Respiratory stimulator nasal formulations

Abstract

Disclosed in certain embodiments is a nasal formulation comprising a compound of formula (I) as disclosed herein and a pharmaceutically acceptable excipient.

Description

Technical Field

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

[0002] The human body relies heavily on a ventilatory control system to adequately take in oxygen and remove carbon dioxide (CO2). Many active agents, such as opioid analgesics, act on μ-opioid receptors expressed on respiratory neurons in the brainstem and can cause respiratory depression in certain situations, such as overdose.

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

[0004] Respiratory depression may also result from nonpharmacological causes such as inflammation or infection.

[0005] There is a need in the art for methods and formulations for treating respiratory depression regardless of cause. Summary of the invention

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

[0007] In certain embodiments, the present disclosure relates to a nasal formulation comprising about 0.01% w / w to about 10% w / w of a compound of formula (I) and a pharmaceutically acceptable excipient.

[0008] In certain embodiments, the present disclosure relates to a nasal formulation comprising a compound of formula (I) as disclosed herein and a pharmaceutically acceptable excipient, wherein the formulation retains at least 90% of the compound after 2 weeks under accelerated storage conditions of 60% relative humidity and 25°C.

[0009] In certain embodiments, the present invention relates to nasal compositions and methods for: (1) treating a patient who has had an accidental or other drug overdose; (2) treating a patient who has had an accidental or other opioid overdose; (3) treating a patient who has had an accidental or other opioid withdrawal syndrome; or (4) prophylactically treating an accidental or other opioid withdrawal syndrome in a patient who has had an accidental or other opioid withdrawal syndrome.

[0010] In certain embodiments, the nasal formulation can be contained in a nasal delivery device, such as a dosing 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 nasal continuous positive pressure device, or a breath-actuated bidirectional delivery device.

[0011] definition

[0012] Unless the context clearly dictates otherwise, as used herein, the singular forms "a", "an", and "the" include plural referents. Thus, for example, reference to "an active agent" includes a single active agent as well as a mixture of two or more different active agents, and reference to "an excipient" includes a single excipient as well as a mixture of two or more different excipients, etc.

[0013] As used herein, the term "about" in relation to a measured amount refers to the normal variation of that measured amount as would be expected by one of ordinary skill in the art when making the measurements and exercising a level of care commensurate with the purpose of the measurement and the precision of the measuring equipment. In certain embodiments, the term "about" includes ±10% of the recited number, such that "about 10" would include 9 to 11.

[0014] As used herein, the terms "active agent," "active ingredient," and "active pharmaceutical ingredient" refer to any substance intended to produce a therapeutic, prophylactic, or other desired effect, whether or not approved for that purpose by a governmental agency. These terms with respect to a particular agent include all pharmaceutically active agents, all pharmaceutically acceptable salts, complexes, stereoisomers, crystalline forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof, wherein the form is pharmaceutically active.

[0015] As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. The stereoisomers include enantiomers and isomers of compounds with one or more chiral centers that are not mirror images of each other (diastereomers).

[0016] The term "enantiomer" or "enantiomerically" refers to a non-superimposable and therefore optically active molecule on its mirror image wherein the enantiomer rotates the plane of polarized light by a certain angle in one direction and its mirror image rotates the plane of polarized light by the same angle but in the opposite direction.

[0017] The term "chiral center" refers to an atom (eg, a carbon atom) to which four different groups are attached.

[0018] The term "patient" refers to a subject, animal or human who has shown clinical manifestations suggesting a need for treatment of one or more specific symptoms, has been treated prophylactically or preventively for a condition, or has been diagnosed with a condition to be treated. The term "subject" includes the definition of the term "patient" and does not exclude otherwise healthy individuals.

[0019] "Pharmaceutically acceptable salts" or "salts" include, but are not limited to, inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, bisulfates, phosphates, nitric acids, carbonates, sulfuric acids, phosphoric acids (including hydrogen phosphates and dihydrogen phosphates), and the like; organic acid salts such as oxalates, malonates, citrates, fumarates, lactates, malates, succinates, formates, acetates, trifluoroacetates, maleates, tartrates, gluconates, benzoates, salicylates, xinafoates, pamoates, ascorbates, adipates, Cinnamate, etc.; sulfonate, such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; amino acid salt, such as arginine salt, asparagine salt, glutamate, etc.; metal salt, such as zinc salt, sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal, such as calcium salt, magnesium salt, etc.; and organic amine salt, such as triethylamine salt, pyridine salt, methylpyridine 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 hydrates, solvates or crystalline polymorphs. In certain embodiments, suitable organic acid can be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic acid and sulfonic acid 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, pamoic acid (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 the corresponding compounds of the present invention by conventional methods, for example by reacting a suitable acid or base with a compound of the present invention. Handbook of Pharmaceutical Salts: Properties, and Use (edited by PHStahl & CG Wermuth, Verlag Helvetica Chimica Acta, 2002) [1].

[0020] The terms "disease," "diseases," or "condition" or "conditions" refer to those medical conditions that can be treated or prevented by administering to a subject an effective amount of an active agent.

[0021] The term "treatment of / treating" includes reducing the severity of a disorder or stopping the disorder, or reducing the severity of a symptom of a disorder or stopping the symptom. In certain embodiments, the term "treatment" with respect to a disorder means administration for the purpose of providing a pharmacodynamic effect, regardless of the outcome. In certain embodiments, "treatment" means "having a positive effect on the disorder," and encompasses a reduction in the severity, improvement, and / or alleviation of at least one symptom of the disorder; a reduction, improvement, and / or alleviation of the severity of the disorder; delaying, preventing, or inhibiting the progression of the disorder; or a perceived improvement or benefit from treatment. Treatment as used herein does not require a complete cure of the disorder. In certain embodiments, the compositions of the present disclosure can improve the patient's quality of life, or delay, prevent, inhibit the onset of one or more symptoms of the disorder, or provide a perceived benefit.

[0022] The terms "prevention of" or "preventing" include avoiding the onset of a condition.

