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLPC), or dioleoyl phosphatidylserine (DOPS).

In some embodiments, the excipient includes a combination of phospholipids. The combination of phospholipids may include DDPC and DSPC. In one embodiment, the pharmaceutical formulations described herein may include from about 2% (w/w) to about 20% (w/w) of DPPC. In one embodiment, the pharmaceutical formulations described herein may include 8.06% (w/w) of DPPC. In one embodiment, the pharmaceutical formulations described herein may include from about 2% (w/w) to about 20% (w/w) of DSPC. In one embodiment, the pharmaceutical formulations described herein may include 8.06% (w/w) of DSPC.

In some embodiments, the pharmaceutical formulations may include excipients such as, but not limited to, one or more pectins. The amount of pectin in the formulation may be from about 20% (w/w) to about 80% (w/w). In one embodiment, the pharmaceutical formulation may include 55.98% (w/w) of pectin.

In some embodiments, the pharmaceutical formulations may include excipients such as, but not limited to, one or more polymers. In some embodiments, the polymer may be a poloxamer such as, but not limited to, P-188. In some embodiments, the amount of P-188 in the formulation may be from about 0.001% (w/w) to about 40% (w/w). In one embodiment, the pharmaceutical formulation may include 22.42% (w/w) of P-188.

In some embodiments, the pharmaceutical formulation may include excipients such as, but not limited to, inorganic salts. Non-limiting examples of inorganic salts include calcium chloride (CaCl₂), sodium chloride (NaCl), magnesium chloride (MgCl₂), sodium bicarbonate (NaHCO₃), potassium chloride (KCl), sodium sulfate (Na₂SO₄), calcium carbonate (CaCO₃), and calcium phosphate (Ca₃(PO4)₂. In some embodiments, the inorganic salt may be calcium chloride and the formulation may include from about 1% (w/w) to about 10% (w/w) of calcium chloride. In one embodiment, the pharmaceutical formulation may include 3.22% (w/w) of calcium chloride.

The pharmaceutical formulations described herein may include therapeutic agents that include disulfiram. In some embodiments, the therapeutic agents may include azlocillin. In some embodiments, pharmaceutical formulations described herein may include two therapeutic agents. In some embodiments, the two therapeutic agents may include azlocillin and disulfiram. The amount of disulfiram present in the formulation may be from about 0.1% (w/w) to about 10% (w/w) of disulfiram. In some embodiments, the amount of disulfiram in the formulation may be from about 1% (w/w) to about 5% (w/w) of disulfiram. In one embodiment, the pharmaceutical formulation may include 2.26% (w/w) of disulfiram. In one embodiment, the pharmaceutical formulation may include 1.13% (w/w) of disulfiram. The amount of azlocillin present in the formulation may be from about 0.1% (w/w) to about 10% (w/w) of azlocillin. In some embodiments, the amount of azlocillin in the formulation may be from about 1% (w/w) to about 5% (w/w) of azlocillin. In one embodiment, the pharmaceutical formulation may include 2.26% (w/w) of azlocillin. In one embodiment, the pharmaceutical formulation may include 1.13% (w/w) of azlocillin. In some embodiments, the pharmaceutical formulations of the present disclosure may include one or more active agent. In some embodiments, the one or more active agent may include an antibiotic. In some embodiments, the antibiotic may be Doxycycline, Amoxicillin, Ceftriaxone, Vancomycin, Telavancin, Dalbavancin, Fosfomycin, D-Cycloserine, Tunicamycin, Bactrim, or Bacitracin. In some embodiments, the one or more active agent includes a chelator. The chelator may be a copper chelator. In one embodiment, the active agent may be an antibody.

In some embodiments, the present disclosure provides methods of treating a subject having a disease by administering a pharmaceutical formulation described herein. In some embodiments, the pharmaceutical formulation may be administered to the subject at a dose of from about 10 mg/kg to about 200 mg/kg body weight of the subject. In one embodiment, the pharmaceutical formulation may be administered to the subject at a dose of 100 mg/kg body weight of the subject. The disease may include Lyme disease or a Lyme disease related disorder.

Also provided herein are methods of modulating aldehyde dehydrogenase levels in a subject having Lyme disease or a Lyme disease related disorder. The methods may include administering to the subject the pharmaceutical formulations described herein. In some embodiments, the aldehyde dehydrogenase may be selected from the group consisting of ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, ALDH1L2, ALDH2, ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1,

ALDH8A1, and ALDH9A1. In one embodiment, the aldehyde dehydrogenase may be

ALDH5A1. In one embodiment, ALDH5A1 levels may be reduced.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features, and advantages will be apparent from the following description of particular embodiments of the present disclosure, as illustrated in the accompanying drawings. The drawings are not necessarily to scale; emphasis instead being placed upon illustrating the principles of various embodiments of the present disclosure.

Figure 1 shows blood azlocillin levels in mice dosed with azlocillin formulations. Figure 2 shows blood azlocillin levels in rats dosed with azlocillin formulations.

Figure 3A shows total Borrelia levels in ear slice of mice dosed with the different formulations described herein at day 21. Figure 3B shows total Borrelia levels in the bladder of mice dosed with the different formulations described herein at day 21. Figure 3C shows total Borrelia levels in ear slice of mice dosed with the different formulations described herein at day 28. Figure 3D shows total Borrelia levels in the bladder of mice dosed with the different formulations described herein at day 28. Figure 4A provides total serum IgG levels in mice treated with formulations and therapeutic agents described herein. In Figure 4A“*” indicates a p value less 0.05;“**” indicates a p value less than 0.01;“***” indicates a p value less than 0.001. Figure 4B provides total serum IgM levels in mice treated with formulations and therapeutic agents described herein. Figure 4C provides total serum IgA levels in mice treated with formulations and therapeutic agents described herein.

Figure 5 shows Borrelia levels in vitro upon treatment with therapeutic agents. In Figure 5,“Azlocillin/Disulfiram” indicates that the log (CFU/ml) values for disulfiram

completely overlapped with the log (CFU/ml) values for azlocillin.

Figure 6A shows the effect of disulfiram pharmaceutical formulations on ALDH5a1 levels in cultured neurons and brain in vivo. In Figure 6A,“**” indicates a p value less than 0.01. Figure 6B shows the effect of disulfiram pharmaceutical formulations on ALDH1a1 levels in cultured neurons and brain in vivo. In Figure 6B“*” indicates a p value less 0.05. Figure 6C shows the effect of disulfiram pharmaceutical formulations on ALDH1a3 levels in cultured neurons and brain in vivo. In Figure 6C,“**” indicates a p value less than 0.01.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure provides therapeutic agents and pharmaceutical formulations of the therapeutic agents described herein for the treatment of disease. In one embodiment, the disease may be Lyme disease. Also provided herein are methods of treating a subject with Lyme disease by administering to the subject, the pharmaceutical formulations and/or therapeutic agents of the present disclosure. Methods for identifying therapeutic agents are described in International Patent Publication, WO2017124080; the contents of which are herein incorporated by reference in their entirety.

In some embodiments, Lyme disease may be caused by Bsl infection. As used herein the term“Lyme disease” may encompass one or more stages of the disease such as, but not limited to, early localized disease (Stage 1); early disseminated Lyme disease (Stage 2); and/or late disseminated Lyme disease (Stage 3). In some embodiments, the therapeutic agents and pharmaceutical formulations described herein may be useful in treating early localized disease (Stage 1) which may occur from about zero days to about thirty days after the initial Bsl infection and may be characterized by symptoms such as, but not limited to, skin rash (which may or may not look like a bull’s eye), flu-like illness, including chills and fever, fatigue, headache and stiff neck, muscle soreness and joint pain, swollen lymph nodes, and/or sore throat. In some embodiments, the therapeutic agents and pharmaceutical formulations described herein may be useful in treating early disseminated Lyme disease (Stage 2) which may occur from about 30 days to about several weeks after the initial Bsl infection and may be characterized by symptoms such as, but not limited to, chills, fever, headaches, fatigue, pain, weakness or numbness in the arms, legs, vision changes, heart problems, such as palpitations, chest pain, rash may appear on body, facial paralysis (Bell’s palsy). In some embodiments, the therapeutic agents and

pharmaceutical formulations described herein may be useful in treating late disseminated Lyme disease (Stage 3) which may occur week and/or years after the initial Bsl infection and may include symptoms such as, but not limited to, severe fatigue, arthritis in joints or near the point of infection, severe headaches or migraines, vertigo, dizziness, migrating pains in joints/tendons, stiff, aching neck, sleep disturbances, insomnia, disturbances in heart rhythm, mental fogginess, difficulty concentrating, numbness in the arms, legs, hands or feet, difficulty following conversations and/or difficulty processing information.

In some embodiments, therapeutic agents described herein may be useful in the treatment of PTLDS. In some embodiments, therapeutic agents described herein may be useful in the treatment of PTLDS caused by Bsl that persist after antibiotic therapy. In some embodiments, therapeutic agents described herein may be useful in the treatment of PTLDS wherein the subject is resistant to antibiotic therapy.

In one embodiment, therapeutic agents may inhibit, retard, eliminate, and/or reduce the growth of Bsl. In some embodiments, Bsl may include one or more morphological forms such as, but not limited to, spirochete form, cell wall deficient forms, cystic forms, round bodies, spheroplasts, microcolony forms, Bsl with membrane blebs, and/or agglomeration of Bsl into bio-film like colonies and/or any combinations thereof. In some embodiments, Bsl may be spirochetes that may be in the logarithmic growth phase. In one embodiment, Bsl may be in non-growing stationary phase. In some embodiments, the therapeutic agent may inhibit, retard, eliminate, and/or reduce growth of one or more morphological forms of Bsl.

In some embodiments, subjects may be treated with pharmaceutical formulations described herein if the presence of one or more biomarkers associated with PTLDS is

detected. Subjects may be tested for one or more biomarkers prior to the onset of PTLDS. In some embodiments, subjects may be tested for one or more biomarkers after the onset of

PTLDS. Non-limiting examples of biomarkers include immune response to VisE membrane- proximal epitopes in PTLDS patients, innate acute C-reactive protein, T-cell chemokine

CCL19, and/or the presence of TLR1-1805GG polymorphism. I. THERAPEUTIC AGENTS

The present disclosure provides formulations for the treatment of diseases such as, but not limited to, Lyme disease. In one embodiment, treatment of the disease in a subject may involve administering an effective amount of a therapeutic agent to a subject. In some embodiments, the therapeutic agent may be disulfiram, azlocillin, penicillin, thiuram, and/or any derivates and/or any combinations of thereof.

In some embodiments, the therapeutic agent may interact with and/or inhibit Bsl proteins such as, but not limited to, OspA, OspB, OspC, OspD, OspE, OspF, DbpA, DbpB, CspA, VlsE, BptA, P13, P66, BesC, BamA, Lmp1 and/or BB0405.

In some embodiments, the therapeutic agent may interact with and/or inhibit Bsl lipids such as, but not limited to, Cholesteryl 6-O-acyl-ȕ-D-galactopyranoside or cholesteryl 6-O-palmitoyl-ȕ-D-galactopyranoside (ACGal/Bb-GL-I), cholesteryl-ȕ-D-galacto-pyranoside (CGal), and/or mono-Į-galactosyl-diacylglycerol (MGalD).

Disulfiram

In some embodiments, the therapeutic agent may be disulfiram. Disulfiram is an FDA approved compound for the treatment of alcohol abuse sold under the tradename“Antabuse”. When orally administered, disulfiram may be rapidly converted, to bis (diethyldithiocarbamato) copper complex (Johansson B; Acta Psychiatr Scand Suppl.1992;369:15-26; the contents of which are herein incorporated by reference in its entirety). Both disulfiram and its metabolite may be absorbed via the gastrointestinal mucosa and distributed into the blood stream. In the blood, both the disulfiram and bis (diethyldithiocarbamato) copper complex may be rapidly degraded to form diethyldithiocarbamic acid (DDC), which may be unstable and may be further degraded to form diethylamine and carbon disulphide. DDC may also be a substrate of phase II metabolism, which involves formation of diethyldithiomethylcarbamate (Me-DDC) and the glucuronic acid of DDC. Me-DDC may also undergo oxidative biotransformation to

diethylthiomethylcarbamate (Me-DTC), which may be further oxidized to its corresponding sulfoxide and sulfone metabolites. Me-DTC may act as an irreversible inhibitor of aldehyde dehydrogenases (ALDH1), whereas the sulfoxide and sulfone metabolites, especially the sulfone metabolite, may be more potent inhibitors of both ALDH 1, and ALDH2. Both ALDH1 and ALDH2 are key enzymes involved in metabolism of alcohol. Thus disulfiram may be considered a prodrug in the context of its use in the treatment of alcohol abuse. In one embodiment, the pharmaceutical formulations described herein may prevent the metabolism of disulfiram to bis (diethyldithiocarbamato) copper complex. In one embodiment, the pharmaceutical formulations described herein may prevent the metabolism of disulfiram to diethyldithiocarbamic acid (DDC). In one embodiment, the pharmaceutical formulations described herein may prevent the metabolism of disulfiram to diethylamine and carbon disulfide. In one embodiment, the pharmaceutical formulations described herein may prevent the metabolism of disulfiram to diethyldithiomethylcarbamate (Me-DDC) and the glucuronic acid of DDC. In one embodiment, the pharmaceutical formulations described herein may prevent the metabolism of disulfiram to diethylthiomethylcarbamate (Me-DTC).

In one embodiment, the therapeutic agent may be bis (diethyldithiocarbamato) copper complex. In one embodiment, the therapeutic agent may be diethyldithiocarbamic acid (DDC). In one embodiment, the therapeutic agent may be diethylamine and/or carbon disulfide. In one embodiment, the therapeutic agent may be diethyldithiomethylcarbamate (Me-DDC) and/or the glucuronic acid of DDC. In one embodiment, the therapeutic agent may be

diethylthiomethylcarbamate (Me-DTC).

In some embodiments, diethyldithiocarbamate (DDC) a metabolite generated following administration of disulfiram may be used to treat chronic alcoholism. In some embodiments, disulfiram may inhibit acetaldehyde dehydrogenase 1 (ALDH1). In some embodiments, disulfiram may be used as a metal chelator since its metabolite DDC may form a copper complex at a 2:1 mole ratio (DDC:Cu2+).

The bactericidal effects of disulfiram against Borrelia spp. have been reported in vitro where disulfiram may likely not be metabolized into Me-DTC, and/or its sulfoxide and sulfone metabolites, suggesting that disulfiram may be the active agent in the context of its bactericidal activity (Pothineni, V.R. et al. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening. Drug Des. Dev. Ther.2016, 10, 1307–1322 ). The efficacy of disulfiram in vivo have been described in International Patent Publication, WO2017124080; and Liegner KB. Antibiotics (Basel).2019;8(2):72 (the contents of each of which are incorporated by reference in their entirety). The rapid metabolism of orally administered disulfiram may limit the efficacy of disulfiram for the treatment of diseases such as Lyme disease. In one embodiment, the present disclosure provides formulations that may increase the half-life of the disulfiram administered to a subject. In one embodiment, pharmaceutical formulations of the present disclosure may prevent the absorption of disulfiram in the stomach. In one embodiment, disulfiram pharmaceutical formulations may be absorbed in the intestine. In one embodiment, disulfiram pharmaceutical formulations may be absorbed in the lower ileum/ upper colon to prevent/slow first pass hepatic metabolism. In some embodiments, disulfiram may modulate the activity and/or levels of TNF alpha receptor, TRADD, NFNB, STAT3, RhoA, FLIP, FADD, bilirubin, transaminases, and/or caspases.

In some embodiments, disulfiram may modulate the activity and/or levels of GABA, GPR91, and/or IL1 beta.

In some embodiments, disulfiram may modulate the activity and/or levels of succinate dehydrogenase, succinic semialdehyde, and/or aldehyde dehydrogenase.

In some embodiments, disulfiram may modulate the activity and/or levels of aldehyde dehydrogenases such as, but not limited to, ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, ALDH1L2, ALDH2, ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, ALDH4A1, ALDH5A1, ALDH6A1, ALDH7A1, ALDH8A1, ALDH9A1, ALDH16A1, and/or ALDH18A1.

In some embodiments, presence of Bsl in a subject may result in a decrease in gamma- aminobutyric acid (GABA) and an increase in lactate among GABA-nergic neurons, astrocytes, and microglia in the Borrelia-infected mouse brain.

In some embodiments, treatment with disulfiram may result in a decrease in gamma- aminobutyric acid (GABA) and an increase in lactate among GABA-nergic neurons, astrocytes, and microglia in the Borrelia-infected mouse brain.

In some embodiments, disulfiram may interact with and/or inhibit Bsl proteins such as, but not limited to, OspA, OspB, OspC, OspD, OspE, OspF, DbpA, DbpB, CspA, VlsE, BptA, P13, P66, BesC, BamA, Lmp1 and/or BB0405.

In some embodiments, disulfiram may interact with and/or inhibit Bsl lipids such as, but not limited to, Cholesteryl 6-O-acyl-ȕ-D-galactopyranoside or cholesteryl 6-O- palmitoyl-ȕ-D-galactopyranoside (ACGal/Bb-GL-I), cholesteryl-ȕ-D-galacto-pyranoside (CGal), and/or mono-Į-galactosyl-diacylglycerol (MGalD).

In one embodiment, disulfiram may be formulated with ethyl cellulose (EAC). The EAC- disulfiram formulation may restrict the availability of disulfiram to the liver.

Table 1 provides the chemical structure of disulfiram. Table 1: Disulfiram Structure

In some embodiments, disulfiram may be administered at a concentration of 1.25 mg/mL, 2.5 mg/mL, 5 mg/mL, 10 mg/mL, 20 mg/mL, 40 mg/mL, and/or 80 mg/mL. Disulfiram administered may be administered at a concentration ranging from about 1-100 mg/mL, from about 1 mg/mL to about 10 mg/mL; from about 5 mg/mL to about 15 mg/mL; from about 10 mg/mL to about 20 mg/mL; from about 15 mg/mL to about 25 mg/mL; from about 20 mg/mL to about 30 mg/mL; from about 25 mg/mL to about 35 mg/mL; from about 30 mg/mL to about 40 mg/mL; from about 35 mg/mL to about 45 mg/mL; from about 40 mg/mL to about 50 mg/mL; from about 45 mg/mL to about 55 mg/mL; from about 50 mg/mL to about 60 mg/mL; from about 55 mg/mL to about 65 mg/mL; from about 60 mg/mL to about 70 mg/mL; from about 65 mg/mL to about 75 mg/mL; from about 70 mg/mL to about 80 mg/mL; from about 75 mg/mL to about 85 mg/mL; from about 80 mg/mL to about 90 mg/mL; from about 85 mg/mL to about 95 mg/mL; and/or from about 90 mg/mL to about 100 mg/mL. Thiuram disulfide analogs

In one embodiment, therapeutic agents of the present disclosure may include chemical analogs of thiuram disulfide. Non-limiting examples of thiuram disulfide analogs are described in Table 2. In one embodiment, the therapeutic agent may be tetraisononyl thiuram disulfide (TINTD). Any of the thiuram analogs described in European Patent Publication EP0588559 may be used as therapeutic agents in the present disclosure (the contents of which are herein incorporated by reference in their entirety). Table 2: Thiuram disulfide analogs:

Azlocillin and penicillin derivatives

In some embodiments, the therapeutic agent may be azlocillin. Azlocillin is a broad spectrum penicillin antibiotic. Bactericidal effects of azlocillin against Borrelia spp. have been reported by Pothineni et al.2017 (Pothineni, V.R. et al. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening. Drug Des. Dev. Ther.2016, 10, 1307–1322; the contents of which are incorporated by reference in their entirety). The present disclosure provides formulations that may increase the half-life of the azlocillin administered to a subject.

In some embodiments, therapeutic agents of the present disclosure may include derivatives of penicillin. Non-limiting examples of penicillin derivatives include but are not limited to Ampicillin, Amoxicillin, Hetacillin, Methicillin, Cloxacillin, Dicloxacillin, Nafcillin, Oxacillin, Carbenicillin, Mezlocillin, Piperacillin, and/or Ticarcillin.

In some embodiments, azlocillin may be administered at a concentration ranging from about 1-50 mg/mL, from about 1 mg/mL to about 10 mg/mL; from about 5 mg/mL to about 15 mg/mL; from about 10 mg/mL to about 20 mg/mL; from about 15 mg/mL to about 25 mg/mL; from about 20 mg/mL to about 30 mg/mL; from about 25 mg/mL to about 35 mg/mL; from about 30 mg/mL to about 40 mg/mL; from about 35 mg/mL to about 45 mg/mL; and/or from about 40 mg/mL to about 50 mg/mL. Combinations

In some embodiments, two or more therapeutic agents may be administered in a combinatorial format. Combinations may be administered concurrently, sequentially and/or serially. In one embodiment, each therapeutic agent in a combination may be formulated as separate pharmaceutical formulations. In one embodiment, the therapeutic agents in a

combination may be prepared as single pharmaceutical formulation.

As a non-limiting example, therapeutic agents, disulfiram and azlocillin may be administered in a combinatorial format. In some embodiments, disulfiram administered in a combinatorial format may be administered at a concentration of 1.25 mg/mL, 2.5 mg/mL, 5 mg/mL, 10 mg/mL, 20 mg/mL, 40 mg/mL, and/or 80 mg/mL. Disulfiram administered in a combinatorial format may be administered at a concentration ranging from about 1-100 mg/mL, from about 1 mg/mL to about 10 mg/mL; from about 5 mg/mL to about 15 mg/mL; from about 10 mg/mL to about 20 mg/mL; from about 15 mg/mL to about 25 mg/mL; from about 20 mg/mL to about 30 mg/mL; from about 25 mg/mL to about 35 mg/mL; from about 30 mg/mL to about 40 mg/mL; from about 35 mg/mL to about 45 mg/mL; from about 40 mg/mL to about 50 mg/mL; from about 45 mg/mL to about 55 mg/mL; from about 50 mg/mL to about 60 mg/mL; from about 55 mg/mL to about 65 mg/mL; from about 60 mg/mL to about 70 mg/mL; from about 65 mg/mL to about 75 mg/mL; from about 70 mg/mL to about 80 mg/mL; from about 75 mg/mL to about 85 mg/mL; from about 80 mg/mL to about 90 mg/mL; from about 85 mg/mL to about 95 mg/mL; and/or from about 90 mg/mL to about 100 mg/mL.

In some embodiments, azlocillin administered in a combinatorial format may be administered at a concentration ranging from about 1-50 mg/mL, from about 1 mg/mL to about 10 mg/mL; from about 5 mg/mL to about 15 mg/mL; from about 10 mg/mL to about 20 mg/mL; from about 15 mg/mL to about 25 mg/mL; from about 20 mg/mL to about 30 mg/mL; from about 25 mg/mL to about 35 mg/mL; from about 30 mg/mL to about 40 mg/mL; from about 35 mg/mL to about 45 mg/mL; and/or from about 40 mg/mL to about 50 mg/mL.

In some embodiments, the therapeutic agents may be formulated and/or administered with one or more additional active agents. In one embodiment, the additional active agent may be an antibiotic. Non-limiting examples of antibiotics include as doxycycline, azithromycin, clarithromycin, and/or erythromycin.

In some embodiments, additional active agent may be vaccine against Borrelia species. In one embodiment, vaccines that stimulate the production of humoral immune response to Borrelia species may be used. The antigen comprising the vaccine preparation may be native or recombinantly produced toxin proteins from Bb, as well as other species (e.g. B. garinii, and B. afzelii).

In some embodiments, therapeutic agents may be formulated with and/or administered with one or more additional active agents such as divalent transition metals. Non-limiting examples of divalent transition metals may include copper, zinc, iron, and/or gold. In one embodiment, the additional active agents may include copper gluconate, copper citrate, copper chloride, zinc gluconate, zinc chloride, and/or zinc citrate.

In some embodiments, the therapeutic agents of the present disclosure may be formulated and/or administered with additional active agents such as chelators or chelating agents. As used herein, the term“chelators” refers to chemical compounds that interact with metal ions to form stable complexes. As a result, the metal ions are no longer available to interact with other compounds or chemicals. As non-limiting examples, chelators of the present disclosure may interact with metal ions such as, but not limited to, copper, iron, silver, zinc, calcium, mercury, and/or silver. In one embodiment, the therapeutic agents may be formulated and/or administered with copper chelators. Non-limiting examples of copper chelators include D- penicillamine (D-pen), Trentine (Triethylenetetramine, Trien), Nitrilotriacetic acid, and/or ammonium tetrathiomolibdate (TTM). In one embodiment, the therapeutic agents of the present disclosure may be formulated with chelators are designated by the Food and Drug Administration as“generally regarded as safe” (GRAS).

In some embodiments, the therapeutic agent may be formulated with and/or co- administered with one or more antibiotics. As used herein, the term,“antibiotic” refers to any substance that inhibits the growth and replication of a bacterium and/or kills the bacterium. The antibiotic may a beta lactam antibiotic, an aminoglycoside, a glycopeptide, an ansamycin, a streptogramin, a sulfonamide, a macrolide, an oxazolidinone, a peptidoglycan, a quinolone, and/or a lipopeptide.

In some embodiments, the antibiotic may be a beta lactam antibiotic. As used herein, the term“beta lactam” refers to any antibiotic that includes a 4 member cyclic amide based lactam ring. In some embodiments, beta lactam antibiotics inhibit cell wall synthesis of Bsl. In one embodiment, the therapeutic agent may be formulated with and/or co-administered with one or more beta lactam antibiotics.

Non-limiting examples of antibiotics include Doxycycline, Amoxicillin, Ceftriaxone, Vancomycin, Telavancin, Dalbavancin, Fosfomycin, D-Cycloserine, Tunicamycin, Bactrim and/or Bacitracin. In some embodiments, the therapeutic agents may be formulated with and/or co- administered with one or more active agents that can disrupt the biofilm of Borrelia spp.

In some embodiments, the therapeutic agent may be formulated with and/or co- administered with one or more antibiotics such as, but not limited to, Miconazole, Camptothecin, Hydroxytamoxifen, Deacetylbaccatin III, , Actinomycin D, Actinonin, Acycloguanosine, Adenine 9-ȕ-D-arabinofuranoside, Alamethicin, Albendazole, Amastatin hydrochloride hydrate, Amikacin (Amikin), Amikacin disulfate, Amikacin hydrate, Amoxicillin (Novamox, Amoxil), Amoxicillin, clavulanate (Augmentin), Amphotericin B, Ampicillin, Ampicillin (Principen), Ampicillin/sulbactam (Unasyn), Anhydroerythromycin A, Anisomycin, Antimycin A,

Aphidicolin, Apicidin, Apoptolidin A, Apramycin, Arsphenamine (Salvarsan), Artesunate, Ascochlorin, Ascomycin, Azaserine, Azithromycin (Zithromax, Sumamed, Xithrone), azlocillin, Aztreonam (Azactam), Bacitracin, Bactenecin, Bafilomycin A1, Bestatin hydrochloride, Bithionol, Blasticidine, Bleomycin, BM-Cyclin, Borrelidin, Brefeldin A, Caerulomycin, Calcium ionophore, Capreomycin (Capastat), Carbacephem, Carbenicillin disodium, Cecropin, Cefaclor (Distaclor, Ceclor, Raniclor), Cefadroxil (Duricef), Cefalexin (Keflex), Cefamandole, Cefazolin, Cefazolin (Ancef, Kefzol), Cefdinir (Omnicef, Cefdiel), Cefditoren (Spectracef, Meiact), Cefepime (Maxipime), Cefixime (Cefspan, Suprax), Cefmetazole, Cefonicid, Cefoperazone (Cefobid), Cefotaxime (Claforan), Cefotaxime sodium, Cefotetan (Ceftan), Cefoxitin,

Cefpodoxime (Vantin, Banadoz), Cefprozil (Cefzil), Cefsulodin, Ceftazidime, Ceftazidime (Fortaz, Ceptaz), Ceftibuten (Cedax), Ceftizoxime, Ceftobiprole (Zeftera), Ceftriaxone,

Ceftriaxone (Rocephin), Cefuroxime (Ceftin, Zinnat), Cephalexin hydrate, Cephalomannine, Cephalothin, Cephapirin, Cephradine, Cercosporin, Cerulenin, Cetylpyridinium chloride, Chloramphenicol, Chloramphenicol(Bs) (Chloromycetin), Chlorhexidine, Chloroquine,

Chlortetracycline, Chromomycin, Chrysomycin, Cinnamycin, Cinoxacin, Ciprofloxacin, Ciprofloxacin (Cipro, Ciproxin, Ciprobay), cis-Diamineplatinum(II) dichloride, Clarithromycin (Biaxin), Clindamycin (Cleocin), Clindamycin 2-phosphate, Clofazimine (Lamprene),

Clotrimazole, Cloxacillin sodium salt, Colistin (Coly-Mycin-S), Colominic acid, Concanamycin A, Cordycepin, Coumermycin A1, Cryptotanshinone, Cycloheximide, Cycloserine (Seromycin), Cyclosporin A, Cyclosporin C, Cytochalasin B, Cytochalasin D, Dacarbazine, Dalbavancin (Dalvance), Dapsone (Avlosulfon), Daptomycin (Cubicin), Daunorubicin hydrochloride, D- Cycloserine, Defensin HNP-1, Defensin HNP-2, Demeclocycline, Demeclocycline

(Declomycin), Dichlorophene, Dicloxacillin, Dicloxacillin (Dynapen), Diethylcarbamazine, Difloxacin hydrochloride, Dihydrostreptomycin sesquisulfate, Dimetridazole, Diminazene, Dirithromycin, Doripenem (Doribax), Doxorubicin, Doxycycline, Doxycycline (Vibramycin), Duramycin, Econazole, Elafin, Embelin, Emetine, Enoxacin (Penetrex), Enrofloxacin, Ertapenem (Invanz), Erythromycin, Erythromycin (Erythocin, Erythroped), Ethambutol dihydrochloride, Ethambutol(Bs) (Myambutol), Ethionamide (Trecator), Etoposide, Fengycin, Fidaxomicin (Dificid), Filipin, Florfenicol, Flubendazol, Flucloxacillin (Floxapen), Fluconazole, Flumequine, Flurbiprofen cyclooxygenase inhibitor, Formycin A, Fosfomycin (Monurol, Monuril),

Fumagillin, Furazolidone, Furazolidone (Furoxone), Fusaric acid, Fusidic acid (Fucidin), G 418 , Ganciclovir, Gatifloxacin (Tequin), Geldanamycin, Gemifloxacin (Factive), Gentamicin, Gentamicin (Garamycin), Gliotoxin, Glycopeptides, Gramicidin A, Gramicidin C, Grepafloxacin (Raxar), Griseofulvin, Herbimycin, Herbimycin A, Hygromycin B, Ikarugamycin , Imipenem, Imipenem/Cilastatin (Primaxin), Ionomycin, Irgasan, Isoniazid (I.N.H.), Itraconazole, Iturin A , Ivermectin, Josamycin, K-252a, Kanamycin , Kanamycin (Kantrex), Kasugamycin, Kendomycin, Ketoconazole, Kirromycin, Lactoferricin B, L-Alanyl-L-1-aminoethylphosphonic acid,

Leptomycin A, Leptomycin B, Levamisol, Levofloxacin, Levofloxacin (Levaquin), Lincomycin (Lincocin), LL-37 , Lomefloxacin, Lomefloxacin (Maxaquin), Loracarbef, Loracarbef (Lorabid), Lysobactin, Lysostaphin, Mafenide (Sulfamylon), Magainin, Mebendazole, Meclocycline , Meropenem (Merrem), Metacycline, Methicillin (Staphcillin), Metronidazole, Metronidazole (Flagyl), Mevastatin, Mezlocillin (Mezlin), Minocycline (Minocin), Minocycline hydrochloride, Mithramycin A, Mitomycin C, Monensin , Moxalactam, Moxalactam sodium salt, Moxifloxacin (Avelox), Mupirocin (Bactroban), Myxothiazol, Nadifloxacin, Nafcillin (Unipen), Naftifine , Nalidixic , Nalidixic acid (NegGram), Narasin , Neomycin , Neomycin (Neo-Fradin), Netilmicin (Netromycin), Netilmicin sulfate salt, Netropsin , Nicarbazin, Niclosamide, Nigericin ,

Nikkomycin Z, Nisin, Nitrofurantoin , Nitrofurantoin(Bs) (Macrodantin, Macrobid), N-Methyl-1- deoxynojirimycin, Nonactin , Norfloxacin , Norfloxacin (Noroxin), Nourseothricin , Novobiocin , Nystatin, Ochratoxin A , Ofloxacin (Floxin, Ocuflox), Ofloxacin fluoroquinolone antibiotic, Oligomycin A , Oritavancin (Orbactiv), Oxacillin (Prostaphlin), Oxacillin sodium salt, Oxantel pamoate , Oxolinic acid , Oxytetra, Oxytetracycline , Oxytetracycline (Terramycin),

Oxytetracycline hydrochloride, Paclitaxel, Paromomycin, Paromomycin , Paromomycin

(Humatin), Patulin, Pediocin , Pefloxacin, Penicillin , Penicillin G , Penicillin G (Pentids), Penicillin G (Pfizerpen), Penicillin G sodium salt, Penicillin V (Veetids), Pentamidine

isethionate, PGLa, Phenazine methosulfate, Phenoxymethylpenicillinic acid, Phleomycin, Phosphomycin , Pimaricin, Pipemidic acid, Piperacillin (Pipracil), Piperacillin/tazobactam (Zosyn), Pirarubicin , Platensimycin, Poly(vinylpyrrolidone), Polymyxin B, Posizolid, Potassium clavulanate: silicon dioxide, Potassium clavulanate:cellulose (1:1), Praziquantel, Praziquantel , Prothionamide, Puromycin , Puromycin aminonucleoside, Pyrantel pamoate , Pyrantel pamoate B, Pyrazinamide (Aldinamide), Pyrazinecarboxamide, Pyronaridine tetraphosphate, Pyrrolnitrin, Quinine, Quinine sulfate, Quinupristin/Dalfopristin (Synercid), Radezolid, Radicicol,

Ramoplanin, Rapamycin, Reveromycin A , Ribavirin antiviral, Ribostamycin , Rifabutin

(Mycobutin), Rifampicin (Rifampin in US) (Rifadin, Rimactane), Rifamycin , Rifapentine (Priftin), Rifaximin, Rifaximin (Xifaxan), Ristomycin monosulfate, Roxithromycin,

Salinomycin, Silver sulfadiazine (Silvadene), Sinefungin, Sisomicin , Sorbic acid, Sordarin, Sparfloxacin, Sparfloxacin (Zagam), Spectinomycin(Bs) (Trobicin), Spergualin, Spiramycin (Rovamycine), Staurosporine, Streptolysin, Streptomycin, Streptomycin solution , Streptonigrin, Streptozocin, Succinylsulfathiazole, Sulfabenzamide , Sulfacetamide , Sulfacetamide (Sulamyd, Bleph-10), Sulfachloropyridazine, Sulfachloropyridazine , Sulfadiazine (Micro-Sulfon),

Sulfadimethoxine , Sulfadimethoxine (Di-Methox, Albon), Sulfadoxin , Sulfaguanidine,

Sulfameter, Sulfamethazine, Sulfamethizole (Thiosulfil Forte), Sulfamethoxazole (Gantanol), Sulfamonomethoxine, Sulfanilamide, Sulfanilimide (archaic), Sulfanitran , Sulfaquinoxaline, Sulfasalazine, Sulfasalazine (Azulfidine), Sulfathiazole, Sulfisoxazole (Gantrisin),

Sulfonamidochrysoidine (archaic) (Prontosil), Surfactin, Swainsonine, Tamoxifen, Tazobactam, Teicoplanin, Teicoplanin (Targocid), Telavancin (Vibativ), Telithromycin (Ketek), Temafloxacin (Omniflox), Temocillin (Negaban), Terbinafine, Terconazole, Tetracycline (Sumycin,

Achromycin V, Steclin), Tetramisole hydrochloride, Thiamphenicol, Thimerosal, Thiolutin, Thiostrepton, Thio-TEPA, Thymol, Tiamulin, Ticarcillin, Ticarcillin/clavulanate (Timentin), Tigecycline(Bs) (Tigacyl), Tinidazole (Tindamax Fasigyn), Tioconazole, Tobramycin (Nebcin), Tolnaftate, Torezolid (Sivextro), Toyocamycin, Trichlorfon, Trimethoprim(Bs) (Proloprim, Trimpex), Trimethoprim-Sulfamethoxazole (Co-trimoxazole) (TMP-SMX) (Bactrim, Septra), Trovafloxacin (Trovan), Tubercidin, Tunicamycin, Tylosin, Valacyclovir, Vancomycin

(Vancocin), Vinblastine sulfate salt, Virginiamycin M1 , Virginiamycin S1.

