Methods for treating non-opioid mediated respiratory depression - Patents.com

Abstract

Disclosed in certain embodiments is a method of treating non-opioid regulated respiratory depression comprising administering to a patient in need thereof an effective amount of a compound selected from Formula (I) disclosed herein.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 274,722, filed November 2, 2021, the entire contents of which are incorporated by reference in their entirety.

[0002] The present disclosure relates to methods and compositions for treating non-opioid mediated respiratory depression. [Background technology]

[0003] The human body is highly dependent on the ventilatory control system for adequate intake of oxygen and removal of carbon dioxide (CO2). Opioid analgesics, acting on μ-opioid receptors expressed on respiratory nerves in the brainstem, can cause respiratory depression in certain circumstances, such as overdose.

[0004] However, there are non-opioid agents that can cause respiratory depression in overdose or other situations. For example, anesthetic agents such as propofol can cause respiratory depression that can be life-threatening.

[0005] There is a need in the art for therapeutic methods and compounds for treating non-opioid mediated respiratory depression. Summary of the Invention

[0006] In certain embodiments, the present disclosure is directed to therapeutic methods and compounds for treating non-opioid mediated respiratory depression.

[0007] In certain embodiments, the present disclosure provides a method for treating non-opioid regulated respiratory depression, comprising administering to a patient in need thereof an effective amount of a compound selected from Formula (I): [ka] (In the formula, R 1 and R2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 is null, (i) Z is H, and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0008] In certain embodiments, as described above with respect to formula (I), R 1 , R 2 , R 3 , and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl.

[0009] In certain embodiments, the compound of formula (I) is administered via a route selected from oral, intravenous, nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, or intrathecal routes.

[0010] In certain embodiments, the present disclosure provides a method for treating non-opioid mediated respiratory depression comprising administering to a subject a compound selected from formula (I) in an effective amount thereof. [ka] (In the formula, R 1 and R 2is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR6 , or C, Y is N or CR 6 If b is 1 is null, (i) Z is H, and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof, and a pharma- ceutically acceptable excipient.

[0011] In certain embodiments, the present disclosure provides 1 , R 2 , R 3 , and R 5 and n is 0-1; and n is 1-2; and n is 1-3. The present invention is directed to an effective amount of a compound selected from formula (I) for treating non-opioid agent-mediated respiratory depression, as described above, wherein at least one substituent selected from the group consisting of is alkynyl or substituted alkynyl.

[0012] In certain embodiments, the present disclosure is directed to methods of preparing any of the pharmaceutical compositions described herein. [Brief description of the drawings]

[0013] [Figure 1] FIG. 1 is a schematic diagram of the treatment and ventilation status during each test period of an embodiment of the present disclosure. [Diagram 2] 1 is a graph showing the estimated mean hypoxia sensitivity (L / min / %) of the examples. [Diagram 3] 1 is a graph showing an overview of the average minute ventilation (L / min) of the examples. [Figure 4] 1 is a graph showing an overview of the average tidal volume (mL) of the examples. [Diagram 5]1 is a graph summarizing average respiratory rate (breaths / min) for an embodiment. [Figure 6] 1 is a graph showing a summary of mean end tidal CO2 (mmHg). [Figure 7] 1 is a graph showing an overview of mean oxygen saturation (%). [Figure 8] 1 is a graph showing the mean plasma concentration of Compound A of the examples by propofol dosing interval. [Figure 9] 1 is a graph showing the mean plasma Compound A concentration-time profile following administration of Compound A (normal scale) of an example. [Figure 10] FIG. 1 is a graph showing the mean plasma Compound A concentration-time profile following administration of Compound A of the Examples using a logarithmic Y-axis.

[0014] definition As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes not only a single active agent but also a mixture of two or more different active agents, reference to "an excipient" includes not only a single excipient but also a mixture of two or more different excipients (as well as others).

[0015] As used herein, the term "about" in relation to a measurand refers to the normal variation of that measurand that would be expected by one of ordinary skill in the art in making the measurement and using a level of care commensurate with the purpose of the measurement and the precision of the measurement device. In certain embodiments, the term "about" includes the recited number ±10%, so that "about 10" includes 9-11.

[0016] As used herein, the terms "active agent," "active ingredient," and "active pharmaceutical ingredient" refer to any material intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved for that purpose by a governmental agency. These terms, with respect to a particular agent, include all pharma- ceutically active agents, all pharma- ceutically acceptable salts, complexes, stereoisomers, crystalline forms, cocrystals, ethers, esters, hydrates, solvates, and mixtures thereof, which forms are pharma- ceutically active.

[0017] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with one or more chiral centers that are not mirror images of one another (diastereomers).

[0018] The term "enantiomer" or "enantiomeric" refers to a molecule that is not superimposable on its mirror image and is therefore optically active, where an enantiomer rotates the plane of polarized light to some extent in one direction and its mirror image rotates the plane of polarized light to the same extent but in the opposite direction.

[0019] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0020] The term "patient" refers to a subject, animal, or human who exhibits clinical manifestations of a particular symptom or symptoms indicating the need for treatment, or who is being treated for preventative or prophylactic purposes for a condition, or who has been diagnosed with a condition to be treated. The term "subject" encompasses the definition of the term "patient" and does not exclude individuals who are otherwise healthy.

[0021] "Pharmaceutically acceptable salts" or "salts" include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, phosphate, nitrate, carbonate, sulfuric, phosphoric (including hydrogen phosphate and dihydrogen phosphate), organic acid salts such as oxalate, malonate, citrate, fumarate, lactate, malate, succinate, formate, acetate, trifluoroacetate, maleate, tartrate, gluconate, benzoate, salicylate, xinafoate, pamoate, ascorbate, adipate, cinnamate, and the like, sulfonic acid salts, and the like. Examples of the salt include salts of methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc., amino acid salts such as alginates, apartates, glutamates, etc., metal salts such as zinc salts, sodium salts, cesium salts, alkaline earth metal salts such as calcium salts, magnesium salts, and organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine, etc. These salts may exist in the form of hydrates, solvates, or crystalline polymorphs. In certain embodiments, suitable organic acids are selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.All of these salts can be prepared by conventional means from the corresponding compounds of the invention, for example by reacting the appropriate acid or base with the compound of the invention. Handbook of Pharmaceutical Salts: Properties, and Use (P.H. Stahl & C.G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002)[1].

[0022] The term "disease(s)" or "condition(s)" refers to a medical condition that can be treated or prevented by administration to a subject of an effective amount of an active agent.

[0023] The terms "treatment" and "treating" include reducing or halting the severity of a condition, or reducing or halting the severity of a symptom of a condition. In certain embodiments, the term "treatment" or "treating" refers to administration with the intent of producing a pharmacodynamic effect in relation to a condition, regardless of outcome. In certain embodiments, "treatment" or "treating" refers to "having a positive effect on a condition," and includes reducing, improving, and / or alleviating the severity of at least one symptom of a condition, reducing, improving, and / or alleviating the severity of a condition, slowing, preventing, or inhibiting the progression of a condition, or a perceived improvement or benefit as a result of treatment. Treatment, as used herein, does not require a complete cure of a condition. In certain embodiments, the compositions of the present disclosure may result in an improvement in the quality of life of a patient, or a delay, prevention, inhibition of the onset of one or more symptoms of a condition, or may provide a perceived benefit.

[0024] The terms "prevention of" and "preventing" include the avoidance of the onset of a condition.

[0025] The term "therapeutically effective amount" is intended to include, for example, an amount of an active agent or an amount of a combination of active agents to treat or prevent a condition in a subject, or to treat a symptom of a condition.

[0026] The term "effective amount" is intended to include an amount of a component or an amount of a combination of components to achieve a particular result or property, e.g., an effective amount of a pH adjuster to achieve a pH of 6.0 is intended to include the amount of one or more pH adjusters to reach a pH of 6.0.

[0027] The terms "application", "applying" and "applying" in connection with the disclosed topical compositions or methods of using the disclosed topical compositions refer to any manner of administering a topical composition to a patient's skin in medical or cosmetic practice that delivers the composition to the patient's skin surface. Smearing, rubbing, spreading, spraying the disclosed topical composition onto a patient's skin, with or without a suitable device, are all included within the scope of the term "application" as used herein. The terms "topical" or "topically" in connection with administration or application of the disclosed formulations refer to epidermal administration or application, or administration on the skin.

[0028] As used herein, "oral delivery" or "oral administration" refers to a route of administration in which the composition is taken in through the mouth. Oral administration is a part of enteral administration, which also includes buccal administration (dissolved inside the cheek), sublabial administration (dissolved under the lip), and sublingual administration (dissolved under the tongue). In certain embodiments, oral administration includes a route of administration in which the composition is ingested. In certain embodiments, oral administration includes a route of administration in which the composition is inhaled.

[0029] As used herein, "parenteral administration" refers to a route of administration whereby a pharmaceutical dosage form is injected, for example, into a muscle (intramuscular administration), into a vein (intravenous administration), or under the skin (subcutaneous administration).

[0030] The phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0031] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise indicated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C10 means 1 to 10 carbon atoms) and includes straight, branched, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred are (C1-C6)alkyls, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0032] As used herein, the term "cycloalkyl," by itself or as part of another substituent, means, unless otherwise indicated, a cyclic chain hydrocarbon having the specified number of carbon atoms (i.e., C3-C6 means a cyclic group containing a ring group of 3 to 6 carbon atoms), including straight chain, branched chain, or cyclic substituents. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred are (C3-C6)cycloalkyls, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0033] As used herein, the term "alkenyl", used alone or in combination with other terms, means, unless otherwise indicated, a stable mono- or di-unsaturated straight or branched chain hydrocarbon group having the specified number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. A functional group representing an alkene is exemplified by -CH2-CH=CH2.

[0034] As used herein, the term "alkynyl," used alone or in combination with other terms, means, unless otherwise indicated, a stable straight or branched chain hydrocarbon group with a triple carbon-carbon bond having the specified number of carbon atoms. Examples include ethynyl and propynyl, as well as the higher homologs and isomers.

[0035] As used herein, the terms "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl", or "substituted alkynyl" refer to alkyl, cycloalkyl, alkenyl, or alkynyl as defined above, and include any of the following: halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH, -N(CH), (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C1-C4)alkyl, -C(=O)N It means an alkyl, cycloalkyl, alkenyl, or alkynyl substituted with one, two, or three substituents selected from the group consisting of H2, -C(=O)NH(C1-C4)alkyl, -C(=O)N((C1-C4)alkyl)2, -SON2NH2, -C(=NH)NH2, and -NO2, preferably selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, more preferably one or two substituents selected from halogen, alkoxy, and -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0036] As used herein, the term "alkoxy", used alone or in combination with other terms, means, unless otherwise indicated, an alkyl group having the specified number of carbon atoms, as defined above, attached to the remainder of the molecule through an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologs and isomers. (C1-C3)alkoxy, such as, but not limited to, ethoxy and methoxy, is preferred.

[0037] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0038] As used herein, the term "heteroalkyl", by itself or in combination with another term, means, unless otherwise indicated, a stable straight or branched chain alkyl group consisting of the specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be located at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached, or may be attached to the most distal carbon atom of the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 or -CH2-CH2-SS-CH3.

[0039] As used herein, the term "heteroalkenyl," by itself or in combination with another term, means, unless otherwise indicated, a stable straight or branched mono- or di-unsaturated hydrocarbon group consisting of the specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Up to two heteroatoms may be arranged consecutively. Examples include -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH2-SH.

[0040] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0041] As used herein, the term "aryl", used alone or in combination with other terms, means, unless otherwise indicated, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), which may be linked together in a pendant fashion, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. Phenyl and naphthyl are preferred, with phenyl being most preferred.

[0042] As used herein, the term "aryl-(C1-C3)alkyl" refers to a functional group in which a one to three carbon alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl or -CH2-phenyl(benzyl). Aryl-CH2- and aryl-CH(CH3)- are preferred. The term "substituted aryl-(C1-C3)alkyl" refers to an aryl-(C1-C3)alkyl functional group in which the aryl group is substituted. Substituted aryl(CH2)- is preferred. Similarly, the term "heteroaryl-(C1-C3)alkyl" refers to a functional group in which a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CH2CH2-pyridyl. Heteroaryl-(CH2)- is preferred. The term "substituted heteroaryl-(C1-C3)alkyl" refers to a heteroaryl-(C1-C3)alkyl functional group in which the heteroaryl group is substituted. Substituted heteroaryl-(CH2)- is preferred.

[0043] The term "heterocycle" or "heterocyclyl" or "heterocyclic" as used herein, by itself or as part of another substituent, means, unless otherwise indicated, a stable, unsubstituted or substituted, monocyclic or polycyclic heterocyclic ring system consisting of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, where the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen atom may be optionally quaternized. The heterocyclic ring system may be attached at any heteroatom or carbon atom that provides a stable structure, unless otherwise indicated. The heterocycle may be aromatic or non-aromatic in nature. In one embodiment, the heterocycle is a heteroaryl.

[0044] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character. Polycyclic heteroaryls may contain one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

[0045] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepine, and hexamethylene oxide.

[0046] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (including, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0047] Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, , but are not limited to, 3-, 4-, 5-, 6-, and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolidinyl, and quinolizidinyl, and quinolizininyl.

[0048] The foregoing lists of heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.

[0049] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent bonded to another group.

[0050] For aryl groups, aryl-(C1-C3)alkyl groups, and heterocyclyl groups, the term "substituted" as applied to the rings of these groups refers to any level of substitution, i.e., mono-, di-, tri-, tetra-, or penta-substitution (where such substitution is permitted). The substituents are independently selected, and the substitution may be at any chemically accessible position. In one embodiment, the substituents vary in number from 1 to 4. In another embodiment, the substituents vary in number from 1 to 3. In yet another embodiment, the substituents vary in number from 1 to 2. In yet another embodiment, the substituents are independently selected from C1-6 Alkyl, -OH, C 1-6 It is selected from the group consisting of alkoxy, halo, amino, acetamido, and nitro. As used herein, when a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight chain, or cyclic, although straight chain is preferred.

