Treatment method for nervous ventilation insufficiency

Abstract

A method of treating neurogenic hypoventilation is disclosed in certain embodiments, the method comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I) disclosed herein.

Description

Technical Field

[0001] The present disclosure relates to methods of use and compositions therefor for the treatment of neurological ventilatory insufficiency in patients or subjects, for example, who have no or insufficient spontaneous ventilation ability.

Background Art

[0002] Apnea of prematurity (AOP) is a respiratory disorder that occurs in many preterm infants and is one of the most common diagnoses in the neonatal intensive care unit (NICU). AOP is not a disease but is mainly related to the physiological immaturity of the respiratory system, and its presence is inversely proportional to the gestational age. Therefore, it is particularly due to the immature state of the pulmonary system with respect to breathing. The definition varies by country and medical society, but recently, the American Academy of Pediatrics Committee on Fetus and Newborn (AAP-COFN) has defined it as a respiratory arrest exceeding 20 seconds in fetuses less than 37 weeks of gestation, or a decrease in oxygen saturation or cyanosis, or the occurrence of a shorter respiratory arrest accompanied by bradycardia less than 100 bpm. The incidence of AOP is inversely proportional to the gestational age and birth weight, such that it occurs in 54% of those born at 30-31 weeks of gestation compared to 7% of those born at 34-35 weeks of gestation. It is almost universal in preterm infants born before 29 weeks of gestation.

[0003] Although there is a potential for side effects, the administration of caffeine citrate is routine for preterm neonates at risk for or diagnosed with AoP. Caffeine is generally effective in reducing the severity of AoP, but caffeine administration has limited side effects as a central stimulant. Patients who do not respond to or tolerate caffeine treatment are often treated with doxapram, a drug not recommended for neonates showing a need for alternative therapy (doxapram contains benzyl alcohol, which is known to be toxic to neonates). There is currently no therapy for AoP that targets peripheral stimulation of the respiratory control loop that can act independently of or synergistically with caffeine.

[0004] For example, there is a need in the art for methods and compositions for treating neurological ventilatory insufficiency in patients or subjects who have no or insufficient spontaneous ventilation ability. This need can address medical conditions including, but not limited to, apnea of prematurity, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), seizure rescue, an alternative to cardiopulmonary resuscitation (CPR), stroke, or nerve fatigue. SUMMARY OF THE INVENTION

[0005] In certain embodiments, the present disclosure relates to a method of treating neurological ventilatory insufficiency, the method comprising administering to a patient in need thereof an effective amount of a compound selected from Formula (I):

Chemical formula

[0006] In certain embodiments, at least one substituent selected from the group consisting of R 1 , R 2 , R 3 , and R 5 described with respect to formula (I) above is alkynyl or substituted alkynyl.

[0007] In certain embodiments, the compound is N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine or a pharmaceutically acceptable salt thereof.

[0008] In certain embodiments, the compound of formula (I) is administered via a route selected from the oral, intravenous, nasal, inhalation, topical, oral, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, ear, intraocular, or intrathecal routes.

[0009] In certain embodiments, the present disclosure provides an effective amount of a compound of formula (I) for treating neurological ventilation failure:

Chemical formula

[0010] In certain embodiments, the disclosure relates to a method of preparing any of the pharmaceutical compositions described herein.

[0011] The above and other features, nature, and various advantages of the present invention will become more apparent upon consideration of the following detailed description in conjunction with the accompanying drawings.

Brief Description of the Drawings

[0012]

Figure 1

Figure 2

Figure 3

[0013] Definitions As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, references to "an active agent" include not only a single active agent but also mixtures of two or more different active agents, and references to "an excipient" include not only a single excipient but also mixtures of two or more different excipients (and so on for others).

[0014] As used herein, the term "about" in relation to a measured quantity refers to the normal variation of that measured quantity that would be expected by a person of ordinary skill in the art in performing the measurement with due care commensurate with the purpose of the measurement and the precision of the measuring device. In certain embodiments, the term "about" includes the stated number ±10%, and thus, "about 10" includes 9 to 11.

[0015] As used herein, the terms "active agent," "active ingredient," and "active pharmaceutical ingredient" refer to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not it has been approved by a government agency for that purpose. These terms with respect to a particular agent include all pharmaceutically active agents, all pharmaceutically acceptable salts, complexes, stereoisomers, crystal forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof, in a form that is pharmaceutically active.

[0016] As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. This includes enantiomers and isomers of compounds having one or more chiral centers that are not mirror images of each other (diastereomers).

[0017] The term "enantiomer" or "enantiomerism" refers to molecules that cannot be superimposed on their mirror images and are thus optically active, where an enantiomer rotates the plane of polarization in one direction to a certain extent and its mirror image rotates the plane of polarization to the same extent but in the opposite direction.

[0018] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0019] The term "patient" refers to a subject, animal, or human in whom clinical findings of specific symptom(s) suggesting a need for treatment are seen, or who is being treated for a condition for preventive or prophylactic purposes, or who is diagnosed with a condition to be treated. The term "subject" includes the definition of the term "patient" and does not exclude otherwise healthy individuals. Animals include domestic animals, zoo animals, and livestock (e.g., dogs, cats, horses, cows, pigs, lambs, goats, etc.).

[0020] "Pharmaceutically acceptable salts" or "salts" include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, phosphate, nitrate, carbonate, sulfuric, phosphoric (including hydrogen phosphate and dihydrogen phosphate), etc., organic acid salts such as oxalate, malonate, citrate, fumarate, lactate, malate, succinate, formate, acetate, trifluoroacetate, maleate, tartrate, gluconate, benzoate, salicylate, xinafoate, pamoate, ascorbate, adipate, cinnamate, etc., sulfonate salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc., amino acid salts such as arginate, asparaginate, glutamate, etc., metal salts such as zinc salt, sodium salt, cesium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc., and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine, etc. These salts can exist in the form of hydrates, solvates, or crystalline polymorphs. In certain embodiments, suitable organic acids are selected from the carboxylic acid and sulfonic acid classes of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.All of these salts can be prepared by conventional means from the corresponding compounds of the present invention, for example, by reacting the appropriate acid or base with the compound of the present invention. Handbook of Pharmaceutical Salts: Properties, and Use (P.H. Stahl & C.G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002) [1].

[0021] The term "disease(s)" or "condition(s)" refers to a medical condition that can be treated or prevented by administering an effective amount of an active agent to a subject.

[0022] The terms "treatment of" and "treating" include reducing or halting the severity of a condition, or reducing or halting the severity of the symptoms of a condition. In certain embodiments, the term "treatment" or "treating" means administration with the intent to produce a pharmacodynamic effect in relation to a condition, regardless of outcome. In certain embodiments, "treatment" or "treating" means "having a positive effect on a condition" and includes reduction, amelioration, and / or alleviation of the severity of at least one symptom of a condition, reduction, amelioration, and / or alleviation of the severity of a condition, delay, prevention, or inhibition of the progression of a condition, or an improvement or benefit perceived as a result of treatment. Treatment, as used herein, does not require complete cure of a condition. In certain embodiments, the compositions of the present disclosure can result in an improvement in the quality of life of a patient, or a delay, prevention, or inhibition of the onset of one or more symptoms of a condition, or a perceived benefit.

[0023] The terms "prevention of" and "preventing" include avoiding the onset of a condition.

[0024] The term "therapeutically effective amount" is intended to include, for example, the amount of an active agent or combination of active agents for treating or preventing a condition in a subject, or for treating the symptoms of a condition.

[0025] The term "effective amount" is intended to include the amount of a component or combination of components to achieve a particular result or property. For example, the effective amount of a pH adjuster to achieve a pH of 6.0 is intended to include the amount of one or more pH adjusters to reach a pH of 6.0.

[0026] The terms "apply", "applying", and "application" refer to any manner of administering a topical composition to a patient's skin surface, in the context of medical or cosmetic practice, in relation to the disclosed topical composition or method of using the disclosed topical composition. Applying, rubbing, spreading, or spraying the disclosed topical composition onto a patient's skin, with or without the use of a suitable device, are all included within the scope of the term "apply" as used herein. The terms "topical" or "topically" refer to epidermal administration or application, or administration on the skin, in relation to the administration or application of the disclosed formulation.

[0027] As used herein, "oral delivery" or "oral administration" refers to the route of administration by which a composition is taken orally. Oral administration is part of enteral administration and includes buccal administration (dissolving inside the cheek), sublabial administration (dissolving under the lip), and sublingual administration (dissolving under the tongue). In certain embodiments, oral administration includes the route of administration by which a composition is ingested. In certain embodiments, oral administration includes the route of administration by which a composition is inhaled.

[0028] As used herein, "parenteral administration" refers to the route of administration by which a pharmaceutical dosage form is injected, for example, into muscle (intramuscular administration), into a vein (intravenous administration), or under the skin (subcutaneous administration).

[0029] The phrase "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0030] As used herein, the term "alkyl", by itself or as part of another substituent, unless otherwise indicated, means a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C10 means 1 to 10 carbon atoms), including straight chain, branched chain, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred are (C1-C6) alkyl such as ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl, but not limited thereto.

[0031] As used herein, the term "cycloalkyl", by itself or as part of another substituent, unless otherwise indicated, means a cyclic chain hydrocarbon having the specified number of carbon atoms (i.e., C3-C6 means a cyclic group containing a ring group consisting of 3 to 6 carbon atoms), including straight chain, branched chain, or cyclic substituents. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred are (C3-C6) cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, but not limited thereto.

[0032] As used herein, the term "alkenyl", used alone or in combination with other terms, unless otherwise indicated, means a stable monovalent or divalent unsaturated straight or branched chain hydrocarbon group having the defined number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. The functional group representing an alkene is exemplified by -CH2-CH=CH2.

[0033] As used herein, the term "alkynyl" is used alone or in combination with other terms and, unless otherwise indicated, means a stable straight or branched chain hydrocarbon group having a specified number of carbon atoms and containing a triple carbon-carbon bond. Examples include ethynyl and propynyl, as well as higher homologs and isomers.

[0034] As used herein, the terms "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl", or "substituted alkynyl" mean an alkyl, cycloalkyl, alkenyl, or alkynyl as defined above, which is substituted with one, two, or three substituents selected from the group consisting of halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -N(CH3)2, (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C1-C4)alkyl, -C(=O)NH2, -C(=O)NH(C1-C4)alkyl, -C(=O)N((C1-C4)alkyl)2, -SO2NH2, -C(=NH)NH2, and -NO2, preferably selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, more preferably one or two substituents selected from halogen, alkoxy, and -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, 3-chloropropyl.

[0035] As used herein, the term "alkoxy" is used alone or in combination with other terms and, unless otherwise indicated, means an alkyl group having a specified number of carbon atoms as defined above, which is connected to the rest of the molecule through an oxygen atom, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), as well as higher homologs and isomers. (C1-C3) alkoxy such as ethoxy and methoxy, but not limited thereto, is preferred.

[0036] As used herein, the term "halo" or "halogen" means fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, more preferably fluorine or chlorine, alone or as part of another substituent, unless otherwise defined.

[0037] As used herein, the term "heteroalkyl" means, by itself or in combination with another term, unless otherwise indicated, a stable straight-chain or branched-chain alkyl group consisting of a defined number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be located at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the moiety to which it is attached, and may be attached to the most distal carbon atom of the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2CH2-S(=O)-CH3. For example, up to two heteroatoms may be consecutive, such as -CH2-NH-OCH3 or -CH2-CH2-S-S-CH3.

[0038] As used herein, the term "heteroalkenyl" means, by itself or in combination with another term, unless otherwise indicated, a stable straight-chain or branched-chain monounsaturated or diunsaturated hydrocarbon group consisting of a defined number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Up to two heteroatoms may be arranged consecutively. Examples include -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH2-SH.

