Methods and compositions for treating drug overdoses

Abstract

In some embodiments, the present invention discloses a method for treating drug overdose, comprising administering a therapeutically effective amount of a respiratory stimulant to a patient in need, wherein the overdose drug comprises an α2-adrenergic receptor agonist.

Description

Technical Field

[0001] In some embodiments, this disclosure relates to methods and compositions for treating drug overdose and / or treating abnormal blood pH. Background Technology

[0002] Xylazine is an alpha-2 adrenergic receptor agonist and a non-opioid veterinary sedative that is not approved for human use. Xylazine is associated with an increased number of overdose deaths in drug addiction and overdose crises. People exposed to xylazine often use it intentionally or unintentionally in combination with other drugs such as fentanyl.

[0003] Xylazine is often added to illicit opioids such as fentanyl to prolong their stimulating effects. Xylazine is a central nervous system depressant that can cause drowsiness, amnesia, slowed breathing, bradycardia, and decreased blood pressure. Combining opioids with xylazine and other central nervous system depressants increases the risk of life-threatening overdose.

[0004] Repeated use of xylazine has also been linked to skin ulcers, abscesses, and related complications, and the drug can be abused by injection, nasal inhalation, swallowing, or inhalation.

[0005] There is a need in the art for methods and compositions for treating drug overdose associated with α2-adrenergic receptor agonists. Summary of the Invention

[0006] In some embodiments, this disclosure relates to methods and compounds for treating drug overdose, the methods comprising administering a therapeutically effective amount of a respiratory stimulant to a patient in need, wherein the overdose drug comprises an α2-adrenergic receptor agonist. In other embodiments, the overdose drug further comprises an opioid, such as fentanyl.

[0007] In some embodiments, this disclosure relates to a method of treating drug overdose, comprising administering a therapeutically effective amount of a respiratory stimulant to a patient in need, wherein the overdose drug comprises an α2-adrenergic receptor agonist, wherein the respiratory stimulant is an effective amount of a compound selected from formula (I):

[0008]

[0009] in:

[0010] R 1 and R 2Independently, it is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, 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 Combined to form a diradical 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;

[0011] R 3 H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 -C(O)OR 1 acyl or aryl;

[0012] R 4 It is H, alkyl, or a substituted alkyl;

[0013] R 5 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 Combining to form a diradical selected from the group consisting of: 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0014] R 6 It can be H, alkyl, substituted alkyl or alkenyl;

[0015] X represents a bond, O, or NR. 4 ;as well as

[0016] Y represents N and CR 6 Or C; where:

[0017] If Y is N or CR 6 Then b 1 It does not exist, and: (i) Z is H, key b 2 It is a single bond, and A is CH; or, (ii) Z does not exist, and bond b2 It does not exist, and A is a single bond; and

[0018] If Y is C, then b 1 It is a single bond, and: (i) Z is CH2, bond b 2 It is a single bond, and A is CH; or, (ii) Z is CH, and bond b 2 It is a double bond, and A is C;

[0019] Or its salt.

[0020] In some embodiments, as described with respect to equation (I) above, at least one selection is made from R. 1 R 2 R 3 and R 5 The substituents of the group are alkynyl groups or substituted alkynyl groups.

[0021] In some embodiments, the route of administration of the compound of formula (I) is selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, tracheal, ear, intraocular, or intrathecal routes.

[0022] In some embodiments, this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a respiratory stimulant for treating drug overdose, wherein the overdose comprises an α2-adrenergic receptor agonist, and wherein the respiratory stimulant is, for example, an effective amount of a compound selected from formula (I):

[0023]

[0024] in:

[0025] R 1 and R 2 Independently, it is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, 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 Combined to form a diradical 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;

[0026] R 3 H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R2 -C(O)OR 1 acyl or aryl;

[0027] R 4 It is H, alkyl, or a substituted alkyl;

[0028] R 5 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 Combining to form a diradical selected from the group consisting of: 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0029] R 6 It can be H, alkyl, substituted alkyl or alkenyl;

[0030] X represents a bond, O, or NR. 4 ;as well as

[0031] Y represents N and CR 6 Or C; where:

[0032] If Y is N or CR 6 Then b 1 It does not exist, and: (i) Z is H, key b 2 It is a single bond, and A is CH; or, (ii) Z does not exist, and bond b 2 It does not exist, and A is a single bond; and

[0033] If Y is C, then b 1 It is a single bond, and: (i) Z is CH2, bond b 2 It is a single bond, and A is CH; or, (ii) Z is CH, and bond b 2 It is a double bond, and A is C;

[0034] or its salt; and

[0035] Pharmaceutically acceptable excipients.

[0036] In some embodiments, this disclosure relates to a pharmaceutical composition comprising an effective amount of a compound selected from formula (I) above, wherein at least one is selected from R. 1 R 2 R 3 and R5 The substituents of the group are alkynyl groups or substituted alkynyl groups.

[0037] In some embodiments, this disclosure relates to a method for preparing any of the pharmaceutical compositions described herein. Attached Figure Description

[0038] Figure 1 The PCO2 value is shown after administering the rescue dose of Example 1.

[0039] Figure 2 The PO2 value is shown after administering the rescue dose of Example 1.

[0040] Figure 3 The blood pH value is shown after administering the rescue dose of Example 1.

[0041] definition

[0042] As used herein, unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” include plural referents. Thus, for example, references to “surfactant” include a single surfactant as well as a mixture of two or more different surfactants, and references to “excipient” include a single excipient as well as a mixture of two or more different excipients, and so on.

[0043] As used herein, the term “about” relates to the quantity of a measurement and refers to the normal variation in the quantity of the measurement, as would be expected by one of ordinary skill in the art when performing measurements and exercising a degree of care commensurate with the accuracy of the measurement target and the measuring equipment. In some embodiments, the term “about” includes ±10% of the referenced number, such that “about 10” would include 9 to 11.

[0044] As used herein, the terms “active agent,” “active ingredient,” and “active pharmaceutical ingredient” refer to any material intended to produce a therapeutic, preventative, or other desired effect, whether or not it has been approved by a government agency for said purpose. These terms with respect to a particular pharmaceutical agent include all pharmaceutically active agents, all their pharmaceutically acceptable salts, complexes, stereoisomers, crystalline forms, cocrystals, ethers, esters, hydrates, solvates, and mixtures thereof, wherein said forms are pharmaceutically active.

[0045] As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the spatial orientation of their atoms. It includes enantiomers and isomers of compounds that are not mirror images of each other (diastereomers).

[0046] The terms “enantiomer” and “enantiomer” refer to a molecule that is not superimposed on its mirror image and is therefore optically active, wherein the enantiomer rotates the plane of polarization by a certain degree in one direction and its mirror image rotates the plane of polarization by the same degree but in the opposite direction.

[0047] The term "chiral center" refers to a carbon atom that is attached to four different groups.

[0048] The term "patient" refers to a subject, animal, or human who exhibits clinical manifestations indicating one or more specific symptoms requiring treatment, has received preventative or prophylactic treatment for their condition, or has been diagnosed with a condition requiring treatment. The term "subject" includes the definition of the term "patient" and does not exclude healthy individuals.

[0049] "Pharmaceutically acceptable salts" or "salts" include, but are not limited to, inorganic acid salts, such as hydrochlorides, hydrobroms, hydroiodates, sulfates, hydrogen sulfates, phosphates, nitrates, carbonates, sulfates, and phosphates (including hydrogen phosphate and dihydrogen phosphate); organic acid salts, such as oxalates, malonates, citrates, fumarates, lactates, malates, succinates, formates, acetates, trifluoroacetates, maleates, tartrates, gluconates, benzoates, salicylates, hydroxynaphthylcarboxylate, dihydroxynaphthylcarboxylate, ascorbate, adipate, cinnamates, etc.; sulfonic acids. Salts, such as methanesulfonates, benzenesulfonates, and p-toluenesulfonates; amino acid salts, such as arginine salts, asparagine salts, and glutamate salts; metal salts, such as zinc salts, sodium salts, potassium salts, and cesium salts; alkaline earth metal salts, such as calcium salts and magnesium salts; and organic amine salts, such as triethylamine salts, pyridine salts, methylpyridine salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-diphenylmethylethylenediamine salts, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine. These salts can exist as hydrates, solvates, or crystalline polymorphs. In some embodiments, suitable organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid 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, methylene dihydroxynaphthyl acid (dihydroxynaphthyl acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactobionic acid, and galacturonic acid. All these salts can be prepared by conventional methods from the corresponding compounds of the present invention by reacting, for example, a suitable acid or base with the compounds of the present invention. Handbook ofPharmaceutical Salts: Properties, and Use (eds. PH Stahl and CG Wermuth, Verlag Helvetica Chimica Acta, 2002) [1].

[0050] The terms “disease” or “diseases” or “condition” or “conditions” refer to those medical conditions that can be treated or prevented by administering an effective amount of an active agent to a subject.

[0051] The terms "treatment of" and "treating" include reducing the severity of or stopping the condition, or reducing the severity of or stopping the symptoms of the condition. In some embodiments, the terms "treatment of" and "treating" in relation to the condition mean administration intended to provide a pharmacodynamic effect, regardless of the outcome. In some embodiments, "treatment of" and "treating" mean "having a positive effect on the condition" and encompass reducing, improving, and / or alleviating the severity of at least one symptom of the condition; reducing, improving, and / or alleviating the severity of the condition; delaying, preventing, or inhibiting the progression of the condition; or perceiving improvement or benefit as a result of treatment. Treatment as described herein does not require a complete cure of the condition. In some embodiments, the compositions of this disclosure may provide an improvement in the patient's quality of life, or delay, prevent, or inhibit the onset of one or more symptoms of the condition, or provide a perceived benefit.

[0052] The terms “prevention of” and “preventing” include preventing the onset of a disease.

[0053] The term “therapeutic effective amount” is intended to include an amount of an active agent or a combination of active agents, for example, for treating or preventing a subject’s condition or for treating the symptoms of a subject’s condition.

[0054] The term "effective amount" is intended to include the amount of a component or combination of components that achieves a certain result or property. For example, the effective amount of a pH adjuster that achieves a pH of 6.0 is intended to include the amount of one or more pH adjusters that achieve a pH of 6.0.

[0055] The terms “application,” “apply,” and “applying” in relation to the disclosed topical compositions or methods of using the disclosed topical compositions refer to any manner in which the topical composition is applied to a patient’s skin, delivering the composition to the surface of the patient’s skin in medical or cosmetic practice. Applying, rubbing, spreading, or spraying the disclosed topical composition onto a patient’s skin, with or without the aid of a suitable device, is included within the scope of the term “application” as used herein. The terms “topical” or “topically” in relation to the administration or application of the disclosed formulations refer to epidermal application or application, or application to the skin.

[0056] As used herein, "oral delivery" or "oral administration" refers to a route of administration in which the composition is taken orally. Oral administration is part of enteral administration and also includes buccal (dissolved in the buccal cavity), sublipal (dissolved under the lip), and sublingual (dissolved under the tongue). In some embodiments, oral administration includes a route of administration in which the composition is ingested. In some embodiments, oral administration includes a route of administration in which the composition is inhaled.

[0057] As used in this article, “parenteral administration” refers to the route of administration in which a drug dosage form is injected into, for example, an intramuscular (intramuscular), intravenous (intravenous), or subcutaneous (subcutaneous).

[0058] The phrase “pharmaceutically acceptable” means those compounds, materials, compositions, and / or dosage forms that, to a reasonable extent of medical judgment, are suitable for use in contact with tissues of humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio.

[0059] As used herein, unless otherwise stated, the term "alkyl" itself, or as part of another substituent, refers to a straight-chain or branched hydrocarbon having a specified number of carbon atoms (i.e., C1-C10 means one to ten carbon atoms), and includes straight-chain, branched, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred are (C1-C6) alkyl groups, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0060] As used herein, unless otherwise stated, the term "cycloalkyl" itself, or as part of another substituent, refers to a cyclic chain hydrocarbon having a specified number of carbon atoms (i.e., C3-C6 means a cyclic group containing a cyclic group consisting of three to six carbon atoms), and includes straight-chain, branched, or cyclic substituents. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred are (C3-C6) cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0061] As used herein, unless otherwise stated, the term "alkenyl" used alone or in combination with other terms refers to a stable monounsaturated or diunsaturated straight-chain or branched hydrocarbon group having the stated number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotonyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologues and isomers. The functional group representing an olefin is exemplified by -CH2-CH═CH2.

[0062] As used herein, unless otherwise stated, the term "alkynyl" used alone or in combination with other terms refers to a stable straight-chain or branched hydrocarbon group having the stated number of carbon atoms and a carbon-carbon triple bond. Examples include ethynyl and propynyl, as well as higher homologues and isomers.

[0063] As used herein, the terms “substituted alkyl,” “substituted cycloalkyl,” “substituted alkenyl,” or “substituted alkynyl” mean an alkyl, cycloalkyl, alkenyl, or alkynyl group as defined above, substituted with one, two, or three substituents selected from the group consisting of: halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -N(CH3)2, (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(═O)OH The substituted alkyl group contains trifluoromethyl, -C≡N, -C(═O)O(C1-C4)alkyl, -C(═O)NH2, -C(═O)NH(C1-C4)alkyl, -C(═O)N((C1-C4)alkyl)2, -SO2NH2, -C(═NH)NH2, and -NO2, preferably containing one or two substituents selected from halogens, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(═O)OH, more preferably substituents selected from halogens, alkoxy, and -OH. Examples of substituted alkyl groups include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0064] As used herein, unless otherwise stated, the term "alkoxy" used alone or in combination with other terms refers to an alkyl group having a specified number of carbon atoms as defined above, connected by an oxygen atom to the rest of the molecule, such as methoxy, ethoxy, 1-propoxy, 2-propoxy ("isopropoxy"), and higher homologues and isomers. Preferred are (C1-C3) alkoxy groups, such as, but not limited to, ethoxy and methoxy.