[0051] The recitation of ranges of values ​​herein is intended to serve merely as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein to the same extent as if it were individually recited herein, unless otherwise indicated herein. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to facilitate understanding of certain materials and methods, and does not limit the scope of the claims. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0052] Certain embodiments of the present disclosure are directed to a method of treating non-opioid-mediated respiratory depression, comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I) as described herein. The method of the present disclosure, in certain embodiments, has been found to be effective against overdosing of non-opioid central depressants such as propofol. In certain embodiments, the method of the present disclosure enhances the body's ability to respond to harmful changes in blood gases. For example, the sensitivity of the internal feedback loop. In certain embodiments, the method of the present disclosure can resensitize the regulatory control mechanisms that are blunted at the central control point by upregulating the peripheral control point. This is different from opioid antagonists such as naloxone, which reverse respiratory depression by competitively displacing opioids from opioid receptors. That is, the antagonist reverses all sequelae of opioids, including beneficial therapeutic effects.

[0053] In certain embodiments of the present disclosure, the methods described herein restore respiratory function despite central blunting.It has also been found in certain embodiments that dosing with the compound enhances sensitivity during exposure to anesthetic agents, but does not overly promote hyperventilation as patients begin to show symptoms.In certain embodiments, at higher doses, breathing can be acutely promoted, while at lower doses, breathing can be regulated.

[0054] Certain embodiments of the present disclosure include a method of treating non-opioid mediated respiratory depression comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I): [ka] (In the formula, R 1 and R 2is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR6 , or C, Y is N or CR 6 If b is 1 is null, (i) Z is H, and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0055] Certain embodiments of the present disclosure include a method of treating non-opioid mediated respiratory depression comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I): [ka] (In the formula, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 1 , R 2 , R 3 , and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 is null, (i) Z is H, and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0056] Certain embodiments of the present disclosure include a method of treating non-opioid mediated respiratory depression comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I): [ka] (In the formula, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 is null, (i) Z is H, and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0057] In one embodiment, R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, or substituted alkenyl. 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, or acyl.

[0058] Certain embodiments of the present disclosure include a method of treating non-opioid mediated respiratory depression comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I): [ka] R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, or substituted alkynyl; R 4 is H, alkyl, or substituted alkyl; R 5 is alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl; R 1 , R 2 , R 3 , and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 is nothing, (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0059] In certain embodiments, (i) R 3 is H, alkyl, or substituted alkyl; R 5 is propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl, or (ii) R 3 is H or alkynyl, R 5 is alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl.

[0060] In one embodiment, at least one compound of formula (I) is represented by the formula (II-a) or a salt thereof, wherein (i) Y is N, bond b1 is null, Z is H, bond b2 is a single bond, and A is CH, and at least one compound is a compound of formula (II-a) or a salt thereof, [ka] and (ii) Y is N, bond b1 is absent, Z is absent, bond b2 is absent, A is a bond, and the compound of the present invention is a compound of formula (II-b) or a salt thereof, selected from the group consisting of: [ka]

[0061] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is CR 6 , bond b1 is null, Z is H, and bond b 2is a single bond, A is CH, and at least one compound is a compound of formula (III-a) or a salt thereof, [ka] and (ii) Y is CR 6 and bond b 1 is null, Z is null, and bond b 2 is nothing, A is a bond, and the compound of the present invention is a pyrimidine of formula (III-b) or a salt thereof, selected from the group consisting of: [ka]

[0062] In one embodiment, Y is C and bond b 1 is a single bond, Z is CH2, and bond b 2 is a single bond, A is CH, and the at least one compound is a compound of formula (IV) or a salt thereof. [ka]

[0063] In one embodiment, Y is C and bond b 1 is a single bond, Z is CH, and bond b 2 is a double bond, A is C, and the at least one compound is a compound of formula (V) or a salt thereof. [ka]

[0064] In one embodiment, the at least one compound is selected from the group consisting of N-(4,6-bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XX), N-(4,6-bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXII), N-(4-cyclopropylmethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV), N-(4-ethylamino)-N-(6-n-propylamino)-[1 ,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXVII), N-(bis-4,6-(2-methylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX), N-(bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI), 4,6-bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (XXXII) I), N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXV), N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide (XL), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI), O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLIII), N-( 4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine (XLVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]oxazinan-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII), N-(4,6-bis-propylamino -[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII), 6-( Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro -ethyl)-hydroxylamine (C), 4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII), 4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV), 4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX), 4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXIII), 4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3 N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nonadeca-1(18),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine (XLVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhydrazine (XLIX), salts thereof, and mixtures thereof. In another embodiment, the salt is a hydrogen sulfate or hydrochloride salt.

[0065] In one embodiment, at least one compound is 2,6-bis-(Nn-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is the hydrogen sulfate salt or the hydrochloride salt.

[0066] In one embodiment, at least one compound is N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is a hydrogen sulfate salt or a hydrochloride salt.

[0067] In one embodiment, the at least one compound is selected from the group consisting of 2-(n-propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidine (CXX XVI), 2,4-bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX), 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLV), salts thereof, and mixtures thereof. In another embodiment, the salt is a hydrogen sulfate salt or a hydrochloride salt.

[0068] In one embodiment, the at least one compound is selected from the group consisting of N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,O-dimethyl-hydroxylamine (CLVIII), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLX), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CLVIII ... In another embodiment, the salt is selected from the group consisting of hydrogen sulfate or hydrochloride.

[0069] In certain embodiments, the compound is selected from the group consisting of O,N-dimethyl-N-[4-(n-propylamino)-6-(prop-2-ynylamino-[1,3,5]triazin-2-yl]-hydroxylamine, N-methyl-N′-n-propyl-N″-prop-2-ynyl-[1,3,5]triazine-2,4,6-triamine, salts thereof, and any combination thereof.

[0070] In certain embodiments, the compound A [ka] or a pharma- ceutically acceptable salt thereof, are utilized in the present invention.

[0071] In certain embodiments, the compound of formula (I) is selected from compounds described in U.S. Pat. No. 9,162,992 and / or U.S. Pat. No. 9,351,972 and / or U.S. Patent Application Publication No. 2015-0291597 (now abandoned), the teachings of which are incorporated herein by reference in their entirety.

[0072] In certain embodiments, the non-opioid agent is a central nervous system depressant.

[0073] In certain embodiments, the central nervous system depressant is a surgical anesthetic.

[0074] In certain embodiments, the surgical anesthetic is propofol, fospropofol, ketamine, thiopental, methohexital, etomidate, sevoflurane, isoflurane, desflurane, or a pharma- ceutically acceptable salt thereof.

[0075] In certain embodiments, the patient exhibits restored ventilatory sufficiency.

[0076] In certain embodiments, patients exhibit restored respiratory adequacy under standard sedation, low sedation, or high sedation.

[0077] In certain embodiments, patients exhibit restored respiratory sufficiency under overdose.

[0078] In certain embodiments, the patient exhibits increased ventilatory responsiveness.

[0079] In certain embodiments, the patient exhibits increased ventilatory responsiveness to a hypoxemic event.

[0080] In certain embodiments, the patient exhibits increased ventilatory responsiveness to a hypercapnic event.

[0081] In certain embodiments, patient ventilatory deterioration is avoided or minimized.

[0082] In certain embodiments, patient ventilatory deterioration is avoided or minimized during periods of hypercapnia.

[0083] In certain embodiments, the route of administration is selected from oral, intravenous, nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, aural, intraocular, or intrathecal routes.

[0084] 13. The method of any one of the preceding claims, wherein the therapeutic effect of the non-opioid agent is maintained.

[0085] In certain embodiments, the therapeutic effect is not diminished.

[0086] In certain embodiments, the anesthetic effect is maintained.

[0087] In certain embodiments, the anesthetic effect is not reduced.

[0088] In certain embodiments, the patient exhibits improvement in hypoxia.

[0089] In certain embodiments, the patient exhibits improvement in hypercapnia.

[0090] In certain embodiments, the improvement is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%.

[0091] In certain embodiments, the patient exhibits improved minute ventilation.

[0092] In certain embodiments, the improvement is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% as measured by hypoxic ventilation sensitivity (Δ ventilation / Δ saturation = hypoxic sensitivity in L / min per % desaturation).

[0093] In certain embodiments, the patient has a positive respiratory response under normocapnic and mild hypercapnic conditions during normoxia.

[0094] In certain embodiments, the patient maintains a positive respiratory response under normocapnic and mild hypercapnic conditions during normoxia.

[0095] In certain embodiments, the patient exhibits no side effects or experiences no clinically significant side effects as measured by one or more of reported adverse events, physical exam, vital signs, 12-lead ECG, clinical laboratory results, and Columbia-Suicide Severity Rating Scale (C-SSRS) response.

[0096] In certain embodiments, the patient does not exhibit a clinically significant alteration in cardiovascular response.

[0097] In certain embodiments, patients exhibit therapeutic benefit as measured by hypoxic sensitivity (Δventilation / Δsaturation).

[0098] In certain embodiments, the patient exhibits therapeutic benefit as measured by tidal volume (VT).

[0099] In certain embodiments, the patient responds to treatment as measured by respiratory rate (breaths / minute).

[0100] In certain embodiments, the patient exhibits a therapeutic benefit as measured by minute ventilation (VE).

[0101] In certain embodiments, the patient exhibits a therapeutic benefit as measured by transcutaneous CO2 measurement and / or end tidal CO2 (mmHg).

[0102] In certain embodiments, the patient responds to treatment as measured by transcutaneous hemoglobin saturation (SpO2 in %).

[0103] In certain embodiments, the patient exhibits a therapeutic benefit as measured by arterial blood gases.

[0104] In certain embodiments, the therapeutic effect is measured by BIS.

[0105] In certain embodiments, the patient exhibits a therapeutic benefit as measured by hemodynamic parameters from arterial line monitoring.

[0106] In certain embodiments, the change is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%.

[0107] In certain embodiments, administration is intravenous.

[0108] In certain embodiments, the compound of formula (I) is administered at a rate of about 0.10 mg / kg / hour to about 10 mg / kg / hour.

[0109] In certain embodiments, the compound of formula (I) is administered at a rate of about 0.50 mg / kg / hour to about 5 mg / kg / hour.

[0110] In certain embodiments, the compound of formula (I) is administered at a rate of about 0.40 mg / kg / hour to about 1.0 mg / kg / hour.

[0111] In certain embodiments, the compound of formula (I) is administered at a rate of about 0.40 mg / kg / hour.

[0112] In certain embodiments, the compound of formula (I) is administered at a rate of about 1.0 mg / kg / hour.

[0113] In certain embodiments, the present invention further comprises administering a loading dose.

[0114] In certain embodiments, the loading dose is from about 0.50 mg / kg / hour to about 5 mg / kg / hour.

[0115] In certain embodiments, the loading dose is from about 1.0 mg / kg / hour to about 3.0 mg / kg / hour.

[0116] In certain embodiments, the loading dose is about 2.0 mg / kg / hour.

[0117] In certain embodiments, the total time of administration is from about 5 minutes to about 24 hours.

[0118] In certain embodiments, the total time is from about 30 minutes to about 6 hours, or from about 1 hour to about 3 hours.

[0119] In certain embodiments, the loading dose is administered as a bolus.

[0120] In certain embodiments, the loading dose is administered over a period of less than 1 hour, less than 45 minutes, less than 30 minutes, less than 25 minutes, less than about 10 minutes, about 10 minutes, or about 20 minutes.

[0121] In certain embodiments, the route of administration may be selected from oral, intravenous (e.g., continuous infusion or bolus injection), nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal (e.g., intratracheal instillation or inhalation), otic, intraocular, or intrathecal routes. Non-limiting exemplary suitable pulmonary administration may be via a metered dose inhaler, nebulizer, soft mist inhaler, high efficiency nebulizer, ultrasonic nebulizer, dry powder inhaler, continuous positive airway pressure (CPAP) machine, bilevel positive airway pressure machine (BiPAP), or mechanical ventilator.

[0122] In certain embodiments, the terminal half-life is about 1 to about 15 hours, about 2 to about 14 hours, about 3 to about 13 hours, about 4 to about 12 hours, about 4 to about 11 hours, about 5 to about 10 hours, about 6 to about 9 hours, or about 7 to about 8 hours.

[0123] In certain embodiments, a compound of formula (I) is administered at a rate of about 0.40 mg / kg / hour and has a terminal half-life of about 2 to about 8 hours, about 3 to about 7 hours, about 3.2 to about 6.7 hours, about 3.4 to about 6.5 hours, about 3.6 to about 6.3 hours, about 3.8 to about 6.1 hours, about 4.0 to about 5.9 hours, about 4.2 to about 5.7 hours, about 4.4 to about 5.5 hours, about 4.6 to about 5.3 hours, or about 4.8 to about 5.1 hours.

[0124] In certain embodiments, the compound of formula (I) is administered at a rate of about 1.0 mg / kg / hour and has a terminal half-life of about 3 to about 9 hours, about 3.3 to about 8.7 hours, about 3.6 to about 8.2 hours, about 3.8 to about 8.0 hours, about 4.0 to about 7.8 hours, about 4.2 to about 7.6 hours, about 4.4 to about 7.4 hours, about 4.6 to about 7.2 hours, about 4.8 to about 7.0 hours, about 5.0 to about 6.8 hours, about 5.2 to about 6.6 hours, about 5.4 to about 6.4 hours, about 5.6 to about 6.2 hours, or about 5.8 to about 6.0 hours.