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as any of the antibiotics described by Wu et al. (Wu, X et al. Antimicrob agents chemother vol.62,11 e01201-18.24 Oct.2018; the contents of which are herein incorporated by reference in their entirety).

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as one or more anticancer drugs. The anticancer drugs may be selected from: a tumor angiogenesis inhibitor (e.g., a protease inhibitor, an epidermal growth factor receptor kinase inhibitor, or a vascular endothelial growth factor receptor kinase inhibitor); a cytotoxic drug (e.g., an antimetabolite, such as purine and pyrimidine analog antimetabolites); an antimitotic agent (e.g., a microtubule stabilizing drug or an antimitotic alkaloid); a platinum coordination complex; an anti-tumor antibiotic; an alkylating agent (e.g., a nitrogen mustard or a nitrosourea); an endocrine agent (e.g., an adrenocorticosteroid, an androgen, an anti-androgen, an estrogen, an anti-estrogen, an aromatase inhibitor, a gonadotropin-releasing hormone agonist, or a somatostatin analog); or a compound that targets an enzyme or receptor that is overexpressed and/or otherwise involved in a specific metabolic pathway that is dysregulated in the tumor cell (e.g., ATP and GTP phosphodiesterase inhibitors, histone deacetylase inhibitors, protein kinase inhibitors (such as serine, threonine and tyrosine kinase inhibitors, e.g., Abelson protein tyrosine kinase inhibitors), various growth factors, their receptors and corresponding kinase inhibitors (such as epidermal growth factor receptor kinase inhibitors, vascular endothelial growth factor receptor kinase inhibitors, fibroblast growth factor inhibitors, insulin-like growth factor receptor inhibitors and platelet-derived growth factor receptor kinase inhibitors)); methionine,

aminopeptidase inhibitors, proteasome inhibitors, cyclooxygenase inhibitors (e.g.,

cyclooxygenase-1 or cyclooxygenase-2 inhibitors), topoisomerase inhibitors (e.g., topoisomerase I inhibitors or topoisomerase II inhibitors), poly ADP ribose polymerase inhibitors (PARP inhibitors), and/or epidermal growth factor receptor (EGFR) inhibitors/antagonists.

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as one or more alkylating agents. Non-limiting examples of alkylating agents include nitrogen mustard (such as cyclophosphamide, mechlorethamine (chlormethine), uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, or

trofosfamide), a nitrosourea (such as carmustine, streptozocin, fotemustine, lomustine, nimustine, prednimustine, ranimustine, or semustine), an alkyl sulfonate (such as busulfan, mannosulfan, or treosulfan), an aziridine (such as hexamethylmelamine (altretamine), triethylenemelamine, 7KLR7(3$^^ȃ^ȃ^ȃ^-triethylenethiophosphoramide), carboquone, or triaziquone), a hydrazine (such as procarbazine), a triazene (such as dacarbazine), or an imidazotetrazine (such as temozolomide).

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as one or more platinum coordination agents. Non-limiting examples of platinum coordination agents include, cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, or triplatin tetranitrate.

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as one or more cytotoxic agents. Non-limiting examples of cytotoxic agents include antimetabolite, including folic acid analog antimetabolites (such as aminopterin, methotrexate, pemetrexed, or raltitrexed), purine analog antimetabolites (such as cladribine, clofarabine, fludarabine, 6-mercaptopurine (including its prodrug form azathioprine), pentostatin, or 6-thioguanine), and pyrimidine analog antimetabolites (such as cytarabine, decitabine, 5-fluorouracil (including its prodrug forms capecitabine and tegafur), floxuridine, gemcitabine, enocitabine, or sapacitabine).

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as one or more anti-tumor antibiotic. Non-limiting examples include, an anthracycline (such as aclarubicin, daunorubicin, doxorubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, or zorubicin), an anthracenedione (such as mitoxantrone, or pixantrone) or an anti-tumor antibiotic isolated from Streptomyces (such as actinomycin

(including actinomycin D), bleomycin, mitomycin (including mitomycin C), or plicamycin).

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as one or more biological agents. Non-limiting examples of biological agents include antibodies, antibody fragments, antibody constructs (for example, single-chain constructs), and/or modified antibodies (such as CDR-grafted antibodies, humanized antibodies, "full humanized" antibodies.) directed against cancer or tumor

markers/factors/cytokines involved in proliferative diseases can be employed in co-therapy approaches with the compounds of the drug combination of the present disclosure. Examples of such biological agents include anti-HER2 antibodies (e.g. trastuzumab, Herceptin^®), anti-CD20 antibodies (e.g. Rituximab, Rituxan^®, MabThera^®, Reditux^®), anti-CD19/CD3 constructs (see, e.g., EP1071752) and anti-TNF antibodies (see, e.g., Taylor PC. Antibody therapy for rheumatoid arthritis. Curr Opin Pharmacol.2003. 3(3):323-328). Further antibodies, antibody fragments, antibody constructs and/or modified antibodies to be used in co-therapy approaches with the compounds of the drug combination of the disclosure can be found, in Taylor PC. Curr Opin Pharmacol.2003.3(3):323-328; or Roxana A. Maedica.2006.1 (1 ):63-65 (the contents of each of which are herein incorporated by reference in their entirety). In one embodiment, the antibody may be an anti-TM4SF1 antibody as described in the international patent publication NO. WO2019046338 (the contents of which are herein incorporated by reference its entirety).

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as anti-androgens Antiandrogens constitute an established class of agents that antagonize, block or prevent androgen receptor signaling. The term

"antiandrogen" thus refers, in particular, to an androgen receptor antagonist (AR antagonist) and/or an androgen receptor signaling antagonist (AR signaling antagonist). The antiandrogen may be a steroidal antiandrogen or a non-steroidal antiandrogen, and is preferably a non-steroidal antiandrogen. Exemplary antiandrogens include, flutamide, nilutamide, bicalutamide, enzalutamide, 2-hydroxyflutamide, BMS-641988, ARN-509, ketoconazole, PF-998425, R2956, cyproterone, cyproterone acetate, benorterone, galeterone, megestrol acetate, mifepristone, chlormadinone acetate, delanterone, dienogest, drospirenone, epitestosterone, inocoterone, metogest, nomegestrol, nomegestrol acetate, nordinone, norgestimate, osaterone, oxendolone, rosterolone, topterone, zanoterone, RU-58642, RU-58841 , and pharmaceutically acceptable salts and solvates of any one of these agents.

In some embodiments, the therapeutic agents may be formulated and/or administered with additional active agents such as Vitamin K antagonists, a class of agents that suppress or reduce the action of vitamin K by inhibiting the conversion of oxidized vitamin K (i.e., vitamin K 2,3-epoxide) to its active reduced form (i.e., vitamin K hydroquinone), by inhibiting the enzyme vitamin K epoxide reductase (EC 1.17.4.4; previously EC 1.1.4.1 ) or vitamin K epoxide reductase complex subunit 1 (VKORC1 ). The term "vitamin K antagonist" may refer, to a vitamin K epoxide reductase inhibitor, and/or a vitamin K epoxide reductase complex subunit 1 inhibitor (VKORC1 inhibitor). In some embodiments, the vitamin K antagonist to be used in accordance with the present disclosure may be, 4-hydroxycoumarin derivative or a 1 ,3- indandione derivative, phenprocoumon, dicoumarol, acenocoumarol, warfarin, ethyl

biscoumacetate, anisindione, phenindione, clorindione, fluindione, 1 -N-methyl-5-thiotetrazole, 5,5'-dithiobis(1 -methyltetrazole), disulfiram, and N-ethylmaleimide.

In some embodiments, the pharmaceutical formulations of the present disclosure may include therapeutic agents such as disulfiram and additional active agents such as, but not limited to, doxorubicin, paclitaxel as described by Tao et al. and Mohammed et al. (Tao et al. Biomater Sci.2018 Jun 25;6(7):1869-1881; and Mohammed et al. Pharm Res.2018 Feb 27;35(4):77; the contents of each of which are herein incorporated by reference in its entirety).

In some embodiments, the therapeutic agents of the present disclosure may be formulated and/or administered with any of the additional active agents described in US Patent No. US 10, 322, 096; US Patent Publication Nos. US20070232692, US20120101154,

US20170281536, US20190117595 and/or International Patent Publication Nos. WO1997005867, WO2008068746, WO2011107755, WO2012024616, WO2012050594, WO2012050594, WO2012076897, WO2013123426, WO2014015157, WO2014102801, WO2014172435, WO2016004218, WO2016170102, WO2016201350, WO2017077336, WO2017095738, and/or WO2017100925 (the contents of each of which are herein incorporated by reference in their entirety).

In some embodiments, the therapeutic agents described herein may be formulated with and/or administered with agents that modulate the activity and/or levels of succinate

dehydrogenase. In some embodiments, the therapeutic agents described herein may be formulated with and/or administered with agents that modulate the activity and/or levels of TNF alpha receptor, TRADD, NFNB, STAT3, RhoA, FLIP, FADD, bilirubin, transaminases, and/or caspases.

In some embodiments, the therapeutic agents described herein may be formulated with and/or administered with agents that modulate the activity and/or levels of GABA, GPR91, and/or IL1 beta.

dehydrogenase, succinic semialdehyde, and/or aldehyde dehydrogenase.

In some embodiments, the therapeutic agents described herein may be formulated with and/or administered with agents that modulate the activity and/or levels of aldehyde

dehydrogenases translated from ALDH mRNA transcripts described herein such as, but not limited to, (i) ALDH1A1 (RefSeq Accession: NM_000689.5; GI: 1519246465); (ii) ALDH1A2 (RefSeq Accession: NM_003888.4; GI: 1519246438); (iii) ALDH1A3 (RefSeq Accession: NM_000693.4; GI: 1519315793); (iv) ALDH1B1(RefSeq Accession: NM_000692.5; GI:

1519315462); (v) ALDH1L1 (RefSeq Accession: NM_012190.4; GI: 1677499365), (vi) ALDH1L2 (RefSeq Accession: NM_001034173.4; GI: 1519242402); (vii) ALDH2 (RefSeq Accession: NM_001204889.2; GI: 1675176138); (viii) ALDH3A1(RefSeq Accession:

NM_001330150.2; GI: 1675144729); (ix) ALDH3A2 (RefSeq Accession: NM_000382.3; GI: 1595488117); (x) ALDH3B1 (RefSeq Accession: NM_001161473.3; GI: 1674986225); (xi) ALDH3B2 (RefSeq Accession: NM_001031615.2; GI: 1229385646); (xii) ALDH4A1 (RefSeq Accession: NM_003748.4; GI: 1519245769); (xiii) ALDH5A1 (RefSeq Accession:

NM_170740.1; GI: 25777720); (xiv) ALDH6A1(RefSeq Accession: NM_005589.4; GI:

1653961765); (xv)ALDH7A1 (RefSeq Accession: NM_001182.5; GI: 1519473752); (xvi) ALDH8A1 (RefSeq Accession: NM_022568.4; GI: 1519246208); and/or (xvii) ALDH9A1 (RefSeq Accession: Accession: NM_000696.3; GI: 115387103.

II. PHARMACEUTICAL FORMULATIONS

In some embodiments, the therapeutic agents described herein may be formulated with any of the excipients described herein for administration and delivery to subjects. In some embodiments, the therapeutic agents may not be formulated with any of the excipients described herein.

In some embodiments, formulations may be administered to humans, human patients, healthy volunteers, or any other subjects. Pharmaceutical formulations described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing one or more therapeutic agents described herein into association with one or more excipients and/or one or more other accessory ingredients including solvents and aqueous solutions, and then, if necessary and/or desirable, dissolving, dividing, sterilizing, filling or shaping and/or packaging the product into a desired single- or multi-use units.

Relative amounts of the therapeutic agent, the excipient and/or any additional ingredients in a pharmaceutical formulation may vary, depending on the subject size, condition of the subject treated, and/or by the route of administration of the pharmaceutical formulation.

In some embodiments, the pharmaceutical formulation may include azlocillin. Azlocillin containing pharmaceutical formulations are herein referred to as“APF”. In one embodiment, azlocillin may be the therapeutic agent.

In some embodiments, the pharmaceutical formulation may include disulfiram.

Disulfiram containing pharmaceutical formulations are herein referred to as“DPF”. In one embodiment, disulfiram may be the therapeutic agent.

In some embodiments, the pharmaceutical formulation may include azlocillin and disulfiram. Azlocillin and disulfiram containing pharmaceutical formulations are herein referred to as“ADCPF”.

In some embodiments, the pharmaceutical formulation may include one or more therapeutic agents at a concentration of from about 0.0001% (w/w) to about 0.001% (w/w), from about 0.001% (w/w) to about 0.01% (w/w), from about 0.01 % (w/w) to about 0.1 % (w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1 % (w/w) to about 10% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about 1% (w/w) to about 10% (w/w), from about 5% (w/w) to about 15% (w/w), from about 10% (w/w) to about 30% (w/w), from about 15% (w/w) to about 45% (w/w), from about 20% (w/w) to about 55% (w/w), from about 25% (w/w) to about 65% (w/w), from about 30% (w/w) to about 70% (w/w), from about 35% (w/w) to about 75% (w/w), from about 40% (w/w) to about 80% (w/w), from about 50% (w/w) to about 85% (w/w), from about 60% (w/w) to about 90% (w/w), from about 75% (w/w) to about 95% (w/w), from about 90% (w/w) to about 96% (w/w), from about 92% (w/w) to about 98% (w/w), from about 95% (w/w) to about 99% (w/w), from about 98% (w/w) to about 99.5% (w/w), or from about 99% (w/w) to about 99.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more therapeutic agents at concentrations such as, but not limited to, 1 % (w/w), 2% (w/w), 3% (w/w), 4% (w/w), 5% (w/w), 6% (w/w), 7% (w/w), 8% (w/w), 9% (w/w), and/or 10% (w/w). In some embodiments, the pharmaceutical formulation may include one or more therapeutic agents at concentrations such as, but not limited to, 1.1 % (w/w), 1.2% (w/w), 1.3% (w/w), 1.4% (w/w), 1.5% (w/w), 1.6% (w/w), 1.7% (w/w), 1.8% (w/w), and/or 1.9% (w/w). In some embodiments, the pharmaceutical formulation may include one or more therapeutic agents at concentrations such as, but not limited to, 1.11 % (w/w), 1.12% (w/w), 1.13% (w/w), 1.14% (w/w), 1.15% (w/w), 1.16% (w/w), 1.17% (w/w), 1.18% (w/w), and/or 1.19% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more therapeutic agents at concentrations such as, but not limited to, 2.1 % (w/w), 2.2% (w/w), 2.3% (w/w), 2.4% (w/w), 2.5% (w/w), 2.6% (w/w), 2.7% (w/w), 2.8% (w/w), 2.9% (w/w) and/or 3% (w/w). In some embodiments, the pharmaceutical formulation may include one or more therapeutic agents at concentrations such as, but not limited to, 2.21 % (w/w), 2.22% (w/w), 2.23% (w/w), 2.24% (w/w), 2.25% (w/w), 2.26% (w/w), 2.27% (w/w), 2.28% (w/w), and/or 2.29% (w/w).

In one embodiment, the pharmaceutical formulation may include one or more therapeutic agents at a concentration of 1.13% (w/w).

In one embodiment, the pharmaceutical formulation may include one or more therapeutic agents at a concentration of 2.26% (w/w).

In some embodiments, therapeutic agents described herein may be formulated using one or more excipients to (i) increase stability; (ii) site specific release of the therapeutic agent (e.g. release in the lower gastrointestinal tract) (iii) decrease the rate of metabolism of the therapeutic agent (iv) increase the half-life of the therapeutic agent (v) alter the release profile. Non-limiting examples of the excipients include any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, and preservatives. Excipients of the present disclosure may also include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, hyaluronidase, nanoparticle mimics and

combinations thereof.

In one embodiment, the therapeutic agents may be formulated with one or more excipients to increase the half-life of the therapeutic agent to be degraded. As used herein, the term“half-life” refers to the time taken for half of an administered amount of the therapeutic agent e.g. disulfiram to be degraded. In some embodiments, the half-life of the therapeutic agent may be at least 1 hour, at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours, at least 9 hours, at least 10 hours, at least 11 hours, at least 12 hours, at least 13 hours, at least 14 hours, at least 15 hours, at least 16 hours, at least 17 hours, at least 18 hours, at least 19 hours, at least 20 hours, at least 21 hours, at least 22 hours, at least 23 hours, at least 24 hours. The in vivo half-life may be measured by determining activity in plasma.

In one embodiment, one of the disulfiram formulations described in International Patent Publication, WO2012076897 may be useful in preparing the pharmaceutical formulations described herein (the contents of which are herein incorporated by reference in its entirety).

Formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the therapeutic agent, and optionally a suitable excipient. Furthermore, the orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form or it may be in the form of a troche or lozenge. The amount of solid carrier may vary widely but may range from about 25 mg to about 1 g per dosage unit. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

In some embodiments, the pharmaceutical formulations described herein may prevent adverse effects reported with disulfiram such as, but not limited to, liver injury, basal ganglia injury, toxic optic neuropathy, peripheral neuropathy, mood disturbance, hypo-mania, paranoid ideation, emotional‘unsettledness’/distress, hypo-mania, neuropathy and/or edema.

As non-limiting examples, the pharmaceutical formulations of the present disclosure may include phosphatidylcholine, phosphatidylglycerol, cholesterol, disulfiram in the ratio (mg) of 50:50:50: 15; phospholipids, phosphatidylglycerol, cholesterol, disulfiram in the ratio (mg) of 50:50:50: 15; phosphatidylcholine, phosphatidylglycerol, cholesterol, disulfiram in the ratio (mg) of 50:50:50:15; DPPC, DPPG, cholesterol, disulfiram in the ratio (mg) of 50:50:50:15;

phosphatidylglycerol, cholesterol, disulfiram in the ratio (mg) of 50:50:15 ; phosphatidylcholine, phosphatidylglycerol, cholesterol, disulfiram in the ratio (mg) of 50:50:50:15; DPPC, DPPG, cholesterol, disulfiram in the ratio (mg) of 50:50:50:15 respectively. In some embodiments, the pharmaceutical formulations may include disulfiram (0.3g), Soybean lecithin (1.2g), Medium chain triglyceride (MCT) (10g), F-68 (0.2g), Sodium oleate (0.025g), Glycerin (2.5g) dissolved in 100 ml of water.

In some embodiments, the pharmaceutical formulations of the present disclosure may include 30% disulfiram, 27.9 % Lactose, 0.6% Magnesium stearate, 25 % Methyl cellulose, 1.5% Stearic acid, 10 % Maize starch, 5 % Microcrystalline cellulose. In some embodiments, the pharmaceutical formulations may include 30% disulfiram, 30 % Lactose, 2% Magnesium stearate, 37% Kollidon, and 1 % silicon dioxide. Any of the formulations described in by Baffoe et al.2014 may be useful in the present disclosure (Baffoe et al.2014, J. Pharmacy and

Pharmacology, 67, pp.189–198189; the contents of which are herein incorporated by reference in their entirety).

In some embodiments, the pharmaceutical formulations of present disclosure may include disulfiram and hydroxylpropyl beta-cyclodextrin (Wang et al. Curr Eye Res.2004 Jul;29(1):51-8 and Wang et al. J Pharm Pharmacol.2004 Oct;56(10):1251-7; the contents of each of which are herein incorporated by reference in their entirety).

In some embodiments, any of the formulations described by Wehbe et al., Zhuo et al., Madla et al. may be useful in the present disclosure (Wehbe et al. Drug Deliv Transl Res.2018 Feb;8(1):239-251; Zhuo X. J Colloid Interface Sci.2018 Nov 1;529:34-43; Madla et al.

Oncotarget.2017 Dec 15;9(3):3459-3482.; the contents of each of which are herein incorporated by reference in their entirety).

In some embodiments, the therapeutic agents of the present disclosure may be formulated with any of the excipients, additional active agents and/or methods described in US Patent No. US 10, 322, 096; US Patent Publication Nos. US20070232692, US20120101154, US20170281536, US20190117595 and/or International Patent Publication Nos. WO1997005867, WO2008068746, WO2011107755, WO2012024616, WO2012050594, WO2012050594, WO2012076897, WO2013123426, WO2014015157, WO2014102801, WO2014172435, WO2016004218, WO2016170102, WO2016201350, WO2017077336, WO2017095738, and/or WO2017100925 (the contents of each of which are herein incorporated by reference in their entirety).

Excipients

In some embodiments, the pharmaceutical formulations described herein may include one or more excipients. As used herein, the term“excipient” may be defined as any substance included in a formulation with an active agent, often serving as a carrier, diluent or vehicle for the active agent. In one embodiment, the active agent may be any of the therapeutic agents described herein.

In some embodiments, excipients may be compounds, compositions or particles approved for use by the US Food and Drug Administration (FDA). Excipients may include, but are not limited to, solvents, diluents, liquid vehicles, dispersion or suspension media or aids, surfactants, thickening agents, emulsifying agents, lipids, liposomes, isotonic agents, buffers, and preservatives. In some embodiments, excipients include lipidoids, lipid, nanoparticles, polymers, lipoplexes, particles, core-shell nanoparticles, peptides, proteins, cells, hyaluronidase, and/or nanoparticles. In some embodiments, excipients included in pharmaceutical formulations described herein may be selected from one or more of sucrose, lactose, phosphate salts, sodium chloride, potassium, phosphate monobasic, potassium phosphate dibasic, sodium phosphate dibasic, sodium phosphate, monobasic, polysorbate 80, phosphate buffer, phosphate buffered saline, sodium hydroxide, sorbitol, mannitol, lactose USP, Starch 1500, microcrystalline cellulose, potassium chloride, sodium borate, boric acid, sodium borate decahydrate, magnesium chloride hexahydrate, calcium chloride dihydrate, sodium hydroxide, Avicel, dibasic calcium phosphate dehydrate, tartaric acid, citric acid, fumaric, acid, succinic acid, malic acid, hydrochloric acid, polyvinylpyrrolidone, copolymers of vinylpyrrolidone and vinylacetate, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol, acacia, and/or sodium carboxymethylcellulose.

Some excipients may include pharmaceutically acceptable excipients. The phrase "pharmaceutically acceptable" as used herein, refers to suitability within the scope of sound medical judgment for contacting subject (e.g., human or animal) tissues and/or bodily fluids with toxicity, irritation, allergic response, or other complication levels yielding reasonable benefit/risk ratios. As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient, other than active agents, that is substantially nontoxic and non-inflammatory in a subject.

Pharmaceutically acceptable excipients may include, but are not limited to, solvents, dispersion media, diluents, inert diluents, buffering agents, lubricating agents, oils, liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical formulations are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of pharmaceutical formulations. Polymers

In some embodiments, pharmaceutical formulations described herein may include excipients such as polymers. As used herein, the term "polymer" refers to any substance formed through linkages between similar modules or units. Individual units are referred to herein as "monomers." Common polymers found in nature include, but are not limited to, carbon chains (e.g., lipids), polysaccharides, nucleic acids, and proteins. In some embodiments, polymers may be synthetic (e.g., thermoplastics, thermosets, elastomers, and synthetic fibers), natural (e.g., chitosan, cellulose, polysaccharides, glycogen, chitin, polypeptides, beta-keratins, nucleic acids, natural rubber, etc.), or a combination thereof. In some embodiments, polymers may be irradiated. Non limiting examples of polymers include ethylcellulose and co-polymers of acrylic and methacrylic acid esters (EUDRAGIT® RS or RL), alginates, sodium

carboxymethylcellulose, carboxypolymethylene, hydroxpropyl methylcellulose, hydroxypropyl cellulose, collagen, hydroxypropyl ethylcellulose, hydroxyethylcellulose, methylcellulose, xanthum gum, polyethylene oxide, polyethylene glycol, polysiloxane, poyphosphazene, low- density polyethylene (LDPE), high-density polyethylene (HDPE), polyvinyl chloride, polystyrene, nylon, nylon 6, nylon 6.6, polytetrafluoroethylene, thermoplastic polyurethanes, polycaprolactone, polyamide, polycarbonate, chitosan, cellulose, polysaccharides, glycogen, starch, chitin, polypeptides, keratins, beta keratins, nucleic acids, natural rubber, hyaluronan, polylactic acid, methacrylates, polyisoprene, shellac, amber, wool, synthetic rubber, silk, phenol formaldehyde resin, neoprene, nylon, polyacrylonitrile, silicone, polyvinyl butyral,

polyhydroxybutyrate (also known as polyhydroxyalkanoate), polyhydroxyurethanes, bioplastics, genetically modified bioplastics, lipid-derived polymers, lignin, carbohydrate polymers, ultra- high-molecular- weight-polyethylene (UHMWPE), gelatin, dextrans, and polyamino acids. Non- limiting examples of specific polymers include, but are not limited to poly(caprolactone) (PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lactic acid-co- glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(L- lactide) (PLLA), poly(D,L-lactide- co-caprolactone), poly(D,L-lactide-co-caprolactone-co- glycolide), poly(D,L-lactide-co-PEO-co- D,L-lactide), poly(D,L-lactide-co-PPO-co-D,L- lactide), polyalkyl cyanoacralate, polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA), polyethyleneglycol, poly-L-glutamic acid, poly(hydroxy acids), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers), polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol) (PEG), polyalkylene oxides (PEO), polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters such as poly(vinyl acetate), polyvinyl halides such as poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS),

polyurethanes, derivatized celluloses such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, hydroxypropylcellulose, carboxymethylcellulose, polymers of acrylic acids, such as poly(methyl(meth)acrylate) (PMMA),

poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate),

poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate),

poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and copolymers and mixtures thereof, polydioxanone and its copolymers, polyhydroxyalkanoates, polypropylene fumarate, polyoxymethylene, poloxamers, poly(ortho)esters, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), and trimethylene carbonate, and/or polyvinylpyrrolidone.

In some embodiments, pharmaceutical formulations of the present disclosure may include poly lactic acid (PLA) and poly glycolic acid (PGA), copolymer poly (lactic- co-glycolic acid) (PLGA) or any combinations thereof. In some embodiments, PLA, PGA and/or PGA may be used to formulate therapeutic agents for depot administration. PLA is a biodegradable thermoplastic aliphatic polyester which is derived from renewable resources such as corn starch, or cane sugar. Usually, bacterial fermentation is used to produce lactic acid. As an example, in the preparation of PLA, lactic acid is first oligomerized, and then catalytically dimerized into the lactide monomer, which is a diester ring, which is followed by ring-opening polymerization. PGA is a biodegradable thermoplastic linear, aliphatic polyester, and in preparation glycolic acid can be reacted to form a glycolide, which can then be polymerized using a ring-opening polymerization. PLGA may have a number average molecular weight of about 5 to about 15kDa, or about 5 to about 12kDa. Preferably, PLGA may have a number average molecular weight of about 8 to about 12 kDa. In some embodiments, the therapeutic agents may be conjugated (e.g. covalently bound e .g. directly or through a linking moiety) to PLGA or polylactic acid (PLA), or a PLGA portion of a copolymer such as PLGA-PEG.

In some embodiments, pharmaceutical formulations that include disulfiram and PLGA may be prepared according to methods described by Wang et al., Zembko et al., Najlah et al., Hoda e al. and/or Fasehee et al. (Wang et al. Nanomedicine.2017 Feb;13(2):641-657; Fasehee et al. J Nanobiotechnology.2016 Apr 21;14:32; Najlah et al. Eur J Pharm Biopharm.2017

Mar;112:224-233; Hoda et al . Future Sci OA.2017 Dec 13;4(2):FSO263; and Zembko et al. J Pharm Sci.2015 Mar;104(3):1076-86; the contents of each of which are herein incorporated by reference in their entirety).

In one embodiment, pharmaceutical formulations described herein may include excipients such as, but not limited to, poloxamers. As described herein, the term“poloxamers” may be defined as block copolymers of ethylene oxide and propylene oxide having a general formula HO(C₂H₄O)_a(C₃H₆O)_b(C₂H₄O)_aH wherein“a” maybe typically from 2 to 130 and“b” may be typically from 15 to 67. Poloxamers have a number of pharmaceutical applications such as viscosity modifiers, solubilizing agents or emulsifiers. Poloxamers may be used in the formulations described herein as thickening agents and/or in order to control and modify the absorption of therapeutic agent into the systemic circulation. Several different types of poloxamers are available commercially, from suppliers such as BASF, and vary with respect to molecular weight and the proportions of ethylene oxide "a" units and propylene oxide "b" units. In some embodiments, poloxamers may have a molecular weight of from about 2,500 to about 18,000 Da, for example from about 7,000 to about 15,000 Da. Non-limiting examples of commercially available poloxamers suitable for use in the present disclosure include poloxamer 188 (herein referred to as P-188), which structurally contains 80 "a" units and 27 "b" units, and has a molecular weight in the range 7680 to 9510 and poloxamer 407 which structurally contains 101 "a" units and 56 "b" units, and has a molecular weight in the range 9840 to 14600 (Handbook of Pharmaceutical Excipients, editor A. H. Kippe, third edition, Pharmaceutical Press, London, UK, 2000; the contents of which are herein incorporated by reference in their entirety). Any of the poloxamers described in US Patent NO: 3,740,421 may be used in the pharmaceutical formulations of the present disclosure (the contents of which are hereby incorporated by reference in their entirety).

