Respiratory irritant nasal preparations

Abstract

In certain embodiments, there is disclosed an intranasal formulation comprising a compound of formula (I) disclosed herein and a pharma- ceutically acceptable excipient.

Description

[Technical field]

[0001] The present disclosure relates to methods and compositions for treating respiratory depression, for example modulated by opioid or non-opioid agents, inflammation or infection. [Background technology]

[0002] The human body is highly dependent on the ventilatory control system for adequate intake of oxygen and removal of carbon dioxide (CO2). Many active agents, 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.

[0003] Other drugs can cause respiratory depression in overdose or other situations. For example, anesthetic drugs such as propofol can cause respiratory depression that can be life-threatening.

[0004] Respiratory depression can also be caused by non-pharmacological reasons such as inflammation or infection.

[0005] There is a need in the art for therapeutic methods and formulations to treat respiratory depression caused by any reason. Summary of the Invention

[0006] In certain embodiments, the present disclosure is directed to intranasal therapeutic methods and formulations for treating respiratory depression caused, for example, by opioid agents, non-opioid agents, inflammation, or infection.

[0007] In certain embodiments, the present disclosure is directed to an intranasal formulation comprising about 0.01% w / w to about 10% w / w of a compound of formula (I) and a pharma- ceutically acceptable excipient.

[0008] In certain embodiments, the present disclosure is directed to a nasal formulation 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. and 60% relative humidity for 2 weeks.

[0009] In certain embodiments, the present invention is directed to intranasal compositions and methods for: (1) treating a patient who has been exposed to a drug overdose, whether by accidental or other means; (2) treating a patient who has been exposed to an opioid overdose, whether by accidental or other means; (3) treating a patient having opioid withdrawal symptoms, whether by accidental or other means; or (4) prophylactically treating a patient against opioid withdrawal symptoms, whether by accidental or other means.

[0010] In certain embodiments, the nasal formulation is administered via a nasal delivery device, including, but not limited to, a metered dose device, a dropper, a spray, a pump spray, a nebulizer, an atomizer, a squeeze tube, a squeeze bottle, a pipette, an ampoule, a nasal cannula, a nasal spray inhaler, a continuous positive nasal pressure device, or a breath-actuated bidirectional delivery device.

[0011] 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).

[0012] 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" includes 9 to 11.

[0013] 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.

[0014] 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).

[0015] 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.

[0016] The term "chiral center" refers to an atom (eg, a carbon atom) to which four different groups are attached.

[0017] 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.

[0018] "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, sulfonate, e.g. Examples of such salts include methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc., amino acid salts such as alginate, aspartate, glutamate, etc., metal salts such as zinc salt, sodium salt, potassium salt, cesium salt, etc., alkaline earth metal salts such as calcium salt, magnesium salt, etc., and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine, etc. These salts may exist in the form of a hydrate, solvate, or a crystalline polymorph. 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 (PH Stahl & CG Wermuth eds., Verlag Helvetica Chimica Acta, 2002) [1].

[0019] 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.

[0020] The terms "treatment of" 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 terms "treatment" or "treating" refer 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," including 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 any improvement or benefit perceived 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, or a perceived benefit from, one or more symptoms of a condition.

[0021] The terms "prevention of" and "preventing" include the avoidance of the onset of a condition.

[0022] 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.

[0023] 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.

[0024] The phrase "pharmacologically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of human beings and animals, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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 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 containing one or two substituents selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2, and -C(=O)OH, more preferably halogen, alkoxy, and -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl, and 3-chloropropyl.

[0030] 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.

[0031] 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.

[0032] 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, and may be attached to the most distal carbon atom of the heteroalkyl group. Examples include -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, and -CH2CH2-S(=O)-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 or -CH2-CH2-SS-CH3.

[0033] As used herein, the term "heteroalkenyl," by itself or in combination with another term, means, unless otherwise indicated, a stable straight or branched chain 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.

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] The foregoing lists of heterocyclyl and heteroaryl moieties are intended to be representative and not limiting.

[0043] As used herein, the term "substituted" means that an atom or group of atoms replaces a hydrogen as a substituent bonded to another group.

[0044] 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 C 1-6 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.

[0045] 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, unless otherwise indicated herein, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein may be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to facilitate understanding of certain materials and methods, and does not limit the scope of the claims. No language in the 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]

[0046] [Figure 1] 1 is a graph showing pH stability profiles (percentage of impurities) at 60° C. of examples according to the present disclosure. [Diagram 2]1 is a graph showing the decomposition of examples according to the present disclosure with pH at various temperatures. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] In certain embodiments, the present invention is directed to an intranasal formulation containing about 0.01% w / w to about 10% w / w of a compound of formula (I) and a pharma- ceutically acceptable excipient.

[0048] In certain embodiments, the pharma- ceutically acceptable excipient comprises a liquid.

[0049] In certain embodiments, the compound of formula (I) is dissolved in a liquid.

[0050] In certain embodiments, the compound of formula (I) is suspended in the liquid.

[0051] In certain embodiments, the pharma- ceutically acceptable excipient is a collection of particles.

[0052] In certain embodiments, the compound of formula (I) is dispersed within each particle.

[0053] In certain embodiments, the compound of formula (I) is coated onto each particle.

[0054] In certain embodiments, the pharma- ceutically acceptable vehicle is a cream, ointment, or gel.

[0055] In certain embodiments, the intranasal formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C. and 75% relative humidity for 2 weeks.

[0056] In certain embodiments, the pH of the formulation is from about 3.5 to about 5.5.

[0057] In certain embodiments, the pH is from about 4 to about 5.

[0058] In certain embodiments, the pH is selected from about 4.0, about 4.5, or about 5.0.

[0059] In certain embodiments, the concentration of the compound is from about 1 mg / mL to about 100 mg / mL.

[0060] In certain embodiments, the excipient is selected from water, ethanol, polyalkylene glycol, alkylene glycol, cyclodextrin, saline, Ringer's solution, dextrose, polyethylene glycol-hydroxystearate, or combinations thereof.

[0061] In certain embodiments, the excipient comprises ethanol.

[0062] 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%.

[0063] In certain embodiments, the excipient comprises propylene glycol.

[0064] 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%.

[0065] In certain embodiments, the excipient comprises polyethylene glycol.

[0066] 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%.

[0067] In certain embodiments, the excipient comprises hydroxypropyl-β-cyclodextrin.

[0068] 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%.

[0069] In certain embodiments, the nasal formulation comprises a buffer solution.

[0070] In certain embodiments, the buffer solution comprises citric acid, glycine, citrate, or acetate.

[0071] In certain embodiments, the buffer solution comprises citrate.

[0072] In certain embodiments, the buffer solution comprises acetate.

[0073] In certain embodiments, the present invention is directed to a method of providing respiratory stimulation comprising intranasally administering an intranasal formulation disclosed herein.

[0074] In certain embodiments, the present invention is directed to a method of treating respiratory depression comprising nasally administering a formulation disclosed herein.

[0075] In certain embodiments, the respiratory depression is caused by an opioid agent.

[0076] In certain embodiments, the respiratory depression is caused by a non-opioid agent.

[0077] In certain embodiments, the respiratory depression is caused by inflammation.

[0078] In certain embodiments, the respiratory depression is caused by an infection.