[0039] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring that has one or more polyunsaturated rings and has aromatic character, i.e., has (4n + 2) delocalized π (pi) electrons (where n is an integer).

[0040] As used herein, the term "aryl", whether used alone or in combination with other terms, unless otherwise indicated, means a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), and such rings may be joined together in a pendant fashion, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. Phenyl and naphthyl are preferred, with phenyl being most preferred.

[0041] As used herein, the term "aryl-(C1-C3)alkyl" means a functional group in which a 1-3 carbon alkylene chain is attached to an aryl group, for example, -CH2CH2-phenyl or -CH2-phenyl (benzyl). Aryl-CH2- and aryl-CH(CH3)- are preferred. The term "substituted aryl-(C1-C3)alkyl" means an aryl-(C1-C3)alkyl functional group in which the aryl group is substituted. Substituted aryl(CH2)- is preferred. Similarly, the term "heteroaryl-(C1-C3)alkyl" means a functional group in which a 1-3 carbon alkylene chain is attached to a heteroaryl group, for example, -CH2CH2-pyridyl. Heteroaryl-(CH2)- is preferred. The term "substituted heteroaryl-(C1-C3)alkyl" means a heteroaryl-(C1-C3)alkyl functional group in which the heteroaryl group is substituted. Substituted heteroaryl-(CH2)- is preferred.

[0042] As used herein, the terms "heterocyclic", "heterocyclyl", or "heterocyclic ring" by themselves or as part of another substituent, unless otherwise indicated, mean an unsubstituted or substituted stable monocyclic or polycyclic heterocyclic ring system consisting of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, wherein nitrogen and sulfur heteroatoms may be optionally oxidized and nitrogen atoms may be optionally quaternized. The heterocyclic ring system may be attached at any heteroatom or carbon atom providing a stable structure, unless otherwise indicated. The heterocyclic ring may be essentially aromatic or non-aromatic. In one embodiment, the heterocyclic ring is heteroaryl.

[0043] As used herein, the terms "heteroaryl" or "heteroaromatic" refer to a heterocyclic ring having aromatic characteristics. The polycyclic heteroaryl may include one or more partially saturated rings. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

[0044] Examples of non-aromatic heterocyclic rings include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophene, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethylene oxide.

[0045] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (e.g., but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0046] Examples of polycyclic heterocycles include indolyl (e.g., but not limited to, 3-, 4-, 5-, 6-, and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (e.g., but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (e.g., but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (e.g., but not limited to, 3-, 4-, 5-, 6-, and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (e.g., but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (e.g., but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolidinyl, and quinolizinyl, and quinolidinyl.

[0047] The foregoing lists of heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.

[0048] As used herein, the term "substituted" means that an atom or group of atoms has replaced hydrogen as a substituent attached to another group.

[0049] For an aryl group, an aryl-(C1-C3)alkyl group, and a heterocyclyl group, the term "substituted" as applied to the rings of these groups refers to any level of substitution, i.e., mono-substitution, di-substitution, tri-substitution, tetra-substitution, or penta-substitution (when such substitution is permitted). The substituents are independently selected and the substitution may be at any chemically accessible position. In one embodiment, the number of substituents varies between 1 and 4. In another embodiment, the number of substituents varies between 1 and 3. In yet another embodiment, the number of substituents varies between 1 and 2. In yet another embodiment, the substituents are independently C 1-6 alkyl, -OH, C 1-6 alkoxy, halo, amino, acetamide, and nitro. As used herein, when a substituent is an alkyl group or an alkoxy group, the carbon chain may be branched, straight-chain, or cyclic, but a straight-chain is preferred.

[0050] The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") presented herein is intended merely to make the description more understandable and does not impose a limitation on the claims. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods.

Mode for Carrying Out the Invention

[0051] Method of Treatment Certain embodiments of the present disclosure relate to a method for treating neurological ventilatory insufficiency, the method comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I): [Chemical formula] (wherein, R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl, or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl, R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl, R 4 is H, alkyl, or substituted alkyl, R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl, R6 is H, alkyl, substituted alkyl, or alkenyl, X is a bond, O, or NR 4 wherein Y is N, CR 6 or C, and in the formula when Y is N or CR 6 then bond b 1 is absent, (i) Z is H, bond b 2 is a single bond, and A is CH, or (ii) Z is absent, bond b 2 is absent, and A is a single bond, when Y is C, bond b 1 is a single bond, (i) Z is CH2, bond b 2 is a single bond, and A is CH, or (ii) Z is CH, bond b 2 is a double bond, and A is C), or a salt thereof, and administering the same.

[0052] Certain embodiments of the present disclosure relate to methods for neurogenic hypoventilation, the method comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I):

Chemical formula

[0053] Certain embodiments of the present disclosure relate to a method for neurogenic hypoventilation, the method comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I):

Chemical formula

[0054] 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.

[0055] Certain embodiments of the present disclosure relate to methods for neurological ventilatory insufficiency, the method comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I):

Chemical formula

[0056] In certain embodiments, (i) R 3 is H, alkyl, or substituted alkyl, and R 5 is propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl, or (ii) R 3 is H or alkynyl, and R 5 is alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl.

[0057] In one embodiment, at least one compound of formula (I) is (i) a compound in which 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 a compound of formula (II-a) or a salt thereof,

Chemical formula

Chemical formula

[0058] In one embodiment, at least one compound of formula (I) is (i) a compound in which Y is CR6, bond b1 is absent, Z is H, bond b2 is a single bond, A is CH, and at least one compound is a compound of formula (III-a) or a salt thereof,

Chemical formula

[0059] In one embodiment, Y is C, bond b 1 is a single bond, Z is CH2, bond b 2 is a single bond, A is CH, and the at least one compound is a compound of formula (IV) or a salt thereof. [Chemical formula]

[0060] In one embodiment, Y is C, bond b 1 is a single bond, Z is CH, bond b 2 is a double bond, A is C, and the at least one compound is a compound of formula (V) or a salt thereof. [Chemical formula]

[0061] In one embodiment, at least one compound is N-(4,6-bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XX), N-(4,6-bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXII), N-(4-cyclopropylmethylamino)-N-(6-n-propylamino)[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV), N-(4-ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXVII), N-(bis-4,6-(2-methylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX), N-(bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI), 4,6-bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (XXXIII), N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXV), N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide (XL), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI), O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine (XLVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-(3,5)-Triazin-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]oxazinane-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII), 6-(methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxylamine (C), 4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII), 4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV), 4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5] (Triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX), 4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXIII), 4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXV), N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nonadeca-1(18),15(19),16(17)-triene-17-yl)-N,O-dimethylhydroxylamine (CXVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N′,N′-dimethylhydrazine (XLVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N′-methylhydrazine (XLIX), their salts, and mixtures thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.,

[0062] In one embodiment, at least one compound is 2,6-bis-(N-n-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.

[0063] In one embodiment, at least one compound is N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.

[0064] In one embodiment, at least one compound is selected from the group consisting of 2-(n-propyl)amino-4-(i-propylamino)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidine (CXXXVI), 2,4-bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLI X), 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLV), their salts, and mixtures thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.

[0065] In one embodiment, at least one compound is selected from the group consisting of N-(2-propylamino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(prop-2-en-1-yl)amino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine (CLVIII), N-(2-(prop-2-en-1-yl)amino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLX), N-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CLXII), N-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLXIV), N-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine (CLXVI), N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine (CLXVIII), N,N-dimethyl-N'-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine (CLXX), their salts, and mixtures thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.

[0066] In certain embodiments, the compound is selected from the group consisting of O,N-dimethyl-N-[4-(n-propylamino)-6-(prop-2-ynylamino-[1,3,5]triazin-2-yl]-hydroxylamine, N-methyl-N'-n-propyl-N''-prop-2-ynyl-[1,3,5]triazine-2,4,6-triamine, their salts, and any combination thereof.

[0067] In certain embodiments, the compound is N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine or a pharmaceutically acceptable salt thereof.

[0068] 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 U.S. Patent Application Publication No. 2015-0291597 (now abandoned), the teachings of which are incorporated herein by reference in their entirety.

[0069] In certain embodiments, the patient has no or insufficient spontaneous ventilation ability.

[0070] In certain embodiments, the patient is an infant, adolescent, or adult.

[0071] In certain embodiments, the patient is an infant with a postmenstrual age of less than 37 weeks, less than 36 weeks, less than 35 weeks, less than 34 weeks, less than 33 weeks, less than 32 weeks, less than 31 weeks, less than 30 weeks, less than 29 weeks, or less than 28 weeks.

[0072] In certain embodiments, the patient is being treated for apnea of prematurity, ALS, COPD, seizure rescue, alternative to CPR, stroke, or nerve fatigue.

[0073] In certain embodiments, the patient does not have drug-induced respiratory depression.

[0074] In certain embodiments, the patient does not have opioid or anesthetic-induced respiratory depression.

[0075] In certain embodiments, the patient has discontinued the use of a ventilator before or after administration.

[0076] In certain embodiments, the patient is simultaneously using a ventilator.

[0077] In certain embodiments, the patient has never used a ventilator before or simultaneously.

[0078] In certain embodiments, the route of administration is selected from oral, intravenous, nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal, otic, intraocular, or intrathecal routes.

[0079] In certain embodiments, the compound is administered in escalating doses.

[0080] In certain embodiments, the compound is administered as a loading dose.

[0081] The method according to any of the preceding claims, wherein the compound is administered intravenously after any loading dose of from about 0.01 mg / kg / hour to about 2.5 mg / kg / hour, from about 0.1 mg / kg / hour to about 2.5 mg / kg / hour, or from about 0.5 mg / kg / hour to about 2.5 mg / kg / hour.

[0082] In certain embodiments, the compound is administered at a loading dose of from about 0.05 mg / kg / hour to about 3.5 mg / kg / hour, from about 0.5 mg / kg / hour to about 3.5 mg / kg / hour, or from about 1.5 mg / kg / hour to about 3.5 mg / kg / hour, followed by an intravenous dose of from about 0.01 mg / kg / hour to about 2.5 mg / kg / hour, from about 0.1 mg / kg / hour to about 2.5 mg / kg / hour, or from about 0.5 mg / kg / hour to about 2.5 mg / kg / hour.

[0083] In certain embodiments, the compound is administered at a loading dose of about 2.0 mg / kg / hour, followed by an intravenous dose of from about 0.01 mg / kg / hour to about 2.5 mg / kg / hour, from about 0.1 mg / kg / hour to about 2.5 mg / kg / hour, or from about 0.5 mg / kg / hour to about 2.5 mg / kg / hour, or about 1.1 mg / kg / hour.

[0084] In certain embodiments, the administration time is from 15 seconds to about 2 weeks, from about 1 hour to about 1 week, from about 1.5 hours to about 3 days, or from about 2 hours to about 24 hours.

[0085] In certain embodiments, the patient shows an increase in minute ventilation within about 30 minutes, about 20 minutes, or about 15 minutes from administration.

[0086] In certain embodiments, the increase in minute ventilation within about 30 minutes, about 20 minutes, or about 15 minutes from administration is at least 500 mL / min, at least 750 mL / min, or at least 1,000 mL / min.

[0087] In certain embodiments, the increase in minute ventilation 2 hours, 3 hours, or 4 hours after administration is at least 1,000 mL / min, at least 1,250 mL / min, or at least 1,500 mL / min.

[0088] In certain embodiments, the patient shows a decrease in end-tidal carbon dioxide.