In one embodiment, the pharmaceutical formulation described herein may include a poloxamer such as P-188. In some embodiments, the pharmaceutical formulation may include one or more polymers at a concentration of from about 0.0001% (w/w) to about 0.001% (w/w), from about 0.001% (w/w) to about 0.01% (w/w), from about 0.01 % (w/w) to about 0.1 % (w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1 % (w/w) to about 10% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about 1% (w/w) to about 10% (w/w),from about 2% (w/w) to about 30% (w/w), from about 5% (w/w) to about 15% (w/w), from about 10% (w/w) to about 30% (w/w), from about 10% (w/w) to about 40% (w/w), from about 15% (w/w) to about 45% (w/w), from about 20% (w/w) to about 55% (w/w), from about 25% (w/w) to about 65% (w/w), from about 30% (w/w) to about 70% (w/w), from about 35% (w/w) to about 75% (w/w), from about 40% (w/w) to about 80% (w/w), from about 50% (w/w) to about 85% (w/w), from about 60% (w/w) to about 90% (w/w), from about 75% (w/w) to about 95% (w/w), from about 90% (w/w) to about 96% (w/w), from about 92% (w/w) to about 98% (w/w), from about 95% (w/w) to about 99% (w/w), from about 98% (w/w) to about 99.5% (w/w), and/or from about 99% (w/w) to about 99.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more polymers at concentrations such as, but not limited to, 20 % (w/w), 21% (w/w), 22% (w/w), 23% (w/w), 24% (w/w), 25% (w/w), 26% (w/w), 27% (w/w), 28% (w/w), 29% (w/w), and/or 30% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more polymers at concentrations such as, but not limited to, 1% (w/w), 2% (w/w), 3% (w/w), 4% (w/w), 5% (w/w), 6% (w/w), 7% (w/w), 8% (w/w), 9% (w/w), and/or 10% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more polymers at concentrations such as, but not limited to, 22.1 % (w/w), 22.2% (w/w), 22.3% (w/w), 22.4% (w/w), 22.5% (w/w), 22.6% (w/w), 22.7% (w/w), 22.8% (w/w), and/or 22.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more polymers at concentrations such as, but not limited to, 22.41 % (w/w), 22.42% (w/w), 22.43% (w/w), 22.44% (w/w), 22.45% (w/w), 22.46% (w/w), 22.47% (w/w), 22.48% (w/w), and/or 22.49% (w/w).

In one embodiment, the pharmaceutical formulation may include one or more polymers at concentrations of 22.42% (w/w). In one embodiment, the pharmaceutical

formulation may include P-188 poloxamer at a concentration of 22.42% (w/w).

In one embodiment, the pharmaceutical formulation may include one or more polymers at concentrations of 8% (w/w). Pectins and Polysachharides

In some embodiments, pharmaceutical formulations described herein may include pectins. Pectins are polysaccharide substances present in the cell walls of all plant tissues. In some embodiments, pectins may be obtained from the dilute acid extract of the inner portion of the rind of citrus fruits or from apple pomace. Pectins are heterogeneous materials, comprising partially methoxylated polygalacturonic acids. The proportion of galacturonic acid moieties in the methyl ester form represents the degree of esterification (DE). The term DE may be represented as the percentage of the total number of carboxyl groups that are esterified i.e. if four out of five acid groups is esterified this represents a degree of esterification of 80%, or as the methoxyl content of the pectin. The respective theoretical maximum for each is 100% and 16% respectively. DE as used herein refers to the total percentage of carboxyl groups that are esterified. The degree of esterification (DE) of pectins found naturally may vary from about 60% to 90%. Pectins may be categorized into non-limiting groups such as (i) pectins with a degree of esterification that may be less than 50% (herein referred to as low DE pectins), and/or (ii) pectins with a degree of esterification that may be 50% or greater (herein referred to as high DE pectins).

In some embodiments, the gelling properties of aqueous pectin solutions may be controlled by the concentration of pectin, the type of pectin, the degree of esterification of the galacturonic acid units, and/or the presence of added salts.

In some embodiments, low DE pectins may be used in the pharmaceutical

formulations of the present disclosure. In some embodiments, pectins having a degree of esterification of less than 35%, such as, but not limited to, from about 5 to about 35%, from about 7 to about 30%, such as from about 10% to about 25%, and/or from about 15 to about 25%.

In some embodiments, high DE pectins may be in the pharmaceutical formulations of the present disclosure. In some embodiments, pectins have a degree of esterification from about 50% to about 60%; from about 55% to about 65%; from about 60% to about 70%; from about 65% to about 75%; from about 70% to about 80%; from about 75% to about 85%; from about 80% to about 90%; from about 85% to about 95%; and/or from about 90% to about 100%.

In some embodiments, divalent metal ions such as, but not limited to, calcium and/or zinc may be added to formulations described herein to cause the pectin to gel. In some embodiments, pharmaceutical formulations described herein are substantially free of agents that cause the pectin to gel. By "substantially free" of divalent metal ions it is meant that the formulation may be greater than 97%, greater than 99%, greater than 99.9% and /or greater than 99.99% free of divalent metal ions. In one embodiment, the pharmaceutical formulations described herein may include amylopectin. Amylopectin has a molecular mass of 107–109 g/mol. Amylopectin includes very large, highly branched molecules with an average degree of polymerization of about 2,000,000. In some embodiments, amylopectin may include chain lengths of from about 20 to about 25 glucose units between the branch points.

In one embodiment, the pharmaceutical formulation may include pectin derived from citrus peel and and/or apples.

In some embodiments, the pharmaceutical formulation may include one or more pectin at a concentration of from about 0.0001% (w/w) to about 0.001% (w/w), from about 0.001% (w/w) to about 0.01% (w/w), from about 0.01 % (w/w) to about 0.1 % (w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1 % (w/w) to about 10% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about 1% (w/w) to about 10% (w/w), from about 5% (w/w) to about 15% (w/w), from about 10% (w/w) to about 30% (w/w), from about 10% (w/w) to about 40% (w/w), from about 15% (w/w) to about 45% (w/w), from about 20% (w/w) to about 55% (w/w), from about 20% (w/w) to about 80% (w/w)from about 25% (w/w) to about 65% (w/w), from about 30% (w/w) to about 70% (w/w), from about 35% (w/w) to about 75% (w/w), from about 40% (w/w) to about 80% (w/w), from about 50% (w/w) to about 85% (w/w), from about 60% (w/w) to about 90% (w/w), from about 75% (w/w) to about 95% (w/w), from about 90% (w/w) to about 96% (w/w), from about 92% (w/w) to about 98% (w/w), from about 95% (w/w) to about 99% (w/w), from about 98% (w/w) to about 99.5% (w/w), and/or from about 99% (w/w) to about 99.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more pectin at concentrations such as, but not limited to, 50 % (w/w), 51% (w/w), 52% (w/w), 53% (w/w), 54% (w/w), 55% (w/w), 56% (w/w), 57% (w/w), 58% (w/w), 59% (w/w) and/or 60% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more pectin at concentrations such as, but not limited to, 55.1 % (w/w), 55.2% (w/w), 55.3% (w/w), 55.4% (w/w), 55.5% (w/w), 55.6% (w/w), 55.7% (w/w), 55.8% (w/w), and/or 55.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more pectin at concentrations such as, but not limited to, 55.91 % (w/w), 55.92% (w/w), 55.93% (w/w), 55.94% (w/w), 55.95% (w/w), 55.96% (w/w), 55.97% (w/w), 55.98% (w/w), and/or 55.99% (w/w).

In one embodiment, the pharmaceutical formulation may include one or more pectin at a concentration of 55.98% (w/w). In some embodiments, the therapeutic agents of the present disclosure may be formulated with one or more polysaccharides. As used herein, the term“polysaccharide” may refer to polymers of carbohydrate molecules bound together by glycosidic linkages. In some embodiments, the polysaccharide may be an alginate. Alginates are anionic polysaccharide that may be derived from brown algae. Alginates are a linear block co-polymer of (l-4)-OLQNHG^ȕ-D- mannuronic acid (M) and a-L-guluronic acid (G). The monomers may be in homopolymeric blocks of consecutive G-residues (G-blocks), consecutive M-residues (M-blocks), and/or alternating M- and G-residues (MG-blocks). In one embodiment, the therapeutic agents of the present disclosure may be formulated with one or more alginates to reduce or prevent liver damage. Any of the alginates or methods of preparation of pharmaceutical formulations that include alginates described in International Patent Publication WO2014102801 may be useful in the present disclosure (the contents of which are herein incorporated by reference in their entirety).

In some embodiments, therapeutic agents may be formulated using one or more lipids or amphiphilic compounds. In some embodiments, therapeutic agents may be formulated with neutral and/or anionic lipids. Suitable neutral and anionic lipids include, but are not limited to, sterols and lipids such as cholesterol, phospholipids, lysolipids, lysophospholipids, sphingolipids or pegylated lipids. In some embodiments, therapeutic agents may be formulated using one or more cationic lipids include, such as but are not limited to, N-[1-(2,3-dioleoyloxy)propyl]- N,N,N-trimethyl ammonium salts, also references as TAP lipids, for example methylsulfate salt. Suitable TAP lipids include, but are not limited to, DOTAP (dioleoyl-), DMTAP (dimyristoyl-), DPTAP (dipalmitoyl-), and DSTAP (distearoyl-). Suitable cationic lipids include, but are not limited to, dimethyldioctadecyl ammonium bromide (DDAB), 1 ,2-diacyloxy-3- trimethylammonium propanes, N-[1-(2,3-dioloyloxy)propyl]-ȃ^ȃ-dimethyl amine (DODAP), 1 ,2-diacyloxy-3-dimethylammonium propanes, N-[1-(2,3-dioleyloxy)propyl]-N,N,N- trimethylammonium chloride (DOTMA), 1 ,2-dialkyloxy-3-dimethylammonium propanes, dioctadecylamidoglycylspermine (DOGS), 3 -[N-(N',N'-dimethylamino- ethane)carbamoyl]cholesterol (DC-Chol); 2,3-dioleoyloxy-N-(2-(sperminecarboxamido)-ethyl)- N,N-dimethyl-1-propanaminium trifluoro-DFHWDWH^^'263$^^^ȕ-alanyl cholesterol, cetyl trimethyl ammonium bromide (CTAB), diC₁₄-amidine, N-ferf-butyl-N'-tetradecyl-3-tetradecylamino- propionamidine, N-(alpha-trimethylammonioacetyl)didodecyl-D-glutamate chloride (TMAG), ditetradecanoyl-N-(trimethylammonio-acetyl)diethanolamine chloride, 1 ,3-dioleoyloxy-2-(6- carboxy-spermyl)-propylamide (DOSPER), and N , N , N' , N'-tetramethyl- , N'-bis(2- hydroxylethyl)-2,3-dioleoyloxy-1 ,4-butanediammonium iodide. In one embodiment, the cationic lipids can be 1-[2-(acyloxy)ethyl]2-alkyl(alkenyl)-3-(2-hydroxyethyl)-imidazolinium chloride derivatives, for example, 1-[2-(9(Z)-octadecenoyloxy)ethyl]-2-(8(Z)-heptadecenyl-3-(2- hydroxyethyl)imidazolinium chloride (DOTIM), and 1-[2-(hexadecanoyloxy)ethyl]-2- pentadecyl-3-(2-hydroxyethyl)imidazolinium chloride (DPTIM). In one embodiment, the cationic lipids can be 2,3-dialkyloxypropyl quaternary ammonium compound derivatives containing a hydroxyalkyl moiety on the quaternary amine, for example, 1 ,2-dioleoyl-3- dimethyl-hydroxyethyl ammonium bromide (DORI), 1 ,2-dioleyloxypropyl-3-dimethyl- hydroxyethyl ammonium bromide (DORIE), 1 ,2-dioleyloxypropyl-3-dimetyl-hydroxypropyl ammonium bromide (DORIE-HP), 1 ,2-dioleyl-oxy-propyl-3-dimethyl-hydroxybutyl ammonium bromide (DORIE-HB), 1 ,2-dioleyloxypropyl-3-dimethyl-hydroxypentyl ammonium bromide (DORIE-Hpe), 1 ,2-dimyristyloxypropyl-3-dimethyl-hydroxylethyl ammonium bromide

(DMRIE), 1 ,2-dipalmityloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DPRIE), and 1 ,2-disteryloxypropyl-3-dimethyl-hydroxyethyl ammonium bromide (DSRIE).

In some embodiments, formulations described herein may include lipids that may exist as solids at room temperature (herein referred to“solid lipids”). Non-limiting examples of solid lipids that may be formulated with the therapeutic agents include higher saturated alcohols, higher fatty acids, sphingolipids, synthetic esters, and mono-, di-, and triglycerides of higher saturated fatty acids. Solid lipids may also include aliphatic alcohols having 10-40, preferably 12-30 carbon atoms, such as cetostearyl alcohol. In some embodiments, solid lipids may include higher fatty acids of 10-40, preferably 12-30 carbon atoms, such as stearic acid, palmitic acid, decanoic acid, and behenic acid. In some embodiments, solid lipids may include glycerides, including monoglycerides, diglycerides, and triglycerides, of higher saturated fatty acids having 10-40, preferably 12-30 carbon atoms, such as glyceryl monostearate, glycerol behenate, glycerol palmitostearate, glycerol trilaurate, tricaprin, trilaurin, trimyristin, tripalmitin, tristearin, and hydrogenated castor oil. In some embodiments, solid lipids may include cetyl palmitate, beeswax, or cyclodextrin

In some embodiments, formulations described herein may include one or

phospholipids. Phospholipids as described herein may include molecules with a glycerol backbone, esterified in positions 1 and 2 with fatty acids and in position 3 with a phosphate moiety. Non-limiting examples of phospholipids include saturated and unsaturated 1,2-diacyl-sn- glycero-3-phosphocholines, 1-acyl-2-acyl-sn-glycero-3-phosphocholines, 1,2-diheptanoyl-SN- glycero-3-phosphocholine) derivatives of the lipids; 1 ,2-diacyl-glycero-3-phosphocholines; phosphatidylserine (PS), phosphatidylglycerol, phosphatidylinositol (PI); glycolipids;

sphingophospholipids such as sphingomyelin and sphingoglycolipids (also known as 1-ceramidyl glucosides) such as ceramide galactopyranoside, gangliosides and cerebrosides; fatty acids, sterols, containing a carboxylic acid group for example, cholesterol; 1 ,2-diacyl-sn-glycero-3- phosphoethanolamine, including, but not limited to, 1 ,2-dioleylphosphoethanolamine (DOPE), 1 ,2-dihexadecylphosphoethanolamine (DHPE), and/or 1 ,2-dimyristoylphosphatidylcholine (DMPC).

Phospholipids may be derived from natural occurring plant and animal sources and may include phospholipids such as, but not limited to, egg lecithin, bovine lecithin, soybean lecithin, phosphatidylserine, soy phosphatidylinositol, wheat germ phosphatidylinositol, bovine phosphatidylethanolamine, plant phosphatidylethanolamine, and/or egg

phosphatidylethanolamine.

In some embodiments, therapeutic agents may be formulated using one or more synthetic phospholipids. As used herein, the term“synthetic phospholipid” may be defined as phospholipids that are artificially prepared using production methods known in the art. In some embodiments, the synthetic phospholipids may include phospholipids that structurally resemble naturally occurring phospholipids. In some embodiments, synthetic phospholipids include but are not limited to lecithin, phosphatidylserine, phosphatidylinositol, and/or

phosphatidylethanolamine. In some embodiments, the synthetic phospholipids may include derivatives of lecithin, phosphatidylserine, phosphatidylinositol, and/or

phosphatidylethanolamine. Non limiting examples of derivative synthetic phospholipids include but are not limited to Dipalmitoyl phosphatidylcholine (DPPC), Distearoyl phosphatidylcholine (DSPC), Dimyristoyl phosphatidylcholine (DMPC), Dioleoyl phosphatidylcholine (DOPC), Dimyristoyl phosphatidylglycerol (DMPG), Dipalmitoyl phosphatidylglycerol (DPPG), Dioleoyl phosphatidylglycerol (DOPG), Distearoyl phosphatidylglycerol (DSPG), Dimyristoyl phosphatidylethanolamine (DMPE), Dipalmitoyl phosphatidylethanolamine (DPPE), Dioleoyl phosphatidylethanolamine (DOPE), Dimyristoyl phosphatidylserine (DMPS), Dipalmitoyl phosphatidylserine (DPPS), diarachidoylphosphatidylcholine (DAPC),

dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine (DTPC),

dilignoceroylphatidylcholine (DLPC)and/or Dioleoyl phosphatidylserine (DOPS).

In one embodiment, the therapeutic agents may be formulated using lipid particles. In some embodiments, lipid particles may be made from one lipid or from a mixture of different lipids. Lipid particles may include lipids which may be neutral, anionic, or cationic at

physiological pH. In one embodiment, the therapeutic agent may be formulated using lipid micelles. Any of the lipid micelles for drug delivery known in the art may be used herein. Lipid micelles may be formed as a water-in-oil emulsion with a lipid surfactant. As used herein, the term“emulsion” may be defined as a blend between two immiscible phases wherein a surfactant is added to stabilize the dispersed droplets. In some embodiments, the lipid micelle may be a microemulsion. A microemulsion may be thermodynamically stable system composed of at least water, oil, and a lipid surfactant producing a transparent and thermodynamically stable system whose droplet size may be less than 1 micron, from about 10 nm to about 500 nm, and/or from about 10 nm to about 250 nm. In some embodiments, lipid micelles may be used for encapsulating hydrophobic therapeutic agents.

In one embodiment, the therapeutic agent may be formulated using one or more liposomes. As used herein, the term“liposome” may be defined as an artificially prepared vesicle which may include a lipid bilayer which may be used as a delivery vehicle for the therapeutic agents described herein. Liposomes may be of different sizes such as, but not limited to, a multilamellar vesicle (MLV), which may be hundreds of nanometers in diameter and may include a series of concentric bilayers separated by narrow aqueous compartments; a small unilamellar vesicle (SUV) which may be smaller than 50 nm in diameter, and large unilamellar vesicle (LUV) which may be between 50 and 500 nm in diameter. In some embodiments, liposomes may have an aqueous core. The aqueous core may include water or a mixture of water and alcohol. Suitable alcohols include, but are not limited to , methanol, ethanol, propanol, (such as isopropanol), butanol (such as n-butanol, isobutanol, sec-butanol, tert-butanol, pentanol (such as amyl alcohol, isobutyl carbinol), hexanol (such as 1-hexanol, 2-hexanol, 3-hexanol), heptanol (such as 1-heptanol, 2-heptanol, 3-heptanol and 4-heptanol) or octanol (such as 1-octanol) or a combination thereof.

In some embodiments, the pharmaceutical formulation may include one or more lipids and/or phospholipids at a concentration of from about 0.0001% (w/w) to about 0.001% (w/w), from about 0.001% (w/w) to about 0.01% (w/w), from about 0.01 % (w/w) to about 0.1 % (w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1 % (w/w) to about 10% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about 1% (w/w) to about 10% (w/w), from about 2% (w/w) to about 20% (w/w)from about 5% (w/w) to about 15% (w/w), from about 5% (w/w) to about 40 % (w/w), from about 10% (w/w) to about 30% (w/w), from about 10% (w/w) to about 40% (w/w), from about 15% (w/w) to about 45% (w/w), from about 20% (w/w) to about 55% (w/w), from about 20% (w/w) to about 80% (w/w)from about 25% (w/w) to about 65% (w/w), from about 30% (w/w) to about 70% (w/w), from about 35% (w/w) to about 75% (w/w), from about 40% (w/w) to about 80% (w/w), from about 50% (w/w) to about 85% (w/w), from about 60% (w/w) to about 90% (w/w), from about 75% (w/w) to about 95% (w/w), from about 90% (w/w) to about 96% (w/w), from about 92% (w/w) to about 98% (w/w), from about 95% (w/w) to about 99% (w/w), from about 98% (w/w) to about 99.5% (w/w), and/or from about 99% (w/w) to about 99.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more lipids and/or phospholipids at concentrations such as, but not limited to, 2 % (w/w), 3% (w/w), 4% (w/w), 5% (w/w), 6% (w/w), 7% (w/w), 8% (w/w), 9% (w/w), 10% (w/w), 11% (w/w), 12 % (w/w), 13 % (w/w), 14% (w/w), 15 % (w/w), 16% (w/w), 17 % (w/w), 18% (w/w), 19% (w/w), and/or 20% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more lipids and/or phospholipids at concentrations such as, but not limited to, 8.1 % (w/w), 8.2% (w/w), 8.3% (w/w), 8.4% (w/w), 8.5% (w/w), 8.6% (w/w), 8.7% (w/w), 8.8% (w/w), and/or 8.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more lipids and/or phospholipids at concentrations such as, but not limited to, 8.01 % (w/w), 8.02% (w/w), 8.03% (w/w), 8.04% (w/w), 8.05% (w/w), 8.06% (w/w), 8.07% (w/w), 8.08% (w/w), and/or 8.09% (w/w).

In one embodiment, the pharmaceutical formulation may include one or more lipids and/or phospholipids at a concentration of 8.06% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more lipids and/or phospholipids at concentrations such as, but not limited to, 21 % (w/w), 22 % (w/w), 23% (w/w), 24% (w/w), 25% (w/w), 26% (w/w), 27% (w/w), 28% (w/w), and/or 29% (w/w).

In some embodiments, the pharmaceutical formulation may include two

phospholipids. In one embodiment, the two phospholipids may be DSPC and DPPC. In one embodiment, the pharmaceutical formulation may include DSPC at a concentration of 8.06% (w/w). In one embodiment, the pharmaceutical formulation may include DPPC at a concentration of 8.06% (w/w).

In one embodiment, the pharmaceutical formulation may include lipid e.g. cholesterol at concentration of about 28% (w/w). Salts

In some embodiments, pharmaceutical formulations described herein may include salts. As used herein, the term“salt” may be defined as any ionic compound formed when an cations reacts with a anions. Salts useful in the present disclosure may be prepared from various inorganic acids are herein referred to as inorganic salts. Inorganic salts may include anions, including but not limited to sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate. Inorganic salts may include cations such as but not limited, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. In some embodiments, the inorganic salt may be calcium chloride (CaCl₂), sodium chloride (NaCl), magnesium chloride (MgCl₂), sodium bicarbonate (NaHCO₃), potassium chloride (KCl), sodium sulfate (Na₂SO₄), calcium carbonate (CaCO₃), and/or calcium phosphate (Ca₃(PO4)₂.

Pharmaceutical formulations of the present disclosure may be formulated with organic salts. As used herein, the term organic salt, may refer to any salt prepared from an organic acid i.e. acids containing one or more covalently bonded carbon atoms. Organic salts may be derived from an organic acid such as, but not limited to, 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4- aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic, naphthalene-1,5- disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, trifluoroacetic, and/or undecylenic acid.

In some embodiments, the pharmaceutical formulation may include one or more salts at a concentration of from about 0.0001% (w/w) to about 0.001% (w/w), from about 0.001% (w/w) to about 0.01% (w/w), from about 0.01 % (w/w) to about 0.1 % (w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1 % (w/w) to about 10% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about 1% (w/w) to about 10% (w/w), from about 2% (w/w) to about 20% (w/w)from about 5% (w/w) to about 15% (w/w), from about 10% (w/w) to about 30% (w/w), from about 10% (w/w) to about 40% (w/w), from about 15% (w/w) to about 45% (w/w), from about 20% (w/w) to about 55% (w/w), from about 20% (w/w) to about 80% (w/w)from about 25% (w/w) to about 65% (w/w), from about 30% (w/w) to about 70% (w/w), from about 35% (w/w) to about 75% (w/w), from about 40% (w/w) to about 80% (w/w), from about 50% (w/w) to about 85% (w/w), from about 60% (w/w) to about 90% (w/w), from about 75% (w/w) to about 95% (w/w), from about 90% (w/w) to about 96% (w/w), from about 92% (w/w) to about 98% (w/w), from about 95% (w/w) to about 99% (w/w), from about 98% (w/w) to about 99.5% (w/w), and/or from about 99% (w/w) to about 99.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more salts at concentrations such as, but not limited to, 2 % (w/w), 3% (w/w), 4% (w/w), 5% (w/w), 6% (w/w), 7% (w/w), 8% (w/w), 9% (w/w), 10% (w/w), 11% (w/w), 12 % (w/w), 13 % (w/w), 14% (w/w), 15 % (w/w), 16% (w/w), 17 % (w/w), 18% (w/w), 19% (w/w), and/or 20% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more salts at concentrations such as, but not limited to, 3.1 % (w/w), 3.2% (w/w), 3.3% (w/w), 3.4% (w/w), 3.5% (w/w), 3.6% (w/w), 3.7% (w/w), 3.8% (w/w), and/or 3.9% (w/w).

In some embodiments, the pharmaceutical formulation may include one or more salts at concentrations such as, but not limited to, 3.21 % (w/w), 3.22% (w/w), 3.23% (w/w), 3.24% (w/w), 3.25% (w/w), 3.26% (w/w), 3.27% (w/w), 3.28% (w/w), and/or 3.29% (w/w).

In one embodiment, the pharmaceutical formulation may include one or more salts at a concentration of 3.22% (w/w).

In one embodiment, the pharmaceutical formulation may include calcium chloride. In one embodiment, the pharmaceutical formulation may include zinc chloride.

In one embodiment, the pharmaceutical formulation may include calcium chloride at a concentration of about 3.22% (w/w).

In one embodiment, the pharmaceutical formulation may include zinc chloride at a concentration of about 3.22% (w/w).

In some embodiments, the pharmaceutical formulation may include two salts such as, but not limited to, calcium chloride and zinc chloride. Inactive Ingredients

In some embodiments, the pharmaceutical formulations may include at least one inactive ingredient. As used herein, the term“inactive ingredient” refers to one or more agents that do not contribute to the activity of the active ingredient (e.g. one of more therapeutic agent) of the pharmaceutical composition included in formulations. In some embodiments, all, none or some of the inactive ingredients which may be used in the formulations of the present disclosure may be approved by the US Food and Drug Administration (FDA). In one embodiment, the pharmaceutical formulations may include inactive ingredients such as, but not limited to, 1,2,6-Hexanetriol; 1,2-Dimyristoyl-Sn-Glycero-3-(Phospho-S-(1- Glycerol)); 1,2-Dimyristoyl-Sn-Glycero-3-Phosphocholine; 1,2-Dioleoyl-Sn-Glycero-3- Phosphocholine; 1,2-Dipalmitoyl-Sn-Glycero-3-(Phospho-Rac-(1-Glycerol)); 1,2-Distearoyl-Sn- Glycero-3-(Phospho-Rac-(1-Glycerol)); 1,2-Distearoyl-Sn-Glycero-3-Phosphocholine; 1-O- Tolylbiguanide; 2-Ethyl-1,6-Hexanediol; Acetic Acid; Acetic Acid, Glacial; Acetic Anhydride; Acetone; Acetone Sodium Bisulfite; Acetylated Lanolin Alcohols; Acetylated Monoglycerides; Acetylcysteine; Acetyltryptophan, DL-; Acrylates Copolymer; Acrylic Acid-Isooctyl Acrylate Copolymer; Acrylic Adhesive 788; Activated Charcoal; Adcote 72A103; Adhesive Tape; Adipic Acid; Aerotex Resin 3730; Alanine; Albumin Aggregated; Albumin Colloidal; Albumin Human; Alcohol; Alcohol, Dehydrated; Alcohol, Denatured; Alcohol, Diluted; Alfadex; Alginic Acid; Alkyl Ammonium Sulfonic Acid Betaine; Alkyl Aryl Sodium Sulfonate; Allantoin; Allyl .Alpha.-Ionone; Almond Oil; Alpha-Terpineol; Alpha-Tocopherol; Alpha-Tocopherol Acetate, Dl-; Alpha-Tocopherol, Dl-; Aluminum Acetate; Aluminum Chlorhydroxy Allantoinate;

Aluminum Hydroxide; Aluminum Hydroxide - Sucrose, Hydrated; Aluminum Hydroxide Gel; Aluminum Hydroxide Gel F 500; Aluminum Hydroxide Gel F 5000; Aluminum Monostearate; Aluminum Oxide; Aluminum Polyester; Aluminum Silicate; Aluminum Starch Octenylsuccinate; Aluminum Stearate; Aluminum Subacetate; Aluminum Sulfate Anhydrous; Amerchol C;

Amerchol-Cab; Aminomethylpropanol; Ammonia; Ammonia Solution; Ammonia Solution, Strong; Ammonium Acetate; Ammonium Hydroxide; Ammonium Lauryl Sulfate; Ammonium Nonoxynol-4 Sulfate; Ammonium Salt Of C-12-C-15 Linear Primary Alcohol Ethoxylate;

Ammonium Sulfate; Ammonyx; Amphoteric-2; Amphoteric-9; Anethole; Anhydrous Citric Acid; Anhydrous Dextrose; Anhydrous Lactose; Anhydrous Trisodium Citrate; Aniseed Oil; Anoxid Sbn; Antifoam; Antipyrine; Apaflurane; Apricot Kernel Oil Peg-6 Esters; Aquaphor; Arginine; Arlacel; Ascorbic Acid; Ascorbyl Palmitate; Aspartic Acid; Balsam Peru; Barium Sulfate; Beeswax; Beeswax, Synthetic; Beheneth-10; Bentonite; Benzalkonium Chloride;

Benzenesulfonic Acid; Benzethonium Chloride; Benzododecinium Bromide; Benzoic Acid; Benzyl Alcohol; Benzyl Benzoate; Benzyl Chloride; Betadex; Bibapcitide; Bismuth Subgallate; Boric Acid; Brocrinat; Butane; Butyl Alcohol; Butyl Ester Of Vinyl Methyl Ether/Maleic Anhydride Copolymer (125000 Mw); Butyl Stearate; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Butylene Glycol; Butylparaben; Butyric Acid; C20-40 Pareth-24; Caffeine; Calcium; Calcium Carbonate; Calcium Chloride; Calcium Gluceptate; Calcium Hydroxide;

Calcium Lactate; Calcobutrol; Caldiamide Sodium; Caloxetate Trisodium; Calteridol Calcium; Canada Balsam; Caprylic/Capric Triglyceride; Caprylic/Capric/Stearic Triglyceride; Captan; Captisol; Caramel; Carbomer 1342; Carbomer 1382; Carbomer 934; Carbomer 934p; Carbomer 940; Carbomer 941; Carbomer 980; Carbomer 981; Carbomer Homopolymer Type B (Allyl Pentaerythritol Crosslinked); Carbomer Homopolymer Type C (Allyl Pentaerythritol

Crosslinked); Carbon Dioxide; Carboxy Vinyl Copolymer; Carboxymethylcellulose;

Carboxymethylcellulose Sodium; Carboxypolymethylene; Carrageenan; Carrageenan Salt;

Castor Oil; Cedar Leaf Oil; Cellulose; Cellulose, Microcrystalline; Cerasynt-Se; Ceresin;

Ceteareth-12; Ceteareth-15; Ceteareth-30; Cetearyl Alcohol/Ceteareth-20; Cetearyl

Ethylhexanoate; Ceteth-10; Ceteth-2; Ceteth-20; Ceteth-23; Cetostearyl Alcohol; Cetrimonium Chloride; Cetyl Alcohol; Cetyl Esters Wax; Cetyl Palmitate; Cetylpyridinium Chloride;

Chlorobutanol; Chlorobutanol Hemihydrate; Chlorobutanol, Anhydrous; Chlorocresol;

Chloroxylenol; Cholesterol; Choleth; Choleth-24; Citrate; Citric Acid; Citric Acid Monohydrate; Citric Acid, Hydrous; Cocamide Ether Sulfate; Cocamine Oxide; Coco Betaine; Coco

Diethanolamide; Coco Monoethanolamide; Cocoa Butter; Coco-Glycerides; Coconut Oil;

Coconut Oil, Hydrogenated; Coconut Oil/Palm Kernel Oil Glycerides, Hydrogenated; Cocoyl Caprylocaprate; Cola Nitida Seed Extract; Collagen; Coloring Suspension; Corn Oil; Cottonseed Oil; Cream Base; Creatine; Creatinine; Cresol; Croscarmellose Sodium; Crospovidone; Cupric Sulfate; Cupric Sulfate Anhydrous; Cyclomethicone; Cyclomethicone/Dimethicone Copolyol; Cysteine; Cysteine Hydrochloride; Cysteine Hydrochloride Anhydrous; Cysteine, Dl-; D&C Red No.28; D&C Red No.33; D&C Red No.36; D&C Red No.39; D&C Yellow No.10;

Dalfampridine; Daubert 1-5 Pestr (Matte) 164z; Decyl Methyl Sulfoxide; Dehydag Wax Sx; Dehydroacetic Acid; Dehymuls E; Denatonium Benzoate; Deoxycholic Acid; Dextran; Dextran 40; Dextrin; Dextrose; Dextrose Monohydrate; Dextrose Solution; Diatrizoic Acid; Diazolidinyl Urea; Dichlorobenzyl Alcohol; Dichlorodifluoromethane; Dichlorotetrafluoroethane;

Diethanolamine; Diethyl Pyrocarbonate; Diethyl Sebacate; Diethylene Glycol Monoethyl Ether; Diethylhexyl Phthalate; Dihydroxyaluminum Aminoacetate; Diisopropanolamine; Diisopropyl Adipate; Diisopropyl Dilinoleate; Dimethicone 350; Dimethicone Copolyol; Dimethicone Mdx4- 4210; Dimethicone Medical Fluid 360; Dimethyl Isosorbide; Dimethyl Sulfoxide;

Dimethylaminoethyl Methacrylate - Butyl Methacrylate - Methyl Methacrylate Copolymer; Dimethyldioctadecylammonium Bentonite; Dimethylsiloxane/Methylvinylsiloxane Copolymer; Dinoseb Ammonium Salt; Dipalmitoylphosphatidylglycerol, Dl-; Dipropylene Glycol; Disodium Cocoamphodiacetate; Disodium Laureth Sulfosuccinate; Disodium Lauryl Sulfosuccinate;

Disodium Sulfosalicylate; Disofenin; Divinylbenzene Styrene Copolymer; Dmdm Hydantoin; Docosanol; Docusate Sodium; Duro-Tak 280-2516; Duro-Tak 387-2516; Duro-Tak 80-1196; Duro-Tak 87-2070; Duro-Tak 87-2194; Duro-Tak 87-2287; Duro-Tak 87-2296; Duro-Tak 87- 2888; Duro-Tak 87-2979; Edetate Calcium Disodium; Edetate Disodium; Edetate Disodium Anhydrous; Edetate Sodium; Edetic Acid; Egg Phospholipids; Entsufon; Entsufon Sodium;

Epilactose; Epitetracycline Hydrochloride; Essence Bouquet 9200; Ethanolamine Hydrochloride; Ethyl Acetate; Ethyl Oleate; Ethyl celluloses; Ethylene Glycol; Ethylene Vinyl Acetate

Copolymer; Ethylenediamine; Ethylenediamine Dihydrochloride; Ethylene-Propylene

Copolymer; Ethylene-Vinyl Acetate Copolymer (28% Vinyl Acetate); Ethylene-Vinyl Acetate Copolymer (9% Vinylacetate); Ethylhexyl Hydroxystearate; Ethylparaben; Eucalyptol;

Exametazime; Fat, Edible; Fat, Hard; Fatty Acid Esters; Fatty Acid Pentaerythriol Ester; Fatty Acids; Fatty Alcohol Citrate; Fatty Alcohols; Fd&C Blue No.1; Fd&C Green No.3; Fd&C Red No.4; Fd&C Red No.40; Fd&C Yellow No.10 (Delisted); Fd&C Yellow No.5; Fd&C Yellow No.6; Ferric Chloride; Ferric Oxide; Flavor 89-186; Flavor 89-259; Flavor Df-119; Flavor Df- 1530; Flavor Enhancer; Flavor Fig 827118; Flavor Raspberry Pfc-8407; Flavor Rhodia

Pharmaceutical No. Rf 451; Fluorochlorohydrocarbons; Formaldehyde; Formaldehyde Solution; Fractionated Coconut Oil; Fragrance 3949-5; Fragrance 520a; Fragrance 6.007; Fragrance 91- 122; Fragrance 9128-Y; Fragrance 93498g; Fragrance Balsam Pine No.5124; Fragrance Bouquet 10328; Fragrance Chemoderm 6401-B; Fragrance Chemoderm 6411; Fragrance Cream No.