[0079] Certain embodiments of the present disclosure are directed to intranasal formulations comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the compound of formula (I) is [ka] During the ceremony,

[0080] 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;

[0081] 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;

[0082] R 4 is H, alkyl, or substituted alkyl;

[0083] 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;

[0084] R6 is H, alkyl, substituted alkyl, or alkenyl;

[0085] X is a bond, O, or NR 4 and

[0086] Y is N, CR 6 or C,

[0087] Y is N or CR 6 If b is 1 is null, (i) Z is H, and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond,

[0088] When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C or or a salt thereof.

[0089] Certain embodiments of the present disclosure are directed to intranasal formulations comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the compound of formula (I) is [ka] During the ceremony,

[0090] 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 R1 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;

[0091] 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;

[0092] R 4 is H, alkyl, or substituted alkyl;

[0093] 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;

[0094] R 6 is H, alkyl, substituted alkyl, or alkenyl;

[0095] X is a bond, O, or NR 4 and

[0096] Y is N, CR 6 or C,

[0097] Y is N or CR 6 If b is 1 is null, (i) Z is H, and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond,

[0098] When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C or or a salt thereof.

[0099] Certain embodiments of the present disclosure are directed to intranasal formulations comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the compound of formula (I) is [ka] During the ceremony,

[0100] 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;

[0101] R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 , -C(O)OR 1 , acyl, or aryl;

[0102] R 4 is H, alkyl, or substituted alkyl;

[0103] 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;

[0104] R 6 is H, alkyl, substituted alkyl, or alkenyl;

[0105] X is a bond, O, or NR 4 and

[0106] Y is N, CR 6 or C,

[0107] Y is N or CR 6 If b is 1is null, (i) Z is H, and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond,

[0108] When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C or or a salt thereof.

[0109] 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.

[0110] Certain embodiments of the present disclosure are directed to intranasal formulations comprising a compound of formula (I) and a pharma- ceutically acceptable excipient, wherein the compound of formula (I) is [ka]

[0111] 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 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;

[0112] R 3 is H, alkyl, substituted alkyl, alkynyl, or substituted alkynyl;

[0113] R 4 is H, alkyl, or substituted alkyl;

[0114] 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;

[0115] R 6 is H, alkyl, substituted alkyl, or alkenyl;

[0116] X is a bond, O, or NR 4 and

[0117] Y is N, CR 6 or C,

[0118] Y is N or CR 6 If b is 1 is nothing, (i) Z is H and bond b 2 is a single bond and A is CH, or (ii) Z is nothing and bond b 2 is zero, A is a single bond,

[0119] When Y is C, bond b 1 is a single bond, (i) Z is CH2, and bond b 2 is a single bond and A is CH, or (ii) Z is CH and bond b 2 is a double bond and A is C; or or a salt thereof.

[0120] 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.

[0121] In one embodiment, at least one compound of formula (I) comprises: (i) Y is N 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 (II-a) or a salt thereof; [ka] and (ii) Y is N 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 (II-b) or a salt thereof. [ka]

[0122] In one embodiment, at least one compound of formula (I) comprises: (i) Y is CR6 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 CR6 and bond b 1 is null, Z is null, and bond b 2 is nothing, A is a bond, and the compound of the present invention is a pyrimidine of formula (III-b) or a salt thereof. [ka]

[0123] 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]

[0124] 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]

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] In certain embodiments, the compound A [ka] or a pharma- ceutically acceptable salt thereof, are utilized in the present invention.

[0132] 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.

[0133] In certain embodiments, the formulation maintains at least 90% of the compound after one month of accelerated storage conditions at 25° C. and 60% relative humidity.

[0134] In certain embodiments, the formulation maintains at least 90% of the compound after two months of accelerated storage conditions at 25° C. and 60% relative humidity.

[0135] In certain embodiments, the formulation maintains at least 90% of the compound after 3 months of accelerated storage conditions at 25° C. and 60% relative humidity.

[0136] In certain embodiments, the formulation maintains at least 95% of the compound after two weeks of accelerated storage conditions at 25° C. and 60% relative humidity.

[0137] In certain embodiments, the formulation maintains at least 95% of the compound after one month of accelerated storage conditions at 25° C. and 60% relative humidity.

[0138] In certain embodiments, the formulation maintains at least 90% of the compound after two months of accelerated storage conditions at 25° C. and 60% relative humidity.

[0139] In certain embodiments, the formulation maintains at least 90% of the compound after 3 months of accelerated storage conditions at 25° C. and 60% relative humidity.

[0140] In certain embodiments, the formulation maintains at least 90% of the compound after two weeks of accelerated storage conditions at 40° C. and 75% relative humidity.

[0141] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C. and 75% relative humidity for 1 month.

[0142] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C. and 75% relative humidity for 2 months.

[0143] In certain embodiments, the formulation maintains at least 90% of the compound after 3 months of accelerated storage conditions at 40° C. and 75% relative humidity.

[0144] In certain embodiments, the formulation maintains at least 95% of the compound after two weeks of accelerated storage conditions at 40° C. and 75% relative humidity.

[0145] In certain embodiments, the formulation maintains at least 95% of the compound after accelerated storage conditions of 40° C. and 75% relative humidity for 1 month.

[0146] In certain embodiments, the formulation maintains at least 90% of the compound after accelerated storage conditions of 40° C. and 75% relative humidity for 2 months.

[0147] In certain embodiments, the formulation maintains at least 90% of the compound after 3 months of accelerated storage conditions at 40° C. and 75% relative humidity.

[0148] In certain embodiments, the pH of the formulation is from about 2.5 to about 5.5.

[0149] In certain embodiments, the pH of the formulation is from about 3.5 to about 5.5.

[0150] In an embodiment, the pH is about 4 to about 5.

[0151] In certain embodiments, the pH is selected from about 4.0, about 4.5, or about 5.0.

[0152] In certain embodiments, the concentration of the compound is from about 1 mg / mL to about 50 mg / mL.

[0153] In certain embodiments, the concentration of the compound is from about 10 mg / mL to about 30 mg / mL.

[0154] In certain embodiments, the concentration of the compound is from about 15 mg / mL to about 25 mg / mL.

[0155] In certain embodiments, the concentration of the compound is selected from about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL.

[0156] In certain embodiments, the excipient is selected from ethanol, polyalkylene glycol, alkylene glycol, cyclodextrin, saline, Ringer's solution, or combinations thereof. In certain embodiments, the excipient is polyethylene glycol-hydroxystearic acid, such as that obtained by reacting 15 moles of ethylene glycol with 1 mole of 12-hydroxystearic acid. It is commercially available from BASF as Kolliphor® HS15.

[0157] In certain embodiments, the excipient comprises ethanol.

[0158] 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%.

[0159] In certain embodiments, the excipient comprises propylene glycol.

[0160] 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%.

[0161] In certain embodiments, the excipient comprises polyethylene glycol.

[0162] 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%.

[0163] In certain embodiments, the excipient comprises hydroxypropyl-β-cyclodextrin.

[0164] 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%.

[0165] In certain embodiments, the present invention is directed to a method of providing respiratory stimulation comprising intranasally administering an intranasal formulation disclosed herein.

[0166] composition In certain embodiments, the nasal pharmaceutical composition is premixed (e.g., the active agent is premixed with one or more pharma- ceutically acceptable excipients, and, optionally, with one or more additional active agents).

