Respiratory stimulant parenteral preparations

Abstract

In certain embodiments, a parenteral formulation is disclosed comprising a compound of formula (I) disclosed herein and a pharma- ceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., at 60% relative humidity for 2 weeks.

Description

[Technical field]

[0001] This invention was made with Government support under Contract 75A50121C00044 awarded by the Biomedical Advanced Research and Development Authority (BARDA). The Government has certain rights in this invention.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 293,985, filed December 27, 2021, and No. 63 / 313,472, filed February 24, 2022, the contents of which are incorporated herein in their entireties.

[0003] The present disclosure relates to methods and compositions for treating respiratory depression, for example, regulated by opioid or non-opioid agents, inflammation, or infection. [Background technology]

[0004] The human body is highly dependent on the ventilatory control system for adequate intake of oxygen and removal of carbon dioxide (CO2). Many active drugs, such as opioid analgesics, can cause respiratory depression in certain situations, such as overdose, by acting on μ-opioid receptors expressed on respiratory nerves in the brainstem.

[0005] Other drugs can cause respiratory depression in overdose or in other situations, for example, anesthetic drugs such as propofol can cause respiratory depression that can be life-threatening.

[0006] Respiratory depression can also be caused by non-pharmacological reasons such as inflammation or infection.

[0007] There is a need in the art for therapeutic methods and formulations for treating respiratory depression caused by any reason. Summary of the Invention

[0008] In certain embodiments, the present disclosure is directed to therapeutic methods and formulations for treating respiratory depression caused, for example, by opioid agents, non-opioid agents, inflammation, or infection.

[0009] In certain embodiments, the present disclosure is directed to a parenteral formulation comprising a compound of formula (I) as disclosed herein and a pharma- ceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., at 60% relative humidity for 2 weeks.

[0010] definition As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" includes not only a single active agent but also a mixture of two or more different active agents, reference to "an excipient" includes not only a single excipient but also a mixture of two or more different excipients (as well as others).

[0011] As used herein, the term "about" in relation to a measurand refers to the normal variation of that measurand that would be expected by one of ordinary skill in the art when making the measurement and using a level of care commensurate with the purpose of the measurement and the precision of the measurement device. In certain embodiments, the term "about" includes the recited number ±10%, so that "about 10" would include 9-11.

[0012] As used herein, the terms "active agent," "active ingredient," and "active pharmaceutical ingredient" refer to any material intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved for that purpose by a governmental agency. These terms, with respect to a particular agent, include all pharma- ceutically active agents, all pharma- ceutically acceptable salts, complexes, stereoisomers, crystalline forms, cocrystals, ethers, esters, hydrates, solvates, and mixtures thereof, which forms are pharma- ceutically active.

[0013] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with one or more chiral centers that are not mirror images of one another (diastereomers).

[0014] The term "enantiomer" or "enantiomeric" refers to a molecule that is not superimposable on its mirror image and is therefore optically active, where an enantiomer rotates the plane of polarized light to some extent in one direction and its mirror image rotates the plane of polarized light to the same extent but in the opposite direction.

[0015] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0016] The term "patient" refers to a subject, animal, or human who exhibits clinical manifestations of a particular symptom or symptoms indicating the need for treatment, or who is being treated for preventative or prophylactic purposes for a condition, or who has been diagnosed with a condition to be treated. The term "subject" encompasses the definition of the term "patient" and does not exclude individuals who are otherwise healthy.

[0017] "Pharmaceutically acceptable salts" or "salts" include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, phosphate, nitrate, carbonate, sulfuric, phosphoric (including hydrogen phosphate and dihydrogen phosphate), organic acid salts such as oxalate, malonate, citrate, fumarate, lactate, malate, succinate, formate, acetate, trifluoroacetate, maleate, tartrate, gluconate, benzoate, salicylate, xinafoate, pamoate, ascorbate, adipate, cinnamate, and the like, sulfonic acid salts, and the like. Examples of the salt include salts of methanesulfonates, benzenesulfonates, p-toluenesulfonates, etc., amino acid salts such as alginates, apartates, glutamates, etc., metal salts such as zinc salts, sodium salts, cesium salts, alkaline earth metal salts such as calcium salts, magnesium salts, and organic amine salts such as triethylamine salts, pyridine salts, picoline salts, ethanolamine salts, triethanolamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine, etc. These salts may exist in the form of hydrates, solvates, or crystalline polymorphs. In certain embodiments, suitable organic acids are selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic (pamoic) acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.All of these salts can be prepared by conventional means from the corresponding compounds of the invention, for example by reacting the appropriate acid or base with the compound of the invention. Handbook of Pharmaceutical Salts: Properties, and Use (P.H. Stahl & C.G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002)[1].

[0018] The term "disease(s)" or "condition(s)" refers to a medical condition that can be treated or prevented by administration to a subject of an effective amount of an active agent.

[0019] The terms "treatment" and "treating" include reducing or halting the severity of a condition, or reducing or halting the severity of a symptom of a condition. In certain embodiments, the term "treatment" or "treating" refers to administration with the intent of producing a pharmacodynamic effect in relation to a condition, regardless of outcome. In certain embodiments, "treatment" or "treating" refers to "having a positive effect on a condition," and includes reducing, improving, and / or alleviating the severity of at least one symptom of a condition, reducing, improving, and / or alleviating the severity of a condition, slowing, preventing, or inhibiting the progression of a condition, or a perceived improvement or benefit as a result of treatment. Treatment, as used herein, does not require a complete cure of a condition. In certain embodiments, the compositions of the present disclosure may result in an improvement in the quality of life of a patient, or a delay, prevention, inhibition of the onset of one or more symptoms of a condition, or may provide a perceived benefit.

[0020] The terms "prevention of" and "preventing" include the avoidance of the onset of a condition.

[0021] The term "therapeutically effective amount" is intended to include, for example, an amount of an active agent or an amount of a combination of active agents to treat or prevent a condition in a subject, or to treat a symptom of a condition.

[0022] The term "effective amount" is intended to include an amount of a component or an amount of a combination of components to achieve a particular result or property, e.g., an effective amount of a pH adjuster to achieve a pH of 6.0 is intended to include the amount of one or more pH adjusters to reach a pH of 6.0.

[0023] The terms "application", "applying" and "applying" in connection with the disclosed topical compositions or methods of using the disclosed topical compositions refer to any manner of administering a topical composition to a patient's skin in medical or cosmetic practice that delivers the composition to the patient's skin surface. Smearing, rubbing, spreading, spraying the disclosed topical composition onto a patient's skin, with or without a suitable device, are all included within the scope of the term "application" as used herein. The terms "topical" or "topically" in connection with administration or application of the disclosed formulations refer to epidermal administration or application, or administration on the skin.

[0024] As used herein, "parenteral administration" refers to a route of administration whereby a pharmaceutical dosage form is injected, for example, into a muscle (intramuscular administration), into a vein (intravenous administration), or under the skin (subcutaneous administration).

[0025] The phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0026] As used herein, the term "alkyl," by itself or as part of another substituent, means, unless otherwise indicated, a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C1-C10 means 1 to 10 carbon atoms) and includes straight, branched, or cyclic substituents. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl. Most preferred are (C1-C6)alkyls, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl, and cyclopropylmethyl.

[0027] As used herein, the term "cycloalkyl," by itself or as part of another substituent, means, unless otherwise indicated, a cyclic chain hydrocarbon having the specified number of carbon atoms (i.e., C3-C6 means a cyclic group containing a ring group of 3 to 6 carbon atoms), including straight chain, branched chain, or cyclic substituents. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred are (C3-C6)cycloalkyls, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0028] As used herein, the term "alkenyl", used alone or in combination with other terms, means, unless otherwise indicated, a stable mono- or di-unsaturated straight or branched chain hydrocarbon group having the specified number of carbon atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyl, 1,4-pentadienyl, and higher homologs and isomers. A functional group representing an alkene is exemplified by -CH2-CH=CH2.

[0029] As used herein, the term "alkynyl," used alone or in combination with other terms, means, unless otherwise indicated, a stable straight or branched chain hydrocarbon group with a triple carbon-carbon bond having the specified number of carbon atoms. Examples include ethynyl and propynyl, as well as the higher homologs and isomers.

[0030] As used herein, the terms "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl", or "substituted alkynyl" refer to alkyl, cycloalkyl, alkenyl, or alkynyl as defined above, and include any of the following: halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH, -N(CH), (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(=O)OH, trifluoromethyl, -C≡N, -C(=O)O(C1-C4)alkyl, -C(=O)N It means an alkyl, cycloalkyl, alkenyl, or alkynyl substituted with one, two, or three substituents selected from the group consisting of H2, -C(=O)NH(C1-C4)alkyl, -C(=O)N((C1-C4)alkyl)2, -SON2NH2, -C(=NH)NH2, and -NO2, preferably selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, more preferably one or two substituents selected from halogen, alkoxy, and -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0031] As used herein, the term "alkoxy", used alone or in combination with other terms, means, unless otherwise indicated, an alkyl group having the specified number of carbon atoms, as defined above, attached to the remainder of the molecule through an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologs and isomers. (C1-C3)alkoxy, such as, but not limited to, ethoxy and methoxy, is preferred.

[0032] As used herein, the terms “halo” or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0033] As used herein, the term "heteroalkyl", by itself or in combination with another term, means, unless otherwise indicated, a stable straight or branched chain alkyl group consisting of the specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be located at any position of the heteroalkyl group, including between the remainder of the heteroalkyl group and the fragment to which it is attached, or may be attached to the most distal carbon atom of the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or -CH2-CH2-SS-CH3.

[0034] As used herein, the term "heteroalkenyl," by itself or in combination with another term, means, unless otherwise indicated, a stable straight or branched mono- or di-unsaturated hydrocarbon group consisting of the specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, where the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Up to two heteroatoms may be arranged consecutively. Examples include -CH=CH-O-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and -CH2-CH=CH-CH2-SH.

[0035] As used herein, the term "aromatic" refers to a carbocyclic or heterocyclic ring with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

[0036] As used herein, the term "aryl", used alone or in combination with other terms, means, unless otherwise indicated, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), which may be linked together in a pendant fashion, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. Phenyl and naphthyl are preferred, with phenyl being most preferred.

[0037] As used herein, the term "aryl-(C1-C3)alkyl" refers to a functional group in which a one to three carbon alkylene chain is attached to an aryl group, e.g., -CH2CH2-phenyl or -CH2-phenyl(benzyl). Aryl-CH2- and aryl-CH(CH3)- are preferred. The term "substituted aryl-(C1-C3)alkyl" refers to an aryl-(C1-C3)alkyl functional group in which the aryl group is substituted. Substituted aryl(CH2)- is preferred. Similarly, the term "heteroaryl-(C1-C3)alkyl" refers to a functional group in which a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CH2CH2-pyridyl. Heteroaryl-(CH2)- is preferred. The term "substituted heteroaryl-(C1-C3)alkyl" refers to a heteroaryl-(C1-C3)alkyl functional group in which the heteroaryl group is substituted. Substituted heteroaryl-(CH2)- is preferred.

[0038] The term "heterocycle" or "heterocyclyl" or "heterocyclic" as used herein, by itself or as part of another substituent, means, unless otherwise indicated, a stable, unsubstituted or substituted, monocyclic or polycyclic heterocyclic ring system consisting of carbon atoms and at least one heteroatom selected from the group consisting of N, O, and S, where the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen atom may be optionally quaternized. The heterocyclic ring system may be attached at any heteroatom or carbon atom that provides a stable structure, unless otherwise indicated. The heterocycle may be aromatic or non-aromatic in nature. In one embodiment, the heterocycle is a heteroaryl.