73457; Fragrance Cs-28197; Fragrance Felton 066m; Fragrance Firmenich 47373; Fragrance Givaudan Ess 9090/1c; Fragrance H-6540; Fragrance Herbal 10396; Fragrance Nj-1085;

Fragrance P O Fl-147; Fragrance Pa 52805; Fragrance Pera Derm D; Fragrance Rbd-9819;

Fragrance Shaw Mudge U-7776; Fragrance Tf 044078; Fragrance Ungerer Honeysuckle K 2771; Fragrance Ungerer N5195; Fructose; Gadolinium Oxide; Galactose; Gamma Cyclodextrin;

Gelatin; Gelatin, Crosslinked; Gelfoam Sponge; Gellan Gum (Low Acyl); Gelva 737; Gentisic Acid; Gentisic Acid Ethanolamide; Gluceptate Sodium; Gluceptate Sodium Dihydrate;

Gluconolactone; Glucuronic Acid; Glutamic Acid, Dl-; Glutathione; Glycerin; Glycerol Ester Of Hydrogenated Rosin; Glyceryl Citrate; Glyceryl Isostearate; Glyceryl Laurate; Glyceryl

Monostearate; Glyceryl Oleate; Glyceryl Oleate/Propylene Glycol; Glyceryl Palmitate; Glyceryl Ricinoleate; Glyceryl Stearate; Glyceryl Stearate - Laureth-23; Glyceryl Stearate/Peg Stearate; Glyceryl Stearate/Peg-100 Stearate; Glyceryl Stearate/Peg-40 Stearate; Glyceryl Stearate- Stearamidoethyl Diethylamine; Glyceryl Trioleate; Glycine; Glycine Hydrochloride; Glycol Distearate; Glycol Stearate; Guanidine Hydrochloride; Guar Gum; Hair Conditioner (18n195- 1m); Heptane; Hetastarch; Hexylene Glycol; High Density Polyethylene; Histidine; Human Albumin Microspheres; Hyaluronate Sodium; Hydrocarbon; Hydrocarbon Gel, Plasticized;

Hydrochloric Acid; Hydrochloric Acid, Diluted; Hydrocortisone; Hydrogel Polymer; Hydrogen Peroxide; Hydrogenated Castor Oil; Hydrogenated Palm Oil; Hydrogenated Palm/Palm Kernel Oil Peg-6 Esters; Hydrogenated Polybutene 635-690; Hydroxide Ion; Hydroxyethyl Cellulose; Hydroxyethylpiperazine Ethane Sulfonic Acid; Hydroxymethyl Cellulose; Hydroxyoctacosanyl Hydroxystearate; Hydroxypropyl Cellulose; Hydroxypropyl Methylcellulose 2906;

Hydroxypropyl-Beta-cyclodextrin; Hypromellose 2208 (15000 Mpa.S); Hypromellose 2910 (15000 Mpa.S); Hypromelloses; Imidurea; Iodine; Iodoxamic Acid; Iofetamine Hydrochloride; Irish Moss Extract; Isobutane; Isoceteth-20; Isoleucine; Isooctyl Acrylate; Isopropyl Alcohol; Isopropyl Isostearate; Isopropyl Myristate; Isopropyl Myristate - Myristyl Alcohol; Isopropyl Palmitate; Isopropyl Stearate; Isostearic Acid; Isostearyl Alcohol; Isotonic Sodium Chloride Solution; Jelene; Kaolin; Kathon Cg; Kathon Cg II; Lactate; Lactic Acid; Lactic Acid, Dl-;

Lactic Acid, L-; Lactobionic Acid; Lactose; Lactose Monohydrate; Lactose, Hydrous; Laneth; Lanolin; Lanolin Alcohol - Mineral Oil; Lanolin Alcohols; Lanolin Anhydrous; Lanolin

Cholesterols; Lanolin Nonionic Derivatives; Lanolin, Ethoxylated; Lanolin, Hydrogenated; Lauralkonium Chloride; Lauramine Oxide; Laurdimonium Hydrolyzed Animal Collagen;

Laureth Sulfate; Laureth-2; Laureth-23; Laureth-4; Lauric Diethanolamide; Lauric Myristic Diethanolamide; Lauroyl Sarcosine; Lauryl Lactate; Lauryl Sulfate; Lavandula Angustifolia Flowering Top; Lecithin; Lecithin Unbleached; Lecithin, Egg; Lecithin, Hydrogenated; Lecithin, Hydrogenated Soy; Lecithin, Soybean; Lemon Oil; Leucine; Levulinic Acid; Lidofenin; Light Mineral Oil; Light Mineral Oil (85 Ssu); Limonene, (+/-)-; Lipocol Sc-15; Lysine; Lysine Acetate; Lysine Monohydrate; Magnesium Aluminum Silicate; Magnesium Aluminum Silicate Hydrate; Magnesium Chloride; Magnesium Nitrate; Magnesium Stearate; Maleic Acid;

Mannitol; Maprofix; Mebrofenin; Medical Adhesive Modified S-15; Medical Antiform A-F Emulsion; Medronate Disodium; Medronic Acid; Meglumine; Menthol; Metacresol;

Metaphosphoric Acid; Methanesulfonic Acid; Methionine; Methyl Alcohol; Methyl Gluceth-10; Methyl Gluceth-20; Methyl Gluceth-20 Sesquistearate; Methyl Glucose Sesquistearate; Methyl Laurate; Methyl Pyrrolidone; Methyl Salicylate; Methyl Stearate; Methylboronic Acid;

Methylcellulose (4000 Mpa.S); Methylcelluloses; Methylchloroisothiazolinone; Methylene Blue; Methylisothiazolinone; Methylparaben; Microcrystalline Wax; Mineral Oil; Mono and

Diglyceride; Monostearyl Citrate; Monothioglycerol; Multisterol Extract; Myristyl Alcohol; Myristyl Lactate; Myristyl-.Gamma.-Picolinium Chloride; N-(Carbamoyl-Methoxy Peg-40)-1,2- Distearoyl-Cephalin Sodium; N,N-Dimethylacetamide; Niacinamide; Nioxime; Nitric Acid; Nitrogen; Nonoxynol Iodine; Nonoxynol-15; Nonoxynol-9; Norflurane; Oatmeal; Octadecene- 1/Maleic Acid Copolymer; Octanoic Acid; Octisalate; Octoxynol-1; Octoxynol-40; Octoxynol-9; Octyldodecanol; Octylphenol Polymethylene; Oleic Acid; Oleth-10/Oleth-5; Oleth-2; Oleth-20; Oleyl Alcohol; Oleyl Oleate; Olive Oil; Oxidronate Disodium; Oxyquinoline; Palm Kernel Oil; Palmitamine Oxide; Parabens; Paraffin; Paraffin, White Soft; Parfum Creme 45/3; Peanut Oil; Peanut Oil, Refined; Pectin; Peg 6-32 Stearate/Glycol Stearate; Peg Vegetable Oil; Peg-100 Stearate; Peg-12 Glyceryl Laurate; Peg-120 Glyceryl Stearate; Peg-120 Methyl Glucose

Dioleate; Peg-15 Cocamine; Peg-150 Distearate; Peg-2 Stearate; Peg-20 Sorbitan Isostearate; Peg-22 Methyl Ether/Dodecyl Glycol Copolymer; Peg-25 Propylene Glycol Stearate; Peg-4 Dilaurate; Peg-4 Laurate; Peg-40 Castor Oil; Peg-40 Sorbitan Diisostearate; Peg-45/Dodecyl Glycol Copolymer; Peg-5 Oleate; Peg-50 Stearate; Peg-54 Hydrogenated Castor Oil; Peg-6 Isostearate; Peg-60 Castor Oil; Peg-60 Hydrogenated Castor Oil; Peg-7 Methyl Ether; Peg-75 Lanolin; Peg-8 Laurate; Peg-8 Stearate; Pegoxol 7 Stearate; Pentadecalactone; Pentaerythritol Cocoate; Pentasodium Pentetate; Pentetate Calcium Trisodium; Pentetic Acid; Peppermint Oil; Perflutren; Perfume 25677; Perfume Bouquet; Perfume E-1991; Perfume Gd 5604; Perfume Tana 90/42 Scba; Perfume W-1952-1; Petrolatum; Petrolatum, White; Petroleum Distillates; Phenol; Phenol, Liquefied; Phenonip; Phenoxyethanol; Phenylalanine; Phenylethyl Alcohol; Phenylmercuric Acetate; Phenylmercuric Nitrate; Phosphatidyl Glycerol, Egg; Phospholipid; Phospholipid, Egg; Phospholipon 90g; Phosphoric Acid; Pine Needle Oil (Pinus Sylvestris); Piperazine Hexahydrate; Plastibase-50w; Polacrilin; Polidronium Chloride; Poloxamer 124; Poloxamer 181; Poloxamer 182; Poloxamer 188; Poloxamer 237; Poloxamer 407; Poly(Bis(P- Carboxyphenoxy)Propane Anhydride):Sebacic Acid;

Poly(Dimethylsiloxane/Methylvinylsiloxane/Methylhydrogensiloxane) Dimethylvinyl Or Dimethylhydroxy Or Trimethyl Endblocked; Poly(Dl-Lactic-Co-Glycolic Acid), (50:50;

Poly(Dl-Lactic-Co-Glycolic Acid), Ethyl Ester Terminated, (50:50; Polyacrylic Acid (250000 Mw); Polybutene (1400 Mw); Polycarbophil; Polyester; Polyester Polyamine Copolymer;

Polyester Rayon; Polyethylene Glycol 1000; Polyethylene Glycol 1450; Polyethylene Glycol 1500; Polyethylene Glycol 1540; Polyethylene Glycol 200; Polyethylene Glycol 300;

Polyethylene Glycol 300-1600; Polyethylene Glycol 3350; Polyethylene Glycol 400;

Polyethylene Glycol 4000; Polyethylene Glycol 540; Polyethylene Glycol 600; Polyethylene Glycol 6000; Polyethylene Glycol 8000; Polyethylene Glycol 900; Polyethylene High Density Containing Ferric Oxide Black (<1%); Polyethylene Low Density Containing Barium Sulfate (20-24%); Polyethylene T; Polyethylene Terephthalates; Polyglactin; Polyglyceryl-3 Oleate; Polyglyceryl-4 Oleate; Polyhydroxyethyl Methacrylate; Polyisobutylene; Polyisobutylene (1100000 Mw); Polyisobutylene (35000 Mw); Polyisobutylene 178-236; Polyisobutylene 241- 294; Polyisobutylene 35-39; Polyisobutylene Low Molecular Weight; Polyisobutylene Medium Molecular Weight; Polyisobutylene/Polybutene Adhesive; Polylactide; Polyols; Polyoxyethylene - Polyoxypropylene 1800; Polyoxyethylene Alcohols; Polyoxyethylene Fatty Acid Esters; Polyoxyethylene Propylene; Polyoxyl 20 Cetostearyl Ether; Polyoxyl 35 Castor Oil; Polyoxyl 40 Hydrogenated Castor Oil; Polyoxyl 40 Stearate; Polyoxyl 400 Stearate; Polyoxyl 6 And Polyoxyl 32 Palmitostearate; Polyoxyl Distearate; Polyoxyl Glyceryl Stearate; Polyoxyl Lanolin; Polyoxyl Palmitate; Polyoxyl Stearate; Polypropylene; Polypropylene Glycol; Polyquaternium-10;

Polyquaternium-7 (70/30 Acrylamide/Dadmac; Polysiloxane; Polysorbate 20; Polysorbate 40; Polysorbate 60; Polysorbate 65; Polysorbate 80; Polyurethane; Polyvinyl Acetate; Polyvinyl Alcohol; Polyvinyl Chloride; Polyvinyl Chloride-Polyvinyl Acetate Copolymer;

Polyvinylpyridine; Poppy Seed Oil; Potash; Potassium Acetate; Potassium Alum; Potassium Bicarbonate; Potassium Bisulfite; Potassium Chloride; Potassium Citrate; Potassium Hydroxide; Potassium Metabisulfite; Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic;

Potassium Soap; Potassium Sorbate; Povidone Acrylate Copolymer; Povidone Hydrogel;

Povidone K17; Povidone K25; Povidone K29/32; Povidone K30; Povidone K90; Povidone K90f; Povidone/Eicosene Copolymer; Povidones; Ppg-12/Smdi Copolymer; Ppg-15 Stearyl Ether; Ppg- 20 Methyl Glucose Ether Distearate; Ppg-26 Oleate; Product Wat; Proline; Promulgen D;

Promulgen G; Propane; Propellant A-46; Propyl Gallate; Propylene Carbonate; Propylene Glycol; Propylene Glycol Diacetate; Propylene Glycol Dicaprylate; Propylene Glycol

Monolaurate; Propylene Glycol Monopalmitostearate; Propylene Glycol Palmitostearate;

Propylene Glycol Ricinoleate; Propylene Glycol/Diazolidinyl

Urea/Methylparaben/Propylparben; Propylparaben; Protamine Sulfate; Protein Hydrolysate; Pvm/Ma Copolymer; Quaternium-15; Quaternium-15 Cis-Form; Quaternium-52; Ra-2397; Ra- 3011; Saccharin; Saccharin Sodium; Saccharin Sodium Anhydrous; Safflower Oil; Sd Alcohol 3a; Sd Alcohol 40; Sd Alcohol 40-2; Sd Alcohol 40b; Sepineo P 600; Serine; Sesame Oil; Shea Butter; Silastic Brand Medical Grade Tubing; Silastic Medical Adhesive, Silicone Type A;

Silica, Dental; Silicon; Silicon Dioxide; Silicon Dioxide, Colloidal; Silicone; Silicone Adhesive 4102; Silicone Adhesive 4502; Silicone Adhesive Bio-Psa Q7-4201; Silicone Adhesive Bio-Psa Q7-4301; Silicone Emulsion; Silicone/Polyester Film Strip; Simethicone; Simethicone Emulsion; Sipon Ls 20np; Soda Ash; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Alkyl Sulfate; Sodium Ascorbate; Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfate; Sodium Bisulfite; Sodium Borate; Sodium Borate Decahydrate; Sodium Carbonate; Sodium Carbonate

Decahydrate; Sodium Carbonate Monohydrate; Sodium Cetostearyl Sulfate; Sodium Chlorate; Sodium Chloride; Sodium Chloride Injection; Sodium Chloride Injection, Bacteriostatic; Sodium Cholesteryl Sulfate; Sodium Citrate; Sodium Cocoyl Sarcosinate; Sodium Desoxycholate;

Sodium Dithionite; Sodium Dodecylbenzenesulfonate; Sodium Formaldehyde Sulfoxylate;

Sodium Gluconate; Sodium Hydroxide; Sodium Hypochlorite; Sodium Iodide; Sodium Lactate; Sodium Lactate, L-; Sodium Laureth-2 Sulfate; Sodium Laureth-3 Sulfate; Sodium Laureth-5 Sulfate; Sodium Lauroyl Sarcosinate; Sodium Lauryl Sulfate; Sodium Lauryl Sulfoacetate;

Sodium Metabisulfite; Sodium Nitrate; Sodium Phosphate; Sodium Phosphate Dihydrate;

Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic, Dodecahydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous;

Sodium Phosphate, Monobasic, Dihydrate; Sodium Phosphate, Monobasic, Monohydrate;

Sodium Polyacrylate (2500000 Mw); Sodium Pyrophosphate; Sodium Pyrrolidone Carboxylate; Sodium Starch Glycolate; Sodium Succinate Hexahydrate; Sodium Sulfate; Sodium Sulfate Anhydrous; Sodium Sulfate Decahydrate; Sodium Sulfite; Sodium Sulfosuccinated Undecyclenic Monoalkylolamide; Sodium Tartrate; Sodium Thioglycolate; Sodium Thiomalate; Sodium Thiosulfate; Sodium Thiosulfate Anhydrous; Sodium Trimetaphosphate; Sodium

Xylenesulfonate; Somay 44; Sorbic Acid; Sorbitan; Sorbitan Isostearate; Sorbitan Monolaurate; Sorbitan Monooleate; Sorbitan Monopalmitate; Sorbitan Monostearate; Sorbitan Sesquioleate; Sorbitan Trioleate; Sorbitan Tristearate; Sorbitol; Sorbitol Solution; Soybean Flour; Soybean Oil; Spearmint Oil; Spermaceti; Squalane; Stabilized Oxychloro Complex; Stannous 2- Ethylhexanoate; Stannous Chloride; Stannous Chloride Anhydrous; Stannous Fluoride; Stannous Tartrate; Starch; Starch 1500, Pregelatinized; Starch, Corn; Stearalkonium Chloride;

Stearalkonium Hectorite/Propylene Carbonate; Stearamidoethyl Diethylamine; Steareth-10; Steareth-100; Steareth-2; Steareth-20; Steareth-21; Steareth-40; Stearic Acid; Stearic

Diethanolamide; Stearoxytrimethylsilane; Steartrimonium Hydrolyzed Animal Collagen; Stearyl Alcohol; Sterile Water For Inhalation; Styrene/Isoprene/Styrene Block Copolymer; Succimer; Succinic Acid; Sucralose; Sucrose; Sucrose Distearate; Sucrose Polyesters; Sulfacetamide Sodium; Sulfobutylether .Beta.-Cyclodextrin; Sulfur Dioxide; Sulfuric Acid; Sulfurous Acid; Surfactol Qs; Tagatose, D-; Talc; Tall Oil; Tallow Glycerides; Tartaric Acid; Tartaric Acid, Dl-; Tenox; Tenox-2; Tert-Butyl Alcohol; Tert-Butyl Hydroperoxide; Tert-Butylhydroquinone;

Tetrakis(2-Methoxyisobutylisocyanide)Copper(I) Tetrafluoroborate; Tetrapropyl Orthosilicate; Tetrofosmin; Theophylline; Thimerosal; Threonine; Thymol; Tin; Titanium Dioxide;

Tocopherol; Tocophersolan; Total parenteral nutrition, lipid emulsion; Triacetin; Tricaprylin; Trichloromonofluoromethane; Trideceth-10; Triethanolamine Lauryl Sulfate; Trifluoroacetic Acid; Triglycerides, Medium Chain; Trihydroxystearin; Trilaneth-4 Phosphate; Trilaureth-4 Phosphate; Trisodium Citrate Dihydrate; Trisodium Hedta; Triton 720; Triton X-200; Trolamine; Tromantadine; Tromethamine (TRIS); Tryptophan; Tyloxapol; Tyrosine; Undecylenic Acid; Union 76 Amsco-Res 6038; Urea; Valine; Vegetable Oil; Vegetable Oil Glyceride, Hydrogenated; Vegetable Oil, Hydrogenated; Versetamide; Viscarin; Viscose/Cotton; Vitamin E; Wax, Emulsifying; Wecobee Fs; White Ceresin Wax; White Wax; Xanthan Gum; Zinc; Zinc Acetate; Zinc Carbonate; Zinc Chloride; and/or Zinc Oxide.

Pharmaceutical formulations disclosed herein may include cations or anions. In one embodiment, the formulations include metal cations such as, but not limited to, Zn2+, Ca2+, Cu2+, Mn2+, Mg+ and combinations thereof.

In some embodiments, pharmaceutical formulations disclosed herein may include solvates. Solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N’-dimethylformamide (DMF), N,N’-dimethylacetamide

(DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)- pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2- pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a“hydrate.”

In one embodiment, the inactive ingredient may be ethyl cellulose.

In some embodiments, the pharmaceutical formulation may include one or more pectin at a concentration of from about 0.0001% (w/w) to about 0.001% (w/w), from about 0.001% (w/w) to about 0.01% (w/w), from about 0.01 % (w/w) to about 0.1 % (w/w), from about 0.1% (w/w) to about 1% (w/w), from about 0.1 % (w/w) to about 10% (w/w), from about 0.5% (w/w) to about 5% (w/w), from about 1% (w/w) to about 10% (w/w), from about 10% (w/w) to about 50% (w/w), from about 5% (w/w) to about 15% (w/w), from about 10% (w/w) to about 30% (w/w), from about 10% (w/w) to about 40% (w/w), from about 15% (w/w) to about 45% (w/w), from about 20% (w/w) to about 55% (w/w), from about 20% (w/w) to about 80% (w/w)from about 25% (w/w) to about 65% (w/w), from about 30% (w/w) to about 70% (w/w), from about 35% (w/w) to about 75% (w/w), from about 40% (w/w) to about 80% (w/w), from about 50% (w/w) to about 85% (w/w), from about 60% (w/w) to about 90% (w/w), from about 75% (w/w) to about 95% (w/w), from about 90% (w/w) to about 96% (w/w), from about 92% (w/w) to about 98% (w/w), from about 95% (w/w) to about 99% (w/w), from about 98% (w/w) to about 99.5% (w/w), and/or from about 99% (w/w) to about 99.9% (w/w).

Particles

In some embodiments, the pharmaceutical formulations of the present disclosure may be particles or may include particles. The term“particle” as used herein refers to a small portion of matter. In some embodiments, the pharmaceutical formulations may include polymeric particles, lipid particles, solid lipid particles, self-assembled particles, composite nanoparticles that include phospholipids, surfactants, proteins, polyaminoacids; inorganic particles, and/or any combinations thereof. In some embodiments, the therapeutic agent may be substantially encapsulated or partially encapsulated in the particles. In some embodiments, the therapeutic agents may be deposited and/or adsorbed on the surface of the particles. In some embodiments, the therapeutic agents may be incorporated into the particles. In some embodiments, the therapeutic agents are part of or a component of the particle. The therapeutic agent may be attached to the surface of the particle with covalent bonds, or via non-covalent interactions.

As used herein, the term“encapsulate” means to enclose, surround or encase. As it relates to the formulation of the therapeutic agents of the disclosure, encapsulation may be substantial, complete or partial. The term“substantially encapsulated” means that at least greater than 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.9 or greater than 99.999% of therapeutic agent of the disclosure may be enclosed, surrounded or encased within the particle.“Partially encapsulation” means that less than 10, 10, 20, 30, 4050 or less of the therapeutic agent may be enclosed, surrounded or encased within the particle. For example, at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the pharmaceutical formulation and/or therapeutic agent are encapsulated in the particle. Encapsulation may be determined by any known method.

Particles of varying sizes may be useful in the present disclosure. In one embodiment, the size of the particles may be adjusted for the intended application. The particles can be nanoparticles or microparticles. Particles with a width of from about 0.1 mm to about 100 mm are referred to herein as“microparticles.” Particles with a width of about 100 nm or less are referred to herein as“nanoparticles.” Microparticles and nanoparticles that are spherical in shape are termed microspheres and nanospheres, respectively. Pharmaceutical formulations described herein may include particles with uniform width or with ranges of widths. In some embodiments, particle preparations include average particle widths of or ranges of particle widths of from about 10 nm to about 25 nm, from about 20 nm to about 50 nm, from about 30 nm to about 75 nm, from about 40 nm to about 80 nm, from about 50 nm to about 100 nm, from about 0.05 mm to about 10 mm, from about 1 mm to about 20 mm, from about 2 mm to about 30 mm, from about 5 mm to about 40 mm, from about 10 mm to about 50 mm, from about 20 mm to about 60 mm, from about 30 mm to about 70 mm, from about 40 mm to about 80 mm, from about 50 mm to about 90 mm, from about 0.05 mm to about 2 mm, from about 0.1 mm to about 3 mm, from about 0.2 mm to about 4 mm, from about 0.5 mm to about 5 mm, from about 1 mm to about 6 mm, from about 2 mm to about 7 mm, from about 5 mm to about 10 mm, from about 10 nm to about 100 mm, from about 10 mm to about 10 mm, from about 50 nm to about 500 mm, from about 50 mm to about 5 mm, from about 100 nm to about 10 mm, or from about 1 mm to about 10 mm. In some embodiments, pharmaceutical formulation particles include average particle widths of at least 10 nm, at least 100 nm, at least 0.5 mm, at least 1 mm, at least 10 mm, at least 100 mm, at least 500 mm, at least 1 mm, or at least 10 mm.

In some embodiments, the therapeutic agent(s) of the present disclosure may be encapsulated in a lipid-based nanoparticulate formulation. The lipid-based nanoparticulate formulation may include micro- or nano-particles that each includes at least one amphipathic layer that comprises lipids and includes a liposome. A liposome, as used herein may be a vesicle comprising a bilayer having amphipathic lipids enclosing an internal solution. The liposome may be a large unilamellar vesicle (LUV). In one embodiment, the diameter of the liposome may be between 60 nm and 120 nm or between 70 and 110 nm. The liposome may comprise lipids including phosphoglycerides and sphingolipids, representative examples of which include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, pahnitoyloleoyl phosphatidylcholine, lysophosphatidylcholine,

lysophosphatidylethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoylphosphatidylcholine or dilinoleoylphosphatidylcholine. Other compounds lacking in phosphorus, such as sphingolipid and glycosphingolipid families may also be encompassed by certain embodiments. The phospholipids may include two acyl chains from 6 to 24 carbon atoms selected independently of one another and with varying degrees of unsaturation. Additionally, the amphipathic lipids described above may be mixed with other lipids including triacylglycerols and sterols. In one embodiment, the liposome may include the lipids l,2-distearoyl-sn-glycero-3- phosophocholine (DSPC)/Cholesterol. The precise ratios of the lipids may vary as required. A non-limiting example of a suitable ratio of DSPC/Cholesterol is 55:45. The liposomes may also include a hydrophilic polymer-lipid conjugate. The hydrophilic polymer may be a polyalkylether, such as polyethylene glycol. The hydrophilic polymer-lipid conjugate may be generally prepared from a lipid that has a functional group at the polar head moiety that is chemically conjugated to the hydrophilic polymer. An example of such a lipid is phosphatidylethanolamine. The inclusion of such hydrophilic polymer-lipid conjugates in a liposome can increase its circulation longevity in the bloodstream after administration. The hydrophilic polymer is biocompatible and has a solubility in water that permits the polymer to extend away from the liposome outer surface. The polymer is generally flexible and may provide uniform surface coverage of the liposome outer surface. In some embodiments, inclusion of one or more hydrophilic polymer-lipid conjugate may increase the amount of the transition metal encapsulated in the liposome. In one

embodiment, the liposome may include a hydrophilic polymer, such as polyethylene glycol (PEG) at between 1 and 20 mol% or between 2 and 10 mol%. An example of a formulation comprising PEG is DSPC/cholesterol/PEG (50:45:5, mole ratio) or DSPC /PEG (95:5, mole ratio). The specific ratios of the lipids, however, may vary according to embodiments visualized by persons skilled in the art.

The liposome may include a metal ion that may be capable of forming a complex with the therapeutic agent. The metal ion may be an ion of a transition metal or a Group lllb metal. The transition metal may be from Group IB, 2B, 3B, 4B, 5B, 6B, 7B and 8B (groups 3-12). Examples of transition metals include copper, zinc, manganese, iron, cobalt and nickel. The Group lllb metal may be from the boron family, which includes boron, aluminum, gallium, indium, thallium and nihonium. In one embodiment, the metal may be in the 2⁺ oxidation state. In another embodiment, the metal may have d-orbitals. The metal ion may be incorporated inside the liposome during its preparation. In another embodiment, the liposome is formed with a lipid having a chelating group that binds a metal ion. In this exemplary embodiment, the metal that is inside the liposome may be associated with a lipid that makes up an inner leaflet of the bilayer.

Any of the lipid nano particles and/or methods of making the same as described in International Patent Publication WO2017100925 may be useful in the preparation of the pharmaceutical formulations described herein (the contents of which are herein incorporated by reference in their entirety).

In some embodiments, the lipid nanoparticles of the present disclosure may also include a fatty alcohol, which may increase the rate of therapeutic agent release . For example, nanoparticles of the disclosure may include a C_g-C₃₀ alcohol such as cetyl alcohol, octanol, stearyl alcohol, arachidyl alcohol, docosonal, or octasonal.

In some embodiments, the nanoparticles may be gold nanoparticles comprising a core of gold atoms that may be functionalized by the addition of a monolayer of moieties containing a thiol group.

In some embodiments, pharmaceutical formulations of the present disclosure may include, lipid nanoparticle that contain disulfiram formulated with D-Į-tocopheryl polyethylene glycol 1000 succinate (vitamin E-TPGS-modified) as described in Baneerjee et al.2019

(Banerjee P, Geng T, Mahanty A, Li T, Zong L, Wang B. Int J Pharm.2019 Feb 25;557:374- 389; the contents of which are incorporated by reference in its entirety). In some embodiments, pharmaceutical formulations of the present disclosure may include, lipid nanoparticle may be disulfiram copper nanoparticles as described in Chen et al. (Chen et al. ACS Appl Mater Interfaces.2018 Dec 5;10(48):41118-41128; the contents of which are herein incorporated by reference in its entirety).

III. ADMINISTRATION & DOSING

Administration

In some embodiments, pharmaceutical formulations that include therapeutic agents may be administered according to one or more administration routes. In some embodiments, administration is enteral (into the intestine), transdermal, intravenous bolus, intralesional (within or introduced directly to a localized lesion), intrapulmonary (within the lungs or its bronchi), diagnostic, intraocular (within the eye), transtympanic (across or through the tympanic cavity), intravesical infusion, sublingual, nasogastric (through the nose and into the stomach), spinal, intracartilaginous (within a cartilage), insufflation (snorting), rectal, intravascular (within a vessel or vessels), buccal (directed toward the cheek), dental (to a tooth or teeth), intratesticular (within the testicle), intratympanic (within the aurus media), percutaneous, intrathoracic (within the thorax), submucosal, cutaneous, epicutaneous (application onto the skin), dental intracornal, intramedullary (within the marrow cavity of a bone), intra-abdominal, epidural (into the dura matter), intramuscular (into a muscle), intralymphatic (within the lymph), iontophoresis (by means of electric current where ions of soluble salts migrate into the tissues of the body), subcutaneous (under the skin), intragastric (within the stomach), nasal administration (through the nose), transvaginal, intravenous drip, endosinusial, intraprostatic (within the prostate gland), soft tissue, intradural (within or beneath the dura), subconjunctival, oral (by way of the mouth), peridural, parenteral, intraduodenal (within the duodenum), intracisternal (within the cisterna magna cerebellomedularis), periodontal, periarticular, biliary perfusion, intracoronary (within the coronary arteries), intrathecal (within the cerebrospinal fluid at any level of the cerebrospinal axis), intrameningeal (within the meninges), intracavernous injection (into a pathologic cavity) intracavitary (into the base of the penis), intrabiliary, subarachnoid, intrabursal, ureteral (to the ureter), intratendinous (within a tendon), auricular (in or by way of the ear), intracardiac (into the heart), enema, intraepidermal (to the epidermis), intraventricular (within a ventricle),

intramyocardial (within the myocardium), intratubular (within the tubules of an organ), vaginal, sublabial, intracorporus cavernosum (within the dilatable spaces of the corporus cavernosa of the penis), intradermal (into the skin itself), intravitreal (through the eye), perineural, cardiac perfusion, irrigation (to bathe or flush open wounds or body cavities), in ear drops, endotracheal, intraosseous infusion (into the bone marrow), caudal block, intrauterine, transtracheal (through the wall of the trachea), intra-articular, intracorneal (within the cornea), endocervical,

extracorporeal, intraspinal (within the vertebral column), transmucosal (diffusion through a mucous membrane), topical, photopheresis, oropharyngeal (directly to the mouth and pharynx), occlusive dressing technique (topical route administration which is then covered by a dressing which occludes the area), transplacental (through or across the placenta), intrapericardial (within the pericardium), intraarterial (into an artery), interstitial, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), intrapleural (within the pleura), infiltration, intrabronchial, intrasinal (within the nasal or periorbital sinuses), intraductal (within a duct of a gland), intracaudal (within the cauda equine), nerve block, retrobulbar (behind the pons or behind the eyeball), intravenous (into a vein), intra-amniotic, conjunctival, intrasynovial (within the synovial cavity of a joint), gastroenteral, intraluminal (within a lumen of a tube), electro-osmosis, intraileal (within the distal portion of the small intestine), intraesophageal (to the esophagus), extra-amniotic administration, hemodialysis, intragingival (within the gingivae), intratumor (within a tumor), eye drops (onto the conjunctiva), laryngeal (directly upon the larynx), urethral (to the urethra), intravaginal administration, intraperitoneal (infusion or injection into the peritoneum), respiratory (within the respiratory tract by inhaling orally or nasally for local or systemic effect), intradiscal (within a disc), ophthalmic (to the external eye), and/or intraovarian (within the ovary).