[0125] In certain embodiments, the plasma concentration of the compound of formula (I) increases over time.

[0126] In certain embodiments, the time to maximum plasma concentration (t max ) is about 2 to about 8 hours, about 3 to about 5 hours, about 3.2 to about 4.7 hours, about 3.5 to about 4.5 hours, or about 3.8 to 4.2 hours.

[0127] In certain embodiments, the mean peak plasma concentration (C max ) is about 200 to about 2500 ng / mL, about 500 to about 2000 ng / mL, or about 1000 to about 1500 ng / mL.

[0128] In certain embodiments, a compound of formula (I) is administered at a rate of about 2.0 mg / kg / hour for 20 minutes followed by 1.1 mg / kg / hour for 250 minutes to achieve mean peak plasma concentrations (C) of about 500 to about 2500 ng / mL, about 1000 to about 2000 ng / mL, about 1050 to about 1950 ng / mL, about 1100 to about 1900 ng / mL, about 1150 to about 1850 ng / mL, about 1200 to about 1800 ng / mL, about 1250 ng / mL to about 1750 ng / mL, about 1300 ng / mL to about 1700 ng / mL, about 1350 to about 1650 ng / mL, or about 1400 ng / mL to about 1500 ng / mL. max ).

[0129] In certain embodiments, the compound of formula (I) has a mean AUC of about 1000 to about 15,000 ng*h / mL, about 2000 to about 12,500 ng*h / mL, about 3000 to about 10,000 ng*h / mL, or about 5000 to about 8000 ng*h / mL. inf has.

[0130] In certain embodiments, the compound of formula (I) is administered at a rate of about 2.0 mg / kg / hour for 20 minutes, followed by 1.1 mg / kg / hour for 250 minutes, to achieve a concentration of about 5000 to about 15,000 ng*h / mL, about 6200 to about 11,000 ng*h / mL, about 6300 to about 10,900 ng*h / mL, about 6400 to about 10,800 ng*h / mL, or about 6500 to about 11,000 ng*h / mL. ng*h / mL, about 6500 to about 10,700ng*h / mL, about 6600 to about 10,600ng*h / mL, about 6700 to about 10,500ng*h / mL, about 6 800 to about 10,400ng*h / mL, about 6900 to about 10,300ng*h / mL, about 7000 to about 10,200ng*h / mL, about 7100 to about 10,10 0ng*h / mL, about 7200 to about 10,000ng*h / mL, about 7300 to about 9,900ng*h / mL, about 7400 to about 9800ng*h / mL, about 75 00~about 9700ng*h / mL, about 7600~about 9600ng*h / mL, about 7700~about 9500ng*h / mL, about 7800~about 9400ng*h / mL, Mean (±SD) AUC of about 7900 to about 9300ng*h / mL, about 8000 to about 9200ng*h / mL, about 8100 to about 9100ng*h / mL, about 8200 to about 9000ng*h / mL, about 8300 to about 8900ng*h / mL, about 8400 to about 8800ng*h / mL, or about 8500 to about 8700ng*h / mL inf has.

[0131] In certain embodiments, the geometric mean C av30-3270min (mean arterial plasma concentration between 30 and 270 min) is about 200 ng / mL to about 2000 ng / mL, 250 ng / mL to about 1800 ng / mL, about 300 ng / mL to about 1500 ng / mL, or about 350 ng / mL to about 1200 ng / mL.

[0132] In certain embodiments, a compound of formula (I) is administered at a rate of about 2.0 mg / kg / hr for 20 minutes followed by 1.1 mg / kg / hr for 250 minutes to achieve a geometric mean C of about 800 ng / mL to about 1800 ng / mL, about 900 ng / mL to about 1600 ng / mL, about 1000 ng / mL to about 1500 ng / mL, about 1050 to about 1450 ng / mL, about 1100 to about 1400 ng / mL, about 1150 to about 1350 ng / mL, or about 1200 to about 1300 ng / mL. av30-3270min (mean arterial plasma concentration between 30 and 270 min).

[0133] In certain embodiments, a compound of formula (I) is administered at a rate of about 2.0 mg / kg / hour for 20 minutes followed by 0.4 mg / kg / hour for 250 minutes to achieve a geometric mean C of about 200 ng / mL to about 800 ng / mL, about 250 ng / mL to about 600 ng / mL, about 300 ng / mL to about 400 ng / mL, about 310 to about 390 ng / mL, about 320 to about 380 ng / mL, about 330 to about 370 ng / mL, or about 340 to about 360 ng / mL. av30-3270min (mean arterial plasma concentration between 30 and 270 min).

[0134] In certain embodiments, the compound of formula (I) is administered at a rate of about 2.0 mg / kg / hour for 20 minutes followed by 0.4 mg / kg / hour for 250 minutes to achieve a mean C of about 200 to about 800 ng / mL, about 375 to about 550 ng / mL, about 400 to about 525 ng / mL, or about 425 to about 500 ng / mL. max has.

[0135] In certain embodiments, a compound of formula (I) is administered at a rate of about 2.0 mg / kg / hr for 20 minutes followed by 0.4 mg / kg / hr for 250 minutes to achieve a mean AUC of about 1000 to about 4000 ng*h / mL, about 1500 to about 3500 ng*h / mL, about 2000 to about 3300 ng*h / mL, about 2200 to about 3000 ng*h / mL, or about 2500 to about 2800 ng*h / mL. inf has.

[0136] In certain embodiments, the average concentration (e.g., Cmax) of a compound of Formula (I) at a given time (e.g., Tmax) increases with increasing dosage of the surgical anesthetic, in certain embodiments, the increase is at least about 5%, at least about 10%, at least about 25%, at least about 35%, at least about 45%, or between about 5% and about 50%, or between about 10% and about 40%, or between about 15% and about 35%.

[0137] In certain embodiments, the average minute ventilation increases during the hypoxemia measurement. In some embodiments, the average minute ventilation may increase by at least about 5%, at least about 10%, at least about 25%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 125%, at least about 150%, or at least about 200%, or any value therein. In some embodiments, the average minute ventilation may increase by about 5% to about 200%, about 15% to about 175%, about 25% to about 150%, about 50% to about 125%, or about 75% to about 100%.

[0138] In certain embodiments, the average tidal volume increases during the hypoxemia measurement. In some embodiments, the average tidal volume may increase by at least about 5%, at least about 10%, at least about 25%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 125%, at least about 150%, or at least about 200%, or any value therein. In some embodiments, the average tidal volume may increase by about 5% to about 200%, about 15% to about 175%, about 25% to about 150%, about 50% to about 125%, or about 75% to about 100%.

[0139] In certain embodiments, the respiratory rate increases during hypoxemia. In some embodiments, the respiratory rate may increase by at least about 5%, at least about 10%, at least about 25%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 125%, at least about 150%, or at least about 200%, or any value therein. In some embodiments, the respiratory rate may increase by about 5% to about 200%, about 15% to about 175%, about 25% to about 150%, about 50% to about 125%, or about 75% to about 100%.

[0140] composition In certain embodiments, the present disclosure is directed to a pharmaceutical composition comprising an effective amount of a compound selected from Formula (I) disclosed herein for treating non-opioid mediated respiratory depression.

[0141] In certain embodiments, the active agent(s) in the pharmaceutical composition is lyophilized.

[0142] In certain embodiments, the pharmaceutical composition is premixed (e.g., the active agent is premixed with one or more pharma- ceutically acceptable excipients, and optionally with one or more additional active agents).

[0143] In certain embodiments, the pharmaceutical composition may be housed in a glass or plastic container.

[0144] In certain embodiments, the pharmaceutical composition further comprises one or more pharma- ceutically acceptable excipients. Suitable pharma- ceutically acceptable excipients may vary based on the final form of the composition and the route of administration.

[0145] Routes of administration of any of the compositions of the invention include inhalation, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, buccal, urethral, ​​vaginal (e.g., vaginal and perivaginal), nasal, and rectal), intravesical, intrapulmonary, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, intraperitoneal, intrathoracic, intrapleural, and topical administration.

[0146] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, salves, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It is understood that the formulations and compositions that would be useful in the present invention are not limited to the specific formulations and compositions described herein.

[0147] In certain embodiments, a pharma- ceutically acceptable excipient may comprise a pharma- ceutically acceptable carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, thickener, solvent, or encapsulating material, that may carry or transport a compound useful within the present invention into or to a subject, thereby performing its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other components of the formulation containing the compound useful within the present invention, and must not be deleterious to the subject. Some examples of materials which can function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surface-active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations. As used herein, "pharmacologically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to a subject. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may further include pharma-ceutically acceptable salts of the compounds useful within the present invention.Other additional ingredients that may be included in pharmaceutical compositions used to practice the invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0148] Useful pharma- ceutically acceptable carriers include, but are not limited to, solutions of glycerol, water, saline, ethanol, and other pharma- ceutically acceptable salts, such as phosphates and salts of organic acids. Examples of these and other pharma- ceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0149] The carrier may be a solvent or dispersion medium, for example, containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable composition may be brought about by including an agent that delays absorption, for example, aluminum monostearate or gelatin, in the composition. In one embodiment, the pharma- ceutical acceptable carrier is not DMSO alone.

[0150] The pharmaceutical preparations may be sterilized and, if desired, may be mixed with auxiliary substances, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic buffers, colorants, flavors, and / or aromatic substances.

[0151] Examples of preservatives useful according to the present invention include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea, and combinations thereof.

[0152] The composition preferably includes an antioxidant and a chelating agent that inhibits the degradation of the compound. Preferred antioxidants for some compounds are BHT, BHA, α-tocopherol, and ascorbic acid in a preferred range of about 0.01% to 0.3% by weight, by total weight of the composition, more preferably BHT in the range of 0.03% to 0.1% by weight. Preferably, the chelating agent is present in an amount of 0.01% to 0.5% by weight, by total weight of the composition. Particularly preferred chelating agents include edetate (e.g., disodium edetate) and citric acid in the range of about 0.01% to 0.20% by weight, more preferably 0.02% to 0.10% by weight, by total weight of the composition. Chelating agents are useful for chelating metal ions in the composition, which may be detrimental to the shelf life of the formulation. BHT and disodium edetate are particularly preferred antioxidants and chelating agents, respectively, for some compounds, but for this reason may be substituted with other suitable and equivalent antioxidants and chelating agents, as would be known to one of skill in the art.

[0153] Liquid suspensions may be prepared using conventional methods to achieve suspension of active ingredients in aqueous or oily vehicles. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further include one or more additional ingredients, including, but not limited to, suspending agents, dispersing agents, or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavoring agents, coloring agents, and sweetening agents. Oily suspensions may further include a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally occurring phospholipids such as lecithin, condensation products of alkylene oxides with fatty acids, with long chain aliphatic alcohols, with partial esters derived from fatty acids and hexitols, or with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0154] A liquid solution of an active ingredient in an aqueous or oily solvent may be prepared in substantially the same manner as a liquid suspension, the main difference being that the active ingredient is dissolved in the solvent rather than suspended. As used herein, an "oily" liquid is a liquid that contains carbon-containing liquid molecules and exhibits less polarity than water. A liquid solution of the pharmaceutical composition of the present invention may contain each of the components described in connection with a liquid suspension, with the understanding that the suspending agent does not necessarily aid in dissolving the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0155] Powder and granular formulations of the pharmaceutical preparation of the present invention can be prepared using known methods. Such formulations can be directly administered to a subject, or can be used, for example, to form tablets, to fill capsules, or to prepare aqueous or oily suspensions or solutions by adding aqueous or oily vehicles thereto. Each of these formulations can further include one or more of dispersing or wetting agents, suspending agents, and preservatives. Additional excipients, such as fillers and sweeteners, flavoring agents, or coloring agents, can also be included in these formulations.

[0156] The pharmaceutical composition of the present invention may also be prepared, packaged, or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a combination thereof. Such compositions may further comprise one or more emulsifiers, such as naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phospholipids, such as soybean or lecithin phospholipids, esters or partial esters derived from the combination of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsions may also comprise additional ingredients, including, for example, sweeteners or flavoring agents.

[0157] In certain embodiments, the one or more additional excipients include a pH adjuster, which may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, or mixtures thereof.

[0158] In certain embodiments, the compositions may include one or more additional excipients, such as, but not limited to, carbohydrates, antioxidants, chelating agents, low molecular weight proteins, high molecular weight polymers, gel formers, stabilizers, additives, wetting agents, emulsifiers, surfactants and / or dispersing agents, alkalizing agents, colorants, synthetic dyes, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0159] In certain embodiments, the composition further comprises an antioxidant. In certain embodiments, the antioxidant may include, for example, trivalent phosphorus such as phosphites, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones. While hindered phenols, thiosynergists, and / or hindered amines are useful for long-term stability of the polymer, the following antioxidants are also suitable for use in situations where the active is subject to oxidation: acids (ascorbic acid, erythorbic acid, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid, etc.), phenols (e.g., BHA, BHT, t-butylhydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic. Salts (calcium ascorbate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, potassium bisulfite, potassium metabisulfite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate), pyranones (maltol), and vitamins (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopherol acetate, d-α-tocopherol acetate, dl-α-tocopheryl acetate). However, other antioxidants known in the art may be used in accordance with the present invention.