[0039] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle having aromatic character. Polycyclic heteroaryls may contain one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuryl.

[0040] Examples of non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepine, and hexamethylene oxide.

[0041] Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (including, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

[0042] Examples of polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, , but are not limited to, 3-, 4-, 5-, 6-, and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (such as, but not limited to, 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (such as, but not limited to, 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl, benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolidinyl, and quinolizidinyl, and quinolizininyl.

[0043] The foregoing lists of heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.

[0044] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent bonded to another group.

[0045] For aryl groups, aryl-(C1-C3)alkyl groups, and heterocyclyl groups, the term "substituted" as applied to the rings of these groups refers to any level of substitution, i.e., mono-, di-, tri-, tetra-, or penta-substitution (where such substitution is permitted). The substituents are independently selected, and the substitution may be at any chemically accessible position. In one embodiment, the substituents vary in number from 1 to 4. In another embodiment, the substituents vary in number from 1 to 3. In yet another embodiment, the substituents vary in number from 1 to 2. In yet another embodiment, the substituents are independently selected from C1-6 Alkyl, -OH, C 1-6 It is selected from the group consisting of alkoxy, halo, amino, acetamido, and nitro. As used herein, when a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight chain, or cyclic, although straight chain is preferred.

[0046] The recitation of ranges of values ​​herein is intended to serve merely as a shorthand method of individually referring to each separate value falling within the range, and each separate value is incorporated herein to the same extent as if it were individually recited herein, unless otherwise indicated herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to facilitate understanding of certain materials and methods, and does not limit the scope of the claims. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the disclosed materials and methods. [Brief description of the drawings]

[0047] [Figure 1] FIG. 1 shows the pH stability profile after storage at 40° C. and 60° C. [Diagram 2] FIG. 2 shows the pH stability profile after storage at 40° C. and 60° C. [Diagram 3] FIG. 3 presents plots of mean plasma concentrations versus time up to 24 hours. [Figure 4] FIG. 4 presents plots of mean plasma concentrations versus time up to 4 hours. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0048] Certain embodiments of the present disclosure are directed to a parenteral formulation comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity, for 2 weeks, and wherein the compound of formula (I) has the following properties: [ka] (In the formula, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 is null, and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0049] Certain embodiments of the present disclosure are directed to a parenteral formulation comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity, for 2 weeks, and wherein the compound of formula (I) has the following properties: [ka] (In the formula, R 1 and R 2is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 1 , R 2 , R 3 , and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl; R6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 is null, and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0050] A parenteral formulation comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity, for 2 weeks, and wherein the compound of formula (I) has the following: [ka] (In the formula, R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl; R 4 is H, alkyl, or substituted alkyl; R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR 1 , -NR 1 R 2 , -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R 3 and R 5 combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 is null, and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, and (i) Z is CH2, and bond b 2is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0051] In one embodiment, R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, or substituted alkenyl. 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, or acyl.

[0052] Certain embodiments of the present disclosure are directed to a parenteral formulation comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity, for 2 weeks, and wherein the compound of formula (I) has the following properties: [ka] R 1 and R 2 is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, or substituted alkynyl; R 4 is H, alkyl, or substituted alkyl; R 5 is alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl; R 1 , R 2 , R 3 , and R 5 At least one substituent selected from the group consisting of is alkynyl or substituted alkynyl; R 6 is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR 4 and Y is N, CR 6 , or C, Y is N or CR 6 If b is 1 is null, and (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond, When Y is C, bond b 1 is a single bond, and (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C) or a salt thereof.

[0053] In certain embodiments, (i) R 3 is H, alkyl, or substituted alkyl; R 5 is propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl, or (ii) R 3 is H or alkynyl, R 5 is alkyl, propargyl, substituted propargyl, homopropargyl, or substituted homopropargyl.

[0054] In one embodiment, at least one compound of formula (I) is represented by the formula (II-a) or a salt thereof, wherein (i) Y is N, bond b1 is null, Z is H, bond b2 is a single bond, and A is CH, and at least one compound is a compound of formula (II-a) or a salt thereof, [ka] and (ii) Y is N, bond b1 is absent, Z is absent, bond b2 is absent, A is a bond, and the compound of the present invention is a compound of formula (II-b) or a salt thereof, selected from the group consisting of: [ka]

[0055] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is CR 6 and bond b 1 is nothing, Z is H, and bond b 2 is a single bond, A is CH, and at least one compound is a compound of formula (III-a) or a salt thereof: [ka] and (ii) Y is CR 6 and bond b 1 is null, Z is null, and bond b 2 is nothing, A is a bond, and the compound of the present invention is a compound of formula (III-b) or a salt thereof, selected from the group consisting of: [ka]

[0056] In one embodiment, Y is C and bond b 1 is a single bond, Z is CH2, and bond b 2 is a single bond, A is CH, and the at least one compound is a compound of formula (IV) or a salt thereof. [ka]

[0057] In one embodiment, Y is C and bond b 1 is a single bond, Z is CH, and bond b 2 is a double bond, A is C, and the at least one compound is a compound of formula (V) or a salt thereof. [ka]

[0058] In one embodiment, the at least one compound is selected from the group consisting of N-(4,6-bis-methylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XX), N-(4,6-bis-ethylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXII), N-(4-cyclopropylmethylamino)-N-(6-n-propylamino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXV), N-(4-ethylamino)-N-(6-n-propylamino)-[1 ,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXVII), N-(bis-4,6-(2-methylpropylamino))[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (XXIX), N-(bis-4,6-(2,2-dimethylpropylamino))[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXI), 4,6-bis-N-cyclopropylamino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (XXXII) I), N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (XXXV), N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide (XL), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-methyl-hydroxylamine (XLI), O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLIII), N-( 4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine (XLVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine (LIII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]oxazinan-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII), N-(4,6-bis-propylamino -[1,3,5]triazin-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-isobutyl-N-methyl-hydroxylamine (LXXXII), 6-( Methyl(thiophen-2-ylmethoxy)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXXIV), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-ethyl-N-methyl-hydroxylamine (XCVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-O-(2,2-difluoro -ethyl)-hydroxylamine (C), 4-N-(2-dimethylaminoethyl)amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII), 4-N-(3-(1-N-methylimidazol-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CV), 4-N-(1-N-methylimidazol-2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX), 4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXIII), 4,6-bis-[N-(tetrahydropyran-4-ylmethyl)amino]-[1,3 N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nonadeca-1(18),15(19),16(17)-trien-17-yl)-N,O-dimethylhydroxylamine (CXVII), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N',N'-dimethylhydrazine (XLVI), N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-N-methyl-N'-methylhydrazine (XLIX), salts thereof, and mixtures thereof. In another embodiment, the salt is a hydrogen sulfate or hydrochloride salt.

[0059] In one embodiment, at least one compound is 2,6-bis-(Nn-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is the hydrogen sulfate salt or the hydrochloride salt.

[0060] In one embodiment, at least one compound is N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propionamide or a salt thereof. In another embodiment, the salt is a hydrogen sulfate salt or a hydrochloride salt.

[0061] In one embodiment, the at least one compound is selected from the group consisting of 2-(n-propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(i-propyl)amino-7-i-propyl-pyrrolidino[2,3-d]pyrimidine (CXX XVI), 2,4-bis-(n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX), 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidino[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidino[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLV), salts thereof, and mixtures thereof. In another embodiment, the salt is a hydrogen sulfate salt or a hydrochloride salt.

[0062] In one embodiment, the at least one compound is selected from the group consisting of N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,O-dimethyl-hydroxylamine (CLVIII), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLX), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CLVIII ... In another embodiment, the salt is selected from the group consisting of hydrogen sulfate or hydrochloride.

[0063] In certain embodiments, the compound is selected from the group consisting of O,N-dimethyl-N-[4-(n-propylamino)-6-(prop-2-ynylamino-[1,3,5]triazin-2-yl]-hydroxylamine, N-methyl-N′-n-propyl-N″-prop-2-ynyl-[1,3,5]triazine-2,4,6-triamine, salts thereof, and any combination thereof.

[0064] In certain embodiments, the compound A [ka] or a pharma- ceutically acceptable salt thereof, such as the hydrogen sulfate, is utilized in the present invention.

[0065] In certain embodiments, the compound of formula (I) is selected from compounds described in U.S. Pat. No. 9,162,992 and / or U.S. Pat. No. 9,351,972 and / or U.S. Patent Application Publication No. 2015-0291597 (now abandoned), the teachings of which are incorporated herein by reference in their entirety.

[0066] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., at 60% relative humidity for two weeks.

[0067] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity for one month.

[0068] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity for 6 weeks.

[0069] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity for 2 months.

[0070] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity for 3 months.

[0071] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after accelerated storage conditions of 25° C. at 60% relative humidity for two weeks.

[0072] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after accelerated storage conditions of 25° C. and 60% relative humidity for one month.

[0073] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after accelerated storage conditions of 25° C. and 60% relative humidity for 6 weeks.

[0074] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after accelerated storage conditions of 25° C., 60% relative humidity for 2 months.

[0075] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after three months of accelerated storage conditions of 60% relative humidity and 25° C. In such embodiments, at three months, the total impurities are about 0.1% to about 0.12%, or about 0.10% or less, about 0.09% or less, or about 0.08% or less.

[0076] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C., 75% relative humidity for two weeks.

[0077] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C., 75% relative humidity for one month.

[0078] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C., 75% relative humidity for 6 weeks.

[0079] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C., 75% relative humidity for 2 months.

[0080] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C., 75% relative humidity for 3 months.

[0081] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after accelerated storage conditions of 40° C. at 75% relative humidity for two weeks.

[0082] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after accelerated storage conditions of 40° C., 75% relative humidity for one month.

[0083] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after accelerated storage conditions of 40° C. and 75% relative humidity for 6 weeks.

[0084] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after accelerated storage conditions of 40° C., 75% relative humidity for 2 months.

[0085] In certain embodiments, the formulation maintains at least 95%, at least 99%, or at least 99.5% of the compound after 2 months of accelerated storage conditions of 75% relative humidity and 40° C. In such embodiments, at 3 months, the total impurities are about 0.1% to about 0.40%, or about 0.35% or less, about 0.20% or less, or about 0.15% or less.

[0086] In certain embodiments, the pH of the formulation is from about 2.5 to about 5.5.

[0087] In certain embodiments, the pH of the formulation is from about 3.5 to about 5.5.

[0088] In certain embodiments, the pH is from about 4 to about 5.

[0089] In certain embodiments, the pH is selected from about 4.0, about 4.5, about 4.6, about 4.8, or about 5.0.

[0090] In certain embodiments, the concentration of the compound is from about 10 mg / mL to about 30 mg / mL.

[0091] In certain embodiments, the concentration of the compound is from about 15 mg / mL to about 25 mg / mL.

[0092] In certain embodiments, the concentration of the compound is selected from about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL.

[0093] In certain embodiments, the excipient is selected from ethanol, polyalkylene glycol, alkylene glycol, cyclodextrin, saline, Ringer's solution, dextrose, or a combination thereof.In certain embodiments, the excipient is polyethylene glycol-hydroxystearate, for example, obtained by reacting 15 moles of ethylene glycol with 1 mole of 12-hydroxystearic acid.It is commercially available as Kolliphor® HS15 from BASF.

[0094] In certain embodiments, the excipient comprises ethanol.

[0095] In certain embodiments, the excipient comprises ethanol in an amount between about 1% and about 30%, between about 5% and about 25%, or between about 10% and about 20%.

[0096] In certain embodiments, the excipient comprises propylene glycol.

[0097] In certain embodiments, the excipient comprises propylene glycol in an amount of about 20% to about 100%, about 50% to about 95%, or about 70% to about 90%.