[0089] In certain embodiments, the decrease 1 hour, 2 hours, 3 hours, or 4 hours after administration is at least 5%, at least 10%, at least 15%, or at least 25%.

[0090] In certain embodiments, the patient shows an increase in tidal volume (Vte (mL)) within about 30 minutes, about 20 minutes, or about 15 minutes from administration.

[0091] In certain embodiments, the increase in tidal volume within about 30 minutes, about 20 minutes, or about 15 minutes after administration is at least 5 mL, at least 15 mL, or at least 20 mL / min.

[0092] In certain embodiments, the increase in tidal volume 2 hours, 3 hours, or 4 hours after administration is at least 15 mL, at least 20 mL / min, or at least 25 mL / min.

[0093] In certain embodiments, the patient shows an increase in tidal volume (Vte (mL / kg)) within about 30 minutes, about 20 minutes, or about 15 minutes from administration.

[0094] In certain embodiments, the tidal volume within about 30 minutes, about 20 minutes, or about 15 minutes from administration is at least 4 mL / kg, at least 5 mL / kg, at least 6 mL / kg, or at least 7 mL / kg.

[0095] In certain embodiments, the tidal volume 2 hours, 3 hours, or 4 hours after administration is at least 4 mL / kg, at least 5 mL / kg, at least 6 mL / kg, or at least 7 mL / kg.

[0096] In certain embodiments, the patient shows an increase in respiratory rate (breaths per minute) within about 30 minutes, about 20 minutes, or about 15 minutes from administration.

[0097] In certain embodiments, the increase in respiratory rate is at least 20 breaths per minute, at least 50 breaths per minute, or at least 75 breaths per minute, or about 30 to about 60 breaths per minute.

[0098] In certain embodiments, the increase in respiratory rate 2 hours, 3 hours, or 4 hours after administration is at least 20 breaths per minute, at least 50 breaths per minute, or at least 75 breaths per minute, or about 30 to about 60 breaths per minute.

[0099] In certain embodiments, the patient shows a stable heart rate and mean arterial pressure at least 30 minutes, at least 1 hour, at least 2 hours, or at least 4 hours after administration.

[0100] In certain embodiments, the method comprises administering any of the compounds described herein in combination with at least one additional active agent, which may be administered simultaneously, sequentially, or concurrently. The additional compounds may be, for example, almitrine, caffeine, theophylline, or doxapram. In certain embodiments, the two agents are administered sequentially such that there is an overlap in the treatment intervals provided by each agent. In sequential administration, the agents are in separate dosage forms and can be administered via the same route of administration (e.g., pulmonary), or via different routes of administration (e.g., parenteral and pulmonary). Suitable and preferred routes for one or more active agents can independently be selected from oral, intravenous (e.g., continuous infusion or bolus injection), nasal, inhalation, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratracheal (e.g., intratracheal instillation or intratracheal inhalation), otic, intraocular, or intrathecal routes. Non-limiting examples of suitable pulmonary administration may be by metered dose inhaler, nebulizer, soft mist inhaler, high efficiency nebulizer, ultrasonic nebulizer, dry powder inhaler, continuous positive airway pressure (CPAP) machine, bilevel positive airway pressure machine (BiPAP), or ventilator.

[0101] As used herein, the term "simultaneously" means that the dosage of one agent is administered at the same time as another agent, regardless of whether the agents are administered separately via the same or different routes of administration, or in a single pharmaceutical composition or dosage form.

[0102] As used herein, the term "sequentially" means that the dosage of one agent is administered first, and then the dosage of another agent is administered second.

[0103] As used herein, the term "concurrently" refers to an overlap in the treatment windows of the compound of Formula I and the additional active agent. Two active agents(s) can be administered concurrently, but concurrent administration is not necessary.

[0104] Composition In certain embodiments, the present disclosure relates to a pharmaceutical composition suitable for treating neurological ventilatory insufficiency. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formula (I): [Chemical formula] (wherein, R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl, or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl, R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl, R 4 is H, alkyl, or substituted alkyl, R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle, or R 3 and R5 combine to form a diradical selected from the group consisting of 3,6,9 - trioxa - undecane - 1,11 - diyl and 3,6 - dioxaoctane - 1,8 - diyl, R 6 is H, alkyl, substituted alkyl, or alkenyl, X is a bond, O, or NR 4 wherein, Y is N, CR 6 or C, and in the formula when Y is N or CR 6 then bond b 1 is absent, (i) Z is H, bond b 2 is a single bond, and A is CH, or (ii) Z is absent, bond b 2 is absent, and A is a single bond, when Y is C, then bond b 1 is a single bond, (i) Z is CH2, bond b 2 is a single bond, and A is CH, or (ii) Z is CH, bond b 2 is a double bond, and A is C), or a salt thereof.

[0105] In certain embodiments, the present disclosure relates to a pharmaceutical composition suitable for treating neurological ventilatory insufficiency. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formula (I) for treating neurological ventilatory insufficiency:

Chemical formula

[0106] In certain embodiments, the present disclosure relates to a pharmaceutical composition suitable for treating neurological ventilatory failure. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formula (I):

Chemical formula

[0107] In certain embodiments, the disclosure relates to a pharmaceutical composition suitable for treating neurological ventilatory insufficiency. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound selected from formula (I):

Chemical formula

[0108] In one embodiment, at least one compound of formula (I) is (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 a compound of formula (II-a) or a salt thereof, [Chemical formula] and (ii) Y is N, bond b1 is absent, Z is absent, bond b2 is absent, A is a bond, and the compound of the present invention is a compound of formula (II-b) or a salt thereof, and is selected from the group consisting of. [Chemical formula]

[0109] In one embodiment, at least one compound of formula (I) is (i) Y is CR6, bond b1 is absent, Z is H, bond b2 is a single bond, A is CH, and at least one compound is a compound of formula (III-a) or a salt thereof, [Chemical formula] and (ii) Y is CR6, bond b1 is absent, Z is absent, bond b2 is absent, A is a bond, and the compound of the present invention is a pyrimidine of formula (III-b) or a salt thereof, and is selected from the group consisting of. [Chemical formula]

[0110] In one embodiment, Y is C, and bond b 1 is a single bond, Z is CH2, and bond b 2 is a single bond, A is CH, and the at least one compound is a compound of formula (IV) or a salt thereof.

Chemical formula

[0111] In one embodiment, Y is C, and bond b 1 is a single bond, Z is CH, and bond b 2 is a double bond, A is C, and the at least one compound is a compound of formula (V) or a salt thereof.

Chemical formula

[0112] In one embodiment, at least one compound is N-(4,6-bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XX), N-(4,6-bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXII), N-(4-cyclopropylmethylamino)-N-(6-n-propylamino)[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV), N-(4-ethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXVII), N-(bis-4,6-(2-methylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX), N-(bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI), 4,6-bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (XXXIII), N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXV), N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide (XL), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI), O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine (XLVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-(3,5)-Triazin-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]oxazinane-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII), 6-(methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro-ethyl)-hydroxylamine (C), 4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII), 4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV), 4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5) (Triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX), 4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXIII), 4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXV), N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nonadeca-1(18),15(19),16(17)-triene-17-yl)-N,O-dimethylhydroxylamine (CXVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N′,N′-dimethylhydrazine (XLVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N′-methylhydrazine (XLIX), their salts, and mixtures thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.,

[0113] In one embodiment, at least one compound is 2,6-bis-(N-n-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.,

[0114] In one embodiment, at least one compound is N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.,

[0115] In one embodiment, at least one compound is selected from the group consisting of 2-(n-propyl)amino-4-(i-propylamino)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidine (CXXXVI), 2,4-bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLI X), 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLV), their salts, and mixtures thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.

[0116] In one embodiment, at least one compound is selected from the group consisting of N-(2-propylamino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(prop-2-en-1-yl)amino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine (CLVIII), N-(2-(prop-2-en-1-yl)amino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLX), N-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CLXII), N-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLXIV), N-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine (CLXVI), N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine (CLXVIII), N,N-dimethyl-N′-(2-n-propylamino-7-methyl-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine (CLXX), their salts, and mixtures thereof. In another embodiment, the salt is a bisulfate or hydrochloride salt.

[0117] 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 U.S. Patent Application Publication No. 2015-0291597 (now abandoned), the teachings of which are hereby incorporated by reference in their entirety.

[0118] In certain embodiments, the pharmaceutical composition comprises a single dose of the compound of formula (I), the single dose comprising a therapeutically effective amount of the compound of formula (I). In certain embodiments, the pharmaceutical composition comprises multiple doses (e.g., two or more, three or more, four or more, etc.) of the compound of formula (I).

[0119] In certain embodiments, the pharmaceutical composition comprises a compound of formula (I) and one or more additional active agents.

[0120] In certain embodiments, the active agent(s) (e.g., the compound of formula (I) and optionally one or more additional active agents) in the pharmaceutical composition are lyophilized.

[0121] 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).

[0122] In certain embodiments, the pharmaceutical composition may be contained in a glass or plastic container.

[0123] In certain embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients may vary based on the final form of the composition and the route of administration.

[0124] Routes of administration for any of the compositions of the invention include inhalation, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)oral, (trans)urethral, vaginal (e.g., transvaginal and perivaginal), (trans)nasal, and (trans)rectal), intravesical, intralung, intraduodenal, intragastric, intrathecal, subcutaneous, intramuscular, intradermal, intraarterial, intravenous, intrabronchial, inhalation, intraperitoneal, intrathoracic, intrathoracic, intrapleural, and topical administration.

[0125] Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel capsules, troches, dispersions, suspensions, solutions (e.g., sterile solutions suitable for parenteral or other administration), syrups, granules, beads, transdermal patches, gels, powders, pellets, magma, troches, creams, pastes, plasters, lotions, disks, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration, and the like. It is understood that the formulations and compositions that may be useful in the present invention are not limited to the specific formulations and compositions described herein.

[0126] In certain embodiments, a pharmaceutically acceptable excipient includes a pharmaceutically acceptable carrier such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, thickening agent, solvent, or encapsulating material, and can perform its intended function by carrying or transporting a compound useful within the present invention within or to a subject. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation containing a compound useful within the present invention and not harmful to the subject. Some examples of materials that can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any coating agent, antibacterial and antifungal agents, and absorption delaying agents, etc., that are compatible with the activity of a compound useful within the present invention and physiologically acceptable to the subject. Auxiliary active compounds can also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include a pharmaceutically acceptable salt of a compound useful within the present invention.Other additional components that may be included in the pharmaceutical composition used in the practice of the present invention are known in the art and are described, for example, in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0127] Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, and solutions of other pharmaceutically acceptable salts such as salts of phosphates and organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0128] The carrier may be, for example, a solvent or dispersion medium containing water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Suitable fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersants, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include in the composition isotonic agents such as sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol. Prolonged absorption of injectable compositions can be brought about by including in the composition agents that delay absorption, such as aluminum monostearate or gelatin. In one embodiment, the pharmaceutically acceptable carrier is not DMSO alone.

[0129] The pharmaceutical formulation may be sterilized and, if desired, may be mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifying agents, salts for affecting osmotic buffers, colorants, flavoring agents, and / or aromatic substances, etc.

[0130] Examples of preservatives useful according to the present invention include, but are not limited to, those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea, and combinations thereof.