[0160] In certain embodiments, suitable antioxidants include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations of the above. Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols, such as, but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylphenol), ... 2,6-di-tert-butyl-4-methoxymethylphenol; nonylphenols having linear or branched side chains, such as 2,6-di-nonyl-4-methylphenol, 2,4-dimethyl-6-(1'-methylundecyl)phenol, 2,4-dimethyl-6-(1'-methylheptadec ... phenol, 2,4-dimethyl-6-(1'-methyltridec-1-yl)phenol, and mixtures thereof, alkylthiomethylphenols, such as, but not limited to, 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-dioctylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol, hydroquinone and alkylated hydroquinones, such as, but not limited to, However, 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-di-tert-butyl-4-hydroxyphenyl) adipate, tocopherols, including but not limited to α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and mixtures thereof (vitamin E), hydroxylated thiodiphenyl ethers, including but not limited to 2,2′-thiobis(6-tert-butyl-4-methylphenol), 2,2′-thiobis(4-octylphenol), 4,4′-thiobis(6-tert-butyl-3-methylphenol), 4,4′-thiobis(6-tert-butyl-4-methylphenol), butyl-2-methylphenol), 4,4'-thiobis(3,6-di-sec-amylphenol), 4,4'-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide, alkylidene bisphenols, such as, but not limited to, 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 2,2'-methylenebis(6-tert-butyl-4-ethylphenol), 2,2'-methylenebis[4-methyl-6-(α-methylcyclohexyl)-phenol], 2,2'-methylenebis(4-methyl-6-cyclohexyl)-phenol], xylphenol), 2,2'-methylenebis(6-nonyl-4-methylphenol), 2,2'-methylenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(6-tert-butyl-4-isobutylphenol), 2,2'-methylenebis[6-(α-methylbenzyl)-4-nonylphenol], 2,2'-methylenebis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4'-methylenebis(2,6-di-tert -butylphenol), 4,4′-methylenebis(6-tert-butyl-2-methylphenol), 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-bis(3-tert-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-tris(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3′-tert-butyl-4′-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methyl-phenyl)dicyclopentadiene, bis[2-(3′-tert-butyl-2′-hydroxy-5′-methylbenzyl)-6-tert-butyl-4-methylphenyl]terephthalate, 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxyphenyl)propane 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane, O-, N-, and S-benzyl compounds, such as, but not limited to, 3,5,3′,5′-tetra-tert-butyl-4,4′-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzyl mercaptoacetate, tris(3,5-di-t tert-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzyl mercaptoacetate, hydroxybenzylated malonates, such as, but not limited to, dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, di-octadecyl-2-(3-tert -butyl-4-hydroxy-5-methylbenzyl)malonate, didodecylmercaptoethyl-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, aromatic hydroxybenzyl compounds, such as, but not limited to, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol, triazine compounds, such as, but not limited to, 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, ,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,3,5-triazine, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenylethyl)-1,3, 5-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxy-phenylpropionyl)-hexahydro-1,3,5-triazine, 1,3,5-tris(3,5-dicyclohexyl-4-hydroxybenzyl)iso-cyanurate, benzyl phosphonates, such as, but not limited to, dimethyl-2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl 3,5-di-tert-butyl-4-hydroxyphenylpropionyl, hydroxybenzyl phosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzyl phosphonate, calcium salt of the monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzyl phosphonic acid, acylaminophenols such as, but not limited to, 4-hydroxylauranilide, 4-hydroxystearanilide, N-(3,5-di-tert-butyl-4-hydroxyphenyl) octyl carbamate, β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid with, for example, monohydric or polyhydric alcohols, for example, methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3- Thioundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid with mono- or polyhydric alcohols, such as methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl Glycol, thiodiethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis-(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]- Esters of 2,4,8,10-tetraoxaspiro[5.5]-undecane, esters of 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols, such as, for example, methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2,2]octane, esters of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with mono- or polyhydric alcohols, e.g., methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters with 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, 6-(3,5-di-tert- butyl-4-hydroxyphenyl)propionic acid amides, such as N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexamethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazide, N,N'-bis[2-(3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyloxy)ethyl]propionyl,

[0113] oxamide (Naugard® XL-1, Uniroyal), ascorbic acid (vitamin C), amine antioxidants, such as, but not limited to, N,N'-di-isopropyl-p-phenylenediamine, N,N'-di-sec-butyl-p-phenylenediamine, N,N'-bis(1,4-dimethylpentyl)-p-phenylenediamine, N,N'-bis(1-ethyl-3-methylpentyl)-p-phenylenediamine, N,N'-bis(1-methylheptyl)-p-phenylenediamine, N,N'-disiloxane, N,N'-diisopropyl-p-phenylenediamine ... cyclohexyl-p-phenylenediamine, N,N'-diphenyl-p-phenylenediamine, N,N'-bis(2-naphthyl)-p-phenylenediamine, N-isopropyl-N'-phenyl-p-phenylenediamine, N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine, N-(1-methylheptyl)-N'-phenyl-p-phenylenediamine, N-cyclohexyl-N'-phenyl-p-phenylenediamine, 4-(p-toluenesulfamoyl)diphenylamine, N,N'-dimethyl-N,N'-di-sec-butyl-p-phenylenediamine, diphenylamine, N-allyldiphenylamine, 4-isopropoxydiphenylamine, N-phenyl-1-naphthylamine, N-(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine, octylated diphenylamines, such as, but not limited to, p,p'-di-tert-octyldiphenylamine, 4-n-butylaminophenol, 4-butyrylaminophenol, , 4-nonanoylaminophenol, 4-dodecanoylaminophenol, 4-octadecanoylaminophenol, bis(4-methoxyphenyl)amine, 2,6-di-tert-butyl-4-dimethylaminomethylphenol, 2,4′-diaminodiphenylmethane, 4,4′-diaminodiphenylmethane, N,N,N′,N′-tetramethyl-4,4′-diaminodiphenylmethane, 1,2-bis[(2-methylphenyl)amino]ethane, 1,2-bis( phenylamino)propane, (o-tolyl)biguanide, bis[4-(1′,3′-dimethylbutyl)phenyl]amine, tert-octylated N-phenyl-1-naphthylamine, mixtures of mono- and dialkylated tert-butyl / tert-octyldiphenylamines, mixtures of mono- and dialkylated nonyldiphenylamines, mixtures of mono- and dialkylated dodecyldiphenylamines, mixtures of mono- and dialkylated isopropyl / isohexyldiphenylamines, mono- and dialkylated tert-butyldiphenylamines, 2,3-dihydro-3,3-dimethyl-4H-1,4-benzothiazine, phenothiazine, mixtures of mono- and dialkylated tert-butyl / tert-octylphenothiazines, mixtures of mono- and dialkylated tert-octyl-phenothiazines, N-allylphenothiazine, N,N,N′,N′-tetraphenyl-1,4-diaminobut-2-ene, and combinations of the above. ,

[0161] In certain embodiments, suitable pharma- ceutically acceptable excipients include acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyalkylene oxides (e.g., polymethylene oxide, polyethylene oxide, polypropylene oxide) polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylates, polycaprolactone, polymethacrylate copolymers thereof, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, croscarmellose sodium, or mixtures thereof), glidants, lubricants, absorption enhancers, surfactants, and the like. The chewable compositions may include, for example, viscosity modifiers, binders, softeners, plasticizers (e.g., lecithin, hydrogenated vegetable oils, glycerol esters, lanolin, methyl esters, pentaerythritol esters, rice bran wax, stearic acid, potassium sodium stearate, and the like), waxes, fats, emulsifiers, fillers, antioxidants, flavors, colorants, diluents, processing aids (e.g., granulation aids), sweeteners such as those described above in connection with the chewable compositions, fixatives (e.g., polyols, including but not limited to, sorbitol, maltitol / isomalt, mannitol, starch, and the like), pH adjusters, viscosity modifiers, solubility enhancers or reducers, osmotic agents, solvents, or combinations thereof.

[0162] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrophilic and hydrophobic materials such as polyvinylpyrrolidone, natural and synthetic gums, polyvinyl alcohol, corn starch, sustained release polymers, acrylic resins, protein-derived materials, waxes, shellac, and solid or semi-solid oils, such as hydrogenated castor oil and hydrogenated vegetable oils. More specifically, the controlled release material can be, for example, alkylcelluloses, such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers (e.g., acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methyl methacrylate alkylamide copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydrides), methyl methacrylate, polymethacrylates, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and mixtures of any of the foregoing), and cellulose ethers such as hydroxyalkylcelluloses (e.g., hydroxypropylmethyl cellulose) and carboxyalkylcelluloses. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (eg, beeswax, carnauba wax, stearic acid, and stearyl alcohol).

[0163] In certain embodiments, suitable pharma- ceutically acceptable excipients include gelling agents, such as, but not limited to, sugars or sugar-derived alcohols, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester ethers, cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl phthalate, cellulose acetate ... methylcellulose (hypromellose acetate succinate, and mixtures thereof), attapulgite, bentonite, dextrin, alginates, alginates such as sodium alginate and potassium alginate, casein, stearic acid, shellac, carrageenan, tragacanth, acacia, arabic, pullulan, dextrin, gellan, agar, tara, karaya, guar, wellan, rhamsan, locust bean, xanthan, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer and carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant / wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.

[0164] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrophilic excipients, such as, but not limited to, water, low molecular weight polyols, such as polyethylene glycol, polypropylene glycol, or combinations thereof.Other suitable hydrophilic carriers include, but are not limited to, polyoxyethylene derivatives of sorbitan esters, such as sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof. Exemplary low molecular weight polyols include, but are not limited to, those having a number average molecular weight of from about 200 Daltons, about 400 Daltons, about 600 Daltons, about 800 Daltons, or about 1000 Daltons to about 2000 Daltons, about 3000 Daltons, about 4000 Daltons, about 5000 Daltons, about 6000 Da, or about 7000 Da, or any subrange or single value therein (e.g., polyethylene glycol 400, polyethylene glycol 600, etc.).

[0165] In certain embodiments, suitable pharma- ceutically acceptable excipients may include plasticizers, such as, but not limited to, triacetin, isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as, but not limited to, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamines, and mixtures thereof. Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers can include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0166] In certain embodiments, suitable pharma- ceutically acceptable excipients include plasticizers, such as, but not limited to, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils, and hydrogenated vegetable oils, including acetylated hydrogenated cottonseed glycerides and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylate glycerin, glyceryl cocoate, mono- and diacetylated monoglycerides, and glyceryl esters. lycerides, nitrobenzene, carbon disulfide, fl-naphthyl salicylate, phthalyl glycolate, diosyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols including cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, and myristyl alcohol;Methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(beta-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(2-ethylhexoate), diethylene glycol monolaurate , Monomeric polyethylene ester, Hydrogenated methyl ester of rosin, Methoxyethyl oleate, Butoxyethyl stearate, Butyl phthalyl butyl glycolate, Glycerol tributyrate, Propylene glycol dipelagonate, Beta-(p-tert-amylphenoxy)ethanol, Beta-(p-tert-butylphenoxy)ethanol, Beta-(p-tert-butylphenoxyethyl)acetate, Bis(beta-p-tert-butylphenoxydiethyl)ether, Camphor, Cumar W-1, Cumar MH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy)ethanol, diphenyl oxide, technical hydroabietyl alcohol, beckolin, benzene hexahydrochloride, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, glycerol alpha-methyl alpha-phenyl ether, chlorinated naphthalenes, HB-40, monoamyl phthalate, Nevillac 10 o-nitrodiphenyl, and Paracril 26;

[0167] In certain embodiments, suitable pharma- ceutically acceptable excipients may include plasticizers, such as, but not limited to, isomalt, maltitol, sorbitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as, but not limited to, glycerin, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamines, and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers can include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0168] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fragrances, such as, but not limited to, natural and / or synthetic fragrance materials. For example, oil-soluble fragrance oils, which may or may not be mixed with water-soluble fragrance oils. Oil-soluble fragrances are natural or natural-like essential oils, such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaf, peppermint oil, cedarwood oil, rosemary oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, germanium oil, menthol, and marjoram oil. Animal fragrances are, for example, musk, castoreum, aber, or civet. Spagellic essences are also known in the art. They are made by fermenting certain herbs and processed into a final product. Synthetic fragrance ingredients are synthetic essential oils, such as those composed of a single compound, for example linalool, terpinol, nerol, citronellal, benzaldehyde, cinnamon aldehyde, vanillin, ethyl vanillin, or methylacetophenone. The fragrance material may also be a synthetic oil-soluble perfume oil selected from the usual group consisting of aromatic hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, polyene derivatives. Other fragrances that may be used are classified and described in reference books and databases such as S. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; reprinted 2000), Allured's Flavor and Fragrance Materials (2005), and the database maintained by the Research Institute for Fragrance Materials at www.rifm.org.

[0169] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fragrance oils.Suitable fragrance oils include mixtures of natural fragrances and synthetic fragrances.Natural fragrances are extracts from flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, cumin, juniper), fruit skins (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calamus), wood (pinewood, sandalwood, guaiacwood, cedarwood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Typical synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol and hydrocarbon type. Fragrance compounds of the ester type are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethyl-methylphenyl glycinate, allyl cyclohexylpropionate, styrallyl propionate and benzyl salicylate. The ethers include, for example, benzyl ethyl ether; the aldehydes include, for example, the linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial, and brujonal; the ketones include, for example, the ionones, α-isomethylionone, and methyl cedryl ketone; the alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol, and terpineol; and the hydrocarbons include primarily the terpenes and balsams.

[0170] In certain embodiments, suitable pharma- ceutically acceptable excipients may include essential oils of relatively low volatility that are primarily used as flavoring ingredients and are also suitable as perfume oils, e.g., sage oil, chamomile oil, oil of clove, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labranum oil, and lavandin oil. Other suitable oils include bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, alpha-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, Boisambrene Forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertal, lavandin oil, clary sage oil, beta-damascene, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, Iso-E-Super, Fixolide NP, Evernyl, Iraldein Gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romirat, irotyl, and floramate, alone or in mixtures.