[0023] The term "therapeutically effective amount" is intended to include an amount of an active agent, or an amount of a combination of active agents, for example, to treat or prevent a disorder in a subject, or to treat a symptom of a disorder.

[0024] The term "effective amount" is intended to include an amount of a component or combination of components used to achieve a certain result or property, for example, an effective amount of a pH adjuster to achieve pH 6.0 is intended to include the amount of one or more pH adjusters used to achieve pH 6.0.

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

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

[0027] As used herein, unless otherwise indicated, the term "cycloalkyl" by itself or as part of another substituent means a cyclic hydrocarbon with a specified number of carbon atoms (i.e., C3-C6 refers to a cyclic group containing a cyclic group consisting of three to six carbon atoms), and includes straight chain, branched or cyclic substituents. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Most preferably (C3-C6) cycloalkyl, such as but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0028] As used herein, unless otherwise indicated, the term "alkenyl" used alone or in combination with other terms refers to a stable monounsaturated or diunsaturated straight or branched hydrocarbon radical having a 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. The functional group representing an alkene is exemplified by -CH2-CH═CH2.

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

[0030] As used herein, the term "substituted alkyl", "substituted cycloalkyl", "substituted alkenyl" or "substituted alkynyl" means an alkyl, cycloalkyl, alkenyl or alkynyl group as defined above, which is substituted with one, two or three substituents selected from the group consisting of halogen, -OH, alkoxy, tetrahydro-2-H-pyranyl, -NH2, -N(CH3)2, (1-methyl-imidazol-2-yl), pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, -C(═O)OH, trifluoromethyl, -C≡N, -C(═O)O(C1-C4)alkyl, -C(═O)NH2, -C(═O)NH(C1-C4)alkyl, -C(═O)N((C1-C4)alkyl)2, -SO2NH2, -C(═NH)NH2 and -NO2, preferably containing one or two substituents selected from halogen, -OH, alkoxy, -NH2, trifluoromethyl, -N(CH3)2 and -C(═O)OH, more preferably selected from halogen, alkoxy and -OH. Examples of substituted alkyl include, but are not limited to, 2,2-difluoropropyl, 2-carboxycyclopentyl and 3-chloropropyl.

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

[0032] As used herein, unless otherwise stated, the term "halo" or "halogen" by itself or as part of another substituent refers to a fluorine, chlorine, bromine or iodine atom, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0033] As used herein, unless otherwise specified, the term "heteroalkyl" by itself or in combination with another term refers to a stable straight or branched alkyl consisting of a specified number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heteroatom may be located at any position of the heteroalkyl, including between the rest of the heteroalkyl and the fragment to which it is attached, and attached to the farthest carbon atom in the heteroalkyl. 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 -CH2-NH-OCH3 or -CH2-CH2-S-S-CH3.

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

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

[0036] As used herein, unless otherwise indicated, the term "aryl", used alone or in combination with other terms, refers to a carbocyclic aromatic system containing one or more rings (usually one, two or three rings), wherein such rings may be attached together in a pendant manner, such as biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracenyl and naphthyl. Phenyl and naphthyl are preferred, and phenyl is most preferred.

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

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

[0039] As used herein, the term "heteroaryl" or "heteroaromatic" refers to a heterocycle with aromatic character. Polycyclic heteroaryl groups may include one or more partially saturated rings. Examples include tetrahydroquinoline and 2,3-dihydrobenzofuranyl.

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

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

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

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

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

[0045] For aryl, aryl-(C1-C3)alkyl and heterocyclyl, 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. Substituents are independently selected, and substitution may be at any chemically accessible position. In one embodiment, the number of substituents varies between one and four. In another embodiment, the number of substituents varies between one and three. In another embodiment, the number of substituents varies between one and two. In another embodiment, substituents are independently selected from the group consisting of: C 1-6 Alkyl, -OH, C 1-6 Alkoxy, halo, amino, acetamido and nitro. As used herein, when the substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic, preferably straight.

[0046] Unless otherwise specified herein, the enumeration of value ranges herein is intended only to be used as a shorthand method for individually representing each individual value belonging to the range, and each individual value is incorporated into the specification as if it were individually described herein. Unless otherwise specified herein or clearly contradictory to the context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to illustrate certain materials and methods and is not intended to limit the scope. The language in the specification should not be considered to indicate that any unclaimed element is necessary for implementing the disclosed materials and methods. DETAILED DESCRIPTION

[0047] In certain embodiments, the present invention is directed to a nasal formulation comprising about 0.01% w / w to about 10% w / w of a compound of formula (I) and a pharmaceutically acceptable excipient.

[0048] In certain embodiments, the pharmaceutically 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 a liquid.

[0051] In certain embodiments, the pharmaceutically 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 on each particle.

[0054] In certain embodiments, the pharmaceutically acceptable excipient is a cream, ointment, or gel.

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

[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 a combination thereof.

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

[0062] In certain embodiments, the excipient comprises ethanol in an amount from about 1% to about 30%, from about 5% to about 25%, or from about 10% to about 20%.

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

[0064] In certain embodiments, the excipient comprises propylene glycol in an amount from about 20% to about 100%, from about 50% to about 95%, or from about 70% to about 90%.

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

[0066] In certain embodiments, the excipient comprises polyethylene glycol in an amount from about 20% to about 100%, from about 50% to about 95%, or from about 70% to about 90%.

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

[0068] In certain embodiments, the excipient comprises hydroxypropyl-β-cyclodextrin in an amount from about 1% to about 50%, from about 10% to about 40%, or from about 20% to about 30%.

[0069] In certain embodiments, nasal formulations comprise a buffered 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 relates to a method of providing respiratory stimulation comprising intranasally administering a nasal formulation as disclosed herein.