[0098] In certain embodiments, the excipient comprises polyethylene glycol.

[0099] In certain embodiments, the excipient comprises polyethylene glycol in an amount of about 20% to about 100%, about 50% to about 95%, or about 70% to about 90%.

[0100] In certain embodiments, the excipient comprises hydroxypropyl-β-cyclodextrin.

[0101] In certain embodiments, the excipient comprises hydroxypropyl-β-cyclodextrin in an amount of about 1% to about 50%, about 10% to about 40%, or about 20% to about 30%.

[0102] In certain embodiments, the formulation is suitable for intramuscular administration.

[0103] In certain embodiments, the formulation is a propylene glycol / acetate buffer in a ratio of about 75 / 25 to about 25 / 75, or about 60 / 40 to about 40 / 60, or about 50 / 50. In such embodiments, the concentration of the active agent can be about 10 mg / mL to about 30 mg / mL, about 15 mg / mL to about 25 mg / mL, about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL. In such embodiments, the pH can be about 4.0, about 4.5, about 4.6, about 4.8, or about 5.0.

[0104] In certain embodiments, the formulation is propylene glycol / macrogol(15)-hydroxystearate / ethanol / acetate buffer in a ratio of about 10-40 / 5-25 / 2-20 / 25-75 or about 25 / 15 / 10 / 5025 to about 25 / 75 or about 60 / 40 to about 40 / 60 or about 50 / 50. In such embodiments, the concentration of the active agent can be 10 mg / mL to about 30 mg / mL, about 15 mg / mL to about 25 mg / mL, about 15 mg / mL, about 20 mg / mL or about 25 mg / mL. In such embodiments, the pH can be about 4.0, about 4.5, about 4.6, about 4.8, or about 5.0.

[0105] In certain embodiments, the present invention is directed to a method of providing respiratory stimulation comprising administering intramuscularly the parenteral formulations disclosed herein.

[0106] In certain embodiments, the formulation is administered at a dosage rate of about 2.0 mg / kg to about 40 mg / kg, about 3.0 mg / kg to about 35 mg / kg, about 4.0 mg / kg to about 30 mg / kg, about 5.0 mg / kg to about 25 mg / kg, about 6.0 mg / kg to about 20 mg / kg, about 7.0 mg / kg to about 15 mg / kg, or about 8.0 mg / kg to about 10 mg / kg. In certain embodiments, the dosage rate is about 4.0 mg / kg to about 5.0 mg / kg, or about 4.8 mg / kg.

[0107] composition In certain embodiments, the pharmaceutical compositions are premixed (e.g., the active agent is premixed with one or more pharma- ceutically acceptable excipients, and, optionally, one or more additional active agents).

[0108] In certain embodiments, the pharmaceutical composition may be housed in a glass or plastic container.

[0109] In certain embodiments, the pharmaceutical composition further comprises one or more pharma- ceutically acceptable excipients. Suitable pharma- ceutically acceptable excipients may vary based on the final form of the composition and the route of administration.

[0110] In certain embodiments, a pharma- ceutically acceptable excipient may comprise a pharma- ceutically acceptable carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, thickener, solvent, or encapsulating material, that may carry or transport a compound useful within the present invention into or to a subject, thereby performing its intended function. Typically, such constructs are carried or transported from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other components of the formulation containing the compound useful within the present invention, and must not be deleterious to the subject. Some examples of materials which can function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; 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, "pharmacologically acceptable carriers" also include any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to a subject. Supplementary active compounds can also be incorporated into the compositions. "Pharmaceutically acceptable carriers" may further include pharma-ceutically acceptable salts of the compounds useful within the present invention.Other additional ingredients that may be included in pharmaceutical compositions used to practice the invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0111] Useful pharma- ceutically acceptable carriers include, but are not limited to, solutions of glycerol, water, saline, ethanol, and other pharma- ceutically acceptable salts, such as phosphates and salts of organic acids. Examples of these and other pharma- ceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0112] The carrier may be a solvent or dispersion medium, for example, containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable composition may be brought about by including an agent that delays absorption, for example, aluminum monostearate or gelatin, in the composition. In one embodiment, the pharma- ceutical acceptable carrier is not DMSO alone.

[0113] The pharmaceutical preparations may be sterilized and, if desired, may be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic buffers, colorants, and the like.

[0114] 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.

[0115] The composition preferably includes an antioxidant and a chelating agent that inhibits the degradation of the compound. Preferred antioxidants for some compounds are BHT, BHA, α-tocopherol, and ascorbic acid in a preferred range of about 0.01% to 0.3% by weight, by total weight of the composition, more preferably BHT in the range of 0.03% to 0.1% by weight. Preferably, the chelating agent is present in an amount of 0.01% to 0.5% by weight, by total weight of the composition. Particularly preferred chelating agents include edetate (e.g., disodium edetate) and citric acid in the range of about 0.01% to 0.20% by weight, more preferably 0.02% to 0.10% by weight, by total weight of the composition. Chelating agents are useful for chelating metal ions in the composition, which may be detrimental to the shelf life of the formulation. BHT and disodium edetate are particularly preferred antioxidants and chelating agents, respectively, for some compounds, but for this reason may be substituted with other suitable and equivalent antioxidants and chelating agents, as would be known to one of skill in the art.

[0116] Liquid suspensions may be prepared using conventional methods to achieve suspension of active ingredients in aqueous or oily vehicles. Aqueous vehicles include, for example, water and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further include one or more additional ingredients, including, but not limited to, suspending agents, dispersing agents, or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavoring agents, coloring agents, and sweetening agents. Oily suspensions may further include a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Known dispersing or wetting agents include, but are not limited to, naturally occurring phospholipids such as lecithin, condensation products of alkylene oxides with fatty acids, with long chain aliphatic alcohols, with partial esters derived from fatty acids and hexitols, or with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin and acacia. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.

[0117] A liquid solution of an active ingredient in an aqueous or oily solvent may be prepared in substantially the same manner as a liquid suspension, the main difference being that the active ingredient is dissolved in the solvent rather than suspended. As used herein, an "oily" liquid is a liquid that contains carbon-containing liquid molecules and exhibits less polarity than water. A liquid solution of the pharmaceutical composition of the present invention may contain each of the components described in connection with a liquid suspension, with the understanding that the suspending agent does not necessarily aid in dissolving the active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as peanut oil, olive oil, sesame oil, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.

[0118] Powder and granular formulations of the pharmaceutical preparation of the present invention can be prepared using known methods. Such formulations can be administered directly to a subject, or can be prepared as aqueous or oily suspensions or solutions by adding aqueous or oily vehicles thereto. Each of these formulations can further include one or more of dispersing or wetting agents, suspending agents, and preservatives. Additional excipients, such as fillers and colorants, can also be included in these formulations.

[0119] The pharmaceutical composition of the present invention may also be prepared, packaged, or sold in the form of an oil-in-water emulsion or a water-in-oil emulsion.The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a combination thereof.Such compositions may further comprise one or more emulsifiers, such as naturally occurring gums, such as gum acacia or gum tragacanth, naturally occurring phospholipids, such as soybean or lecithin phospholipids, esters or partial esters derived from the combination of fatty acids and hexitol anhydrides, such as sorbitan monooleate, and the condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.

[0120] In certain embodiments, the one or more additional excipients include a pH adjuster, which may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, or mixtures thereof.

[0121] In certain embodiments, the compositions may include one or more additional excipients, such as, but not limited to, carbohydrates, antioxidants, chelating agents, low molecular weight proteins, high molecular weight polymers, gel formers, stabilizers, additives, wetting agents, emulsifiers, surfactants and / or dispersing agents, alkalizing agents, colorants, synthetic dyes, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0122] In certain embodiments, the composition further comprises an antioxidant. In certain embodiments, the antioxidant may include, for example, trivalent phosphorus such as phosphites, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones. While hindered phenols, thiosynergists, and / or hindered amines are useful for long-term stability of the polymer, the following antioxidants are also suitable for use in situations where the active is subject to oxidation: acids (ascorbic acid, erythorbic acid, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid, etc.), phenols (e.g., BHA, BHT, t-butylhydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic. Salts (calcium ascorbate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, potassium bisulfite, potassium metabisulfite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate), pyranones (maltol), and vitamins (tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopherol acetate, d-α-tocopherol acetate, dl-α-tocopheryl acetate). However, other antioxidants known in the art may be used in accordance with the present invention.

[0123] In certain embodiments, suitable antioxidants include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations of the above. Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols, such as, but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylphenol), ... 2,6-di-tert-butyl-4-methoxymethylphenol; nonylphenols having linear or branched side chains, such as 2,6-di-nonyl-4-methylphenol, 2,4-dimethyl-6-(1'-methylundecyl)phenol, 2,4-dimethyl-6-(1'-methylheptadecyl)phenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4-methoxymethylphenol; phenol, 2,4-dimethyl-6-(1'-methyltridec-1-yl)phenol, and mixtures thereof, alkylthiomethylphenols, such as, but not limited to, 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-dioctylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol, hydroquinone and alkylated hydroquinones, such as, but not limited to, However, 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-di-tert-butyl-4-hydroxyphenyl) adipate, tocopherols, including but not limited to α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and mixtures thereof (vitamin E), hydroxylated thiodiphenyl ethers, including but not limited to 2,2′-thiobis(6-tert-butyl-4-methylphenol), 2,2′-thiobis(4-octylphenol), 4,4′-thiobis(6-tert-butyl-3-methylphenol), 4,4′-thiobis(6-tert-butyl-4-methylphenol), butyl-2-methylphenol), 4,4'-thiobis(3,6-di-sec-amylphenol), 4,4'-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide, alkylidene bisphenols, such as, but not limited to, 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 2,2'-methylenebis(6-tert-butyl-4-ethylphenol), 2,2'-methylenebis[4-methyl-6-(α-methylcyclohexyl)-phenol], 2,2'-methylenebis(4-methyl-6-cyclohexyl)-phenol], xylphenol), 2,2'-methylenebis(6-nonyl-4-methylphenol), 2,2'-methylenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(6-tert-butyl-4-isobutylphenol), 2,2'-methylenebis[6-(α-methylbenzyl)-4-nonylphenol], 2,2'-methylenebis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4'-methylenebis(2,6-di-tert -butylphenol), 4,4′-methylenebis(6-tert-butyl-2-methylphenol), 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-bis(3-tert-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-tris(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3′-tert-butyl-4′-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methyl-phenyl)dicyclopentadiene, bis[2-(3′-tert-butyl-2′-hydroxy-5′-methylbenzyl)-6-tert-butyl-4-methylphenyl]terephthalate, 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxyphenyl)propane 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane, O-, N-, and S-benzyl compounds, such as, but not limited to, 3,5,3′,5′-tetra-tert-butyl-4,4′-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzyl mercaptoacetate, tris(3,5-di-t tert-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzyl mercaptoacetate, hydroxybenzylated malonates, such as, but not limited to, dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, di-octadecyl-2-(3-tert -butyl-4-hydroxy-5-methylbenzyl)malonate, didodecylmercaptoethyl-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, aromatic hydroxybenzyl compounds, such as, but not limited to, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol, triazine compounds, such as, but not limited to, 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, ,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,3,5-triazine, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenylethyl)-1,3, 5-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxy-phenylpropionyl)-hexahydro-1,3,5-triazine, 1,3,5-tris(3,5-dicyclohexyl-4-hydroxybenzyl)iso-cyanurate, benzyl phosphonates, such as, but not limited to, dimethyl-2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl 3,5-di-tert-butyl-4-hydroxyphenylpropionyl, hydroxybenzyl phosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzyl phosphonate, calcium salt of the monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzyl phosphonic acid, acylaminophenols such as, but not limited to, 4-hydroxylauranilide, 4-hydroxystearanilide, N-(3,5-di-tert-butyl-4-hydroxyphenyl) octyl carbamate, β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid with, for example, monohydric or polyhydric alcohols, for example, methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3- Thioundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid with mono- or polyhydric alcohols, such as methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl Glycol, thiodiethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis-(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]- Esters of 2,4,8,10-tetraoxaspiro[5.5]-undecane, esters of 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols, such as, for example, methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2,2]octane, esters of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with mono- or polyhydric alcohols, e.g., methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters with 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, 6-(3,5-di-tert- butyl-4-hydroxyphenyl)propionic acid amides, such as N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexamethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazide, N,N'-bis[2-(3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyloxy)ethyl]propionyl,