[0171] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives. As used herein, the term "preservative" refers to an agent that extends the shelf life of a dosage form by delaying or preventing deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety. A preservative need not provide a lethal, irreversible action that results in partial or complete microbial cell destruction or incapacitation. Sterilants, cleaners, disinfectants, sporicides, virucides, and tuberculocides provide such an irreversible mode of action, which is sometimes referred to as a "bactericidal" action. In contrast, a preservative can provide an inhibitory or bacteriostatic action that is reversible in that the target microorganism can resume growth if the preservative is removed. The main difference between a preservative and a cleaner is primarily the mode of action (preservatives prevent growth of microorganisms rather than killing them) and the exposure time (preservatives take days to months to act, whereas cleaners take no more than a few minutes to act). Suitable preservatives include, but are not limited to, phenoxyethanol, parabens, pentanediol, and sorbic acid solutions, as well as silver complexes.

[0172] In certain embodiments, suitable pharma- ceutically acceptable excipients may include colorants, such as, but not limited to, dyes, e.g., white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown.

[0173] In certain embodiments, suitable pharma- ceutically acceptable excipients may include, but are not limited to, "flavor extracts" obtained by extracting a source, e.g., a portion of an animal or plant material, often using a solvent such as ethanol or water, natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from whole plants. Additional exemplary flavorants of the compositions described herein may include, but are not limited to, menthol, spearmint, and other flavors or fragrances, such as cinnamon, coffee bean, fruit flavors (e.g., cherry, orange, grape, etc.), and quaternary ammonium bases. The effect of the flavorant may be enhanced using flavor enhancers, such as tartaric acid, citric acid, vanillin, etc.

[0174] In certain embodiments, suitable pharma- ceutically acceptable excipients may include sweeteners, such as, but not limited to, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as the potassium salt (available as Sunett®), alitam, aspartame (available as NutraSweet® and Equal®), aspartame-acesulfame salt (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as the sodium salt (available as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogrosides. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet (registered trademark)); natural intense sweeteners such as Stevia rebaudiana (stevioside) and Lo Han Kuo; polyols such as sorbitol, mannitol, xylitol, and erythritol.

[0175] In certain embodiments, suitable pharma- ceutically acceptable excipients may include alkylating agent(s), such as, but not limited to, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, and / or disodium phosphate.

[0176] In certain embodiments, suitable pharma- ceutically acceptable excipients may include lubricant(s) / release agent(s), such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants include, but are not limited to, glyceryl behenate (Compritol™ 888), metal stearates (e.g., magnesium, calcium, and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g., Sterotex™), talc, waxes such as beeswax and carnauba wax, silica, fumed silica, colloidal silica, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-leucine, polyethylene glycols (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv™), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin, propylene glycol, and combinations thereof.

[0177] In certain embodiments, suitable pharma- ceutically acceptable excipients may include diluents such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dicalcium phosphate dihydrate NF, sucrose-based diluents, confectioners' sugar, dicalcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules NF, dextrates NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed grain solids such as Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like.

[0178] In certain embodiments, suitable pharma- ceutically acceptable excipients can include oils and fats, such as, but not limited to, almond oil, argan oil, avocado oil, rapeseed oil, cashew oil, castor oil, cocoa butter, coconut oil, canola oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, and watermelon seed oil. Other oils and fats that may be in the filling of the PVA shell include, but are not limited to, fish oil (omega 3), krill oil, animal or vegetable fats, such as in hydrogenated form, mono-, di-, and triglycerides having C12, C14, C16, C18, C20, and C22 fatty acids.

[0179] In certain embodiments, suitable pharma- ceutically acceptable excipients include vegetable proteins, such as sunflower protein, soy protein, cottonseed protein, peanut protein, grapeseed protein, whey protein, whey protein isolate, blood protein, egg protein, acrylated proteins, water soluble polysaccharides, such as alginates, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic, and related gums (gum ghatti, gum karaya, gum tragacanth), pectin, water soluble derivatives of cellulose: alkylcelluloses, hydroxyalkylcelluloses, and hydroxyalkylalkylcelluloses, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters, and hydroxyalkylcellulose esters, such as cellulose acetate phthalate (CAP), hydroxypropylcellulose, ... Suitable polymers include carboxypropylmethylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, such as carboxymethylcellulose, and alkali metal salts thereof; water-soluble synthetic polymers, such as polyacrylic acid, polyacrylamide, and polyacrylic acid esters, polymethacrylic acid, polymethacrylamide, and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymers, and polycrotonic acid; phthalated gelatin, succinic gelatin, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates bearing tertiary or quaternary amino groups, e.g., diethylaminoethyl groups, which may be quaternized if desired; and other similar polymers; inorganic fillers, such as oxides of magnesium, aluminum, silicon, titanium, and the like.

[0180] In certain embodiments, suitable pharma- ceutically acceptable excipients include hydrophobic materials, such as, but not limited to, digestible long chain (C8-C50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as natural or synthetic waxes (such as beeswax, glycowax, castor wax, and carnauba wax), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl, or preferably cetostearyl alcohol), fatty acids, such as, but not limited to, mono-diglycerides of medium chain fatty acids (such as caprylic acid, capric acid, caproic acid, lauric acid, oleic acid, linoleic acid, etc.), medium chain triglycerides, fatty acid esters, fatty acid glycerides (mono-, di-, and triglycerides), hydrogenated fats, hydrocarbons, regular waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials having a hydrocarbon backbone.

[0181] In certain embodiments, suitable pharma- ceutically acceptable excipients may include polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetate, polycarboxylic acids and salts, acetic acid, caprylic acid, oleic acid, polyamino acids or peptides, polyamides, polyacrylamides, maleic acid / acrylic acid copolymers, polysaccharides including starch and gelatin, natural gums such as xanthan and carrageenan. For example, the polymer may be selected from polyacrylates and water soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, maltodextrin, polymethacrylates, and combinations thereof, or may be selected from polyvinyl alcohol, polyvinyl alcohol copolymers, and hydroxypropylmethylcellulose (HPMC), methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimethylate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caprylocaproyl polyoxy-8 glyceride, distearate glyceride, and combinations thereof.

[0182] In certain embodiments, suitable pharma- ceutically acceptable excipients may include high HLB surfactants, such as, but not limited to, polysorbate 80-polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, caprylocaproyl macrogol glycerides, and combinations thereof.

[0183] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fillers, such as, but not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0184] In certain embodiments, suitable pharma- ceutically acceptable excipients may include natural gums (e.g., natural vegetable gums), including, but not limited to, guar gum, locust bean gum, konjac gum, xanthan gum, sclerotium gum, acacia gum, cellulose gum (modified or unmodified), or combinations thereof.

[0185] In certain embodiments, suitable pharma- ceutically acceptable excipients include emulsifiers, such as, but not limited to, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-40 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 olivate, PEG-8 oleate, PEG-8 laurate, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-1 00 stearate, PEG-80 sorbitan laurate, steareth-2, steareth-12, oleth-2, ceteth-2, laureth-4, oleth-10, oleth-10 / polyoxyl 10 oleyl ether, ceteth-10, isosteareth-20, ceteareth-20, oleth-20, steareth-20, steareth-21, ceteth-20, isoceteth-20, laureth-23, steareth-100, glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, salts of stearic acid, polyglyceryl-3-methylglycose distearate, or combinations thereof.

[0186] Further suitable emulsifiers are phosphoric acid esters and their salts, such as cetyl phosphate (Amphisol® A), diethanolamine cetyl phosphate (Amphisol® DEA), potassium cetyl phosphate (Amphisol® K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphate, and mixtures thereof. Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate, and hydrated polyisobutene. Furthermore, one or more synthetic polymers may be used as emulsifiers. For example, PVP eicosene copolymer, acrylate / C 10 -3o alkyl acrylate crosspolymer, acrylates / steareth-20 methacrylate copolymer, PEG-22 / dodecyl glycol copolymer, PEG-45 / dodecyl glycol copolymer, and mixtures thereof.

[0187] In certain embodiments, suitable pharma- ceutically acceptable excipients may include chelating agents, such as, but not limited to, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).

[0188] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fatty alcohols, such as Guerbet alcohols based on fatty alcohols having 6-18, preferably 8-10, carbon atoms, including, but not limited to, cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, benzoates of C12-C15 alcohols, acetylated lanolin alcohol, and the like.

[0189] In certain embodiments, suitable pharma- ceutically acceptable excipients include esters of fatty acids, such as, but not limited to, linear C6-C 24 Straight chain C3-C fatty acids 24 Esters with alcohols, branched C6-C 13 Straight chain C6-C carboxylic acids 24 Esters with fatty alcohols, linear C6-C 24 Esters of fatty acids with branched alcohols, in particular 2-ethylhexanol, linear or branched C6-C hydroxycarboxylic acids 22Esters with fatty alcohols, in particular dioctyl maleate, esters of linear and / or branched fatty acids with polyhydric alcohols (e.g. propyl glycol, dimer diol or trimer diol) and / or Guerbet alcohols, such as caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, linolenic acid, eleostearic acid, arachidic acid, gadoleic acid, behenic acid and erucic acid, as well as technical grade mixtures thereof (obtained, for example, in the pressure stripping of natural fats and oils, in the reduction of aldehydes from the Roelen oxosynthesis or in the dimerization of saturated fatty acids), alcohols, such as isopropyl alcohol, capric acid, oleic acid, lin ...ic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, and polyols such as propylene, capryl, 2-ethylhexyl, capric, lauryl, isotridecyl, myristyl, cetyl, palmoleyl, stearyl, isostearyl, oleyl, elaidyl, petroselinyl, linoyl, linolenyl, eleostearyl, arachidyl, gadoleyl, behenyl, erucyl, and brassylic alcohols, and technical grade mixtures thereof (obtained, for example, in the high pressure hydrogenation of technical grade methyl esters based on fats and oils, or as aldehydes from Roelen's oxo synthesis, and as monomeric fractions in the dimerization of unsaturated fatty alcohols).Additional suitable examples of ester oils include isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl oleate. These include oleyl acetate, oleyl erucate, erucyl oleate, erucyl erucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl behenate, cetyl acetate, myristyl myristate, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate / caprylate, stearyl heptanoate, diisostearyl malate, and octyl hydroxystearate.

[0190] In certain embodiments, suitable pharma- ceutically acceptable excipients may include other adjuvants, such as, but not limited to, 2,6-diethylhexyl naphthalate, di-n-butyl adipate, di(2-ethylhexyl)-adipate, di(2-ethylhexyl)-succinate, and diisotridecyl acetate, as well as diol esters, such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dipelargonate, butanediol diisostearate, and neopentyl glycol dicaprylate. 24 Esters of fatty alcohols and / or Guerbet alcohols with aromatic carboxylic acids, saturated and / or unsaturated, in particular with benzoic acid, C2-C 12 Esters of dicarboxylic acids with linear or branched alcohols having 1 to 22 carbon atoms or with polyols having 2 to 10 carbon atoms and 2 to 6 hydroxy groups.

[0191] In certain embodiments, suitable pharma- ceutically acceptable excipients include natural or synthetic triglycerides (including glyceryl esters and derivatives), such as, but not limited to, C6-C 18 Fatty acid based di- or triglycerides (such as caprylic / capric triglyceride, wheat germ triglyceride, etc.) may be included. Fatty acid esters of polyglycerol (polyglyceryl-n, e.g., polyglyceryl-4 caprate, polyglyceryl-2 isostearate, etc., or castor oil, hydrogenated vegetable oils, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borage oil, etc. Additional suitable excipients include waxes containing esters of long-chain acids and alcohols, as well as compounds with wax-like properties, e.g., carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ozokerite, Japan wax, paraffin wax, microcrystalline wax, ceresin, cetearyl ester wax, synthetic beeswax, etc. Also hydrophilic waxes as cetearyl alcohol or partial glycerides.

[0192] In certain embodiments, suitable pharma- ceutically acceptable excipients may include pearlescent waxes, such as, but not limited to, alkylene glycol esters, particularly ethylene glycol distearate; fatty acid alkanolamides, particularly coco fatty acid diethanolamide; partial glycerides, particularly stearic acid monoglyceride; esters of polyhydric unsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, particularly long chain esters of tartaric acid; fatty substances, such as fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers, and fatty carbonates having a total of at least 24 carbon atoms, particularly lauryl and distearyl ether; fatty acids, such as stearic acid, hydroxystearic acid, or behenic acid, ring-opening products of olefin epoxides having 12 to 22 carbon atoms with fatty alcohols having 12 to 22 carbon atoms and / or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxy groups, and mixtures thereof.

[0193] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrocarbon oils such as, but not limited to, mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline wax, paraffin and isoparaffin compounds, hydrogenated isoparaffin molecules such as polydecene and polybutene, hydrogenated polyisobutene, squalane, isohexadecane, isododecane, and others from the plant and animal kingdoms.

[0194] In certain embodiments, suitable pharma- ceutically acceptable excipients may include silicones or siloxanes (organo-substituted polysiloxanes), such as, but not limited to, dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic silicones, as well as amino, fatty acid, alcohol, polyether, epoxy, fluorine, glycoside, and / or alkyl modified silicone compounds, which may be in either liquid or resin form at room temperature. Linear polysiloxanes, dimethicones (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluids, cyclopentasiloxane volatiles (Dow Corning 345 fluid), phenyl trimethicones (Dow Corning 556 fluid). Also suitable is simethicone, a mixture of dimethicones with an average chain length of 200-300 dimethylsiloxane units and hydrogenated silicate. In addition, a detailed review of suitable volatile silicones by Todd et al. can be found in Cosm. Toil. 91, 27 (1976).

