Method and composition for treating drug overdose

Abstract

A method for treating a drug overdose is disclosed, comprising the step of administering a therapeutically effective amount of a respiratory stimulant to a patient requiring treatment for the drug overdose in a specific embodiment, wherein the overdose drug comprises an α2 adrenergic receptor agonist.

Description

Technology Field

[0001] In certain embodiments, the present disclosure relates to a method and a composition for treating drug overdose and / or abnormal blood pH. Background Technology

[0002] Xylazine is an α2 adrenergic receptor agonist and a non-opioid veterinary tranquilizer not approved for human use. This is associated with an increased number of overdose deaths in drug intoxication 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 increase euphoria. Xylazine is a central nervous system depressant that can cause drowsiness, amnesia, and a decrease in respiration, heart rate, and blood pressure. Taking opioids combined with xylazine and other central nervous system depressants increases the risk of life-threatening overdose.

[0004] Repeated use of xylazine is associated with skin ulcers, abscesses, and related complications, and the drug may be abused by injection, nasal inhalation, swallowing, or inhalation.

[0005] There is a need in the field for methods and compositions for treating drug overdose associated with α2 adrenergic receptor agonists.

[0006] In certain embodiments, the present disclosure relates to a treatment method and a compound for treating a drug overdose, comprising administering a therapeutically effective amount of a respiratory stimulant to a patient requiring treatment for the drug overdose, 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 a specific embodiment, the present disclosure relates to a method for treating a drug overdose comprising administering a therapeutically effective amount of a respiratory stimulant to a patient requiring treatment for the drug overdose, wherein the overdose drug comprises an α2 adrenergic receptor agonist, and the respiratory stimulant is an effective amount of a compound selected from formula (I) or a salt thereof:

[0008]

[0009] In the above formula,

[0010] R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; R 1 and R 2 ... combines to form an radical 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, and;

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

[0013] R 5 is H, alkyl, propargyl, substituted propargyl, homopropagyl, substituted homopropagyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, or R 3 and R 5 It combines to form an radical 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 is H, alkyl, substituted alkyl, or alkenyl;

[0015] X is bonded, O, or NR 4 And;

[0016] Y is N, CR 6 or C and;

[0017] Y is N or CR 6 If so, combination b 1 nil: (i) Z is H, and bond b 2 is a single bond, and A is CH or; (ii) Z is absent, and bond b 2 There is none, and A is a single bond;

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

[0019] In a specific embodiment, as described in relation to the above formula (I), R 1 , R 2 , R 3 and R 5 At least one substituent selected from the group consisting of is an alkynyl or a substituted alkynyl.

[0020] In certain embodiments, the compound of formula (I) is administered via a route selected from oral, intravenous, nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, tracheal, ear, ocular, or spinal canal.

[0021] In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a respiratory stimulant for treating a drug overdose; and a pharmaceutically acceptable excipient, wherein the overdose drug comprises an α2 adrenergic receptor agonist, and the respiratory stimulant is, for example, an effective amount of a compound selected from formula (I) or a salt thereof:

[0022]

[0023] In the above formula,

[0024] R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; R 1 and R 2 ... combines to form an radical 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;

[0025] 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, and;

[0026] R 4 is H, alkyl, or substituted alkyl;

[0027] R 5 is H, alkyl, propargyl, substituted propargyl, homopropagyl, substituted homopropagyl, 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 It combines to form an radical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0028] R 6 is H, alkyl, substituted alkyl, or alkenyl;

[0029] X is bonded, O, or NR 4 And;

[0030] Y is N, CR 6 or C and;

[0031] Y is N or CR 6 If so, combination b 1 There is no: (i) Z is H, and bond b 2 is a single bond, and A is CH or; (ii) Z is absent, and bond b 2 There is none, and A is a single bond;

[0032] If Y is C, then combination b 1 is a single bond and: (i) Z is CH2, and bond b 2 is a single bond, and A is CH or; (ii) Z is CH, and bond b 2 is a double bond, and A is C.

[0033] In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising an effective amount of a compound selected from the formula (I) described above, and R 1 , R 2 , R 3 and R 5At least one substituent selected from the group consisting of is an alkynyl or a substituted alkynyl.

[0034] In certain embodiments, the present disclosure relates to a method for preparing any pharmaceutical composition described herein. Brief explanation of the drawing

[0035] Figure 1 shows the PCO2 value after administration of the rescue dose of Example 1. Figure 2 shows the PO2 value after administration of the structural dose of Example 1. Figure 3 shows the blood pH value after administration of the structural dose of Example 1. Specific details for implementing the invention

[0036] definition

[0037] The singular forms used herein (“one,” “one,” and “two”) include plural indicators unless the context clearly indicates otherwise. Thus, for example, the reference to “active agent” includes not only a single active agent but also a mixture of two or more different active agents, and the reference to “excipient” includes not only a single excipient but also a mixture of two or more different excipients and others.

[0038] The term “about” as used herein in connection with the measured quantity refers to a normal variation in the measured quantity that a person skilled in the art would expect to perform the measurement while conducting a level of control corresponding to the purpose of the measurement and the precision of the measuring equipment. In certain embodiments, the term “about” includes ±10% of the mentioned number, and “about 10” will include 9 to 11.

[0039] As used herein, the terms “active agent,” “active ingredient,” and “effective pharmaceutical ingredient” refer to any material intended to produce a therapeutic effect, a prophylactic effect, or any other intended effect, regardless of whether it has been approved by a government agency for that purpose. These terms with respect to specific formulations include all pharmaceutical active agents, all pharmaceutically acceptable salts, complexes, stereoisomers, crystalline forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof, the form of which is pharmaceutically active.

[0040] 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. This includes enantiomers and isomers (diastereoisomers) of compounds having one or more chiral centers that are not mirror images of each other.

[0041] The terms "enantiomer" or "enantiomerism" refer to a molecule that is optically active and does not overlap with its mirror image, wherein the enantiomer rotates the plane of polarization in one direction by a certain degree, and its mirror image rotates the plane of polarization by the same degree but in the opposite direction.

[0042] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0043] The term "patient" refers to an entity, animal, or human that presents specific symptoms or clinical signs of symptoms suggesting the need for treatment, is being treated prophylactically or preventively for a pathological condition, or is diagnosed with a pathological condition requiring treatment. The term "entity" includes the definition of the term "patient" and does not exclude other healthy individuals.

[0044] "Pharmaceuticalally acceptable salts" or "salts" are inorganic acid salts, e.g., hydrochloride, hydrobromide, hydroiodine, sulfate, hydrogen sulfate, phosphate, nitrate, carbonate, sulfate, phosphoric acid (including hydrogen phosphate and dihydrogen phosphate), and others; organic acid salts, e.g., oxalate, malonate, citrate, fumarate, lactate, maleate, succinate, formate, acetate, trifluoroacetate, maleate, tartrate, gluconate, benzoate, salicylate, sinapoate, pamoate, ascorbate, adipate, cinnamate, and others; sulfonates, e.g., methanesulfonate, benzenesulfonate, p-toluenesulfonate, and others; amino acid salts, e.g., arginate, asparagine, glutamate, and others; metal salts, e.g., zinc salt, sodium salt, potassium salt, cesium salt, and others; Alkaline earth metals, e.g., calcium salts, magnesium salts and others; and organic amine salts, e.g., triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, discyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine and others, including but not limited to these. These salts may exist as hydrates, solvates, or crystalline polymorphs.In certain embodiments, a suitable organic acid may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfone series organic acids, examples thereof being 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, pyruvate, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, emvonic acid (famosan), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, It may be selected from β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid. All of these salts may be prepared by conventional means from the corresponding compound of the present invention, for example, by reacting the compound of the present invention with a suitable acid or base. Literature[. Handbook of Pharmaceutical Salts: Properties, and Use (PH Stahl & CG Wermuth eds., Verlag Helvetica Chimica Acta, 2002)] [1].

[0045] The terms "disease" or "diseases" or "pathological condition" or "pathological conditions" refer to medical conditions that can be treated or prevented by the administration of an effective amount of an active agent to the subject.

[0046] The terms “treatment” and “treating” include reducing the severity or discontinuation of a condition or reducing the severity or discontinuation of symptoms of a condition. In certain embodiments, the terms “treatment” or “treating” with respect to a condition mean an administration intended to provide a pharmacodynamic effect regardless of the outcome. In certain embodiments, “treatment” or “treating” means “positively affecting a condition” and includes a reduction, improvement, and / or alleviation of the severity of at least one symptom of the condition; a reduction, improvement, and / or remission of the severity of the condition; a delay, prevention, or inhibition of the progression of the condition; or a perceived improvement or benefit as a result of treatment. The treatment used herein does not require a complete cure of the condition. In certain embodiments, the compositions of this disclosure may provide an improvement in the patient’s quality of life, delay, prevent, or inhibit the onset of one or more symptoms of the condition, or provide a perceived benefit.

[0047] The terms "prevention" and "preventing" include the avoidance of the manifestation of a pathological condition.

[0048] The term "therapeutic effective dose" is intended to include, for example, an amount of an active agent or a combination of active agents to treat or prevent a pathological condition in a subject, or to treat the symptoms of a pathological condition.

[0049] The term “effective amount” is intended to include an amount of a component or a combination of components to achieve a desired result or characteristic, for example, an effective amount of a pH adjuster to achieve a pH of 6.0 is intended to include an amount of one or more pH adjusters to reach a pH of 6.0.

[0050] The terms “application,” “apply,” and “applying” relating to the disclosed topical composition or methods of using the disclosed topical composition refer to any manner of administering a topical composition to a patient’s skin in medical or cosmetic practice, delivering the composition to the surface of the patient’s skin. Smearing, rubbing, applying, or spraying the disclosed topical composition onto a patient’s skin, with or without the aid of a suitable device, are all included within the scope of the term “application” as used herein. With respect to the administration or application of the disclosed formulation, the terms “local” or “topically” refer to transdermal administration or application, or administration to the skin.

[0051] As used herein, “oral delivery” or “oral administration” refers to a route of administration in which the composition is ingested through the mouth. Oral administration is part of enteral administration and also includes buccal administration (dissolved inside the cheek), sublingual administration (dissolved under the lip), and sublingual administration (dissolved under the tongue). In certain embodiments, oral administration includes a route of administration in which the composition is ingested. In certain embodiments, oral administration includes a route of administration in which the composition is inhaled.

[0052] As used herein, "parenteral administration" refers to drug administration methods such as injection into a muscle (intramuscular administration), injection into a vein (intravenous administration), or injection under the skin (subcutaneous administration).

[0053] The phrase "pharmaceuticalally acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications within the scope of sufficient medical judgment and correspond to a reasonable benefit-to-risk ratio.

[0054] The term "alkyl" as used herein, either alone or as part of another substituent, means a straight-chain or branched-chain hydrocarbon having a specified number of carbon atoms, unless otherwise described (i.e., C1-C 10 (meaning 1 to 10 carbon atoms), includes straight-chain, branched-chain, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. (C1-C6)alkyl, e.g., ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl are most preferred as non-limiting examples.

[0055] The term “cycloalkyl” as used herein, either alone or as part of another substituent, means a cyclic chain hydrocarbon having a specified number of carbon atoms (i.e., C3-C6 means a cyclic group comprising a ring group consisting of 3 to 6 carbon atoms), and includes a straight chain, a branched chain, or a cyclic substituent. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. (C3-C6)cycloalkyls, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl as non-limiting examples, are most preferred.

[0056] The term “alkenyl” as used herein, whether used alone or in combination with other terms, means a stable monounsaturated or diunsaturated straight-chain or branched-chain hydrocarbon group having the stated number of carbon atoms, unless otherwise specified. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher-order homologues and isomers. The functional group representing the alkene is represented as -CH2-CH-CH2.

[0057] The term “alkynyl” as used herein, whether alone or in combination with other terms, means a stable straight-chain or branched-chain hydrocarbon group having a triple carbon-carbon bond having the number of carbon atoms stated, unless otherwise described. Examples include etynyl and propynyl and higher-order homologues and isomers.

[0058] The terms "substituted alkyl," "substituted cycloalkyl," "substituted alkenyl," or "substituted alkynyl" as used herein refer to halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(-O)OH, more preferably containing one or two substituents selected from halogen, alkoxy, and -OH, halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -N(CH3)2, (1-methyl-imidazole-2-yl), pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, -C(-O)OH, trifluoromethyl, -C≡N, -C(-O)O(C1-C4)alkyl, -C(-O)NH2, -C(-O)NH(C1-C4)alkyl, It means the alkyl, cycloalkyl, alkenyl, or alkynyl defined above that is substituted with one, two, or three substituents selected from the group consisting of -C(-O)N((C1-C4)alkyl)2, -SO2NH2, -C(-NH)NH2, and -NO2. Examples of substituted alkyls include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0059] The term “alkoxy” as used herein, used alone or in combination with other terms, means an alkyl group having the specified number of carbon atoms defined above that is connected to the rest of the molecule through an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher-order homologues and isomers, unless otherwise described. (C1-C3)alkoxy, e.g., ethoxy and methoxy are preferred as non-limiting examples.

[0060] The terms “halo” or “halogen” as used herein, either alone or as part of other substituents, mean a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, chlorine, or bromine atom, more preferably a fluorine or chlorine atom, unless otherwise stated.