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

[0124] In certain embodiments, suitable pharma- ceutically acceptable excipients include acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyalkylene oxides (e.g., polymethylene oxide, polyethylene oxide, polypropylene oxide) polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylates, polycaprolactone, polymethacrylate copolymers thereof, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, croscarmellose sodium, or mixtures thereof), flow enhancers, and the like. The additives may include, for example, additives such as, but not limited to, additives, lubricants, absorption enhancers, surfactants, binders, softeners, plasticizers (e.g., lecithin, hydrogenated vegetable oils, glycerol esters, lanolin, methyl esters, pentaerythritol esters, rice bran wax, stearic acid, potassium sodium stearate, and the like), waxes, fats, emulsifiers, fillers, antioxidants, colorants, diluents, processing aids (e.g., granulation aids), fixatives (e.g., polyols, including but not limited to, sorbitol, maltitol / isomalt, mannitol, starch, and the like), pH adjusters, viscosity adjusters, solubility enhancers or reducers, osmotic agents, solvents, or combinations thereof.

[0125] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrophilic and hydrophobic materials such as polyvinylpyrrolidone, natural and synthetic gums, polyvinyl alcohol, corn starch, sustained release polymers, acrylic resins, protein-derived materials, waxes, shellac, and solid or semi-solid oils, such as hydrogenated castor oil and hydrogenated vegetable oils. More specifically, the controlled release material can be, for example, alkylcelluloses, such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers (e.g., acrylic and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methyl methacrylate alkylamide copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydrides), methyl methacrylate, polymethacrylates, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamides, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and mixtures of any of the foregoing), and cellulose ethers such as hydroxyalkylcelluloses (e.g., hydroxypropylmethyl cellulose) and carboxyalkylcelluloses. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (eg, beeswax, carnauba wax, stearic acid, and stearyl alcohol).

[0126] In certain embodiments, suitable pharma- ceutically acceptable excipients include gelling agents, such as, but not limited to, sugars or sugar-derived alcohols, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives (e.g., microcrystalline cellulose, sodium carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester ethers, cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl phthalate, cellulose acetate ... methylcellulose (hypromellose acetate succinate, and mixtures thereof), attapulgite, bentonite, dextrin, alginates, alginates such as sodium alginate and potassium alginate, casein, stearic acid, shellac, carrageenan, tragacanth, acacia, arabic, pullulan, dextrin, gellan, agar, tara, karaya, guar, wellan, rhamsan, locust bean, xanthan, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer and carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant / wetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.

[0127] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrophilic excipients, such as, but not limited to, water, low molecular weight polyols, such as polyethylene glycol, polypropylene glycol, or combinations thereof.Other suitable hydrophilic carriers include, but are not limited to, polyoxyethylene derivatives of sorbitan esters, such as sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof. Exemplary low molecular weight polyols include, but are not limited to, those having a number average molecular weight of from about 200 Daltons, about 400 Daltons, about 600 Daltons, about 800 Daltons, or about 1000 Daltons to about 2000 Daltons, about 3000 Daltons, about 4000 Daltons, about 5000 Daltons, about 6000 Da, or about 7000 Da, or any subrange or single value therein (e.g., polyethylene glycol 400, polyethylene glycol 600, etc.).

[0128] In certain embodiments, suitable pharma- ceutically acceptable excipients may include plasticizers, such as, but not limited to, triacetin, isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as, but not limited to, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamines, and mixtures thereof. Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers can include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0129] In certain embodiments, suitable pharma- ceutically acceptable excipients include plasticizers, such as, but not limited to, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils, and hydrogenated vegetable oils, including acetylated hydrogenated cottonseed glycerides and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylate glycerin, glyceryl cocoate, mono- and diacetylated monoglycerides, glyceryl ... lycerides, nitrobenzene, carbon disulfide, fl-naphthyl salicylate, phthalyl glycolate, diosyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols including cetostearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol, and myristyl alcohol;Methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(beta-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(2-ethylhexoate), diethylene glycol monolaurate , Monomeric polyethylene ester, Hydrogenated methyl ester of rosin, Methoxyethyl oleate, Butoxyethyl stearate, Butyl phthalyl butyl glycolate, Glycerol tributyrate, Propylene glycol dipelagonate, Beta-(p-tert-amylphenoxy)ethanol, Beta-(p-tert-butylphenoxy)ethanol, Beta-(p-tert-butylphenoxyethyl)acetate, Bis(beta-p-tert-butylphenoxydiethyl)ether, Camphor, Cumar W-1, Cumar MH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy)ethanol, diphenyl oxide, technical hydroabietyl alcohol, beckolin, benzene hexahydrochloride, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, glycerol alpha-methyl alpha-phenyl ether, chlorinated naphthalenes, HB-40, monoamyl phthalate. May also include Nevillac 10 o-nitrodiphenyl, and Paracril 26;

[0130] In certain embodiments, suitable pharma- ceutically acceptable excipients may include plasticizers, such as, but not limited to, isomalt, maltitol, sorbitol, xylitol, erythritol, adonitol, dulcitol, pentaerythritol, or mannitol; or polyol plasticizers, such as, but not limited to, glycerin, diglycerin, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycols up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamines, and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyls, ester-type plasticizers, glycol ethers, poly(propylene glycol), multiblock polymers, single block polymers, citrate ester-type plasticizers, and triacetin. Such plasticizers can include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate, and allyl glycolate, and mixtures thereof.

[0131] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fragrances, such as, but not limited to, natural and / or synthetic fragrance materials. For example, oil-soluble fragrance oils, which may or may not be mixed with water-soluble fragrance oils. Oil-soluble fragrances are natural or natural-like essential oils, such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaf, peppermint oil, cedarwood oil, rosemary oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, germanium oil, menthol, and marjoram oil. Animal fragrances are, for example, musk, castoreum, aber, or civet. Spagellic essences are also known in the art. They are made by fermenting certain herbs and processed into a final product. Synthetic fragrance ingredients are synthetic essential oils, such as those composed of a single compound, for example linalool, terpinol, nerol, citronellal, benzaldehyde, cinnamon aldehyde, vanillin, ethyl vanillin, or methylacetophenone. The fragrance material may also be a synthetic oil-soluble perfume oil selected from the usual group consisting of aromatic hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, polyene derivatives. Other fragrances that may be used are classified and described in reference books and databases such as S. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; reprinted 2000), Allured's Flavor and Fragrance Materials (2005), and the database maintained by the Research Institute for Fragrance Materials at www.rifm.org.

[0132] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fragrance oils.Suitable fragrance oils include mixtures of natural fragrances and synthetic fragrances.Natural fragrances are extracts from flowers (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, cumin, juniper), fruit skins (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calamus), wood (pinewood, sandalwood, guaiacwood, cedarwood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Typical synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol and hydrocarbon type. Fragrance compounds of the ester type are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethyl-methylphenyl glycinate, allyl cyclohexylpropionate, styrallyl propionate and benzyl salicylate. The ethers include, for example, benzyl ethyl ether; the aldehydes include, for example, the linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial, and brujonal; the ketones include, for example, the ionones, α-isomethylionone, and methyl cedryl ketone; the alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol, and terpineol; and the hydrocarbons include primarily the terpenes and balsams.

[0133] In certain embodiments, suitable pharma- ceutically acceptable excipients may include essential oils of relatively low volatility that are primarily used as flavoring ingredients and are also suitable as perfume oils, e.g., sage oil, chamomile oil, oil of clove, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labranum oil, and lavandin oil. Other suitable oils include bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, alpha-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, boisambrene forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertal, lavandin oil, clary sage oil, beta-damascene, geranium oil bourbon, cyclohexyl salicylate, Vertofix coeur, iso-E-Super, Fixolide NP, evernyl, iraldein Gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romirat, irotyl, and floramate, alone or in mixtures.

[0134] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives. As used herein, the term "preservative" refers to an agent that extends the shelf life of a dosage form by delaying or preventing deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety. Preservatives need not provide a lethal, irreversible action that results in partial or complete microbial cell destruction or incapacitation. Sterilants, cleaners, disinfectants, sporicides, virucides, and tuberculocides provide such an irreversible mode of action, which is sometimes referred to as a "bactericidal" action. In contrast, preservatives can provide an inhibitory or bacteriostatic action that is reversible in that the target microorganisms can resume growth if the preservative is removed. The main difference between preservatives and cleaners is primarily the mode of action (preservatives prevent growth of microorganisms rather than killing them) and the exposure time (preservatives take days to months to act, whereas cleaners take no more than a few minutes to act). Suitable preservatives include, but are not limited to, phenoxyethanol, parabens, pentanediol, and sorbic acid solutions, as well as silver complexes.

[0135] In certain embodiments, suitable pharma- ceutically acceptable excipients may include colorants, such as, but not limited to, dyes, e.g., white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown.

[0136] In certain embodiments, suitable pharma- ceutically acceptable excipients may include alkylating agent(s), such as, but not limited to, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, and / or disodium phosphate.

[0137] In certain embodiments, suitable pharma- ceutically acceptable excipients may include lubricant(s) / release agent(s), such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants include, but are not limited to, glyceryl behenate (Compritol™ 888), metal stearates (e.g., magnesium, calcium, and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g., Sterotex™), talc, waxes such as beeswax and carnauba wax, silica, fumed silica, colloidal silica, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-leucine, polyethylene glycols (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv™), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin, propylene glycol, and combinations thereof.

[0138] In certain embodiments, suitable pharma- ceutically acceptable excipients may include diluents such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dicalcium phosphate dihydrate NF, sucrose-based diluents, confectioners' sugar, dicalcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules NF, dextrates NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed grain solids such as Maltrons™ and Mor-Rex™, amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like.

[0139] In certain embodiments, suitable pharma- ceutically acceptable excipients can include oils and fats, such as, but not limited to, almond oil, argan oil, avocado oil, rapeseed oil, cashew oil, castor oil, cocoa butter, coconut oil, canola oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, and watermelon seed oil. Other oils and fats that may be in the filling of the PVA shell include, but are not limited to, fish oil (omega 3), krill oil, animal or vegetable fats, such as in hydrogenated form, mono-, di-, and triglycerides having C12-, C14-, C16-, C18-, C20-, and C22-fatty acids.

[0140] In certain embodiments, suitable pharma- ceutically acceptable excipients include vegetable proteins, such as sunflower protein, soy protein, cottonseed protein, peanut protein, grapeseed protein, whey protein, whey protein isolate, blood protein, egg protein, acrylated proteins, water soluble polysaccharides, such as alginates, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic, and related gums (gum ghatti, gum karaya, gum tragacanth), pectin, water soluble derivatives of cellulose: alkylcelluloses, hydroxyalkylcelluloses, and hydroxyalkylalkylcelluloses, such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters, and hydroxyalkylcellulose esters, such as cellulose acetate phthalate (CAP), hydroxypropylcellulose, ... Suitable polymers include carboxypropylmethylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, such as carboxymethylcellulose, and alkali metal salts thereof; water-soluble synthetic polymers, such as polyacrylic acid, polyacrylamide, and polyacrylic acid esters, polymethacrylic acid, polymethacrylamide, and polymethacrylic acid esters, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), PVY / vinyl acetate copolymers, and polycrotonic acid; phthalated gelatin, succinic gelatin, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates bearing tertiary or quaternary amino groups, e.g., diethylaminoethyl groups, which may be quaternized if desired; and other similar polymers; inorganic fillers, such as oxides of magnesium, aluminum, silicon, titanium, and the like.