[0195] In certain embodiments, suitable pharma- ceutically acceptable excipients may include emulsifiers, such as, but not limited to, carboxylic acids and their salts: alkaline soaps of sodium, potassium, and ammonium, metal soaps of calcium or magnesium, organic soaps, such as lauric acid, palmitic acid, stearic acid, and oleic acid; alkyl phosphates or phosphoric acid esters, acid phosphates, diethanolamine phosphate, potassium cetyl phosphate; ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acylates; linear fatty alcohols having 8-22 carbon atoms, branched from 2-30 moles of ethylene oxide and / or 0-5 moles of propylene oxide with fatty acids having 12-22 carbon atoms and alkylphenols having 8-15 carbon atoms in the alkyl group; fatty alcohol polyglycol ethers, such as laureth-n, ceteareth-n, steareth-n, oleth-n; fatty acid polyglycol ethers, such as PEG-n stearate, PEG-n oleate, PEG-n cocoate. Monoglycerides and polyol esters. C12-C22 fatty acid mono- and diesters of addition products of 1 to 30 moles of ethylene oxide with polyols. Fatty acid and polyglycerol esters, such as monostearate glycerol, diisostearoyl polyglyceryl-3-diisostearate, polyglyceryl-3-diisostearate, triglyceryl diisostearate, polyglyceryl-2-sesquiisostearate or polyglyceryl dimerate. Mixtures of compounds from several of these substance classes are also suitable. Fatty acid polyglycol esters, such as monostearate diethylene glycol, fatty acid and polyethylene glycol esters, fatty acid and saccharose esters, such as sucroesters, glycerol and saccharose esters, such as sucroglycerides. Sorbitol and sorbitan, sorbitan mono- and diesters of saturated and unsaturated fatty acids having 6 to 22 carbon atoms and ethylene oxide addition products.Polysorbate-n series, sorbitan esters such as sesquiisostearate, sorbitan, PEG-(6)-isostearate sorbitan, PEG-(10)-sorbitan laurate, PEG-17-dioleate sorbitan. Glucose derivatives, C8-C22 alkyl mono- and oligoglycosides, as well as ethoxylated analogues, with glucose being preferred as the sugar component. O / W emulsifiers such as methyl gluceth-20 sesquistearate, sorbitan stearate / sucrose cocoate, methyl glucose sesquistearate, cetearyl alcohol / cetearyl glucoside. W / O emulsifiers such as methyl glucose dioleate / methyl glucose isostearate. Sulfates and sulfonated derivatives, dialkyl sulfosuccinates, dioctyl succinates, alkyl lauryl sulfonates, linear sulfonated paraffins, sulfonated tetrapropienesulfonates, sodium lauryl sulfate, ammonium and ethanolamine lauryl sulfate, lauryl ether sulfate, sodium laureth sulfate, sulfosuccinates, acetyl isothionates, alkanolamide sulfates, taurine, methyl taurine, imidazole sulfate. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicone, copolyols, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ethers (Meroxapol), Polaxamer or poly(oxyethylene) m-block-poly(oxypropylene) n-block (oxyethylene). Zwitterionic surfactants carrying at least one quaternary ammonium group and at least one carboxylate and / or sulfonate group in the molecule.Particularly suitable zwitterionic surfactants are betaines, such as N-alkyl-N,N-dimethylammonium glycinates, cocoalkyldimethylammonium glycinates, N-acylaminopropyl-N,N-dimethylammonium glycinates, cocoacylaminopropyldimethylammonium glycinates, and 2-alkyl-3-carboxymethyl-3-hydroxyethyl imidazolines, each having 8 to 18 carbon atoms in the alkyl or acyl group, as well as cocoacylaminoethyl hydroxyethyl carboxymethyl glycinates, N-alkyl betaines, N-alkyl amino betaines, alkyl imidazolines, alkyl peptides, lipoamino acids, self-emulsifying bases, and compounds described in KF DePolo, A short textbook of cosmetology, Chapter 8, Table 8-7, p 250-251.

[0196] Suitable non-ionic bases include, but are not limited to, PEG-6 beeswax (and) PEG-6 stearate (and) polyglyceryl-2-isostearate (and), glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglyceryl-3 ricinoleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and ceteth-20, cetearyl alcohol and polysorbate 60 and PEG-150 and stearate-20, cetearyl alcohol and cetearyl polyglucoside, cetearyl alcohol and ceteareth-20, cetearyl alcohol and PEG-40 castor oil, cetearyl alcohol and cetearyl glyceryl stearate ... Tearyl alcohol and PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and steareth-7 and steareth-10, cetearyl alcohol and steareth-7 and steareth-10, glyceryl stearate and PEG-75 stearate, propylene glycol ceteth-3 acetate, propylene glycol isoceteth-3 acetate, cetearyl alcohol and ceteth-12 and oleth-12, PEG-6 stearate and PEG-32 stearate, PEG-6 stearate and ceteth-20 and steareth-20, PEG-6 stearate and ceteth-20 and glyceryl stearate and steareth-20, glyceryl stearate and ceteareth-20.

[0197] Suitable anionic alkali bases include, but are not limited to, PEG-2 stearate SE, glyceryl stearate SE, propylene glycol stearate. Anionic acid bases, such as cetearyl alcohol and sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, trilaneth-4 phosphate and glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulfate. Cationic acid bases, such as cetearyl alcohol and cetrimonium bromide.

[0198] In certain embodiments, suitable pharma- ceutically acceptable excipients may include adjuvants and additives, such as, but not limited to, surfactants, super-fatting agents, consistency regulators, thickeners, polymers, stabilizers, bioactive ingredients, swelling agents, additional UV photoprotective agents, antioxidants, hydrotropes, preservatives, self-tanning agents, solubilizers, balms, colorants, bacterial inhibitors, and the like.

[0199] In certain embodiments, suitable pharma- ceutically acceptable excipients may include superfatting agents, such as, but not limited to, lanolin and lecithin, as well as polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides, and fatty acid alkanolamides, the latter of which simultaneously act as foam stabilizers.

[0200] In certain embodiments, suitable pharma- ceutically acceptable excipients may include surfactants, such as, but not limited to, fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and / or dialkyl sulfosuccinates, fatty acid isetinates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, alpha-olefin sulfonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkylamidobetaines, and / or protein fatty acid condensation products, the latter preferably based on wheat protein.

[0201] In certain embodiments, suitable pharma- ceutically acceptable excipients may include consistency regulators / thickeners and rheology modifiers, such as, but not limited to, silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or derivatives thereof, such as hyaluronic acid, xanthan gum, guar guar, agar, alginate, carrageenan, gellan, pectin, or modified celluloses, such as hydroxycellulose, hydroxypropyl methylcellulose. In addition, polyacrylates or homopolymers of reticulated acrylic acid and polyacrylamide, Carbomers (CARBOPOL types 980, 981, 1382, ETD2001, ETD2020, ULTREZ10), or SALCARE products such as SALCARE SC80 (steareth-10 allyl ether / acrylates copolymer), Salcare SC81 (acrylates copolymer), Salcare SC91 and Salcare AST (sodium acrylates copolymer / PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide / laureth-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer), STABILEN 30 (acrylates / vinyl isodecanoate crosspolymer), PEMULEN TR-1 (acrylates / C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (Sodium Acrylate Copolymer), ACULYN 28 (Acrylates / Beheneth-25 Methacrylate Copolymer), etc.

[0202] In certain embodiments, suitable pharma- ceutically acceptable excipients include polymers, including, but not limited to, anionic, zwitterionic, amphoteric, and nonionic polymers, and may include, for example, vinyl acetate / crotonic acid copolymers, vinyl pyrrolidone / vinyl acrylate copolymers, vinyl acetate / butyl maleate / isobornyl acrylate copolymers, methyl vinyl ether / maleic anhydride copolymers and esters thereof, uncrosslinked polyacrylic acid and polyol-crosslinked polyacrylic acid, acrylamidopropyl-trimethylammonium chloride / acrylate copolymers, octylacrylamide / methyl methacrylate-tert-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymers, polyvinyl pyrrolidone, vinyl pyrrolidone / vinyl acetate copolymers, vinyl pyrrolidone / dimethylaminoethyl methacrylate / vinyl caprolactam terpolymers, as well as optionally derivatized cellulose ethers and silicones. Additionally, the polymers described in EP1093796 (pages 3-8, paragraphs 17-68) may be used.

[0203] In certain embodiments, suitable pharma- ceutically acceptable excipients include antioxidants, such as, but not limited to, amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., urocanic acid) and their derivatives, peptides, such as D,L-carnosine, D-carnosine, L-carnosine and its derivatives (e.g., anserine), carotenoids, carotene, lycopene and its derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g., dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine, and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cobalt, oleyl, linoleyl ... esteryl, and their glyceryl esters), as well as their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid, and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts), as well as sulfoximine compounds (e.g., buthionine sulfoximine, homocysteine ​​sulfoximine, buthionine sulfone, penta-, hexa-, hepta-thionine sulfoximine), and (metal) chelating agents (e.g., hydroxythio ... fatty acids, palmitic acid, phytic acid, lactoferrin), hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, bile acids, bile extracts, bilirubin, biliverdin, EDTA, EDDS, EGTA, and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g., linoleic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives thereof (e.g., ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), triglycerides, glycerides, glyceryl phosphate, glyceryl acetate ... Copherol and derivatives (e.g., vitamin E acetate), vitamin A and derivatives (e.g., vitamin A palmitate), as well as coniferyl benzoate of benzoin resin, rutinic acid and its derivatives, glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butylated hydroxytoluene, butylated hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, superoxide dismutase, N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl]sulfanilic acid (and its salts, e.g., the disodium salt), selenium and its derivatives (e.g., selenium methionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), as well as derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids) suitable according to the invention of these aforementioned active ingredients. HALS (= "Hindered Amine Light Stabilizers") compounds may also be mentioned.

[0204] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrotopic agents, such as, but not limited to, ethoxylated or non-ethoxylated monoalcohols, diols or polyols with a low number of carbon atoms or their ethers (e.g., ethanol, isopropanol, 1,2-dipropanediol, propylene glycol, glycerin, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, and similar products). Polyols considered for this purpose preferably have 2 to 15 carbon atoms and at least two hydroxy groups. Polyols may also contain further functional groups, in particular amino groups, and / or may be modified with nitrogen. Typical examples are: glycerol, alkylene glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol, and also polyethylene glycols with an average molecular weight of 100 to 1000 Daltons; technical oligoglycerol mixtures with an inherent degree of condensation of 1.5 to 10, for example technical diglycerol mixtures with a diglycerol content of 40 to 50% by weight; methylol compounds, such as, in particular, trimethylolethane ... butylolpropane, trimethylolbutane, pentaerythritol, and dipentaerythritol; lower alkyl glucosides, especially those having 1 to 8 carbon atoms in the alkyl radical, such as methyl and butyl glucoside; sugar alcohols having 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars having 5 to 12 carbon atoms, such as glucose or saccharose; amino sugars, such as glucamine; dialcoholamines, such as diethanolamine or 2-1,3-propanediol.

[0205] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives, such as, but not limited to, methyl-, ethyl-, propyl-, butyl-paraben, benzalkonium chloride, 2-bromo-2-nitro-propane-1,3-diol, dehydroacetic acid, diazolidinyl urea, 2-dichloro-benzyl alcohol, DMDM ​​hydantoin, formaldehyde solution, methyldibromoglutanitrile, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan, and additional classes of substances listed in the following references: KFDePolo-A short textbook of cosmetology, Chapter 7, Tables 7-2, 7-3, 7-4 and 7-5, p 210-219.

[0206] In certain embodiments, suitable pharma- ceutically acceptable excipients may include bacterial inhibitors, such as, but not limited to, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, chlorhexidine (1,6-di(4-chlorophenyl-biguanide)hexane), or TCC (3,4,4'-trichlorocarbanilide). A number of aromatic substances and ethereal oils also have antibacterial properties. Typical examples are eugenol, menthol, and thymol, which are active ingredients in clove oil, mint oil, and thyme oil. A natural deodorant of interest is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol), which is present in lime blossom oil. Glycerol monolaurate has also been shown to be a bacteriostatic agent.

[0207] Other pharma- ceutically acceptable excipients may also be utilized as will be recognized by those skilled in the art.

[0208] In certain embodiments, the pharma- ceutically acceptable excipients may be included (individually or cumulatively) in the pharmaceutical compositions described herein at a concentration ranging from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight to about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% by weight, based on the total weight of the composition, or any subrange or single value therein.

[0209] Preparation method In certain embodiments, the present disclosure is directed to the method of preparing any of the compositions described herein.In certain embodiments, the method includes combining a therapeutically effective amount of the compound disclosed herein with one or more pharma- ceutically acceptable excipients.