[0065] Unless otherwise stated, the terms “halogenated” or “halogen” as used herein, alone or as part of another substituent, refer to a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0066] As used herein, unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term refers to a stable straight-chain or branched alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heteratoms may be located at any position on the heteroalkyl group, including between the remainder of the heteroalkyl group and the segment to which it is attached, and with 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. At most two heteroatoms may be consecutive, for example, -CH2-NH-OCH3 or -CH2-CH2-SS-CH3.

[0067] As used herein, unless otherwise stated, the term "heteroalkenyl" on its own or in combination with another term means a stable straight-chain or branched monounsaturated or diunsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed sequentially. 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.

[0068] As used herein, the term "aromatic" refers to a carbon ring or heterocycle having one or more polyunsaturated rings and exhibiting aromatic characteristics (i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer).

[0069] As used herein, unless otherwise stated, the term "aryl" used alone or in combination with other terms refers to a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein these rings may be linked together in a side-chain manner, such as biphenyl, or may be fused together, such as naphthalene. Examples include phenyl, anthracene, and naphthyl. Phenyl and naphthyl are preferred, with phenyl being the most preferred.

[0070] As used herein, the term "aryl-(C1-C3)alkyl" means a functional group in which one or more carbonyl chains are attached to an aryl group, such as -CH2CH2-phenyl or -CH2-phenyl(benzyl). Preferably, it is aryl-CH2- and aryl-CH(CH3)-. The term "substituted aryl-(C1-C3)alkyl" means an aryl-(C1-C3)alkyl functional group in which the aryl group is substituted. Preferably, it is substituted aryl(CH2)-. Similarly, the term "heteroaryl-(C1-C3)alkyl" means a functional group in which one or more carbonyl chains are attached to a heteroaryl group, such as -CH2CH2-pyridyl. Preferably, it is heteroaryl-(CH2)-. The term "substituted heteroaryl-(C1-C3)alkyl" means a heteroaryl-(C1-C3)alkyl functional group in which the heteroaryl group is substituted. Preferably, it is a substituted heteroaryl-(CH2)-.

[0071] As used herein, unless otherwise stated, the terms "heterocyclic," "heterocyclic group," or "heterocyclic" themselves, or as part of another substituent, refer to an unsubstituted or substituted, stable monocyclic or polycyclic heterocyclic system consisting of a carbon atom and at least one heteroatom selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen atom may optionally be quaternized. Unless otherwise stated, heterocyclic systems may be linked at any heteroatom or carbon atom that provides a stable structure. Heterocyclic systems may be aromatic or non-aromatic in nature. In one embodiment, the heterocycle is a heteroaryl group.

[0072] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle that has aromatic characteristics. Polycyclic heteroaryl groups may include one or more partially saturated rings. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuranyl.

[0073] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, ethylene oxide, thiocyclopropane, aziridine, oxacyclobutane, thiocyclobutane, pyrrolidine, pyrrololine, imidazoline, pyrazolidine, dioxacyclopentane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophene, 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-dioxacycloheptane, 4,7-dihydro-1,3-dioxacycloheptane, and hexamethylene oxide.

[0074] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (e.g., but not limited to 2- and 4-pyrimidinyl), pyridazinyl, thiopheneyl, furanyl, pyrroleyl, 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.

[0075] Examples of polycyclic heterocyclic compounds include indolyl (e.g., but not limited to 3-, 4-, 5-, 6-, and 7-indolyl), dihydroindolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl (e.g., but not limited to 1- and 5-isoquinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, cyclolinyl, quinoxalinyl (e.g., but not limited to 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthidyl, 1,4-benzodioxane, coumarin, dihydrocoumarin, 1,5-naphthidyl, and benzene. benzofuranyl (e.g., but not limited to 3-, 4-, 5-, 6- and 7-benzofuranyl), 2,3-dihydrobenzofuranyl, 1,2-benzoisoxazolyl, benzothiophene (e.g., but not limited to 3-, 4-, 5-, 6- and 7-benzothiophene), benzoxazolyl, benzothiazolyl (e.g., but not limited to 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthyl, carbazolyl, carbaolinyl, acridineyl, pyrrolylyl, and quinazinyl.

[0076] The aforementioned list of heterocyclic or heteroaryl moieties is intended to be representative rather than restrictive.

[0077] As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as a substituent attached to another group.

[0078] For aryl, aryl-(C1-C3)alkyl, and heterocyclic groups, the term "substituted" applied to the ring of these groups means any level of substitution, i.e., monosubstituted, disubstituted, trisubstituted, tetrasubstituted, or pentasubstituted, where such substitution is permitted. The substituents are chosen independently, and substitution can occur at any chemically accessible position. In one embodiment, the number of substituents varies between one and four. In another embodiment, the number of substituents varies between one and three. In yet another embodiment, the number of substituents varies between one and two. In yet another embodiment, the substituents are independently selected from C1-C3 alkyl groups. 1-6 Alkyl, -OH, C 1-6 The group consisting of alkoxy, halogen, amino, acetamino, and nitro groups. As used herein, when the substituent is alkyl or alkoxy, the carbon chain can be branched, straight, or cyclic, with straight chains being preferred.

[0079] Unless otherwise stated herein, the descriptions of ranges of values ​​herein are intended only as a shorthand for referring to each individual value falling within the range, and each individual value is incorporated herein as if separately referenced. Unless otherwise stated herein or otherwise clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all examples or exemplary language (e.g., “suchas”) provided herein is intended only to illustrate certain materials and methods and does not constitute a limitation on the scope. No language in this specification should be construed as indicating that any unclaimed element is essential for the practice of the disclosed materials and methods. Detailed Implementation

[0080] Some embodiments of this disclosure relate to a method for treating drug overdose, comprising administering a therapeutically effective amount of a respiratory stimulant to a patient in need, wherein the overdose drug comprises an α2-adrenergic receptor agonist.

[0081] In some embodiments, this disclosure relates to a method of treating low blood pH caused by respiratory failure, comprising administering a therapeutically effective amount of a respiratory stimulant to a patient in need. The respiratory failure may be caused by drug overdose, such as an α2-adrenergic receptor agonist. In some embodiments, the blood pH increases to about 7.35 to about 7.45, or to about 7.38 to about 7.42, or to about 7.4. In some embodiments, the pH increases from about 7.0 to about 7.35 or less than 7.35, or from about 7.0, about 7.05, about 7.1, about 7.15, about 7.2, about 7.25, or about 7.3. In other embodiments, the administration of the invention maintains the blood pH at about 7.35 to about 7.45, or to about 7.38 to about 7.42, or to about 7.4.

[0082] In some embodiments, the present invention protects subjects from drug overdose and from the long-term effects of low blood pH exhibited during overdose.

[0083] In some embodiments, this disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a respiratory stimulant and a pharmaceutically acceptable excipient for treating drug overdose, wherein the overdose comprises an α2-adrenergic receptor agonist.

[0084] In some embodiments, the drug overdose is accompanied by respiratory depression, sedation, hypotension, adverse central nervous system effects, adverse cardiac effects, or a combination thereof.

[0085] In some embodiments, the drug overdose is accompanied by respiratory depression.

[0086] In some embodiments, the α2-adrenergic receptor agonist comprises 4-NEMD, 7-me-marsanidine, agmatine, araclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfacine, lofexidine, etc. Lofexidine, marsanidine, medetomidine, methyldopa, mivazerol, rilmenidine, romifidine, talipexole, tiamenidine, tizanidine, tolonidine, xylazine, xylometazoline, and their pharmaceutically acceptable salts and combinations thereof.

[0087] In some embodiments, the α2-adrenergic receptor agonist comprises xylazine or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the overdose of the drug comprises an opioid agonist.

[0089] Opioid agonists can be, for example, morphine; codeine; thebaine; oripavine; diacetylmorphine; 2,4-dinitrophenylmorphine; methylenedioxydimethylamphetamine; chlomaltrexamine; dihydromorphine; hydromorphinol; nicomorphine; desomorphine; acetylpropionylmorphine; methyldesorp... hine); N-phenethylnormorphine; 14-hydroxydihydrocodeine (RAM-318); 7,8-dihydro-14-hydroxy-N-phenethylnormorphine (RAM-378); benzoylmorphine; diacetyldihydromorphine; benzoylmorphine; 6-monoacetylcodeine (6-MAC); acetyldihydrocodeine; dihydrocodeine; nalbuphine; nicocodeine; nicodihydrocodeine; oxymorphazone; 1-iodomorphine; morphine-6-uronic acid (M6G); 6-monoacetyl Morphine (6-MAM); Norcodeine; Normorphine; Genomorphine; Dextrorotatory lorphan (DXA); Cyclorphan; Dihydroisocodeine; Pholcodine; Myrophine; 14-Cinnamyloxycodeinone; 14-Ethoxymetopon; 14-Methoxymetopon; 14-Phenylacetoxymetopon (PPOM); 7-Spiroindanyloxymorphone Acetylmorphone; codeinone; conorphone; codoxime; thebacon; metopon; N-phenylethyl-14-ethoxymetopon; morphone; benzylmorphine; codeine methyl bromide; ethylmorphine; isocodeine; hydromorphone; hydrocodone; oxycodone; oxymorphone; pentamorphone; semorphone; chloromorphide.Ethylmorphine; Buprenorphine; Fentanyl; Alfentanil; Sufentanil; Remifentanil; Carfentanyl; Ohmefentanyl; Pethidine; Ketobemidone; Desmethylprodine (MPPP); Allylprodine rodine); prodine; 1-methyl-4-phenyl-4-propionyloxypiperidine (PEPAP); propoxyphene; dextropropoxyphene; dextromoramide; bezitramide; piritriamide; levorphanol; methadone; dipipanone; levomethadyl acetate, LAAM); difenoxin; diphenoxylate; loperamide; dezocine; pentazocine; phenazocine; dihydroetorphine; etorphine; butorphanol; nalbuphine; levomethorphan; levophenacylmorphan; norlevorphanol; oxilorphan; phenormorphine (ph enomorphan); furethylnorlevorphanol; xorphanol; butorphanol; cyprodime; drotebanol; 7-PET; acetorphine; BU-48; cyprenorphine; norbuprenorphine; lefetamine; meptazinol; mitragynine; tilidine; tramadol; tapentadolDextropropoxyphene; endorphins; enkephalins; dynorphins; endomorphins, or combinations thereof.

[0090] In some embodiments, the opioid agonist comprises oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, sufentanil, morphine, tramadol, buprenorphine, pharmaceutically acceptable salts thereof, and combinations thereof.

[0091] In some embodiments, the opioid is fentanyl or a pharmaceutically acceptable salt thereof.

[0092] In other embodiments, the overdose drug may be a κ opioid receptor agonist, such as butorphanol, nalbuphine, levorphanol, levallorphan, pentazocine, finazocine, eptazocine, a pharmaceutically acceptable salt thereof, or a combination thereof.

[0093] In some embodiments, the respiratory stimulant comprises a compound selected from formula (I) disclosed herein.

[0094] In some embodiments, the compound is N-(4,6-bis-n-propylamino-[1,3,5]triazine-2-yl)-O,N-dimethyl-hydroxylamine or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the administration does not contain an opioid antagonist.

[0096] In some embodiments, the administration also includes an opioid antagonist.

[0097] In some embodiments, the antagonist and the stimulant are administered simultaneously or sequentially.

[0098] In some embodiments, the antagonist and the stimulant are administered via the same route of administration.

[0099] In some embodiments, the antagonist and the stimulant are administered via different routes of administration.

[0100] In some embodiments, the antagonist and the stimulant are administered in the same pharmaceutical composition.

[0101] In some embodiments, the antagonist and the stimulant are administered in different pharmaceutical compositions.

[0102] In some embodiments, the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, and pharmaceutically acceptable salts thereof.

[0103] In some embodiments, the respiratory stimulant is selected from the group consisting of doxapram, almitrine, caffeine, and pharmaceutically acceptable salts thereof.

[0104] In some embodiments, the stimulant is administered at a therapeutic dose sufficient to restore or improve the respiratory rhythm of an overdosed patient.

[0105] In some embodiments, the stimulant is administered at a therapeutic dose that does not induce hyperventilation or significant hyperventilation in the overdosed patient.

[0106] In some embodiments, if the antagonist is administered in the absence of the stimulant, the antagonist is provided at a subtherapeutic or supertherapeutic dose.

[0107] In some embodiments, if the antagonist is administered in the absence of the stimulant, the antagonist is provided at a therapeutic dose.

[0108] In some embodiments, if administered in the absence of the antagonist, the stimulant is provided at a subtherapeutic or supertherapeutic dose.

[0109] In some embodiments, the stimulant is provided at a therapeutic dose if administered in the absence of the antagonist.

[0110] In some embodiments, the overdose of the drug includes benzodiazepines, barbiturates, gabapentinoids, or combinations thereof.

[0111] In some embodiments, the route is selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, tracheal, ear, intraocular, or intrathecal routes.

[0112] In some embodiments of opioid antagonist administration, the route is independently selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, tracheal, ear, intraocular, or intrathecal routes.

[0113] In some embodiments, the application causes a decrease in blood PCO2. In some embodiments, the decrease occurs 5 minutes or less, 10 minutes or less, or 15 minutes or less after application. In some embodiments, blood PCO2 decreases to about 35 to about 55 mmHg or about 41 to about 51 mmHg.

[0114] In some embodiments, the application causes an increase in blood PO2. In some embodiments, the increase occurs 5 minutes or less, 10 minutes or less, or 15 minutes or less after application. In some embodiments, blood PO2 decreases to about 25 to about 45 mmHg or about 30 to about 40 mmHg.