[0141] In certain embodiments, suitable pharma- ceutically acceptable excipients include hydrophobic materials, such as, but not limited to, digestible long chain (C8-C50 , especially C 12 -C 40 ), substituted or unsubstituted hydrocarbons, such as natural or synthetic waxes (such as beeswax, glycowax, castor wax, and carnauba wax), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl, or preferably cetostearyl alcohol), fatty acids, such as, but not limited to, mono-diglycerides of medium chain fatty acids (such as caprylic acid, capric acid, caproic acid, lauric acid, oleic acid, linoleic acid, etc.), medium chain triglycerides, fatty acid esters, fatty acid glycerides (mono-, di-, and triglycerides), hydrogenated fats, hydrocarbons, regular waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials having a hydrocarbon backbone.

[0142] In certain embodiments, suitable pharma- ceutically acceptable excipients may include polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetate, polycarboxylic acids and salts, acetic acid, caprylic acid, oleic acid, polyamino acids or peptides, polyamides, polyacrylamides, maleic acid / acrylic acid copolymers, polysaccharides including starch and gelatin, natural gums such as xanthan and carrageenan. For example, the polymer may be selected from polyacrylates and water soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, maltodextrin, polymethacrylates, and combinations thereof, or may be selected from polyvinyl alcohol, polyvinyl alcohol copolymers, and hydroxypropylmethylcellulose (HPMC), methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate copolymer, shellac, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose trimethylate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caprylocaproyl polyoxy-8 glyceride, distearate glyceride, and combinations thereof.

[0143] In certain embodiments, suitable pharma- ceutically acceptable excipients may include high HLB surfactants, such as, but not limited to, polysorbate 80-polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, caprylocaproyl macrogol glycerides, and combinations thereof.

[0144] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fillers, such as, but not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0145] In certain embodiments, suitable pharma- ceutically acceptable excipients may include natural gums (e.g., natural vegetable gums), including, but not limited to, guar gum, locust bean gum, konjac gum, xanthan gum, sclerotium gum, acacia gum, cellulose gum (modified or unmodified), or combinations thereof.

[0146] In certain embodiments, suitable pharma- ceutically acceptable excipients include emulsifiers, such as, but not limited to, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-40 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 olivate, PEG-8 oleate, PEG-8 laurate, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-1 00 stearate, PEG-80 sorbitan laurate, steareth-2, steareth-12, oleth-2, ceteth-2, laureth-4, oleth-10, oleth-10 / polyoxyl 10 oleyl ether, ceteth-10, isosteareth-20, ceteareth-20, oleth-20, steareth-20, steareth-21, ceteth-20, isoceteth-20, laureth-23, steareth-100, glyceryl stearate citrate, glyceryl stearate SE (self-emulsifying), stearic acid, salts of stearic acid, polyglyceryl-3-methylglycose distearate, or combinations thereof.

[0147] Further suitable emulsifiers are phosphoric acid esters and their salts, such as cetyl phosphate (Amphisol® A), cetyl diethanolamine phosphate (Amphisol® DEA), potassium cetyl phosphate (Amphisol® K), sodium cetearyl sulfate, sodium glyceryl oleate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphates, and mixtures thereof. Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate, and hydrated polyisobutene. Furthermore, one or more synthetic polymers may be used as emulsifiers. For example, PVP eicosene copolymer, acrylate / C 10 -3o alkyl acrylate crosspolymer, acrylates / steareth-20 methacrylate copolymer, PEG-22 / dodecyl glycol copolymer, PEG-45 / dodecyl glycol copolymer, and mixtures thereof.

[0148] In certain embodiments, suitable pharma- ceutically acceptable excipients may include chelating agents, such as, but not limited to, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).

[0149] In certain embodiments, suitable pharma- ceutically acceptable excipients may include fatty alcohols, such as Guerbet alcohols based on fatty alcohols having 6-18, preferably 8-10, carbon atoms, including, but not limited to, cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, benzoates of C12-C15 alcohols, acetylated lanolin alcohol, and the like.

[0150] In certain embodiments, suitable pharma- ceutically acceptable excipients include esters of fatty acids, such as, but not limited to, linear C6-C 24 Straight chain C3-C fatty acids 24 Esters with alcohols, branched C6-C 13 Straight chain C6-C carboxylic acids 24 Esters with fatty alcohols, linear C6-C 24 Esters of fatty acids with branched alcohols, in particular 2-ethylhexanol, linear or branched C6-C hydroxycarboxylic acids 22Esters with fatty alcohols, in particular dioctyl maleate, esters of linear and / or branched fatty acids with polyhydric alcohols (e.g. propyl glycol, dimer diol or trimer diol) and / or Guerbet alcohols, such as caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petroselinic acid, linoleic acid, linolenic acid, eleostearic acid, arachidic acid, gadoleic acid, behenic acid and erucic acid, as well as technical grade mixtures thereof (obtained, for example, in the pressure stripping of natural fats and oils, in the reduction of aldehydes from the Roelen oxosynthesis or in the dimerization of saturated fatty acids), alcohols, such as isopropyl alcohol, capric acid, oleic acid, lin ...ic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, linoleic acid, and polyols such as propylene, capryl, 2-ethylhexyl, capric, lauryl, isotridecyl, myristyl, cetyl, palmoleyl, stearyl, isostearyl, oleyl, elaidyl, petroselinyl, linoyl, linolenyl, eleostearyl, arachidyl, gadoleyl, behenyl, erucyl, and brassylic alcohols, and technical grade mixtures thereof (obtained, for example, in the high pressure hydrogenation of technical grade methyl esters based on fats and oils, or as aldehydes from Roelen's oxo synthesis, and as monomeric fractions in the dimerization of unsaturated fatty alcohols).Additional suitable examples of ester oils include isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleic acid These include oleyl, oleyl erucate, erucyl oleate, erucyl erucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl oleate, cetyl behenate, cetyl acetate, myristyl myristate, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate / caprylate, stearyl heptanoate, diisostearyl malate, and octyl hydroxystearate.

[0151] In certain embodiments, suitable pharma- ceutically acceptable excipients may include other adjuvants, such as, but not limited to, 2,6-diethylhexyl naphthalate, di-n-butyl adipate, di(2-ethylhexyl)-adipate, di(2-ethylhexyl)-succinate, and diisotridecyl acetate, as well as diol esters, such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dipelargonate, butanediol diisostearate, and neopentyl glycol dicaprylate. 24 Esters of fatty alcohols and / or Guerbet alcohols with aromatic carboxylic acids, saturated and / or unsaturated, in particular with benzoic acid, C2-C 12 Esters of dicarboxylic acids with linear or branched alcohols having 1 to 22 carbon atoms or with polyols having 2 to 10 carbon atoms and 2 to 6 hydroxy groups.

[0152] In certain embodiments, suitable pharma- ceutically acceptable excipients include natural or synthetic triglycerides (including glyceryl esters and derivatives), such as, but not limited to, C6-C 18 Fatty acid based di- or triglycerides (such as caprylic / capric triglyceride, wheat germ triglyceride, etc.) may be included. Fatty acid esters of polyglycerol (polyglyceryl-n, e.g., polyglyceryl-4 caprate, polyglyceryl-2 isostearate, etc., or castor oil, hydrogenated vegetable oils, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borage oil, etc. Additional suitable excipients include waxes containing esters of long-chain acids and alcohols, as well as compounds with wax-like properties, e.g., carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ozokerite, Japan wax, paraffin wax, microcrystalline wax, ceresin, cetearyl ester wax, synthetic beeswax, etc. Also hydrophilic waxes as cetearyl alcohol or partial glycerides.

[0153] In certain embodiments, suitable pharma- ceutically acceptable excipients may include pearlescent waxes, such as, but not limited to, alkylene glycol esters, particularly ethylene glycol distearate; fatty acid alkanolamides, particularly coco fatty acid diethanolamide; partial glycerides, particularly stearic acid monoglyceride; esters of polyhydric unsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, particularly long chain esters of tartaric acid; fatty substances, such as fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers, and fatty carbonates having a total of at least 24 carbon atoms, particularly lauryl and distearyl ether; fatty acids, such as stearic acid, hydroxystearic acid, or behenic acid, ring-opening products of olefin epoxides having 12 to 22 carbon atoms with fatty alcohols having 12 to 22 carbon atoms and / or polyols having 2 to 15 carbon atoms and 2 to 10 hydroxy groups, and mixtures thereof.

[0154] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrocarbon oils such as, but not limited to, mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline wax, paraffin and isoparaffin compounds, hydrogenated isoparaffin molecules such as polydecene and polybutene, hydrogenated polyisobutene, squalane, isohexadecane, isododecane, and others from the plant and animal kingdoms.

[0155] In certain embodiments, suitable pharma- ceutically acceptable excipients may include silicones or siloxanes (organo-substituted polysiloxanes), such as, but not limited to, dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic silicones, as well as amino, fatty acid, alcohol, polyether, epoxy, fluorine, glycoside, and / or alkyl modified silicone compounds, which may be in either liquid or resin form at room temperature. Linear polysiloxanes, dimethicones (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluids, cyclopentasiloxane volatiles (Dow Corning 345 fluid), phenyl trimethicones (Dow Corning 556 fluid). Also suitable is simethicone, a mixture of dimethicones with an average chain length of 200-300 dimethylsiloxane units and hydrogenated silicate. In addition, a detailed review of suitable volatile silicones by Todd et al. can be found in Cosm. Toil. 91, 27 (1976).