In some embodiments, pharmaceutical formulations that include therapeutic agents may be administered by intraarticular administration, extracorporeal administration,

intrabronchial administration, endocervical administration, endosinusial administration, endotracheal administration, enteral administration, epidural administration, intra-abdominal administration, intrabiliary administration, intrabursal administration, oropharyngeal

administration, interstitial administration, intracardiac administration, intracartilaginous administration, intracaudal administration, intracavernous administration, intracerebral administration, intracorporous cavernosum, intracavitary administration, intracorneal

administration, intracisternal administration, cranial administration, intracranial administration, intradermal administration, intralesional administration, intratympanic administration, intragingival administration, intraocular administration, intradiscal administration, intraductal administration, intraduodenal administration, ophthalmic administration, intradural

administration, intraepidermal administration, intraesophageal administration, nasogastric administration, nasal administration, laryngeal administration, intraventricular administration, intragastric administration, intrahepatic administration, intraluminal administration, intravitreal administration, intravesicular administration, intralymphatic administration, intramammary administration, intramedullary administration, intrasinal administration, intrameningeal administration, intranodal administration, intraovarian administration, intraperitoneal administration, intrapleural administration, intraprostatic administration, intraluminal administration, intraspinal administration, intrasynovial administration, intratendinous administration, intratesticular administration, subconjunctival administration,

intracerebroventricular administration, epicutaneous administration, intravenous administration, retrobulbar administration, periarticular administration, intrathoracic administration, subarachnoid administration, intratubular administration, periodontal administration, transtympanic administration, transtracheal administration, intratumor administration, vaginal administration, urethral administration, intrauterine administration, oral administration, gastroenteral administration, parenteral administration, sublingual administration, ureteral administration, percutaneous administration, peridural administration, transmucosal

administration, perineural administration, transdermal administration, rectal administration, soft tissue administration, intraarterial administration, subcutaneous administration, topical administration, extra-amniotic administration, ear drops, or intravesical infusion.

Pharmaceutical formulations of the present disclosure may be administered orally but any suitable route of administration may be employed for providing a subject with an effective dosage of drugs of the chemical compositions described herein. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. In certain embodiments, it may be advantageous that the compositions described herein be administered orally.

Pharmaceutical formulations of the present disclosure may be administered in the conventional manner by any route where they are active. Administration can be systemic, parenteral, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal,

transdermal, oral, buccal, or ocular routes, or intravaginally, by inhalation, by depot injections, or by implants. Thus, modes of administration of the composition of the present disclosure (either alone or in combination with other pharmaceuticals) can be, but are not limited to, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), or by use of vaginal creams, suppositories, pessaries, vaginal rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams. For administration by inhalation or intranasal, pharmaceutical formulation may be delivered in the form of an aerosol spray presentation from pressurized packs or nebulizers. The compounds may also be delivered in the form of a cream, liquid, spray, powder, or suppository. A metered dose of the formulation can be provided from a reservoir of the formulation. In addition, predetermined dosages can be provided, for example, suppository forms can be provided for insertion into the nose having a

predetermined dosage. Kits can be provided, where prepared dosage forms and

instructions for administering the dosages are included.

Suitable topical formulations for use in the present embodiments may also include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, gels, and the like.

In some embodiments, pharmaceutical formulations present disclosure may be administered parenterally. Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients (e.g. therapeutic agent), liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments for parenteral administration, formulations are prepared by the inclusion of solubilizing agents such as CREMOPHOR^®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof. In other embodiments, surfactants are included such as hydroxypropylcellulose.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables.

Injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of active ingredients, it is often desirable to slow the absorption of active ingredients from subcutaneous or intramuscular injections. This may be accomplished by the use of liquid suspensions of crystalline or amorphous material with poor water solubility. The rate of absorption of active ingredients depends upon the rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered therapeutic agent form may be accomplished by dissolving or suspending the therapeutic agent in an oil vehicle. Injectable depot forms are made by forming micro encapsulated matrices of the therapeutic agent in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of therapeutic agent to polymer and the nature of the particular polymer employed, the rate of therapeutic agent release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).

Depot injectable formulations are prepared by entrapping the therapeutic agent in liposomes or microemulsions which are compatible with body tissues.

In one embodiment, disulfiram pharmaceutical formulations may be administered via injections using methods described by Wehbe et al., Phillips et al. and/or Cid et al. (Wehbe et al. Int J Nanomedicine.2017 May 31;12:4129-4146; Philips et al. Am J Hosp Pharm.1985

Feb;42(2):343-5; Cid et al. Biopharm Drug Dispos.1991 Mar;12(2):163-9; the contents of each of which are herein incorporated by reference in their entirety). Rectal and vaginal administration

In some embodiments, pharmaceutical formulations of the present disclosure may be administered rectally and/or vaginally. Formulations for rectal or vaginal administration are typically suppositories which may be prepared by mixing compositions with suitable non- irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

In one embodiment, disulfiram pharmaceutical formulations may be administered using vaginal tablets as described by Baffoe et al. 2014 (Baffoe et al.2014, J. Pharmacy and Pharmacology, 67, pp.189–198189; the contents of which are herein incorporated by reference in their entirety). Ocular administration

In some embodiments, pharmaceutical formulations of the present disclosure may be administered through the ocular route. In some embodiments, the pharmaceutical formulations may be prepared for topical ocular delivery using any of the methods described in Wang et al. (Wang et al. Curr Eye Res.2004 Jul;29(1):51-8 and Wang et al. J Pharm Pharmacol.2004 Oct;56(10):1251-7; the contents of each of which are herein incorporated by reference in their entirety). Any of the methods for ocular delivery described by Nagai et al.2016, Nagai et al. 2015, Nabekura et al.2000, and/or Ito et al.2000 may be useful in the use and/or delivery of the pharmaceutical formulations of the present disclosure (Nagai et al.2016;136(10):1385-1390; Nagai et al. Biol Pharm Bull.2016;39(11):1881-1887; Nagai et al.2015 Exp Eye Res.2015 Mar;132:115-23; Nabekura et al.2000 Biol Pharm Bull.2000 May;23(5):616-20; Ito et al. Biol Pharm Bull.2000 Mar;23(3):327-33; the contents of each of which are herein incorporated by reference in their entirety). Oral administration

In some embodiments, pharmaceutical formulations of the present disclosure may be administered orally. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, an active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient such as sodium citrate or dicalcium phosphate and/or fillers or extenders (e.g. starches, lactose, sucrose, glucose, mannitol, and silicic acid), binders (e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), humectants (e.g. glycerol), disintegrating agents (e.g. agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution retarding agents (e.g.

paraffin), absorption accelerators (e.g. quaternary ammonium compounds), wetting agents (e.g. cetyl alcohol and glycerol monostearate), absorbents (e.g. kaolin and bentonite clay), and lubricants (e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents. Besides inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. Topical or transdermal administration

As described herein, pharmaceutical formulations of the present disclosure may be formulated for administration topically. The skin may be an ideal target site for delivery as it is readily accessible. Three routes may be commonly considered to deliver pharmaceutical formulations of the present disclosure to the skin: (i) topical application (e.g. for local/regional treatment and/or cosmetic applications); (ii) intradermal injection (e.g. for local/regional treatment and/or cosmetic applications); and (iii) systemic delivery (e.g. for treatment of dermatologic diseases that affect both cutaneous and extracutaneous regions). pharmaceutical formulations of the present disclosure may be delivered to the skin by several different approaches known in the art.

Dosage forms for topical and/or transdermal administration may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, active ingredients are admixed under sterile conditions with pharmaceutically acceptable excipients and/or any needed preservatives and/or buffers.

Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.

Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of active ingredient may be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

As described herein, in some embodiments, pharmaceutical formulations of the present disclosure may be formulated in depots for extended release. Generally, specific organs or tissues (“target tissues”) may be targeted for administration.

In some aspects of the disclosure, pharmaceutical compositions, therapeutic agents of the present disclosure are spatially retained within or proximal to target tissues. Provided are methods of providing pharmaceutical formulations, therapeutic agents, to target tissues of mammalian subjects by contacting target tissues (which comprise one or more target cells) with pharmaceutical formulations, therapeutic agents, under conditions such that they are substantially retained in target tissues, meaning that at least 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the composition is retained in the target tissues. Advantageously, retention is determined by measuring the amount of pharmaceutical formulations, therapeutic agents, that enter one or more target cells. For example, at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9%, 99.99% or greater than 99.99% of pharmaceutical formulations, therapeutic agents, administered to subjects are present intracellularly at a period of time following administration.

Any of the methods for depot preparation and/or administration described in U.S. Patent No.6,203,813 may be used herein (the contents of which are herein incorporated by reference in its entirety). Pulmonary administration

In some embodiments, pharmaceutical formulations, therapeutic agents of the present disclosure may be prepared, packaged, and/or sold in formulations suitable for pulmonary administration. In some embodiments, such administration is via the buccal cavity. In some embodiments, formulations may comprise dry particles comprising active ingredients. In such embodiments, dry particles may have a diameter in the range from about 0.5 nm to about 7 nm or from about 1 nm to about 6 nm. In some embodiments, formulations may be in the form of dry powders for administration using devices comprising dry powder reservoirs to which streams of propellant may be directed to disperse such powder. In some embodiments, self-propelling solvent/powder dispensing containers may be used. In such embodiments, active ingredients may be dissolved and/or suspended in low-boiling propellant in sealed containers. Such powders may comprise particles wherein at least 98% of the particles by weight have diameters greater than 0.5 nm and at least 95% of the particles by number have diameters less than 7 nm. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nm and at least 90% of the particles by number have a diameter less than 6 nm. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally, propellants may constitute 50% to 99.9% (w/w) of the composition, and active ingredient may constitute 0.1% to 20% (w/w) of the composition. Propellants may further comprise additional ingredients such as liquid non-ionic and/or solid anionic surfactant and/or solid diluent (which may have particle sizes of the same order as particles comprising active ingredients).

Pharmaceutical formulations prepared for pulmonary delivery may provide active ingredients in the form of droplets of solution and/or suspension. Such formulations may be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising active ingredients, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as

methylhydroxybenzoate. Droplets provided by this route of administration may have an average diameter in the range from about 0.1 nm to about 200 nm. Intranasal, nasal and buccal administration

In some embodiments, pharmaceutical compositions, therapeutic agents of the present disclosure may be administered nasally and/or intranasal. In some embodiments, formulations described herein useful for pulmonary delivery may also be useful for intranasal delivery. In some embodiments, formulations for intranasal administration comprise a coarse powder comprising the active ingredient (e.g. therapeutic agent) and having an average particle from about 0.2 Pm to 500 Pm. Such formulations are administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose.

Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical formulation may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using

conventional methods, and may, for example, 0.1% to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise powders and/or an aerosolized and/or atomized solutions and/or suspensions comprising active ingredients. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may comprise average particle and/or droplet sizes in the range of from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein. Controlled release

In some embodiments, therapeutic agents of the present disclosure may be formulated for controlled release. As used herein, the term“controlled release” refers to the regulated movement of factors from specific locations to surrounding areas. In some embodiments, the specific location is a depot. Controlled release of factors from depots may be regulated by interactions between therapeutic agents and depot components. Such interactions may, for example, modulate therapeutic agent diffusion rate and/or affect therapeutic agent stability and/or degradation.

In some embodiments, controlled release may be used to extend the therapeutic agent half-life. As used herein, the term“half-life” refers to the length of time necessary for levels of a factor to be reduced (e.g., through clearance or degradation) by 50%. Some therapeutic agents and/or active agents may exhibit shortened half-life in water (e.g., due to hydrolysis).

Pharmaceutical formulations described herein may protect therapeutic agents from exposure to water, thereby improving payload half-life. ). Pharmaceutical formulations described herein may protect therapeutic agents from exposure to acidic conditions (e.g., gastric pH) and maintain encapsulation/stabilization of the payloads. In some embodiments, methods of controlled release and formulations for controlled release may include any of those described in United States Publication US20170281536, the contents of which are herein incorporated by reference in their entirety. Methods of improving payload half-life may be carried out in vitro or in vivo.

Dosing

Pharmaceutical formulations described herein may be administered to a subject using any amount and any route of administration effective treating a disease, disorder, and/or condition. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular formulation, its mode of administration, its mode of activity, and the like.

In some embodiments, formulations in accordance with present disclosure may be administered at dosage levels sufficient to deliver a therapeutic agent dose of about 0.1 mg/kg to about 500 mg/kg body weight, from about 0.1 mg/kg to about 250 mg/kg body weight, from about 0.1 mg/kg to about 100 mg/kg body weight, from about 0.1 mg/kg to about 50 mg/kg body weight, from about 0.1 mg/kg to about 10 mg/kg body weight, and/or about 0.1 mg/kg to about 5 mg/kg body weight, from about 1 mg/kg to about 2 mg/kg body weight, from about 1mg/kg to about 10 mg/kg, from about 5mg/kg to about 15mg//kg, from about 10 mg/kg to about 20 mg/kg body weight, from about 20 mg/kg to about 30 mg/kg body weight, from about 30 mg/kg to about 40 mg/kg body weight, from about 40 mg/kg to about 50 mg/kg body weight, from about 50 mg/kg to about 60 mg/kg body weight, from about 60 mg/kg to about 70 mg/kg body weight, from about 70 mg/kg to about 80 mg/kg body weight, from about 80 mg/kg to about 90 mg/kg body weight, from about 90 mg/kg to about 100 mg/kg body weight, from about 100 mg/kg to about 110 mg/kg body weight, from about 110 mg/kg to about 120 mg/kg body weight, from about 120 mg/kg to about 130 mg/kg body weight, from about 130 mg/kg to about 140 mg/kg body weight, from about 140 mg/kg to about 150 mg/kg body weight, from about 150 mg/kg to about 160 mg/kg body weight, from about 160 mg/kg to about 170 mg/kg body weight, from about 170 mg/kg to about 180 mg/kg body weight, from about 180 mg/kg to about 190 mg/kg body weight, from about 190 mg/kg to about 200 mg/kg body weight, from about 15 mg/kg to about 25 mg/kg body weight, from about 25 mg/kg to about 35 mg/kg body weight, from about 35 mg/kg to about 45 mg/kg body weight, from about 45 mg/kg to about 55 mg/kg body weight, from about 55 mg/kg to about 65 mg/kg body weight, from about 65 mg/kg to about 75 mg/kg body weight, from about 75 mg/kg to about 85 mg/kg body weight, from about 85 mg/kg to about 95 mg/kg body weight, from about 95 mg/kg to about 105 mg/kg body weight, from about 105 mg/kg to about 115 mg/kg body weight, from about 115 mg/kg to about 125 mg/kg body weight, from about 125 mg/kg to about 135 mg/kg body weight, from about 135 mg/kg to about 145 mg/kg body weight, from about 145 mg/kg to about 155 mg/kg body weight, from about 155 mg/kg to about 165 mg/kg body weight, from about 165 mg/kg to about 175 mg/kg body weight, from about 175 mg/kg to about 185 mg/kg body weight, from about 185 mg/kg to about 195 mg/kg body weight, from about 195 mg/kg to about 205 mg/kg body weight.

In some embodiments, therapeutic agents described herein may be

administered at a dose of about 10-50ug/mL, 20ug/mL, or 40ug/mL.

In some embodiments, pharmaceutical formulations of the present disclosure are provided in one or more doses and are administered one or more times to subjects. Some pharmaceutical formulations are provided in only a single administration. Some pharmaceutical formulations are provided according to a dosing schedule that include two or more

administrations. Each administration may be at the same dose or may be different from a previous and/or subsequent dose. In some embodiments, subjects are provided an initial dose that is higher than subsequent doses (referred to herein as a“loading dose”). In some embodiments, doses are decreased over the course of administration. In some embodiments, dosing schedules include pharmaceutical formulation administration from about every 2 hours to about every 10 hours, from about every 4 hours to about every 20 hours, from about every 6 hours to about every 30 hours, from about every 8 hours to about every 40 hours, from about every 10 hours to about every 50 hours, from about every 12 hours to about every 60 hours, from about every 14 hours to about every 70 hours, from about every 16 hours to about every 80 hours, from about every 18 hours to about every 90 hours, from about every 20 hours to about every 100 hours, from about every 22 hours to about every 120 hours, from about every 24 hours to about every 132 hours, from about every 30 hours to about every 144 hours, from about every 36 hours to about every 156 hours, from about every 48 hours to about every 168 hours, from about every 2 days to about every 10 days, from about every 4 days to about every 15 days, from about every 6 days to about every 20 days, from about every 8 days to about every 25 days, from about every 10 days to about every 30 days, from about every 12 days to about every 35 days, from about every 14 days to about every 40 days, from about every 16 days to about every 45 days, from about every 18 days to about every 50 days, from about every 20 days to about every 55 days, from about every 22 days to about every 60 days, from about every 24 days to about every 65 days, from about every 30 days to about every 70 days, from about every 2 weeks to about every 8 weeks, from about every 3 weeks to about every 12 weeks, from about every 4 weeks to about every 16 weeks, from about every 5 weeks to about every 20 weeks, from about every 6 weeks to about every 24 weeks, from about every 7 weeks to about every 28 weeks, from about every 8 weeks to about every 32 weeks, from about every 9 weeks to about every 36 weeks, from about every 10 weeks to about every 40 weeks, from about every 11 weeks to about every 44 weeks, from about every 12 weeks to about every 48 weeks, from about every 14 weeks to about every 52 weeks, from about every 16 weeks to about every 56 weeks, from about every 20 weeks to about every 60 weeks, from about every 2 months to about every 6 months, from about every 3 months to about every 12 months, from about every 4 months to about every 18 months, from about every 5 months to about every 24 months, from about every 6 months to about every 30 months, from about every 7 months to about every 36 months, from about every 8 months to about every 42 months, from about every 9 months to about every 48 months, from about every 10 months to about every 54 months, from about every 11 months to about every 60 months, from about every 12 months to about every 66 months, from about 2 years to about 5 years, from about 3 years to about 10 years, from about 4 years to about 15 years, from about 5 years to about 20 years, from about 6 years to about 25 years, from about 7 years to about 30 years, from about 8 years to about 35 years, from about 9 years to about 40 years, from about 10 years to about 45 years, from about 15 years to about 50 years, or more than every 50 years.

The desired dosage may be delivered for a duration of about 5 days to 365 days, about 5 days to 300 days, about 5 days to 300 days, about 5 days to 250 days, about 5 days to 200 days, about 5 days to 100 days, about 5 days to 60 days, about days to 30 days, about 5 days to 14 days, or about 3 days to 7 days, preferably about 21 days to 28 days. In one embodiment, the desired dosage of the formulations described herein may be administered once daily or multiple times in a day. For example, a treatment regimen may include administering a dosage level sufficient to deliver 10 mg/kg body weight twice daily, 20 mg/kg body weight twice daily, 50 mg/kg body weight once daily, 10 mg/kg body weight three times daily, 20 mg/kg body weight four times daily, or 50 mg/kg body weight twice daily.

In some embodiments, pharmaceutical compositions or formulations of the disclosure may be adapted to deliver a prescribed dosage of one or more therapeutic agents to a cell, a group of cells, an organ or tissue, an animal or a human. Methods of incorporating therapeutic agents into pharmaceutical preparations are widely known in the art. The determination of an appropriate prescribed dosage of a pharmacologically active compound to include in a pharmaceutical formulation in order to achieve a desired biological outcome is within the skill level of an ordinary practitioner of the art. The pharmaceutical formulation may include excipients, such as without limitation, binders, coating, disintegrants, fillers, diluents, flavors, colors, lubricants, glidants, preservatives, sorbents, sweeteners, conjugated linoleic acid (CLA), gelatin, beeswax, purified water, glycerol, any type of oil, including, without limitation, fish oil or soybean oil, or the like. Pharmaceutical formulations can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as, e.g., polyethylene glycols. It will further be appreciated by an ordinary practitioner of the art that the term also encompasses those pharmaceutical formulations that contain an admixture of two or more pharmacologically active compounds, such compounds being administered, for example, as a combination therapy.

A pharmaceutical formulation in accordance with the present disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a“unit dose” refers to a discrete amount of the pharmaceutical formulation comprising a predetermined amount of therapeutic agent or other compounds. The amount of therapeutic agent may generally be equal to the dosage of therapeutic agent administered to a subject and/or a convenient fraction of such dosage including, but not limited to, one-half or one-third of such a dosage. Pulse dosing

In some embodiments, subjects may be administered a pulse dose of the

pharmaceutical formulations of the present disclosure. As used herein,“pulse” refers to the plurality of doses at spaced apart time intervals. Generally, upon administration of the first dose, the growth of Bsl may be inhibited, retarded and/or the bacteria may be killed. Following, the first dose, the Bsl bacteria levels may increase; and a second dose may be initiated. Eradication of Bsl may therefore be achieved by several rounds of pulse dosing. Pulse dosing may be employed to eliminate persistent Bsl. In some embodiments, pulse dosing schedules include pharmaceutical formulation administration from about every 2 hours to about every 10 hours, from about every 4 hours to about every 20 hours, from about every 6 hours to about every 30 hours, from about every 8 hours to about every 40 hours, from about every 10 hours to about every 50 hours, from about every 12 hours to about every 60 hours, from about every 14 hours to about every 70 hours, from about every 16 hours to about every 80 hours, from about every 18 hours to about every 90 hours, from about every 20 hours to about every 100 hours, from about every 22 hours to about every 120 hours, from about every 24 hours to about every 132 hours, from about every 30 hours to about every 144 hours, from about every 36 hours to about every 156 hours, from about every 48 hours to about every 168 hours, from about every 2 days to about every 10 days, from about every 4 days to about every 15 days, from about every 6 days to about every 20 days, from about every 8 days to about every 25 days, from about every 10 days to about every 30 days, from about every 12 days to about every 35 days, from about every 14 days to about every 40 days, from about every 16 days to about every 45 days, from about every 18 days to about every 50 days, from about every 20 days to about every 55 days, from about every 22 days to about every 60 days, from about every 24 days to about every 65 days, from about every 30 days to about every 70 days, from about every 2 weeks to about every 8 weeks, from about every 3 weeks to about every 12 weeks, from about every 4 weeks to about every 16 weeks, from about every 5 weeks to about every 20 weeks, from about every 6 weeks to about every 24 weeks, from about every 7 weeks to about every 28 weeks, from about every 8 weeks to about every 32 weeks, from about every 9 weeks to about every 36 weeks, from about every 10 weeks to about every 40 weeks, from about every 11 weeks to about every 44 weeks, from about every 12 weeks to about every 48 weeks, from about every 14 weeks to about every 52 weeks, from about every 16 weeks to about every 56 weeks, from about every 20 weeks to about every 60 weeks, from about every 2 months to about every 6 months, from about every 3 months to about every 12 months, from about every 4 months to about every 18 months, from about every 5 months to about every 24 months, from about every 6 months to about every 30 months, from about every 7 months to about every 36 months, from about every 8 months to about every 42 months, from about every 9 months to about every 48 months, from about every 10 months to about every 54 months, from about every 11 months to about every 60 months, from about every 12 months to about every 66 months, from about 2 years to about 5 years, from about 3 years to about 10 years, from about 4 years to about 15 years, from about 5 years to about 20 years, from about 6 years to about 25 years, from about 7 years to about 30 years, from about 8 years to about 35 years, from about 9 years to about 40 years, from about 10 years to about 45 years, from about 15 years to about 50 years, or more than every 50 years.

In one embodiment, the disulfiram pharmaceutical formulations may be administered at a dose of 40 mg/kg of body weight three time a day every day for three weeks. Any of the dosing schedules described in International Patent Publication WO2008068746 may be useful in the present disclosure (the contents of which are herein incorporated by reference in their entirety).

In some embodiments, the therapeutic agents of the present disclosure may be administered using any of the dosing schedules described in US Patent No. US 10, 322, 096; US Patent Publication Nos. US20070232692, US20120101154, US20170281536, US20190117595 and/or International Patent Publication Nos. WO1997005867, WO2008068746, WO2011107755, WO2012024616, WO2012050594, WO2012050594, WO2012076897, WO2013123426, WO2014015157, WO2014102801, WO2014172435, WO2016004218, WO2016170102, WO2016201350, WO2017077336, WO2017095738, and/or WO2017100925 (the contents of each of which are herein incorporated by reference in their entirety).

Combinations

In some embodiments, the pharmaceutical formulations of the present disclosure may be used in combination additional active agents such as antibiotics and/or vaccine. By “in combination with,” it is not intended to imply that the agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of the present disclosure.

In some embodiments, the present disclosure encompasses the delivery of

pharmaceutical, prophylactic, research, or diagnostic formulations in combination with agents that may improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.

The formulations of the present disclosure and the additional active agents may be administered simultaneously, sequentially or at any order. The formulations of the present disclosure and additional active agents may be administered at different dosages, with different dosing frequencies and/or different routes, whichever is suitable. The term “administered simultaneously”, as used herein, may mean that formulations of the present disclosure and the additional active agent may be substantially administered at the same time, e.g. as a mixture or in immediate subsequent sequence. The term“administered sequentially”, as used herein, may mean that the formulations of the present disclosure and the additional active agent may not be administered at the same time but one after the other, or in groups, with a specific time interval between administrations. The time interval may be the same or different between the respective administrations of the formulations of the present disclosure and the additional active agent and may be selected, for example, from the range of 2 minutes to 96 hours, 1 to 7 days or one, two or three weeks. Generally, the time interval between the administrations may be in the range of a few minutes to hours, such as in the range of 2 minutes to 72 hours, 30 minutes to 24 hours, or 1 to 12 hours.

IV. METHODS & USES

The present disclosure provides methods related to using the pharmaceutical formulations for the treatment and/or prevention of one or more diseases described herein. In some embodiments, the pharmaceutical formulations may be administered to the subject for the treatment of Lyme disease and Lyme disease related disorder including post- treatment Lyme disease syndrome (PTLDS), chronic Lyme disease (CLD) and/or inflammation. In some embodiments, the pharmaceutical formulations of the present disclosure may be administered to the subject to prevent the onset of Lyme disease, post- treatment Lyme disease syndrome (PTLDS), chronic Lyme disease (CLD) and/or inflammation.

Also provided herein are methods of evaluating the efficacy of the pharmaceutical formulations described herein in the treatment of Lyme disease, post- treatment Lyme disease syndrome (PTLDS), chronic Lyme disease (CLD) and/or inflammation. Efficacy of the pharmaceutical formulations may be evaluated using one or more parameters described herein.

In one embodiment, efficacy of the pharmaceutical formulations described herein may be evaluated using a Fatigue Severity Scale (FSS), a psychometrically validated self-report measure of fatigue. The measure may include 11 items inquiring about the severity of fatigue encountered by the subject in different situations. Scores for each item may range from 1 to 7, where 1 indicates strong disagreement and 7 strong agreement. Higher scores may indicate higher levels of fatigue. FSS may be assessed weekly over a 10 week period.

In one embodiment, efficacy of the pharmaceutical formulations described herein may be evaluated using a Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF), a self-reported questionnaire, with 16 items, that evaluate overall enjoyment and satisfaction with physical health, mood, work, household and leisure activities, social and family relationships, daily functioning, sexual life, economic status, overall well-being and medications. Responses may be scored on a 5-point scale ('not at all or never' to 'frequently or all the time'), where higher scores may indicate better enjoyment and satisfaction with life (possible range 14-70). The fourteen summated items may be used to create the total Q-LES-Q - SF score. Medications and overall life satisfaction parameters may be considered and scored independently Q-LES-Q-SF may he assessed weekly over a 10 week period.

In one embodiment, efficacy of the pharmaceutical formulations described herein may be evaluated using a health survey which may be a 36-item, patient-reported survey of patient health. The health survey may include eight scaled scores, which are the weighted sums of the questions in their section. The 8 scales may include-vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning mental health. Each scale may be directly transformed into a 0-100 scale, the lower the score the more disability and the higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.

In one embodiment, efficacy of the pharmaceutical formulations described herein may be evaluated using a general symptom questionnaire (GSQ-30), which assess multi systemic symptom burden. GSQ-30 may be a psychometrically validated 30 item self-report measure of symptom burden. The measure asks participants to rate how bothered they have been with a particular symptom over a 2-week time frame. Responses may be made on 5-point Likert scale ranging from "not at all" to "very much" (scored 0-4); and the total score ranges from 0-120. Higher scores may indicate more symptom severity.

In one embodiment, efficacy of the pharmaceutical formulations described herein maybe evaluated using PROMIS-29, a psychometrically validated 29 item self-report measure of 7 domains. These 7 domains may include- Depression, Anxiety, Physical Function, Pain

Interference, Fatigue, Sleep Disturbance, and Ability_' to Participate in Social Roles and Activities. The questions may be ranked on a 5-point Likert. Scale. PROMIS-29 may also include a 11-point rating scale for pain intensity. Norm-based scores may be calculated for each domain on the PROMIS measure. High scores represent more of the domain being measured. Thus, on symptom oriented domains of PROMIS-29 (anxiety-, depression, fatigue, pain interference, and sleep disturbance), higher scores represent worse symptomatology. On the function oriented domains (physical functioning and social role) higher scores may represent better functioning. In some embodiments, any of the parameters and/or outcomes measured in U.S.

clinical trial, NCT03891667 may be used to evaluate the efficacy of the pharmaceutical formulations described herein in the treatment of Lyme disease. Therapeutic uses

Cancer

Various cancers may be treated with pharmaceutical formulations of the present disclosure. As used herein, the term“cancer” refers to any of various malignant neoplasms characterized by the proliferation of anaplastic cells that tend to invade surrounding tissue and metastasize to new body sites and also refers to the pathological condition characterized by such malignant neoplastic growths. Cancers may be tumors or hematological malignancies, and include but are not limited to, all types of lymphomas/leukemias, carcinomas and sarcomas, such as those cancers or tumors found in the anus, bladder, bile duct, bone, brain, breast, cervix, colon/rectum, endometrium, esophagus, eye, gallbladder, head and neck, liver, kidney, larynx, lung, mediastinum (chest), mouth, ovaries, pancreas, penis, prostate, skin, small intestine, stomach, spinal marrow, tailbone, testicles, thyroid and uterus.

Types of carcinomas which may be treated with the pharmaceutical formulations of the present disclosure. include, but are not limited to, papilloma/carcinoma, choriocarcinoma, endodermal sinus tumor, teratoma, adenoma/adenocarcinoma, melanoma, fibroma, lipoma, leiomyoma, rhabdomyoma, mesothelioma, angioma, osteoma, chondroma, glioma,

lymphoma/leukemia, squamous cell carcinoma, small cell carcinoma, large cell undifferentiated carcinomas, basal cell carcinoma and sinonasal undifferentiated carcinoma.

Types of carcinomas which may be treated with the pharmaceutical formulations of the present disclosure include, but are not limited to, soft tissue sarcoma such as alveolar soft part sarcoma, angiosarcoma, dermatofibrosarcoma, desmoid tumor, desmoplastic small round cell tumor, extraskeletal chondrosarcoma, extraskeletal osteosarcoma, fibrosarcoma,

hemangiopericytoma, hemangiosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, lymphosarcoma, malignant fibrous histiocytoma, neurofibrosarcoma, rhabdomyosarcoma, synovial sarcoma, and Askin's tumor, Ewing's sarcoma (primitive neuroectodermal tumor), malignant hemangioendothelioma, malignant schwannoma,

osteosarcoma, and chondrosarcoma.