[0115] In some embodiments, the application causes an increase in blood pH. In some embodiments, the increase occurs 5 minutes or less, 10 minutes or less, or 15 minutes or less after application.

[0116] In some embodiments, the compound is administered at an amount of about 1 mg / kg to about 5 mg / kg, about 2 mg / kg to about 4 mg / kg, or about 3 mg / kg.

[0117] Some embodiments of this disclosure relate to a method of treating respiratory depression induced by non-opioid drugs, comprising administering to a patient in need an effective amount of a compound selected from formula (I):

[0118]

[0119] in:

[0120] R 1 and R 2 Independently, it is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, 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 Combined to form a diradical 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;

[0121] R 3 H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R2 -C(O)OR 1 acyl or aryl;

[0122] R 4 It is H, alkyl, or a substituted alkyl;

[0123] R 5 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 Combining to form a diradical selected from the group consisting of: 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0124] R 6 It can be H, alkyl, substituted alkyl or alkenyl;

[0125] X represents a bond, O, or NR. 4 ;as well as

[0126] Y represents N and CR 6 Or C; where:

[0127] If Y is N or CR 6 Then b 1 It does not exist, and: (i) Z is H, key b 2 It is a single bond, and A is CH; or, (ii) Z does not exist, and bond b 2 It does not exist, and A is a single bond; and

[0128] If Y is C, then b 1 It is a single bond, and: (i) Z is CH2, bond b 2 It is a single bond, and A is CH; or, (ii) Z is CH, and bond b 2 It is a double bond, and A is C;

[0129] Or its salt.

[0130] Some embodiments of this disclosure relate to a method of treating respiratory depression induced by non-opioid drugs, comprising administering to a patient in need an effective amount of a compound selected from formula (I):

[0131]

[0132] in:

[0133] R 1 and R 2 Independently, it is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, 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 Combined to form a diradical 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;

[0134] R 3 H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 -C(O)OR 1 acyl or aryl;

[0135] R 4 It is H, alkyl, or a substituted alkyl;

[0136] R 5 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 Combined 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; wherein at least one of them is selected from R 1 R 2 R 3 and R 5 The substituents in the group are ynyl groups or substituted ynyl groups;

[0137] R 6 It can be H, alkyl, substituted alkyl or alkenyl;

[0138] X represents a bond, O, or NR. 4 ;as well as

[0139] Y represents N and CR6 Or C; where:

[0140] If Y is N or CR 6 Then b 1 It does not exist, and: (i) Z is H, key b 2 It is a single bond, and A is CH; or, (ii) Z does not exist, and bond b 2 It does not exist, and A is a single bond; and

[0141] If Y is C, then b 1 It is a single bond, and: (i) Z is CH2, bond b 2 It is a single bond, and A is CH; or, (ii) Z is CH, and bond b 2 It is a double bond, and A is C;

[0142] Or its salt.

[0143] Some embodiments of this disclosure relate to a method of treating respiratory depression induced by non-opioid drugs, comprising administering to a patient in need an effective amount of a compound selected from formula (I):

[0144]

[0145] in:

[0146] R 1 and R 2 Independently, it is 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 Combined to form a diradical 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;

[0147] R 3 H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 -C(O)OR 1 acyl or aryl;

[0148] R 4 It is H, alkyl, or a substituted alkyl;

[0149] R 5H, 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 Combining to form a diradical selected from the group consisting of: 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0150] R 6 It can be H, alkyl, substituted alkyl or alkenyl;

[0151] X represents a bond, O, or NR. 4 ;as well as

[0152] Y represents N and CR 6 Or C; where:

[0153] If Y is N or CR 6 Then b 1 It does not exist, and: (i) Z is H, key b 2 It is a single bond, and A is CH; or, (ii) Z does not exist, and bond b 2 It does not exist, and A is a single bond; and

[0154] If Y is C, then b 1 It is a single bond, and: (i) Z is CH2, bond b 2 It is a single bond, and A is CH; or, (ii) Z is CH, and bond b 2 It is a double bond, and A is C;

[0155] Or its salt.

[0156] In one embodiment, R 3 It is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, or substituted alkenyl. In another embodiment, R 5 It can be H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl or acyl.

[0157] Some embodiments of this disclosure relate to a method of treating respiratory depression induced by non-opioid drugs, comprising administering to a patient in need an effective amount of a compound selected from formula (I):

[0158]

[0159] R 1 and R 2Independently, it is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, 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 Combined to form a diradical 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;

[0160] R 3 It is H, alkyl, substituted alkyl, alkynyl or substituted alkynyl;

[0161] R 4 It is H, alkyl, or a substituted alkyl;

[0162] R 5 It is an alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl, wherein at least one of them is selected from R. 1 R 2 R 3 and R 5 The substituents in the group are ynyl groups or substituted ynyl groups;

[0163] R 6 It can be H, alkyl, substituted alkyl or alkenyl;

[0164] X represents a bond, O, or NR. 4 ;as well as

[0165] Y represents N and CR 6 Or C; where:

[0166] If Y is N or CR 6 Then b 1 It does not exist, and:

[0167] (i) Z is H, and the bond b 2 It is a single bond, and A is CH; or,

[0168] (ii) Z does not exist, key b 2 It does not exist, and A is a single bond; and

[0169] If Y is C, then b 1 It is a single bond, and:

[0170] (i) Z is CH2, bond b 2 It is a single bond, and A is CH; or,

[0171] (ii) Z is CH, bond b 2 It is a double bond, and A is C;

[0172] Or its salt.

[0173] In some embodiments, (i)R 3 It is H, alkyl, or a substituted alkyl group, and R 5 It is propargyl, substituted propargyl, homopropargyl or substituted homopropargyl, or (ii) R 3 It is an or alkynyl group, and R 5 It is alkyl, propargyl, substituted propargyl, homopropargyl or substituted homopropargyl.

[0174] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is N, b1 is absent, Z is H, bond b2 is a single bond, A is CH, and at least one compound is a compound of formula (II-a) or a salt thereof:

[0175]

[0176] as well as

[0177] (ii) Y is N, b1 does not exist, Z does not exist, bond b2 does not exist, A is a bond, and the compound of the present invention is a compound of formula (II-b) or a salt thereof:

[0178] .

[0179] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is CR 6 b 1 It does not exist, Z is H, and the key is b. 2 It is a single bond, A is CH, and at least one compound is a compound of formula (III-a) or a salt thereof:

[0180]

[0181] as well as

[0182] (ii) Y is CR 6 b 1 It does not exist, Z does not exist, key b 2 No, A is a bond, and the compounds of this invention are pyrimidines of formula (III-b) or their salts:

[0183] .

[0184] In one embodiment, Y is C, b 1 It is a single bond, Z is CH2, and the bond b 2A is a single bond, A is CH, and the at least one compound is a compound of formula (IV) or a salt thereof:

[0185] .

[0186] In one embodiment, Y is C, b 1 For single bonds, Z represents CH, and the bond b 2 The compound is a double bond, A is C, and the at least one compound is a compound of formula (V) or a salt thereof:

[0187] .

[0188] In one embodiment, at least one compound is selected from the group consisting of: N-(4,6-bismethylamino-[1,3,5]triazin-2-yl)-N,O-dimethylhydroxylamine (XX), N-(4,6-bisethylamino-[1,3,5]triazin-2-yl)-N,O-dimethylhydroxylamine (XXII), N-(4-cyclopropylmethylamino)-N-(6-n-propylamino)[1,3,5]triazin-2-yl)-N,O-dimethylhydroxylamine (XXV), N-(4-ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethylhydroxylamine (XXVII), N-(bis-4,6-(2-methylpropylamino))[1,3... [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 (XXXIII), N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N,O-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-dipropylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLIII), N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazin-2,4-diamine (XLVII), N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzylmethyl-N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII), N ... [3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]oxazin-2-yl-N,N'-dipropyl-[1,3,5]triazin-2,4-diamine (LVII), N-(4,6-bispropylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzylmethyl-N-(4,6-bispropylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII), N-(4,6-bispropylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzoxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazin-2,4-Diamine (LXXII), N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII), 6-(methyl(thiophene-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazin-2,4-diamine (LXXXIV), N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine [3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCVI), N-(4,6-dipropylamino-[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-dimethylhydroxylamine (CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethylhydroxylamine (CIX), 4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethylhydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethylhydroxylamine (CXIII), 4,6-bis-[N-(tetrahydropyran-4-yl ... [-(1,3,5)triazin-2-yl)-N,O-dimethylhydroxylamine (CXV), N-(5,8,11-trioxa-2,14,16,18,19-pentazabicyclo[13.3.1]-nonadecan-1(18),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII), N-(4,6-dipropylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine (XLVI), N-(4,6-dipropylamino-[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.

[0189] In one embodiment, at least one compound is 2,6-bis-(N-n-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethylhydroxylamine 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 or hydrochloride.

[0190] 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 or hydrochloride.

[0191] In one embodiment, at least one compound is selected from the group consisting of: 2-(n-propyl)amino-4-(isopropylamino-7-methylpyrrolidano[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methylpyrrolidano[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methylpyrrolidano[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(isopropyl)amino-7-isopropyl ...XXVIII), 2-(n-propyl)amino-4-methylamino-7-methylpyrrolidano[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(isopropyl)amino-7-isopropylpyrrolidano[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-(isopropyl)amino-7-isopropylpyrrolidano[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methylpyrrolidano[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(isopropyl)amino-7-isopropylpyrrolidano[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methylpyrrolidano[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-(isopropyl)amino-7-isopropylpyrrolidano[2,3-d]pyrimidine (CXXVI), 2-(n- [3-d]pyrimidine (CXXXVI), 2,4-bis(n-propyl)amino-7H-pyrrolidine[2,3-d]pyrimidine (CXLIX), 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidine[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidine[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-3-ol (CLV), their salts, and mixtures thereof. In another embodiment, the salt is a hydrogen sulfate or hydrochloride salt.

[0192] In one embodiment, at least one compound is selected from the group consisting of: N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethylhydroxylamine (CXLI), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethylhydroxylamine (CLVIII), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methylhydroxylamine (CLX), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O N-dimethylhydroxylamine (CLXII), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methylhydroxylamine (CLXIV), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXVI), N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXVIII), N,N-dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXX), their salts, and mixtures thereof. In another embodiment, the salt is a hydrogen sulfate or hydrochloride.

[0193] In some 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]triazin-2,4,6-triamine; its salts; and any combination thereof.

[0194] In some embodiments, the following compound A used in this invention is

[0195]

[0196] Or its pharmaceutically acceptable salt.

[0197] In some embodiments, the compounds of formula (I) are selected from those described in U.S. Patent No. 9,162,992 and / or U.S. Patent 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.

[0198] In some embodiments, the patient's ventilation function is restored.

[0199] In some embodiments, the patient's ventilation was restored in the event of an overdose of medication.

[0200] In some embodiments, the patient’s ventilation responsiveness is enhanced.

[0201] In some embodiments, the patient’s ventilatory responsiveness to hypoxemia events is enhanced.

[0202] In some embodiments, the patient’s ventilatory responsiveness to hypercapnia events is enhanced.

[0203] In some embodiments, the decline in the patient's ventilation function is avoided or minimized.

[0204] In some embodiments, the decline in the patient's ventilation is avoided or minimized during hypercapnia.

[0205] In some embodiments, the route of administration is selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, tracheal, ear, intraocular, or intrathecal routes.

[0206] In some embodiments, the patient's hypercapnia improved. In some embodiments, the improvement was at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%.

[0207] In some embodiments, the patient's minute ventilation improved. In some embodiments, based on hypoxia ventilation sensitivity (… ventilation / Saturation = hypoxia sensitivity (unit: L / min / desaturation %) is measured and improved to at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%.

[0208] In some embodiments, patients exhibited a positive ventilator response during normoxic conditions with both normocytemia and mild hyperocytemia.

[0209] In some embodiments, patients maintain ventilator responsiveness under conditions of normoxic and mild hypercapnia during normoxic conditions.

[0210] In some embodiments, patients do not exhibit side effects or experience clinically significant side effects, which are measured by one or more of the following: reported adverse events, physical examination, vital signs, 12-lead ECG, clinical laboratory test results, and Columbia Suicide Severity Rating Scale (C-SSRS) response.

[0211] In some embodiments, the patient's cardiovascular response does not show clinically significant changes.

[0212] In some embodiments, the therapeutic effect exhibited by the patient can be assessed by reducing hypoxia sensitivity ( ventilation / It is measured by saturation.

[0213] In some embodiments, the therapeutic effect observed by the patient is measured by tidal volume (VT).

[0214] In some embodiments, the therapeutic effect observed by the patient is measured by respiratory rate (breaths / minute).

[0215] In some embodiments, the therapeutic effect observed by the patient is measured by minute ventilation (VE).

[0216] In some embodiments, the therapeutic effect observed by the patient is measured by transcutaneous CO2 measurement and / or end-tidal CO2 (mmHg).

[0217] In some embodiments, the therapeutic effect observed by the patient is measured by transdermal hemoglobin saturation (SpO2, %).

[0218] In some embodiments, the therapeutic effect observed in patients is measured by arterial blood gas analysis.

[0219] In some embodiments, the therapeutic effect is measured using BIS.

[0220] In some embodiments, the therapeutic effect observed in the patient is measured by hemodynamic parameters monitored via arterial lines. In some embodiments, the variation is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%.

[0221] Composition

[0222] In some embodiments, this disclosure relates to a pharmaceutical composition comprising an effective amount of a compound selected from formula (I) disclosed herein, for treating drug overdose and / or treating abnormal blood pH.

[0223] In some embodiments, the active agent in the pharmaceutical composition is lyophilized.