[0156] In certain embodiments, suitable pharma- ceutically acceptable excipients may include emulsifiers, such as, but not limited to, carboxylic acids and their salts: alkaline soaps of sodium, potassium, and ammonium, metal soaps of calcium or magnesium, organic soaps, such as lauric acid, palmitic acid, stearic acid, and oleic acid; alkyl phosphates or phosphoric acid esters, acid phosphates, diethanolamine phosphate, potassium cetyl phosphate; ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acylates; linear fatty alcohols having 8-22 carbon atoms, branched from 2-30 moles of ethylene oxide and / or 0-5 moles of propylene oxide with fatty acids having 12-22 carbon atoms and alkylphenols having 8-15 carbon atoms in the alkyl group; fatty alcohol polyglycol ethers, such as laureth-n, ceteareth-n, steareth-n, oleth-n; fatty acid polyglycol ethers, such as PEG-n stearate, PEG-n oleate, PEG-n cocoate. Monoglycerides and polyol esters. C12-C22 fatty acid mono- and diesters of addition products of 1 to 30 moles of ethylene oxide with polyols. Fatty acid and polyglycerol esters, such as monostearate glycerol, diisostearoyl polyglyceryl-3-diisostearate, polyglyceryl-3-diisostearate, triglyceryl diisostearate, polyglyceryl-2-sesquiisostearate or polyglyceryl dimerate. Mixtures of compounds from several of these substance classes are also suitable. Fatty acid polyglycol esters, such as monostearate diethylene glycol, fatty acid and polyethylene glycol esters, fatty acid and saccharose esters, such as sucroesters, glycerol and saccharose esters, such as sucroglycerides. Sorbitol and sorbitan, sorbitan mono- and diesters of saturated and unsaturated fatty acids having 6 to 22 carbon atoms and ethylene oxide addition products.Polysorbate-n series, sorbitan esters such as sesquiisostearate, sorbitan, PEG-(6)-isostearate sorbitan, PEG-(10)-sorbitan laurate, PEG-17-dioleate sorbitan. Glucose derivatives, C8-C22 alkyl mono- and oligoglycosides, as well as ethoxylated analogues, with glucose being preferred as the sugar component. O / W emulsifiers such as methyl gluceth-20 sesquistearate, sorbitan stearate / sucrose cocoate, methyl glucose sesquistearate, cetearyl alcohol / cetearyl glucoside. W / O emulsifiers such as methyl glucose dioleate / methyl glucose isostearate. Sulfates and sulfonated derivatives, dialkyl sulfosuccinates, dioctyl succinates, alkyl lauryl sulfonates, linear sulfonated paraffins, sulfonated tetrapropienesulfonates, sodium lauryl sulfate, ammonium and ethanolamine lauryl sulfate, lauryl ether sulfate, sodium laureth sulfate, sulfosuccinates, acetyl isothionates, alkanolamide sulfates, taurine, methyl taurine, imidazole sulfate. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicone, copolyols, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ethers (Meroxapol), Polaxamer or poly(oxyethylene) m-block-poly(oxypropylene) n-block (oxyethylene). Zwitterionic surfactants carrying at least one quaternary ammonium group and at least one carboxylate and / or sulfonate group in the molecule.Particularly suitable zwitterionic surfactants are betaines, such as N-alkyl-N,N-dimethylammonium glycinates, cocoalkyldimethylammonium glycinates, N-acylaminopropyl-N,N-dimethylammonium glycinates, cocoacylaminopropyldimethylammonium glycinates, and 2-alkyl-3-carboxymethyl-3-hydroxyethyl imidazolines, each having 8 to 18 carbon atoms in the alkyl or acyl group, as well as cocoacylaminoethyl hydroxyethylcarboxymethyl glycinates, N-alkyl betaines, N-alkylamino betaines, alkyl imidazolines, alkyl peptides, lipoamino acids, self-emulsifying bases, and compounds described in KF DePolo, A short textbook of cosmetology, Chapter 8, Table 8-7, p250-251.

[0157] Suitable non-ionic bases include, but are not limited to, PEG-6 beeswax (and) PEG-6 stearate (and) polyglyceryl-2-isostearate (and), glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglyceryl-3 ricinoleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and ceteth-20, cetearyl alcohol and polysorbate 60 and PEG-150 and stearate-20, cetearyl alcohol and cetearyl polyglucoside, cetearyl alcohol and ceteareth-20, cetearyl alcohol and PEG-40 castor oil, cetearyl alcohol and cetearyl glyceryl stearate ... Tearyl alcohol and PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and steareth-7 and steareth-10, cetearyl alcohol and steareth-7 and steareth-10, glyceryl stearate and PEG-75 stearate, propylene glycol ceteth-3 acetate, propylene glycol isoceteth-3 acetate, cetearyl alcohol and ceteth-12 and oleth-12, PEG-6 stearate and PEG-32 stearate, PEG-6 stearate and ceteth-20 and steareth-20, PEG-6 stearate and ceteth-20 and glyceryl stearate and steareth-20, glyceryl stearate and ceteareth-20.

[0158] Suitable anionic alkali bases include, but are not limited to, PEG-2 stearate SE, glyceryl stearate SE, propylene glycol stearate. Anionic acid bases, such as cetearyl alcohol and sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, trilaneth-4 phosphate and glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulfate. Cationic acid bases, such as cetearyl alcohol and cetrimonium bromide.

[0159] In certain embodiments, suitable pharma- ceutically acceptable excipients may include adjuvants and additives, such as, but not limited to, surfactants, super-fatting agents, consistency regulators, thickeners, polymers, stabilizers, bioactive ingredients, swelling agents, additional UV photoprotective agents, antioxidants, hydrotropes, preservatives, self-tanning agents, solubilizers, balms, colorants, bacterial inhibitors, and the like.

[0160] In certain embodiments, suitable pharma- ceutically acceptable excipients may include superfatting agents, such as, but not limited to, lanolin and lecithin, as well as polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides, and fatty acid alkanolamides, the latter of which simultaneously act as foam stabilizers.

[0161] In certain embodiments, suitable pharma- ceutically acceptable excipients may include surfactants, such as, but not limited to, fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and / or dialkyl sulfosuccinates, fatty acid isetinates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, alpha-olefin sulfonates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkylamidobetaines, and / or protein fatty acid condensation products, the latter preferably based on wheat protein.

[0162] In certain embodiments, suitable pharma- ceutically acceptable excipients may include consistency regulators / thickeners and rheology modifiers, such as, but not limited to, silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or derivatives thereof, such as hyaluronic acid, xanthan gum, guar guar, agar, alginates, carrageenan, gellan, pectin, or modified celluloses, such as hydroxycellulose, hydroxypropylmethylcellulose. In addition, polyacrylates or homopolymers of reticulated acrylic acid and polyacrylamide, Carbomers (CARBOPOL types 980, 981, 1382, ETD2001, ETD2020, ULTREZ10), or SALCARE products such as SALCARE SC80 (steareth-10 allyl ether / acrylates copolymer), Salcare SC81 (acrylates copolymer), Salcare SC91 and Salcare AST (sodium acrylates copolymer / PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide / laureth-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer), STABILEN 30 (acrylates / vinyl isodecanoate crosspolymer), PEMULEN TR-1 (acrylates / C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (Sodium Acrylate Copolymer), ACULYN 28 (Acrylates / Beheneth-25 Methacrylate Copolymer), etc.

[0163] In certain embodiments, suitable pharma- ceutically acceptable excipients include polymers, including, but not limited to, anionic, zwitterionic, amphoteric, and nonionic polymers, and may include, for example, vinyl acetate / crotonic acid copolymers, vinyl pyrrolidone / vinyl acrylate copolymers, vinyl acetate / butyl maleate / isobornyl acrylate copolymers, methyl vinyl ether / maleic anhydride copolymers and esters thereof, uncrosslinked polyacrylic acid and polyol-crosslinked polyacrylic acid, acrylamidopropyl-trimethylammonium chloride / acrylate copolymers, octylacrylamide / methyl methacrylate-tert-butylaminoethyl methacrylate / 2-hydroxypropyl methacrylate copolymers, polyvinyl pyrrolidone, vinyl pyrrolidone / vinyl acetate copolymers, vinyl pyrrolidone / dimethylaminoethyl methacrylate / vinyl caprolactam terpolymers, as well as optionally derivatized cellulose ethers and silicones. Additionally, the polymers described in EP1093796 (pages 3-8, paragraphs 17-68) may be used.

[0164] In certain embodiments, suitable pharma- ceutically acceptable excipients include antioxidants, such as, but not limited to, amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., urocanic acid) and their derivatives, peptides, such as D,L-carnosine, D-carnosine, L-carnosine and its derivatives (e.g., anserine), carotenoids, carotene, lycopene and its derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g., dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine, and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cobalt, oleyl, linoleyl ... esteryl, and their glyceryl esters), as well as their salts, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid, and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides, and salts), as well as sulfoximine compounds (e.g., buthionine sulfoximine, homocysteine ​​sulfoximine, buthionine sulfone, penta-, hexa-, hepta-thionine sulfoximine), and (metal) chelating agents (e.g., hydroxythio ... fatty acids, palmitic acid, phytic acid, lactoferrin), hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, bile acids, bile extracts, bilirubin, biliverdin, EDTA, EDDS, EGTA, and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g., linoleic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives thereof (e.g., ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), triglycerides, glycerides, glyceryl phosphate, glyceryl acetate ... Copherol and derivatives (e.g., vitamin E acetate), vitamin A and derivatives (e.g., vitamin A palmitate), as well as coniferyl benzoate of benzoin resin, rutinic acid and its derivatives, glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butylated hydroxytoluene, butylated hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and its derivatives, mannose and its derivatives, superoxide dismutase, N-[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionyl]sulfanilic acid (and its salts, e.g., the disodium salt), selenium and its derivatives (e.g., selenium methionine), stilbene and its derivatives (e.g., stilbene oxide, trans-stilbene oxide), as well as derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides, and lipids) suitable according to the invention of these aforementioned active ingredients. HALS (= "Hindered Amine Light Stabilizers") compounds may also be mentioned.

[0165] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrotopic agents, such as, but not limited to, ethoxylated or non-ethoxylated monoalcohols, diols or polyols with a low number of carbon atoms or their ethers (e.g., ethanol, isopropanol, 1,2-dipropanediol, propylene glycol, glycerin, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, and similar products). Polyols considered for this purpose preferably have 2 to 15 carbon atoms and at least two hydroxy groups. Polyols may also contain further functional groups, in particular amino groups, and / or may be modified with nitrogen. Typical examples are: glycerol, alkylene glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol, and also polyethylene glycols with an average molecular weight of 100 to 1000 Daltons; technical oligoglycerol mixtures with an inherent degree of condensation of 1.5 to 10, for example technical diglycerol mixtures with a diglycerol content of 40 to 50% by weight; methylol compounds, such as, in particular, trimethylolethane ... lower alkyl glucosides, especially those having 1 to 8 carbon atoms in the alkyl radical, such as methyl and butyl glucoside; sugar alcohols having 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars having 5 to 12 carbon atoms, such as glucose or saccharose; amino sugars, such as glucamine; dialcoholamines, such as diethanolamine or 2-1,3-propanediol.

[0166] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives, such as, but not limited to, methyl-, ethyl-, propyl-, butyl-paraben, benzalkonium chloride, 2-bromo-2-nitro-propane-1,3-diol, dehydroacetic acid, diazolidinyl urea, 2-dichloro-benzyl alcohol, DMDM ​​hydantoin, formaldehyde solution, methyldibromoglutanitrile, phenoxyethanol, sodium hydroxymethylglycinate, imidazolidinyl urea, triclosan, and additional classes of substances listed in the following references: KFDePolo-A short textbook of cosmetology, Chapter 7, Tables 7-2, 7-3, 7-4 and 7-5, p 210-219.

[0167] In certain embodiments, suitable pharma- ceutically acceptable excipients may include bacterial inhibitors, such as, but not limited to, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, chlorhexidine (1,6-di(4-chlorophenyl-biguanide)hexane), or TCC (3,4,4'-trichlorocarbanilide). A number of aromatic substances and ethereal oils also have antibacterial properties. Typical examples are eugenol, menthol, and thymol, which are active ingredients in clove oil, mint oil, and thyme oil. A natural deodorant of interest is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol), which is present in lime blossom oil. Glycerol monolaurate has also been shown to be a bacteriostatic agent.

[0168] Other pharma- ceutically acceptable excipients may also be utilized as will be recognized by those skilled in the art.

[0169] In certain embodiments, the pharma- ceutically acceptable excipients may be included (individually or cumulatively) in the pharmaceutical compositions described herein at a concentration ranging from about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight to about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% by weight, based on the total weight of the composition, or any subrange or single value therein.