[0167] In certain embodiments, the pharmaceutical composition may be contained in a glass or plastic container or device suitable for intranasal administration.

[0168] In certain embodiments, pharma- ceutically acceptable excipients for nasal administration include pharma- ceutically acceptable carriers such as liquid or solid fillers, stabilizers, dispersing agents, suspending agents, diluents, thickeners, agents, solvents, or encapsulating materials, depending on whether the formulation is liquid or solid. Each carrier should be "acceptable" in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not 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, "pharmaceutically acceptable carrier" also includes any and all coating agents, antibacterial and antifungal agents, and absorption delaying agents, etc., that are compatible with the activity of the compounds useful within the present invention and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may further include pharmaceutically acceptable salts of the compounds useful within the present invention. Other additional components that may be included in the pharmaceutical compositions used to practice the present invention are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.

[0169] 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).

[0170] The carrier may be a solvent or dispersion medium, for example, containing water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Proper fluidity can 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 can 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 an isotonic agent, for example, sugar, sodium chloride, or a polyalcohol such as mannitol and sorbitol, in the composition. Prolonged absorption of nasal compositions can be brought about by including an agent that delays absorption, for example, aluminum monostearate or gelatin, in the composition.

[0171] 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 buffering agents, colorants, and the like.

[0172] 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.

[0173] The present compositions preferably include antioxidants and chelating agents that inhibit degradation of the compounds. Preferred antioxidants for some compounds are butyl hydroxytoluene (BHT), butyl hydroxyanisole (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., edetate disodium) 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 present compositions, 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.

[0174] Liquid suspensions may be prepared to achieve suspension of the active ingredient in an aqueous or oily vehicle. 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.

[0175] 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.

[0176] Powder or microparticle formulations may also be prepared for nasal delivery. Additional excipients, such as fillers and colorants, may also be included in these formulations.

[0177] The nasal pharmaceutical composition of the present invention can also be prepared, packaged, or sold in the form of oil-in-water emulsion or water-in-oil emulsion.The oily phase can be vegetable oil such as olive oil or arachis oil, mineral oil such as liquid paraffin, or a combination thereof.Such compositions can 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.

[0178] 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 a mixture thereof.

[0179] 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.

[0180] 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, etc. 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 (such as ascorbic acid, erythorbic acid, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid, etc.), phenols (such as 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.

[0181] In certain embodiments, suitable antioxidants include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations of the above. Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols, such as, but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylphenol), ... 2,6-di-tert-butyl-4-methoxymethylphenol; nonylphenols having linear or branched side chains, such as 2,6-di-nonyl-4-methylphenol, 2,4-dimethyl-6-(1'-methylundecyl)phenol, 2,4-dimethyl-6-(1'-methylheptadec ... phenol, 2,4-dimethyl-6-(1'-methyltridec-1-yl)phenol, and mixtures thereof, alkylthiomethylphenols, such as, but not limited to, 2,4-dioctylthiomethyl-6-tert-butylphenol, 2,4-dioctylthiomethyl-6-methylphenol, 2,4-dioctylthiomethyl-6-ethylphenol, 2,6-di-dodecylthiomethyl-4-nonylphenol, hydroquinone and alkylated hydroquinones, such as, but not limited to, However, 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-di-tert-butyl-4-hydroxyphenyl) adipate, tocopherols, including but not limited to α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, and mixtures thereof (vitamin E), hydroxylated thiodiphenyl ethers, including but not limited to 2,2′-thiobis(6-tert-butyl-4-methylphenol), 2,2′-thiobis(4-octylphenol), 4,4′-thiobis(6-tert-butyl-3-methylphenol), 4,4′-thiobis(6-tert-butyl-4-methylphenol), butyl-2-methylphenol), 4,4'-thiobis(3,6-di-sec-amylphenol), 4,4'-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide, alkylidene bisphenols, such as, but not limited to, 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 2,2'-methylenebis(6-tert-butyl-4-ethylphenol), 2,2'-methylenebis[4-methyl-6-(α-methylcyclohexyl)-phenol], 2,2'-methylenebis(4-methyl-6-cyclohexyl)-phenol], xylphenol), 2,2'-methylenebis(6-nonyl-4-methylphenol), 2,2'-methylenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(4,6-di-tert-butylphenol), 2,2'-ethylidenebis(6-tert-butyl-4-isobutylphenol), 2,2'-methylenebis[6-(α-methylbenzyl)-4-nonylphenol], 2,2'-methylenebis[6-(α,α-dimethylbenzyl)-4-nonylphenol], 4,4'-methylenebis(2,6-di-tert -butylphenol), 4,4′-methylenebis(6-tert-butyl-2-methylphenol), 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 2,6-bis(3-tert-butyl-5-methyl-2-hydroxybenzyl)-4-methylphenol, 1,1,3-tris(5-tert-butyl-4-hydroxy-2-methylphenyl)butane, 1,1-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-3-n-dodecylmercaptobutane, ethylene glycol bis[3,3-bis(3′-tert-butyl-4′-hydroxyphenyl)butyrate], bis(3-tert-butyl-4-hydroxy-5-methyl-phenyl)dicyclopentadiene, bis[2-(3′-tert-butyl-2′-hydroxy-5′-methylbenzyl)-6-tert-butyl-4-methylphenyl]terephthalate, 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxyphenyl)propane 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)pentane, O-, N-, and S-benzyl compounds, such as, but not limited to, 3,5,3′,5′-tetra-tert-butyl-4,4′-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzyl mercaptoacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzyl mercaptoacetate, tris(3,5-di-t tert-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl)sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzyl mercaptoacetate, hydroxybenzylated malonates, such as, but not limited to, dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl)malonate, di-octadecyl-2-(3-tert -butyl-4-hydroxy-5-methylbenzyl)malonate, didodecylmercaptoethyl-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, bis[4-(1,1,3,3-tetramethylbutyl)phenyl]-2,2-bis(3,5-di-tert-butyl-4-hydroxybenzyl)malonate, aromatic hydroxybenzyl compounds, such as, but not limited to, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-2,4,6-trimethylbenzene, 1,4-bis(3,5-di-tert-butyl-4-hydroxybenzyl)-2,3,5,6-tetramethylbenzene, 2,4,6-tris(3,5-di-tert-butyl-4-hydroxybenzyl)phenol, triazine compounds, such as, but not limited to, 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, ,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,3,5-triazine, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenylethyl)-1,3, 5-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxy-phenylpropionyl)-hexahydro-1,3,5-triazine, 1,3,5-tris(3,5-dicyclohexyl-4-hydroxybenzyl)iso-cyanurate, benzyl phosphonates, such as, but not limited to, dimethyl-2,5-di-tert-butyl-4-hydroxybenzylphosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzylphosphonate, dioctadecyl 3,5-di-tert-butyl-4-hydroxyphenylpropionyl, hydroxybenzyl phosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzyl phosphonate, calcium salt of the monoethyl ester of 3,5-di-tert-butyl-4-hydroxybenzyl phosphonic acid, acylaminophenols such as, but not limited to, 4-hydroxylauranilide, 4-hydroxystearanilide, N-(3,5-di-tert-butyl-4-hydroxyphenyl) octyl carbamate, β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid with, for example, monohydric or polyhydric alcohols, for example, methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3- Thioundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, β-(5-tert-butyl-4-hydroxy-3-methylphenyl)propionic acid with mono- or polyhydric alcohols, such as methanol, ethanol, n-octanol, i-octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl Glycol, thiodiethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis-(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methylphenyl)propionyloxy}-1,1-dimethylethyl]- Esters of 2,4,8,10-tetraoxaspiro[5.5]-undecane, esters of 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols, such as, for example, methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters of 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2,2]octane, esters of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with mono- or polyhydric alcohols, such as methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propanediol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3-thiapentadecanol, trimethylhexanediol, trimethylolpropane, esters with 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane, 6-(3,5-di-tert-butyl) amides of N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, for example, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexamethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylenediamide, N,N'-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazide, N,N'-bis[2-(3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyloxy)ethyl oxamide (Naugard® XL-1, 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′-dimethylpentyl-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, phenol, 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, mono- and dialkylated isopropyl / isohexyldiphenylamines. mixtures of 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-octylphenothiazines, N-allylphenothiazine, N,N,N',N'-tetraphenyl-1,4-diaminobut-2-ene, and combinations thereof.