[0224] In some embodiments, the pharmaceutical composition is premixed (e.g., the active agent is premixed with one or more pharmaceutically acceptable excipients and optionally with one or more additional active agents).

[0225] In some embodiments, the pharmaceutical composition may be packaged in a glass or plastic container.

[0226] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients may vary depending on the final form of the composition and the route of administration.

[0227] The routes of administration for any of the compositions of the present invention include inhalation, oral administration, nasal administration, rectal administration, parenteral administration, sublingual administration, transdermal administration, transmucosal administration (e.g., sublingual, tongue, buccal, urethral, ​​vaginal administration (e.g., vaginal and perivallary), nasal administration, and transrectal administration, intrabladder administration, intrapulmonary administration, intraduodenal administration, intragastric administration, intrathecal administration, intrasheath administration, subcutaneous administration, intramuscular administration, intradermal administration, intraarterial administration, intravenous administration, intrabronchial administration, inhalation, intraperitoneal administration, intrapleural administration, intrapleural administration, and topical administration.

[0228] Suitable compositions and dosage forms include, for example, tablets, capsules, microcapsules, pills, capsule tablets, sac tablets, dispersants, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, emulsions, lozenges, creams, pastes, plasters, lotions, tablets, suppositories, liquid sprays for nasal or oral administration, dry powders or nebulized formulations for inhalation, and compositions and formulations for intravesical administration. It should be understood that the formulations and compositions used in this invention are not limited to the specific formulations and compositions described herein.

[0229] In some embodiments, pharmaceutically acceptable excipients include pharmaceutically acceptable carriers, such as liquid or solid fillers, stabilizers, dispersants, suspending agents, diluents, excipients, thickeners, solvents, or encapsulating materials, which relate to carrying or transporting, within or to a subject, a compound useful in the present invention to enable it to perform its intended function. Typically, such constructs carry or transport from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable," meaning compatible with other components of the formulation, including compounds useful in the present invention, and will not cause harm to the subject. Some examples of materials that can serve as pharmaceutically 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered astragalus gum; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; 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 glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic and compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coating agents, antibacterial and antifungal agents, and absorption delay agents that are compatible with the activity of compounds useful within the present invention and are physiologically acceptable to a subject. Complementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may also include pharmaceutically acceptable salts of compounds useful within the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used to practice the present invention are known in the art and described, for example, in Remington's Pharmaceutical Sciences (edited by Genaro, Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0230] Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, and other pharmaceutically acceptable salt solutions, such as salts of phosphates and organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0231] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. Appropriate flowability can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the dispersed state, and by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include an isotonic agent in the composition, such as sugar, sodium chloride, or polyols (e.g., mannitol and sorbitol). The absorption of the injectable composition can be prolonged by including an absorption-delaying agent (e.g., aluminum monostearate or gelatin) in the composition. In one embodiment, a pharmaceutically acceptable carrier is not DMSO alone.

[0232] Pharmaceutical preparations can be sterilized and, if necessary, can be mixed with adjuvants such as lubricants, preservatives, stabilizers, humectants, emulsifiers, salts that affect osmotic pressure, buffers, colorants, flavorings, and / or aromatic substances.

[0233] Examples of preservatives useful according to the invention include, but are not limited to, those preservatives selected from the group consisting of: benzyl alcohol, sorbic acid, parabens, imiduridine urea, and combinations thereof.

[0234] The composition preferably includes an antioxidant and a chelating agent that inhibit the degradation of the compound. Preferred antioxidants for some compounds are BHT, BHA, α-tocopherol, and ascorbic acid, preferably ranging from about 0.01% to 0.3% by weight of the total composition, more preferably from 0.03% to 0.1% for BHT. Preferably, the chelating agent is present in an amount of 0.01% to 0.5% by weight of the total composition. Particularly preferred chelating agents include ethylenediaminetetraacetic acid (e.g., disodium ethylenediaminetetraacetate) and citric acid, ranging from about 0.01% to 0.20% by weight of the total composition, more preferably from 0.02% to 0.10%. The chelating agent can be used to chelate metal ions in the composition that may be detrimental to the shelf life of the formulation. Although BHT and disodium ethylenediaminetetraacetate are particularly preferred antioxidants and chelating agents for some compounds, other suitable and equivalent antioxidants and chelating agents can be substituted, as is known to those skilled in the art.

[0235] Liquid suspensions can be prepared using conventional methods to suspend the active ingredient in an aqueous or oil-based medium. Aqueous mediums include, for example, water and isotonic saline. Oil-based mediums include, for example, almond oil, oily esters, ethanol, 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 also contain one or more additional ingredients, including but not limited to suspending agents, dispersants or wetting agents, emulsifiers, modifiers, preservatives, buffers, salts, flavoring agents, coloring agents, and sweeteners. Oil-based suspensions may also contain thickeners. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, astragalus gum, gum arabic, and cellulose derivatives such as sodium carboxymethyl cellulose, methylcellulose, and hydroxypropyl methylcellulose. Known dispersants or wetting agents include, but are not limited to, naturally occurring phospholipids (such as lecithin), condensation products of epoxides with fatty acids, with long-chain aliphatic alcohols, with esters derived from fatty acids and hexitols, or with esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecanethoxylated cetyl alcohol, polyoxyethylene sorbitan monooleate, and polyoxyethylene dehydrated sorbitan monooleate, respectively). Known emulsifiers include, but are not limited to, lecithin and gum arabic. Known preservatives include, but are not limited to, methylparaben, ethylparaben, or n-propylparaben, ascorbic acid, and sorbic acid. Known sweeteners include, for example, glycerin, propylene glycol, sorbitol, sucrose, and saccharin. Known thickeners for oily suspensions include, for example, beeswax, paraffin wax, and cetyl alcohol.

[0236] Liquid solutions of the active ingredient in aqueous or oily solvents can be prepared in substantially the same manner as liquid suspensions, the main difference being that the active ingredient is dissolved in the solvent rather than suspended in it. As used herein, an "oily" liquid is a liquid containing carbon-containing liquid molecules and exhibiting lower polarity than water. Liquid solutions of the pharmaceutical compositions of the present invention may contain each of the components described with respect to liquid suspensions, and it should be understood that suspending agents do not necessarily contribute to the dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethanol, vegetable oils (such as peanut oil, olive oil, sesame oil, or coconut oil), fractionated vegetable oils, and mineral oils (such as liquid paraffin).

[0237] The powder and granule formulations of the pharmaceutical preparations of the present invention can be prepared using known methods. Such formulations can be administered directly to a subject, used for example to form tablets, fill capsules, or to prepare aqueous or oily suspensions or solutions by adding an aqueous or oily mediator. Each of these formulations may also contain one or more of a dispersant or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and sweeteners, flavoring agents, or coloring agents, may also be included in these formulations.

[0238] The pharmaceutical compositions of the present invention can also be prepared, packaged, or sold as oil-in-water emulsions or water-in-oil emulsions. The oil phase can be a vegetable oil (such as olive oil or peanut oil), a mineral oil (such as liquid paraffin), or a combination thereof. Such compositions may also contain one or more emulsifiers, such as naturally occurring gums (such as gum arabic or astragalus gum), naturally occurring phospholipids (such as soybean phospholipids or lecithin), esters or metaesters derived from combinations of fatty acids and hexitan anhydrides (such as sorbitan monooleate), and condensation products of such metaesters with ethylene oxide (such as polyoxyethylene sorbitan monooleate). These emulsions may also contain other ingredients, including, for example, sweeteners or flavorings.

[0239] In some embodiments, one or more additional excipients include a pH adjuster that 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.

[0240] In some embodiments, the composition 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, gelling agents, stabilizers, additives, wetting agents, emulsifiers, surfactants and / or dispersants, alkalizing agents, colorants, synthetic molds, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0241] In some embodiments, the composition further includes an antioxidant. In some embodiments, the antioxidant may include trivalent phosphorus (such as phosphites), phenolic antioxidants, hydroxylamine, and lactones (such as substituted benzofuranones). Hindered phenols, thiosynergists, and / or hindered amines can be used for the long-term stability of the polymer, while the following antioxidants are also suitable for situations where the active substance is subjected to oxidation: acids (ascorbic acid, isoascorbic acid, hydroxyethyl phosphate, gallic acid, hypophosphite, nordihydroguaiacol). (e.g., acid), propionic acid, etc.), phenols (e.g., BHA, BHT, tert-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, distearate thiodipropionate), pyranones (maltol), and vitamin E (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopheryl acetate, D-α-tocopheryl acetate, DL-α-tocopheryl acetate). However, according to the present invention, other antioxidants known in the art may also be used.

[0242] In some embodiments, suitable antioxidants may include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations thereof. Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols, including but not limited to 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-dimethylphenol, 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-methylcyclohexyl)-4,6-dimethylphenol, 2,6-bis(octadecyl-4-methylphenol), 2,4,6-tricyclohexylphenol, and 2,6-di-tert-butyl-4-methoxymethylphenol. Nonylphenols, including those with straight or branched side chains such as 2,6-dinonyl-4-methylphenol, 2,4-dimethyl-6-(1'-methylundec-1'-yl)phenol, 2,4-dimethyl-6-(1'-methylheptadecane-1'-yl)phenol, 2,4-dimethyl-6-(1'-methyltetrazane-1'-yl)phenol, and mixtures thereof; alkyl thiomethylphenols, including but not limited to 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, and 2,4-diethylthiomethyl-6-ethylphenol. Phenol, 2,6-bisdodecylthiomethyl-4-nonylphenol; hydroquinone and alkylated hydroquinone, including but not limited to 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-pentylhydroquinone, 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-ethylphenol), 4,4'-thiobis(6-tert-butyl-3-methylphenol), 4,4'-thiobis(6-tert-butyl-2-methylphenol), 4,4'-thiobis(3,6-disec-pentylphenol), and 4,4'-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide;Alkylbisphenols, including 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-cyclohexylphenol), 2,2'-methylenebis(6-nonyl-4-methylphenol), 2,2'-methylenebis(4,6-di-tert-butylphenol), 2,2'-ethylbis(4,6-di-tert-butylphenol), 2,2'-ethylbis(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-dodecyl Alkyl mercaptobutane, 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-hydroxy-2-methylphenyl)-4-n-dodecyl mercaptobutane, 1,5,5-tetra-(5-tert-butyl-4-hydroxy) (2-methylphenyl)pentane; O-, N- and S-benzyl compounds, including but not limited to 3,5,3',5'-tetratert-butyl-4,4'-dihydroxybenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl-4-hydroxy-3,5-ditert-butylbenzyl mercaptoacetate, tris(3,5-ditert-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-ditert-butyl-4-hydroxybenzyl)sulfide, and isooctyl-3,5-ditert-butyl-4-hydroxybenzyl mercaptoacetate;Hydroxyphenylmethylated malonates, including but not limited to bis(octadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxyphenylmethyl)malonate, bis(octadecyl-2-(3-tert-butyl-4-hydroxy-5-methylphenylmethyl)malonate, bis(dodecylmercaptoethyl-2,2-bis(3,5-di-tert-butyl-4-hydroxyphenylmethyl)malonate, and bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxyphenylmethyl)malonate; aromatic hydroxyphenylmethyl compounds, including but not limited to 1,3,5-tris(3,5-di-tert-butyl-4-hydroxyphenyl)malonate. 2,4,6-Trimethylbenzene (-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, including but not limited to 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyaniline)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,3,5-triazine, 2-octylmercapto-4,6-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-hydroxyphenylmethyl)isocyanurate, 1,3,5-Tris(4-tert-butyl-3-hydroxy-2,6-dimethylphenylmethyl)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-hydroxyphenylpropionyl)-hexahydro-1,3,5-Triazine, 1,3,5-Tris(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)-hexahydro-1,3,5-Triazine, 1,3,5-Tris(3,5-dicyclohexyl-4- Hydroxyphenylmethyl isocyanurate; benzyl phosphonates, including but not limited to calcium salts of monoethyl esters of dimethyl-2,5-di-tert-butyl-4-hydroxyphenylmethylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxyphenylmethylphosphonate, dioctadecyl-3,5-di-tert-butyl-4-hydroxyphenylmethylphosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylphenylmethylphosphonate, and 3,5-di-tert-butyl-4-hydroxyphenylmethylphosphonic acid; acylaminophenols, including but not limited to 4-hydroxylauroyl aniline, 4-hydroxystearoyl aniline, and N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamate;Esters of β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols, such as with methanol, ethanol, n-octanol, isooctanol, octadecyl alcohol, 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)oxalamide, 3-undecylthiol, 3-pentadecanthiol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; β-(5-tert-butyl-4-hydroxy- Esters of 3-methylphenyl)propionic acid with monohydric or polyhydric alcohols, such as methanol, ethanol, n-octanol, isooctanol, octadecyl alcohol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tri(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxalamide, 3-undecylthiol, 3-pentadecanthiol, 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-methyl] [Phenyl)propionyloxy]-1,1-dimethylethyl]-2,4,8,10-tetraoxaziro[5.5]-undecane; esters of 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols, such as with methanol, ethanol, octanol, octadecyl alcohol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tri(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxalamide, 3-undecylthiol, 3-pentadecanthiol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phosphazene Esters of -2,6,7-trioxabicyclo[2.2.2]octane; esters of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with monohydric or polyhydric alcohols, such as with methanol, ethanol, octanol, octadecyl alcohol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tri(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxalamide, 3-undecylthiol, 3-pentadecanthiol, trimethylhexanediol, trimethylolpropane, and 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane;Amides of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, such as N,N'-bis(3,5-di-tert-butyl-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]oxalamide (Naugard® XL-1, supplied by Uniroyal); ascorbic acid (vitamin C); amine antioxidants, including but not limited to N,N'-diisopropyl-p-phenylenediamine, N,N'-disec-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'-dicyclohexyl-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-toluenesulfonyl)diphenylamine, N,N'-dimethyl-N,N'-disec-butyl-p-phenylenediamine, diphenylamine, N-allyl diphenylamine, 4 -Isopropoxydiphenylamine, N-phenyl-1-naphthylamine, N-(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine; octylated diphenylamine, including 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 Alkane, (o-tolyl)biguanidine, bis[4-(1',3'-dimethylbutyl)phenyl]amine, tert-octylated N-phenyl-1-naphthylamine; mixtures of monoalkylated and dialkylated tert-butyl / tert-octyl diphenylamine; mixtures of monoalkylated and dialkylated nonyl diphenylamine; mixtures of monoalkylated and dialkylated dodecyl diphenylamine; mixtures of monoalkylated and dialkylated isopropyl / isohexyl diphenylamine; mixtures of monoalkylated and dialkylated tert-butyl diphenylamine; 2,3-dihydro-3,3-dimethyl-4H-1,4-benzothiazine; phenothiazine; mixtures of monoalkylated and dialkylated tert-butyl / tert-octylphenothiazine; mixtures of monoalkylated and dialkylated tert-octylphenothiazine; N-allylphenothiazine;N,N,N',N'-Tetraphenyl-1,4-diaminobut-2-ene; and combinations thereof.