[0170] Treatment methods The formulations disclosed herein can be utilized for the treatment of respiratory control disorders or diseases that are inherent or caused by external factors such as drug overdose (e.g., opioids such as oxycodone, morphine, hydrocodone, heroin or fentanyl, or drugs such as propafol). In certain embodiments, the disorder or disease can be selected from respiratory depression, sleep apnea, apnea of ​​prematurity, obesity hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia, and chronic obstructive pulmonary disease (COPD), and the respiratory depression can be caused by anesthetics, sedatives, anxiolytics, hypnotics, alcohol, or narcotics. In certain embodiments, the patient or subject is further administered a composition comprising at least one additional compound useful for treating the respiratory disorder or disease, such as acetazolamide, almitrine, theophylline, caffeine, methylprogesterone, serotinergic modulators, cannabinoids, and ampakines. In another embodiment, the formulation is administered in conjunction with the use of mechanical ventilation or positive pressure breathing apparatus to the subject, or after the withdrawal of such apparatus.In certain embodiments, the formulation disclosed herein can be used to treat diseases or conditions regulated by large conductance potassium channels, such as neurological disorders, such as epilepsy, paroxysmal dyskinesia, or schizophrenia; cardiac disorders, such as cardiac ischemia or cardiac hypoxia; or brain disorders, such as cerebral ischemia or cerebral hypoxia.In one embodiment, the subject is a mammal.In yet another embodiment, the mammal is a human.In yet another embodiment, the formulation disclosed herein can be administered to the patient or subject by inhalation, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, or intravenous routes.

[0171] Preparation method In certain embodiments, the present disclosure is directed to the method of preparing any of the compositions described herein.In certain embodiments, the method includes combining a therapeutically effective amount of the compound disclosed herein with one or more pharma- ceutically acceptable excipients.

[0172] The various compositions described herein may be formulated to have a customized release profile for the active agent, such as, but not limited to, an immediate release profile, a controlled release profile, a delayed release profile, a zero order release profile, a first order release profile, a pulsatile release profile, a targeted release at a particular location within the body (such as a targeted location within the gastrointestinal tract), etc. EXAMPLES

[0173] Specific embodiments of the present invention will now be illustrated with reference to the following examples, which should be understood to be disclosed only by way of illustrating the present invention and should not be construed as limiting the scope of the present invention in any manner.

[0174] stability studies Formulations were prepared with the active agent (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine hydrogen sulfate) in the formulations presented in Table 1. [Table 1]

[0175] The stability of the samples in Table 1 was tested after 4 weeks at 25° C. and 40° C. The results are presented below in Table 2. Please note that the concentrations in Table 2 are of the filtered concentrations. [Table 2]

[0176] Another embodiment was prepared with a concentration of 15 mg / mL and the stability was tested over a period of 2 weeks at 40° C. and 60° C. The 15 mg / mL concentration was prepared using 50% polyethylene glycol at pH 4.0 and 5.0. The results of the stability study are presented in Tables 3-5. [Table 3] [Table 4] [Table 5]

[0177] Another embodiment was prepared with a concentration of 25 mg / mL and the stability was tested over a period of 2 weeks at 40° C. and 60° C. The 25 mg / mL concentration was prepared using 50% polyethylene glycol at pH 4.0 and 5.0. The results of the stability study are presented in Tables 6-8. [Table 6] [Table 7] [Table 8]

[0178] Additionally, stability studies were performed using different excipients with a concentration of 50 mg / mL at a pH of 5.0. The results of the stability studies are presented in Tables 9-11 below. [Table 9] [Table 10-1] [Table 10-2] [Table 11-1] [Table 11-2]

[0179] Solubility of formulations as a function of pH A pH solubility study was performed to evaluate the feasibility of formulating the active agent (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) as a simple buffered solution at a reasonable pH for IV formulation.

[0180] Methodology: A solution of activator (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) and H2SO4 at a concentration of approximately 107 mg / mL in 100 mM citric acid at pH 2.5 was prepared. Approximately 150 μL of this solution was transferred to six separate glass HPLC vials. Each aliquot was titrated with 6 N sodium hydroxide to different pH values ​​ranging from 3 to 5.5, as shown in Table 12. All samples, including the pH 2.5 solution, were shaken overnight at room temperature using an orbital shaker. After shaking, the samples were visually evaluated for the presence of precipitates and then spin-filtered through 0.45 μm syringe-tip filters (4 mm diameter) at 3000 rpm for 20 minutes. The final pH values ​​of the filtrates were measured. The filtrate was then appropriately diluted and analyzed for activator (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine).H2SO4 concentration using an HPLC assay.

[0181] Results: The pH values, appearance, and concentration of the samples before and after shaking overnight are shown in Table 12. Solutions prepared at target pH values ​​of 2.5, 3.0, and 3.5 were clear (no excess solids present), therefore the concentration values ​​of these samples do not represent saturated solubility values. [Table 12]

[0182] Stability as a function of pH The active agent (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) is estimated to have a pKa of 5.6 and a theoretical free base solubility of about 0.18 mg / mL. Thus, the inventors believe that the drug solubility will be insufficient for intended product concentrations above about pH 3.6. However, the medical product is diluted prior to injection and then slowly infused intravenously, and while such low pH is unlikely to present a safety or patient comfort issue, stability of the drug in solution may be an issue at such low pH. The purpose of this experiment was to evaluate the stability of the drug as a function of pH.

[0183] An important consideration in such experiments is the concentration of drug and buffer used. The use of a buffer is essential because if the pH changes dramatically during the experiment, the data will be meaningless. However, it is desirable to keep the buffer at a minimum strength to minimize the effects of buffer catalysis. By keeping the drug concentration low, buffer strength can be minimized. Keeping the drug concentration low also minimizes confounding the data with solubility limits (i.e., the drug precipitates out of solution).

[0184] Methodology: Buffer solutions containing approximately 10 mM each of citric acid and glycine in the pH range of 2-6 were prepared by titrating a single stock containing 250 mL of both buffers with 1N NaOH / 1N HCl and removing a 50 mL aliquot at the given pH value. Solutions of 1 mg / mL were prepared by dissolving approximately 25 mg of the compound with the activator (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine)H2SO4 in approximately 23 mL of a given buffer in a pH 2-5 buffer, adjusting the pH to target, and bringing the volume to 25.0 mL in a volumetric flask. A solution at pH 6 was prepared similarly but with a lower drug concentration of 0.25 mg / mL using 6.68 mg of compound with the activator (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-1-hydroxylamine)H2SO4.

[0185] Each of the buffer solutions was filtered through a 0.2 μm polyethersulfone syringe filter into a volumetric flask that had been pre-rinsed with 70% ethanol and dried in a laminar flow hood. After filtration, each buffer solution was divided into 10 aliquots (9 aliquots of 2.5 mL each and 1 aliquot of 2 mL each) into 5 mL serum vials that had been pre-rinsed with 70% ethanol and dried in a laminar flow hood. Filtration and preparation of aliquots were performed in a laminar flow hood. A 2 mL aliquot of each buffer solution was submitted for TO analysis (HPLC assay and related substances). Of the nine 2.5 mL aliquots, three aliquots were stored at 40° C. and 60° C., respectively, two aliquots were stored at 25° C., and one aliquot was stored at −70° C. Samples stored at 40° C. and 60° C. were evaluated for physical appearance, pH, assay, and related substances after 1, 2, and 4 weeks of storage. The 25°C and -70°C samples served as controls for analysis as required.

[0186] Results: pH stability data is shown in Table 13. All samples remained clear, colorless, and particle free during storage up to 4 weeks at both 40°C and 60°C. At both storage temperatures, the pH values ​​of all samples remained relatively constant for up to 4 weeks. Both assay and impurity data indicate that the solutions were significantly less stable at pH 2 compared to the remaining pH values ​​evaluated. No particular trends were observed in the pH range 3-6. The pH stability profile at 60°C is shown in Figure 1 (% impurities). [Table 13]

[0187] Stability as a function of pH – Narrow pH range The pH stability studies described above showed that the compound was unstable at pH 2.0, but more stable at higher pH values. Therefore, the stability of the compound was evaluated in the pH range 2-3.6.

[0188] Methodology: Buffer solutions containing approximately 10 mM each of citric acid and glycine in the pH range of 2-3.6 were prepared by titrating a single stock containing 250 mL of both buffers with 1 N NaOH / 1 N HCl and removing a 50 mL aliquot at the given pH value. 1 mg / mL solutions were prepared in buffers by dissolving approximately 25 mg of compound in approximately 23 mL of a given buffer, adjusting the pH to target, and bringing the volume to 25.0 mL in a volumetric flask.

[0189] Each of the buffer solutions was filtered through a 0.2 μm polyethersulfone syringe filter into a volumetric flask that had been pre-rinsed with 70% ethanol and dried in a laminar flow hood. After filtration, each buffer solution was divided into nine aliquots in 5 mL serum vials that had been pre-rinsed with 70% ethanol and dried in a laminar flow hood. Filtration and preparation of aliquots were performed in a laminar flow hood. Of the nine aliquots, three aliquots were stored at 40° C. and 60° C., respectively, two aliquots were stored at 25° C., and one aliquot was submitted for T0 testing. Samples were evaluated for pH, assay, and related substances at T0, and after 1 week, 2 weeks, and 4 weeks of storage at 40° C. and 60° C. Samples stored at 25° C. served as controls for analysis as required. The results are presented in Table 14 and Figure 2.

[0190] The most striking result from this study is that impurity levels decrease significantly as pH increases across the entire pH range studied during storage at both 40° C. and 60° C. This means that any increase in the pH of the formulation results in improved stability within the pH range that is achievable for the aqueous formulation. [Table 14]

[0191] Stability of API Methodology: Approximately 100 mg of API (Lot 009MSB058) was stored in closed Type I glass vials at each of 40° C. and 60° C. Samples were analyzed for appearance and percent purity at TO and after 1 week, 2 weeks, and 4 weeks of storage.

[0192] Results: As shown in Table 15, the API was very stable even at 60° C. for 4 weeks. There were no visible signs of degradation (i.e., discoloration, etc.). [Table 15]

[0193] Stability of a simple prototype An experiment was conducted to determine the stability of an API in a simple formulation prototype. A solution was prepared having a concentration of 25 mg / mL of the active agent (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) (also referred to as the compound having formula (I)) API as free base, corresponding to 35 mg / mL of the compound having H2SO4.

[0194] Methodology: A total of nine prototypes were prepared, including simple buffer solutions, co-solvent systems, and non-aqueous solutions, as shown in Table 16. [Table 16]

[0195] Prototypes 6, 7, and 8 resulted in significant precipitation during preparation and were not evaluated further. The remaining prototypes were stored in serum vials at 2-8°C, room temperature, 40°C, and 60°C. Samples stored at 2-8°C and room temperature were analyzed at selected time points.

[0196] Results: Data are provided in Tables 17-22. The aqueous buffered formulation (Prototype #1) was found to be stable at room temperature and under refrigeration, however, some degradation was observed under accelerated conditions. A very small amount of precipitate, described as one or two snowflake-like particles, was observed after 2 weeks at 60°C and after 8 weeks at 40°C. The appearance of this precipitate during storage at 60°C is consistent with an actual decrease in the primary impurity peak, so the possibility of insoluble degradants is investigated.

[0197] Prototype #2 was unstable in 50% PEG / 50% water without pH adjustment. The instability was likely due to the low pH of this formulation. The drug was found to be much more stable in prototype #3, which has the same 50% PEG base, but also contains enough sodium hydroxide to bring the apparent pH to about 4.5. Similarly, good stability was seen in prototype #9, 70% propylene glycol / 30% water, which contains ammonium acetate buffer to bring the apparent pH to about 5.3. Good stability was also seen in simple solutions of salts in PEG or propylene glycol, likely due to the absence of water as a reactant. [Table 17] [Table 18] [Table 19] [Table 20] [Table 21] [Table 22]

[0198] From the narrow range pH stability study, it is clear that the stability improves substantially as the pH increases, even at the top of the range studied. Since the upper pH limit is defined by the solubility of the drug, a reduction in the concentration of the drug that needs to be dissolved allows the product to be formulated at a higher pH, which improves the stability of the product. Specifically, by halving the concentration, the pH of the formulation can be increased by approximately 0.3 units, and as can be seen in Table 6, a 0.3 unit increase in pH substantially improves the stability of the formulation. Based on this consideration, it was decided to reduce the (N-(4,6-bis--n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) concentration in the formulation from 25 mg / mL to 10 mg / mL, increasing the target pH from 3.0 to 3.2. The buffer concentration was proportionally reduced from 50 mM to 20 mM. The final formulation is provided in Table 23. [Table 23]

[0199] Formulation Research Studies were conducted to formulate a compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) for intramuscular (IM) administration as a treatment for substance-induced respiratory depression.