[0182] In certain embodiments, suitable pharma- ceutically acceptable excipients include acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyalkylene oxides (e.g., polymethylene oxide, polyethylene oxide, polypropylene oxide) polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylates, polycaprolactone, polymethacrylate copolymers thereof, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, croscarmellose sodium, or mixtures thereof), glidants, , lubricants, absorption enhancers, surfactants, 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.

[0183] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrophilic and hydrophobic materials such as polyvinylpyrrolidone, natural and synthetic gums, polyvinyl alcohols, 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).

[0184] 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.

[0185] 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 examples of 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.).

[0186] 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.

[0187] In certain embodiments, suitable pharma- ceutically acceptable excipients include plasticizers, such as, but not limited to, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils, and hydrogenated vegetable oils, including acetylated hydrogenated cottonseed glycerides and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylate glycerin, glyceryl cocoate, mono- and diacetylated monoglycerides, and the like. Ceride, 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(beta-ethyl butyrate) polyethylene glycol di(2-ethylhexoate), diethylene glycol monolaurate, monomeric polyethylene esters, hydrogenated methyl esters of rosin, methoxyethyl oleate, butyric acid esters. xyethyl, butyl phthalyl butyl glycolate, glycerol tributyrate, triethylene glycol dipelagonate, beta-(p-tert-amylphenoxy)ethanol, beta-(p-tert-butylphenoxy)ethanol, beta-(p-tert-butylphenoxyethyl)acetate, bis(beta-p-tert-butylphenoxydiethyl)ether, camphor, CumarW-1, CumarMH-1, CumarV-1, diamyl phthalate, (diamylphenoxy)ethanol, diphenyl oxide, technical hydroabietyl alcohol, beckolin, benzene hexahydrochloride, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, glycerol alpha-methyl alpha-phenyl ether, chlorinated naphthalenes, HB-40, monoamyl phthalate, Nevillac 10 o-nitrodiphenyl, and Paracril 26.

[0188] 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 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 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.

[0189] 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. Spagyric essences are also known in the art. They are produced 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.

[0190] 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.

[0191] In certain embodiments, suitable pharma- ceutically acceptable excipients may include essential oils of relatively low volatility, such as 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, which are primarily used as flavoring ingredients and are also suitable as perfume oils. 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, Vertofixcoeur, Iso-E-Super, Fixolide NP, Evernyl, Iraldine Gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romirat, irotyl, and floramate, either alone or in mixtures.

[0192] In certain embodiments, suitable pharma- ceutically acceptable excipients may include preservatives. As used herein, the term "preservative" refers to an agent that extends the shelf life of a dosage form by delaying or preventing deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety. A preservative need not produce a lethal, irreversible action that results in partial or complete microbial cell destruction or incapacitation. Sterilants, cleaners, disinfectants, sporicides, virucides, and tuberculocides produce such an irreversible mode of action, which is sometimes referred to as a "bactericidal" action. In contrast, a preservative can produce an inhibitory or bacteriostatic action that is reversible in that the target microorganism can resume growth if the preservative is removed. The main difference between a preservative and a cleaner is primarily the mode of action (preservatives prevent the growth of microorganisms rather than killing them) and the exposure time (preservatives take days to months to act, whereas cleaners take only minutes at most to act). Suitable preservatives include, but are not limited to, phenoxyethanol, parabens, pentanediol, and sorbic acid solutions, as well as silver complexes.

[0193] 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.

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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 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, such as 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.

[0199] 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, monodiglycerides 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.

[0200] 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.

[0201] In certain embodiments, suitable pharma- ceutically acceptable excipients may include 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.

[0202] In certain embodiments, suitable pharma- ceutically acceptable excipients can include fillers, such as, but not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0203] 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.

[0204] 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-10 0 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.

[0205] Further suitable emulsifiers are phosphoric acid esters and their salts, such as cetyl phosphate (Amphisol® A), diethanolamine cetyl phosphate (Amphisol® DEA), potassium cetyl phosphate (Amphisol® K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphate, and mixtures thereof. Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate, and hydrated polyisobutene. In addition, 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.

[0206] In certain embodiments, suitable pharma- ceutically acceptable excipients may include chelating agents, such as, but not limited to, ethylenediaminetetraacetic acid disodium salt (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).

[0207] 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.

[0208] 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. propylen 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 oxo synthesis or in the dimerization of unsaturated fatty acids), with alcohols, such as isopropyl alcohol. , caproic alcohol, capryl alcohol, 2-ethylhexyl alcohol, capric alcohol, lauryl alcohol, isotridecyl alcohol, myristyl alcohol, cetyl alcohol, palmoleyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, petroselinyl alcohol, linoyl alcohol, linolenyl alcohol, eleostearyl alcohol, arachidyl alcohol, gadoleyl alcohol, behenyl alcohol, erucyl alcohol, and brassydyl alcohol, 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 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 stearic acid, 2-octyldodecyl palmitate, oleic acid ... These include oleyl leate, oleyl erucate, erucyl oleate, erucyl erucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl behenate, cetyl acetate, myristyl myristate, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate / caprylate, stearyl heptanoate, diisostearyl malate, and octyl hydroxystearate.

[0209] 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.

[0210] 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 Based on fatty acids, diglycerides or triglycerides (caprylic / capric triglyceride, wheat germ glyceride, 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 oil, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borage oil, etc. Suitable excipients include waxes including esters of long chain acids and alcohols, and compounds with wax-like properties, such as 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.

[0211] 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 coconut 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.

[0212] 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.

[0213] In certain embodiments, suitable pharma- ceutically acceptable excipients may include silicones or siloxanes (organo-substituted polysiloxanes), such as, but not limited to, dimethylpolysiloxane, methylphenylpolysiloxane, 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 hydrosilicate. In addition, a detailed review of suitable volatile silicones by Todd et al. can be found in Cosm. Toil. 91, 27 (1976).