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

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

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

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

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

[0079] Certain embodiments of the present disclosure relate to a nasal formulation comprising a compound of formula (I) and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is selected from:

[0080]

[0081] in:

[0082] R 1 and R 2 R is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 Combined to form a dibasic group 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;

[0083] R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 ,—C(O)OR1 , acyl or aryl;

[0084] R 4 is H, alkyl or substituted alkyl;

[0085] 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 Combined to form a dibasic group selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0086] R 6 is H, alkyl, substituted alkyl or alkenyl;

[0087] X is a bond, O or NR 4 ;and,

[0088] Y is N, CR 6 or C; where:

[0089] If Y is N or CR 6 , then key b 1 is empty, and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is empty, bond b 2 is empty, and A is a single bond; and,

[0090] If Y is C, then key b 1 is a single bond, and: (i) Z is CH2, bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof.

[0091] Certain embodiments of the present disclosure relate to a nasal formulation comprising a compound of formula (I) and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is selected from:

[0092]

[0093] in:

[0094] R 1 and R 2R is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 Combined to form a dibasic group 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;

[0095] 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;

[0096] R 4 is H, alkyl or substituted alkyl;

[0097] 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 Combined to form a dibasic group selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; wherein selected from R 1 , R 2 , R 3 and R 5 At least one substituent of the group consisting of is an alkynyl group or a substituted alkynyl group;

[0098] R 6 is H, alkyl, substituted alkyl or alkenyl;

[0099] X is a bond, O or NR 4 ;and,

[0100] Y is N, CR 6 or C; where:

[0101] If Y is N or CR 6 , then key b1 is empty, and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is empty, bond b 2 is empty, and A is a single bond; and,

[0102] If Y is C, then key b 1 is a single bond, and: (i) Z is CH2, bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof.

[0103] Certain embodiments of the present disclosure relate to a nasal formulation comprising a compound of formula (I) and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is selected from:

[0104]

[0105] in:

[0106] R 1 and R 2 R 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 2 Combined to form a dibasic group 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;

[0107] R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, -NR 1 R 2 ,—C(O)OR 1 , acyl or aryl;

[0108] R 4 is H, alkyl or substituted alkyl;

[0109] 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 R3 and R 5 Combined to form a dibasic group selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl;

[0110] R 6 is H, alkyl, substituted alkyl or alkenyl;

[0111] X is a bond, O or NR 4 ;and,

[0112] Y is N, CR 6 or C; where:

[0113] If Y is N or CR 6 , then key b 1 is empty, and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is empty, bond b 2 is empty, and A is a single bond; and,

[0114] If Y is C, then key b 1 is a single bond, and: (i) Z is CH2, bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof.

[0115] In one embodiment, R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl or substituted alkenyl. In another embodiment, R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl or acyl.

[0116] Certain embodiments of the present disclosure relate to a nasal formulation comprising a compound of formula (I) and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is selected from:

[0117]

[0118] R 1 and R 2 R 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 2Combined to form a dibasic group 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;

[0119] R 3 is H, alkyl, substituted alkyl, alkynyl or substituted alkynyl;

[0120] R 4 is H, alkyl or substituted alkyl;

[0121] R 5 is alkyl, propargyl, substituted propargyl, homopropargyl or substituted homopropargyl, wherein R 1 , R 2 , R 3 and R 5 At least one substituent of the group consisting of is an alkynyl group or a substituted alkynyl group;

[0122] R 6 is H, alkyl, substituted alkyl or alkenyl;

[0123] X is a bond, O or NR 4 ;and,

[0124] Y is N, CR 6 or C; where:

[0125] If Y is N or CR 6 , then key b 1 is empty, and:

[0126] (i) Z is H, bond b 2 is a single bond, and A is CH; or,

[0127] (ii) Z is empty, key b 2 is empty, and A is a single bond; and,

[0128] If Y is C, then key b 1 is a single bond, and:

[0129] (i) Z is CH2, bond b 2 is a single bond, and A is CH; or,

[0130] (ii) Z is CH, bond b 2 is a double bond, and A is C;

[0131] or a salt thereof.

[0132] In certain embodiments, (i) R 3 is H, alkyl or substituted alkyl, and R 5is propargyl, substituted propargyl, homopropargyl or substituted homopropargyl, or (ii) R 3 is H or alkynyl, and R 5 is alkyl, propargyl, substituted propargyl, homopropargyl or substituted homopropargyl.

[0133] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is N, bond b1 is empty, Z is H, bond b2 is a single bond, A is CH, and at least one compound is a compound of formula (II-a) or a salt thereof:

[0134]

[0135] and

[0136] (ii) Y is N, bond b1 is empty, Z is empty, bond b2 is empty and A is a bond, and the compound of the present invention is a compound of formula (II-b) or a salt thereof:

[0137]

[0138] In one embodiment, at least one compound of formula (I) is selected from the group consisting of: (i) Y is CR 6 , key b 1 is empty, Z is H, key 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:

[0139]

[0140] and

[0141] (ii) Y is CR 6 , key b 1 is empty, Z is empty, key b 2 is empty and A is a bond, and the compound of the present invention is a pyrimidine or a salt thereof of formula (III-b):

[0142]

[0143] In one embodiment, Y is C, bond b 1 is a single bond, Z is CH2, bond b 2 is a single bond, A is CH, and the at least one compound is a compound of formula (IV) or a salt thereof:

[0144]

[0145] In one embodiment, Y is C, bond b 1 is a single bond, Z is CH, bond b 2is a double bond, A is C, and the at least one compound is a compound of formula (V) or a salt thereof:

[0146]