[0061] The term “heteroalkyl” as used herein, either alone or in combination with other terms, means a stable straight-chain or branched-chain alkyl group consisting of one or two heteroatoms selected from the group consisting of the number of carbon atoms described and O, N, and S, wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be located at any position in the heteroalkyl group between the remainder of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in 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. For example, two or fewer heteroatoms, such as -CH2-NH-OCH3 or -CH2-CH2-SS-CH3, can be continuous.

[0062] The term “heteroalkenyl” as used herein, alone or in combination with other terms, means a stable straight-chain or branched-chain monounsaturated or diunsaturated hydrocarbon group consisting of one or two heteroatoms selected from the group consisting of the number of carbon atoms and O, N, and S, unless otherwise described, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Two or fewer heteroatoms may be located consecutively. Examples include -CH-CH-O-CH3, -CH-CH-CH2-OH, -CH2-CH-N-OCH3, -CH-CH-N(CH3)-CH3, and -CH2-CH-CH-CH2-SH.

[0063] The term “aromatic” as used herein refers to a carbocycle or heterocycle having one or more polyunsaturated rings and aromatic characteristics, that is, having (4n+2) delocalized π (pi) electrons (where n is an integer).

[0064] The term “aryl” as used herein, used alone or in combination with other terms, means a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), unless otherwise described, wherein these rings may be attached together in a pentant manner, as in biphenyl, or fused, as in naphthalene. Examples include phenyl, anthracyl, and naphthyl. Phenyl and naphthyl are preferred, and phenyl is most preferred.

[0065] As used herein, the term "aryl-(C1-C3)alkyl" refers to a functional group in which one to three carbon alkylene chains are attached to an aryl group, e.g., -CH2CH2-phenyl or -CH2-phenyl(benzyl). Aryl-CH2- and aryl-CH(CH3)- are preferred. The term "substituted aryl-(C1-C3)alkyl" refers to an aryl-(C1-C3)alkyl functional group in which an aryl group is substituted. Substituted aryl(CH2)- is preferred. Similarly, the term "heteroaryl-(C1-C3)alkyl" refers to a functional group in which one to three carbon alkylene chains are attached to a heteroaryl group, e.g., -CH2CH2-pyridyl. Heteroaryl-(CH2)- is preferred. The term "substituted heteroaryl-(C1-C3)alkyl" refers to a heteroaryl-(C1-C3)alkyl functional group substituted with a heteroaryl group. Substituted heteroaryl-(CH2)- is preferred.

[0066] The terms “heterocycle,” “heterocyclyl,” or “heterocyclic” as used herein, either alone or in combination with other terms, mean an unsubstituted or substituted, stable mono-cyclic or multi-cyclic heterocyclic ring system composed of a carbon atom and at least one heteroatom selected from the group consisting of N, O, and S, unless otherwise described, wherein the nitrogen heteroatom and the sulfur heteroatom may optionally be oxidized and the nitrogen atom may optionally be quaternized. Unless otherwise described, the heterocyclic system may be attached to any heteroatom or carbon atom that provides a stable structure. The heterocycle may be aromatic or non-aromatic in nature. In one embodiment, the heterocyclyl is a heteroaryl.

[0067] As used herein, the terms "heteroaryl" or "heteroaromatic" refer to heterocycles having aromatic properties. Polycyclic heteroaryls may comprise one or more partially saturated rings. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

[0068] Examples of non-aromatic heterocycles include monocyclic groups, such as aziridine, oxiran, thiran, azetidine, oxetane, thiethane, pyrrolidone, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethylene oxide.

[0069] The heteroaryl group includes pyridyl, pyrazinil, pyrimidinil (e.g., 2-pyrimidinil and 4-pyrimidinil as non-limiting examples), pyridazinil, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0070] Examples of polycyclic heterocycles include indolyl (e.g., as non-limiting examples, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolinyl, isoquinolinyl (e.g., as non-limiting examples, 1-isoquinolinyl and 5-isoquinolinyl), 1,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, quinoxalinyl (e.g., as non-limiting examples, 2-quinoxalinyl and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naftiridinyl, 1,4-benzodioxanil, coumarin, dihydrocoumarin, 1,5-naftiridinyl, and benzofuryl (e.g., as non-limiting examples Includes 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (e.g., as non-limiting examples, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl and 7-benzothienyl), benzoxazolyl, benzothiazolyl (e.g., as non-limiting examples, 2-benzothiazolyl and 5-benzothiazolyl), furinyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl and quinolizidinyl.

[0071] The aforementioned list of heterocyclil moiety and heteroaryl moiety is intended to be representative and not limiting.

[0072] The term "substituted" as used herein means that an atom or group of atoms has hydrogen replaced by a substituent attached to another group.

[0073] For aryl, aryl-(C1-C3)alkyl, and heterocyclyl groups, when applied to the ring of these groups, the term “substituted” refers to any level of substitution where such substitution is permitted, namely monosubstitution, double substitution, triple substitution, quadruple substitution, or pentubilization. Substituents are selected independently, and the substitutions may be at any chemically accessible position. In one embodiment, the number of substituents varies from one to four. In another embodiment, the number of substituents varies from one to three. In yet another embodiment, the number of substituents varies from one to two. In even further another embodiment, the substituent is C 1-6 Alkyl, -OH, C 1-6 It is independently selected from the group consisting of alkoxy, halo, amino, acetamido, and nitro. When the substituent used herein is an alkyl or alkoxy group, the carbon chain may be branched, linear, or cyclic, and linear is preferred.

[0074] References to ranges of values ​​in this specification are intended to serve merely as abbreviations for each distinct value individually falling within the range, unless otherwise indicated herein, and each distinct value is included in this specification as individually mentioned herein. All methods described herein may be performed in any suitable order unless otherwise indicated herein or if the context clearly contradicts it. Any and all examples provided herein, or the use of exemplary language (e.g., “e.g., for example”), are intended merely to exemplify a given material and method and do not impose any limitations on the scope. The language in this specification should not be interpreted as indicating any unclaimed element essential to the practice of the disclosed material and method.

[0075] details

[0076] A specific embodiment of the present disclosure relates to a method for treating a drug overdose comprising the step of administering a therapeutically effective amount of a respiratory stimulant to a patient requiring treatment for the drug overdose, wherein the overdose drug comprises an α2 adrenergic receptor agonist.

[0077] In certain embodiments, the present disclosure relates to a method for treating low blood pH caused by respiratory failure, comprising the step of administering a therapeutically effective amount of a respiratory stimulant to a patient requiring treatment for low blood pH. Respiratory failure may be caused by an overdose of a drug, such as an α2 adrenergic receptor agonist, for example. In certain embodiments, the blood pH is raised to about 7.35 to about 7.45 or about 7.38 to about 7.42 or about 7.4. In certain embodiments, the pH is raised to about 7.0 to about 7.35 or less than 7.35 or 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 present invention maintains the blood pH to about 7.35 to about 7.45 or about 7.38 to about 7.42 or to about 7.4.

[0078] In certain embodiments, the present invention rescues a subject from drug overdose and protects the subject from the long-term effects of low blood pH occurring during overdose.

[0079] In certain embodiments, the present disclosure relates to a drug composition comprising a therapeutically effective amount of a respiratory stimulant and a pharmaceutically acceptable excipient for treating a drug overdose, wherein the overdose drug comprises an α2 adrenergic receptor agonist.

[0080] In certain embodiments, drug overdose is accompanied by respiratory depression, sedation, hypotension, central nervous system side effects, cardiac side effects, or a combination thereof.

[0081] In certain embodiments, drug overdose is accompanied by respiratory depression.

[0082] In certain embodiments, α2 adrenergic receptor agonists comprise 4-NEMD, 7-me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, padolmidine, guanabenz, guanfacine, lopexidine, marsanidine, medetomidine, methyldopa, mibazerol, rilmenidine, romipidine, talipexol, thiamenidine, tizanidine, tolonidine, xylazine, xylometazoline, pharmaceutically acceptable salts thereof, and combinations thereof.

[0083] In certain embodiments, the α2-adrenergic receptor agonist comprises xylazine or a pharmaceutically acceptable salt thereof.

[0084] In certain embodiments, the overdose of the drug includes an opioid agonist.

[0085] Opioid agonists are, for example, morphine; codeine; thebaine; orifabine; diacetylmorphine; 2,4-dinitrophenylmorphine; methylenedioxydimethylamphetamine; clomaltrexamine; dihydromorphine; hydromorphinol; nicomorphine; dipropanoylmorphine; desomorphine; acetylpropionylmorphine; methyldesorphine; N-phenethylnormhine; 14-hydroxydihydrocodeine (RAM-318); 7,8-dihydro-14-hydroxy-N-phenethylnormhine (RAM-378); dibenzoylmorphine; diacetyldihydromorphine; dibenzoylmorphine; 6-monoacetylcodeine (6-MAC); acetyldihydrocodeine; dihydrocodeine; nalbuphine; Nicocodeine; Nicodicodine; Oxynorpazone; 1-Iodomorphine; Morphine-6-Glycuronide (M6G); 6-Monoacetylmorphine (6-MAM); Norcodeine; Normorphine; Xenomorphine; Dextralorphane (DXA); Cychlorphane; Dihydroheterocodeine; Folcodin; Myropin; 14-Cinnamoyloxycodainone; 14-Ethoxymethofone; 14-Methoxymethofone; 14-Phenylpropoxymethofone (PPOM); 7-Spiroindanyloxymorphone; Acetylmorphone; Codeinone; Conorphon; Codoxime; Tevacon; Metopone; N-Phenethyl-14-Ethoxymethofone; Morphinone; Benzylmorphine; Codeine Methylbromide; Ethylmorphine; Heterocodeine; Hydromorphone; Hydrocodone; Oxycodone; Oxymorphone; Pentamorphone; Semorphone; Chloromorphide; Ethylmorphine; Buprenorphine; Fentanyl; Alpha-methylfentanyl; Alfentanil; Sufentanil; Remifentanil; Carfentanil; Omefentanil; Pethidine; Ketovemidone; Desmethylprodine (MPPP); Allylprodine; Prodine; 1-Methyl-4-phenyl-4-propionoxypiperidine (PEPAP); Propoxyphen; Dextropropoxyphen; Dextromoramide; Benzitramide; Pyritramide; Levorphanol; Methadone; Dipipanone; Levometadyl Acetate (LAAM); Diphenoxin; Diphenoxylate; Loperamide; Dezosin; Pentazosin; Phenazocin; Dihydroetorphine; Etorphine; Butorphanol; Nalbuphine; Levometorphan; Levopheneacylmorphan; Norlevorphanol; Oxilorphan; Phenomorphan; Furethylnorlevorphanol;Zorfanol; butorphanol; ciprodig; drotebannol; 7-PET; acetorphine; BU-48; ciprenorphine; norbuprenorphine; repetamine; mephtaginol; mitrazinin; thylidin; tramadol; tapentadol; dextropropoxyphen; endorphin; enkephalin; dinorphin; endomorphin or a combination thereof.;

[0086] In certain embodiments, opioid agonists include oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, sufentanyl, morphine, tramadol, buprenorphine, pharmaceutically acceptable salts thereof, and combinations thereof.

[0087] In certain embodiments, the opioid is fentanyl or a pharmaceutically acceptable salt thereof.

[0088] In another embodiment, the overdose of the drug may be a kappa opioid receptor agonist, for example, butorphanol, nalbuphine, levorpanol, levalofane, pentazocine, phenazocine, eptazosine, or a combination thereof.

[0089] In certain embodiments, the respiratory stimulant comprises a compound selected from the formula (I) disclosed herein.

[0090] In certain 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.

[0091] In certain embodiments, the administration does not include an opioid antagonist.

[0092] In certain embodiments, the administration further includes an opioid antagonist.

[0093] In certain embodiments, the antagonist and the stimulant are administered simultaneously or sequentially.

[0094] In certain embodiments, the antagonist and the stimulant are administered by the same route of administration.

[0095] In certain embodiments, the antagonist and the stimulant are administered by different routes of administration.

[0096] In certain embodiments, the antagonist and the stimulant are administered as the same pharmaceutical composition.

[0097] In certain embodiments, the antagonist and the stimulant are administered in different pharmaceutical compositions.

[0098] In certain embodiments, the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, nalmephen, and pharmaceutically acceptable salts thereof.

[0099] In certain embodiments, the respiratory stimulant is selected from the group consisting of doxapram, almitrin, caffeine, and pharmaceutically acceptable salts thereof.

[0100] In certain embodiments, the stimulant is provided in a therapeutic dose sufficient to restore or improve the breathing rhythm of an overdoseed patient.

[0101] In certain embodiments, the stimulant is provided at a therapeutic dose that does not cause hyperventilation or substantial hyperventilation in patients overdoseed.

[0102] In certain embodiments, the antagonist is provided at a sub-therapeutic dose or a super-therapeutic dose, assuming it is administered without a stimulant.

[0103] In certain embodiments, the antagonist is provided at a therapeutic dose assuming it is administered without a stimulant.

[0104] In certain embodiments, the stimulant is provided at a dose below or above the therapeutic dose, assuming it is administered without an antagonist.

[0105] In certain embodiments, the stimulant is provided at a therapeutic dose assuming it is administered without an antagonist.

[0106] In certain embodiments, the overdose of the drug comprises benzodiazepines, barbiturates, gabapentinoids, or combinations thereof.

[0107] In certain embodiments, the route is selected from oral, intravenous, nasal, inhaled, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, tracheal, ear, intraocular, or spinal route.