[0200] The study consisted of conducting a bioequivalence (BE) study in minipigs. Two formulations of the compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) were tested in the study as follows: Formulation 1: 20 mg / mL in 50 / 50 propylene glycol / acetate buffer, pH approximately 4.8 Formulation 2: 20 mg / mL in 25 / 15 / 10 / 50 propylene glycol / Kolliphor HS15 / ethanol / acetate buffer, pH approx. 4.6

[0201] For IV administration, minipigs (n=3) received a single IV bolus (1-2 min) administration of a compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) via a VAP (vascular access port) in the jugular vein. For IM administration, minipigs (n=3) received a single IM administration of a compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) via the lateral neck muscle (behind the ear). Animals were dosed before noon on the day of administration. The route allowed for the determination of the pharmacokinetics of a compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) from IV and IM administration.

[0202] The stability data for both Formulations 1 and 2 are presented below in Table 24. The 12-week stability results showed that the IM formulation was stable at room temperature (25° C. / 60% RH) and accelerated conditions (40° C. / 75% RH). [Table 24]

[0203] A three-phase pharmacokinetic (PK) study in minipigs PK studies were conducted in male Gottingen minipigs (n=3) administered a single IV followed by an IM dose using the dosing scheme outlined in Table 25. There was a minimum 3-day washout period between dose events. [Table 25]

[0204] The mean dose for IV dose group 1 was 4.79 + / - 0.012 mg / kg. The mean dose for IM dose group 2 was 4.82 + / - 0.036 mg / kg. The mean dose for IM dose group 3 was 4.79 + / - 0.033 mg / kg. The nominal dose across all groups was 4.8 mg / kg. These doses were based on the nominal concentration (corrected for purity, moisture, and salt content) of the compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) in the dose formulation.

[0205] For IV administration, minipigs (n=3) received a single IV bolus (1-2 min) administration of compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) via a vascular access port (VAP) in the jugular vein. For IM administration, minipigs (n=3) received a single IM administration of each IM formulation via the lateral neck muscle (behind the ear). For each dose event, blood samples were collected at eight time points: 0.083, 0.167, 0.25, 0.5, 1, 2, 4, and 24 hours post-dose. General observations were performed twice daily for any treatment-related effects / toxicity and / or tolerability. Table 26 includes plasma concentration descriptive statistics for the compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine). Table 27 shows plasma concentration pharmacokinetic parameters for the compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine). [Table 26] [Table 27]

[0206] Figure 3 represents a plot of mean plasma concentration versus time out to 24 hours, and Figure 4 represents a plot of mean plasma concentration versus time out to 4 hours. When interpreting this PK data, it should be noted that the 4.8 mg / kg dose selected for the bioequivalence study in minipigs is conservative; for example, in previous studies, the highest dose tested was 30 mg / kg.

[0207] Plasma concentration data and pharmacokinetic parameters Plasma concentration descriptive statistics for the compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) are presented in Table 28. [Table 28]

[0208] Pharmacokinetic parameters for dose events 1, 2, and 3 are presented in Table 29. After IV administration, T max The mean time to death was 0.083 hours in Group 1. After IM administration, T max The duration of treatment was 0.5 hours in group 2 (50 / 50 propylene glycol / acetate buffer at pH 4.8) and 1 hour in group 3 (25 / 15 / 10 / 50 propylene glycol / Kolliphor HS15 / ethanol / acetate buffer at pH 4.6). 1 / 2 Values ​​were 3.0 hours in IV group 1, 3.2 hours and 2.7 hours in IM groups 2 and 3.

[0209] For IV administration, C max was 2820ng / mL, and AUC last The mean mean natriuretic peptide concentration was 2313 h*ng / mL. max was 466 ng / mL in group 2, and AUC last is 2617 h*ng / mL, and C max was 601ng / mL in group 3, and AUC last The mean mean sigma-positive rate was 2711 h*ng / mL. For each dose level, C max was higher with IV administration than with IM administration, but AUC lastwas higher with IM administration than with IV administration. [Table 29]

[0210] The IV and IM bioavailability of the compound having formula (I) (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) is presented in Table 30. The bioavailability from IV administration was calculated to be 100% and 113.1% in group 2 and 117.2% in group 3. [Table 30]

[0211] A commentary on the results from the minipig study is given in C. max Similar to previous data on IV infusion in minipigs, C max Both IM formulations provided rapid absorption, as shown by area under the curve plasma exposure (AUC). A single injection of the IV formulation provided a higher C max and C max Shorter time to max The results showed that IM formulation 2 had a higher C than IM formulation 1. max (601 vs. 466 ng / mL), and IM formulation 1 had a shorter T max This pharmacokinetic study showed that IM formulation 1 had high solubility and T max Although it is a shorter and simpler formulation, IM formulation 2 appears to have a higher absorption in both rats and minipigs.

[0212] For ease of explanation, embodiments of the methods of the present disclosure are depicted and described as a series of acts. However, acts in accordance with the present disclosure can be performed in various orders and / or simultaneously, as well as with other acts not shown or described herein. Moreover, not all illustrated acts are required to implement a methodology in accordance with the disclosed subject matter. In addition, those skilled in the art will understand and appreciate that the methodology can be represented as or via a state diagram or events as a series of interrelated states.

[0213] In the above description, many specific details are set forth, such as specific materials, dimensions, process parameters, etc., to provide a thorough understanding of the invention. Particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments. The word "example" or "exemplary" is used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as "example" or "exemplary" should not necessarily be construed as preferred or advantageous over other aspects or designs. Rather, the use of the word "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 all natural inclusive permutations. That is, if X includes A, if X includes B, or if X includes both A and B, then "X includes A or B" is satisfied under any of the above examples. References throughout this specification to "an embodiment," "a particular embodiment," or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "one embodiment," "a particular embodiment," or "one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0214] The invention has been described with reference to specific exemplary embodiments thereof. The specification and drawings are accordingly to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

1. A parenteral formulation comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25° C., 60% relative humidity, for 2 weeks, and wherein the compound of formula (I) has the following properties: 【Chemistry 1】 (In the formula, R １ and R ２ is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R １ and R ２ combine to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl; R ３ is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR １ R ２ , -C(O)OR １ , acyl, or aryl; R ４ is H, alkyl, or substituted alkyl; R ５ is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR １ , -NR １ R ２ , -C(O)OR １ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R ３ and R ５ combine to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R ６ is H, alkyl, substituted alkyl, or alkenyl; X is a bond, O, or NR ４ and Y is N, CR ６ or C, Y is N or CR ６ If so, then bond b １ is nothing, and (i) Z is H, and bond b ２ is a single bond, A is CH, or (ii) Z is nothing and bond b ２ is nothing, A is a single bond, When Y is C, bond b １ is a single bond, and (i) Z is CH ２ and bond b ２ is a single bond and A is CH, or (ii) Z is CH and bond b ２ is a double bond and A is C) or a salt thereof.

2. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for one month.

3. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for two months.

4. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25°C, 60% relative humidity for three months.

5. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 95% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for 2 weeks.

6. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 95% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for one month.

7. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for two months.

8. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25°C, 60% relative humidity for three months.

9. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for two weeks.

10. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for one month.

11. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for two months.

12. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for three months.

13. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 95% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for two weeks.

14. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 95% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for one month.

15. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for two months.

16. 10. The parenteral formulation of claim 1, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for three months.

17. 2. The parenteral formulation according to any one of the preceding claims, wherein the pH of the formulation is from about 3.5 to about 5.

5.

18. 18. The parenteral formulation of claim 17, wherein the pH is from about 4 to about 5.

19. 20. The parenteral formulation of claim 18, wherein the pH is selected from about 4.0, about 4.5, or about 5.

0.

20. 20. The parenteral formulation of any one of the preceding claims, wherein the concentration of the compound is from about 10 mg / mL to about 30 mg / mL.

21. 21. The parenteral formulation of claim 20, wherein the concentration of the compound is from about 15 mg / mL to about 25 mg / mL.

22. 22. The parenteral formulation of claim 21, wherein the concentration of the compound is selected from about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL.

23. 10. The parenteral formulation of any one of the preceding claims, wherein the excipient is selected from ethanol, polyalkylene glycols, alkylene glycols, cyclodextrins, saline, Ringer's solution, dextrose, polyethylene glycol-hydroxystearate, or combinations thereof.

24. 24. The parenteral formulation of claim 23, wherein the excipient comprises ethanol.

25. 24. The parenteral formulation of claim 23, wherein the excipient comprises ethanol in an amount from about 1% to about 30%, from about 5% to about 25%, or from about 10% to about 20%.

26. 24. The parenteral formulation of claim 23, wherein the excipient comprises propylene glycol.

27. 24. The parenteral formulation of claim 23, wherein the excipient comprises propylene glycol in an amount from about 20% to about 100%, from about 50% to about 95%, or from about 70% to about 90%.

28. 24. The parenteral formulation of claim 23, wherein the excipient comprises polyethylene glycol.

29. 24. The parenteral formulation of claim 23, wherein the excipient comprises polyethylene glycol in an amount from about 20% to about 100%, from about 50% to about 95%, or from about 70% to about 90%.

30. 24. The parenteral formulation of claim 23, wherein the excipient comprises hydroxypropyl-β-cyclodextrin.

31. 24. The parenteral formulation of claim 23, wherein the excipient comprises hydroxypropyl-β-cyclodextrin in an amount of about 1% to about 50%, about 10% to about 40%, or about 20% to about 30%.

32. 10. A parenteral formulation according to any one of the preceding claims, which is suitable for intramuscular administration.

33. 33. A method of providing respiratory stimulation comprising administering intramuscularly the parenteral formulation of claim 32.

34. 10. The parenteral formulation of claim 1, further comprising a buffer solution.

35. 35. The parenteral formulation of claim 34, wherein the buffer solution comprises citric acid, glycine, a citrate salt, or an acetate salt.

36. 35. The parenteral formulation of claim 34, wherein the buffer solution comprises citrate.

37. 35. The parenteral formulation of claim 34, wherein the buffer solution comprises an acetate salt.

38. A method for treating respiratory depression comprising parenterally administering a formulation according to any one of claims 1 to 37.

39. 39. The method of claim 38, wherein the respiratory depression is caused by an opioid agent.

40. 39. The method of claim 38, wherein the respiratory depression is caused by a non-opioid agent.

41. 39. The method of claim 38, wherein the respiratory depression is caused by inflammation.

42. 39. The method of claim 38, wherein the respiratory depression is caused by an infection.

43. 42. The method of claim 41, wherein the formulation is administered at a dosage rate of about 2.0 mg / kg to about 40 mg / kg, about 3.0 mg / kg to about 35 mg / kg, about 4.0 mg / kg to about 30 mg / kg, about 5.0 mg / kg to about 25 mg / kg, about 6.0 mg / kg to about 20 mg / kg, about 7.0 mg / kg to about 15 mg / kg, or about 8.0 mg / kg to about 10 mg / kg.

44. 42. The method of claim 41, wherein the formulation is administered at a dosage rate of about 4.0 mg / kg to about 5.0 mg / kg, or about 4.8 mg / kg.

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