[0147] In one embodiment, 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]triazine-2-yl)-N,O-dimethyl-hydroxylamine (XXIX), N-(bis-4,6-(2,2-dimethylpropylamino)) [1,3,5]triazine-2-yl)-O,N-dimethyl-hydroxylamine (XXXI), 4,6-bis-N-cyclopropylamino-[1,3,5]triazine-2-yl)-N,O-dimethyl-hydroxylamine hydrochloride (XXXIII), N-(4,6-bis-n-propylamino-[1,3,5]triazine-2-yl)-O,N-dimethyl-hydroxylamine (XXXV), N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazine-2-yl)propionamide (X L), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-methyl-hydroxylamine (XLI), O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-hydroxylamine (XLIII), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-hydroxylamine (XLV), 6-(methoxy(methyl)amino)-N2-propyl-1,3,5-triazine-2,4-diamine (XLVII), N-(4 ,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-methyl-hydroxylamine (XLVIII), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-methyl-hydroxylamine (LIII), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-isopropyl-hydroxylamine (LV), 6-[1,2]oxazinane-2-yl-N,N′-dipropyl-[1,3,5]triazine-2,4-diamine (LVI I), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXIV), O-benzyl-N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-ethyl-hydroxylamine (LXVIII), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-isopropyl-hydroxylamine (LXX), 6-((benzyloxy)(isopropyl)amino)-N2,N4-dipropyl-1,3,5-triazine-2,4-diamine (LXXII), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-N-ethyl-O-isopropyl-hydroxylamine (LXXVI), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-isopropyl-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]triazine-2-yl)-O-cyclopropylmethyl-N-methyl-hydroxylamine (XCI), N-(4,6-bis-propylamino-[1,3,5]triazine-2-yl)-O-isopropyl-N-methyl-hydroxylamine (LXXXII), -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-methylimidazole-2-yl)-propyl)-amino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIII), -2-yl)-methylamino-6-N-(n-propyl)amino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine (CVII), 4,6-bis-(N-(2-dimethylaminoethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CIX), 4,6-bis-(N-(pyridin-4-ylmethyl)amino)-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXI), 4,6-bis-[N-(3-methoxy-n-propyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXIII), 4,6-bis-[N-(tetrahydropyran -4-ylmethyl)amino]-[1,3,5]triazin-2-yl)-N,O-dimethyl-hydroxylamine (CXV), N-(5,8,11-trioxa-2,14,16,18,19-pentaazabicyclo[13.3.1]-nineteen-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 salt or a hydrochloride salt. ,

[0148] In one embodiment, at least one compound is 2,6-bis-(N-n-propylamino)-[1,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propanamide or a salt thereof. In another embodiment, the salt is a hydrogen sulfate salt or a hydrochloride salt.

[0149] In one embodiment, at least one compound is N-(4-(methoxy(methyl)amino)-6-(propylamino)-1,3,5-triazin-2-yl)propanamide or a salt thereof. In another embodiment, the salt is a hydrogen sulfate salt or a hydrochloride salt.

[0150] In one embodiment, at least one compound is selected from the group consisting of 2-(n-propyl)amino-4-(isopropylamino-7-methyl-pyrrolidinone[2,3-d]pyrimidine (CXXVI), 2-(n-propyl)amino-4-dimethylamino-7-methyl-pyrrolidinone[2,3-d]pyrimidine (CXXVIII), 2-(n-propyl)amino-4-methylamino-7-methyl-pyrrolidinone[2,3-d]pyrimidine (CXXXI), 2-(n-propyl)amino-4-(isopropyl)amino-7-isopropyl-pyrrolidinone[2,3-d]pyrimidine (CXXVIII), 3-d]pyrimidine (CXXXVI), 2,4-bis-(n-propyl)amino-7H-pyrrolidin-[2,3-d]pyrimidine (CXLIX), 2-(n-propyl)amino-4-(4-hydroxypiperidin-1-yl)-7-methyl-pyrrolidin-[2,3-d]pyrimidine (CLII), 8-(7-methyl-2-(propylamino)-pyrrolidin-[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.

[0151] In one embodiment, at least one compound is selected from the group consisting of: N-(2-propylamino-7H-pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2-(propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,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 (CLXII), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-O-methyl-hydroxylamine (CLXIV), N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXVI), N-methyl-N-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXVIII), N,N-dimethyl-N′-(2-n-propylamino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-hydrazine (CLXX), salts thereof, and mixtures thereof. In another embodiment, the salt is a hydrogen sulfate salt or a hydrochloride salt.

[0152] 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]triazine-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.

[0153] In certain embodiments, the following compound A used in the present invention is

[0154]

[0155] or a pharmaceutically acceptable salt thereof.

[0156] 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 now abandoned U.S. Patent Application Publication No. 2015-0291597, the teachings of which are incorporated herein by reference in their entireties.

[0157] In certain embodiments, the formulation retains at least 90% of the compound after one month under accelerated storage conditions of 60% relative humidity and 25°C.

[0158] In certain embodiments, the formulation retains at least 90% of the compound after 2 months under accelerated storage conditions of 60% relative humidity and 25°C.

[0159] In certain embodiments, the formulation retains at least 90% of the compound after 3 months under accelerated storage conditions of 60% relative humidity and 25°C.

[0160] In certain embodiments, the formulation retains at least 95% of the compound after 2 weeks under accelerated storage conditions of 60% relative humidity and 25°C.

[0161] In certain embodiments, the formulation retains at least 95% of the compound after one month under accelerated storage conditions of 60% relative humidity and 25°C.

[0162] In certain embodiments, the formulation retains at least 90% of the compound after 2 months under accelerated storage conditions of 60% relative humidity and 25°C.

[0163] In certain embodiments, the formulation retains at least 90% of the compound after 3 months under accelerated storage conditions of 60% relative humidity and 25°C.

[0164] In certain embodiments, the formulation retains at least 90% of the compound after 2 weeks under accelerated storage conditions of 75% relative humidity and 40°C.

[0165] In certain embodiments, the formulation retains at least 90% of the compound after one month under accelerated storage conditions of 75% relative humidity and 40°C.

[0166] In certain embodiments, the formulation retains at least 90% of the compound after 2 months under accelerated storage conditions of 75% relative humidity and 40°C.

[0167] In certain embodiments, the formulation retains at least 90% of the compound after 3 months under accelerated storage conditions of 75% relative humidity and 40°C.

[0168] In certain embodiments, the formulation retains at least 95% of the compound after 2 weeks under accelerated storage conditions of 75% relative humidity and 40°C.

[0169] In certain embodiments, the formulation retains at least 95% of the compound after one month under accelerated storage conditions of 75% relative humidity and 40°C.

[0170] In certain embodiments, the formulation retains at least 90% of the compound after 2 months under accelerated storage conditions of 75% relative humidity and 40°C.