[0131] The composition preferably includes antioxidants and chelating agents that inhibit the decomposition of the compounds. Preferred antioxidants for some compounds are BHT, BHA, α-tocopherol, and ascorbic acid in a preferred range of about 0.01 wt% to 0.3 wt% based on the total weight of the composition, more preferably BHT in the range of 0.03 wt% to 0.1 wt%. Preferably, the chelating agent is present in an amount of 0.01 wt% to 0.5 wt% based on the total weight of the composition. Particularly preferred chelating agents include edetates (e.g., disodium edetate) and citric acid in a range of about 0.01 wt% to 0.20 wt%, more preferably in the range of 0.02 wt% to 0.10 wt% based on the total weight of the composition. Chelating agents are useful for chelating metal ions in the composition, which can be detrimental to the shelf life of the formulation. BHT and disodium edetate are particularly preferred antioxidants and chelating agents, respectively, for some compounds, but for this reason, as known to those skilled in the art, they can be replaced with other suitable and equivalent antioxidants and chelating agents.

[0132] To achieve suspension of the active ingredient in an aqueous or oily vehicle, a liquid suspension may be prepared using conventional methods. Examples of aqueous vehicles include water and isotonic saline. Examples of oily vehicles include 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 include one or more additional components including, but not limited to, suspending agents, dispersing agents, or wetting agents, emulsifiers, lubricants, preservatives, buffers, salts, flavoring agents, coloring agents, and sweetening agents. The oily suspension may further include 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, hydroxypropylmethylcellulose. Known dispersing or wetting agents include naturally occurring phospholipids such as lecithin, condensation products of alkylene oxides with fatty acids, with long-chain fatty alcohols, with partial esters derived from fatty acids and hexitols, or with partial esters derived from fatty acids and hexitol anhydrides (such as polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively), but are not limited to these. 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 sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0133] A liquid solution of the active ingredient in an aqueous or oily solvent may be prepared in substantially the same manner as a liquid suspension, the main difference being that the active ingredient is dissolved rather than suspended in the solvent. As used herein, an "oily" liquid is a liquid that contains carbon-containing liquid molecules and exhibits a lower polarity than water. The liquid solutions of the pharmaceutical compositions of the present invention may contain each of the components described in connection with the liquid suspensions, it being understood that suspending agents do not necessarily assist in the dissolution of the active ingredient in the solvent. Examples of aqueous solvents include, for example, water and isotonic saline. Examples of 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.

[0134] The powder and granule formulations of the pharmaceutical preparations of the present invention can be prepared using known methods. Such formulations may be administered directly to the subject and may be used, for example, to form tablets, to fill capsules, or to prepare aqueous or oily suspensions or solutions by adding an aqueous or oily vehicle thereto. Each of these formulations may further contain one or more of a dispersing or wetting agent, a suspending agent, and a preservative. Filling agents and additional excipients such as sweetening agents, flavoring agents, or coloring agents may also be included in these formulations.

[0135] The pharmaceutical composition of the present invention may also be prepared, packaged, or sold in the form of a water-in-oil emulsion or an oil-in-water emulsion. The oily 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 include one or more emulsifiers, for example, natural gums such as gum acacia or tragacanth gum, natural phospholipids such as soybean or lecithin phospholipids, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients, for example, sweeteners or flavoring agents.

[0136] In certain embodiments, one or more additional excipients include a pH adjuster, which may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, acetic acid, or mixtures thereof.

[0137] In certain embodiments, the composition may include one or more additional excipients, for example, but not limited to, 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 dyes, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0138] In certain embodiments, the composition further comprises an antioxidant. In certain embodiments, the antioxidant may include, for example, trivalent phosphorus such as phosphite, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranone. Hindered phenols, thio synergists, and / or hindered amines are useful for the long-term stability of polymers, but the following antioxidants are also suitable for use in situations where the active substance is subjected to oxidation: acids (ascorbic acid, erythorbic acid, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid, etc.), phenols (e.g., BHA, BHT, t-butylhydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic salts (calcium ascorbate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, potassium bisulfite, potassium metabisulfite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate), pyranones (maltol), and vitamins (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopherol acetate, d-α-tocopherol acetate, dl-α-tocopheryl acetate). However, other antioxidants known in the art may also be used in accordance with the present invention.

[0139] In certain embodiments, suitable antioxidants include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations thereof. Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols such as, but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-dimethylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylcyclohexyl)-4,6-dimethylphenol, 2,6-dioctadecyl-4-methylphenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4-methoxymethylphenol, nonylphenols with linear or branched side chains such as, but not limited to, 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 such as, but not limited to, 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-dioctylthiomethyl-6-ethylphenol, 2,6-didodecylthiomethyl-4-nonylphenol, hydroquinone and alkylated hydroquinones such as, but not limited to, 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-Di-tert-butyl-4-hydroxyphenyl) adipate, tocopherols, such as, but not limited to, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and mixtures thereof (vitamin E), hydroxylated thiodiphenyl ethers, such as, but not limited to, 2,2′-thiobis(6-tert-butyl-4-methylphenol), 2,2′-thiobis(4-octylphenol), 4,4′-thiobis(6-tert-butyl-3-methylphenol), 4,4′-thiobis(6-tert-butyl-2-methylphenol), 4,4′-thiobis(3,6-di-sec-amylphenol), 4,4′-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide, alkylidenebisphenols, such as, but not limited to, 2,2′-methylenebis(6-tert-butyl-4-methylphenol), 2,2′-methylenebis(6-tert-butyl-4-ethylphenol), 2,2′-methylenebis[4-methyl-6-(α-methylcyclohexyl)-phenol], 2,2′-methylenebis(4-methyl-6-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-methyl-phenyl)-3-n-dodecyl mercaptobutane, ethylene glycol bis[3,3-Bis(3′-tert-butyl-4′-hydroxyphenyl)butyrate, bis(3-tert-butyl-4-hydroxy-5-methyl-phenyl)dicyclopentadiene, bis[2-(3′-tert-butyl-2′-hydroxy-5′-methylbenzyl)-6-tert-butyl-4-methylphenyl]terephthalate, 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-4-n-dodecylmercaptobutane, 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane, O-, N-, and S-benzyl compounds, such as, but not limited to, 3,5,3′,5′-tetra-tert-butyl.-4,4′-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzylmercaptoacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzylmercaptoacetate, tris(3,5-di-tert-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithiophthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzylmercaptoacetate, hydroxybenzylated malonate, such as, but not limited to, dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, di-octadecyl-2-(3-tert-butyl-4-hydroxy-5-methylbenzyl)malonate, dodecylmercaptoethyl-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, aromatic hydroxybenzyl compounds, such as, but not limited to, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-Di-tert-butyl-4-hydroxybenzyl)-2,3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol, triazine compounds, for example, but not limited to, 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-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, for example, but not limited to, dimethyl-2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl 3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzylphosphonate, calcium salt of the monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzylphosphonic acid, acylaminophenols, for example, but not limited to, 4-hydroxylauranilide, 4-hydroxystearanilide, N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamic acid octyl, β-(3,Esters of (5-di-tert-butyl-4-hydroxyphenyl)propionic acid with, for example, monohydric or polyhydric alcohols such as methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; esters of β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid with monohydric or polyhydric alcohols such as methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis-(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; esters of 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]-2,4,8,10-tetraoxaspiro[5.5]undecane; esters of 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols such as methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, ester with 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with a monohydric or polyhydric alcohol, 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 - thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters with 4 - hydroxymethyl - 1 - phospha - 2,6,7 - trioxabicyclo[2.2.2]octane, amides of 6-(3,5 - di - tert - butyl - 4 - hydroxyphenyl)propionic acid, for example, N,N′-bis(3,5 - di - tert - butyl - 4 - hydroxyphenylpropionyl)hexamethylenediamide, N,N′-bis(3,5 - di - tert - butyl - 4 - hydroxyphenylpropionyl)trimethylenediamide, N,N′-bis(3,5 - di - tert - butyl - 4 - hydroxyphenylpropionyl)hydrazide, N,N′-bis[2-(3 - [3,5 - di - tert - butyl - 4 - hydroxyphenyl]propionyloxy)ethyl]oxamide (Naugard® XL - 1, manufactured by Uniroyal), ascorbic acid (vitamin C), amine - based antioxidants, for example, but not limited to, N,N′-di - isopropyl - p - phenylenediamine, N,N′-di - sec - butyl - p - phenylenediamine, N,N′-bis(1,4 - dimethylpentyl)-p - phenylenediamine, N,N′-bis(1 - ethyl - 3 - methylpentyl)-p - phenylenediamine, N,N′-bis(1 - methylheptyl)-p - phenylenediamine, N,N′-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, for example, but not limited to, p,p'-di-tert-octyldiphenylamine, 4-n-butylaminophenol, 4-butyrylaminophenol, 4-nonanoylaminophenol, 4-dodecanoylaminophenol, 4-octadecanoylaminophenol, bis(4-methoxyphenyl)amine, 2,6-di-tert-butyl-4-dimethylaminomethylphenol, 2,4'-diaminodiphenylmethane, 4,4'-diaminodiphenylmethane, N,N,N',N'-tetramethyl-4,4'-diaminodiphenylmethane, 1,2-bis[(2-methylphenyl)amino]ethane, 1,2-bis(phenylamino)propane, (o-tolyl)biguanide, bis[4-(1',3'-dimethylbutyl)phenyl]amine, tert-octylated N-phenyl-1-naphthylamine, mixtures of mono- and dialkylated tert-butyl / tert-octyldiphenylamine, mixtures of mono- and dialkylated nonyldiphenylamine, mixtures of mono- and dialkylated dodecyldiphenylamine, mixtures of mono- and dialkylated isopropyl / isohexyldiphenylamine, mixtures of mono- and dialkylated t-butyl diphenyalmine, 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-octylphenothiazine, N-allylphenothiazine, N,N,N',N'-tetraphenyl-1,4-diaminobut-2-ene, and combinations thereof.,

[0140] In certain embodiments, suitable pharmaceutically acceptable excipients include acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyalkylene oxides (e.g., polymethylene oxide, polyethylene oxide, polypropylene oxide), polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, polycaprolactone, polymethacrylate, copolymers thereof, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, croscarmellose sodium, or mixtures thereof), glidants, lubricants, absorption enhancers, surfactants, binders, emollients, plasticizers (e.g., lecithin, hydrogenated vegetable oil, glycerol esters, lanolin, methyl esters, pentaerythritol esters, rice bran wax, stearic acid, potassium sodium stearate, etc.), waxes, fats, emulsifiers, fillers, antioxidants, flavors, colorants, diluents, processing aids (e.g., granulation aids), sweeteners as described above for chewable compositions, fixatives (e.g., polyols, e.g., but not limited to, sorbitol, maltitol / isomalt, mannitol, starch, etc.), pH adjusters, viscosity modifiers, solubility increasing or decreasing agents, osmotic agents, solvents, or combinations thereof may be mentioned.

[0141] In certain embodiments, suitable pharmaceutically acceptable excipients can include hydrophilic and hydrophobic materials such as polyvinylpyrrolidone, natural and synthetic rubbers, polyvinyl alcohol, corn starch, sustained release polymers, acrylic resins, protein-derived materials, waxes, shellac, and solid or semi-solid oils such as hydrogenated castor oil and hydrogenated vegetable oils. More specifically, the controlled release materials can be, for example, alkyl celluloses such as ethyl cellulose, acrylic and methacrylic acid polymers and copolymers (e.g., copolymers of acrylic acid and methacrylic acid, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methyl methacrylate alkylamide copolymers, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and mixtures of any of the foregoing), and cellulose ethers such as hydroxyalkyl celluloses (e.g., hydroxypropylmethyl cellulose) and carboxyalkyl celluloses. Examples of waxes include natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (e.g., beeswax, carnauba wax, stearic acid, and stearyl alcohol).