As a non-limiting example, the carcinoma which may be treated may be Acute granulocytic leukemia, Acute lymphocytic leukemia, Acute myelogenous leukemia,

Adenocarcinoma, Adenosarcoma, Adrenal cancer, Adrenocortical carcinoma, Anal cancer, Anaplastic astrocytoma, Angiosarcoma, Appendix cancer, Astrocytoma, Basal cell carcinoma, B- Cell lymphoma ), Bile duct cancer, Bladder cancer, Bone cancer, Bowel cancer, Brain cancer, Brain stem glioma, Brain tumor, Breast cancer, Carcinoid tumors, Cervical cancer,

Cholangiocarcinoma, Chondrosarcoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Colon cancer, Colorectal cancer, Craniopharyngioma, Cutaneous lymphoma,

Cutaneous melanoma, Diffuse astrocytoma, Ductal carcinoma in situ, Endometrial cancer, Ependymoma, Epithelioid sarcoma, Esophageal cancer, Ewing sarcoma, Extrahepatic bile duct cancer, Eye cancer, Fallopian tube cancer, Fibrosarcoma, Gallbladder cancer, Gastric cancer, Gastrointestinal cancer, Gastrointestinal carcinoid cancer, Gastrointestinal stromal tumors, General, Germ cell tumor, Glioblastoma multiforme, Glioma, Hairy cell leukemia, Head and neck cancer, Hemangioendothelioma, Hodgkin lymphoma, Hodgkin's disease, Hodgkin's lymphoma, Hypopharyngeal cancer, Infiltrating ductal carcinoma, Infiltrating lobular carcinoma, Inflammatory breast cancer, Intestinal Cancer, Intrahepatic bile duct cancer, Invasive / infiltrating breast cancer, Islet cell cancer, Jaw cancer, Kaposi sarcoma, Kidney cancer, Laryngeal cancer, Leiomyosarcoma, Leptomeningeal metastases, Leukemia, Lip cancer, Liposarcoma, Liver cancer, Lobular carcinoma in situ, Low-grade astrocytoma, Lung cancer, Lymph node cancer, Lymphoma, Male breast cancer, Medullary carcinoma, Medulloblastoma, Melanoma,

Meningioma, Merkel cell carcinoma, Mesenchymal chondrosarcoma, Mesenchymous,

Mesothelioma, Metastatic breast cancer, Metastatic melanoma, Metastatic squamous neck cancer, Mixed gliomas, Mouth cancer, Mucinous carcinoma, Mucosal melanoma, Multiple myeloma, Nasal cavity cancer, Nasopharyngeal cancer, Neck cancer, Neuroblastoma,

Neuroendocrine tumors, Non-Hodgkin lymphoma, Non-Hodgkin's lymphoma, Non-small cell lung cancer, Oat cell cancer, Ocular cancer, Ocular melanoma, Oligodendroglioma, Oral cancer, Oral cavity cancer, Oropharyngeal cancer, Osteogenic sarcoma, Osteosarcoma, Ovarian cancer, Ovarian epithelial cancer, Ovarian germ cell tumor, Ovarian primary peritoneal carcinoma, Ovarian sex cord stromal tumor, Paget's disease, Pancreatic cancer, Papillary carcinoma, Paranasal sinus cancer, Parathyroid cancer, Pelvic cancer, Penile cancer, Peripheral nerve cancer, Peritoneal cancer, Pharyngeal cancer, Pheochromocytoma, Pilocytic astrocytoma, Pineal region tumor, Pineoblastoma, Pituitary gland cancer, Primary central nervous system lymphoma, Prostate cancer, Rectal cancer, Renal cell cancer, Renal pelvis cancer, Rhabdomyosarcoma, Salivary gland cancer, Sarcoma, Sarcoma, bone, Sarcoma, soft tissue, Sarcoma, uterine, Sinus cancer, Skin cancer, Small cell lung cancer, Small intestine cancer, Soft tissue sarcoma, Spinal cancer, Spinal column cancer, Spinal cord cancer, Spinal tumor, Squamous cell carcinoma, Stomach cancer, Synovial sarcoma, T-cell lymphoma ), Testicular cancer, Throat cancer, Thymoma / thymic carcinoma, Thyroid cancer, Tongue cancer, Tonsil cancer, Transitional cell cancer, Transitional cell cancer, Transitional cell cancer, Triple-negative breast cancer, Tubal cancer, Tubular carcinoma, Ureteral cancer, Ureteral cancer, Urethral cancer, Uterine

adenocarcinoma, Uterine cancer, Uterine sarcoma, Vaginal cancer, and Vulvar cancer. Diseases and toxins

Various infectious diseases may be treated with the pharmaceutical formulations of the present disclosure. As used herein, the term“infectious disease” refers to any disorders caused by organisms such as bacteria, viruses, fungi or parasites. As a non-limiting example, the infectious disease may be Acute bacterial rhinosinusitis, 14-day measles, Acne, Acrodermatitis chronica atrophicans (ACA)-(late skin manifestation of latent Lyme disease), Acute hemorrhagic conjunctivitis, Acute hemorrhagic cystitis, Acute rhinosinusitis, Adult T-cell Leukemia- Lymphoma (ATLL), African Sleeping Sickness, AIDS (Acquired Immunodeficiency Syndrome), Alveolar hydatid, Amebiasis, Amebic meningoencephalitis, Anaplasmosis, Anthrax, Arboviral or parainfectious, Ascariasis -(Roundworm infections ), Aseptic meningitis, Athlete's foot (Tinea pedis ), Australian tick typhus, Avian Influenza, Babesiosis, Bacillary angiomatosis, Bacterial meningitis, Bacterial vaginosis, Balanitis, Balantidiasis, Bang's disease, Barmah Forest virus infection, Bartonellosis (Verruga peruana; Carrion's disease; Oroya fever ), Bat Lyssavirus Infection, Bay sore (Chiclero's ulcer ), Baylisascaris infection (Racoon roundworm infection), Beaver fever, Beef tapeworm, Bejel (endemic syphilis ), Biphasic meningoencephalitis, Black Bane, Black death , Black piedra, Blackwater Fever, Blastomycosis, Blennorrhea of the newborn, Blepharitis, Boils, Bornholm disease (pleurodynia), Borrelia miyamotoi Disease, Botulism, Boutonneuse fever, Brazilian purpuric fever, Break Bone fever, Brill, Bronchiolitis, Bronchitis, Brucellosis (Bang's disease ), Bubonic plague, Bullous impetigo, Burkholderia mallei (Glanders), Burkholderia pseudomallei (Melioidosis), Buruli ulcers (also Mycoburuli ulcers), Busse, Busse- Buschke disease (Cryptococcosis), California group encephalitis, Campylobacteriosis,

Candidiasis, Canefield fever (Canicola fever; 7-day fever; Weil's disease; leptospirosis; canefield fever), Canicola fever, Capillariasis, Carate, Carbapenem-resistant Enterobacteriaceae (CRE), Carbuncle, Carrion's disease, Cat Scratch fever, Cave disease, Central Asian hemorrhagic fever, Central European tick, Cervical cancer, Chagas disease, Chancroid (Soft chancre ), Chicago disease, Chickenpox (Varicella), Chiclero's ulcer, Chikungunya fever, Chlamydial infection, Cholera, Chromoblastomycosis, Ciguatera, Clap, Clonorchiasis (Liver fluke infection ),

Clostridium Difficile Infection, ClostriDium Perfringens (Epsilon Toxin), Coccidioidomycosis fungal infection (Valley fever; desert rheumatism), Coenurosis, Colorado tick fever, Condyloma accuminata, Condyloma accuminata( Warts), Condyloma lata, Congo fever, Congo hemorrhagic fever virus, Conjunctivitis , cowpox, Crabs, Crimean, Croup, Cryptococcosis, Cryptosporidiosis (Crypto), Cutaneous Larval Migrans, Cyclosporiasis, Cystic hydatid, Cysticercosis, Cystitis, Czechoslovak tick, D68 (EV-D68), Dacryocytitis, Dandy fever, Darling's Disease, Deer fly fever, Dengue fever (1, 2, 3 and 4), Desert rheumatism, Devil's grip, Diphasic milk fever, Diphtheria, Disseminated Intravascular Coagulation, Dog tapeworm, Donovanosis, Donovanosis (Granuloma inguinale), Dracontiasis, Dracunculosis, Duke's disease, Dum Dum Disease, Durand-Nicholas- Favre disease, Dwarf tapeworm, E. Coli infection (E.coli), Eastern equine encephalitis, Ebola Hemorrhagic Fever (Ebola virus disease EVD), Ectothrix, Ehrlichiosis (Sennetsu fever),

Encephalitis, Endemic Relapsing fever, Endemic syphilis, Endophthalmitis, Endothrix,

Enterobiasis (Pinworm infection), Enterotoxin - B Poisoning (Staph Food Poisoning),

Enterovirus Infection, Epidemic Keratoconjunctivitis, Epidemic Relapsing fever, Epidemic typhus, Epiglottitis, Erysipelis, Erysipeloid (Erysipelothricosis), Erythema chronicum migrans, Erythema infectiosum, Erythema marginatum, Erythema multiforme, Erythema nodosum, Erythema nodosum leprosum, Erythrasma, Espundia, Eumycotic mycetoma, European blastomycosis, Exanthem subitum (Sixth disease ), Eyeworm, Far Eastern tick, Fascioliasis, Fievre boutonneuse( Tick typhus), Fifth Disease (erythema infectiosum), Filatow-Dukes' Disease (Scalded Skin Syndrome; Ritter's Disease), Fish tapeworm, Fitz-Hugh-Curtis syndrome - Perihepatitis, Flinders Island Spotted Fever, Flu (Influenza), Folliculitis, Four Corners Disease, Four Corners Disease (Human Pulmonary Syndrome (HPS)), Frambesia, Francis disease, Furunculosis, Gas gangrene, Gastroenteritis, Genital Herpes, Genital Warts, German measles, Gerstmann-Straussler-Scheinker (GSS), Giardiasis, Gilchrist’s disease, Gingivitis,

Gingivostomatitis, Glanders, Glandular fever (infectious mononucleosis), Gnathostomiasis, Gonococcal Infection (Gonorrhea), Gonorrhea, Granuloma inguinale (Donovanosis), Guinea Worm, Haemophilus Influenza disease, Hamburger disease, Hansen's disease - leprosy, Hantaan disease, Hantaan-Korean hemorrhagic fever, Hantavirus Pulmonary Syndrome , Hantavirus Pulmonary Syndrome (HPS), Hard chancre, Hard measles, Haverhill fever - Rat bite fever, Head and Body Lice, Heartland fever, Helicobacterosis, Hemolytic Uremic Syndrome (HUS),

Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, Herpangina, Herpes- genital, Herpes labialis, Herpes- neonatal, Hidradenitis, Histoplasmosis, Histoplasmosis infection

(Histoplasmosis), His-Werner disease, HIV infection, Hookworm infections, Hordeola, Hordeola (Stye), HTLV, HTLV- associated myelopathy (HAM), Human granulocytic ehrlichiosis, Human monocytic ehrlichiosis, Human Papilloma virus (HPV), Human Pulmonary Syndrome , Hydatid cyst , Hydrophobia, Impetigo, Including congenital (German Measles), Inclusion conjunctivitis, Inclusion conjunctivitis - Swimming Pool conjunctivitis- Pannus, Infantile diarrhea, Infectious Mononucleosis, Infectious myocarditis, Infectious pericarditis, Influenza, Isosporiasis, Israeli spotted fever, Japanese Encephalitis, Jock itch, Jorge Lobo disease - lobomycosis, Jungle yellow fever, Junin Argentinian hemorrhagic fever, Kala Azar, Kaposi's sarcoma, Keloidal

blastomycosis, Keratoconjunctivitis , Kuru, Kyasanur forest disease, LaCrosse encephalitis, Lassa hemorrhagic fever, Legionellosis (Legionnaires Disease), Legionnaire's pneumonia, Lemierre's Syndrome (Postanginal septicemia), Lemming fever, Leprosy , Leptospirosis

(Nanukayami fever; Weil's disease), Listeriosis (Listeria), Liver fluke infection, Lobo's mycosis, Lockjaw, Loiasis, Louping Ill, Ludwig's angina, Lung fluke infection, Lung fluke infection (Paragonimiasis), Lyme disease, Lymphogranuloma venereum infection (LGV), Machupo Bolivian hemorrhagic fever, Madura foot, Mal del pinto, Malaria, Malignant pustule, Malta fever, Marburg hemorrhagic fever, Masters disease, Maternal Sepsis (Puerperal fever), Measles, Mediterranean spotted fever, Melioidosis (Whitmore's disease), Meningitis, Meningococcal Disease, MERS, Milker's nodule, Molluscum contagiosum, Moniliasis, monkeypox,

Mononucleosis, Mononucleosis-like syndrome, Montezuma's Revenge, Morbilli, MRSA

(methicillin-resistant Staphylococcus aureus) infection, Mucormycosis- Zygomycosis, Multiple Organ Dysfunction Syndrome or MODS, Multiple-system atrophy (MSA), Mumps, Murine typhus, Murray Valley Encephalitis(MVE), Mycoburuli ulcers, Mycoburuli ulcers- Buruli ulcers, Mycotic vulvovaginitis, Myositis, Nanukayami fever, Necrotizing fasciitis, Necrotizing fasciitis- Type 1, Necrotizing fasciitis- Type 2, Negishi, New world spotted fever, Nocardiosis,

Nongonococcal urethritis, Non-Polio (Non-Polio Enterovirus), Norovirus infection, North American blastomycosis, North Asian tick typhus, Norwalk virus infection, Norwegian itch, O'Hara disease, Omsk hemorrhagic fever, Onchoceriasis, Onychomycosis, Opisthorchiasis, Opthalmia neonatorium, Oral hairy leukoplakia, Orf, Oriental Sore, Oriental Spotted Fever, Ornithosis (Parrot fever; Psittacosis), Oroya fever, Otitis externa, Otitis media, Pannus,

Paracoccidioidomycosis, Paragonimiasis, Paralytic Shellfish Poisoning (Paralytic Shellfish Poisoning), Paronychia (Whitlow), Parotitis, PCP pneumonia, Pediculosis, Peliosis hepatica, Pelvic Inflammatory Disease , Pertussis (also called Whooping cough), Phaeohyphomycosis, Pharyngoconjunctival fever, Piedra (White Piedra), Piedra(Black Piedra), Pigbel, Pink eye conjunctivitis , Pinta, Pinworm infection, Pitted Keratolysis, Pityriasis versicolor (Tinea versicolor), Plague; Bubonic, Pleurodynia, Pneumococcal Disease, Pneumocystosis, Pneumonia, Pneumonic (Plague), Polio or Poliomyelitis, Polycystic hydatid, Pontiac fever, Pork tapeworm, Posada-Wernicke disease, Postanginal septicemia, Powassan, Progressive multifocal

leukencephalopathy, Progressive Rubella Panencephalitis, Prostatitis, Pseudomembranous colitis, Psittacosis, Puerperal fever, Pustular Rash diseases (Small pox), Pyelonephritis, Pylephlebitis, Q- Fever, Quinsy, Quintana fever (5-day fever), Rabbit fever, Rabies, Racoon roundworm infection, Rat bite fever, Rat tapeworm, Reiter Syndrome, Relapsing fever, Respiratory syncytial virus (RSV) infection, Rheumatic fever, Rhodotorulosis, Ricin Poisoning, Rickettsialpox, Rickettsiosis , Rift Valley Fever, Ringworm, Ritter's Disease, River Blindness, Rocky Mountain spotted fever, Rose Handler's disease (Sporotrichosis), Rose rash of infants, Roseola, Ross River fever, Rotavirus infection, Roundworm infections, Rubella, Rubeola, Russian spring, Salmonellosis gastroenteritis, San Joaquin Valley fever, Sao Paulo Encephalitis, Sao Paulo fever, SARS, Scabies Infestation (Scabies) (Norwegian itch ), Scalded Skin Syndrome, Scarlet fever

(Scarlatina), Schistosomiasis, Scombroid, Scrub typhus, Sennetsu fever, Sepsis (Septic shock), Severe Acute Respiratory Syndrome, Severe Acute Respiratory Syndrome (SARS), Shiga Toxigenic Escherichia coli (STEC/VTEC), Shigellosis gastroenteritis (Shigella), Shinbone fever, Shingles , Shipping fever, Siberian tick typhus, Sinusitis, Sixth disease, Slapped cheek disease , Sleeping sickness, Smallpox (Variola), Snail Fever, Soft chancre, Southern tick associated rash illness, Sparganosis, Spelunker’s disease, Sporadic typhus, Sporotrichosis, Spotted fever, Spring, St. Louis encephalitis, Staphylococcal Food Poisoning, Staphylococcal Infection, Strep. throat, Streptococcal Disease, Streptococcal Toxic-Shock Syndrome, Strongyloiciasis, Stye, Subacute Sclerosing Panencephalitis , Subacute Sclerosing Panencephalitis (SSPE), Sudden Acute

Respiratory Syndrome, Sudden Rash, Swimmer's ear, Swimmer's Itch, Swimming Pool conjunctivitis, Sylvatic yellow fever, Syphilis, Systemic Inflammatory Response Syndrome (SIRS), Tabes dorsalis (tertiary syphilis), Taeniasis, Taiga encephalitis, Tanner's disease, Tapeworm infections, Temporal lobe encephalitis, Temporal lobe encephalitis , tetani (Lock Jaw), Tetanus Infection, Threadworm infections, Thrush, Tick, Tick typhus, Tinea barbae, Tinea capitis, Tinea corporis, Tinea cruris, Tinea manuum, Tinea nigra, Tinea pedis, Tinea unguium, Tinea versicolor, Torulopsosis, Torulosis, Toxic Shock Syndrome, Toxoplasmosis, transmissible spongioform (CJD), Traveler's diarrhea, Trench fever 5, Trichinellosis, Trichomoniasis,

Trichomycosis axillaris, Trichuriasis, Tropical Spastic Paraparesis (TSP), Trypanosomiasis, Tuberculosis (TB), Tuberculosis, Tularemia, Typhoid Fever, Typhus fever, Ulcus molle, Undulant fever, Urban yellow fever, Urethritis, Vaginitis, Vaginosis, Vancomycin Intermediate (VISA), Vancomycin Resistant (VRSA), Varicella, Venezuelan Equine encephalitis, Verruga peruana, Vibrio cholerae (Cholera), Vibriosis (Vibrio), Vincent's disease or Trench mouth, Viral conjunctivitis , Viral Meningitis, Viral meningoencephalitis, Viral rash, Visceral Larval Migrans, Vomito negro, Vulvovaginitis, Warts, Waterhouse, Weil's disease, West Nile Fever, Western equine encephalitis, Whipple's disease, Whipworm infection, White Piedra, Whitlow, Whitmore's disease, Winter diarrhea, Wolhynia fever, Wool sorters' disease, Yaws, Yellow Fever,

Yersinosis, Yersinosis (Yersinia), Zahorsky's disease, Zika virus disease, Zoster, Zygomycosis, John Cunningham Virus (JCV), Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B, Hepatitis C, Hepatitis D, Respiratory syncytial virus (RSV), Herpes simplex virus 1 and 2, Human Cytomegalovirus, Epstein-Barr virus , Varicella zoster virus, Coronaviruses , Poxviruses, Enterovirus 71, Rubella virus, Human papilloma virus, Streptococcus pneumoniae, Streptococcus viridans. , Staphylococcus aureus (S. aureus), Methicillin-resistant Staphylococcus aureus (MRSA), Vancomycin-intermediate Staphylococcus aureus (VISA) , Vancomycin- resistant Staphylococcus aureus (VRSA), Staphylococcus epidermidis (S. epidermidis),

Clostridium Tetani, Bordetella pertussis, Bordetella paratussis, Mycobacterium, Francisella Tularensis, Toxoplasma gondii, Candida (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei and C. lusitaniae) and/or any other infectious diseases, disorders or syndromes.

Various toxins may be treated with the pharmaceutical formulations of the present disclosure. Non-limited examples of toxins include Ricin, Bacillus anthracis, Shiga toxin and Shiga-like toxin, Botulinum toxins.

Various tropical diseases may be treated with the pharmaceutical formulations of the present disclosure. Non-limited examples of tropical diseases include Chikungunya fever, Dengue fever, Chagas disease, Rabies, Malaria, Ebola virus, Marburg virus, West Nile Virus, Yellow Fever, Japanese encephalitis virus, St. Louis encephalitis virus.

Various foodborne illnesses and gastroenteritis may be treated with the pharmaceutical formulations of the present disclosure. Non-limited examples of foodborne illnesses and gastroenteritis include Rotavirus, Norwalk virus (Norovirus), Campylobacter jejuni, Clostridium difficile, Entamoeba histolytica, Helicobacter pylori, Enterotoxin B of Staphylococcus aureus, Hepatitis A virus (HAV), Hepatitis E, Listeria monocytogenes, Salmonella, Clostridium perfringens, and Salmonella.

Various infectious agents may be treated with the pharmaceutical formulations of the present disclosure. Non-limited examples of infectious agents include adenoviruses, Anaplasma phagocytophilium, Ascaris lumbricoides, Bacillus anthracis, Bacillus cereus, Bacteriodes sp, Barmah Forest virus, Bartonella bacilliformis, Bartonella henselae, Bartonella quintana, beta- toxin of Clostridium perfringens, Bordetella pertussis, Bordetella parapertussis, Borrelia burgdorferi, Borrelia miyamotoi, Borrelia recurrentis, Borrelia sp., Botulinum toxin, Brucella sp., Burkholderia pseudomallei, California encephalitis virus, Campylobacter, Candida albicans, chikungunya virus, Chlamydia psittaci, Chlamydia trachomatis, Clonorchis sinensis, Clostridium difficile bacteria, Clostridium tetani, Colorado tick fever virus, Corynebacterium diphtheriae, Corynebacterium minutissimum, Coxiella burnetii, coxsackie A, coxsackie B, Crimean-Congo hemorrhagic fever virus, cytomegalovirus, dengue virus, Eastern Equine encephalitis virus, Ebola viruses, echovirus, Ehrlichia chaffeensis., Ehrlichia equi., Ehrlichia sp., Entamoeba histolytica, Enterobacter sp., Enterococcus faecalis, Enterovirus 71, Epstein-Barr virus (EBV),

Erysipelothrix rhusiopathiae, Escherichia coli, Flavivirus, Fusobacterium necrophorum, Gardnerella vaginalis, Group B streptococcus, Haemophilus aegyptius, Haemophilus ducreyi, Haemophilus influenzae, hantavirus, Helicobacter pylori, Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, Hepatitis E, herpes simplex virus 1 and 2,, human herpes virus 6, human herpes Virus 8, human immunodeficiency virus 1 and 2, human T-cell leukemia viruses I and II, influenza viruses (A, B, C), Jamestown Canyon virus, Japanese encephalitis antigenic, Japanese encephalitis virus, John Cunninham virus, juninvirus, Kaposi's Sarcoma-associated Herpes Virus (KSHV), Klebsiella granulomatis, Klebsiella sp., Kyasanur Forest Disease virus, La Crosse virus, Lassavirus, Legionella pneumophila, Leptospira interrogans, Listeria monocytogenes, lymphocytic choriomeningitis virus, lyssavirus, Machupovirus, Marburg virus, measles virus, MERS coronavirus (MERS-CoV), Micrococcus sedentarius, Mobiluncus sp., Molluscipoxvirus, Moraxella catarrhalis, Morbilli- Rubeola virus, Mumpsvirus, Mycobacterium leprae,

Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycoplasma genitalium, Mycoplasma sp, Nairovirus,, Neisseria gonorrhoeae, Neisseria meningitidis, Nocardia, Norwalk virus, norovirus, Omsk hemorrhagic fever virus, papilloma virus, parainfluenza viruses 1-3, parapoxvirus, parvovirus B19, Peptostreptococccus sp., Plasmodium sp., polioviruses types I, II, and III, Proteus sp., Pseudomonas aeruginosa, Pseudomonas pseudomallei, Pseudomonas sp., rabies virus, respiratory syncytial virus, ricin toxin, Rickettsia australis, Rickettsia conori, Rickettsia honei, Rickettsia prowazekii, Ross River Virus, rotavirus, rubellavirus, Saint Louis encephalitis, Salmonella Typhi, Sarcoptes scabiei, SARS-associated coronavirus (SARS-CoV), Serratia sp., Shiga toxin and Shiga-like toxin, Shigella sp., Sin Nombre Virus, Snowshoe hare virus,

Staphylococcus aureus, Staphylococcus epidermidis, Streptobacillus moniliformis, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus agalactiae, Streptococcus group A-H, Streptococcus pneumoniae, Streptococcus pyogenes, Treponema pallidum subsp. Pallidum, Treponema pallidum var. carateum, Treponema pallidum var. endemicum, Tropheryma whippelii, Ureaplasma urealyticum, Varicella-Zoster virus, variola virus, Vibrio cholerae, West Nile virus, yellow fever virus, Yersinia enterocolitica, Yersinia pestis, and Zika virus.

Various rare diseases may be treated with the pharmaceutical formulations of the present disclosure. As used herein, the term“rare disease” refers to any disease that affects a small percentage of the population. As a non-limiting example, the rare disease may be Acrocephalosyndactylia, Acrodermatitis, Addison Disease, Adie Syndrome, Alagille Syndrome, Amylose, Amyotrophic Lateral Sclerosis, Angelman Syndrome, Angiolymphoid Hyperplasia with Eosinophilia, Arnold-Chiari Malformation, Arthritis, Juvenile Rheumatoid, Asperger Syndrome, Bardet-Biedl Syndrome, Barrett Esophagus, Beckwith-Wiedemann Syndrome, Behcet Syndrome, Bloom Syndrome, Bowen's Disease, Brachial Plexus Neuropathies, Brown- Sequard Syndrome, Budd-Chiari Syndrome, Burkitt Lymphoma, Carcinoma 256, Walker, Caroli Disease, Charcot-Marie-Tooth Disease, Chediak-Higashi Syndrome, Chiari-Frommel Syndrome, Chondrodysplasia Punctata, Colonic Pseudo-Obstruction, Colorectal Neoplasms, Hereditary Nonpolyposis, Craniofacial Dysostosis, Creutzfeldt-Jakob Syndrome, Crohn Disease, Cushing Syndrome, Cystic Fibrosis, Dandy-Walker Syndrome, De Lange Syndrome, Dementia, Vascular, Dermatitis Herpetiformis, DiGeorge Syndrome, Diffuse Cerebral Sclerosis of Schilder, Duane Retraction Syndrome, Dupuytren Contracture, Ebstein Anomaly, Eisenmenger Complex, Ellis- Van Creveld Syndrome, Encephalitis, Enchondromatosis, Epidermal Necrolysis, Toxic, Facial Hemiatrophy, Factor XII Deficiency, Fanconi Anemia, Felty's Syndrome, Fibrous Dysplasia, Polyostotic, Fox-Fordyce Disease, Friedreich Ataxia, Fusobacterium, Gardner Syndrome, Gaucher Disease, Gerstmann Syndrome, Giant Lymph Node Hyperplasia, Glycogen Storage Disease Type I, Glycogen Storage Disease Type II, Glycogen Storage Disease Type IV,

Glycogen Storage Disease Type V, Glycogen Storage Disease Type VII, Goldenhar Syndrome, Guillain-Barre Syndrome, Hallermann's Syndrome, Hamartoma Syndrome, Multiple, Hartnup Disease, Hepatolenticular Degeneration, Hepatolenticular Degeneration, Hereditary Sensory and Motor Neuropathy, Hirschsprung Disease, Histiocytic Necrotizing Lymphadenitis, Histiocytosis, Langerhans-Cell, Hodgkin Disease, Horner Syndrome, Huntington Disease, Hyperaldosteronism, Hyperhidrosis, Hyperostosis, Diffuse Idiopathic Skeletal, Hypopituitarism, Inappropriate ADH Syndrome, Intestinal Polyps, Isaacs Syndrome, Kartagener Syndrome, Kearns-Sayre Syndrome, Klippel-Feil Syndrome, Klippel-Trenaunay-Weber Syndrome, Kluver-Bucy Syndrome,

Korsakoff Syndrome, Lafora Disease, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome, Langer-Giedion Syndrome, Leigh Disease, Lesch-Nyhan Syndrome, Leukodystrophy, Globoid Cell, Li-Fraumeni Syndrome, Long QT Syndrome, Machado-Joseph Disease, Mallory- Weiss Syndrome, Marek Disease, Marfan Syndrome, Meckel Diverticulum, Meige Syndrome, Melkersson-Rosenthal Syndrome, Meniere Disease, Mikulicz' Disease, Miller Fisher Syndrome, Mobius Syndrome, Moyamoya Disease, Mucocutaneous Lymph Node Syndrome,

Mucopolysaccharidosis I, Mucopolysaccharidosis II, Mucopolysaccharidosis III,

Mucopolysaccharidosis IV, Mucopolysaccharidosis VI, Multiple Endocrine Neoplasia Type 1, Munchausen Syndrome by Proxy, Muscular Atrophy, Spinal, Narcolepsy, Neuroaxonal Dystrophies, Neuromyelitis Optica, Neuronal Ceroid-Lipofuscinoses, Niemann-Pick Diseases, Noonan Syndrome, Optic Atrophies, Hereditary, Osteitis Deformans, Osteochondritis,

Osteochondrodysplasias, Osteolysis, Essential, Paget Disease Extramammary, Paget's Disease, Mammary, Panniculitis, Nodular Nonsuppurative, Papillon-Lefevre Disease, Paralysis,

Pelizaeus-Merzbacher Disease, Pemphigus, Benign Familial, Penile Induration, Pericarditis, Constrictive, Peroxisomal Disorders, Peutz-Jeghers Syndrome, Pick Disease of the Brain, Pierre Robin Syndrome, Pigmentation Disorders, Pityriasis Lichenoides, Polycystic Ovary Syndrome, Polyendocrinopathies, Autoimmune, Prader-Willi Syndrome, Pupil Disorders, Rett Syndrome, Reye Syndrome, Rubinstein-Taybi Syndrome, Sandhoff Disease, Sarcoma, Ewing's, Schnitzler Syndrome, Sjogren's Syndrome, Sjogren-Larsson Syndrome, Smith-Lemli-Opitz Syndrome, Spinal Muscular Atrophies of Childhood, Sturge-Weber Syndrome, Sweating, Gustatory, Takayasu Arteritis, Tangier Disease, Tay-Sachs Disease, Thromboangiitis Obliterans,

Thyroiditis, Autoimmune, Tietze's Syndrome, Togaviridae Infections, Tolosa-Hunt Syndrome, Tourette Syndrome, Uveomeningoencephalitic Syndrome, Waardenburg's Syndrome, Wegener Granulomatosis, Weil Disease, Werner Syndrome, Williams Syndrome, Wilms Tumor, Wolff- Parkinson-White Syndrome, Wolfram Syndrome, Wolman Disease, Zellweger Syndrome, Zollinger-Ellison Syndrome, and von Willebrand Diseases.