[0243] In some embodiments, suitable pharmaceutically acceptable excipients may include acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyoxyethylene (e.g., polymethylene oxide, polyethylene oxide, polypropylene oxide), polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, polycaprolactone, their polymethyl methacrylate copolymers, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium glycolate starch, croscarmellose sodium, or mixtures thereof), flow aids, lubricants, absorption enhancers, and surfactants. Adhesives, softeners, plasticizers (e.g., lecithin, hydrogenated vegetable oil, glycerides, lanolin, methyl esters, pentaerythritol esters, rice bran wax, stearic acid, potassium sodium stearate, etc.), waxes, fats, emulsifiers, fillers, antioxidants, flavoring agents, coloring agents, diluents, processing aids (e.g., granulation aids), sweeteners (such as those described above with respect to chewing compositions), fixatives (e.g., polyols, such as but not limited to sorbitol, maltitol / isomaltitol, mannitol, starch, etc.), pH adjusters, viscosity adjusters, solubility increasers or decreasers, penetrants, solvents, or combinations thereof.

[0244] In some embodiments, suitable pharmaceutically acceptable excipients may include polyvinylpyrrolidone, natural and synthetic gums, polyvinyl alcohol, corn starch, hydrophilic and hydrophobic materials such as sustained-release polymers, acrylic resins, protein-derived materials, waxes, shellac, and solid or semi-solid oils such as hydrogenated castor oil and hydrogenated vegetable oil. More specifically, the controlled-release material may be, for example, alkyl cellulose such as ethyl cellulose, 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), alkylamide methacrylate copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and mixtures of any of the foregoing substances) and cellulose ethers, such as hydroxyalkyl cellulose (e.g., hydroxypropyl methylcellulose) and carboxyl cellulose. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols and mixtures thereof (e.g., beeswax, carnauba wax, stearic acid and stearyl alcohol).

[0245] In some embodiments, suitable pharmaceutically acceptable excipients may include gelling agents, such as, but not limited to, sugars or sugar-derived alcohols, such as mannitol, sorbitol, etc., starch and starch derivatives, cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, 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 methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hydroxypropyl methyl cellulose acetate succinate) and mixtures thereof), palygorskite, bentonite, dextrin, alginate, alginate such as sodium alginate and potassium alginate, casein, stearic acid, shellac, carrageenan, astragalus gum, gum arabic, gum arabic, pullulan gum), dextrin, gellan gum, agar gum, tara gum, karaya gum, guar gum, welan gum, rhamsan gum, locust bean gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer and carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silica, surfactants, mixed surfactant / wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.

[0246] In some embodiments, suitable pharmaceutically 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. Examples of other suitable hydrophilic carriers include, but are not limited to, polyoxyethylene derivatives of sorbitol esters, such as sorbitol monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitol 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 polyols with a number average molecular weight of any one of about 200 Daltons, about 400 Daltons, about 600 Daltons, about 800 Daltons, or about 1,000 Daltons to any one of about 2,000 Daltons, about 3,000 Daltons, about 4,000 Daltons, about 5,000 Daltons, about 6,000 Da, or about 7,000 Da, or any subrange or single value thereof (e.g., polyethylene glycol 400, polyethylene glycol 600, etc.).

[0247] In some embodiments, suitable pharmaceutically acceptable excipients may include plasticizers, such as, but not limited to, sugar alcohol plasticizers, such as triacetin, isomaltitol, maltitol, xylitol, erythritol, arbutinol, galactitol, pentaerythritol, or mannitol; or polyol plasticizers, such as diglycerides, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; 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 having aliphatic hydroxyl groups, ester plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, monoblock polymers, citrate ester plasticizers, and triacetin. Such plasticizers may include 1,2-butanediol, 2,3-butanediol, styrene diol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, tributyl acetylacetonate, triethyl citrate, glyceryl monostearate, polysorbate 80, triethyl acetylacetonate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0248] In some embodiments, suitable pharmaceutically acceptable excipients may include plasticizers, such as, but not limited to, phosphate esters; phthalates; amides; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils, and hydrogenated vegetable oils, including acetylated hydrogenated cottonseed glycerol and acetylated hydrogenated soybean oil glycerol; acetylated tributyl citrate, acetylated triethyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylate glycerol, cocoyl glycerol, monoacetylated and diacetylated monoglycerides, nitrobenzene, carbon disulfide, fl-naphthyl salicylate, phthaloyl glycolate, dioctyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; α-tocopherol polyethylene glycol succinate, phosphate esters; phthalates; amides; mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols including cetearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, and myristica fragrans. Alcohols; Methyl rosinate, Tributyl acetyl citrate, Triethyl acetyl citrate, Diisooctyl adipate, Amyl oleate, Butyl castor oil, Benzoate, Butyl and ethylene glycol esters of fatty acids, Butyl diethylene glycol carbonate, Butyl oleate, Butyl stearate, Di(β-methoxyethyl) adipate, Dibutyl sebacate, Dibutyl tartrate, Diisobutyl adipate, Dihexyl adipate, Di(β-ethylbutyrate), Polyethylene glycol Di(2-ethylhexanoate), diethylene glycol monolaurate, monomeric polyethylene ester, rosin hydrogenated methyl ester, methoxyethyl oleate, butoxyethyl stearate, butyl phthaloyl butyl glycolate, glyceryl tributate, triethylene glycol dinonanoate, β-(p-tert-amylphenoxy)ethanol, β-(p-tert-butylphenoxy)ethanol, β-(p-tert-butylphenoxyethyl)acetate, bis(β-p-tert-butylphenoxydiethyl) ether, camphor, Cumar W-1, Cumar MH-1, Cumar V-1, dipentyl phthalate, (dipentylphenoxy)ethanol, diphenyl ether, technical hydroabietyl alcohol, beckolin, hexachlorobenzene, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, glycerol α-methyl α-phenyl ether, naphthalene chloride, HB-40, monopentyl phthalate, Nevillac 10, o-nitrobisphenyl and Paracril 26.

[0249] In some embodiments, suitable pharmaceutically acceptable excipients may include plasticizers, such as, but not limited to, sugar alcohol plasticizers, such as isomaltitol, maltitol, sorbitol, xylitol, erythritol, arbutinol, galactitol, pentaerythritol, or mannitol; or polyol plasticizers, such as glycerol, diglycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; 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 having aliphatic hydroxyl groups, ester plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, monoblock polymers, citrate plasticizers, and triacetin. Such plasticizers may include 1,2-butanediol, 2,3-butanediol, styrene diol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, tributyl acetylacetonate, triethyl citrate, glyceryl monostearate, polysorbate 80, triethyl acetylacetonate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0250] In some embodiments, suitable pharmaceutically acceptable excipients may include fragrances, such as, but not limited to, natural and / or synthetic aromatic raw materials. For example, oil-soluble fragrance oils, which may or may not be mixed with water-soluble fragrance oils. Oil-soluble fragrance materials are natural or naturally equivalent essential oils, such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaf oil, peppermint oil, cedarwood oil, rosemary oil, bergamot oil, mixed lavender oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, geranium oil, menthol, and marjoram oil. Animal fragrances are, for example, musk, castoreum, aber, or zibet. Spagyric essences are also known in the art. They are prepared by fermenting certain herbs and then processing them into a final product. Synthetic aromatic components are, for example, synthetic essential oils, composed of single compounds such as linalool, terpineol, nerol, citronellol, benzaldehyde, cinnamaldehyde, vanillin, ethyl vanillin, or methyl acetophenone. Aromatic materials can also be synthetic oil-soluble fragrance oils, typically selected from the group consisting of: aromatic hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, and polyene derivatives. Other fragrances that can be used are listed and described in references and databases such as S. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; 2000 reprint); Allured's Flavor and Fragrance Materials (2005); and the database maintained by the Fragrance Institute. www.rifm.org .

[0251] In some embodiments, suitable pharmaceutically acceptable excipients may include fragrance oils. Suitable fragrance oils include mixtures of natural and synthetic aromatics. Natural aromatics are extracts derived from flowers (lily, lavender, rose, jasmine, orange blossom, ylang-ylang), stems and leaves (geranium, patchouli, bitter orange leaf), fruits (fennel, coriander, cumin, juniper), peels (bergamot, lemon, orange), roots (nutmeg, angelica, celery, cardamom, costus root, iris, calamus), woods (pine, sandalwood, guaiac, cedar, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), conifers and branches (spruce, fir, pine, dwarf pine), resins and balsams (white pine, elm, benzoin, myrrh, frankincense, opoponax). Typical synthetic aromatic compounds are products of the ester, ether, aldehyde, ketone, alcohol, and hydrocarbon types. Ester aromatic compounds include, for example, benzoyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzyl acetate, ethyl acetate, linalyl benzoate, benzoate, glycine ethyl methylphenyl ester, allyl cyclohexylpropionate, styrallyl propionate, and benzoyl salicylate. Ethers include, for example, benzyl ethyl ether; aldehydes include, for example, straight-chain alkanes having 8 to 18 carbon atoms, citral, citronellol, citronelloloxyacetaldehyde, cyclamenaldehyde, hydroxycitronellol, lily of the valley aldehyde, and bourgeonal; ketones include, for example, ionone, α-isomethylionone, and methyl cedrol; alcohols include, for example, anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenethyl alcohol, and terpineol; and hydrocarbons mainly include terpenes and balsams.

[0252] In some embodiments, suitable pharmaceutically acceptable excipients may include essential oils with low volatility that are primarily used as aromatic components and are also suitable as fragrance oils, such as sage oil, chamomile oil, clove oil, lemon balm oil, peppermint oil, cinnamon leaf oil, linden flower oil, juniper berry oil, vetiver oil, frankincense oil, white pine resin oil, labdanum oil, and mixed lavender oil. Other suitable oils include bergamot oil, dihydromyrcenol, lily aldehyde, lyral, citronellol, phenethyl alcohol, α-hexylcinnamaldehyde, geraniol, benzoacetone, cyclamen aldehyde, linalool, boisambrene forte, ambroxan, indole, hedione, sandelice, lemon oil, citrus oil, orange oil, allyl pentyl glycolate, cyclovertal, lavender oil, clary sage oil, β-dihydrodamascone, bourbon geranium oil, cyclohexyl salicylate, vertofix coeur, iso-E-super, fixolide NP, evernyl, and methyl α-ionone (γ-iraldein). gamma), phenylacetic acid, geraniol acetate, benzyl acetate, rose ether, romilat, irotyl, and floralamet.

[0253] In some embodiments, suitable pharmaceutically 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 degradation of flavor, odor, color, texture, appearance, therapeutic value, or safety. Preservatives do not necessarily provide a lethal, irreversible effect that causes partial or complete destruction or incapacitation of microbial cells. Sterilizers, bactericides, disinfectants, sporicides, viricides, and tuberculicides provide this irreversible mode of action, sometimes referred to as "bactericidal" action. In contrast, preservatives can provide reversible inhibition or bacteriostatic action, meaning that if the preservative is removed, the target microorganism can resume reproduction. The main differences between preservatives and bactericides primarily involve the mode of action (preservatives prevent growth rather than kill microorganisms) and exposure time (preservatives act for days to months, while bactericides act for at most minutes). Suitable preservatives include, but are not limited to, phenoxyethanol, paraben solutions, pentylene glycol and sorbic acid, and silver complexes.

[0254] In some embodiments, suitable pharmaceutically acceptable excipients may include colorants, such as, but not limited to, the following colors: white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown.

[0255] In some embodiments, suitable pharmaceutically acceptable excipients may include, but are not limited to, “flavor extracts” obtained by extracting a portion of a raw material (e.g., animal or plant material), typically using solvents such as ethanol or water; and natural flavorings obtained by extracting essential oils from flowers, fruits, roots, etc., or from the whole plant. Other exemplary flavoring agents used in the compositions described herein may include, but are not limited to, menthol, spearmint and cinnamon, coffee beans, other flavorings or aromas such as fruit flavorings (e.g., cherry, orange, grape, etc.), and quaternary ammonium bases. The flavor effect may be enhanced using flavor enhancers such as tartaric acid, citric acid, and vanillin.

[0256] In some embodiments, suitable pharmaceutically acceptable excipients may include sweeteners, such as, but not limited to, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame and its various salts, such as potassium salts (available as Sunett®); alitame; aspartame (available as NutraSweet® and Equal®); aspartame-acesulfame salts (available as Twinsweet®); neohesperidin dihydrochalcone; naringin dihydrochalcone; dihydrochalcone compounds; neotame; cyclamate; saccharin and its various salts, such as sodium salts (available as Sweet'N Low®); stevia; chlorinated 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 glycyrrhizate (sold under the trade name MagnaSweet®); stevia (stevioside), natural high-potency sweeteners (such as monk fruit), and polyols (such as sorbitol, mannitol, xylitol, erythritol, etc.).