[0214] 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 phosphate esters, acidic phosphate esters, 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 tetrapropene sulfonates, sodium lauryl sulfate, ammonium and ethanolamine lauryl sulfate, lauryl ether sulfate, sodium laureth sulfate, sulfosuccinates, acetyl isothionates, alkanolamide sulfates, taurine, methyl taurine, imidazole sulfate. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicone, copolyols, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ethers (Meroxapol), Polaxamer or poly(oxyethylene) m-block-poly(oxypropylene) n-block (oxyethylene). Zwitterionic surfactants carrying at least one quaternary ammonium group and at least one carboxylate and / or sulfonate group in the molecule.Particularly suitable zwitterionic surfactants are betaines, such as N-alkyl-N,N-dimethylammonium glycinates, cocoalkyldimethylammonium glycinates, N-acylaminopropyl-N,N-dimethylammonium glycinates, cocoacylaminopropyldimethylammonium glycinates, and 2-alkyl-3-carboxymethyl-3-hydroxyethyl imidazolines, each having 8 to 18 carbon atoms in the alkyl or acyl group, as well as cocoacylaminoethyl hydroxyethyl carboxymethyl glycinates, N-alkyl betaines, N-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, p 250-251.

[0215] Suitable non-ionic bases include, but are not limited to, PEG-6 beeswax (and) PEG-6 stearate (and) polyglyceryl-2-isostearate, glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglyceryl-3 ricinoleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and 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 ... Examples of suitable oleic acid salts include glyceryl stearate 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, and glyceryl stearate and ceteareth-20.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] In certain embodiments, suitable pharma- ceutically acceptable excipients may include consistency regulators / thickeners and rheology modifiers, such as, but not limited to, silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or derivatives thereof, such as hyaluronic acid, xanthan gum, guar guar, agar, alginate, carrageenan, gellan, pectin, or modified celluloses, such as hydroxycellulose, hydroxypropyl methylcellulose. In addition, polyacrylates or homopolymers of reticulated acrylic acid and polyacrylamide, Carbomers (CARBOPOL types 980, 981, 1382, ETD2001, ETD2020, ULTREZ10), or SALCARE products such as SALCARE SC80 (steareth-10 allyl ether / acrylates copolymer), Salcare SC81 (acrylates copolymer), Salcare SC91 and Salcare AST (sodium acrylates copolymer / PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide / laureth-7), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer), STABILEN 30 (acrylates / vinyl isodecanoate crosspolymer), PEMULEN TR-1 (acrylates / C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (Sodium Acrylate Copolymer), ACULYN 28 (Acrylates / Beheneth-25 Methacrylate Copolymer), etc.

[0221] 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.

[0222] 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.

[0223] In certain embodiments, suitable pharma- ceutically acceptable excipients may include hydrotopic agents, such as, but not limited to, ethoxylated or non-ethoxylated monoalcohols, diols or polyols with a low number of carbon atoms or their ethers (e.g., ethanol, isopropanol, 1,2-dipropanediol, propylene glycol, glycerin, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, and similar products). Polyols considered for this purpose preferably have 2 to 15 carbon atoms and at least two hydroxy groups. Polyols may also contain further functional groups, in particular amino groups, and / or may be modified with nitrogen. Typical examples are: glycerol, alkylene glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol, and also polyethylene glycols with an average molecular weight of 100 to 1000 Daltons; technical oligoglycerol mixtures with an inherent degree of condensation of 1.5 to 10, for example technical diglycerol mixtures with a diglycerol content of 40 to 50% by weight; methylol compounds, such as, in particular, trimethylolethane ... butylolpropane, trimethylolbutane, pentaerythritol, and dipentaerythritol; lower alkyl glucosides, especially those having 1 to 8 carbon atoms in the alkyl radical, such as methyl and butyl glucoside; sugar alcohols having 5 to 12 carbon atoms, such as sorbitol or mannitol; sugars having 5 to 12 carbon atoms, such as glucose or saccharose; amino sugars, such as glucamine; dialcoholamines, such as diethanolamine or 2-1,3-propanediol.

[0224] 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 further classes of substances listed in the following reference: KF DePolo-A short textbook of cosmetology, Chapter 7, Tables 7-2, 7-3, 7-4 and 7-5, p 210-219.

[0225] 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). Many 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.

[0226] In certain embodiments, pharma- ceutically acceptable excipients may be included (individually or cumulatively) in the pharmaceutical compositions described herein at a concentration ranging from about any of 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 any of 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.

[0227] Preparation method In certain embodiments, the present disclosure is directed to a method for preparing any of the nasal compositions described herein. In certain embodiments, the method includes combining a therapeutically effective amount of a compound disclosed herein with one or more nasal pharma- ceutically acceptable excipients and placing the formulation in a container or device suitable for nasal delivery.

[0228] Additional Active Agents and Embodiments In certain embodiments, the present invention is directed to a method of treating opioid overdose or a method of prophylactically treating opioid overdose comprising administering to a patient in need thereof an opioid receptor antagonist and a respiratory stimulant (e.g., Formula I).

[0229] In another aspect, the present invention is directed to an intranasal pharmaceutical composition or system (formulation in a device) comprising a combination of an opioid receptor antagonist and a respiratory stimulant (e.g., of Formula I), the combination treating or prophylactically treating opioid overdose in a patient in need thereof in an effective amount.

[0230] In certain embodiments, the present invention is directed to a method of treating opioid withdrawal or a method of prophylactically treating opioid withdrawal comprising administering to a patient in need thereof an opioid receptor antagonist and a respiratory stimulant (e.g., Formula I).

[0231] In another aspect, the present invention is directed to an intranasal pharmaceutical composition or system (formulation in a device) comprising a combination of an opioid receptor antagonist and a respiratory stimulant (e.g., of Formula I), wherein the combination treats or prophylactically treats opioid withdrawal symptoms in a patient in need thereof in an effective amount.

[0232] In certain embodiments, the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, and pharma- ceutically acceptable salts thereof.

[0233] In one aspect, the weight ratio of antagonist to respiratory stimulant can be from about 1:9 to about 9:1, from about 1:7 to about 7:1, from about 1:5 to about 5:1, or from about 1:3 to about 3:1.

[0234] In some aspects of the nasal formulation, the pharmaceutical composition of the respiratory stimulant and optional antagonist comprises one or more excipients selected from water, NaCl, benzalkonium chloride, sodium edetate, disodium edetate, and hydrochloric acid.

[0235] In some embodiments of the nasal formulation, the pharmaceutical composition further comprises water, NaCl, benzalkonium chloride, edetate disodium, and hydrochloric acid.

[0236] In some embodiments of intranasal formulations, the pharmaceutical composition includes an isotonicity agent, a preservative, a stabilizer, a sufficient amount of acid to achieve a pH or between 3.5 and 5.5, and an amount of water.

[0237] In some embodiments of the intranasal formulation, the pharmaceutical composition includes about 0.2 mg to about 1.2 mg of an isotonicity agent, about 0.005 mg to about 0.015 mg of a preservative, about 0.1 mg to about 0.5 mg of a stabilizer, an acid in an amount sufficient to achieve a pH or between 3.5 and 5.5, and an amount of water.

[0238] In some embodiments of the nasal formulation, the isotonicity agent is NaCl, the preservative is benzalkonium chloride, the stabilizer is edetate disodium, and the acid is hydrochloric acid.

[0239] In some embodiments of the intranasal formulation, the pharmaceutical composition comprises about 0.74 mg of NaCl, about 0.01 mg of benzalkonium chloride, about 0.2 mg of disodium edetate, a sufficient amount of hydrochloric acid to achieve a pH of 3.5 to 5.5, and a quantity of water.