[0108] In a specific embodiment of the administration of an opioid antagonist, the route is independently selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, ear, intraocular, or spinal routes.

[0109] In certain embodiments, administration results in a decrease in blood PCO2. In certain embodiments, the decrease occurs 5 minutes or less after administration, 10 minutes or less after administration, or 15 minutes or less after administration. In certain embodiments, blood PCO2 is lowered to about 35 to about 55 mmHg or about 41 to about 51 mmHg.

[0110] In certain embodiments, administration results in an increase in blood PO2. In certain embodiments, the increase occurs 5 minutes or less after administration, 10 minutes or less after administration, or 15 minutes or less after administration. In certain embodiments, blood PO2 is lowered to about 25 to about 45 mmHg or about 30 to about 40 mmHg.

[0111] In certain embodiments, administration causes an increase in blood pH. In certain embodiments, the increase occurs 5 minutes or less after administration, 10 minutes or less after administration, or 15 minutes or less after administration.

[0112] In certain embodiments, 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.

[0113] A specific embodiment of the present disclosure relates to a method for treating respiratory depression controlled by a non-opioid preparation, comprising the step of administering an effective amount of a compound selected from formula (I) to a patient in need thereof:

[0114]

[0115] In the above formula,

[0116] R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; R 1 and R 2 ... combines to form an radical 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;

[0117] 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, and;

[0118] R 4 is H, alkyl, or substituted alkyl;

[0119] R 5 is H, alkyl, propargyl, substituted propargyl, homopropagyl, substituted homopropagyl, 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 It combines to form an radical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0120] R 6 is H, alkyl, substituted alkyl, or alkenyl;

[0121] X is bonded, O, or NR 4 And;

[0122] Y is N, CR 6 or C and;

[0123] Y is N or CR 6 If so, combination b 1 There is no: (i) Z is H, and bond b 2 is a single bond, and A is CH or; (ii) Z is absent, and bond b 2 There is none, and A is a single bond;

[0124] If Y is C, then combination b 1 is a single bond and: (i) Z is CH2, and bond b 2 is a single bond, and A is CH or; (ii) Z is CH, and bond b 2 is a double bond, and A is C.

[0125] A specific embodiment of the present disclosure relates to a method for treating respiratory depression controlled by a non-opioid preparation, comprising the step of administering an effective amount of a compound selected from formula (I) to a patient in need thereof:

[0126]

[0127] In the above formula,

[0128] R 1 and R 2is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; R 1 and R 2 ... combines to form an radical 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;

[0129] 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, and;

[0130] R 4 is H, alkyl, or substituted alkyl;

[0131] R 5 is H, alkyl, propargyl, substituted propargyl, homopropagyl, substituted homopropagyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, or R 3 and R 5 combine to form an radical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 1 , R 2 , R 3 and R 5 At least one substituent selected from the group consisting of is an alkynyl or a substituted alkynyl;

[0132] R 6 is H, alkyl, substituted alkyl, or alkenyl;

[0133] X is bonded, O, or NR 4 And;

[0134] Y is N, CR 6 or C and;

[0135] Y is N or CR 6 If so, combination b 1 There is no: (i) Z is H, and bond b 2 is a single bond, and A is CH or; (ii) Z is absent, and bond b 2 There is none, and A is a single bond;

[0136] If Y is C, then combination b 1 is a single bond and: (i) Z is CH2, and bond b 2 is a single bond, and A is CH or; (ii) Z is CH, and bond b 2 is a double bond, and A is C.

[0137] A specific embodiment of the present disclosure relates to a method for treating respiratory depression controlled by a non-opioid preparation, comprising the step of administering an effective amount of a compound selected from formula (I) to a patient in need thereof:

[0138]

[0139] In the above formula,

[0140] R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; R 1 and R 2... combines to form an radical 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;

[0141] R 3 H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl or aryl, and;

[0142] R 4 is H, alkyl, or substituted alkyl;

[0143] R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, or R 3 and R 5 It combines to form an radical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0144] R 6 is H, alkyl, substituted alkyl, or alkenyl;

[0145] X is bonded, O, or NR 4 And;

[0146] Y is N, CR 6 or C and;

[0147] Y is N or CR 6 If so, combination b 1 There is no: (i) Z is H, and bond b 2 is a single bond, and A is CH or; (ii) Z is absent, and bond b 2 There is none, and A is a single bond;

[0148] If Y is C, then combination b 1 is a single bond and: (i) Z is CH2, and bond b 2 is a single bond, and A is CH or; (ii) Z is CH, and bond b 2 is a double bond, and A is C.

[0149] In one embodiment, R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, or substituted alkenyl. In another embodiment, R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, or acyl.

[0150] A specific embodiment of the present disclosure relates to a method for treating respiratory depression controlled by a non-opioid preparation, comprising the step of administering an effective amount of a compound selected from formula (I) to a patient in need thereof:

[0151]

[0152] R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; R 1 and R 2 ... combines to form an radical 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;

[0153] R 3 is H, alkyl, substituted alkyl, alkynyl, or substituted alkynyl;

[0154] R 4 is H, alkyl, or substituted alkyl;

[0155] R 5 is an alkyl, propargyl, substituted propargyl, homopropagyl, or substituted homopropagyl, and R 1 , R 2 , R 3 and R 5 At least one substituent selected from the group consisting of is an alkynyl or a substituted alkynyl;

[0156] R 6 is H, alkyl, substituted alkyl, or alkenyl;

[0157] X is bonded, O, or NR 4 And;

[0158] Y is N, CR 6 or C and;

[0159] Y is N or CR 6 If so, combination b 1 There is none:

[0160] (i) Z is H, and bond b 2 is a single bond, and A is CH or;

[0161] (ii) There is no Z, and the combination b 2 There is none, and A is a single bond;

[0162] If Y is C, then combination b 1 is a single bond and:

[0163] (i) Z is CH2, and bond b 2 is a single bond, and A is CH or;

[0164] (ii) Z is CH, and bond b 2 is a double bond, and A is C.

[0165] In certain embodiments, (i) R 3 is H, alkyl or substituted alkyl, and R 5 is propargyl, substituted propargyl, homopropagyl, or substituted homopropagyl, or (ii) R 3 is H or alkynyl, and R 5is an alkyl, propargyl, substituted propargyl, homopropagyl, or substituted homopropagyl.

[0166] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is N, bond b1 is absent, Z is H, bond b2 is a single bond, A is CH, and at least one compound is formula (II-a) or a salt thereof:

[0167]

[0168] (ii) Y is N, bond b1 is absent, Z is absent, bond b2 is absent, A is a bond, and the compound of the present invention is a compound of formula (II-b) or a salt thereof:

[0169]

[0170] In one embodiment, at least one compound of formula (I) is selected from the group consisting of the following: (i) Y is CR 6 and, combination b 1 There is none, Z is H, and bond b 2 is a single bond, A is CH, and at least one compound is of formula (III-a) or a salt thereof:

[0171]

[0172] and

[0173] (ii) Y is CR 6 and, combination b 1 There is none, there is no Z, and combination b 2 There is no, A is a bond, and the compound of the present invention is a pyrimidine of formula (III-b) or a salt thereof:

[0174]

[0175] In one embodiment, Y is C, and bond b 1 is a single bond, Z is CH2, and bond b 2is a single bond, A is CH, and at least one compound is a compound of formula (IV) or a salt thereof:

[0176]

[0177] In one embodiment, Y is C, and bond b 1 is a single bond, Z is CH, and bond b 2 is a double bond, A is C, and at least one of the compounds is a compound of formula (V) or a salt thereof:

[0178]

[0179] In one embodiment, at least one compound is N-(4,6-bis-methylamino-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XX), N-(4,6-bis-ethylamino-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXII), N-(4-cyclopropylmethylamino)-N-(6-n-propylamino) [1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXV), N-(4-ethylamino)-N-(6-n-propylamino)-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXVII), N-(bis-4,6-(2-methylpropylamino)) [1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXIX), N-(bis-4,6-(2,2-dimethylpropylamino)) [1,3,5]triazine-2-yl)-O,N-dimethyl-hydroxylamine(XXXI), 4,6-bis-N-cyclopropylamino-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride(XXXIII), N-(4,6-bis-n-propylamino-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine(XXXV), N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazine-2-yl)propionamide(XL), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-methyl-hydroxylamine(XLI), O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-hydroxylamine (XLIII), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine (XLVII), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-methyl-hydroxylamine (LIII), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]Oksajinan-2-il-N,N′-diprofile-[1,3,5]Triazine-2,4-Diamine (LVII), N-(4,6-bis-propylamino-[1,3,5]Triazine-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]Triazine-2-yl)-N-ethyl-hydroxylamine (LXVIII), N-(4,6-bis-propylamino-[1,3,5]Triazine-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXII), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII), 6-(methyl(thiophene-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCVI), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-(2,2-difluoro-ethyl)-hydroxylamine(C), 4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine(CIII), 4-N-(3-(1-N-methylimidazole-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine(CV), 4-N-(1-N-methylimidazole-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazine-2-yl)-O,N-dimethyl-hydroxylamine(CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine(CIX), 4,6-bis-(N-(pyridine-4-ylmethyl)amino)-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (CXIII), 4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine (CXV), N-(5,8,11-trioxa-2,14,16,18,19-pentazabicyclo[13.3.1]-nonadeca-1(18),15(19),16(17)-triene-17-yl)-N,O-dimethylhydroxylamine (CXVII), It is selected from the group consisting of N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N′,N′-dimethylhydrazine (XLVI), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-methyl-N′-methylhydrazine (XLIX), salts thereof, and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0180] In one embodiment, at least one compound is 2,6-bis-(Nn-propylamino)-[1,3]pyrimidine-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazine-2-yl)propionamide or a salt thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0181] In one embodiment, at least one compound is N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazine-2-yl)propionamide or a salt thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0182] In one embodiment, at least one compound is 2-(n-propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidine (CXXXVI), 2,4-bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX), It is selected from the group consisting of 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidine-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLV), salts thereof, and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0183] In one embodiment, at least one compound is N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidine-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(propene-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidine-4-yl)-N,O-dimethyl-hydroxylamine (CLVIII), N-(2-(propene-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidine-4-yl)-O-methyl-hydroxylamine (CLX), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine-4-yl)-O,N-dimethyl-hydroxylamine (CLXII), It is selected from the group consisting of N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine-4-yl)-O-methyl-hydroxylamine (CLXIV), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine-4-yl)-hydrazine (CLXVI), N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine-4-yl)-hydrazine (CLXVIII), N,N-dimethyl-N′-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidine-4-yl)-hydrazine (CLXX), salts thereof, and mixtures thereof. In another embodiment, the salt is hydrogen sulfate or hydrochloride.

[0184] In certain embodiments, the compound is selected from the group consisting of O,N-dimethyl-N-[4-(n-propylamino)-6-(prop-2-inylamino-[1,3,5]triazine-2-yl]-hydroxylamine; N-methyl-N′-n-propyl-N″-prop-2-inyl-[1,3,5]triazine-2,4,6-triamine; salts thereof; and any combination thereof.

[0185] In a specific embodiment, the following compound A used in the present invention is as follows:

[0186]

[0187] In certain embodiments, the compound of formula (I) is selected from the compounds described in U.S. Patent No. 9,162,992 and / or U.S. Patent No. 9,351,972 and / or the now-abandoned U.S. Patent Application Publication 2015-0291597, the teachings of which are incorporated herein by reference in their entirety.

[0188] In a specific embodiment, the patient exhibits recovered mechanical ventilation ability.

[0189] In a specific embodiment, the patient exhibits a recovered ventilator capacity under overdose.

[0190] In a specific embodiment, the patient shows increased responsiveness to artificial respiration.

[0191] In a specific embodiment, the patient shows increased mechanical ventilation responsiveness to hypoxic events.

[0192] In a specific embodiment, the patient shows increased responsiveness to mechanical ventilation for hypercapnia events.

[0193] In certain embodiments, the patient's reduction in artificial respiration is avoided or minimized.

[0194] In certain embodiments, the patient's reduction in artificial respiration during the hypercapnia period is avoided or minimized.

[0195] In certain embodiments, the route of administration is selected from oral, intravenous, nasal, inhalation, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, tracheal, ear, intraocular, or spinal routes.

[0196] In certain embodiments, the patient shows improvement in hypercapnia. In certain embodiments, the improvement is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%.

[0197] In certain embodiments, the patient exhibits an improvement in microventilation. In certain embodiments, the improvement is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25% as measured by hypoxic ventilation sensitivity (hypoxic sensitivity of Δventilation / Δsaturation = % desaturation in L / min).

[0198] In a specific embodiment, the patient has a positive ventilator response under normal carbonic acid and a mild hypercapnia state during normal oxygenation.

[0199] In a specific embodiment, the patient maintains a mild hypercapnia state during the ventilator response and normal oxygenation under normal carbon dioxide.

[0200] In certain embodiments, the patient does not exhibit adverse effects or experience clinically significant adverse effects when evaluated against one or more of the reported adverse events, physical examination, vital signs, 12-lead ECG, clinical laboratory test results, and Columbia-Suicide Severity Rating Scale (C-SSRS) responses.

[0201] In certain embodiments, the patient does not show clinically significant changes in cardiovascular response.

[0202] In certain embodiments, the patient exhibits a therapeutic effect measured by hypoxic sensitivity (Δventilation / Δsaturation).