Various autoimmune diseases and autoimmune-related diseases may be treated with the pharmaceutical formulations of the present disclosure. As used herein, the term“autoimmune disease” refers to a disease in which the body produces antibodies that attack its own tissues. As a non-limiting example, the autoimmune disease may be Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease,

Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti- TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune

hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmune oophoritis, Autoimmune pancreatitis, Autoimmune retinopathy, Autoimmune thrombocytopenic purpura (ATP), Autoimmune thyroid disease, Autoimmune urticaria, Axonal & neuronal neuropathies, Balo disease, Behcet’s disease, Bullous pemphigoid, Cardiomyopathy, Castleman disease, Celiac disease, Chagas disease, Chronic fatigue syndrome, Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronic recurrent multifocal ostomyelitis (CRMO), Churg-Strauss syndrome, Cicatricial

pemphigoid/benign mucosal pemphigoid, Crohn’s disease, Cogans syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST disease, Essential mixed cryoglobulinemia, Demyelinating neuropathies, Dermatitis herpetiformis, Dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressler’s syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic fasciitis, Erythema nodosum, Experimental allergic encephalomyelitis, Evans syndrome, Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis (temporal arteritis), Giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis (GPA) (formerly called Wegener’s Granulomatosis), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, Hemolytic anemia, Henoch-Schonlein purpura, Herpes gestationis, Hypogammaglobulinemia, Idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease,

Immunoregulatory lipoproteins, Inclusion body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus, Lichen sclerosis, Ligneous conjunctivitis, Linear IgA disease (LAD), Lupus (SLE), Lyme disease, chronic, Meniere’s disease, Microscopic polyangiitis, Mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis, Myositis, Narcolepsy, Neuromyelitis optica (Devic’s), Neutropenia, Ocular cicatricial pemphigoid, Optic neuritis, Palindromic rheumatism, PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), Paraneoplastic cerebellar degeneration, Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Parsonnage-Turner syndrome, Pars planitis (peripheral uveitis), Pemphigus, Peripheral neuropathy, Perivenous encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa, Type I, II, & III autoimmune polyglandular syndromes, Polymyalgia rheumatica, Polymyositis, Postmyocardial infarction syndrome, Postpericardiotomy syndrome, Progesterone dermatitis, Primary biliary cirrhosis, Primary sclerosing cholangitis, Psoriasis, Psoriatic arthritis, Idiopathic pulmonary fibrosis, Pyoderma gangrenosum, Pure red cell aplasia, Raynauds phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter’s syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis, Scleroderma, Sjogren’s syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis (SBE), Susac’s syndrome, Sympathetic ophthalmia, Takayasu’s arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome,

Transverse myelitis, Ulcerative colitis, Undifferentiated connective tissue disease (UCTD), Uveitis, Vasculitis, Vesiculobullous dermatosis, Vitiligo, and Wegener’s granulomatosis (now termed Granulomatosis with Polyangiitis (GPA). Various kidney diseases may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the kidney disease Abderhalden–Kaufmann– Lignac syndrome (Nephropathic Cystinosis), Abdominal Compartment Syndrome, Acute Kidney Failure/Acute Kidney Injury, Acute Lobar Nephronia, Acute Phosphate Nephropathy, Acute Tubular Necrosis, Adenine Phosphoribosyltransferase Deficiency, Adenovirus Nephritis, Alport Syndrome, Amyloidosis, ANCA Vasculitis Related to Endocarditis and Other Infections, Angiomyolipoma, Analgesic Nephropathy, Anorexia Nervosa and Kidney Disease, Angiotensin Antibodies and Focal Segmental Glomerulosclerosis, Antiphospholipid Syndrome, Anti-TNF-Į^ Therapy-related Glomerulonephritis, APOL1 Mutations, Apparent Mineralocorticoid Excess Syndrome, Aristolochic Acid Nephropathy, Chinese Herbal Nephropathy, Balkan Endemic 1HSKURSDWK\^^%DUWWHU^6\QGURPH^^%HHWXULD^^ȕ-Thalassemia Renal Disease, Bile Cast Nephropathy, BK Polyoma Virus Nephropathy in the Native Kidney, Bladder Rupture, Bladder Sphincter Dyssynergia, Bladder Tamponade, Border-Crossers' Nephropathy, Bourbon Virus and Acute Kidney Injury, Burnt Sugarcane Harvesting and Acute Renal Dysfunction, Byetta and Renal Failure, C1q Nephropathy, Cannabinoid Hyperemesis Acute Renal Failure, Cardiorenal syndrome, Carfilzomib-Indiced Renal Injury, CFHR5 nephropathy, Charcot–Marie–Tooth Disease with Glomerulopathy, Cherry Concentrate and Acute Kidney Injury, Cholesterol Emboli, Churg–Strauss syndrome, Chyluria, Colistin Nephrotoxicity, Collagenofibrotic Glomerulopathy, Collapsing Glomerulopathy, Collapsing Glomerulopathy Related to CMV, Congenital Nephrotic Syndrome, Conorenal syndrome (Mainzer-Saldino Syndrome or Saldino-Mainzer Disease), Contrast Nephropathy, Copper Sulpfate Intoxication, Cortical Necrosis, Crizotinib-related Acute Kidney Injury, Cryoglobuinemia, Crystalglobulin-Induced Nephropathy, Crystal-Induced Acute Kidney injury, Cystic Kidney Disease, Acquired, Cystinuria, Dasatinib-Induced Nephrotic-Range Proteinuria, Dense Deposit Disease (MPGN Type 2), Dent Disease (X-linked Recessive

Nephrolithiasis), Dialysis Disequilibrium Syndrome, Diabetes and Diabetic Kidney Disease, Diabetes Insipidus, Dietary Supplements and Renal Failure, Drugs of Abuse and Kidney Disease, Duplicated Ureter, EAST syndrome, Ebola and the Kidney, Ectopic Kidney, Ectopic Ureter, Edema, Swelling, Erdheim-Chester Disease, Fabry’s Disease, Familial Hypocalciuric

Hypercalcemia, Fanconi Syndrome, Fraser syndrome, Fibronectin Glomerulopathy, Fibrillary Glomerulonephritis and Immunotactoid Glomerulopathy, Fraley syndrome, Focal Segmental Glomerulosclerosis, Focal Sclerosis, Focal Glomerulosclerosis, Galloway Mowat syndrome, Giant Cell (Temporal) Arteritis with Kidney Involvement, Gestational Hypertension, Gitelman Syndrome, Glomerular Diseases, Glomerular Tubular Reflux, Glycosuria, Goodpasture

Syndrome, Hair Dye Ingestion and Acute Kidney Injury, Hantavirus Infection Podocytopathy, Hematuria (Blood in Urine), Hemolytic Uremic Syndrome (HUS), Atypical Hemolytic Uremic Syndrome (aHUS), Hemophagocytic Syndrome, Hemorrhagic Cystitis, Hemorrhagic Fever with Renal Syndrome (HFRS, Hantavirus Renal Disease, Korean Hemorrhagic Fever, Epidemic Hemorrhagic Fever, Nephropathis Epidemica), Hemosiderosis related to Paroxysmal Nocturnal Hemoglobinuria and Hemolytic Anemia, Hepatic Glomerulopathy, Hepatic Veno-Occlusive Disease, Sinusoidal Obstruction Syndrome, Hepatitis C-Associated Renal Disease, Hepatorenal Syndrome, Herbal Supplements and Kidney Disease, High Blood Pressure and Kidney Disease, HIV-Associated Nephropathy (HIVAN), Horseshoe Kidney (Renal Fusion), Hunner's Ulcer, Hyperaldosteronism, Hypercalcemia, Hyperkalemia, Hypermagnesemia, Hypernatremia, Hyperoxaluria, Hyperphosphatemia, Hypocalcemia, Hypokalemia, Hypokalemia-induced renal dysfunction, Hypokalemic Periodic Paralysis, Hypomagnesemia, Hyponatremia,

Hypophosphatemia, IgA Nephropathy, IgG4 Nephropathy, Interstitial Cystitis, Painful Bladder Syndrome (Questionnaire), Interstitial Nephritis, Ivemark's syndrome, Ketamine-Associated Bladder Dysfunction, Kidney Stones, Nephrolithiasis, Kombucha Tea Toxicity, Lead

Nephropathy and Lead-Related Nephrotoxicity, Leptospirosis Renal Disease, Light Chain Deposition Disease, Monoclonal Immunoglobulin Deposition Disease, Liddle Syndrome, Lightwood-Albright Syndrome, Lipoprotein Glomerulopathy, Lithium Nephrotoxicity, LMX1B Mutations Cause Hereditary FSGS, Loin Pain Hematuria, Lupus, Systemic Lupus Erythematosis, Lupus Kidney Disease, Lupus Nephritis, Lupus Nephritis with Antineutrophil Cytoplasmic Antibody Seropositivity, Lyme Disease-Associated Glomerulonephritis, Malarial Nephropathy, Malignancy-Associated Renal Disease, Malignant Hypertension, Malakoplakia, Meatal Stenosis, Medullary Cystic Kidney Disease, Medullary Sponge Kidney, Megaureter, Melamine Toxicity and the Kidney, Membranoproliferative Glomerulonephritis, Membranous Nephropathy, MesoAmerican Nephropathy, Metabolic Acidosis, Metabolic Alkalosis, Methotrexate-related Renal Failure, Microscopic Polyangiitis, Milk-alkalai syndrome, Minimal Change Disease, MDMA (Molly; Ecstacy; 3,4-Methylenedioxymethamphetamine) and Kidney Failure,

Multicystic dysplastic kidney, Multiple Myeloma, Myeloproliferative Neoplasms and

Glomerulopathy, Nail-patella Syndrome, Nephrocalcinosis, Nephrogenic Systemic Fibrosis, Nephroptosis (Floating Kidney, Renal Ptosis), Nephrotic Syndrome, Neurogenic Bladder, Nodular Glomerulosclerosis, Non-Gonococcal Urethritis, Nutcracker syndrome, Orofaciodigital Syndrome, Orotic Aciduria, Orthostatic Hypotension, Orthostatic Proteinuria, Osmotic Diuresis, Ovarian Hyperstimulation Syndrome, Page Kidney, Papillary Necrosis, Papillorenal Syndrome (Renal-Coloboma Syndrome, Isolated Renal Hypoplasia), Parvovirus B19 and the Kidney, The Peritoneal-Renal Syndrome, Posterior Urethral Valve, Post-infectious Glomerulonephritis, Post- streptococcal Glomerulonephritis, Polyarteritis Nodosa, Polycystic Kidney Disease, Posterior Urethral Valves, Preeclampsia, Propofol infusion syndrome, Proliferative Glomerulonephritis with Monoclonal IgG Deposits (Nasr Disease), Propolis (Honeybee Resin) Related Renal Failure, Proteinuria (Protein in Urine), Pseudohyperaldosteronism, Pseudohypobicarbonatemia, Pseudohypoparathyroidism, Pulmonary-Renal Syndrome, Pyelonephritis (Kidney Infection), Pyonephrosis, Radiation Nephropathy, Ranolazine and the Kidney, Refeeding syndrome, Reflux Nephropathy, Rapidly Progressive Glomerulonephritis, Renal Abscess, Peripnephric Abscess, Renal Agenesis, Renal Arcuate Vein Microthrombi-Associated Acute Kidney Injury, Renal Artery Aneurysm, Renal Artery Stenosis, Renal Cell Cancer, Renal Cyst, Renal Hypouricemia with Exercise-induced Acute Renal Failure, Renal Infarction, Renal Osteodystrophy, Renal Tubular Acidosis, Renin Secreting Tumors (Juxtaglomerular Cell Tumor), Reset Osmostat, Retrocaval Ureter, Retroperitoneal Fibrosis, Rhabdomyolysis, Rhabdomyolysis related to Bariatric surgery, Rheumatoid Arthritis-Associated Renal Disease, Sarcoidosis Renal Disease, Salt Wasting, Renal and Cerebral, Schistosomiasis and Glomerular Disease, Schimke immuno- osseous dysplasia, Scleroderma Renal Crisis, Serpentine Fibula-Polycystic Kidney Syndrome, Exner Syndrome, Sickle Cell Nephropathy, Silica Exposure and Chronic Kidney Disease, Sri Lankan Farmers' Kidney Disease, Sjögren's Syndrome and Renal Disease, Synthetic Cannabinoid Use and Acute Kidney Injury, Kidney Disease Following Hematopoietic Cell Transplantation, Kidney Disease Related to Stem Cell Transplantation, Thin Basement Membrane Disease, Benign Familial Hematuria, Trigonitis, Tuberculosis, Genitourinary, Tuberous Sclerosis, Tubular Dysgenesis, Immune Complex Tubulointerstitial Nephritis Due to Autoantibodies to the

Proximal Tubule Brush Border, Tumor Lysis Syndrome, Uremia, Uremic Optic Neuropathy, Ureteritis Cystica, Ureterocele, Urethral Caruncle, Urethral Stricture, Urinary Incontinence, Urinary Tract Infection, Urinary Tract Obstruction, Vesicointestinal Fistula, Vesicoureteral Reflux, Volatile Anesthetics and Acute Kidney Injury, Von Hippel-Lindau Disease,

Waldenstrom's Macroglobulinemic Glomerulonephritis, Warfarin-Related Nephropathy, Wasp Stings and Acute Kidney Injury, Wegener’s Granulomatosis, Granulomatosis with Polyangiitis, West Nile Virus and Chronic Kidney Disease, and Wunderlich syndrome.

Various cardiovascular diseases may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the cardiovascular disease may be Ischemic heart disease also known as coronary artery disease, Cerebrovascular disease (Stroke), Peripheral vascular disease, Heart failure, Rheumatic heart disease, and Congenital heart disease.

Various antibody deficiencies may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the antibody deficiencies may be X-Linked Agammaglobulinemia (XLA), Autosomal Recessive Agammaglobulinemia (ARA), Common Variable Immune Deficiency (CVID), IgG (IgG1, IgG2, IgG3 and IgG4) Subclass Deficiency, Selective IgA Deficiency, Specific Antibody Deficiency (SAD), Transient

Hypogammaglobulinemia of Infancy, Antibody Deficiency with Normal or Elevated

Immunoglobulins, Selective IgM Deficiency, Immunodeficiency with Thymoma (Good’s Syndrome), Transcobalamin II Deficiency, Warts, Hypogammaglobulinemia, Infection, Myelokathexis (WHIM) Syndrome, Drug-Induced Antibody Deficiency, Kappa Chain

Deficiency, Heavy Chain Deficiencies, Post-Meiotic Segregation (PMS2) Disorder, and

Unspecified Hypogammaglobulinemia.

Various ocular diseases may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the ocular disease may be thyroid eye disease (TED), Graves' disease (GD) and orbitopathy, Retina Degeneration, Cataract, optic atrophy, macular degeneration, Leber congenital amaurosis, retinal degeneration, cone-rod dystrophy, Usher syndrome, leopard syndrome, photophobia, and photoaversion.

Various neurological diseases may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the neurological disease may be Absence of the Septum Pellucidum, Acid Lipase Disease, Acid Maltase Deficiency, Acquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis, Attention Deficit-Hyperactivity Disorder (ADHD), Adie's Pupil, Adie's Syndrome, Adrenoleukodystrophy, Agenesis of the Corpus Callosum, Agnosia, Aicardi Syndrome, Aicardi-Goutieres Syndrome Disorder, AIDS - Neurological Complications, Alexander Disease, Alpers' Disease, Alternating Hemiplegia, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Antiphospholipid Syndrome, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari Malformation, Arteriovenous Malformation, Asperger Syndrome, Ataxia, Ataxia Telangiectasia, Ataxias and Cerebellar or Spinocerebellar

Degeneration, Atrial Fibrillation and Stroke, Attention Deficit-Hyperactivity Disorder, Autism Spectrum Disorder, Autonomic Dysfunction, Back Pain, Barth Syndrome, Batten Disease, Becker's Myotonia, Behcet's Disease, Bell's Palsy, Benign Essential Blepharospasm, Benign Focal Amyotrophy, Benign Intracranial Hypertension, Bernhardt-Roth Syndrome, Binswanger's Disease, Blepharospasm, Bloch-Sulzberger Syndrome, Brachial Plexus Birth Injuries, Brachial Plexus Injuries, Bradbury-Eggleston Syndrome, Brain and Spinal Tumors, Brain Aneurysm, Brain Injury, Brown-Sequard Syndrome, Bulbospinal Muscular Atrophy, Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL), Canavan Disease, Carpal Tunnel Syndrome, Causalgia, Cavernomas, Cavernous Angioma, Cavernous Malformation, Central Cervical Cord Syndrome, Central Cord Syndrome, Central Pain Syndrome, Central Pontine Myelinolysis, Cephalic Disorders, Ceramidase Deficiency, Cerebellar Degeneration, Cerebellar Hypoplasia, Cerebral Aneurysms, Cerebral Arteriosclerosis, Cerebral Atrophy, Cerebral Beriberi, Cerebral Cavernous Malformation, Cerebral Gigantism, Cerebral Hypoxia, Cerebral Palsy, Cerebro-Oculo-Facio-Skeletal Syndrome (COFS), Charcot- Marie-Tooth Disease, Chiari Malformation, Cholesterol Ester Storage Disease, Chorea,

Choreoacanthocytosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Orthostatic Intolerance, Chronic Pain, Cockayne Syndrome Type II, Coffin Lowry Syndrome, Colpocephaly, Coma, Complex Regional Pain Syndrome, Congenital Facial Diplegia, Congenital Myasthenia, Congenital Myopathy, Congenital Vascular Cavernous Malformations, Corticobasal Degeneration, Cranial Arteritis, Craniosynostosis, Cree encephalitis, Creutzfeldt-Jakob Disease, Cumulative Trauma Disorders, Cushing's Syndrome, Cytomegalic Inclusion Body Disease, Cytomegalovirus Infection, Dancing Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome, Dawson Disease, De Morsier's Syndrome, Dejerine-Klumpke Palsy, Dementia, Dementia -Multi- Infarct, Dementia - Semantic, Dementia -Subcortical, Dementia With Lewy Bodies, Dentate Cerebellar Ataxia, Dentatorubral Atrophy, Dermatomyositis, Developmental Dyspraxia, Devic's Syndrome, Diabetic Neuropathy, Diffuse Sclerosis, Dravet Syndrome, Dysautonomia,

Dysgraphia, Dyslexia, Dysphagia, Dyspraxia, Dyssynergia Cerebellaris Myoclonica,

Dyssynergia Cerebellaris Progressiva, Dystonias, Early Infantile Epileptic Encephalopathy, Empty Sella Syndrome, Encephalitis, Encephalitis Lethargica, Encephaloceles, Encephalopathy, Encephalopathy (familial infantile), Encephalotrigeminal Angiomatosis, Epilepsy, Epileptic Hemiplegia, Erb's Palsy, Erb-Duchenne and Dejerine-Klumpke Palsies, Essential Tremor, Extrapontine Myelinolysis, Fabry Disease, Fahr's Syndrome, Fainting, Familial Dysautonomia, Familial Hemangioma, Familial Idiopathic Basal Ganglia Calcification, Familial Periodic Paralyses, Familial Spastic Paralysis, Farber's Disease, Febrile Seizures, Fibromuscular

Dysplasia, Fisher Syndrome, Floppy Infant Syndrome, Foot Drop, Friedreich's Ataxia,

Frontotemporal Dementia, Gaucher Disease, Generalized Gangliosidoses, Gerstmann's

Syndrome, Gerstmann-Straussler-Scheinker Disease, Giant Axonal Neuropathy, Giant Cell Arteritis, Giant Cell Inclusion Disease, Globoid Cell Leukodystrophy, Glossopharyngeal Neuralgia, Glycogen Storage Disease, Guillain-Barré Syndrome, Hallervorden-Spatz Disease, Head Injury, Headache, Hemicrania Continua, Hemifacial Spasm, Hemiplegia Alterans,

Hereditary Neuropathies, Hereditary Spastic Paraplegia, Heredopathia Atactica

Polyneuritiformis, Herpes Zoster, Herpes Zoster Oticus, Hirayama Syndrome, Holmes-Adie syndrome, Holoprosencephaly, HTLV-1 Associated Myelopathy, Hughes Syndrome, Huntington's Disease, Hydranencephaly, Hydrocephalus, Hydrocephalus - Normal Pressure, Hydromyelia, Hypercortisolism, Hypersomnia, Hypertonia, Hypotonia, Hypoxia, Immune- Mediated Encephalomyelitis, Inclusion Body Myositis, Incontinentia Pigmenti, Infantile

Hypotonia, Infantile Neuroaxonal Dystrophy, Infantile Phytanic Acid Storage Disease, Infantile Refsum Disease, Infantile Spasms, Inflammatory Myopathies, Iniencephaly, Intestinal

Lipodystrophy, Intracranial Cysts, Intracranial Hypertension, Isaacs' Syndrome, Joubert

Syndrome, Kearns-Sayre Syndrome, Kennedy's Disease, Kinsbourne syndrome, Kleine-Levin Syndrome, Klippel-Feil Syndrome, Klippel-Trenaunay Syndrome (KTS), Klüver-Bucy

Syndrome, Korsakoff's Amnesic Syndrome, Krabbe Disease, Kugelberg-Welander Disease, Kuru, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome, Lateral Femoral Cutaneous Nerve Entrapment, Lateral Medullary Syndrome, Learning Disabilities, Leigh's Disease, Lennox-Gastaut Syndrome, Lesch-Nyhan Syndrome, Leukodystrophy, Levine-Critchley Syndrome, Lewy Body Dementia, Lipid Storage Diseases, Lipoid Proteinosis, Lissencephaly, Locked-In Syndrome, Lou Gehrig's Disease, Lupus - Neurological Sequelae, Lyme Disease - Neurological Complications, Machado-Joseph Disease, Macrencephaly, Megalencephaly, Melkersson-Rosenthal Syndrome, Meningitis, Meningitis and Encephalitis, Menkes Disease, Meralgia Paresthetica, Metachromatic Leukodystrophy, Microcephaly, Migraine, Miller Fisher Syndrome, Mini Stroke, Mitochondrial Myopathy, Moebius Syndrome, Monomelic Amyotrophy, Motor Neuron Diseases, Moyamoya Disease, Mucolipidoses, Mucopolysaccharidosis, Multi- Infarct Dementia, Multifocal Motor Neuropathy, Multiple Sclerosis, Multiple System Atrophy, Multiple System Atrophy with Orthostatic Hypotension, Muscular Dystrophy, Myasthenia - Congenital, Myasthenia Gravis, Myelinoclastic Diffuse Sclerosis, Myoclonic Encephalopathy of Infants, Myoclonus, Myopathy, Myopathy- Congenital, Myopathy -Thyrotoxic, Myotonia, Myotonia Congenita, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with Brain Iron Accumulation, Neurofibromatosis, Neuroleptic Malignant Syndrome, Neurological

Complications of AIDS, Neurological Complications of Lyme Disease, Neurological

Consequences of Cytomegalovirus Infection, Neurological Manifestations of Pompe Disease, Neurological Sequelae Of Lupus, Neuromyelitis Optica, Neuromyotonia, Neuronal Ceroid Lipofuscinosis, Neuronal Migration Disorders, Neuropathy- Hereditary, Neurosarcoidosis, Neurosyphilis, Neurotoxicity, Nevus Cavernosus, Niemann-Pick Disease, O'Sullivan-McLeod Syndrome, Occipital Neuralgia, Ohtahara Syndrome, Olivopontocerebellar Atrophy, Opsoclonus Myoclonus, Orthostatic Hypotension, Overuse Syndrome, Pain -Chronic, Pantothenate Kinase- Associated Neurodegeneration, Paraneoplastic Syndromes, Paresthesia, Parkinson's Disease, Paroxysmal Choreoathetosis, Paroxysmal Hemicrania, Parry-Romberg, Pelizaeus-Merzbacher Disease, Pena Shokeir II Syndrome, Perineural Cysts, Periodic Paralyses, Peripheral Neuropathy, Periventricular Leukomalacia, Persistent Vegetative State, Pervasive Developmental Disorders, Phytanic Acid Storage Disease, Pick's Disease, Pinched Nerve, Piriformis Syndrome, Pituitary Tumors, Polymyositis, Pompe Disease, Porencephaly, Post-Polio Syndrome, Postherpetic Neuralgia, Post infectious Encephalomyelitis, Postural Hypotension, Postural Orthostatic Tachycardia Syndrome, Postural Tachycardia Syndrome, Primary Dentatum Atrophy, Primary Lateral Sclerosis, Primary Progressive Aphasia, Prion Diseases, Progressive Hemifacial Atrophy, Progressive Locomotor Ataxia, Progressive Multifocal Leukoencephalopathy, Progressive Sclerosing Poliodystrophy, Progressive Supranuclear Palsy, Prosopagnosia, Pseudo-Torch syndrome, Pseudotoxoplasmosis syndrome, Pseudotumor Cerebri, Psychogenic Movement, Ramsay Hunt Syndrome I, Ramsay Hunt Syndrome II, Rasmussen's Encephalitis, Reflex

Sympathetic Dystrophy Syndrome, Refsum Disease, Refsum Disease - Infantile, Repetitive Motion Disorders, Repetitive Stress Injuries, Restless Legs Syndrome, Retrovirus-Associated Myelopathy, Rett Syndrome, Reye's Syndrome, Rheumatic Encephalitis, Riley-Day Syndrome, Sacral Nerve Root Cysts, Saint Vitus Dance, Salivary Gland Disease, Sandhoff Disease,

Schilder's Disease, Schizencephaly, Seitelberger Disease, Seizure Disorder, Semantic Dementia, Septo-Optic Dysplasia, Severe Myoclonic Epilepsy of Infancy (SMEI), Shaken Baby Syndrome, Shingles, Shy-Drager Syndrome, Sjögren's Syndrome, Sleep Apnea, Sleeping Sickness, Sotos Syndrome, Spasticity, Spina Bifida, Spinal Cord Infarction, Spinal Cord Injury, Spinal Cord Tumors, Spinal Muscular Atrophy, Spinocerebellar Atrophy, Spinocerebellar Degeneration, Steele-Richardson-Olszewski Syndrome, Stiff-Person Syndrome, Striatonigral Degeneration, Stroke, Sturge-Weber Syndrome, Subacute Sclerosing Panencephalitis, Subcortical

Arteriosclerotic Encephalopathy, Short-lasting, Unilateral, Neuralgiform (SUNCT) Headache, Swallowing Disorders, Sydenham Chorea, Syncope, Syphilitic Spinal Sclerosis,

Syringohydromyelia, Syringomyelia, Systemic Lupus Erythematosus, Tabes Dorsalis, Tardive Dyskinesia, Tarlov Cysts, Tay-Sachs Disease, Temporal Arteritis, Tethered Spinal Cord

Syndrome, Thomsen's Myotonia, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Tic

Douloureux, Todd's Paralysis, Tourette Syndrome, Transient Ischemic Attack, Transmissible Spongiform Encephalopathies, Transverse Myelitis, Traumatic Brain Injury, Tremor, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Troyer Syndrome, Tuberous Sclerosis, Vascular Erectile Tumor, Vasculitis Syndromes of the Central and Peripheral Nervous Systems, Von Economo’s Disease, Von Hippel-Lindau Disease (VHL), Von Recklinghausen's Disease, Wallenberg's Syndrome, Werdnig-Hoffman Disease, Wernicke-Korsakoff Syndrome, West Syndrome, Whiplash, Whipple's Disease, Williams Syndrome, Wilson Disease, Wolman’s Disease, X- Linked Spinal and Bulbar Muscular Atrophy.

Various psychological disorders may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the psychological disorders may be Aboulia, Absence epilepsy, Acute stress Disorder, Adjustment Disorders, Adverse effects of medication NOS, Age related cognitive decline, Agoraphobia, Alcohol Addiction, Alzheimer’s Disease, Amnesia (also known as Amnestic Disorder), Amphetamine Addiction, Anorexia Nervosa, Anterograde amnesia, Antisocial personality disorder (also known as Sociopathy), Anxiety Disorder (Also known as Generalized Anxiety Disorder), Anxiolytic related disorders, Asperger’s Syndrome (now part of Autism Spectrum Disorder), Attention Deficit Disorder (Also known as ADD), Attention Deficit Hyperactivity Disorder (Also known as ADHD), Autism Spectrum Disorder (also known as Autism), Autophagia, Avoidant Personality Disorder, Barbiturate related disorders, Benzodiazepine related disorders, Bereavement, Bibliomania, Binge Eating Disorder, Bipolar disorder (also known as Manic Depression, includes Bipolar I and Bipolar II), Body Dysmorphic Disorder, Borderline intellectual functioning, Borderline Personality Disorder, Breathing-Related Sleep Disorder, Brief Psychotic Disorder, Bruxism, Bulimia Nervosa, Caffeine Addiction, Cannabis Addiction, Catatonic disorder, Catatonic schizophrenia, Childhood amnesia, Childhood Disintegrative Disorder (now part of Autism Spectrum Disorder), Childhood Onset Fluency Disorder (formerly known as Stuttering), Circadian Rhythm Disorders, Claustrophobia, Cocaine related disorders, Communication disorder, Conduct Disorder, Conversion Disorder, Cotard delusion, Cyclothymia (also known as Cyclothymic Disorder), Delerium, Delusional Disorder, dementia , Dependent Personality Disorder (also known as Asthenic Personality Disorder), Depersonalization disorder (now known as Depersonalization / Derealization Disorder), Depression (also known as Major Depressive Disorder), Depressive personality disorder, Derealization disorder (now known as

Depersonalization / Derealization Disorder), Dermotillomania, Desynchronosis, Developmental coordination disorder, Diogenes Syndrome, Disorder of written expression, Dispareunia, Dissocial Personality Disorder, Dissociative Amnesia, Dissociative Fugue, Dissociative Identity Disorder (formerly known as Multiple Personality Disorder), Down syndrome, Dyslexia, Dyspareunia, Dysthymia (now known as Persistent Depressive Disorder), Eating disorder NOS, Ekbom’s Syndrome (Delusional Parasitosis), Emotionally unstable personality disorder, Encopresis, Enuresis (bedwetting), Erotomania, Exhibitionistic Disorder, Expressive language disorder, Factitious Disorder, Female Sexual Disorders, Fetishistic Disorder, Folie à deux, Fregoli delusion, Frotteuristic Disorder, Fugue State, Ganser syndrome, Gambling Addiction, Gender Dysphoria (formerly known as Gender Identity Disorder), Generalized Anxiety Disorder, General adaptation syndrome, Grandiose delusions, Hallucinogen Addiction, Haltlose personality disorder, Histrionic Personality Disorder, Primary hypersomnia, Huntington’s Disease,

Hypoactive sexual desire disorder, Hypochondriasis, Hypomania, Hyperkinetic syndrome, Hypersomnia, Hysteria, Impulse control disorder, Impulse control disorder NOS, Inhalant Addiction, Insomnia, Intellectual Development Disorder, Intermittent Explosive Disorder, Joubert syndrome, Kleptomania, Korsakoff’s syndrome, Lacunar amnesia, Language Disorder, Learning Disorders, Major Depression (also known as Major Depressive Disorder), major depressive disorder, Male Sexual Disorders, Malingering, Mathematics disorder, Medication- related disorder, Melancholia, Mental Retardation (now known as Intellectual Development Disorder), Misophonia, Morbid jealousy, Multiple Personality Disorder (now known as

Dissociative Identity Disorder), Munchausen Syndrome, Munchausen by Proxy, Narcissistic Personality Disorder, Narcolepsy, Neglect of child, Neurocognitive Disorder (formerly known as Dementia), Neuroleptic-related disorder, Nightmare Disorder, Non Rapid Eye Movement, Obsessive-Compulsive Disorder, Obsessive-Compulsive Personality Disorder (also known as Anankastic Personality Disorder), Oneirophrenia, Onychophagia, Opioid Addiction,

Oppositional Defiant Disorder, Orthorexia (ON), Pain disorder, Panic attacks, Panic Disorder, Paranoid Personality Disorder, Parkinson’s Disease, Partner relational problem, Passive- aggressive personality disorder, Pathological gambling, Pedophilic Disorder, Perfectionism, Persecutory delusion, Persistent Depressive Disorder (also known as Dysthymia), Personality change due to a general medical condition, Personality disorder, Pervasive developmental disorder (PDD), Phencyclidine related disorder, Phobic disorder, Phonological disorder, Physical abuse, Pica, Polysubstance related disorder, Postpartum Depression, Post-traumatic embitterment disorder (PTED), Post-Traumatic Stress Disorder, Premature ejaculation, Premenstrual

Dysphoric Disorder, Psychogenic amnesia, Psychological factor affecting medical condition, Psychoneurotic personality disorder, Psychotic disorder, not otherwise specified, Pyromania, Reactive Attachment Disorder, Reading disorder, Recurrent brief depression, Relational disorder, REM Sleep Behavior Disorder, Restless Leg Syndrome, Retrograde amnesia, Retts Disorder (now part of Autism Spectrum Disorder), Rumination syndrome, Sadistic personality disorder, Schizoaffective Disorder, Schizoid Personality Disorder, Schizophrenia, Schizophreniform disorder, Schizotypal Personality Disorder, Seasonal Affective Disorder, Sedative, Hypnotic, or Anxiolytic Addiction, Selective Mutism, Self-defeating personality disorder, Separation Anxiety Disorder, Sexual Disorders Female, Sexual Disorders Male, Sexual Addiction, Sexual

Masochism Disorder, Sexual Sadism Disorder, Shared Psychotic Disorder, Sleep Arousal Disorders, Sleep Paralysis, Sleep Terror Disorder (now part of Nightmare Disorder, Social Anxiety Disorder, Somatization Disorder, Specific Phobias, Stendhal syndrome, Stereotypic movement disorder, Stimulant Addiction, Stuttering (now known as Childhood Onset Fluency Disorder), Substance related disorder, Tardive dyskinesia, Tobacco Addiction, Tourettes

Syndrome, Transient tic disorder, Transient global amnesia, Transvestic Disorder,

Trichotillomania, Undifferentiated Somatoform Disorder, Vaginismus, and Voyeuristic Disorder.

Various lung diseases may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the lung diseases may be Asbestosis, Asthma, Bronchiectasis, Bronchitis, Chronic Cough, Chronic Obstructive Pulmonary Disease (COPD), Croup, Cystic Fibrosis, Hantavirus, Idiopathic Pulmonary Fibrosis, Pertussis, Pleurisy,

Pneumonia, Pulmonary Embolism, Pulmonary Hypertension, Sarcoidosis, Sleep Apnea,

Spirometry, Sudden Infant Death Syndrome (SIDS), Tuberculosis, Alagille Syndrome,

Autoimmune Hepatitis, Biliary Atresia, Cirrhosis, ERCP (Endoscopic Retrograde

Cholangiopancreatography), and Hemochromatosis. Nonalcoholic Steatohepatitis, Porphyria, Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis.

Various bone diseases may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the bone diseases may be osteoporosis, neurofibromatosis, osteogenesis imperfecta (OI), rickets, osteosarcoma, achondroplasia, fracture, osteomyelitis, Ewing tumor of bone, osteomalacia, hip dysplasia, Paget disease of bone, marble bone disease, osteochondroma, bone cancer, bone disease, osteochondrosis, osteoma, fibrous dysplasia, cleidocranial dysostosis, osteoclastoma, bone cyst, metabolic bone disease, melorheostosis, callus, Caffey syndrome, and mandibulofacial dysostosis.

Various blood diseases may be treated with the pharmaceutical formulations of the present disclosure. As a non-limiting example, the blood diseases may be Anemia and CKD (for health care professionals), Aplastic Anemia and Myelodysplastic Syndromes, Deep Vein

Thrombosis, Hemochromatosis, Hemophilia, Henoch-Schönlein Purpura, Idiopathic

Thrombocytopenic Purpura, Iron-Deficiency Anemia, Pernicious Anemia, Pulmonary Embolism, Sickle Cell Anemia, Sickle Cell Trait and Other Hemoglobinopathies, Thalassemia, Thrombotic Thrombocytopenic Purpura, and Von Willebrand Disease.

In one embodiment, pharmaceutical formulations described herein such as, but not limited to, disulfiram pharmaceutical formulations may include or may be used in conjunction with Vorinostat for the treatment of HIV.

In one embodiment, pharmaceutical formulations described herein such as, but not limited to, disulfiram pharmaceutical formulations may include or may be used in conjunction with cisplatin and/or vinorelbine for the treatment of non-small cell lung carcinoma (see

Nechushtan et al.2014 The Oncologist 2015;20:366–367; the contents of which are herein incorporated by reference in their entirety).

In one embodiment, pharmaceutical formulations described herein may be used for the treatment of cocaine dependence and/or alcohol dependence (see

https://doi.org/10.1002/14651858.CD007024.pub2; the contents of which are incorporated herein by reference in its entirety).

V. DEFINITIONS

Administering: The term "administering" when used in conjunction with a therapeutic means to administer a therapeutic agent to a patient whereby the therapeutic positively impacts the tissue or the organ to which it is targeted. The therapeutic agents described herein can be administered either alone or in combination (concurrently or serially) with other pharmaceuticals. For example, the therapeutic agents can be administered in combination with other vaccines, antibiotics, antiviral agents, anti-cancer or anti-neoplastic agents, or in combination with other treatment modalities such as herbal therapy, acupuncture, naturopathy, etc.

Amphiphilic: The term“amphiphilic”, as used herein, refers to a molecule combining hydrophilic and lipophilic (hydrophobic) properties.“Amphiphilic material” as used herein refers to a material containing a hydrophobic or more hydrophobic oligomer or polymer (e.g., biodegradable oligomer or polymer) and a hydrophilic or more hydrophilic oligomer or polymer.

Effective Amount: The term "effective amount" as used herein generally refers to a sufficient amount of the therapeutic agent that is added to decrease, prevent or inhibit the disease. The amount will vary for each compound and upon known factors related to the item or use to which the therapeutic agent is applied.