[0171] In certain embodiments, the formulation retains at least 90% of the compound after 3 months under accelerated storage conditions of 75% relative humidity and 40°C.

[0172] In certain embodiments, the pH of the formulation is from about 2.5 to about 5.5.

[0173] In certain embodiments, the pH of the formulation is from about 3.5 to about 5.5

[0174] In certain embodiments, the pH is from about 4 to about 5.

[0175] In certain embodiments, the pH is selected from about 4.0, about 4.5, or about 5.0.

[0176] In certain embodiments, the concentration of the compound is from about 1 mg / mL to about 50 mg / mL.

[0177] In certain embodiments, the concentration of the compound is from about 10 mg / mL to about 30 mg / mL.

[0178] In certain embodiments, the concentration of the compound is from about 15 mg / mL to about 25 mg / mL.

[0179] In certain embodiments, the concentration of the compound is selected from about 15 mg / mL, about 20 mg / mL, or about 25 mg / mL.

[0180] In certain embodiments, the excipient is selected from ethanol, polyalkylene glycol, alkylene glycol, cyclodextrin, saline, Ringer's solution, glucose or a combination thereof. In certain embodiments, the excipient is a polyethylene glycol-hydroxystearate obtained, for example, by reacting 15 moles of ethylene glycol with 1 mole of 12-hydroxystearic acid. This can be commercially available from BASF as Kolliphor® HS15.

[0181] In certain embodiments, the excipient comprises ethanol.

[0182] In certain embodiments, the excipient comprises ethanol in an amount from about 1% to about 30%, from about 5% to about 25%, or from about 10% to about 20%.

[0183] In certain embodiments, the excipient comprises propylene glycol.

[0184] In certain embodiments, the excipient comprises propylene glycol in an amount from about 20% to about 100%, from about 50% to about 95%, or from about 70% to about 90%.

[0185] In certain embodiments, the excipient comprises polyethylene glycol.

[0186] In certain embodiments, the excipient comprises polyethylene glycol in an amount from about 20% to about 100%, from about 50% to about 95%, or from about 70% to about 90%.

[0187] In certain embodiments, the excipient comprises hydroxypropyl-β-cyclodextrin.

[0188] In certain embodiments, the excipient comprises hydroxypropyl-β-cyclodextrin in an amount from about 1% to about 50%, from about 10% to about 40%, or from about 20% to about 30%.

[0189] In certain embodiments, the present invention relates to a method of providing respiratory stimulation comprising intranasally administering a nasal formulation as disclosed herein.

[0190] Composition

[0191] In certain embodiments, the nasal pharmaceutical composition is premixed (eg, the active agent is premixed with one or more pharmaceutically acceptable excipients and optionally one or more additional active agents).

[0192] In certain embodiments, the pharmaceutical composition may be contained within a glass container or device, or within a plastic container or device suitable for intranasal delivery.

[0193] In certain embodiments, pharmaceutically acceptable excipients for nasal administration include pharmaceutically acceptable carriers, such as liquid or solid fillers, stabilizers, dispersants, suspending agents, diluents, thickeners, 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 compounds useful in the present invention) and not harmful to the subject. Some examples of materials that can be used as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; surfactants; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered solutions; and other nontoxic compatible substances used in pharmaceutical formulations. As used herein, "pharmaceutically acceptable carrier" also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, etc., that are compatible with the activity of the compounds useful in the present invention and physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the composition. "Pharmaceutically acceptable carrier" may also include pharmaceutically acceptable salts of the compounds useful in the present invention. Other additional ingredients that may be included in the pharmaceutical compositions for practicing 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.

[0194] Useful pharmaceutically acceptable carriers include, but are not limited to, glycerol, water, saline, ethanol, and other pharmaceutically acceptable salt solutions, such as phosphates and organic acid salts. Examples of these and other pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey).

[0195] The carrier can be a solvent or dispersion medium, including, for example, water, ethanol, polyols (such as glycerol, propylene glycol and liquid polyethylene glycol, etc.), suitable mixtures thereof and vegetable oils. Suitable fluidity can be maintained by, for example, using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion and by using a surfactant. The effect of preventing microorganisms can be achieved by various antibacterial and antifungal agents (for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, it is preferred to include isotonic agents in the composition, such as sugar, sodium chloride or polyols such as mannitol and sorbitol. The extended absorption of nasal compositions can be achieved by including a medicament (for example, aluminum monostearate or gelatin) that delays absorption in the composition.

[0196] The pharmaceutical preparations may be sterilized and, if necessary, may be mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorants and the like.

[0197] Examples of preservatives useful in accordance with 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.

[0198] Said composition preferably comprises antioxidant and chelating agent that inhibits compound degradation.Preferred antioxidant of some compounds is butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), alpha-tocopherol and ascorbic acid in the preferred range of about 0.01 wt % to 0.3 wt % by the total weight of composition, and more preferably BHT in the range of 0.03 wt % to 0.1 wt %.Preferably, chelating agent is present in the amount of 0.01 wt % to 0.5 wt % by the total weight of composition.Particularly preferred chelating agent includes edetate (for example, disodium edetate) and citric acid, and its weight range is about 0.01 wt % to 0.20 wt % by the total weight of composition, and more preferably range is 0.02 wt % to 0.10 wt %.Chelating agent can be used for metal ions in chelating composition, which may be harmful to the shelf life of preparation. Although BHT and disodium edetate are particularly preferred antioxidants and chelating agents, respectively, for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted as known to those skilled in the art.