[0203] In certain embodiments, the patient exhibits a therapeutic effect measured in tidal volume (VT).

[0204] In a specific embodiment, the patient exhibits a therapeutic effect measured by respiratory rate (respiratory rate per minute).

[0205] In certain embodiments, the patient exhibits a therapeutic effect measured in minute ventilation (VE).

[0206] In certain embodiments, the patient exhibits a therapeutic effect measured by transcutaneous CO2 measurement and / or respiratory CO2 (mmHg).

[0207] In certain embodiments, the patient exhibits a therapeutic effect measured by transcutaneous hemoglobin saturation (% SpO2).

[0208] In a specific embodiment, the patient exhibits a therapeutic effect measured by arterial blood gas.

[0209] In certain embodiments, the therapeutic effect is measured by BIS.

[0210] In a specific embodiment, the patient exhibits a therapeutic effect measured by hemodynamic parameters of arterial line monitoring. In a specific embodiment, the change is at least 5%, at least 10%, at least 15%, at least 20%, or at least 25%.

[0211] composition

[0212] In certain embodiments, the present 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 abnormal blood pH.

[0213] In certain embodiments, the active agent(s) in the pharmaceutical composition are freeze-dried.

[0214] In certain embodiments, the pharmaceutical composition is pre-mixed (e.g., the active agent is pre-mixed with one or more pharmaceutically acceptable excipients and optionally one or more additional active agents).

[0215] In certain embodiments, the pharmaceutical composition may be contained in a glass container or a plastic container.

[0216] In certain 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.

[0217] Routes of administration of any composition of the present invention include inhalation, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, tongue, buccal (trans-), urethral (trans-), vaginal (e.g., trans-vaginal and perivaginal), nasal (intra) and rectal (trans-)), intravesical, intrapulmonary, duodenal, gastric, spinal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, intraperitoneal, intrathoracic, intrapleural, and local administration.

[0218] Suitable compositions and forms of administration include, for example, tablets, capsules, coated tablets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powders or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, etc. It should be understood that the formulations and compositions useful for the present invention are not limited to the specific formulations and compositions described herein.

[0219] In certain embodiments, pharmaceutically acceptable excipients comprise pharmaceutically acceptable carriers, such as liquid or solid fillers, stabilizers, dispersants, suspending agents, diluents, thickeners, solvents, or encapsulating materials, which are involved in carrying or transporting a compound useful in the present invention into or to a subject so as to perform its intended function. Typically, such formulations may be carried or transported from one organ or body part to another organ or body part. Each carrier must be "acceptable" in that it is compatible with other components of a formulation containing a compound useful in the present invention and is not harmful to the subject. Some examples of materials that may serve as pharmaceutically acceptable carriers include sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanths; malt; gelatin; talc; Excipients, e.g., cocoa butter and suppository waxes; oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, e.g., propylene glycol; polyols, e.g., glycerin, sorbitol, mannitol and polyethylene glycol; esters, e.g., ethyl oleate and ethyl laurate; agar; buffers, e.g., magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free substances; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer; and other non-toxic, compatible substances used in pharmaceutical formulations. As used herein, "pharmaceuticalally acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, and absorption retardants, and others that are physiologically acceptable to the subject and are compatible with the activity of compounds useful within the present invention. Supplemental active compounds may also be incorporated into the composition.The “pharmaceuticalally acceptable carrier” may further comprise a pharmaceutically acceptable salt of a compound useful within the present invention. Other additional components that may be used in the pharmaceutical composition used in the practice of the present invention are known in the art and are described, for example, in the literature incorporated herein by reference [Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.)].

[0220] Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline solution, 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 the literature [Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey)].

[0221] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and others), suitable mixtures thereof, and vegetable oil. Suitable fluidity may be maintained, for example, by the use of a coating such as lecithin, by maintaining the particle size required in the case of dispersion, and by the use of a surfactant. Prevention of microbial action may be achieved by various antiviral and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and others. In many cases, it will be desirable to include an isotonic agent, for example, sugar, sodium chloride, or a polyalcohol, such as mannitol and sorbitol, in the composition. Long-term absorption of the injectable composition may occur by including a substance that delays absorption, for example, aluminum monostearate or gelatin, in the composition. In one embodiment, the pharmaceutically acceptable carrier is not DMSO alone.

[0222] Pharmaceutical preparations are sterilized and, if desired, may be mixed with adjuvants, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure buffers, coloring agents, flavoring agents and / or aromatic substances and others.

[0223] Examples of useful preservatives according to the present invention include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidourea, and combinations thereof.

[0224] The composition preferably comprises an antioxidant and a chelating agent that inhibit the degradation of the compound. Antioxidants preferred for some compounds are BHT, BHA, alpha-tocopherol, and ascorbic acid in a preferred range of about 0.01% to 0.3% based on the total weight of the composition, and more preferably BHT in a range of 0.03% to 0.1% by weight. Preferably, the chelating agent is present in an amount of 0.01% to 0.5% by weight based on the total weight of the composition. Particularly preferred chelating agents include edetate salts (e.g., disodium edetate) and citric acid in a range of about 0.01% to 0.20% by weight based on the total weight of the composition, and more preferably in a range of 0.02% to 0.10% by weight based on the total weight of the composition. Chelating agents are useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. Although BHT and disodium edetate are particularly desirable antioxidants and chelating agents, respectively, for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted for them as known to those skilled in the art.

[0225] A liquid suspension may be prepared using conventional methods to achieve suspension of an active ingredient in an aqueous or oily vehicle. An aqueous vehicle comprises, for example, water and isotonic saline solution. An oily vehicle comprises, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. The liquid suspension may further comprise one or more additional components, as non-limiting examples, including a suspending agent, a dispersant or wetting agent, an emulsifier, a lubricant, a preservative, a buffer, a salt, a flavoring agent, a coloring agent, and a sweetener. An oily suspension may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, tragacanth gum, acacia gum, and cellulose derivatives, such as sodium carboxymethylcellulose, methylcellulose, and hydroxypropylmethylcellulose. Known dispersing agents or wetting agents include, but are not limited to, naturally occurring phosphatides, such as lecithin, alkylene oxides, and condensation products with fatty acids, long-chain aliphatic alcohols, partial esters derived from fatty acids and hexitol, or partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifiers include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoate, ascorbic acid, and sorbic acid. Known sweeteners include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickeners for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0226] A liquid solution of an active ingredient in an aqueous or oily solvent can be prepared in substantially the same manner as a liquid suspension, the main difference being that the active ingredient is dissolved rather than suspended in the solvent. As used herein, the "oil" liquid contains carbon-containing liquid molecules and exhibits properties that are less polar than water. A liquid solution of the pharmaceutical composition of the present invention may contain each of the components described in relation to the liquid suspension, and it is understood that the suspending agent does not necessarily aid in the dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline solution. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0227] The powdered and granular formulations of the pharmaceutical preparations of the present invention may be prepared using known methods. These formulations are administered directly to a subject and may be used to form, for example, tablets or fill capsules, or to prepare aqueous or oily suspensions or solutions by adding an aqueous or oily vehicle to them. Each of these formulations may further comprise 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.

[0228] The pharmaceutical composition of the present invention may also be manufactured, packaged, or sold in the form of an oil-in-water emulsion or an oil-in-water emulsion. The oil phase may 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 further comprise one or more emulsifiers, such as a naturally occurring gum, such as acacia gum or tragacanth gum; a naturally occurring phosphatide, such as soybean or lecithin phosphatide; an ester or partial ester derived from a combination of a fatty acid and hexitol anhydride, such as sorbitan monooleate; and a condensation product of such partial ester and ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain additional ingredients, such as sweeteners or flavoring agents.

[0229] In certain embodiments, one or more additional excipients comprise 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 a mixture thereof.

[0230] In certain embodiments, the composition may include one or more additional excipients, e.g., without limitation, carbohydrates, antioxidants, chelating agents, low molecular weight proteins, high molecular weight polymers, gel-forming agents, stabilizers, additives, wetting agents, emulsifiers, surfactants and / or dispersants, alkalizing agents, coloring agents, synthetic dies, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0231] In certain embodiments, the composition further comprises an antioxidant. In certain embodiments, the antioxidant may include, for example, a phosphite, a phenolic antioxidant, a hydroxylamine, a lactone, or a trivalent phosphorus such as substituted benzofuranone. Hindered phenols, thiosynergists, and / or hindered amines are useful for the long-term stability of polymers, but acids (ascorbic acid, erythorbic acid, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguayretic acid, propionic acid, etc.), phenols (e.g., BHA, BHT, t-butyl hydroquinone, 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, distearyl thiodipropionate), pyranones (maltol), and vitamin E (tocopherol, Antioxidants of D-α-tocopherol, DL-α-tocopherol, tocopherol acetate, d-α-tocopheryl acetate, and dl-α-tocopheryl acetate are suitable for use even when the active substance is treated by oxidation. However, according to the present invention, other antioxidants known in the art may be used.

[0232] In certain embodiments, suitable antioxidants may include, without limitation, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations thereof. Other suitable examples of antioxidants are alkylated monophenols, such as, for non-limiting examples, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylcyclohexyl)-4,6-dimethylphenol, 2,6-dioctadecyl-4-methylphenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4-methoxymethylphenol, and nonylphenols that are linear or branched in their side chains, for example, 2,6-di-nonyl-4-methylphenol. 2,4-dimethyl-6-(1′-methylundec-1′-yl)phenol, 2,4-dimethyl-6-(1′-methylheptadec-1′-yl)phenol, 2,4-dimethyl-6-(1′-methyltridec-1-yl)phenol and mixtures thereof, alkylthiomethylphenols, e.g., non-limiting examples 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-dioctylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol, hydroquinone and alkylated hydroquinone, e.g., non-limiting examples 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-di-tert-butyl-4-hydroxyphenyl) adipate, tocopherol, e.g., non-limiting examples α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol and mixtures thereof (vitamin E), hydroxylated thiodiphenyl ether, e.g., non-limiting example 2,2′-thiobis(6-tert-butyl-4-methylphenol),2,2′-thiobis(4-octylphenol), 4,4′-thiobis(6-tert-butyl-3-methylphenol), 4,4′-thiobis(6-tert-butyl-2-methylphenol), 4,4′-thiobis(3,6-di-sec-amylphenol), 4,4′-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide, alkylidene bisphenol, e.g., as non-limiting examples, 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′-Ethylidenebis(4,6-di-tert-butylphenol), 2,2′-Ethylidenebis(6-tert-butyl-4-isobutylphenol), 2,2′-Methylenebis[6-(α-methylbenzyl)-4-nonylphenol], 2,2′-Methylenebis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4′-Methylenebis(2,6-di-tert-butylphenol), 4,4′-Methylenebis(6-tert-butyl-2-methylphenol), 1,1-Bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-Bis(3-tert-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-Tris(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 1,1-Bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3′-tert-butyl-4′-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methylphenyl)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-dodecylmercaptobutane, 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane, O-,N- and S-benzyl compounds, for example, non-limiting examples include 3,5,3′,5′-tetra-tert-butyl.-4,4′-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzyl mercaptoacetate, tris(3,5-di-tert-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzyl mercaptoacetate, hydroxybenzylated malonate, for example, non-limiting examples Dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, di-octadecyl-2-(3-tert-butyl-4-hydroxy-5-methylbenzyl)malonate, didodecyl mercaptoethyl-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, aromatic hydroxybenzyl compounds, e.g., as a non-limiting example, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol, triazine compounds, e.g., as non-limiting examples, 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,3,5-triazine, 2,4,6-Tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-Tris(3,5-di-tert-butyl-4-hydroxybenzyl)isocyanurate, 1,3,5-Tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenylethyl)-1,3,5-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxy-phenylpropionyl)-hexahydro-1,3,5-triazine, 1,3,5-tris(3,5-dicyclohexyl-4-hydroxybenzyl)iso-cyanurate, benzylphosphonates, e.g., as non-limiting examples, dimethyl-2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl 3,5-di-tent-butyl-4-hydroxybenzylphosphonate, Dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzylphosphonate, calcium salt of the monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzylphosphonic acid, acylaminophenol, e.g., non-limiting examples 4-hydroxyauranilide, 4-hydroxystearanilide, octyl N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamate, β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid and monohydric or polyhydric alcohols, e.g., methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene Glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thioundecanol, 3-thipentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid and monohydric or polyhydric alcohols, e.g., methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, Tris(hydroxyethyl)isocyanurate, N,N′-bis-(hydroxyethyl)oxamide, 3-thioundecanol, 3-thipentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2] ester of octane; 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]-2,4,8,10-tetraoxaspiro[5.5]-undecane, 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid and monohydric or polyhydric alcohols, e.g. methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thioundecanol, 3-thipentadecanol, Trimethylhexanediol, trimethylolpropane, ester of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2,2,2]octane, 3,5-di-tert-butyl-4-hydroxyphenylacetic acid and monohydric or polyhydric alcohols, e.g. methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thioundecanol, 3-thipentadecanol, trimethylhexanediol, trimethylolpropane, Esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, amides of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, e.g. N,N′-bis(3,5-di-tert-butyl A-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]oxamide (Naugard®XL-1, Uniroyal supply), ascorbic acid (vitamin C), amineous antioxidants, e.g., non-limiting examples include N,N′-di-isopropyl-p-phenylenediamine, N,N′-di-sec-butyl-p-phenylenediamine, N,N′-bis(1,4-dimethylpentyl)-p-phenylenediamine, N,N′-bis(1-ethyl-3-methylpentyl)-p-phenylenediamine, N,N′-bis(1-methylheptyl)-p-phenylenediamine, N,N′-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-toluenesulfamoyl)diphenylamine, N,N′-dimethyl-N,N′-di-sec-butyl-p-phenylenediamine, diphenylamine, N-allyldiphenylamine, 4-isopropoxydiphenylamine, N-phenyl-1-naphthylamine, N-(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine, octylated diphenylamine, e.g., as non-limiting examples, p,p′-di-tert-octyldiphenylamine, 4-n-butylaminophenol, 4-butyrylaminophenol, 4-nonanoylaminophenol, 4-dodecanoylaminophenol, 4-octadecanoylaminophenol, bis(4-methoxyphenyl)amine, 2,6-di-tert-butyl-4-dimethylaminomethylphenol, 2,4′-diaminodiphenylmethane, 4,4′-diaminodiphenylmethane, N,N,N′,N′-tetramethyl-4,4′-diaminodiphenylmethane, 1,2-bis[(2-methylphenyl)amino]ethane, 1,2-bis(phenylamino)propane, (o-tolyl)biguanide, bis[4-(1′,3′-dimethylbutyl)phenyl]amine, tert-octylated N-phenyl-1-naphthylamine, mixture of mono- and dialkylated tert-butyl / tert-octyldiphenylamine, mixture of mono- and dialkylated nonyldiphenylamine, mono- and dialkylated Mixture of dodecyldiphenylamine, mixture of mono- and dialkylated isopropyl / isohexyldiphenylamine,Mixtures of mono- and dialkylated tert-butyldiphenylamine, 2,3-dihydro-3,3-dimethyl-4H-1,4-benzothiazine, phenothiazine, mixtures of mono- and dialkylated tert-butyl / tert-octylphenothiazine, mixtures of mono- and dialkylated tert-octyl-phenothiazine, N-allylphenothiazine, N,N,N′,N′-tetraphenyl-1,4-diaminobut-2-ene, and combinations thereof, including but not limited to these.