[0142] In certain embodiments, suitable pharmaceutically acceptable excipients can include gelling agents such as, but not limited to, sugars or sugar-derived alcohols such as mannitol, sorbitol, etc., starches and starch derivatives, cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester ethers, cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate (hypromellose acetate succinate), and mixtures thereof), attapulgite, bentonite, dextrin, alginates such as sodium alginate and potassium alginate, casein, stearic acid, shellac, carrageenan, tragacanth gum, acacia gum, gum arabic, pullulan gum, dextrin, gellan gum, agar gum, tara gum, karaya gum, guar gum, welan gum, ramson gum, locust bean gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomers and carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant / wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.

[0143] In certain embodiments, suitable pharmaceutically acceptable excipients can include hydrophilic excipients such as, but not limited to, water, low molecular weight polyols such as polyethylene glycol, polypropylene glycol, or combinations thereof. Examples of other suitable hydrophilic carriers include, but are not limited to, polyoxyethylene derivatives of sorbitan esters such as sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof. Exemplary low molecular weight polyols include, but are not limited to, those having a number average molecular weight from any of about 200 daltons, about 400 daltons, about 600 daltons, about 800 daltons, or about 1000 daltons to any of 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, etc.).

[0144] In certain embodiments, suitable pharmaceutically acceptable excipients include plasticizers such as, but not limited to, triacetin, isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers such as, but not limited to, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene 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 include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, organic small molecules, low molecular weight polyols having aliphatic hydroxyls, ester - type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single - block polymers, citrate - type plasticizers, and triacetin. Such plasticizers 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.

[0145] In certain embodiments, suitable pharmaceutically acceptable excipients include plasticizers such as, but not limited to, phosphate esters; phthalate esters; amides; mineral oil; fatty acids and esters; fatty alcohols, vegetable oils, and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glycerides and acetylated hydrogenated soybean oil glycerides; tributyl acetyl citrate, triethyl acetyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylate glycerin, glyceryl cocoate, mono- and diacetylated monoglycerides, nitrobenzene, carbon disulfide, fl-naphthyl salicylate, phthalyl glycolate, dioctyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalate esters; amides; mineral oil; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols including cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, and myristyl alcohol;Methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(β-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(β-ethylbutyrate) polyethylene glycol di(2-ethylhexoate), diethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated methyl ester of rosin, methoxyethyl oleate, butoxyethyl stearate, butyl phthalyl butyl glycolate, glycerol tributyrate, triethylene glycol diperargonate, β-(p-tert-amylphenoxy)ethanol, β-(p-tert-butylphenoxy)ethanol, β-(p-tert-butylphenoxyethyl)acetate, bis(β-p-tert-butylphenoxydiethyl) ether, borneol, CumarW-1, CumarMH-1, CumarV-1, diamyl phthalate, (diamylphenoxy)ethanol, diphenyl oxide, industrial hydroabietyl alcohol, beckolin, benzene hexahydrochloride, Clorafin40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, glycerol α-methyl α-phenyl ether, chlorinated naphthalene, HB-40, monoamyl phthalate, Nevillac 10 o-nitrodiphenyl, and Paracril 26 may be included.;

[0146] In certain embodiments, suitable pharmaceutically acceptable excipients include plasticizers such as, but not limited to, isomalt, maltitol, sorbitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers such as 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 include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, organic small molecules, low molecular weight polyols having aliphatic hydroxyls, ester - type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single - block polymers, citrate - type plasticizers, and triacetin. Such plasticizers can include 1,2 - butylene glycol, 2,3 - butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0147] In certain embodiments, suitable pharmaceutically acceptable excipients may include fragrances, for example, but not limited to, natural and / or synthetic fragrance materials. For example, it may be an oil-soluble fragrance oil whether or not it is mixed with a water-soluble fragrance oil. Oil-soluble fragrances are natural or natural-like essential oils such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaf, peppermint oil, cedarwood oil, rosemary oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, germanium oil, menthol, and marjoram oil. Animal-derived fragrances are, for example, musk, castoreum, aber, or civet. Spagyric essences are also known in the art. These are produced by fermenting certain herbs and processed into the final product. Synthetic fragrance components are, for example, synthetic essential oils composed of a single compound such as linalool, terpineol, nerol, citronellal, benzaldehyde, cinnamon aldehyde, vanillin, ethyl vanillin, or methyl acetophenone. The fragrance material may also be a synthetic oil-soluble fragrance oil selected from the usual group consisting of aromatic hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, polyene derivatives. Other fragrances that may be used are classified and described in references and databases such as S. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; reprinted 2000), Allured’s Flavor and Fragrance Materials (2005), and the database maintained by the Research Institute for Fragrance Materials at www.rifm.org.

[0148] In certain embodiments, suitable pharmaceutically acceptable excipients may include essential oils. Suitable essential oils include mixtures of natural and synthetic fragrances. Natural fragrances include extracts from flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, cumin, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calamus), woods (pinewood, sandalwood, guaiacwood, cedarwood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (fir, spruce, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Typical synthetic fragrance compounds are ester, ether, aldehyde, ketone, alcohol, and hydrocarbon type products. Ester type fragrance compounds are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethyl-methylphenyl glycinate, allyl cyclohexylpropionate, styrallyl propionate, and benzyl salicylate. Ethers include, for example, benzyl ethyl ether, aldehydes include, for example, straight-chain alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, linalool, and bourgeonal, 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 balsams.

[0149] In certain embodiments, suitable pharmaceutically acceptable excipients may include relatively low volatility essential oils that are mainly used as fragrance components and are also suitable as perfuming oils, such as 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, labdanum oil, and lavandin oil. Other suitable oils include bergamot oil, dihydromyrcenol, linalool, linalyl acetate, citronellol, phenylethyl alcohol, α-hexylcinnamaldehyde, geraniol, benzylacetone, cyclamen aldehyde, linalool, Boisambrene Forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertal, lavandin oil, clary sage oil, β-damascone, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, Iso-E-Super, Fixolide NP, Evernyl, ildarid gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romilat, iloty, and floramat alone or in mixtures.

[0150] In certain embodiments, suitable pharmaceutically acceptable excipients may include preservatives. As used herein, the term "preservative" refers to an agent that extends the shelf life of a dosage form by delaying or preventing deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety. A preservative need not have a lethal and irreversible effect that results in partial or complete microbial cell destruction or inactivation. Bactericides, detergents, disinfectants, sporicides, virucides, and tuberculocides result in such an irreversible mode of action, which may also be referred to as a "sterilizing" action. In contrast, a preservative can provide an inhibitory or bacteriostatic action that is reversible in that the target microorganism can resume growth if the preservative is removed. The primary difference between a preservative and a detergent is mainly the mode of action (a preservative prevents growth rather than killing microorganisms) and the exposure time (a preservative takes days to months to act, while a detergent takes at most a few minutes to act). Suitable preservatives include, but are not limited to, solutions of phenoxyethanol, parabens, pentanediol, and sorbic acid, and silver complexes.

[0151] In certain embodiments, suitable pharmaceutically acceptable excipients may include colorants, such as, but not limited to, dyes such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown.

[0152] In certain embodiments, suitable pharmaceutically acceptable excipients may include, but are not limited to, “flavor extracts” obtained by using a solvent such as ethanol or water in many cases to extract a raw material, for example, a part of an animal or plant material, natural essences obtained by extracting essential oils from flowers, fruits, roots, etc., or from the whole plant. Additional exemplary flavoring agents for the compositions described herein may include, but are not limited to, menthol, spearmint, and cinnamon, other flavoring agents or fragrances such as coffee beans, fruit flavors (e.g., cherry, orange, grape, etc.), and quaternary ammonium bases. The flavor effect can be enhanced by using flavor enhancers such as tartaric acid, citric acid, vanillin, etc.

[0153] In certain embodiments, suitable pharmaceutically acceptable excipients may include sweetening agents such as, but not limited to, one or more artificial sweetening agents, one or more natural sweetening agents, or combinations thereof. Examples of artificial sweetening agents include, for example, acesulfame and its various salts, such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), salts of aspartame-acesulfame (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts, such as the sodium salt (available as Sweet’N Low®), stevia, chloro derivatives of sucrose, such as sucralose (available as Kaltame® and Splenda®), and mogroside. Examples of natural sweeteners include, for example, glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin, monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®), stevia (stevioside), natural high-intensity sweeteners (e.g., Luo Han Guo), polyols (e.g., sorbitol, mannitol, xylitol, erythritol, etc.).

[0154] In certain embodiments, suitable pharmaceutically acceptable excipients may include alkylating agent(s), e.g., but not limited to, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, and / or disodium phosphate.

[0155] In certain embodiments, suitable pharmaceutically acceptable excipients may include lubricant(s) / release agent(s), e.g., but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants include, but are not limited to, glyceryl behenate (Compritol™ 888), metal stearates (e.g., magnesium, calcium, and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g., Sterotex™), talc, waxes such as beeswax and carnauba wax, silica, fumed silica, colloidal silica, calcium stearate, long-chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-leucine, polyethylene glycols (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv™), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin, propylene glycol, and combinations thereof.

[0156] In certain embodiments, suitable pharmaceutically acceptable excipients include diluents such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dibasic calcium phosphate dihydrate NF, sucrose-based diluents, confectioner's sugar, calcium sulfate hemihydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules NF, dextrates NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed cereal solids such as Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like.

[0157] In certain embodiments, suitable pharmaceutically acceptable excipients include oils and fats such as, but not limited to, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, and watermelon seed oil. Other oils and fats that may be present in the filling of the PVA shell include, but are not limited to, fish oil (omega 3), krill oil, animal or vegetable fats in hydrogenated form, mono-, di-, and triglycerides having C12, C14, C16, C18, C20, and C22 fatty acids.

[0158] In certain embodiments, suitable pharmaceutically acceptable excipients include vegetable proteins such as sunflower protein, soybean protein, cottonseed protein, peanut protein, grape seed protein, whey protein, whey protein isolate, blood protein, egg protein, acrylated protein, water-soluble polysaccharides such as alginate, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic, and related gums (gatti gum, karaya gum, tragacanth gum), pectin, water-soluble derivatives of cellulose: alkyl celluloses, hydroxyalkyl celluloses, and hydroxyalkylalkyl celluloses such as methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, hydroxybutylmethyl cellulose, cellulose esters, and hydroxyalkyl cellulose esters such as cellulose acetate phthalate (CAP), hydroxypropylmethyl cellulose (HPMC); carboxyalkyl celluloses, carboxyalkylalkyl celluloses, carboxyalkyl cellulose esters such as carboxymethyl cellulose, and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acid, polyacrylamide, and polyacrylic acid esters, polymethacrylic acid, polymethacrylamide, and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), PVY / vinyl acetate copolymer, and polycrotonic acid may be included, phthalated gelatin, succinated gelatin, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, which may be quaternized if desired, such as those bearing tertiary or quaternary amino groups such as diethylaminoethyl groups, cation-modified acrylates and methacrylates; and other similar polymers; inorganic fillers such as magnesium, aluminum, silicon, titanium oxides, etc. are also suitable.

[0159] In certain embodiments, suitable pharmaceutically acceptable excipients include hydrophobic materials such as, but not limited to, digestible long-chain (C8-C50 , especially C 12 -C 40 ) substituted or unsubstituted hydrocarbons, such as natural or synthetic waxes (such as beeswax, glyceryl wax, castor wax, and carnauba wax), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl, or preferably cetostearyl alcohol), fatty acids, such as, but not limited to, monoglycerides of medium-chain fatty acids (such as caprylic acid, capric acid, caproic acid, lauric acid, oleic acid, linoleic acid), medium-chain triglycerides, fatty acid esters, fatty acid glyceroserides (mono, di, and triglyceroserides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials having a hydrocarbon backbone may be included.