[0210] The various compositions described herein may be formulated to have a customized release profile for an active agent, such as, but not limited to, an immediate release profile, a controlled release profile, a delayed release profile, an enteric release profile, a zero order release profile, a first order release profile, a pulsatile release profile, a targeted release at a particular location in the body (such as a targeted location in the gastrointestinal tract), etc. EXAMPLES

[0211] A study is conducted on Compound A. The study is a three-period randomized, placebo-controlled, double-blind, crossover study in healthy subjects. The primary objective of the study was to determine the safety and tolerability of Compound A in healthy participants after low and high doses of Compound A under hypoxic and hypercapnic conditions in conjunction with low and high doses of Propofol. Another primary objective of the study was to determine the ventilatory response of low and high doses of Compound A under hypoxic and hypercapnic conditions in conjunction with low and high doses of Propofol. A secondary objective of the study was to determine the cardiovascular response of low and high doses of Compound A during hypoxic and hypercapnic conditions in conjunction with low and high doses of Propofol. Another secondary objective of the study was to evaluate the ventilatory response after administration of Compound A and Propofol under different ventilation conditions. The different ventilation conditions are the same sequence of hypoxic and hyperxic exposure in normocapnic conditions followed by hypercapnia. The study was conducted in accordance with Good Clinical Practice. This study was a randomized, double-blind, placebo-controlled, three-way crossover study to evaluate the safety, tolerability, respiratory PD, and PK of Compound A in healthy male and female participants. Subjects were initially screened up to 6 weeks prior to randomization. Upon passing the initial medical screen, subjects were scheduled into the study and given a randomization number. Subjects underwent three separate treatment periods. In each of these periods, low or high doses of Compound A or placebo were continuously perfused over a period of 270 minutes. During each period, subjects received different intravenous propofol dosages or placebo in a fixed sequence: placebo-propofol low-propofol high. Each propofol or placebo treatment session lasted 70 minutes. During each propofol treatment session, different ventilatory conditions were applied: hypoxia and hypercapnia (Figure 1). A single evaluation period is presented, with the graded hypoxic, hyperoxic, and hypercapnic regimens indicated by colored lines in Figure 1. Each evaluation period (i.e., "run") consists of one identical sequence of hypoxic / hyperoxic exposures in normocapnia followed by hypercapnia. A total of 12 participants completed all planned treatments according to the protocol. Participants received the following treatments in random order during the dosing period: Placebo + placebo / propofol low / propofol high / Compound A low + placebo / propofol low / propofol high Compound A high + placebo / propofol low / propofol high Subjects were admitted to the investigational site on Day -1 for pre-dosing procedures, re-evaluation of eligibility, and overnight stay. On each dosing day (Day 1), subjects were transferred to a specialized unit at the study site in the morning (or early afternoon) after an overnight fast of at least 8 hours. After placement of respiratory and cardiovascular monitoring / assessment devices, including arterial lines, subjects were placed in a semi-recumbent position, allowing sufficient time for the subjects to resume normal breathing patterns. After baseline assessments were completed, all measurements were performed according to the assessment schedule. Once all measurements were completed on the day of dosing, subjects were monitored overnight and evaluated the following morning (at least 12 hours after study treatment) before being discharged (Day 2). If prolonged care was required (e.g., due to adverse events, residual sedation, etc.), subjects were not immediately discharged and were treated as needed. Duration of treatment: Participation was approximately 10 weeks, split as follows: Screening: Up to 42 days prior to first dose The treatment phase lasted approximately 21 days, including three treatment periods of 3 days each, separated by approximately 7 days (minimum 3) between dosing days, and the study evaluation period. Follow-up 7 days after the last dose Healthy adult subjects were selected for the study. The study center research pharmacist and an independent statistician will be unblinded to Compound A treatment. Treatment administered The investigational product was prepared as follows: Compound A 10 mg / mL was supplied as a 50 mL vial (Batch No. B210239). An infusion bag of a fixed concentration of Compound A approximately 0.8 mg / mL in Lactated Ringer's solution was prepared for dosing by the LUMC investigational pharmacy according to the pharmacy manual. Compound A was administered intravenously over a period of 270 minutes based on the participant's weight. Investigational product was dispensed to each participant according to the randomization list. A loading dose was administered at 2.0 mg / kg / h for 10 minutes (low dose) or 20 minutes (high dose) for both the low and high doses, followed by a continuous infusion of the following for 250-260 minutes, for a total infusion time of 270 minutes: The low dose is 2 mg / kg / hour for 10 minutes followed by a fixed rate of 0.4 mg / kg / hour for 260 minutes, or The high dose was a fixed rate of 2 mg / kg / h for 20 min, followed by 1.1 mg / kg / h for 250 min. Propofol was administered over a 155 minute period per dosing / treatment session, which consisted of two 70 minute low / high dosing regimens separated by a 15 minute transition dose. Propofol was infused from a 10 mg / ml preparation as follows: Low dose: 239μg / kg / min for 3 minutes, 0μg / kg / min for 6 minutes, 24μg / kg / min for 61 minutes Transition dose: 47μg / kg / min in 15 minutes High dose: 239μg / kg / min for 3 minutes, 0μg / kg / min for 6 minutes, 44μg / kg / min for 61 minutes Both products were for IV injection and were prepared as sterile products ready for use for each subject by the study pharmacy according to the randomization schedule. To prevent treatment-induced nausea, participants received ondansetron 4 mg IV approximately 15 minutes before dosing on each study day. To prepare the control product, placebo infusion bags containing lactated Ringer's solution were prepared that matched the study product in appearance (batch numbers: 21H28E8M, 21F11E7C, and 21L10E3T). Thus, the corresponding placebo for Compound A consisted of the solution used as the diluent for Compound A. Propofol 10 mg / mL for injection was provided as a sterile product ready for injection (batch numbers 16QF1624 and 16QG1950). Compound A solution is colorless and its attributes (before dilution and when mixed for injection) are similar to sterile normal saline or lactated Ringer's solution. The interim analysis was performed after completion of all treatments and procedures for the first six subjects. Data supporting the interim analysis (i.e., PD and safety reports) will be archived. The analysis will include blinded safety (AE, BP, ECG) (unblinded as necessary), and PD parameters will include ventilation measurements and ETCO2. PD will be unblinded to treatment, but not to subjects. Dosing for the last six subjects will proceed in parallel, independent of the interim analysis. The primary PD endpoint was hypoxia sensitivity, which was analyzed using a mixed model analysis of variance with fixed factors treatment, condition, and treatment by condition, and random factors participants, participants by treatment, and participants by condition (combinations of propofol condition and ventilation condition). BIS was analyzed using a mixed model analysis of covariance with fixed factors treatment, time, treatment by time, and random factors participants, participants by treatment, and participants by time, and pre-value as a covariate. General treatment effects and specific contrasts were reported with estimated differences and 95% confidence intervals, least-squares mean estimates, and p-values. Individual Compound A and Propofol plasma concentrations were listed and plotted in panel plots for each Compound A treatment period using both linear and logarithmic y-axes. Individual plasma Compound A and Propofol concentrations were summarized by Compound A treatment period and time, and also depicted graphically as averages over time with standard deviations as error bars. Summary statistics were provided including all plasma concentration samples, regardless of sampling time. Individual PK parameters were summarized by treatment and propofol treatment interval, and depicted graphically as box plots.

[0212] Nature of participants A total of 45 participants were screened and 14 participants were randomized. Per protocol, 12 participants were planned to be enrolled in the study. Two participants discontinued the study (one withdrew consent during the first treatment visit and the other was removed by the investigator after the first treatment visit) and were recruited. Data from these participants were used in the safety and PD analysis populations, but PK data were not available for these participants. No important protocol deviations that affected the study were identified.

[0213] Pharmacodynamic evaluation Hypoxic Ventilatory Sensitivity Hypoxic sensitivity (ventilation in L / min per % desaturation) was the primary PD outcome measure in this study. Hypoxic sensitivity is a marker of carotid body activity. All participants experienced increased respiration during hypoxemia, which was generally more severe during hypercapnia than normocapnia.

[0214] Administration of Compound A produced a significant treatment effect on hypoxia sensitivity (p<0.001), as shown in Table 1. This effect was independent of visit, as shown by the non-significant "duration," and was not affected by the combination of the two ventilation states (i.e., normocapnia and hypercapnia) and the three propofol dosing intervals, as shown by the non-significant "treatment by condition." Because the main treatment effect was significant, separate contrasts of low and high doses of Compound A versus placebo were calculated. This showed that the low dose of Compound A trended toward a significant treatment effect, and that the high dose of Compound A was significant. [Table 1]

[0215] As is evident from Figure 2, propofol reduced hypoxia sensitivity during placebo infusion and attenuated the additional effect of hypercapnia, especially during high-dose propofol. However, coadministration of high-dose Compound A appeared to keep hypoxia sensitivity similar to pre-propofol values. Also, the (physiological) increase in minute ventilation induced by hypercapnia during high-dose propofol was more pronounced in the high-dose Compound A group.

[0216] Ventilation parameters During hypoxic measurements, as seen in Figure 3, all treatments increased mean minute ventilation compared to pre-hypoxic baseline, with a dose-dependent increase observed with Compound A treatment. This increase was smaller after co-administration with propofol, which was particularly evident in the placebo and low-dose Compound A groups. During placebo treatment, minute ventilation increased from 7.7 L / min to 25.9 L / min during the first hypoxic measurement under hypercapnic conditions (i.e., without co-administration of propofol) and from 6.6 L / min to 13.7 L / min during the hypoxic / hypercapnic measurements during high-dose propofol administration. During treatment with low-dose Compound A, minute ventilation increased from 8.1 L / min to 30.3 L / min during the first hypoxic measurement under hypercapnic conditions and from 6.3 L / min to 15.0 L / min during the hypoxic / hypercapnic measurements during high-dose propofol administration. However, during treatment with Compound A, minute ventilation increased from 8.5 to 38.8 L / min during the first hypoxic measurement under hypercapnic conditions and from 8.4 to 27.4 L / min during the hypoxic / hypercapnic measurement during the high-dose propofol administration, so that a similar increase relative to pre-propofol levels was maintained after placebo treatment. Minute ventilation did not increase during treatment with Compound A if participants were not exposed to hypoxia.

[0217] Minute ventilation was a composite of tidal volume in mL per breath (Figure 4) and respiratory rate in breaths per minute (Figure 5). The same trends as for minute ventilation were observed for these two parameters, indicating that increased ventilation was the result of both increased respiratory volume and increased respiratory rate per minute. Differences in respiratory rate for the high dose of Compound A compared to placebo and the low dose of Compound A were observed during propofol infusion at pre-hypoxic time points.

[0218] To perform another hypoxic measurement with hypercapnia, ETCO2 (Figure 6) was increased after the first hypoxic measurement of each propofol dosing interval. Values ​​recorded for the low dose of Compound A were comparable to placebo treatment. However, values ​​recorded for the high dose of Compound A were lower compared to placebo, both at the pre-hypoxia time point and during hypoxia and hypercapnia. Although no statistical analysis for ETCO2 was defined in the statistical analysis plan, the differences between treatments were evident from the summary graph in Figure 6.

[0219] Oxygen saturation SpO2 was also measured and is shown in Figure 7. SpO2 remained above 96.4% at the pre-hypoxia baseline time point for all three treatments. During hypoxia measurements, SpO2 ranged from 80.4-84.3%, 81.2-83.7%, and 80.4-84.2% for placebo, low dose and high dose of Compound A, respectively. Given that SpO2 was manipulated during measurements by investigator-administered inhaled gas mixtures, this was not considered an independent variable but rather a confirmation that measurements were performed according to protocol.

[0220] Summary of Pharmacodynamic Findings The above study demonstrated that (1) Compound A provided a significant treatment effect (p<0.0001) versus placebo on hypoxia sensitivity, the primary PD outcome measure of the study; (2) mean minute ventilation increased during hypoxia measurements for all treatments, with a dose-dependent increase observed for Compound A; (3) increases during hypoxia measurements were observed for mean tidal volume and respiratory rate for all treatments, indicating that the increase in minute ventilation was the result of an increase in both of these parameters; and (4) mean ETCO2 values ​​recorded for the high dose of Compound A were significantly greater than those observed for the low dose of Compound A. It was found that (1) the mean BIS values ​​were significantly lower than those of Compound A low dose and placebo at all time points (both pre-hypoxic and during hypoxia and hypercapnia), (2) the mean BIS values ​​were within the target range according to the protocol, (3) no treatment differences were observed in mean BIS values, (4) no clinically significant differences in cardiovascular responses were observed following treatment with Compound A versus placebo, and (5) no clinically significant differences in arterial blood gases were observed following treatment with Compound A versus placebo.

[0221] Pharmacokinetic evaluation Pharmacokinetic samples were measured up to 24 hours after the start of the IV infusion. Concentrations reached maximum levels of 857.000 and 1162.833 ng / mL on average after the 10- and 20-minute IV infusion loading doses of the low and high doses of Compound A, respectively. Thus, a rapid decrease in concentration was observed, followed by a slow increase. Based on visual inspection of the PK profiles and the mean concentrations per propofol dosing interval (FIG. 8), steady-state concentrations were not reached within the subsequent 260- and 250-minute infusions.

[0222] After the continuous infusion was stopped, the plasma concentration of Compound A decreased rapidly. From 4 hours and 30 minutes, the plasma concentration of Compound A followed a biexponential decline (Figures 9 and 10). At 5 hours, blood sampling from the arterial line was stopped and venous samples were taken from it. Values ​​were above the LLOQ at 24 hours post-dose in all participants for both Compound A dose levels.

[0223] Pharmacokinetic parameters are shown in Table 2. The mean peak concentration was at the end of the infusion, with a t of 4.260 hours for the low dose of Compound A. max , and at the high dose of Compound A, it occurred at 3.965 hours. Mean (±SD) C max was observed to be 467.9 ± 68.20 ng / mL for the low dose of Compound A and 1557.5 ± 437.02 ng / mL for the high dose of Compound A, with mean (± SD) AUC inf were 2674.9 ± 330.47 and 8711.4 ± 2422.64 ng*h / mL, respectively. The highest individual C values ​​achieved at the high dose of Compound A were max was 2600 ng / mL, the highest individual AUC reached at the high dose of Compound A inf was 13763 ng*h / mL. Mean Compound A concentrations increased with increasing propofol dosing interval (i.e., no propofol from 30-100 min, low propofol from 115-185 min, and high propofol from 200-270 min). The mean concentrations of the low dose of Compound A were 323.41, 359.75, and 427.54 ng / mL, respectively, and the mean concentrations of the high dose of Compound A were 971.79, 1206.27, and 1412.28 ng / mL, respectively. The geometric mean C of the low and high doses of Compound A was 1.0, 1.0, 1.2 ... av30-270min The mean arterial plasma ENA-001 concentrations (from 30 to 270 min) were 366.40 and 1161.69 ng / mL, respectively. The increases were not related to propofol dose, but rather to the fact that steady state had not been reached.