Hydrophilic: The term“hydrophilic”, as used herein, refers to substances that have strongly polar groups that readily interact with water.

Hydrophobic: The term“hydrophobic”, as used herein, refers to substances that lack an affinity for water; tending to repel and not absorb water as well as not dissolve in or mix with water.

Immune response: The term“”immune response”, as used herein refers to activity of the cells of the immune system upon exposure to a stimulus such as, but not limited to, an antigen. In one embodiment, the antigen may be derived from Bsl. Modulation: The term“modulation” is art-recognized and refers to up regulation (i.e., activation or stimulation), down regulation (i.e., inhibition or suppression) of a response, or the two in combination or apart.

Molecular weight: The term“molecular weight”, as used herein, generally refers to the mass or average mass of a material. If a polymer or oligomer, the molecular weight can refer to the relative average chain length or relative chain mass of the bulk polymer. In practice, the molecular weight of polymers and oligomers can be estimated or characterized in various ways including gel permeation chromatography (GPC) or capillary viscometry. GPC molecular weights are reported as the weight-average molecular weight (Mw) as opposed to the number- average molecular weight (Mn). Capillary viscometry provides estimates of molecular weight as the inherent viscosity determined from a dilute polymer solution using a particular set of concentration, temperature, and solvent conditions.

Pharmaceutically acceptable: The term“pharmaceutically acceptable”, as used herein, refers to compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio, in accordance with the guidelines of agencies such as the U.S. Food and Drug Administration. A“pharmaceutically acceptable carrier”, as used herein, refers to all components of a pharmaceutical formulation that facilitate the delivery of the composition in vivo. Pharmaceutically acceptable carriers include, but are not limited to, diluents, preservatives, binders, lubricants, disintegrators, swelling agents, fillers, stabilizers, and combinations thereof.

Prodrug: The term "prodrug" refers to an agent, including a compound, nucleic acid or protein that is converted into a biologically active form in vitro and/or in vivo. Prodrugs can be useful because, in some situations, they may be easier to administer than the parent compound. For example, a prodrug may be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have improved solubility in pharmaceutical compositions compared to the parent drug. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. Harper, N.J. (1962) Drug Latentiation in Jucker, ed. Progress in Drug Research, 4:221-294; Morozowich et al. (1977) Application of Physical Organic Principles to Prodrug Design in E. B. Roche ed. Design of Biopharmaceutical Properties through Prodrugs and Analogs, APhA; Acad. Pharm. Sci.; E. B. Roche, ed. (1977) Bioreversible Carriers in Drug in Drug Design, Theory and Application, APhA; H. Bundgaard, ed. (1985) Design of Prodrugs, Elsevier; Wang et al. (1999) Prodrug approaches to the improved delivery of peptide drug, Curr. Pharm. Design.5(4):265-287; Pauletti et al. (1997) Improvement in peptide bioavailability: Peptidomimetics and Prodrug Strategies, Adv. Drug. Delivery Rev. 27:235-256; Mizen et al. (1998). The Use of Esters as Prodrugs for Oral Delivery of ȕ-Lactam antibiotics, Pharm. Biotech.11:345-365; Gaignault et al. (1996) Designing Prodrugs and

Bioprecursors I. Carrier Prodrugs, Pract. Med. Chem.671-696; M. Asgharnejad (2000).

Improving Oral Drug Transport Via Prodrugs, in G. L. Amidon, P. I. Lee and E. M. Topp, Eds., Transport Processes in Pharmaceutical Systems, Marcell Dekker, p.185-218; Balant et al.

(1990) Prodrugs for the improvement of drug absorption via different routes of administration, Eur. J. Drug Metab. Pharmacokinet., 15(2): 143-53; Balimane and Sinko (1999). Involvement of multiple transporters in the oral absorption of nucleoside analogs, Adv. Drug Delivery Rev., 39(1- 3):183-209; Browne (1997). Fosphenytoin (Cerebyx), Clin. Neuropharmacol.20(1): 1-12;

Bundgaard (1979). Bioreversible derivatization of drugs--principle and applicability to improve the therapeutic effects of drugs, Arch. Pharm. Chemi.86(1): 1-39; H. Bundgaard, ed. (1985) Design of Prodrugs, New York: Elsevier; Fleisher et al. (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Adv. Drug Delivery Rev.19(2): 115-130; Fleisher et al. (1985) Design of prodrugs for improved gastrointestinal absorption by intestinal enzyme targeting, Methods Enzymol.112: 360-81; Farquhar D, et al. (1983) Biologically

Reversible Phosphate-Protective Groups, J. Pharm. Sci., 72(3): 324-325; Han, H.K. et al. (2000) Targeted prodrug design to optimize drug delivery, AAPS PharmSci., 2(1): E6; Sadzuka Y.

(2000) Effective prodrug liposome and conversion to active metabolite, Curr. Drug Metab., 1(1):31-48; D.M. Lambert (2000) Rationale and applications of lipids as prodrug carriers, Eur. J. Pharm. Sci., 11 Suppl.2:S15-27; Wang, W. et al. (1999) Prodrug approaches to the improved delivery of peptide drugs. Curr. Pharm. Des., 5(4):265-87.

Subject: A "subject" may include a human subject for medical purposes, such as for the treatment of an existing disease, disorder, condition or the prophylactic for preventing the onset of a disease, disorder, or condition or an animal subject for medical, veterinary purposes, or developmental purposes. Suitable animal subjects include mammals including, but not limited to, primates, e.g., humans, monkeys, apes, gibbons, chimpanzees, orangutans, macaques and the like; bovines, e.g., cattle, oxen, and the like; ovines, e.g., sheep and the like; caprines, e.g., goats and the like; porcines, e.g., pigs, hogs, and the like; equines, e.g., horses, donkeys, zebras, and the like; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits, hares, and the like; and rodents, including mice, rats, guinea pigs, and the like. An animal may be a transgenic animal. In some embodiments, the subject is a human including, but not limited to, fetal, neonatal, infant, juvenile, and adult subjects. Further, a "subject" can include a patient afflicted with or suspected of being afflicted with a disease, disorder, or condition. Thus, the terms "subject" and "patient" are used interchangeably herein. Subjects also include animal disease models (e.g., rats or mice used in experiments, and the like).

Therapeutic agent: As used herein, the term“therapeutic agent” refers to any substance used to restore or promote the health and/or wellbeing of a subject and/or to treat, prevent, alleviate, cure, or diagnose a disease, disorder, or condition.

Treatment or Treating: The term "treatment" or "treating" is an intervention performed with the intention of preventing the development or altering the pathology or symptoms of a disorder. Accordingly, "treatment" can refer to therapeutic treatment or prophylactic or preventative measures. In some embodiments, the treatment is for therapeutic treatment. In some embodiments, the treatment is for prophylactic or preventative treatment. Those in need of treatment can include those already with the disorder as well as those in which the disorder is to be prevented. In some embodiments, the treatment is for experimental treatment.

EQUIVALENTS AND SCOPE

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the disclosure described herein. The scope of the present disclosure is not intended to be limited to the above Description, but rather is as set forth in the appended claims.

In the claims, articles such as“a,”“an,” and“the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include“or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or the entire group members are present in, employed in or otherwise relevant to a given product or process.

It is also noted that the term“comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term“comprising” is used herein, the term“consisting of” is thus also encompassed and disclosed.

Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

In addition, it is to be understood that any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the disclosure (e.g., any antibiotic, therapeutic or active ingredient; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the disclosure in its broader aspects.

While the present disclosure has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with references to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope of the disclosure. The present disclosure is further illustrated by the following nonlimiting examples.

All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, section headings, the materials, methods, and examples are illustrative only and not intended to be limiting.

EXAMPLES

Example 1: Azlocillin and disulfiram-based formulations

Table 3, Table 4, and Table 5 provide non-limiting examples of azlocillin (APF), disulfiram (DPF) and azlocillin-disulfiram combination pharmaceutical formulations (ADCPF) respectively. EAC- disulfiram pharmaceutical formulations were prepared to target disulfiram delivery to the liver (Table 6). Table 7 provides Doxycycline formulation.

Table 3: Azlocillin pharmaceutical formulation

Table 4: Disulfiram pharmaceutical formulation

Table 5: Disulfiram & azlocillin comaination pharmaceutical formulation

Table 6: EAC-disulfiram pharmaceutical formulation

Table 7: Doxycycline formulation

Example 2. Preparation of pectin based formulations using spray drying methods

5 mg pectin was weighed and dissolved in 100 ml of water by slow addition in small portions to a stirring solution of water. Stirring was continued overnight to obtain a viscous solution of 5% Pectin.200 mg of disulfiram, thiuram disulfide analogs, and/or azlocillin.2g of Poloxamer was added to the pectin solution. The solution was diluted with 800 ml of water and 200 ml of ethanol was also added. The solution was stirred to obtain a homogeneous solution. The solutions were spray dried with the inlet temperature of 60 °C, and aspirator set to 90-95°C, and the condenser temperature was set to 4 °C. The preparation of the resultant pectin-therapeutic agent particles is also described in Table 8. In Table 8,“N/A” indicates not applicable.

Table 8: Preparation pectin-therapeutic agent particles

The pectin -therapeutic agent particles accumulated in the collection vessel were transferred to a desiccator.5 g of the particles were suspended in a solution containing 500 mg of DSPC, 500 mg of DPPC and 200 mg of Calcium chloride in acetone. The suspensions were stirred overnight and the acetone was evaporated under vacuum using a rotavapor to prepare . The preparation of the resultant pectin-therapeutic agent liposome is provided in Table 9 and Table 10 provides the preparation of azlocillin pharmaceutical formulation (APF) and the disulfiram pharmaceutical formulations (DPF).

Table 9: Preparation of Pectin -therapeutic agent liposomes

Table 10: Preparation of DPF and APF

Example 3. Preparation of pectin based formulations using microemulsion method

5 mg pectin was weighed and dissolved in 100 ml of water by slow addition in small portions to a stirring solution of water. Stirring was continued overnight to obtain a viscous solution of 5% Pectin.200 mg of disulfiram, thiuram disulfide analogs, and/or azlocillin; and 2g of Poloxamer were added to the pectin solution. The solution was diluted using 100 ml of water followed by 800 ml of DCM. The solution was stirred to obtain an emulsion. A solution containing 500 mg of DSPC, 500 mg of DPPC and 200 mg of calcium chloride in acetone was added to the emulsion and the mixture was stirred overnight. The solvent was evaporated under vacuum using a rotavapor. Table 11 provides the preparation of the resultant pectin-therapeutic agent emulsion and Table 12 provides the preparation of azlocillin pharmaceutical formulation (APF) and the disulfiram pharmaceutical formulations (DPF). In Table 11, N/A indicates not applicable.

Table 11: Preparation of pectin-therapeutic agent emulsion

Table 12: Preparation of DPF and APF

Example 4. Preparation EAC-Disulfiram formulation

1g of DPPC and 0.3g of cholesterol were dissolved in 200 mL of ethanol. The solution was stirred until a clear solution was obtained.1g of disulfiram followed by 0.3g of poloxamer- 188 and 1g of ethyl cellulose (EAC) were added to the solution and stirring was continued until a homogeneous solution was obtained. The solvent was evaporated using a rotavapor under vacuum. Example 5. Azlocillin formulation pharmacokinetic studies

Azlocillin pharmaceutical formulations prepared by methods described herein were orally administered to mice at 50 mg/kg. Blood plasma samples were obtained from mice 30 minutes, 1 hour and 2 hours after administration and azlocillin levels were measured in the blood using Liquid chromatography–mass spectrometry (LC-MS). Figure 1 shows the pharmacokinetic data for the azlocillin pharmaceutical formulations (APF). Compared to the azlocillin in water formulations, APF demonstrated increased azlocillin levels in the blood at all time points tested. While intraperitoneal administration of azlocillin showed increase azlocillin levels at 30 minutes, and 1 hour, azlocillin pharmaceutical formulations showed higher levels at 2 hours. Table 13 provides the area under the plasma drug concentration-time curve (AUC) which reflects the actual body exposure to drug after administration of a dose of the drug and is expressed in ng x h/mL. Also provided in Table 13 is the Cmax values defined herein as the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ of a subject after a dose of the drug is given. Table 13: Pharmacokinetics of Azlocillin Formulations

Azlocillin pharmaceutical formulations prepared by methods described herein were orally administered to rats. Blood samples were obtained from rats 20 minutes, 40 minutes, 1 hour, 2 hours and 4 hours after administration and azlocillin levels were measured in the blood. Figure 2 shows the pharmacokinetic data for the azlocillin pharmaceutical formulations.

Azlocillin pharmaceutical formulations of the present disclosure demonstrated higher levels of azlocillin in blood at 2 hour and 4-hour time points when compared to azlocillin in water formulations, as well as the intraperitoneal administration of azlocillin.

Example 6. Borrelia levels after in vivo dosing with formulations

C3H mice of 4-6-week-old were infected subcutaneously in the abdominal area with 0.1 ml of BSK-11 medium containing 10⁵ Bb (stain BB31) with a 25G tuberculin syringe.14 days after infecting with Borrelia spp., mice were dosed for 5 days with formulations including APF and dosing regimen described in Table 14. Saline treated mice were included as a negative control and doxycycline treated mice were used as a positive control. The lipidated disulfiram formulation was used at a dose of 100mg/kg which included disulfiram at a dose of 50mg/kg. In Table 14, the dose per mouse were calculated for a 25-gram mouse.

Table 14: In vivo study dosing regimen

Mice were euthanized 48 hours after the last dose and tissues samples from the heart, brain, ear, bladder, blood (serum), and spleen were collected.

Total Borrelia levels were measured in an ear slice (Figure 3A) and in the bladder (Figure 3B). As shown in Figure 3A and Figure 3B the total levels of Borrelia in mice treated with APF described herein was comparable to the naïve control mice indicating the eradication of the Borrelia infection. The total Borrelia levels in APF treated mice were also comparable to mice dosed intraperitoneally with Doxycycline, which is considered to be the standard of care for treating patients with Lyme disease. Intraperitoneal delivery of disulfiram or lipidated disulfiram were not as effective APF in reducing total Borrelia levels in the bladder but were effective in reducing total Borrelia levels in the ear slices measured. The EAC- disulfiram formulation may restrict the availability of disulfiram to the liver and was predicted to have no effect on total Borrelia levels. As expected, the EAC-disulfiram formulation showed total Borrelia levels similar to mice treated with saline (negative control) indicating that the EAC disulfiram formulation was not able to reduce total Borrelia levels in ear and bladder.

In a separate study, C3H mice of 4-6 week old were infected subcutaneously in the abdominal area with 0.1 ml of BSK-11 medium containing 10⁵ Bb (BB31) with a 25G tuberculin syringe.21 days after infecting with Borrelia spp., mice were dosed for 5 days with formulations including APF or DPF and dosing regimen described in Table 15. Saline treated mice were included as a negative control and doxycycline treated mice were used as a positive control. In Table 15, the dose per mouse was calculated for a 25-gram mouse.

Table 15: In vivo study dosing regimen

Mice were euthanized 48-72 hours after the last dose and tissues samples from the heart, brain, ear, bladder, blood (serum), and spleen were collected.

Total Borrelia levels were measured in an ear slice (Figure 3C) and in the bladder (Figure 3D). As shown in Figure 3C and Figure 3D the total levels of Borrelia in mice treated with DPF were comparable to mice dosed intraperitoneally with Doxycycline, which is considered to be the standard of care for treating patients with Lyme disease. In fact, zero Borrelia levels were measured in the DPF dosed mice, whereas Borrelia levels were detected in mice dosed intraperitoneally with disulfiram suggesting that orally delivered DPF may be more efficacious than IP delivery of disulfiram. APF dosed mice also demonstrated a reduction in total borrelia levels when compared to levels in saline treated mice.

Together these data show that APF and DPF were successfully able to reduce total Borrelia levels in mice.

Example 7. In vivo immune response

Infection with Bsl can trigger immune responses in the host and may contribute to the pathogenesis of Lyme disease. Immune responses were measured in mice dosed with APF and DPF as described in Table 14 and Table 15.

Humoral immune response was measured by evaluating total serum levels of IgG, IgM and IgA using methods known in the art. The serum immunoglobulin levels measured at following dosing regimen described in Table 14. Data was analyzed using GraphPad Prism software. Single comparisons within naive and Bsl infected groups were analyzed using two- tailed paired t-test; unpaired t-test with Welch’s correction; and using multiple t-WHVWV^^Į^ ^^^^^^ for all tests. In Figure 4A, Figure 4B, and Figure 4C,“*” indicates a p value less 0.05;“**” indicates a p value less than 0.01;“***” indicates a p value less than 0.001. Serum samples from patients with early localized disease (Stage 1) are known to have detectable total IgM levels in response to Borrelia antigens, whereas late disseminated Lyme disease (Stage 3) are known to have a detectable total IgG levels in response to Borrelia antigens. Figure 4A shows the serum total IgG levels at day 21. IgG response in APF treated mice as well as DSF treated mice was significantly (p value less than 0.01) lower than the total IgG levels observed in mice dosed with saline. As expected, the serum total IgG levels in saline treated mice was significantly (p value less than 0.001) higher than control untreated mice. No change in serum total IgM levels were observed in azlocillin or disulfiram dosed mice compared to mice dosed with saline was observed (Figure 4B). As expected, the negative control i.e. total IgA serum levels did not show any changes among any of the treatment groups as well as the controls (namely naïve mice and saline treated mice) (Figure 4C).

Together these data show that orally dosed APF may be effective in treating and/or preventing the onset late disseminated Lyme disease.

Example 8. Azlocillin and disulfiram efficacy in vitro

10⁶ cells of Bb (CA8 strain) were cultured with drugs at different concentration for 5 days. The pellets were extracted and grown on BSKII agarose plates. The colonies were counted after 21 days (even 45 days). As shown in Figure 5, disulfiram and azlocillin eradicates drug- tolerant persister at 5 mg dose. Further, disulfiram and azlocillin were more effective than doxycycline at eliminating Borrelia.

Example 9. Clearance of Bsl infection in immune compromised mouse models

Patients with Lyme disease may or may not be able to mount immune responses that are typically observed in healthy individuals. The severe combined immunodeficient (SCID) mouse model may be used to mimic this variability. The SCID mice are deficient in both T and B cells, which may result in higher B. burgdorferi burden. Mice are infected with N40 strain of Bsl and dosed with azlocillin and disulfiram pharmaceutical formulations at doses ranging from 10- 200 mg/kg of body weight, once or twice a day.5 days after treatment, B. burgdorferi N40 cultures are prepared from the ear punches of mice. It is expected that there will be fewer Bsl cultured obtained from mice treated with APF and/or DPF than mice treated with the standard of care, i.e. doxycycline.

Example 10. Clearance of persistent Borrelia burgdorferi

Sharma et al. have shown that one strategy for targeting Borrelia burgdorferi that persist after treatment with doxycycline and other standard of care therapies for Lyme disease is to utilize pulse dosing (Sharma B et al. Antimicrob Agents Chem. Jul 2015, 59 (8) 4616-4624; the contents of which are herein incorporated by reference in its entirety). In the pulse dosing regimen, Bsl are cultured in liquid BSK-II medium for 3 days to achieve late exponential grown phase or for 5 days to achieve stationary phase. The cultures are treated with pharmaceutical formulations of therapeutic agents namely azlocillin and disulfiram for 5 days. After 5 days, the Bsl cultures are washed twice in BSK-II medium and resuspended in fresh BSK-II media and are allowed to recover for several hours. The Bsl cultures are then treated again with the

pharmaceutical formulations. The treatment and wash cycles are repeated several time. It is expected that the persistent Borrelia burgdorferi will diminish after 3-4 rounds of treatment with the pharmaceutical formulations described herein. The pharmaceutical formulations are also more likely to be effective in eliminating persistent Borrelia when compared with standard of care therapies e.g. doxycycline.

Example 11. ALDH levels in vitro and in vivo

Upon consumption, alcohol (ethanol) is metabolized to acetaldehyde which is subsequently metabolized to acetyl CoA and acetic acid. When non-formulated disulfiram is administered to a subject, it may be further metabolized to its downstream metabolites which are known to inhibit aldehyde dehydrogenase (ALDH). Thus, when disulfiram is administered to a patient who has consumed alcohol, aldehyde dehydrogenase is inhibited leading to the increase in the acetaldehyde levels in the subject resulting in very unpleasant side effects such as flushing, headache, nausea, vomiting, and hypotension. ALDH levels were measured in cultured neurons to test if disulfiram pharmaceutical formulations affect ALDH levels. Specifically, ALDH5a1, ALDH1a1, and ALDH1a3 levels were measured in control untreated and uninfected cells, and Bsl infected cells treated with saline, disulfiram pharmaceutical formulations, doxycycline pharmaceutical formulations or vehicle control. ALDH densitometric measurements are shown in Figure 6A, Figure 6B, Figure 6C as arbitrary units. As shown in Figure 6A, ALDH5a1 levels were increased in infected cells treated with saline, or doxycycline pharmaceutical formulations. In cells treated with disulfiram pharmaceutical formulations ALDH5a1 levels were reduced in comparison and were even similar to the ALDH5a1 levels observed in control cells. Similar results were observed with ALDH1a3 (Figure 6C), in fact, the ALDH1a3 levels were even lower than the control uninfected cells. Infection with Bsl resulted in a decrease in ALDH1a1 levels in saline treated with cells compared to control and treatment with either doxycycline and/or disulfiram pharmaceutical formulations restored the levels of ALDH1a1.

To study the effect of the formulations on ALDH levels in vivo, mice were dosed with the pharmaceutical formulations described herein using methods described in Examples 5 through 10. Brain tissue was extracted from mice at day 25 (post infection with Bsl) and

ALDH5a1, ALDH1a3, ALDH1a1 were measured via western blot. Consistent with the in vitro studies in neurons, ALDH5a1 levels were reduced in mice treated with disulfiram pharmaceutical formulations and compared to the saline treated Bsl infected mice and Bsl infected mice treated with doxycycline pharmaceutical formulations. ALDH5a1 levels in DPF treated mice were even comparable to ALDH5a1 levels in control uninfected mice. Similar to the in vitro neuron studies, infection with Bsl resulted in a decrease in ALDH1a1 levels in saline treated with mice compared to control and treatment with either doxycycline and/or disulfiram pharmaceutical formulations restored the levels of ALDH1a1.

Example 12. Preparation of Thiuram/disulfiram analogs formulation

Various chemical analogs for thiuram/disulfiram and/or their metal complexes are being tested for in vitro and in vivo analysis against borrelia burgdorferi for the treatment of Lyme disease. Further disulfiram or other new thiuram disulfide compounds in combination with divalent metal ion salts are also tested. The molecules and their complexes are formulated using pectin-based formulation. The formulation was prepared with two different methods, spray- drying method and microemulsion methods. The formulation is designed to release the therapeutic molecule in the intestine. The formulation contains pectin, poloxamer, DSPC, DPPC and calcium chloride.

Preparation of thiuram/disulfiram analogs formulation by spray drying technique

Weigh 5 mg pectin and dissolve in 100 ml of water by slow addition in small portions to a stirring solution of water. Continue the stirring for overnight to obtain a viscous solution of 5% Pectin. Add 200 mg of Thiuram/disulfiram analogs and 2g of Poloxamer to the pectin solution and dilute the solution to 800 ml of water followed by adding 200 ml of ethanol. Stir the solution to obtain a homogeneous solution. Spray dry the solution with the inlet temperature of 60 °C, and aspirator set to 90-95, and the condenser temperature set to 4 °C. Transfer the particles accumulated in the collection vessel to a desiccator. Take 5 g of the particles and suspend in a solution containing 500 mg of DSPC, 500 mg of DPPC and 200 mg of calcium chloride in acetone. Stir the suspension for overnight. Evaporate the acetone under vacuum using a rotavapor. Take the calculated amount of the dosage for the animal. Suspend the particles in water just before the oral administration to rats.

Preparation of Thiuram/disulfiram analogs formulation by microemulsion technique

Weigh 5 mg pectin and dissolve in 100 ml of water by slow addition in small portions to a stirring solution of water. Continue the stirring for overnight to obtain a viscous solution of 5% Pectin. Add 200 mg of Thiuram/disulfiram analogs and 2g of Poloxamer to the pectin solution and dilute the solution to 100 ml of water followed by adding 800 ml of DCM. Stir the solution to obtain an emulsion. To the emulsion add a solution containing 500 mg of DSPC, 500 mg of DPPC and 200 mg of calcium chloride in acetone. Stir the suspension for overnight.

Evaporate the solvent under vacuum using a rotavapor. Take the calculated amount of the dosage for the animal. Suspend the particles in water just before the oral administration to rats.

Example 13. Preparation of pectin based formulation for azlocillin and other penicillin derivatives

The work involves development of oral formulation for azlocillin and derivatives of penicillin that are currently considered as suitable for only intravenous formulations. These molecules are being tested for in vitro and in vivo analysis against borrelia burgdorferi for the treatment of Lyme disease using oral formulations. The molecules are formulated using pectin- based formulation. The formulation was prepared with two different methods, spray-drying method and microemulsion methods. The formulation is designed to release the therapeutic molecule in the intestine. The formulation contains pectin, poloxamer, DSPC, DPPC and calcium chloride.

Preparation of Azlocillin/penicillin derivatives formulation by spray drying technique

Weigh 5 mg pectin and dissolve in 100 ml of water by slow addition in small portions to a stirring solution of water. Continue the stirring for overnight to obtain a viscous solution of 5% Pectin. Add 200 mg of Azlocillin/penicillin derivatives and 2g of Poloxamer to the pectin solution and dilute the solution to 800 ml of water followed by adding 200 ml of ethanol. Stir the solution to obtain a homogeneous solution. Spray dry the solution with the inlet temperature of 60 °C, and aspirator set to 90-95, and the condenser temperature set to 4 °C. Transfer the particles accumulated in the collection vessel to a desiccator. Take 5 g of the particles and suspend in a solution containing 500 mg of DSPC, 500 mg of DPPC and 200 mg of Calcium chloride in acetone. Stir the suspension for overnight. Evaporate the acetone under vacuum using a rotavapor. Take the calculated amount of the dosage for the animal. Suspend the particles in water just before the oral administration to rats.

Preparation of azlocillin/penicillin derivatives formulation by microemulsion technique

Weigh 5 mg pectin and dissolve in 100 ml of water by slow addition in small portions to a stirring solution of water. Continue the stirring for overnight to obtain a viscous solution of 5% Pectin. Add 200 mg of Azlocillin/penicillin derivatives and 2g of Poloxamer to the pectin solution and dilute the solution to 100 ml of water followed by adding 800 ml of DCM. Stir the solution to obtain an emulsion. To the emulsion add a solution containing 500 mg of DSPC, 500 mg of DPPC and 200 mg of calcium chloride in acetone. Stir the suspension for overnight.

Claims

1. A pharmaceutical formulation comprising:

at least one therapeutic agent, wherein the at least one therapeutic agent comprises one or more compound selected from the group consisting of azlocillin, disulfiram, penicillin, thiuram, and derivates thereof; and

an excipient, wherein the excipient comprises one or more compound selected from the group consisting of a phospholipid, a pectin, a polymer, and an inorganic salt.

2. The pharmaceutical formulation of claim 1, wherein the excipient comprises a phospholipid.

3. The pharmaceutical formulation of claim 2, wherein the phospholipid is a synthetic phospholipid selected from the group consisting of a dipalmitoyl phosphatidylcholine (DPPC), distearoyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylcholine (DMPC), dioleoyl phosphatidylcholine (DOPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), dioleoyl phosphatidylglycerol (DOPG), distearoyl

diarachidoylphosphatidylcholine (DAPC), dibehenoylphosphatidylcholine (DBPC), ditricosanoylphosphatidylcholine (DTPC), dilignoceroylphatidylcholine (DLPC), or dioleoyl phosphatidylserine (DOPS).

4. The pharmaceutical formulation of any one of claims 1-3, wherein the excipient comprises a combination of phospholipids.

5. The pharmaceutical formulation of claim 4, wherein the combination of phospholipids comprises a combination of DPPC and DSPC.

6. The pharmaceutical formulation of claim 5 comprising from about 2% (w/w) to about 20% (w/w) of DPPC.

7. The pharmaceutical formulation of claim 6 comprising 8.06% (w/w) of DPPC.

8. The pharmaceutical formulation of claim 5 comprising from about 2% (w/w) to about 20% (w/w) DSPC.

9. The pharmaceutical formulation of claim 8 comprising 8.06% (w/w) of DSPC.

10. The pharmaceutical formulation of any one of claims 1-9, wherein the excipient comprises a pectin.

11. The pharmaceutical formulation of claim 10 comprising from about 20% (w/w) to about 80% (w/w) of pectin.

12. The pharmaceutical formulation of claim 11 comprising 55.98 % (w/w) of pectin.

13. The pharmaceutical formulation of any one of claims 1-12, wherein the excipient comprises a polymer.

14. The pharmaceutical formulation of claim 13, wherein the polymer is a poloxamer.

15. The pharmaceutical formulation of claim 14, wherein the poloxamer is P-188.

16. The pharmaceutical formulation of claim 15 comprising from about 0.001% (w/w) to about 40% (w/w) of P-188.

17. The pharmaceutical formulation of claim 16 comprising 22.42% (w/w) of P-188.

18. The pharmaceutical formulation of any one of claims 1-17, wherein the excipient comprises an inorganic salt.

19. The pharmaceutical formulation of claim 18, wherein the inorganic salt is selected from the group consisting of calcium chloride (CaCl₂), sodium chloride (NaCl), magnesium chloride (MgCl₂), sodium bicarbonate (NaHCO₃), potassium chloride (KCl), sodium sulfate (Na₂SO₄), calcium carbonate (CaCO₃), and calcium phosphate (Ca₃(PO4)₂.

20. The pharmaceutical formulation of claim 19, wherein the inorganic salt is calcium chloride (CaCl₂).

21. The pharmaceutical formulation of claim 20 comprising from about 1% (w/w) to about 10% (w/w) of calcium chloride. 22. The pharmaceutical formulation of claim 21 comprising 3.

22% (w/w) of calcium chloride.

23. The pharmaceutical formulation of any one of claims 1-22, wherein the at least one therapeutic agent comprises disulfiram.

24. The pharmaceutical formulation of claim 23 comprising from about 0.1 % (w/w) to about 10 % (w/w) of disulfiram.

25. The pharmaceutical formulation of claim 24 comprising from about 1% (w/w) to about 5% (w/w) of disulfiram. 26. The pharmaceutical formulation of claim 25 comprising 2.

26% (w/w) of disulfiram.

27. The pharmaceutical formulation of claim 25 comprising 1.13% (w/w) of disulfiram.

28. The pharmaceutical formulation of any one of claims 1-27, wherein the at least one therapeutic agent comprises azlocillin.

29. The pharmaceutical formulation of claim 28 comprising from about 0.1% (w/w) to about 10% (w/w) of azlocillin.

30. The pharmaceutical formulation of claim 29 comprising from about 1% (w/w) to about 5% (w/w) of azlocillin.

31. The pharmaceutical formulation of claim 30 comprising 2.26% (w/w) of azlocillin.

32. The pharmaceutical formulation of claim 30 comprising 1.13% (w/w) of azlocillin.

33. The pharmaceutical formulation of any one of claims 1-32, wherein the at least one therapeutic agent comprises azlocillin and disulfiram.

34. The pharmaceutical formulation of claim 33 comprising from about 0.1% (w/w) to about 10% (w/w) azlocillin.

35. The pharmaceutical formulation of claim 34 comprising 1.13% (w/w) azlocillin.

36. The pharmaceutical formulation of claim 35 comprising from about 0.1% (w/w) to about 10% (w/w) disulfiram.

37. The pharmaceutical formulation of claim 36 comprising 1.13% (w/w) disulfiram.

38. The pharmaceutical formulation of any one of claims 1-37, further comprising one more active agent.

39. The pharmaceutical formulation of claim 38, wherein the one or more active agent comprises an antibiotic.

40. The pharmaceutical formulation of claim 39, wherein the antibiotic is selected from the group consisting of Doxycycline, Amoxicillin, Ceftriaxone, Vancomycin, Telavancin, Dalbavancin, Fosfomycin, D-Cycloserine, Tunicamycin, Bactrim, and Bacitracin.

41. The pharmaceutical formulation of claim 38, wherein the one or more active agent comprises a chelator.

42. The pharmaceutical formulation of claim 41, wherein the chelator is a copper chelator.

43. The pharmaceutical formulation of claim 38, wherein the one or more active agent comprises an antibody.

44. A method of treating a subject having a disease, the method comprising administering to the subject, the pharmaceutical formulation of any one of claims 1-43.

45. The method of claim 44, wherein the pharmaceutical formulation is administered to the subject at a dose of from about 10 mg/kg to about 200 mg/kg body weight of the subject.

46. The method of claim 45, wherein the pharmaceutical formulation is administered to the subject at a dose of 100 mg/kg body weight of the subject.

47. The method of any one of claims 44-46, wherein the disease is Lyme disease or a Lyme disease related disorder.

48. A method of modulating aldehyde dehydrogenase levels in a subject having Lyme disease or a Lyme disease related disorder, the method comprising administering to the subject the pharmaceutical formulation of any one of claims 1-43.

49. The method of claim 48, wherein the aldehyde dehydrogenase is selected from the group consisting of ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, ALDH1L1, ALDH1L2, ALDH2, ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, ALDH4A1, ALDH5A1, ALDH6A1,

ALDH7A1, ALDH8A1, and ALDH9A1.

50. The method of claim 49, wherein the aldehyde dehydrogenase is ALDH5A1.