[0233] In certain embodiments, suitable pharmaceutically acceptable excipients are acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyalkylene oxides (e.g., polymethylene oxide, polyethylene oxide, polypropylene oxide), polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylates, polycaprolactone, polymethacrylates, copolymers thereof and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, sodium croscarmellose or mixtures thereof), flow promoters, lubricants, absorption enhancers, surfactants, binders, emollients, plasticizers (e.g., lecithin, hydrogenated vegetable oils, glycerol esters, lanolin, methyl esters, pentaerythritol esters, rice bran wax, stearic acid, potassium stearate, and others), waxes, fats, emulsifiers, fillers, It may include antioxidants, flavors, coloring agents, diluents, processing aids (e.g., granulation aids), sweeteners such as those described above in relation to chewable compositions, fixatives (e.g., polyols, e.g., sorbitol, maltitol / isomalt, mannitol, starch, and others, without limitation), pH adjusters, viscosity adjusters, solubility increasing or decreasing agents, osmotic agents, solvents, or combinations thereof.

[0234] In certain embodiments, suitable pharmaceutically acceptable excipients may include polyvinylpyrrolidone, natural gums and synthetic gums, polyvinyl alcohol, corn starch, hydrophilic materials 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 is, for example, ethylcellulose, e.g., ethylcellulose, acrylic acid and methacrylic acid polymers and copolymers (e.g., acrylic acid and methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), alkylamide methacrylate copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymer, and any mixture of the above), and cellulose ether, e.g., hydroxyalkylcellulose (e.g., It may include hydroxypropylmethylcellulose) and carboxyalkylcellulose. Waxes include, for example, natural waxes and synthetic waxes, fatty acids, fatty alcohols and mixtures thereof (e.g., beeswax, carnauba wax, stearic acid and stearyl alcohol).

[0235] In certain embodiments, suitable pharmaceutically acceptable excipients are gelling agents, e.g., without limitation, sugars or sugar-derived alcohols, e.g., mannitol, sorbitol, and others, starch and starch derivatives, cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 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 (hypermellose acetate succinate) and mixtures thereof), atapulgite, bentonite, dextrin, alginate, alginate, e.g., sodium alginate and potassium alginate, casein, stearic acid, shellac, carrageenan, gum tragacanth, gum acacia, Arabian gum, pullulan gum, dextrin, gellan gum, agar gum, tara gum, karaya, guar gum, welan gum, ramicane gum, locust bean gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer and carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant / wetting agent systems, emulsifiers, other polymeric materials and their It may include a mixture.

[0236] In certain embodiments, suitable pharmaceutically acceptable excipients may include hydrophilic excipients, e.g., water, low molecular weight polyols, e.g., polyethylene glycol, polypropylene glycol, or combinations thereof, without limitation. Other suitable hydrophilic carriers include, without limitation, polyoxyethylene derivatives of sorbitan esters, e.g., sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof. Exemplary low molecular weight polyols include, without limitation, those having a number average molecular weight of any of about 200 daltons, about 400 daltons, about 600 daltons, about 800 daltons, or about 1000 daltons to about 2000 daltons, about 3000 daltons, about 4000 daltons, about 5000 daltons, about 6000 Da, or about 7000 Da, or any sub-range or single value therein (e.g., polyethylene glycol 400, polyethylene glycol 600, or others).

[0237] In certain embodiments, suitable pharmaceutically acceptable excipients may include sugar alcohol plasticizers, such as triacetin, isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol or mannitol; or polyol plasticizers, such as diglycerin, 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 polyol, ethanolamine; and mixtures thereof, but not limited thereto. Other exemplary plasticizers may also include, without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, homoblock polymers, citrate ester-type plasticizers, and triacetin. These plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

[0238] In certain embodiments, suitable pharmaceutically acceptable excipients are plasticizers, e.g., without limitation, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glycerides and acetylated hydrogenated soybean oil glycerides; acetyl tribubutyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylate glycerin, glyceryl cocoate, monoacetylated monoglycerides and diacetylated monoglycerides, nitrobenzene, carbon disulfide, fl-naphthyl salicylate, phthalyl glycolate, dioctyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; α-tocopheryl polyethylene glycol succinate, phosphate esters; phthalate esters; amides; Mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, including tosteaaryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, and myristyl alcohol;Methyl abietate, acetyl tribubutyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl lysine oleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(beta-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(beta-ethyl butyrate), polyethylene glycol di(2-ethyl hexoate), diethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethyl stearate, butyl phthalyl butyl glycolate, glycerol tributyrate, triethylene glycol dipelagonate, It may include beta-(p-tert-amylphenoxy)ethanol, beta-(p-tert-butylphenoxy)ethanol, beta-(p-tert-butylphenoxyethyl)acetate, bis(beta-p-tert-butylphenoxydiethyl)ether, camphor, Cumar W-1, Cumar MH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy)ethanol, diphenyl oxide, technical hydroabieethyl alcohol, becolline, benzene hexahydrochloride, Clorafin 40, Picolastick A-5, Picolastick A-25, Flexol B-400, glycerol alpha-methyl alpha-phenyl ether, chlorinated naphthalene, HB-40, monoamyl phthalate. Nevilac 10 o-nitrodiphenyl and paraacrylate 26.;

[0239] In certain embodiments, suitable pharmaceutically acceptable excipients may comprise plasticizers, e.g., without limitation, sugar alcohol plasticizers, e.g., isomalt, maltitol, sorbitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol or mannitol; or polyol plasticizers, e.g., glycerin, diglycerin, 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 polyol, ethanolamine; and mixtures thereof. Other exemplary plasticizers may include, without limitation, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, homoblock polymers, citrate ester-type plasticizers, and triacetin. These plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

[0240] In certain embodiments, suitable pharmaceutically acceptable excipients may include, without limitation, flavors such as natural and / or synthetic flavoring materials. For example, oil-soluble flavoring oils may or may not be mixed with water-soluble flavoring oils. Oil-soluble flavoring materials are natural or natural equivalent essential oils, such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaf, peppermint oil, cedarwood oil, rosemary oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, germanium oil, menthol, and marjoram oil. Animal flavorings are, for example, musk, castoreum, aberrant, or gibbet. Spagiri essences are also known in the art. These are made by fermenting certain herbs and then processing them into a final product. Synthetic fragrance components are synthetic essential oils composed, for example, of single compounds such as linalool, terpinerol, nerol, citronellal, benzaldehyde, cinnamonaldehyde, vanillin, ethyl vanillin, or methylacetophenone. Fragrance materials may also be synthetic oil-soluble fragrance oils selected from a general group consisting of fragrance hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, and polyethylene derivatives. Other fragrances that may be used are referenced in references and databases, such as [S. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; reprint 2000)]; [Allured's Flavor and Fragrance Materials (2005)]; and www.rifm.org It is listed and described in the database maintained by the Research Institute for Fragrance Materials.

[0241] In certain embodiments, suitable pharmaceutically acceptable excipients may include fragrance oils. Suitable fragrance oils include a mixture of natural fragrances and synthetic fragrances. Natural fragrances are extracts of flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (aniseed, coriander, cumin, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), trees (pine, sandalwood, guaiac, cedar, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), conifers and branches (spruce, fir, pine, dwarf pine), resins and valams (galbanum, elemi, benzoin, myrrh, olibanum, oponax). Common synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol, and hydrocarbon types. Fragrance compounds of the ester type are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethyl-methylphenyl glycinate, allyl cyclohexylpropionate, styallyl propionate, and benzyl salicylate. Ethers include, for example, benzyl ethyl ether; aldehydes include, for example, linear alkalis having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamenaldehyde, hydroxycitronellal, lilyl and bourgenal; ketones include, for example, ionone, α-isomethylionone and methyl cedryl ketone; alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol and terpineol; and hydrocarbons mainly include terpenes and valams.

[0242] In certain embodiments, suitable pharmaceutically acceptable excipients may include a relatively low-volatility essential oil used primarily as a fragrance component, which is also suitable as a fragrance oil, e.g., sage oil, chamomile oil, clove oil, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, lavolanum oil, and lavandin oil. Other suitable oils include bergamot oil, dihydromyrcenol, lilial, liral, citronellol, phenylethyl alcohol, α-hexyl cinnamaldehyde, geraniol, benzylacetone, cyclamenaldehyde, linalool, boisambren forte, ambroxane, indole, hedione, sandelis, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclobutal, lavandin oil, clary sage oil, β-damaskone, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, iso-E-super, Fixolide NP, ebenyl, irardane gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romilat, irotil, and floramat, either alone or in a mixture.

[0243] In certain embodiments, suitable pharmaceutically acceptable excipients may include preservatives. As used herein, the term “preservative” refers to a agent that extends the shelf life of a formulation by delaying or preventing the deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety. Preservatives do not need to provide a lethal and irreversible action that results in partial or complete destruction or inactivation of microbial cells. Sterilizers, disinfectants, fungicides, sprayers, viracides, and tuberculocidal agents provide this irreversible mode of action, which is sometimes referred to as “bactericidal” action. On the other hand, preservatives may provide a reversible inhibitory or bacteriostatic action in that growth may resume once the target microorganism is eliminated. The main difference between preservatives and fungicides lies primarily in the mode of action (preservatives prevent growth rather than kill microorganisms) and the duration of exposure (preservatives take days to months to act, whereas fungicides take up to a few minutes to act). Suitable preservatives include, without limitation, phenoxyethanol, paraben solutions, pentanediol and sorbic acid, as well as silver complexes.

[0244] In certain embodiments, suitable pharmaceutically acceptable excipients may include coloring agents, such as, for example, without limitation, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown.

[0245] In certain embodiments, suitable pharmaceutically acceptable excipients may include “flavor extracts” obtained by extracting a portion of the raw material without limitation, for example, animal or plant material obtained using a solvent such as ethanol or water; essential oils extracted from flowers, fruits, roots, etc., or natural essences obtained from whole plants. Additional exemplary flavorings for the compositions described herein may include, but are not limited to, menthol, spearmint and cinnamon, coffee beans, other flavors or flavorings, such as fruit flavors (e.g., cherry, orange, grape, etc.), and quaternary ammonium bases. The effect of the flavoring may be enhanced by using flavor enhancers such as tartaric acid, citric acid, vanillin, or others.

[0246] In certain embodiments, suitable pharmaceutically acceptable excipients may include, without limitation, one or more artificial sweeteners, one or more natural sweeteners, or combinations thereof. Artificial sweeteners include, for example, acesulfame and various salts thereof, such as potassium salt (provided as Sunett®), alitam, aspartame (provided as NutraSweet® and Equal®), aspartame-acesulfame salt (provided as Twinsweet®), neohesperidin dihydrochalcone, narindin dihydrochalcone, dihydrochalcone compounds, neotame, cyclamate sodium, saccharin and various salts thereof, such as sodium salt (provided as Sweet'N Low®), stevia, chloro derivatives of sucrose, such as sucralose (provided as Kaltame® and Splenda®), and mogroside. Natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the brand name MagnaSweet®); stevia rebaudiana (stevioside), natural intensive sweeteners, such as Lo Han Kuo, polyols, such as sorbitol, mannitol, xylitol, erythritol, and others.

[0247] In certain embodiments, suitable pharmaceutically acceptable excipients may include alkalizing agents, such as, without limitation, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate and / or disodium phosphate.