[0160] In certain embodiments, suitable pharmaceutically acceptable excipients can include polyvinyl alcohol, polyvinyl pyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetate, polycarboxylic acids and salts, acetic acid, caprylic acid, oleic acid, polyamino acids or peptides, polyamides, polyacrylamides, copolymers of maleic acid / acrylic acid, polysaccharides including starch and gelatin, and natural rubbers such as xanthan and carrageenan. For example, the polymer can be selected from polyacrylates and water-soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, maltodextrin, polymethacrylate, and combinations thereof, or can be selected from polyvinyl alcohol, polyvinyl alcohol copolymers, and hydroxypropylmethylcellulose (HPMC), methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caprylocaprylyl macrogol glyceride, glyceryl distearate, and combinations thereof.

[0161] In certain embodiments, suitable pharmaceutically acceptable excipients can include high HLB surfactants such as, but not limited to, polysorbate 80 - polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, caprylocaprylyl macrogol glyceride, and combinations thereof.

[0162] In certain embodiments, suitable pharmaceutically acceptable excipients can include fillers such as, but not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0163] In certain embodiments, suitable pharmaceutically acceptable excipients may include natural rubbers (e.g., natural plant rubbers). Suitable natural rubbers include, but are not limited to, guar gum, locust bean gum, konjac gum, xanthan gum, sclerotium gum, acacia gum, cellulose gum (modified or unmodified), or combinations thereof.

[0164] In certain embodiments, suitable pharmaceutically acceptable excipients may include emulsifiers such as, but not limited to, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-40 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 almond glyceride, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 oleate, PEG-8 oleate, PEG-8 laurate, PEG-60 almond glyceride, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-100 stearate, PEG-80 sorbitan laurate, steareth-2, steareth-12, oleth-2, ceteth-2, laureth-4, oleth-10, oleth-10 / polyoxyl 10 oleyl ether, ceteth-10, isosteareth-20, ceteareth-20, oleth-20, steareth-20, steareth-21, ceteareth-20, isoceteareth-20, laureth-23, steareth-100, glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, salts of stearic acid, polyglyceryl-3-methylglycoside distearate, or combinations thereof.

[0165] Further 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 ceteareth sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphate, and mixtures thereof. Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, ceteareth glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate, and hydrated polyisobutene. Further, one or more synthetic polymers may be used as emulsifiers. For example, PVP eicosene copolymer, acrylate / C 10 -3o alkyl acrylate crosspolymer, acrylate / steareth-20 methacrylate copolymer, PEG-22 / dodecyl glycol copolymer, PEG-45 / dodecyl glycol copolymer, and mixtures thereof.

[0166] In certain embodiments, suitable pharmaceutically acceptable excipients may include chelating agents such as, but not limited to, disodium ethylenediaminetetraacetate (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).

[0167] In certain embodiments, suitable pharmaceutically acceptable excipients may include fatty alcohols, such as, but not limited to, cetyl alcohol, stearyl alcohol, ceteareth alcohol, oleyl alcohol, octyldodecanol, benzoates of C12-C15 alcohols, acetylated lanolin alcohol, and the like, and gell alcohols based on fatty alcohols having 6 to 18 carbon atoms, preferably 8 to 10 carbon atoms.

[0168] In certain embodiments, suitable pharmaceutically acceptable excipients include esters of fatty acids, such as, but not limited to, straight-chain C6-C 24 Straight-chain C3-C of fatty acids 24 Esters with alcohols, branched-chain C6-C 13 Straight-chain C6-C of carboxylic acids 24 Esters with fatty alcohols, straight-chain C6-C 24 Esters of branched-chain alcohols with fatty acids, in particular 2-ethylhexanol, straight-chain or branched-chain C6-C of hydroxycarboxylic acids 22Esters with fatty alcohols, in particular dioctyl maleate, esters with polyhydric alcohols (e.g., propylene glycol, dimer diol, or trimer diol) of linear and / or branched fatty acids and / or esters with guerbet alcohols, e.g., caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, linolenic acid, elaeostearic acid, arachidic acid, gadoleic acid, behenic acid, and erucic acid, and their industrial grade mixtures (e.g., obtained in the pressure removal of natural fats and oils, in the reduction of aldehydes from Roelen's oxo synthesis, or in the dimerization of unsaturated fatty acids), with alcohols, e.g., isopropyl alcohol, capron alcohol, capryl alcohol, 2-ethylhexyl alcohol, capric alcohol, lauryl alcohol, isotridecyl alcohol, myristyl alcohol, cetyl alcohol, palmoleyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, petroselinyl alcohol, linoyl alcohol, linolenyl alcohol, elaeostearyl alcohol, arachidyl alcohol, gadoleyl alcohol, behenyl alcohol, erucyl alcohol, and brassidyl alcohol, and their industrial grade mixtures (e.g., obtained as the monomer fraction in the high-pressure hydrogenation of industrial grade methyl esters based on fats and oils, or in the dimerization of aldehydes from Roelen's oxo synthesis and unsaturated fatty alcohols), may be included.Preferable examples of the ester oil include isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyl decyl stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, elsyl oleate, elsyl erucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl behenate, cetyl acetate, myristyl myristate, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate / caprate, stearyl heptanoate, diisostearyl malate, octyl hydroxystearate, and the like.

[0169] In certain embodiments, suitable pharmaceutically acceptable excipients include other adjuvants such as, but not limited to, diethylhexyl naphthalate, di-n-butyl adipate, di(2-ethylhexyl)-adipate, di(2-ethylhexyl)-succinate, and diisotridecyl acetate, as well as diol esters such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2-ethylhexanoate), propylene glycol diisostearate, propylene glycol diperargonate, butanediol diisostearate, and neopentyl glycol dicaprylate. C6-C 24 Esters of aliphatic alcohols and / or geranylgeraniol with aromatic carboxylic acids, saturated and / or unsaturated, particularly benzoic acid, C2-C 12 Esters of dicarboxylic acids with straight-chain or branched-chain alcohols having 1 to 22 carbon atoms or with polyols having 2 to 10 carbon atoms and 2 to 6 hydroxy groups.

[0170] In certain embodiments, suitable pharmaceutically acceptable excipients include natural or synthetic triglycerides (including glycerol esters and derivatives), for example, but not limited to, C6-C 18 Diglycerides or triglycerides based on fatty acids (such as caprylic / capric triglyceride, wheat germ glyceride, etc.) may be included. Fatty acid esters of polyglycerin (polyglyceryl-n, for example, polyglyceryl-4 caprylate, polyglyceryl-2 isostearate, etc.), or castor oil, hydrogenated vegetable oil, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borage oil, etc. Suitable excipients include esters of long-chain acids and alcohols, and waxes including compounds having wax-like properties, for example, carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ozokerite, wood wax, paraffin wax, microcrystalline wax, ceresin, cetearyl ester wax, synthetic beeswax, etc. Also, hydrophilic waxes as cetearyl alcohol or partial glycerides.

[0171] In certain embodiments, suitable pharmaceutically acceptable excipients include pearlescent waxes such as, but not limited to, alkylene glycol esters, particularly ethylene glycol distearate; fatty acid alkanolamides, particularly coconut fatty acid diethanolamide; partial glycerides, particularly monoglyceride stearate; esters of polyvalent unsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, particularly long-chain esters of tartaric acid; fatty substances such as fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers, and fatty carbonates having in total at least 24 carbon atoms, particularly lauryl and distearyl ethers; fatty acids such as stearic acid, hydroxystearic acid, or behenic acid, ring-opening products of olefin epoxides having 12 to 22 carbon atoms with fatty alcohols having 12 to 22 carbon atoms and / or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxy groups, and mixtures thereof may be included.

[0172] In certain embodiments, suitable pharmaceutically acceptable excipients include hydrocarbon oils such as, but not limited to, mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline wax, paraffin and isoparaffin compounds, hydrogenated isoparaffin molecules as polydecene and polybutene, hydrogenated polyisobutene, squalane, isohexadecane, isododecane, and others from the plant and animal kingdoms may be included.

[0173] In certain embodiments, suitable pharmaceutically acceptable excipients include silicones or siloxanes (organically substituted polysiloxanes), such as, but not limited to, dimethylpolysiloxane, methylphenylpolysiloxane, cyclic silicones, as well as similarly amino, fatty acid, alcohol, polyether, epoxy, fluorine, glycoside, and / or alkyl modified silicone compounds, which may be in either liquid or resin form at room temperature. Linear polysiloxanes, dimethicone (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluids, cyclopentasiloxane volatiles (Dow Corning 345 fluid), phenyltrimethicone (Dow Corning 556 fluid). Also suitable is simethicone, which is a mixture of dimethicone and hydrogenated silicate having an average chain length of 200 to 300 dimethylsiloxane units. Additionally, a detailed investigation of suitable volatile silicones by Todd et al. can be found in Cosm. Toil. 91, 27 (1976).

[0174] In certain embodiments, suitable pharmaceutically acceptable excipients include emulsifiers such as, but not limited to, carboxylic acids and their salts: alkali soaps of sodium, potassium, and ammonium, metal soaps of calcium or magnesium, organic soaps such as lauric acid, palmitic acid, stearic acid, and oleic acid. Alkyl phosphate esters or phosphate esters, acidic phosphate esters, diethanolamine phosphate, cetyl potassium phosphate. Ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acrylates. Linear fatty alcohols having 8 to 22 carbon atoms branched from fatty acids having 12 to 22 carbon atoms and alkylphenols having 8 to 15 carbon atoms in the alkyl group with 2 to 30 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide. Fatty alcohol polyglycol ethers such as laureth-n, ceteareth-n, steareth-n, oleth-n. Fatty acid polyglycol ethers such as PEG-n stearate, PEG-n oleate, PEG-n cocoate. Monoglycerides and polyol esters. C12-C22 fatty acid monoesters and diesters that are addition products of 1 to 30 moles of ethylene oxide with polyols. Fatty acids and polyglycerol esters such as glyceryl monostearate, diisostearoyl polyglyceryl-3-diisostearate, polyglyceryl-3-diisostearate, triglyceryl diisostearate, polyglyceryl-2-sesquiisostearate, or polyglyceryl dimelate. Mixtures of compounds from multiple of these substance classes are also suitable. Fatty acid polyglycol esters such as diethylene glycol monostearate, fatty acids and polyethylene glycol esters, fatty acids and sucrose esters such as sucroesters, glycerol and sucrose esters such as sucroglycerides. Sorbitol and sorbitan, sorbitan monoesters and diesters of saturated and unsaturated fatty acids having 6 to 22 carbon atoms, and ethylene oxide addition products.Polysorbate-n series, sorbitan esters such as sesquiisostearate, sorbitan, PEG-(6)-isostearate sorbitan, PEG-(10)-sorbitan laurate, PEG-17-dioleate sorbitan. Glucose derivatives, C8-C22 alkyl mono- and oligoglycosides, and ethoxylated analogs, with glucose being the preferred sugar component. O / W emulsifiers such as methyl gluceth-20 sesquistearate, sorbitan stearate / sucrose cocoate, methyl glucose sesquistearate, cetearyl alcohol / cetearyl glucoside. W / O emulsifiers such as methyl glucose dioleate / methyl glucose isostearate. Sulfates and sulfonated derivatives, dialkyl sulfosuccinate, dioctyl succinate, alkyl lauryl sulfonate, linear sulfonated paraffin, sulfonated tetrapropylene sulfonate, sodium lauryl sulfate, ammonium and ethanolamine lauryl sulfate, lauryl ether sulfate, sodium laureth sulfate, sulfosuccinate, acetyl isothionate, alkanolamide sulfate, taurine, methyl taurine, imidazole sulfate. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicone, copolyol, silicone polyethylene oxide copolymer, silicone glycol copolymer. Propoxylated or POE-n ethers (Meroxapol), Polaxamer or poly(oxyethylene)m-block-poly(oxypropylene)n-block(oxyethylene). Zwitterionic surfactants carrying at least one quaternary ammonium group and at least one carboxylate and / or sulfonate group in the molecule.Particularly preferred zwitterionic surfactants are betaines, for example, N-alkyl-N,N-dimethylammonium glycinate, cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium glycinate, cocoacylaminopropyldimethylammonium glycinate, and 2-alkyl-3-carboxymethyl-3-hydroxyethylimidazoline each having 8 to 18 carbon atoms in the alkyl or acyl group, and cocoacylaminoethylhydroxyethylcarboxymethyl glycinate, N-alkyl betaine, N-alkylaminobetaine. Alkylimidazoline, alkyl peptide, lipoamino acid, self-emulsifying base, and compounds described in K.F. DePolo, A short textbook of cosmetology, Chapter 8, Table 8-7, p 250-251.