[0199] Liquid suspensions can be prepared to realize the suspension of active ingredients in aqueous or oily vehicles. Aqueous vehicles include, for example, water and isotonic saline. Oily excipients include, for example, almond oil, oily esters, ethanol, vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, fractionated vegetable oils and mineral oils such as liquid paraffin. Liquid suspensions may also include one or more additional ingredients, including but not limited to suspending agents, dispersants or wetting agents, emulsifiers, mitigating agents, preservatives, buffers, salts, flavoring agents, coloring agents and sweeteners. Oily suspensions may also include thickeners. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinyl pyrrolidone, tragacanth gum, gum arabic and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose. Known dispersants or wetting agents include but are not limited to naturally occurring phosphatides, such as lecithin, alkylene oxide and fatty acid, long-chain fatty alcohol, the condensation product of the partial ester derived from fatty acid and hexitol or the partial ester derived from fatty acid and hexitol anhydride (for example, respectively polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate and polyoxyethylene sorbitan monooleate). Known emulsifiers include but are not limited to lecithin and gum arabic. Known preservatives include but are not limited to methyl parahydroxybenzoate, ethyl parahydroxybenzoate or n-propyl parahydroxybenzoate, ascorbic acid and sorbic acid. Known sweeteners include, for example, glycerol, propylene glycol, sorbitol, sucrose and saccharin. Known thickeners for oily suspensions include, for example, beeswax, hard paraffin and cetyl alcohol.

[0200] The liquid solution of active ingredient in aqueous or oily solvent can be prepared in the same manner as liquid suspension, and the main difference is that the active ingredient is dissolved in the solvent, rather than being suspended in the solvent. As used herein, "oiliness" liquid is a liquid comprising carbon-containing liquid molecules and showing a polarity characteristic lower than water. The liquid solution of the pharmaceutical composition of the present invention can include each component described about the liquid suspension, and it should be understood that suspending agents do not necessarily contribute to the dissolution of active ingredient in the solvent. Aqueous solvents include, for example, water and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethanol, vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, fractionated vegetable oils and mineral oils such as liquid paraffin.

[0201] Powdered or granular formulations for nasal delivery can also be prepared. These formulations may also contain additional excipients, such as fillers and colorants.

[0202] Nasal pharmaceutical compositions of the present invention can also be prepared, packaged or sold in the form of oil-in-water emulsions or water-in-oil emulsions. The oil phase can be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin or a combination of these. Such compositions can also include one or more emulsifiers, such as naturally occurring gums such as gum arabic or tragacanth, naturally occurring phospholipids such as soybean lecithin or lecithin phospholipids, esters or partial esters such as sorbitan monooleate derived from a combination of a fatty acid and a hexitol anhydride, and condensation products of this partial ester and ethylene oxide such as polyoxyethylene sorbitan monooleate.

[0203] In certain embodiments, the one or more additional excipients include a pH adjuster, which can be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, or mixtures thereof.

[0204] In certain embodiments, the composition may include one or more additional excipients, such as, but not limited to, carbohydrates, antioxidants, chelating agents, low molecular weight proteins, high molecular weight polymers, gelling agents, stabilizers, additives, wetting agents, emulsifiers, surfactants and / or dispersants, alkalizing agents, colorants, synthetic molds, fillers, diluents, mineral oxides, preservatives, or mixtures thereof.

[0205] In certain embodiments, the composition further comprises an antioxidant. In certain embodiments, the antioxidant may include trivalent phosphorus, such as, for example, phosphites, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones. Hindered phenols, thiosynergists and / or hindered amines are useful for the long-term stability of the polymer, while the following antioxidants are also suitable when the active substance is susceptible to oxidation: acids (ascorbic acid, isoascorbic acid, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguaiaretic acid, propionic acid, etc.), phenols (e.g. BHA, BHT, tert-butylhydroquinone, dodecyl gallate, octyl gallate, 1,3,5-trihydroxybenzene), organic and inorganic salts (calcium ascorbate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, sodium sulfite, potassium bisulfite, potassium metabisulfite), esters (calcium ascorbate, dilauryl thiodipropionate, dimyristyl thiodipropionate, distearyl thiodipropionate), pyranone (maltol) and vitamin E (Tocopherol, D-α-tocopherol, DL-α-tocopherol, tocopherol acetate, d-α-tocopherol acetate, dl-α-tocopherol acetate) However, other antioxidants known in the art may be used according to the present invention.