[0248] In certain embodiments, suitable pharmaceutically acceptable excipients may include, as non-limiting examples, lubricant(s) / release agent(s) such as fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants include glyceryl behenate (Compritol™ 888), metallic stearates (e.g., magnesium stearate, calcium stearate, and sodium stearate), stearic acid, hydrogenated vegetable oil (e.g., Sterotex™), talc, waxes, such as beeswax and carnauba wax, silica, fumigated 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 stearyl fumarate (Pruv™), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, It may include, but is not limited to, glycerin, propylene glycol and combinations thereof.

[0249] In certain embodiments, suitable pharmaceutically acceptable excipients include, as non-limiting examples, lactose USP, lactose USP (anhydrous), lactose USP (dry spray), starch USP, direct pressed starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dibasic calcium phosphate dihydrate NF, sucrose-based diluents, confectionery, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules NF, dextrate NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed cereal solids, e.g., Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycerin, bentonite, polyvinylpyrrolidone, and other diluents. It can be included.

[0250] In certain embodiments, suitable pharmaceutically acceptable excipients may include, as non-limiting examples, oils and fats such as almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, coconut oil, kolja oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, Manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine 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 fillers for PVA shells include fish oil (omega-3), krill oil, animal or vegetable fats in hydrogenated form, and mono-glycerides, di-glycerides, and tri-glycerides with C12-, C14-, C16-, C18-, C20-, and C22- fatty acids.

[0251] In certain embodiments, suitable pharmaceutically acceptable excipients are vegetable proteins, e.g., sunflower protein, soy protein, cottonseed protein, peanut protein, grapeseed protein, whey protein, whey protein isolate, blood protein, egg protein, acrylated protein, water-soluble polysaccharides, e.g., alginate, carrageenan, guar gum, agar-agar, xanthan gum, gellan gum, gum arabic and related gums (ghatti gum, karaya gum, tragan gum), pectin, and water-soluble derivatives of cellulose: alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcellulose, e.g., methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters, e.g., cellulose acetate Phthalate (CAP), hydroxypropylmethylcellulose (HPMC); carboxyalkylcellulose, carboxyalkylalkylcellulose, carboxyalkylcellulose esters, e.g., carboxymethylcellulose and alkali metal salts thereof; water-soluble synthetic polymers, e.g., polyacrylic acid, polyacrylamide, and polyacrylic acid esters, polymethacrylic acid, polymethacrylamide, and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymer and polycrotic acid may be included; Phthalate-treated gelatin, gelatin succinate, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, for example, cationic modified acrylates and methacrylates having tertiary or quaternary amino groups, e.g., diethylaminoethyl groups which can be quaternified if desired; and other similar polymers; inorganic fillers such as magnesium oxide, silicon oxide, titanium oxide, etc. are also suitable.

[0252] In certain embodiments, suitable pharmaceutically acceptable excipients are hydrophobic materials, such as digestible, long-chain (C8-C8) materials, as a non-limiting example. 50 , especially C 12 -C 40 It may include ), substituted or unsubstituted hydrocarbons, such as natural or synthetic waxes (e.g., beeswax, glycowax, castor wax and carnauba wax), fatty alcohols (e.g., lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, such as mono-diglycerides, medium-chain triglycerides, fatty acid esters, fatty acid glycerides (mono-glycerides, di-glycerides and tri-glycerides) of medium-chain fatty acids (e.g., caprylic acid, capric acid, caproic acid, lauric acid, oleic acid, linoleic acid) as non-limiting examples, hydrogenated fats, hydrocarbons, common waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials having a hydrocarbon backbone.

[0253] In certain embodiments, suitable pharmaceutically acceptable excipients may include polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene oxide, polyacrylic acid, cellulose, cellulose ether, cellulose ester, cellulose amide, polyvinyl acetate, polycarboxylic acid and salt, acetic acid, caprylic acid, oleic acid, polyamino acid or peptide, polyamide, polyacrylamide, copolymer of maleic acid / acrylic acid, polysaccharides including starch and gelatin, natural gums, such as xanthan and carrageenan. For example, the polymer is a polyacrylate and water-soluble acrylate copolymer, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, maltodextrin, polymethacrylate, and combinations thereof, or polyvinyl alcohol, polyvinyl alcohol copolymer and hydroxypropyl methylcellulose (HPMC), methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate / methyl methacrylate copolymer, shellac, hydroxypropyl methylcellulose phthalate, hydroxylpropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caplilocaproyl Polyoxyl-8 glycerides, glyceryl distearate, and combinations thereof may be selected.

[0254] In certain embodiments, suitable pharmaceutically acceptable excipients may include high HLB surfactants, such as, without limitation, polysorbate 80-polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated caster oil, polyoxyl 35 caster oil, caplylocaproyl magrogol glyceride, and combinations thereof.

[0255] In certain embodiments, suitable pharmaceutically acceptable excipients may include fillers, e.g., without limitation, lactose, microcrystalline cellulose, and combinations thereof.

[0256] In certain embodiments, suitable pharmaceutically acceptable excipients may include natural gums (e.g., natural plant gums). Suitable natural gums include, without limitation, guar gum, carob gum, konjac gum, xanthan gum, sclerotium gum, acacia gum, cellulose gum (modified or unmodified), or combinations thereof.

[0257] In certain embodiments, suitable pharmaceutically acceptable excipients are emulsifiers, e.g., without limitation, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-40 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 olivine, PEG-8 oleate, PEG-8 laurate, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-100 stearate, PEG-80 sorbitan laurate, steareth-2, steareth-12, oleeth-2, It may include ceteth-2, laureth-4, oleth-10, oleth-10 / polyoxyl 10 oleyl ether, ceteth-10, isosteareth-20, ceteareth-20, oleth-20, steareth-20, steareth-21, ceteth-20, isoceteareth-20, laureth-23, steareth-100, glyceryl stearate citrate, glyceryl stearate SE (autoemulsifying), stearic acid, salt of stearic acid, polyglyceryl-3-methylglycose distearate, or a combination thereof.

[0258] Additionally, suitable emulsifiers are phosphate esters and their salts, such as cetyl phosphate (Amphisol® A), diethanolamine cetyl phosphate (Amphisol ® DEA), potassium cetyl phosphate (Amphisol ® K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphate, and mixtures thereof. Additionally, suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate, and hydrated polyisobutene. Furthermore, one or more synthetic polymers may be used as emulsifiers. For example, PVP eicocene copolymer, acrylate / C 10 -3o alkyl acrylate crosslinked polymer, acrylate / stearate-20 methacrylate copolymer, PEG-22 / dodecyl glycol copolymer, PEG-45 / dodecyl glycol copolymer, and mixtures thereof.

[0259] In certain embodiments, suitable pharmaceutically acceptable excipients may include chelating agents, such as, but not limited to, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA) and nitrilotriacetic acid (NTA).

[0260] In certain embodiments, suitable pharmaceutically acceptable excipients may include gourbet alcohols based on fatty alcohols having 6 to 18, preferably 8 to 10, carbon atoms, including, without limitation, cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, benzoates of C12-C15 alcohols, acetylated lanolin alcohol, etc.

[0261] In certain embodiments, suitable pharmaceutically acceptable excipients are esters of fatty acids, e.g., linear C6-C without limitation. 24 Fatty acids and linear C3-C 24 Alcohol esters, branched C6-C 13 Carboxylic acid and linear C6-C 24 esters of fatty alcohols, linear C6-C 24 Fatty acids and branched alcohols, particularly esters of 2-ethylhexanol, hydroxycarboxylic acids, particularly dioctyl maleate and linear or branched C6-C 22Esters of fatty alcohols, esters of linear and / or branched fatty acids and polyhydric alcohols (e.g., propylene glycol, dimeric diols, or trimeric triols) and / or Guerbet alcohols, e.g., caproic acid, caprylic acid, 2-ethylhexanoic acid, caprylic acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitolic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, linolenic acid, elaistearic acid, arachidic acid, gadoleic acid, behenic acid, and erucic acid, and technical grade mixtures thereof with alcohols (e.g., obtained from depressurization of natural fats and oils, reduction of aldehydes from the oxidation of Roelen, or dimerization of unsaturated fatty acids), e.g., isopropyl alcohol, capro alcohol, capryl alcohol, 2-ethylhexyl alcohol, capr alcohol, It may include esters of lauryl alcohol, isotridecyl alcohol, myristyl alcohol, cetyl alcohol, palmoleyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, petroselinyl alcohol, linoleyl alcohol, linolenyl alcohol, elaeostearyl alcohol, arachidyl alcohol, gadoleyl alcohol, behenyl alcohol, erucyl alcohol, and brassidyl alcohol and technical grade mixtures thereof (e.g., obtained as monomer fractions from the high-pressure hydrogenation of technical grade methyl esters based on fats and oils or aldehydes obtained from the oxygen synthesis of roelene and the dimerization of unsaturated fatty alcohols).Examples of additional suitable ester oils include isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, iso-nonyl stearate, isononyl isonanoate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl lucate, erucyl oleate, erucyl erucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl oleate, cetyl behenate, cetyl acetate, myristyl myristate, myristyl behenate, and myristyl These include oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate / caprate, stearyl heptanoate, diisostearyl maleate, octyl hydroxystearate, etc.

[0262] In certain embodiments, suitable pharmaceutically acceptable excipients may include other adjuvants, e.g., without limitation, diethylhexyl 2,6-naphthalate, di-n-butyl adipate, di(2-ethylhexyl)-adipate, di(2-ethylhexyl)-succinate and diisotridecyl acetate, and also diol esters, e.g., ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dipelargonate, butanediol diisostearate and neopentyl glycol dicaprylate. Aromatic carboxylic acids, saturated and / or unsaturated, particularly benzoic acids, particularly benzoic acids and C6-C 24 Esters of fatty alcohols and / or Gourbet alcohols, linear or branched alcohols having 1 to 22 carbon atoms, or polyols having 2 to 10 carbon atoms and 2 to 6 hydroxyl groups, and C2-C 12 Dicarboxylic acid ester.

[0263] In certain embodiments, suitable pharmaceutically acceptable excipients are natural or synthetic triglycerides (including glyceryl esters and derivatives), e.g., C6-C modified by reaction with other alcohols (capryl / capric triglycerides, malt glycerides, etc.), without limitation. 18 It may include fatty acid-based diglycerides or triglycerides. Fatty acid esters of polyglycerin (polyglyceryl-n, e.g., polyglyceryl-4 caprate, polyglyceryl-2 isostearate, etc.) or castor oil, hydrogenated vegetable oil, sweet almond oil, malt oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borage oil, etc. Additional suitable excipients include waxes containing esters of long-chain acids and alcohols, as well as compounds having wax-like properties, e.g., carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ozokite, Japanese wax, paraffin wax, microcrystalline wax, ceresin, cetearyl ester wax, synthetic beeswax, etc. In addition, hydrophilic wax as cetearyl alcohol or partial glyceride.

[0264] In certain embodiments, suitable pharmaceutically acceptable excipients are pearlescent waxes, e.g., without limitation, alkylene glycol esters, particularly ethylene glycol distearate; fatty acid alkanolamides, particularly coco fatty acid diethanolamide; partial glycerides, particularly stearic acid monoglycerides; esters of polyvalent unsubstituted or hydroxysubstituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, particularly long-chain esters of tartaric acid; fatty substances, e.g., fatty alcohols having a total of at least 24 carbon atoms, fatty ketones, fatty aldehydes, fatty ethers, and fatty carbonates, particularly lauryl and distearyl ethers; It may include ring-opening products of olefin epoxides having 12 to 22 carbon atoms with fatty acids, such as stearic acid, hydroxystearic acid or behenic acid, fatty alcohols having 12 to 22 carbon atoms and / or polyols having 2 to 15 carbon atoms and polyols having 2 to 10 hydroxyl groups, and mixtures thereof.

[0265] In certain embodiments, suitable pharmaceutically acceptable excipients may include hydrocarbon oils, e.g., without limitation, mineral oil (light or heavy), petroleum (yellow or white), microcrystalline waxes, paraffin and isoparaffin compounds, hydrogenated isoparaffin molecules as polydecene and polybutene, hydrogenated polyisobutene, squalane, isohexadecane, isododecane, and others from the plant and animal kingdoms.

[0266] In certain embodiments, suitable pharmaceutically acceptable excipients may include silicones or siloxanes (organo-substituted polysiloxanes), e.g., without limitation, dimethylpolysiloxane, methylphenylpolysiloxane, cyclic silicones, and also amino, fatty acid, alcohol, polyether, epoxy, fluorine, glycoside and / or alkyl-modified silicone compounds that may be in liquid or resin form at room temperature. Linear polysiloxanes, dimethicone (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethicone, cyclic silicone fluids, cyclopentasiloxane volatiles (Dow Corning 345 fluid), phenyltrimethicone (Dow Corning 556 fluid). Simethicone, which is a mixture of dimethicone and hydrogenated silicate having an average chain length of 200 to 300 dimethylsiloxane units, is also suitable. For a detailed investigation of suitable volatile silicones, refer to the literature [Cosm. Toil. This can also be confirmed in 91, 27 (1976).