[0175] Suitable non-ionic bases include, but are not limited to, 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 ricinoleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and ceteareth-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 hydrogenated castor oil, cetearyl alcohol and PEG-40 hydrogenated castor oil and sodium cetearyl sulfate, stearyl alcohol and steareth-7 and steareth-10, cetearyl alcohol and steareth-7 and steareth-10, glyceryl stearate and PEG-75 stearate, propylene glycol ceteareth-3 acetate, propylene glycol isoceteareth-3 acetate, cetearyl alcohol and ceteareth-12 and oleth-12, PEG-6 stearate and PEG-32 stearate, PEG-6 stearate and ceteareth-20 and steareth-20, PEG-6 stearate and ceteareth-20 and glyceryl stearate and steareth-20, glyceryl stearate and ceteareth-20.

[0176] Suitable anionic alkaline bases include, but are not limited to, PEG-2 stearate SE, glyceryl stearate SE, propylene glycol stearate. Anionic acid bases, for example, cetearyl alcohol and sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, trilamine-4 phosphate and glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulfate. Cationic acid bases, for example, cetearyl alcohol and cetrimonium bromide.

[0177] In certain embodiments, suitable pharmaceutically acceptable excipients can include adjuvants and additives such as, but not limited to, surfactants, super-fatting agents, consistency regulators, thickeners, polymers, stabilizers, bioactive ingredients, swelling agents, additional UV light protection factors, antioxidants, hydrotropes, preservatives, self-tanning agents, solubilizers, essential oils, colorants, bacteriostatic agents, and the like.

[0178] In certain embodiments, suitable pharmaceutically acceptable excipients can include super-fatting agents such as, but not limited to, lanolin and lecithin, as well as polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides, and fatty acid alkanolamides, the latter of which also act as foam stabilizers.

[0179] In certain embodiments, suitable pharmaceutically acceptable excipients can include surfactants such as, but not limited to, fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and / or dialkyl sulfosuccinates, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, alpha-olefin sulfonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkyl amide betaines, and / or protein fatty acid condensation products, the latter of which are preferably based on wheat protein.

[0180] In certain embodiments, suitable pharmaceutically acceptable excipients may include consistency modifiers / thickeners and rheology modifiers such as, but not limited to, silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or their derivatives such as hyaluronic acid, xanthan gum, guar gum, agar, alginate, carrageenan, gellan, pectin, or modified cellulose such as hydroxycellulose, hydroxypropylmethylcellulose. Additionally, polyacrylates or homopolymers of crosslinked acrylic acid and polyacrylamide, carbomers (CARBOPOL types 980, 981, 1382, ETD2001, ETD2020, ULTREZ10), or SALCARE products such as SALCARE SC80 (steareth-10 allyl ether / acrylate copolymer), Salcare SC81 (acrylate copolymer), Salcare SC91 and Salcare AST (sodium acrylate copolymer / PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide / laures-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer), STABILEN 30 (acrylate / vinyl isodecanoate crosspolymer), PEMULEN TR-1 (acrylate / C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (sodium acrylate copolymer), ACULYN 28 (acrylate / beheneth-25 methacrylate copolymer), etc.

[0181] In certain embodiments, suitable pharmaceutically acceptable excipients include polymers such as, but not limited to, anionic, zwitterionic, amphoteric, and nonionic polymers, such as vinyl acetate / crotonic acid copolymer, vinyl pyrrolidone / vinyl acrylate copolymer, vinyl acetate / butyl maleate / isobornyl acrylate copolymer, methyl vinyl ether / maleic anhydride copolymer and its esters, uncrosslinked polyacrylic acid and polyacrylic acid crosslinked with polyols, acrylamide propyl-trimethylammonium chloride / acrylate copolymer, octyl acrylamide / methyl methacrylate-tert-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymer, polyvinyl pyrrolidone, vinyl pyrrolidone / vinyl acetate copolymer, vinyl pyrrolidone / dimethylaminoethyl methacrylate / vinyl caprolactam terpolymer, and similarly optionally derivatized cellulose ethers and silicones may be included. Further, the polymers described in EP1093796 (pages 3-8, paragraphs 17-68) may be used.

[0182] In certain embodiments, suitable pharmaceutically acceptable excipients include antioxidants such as, but not limited to, amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., urocanic acid) and their derivatives, peptides such as, D,L-carnosine, D-carnosine, L-carnosine, and its derivatives (e.g., anserine), carotenoids, carotenes, lycopene, and its derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g., dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine, and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cholesteryl, and their glyceryl esters), and likewise their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid, and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts), and likewise sulfoximine compounds (e.g., buthionine sulfoximine, homocysteine sulfoximine, buthionine sulfone, penta-, hexa-, hepta-thionine sulfoximine), also (metal) chelating agents (e.g., hydroxy fatty acids, phytic acid palmitic 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 their derivatives, vitamin C and its 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 likewise coniferyl benzoate of benzoin resin, rutinic acid and its derivatives, glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine, butylated hydroxytoluene, butylated hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, superoxide dismutase, N-[3-(3,(5-Di-tert-butyl-4-hydroxyphenyl)propionyl]sulfanylic acid (and its salts, e.g., disodium salt), selenium and its derivatives (e.g., selenomethionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), and suitable derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids) of these aforementioned active ingredients according to the present invention may be included. HALS (= "Hindered Amine Light Stabilizers") compounds may also be mentioned.,

[0183] In certain embodiments, suitable pharmaceutically acceptable excipients include hydrotropic agents such as, but not limited to, ethoxylated or non-ethoxylated monoalcohols, lower diols or polyols or their ethers (e.g., ethanol, isopropanol, 1,2-dipropanediol, propylene glycol, glycerin, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, and similar products). The polyols contemplated for that purpose preferably have from 2 to 15 carbon atoms and at least two hydroxy groups. The polyols may also contain additional functional groups, particularly amino groups, and / or may be modified with nitrogen. Typical examples are as follows: glycerol, alkylene glycols such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol, and polyethylene glycol with an average molecular weight of from 100 to 1000 daltons as well; industrial oligoglycerol mixtures with an intrinsic degree of condensation of from 1.5 to 10, such as industrial diglycerol mixtures with a diglycerol content of from 40 to 50% by weight; methylol compounds such as, in particular, trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol, and dipentaerythritol; lower alkyl glucosides, particularly those with 1 to 8 carbon atoms in the alkyl radical, such as methyl and butyl glucoside; sugar alcohols with 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars with 5 to 12 carbon atoms, such as glucose or sucrose; amino sugars such as glucamine; dialcohol amines such as diethanolamine or 2-1,3-propanediol.

[0184] In certain embodiments, suitable pharmaceutically acceptable excipients include preservatives such as, but not limited to, methyl-, ethyl-, propyl-, butyl-paraben, benzalkonium chloride, 2-bromo-2-nitro-propane-1,3-diol, dehydroacetic acid, diazolidinyl urea, 2-dichloro-benzyl alcohol, DMDM hydantoin, formaldehyde solution, methyl dibromo glutaronitrile, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan, and further classes of substances listed in the following references, K.F. DePolo - A short textbook of cosmetology, Chapter 7, Tables 7-2, 7-3, 7-4 and 7-5, p 210-219 may be included.

[0185] In certain embodiments, suitable pharmaceutically acceptable excipients include bacteriostatic agents such as, but not limited to, 2,4,4’-trichloro-2’-hydroxydiphenyl ether, chlorhexidine (1,6-di(4-chlorophenyl-biguanide)hexane), or TCC (3,4,4’-trichlorocarbanilide). A number of aromatic substances and ether oils also have antibacterial properties. Typical examples are the active ingredients eugenol, menthol, and thymol in clove oil, mint oil, and thyme oil. A natural deodorant of interest is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol), which is present in lime blossom oil. Glycerol monolaurate has also been shown to be a bacteriostatic agent.

[0186] Other pharmaceutically acceptable excipients may also be utilized as would be recognized by those skilled in the art.

[0187] In certain embodiments, the pharmaceutically acceptable excipients can be included (individually or cumulatively) in the pharmaceutical compositions described herein at a concentration in the range of from any of about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% to any of 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% based on the total weight of the composition, or at any sub-range or single value within that range.

[0188] Preparation method In certain embodiments, the present disclosure relates to a method of preparing any of the compositions described herein. In certain embodiments, the method comprises combining a therapeutically effective amount of a compound of formula (I) with one or more pharmaceutically acceptable excipients.

[0189] The various compositions described herein may be formulated to have a customized release profile for the active agent, for example, but not limited to, an immediate release profile, a controlled release profile, a delayed release profile, an enteric release profile, a zero-order release profile, a first-order release profile, a pulsatile release profile, a targeted release at a particular location in the body (such as a target location in the gastrointestinal tract), etc.

[0190] For the sake of brevity, embodiments of the methods of the present disclosure are depicted and described as a series of acts. However, the acts in accordance with the present disclosure can be performed in various orders and / or simultaneously, and together with other acts not presented or described herein. Further, not all of the illustrated acts may be required to implement the methods in accordance with the disclosed subject matter. Additionally, one skilled in the art will understand and recognize that the methods can alternatively be represented as a series of interrelated states via a state diagram or events.

[0191] In the above description, many specific details such as specific materials, dimensions, process parameters, etc. have been described to provide a complete understanding of the present invention. Specific features, structures, materials, or characteristics can be combined in any suitable way in one or more embodiments. The words "example" or "exemplary" are used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as an "example" or "exemplary" should not necessarily be construed as being more preferred or advantageous than other aspects or designs. Rather, the use of the words "example" or "exemplary" is intended to illustrate the concept in a specific manner. As used in this application, "or" is intended to mean an inclusive "or" rather than an exclusive "or". That is, unless otherwise specified or clear from the context, "X includes A or B" is intended to mean any of the natural inclusive substitutions. That is, "X includes A or B" is satisfied under any of the above examples when X includes A, when X includes B, or when X includes both A and B. References throughout this specification to "an embodiment", "certain embodiments", or "one embodiment" mean that the particular features, functions, structures, or characteristics described in relation to that embodiment are included in at least one embodiment. Thus, the phrases "an embodiment", "certain embodiments", or "one embodiment" that appear in various places throughout this specification do not necessarily all refer to the same embodiment.