[0224] Mean apparent terminal t 1 / 2 The ranges of t were similar for the low and high dose groups of Compound A (3.00-6.99 and 3.39-8.40 hours, respectively). min Low variability was observed in all PK parameters at low doses of Compound A, as indicated by CVs less than 25%, except for t, which had a CV of 82.1%. minLow to moderate variability (CVs ranging from 21.1 to 36.2%) was observed for all parameters at the high dose of Compound A, except for the mean t min was 1.201 h for the low dose of Compound A and 1.133 h for the high dose of Compound A. The sample scheduled at 3 h 20 min was taken later than planned in participant 6 during the high dose of Compound A after the infusion was temporarily interrupted for a few minutes for a bathroom break. This resulted in plasma concentrations of Compound A apparently lower than would be expected at that time point.

[0225] Dose proportionality of PK over the dose range investigated was demonstrated by AUC int and C av Based on the dose-normalized values ​​of Compound A, no apparent interactions were observed between Compound A and Compound A based on the PK parameters associated with Compound A infusion. [Table 2]

[0226] Summary of pharmacokinetic results for Compound A From the above study, (1) the plasma concentration of Compound A declined biexponentially, and the terminal t 1 / 2 (2) plasma concentrations increased over time, peaking at approximately 3.965 hours, with mean (± SD) peak concentrations of 1557.5 ± 437.02 ng / mL at the high dose level (2 mg / kg / h for 20 minutes, followed by 1.1 mg / kg / h for 250 minutes); (3) mean (± SD) AUC of 8711.4 ± 2422.64 ng*h / mL. inf was reached at the highest dose level tested; (4) the geometric mean C av30-270min(5) mean arterial plasma Compound A concentrations increased with increasing dosing interval of propofol, being 323.41, 359.75, and 427.54 ng / mL, respectively, for the low dose of Compound A and 971.79, 1206.27, and 1412.28 ng / mL, respectively, for the high dose of ENA-001; (6) dose proportionality of PK was evident across the dose range investigated, with C max It was found that low to moderate levels of interindividual variability in the distribution and elimination phase were observed, and (7) no clear effect of propofol on Compound A concentrations was observed.

[0227] Pharmacokinetic results Propofol Pharmacokinetic results of propofol were also examined and found that: (1) plasma concentrations increased over time, peaking at mean (±SD) concentrations of 1880.8 ± 265.45, 2534.2 ± 1192.34, and 2620.0 ± 1093.86 ng / mL during infusions of placebo and low and high doses of Compound A, respectively; (2) the geometric mean C av115-185min and C av200-270min (3) mean arterial plasma concentrations during the 115-185 min interval for the low-dose propofol and the 200-270 min interval for the high-dose propofol ranged from 452.62 to 559.80 and 1525.12 to 1862.45 ng / mL, respectively; and (4) mean AUCs of 4599.1 ± 547.80, 5745.9 ± 1181.39, and 6151.6 ± 1166.70 ng*h / mL. last were achieved during infusion of low and high doses of placebo and Compound A, respectively; (4) greater than dose-proportional increases in plasma concentrations were evident across the dose range investigated, with low levels of interindividual variability in the distribution and elimination phases observed; max(5) propofol plasma concentrations tended to be higher during infusions of Compound A compared to placebo infusions, although no clear effect of dosage level was observed.

[0228] exposure:

[0229] A total of 12 participants were exposed to two dose levels of Compound A administered as a continuous infusion for 270 minutes as described in the methodology. These 12 participants were also exposed to placebo treatment. The two withdrawn participants were exposed to the high dose of Compound A only, one participant discontinued treatment after 97 minutes, and the other participant completed the first treatment visit but was subsequently excluded due to a reaction to propofol.

[0230] It was therefore concluded that Compound A was safe and well tolerated in healthy participants at the two dose levels administered in this study. Treatment with Compound A, with or without concomitant administration of clinically relevant plasma concentrations of propofol, increased hypoxic sensitivity compared to placebo. Compound A administration also did not affect the level of propofol-induced sedation as measured by BIS.

[0231] The study found that Compound A produced a significant treatment effect (p<0.0001) on hypoxia sensitivity, the primary PD outcome measure of the study, versus placebo. Additionally, mean minute ventilation increased during hypoxia measurements for all treatments, with a dose-dependent increase observed for Compound A. Increases during hypoxia measurements were observed for mean tidal volume and respiratory rate for all treatments, indicating that the increase in minute ventilation was the result of an increase in both of these parameters. Also, the mean ETCO2 values ​​recorded for the high dose of Compound A were clearly lower at all time points (both at pre-hypoxic time points and during hypoxia and hypercapnia) compared to the low dose of Compound A and placebo. It was also found that the controlled SpO2 values ​​were within the target range according to the protocol. No differences between treatments were observed for mean BIS values. No clinically meaningful differences in cardiovascular responses were observed following treatment with Compound A versus placebo. No clinically meaningful differences in arterial blood gases were observed following treatment with Compound A versus placebo.

[0232] Assessment of response to study treatment The primary objective of this study was to determine the safety, tolerability, and ventilatory response of Compound A infusion in healthy participants following low and high doses of Compound A under hypoxic and hypercapnic conditions in conjunction with low and high doses of propofol.

[0233] The safety data presented showed that Compound A had a good safety and tolerability profile in healthy participants at the two doses administered in this study. No treatment-related SAEs occurred in this study. No trends in AEs were recorded, except for mild injection site pain and related events, which were expected based on previous studies with Compound A. The only participant who developed phlebitis received placebo. Additionally, given that nausea has been associated with administration of Compound A in previous studies, all participants received IV ondansetron before the start of each treatment period. As a result, only a one-time occurrence of mild nausea possibly related to Compound A treatment was recorded in participants who received the high dose of Compound A. No clinically significant differences between treatments were identified in any other safety parameters.

[0234] The primary PD endpoint of the study was hypoxia sensitivity, defined by the increase in minute ventilation as a function of the decrease in SpO2 (Δ ventilation / Δ saturation = hypoxia sensitivity in L / min per % desaturation). Summary graphs showed that the decrease in blood oxygen levels as a result of hypoxia and the increase in ETCO2 during hypercapnia were targeted according to the protocol. As expected, a decrease in hypoxia sensitivity was observed as a result of propofol infusion. Concomitant administration of 1.1 mg / kg / h Compound A (high dose) significantly increased hypoxia sensitivity, keeping it similar to pre-propofol values. When low and high doses of Compound A were analyzed separately, the low dose trended toward a significant effect, but only the high dose produced statistically significant results versus placebo. This would have been expected based on data from a previous study showing that a low dose of Compound A (0.4 mg / kg / h) had no / minimal stimulatory effect on minute ventilation (McLeod et al., 2014), whereas a high dose of Compound A (1.1 mg / kg / h) produced a clear ventilatory stimulation and significantly attenuated alfentanil-induced ventilatory depression in healthy participants (Roozekrans et al., 2014).

[0235] Importantly, the finding that minute ventilation increased only during hypoxic measurements indicates that the administered dose of Compound A did not result in hyperventilation during breathing of room air. Compound A administration only enhanced the ventilatory response to oxygen desaturation.

[0236] In addition, lower values ​​of ETCO2 before each hypoxemia measurement were consistently observed for the high dose of Compound A compared to placebo and the low dose of Compound A. Although the difference of approximately 3 mmHg may not be clinically meaningful, these data suggest that a shift occurred across the metabolic hyperbola due to respiratory stimulation, reflected in a decrease in ETCO2 without still increasing minute ventilation.

[0237] Despite the clear ventilatory response, administration of Compound A did not result in significant differences in emergence compared to placebo, as measured by BIS, following administration of a clinically relevant dose of propofol comparable to sedative anesthesia. In other words, the level of sedation with propofol was as expected at the target plasma concentrations, and no clear differences were observed between treatments. Furthermore, no clinically meaningful differences in cardiovascular responses were observed between treatments. These findings support the use case for Compound A in clinical settings, where the goal is a ventilatory response that does not affect the effects of other administered drugs.

[0238] The infusion regimen in the current study was designed to maintain stable Compound A and propofol (low and high dose) concentrations during each dosing interval. Compound A PK demonstrated dose proportionality over the dose range investigated, and exposure levels were within the target range based on PK modeling performed in preparation for this study. max Low levels of interindividual variability in the infusion, distribution, and elimination phases were observed. However, Compound A did not reach a steady state and concentrations increased during continuous infusion until the infusion was stopped. Differences in plasma concentrations were not reflected in safety parameters, and the ventilatory response of Compound A was evident throughout the treatment period. No obvious effect of propofol on Compound A concentrations was observed.

[0239] The relationship between plasma concentrations of Compound A and PD response is further described in a separate PK-PD modeling report.

[0240] The propofol dosing regimen was designed to simulate infusion with a target-controlled infusion pump, targeting plasma concentrations of 600 and 1200 ng / mL during low and high doses of propofol, respectively. Plasma concentrations during low dose infusions were similar to the target concentrations, while high doses produced plasma concentrations that exceeded the target concentrations. Dose proportionality of propofol PK over the dose range investigated was not evident, with relatively high plasma concentrations recorded during high dose infusions. Note that despite these higher propofol plasma concentrations, the effect of Compound A on ventilation was significant.

[0241] From this study it can be concluded that Compound A was safe and well tolerated in healthy participants at the two dose levels administered in this study. Treatment with Compound A, with or without concomitant administration of clinically relevant plasma concentrations of propofol, increased hypoxic sensitivity compared to placebo. Administration of Compound A did not affect the level of propofol-induced sedation as measured by BIS.

[0242] For ease of explanation, embodiments of the methods of the present disclosure are depicted and described as a series of acts. However, acts in accordance with the present disclosure can be performed in various orders and / or simultaneously, as well as with other acts not shown or described herein. Moreover, not all illustrated acts are required to implement a methodology in accordance with the disclosed subject matter. In addition, those skilled in the art will understand and appreciate that the methodology can be represented as or via a state diagram or events as a series of interrelated states.

[0243] In the above description, many specific details are set forth, such as specific materials, dimensions, process parameters, etc., to provide a thorough understanding of the invention. Particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The words "example" or "exemplary" are used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as "example" or "exemplary" should not necessarily be construed as preferred or advantageous over other aspects or designs. Rather, the use of the words "example" or "exemplary" is intended to illustrate the concept in a specific manner. As used in this application, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or." That is, unless otherwise specified or clear from the context, "X includes A or B" is intended to mean all natural inclusive permutations. That is, if X includes A, if X includes B, or if X includes both A and B, then "X includes A or B" is satisfied under any of the above examples. References throughout this specification to "an embodiment," "a particular embodiment," or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "embodiment," "a particular embodiment," or "one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0244] The invention has been described with reference to specific exemplary embodiments thereof. The specification and drawings are accordingly to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to be included within the scope of the appended claims.

Claims

1. 1. A pharmaceutical composition comprising a compound selected from formula (I) for use in a method for treating non-opioid-mediated respiratory depression, said method comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I). 【Chemistry 1】 (In the formula, R １ and R ２ is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R １ and R ２ combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R ３ is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR １ R ２ , -C(O)OR １ , acyl, or aryl; R ４ is H, alkyl, or substituted alkyl; R ５ is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR １ , -NR １ R ２ , -C(O)OR １ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R ３ and R ５ combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ６ is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR ４ and Y is N, CR ６ , or C, Y is N or CR ６ If １ is nothing, (i) Z is H, and bond b ２ is a single bond, A is CH, or (ii) Z is nothing, and bond b ２ is nothing, A is a single bond, When Y is C, bond b １ is a single bond, and (i) Z is CH ２ and bond b ２ is a single bond and A is CH, or (ii) Z is CH and bond b ２ is a double bond and A is C) or a salt thereof.

2. As described with respect to formula (I), R １ , R ２ , R ３ , and R ５ 2. The pharmaceutical composition of claim 1, wherein at least one substituent selected from the group consisting of: is alkynyl or substituted alkynyl.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the non-opioid agent is a central nervous system depressant.

4. 4. The pharmaceutical composition of claim 3, wherein the central nervous system depressant is a surgical anesthetic.

5. 5. The pharmaceutical composition of claim 4, wherein the surgical anesthetic is propofol, fospropofol, ketamine, thiopental, methohexital, etomidate, sevoflurane, isoflurane, desflurane, or a pharmaceutically acceptable salt thereof.

6. 3. The pharmaceutical composition of claim 1 or 2, wherein the patient exhibits restored ventilatory adequacy.

7. 3. The pharmaceutical composition of claim 1 or 2, wherein the patient exhibits increased ventilatory responsiveness.

8. 3. The pharmaceutical composition of claim 1 or 2, wherein ventilatory deterioration of the patient is avoided or minimized.

9. The pharmaceutical composition of claim 1, wherein the route of administration is selected from oral, intravenous, nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, or intrathecal routes.

10. 3. The pharmaceutical composition of claim 1 or 2, wherein the therapeutic effect of the non-opioid agent is maintained.

11. 3. The pharmaceutical composition of claim 1 or 2, wherein the patient exhibits improvement in hypoxia.

12. 3. The pharmaceutical composition of claim 1 or 2, wherein the patient exhibits improved minute ventilation.

13. 3. The pharmaceutical composition of claim 1 or 2, wherein the administration is intravenous.

14. 14. The pharmaceutical composition of claim 13, wherein the compound of formula (I) is administered at a rate of 0.10 mg / kg / hour to 10 mg / kg / hour.

15. The pharmaceutical composition of claim 14, wherein the method further comprises administering a loading dose.

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