[0267] In certain embodiments, suitable pharmaceutically acceptable excipients may include emulsifiers, e.g., without limitation, carboxylic acids and their salts: alkaline soaps of sodium, potassium and ammonium, metallic soaps of calcium or magnesium, organic basic soaps such as lauric acid, palmitic acid, stearic acid and oleic acid, etc. Alkyl phosphates or phosphate esters, acid phosphates, diethanolamine phosphates, potassium cetyl phosphate. Ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acylates. 2 to 30 mol of ethylene oxide and / or 0 to 5 mol of propylene oxide and a linear fatty alcohol having 8 to 22 carbon atoms branched from a fatty acid having 12 to 22 carbon atoms and an alkylphenol having 8 to 15 carbon atoms in an alkyl group. Fatty alcohol polyglycol ethers, e.g., laureth-n, ceteareth-n, steareth-n, oleth-n. Fatty acid polyglycol ethers, e.g., PEG-n stearate, PEG-n oleate, PEG-n cocoate. Monoglycerides and polyol esters. C12-C22 fatty acid mono-esters and di-esters of the addition product of 1 to 30 mol of ethylene oxide and a polyol. Fatty acid and polyglycerol esters, e.g., monostearate glycerol, diisostearoyl polyglyceryl-3-diisostearate, polyglyceryl-3-diisostearate, triglyceryl diisostearate, polyglyceryl-2-sesquiisostearate, or polyglyceryl dimerate. Mixtures of compounds of multiple of these types of substances are also suitable. Fatty acid polyglycol esters, e.g., monostearate diethylene glycol, fatty acid and polyethylene glycol esters, fatty acid and saccharose esters, e.g., sucrose esters, glycerol and saccharose esters, e.g., sucrose glycerides. Sorbitol and sorbitan, sorbitan mono-esters and di-esters of saturated and unsaturated fatty acids having 6 to 22 carbon atoms and ethylene oxide adducts.Polysorbate-n series, sorbitan esters, e.g., sesquiisostearate, sorbitan, PEG-(6)-isostearate sorbitan, PEG-(10)-sorbitan laurate, PEG-17-dioleate sorbitan. Glucose derivatives, C8-C22 alkyl-mono and oligo-glycosides and ethoxylated analogs (glucose is preferred as the sugar component). O / W emulsifiers, e.g., methyl glucose-20 sesquistearate, sorbitan stearate / sucrose cocoate, methyl glucose sesquistearate, cetearyl alcohol / cetearyl glucoside. W / O emulsifiers, e.g., methyl glucose dioleate / methyl glucose isostearate. Sulfates and sulfonated derivatives, dialkylsulfosuccinates, dioctyl succinates, alkyl lauryl sulfonates, linear sulfonated paraffins, sulfonated tetrapropylene sulfonates, sodium lauryl sulfate, ammonium and ethanolamine lauryl sulfate, lauryl ether sulfate, sodium laureth sulfate, sulfosuccinates, acetyl isothionate, alkanolamide sulfates, taurine, methyl taurine, imidazole sulfate. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicones, copolyols, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ethers (Meroxapol), Polaxamer, or poly(oxyethylene)m-block-poly(oxypropylene)n-block(oxyethylene). An amphoteric surfactant having at least one quaternary ammonium group and at least one carboxylate and / or sulfonate group within the molecule.Particularly suitable amphoteric surfactants are betaines, such as N-alkyl-N,N-dimethylammonium glycinate, cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium glycinate, cocoacylaminopropyldimethylammonium glycinate, and 2-alkyl-3-carboxymethyl-3-hydroxyethylimidazoline having 8 to 18 carbon atoms in each alkyl or acyl group, and also cocoacylaminoethylhydroxyethylcarboxymethylglycinate, N-alkyl betaine, N-alkylaminobetaine, alkylimidazoline, alkylopeptides, lipoamino acids, autoemulsifying bases, and compounds described in the literature [KF DePolo, A short textbook of cosmetology, Chapter 8, Table 8-7, pp. 250-251].

[0268] Suitable nonionic bases are, without limitation, PEG-6 wax (and) PEG-6 stearate (and) polyglyceryl-2-isostearate, glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglyceryl-3 lysine oleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and ceteth-20, cetearyl alcohol and polysorbate 60 and PEG-150 and stearate-20, cetearyl alcohol and cetearyl polyglucoside, cetearyl alcohol and ceteareth-20, cetearyl alcohol and PEG-40 castor oil, cetearyl alcohol and PEG-40 castor oil and sodium It includes cetearyl sulfate, stearyl alcohol and steareth-7 and steareth-10, cetearyl alcohol and steareth-7 and steareth-10, glyceryl stearate and PEG-75 stearate, propylene glycol ceteth-3 acetate, propylene glycol isoceth-3 acetate, cetearyl alcohol and ceteth-12 and oleth-12, PEG-6 stearate and PEG-32 stearate, PEG-6 stearate and ceteth-20 and steareth-20, PEG-6 stearate and ceteth-20 and glyceryl stearate and steareth-20, glyceryl stearate and ceteareth-20.

[0269] Suitable anionic alkali bases include, without limitation, PEG-2 stearate SE, glyceryl stearate SE, and propylene glycol stearate. Anionic acid bases, e.g., cetearyl alcohol and sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, trilaneth-4 phosphate and glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulfate. Cationic acid bases, e.g., cetearyl alcohol and cetrimonium bromide.

[0270] In certain embodiments, suitable pharmaceutically acceptable excipients may include adjuvants and additives, e.g., without limitation, surfactants, superfat-forming agents, viscosity modifiers, thickeners, polymers, stabilizers, bioactive ingredients, swelling agents, additional UV photoprotective factors, antioxidants, hydrophobic agents, preservatives, self-tanning agents, solubilizers, fragrance oils, colorants, antibacterial agents, and others.

[0271] In certain embodiments, suitable pharmaceutically acceptable excipients may include super-fatting agents, such as, without limitation, lanolin and lecithin and also polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides and fatty acid alkanolamides (the latter may simultaneously act as foam stabilizers).

[0272] In certain embodiments, suitable pharmaceutically acceptable excipients may include surfactants, e.g., without limitation, fatty alcohol polyglycol ether sulfate, monoglyceride sulfate, mono- and / or di-alkyl sulfosuccinate, fatty acid isethionate, fatty acid sarcosinate, fatty acid tauride, fatty acid glutamate, alpha-olefin sulfonate, ethercarboxylic acid, alkyl oligoglucoside, fatty acid glucamide, alkylamidobetaine and / or protein fatty acid condensation product (the latter preferably based on wheat protein).

[0273] In certain embodiments, suitable pharmaceutically acceptable excipients may include viscosity modifiers / thickeners and rheology modifiers, e.g., without limitation, silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or derivatives thereof, e.g., hyaluronic acid, xanthan gum, guar-guar, agar-agar, alginate, carrageenan, gellan, pectin, or modified cellulose, e.g., hydroxycellulose, hydroxypropylmethylcellulose. In addition, homopolymers of polyacrylates or network acrylic acids and polyacrylamides, carbomers (CARBOPOL types 980, 981, 1382, ETD 2001, ETD2020, ULTREZ 10), or the SALCARE range, e.g., SALCARE SC80 (Stealess-10 allyl ether / acrylate copolymer), Salcare SC81 (acrylate copolymer), Salcare SC91 and Salcare AST (sodium acrylate copolymer / PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide / laureth-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer), STABILEN 30 (acrylate / vinyl isodecanoate crosslinked polymer), PEMULEN TR-1 (acrylate / C10-30 alkyl acrylate crosslinked polymer), LUVIGEL EM (sodium acrylate copolymer), ACULYN 28 (acrylate / Beneth-25 methacrylate copolymer), etc.

[0274] In certain embodiments, suitable pharmaceutically acceptable excipients may comprise polymers, e.g., without limitation, anionic, amphoteric, amphoteric and nonionic polymers, e.g., vinyl acetate / crotonic acid copolymer, vinylpyrrolidone / vinyl acrylate copolymer, vinyl acetate / butyl maleate / isobornyl acrylate copolymer, methyl vinyl ether / maleic anhydride copolymer and esters thereof, non-crosslinked polyacrylic acid and polyacrylic acid crosslinked with polyol, acrylamidopropyl-trimethylammonium chloride / acrylate copolymer, octyl acrylamide / methyl methacrylate-tert-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymer, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, vinylpyrrolidone / dimethylaminoethyl methacrylate / vinyl caprolactam terpolymer, and also optionally Derivatized cellulose ethers and silicon are considered. Furthermore, polymers described in European Patent EP 1093796 (pages 3-8, paragraphs 17-68) may be used.

[0275] In certain embodiments, suitable pharmaceutically acceptable excipients are antioxidants, e.g., without limitation, amino acids (e.g., glycerin, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g., urocanic acid) and derivatives thereof, peptides, e.g., D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (e.g., anserine), carotenoids, carotenes, lycopene and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (e.g., dihydrolipoic acid), orothioglycoses, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cholesteryl and glyceryl esters thereof) and also their Salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts) and also sulfoximine compounds (e.g., butionine sulfoximine, homocysteine ​​sulfoximine, butionine sulfone, penta-, hexa-, hepta-thionine sulfoximine), also (metal) chelating agents (e.g., hydroxy fatty acids, palmitate, phytic acid, lactoferrin), hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, bile acids, bile extracts, bilirubin, biliverdin, EDTA, EDDS, EGTA and their derivatives, unsaturated fatty acids and their derivatives (e.g., linolenic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives (e.g., ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and derivatives (e.g., vitamin E acetate), vitamin A and derivatives (e.g., vitamin A palmitate), and also coniferyl benzoate of benzoin resin, rutinic acid and derivatives thereof, glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine,It may include butyl hydroxytoluene, butyl hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, superoxide dismutase, N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl]sulfanilic acid (and its salts, e.g., disodium salts), selenium and its derivatives (e.g., selenium methionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), and suitable derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids) of the mentioned active ingredients according to the present invention. HALS ("hindered amine light stabilizers") compounds may also be mentioned.

[0276] In certain embodiments, suitable pharmaceutically acceptable excipients may comprise hydrotropic agents, e.g., without limitation, ethoxylated or non-ethoxylated mono-alcohols, diols or polyols having a small number of carbon atoms, or ethers thereof (e.g., ethanol, isopropanol, 1,2-dipropanediol, propylene glycol, glycerin, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether; diethylene glycol monoethyl ether, diethylene glycol monobutyl ether and similar products). The polyols considered for this purpose preferably have 2 to 15 carbon atoms and at least 2 hydroxyl groups. The polyols may also contain additional functional groups, particularly amino groups, and / or may be modified with nitrogen. Common examples are as follows: glycerol, alkylene glycols, e.g., ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol, and also polyethylene glycol having an average molecular weight of 100 to 1000 daltons; technical oligoglycerol mixtures having an internal degree of condensation of 1.5 to 10, e.g., technical diglycerol mixtures having a diglycerol content of 40 to 50 weight%; methylol compounds, e.g., particularly trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol, and dipentaerythritol; lower alkyl-glucosides, in particular those having 1 to 8 carbon atoms in the alkyl radical, e.g., methyl and butyl glucosides; sugar alcohols having 5 to 12 carbon atoms, e.g., sorbitol or mannitol; Sugars having 5 to 12 carbon atoms, e.g., glucose or saccharose; amino sugars, e.g., glucamine; diallamines, e.g., diethanolamine or 2-amino-1,3-propanediol.

[0277] In certain embodiments, suitable pharmaceutically acceptable excipients may include preservatives, e.g., without limitation, methyl-, ethyl-, propyl-, butyl-paraben, benzalkonium chloride, 2-bromo-2-nitro-propane-1,3-diol, dehydroacetic acid, diazolidinyl urea, 2-dichloro-benzyl alcohol, DMDM ​​hydantoin, formaldehyde solution, methyldibromoglutanitrile, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan, and additional substances listed in reference to the literature [KF DePolo-A short textbook of cosmetology, Chapter 7, Table 7-2, 7-3, 7-4 and 7-5, p 210-219].

[0278] In certain embodiments, suitable pharmaceutically acceptable excipients may include antibacterial inhibitors, e.g., without limitation, 2,4,4′-trichloro-2′-hydroxydiphenyl ether, chlorhexidine (1,6-di(4-chlorophenyl-biguanido)hexane), or TCC (3,4,4′-trichlorocarbanilide). Many aromatic substances and ether oils also possess antimicrobial properties. Common examples include eugenol, menthol, and thymol, which are active ingredients in clove oil, mint oil, and thyme oil. A natural deodorant of interest is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol) present in calcined oil. Glycerol monolaurate has also been proven to be a bacteriostatic agent.

[0279] Other pharmaceutically acceptable excipients may also be used as recognized by those skilled in the art.

[0280] In certain embodiments, pharmaceutically acceptable excipients may be included in the pharmaceutical composition described herein (individually or cumulatively) at concentrations of any 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 any 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 sub-range or single value range within the total weight of the composition.

[0281] Manufacturing method

[0282] In certain embodiments, the present disclosure relates to a method for preparing any of the compositions described herein. In certain embodiments, the method comprises combining a therapeutically effective amount of a compound disclosed herein with one or more pharmaceutically acceptable excipients.

[0283] The various compositions described herein may be formulated to have customized release profiles for the active agent, e.g., without limitation, immediate release profile, controlled release profile, delayed release profile, intestinal release profile, zero-order release profile, primary release profile, pulsed release profile, targeted release profile at a specific location in the body (e.g., a target location in the gastrointestinal tract), and others.