[0206] In certain embodiments, suitable antioxidants may include, but are not limited to, sterically hindered phenols, arylamines, thioureas, thiocarbamates, phosphites (salts), thioether esters, and combinations of the foregoing. Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols, including, but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert-butyl-4,6-dimethylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol, 2,6-di-tert-butyl-4-isobutylphenol, 2,6-dicyclopentyl-4-methylphenol, 2-(α-methylcyclohexyl)-4,6-dimethylphenol, 2,6-di(octadecyl)-4-methylphenol, 2,4,6-tricyclohexylphenol, 2,6-di-tert-butyl-4- Methoxymethylphenol; nonylphenol with a linear or branched side chain, such as 2,6-dinonyl-4-methylphenol, 2,4-dimethyl-6-(1′-methylundecane-1′-yl)phenol, 2,4-dimethyl-6-(1′-methylheptadecan-1′-yl)phenol, 2,4-dimethyl-6-(1′-methyltridecane-1-yl)phenol and mixtures thereof; alkylmethylthiophenols, including 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 hydroquinone, including but not limited to 2,6-di-tert-butyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tert-amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-dibutyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyphenyl stearate, bis(3,5-dibutyl-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-2-methylphenol), 4,4′-thiobis(3,6-di-sec-pentylphenol), 4,4′-bis(2,6-dimethyl-4-hydroxyphenyl)-disulfide;Alkylene bisphenols, including but not limited to 2,2′-methylenebis(6-tert-butyl-4-methylphenol), 2,2′-methylenebis(6-tert-butyl-4-ethylphenol), 2,2′-methylenebis[4-methyl-6-(α-methylcyclohexyl)-phenol], 2,2′-methylenebis(4-methyl-6-cyclohexylphenol), 2,2′-methylene yellow(6-nonyl-4-methylphenol), 2,2′-methylenebis(4,6-di-tert-butylphenol), 2,2′-ethylenebis(4,6-di-tert-butylphenol), 2,2′-ethylenebis(6-tert-butyl-4-isobutylphenol), 2,2′-methylenebis[6-(α-methylbenzylphenol)- 4-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 1,1-bis-(3,5-dimethyl-2-hydroxyphenyl)butane, 2,2-bis(3,5-di-tert-butyl-4-hydroxyphenyl)propane, 2,2-bis(5-tert-butyl-4-hydroxy-2-methylphenyl)-4-n-dodecylmercaptobutane, 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2-methylphenyl)-4-n-dodecylmercaptobutane, 1,5,5-tetra-(5-tert-butyl-4-hydroxy-2 -methylphenyl)pentane; O-benzyl, N-benzyl and S-benzyl compounds, including but not limited to 3,5,3′,5′-tetra-tert-butyl-4,4′-dihydroxydibenzyl ether, octadecyl-4-hydroxy-3,5-dimethylbenzylthioacetate, tridecyl-4-hydroxy-3,5-di-tert-butylbenzylthioacetate, tris(3,5-di-tert-butyl-4-hydroxybenzyl)amine, bis(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl)dithioterephthalate, bis(3,5-di-tert-butyl-4-hydroxybenzyl) sulfide, isooctyl-3,5-di-tert-butyl-4-hydroxybenzylthioacetate;Hydroxybenzylated malonates, including but not limited to dioctadecyl-2,2-bis(3,5-di-tert-butyl-2-hydroxybenzyl) malonate, dioctadecyl-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-dibutyl-4-hydroxybenzyl) malonate; aromatic hydroxybenzyl compounds, including 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, including but not limited to 2,4-bis(octylmercapto)-6-(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyanilino)-1,3,5-triazine, 2-octylmercapto-4,6-bis(3,5-di-tert-butyl-4-hydroxyphenoxy)- 1,3,5-triazine, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenoxy)-1,2,3-triazine, 1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl) isocyanurate, 1,3,5-tris(4-tert-butyl-3-hydroxy-2,6-dimethylbenzyl) isocyanurate, 2,4,6-tris-(3,5-di-tert-butyl-4-hydroxyphenethyl)-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-di-tert-butyl-4-hydroxy-phenylpropionyl)-hexahydro-1,3,5-triazine, 1,3,5-tris(3,5-dicyclohexyl-4- Benzyl phosphonates, including but not limited to dimethyl-2,5-di-tert-butyl-4-hydroxybenzyl phosphonate, diethyl-3,5-di-tert-butyl-4-hydroxybenzyl phosphonate, dioctadecyl-3,5-di-tert-butyl-4-hydroxybenzyl phosphonate, dioctadecyl-5-tert-butyl-4-hydroxy-3-methylbenzyl phosphonate, and calcium salt of 3,5-di-tert-butyl-4-hydroxybenzyl phosphonate; acylaminophenols, including but not limited to 4-hydroxylauroylanilide, 4-hydroxystearic acid anilide, and N-(3,5-di-tert-butyl-4-hydroxyphenyl)carbamic acid octyl ester;Esters of β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid with mono- or polyhydric alcohols, for example, with methanol, ethanol, n-octanol, isooctyl alcohol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propylene glycol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thioundecanol, 3-thiopentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; β-(5-tert-butyl-4-hydroxy-3 Esters of mono- or polyhydric alcohols, for example, esters of methanol, ethanol, n-octanol, isooctyl alcohol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propylene glycol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis-(hydroxyethyl)oxamide, 3-thioundecanol, 3-thiopentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane; 3,9-bis[2-{3-(3-tert-butyl-4-hydroxy-5-methyl)-1-ol]- esters of 6-(3,5-dicyclohexyl-4-hydroxyphenyl)propionic acid with monohydric or polyhydric alcohols, for example with methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propylene glycol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxalamide, 3-thioundecanol, 3-thiopentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phosphane esters of 3,5-di-tert-butyl-4-hydroxyphenylacetic acid with mono- or polyhydric alcohols, for example with methanol, ethanol, octanol, octadecanol, 1,6-hexanediol, 1,9-nonanediol, ethylene glycol, 1,2-propylene glycol, neopentyl glycol, thiodiethylene glycol, diethylene glycol, triethylene glycol, pentaerythritol, tris(hydroxyethyl)isocyanurate, N,N′-bis(hydroxyethyl)oxamide, 3-thioundecanol, 3-thiopentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-1-phospha-2,6,7-trioxabicyclo[2.2.2]octane;Amides of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, such as N,N′-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hexamethylene diamide, N,N′-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)trimethylene diamide, N,N′-bis(3,5-di-tert-butyl-4-hydroxyphenylpropionyl)hydrazide, N,N′-bis[2-(3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyloxy)ethyl]oxalamide (Naugard® XL-1, supplied by Uniroyal), ascorbic acid (vitamin C); amino antioxidants, including but not limited to N,N′-diisopropyl-p-phenylenediamine, N,N′-di-sec-butyl-p-phenylenediamine, N,N′-bis(1,4-di- p-phenylenediamine, N,N′-bis(1-ethyl-3-methylpentyl)-p-phenylenediamine, N,N′-bis(1-methylheptyl)-p-phenylenediamine, N,N′-dicyclohexyl-p-phenylenediamine, N,N′-diphenyl-p-phenylenediamine, N,N′-bis(2-naphthyl)-p-phenylenediamine, N-isopropyl-N′-phenyl-p-phenylenediamine, N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine, N-(1-methylheptyl)-N′-phenyl-p-phenylenediamine, N-cyclohexyl-N′-phenyl-p-phenylenediamine, 4-(p-toluenesulfonyl)diphenylamine, N,N′-dimethyl-N,N′-di-sec-butyl-p-phenylenediamine, diphenylamine, N-allyl diphenylamine, 4-isopropoxy diphenylamine, N-phenyl-1-naphthylamine, N -(4-tert-octylphenyl)-1-naphthylamine, N-phenyl-2-naphthylamine; octylated diphenylamines, including but not limited to p,p′-di-tert-octyldiphenylamine, 4-n-butylaminophenol, 4-butyrylaminophenol, 4-nonanoylaminophenol, 4-dodecanoylaminophenol, 4-octadecanoylaminophenol, bis(4-methoxyphenyl)amine, 2,6-di-tert-butyl-4-dimethylaminomethylphenol, 2,4′-diaminodiphenylmethane, 4,4′-diaminodiphenylmethane, N,N,N′,N′-tetramethyl-4,4′-diaminodiphenylmethane, 1,2-bis[(2-methylphenyl)amino]ethane, 1,2-bis(phenylamino)propane, (o-tolyl)biguanide, bis[4-(1′,3′-dimethylbutyl)phenyl]amine, tert-octylated N-phenyl-1-naphthylamine, a mixture of mono- and di-alkylated tert-butyldiphenylamine / tert-octyldiphenylamine, a mixture of mono- and di-alkylated nonyldiphenylamine, a mixture of mono- and di-alkylated dodecyldiphenylamine, a mixture of mono- and di-alkylated isopropyldiphenylamine / isohexyldiphenylamine, a mixture of mono- and di-alkylated tert-butyldiphenylamine, 2,3-dihydro-3,3-dimethyl-4H-1,4-benzothiazine, phenothiazine, a mixture of mono- and di-alkylated tert-butylphenothiazine / tert-octylphenothiazine, a mixture of mono- and di-alkylated tert-octylphenothiazine, N-allylphenothiazine, N,N,N′,N′-tetraphenyl-1,4-diaminobut-2-ene; and combinations thereof. ;