[0240] In one embodiment of the nasal formulation, the antagonist is naloxone in an amount equivalent to about 4 mg to about 10 mg of naloxone hydrochloride. In some embodiments, the therapeutically effective amount is equivalent to an amount selected from about 2 mg of naloxone hydrochloride, about 4 mg of naloxone hydrochloride, and about 8 mg of naloxone hydrochloride.

[0241] In some embodiments of the nasal formulation, the amount of naloxone is equivalent to about 2 mg of naloxone hydrochloride. In some embodiments of the nasal formulation, the amount of naloxone is equivalent to about 4 mg of naloxone hydrochloride. In some embodiments of the nasal formulation, the amount of naloxone is equivalent to about 8 mg of naloxone hydrochloride. In some embodiments of the nasal formulation, the amount of naloxone is equivalent to about 3.4 mg of naloxone hydrochloride.

[0242] In some embodiments of the nasal formulation, the amount of naloxone is about 2.2 mg to about 13.2 mg of naloxone hydrochloride dihydrate. In some embodiments of the nasal formulation, the amount of naloxone is about 4.4 mg to about 11 mg of naloxone hydrochloride dihydrate. In some embodiments, the amount of naloxone is an amount selected from about 2.2 mg of naloxone hydrochloride dihydrate, about 4.4 mg of naloxone hydrochloride dihydrate, and about 8.8 mg of naloxone hydrochloride dihydrate. In some embodiments of the nasal formulation, the amount of naloxone is about 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments of the nasal formulation, the amount of naloxone is about 4.4 mg of naloxone hydrochloride dihydrate. In some embodiments of the nasal formulation, the amount of naloxone is about 8.8 mg of naloxone hydrochloride dihydrate.

[0243] In some embodiments of the intranasal formulation, the pharmaceutical composition includes about 0.2 mg to about 1.2 mg of an isotonicity agent, about 0.005 mg to about 0.015 mg of a preservative, about 0.1 mg to about 0.5 mg of a stabilizer, an acid in an amount sufficient to achieve a pH or between 3.5 and 5.5, and an amount of water.

[0244] In some embodiments of the nasal formulation, the isotonicity agent is NaCl, the preservative is benzalkonium chloride, the stabilizer is edetate disodium, and the acid is hydrochloric acid.

[0245] In some embodiments of the intranasal formulation, the pharmaceutical composition comprises about 0.74 mg of NaCl, about 0.01 mg of benzalkonium chloride, about 0.2 mg of disodium edetate, a sufficient amount of hydrochloric acid to achieve a pH of 3.5 to 5.5, and a quantity of water.

[0246] Drugs of abuse that are the subject of overmedication treatment include opioids, such as morphine, codeine, thebaine, oripavine, diacetylmorphine, 2,4-dinitrophenylmorphine, methylenedioxydimethylamphetamine, clomaltrexamine, dihydromorphine, hydromorphinol, nicomorphine, dipropanoylmorphine, desomorphine, acetylproprionylmorphine, methyldesorphine, N-phenethylnormorphine, 14 -Hydroxydihydrocodeine (RAM-318), 7,8-dihydro-14-hydroxy-N-phenethylnormorphine (RAM-378), dibenzoylmorphine, diacetyldihydromorphine, dibenzoylmorphine, 6-monoacetylcodine (6-MAC), acetyldihydrocodeine, dihydrocodeine, nalbuphine, nicocodeine, nicodicodeine, oxymorphazone, 1-iodomorphine, morphine-6-glycuronide (M6G ), 6-monoacetylmorphine (6-MAM), norcodeine, normorphine, genomorphine, dextralphan (DXA), cyclophane, dihydroheterocodeine, pholcodine, mylophine, 14-cinnamoyloxycodinone, 14-ethoxymethopone, 14-methoxymethopone, 14-phenylpropoxymethopone (PPOM), 7-spiroindodanyloxymorphone, acetylmorphone, codenone, conorphone, codoxime, thebacon , Metopon, N-phenethyl-14-ethoxymethopon, Morphinone, Benzylmorphine, Codeine methyl bromide, Ethylmorphine, Heterocodeine, Hydromorphone, Hydrocodone, Oxycodone, Oxymorphone, Pentamorphone, Cermorphone, Chloromorphide, Ethylmorphine, Buprenorphine, Fentanyl, Alpha-methylfentanyl, Alfentanil; Sufentanil, Remifentanil; Carfentanil, Omefentanil;Pethidine, ketobemidone, desmethylprodine (MPPP), allylprodine, prodine, 1-methyl-4-phenyl-4-propionoxypiperidine (PEPAP), propoxyphene, dextropropoxyphene, dextromoramide, bezitramide, piritramide, levorphanol, methadone, dipipanone, levomethadyl acetate (LAAM), difenoxin, diphenoxylate, loperamide, dezocine, pentazocine, phenazocine, dihydroetorphine, etorphine, butorphanol, nalbuphine , remethorphan, levophenacylmorphan, norlevorphanol, oxyorphan, phenomorphan, fretylnorlevorphanol, xorphanol, butorphanol, cyprodim, drotebanol, 7-PET, acetorphine, BU-48; cyprenorphine, norbuprenorphine, lephetamine, meptazinol, mitragynine, tilidine, tramadol, tapentadol, dextropropoxyphene, endorphins, enkephalins; dynorphins, and endomorphins. In some embodiments, the opioid is oxymorphone. In further embodiments, the opioid is oxycodone. The above list of opioids also includes pharma- ceutically acceptable salts thereof.;

[0247] In certain embodiments, the respiratory stimulant can be selected from the group consisting of doxapram, almitrine, compounds of formula I, and pharma- ceutically acceptable salts thereof.

[0248] device In certain embodiments, a nasal drug delivery device is provided that comprises the pharmaceutical composition described herein.The advantages of nasal delivery include needle-free systemic drug delivery, especially when rapid absorption and effect are desired.In addition, nasal delivery may help address the problems associated with low bioavailability, slow absorption, drug degradation, and adverse events (AE) in the gastrointestinal tract, and avoids first-pass metabolism in the liver.

[0249] The liquid nasal formulation may be an aqueous solution, suspension, or emulsion. Certain spray pump systems may contain antimicrobial preservatives to maintain microbiological stability.

[0250] In certain embodiments, the nasal formulations disclosed herein may be in a metered spray pump.

[0251] The pump can deliver, for example, 0.05 ml to about 0.5 mL, or about 0.1 mL. In certain embodiments, the formulation includes a preservative, and in other embodiments, the formulation does not include a preservative. In certain embodiments, the spray pump of the present invention includes a preservative to replace the emitted liquid with air, thus preventing contamination. In other embodiments, the system uses a collapsible bag, a movable piston, or compressed gas to compensate for the volume of liquid emitted. Solutions with a collapsible bag and a movable piston that compensate for the volume of liquid expelled provide the added advantage of being able to expel upside down without the risk of aspirating air into the dip tube and compromising subsequent spraying. This can be useful for some products where it is recommended that the patient be applied while lying down, head down. Another method is to filter the air that replaces the emitted liquid with a sterile air filter. Additionally, some systems have a ball valve at the tip to prevent contamination of the liquid inside the applicator tip.

[0252] In certain embodiments, metered dose spray pumps require priming and some degree of overfill to maintain dose conformity to the labeled dose number. In other embodiments, single or dual dose spray devices are preferred.