[0257] In some embodiments, suitable pharmaceutically acceptable excipients may include alkalizing agents, such as, but not limited to, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, and / or disodium phosphate.

[0258] In some embodiments, suitable pharmaceutically acceptable excipients may include lubricants / release agents, 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 may include, but are not limited to, glyceryl behenate (Compritol™ 888), metal stearates (e.g., magnesium stearate, calcium stearate, 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 glycol (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearoyl fumarate (Pruv™), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin wax, microcrystalline cellulose, glycerin, propylene glycol, and combinations thereof.

[0259] In some embodiments, suitable pharmaceutically acceptable excipients may include diluents, such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, direct compressible starch, mannitol USP, sorbitol, glucose monohydrate, microcrystalline cellulose NF, calcium hydrogen phosphate dihydrate NF, sucrose-based diluents, powdered sugar, calcium dihydrogen sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules NF, glucose binders NF (e.g., Emdex™), glucose (e.g., Cerelose™), inositol, hydrolyzed cereal solids such as Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, etc.

[0260] In some embodiments, suitable pharmaceutically acceptable excipients may include oils and fats, such as, but not limited to, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, flaxseed 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 filler of the PVA shell may include, but are not limited to, fish oil (ω-3), krill oil, animal or vegetable fats (e.g., in their hydrogenated form), monoglycerides, diglycerides and triglycerides having C12-, C14-, C16-, C18-, C20- and C22- fatty acids.

[0261] In some embodiments, suitable pharmaceutically acceptable excipients may include plant proteins such as sunflower protein, soybean protein, cottonseed protein, peanut protein, grape seed protein, whey protein, whey protein isolate, hemoglobin, ovalbumin, and acrylated protein; water-soluble polysaccharides such as alginate, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic and related gums (guar gum, ebony gum, astragalus gum); pectin; and water-soluble derivatives of cellulose such as alkylcellulose, hydroxyalkylcellulose, and hydroxyalkylalkylcellulose, including methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters, and hydroxyalkylcellulose esters such as cellulose acetate (CAP) and hydroxypropylmethylcellulose (HPMC). Carboxyalkyl cellulose, carboxyalkyl cellulose, carboxyalkyl cellulose esters such as carboxymethyl cellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acid, polyacrylamide and polyacrylates, polymethacrylic acid, polymethacrylamide and polymethacrylates, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymers and polybutenoic acid; also suitable are phthalate-esterified gelatin, gelatin succinate, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, cationic modified acrylates and methacrylates having, for example, tertiary amino or quaternary amino groups, such as diethylaminoethyl, which may be quaternized where necessary; and other similar polymers; inorganic fillers such as oxides of magnesium, aluminum, silicon, titanium, etc.

[0262] In some embodiments, suitable pharmaceutically acceptable excipients may include hydrophobic materials, including but not limited to digestible long-chain (C8-C5) excipients. 50 Especially C 12 -C 40 Substituted or unsubstituted hydrocarbons, such as natural or synthetic waxes (e.g., beeswax, sugar wax, castor wax, and carnauba wax), fatty alcohols (e.g., lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol, or preferably cetearyl alcohol), fatty acids, including but not limited to mono- and diglycerides, medium-chain triglycerides, fatty acid esters, fatty acid glycerides (monoglycerides, diglycerides, and triglycerides) of medium-chain fatty acids (e.g., caprylic acid, capric acid, hexanoic acid, lauric acid, oleic acid, and linoleic acid), hydrogenated fatty acids, hydrocarbons, common waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials with a hydrocarbon backbone.

[0263] In some embodiments, suitable pharmaceutically acceptable excipients may include polyvinyl alcohol, polyvinylpyrrolidone, polyepoxide, polyacrylic acid, cellulose, cellulose ether, cellulose ester, cellulose amide, polyvinyl acetate, polycarboxylic acids and salts, acetic acid, octanoic acid, oleic acid, polyamino acids or peptides, polyamide, polyacrylamide, maleic acid / acrylic acid copolymers, polysaccharides including starch and gelatin, and natural gums such as xanthan gum and carrageenan. For example, the polymer may be selected from polyacrylate and water-soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, maltodextrin, polymethyl methacrylate and combinations thereof, or from polyvinyl alcohol, polyvinyl alcohol copolymer and hydroxypropylmethylcellulose (HPMC), methacrylate / methyl methacrylate, methacrylate / ethyl acrylate copolymer, methacrylate / methyl acrylate / methyl methacrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, capryloyl hexanoyl polyoxy-8 glycerol, distearate and combinations thereof.

[0264] In some embodiments, suitable pharmaceutically acceptable excipients may include high HLB surfactants, such as, but not limited to, polysorbate 80-polyoxyethylene (20) dehydrated sorbitol monooleate, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, capryloyl hexanoyl polyethylene glycol glyceride, and combinations thereof.

[0265] In some embodiments, suitable pharmaceutically acceptable excipients may include, but are not limited to, fillers such as lactose, microcrystalline cellulose, and combinations thereof.

[0266] In some embodiments, suitable pharmaceutically acceptable excipients may include natural gums (such as natural plant gums). Suitable natural gums include, but are not limited to, guar gum, carob gum, konjac gum, xanthan gum, sclerotium gum, gum arabic, cellulose gum (modified or unmodified), or combinations thereof.

[0267] In some embodiments, suitable pharmaceutically acceptable excipients may include emulsifiers, such as, but not limited to, PEG-30 dihydroxystearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-40 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 amygdalinyl glyceride, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 olive oil ester, PEG-8 oleate, PEG-8 laurate, PEG-60 amygdalinyl glyceride, PEG-20 methylglucose sesquistearate, PEG-40 stearate, PEG-100 stearate, P EG-80 dehydrated sorbitol lauryl ester, stearyl alcohol polyether-2, stearyl alcohol polyether-12, oleyl alcohol polyether-2, cetyl alcohol polyether-2, lauryl alcohol polyether-4, oleyl alcohol polyether-10, oleyl alcohol polyether-10 / polyoxyethylene 10 oleyl ether, cetyl alcohol polyether-10, isostearyl alcohol polyether-20, cetyl stearyl alcohol polyether-20, oleyl alcohol polyether-20, stearyl alcohol polyether-20, stearyl alcohol polyether-21, cetyl alcohol polyether-20, isocetyl alcohol polyether-20, lauryl alcohol polyether-23, stearyl alcohol polyether-100, glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, stearate, polyglycerol-3-methylglucose distearate or combinations thereof.

[0268] Other suitable emulsifiers are phosphate esters and their salts, such as cetyl phosphate (Amphisol). ® A) Diethanolamine cetyl phosphate (Amphisol) ® DEA), Amphisol potassium cetyl phosphate ® K), sodium cetearyl sulfate, sodium glycerol oleate phosphate, hydrogenated vegetable glycerol phosphate, and mixtures thereof. Other suitable emulsifiers are sorbitol oleate, sorbitol sesquioleate, sorbitol isostearate, sorbitol trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate, and hydrated polyisobutylene. In addition, one or more synthetic polymers can be used as emulsifiers. For example, PVP eicosene copolymer, acrylate / acrylate C 10 -3o alkyl ester crosspolymers, acrylate / stearyl alcohol polyether-20 methacrylate copolymers, PEG-22 / dodecyl glycol copolymers, PEG-45 / dodecyl glycol copolymers and mixtures thereof.

[0269] In some embodiments, suitable pharmaceutically acceptable excipients may include chelating agents, such as, but not limited to, disodium ethylenediaminetetraacetate (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrotriacetic acid (NTA).

[0270] In some embodiments, suitable pharmaceutically acceptable excipients may include fatty alcohols, such as, but not limited to, guerbet alcohols based on fatty alcohols having 6 to 18, preferably 8 to 10 carbon atoms, including cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecyl alcohol, benzoates of C12-C15 alcohols, acetylated lanolin alcohol, etc.

[0271] In some embodiments, suitable pharmaceutically acceptable excipients may include esters of fatty acids, such as, but not limited to, straight-chain C6-C... 24 Fatty acids and straight-chain C3-C 24 Esters of alcohols, branched C6-C 13 Carboxylic acids and straight-chain C6-C 24 Fatty alcohol esters, straight-chain C6-C 24 Esters of fatty acids and branched alcohols (especially 2-ethylhexanol), hydroxycarboxylic acids and straight-chain or branched C6-C... 22Esters of fatty alcohols (especially dioctyl malate), straight-chain and / or branched-chain fatty acids with polyols (e.g., propylene glycol, glycol or trimerol) and / or esters of guerbert alcohols, such as hexanoic acid, octanoic acid, 2-ethylhexanoic acid, decanoic acid, lauric acid, isotriadecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, transoleic acid, phellandrene, linoleic acid, linolenic acid, tung oil, arachidic acid, codoleic acid, behenic acid, and erucic acid, and their industrial-grade mixtures with alcohols (e.g., in the pressure removal of natural fats and oils, in the oxygenation process from Roelen's...). Alcohols such as isopropanol, hexanol, octanol, 2-ethylhexanol, decanol, lauryl alcohol, isotriadecyl alcohol, myristol, cetyl alcohol, palmitol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, transoleyl alcohol, phellandrene alcohol, linoleyl alcohol, linolenic acid alcohol, tung oil alcohol, arachidonic acid alcohol, eicosenoyl alcohol, behenol, mustard alcohol, and docosenoyl alcohol, as well as their industrial-grade mixtures (e.g., obtained by high-pressure hydrogenation of industrial-grade methyl esters based on fats and oils or aldehydes from lorene oxidation, or as monomer fractions in the dimerization of unsaturated fatty alcohols). Other suitable examples of ester oils are 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-octyl dodecyl palmitate, oleyl oleate, and oleyl erucate. Examples of products containing cetearyl oleate, cetearyl erucic acid ester, cetearyl palmitate, cetearyl stearate, cetearyl oleate, cetearyl behenate, cetearyl acetate, myristate myristate, myristate behenate, myristate oleate, myristate stearate, myristate palmitate, myristate lactate, propylene glycol dicaprylate / caprylate, stearyl heptanoate, diisostearate malate, octyl hydroxystearate, etc.

[0272] In some embodiments, suitable pharmaceutically acceptable excipients may include other adjuvants, such as, but not limited to, diethylhexyl 2,6-naphthalenedicarboxylate, di-n-butyl adipate, di(2-ethylhexyl) adipate, di(2-ethylhexyl) succinate, and diisotridecyl adipate, as well as glycol esters, such as ethylene glycol dioleate, ethylene glycol diisotridecyl ester, propylene glycol di(2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dinonanoate, butylene glycol diisostearate, and neopentyl glycol dioctanoate. C6-C 24 Fatty alcohols and / or Guerbert alcohols with esters of saturated and / or unsaturated aromatic carboxylic acids, especially benzoic acid, C2-C 12 Esters of dicarboxylic acids with straight-chain or branched alcohols having 1 to 22 carbon atoms or polyols having 2 to 10 carbon atoms and 2 to 6 hydroxyl groups.

[0273] In some embodiments, suitable pharmaceutically acceptable excipients may include natural or synthetic triglycerides (including glycerides and derivatives), such as, but not limited to, C6-C based. 18 Diglycerides or triglycerides of fatty acids that are modified by reacting with other alcohols (e.g., caprylic / capric triglycerides, wheat germ glycerides). Fatty acid esters of polyglycerol (polyglycerol-n, such as polyglycerol-4-decanoate, polyglycerol-2-isostearate, etc., or castor oil, hydrogenated vegetable oil, 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 oil, olive oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borage oil, etc.) Additional suitable excipients include waxes, including esters of long-chain acids and alcohols, and compounds with waxy properties, such as carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ceresin wax, Japanese wax, paraffin wax, microcrystalline wax, pure ceresin wax, cetearyl ester wax, synthetic beeswax, etc. Additionally, hydrophilic waxes such as cetearyl alcohol or metaglycerol esters are also suitable.

[0274] In some embodiments, suitable pharmaceutically acceptable excipients may include pearlescent waxes, such as, but not limited to, alkylene glycol esters, especially ethylene glycol distearate; fatty acid alkanolamides, especially coconut fatty acid diethanolamides; glyceryl esters, especially glyceryl monostearate; esters of polyvalent, unsubstituted or hydroxylated carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, especially 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, especially lauryl ethers and distearate ethers; fatty acids, such as stearic acid, hydroxystearic acid or behenic acid; ring-opening products of olefin epoxides having 12 to 22 carbon atoms and fatty alcohols having 12 to 22 carbon atoms and / or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxyl groups, and mixtures thereof.

[0275] In some embodiments, suitable pharmaceutically acceptable excipients may include hydrocarbon oils, such as, but not limited to, mineral oils (light or heavy), petrolatum (yellow or white), microcrystalline waxes, alkanes and isoalkanes, hydrogenated isoalkanes such as polydecene and polybutene, hydrogenated polyisobutylene, squalane, isohexadecane, isododecane, and other substances from the plant and animal kingdoms.

[0276] In some embodiments, suitable pharmaceutically acceptable excipients may include silicones or siloxanes (organically substituted polysiloxanes), such as, but not limited to, dimethylpolysiloxane, methylphenylpolysiloxane, cyclic silicones, and amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside-, and / or alkyl-modified silicone compounds, which may be in liquid or resin form at room temperature. Linear polysiloxanes, polydimethylsiloxane (Dow Corning 200 fluid, RhodiaMirasil DM), polydimethylsiloxane alcohols, cyclic silicone fluids, cyclopentadiene siloxane volatiles (Dow Corning 345 fluid), and phenyltrimethylsiloxane (Dow Corning 556 fluid) are also suitable. Simethicone, a mixture of polydimethylsiloxane with an average chain length of 200 to 300 dimethylsiloxane units and a hydrogenated silicate, is also suitable. In addition, a detailed investigation of suitable volatile silicones by Todd et al. can be found in Cosm. Toil. 91, 27 (1976).