[0284] Examples

[0285] Three SD rats (approx. 300 gm) received IV bolus administration of Challenge (3 mg / kg xylazine and 20 μg / kg fentanyl) and Rescue (3 mg / kg). PCO2, PO2, and blood pH were measured at 5, 10, and 15 minutes after Rescue, and the data are shown in Figures 1 to 3. The data show arterial and venous blood values.

[0286] The sham group was not rescued. After further observation, the rat did not fully recover. This suggests that the time the blood pH remained low even after xylazine / fentanyl was removed from the system had a harmful effect on the subject. Therefore, in addition to saving lives from overdose, the present invention can have a positive long-term effect on the patient.

[0287] For the sake of simplification of description, embodiments of the method of the present disclosure are illustrated and described as a series of actions. However, actions according to the present disclosure may occur in various order and / or simultaneously, and may occur with other actions not presented or described herein. Furthermore, not all illustrated actions may be required to implement the method according to the subject matter disclosed. Additionally, those skilled in the art will understand and recognize that the method may alternatively be represented as a series of interrelated states through state diagrams or events.

[0288] In the foregoing description, numerous specific details, such as specific materials, dimensions, process parameters, etc., are presented to provide a thorough understanding of the invention. In one or more embodiments, specific characteristics, structures, materials, or features may be combined in any suitable manner. The words “e.g.” or “exemplary” are used herein to mean that they serve as examples, cases, or examples. Any embodiment or design described herein as “e.g.” or “exemplary” is not to be interpreted as being more desirable or advantageous than other embodiments or designs. Rather, the use of the words “e.g.” or “exemplary” is intended to present a concept in a specific manner. The term “or” as used in this application is intended to mean an inclusive “or” rather than an exclusive “or.” That is, unless otherwise stated or is not evident from the context, “X contains A or B” is intended to mean any natural permutation of inclusion. That is, if X contains A; X contains B; or X contains both A and B, “X contains A or B” is satisfied under any of the following cases. References throughout this specification to “one embodiment,” “a specific embodiment,” or “one embodiment” mean that a specific characteristic, structure, or feature described in connection with such embodiment is included in at least one embodiment. As such, the appearance of phrases such as “one embodiment,” “a specific embodiment,” or “one embodiment” at various locations throughout this specification does not necessarily refer to the same embodiment.

[0289] The present invention is described in connection with specific exemplary embodiments thereof. The specification and drawings are therefore to be understood as exemplary rather than restrictive. Various variations of the invention, other than those depicted and described herein, will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

Claim 1 A method for treating drug overdose, comprising the step of administering a therapeutically effective amount of a respiratory stimulant to a patient requiring treatment for drug overdose, wherein the overdose drug comprises an α2 adrenergic receptor agonist. Claim 2 A method according to claim 1, wherein the overdose of the drug is accompanied by respiratory depression, sedation, hypotension, central nervous system side effects, cardiac side effects, or a combination thereof. Claim 3 In paragraph 2, the method wherein the overdose of the above drug is accompanied by respiratory depression. Claim 4 A 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, padolmidine, guanabenz, guanfacine, lopexidine, marsanidine, medetomidine, methyldopa, mibazerol, rilmenidine, romipidine, talipexol, thiamenidine, tizanidine, tolonidine, xylazine, xylometazoline, pharmaceutically acceptable salts thereof, and combinations thereof. Claim 5 In paragraph 4, the method comprises an α2 adrenergic receptor agonist comprising xylazine or a pharmaceutically acceptable salt thereof. Claim 6 A method according to any one of claims 1 to 4, wherein the overdose drug comprises an opioid agonist. Claim 7 In claim 6, the opioid agonist comprises oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, sufentanyl, morphine, tramadol, buprenorphine, kappa opioid receptor agonists (e.g., butorpanol, nalbuphine, levorpanol, levalofane, pentazocine, phenazocine, eptazosin), pharmaceutically acceptable salts thereof and combinations thereof. Claim 8 In claim 7, the method wherein the opioid is fentanyl or a pharmaceutically acceptable salt thereof. Claim 9 Method of claim 1, wherein the respiratory stimulant comprises a compound selected from formula (I) or a pharmaceutically acceptable salt thereof: In the above formula, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; R 1 and R 2 ... combines to form an radical 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 and;R 4 is H, alkyl, or substituted alkyl and;R 5 is H, alkyl, propargyl, substituted propargyl, homopropagyl, substituted homopropagyl, 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 ... combines to form an radical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl or alkenyl; X is a bond, O or NR 4 And;Y is N, CR 6 or C and; Y is N or CR 6 If so, combination b 1 There is no: (i) Z is H, and bond b 2 is a single bond, and A is CH or; (ii) Z is absent, and bond b 2 There is none, A is a single bond; if Y is C, then bond b 1 is a single bond and: (i) Z is CH2, and bond b 2 is a single bond, and A is CH or; (ii) Z is CH, and bond b 2 is a double bond, and A is C. Claim 10 The method of claim 1, wherein 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. Claim 11 A method according to any one of claims 1 to 10, wherein the administration does not include an opioid antagonist. Claim 12 A method according to any one of claims 1 to 11, wherein the administration further comprises an opioid antagonist. Claim 13 A method according to claim 12, wherein the antagonist and the stimulant are administered simultaneously or sequentially. Claim 14 In paragraph 12, the method wherein the antagonist and the stimulant are administered by the same route of administration. Claim 15 In paragraph 12, the method wherein the antagonist and the stimulant are administered by different routes of administration. Claim 16 In claim 12, the method wherein the antagonist and the stimulant are administered as the same pharmaceutical composition. Claim 17 In claim 12, the method wherein the antagonist and the stimulant are administered in different pharmaceutical compositions. Claim 18 A method according to any one of claims 12 to 17, wherein the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, nalmephen, and pharmaceutically acceptable salts thereof. Claim 19 A method according to claim 1, wherein the respiratory stimulant is selected from the group consisting of doxapram, almitrin, caffeine, and pharmaceutically acceptable salts thereof. Claim 20 A method according to claim 1, wherein the stimulant is provided in a therapeutic dose sufficient to restore or improve the breathing rhythm of a patient who has been overdosed. Claim 21 The method of claim 1, wherein the stimulant is provided at a therapeutic dose that does not induce hyperventilation or substantial hyperventilation in a patient overdoseed. Claim 22 In claim 12, the method wherein the antagonist is provided at a dose less than or greater than the therapeutic dose, assuming the case where it is administered without the stimulant. Claim 23 In claim 12, the method wherein the above-mentioned antagonist is provided at a therapeutic dose assuming it is administered without a stimulant. Claim 24 In paragraph 12, the method wherein the stimulant is provided at a dose less than or greater than the therapeutic dose, assuming the case where it is administered without the antagonist. Claim 25 In paragraph 12, the method is provided at a therapeutic dose, assuming the stimulant is administered without an antagonist. Claim 26 A method according to any one of claims 1 to 25, wherein the overdose of the drug comprises a benzodiazepine, a barbiturate, a gabapentinoid, or a combination thereof. Claim 27 The method according to claim 1, wherein the route is selected from oral, intravenous, nasal, inhaled, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, tracheal, ear, intraocular, or spinal canal routes. Claim 28 In paragraph 15, the above route is independently selected from oral, intravenous, nasal, inhaled, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, ear, intraocular, or spinal route. Claim 29 A method according to any one of claims 1 to 28, wherein the administration results in a decrease in blood PCO2. Claim 30 In paragraph 29, the above reduction occurs at 5 minutes or less after administration, 10 minutes or less after administration, or 15 minutes or less after administration. Claim 31 A method according to any one of claims 1 to 30, wherein the administration results in an increase in blood PO2. Claim 32 In paragraph 31, the above increase occurs within 5 minutes or less after administration, within 10 minutes or less after administration, or within 15 minutes or less after administration. Claim 33 A method according to any one of claims 1 to 32, wherein the administration results in an increase in blood pH. Claim 34 In paragraph 33, the above increase occurs within 5 minutes or less after administration, within 10 minutes or less after administration, or within 15 minutes or less after administration. Claim 35 A method according to 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. Claim 36 A method for treating low blood pH caused by respiratory failure, comprising the step of administering a therapeutically effective amount of a respiratory stimulant to a patient requiring treatment for low blood pH. Claim 37 In paragraph 36, the above respiratory failure is due to drug overdose. Claim 38 In claim 37, the method wherein the overdose of the drug comprises an α2 adrenergic receptor agonist. Claim 39 A method according to any one of claims 36 to 38, wherein the α2 adrenergic receptor agonist comprises 4-NEMD, 7-me-marsanidine, agmatine, apraclonidine, brimonidine, cannabigerol, clonidine, detomidine, dexmedetomidine, padolmidine, guanabenz, guanfacine, lopexidine, marsanidine, medetomidine, methyldopa, mibazerol, rilmenidine, romipidine, talipexol, thiamenidine, tizanidine, tolonidine, xylazine, xylometazoline, pharmaceutically acceptable salts thereof, and combinations thereof. Claim 40 In paragraph 39, the method comprises an α2 adrenergic receptor agonist comprising xylazine or a pharmaceutically acceptable salt thereof. Claim 41 A method according to any one of claims 36 to 39, wherein the overdose drug comprises an opioid agonist. Claim 42 In claim 41, the opioid agonist comprises oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, sufentanyl, morphine, tramadol, buprenorphine, pharmaceutically acceptable salts thereof, and combinations thereof. Claim 43 In paragraph 42, the method wherein the opioid is fentanyl or a pharmaceutically acceptable salt thereof. Claim 44 Method of claim 1, wherein the respiratory stimulant comprises a compound selected from formula (I) or a pharmaceutically acceptable salt thereof: In the above formula, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; R 1 and R 2 ... combines to form an radical 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 and;R 4 is H, alkyl, or substituted alkyl and;R 5 is H, alkyl, propargyl, substituted propargyl, homopropagyl, substituted homopropagyl, 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 ... combines to form an radical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl or alkenyl; X is a bond, O or NR 4 And;Y is N, CR 6 or C and;Y is N or CR 6 If so, combination b 1 There is no: (i) Z is H, and bond b 2 is a single bond, and A is CH or; (ii) Z is absent, and bond b 2 There is none, A is a single bond; if Y is C, then bond b 1 is a single bond and: (i) Z is CH2, and bond b 2 is a single bond, and A is CH or; (ii) Z is CH, and bond b 2 is a double bond, and A is C. Claim 45 In paragraph 44, the method wherein 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. Claim 46 A method according to any one of claims 36 to 45, wherein the administration does not include an opioid antagonist. Claim 47 A method according to any one of claims 36 to 45, wherein the administration further comprises an opioid antagonist. Claim 48 In paragraph 47, the method wherein the antagonist and the stimulant are administered simultaneously or sequentially. Claim 49 In paragraph 47, the method wherein the antagonist and the stimulant are administered by the same route of administration. Claim 50 In paragraph 47, the method wherein the antagonist and the stimulant are administered by different routes of administration. Claim 51 In claim 47, the method wherein the antagonist and the stimulant are administered as the same pharmaceutical composition. Claim 52 In paragraph 47, the method wherein the antagonist and the stimulant are administered in different pharmaceutical compositions. Claim 53 A method according to any one of claims 47 to 52, wherein the opioid receptor antagonist is selected from the group consisting of naltrexone, naloxone, nalmephen, and pharmaceutically acceptable salts thereof. Claim 54 In paragraph 36, the method wherein the respiratory stimulant is selected from the group consisting of doxapram, almitrin, caffeine, and pharmaceutically acceptable salts thereof. Claim 55 In paragraph 36, the method wherein the stimulant is provided in a therapeutic dose sufficient to restore or improve the breathing rhythm of a patient who has been overdosed. Claim 56 In paragraph 36, the method wherein the stimulant is provided at a therapeutic dose that does not induce hyperventilation or substantial hyperventilation in a patient overdoseed. Claim 57 In paragraph 47, the method wherein the antagonist is provided at a dose less than or greater than the therapeutic dose, assuming the case where it is administered without the stimulant. Claim 58 In paragraph 47, the method wherein the antagonist is provided in a therapeutic dose assuming it is administered without the stimulant. Claim 59 In paragraph 47, the method wherein the stimulant is provided at a dose less than or greater than the therapeutic dose, assuming the case where it is administered without the antagonist. Claim 60 In paragraph 47, the method wherein the stimulant is provided in a therapeutic dose assuming it is administered without the antagonist. Claim 61 A method according to any one of claims 36 to 60, wherein the overdose of the drug comprises a benzodiazepine, a barbiturate, a gabapentinoid, or a combination thereof. Claim 62 In paragraph 36, the above route is selected from oral, intravenous, nasal, inhaled, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, percutaneous, epidural, intratracheal, ear, intraocular, or spinal canal routes. Claim 63 In paragraph 47, the above route is independently selected from oral, intravenous, nasal, inhaled, local, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, ear, intraocular, or spinal route. Claim 64 In paragraph 36, a method for causing an increase in blood pH. Claim 65 In paragraph 64, the above increase occurs at 5 minutes or less after administration, 10 minutes or less after administration, or 15 minutes or less after administration. Claim 66 A method for bringing about a physiologically acceptable blood pH after administration in any one of claims 36 to 65. Claim 67 In paragraph 66, the method wherein the physiologically acceptable blood pH is obtained at 5 minutes or less after administration, 10 minutes or less after administration, or 15 minutes or less after administration. Claim 68 A pharmaceutical composition comprising a therapeutically effective amount of a respiratory stimulant for treating drug overdose, wherein the overdose drug comprises an α2 adrenergic receptor agonist.

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