[0253] In certain embodiments, the system is terminally sterilized. The product may be filled and sealed in a controlled environment to minimize the microbial and particulate content of the in-process product and help ensure that the subsequent sterilization process is successful. In certain embodiments, the product in the final container is then subjected to a sterilization process, such as heat or irradiation. In an aseptic process, the pharmaceutical product, container, and closure may be initially subjected to a sterilization method separately, if desired, and then combined.

[0254] Pharmacodynamics In some embodiments, the patient is free from respiratory depression for at least about 30 minutes, at least about 1 hour, at least about 2 hours, at least about 3 hours, at least about 4 hours, at least about 6 hours, or at least about 8 hours following a treatment comprising delivery of a therapeutically effective amount of a respiratory stimulant and an optional antagonist.

[0255] In some embodiments, the device is a two-dose device, wherein a first volume of the pharmaceutical composition is present in a first reservoir and a second volume of the pharmaceutical composition is present in a second reservoir, and a therapeutically effective amount is delivered essentially by a first actuation of the device into a first nostril of the patient and a second actuation of the device into the same or a second nostril of the patient.

[0256] In certain embodiments using two agents, each formulation in a two-dose device may be combined in both reservoirs, while in other embodiments each active agent is separate in each reservoir.

[0257] In some embodiments, upon nasal delivery of the pharmaceutical composition to a patient, less than about 20%, less than about 10%, or less than about 5% of the pharmaceutical composition exits the nasal cavity via nasopharynx drainage or external drainage.

[0258] Working Example Specific embodiments of the present invention will now be described by reference to the following examples, which are disclosed solely for the purpose of illustrating the present invention and should not be construed as limiting the scope of the present invention in any way.

[0259] Stability testing Formulations were prepared using the formulations presented in Table 1. The formulations contain the hydrogen sulfate salt of Compound A (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine) as the active agent. [ka] [Table 1]

[0260] 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. Note that the concentrations in Table 2 are those of the filtered concentrate. [Table 2]

[0261] Another embodiment having a concentration of 15 mg / mL was prepared and stability tested over a 2 week period 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 testing are shown in Tables 3-5. [Table 3] [Table 4] [Table 5]

[0262] Another embodiment having a concentration of 25 mg / mL was prepared and stability was examined over a 2 week period 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 shown in Tables 6-8. [Table 6] [Table 7] [Table 8]

[0263] Additionally, stability studies were performed using different excipients at a concentration of 50 mg / mL at pH 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]

[0264] Solubility of formulations as a function of pH To assess the feasibility of formulating compounds having formula (I) as simple buffered solutions at a pH appropriate for intranasal formulations, pH solubility studies were performed.

[0265] Methodology: A solution of the compound having formula (I) and H2SO4 at a concentration of approximately 107 mg / mL in 100 mM citric acid at pH 2.5 was prepared. Approximately 150 μL aliquots of this solution were 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 a 0.45 μm syringe tip filter (4 mm diameter) at 3000 rpm for 20 minutes. The final pH value of the filtrate was measured. The filtrate was then appropriately diluted and analyzed for compound having formula (I).H2SO4 concentration using the HPLC assay.

[0266] Results: The pH values, appearances, and concentrations of the samples before and after overnight shaking 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 saturation solubility values. [Table 12]

[0267] Stability as a function of pH The compound having formula (I) is estimated to have a pKa of 5.6 and a theoretical free base solubility of about 0.18 mg / mL.Therefore, the inventors believe that the solubility of the drug above about pH 3.6 is insufficient for the intended product concentration.At such low pH, the stability of the drug in solution may be problematic.The purpose of this experiment was to evaluate the stability of the drug as a function of pH.

[0268] The main consideration in such experiments is the concentration of drug and buffer used. A buffer is used because dramatic changes in pH during the experiment would render the data meaningless. However, it is desirable to keep the buffer to a minimum strength to minimize the effects of buffer catalysis. Buffer strength can be minimized by keeping the drug concentration low. Keeping the drug concentration low also minimizes confounding of the data with solubility limits (i.e., drug precipitation from solution).

[0269] Methodology: Buffer solutions containing approximately 10 mM each of citric acid and glycine in the pH range of 2-6 were prepared by titrating 250 mL of a single stock containing both buffers with 1N NaOH / 1N HCl and removing a 50 mL aliquot at the given pH value. 1 mg / mL solutions were prepared in pH 2-5 buffers by dissolving approximately 25 mg of compound having formula (I).H2SO4 in approximately 23 mL of a given buffer, adjusting the pH to the target, and fixing the volume to 25.0 mL in a volumetric flask. A pH 6 solution was prepared similarly but with a lower drug concentration of 0.25 mg / mL using 6.68 mg of compound having formula (I).H2SO4.

[0270] Each buffer solution was placed in a volumetric flask that was dried in a laminar flow hood, filtered through a 0.2 μm polyethersulfone syringe filter, and previously rinsed with 70% ethanol. After filtration, each buffer solution was divided into 10 aliquots (9 aliquots of 2.5 mL each, and 1 aliquot of 2 mL) in 5 mL serum vials previously rinsed with 70% ethanol and dried in a laminar flow hood. Filtration and preparation of the aliquots were performed in a laminar flow hood. A 2 mL aliquot of each buffer solution was submitted for T0 analysis (HPLC assay and related substances). Of the nine 2.5 mL aliquots, three aliquots were stored at 40°C and 60°C, 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. Samples at 25°C and -70°C served as controls to be analysed as necessary.

[0271] Results: pH stability data is shown in Table 13. After storage at both 40°C and 60°C for up to 4 weeks, all samples remained clear, colorless, and particle free. The pH values ​​of all samples remained relatively constant for up to 4 weeks at both storage temperatures. Both assay and impurity data indicate that the solutions were significantly less stable at pH 2 compared to the remaining pH values ​​evaluated. No specific trends were observed in the pH range of 3-6. The pH stability profile (percentage of impurities) at 60°C is shown in Figure 1. [Table 13]

[0272] Stability as a function of pH – narrow pH range The pH stability test above showed that the compound was unstable at pH 2.0, but was more stable at lower pH values. Therefore, the stability of the compound was evaluated in the pH range of 2 to 3.6.

[0273] 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 250 mL stock containing both buffers with 1N NaOH / 1N HCl and removing a 50 mL aliquot at the desired pH value. 1 mg / mL solutions were prepared by dissolving approximately 25 mg of compound in approximately 23 mL of a given buffer, adjusting the pH to target, and fixing the volume to 25.0 mL in a volumetric flask.

[0274] Each buffer solution 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 9 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 the aliquots were performed in a laminar flow hood. Of the nine aliquots, three aliquots were stored at 40° C. and 60° C., two aliquots were stored at 25° C., and one aliquot was subjected to T0 testing. After T0 and 1, 2, and 4 weeks of storage at 40° C. and 60° C., the samples were evaluated for pH, assay, and related substances. The 25° C. sample served as a control to be analyzed as necessary. The results are presented in Table 14 and Figure 2.