[0277] In some embodiments, suitable pharmaceutically acceptable excipients may include emulsifiers, such as, but not limited to, carboxylic acids and their salts: basic soaps of sodium, potassium, and ammonium; metallic soaps of calcium or magnesium; organic soaps, such as lauric acid, palmitic acid, stearic acid, and oleic acid; alkyl phosphates or phosphates, acid phosphates, diethanolamine phosphates, cetyl phosphates; ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acrylates; straight-chain fatty alcohols having 8 to 22 carbon atoms, branched by reacting 2 to 30 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide with a fatty acid having 12 to 22 carbon atoms and an alkylphenol having 8 to 15 carbon atoms in the alkyl chain; fatty alcohol polyethylene glycol ethers, such as lauryl ether-n, cetearyl ether-n, stearyl ether-n, oleyl ether-n; fatty acid polyethylene glycol ethers, such as PEG-n stearate, PEG-n oleate, PEG-n cocoate. Glyceryl monoesters and polyol esters. C12-C22 fatty acid monoesters and diesters of 1 to 30 moles of ethylene oxide added to polyols. Fatty acids and polyglycerol esters, such as glyceryl monostearate, diisostearoyl polyglycerol-3-diisostearate, polyglycerol-3-diisostearate, triglyceride diisostearate, polyglycerol-2-sesquiisostearate, or polyglycerol dimyristic acid ester. Mixtures of multiple compounds in these categories are also suitable. Fatty acid polyethylene glycol esters, such as diethylene glycol monostearate, fatty acids and polyethylene glycol esters, fatty acids and sucrose esters such as sucrose esters, glycerol and sucrose esters such as sucrose glyceride. Sorbitol and dehydrated sorbitol, dehydrated sorbitol monoesters and diesters of saturated and unsaturated fatty acids having 6 to 22 carbon atoms, and ethylene oxide addition products. Polysorbate-n series, including sorbitol esters such as sesquiisostearate, sorbitol, PEG-(6)-isostearate sorbitol ester, PEG-(10)-sorbitol laurate, and PEG-17-dioleoate sorbitol ester. Glucose derivatives, C8-C22 alkyl monosaccharides and oligosaccharides, and ethoxylated analogs, wherein glucose is preferred as the sugar component. O / W emulsifiers, such as methyl glucitol polyether-20 sesquistearate, sorbitol stearate / sucrose cocoate, methyl glucose sesquistearate, and cetearyl alcohol / cetearyl glucoside. W / O emulsifiers, such as methyl glucose dioleate / methyl glucose isostearate. Sulfates and sulfonated derivatives, dialkyl sulfosuccinates, dioctyl succinate, alkyl lauryl sulfonates, linear sulfonated paraffins, sulfonated tetrapropylene sulfonate, sodium lauryl sulfate, ammonium lauryl sulfate and ethanolamine, lauryl ether sulfate, sodium lauryl ether sulfate, sulfosuccinates, acetyl isothiosulfonates, alkanolamide sulfates, taurine, methyl taurine, imidazole sulfates.Polysiloxane / polyalkyl / polyether copolymers and derivatives, polydimethylsiloxane, copolyols, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ethers (Meroxapol), poloxamer, or poly(ethylene oxide) m-block-poly(propylene oxide) n-block (ethylene oxide). Amphoteric surfactants having at least one quaternary ammonium group and at least one carboxyl and / or sulfonate group in their molecule. Particularly suitable zwitterionic surfactants are betaines, such as N-alkyl-N,N-dimethylglycinate ammonium, cocoalkyldimethylglycinate ammonium, N-acylaminopropyl-N,N-dimethylglycinate ammonium, cocoylaminopropyldimethylglycinate ammonium, and 2-alkyl-3-carboxymethyl-3-hydroxyethylimidazoline, each having 8 to 18 carbon atoms in the alkyl or acyl group, as well as cocoylaminoethylhydroxyethylcarboxymethylglycinate, N-alkyl betaine, N-alkylamino betaine, alkylimidazoline, alkyl peptides, lipoamino acids, self-emulsifying bases, and compounds described in KF DePolo, A short textbook of cosmetology, Chapter 8, Tables 8-7, pp. 250-251.

[0278] Suitable nonionic bases include, but are not limited to, PEG-6 beeswax (and) PEG-6 stearate (and) polyglycerol-2-isostearate, glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglycerol-3 castor oil ester, sorbitan stearate and sucrose cocoate, glyceryl stearate and lauryl ether-23, cetearyl alcohol and cetearyl ether-20, cetearyl alcohol and polysorbate 60 and PEG-150 and stearate-20, cetearyl alcohol and cetearyl polyglucoside, cetearyl alcohol and cetearyl alcohol ether-20, cetearyl alcohol and PEG-40 castor oil, cetearyl alcohol And PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and stearyl alcohol polyether-7 and stearyl alcohol polyether-10, cetearyl alcohol and stearyl alcohol polyether-7 and stearyl alcohol polyether-10, glyceryl stearate and PEG-75 stearate, propylene glycol cetyl alcohol polyether-3 acetate, propylene glycol isocetyl alcohol polyether-3 acetate, cetearyl alcohol and cetyl alcohol polyether-12 and oleyl alcohol polyether-12, PEG-6 stearate and PEG-32 stearate, PEG-6 stearate and cetyl alcohol polyether-20 and stearyl alcohol polyether-20, PEG-6 stearate and cetyl alcohol polyether-20 and glyceryl stearate and stearyl alcohol polyether-20, glyceryl stearate and cetyl stearyl alcohol polyether-20.

[0279] Suitable anionic basic bases include, but are not limited to, PEG-2 stearate SE, glyceryl stearate SE, and propylene glycol stearate. Anionic acids and bases include, for example, cetearyl alcohol and sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, trilanol polyether-4 phosphate and ethylene glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulfate. Cationic acids and bases include, for example, cetearyl alcohol and cetrimonium bromide.

[0280] In some embodiments, suitable pharmaceutically acceptable excipients may include adjuvants and additives, such as, but not limited to, surfactants, hyperesterifiers, consistency modifiers, thickeners, polymers, stabilizers, bioactive ingredients, swelling agents, other UV photoprotective factors, antioxidants, solubilizers, preservatives, sun-inducing agents, solubilizers, aromatic oils, colorants, antibacterial agents, etc.

[0281] In some embodiments, suitable pharmaceutically acceptable excipients may include hyperlipidifiers, 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 also serve as foam stabilizers.

[0282] In some embodiments, suitable pharmaceutically acceptable excipients may include surfactants, such as, but not limited to, fatty alcohol polyethylene glycol ether sulfates, glyceryl monoester sulfates, mono- and / or dialkyl sulfosuccinates, fatty acid hydroxyethyl sulfonates, fatty acid sarcosine salts, fatty acid taurine salts, fatty acid glutamate salts, α-olefin sulfonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucosamides, alkyl amide betaines, and / or protein fatty acid condensation products, the latter preferably being wheat protein-based.

[0283] In some embodiments, suitable pharmaceutically acceptable excipients may include consistency regulators / thickeners and rheology modifiers, such as, but not limited to, silica, magnesium silicate, aluminum silicate, polysaccharides or derivatives thereof, such as hyaluronic acid, xanthan gum, guar gum, agar, alginate, carrageenan, gellan gum, pectin, or modified cellulose, such as hydroxycellulose or hydroxypropyl methylcellulose. In addition, homopolymers of polyacrylates or reticulated acrylic acid and polyacrylamide, carbomer (CARBOPOL models 980, 981, 1382, ETD 2001, ETD2020, ULTREZ 10) or the SALCARE series, such as SALCARE SC80 (stearyl ether-10 allyl ether / acrylate copolymer), Salcare SC81 (acrylate copolymer), Salcare SC91 and Salcare AST (sodium acrylate copolymer / PPG-1 tridecyl alcohol polyether-6), SEPIGEL 305 (polyacrylamide / lauryl ether-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate / sodium acryloyl dimethyl taurate copolymer), STABILEN 30 (acrylate / vinyl isodecanoate crosspolymer), PEMULEN TR-1 (acrylate / C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (sodium acrylate copolymer), ACULYN 28 (acrylate / behenol polyether-25 methacrylate copolymer), etc.

[0284] In some embodiments, suitable pharmaceutically acceptable excipients may include polymers, such as, but not limited to, anionic, amphoteric, amphoteric, and nonionic polymers, such as vinyl acetate / butenoic acid copolymers, vinylpyrrolidone / vinyl acrylate copolymers, vinyl acetate / butyl maleate / isoborneol acrylate copolymers, methyl vinyl ether / maleic anhydride copolymers and their esters, uncrosslinked polyacrylic acid and polyacrylic acid crosslinked with polyols, acrylamide propyltrimethylammonium chloride / acrylate copolymers, octylacrylamide / methyl methacrylate-tert-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, vinylpyrrolidone / dimethylaminoethyl methacrylate / vinylcaprolactam terpolymers, and optionally derived cellulose ethers and silicones. Additionally, polymers described in EP 1093796 (pages 3-8, paragraphs 17-68) may also be used.

[0285] In some embodiments, suitable pharmaceutically acceptable excipients may include antioxidants, such as, but not limited to, amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives; imidazoles (e.g., uric acid) and their derivatives; peptides, such as D,L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g., anserine); carotenoids, carotene, lycopene and their 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 their glycosyl, N-acetyl, methyl, ethyl, propyl, pentyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cholesterol, and glyceryl esters) and their salts; dilauryl thiodipropionate, distearate thiodipropionate, thiodipropionate and their derivatives (esters, ethers, peptides, lipids, nucleotides, etc.). Nucleosides and salts); and sulfoxide compounds (e.g., sulfoxide of butylthionine, homocysteine, sulfone of butylthionine, pentyl, hexa-, and hepta-thionine sulfoxides), as well as (metal) chelating agents (e.g., hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin); hydroxy acids (e.g., citric acid, lactic acid, malic acid); humic acids; bile acids, bile extracts, bilirubin, biliverdin; EDTA, EDDS, EGTA and their derivatives; unsaturated fatty acids and their derivatives (e.g., linolenic acid, linoleic acid, oleic acid); folic acid and its derivatives; ubiquinone and panthenol and their derivatives; vitamin C and its derivatives (e.g., ascorbate palmitate, magnesium ascorbate phosphate, ascorbate acetate); tocopherol and its derivatives (e.g., vitamin E acetate); vitamin A and its derivatives (e.g., vitamin A palmitate); and benzoic acid coniferate, rutinic acid, etc. of benzoin resin. The following are considered active ingredients according to the invention: rutin, ferulic acid, furfuryl glucosyl alcohol, carnosine, butylated hydroxytoluene, butylated hydroxyanisole, nordihydroguaiac acid, trihydroxyphenylbutanone, uric acid and its derivatives; mannose and its derivatives; superoxide dismutase, N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl]p-aminobenzenesulfonic acid (and its salts, such as disodium salts); selenium and its derivatives (e.g., selenomethionine selenium); stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide) and suitable derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids) of those mentioned active ingredients. HALS (=“hindered amine light stabilizers”) compounds may also be mentioned.

[0286] In some embodiments, suitable pharmaceutically acceptable excipients may include cosolvents, such as, but not limited to, ethoxylated or nonethoxylated monohydric alcohols, glycols, or polyhydric alcohols or their ethers having a low number of carbon atoms (e.g., ethanol, isopropanol, 1,2-dipropylene glycol, propylene glycol, glycerol, 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). Polyhydric alcohols contemplated for this purpose preferably have 2 to 15 carbon atoms and at least two hydroxyl groups. Polyhydric alcohols may also contain additional functional groups, especially amino groups, and / or may be modified with nitrogen. Typical examples include: glycerol, alkyl glycols such as ethylene glycol, diethylene glycol, propylene glycol, butanediol, hexanediol, and polyethylene glycol with an average molecular weight of 100 to 1000 Daltons; industrial-grade oligoglycerol mixtures with an inherent degree of condensation of 1.5 to 10, such as industrial-grade diglycerol mixtures with a diglycerol content of 40 to 50% by weight; hydroxymethyl compounds, especially, for example, trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol, and dipentaerythritol; low-carbon alkyl glucosides, especially those with 1 to 8 carbon atoms in the alkyl group, such as methyl and butyl glucosides; sugar alcohols with 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars with 5 to 12 carbon atoms, such as glucose or sucrose; amino sugars, such as glucosamine; and diethanolamines, such as diethanolamine or 2-amino-1,3-propanediol.

[0287] In some embodiments, suitable pharmaceutically acceptable excipients may include preservatives, such as, but not limited to, methylparaben, ethylparaben, propylparaben, butylparaben, benzalkonium chloride, 2-bromo-2-nitro-propane-1,3-diol, dehydroacetic acid, diazolidinyl urea, 2-dichlorobenzyl alcohol, DMDM ​​hydantoin, formaldehyde solution, methyldibromoglutaronitrile, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan, and other categories of substances listed in the following reference: KF DePolo - A short textbook of cosmetology, Chapter 7, Tables 7-2, 7-3, 7-4 and 7-5, pp. 210-219.

[0288] In some embodiments, suitable pharmaceutically 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-biguanidinyl)hexane), or TCC (3,4,4'-trichlorosymmetrical diphenylurea). A large number of aromatic substances and ether oils also possess antimicrobial properties. Typical examples are the active ingredients eugenol, menthol, and thymol in clove oil, peppermint oil, and thyme oil. A natural deodorant of interest is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecanetrien-1-ol), which is found in lime blossom oil. Glyceryl monolaurate has also been shown to be an antibacterial agent.