[0192] The present invention has been described with reference to its specific exemplary embodiments. Accordingly, the specification and drawings are to be regarded as illustrative rather than restrictive. In addition to what is shown and described herein, various modifications of the present invention will become apparent to those skilled in the art and are intended to be included within the scope of the appended claims. List of Articles In certain embodiments, the invention relates to one or more of the following clauses. 1. A method for treating neurogenic hypoventilation, comprising administering to a patient in need thereof an effective amount of a compound selected from formula (I):

Chemical formula

Chemical formula

Example

[0193] Materials and methods A set of twin lambs were preterm by cesarean section and were scheduled to be stabilized and managed for 4 hours. Based on the experience of the model, the researchers expected that the lambs would have the drive for spontaneous breathing, and thus the control animals could be managed with continuous positive airway pressure (CPAP) for 4 hours, i.e., they did not require mechanical ventilation. This protocol was reviewed and approved by the Animal Experimentation Committee of Thomas D. Morris, Inc., where the study was conducted.

[0194] During delivery, local anesthesia (1 ml, 2% lidocaine) was administered, and an endotracheal tube, as well as carotid and jugular catheters, were inserted into the lambs through an incision approximately in the center of the anterior neck. When the umbilical cord was ligated and cut, the lambs were transferred to a surgical bed warmed under radiant heat to warm the lambs. The arterial catheter was connected to a transducer for pressure monitoring, and the venous catheter was connected to a pump for continuous infusion of 5% dextrose in water (D5W) at a rate of 6 ml / kg / h. A response thermistor was inserted to monitor the temperature, and the lambs were covered with plastic to minimize heat loss by evaporation. The airway was suctioned, and surfactant (Curosurf, 2.5 ml / kg) was administered endotracheally over 5 minutes in four positions (Trendelenburg position, reverse Trendelenburg position, left and right lateral positions). The lambs received four mechanical ventilations for lung recovery, after which CPAP was initiated at 5 cmH2O and continuously optimized with the fraction of inspired oxygen (FIO2) (4 - 8 cmH2O) during the study period.

[0195] After a 15 - minute stabilization period from delivery, the first lamb received a continuous infusion of compound 1 (XXXV) (N-(4,6 - bis - n - propylamino - [1,3,5]triazin - 2 - yl)-O,N - dimethylhydroxylamine). The structure of compound 1 is as follows:

Chemical formula

[0196] The formulation used was an aqueous solution of 10 mg / mL containing citrate buffer and pH 3.2 (adjusted for bisulfate and impurities). The infusion was carried out using a gradually increasing dose every hour, but the second lamb served as a sham control. Compound 1 was started without a loading dose, and as a result, the plasma concentration would increase every hour and should contribute to the escalating dose effect. The four hourly doses are listed in Table 1. The first three doses have been used in human efficacy studies. At low doses, the effect is minimal. The second dose was intended as the adult therapeutic dose (following the loading dose), the third dose was intended as the adult loading dose, and the last hourly dose, which is 10 times the intended adult therapeutic dose, was administered to assist in the toxicity analysis of immature tissues.

Table 1

[0197] Lung function evaluations were performed every 15 minutes, along with recording of vital signs and collection of samples for arterial blood gas and compound 1 concentration. For lung function evaluation, a respiratory flowmeter was placed between the endotracheal tube and the CPAP connector. Using a lung function system designed for neonatal research (NewLifeBox-R, AdvancedLifeDiagnostics, Vienna, Germany), at least 10 representative breaths without non-standard respiratory artifacts were recorded. The rate, tidal volume, and minute ventilation for each period were derived from the average of 10 breaths. To maintain a stable stage of anesthesia, fentanyl (1 μg IM) was administered in repeated doses as needed throughout the protocol based on the blood pressure response to stimulation. At the end of the study, the animals were sacrificed and tissue samples were collected for subsequent histopathological examination.

[0198] Results Two lambs were born, one weighing 3.2 kg (test animal) and the other 4.1 kg (sham animal). The instrument was used without problems, but neither lamb showed spontaneous respiratory drive. Each animal required manual ventilation with no spontaneous effort throughout the stabilization period and thereafter. Thus, each animal had its own clinical course based on treatment assignment.

[0199] Clinical viability: Test animal Despite a poor prognosis due to lack of respiratory effort, a continuous infusion of the first dose of Compound 1 was started 20 minutes after birth. The test animal continued to require manual ventilation, which continued for an additional 10 minutes.

[0200] Since the purpose of this study was to validate the model, a decision was made to provide a loading dose as an intravenous bolus injection of Compound 1. 1 mL of the stock solution of Compound 1 (10 mg / ml) was withdrawn and injected through an intravenous catheter. Considering the lamb's weight of 3.2 kg, this bolus was selected to be 3.1 mg / kg, as this bolus intravenous injection results in a transient therapeutic plasma level in animal studies previously conducted to develop the use of Compound 1 as a bolus at 3 mg / kg.

[0201] Almost immediately after IV bolus delivery, the lamb spontaneously began to breathe and required no manual intervention for the remainder of the study. A CPAP system was connected to the endotracheal tube and the pressure was decreased to 4 cmH2O. For the remaining 4 hours after the start of the first infusion dose, the dose was changed every hour, the radiant heat was adjusted to maintain temperature, and physiological data were recorded every 15 minutes according to the protocol. Four hours after the start of the continuous infusion, the animal was sacrificed for tissue collection.

[0202] Clinical viability: Sham animal The sham animal gave birth approximately 1 hour after the test animal. That is, after the test animal breathed and stabilized, the second delivery was performed. Similar to the test animal, the sham animal had no spontaneous respiratory effort. A decision was made to manually ventilate for 30 minutes in accordance with the progress of the test animal, and if it did not breathe, it was judged to be non-viable and was sacrificed for control tissue samples.

[0203] At the 30-minute time point, considering the purpose of this study again, a 1 mL intravenous bolus injection of Compound 1 (10 mg / mL) was delivered. For the weight of this lamb, the bolus was less than 2.4 mg / kg. Almost immediately after the IV bolus delivery, the lamb began to breathe spontaneously. After a few minutes, the effort of spontaneous breathing weakened and manual ventilation was resumed. Next, the animal was sacrificed for tissue collection.

[0204] Physiology of Treated Animals The treated lambs required 6 bolus intravenous injections of 1 μg of fentanyl to maintain stable anesthesia according to the protocol. At delivery, the first dose was administered, 4 doses were administered during the 4-hour experimental period, and the 6th dose was administered immediately before death. The timing of the 4 doses administered during the experimental period is indicated by the arrows in Figures 1-3 and coincides with the inflection points of the respiratory rate, tidal volume, or respiratory pattern.

[0205] At baseline (at the start of injection) and for the subsequent 10 minutes, the spontaneous minute ventilation (MV) was zero (Figure 1A). Immediately after the bolus loading administration, the spontaneous MV immediately changed from zero to approximately 1,100 mL / min. The MV continued to increase over 4 hours, and at the same time, the end-tidal carbon dioxide concentration (EtCO2, Figure 1B) decreased.

[0206] Compound 1 had the most dramatic effect on minute ventilation, with a consistent increase over 4 hours (Figure 2A). When reported as minute ventilation per kg of body weight (Figure 2B), spontaneous breathing was at least as deep and ultimately exceeded 4 - 6 mL / kg in the lung protective range. Respiratory rate (RR, Figure 2C) gradually decreased over 4 hours and responded more precisely to fentanyl administration. Nevertheless, the RR was always significantly higher than the normal respiratory rate of neonatal lambs.

[0207] Figure 3 shows the trends in heart rate and mean arterial pressure over 4 hours. Both indicators of hemodynamics are stable and appear to reflect the cumulative effect of fentanyl by 3 hours. The increase in arterial pressure at baseline reflects the effort of positive pressure ventilation.

[0208] Arterial oxygen saturation (SpO2) was recorded between 97 - 100%, except for three measurement periods where the pulse oximetry signal was unachievable or unreliable. Due to technical problems (the blood gas analyzer was not functioning on the day of the experiment), blood chemistry data were not obtained.

[0209] Histopathology and pharmacokinetic samples Since the situations of test animals and mock animals are very different, tissue samples from these animals were not analyzed independently. At present, pharmacokinetic samples have not been analyzed. Following this proof - of - concept study, an assay for compound 1 in lamb plasma is being developed to support further research.

[0210] Discussion The purpose of this study using a group of lambs was to verify that Compound 1 promotes ventilation in the immature ventilatory circuit before a larger study is designed. A progressive dosing scheme in the treated animals was expected to yield a strong dosing response, by which the treated lambs would be substantially distinguishable from a matched twin control group. However, the complete absence of the drive for spontaneous breathing was unexpected, and after managing the first lamb for the first 30 minutes, the researchers were considering stopping the study, judging that the lamb could not survive without mechanical ventilation.

[0211] After a bolus administration of the loading dose, the effect of Compound 1 was clear and remarkable, changing from a state of no respiratory effort in the animal to a complete, continuous, and effective spontaneous effort. Compound 1 immediately brought about spontaneous breathing in both lambs. In the lamb with continuous infusion of Compound 1, strong breathing continued without remission even at the lowest dose shown to have limited effectiveness in enhancing the existing ventilatory drive in adults.

[0212] Despite the technical problems of the machine that prevented the measurement of arterial blood gas, EtCO2 showed a gradual decline. The researchers should take into account that hypercapnia increased during the initial period of manual ventilation before delivering the loading dose of Compound 1 due to the inability to monitor in real time the delivery of surfactant, the pause to allow spontaneous floating efforts, and effective ventilation. Therefore, EtCO2 was initially high. Furthermore, compared with the existing data on the ventilation of neonatal lambs, the current ventilation data suggest that there was at least effective and sufficient spontaneous ventilation during the delivery of Compound 1. The normal range of the respiratory rate of neonatal lambs is 36 - 48 (times / minute), and past literature on the management of premature lambs by mechanical ventilation limits it not to exceed 70 (times / minute). In the current study, the respiratory rate did not fall below 70 breaths per minute. Additionally, in the previous literature on the mechanical ventilation of lambs, the tidal volume is limited to 4 - 6 mL / kg, which, combined with the maximum allowable respiratory rate (70 times / minute), would result in a maximum MV value of 1,344 mL / min for this lamb. However, in this study, the lambs had an MV exceeding 1,344 mL / min in all measurements except the first three measurements of spontaneous breathing and were always within or above the described target tidal volume range. Therefore, it is highly likely that the lambs were in a state of hyperventilation by the end of the study period.

[0213] Furthermore, due to the stimulation by intense respiratory efforts, the test animals required a significant amount of fentanyl during the study period. Nevertheless, despite the acute effect on the respiratory rate and the cumulative exposure to fentanyl, a strong respiratory drive continued. Interestingly, 3.25 hours after the start of the experiment, after administering fentanyl, a significant change to abdominal breathing was observed, and at this point, the tidal volume exceeded the above target range. This period was confounded by several factors that need to be elucidated in further studies, including hyperventilation induced by a very high dose of Compound 1, fatigue due to prolonged intense respiratory efforts, and the cumulative effect of 1.6 μg / kg of fentanyl in less than 4 hours.

[0214] When interpreting the data, it must be noted that there was no intended loading dose for each of the four infusion doses defined by the protocol. Therefore, it is not surprising that spontaneous breathing did not start without the first bolus administration, as it takes considerably longer than 10 minutes to reach an effective plasma concentration at this first low dose. That is, the fetal lamb at 134 days of gestation was expected to have baseline respiratory effort. Furthermore, considering the absence of a loading dose in combination with subsequent escalating doses over the last 3 hours, it was not expected that there would not be a clear plateau in the effect, but rather a further continuous increase in response. Therefore, these data on respiratory parameters fully demonstrate what was expected in this proof-of-concept model.

[0215] In conclusion, this proof-of-concept study demonstrates that Compound 1 has a profound effect on the ventilatory drive of neonatal lambs. This effect is shown to occur at a developmental stage where the innate spontaneous drive is lacking.

Claims

[Claim 1] The invention described in the present specification.

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