[0275] The most notable result from this study is that the levels of impurities decrease significantly as the pH increases across the entire pH range tested, both at storage at 40° C. and 60° C. This means that any increase in the pH of the formulation leads to improved stability within the pH range for which the aqueous formulation is suitable. [Table 14]

[0276] Stability of API Methodology: Approximately 100 mg of API (Lot 009MSB058) was stored in closed Type I glass vials at 40° C. and 60° C., respectively. Samples were analyzed for appearance and purity percentage at TO and after 1, 2, and 4 weeks of storage.

[0277] 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]

[0278] Stability of a simple prototype An experiment was conducted to determine the stability of the API in a prototype simple formulation. A solution was prepared having a concentration of 25 mg / mL of the API as the free base, which corresponds to 35 mg / mL of the compound having formula (I).H2SO4.

[0279] 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]

[0280] Prototypes 6, 7, and 8 underwent significant precipitation during preparation and were therefore 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.

[0281] Results: The data are shown in Tables 17-22. The aqueous buffered formulation (Prototype No. 1) was found to be stable at room temperature and under refrigeration, however, some decomposition 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 coincided with an actual decrease in the major impurity peak, so the possibility of insolubility of the decomposer is under investigation.

[0282] 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 was also 50% PEG based but also contained enough sodium hydroxide to bring the apparent pH up to about 4.5. Similarly, good stability was seen in Prototype #9, which was 70% propylene glycol / 30% water with the addition of 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] The formulations disclosed above are placed into a suitable nose drop, nasal spray, atomizer, nebulizer, or other device suitable for administration to the nasal cavity.

[0283] From the narrow range pH stability testing, it is clear that there is a significant improvement in stability with increasing pH, even at the top of the range tested. The upper pH limit is set by the solubility of the drug, and the reduction in the drug concentration required for dissolution allows the product to be formulated at a higher pH, which improves the stability of the product. Specifically, by reducing the concentration in half, 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 significantly improves the stability of the formulation. Based on this consideration, it was decided to reduce the concentration of Cmp.A in the formulation from 25 mg / mL to 10 mg / mL, and to increase 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 shown in Table 23. [Table 23]

[0284] 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 may occur in various orders and / or simultaneously, as well as with other acts not shown or described herein. Moreover, not all illustrated acts may be 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 may alternatively be represented as a series of interrelated states via a state diagram or events.

[0285] 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 any of the 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 illustrative examples. References throughout this specification to "an embodiment," "certain embodiment," or "one embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment. Thus, the appearances of the phrases "embodiment," "certain embodiment," or "one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0286] 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 nasal preparation comprising a compound of formula (I) in an amount of 0.01% w / w to 10% w / w and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is 【Chemistry 1】 During the ceremony, R １ and R ２ However, 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 However, when combined, they form a biradical selected from the group consisting of 3-hydroxypentane-1,5-diyl, 6-hydroxycycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl, and pentane-1,5-diyl. R ３ However, 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 However, H, alkyl, propagyl, substituted propagyl, homopropagyl, substituted homopropagyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -OR １ , -NR １ R ２ , -C(O)OR １ , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic, or R ３ and R ５ However, when combined, they 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 However, it is H, alkyl, substituted alkyl, or alkenyl, X is a bond, O, or NR ４ And, Y is N, CR ６ , or C, Compound Y is N or CR ６ If so, then combination b １ (i) Z is H, and bond b ２ (ii) Z is a single bond, and A is CH, or (ii) Z is absent, and bond b ２ If there is no bond, and A is a single bond, If Y is C, then bond b １ (i) Z is a single bond, and ２ And, bond b ２ (ii) Z is a single bond and A is CH, or (ii) Z is CH and bond b ２ It is a double bond, and A is C, The nasal formulation, selected from or a salt thereof, wherein the formulation is contained in a nasal delivery device.

2. The nasal preparation according to claim 1, wherein the pharmaceutically acceptable excipients include liquids.

3. The nasal preparation according to claim 1, wherein the compound of formula (I) is dissolved in the liquid.

4. The nasal preparation according to claim 1, wherein the compound of formula (I) is suspended in the liquid.

5. The nasal preparation according to claim 1, wherein the pharmaceutically acceptable excipient is an aggregate of particles.

6. The nasal preparation according to claim 1, wherein the compound of formula (I) is dispersed inside each particle.

7. The nasal preparation according to claim 1, wherein the compound of formula (I) is coated on each particle.

8. The nasal preparation according to claim 1, wherein the pharmaceutically acceptable excipient is a cream, ointment, or gel.

9. The nasal preparation according to claim 1, wherein the nasal preparation retains at least 90% of the compound after accelerated storage conditions of 2 weeks at 40°C and 75% relative humidity.

10. The nasal preparation according to claim 1, wherein the pH of the preparation is 3.5 to 5.

5.

11. The nasal preparation according to claim 10, wherein the pH is 4 to 5.

12. The nasal preparation according to claim 11, wherein the pH is selected from 4.0, 4.5, or 5.

0.

13. The nasal preparation according to claim 1, wherein the concentration of the compound is 1 mg / ml to 100 mg / ml.

14. The nasal preparation according to claim 1, wherein the excipient is selected from water, ethanol, polyalkylene glycol, alkylene glycol, cyclodextrin, physiological saline, Ringer's solution, dextrose, polyethylene glycol-hydroxystearate, or a combination thereof.

15. The nasal preparation according to claim 13, wherein the excipient comprises ethanol.

16. The nasal preparation according to claim 15, wherein the excipient contains ethanol in an amount of 1% to 30%, 5% to 25%, or 10% to 20%.

17. The nasal preparation according to claim 13, wherein the excipient comprises propylene glycol.

18. The nasal preparation according to claim 17, wherein the excipient contains propylene glycol in an amount of 20% to 100%, 50% to 95%, or 70% to 90%.

19. The nasal preparation according to claim 13, wherein the excipient comprises polyethylene glycol.

20. The nasal preparation according to claim 19, wherein the excipient contains polyethylene glycol in an amount of 20% to 100%, 50% to 95%, or 70% to 90%.

21. The nasal preparation according to claim 13, wherein the excipient comprises hydroxypropyl-β-cyclodextrin.

22. The nasal preparation according to claim 21, wherein the excipient contains hydroxypropyl-β-cyclodextrin in an amount of 1% to 50%, 10% to 40%, or 20% to 30%.

23. The nasal preparation according to claim 1, further comprising a buffer solution.

24. The nasal preparation according to claim 23, wherein the buffer solution comprises citric acid, glycine, citrate, or acetate.

25. The nasal preparation according to claim 1, wherein the compound is N-(4,6-bis-n-propylamino-[1,3,5]triazine-2-yl)-O,N-dimethylhydroxylamine or a pharmaceutically acceptable salt thereof.

26. The nasal preparation according to claim 1, wherein the compound is the bis(4,6-bis-n-propylamino-[1,3,5]triazine-2-yl)-O,N-dimethylhydroxylamine bisulfate.

27. ​​A nasal preparation according to any one of claims 1 to 26 for providing respiratory stimulation.

28. A nasal preparation according to any one of claims 1 to 26 for treating respiratory depression.

29. The nasal preparation according to claim 28, wherein the respiratory depression is caused by an opioid agent.

30. The nasal preparation according to claim 28, wherein the respiratory depression is caused by a non-opioid agent.

31. The nasal preparation according to claim 28, wherein the respiratory depression is caused by inflammation.

32. The nasal preparation according to claim 28, wherein the respiratory depression is caused by infection.

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