[0289] As will be recognized by those skilled in the art, other pharmaceutically acceptable excipients may also be used.

[0290] In some embodiments, pharmaceutically acceptable excipients may be included (alone or cumulatively) in the pharmaceutical compositions described herein, in concentration ranges of any one of about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% to about 55 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, or about 99 wt%, or any subrange or single value thereof, based on the total weight of the compositions.

[0291] Preparation method

[0292] In some embodiments, this disclosure relates to methods for preparing any of the compositions described herein. In some embodiments, the method includes combining a therapeutically effective amount of the disclosed compound with one or more pharmaceutically acceptable excipients.

[0293] The various compositions described herein can be formulated to have customized active agent release characteristics, such as, but not limited to, immediate release characteristics, controlled release characteristics, delayed release characteristics, intestinal release characteristics, zero-order release characteristics, first-order release characteristics, pulsatile release characteristics, targeted release at specific sites in vivo (e.g., target sites in the gastrointestinal tract).

[0294] Example

[0295] Three SD rats (approximately 300 gm) received intravenous boluses of a challenge dose (3 mg / kg xylazine and 20 μg / kg fentanyl) and a rescue dose (3 mg / kg). PCO2, PO2, and blood pH were measured at 5, 10, and 15 minutes after the rescue dose, and data showed that... Figure 1-3 The data shows arterial and venous blood levels.

[0296] The sham treatment group did not receive a rescue dose. Upon further observation, the rats never fully recovered. This indicates that even after xylazine / fentanyl was cleared from the system, the period of decreased blood pH still had an adverse effect on the subjects. Therefore, this invention, in addition to rescuing patients from overdose, also has long-term positive effects on patients.

[0297] For the sake of simplicity, embodiments of the methods of this disclosure are depicted and described as a series of actions. However, the actions according to this disclosure may occur in various orders and / or simultaneously, and may include other actions not presented and described herein. Furthermore, not all of the described actions may be necessary to implement the methods according to the disclosed subject matter. Additionally, those skilled in the art will understand and recognize that the methods may alternatively be represented by a state diagram or events as a series of interrelated states.

[0298] In the foregoing description, numerous specific details, such as specific materials, dimensions, and process parameters, have been set forth to provide a thorough understanding of the invention. In one or more embodiments, particular features, structures, materials, or properties may be combined in any suitable manner. The terms “example” or “exemplary” are used herein to mean serving as an example, illustration, or description. Any aspect or design described herein as “example” or “exemplary” should not necessarily be construed as preferred or advantageous over other aspects or designs. In fact, the use of the terms “example” or “exemplary” is intended to present concepts 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 any inclusive arrangement of natural inclusion. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied in any of the foregoing cases. References throughout the specification to “embodiment,” “some embodiments,” or “one embodiment” mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Therefore, the phrases “example,” “some examples,” or “one example” appearing throughout the specification do not necessarily refer to the same example.

[0299] The invention has been described with reference to specific exemplary embodiments thereof. Therefore, the specification and drawings should be considered illustrative rather than restrictive. Various modifications to the methods shown and described herein will be apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

1. A method for treating drug overdose, comprising administering a therapeutically effective amount of a respiratory stimulant to a patient in need, wherein the overdose drug comprises an α2-adrenergic receptor agonist.

2. The method according to claim 1, wherein the drug overdose is accompanied by respiratory depression, sedation, hypotension, adverse central nervous system effects, adverse cardiac effects, or a combination thereof.

3. The method according to claim 2, wherein the drug overdose is accompanied by respiratory depression.

4. The method according to any one of claims 1 to 3, wherein the α2-adrenergic receptor agonist comprises 4-NEMD, 7-me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, fadolmidine, guanabenz, guanfac The following are pharmaceutically acceptable salts and combinations thereof: ine, lofexidine, marsanidine, medetomidine, methyldopa, mivazerol, rilmenidine, romifidine, talipexole, tiamenidine, tizanidine, tolonidine, xylazine, xylometazoline, and their combinations.

5. The method of claim 4, wherein the α2-adrenergic receptor agonist comprises xylazine or a pharmaceutically acceptable salt thereof.

6. The method according to any one of claims 1 to 4, wherein the overdose of the drug comprises an opioid agonist.

7. The method of claim 6, wherein the opioid agonist comprises oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, sufentanyl, morphine, tramadol, buprenorphine, κ opioid receptor agonists (e.g., butorphanol, nalbuphine, levorphanol, levallorphan, pentazocine, phenazocine, eptazocine), pharmaceutically acceptable salts thereof, and combinations thereof.

8. The method of claim 7, wherein the opioid is fentanyl or a pharmaceutically acceptable salt thereof.

9. The method of claim 1, wherein the respiratory stimulant comprises a compound selected from formula (I). in: R 1 and R 2 Independently, it is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, ynyl, substituted ynyl, 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 Combined to form a diradical 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 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 It is H, alkyl, or a substituted alkyl; R 5 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 Combining to form a diradical selected from the group consisting of: 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 It can be H, alkyl, substituted alkyl or alkenyl; X represents a bond, O, or NR. 4 ; as well as Y represents N and CR 6 Or C; where: If Y is N or CR 6 Then key b 1 It does not exist, and: (i) Z is H, key b 2 It is a single bond, and A is CH; or, (ii) Z does not exist, and bond b 2 It does not exist, and A is a single bond; and If Y is C, then key b 1 It is a single bond, and: (i) Z is CH2, bond b 2 It is a single bond, and A is CH; or, (ii) Z is CH, and bond b 2 It is a double bond, and A is C; Or its pharmaceutically acceptable salt.

10. The method according to claim 1, wherein the compound is N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine or a pharmaceutically acceptable salt thereof.

11. The method according to any one of the preceding claims, wherein the administration does not contain an opioid antagonist.

12. The method according to any one of the preceding claims, wherein the administration further comprises an opioid antagonist.

13. The method of claim 12, wherein the antagonist and the stimulant are administered simultaneously or sequentially.

14. The method of claim 12, wherein the antagonist and the stimulant are administered via the same route of administration.

15. The method of claim 12, wherein the antagonist and the stimulant are administered via different routes of administration.

16. The method of claim 12, wherein the antagonist and the stimulant are administered in the same pharmaceutical composition.

17. The method of claim 12, wherein the antagonist and the stimulant are administered in different pharmaceutical compositions.

18. The method according to any one of claims 12 to 17, wherein the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, and pharmaceutically acceptable salts thereof.

19. The method of claim 1, wherein the respiratory stimulant is selected from the group consisting of doxapram, almitrine, caffeine, and pharmaceutically acceptable salts thereof.

20. The method of claim 1, wherein the stimulant is provided at a therapeutic dose sufficient to restore or improve the respiratory rhythm of an overdosed patient.

21. The method of claim 1, wherein the stimulant is administered at a therapeutic dose that will not induce hyperventilation or significant hyperventilation in patients with overdose.

22. The method of claim 12, wherein if administered in the absence of the stimulant, the antagonist is provided at a subtherapeutic or supertherapeutic dose.

23. The method of claim 12, wherein if administered in the absence of the stimulant, the antagonist is provided at a therapeutic dose.

24. The method of claim 12, wherein if administered in the absence of the antagonist, the stimulant is provided at a subtherapeutic or supertherapeutic dose.

25. The method of claim 12, wherein if administered in the absence of the antagonist, the stimulant is provided at a therapeutic dose.

26. The method according to any one of the preceding claims, wherein the overdose of the drug comprises benzodiazepine, barbiturate, gabapentinoid, or a combination thereof.

27. The method according to claim 1, wherein the route is selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, tracheal, ear, intraocular, or intrathecal routes.

28. The method of claim 15, wherein the route is independently selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, tracheal, ear, intraocular, or intrathecal routes.

29. The method according to any one of the preceding claims, wherein the administration causes a decrease in blood PCO2.

30. The method of claim 29, wherein the drop occurs 5 minutes or less, 10 minutes or less, or 15 minutes or less after application.

31. The method according to any one of the preceding claims, wherein the administration causes an increase in blood PO2.

32. The method of claim 31, wherein the rise occurs 5 minutes or less, 10 minutes or less, or 15 minutes or less after application.

33. The method according to any one of the preceding claims, wherein the application causes an increase in blood pH.

34. The method of claim 33, wherein the rise occurs 5 minutes or less, 10 minutes or less, or 15 minutes or less after application.

35. The method of claim 10, wherein the compound is administered in an amount of about 1 mg / kg to about 5 mg / kg, about 2 mg / kg to about 4 mg / kg, or about 3 mg / kg.

36. A method for treating low blood pH due to respiratory failure, comprising administering a therapeutically effective amount of a respiratory stimulant to a patient in need.

37. The method of claim 36, wherein the respiratory failure is caused by drug overdose.

38. The method of claim 37, wherein the overdose of the drug comprises an α2-adrenergic receptor agonist.

39. The method according to any one of claims 36 to 38, wherein the α2-adrenergic receptor agonist comprises 4-NEMD, 7-me-malzanidine, guanidine, aclomid, brimonidine, cannabinol, clonidine, dexmedetomidine, fadomidin, guanazin, guanofaxin, lofexidin, malzanidine, medetomidine, methyldopa, mirtazapine, limeridin, romifedipine, tarikexol, timenidine, tizanidine, tolonidine, xylazine, xylometazoline, pharmaceutically acceptable salts thereof, and combinations thereof.

40. The method of claim 39, wherein the α2-adrenergic receptor agonist comprises xylazine or a pharmaceutically acceptable salt thereof.

41. The method according to any one of claims 36 to 39, wherein the overdose of the drug comprises an opioid agonist.

42. The method of claim 41, wherein the opioid agonist comprises oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, sufentanil, morphine, tramadol, buprenorphine, pharmaceutically acceptable salts thereof, and combinations thereof.

43. The method of claim 42, wherein the opioid is fentanyl or a pharmaceutically acceptable salt thereof.

44. The method of claim 1, wherein the respiratory stimulant comprises a compound selected from formula (I). in: R1 and R2 are 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 R1 and R2 are combined to form a diradical 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; R3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR1R2, -C(O)OR1, acyl or aryl. R4 is H, an alkyl group, or a substituted alkyl group; R5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR1, -NR1R2, -C(O)OR1, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; or R3 and R5 are combined to form a diradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl. R6 is H, alkyl, substituted alkyl or alkenyl; X represents a bond, O, or NR4; and Y is N, CR6, or C; where: If Y is N or CR6, then bond b1 does not exist, and: (i) Z is H, bond b2 is a single bond, and A is CH; or, (ii) Z does not exist, bond b2 does not exist, and A is a single bond; and If Y is C, then bond b1 is a single bond, and: (i) Z is CH2, bond b2 is a single bond, and A is CH; or, (ii) Z is CH, bond b2 is a double bond, and A is C; Or its pharmaceutically acceptable salt.

45. The method according to claim 44, wherein the compound is N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine or a pharmaceutically acceptable salt thereof.

46. ​​The method according to any one of claims 36 to 45, wherein the application does not contain an opioid antagonist.

47. The method according to claims 36 to 45, wherein the administration further comprises an opioid antagonist.

48. The method of claim 47, wherein the antagonist and the stimulant are administered simultaneously or sequentially.

49. The method of claim 47, wherein the antagonist and the stimulant are administered via the same route of administration.

50. The method of claim 47, wherein the antagonist and the stimulant are administered via different routes of administration.

51. The method of claim 47, wherein the antagonist and the stimulant are administered in the same pharmaceutical composition.

52. The method of claim 47, wherein the antagonist and the stimulant are administered in different pharmaceutical compositions.

53. The method according to any one of claims 47 to 52, wherein the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, and pharmaceutically acceptable salts thereof.

54. The method of claim 36, wherein the respiratory stimulant is selected from the group consisting of: doxapram, amitriazine, caffeine, and pharmaceutically acceptable salts thereof.

55. The method of claim 36, wherein the stimulant is provided at a therapeutic dose sufficient to restore or improve the respiratory rhythm of an overdosed patient.

56. The method of claim 36, wherein the stimulant is administered at a therapeutic dose that does not induce hyperventilation or significant hyperventilation in the overdosed patient.

57. The method of claim 47, wherein if administered in the absence of the stimulant, the antagonist is provided at a subtherapeutic or supertherapeutic dose.

58. The method of claim 47, wherein if administered in the absence of the stimulant, the antagonist is provided at a therapeutic dose.

59. The method of claim 47, wherein if administered in the absence of the antagonist, the stimulant is provided at a subtherapeutic or supertherapeutic dose.

60. The method of claim 47, wherein if administered in the absence of the antagonist, the stimulant is provided at a therapeutic dose.

61. The method according to any one of claims 36 to 60, wherein the overdose of the drug comprises benzodiazepines, barbiturates, gabapentin, or combinations thereof.

62. The method of claim 36, wherein the route of administration is selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, tracheal, ear, intraocular, or intrathecal routes.

63. The method of claim 47, wherein the route of administration is independently selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, tracheal, ear, intraocular, or intrathecal routes.

64. The method of claim 36, wherein the method causes an increase in blood pH.

65. The method of claim 64, wherein the rise occurs 5 minutes or less, 10 minutes or less, or 15 minutes or less after application.

66. The method according to any one of claims 36 to 65, wherein the method produces a physiologically acceptable blood pH after administration.

67. The method of claim 66, wherein the physiologically acceptable blood pH is obtained 5 minutes or less, 10 minutes or less, or 15 minutes or less after administration.

68. A pharmaceutical composition comprising a therapeutically effective amount of a respiratory stimulant to treat drug overdose, wherein the overdose comprises an α2-adrenergic receptor agonist.

Images