[0207] In certain embodiments, suitable pharmaceutically acceptable excipients may include acrylics, cellulose derivatives, polysaccharides, monosaccharides, gums, natural or synthetic polymers (e.g., polyalkylene oxides (e.g., polymethylene oxides, polyethylene oxide, polypropylene oxide), polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylates, polycaprolactone, polymethacrylate copolymers, and mixtures thereof), liposomes, disintegrants (e.g., polyvinyl pyrrolidone, sodium starch glycolate, cross-linked sodium carboxymethylcellulose, or mixtures thereof). ), glidants, lubricants, absorption promoters, surfactants, binders, softeners, plasticizers (e.g., lecithin, hydrogenated vegetable oils, glycerides, lanolin, methyl esters, pentaerythritol esters, rice bran wax, stearic acid, sodium potassium stearate, etc.), waxes, fats, emulsifiers, fillers, antioxidants, colorants, diluents, processing aids (e.g., granulation aids), fixatives (e.g., polyols such as but not limited to sorbitol, maltitol / isomalt, mannitol, starch, etc.), pH adjusters, viscosity adjusters, solubility increasers or reducers, osmotic agents, solvents, or combinations thereof.

[0208] In certain embodiments, suitable pharmaceutically acceptable excipients can include polyvinyl pyrrolidone, natural and synthetic gums, polyvinyl alcohol, corn starch, hydrophilic and hydrophobic materials such as slow-release polymers, acrylic resins, protein-derived materials, waxes, shellac, and solid or semisolid oils such as hydrogenated castor oil and hydrogenated vegetable oils. More specifically, controlled release materials can be, for example, alkylcelluloses such as ethylcellulose, acrylic acid and methacrylic acid polymers and copolymers (e.g., acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylate, cyanoethyl methacrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymers, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymers, polyacrylamide, aminoalkyl methacrylate copolymers, poly(methacrylic anhydride), glycidyl methacrylate copolymers, and mixtures of any of the foregoing), and cellulose ethers, such as hydroxyalkyl celluloses (e.g., hydroxypropyl methylcellulose) and carboxyalkyl cellulose. Waxes include, for example, natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof (eg, beeswax, carnauba wax, stearic acid, and stearyl alcohol).

[0209] In certain embodiments, suitable pharmaceutically acceptable excipients may include gelling agents (such as, but not limited to, sugars or sugar-derived alcohols such as mannitol, sorbitol, etc.), starches and starch derivatives, cellulose derivatives (such as 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 acetates, cellulose diacetates, cellulose triacetates, cellulose acetate propionates, cellulose acetate butyrates, cellulose acetate succinates, cellulose acetate phthalates, hydroxypropylmethylcellulose phthalates, hydroxypropylmethylcellulose acetate succinates (hydroxypropylmethylcellulose acetate succinates) and mixtures thereof), attapulgite, bentonite, dextrins, alginates, alginates, salt) (such as sodium alginate and potassium alginate), casein, stearic acid, shellac, carrageenan, tragacanth, acacia, gum arabic, pullulan, dextrin, gellan gum, agar gum, tara gum, karaya gum, guar gum, welan gum, rhamsan gum, locust bean gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomers and carbopols, polyvinyl pyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactant / wetting agent systems, emulsifiers, other polymeric materials and mixtures thereof.

[0210] In certain embodiments, suitable pharmaceutically acceptable excipients may include hydrophilic excipients, such as but not limited to water, low molecular weight polyols, such as polyethylene glycol, polypropylene glycol, or combinations thereof. Examples of other suitable hydrophilic carriers include but are not limited to polyoxyethylene derivatives of sorbitan esters, such as sorbitan monolaurate (polysorbate 20), polysorbate 80, polysorbate 60, polyoxyethylene 20 sorbitan trioleate (polysorbate 85), acetic acid, formic acid, other hydrophilic surfactants, and mixtures thereof. Exemplary low molecular weight polyols include, but are not limited to, those having a number average molecular weight from any of about 200 Daltons, about 400 Daltons, about 600 Daltons, about 800 Daltons, or about 1000 Daltons to any of about 2000 Daltons, about 3000 Daltons, about 4000 Daltons, about 5000 Daltons, about 6000 Daltons, or about 7000 Da, or any subrange or individual value therein (e.g., polyethylene glycol 400, polyethylene glycol 600, etc.).

[0211] In certain embodiments, suitable pharmaceutically acceptable excipients may include plasticizers, such as, but not limited to, sugar alcohol plasticizers, such as triacetin, isomalt, maltitol, xylitol, erythritol, adonitol, galactitol, pentaerythritol, or mannitol; or polyol plasticizers, such as diglycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; and mixtures thereof. Other exemplary plasticizers may also include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester-type plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single-block polymers, citrate-type plasticizers, and triacetin. Such plasticizers may include 1,2-butanediol, 2,3-butanediol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

[0212] In certain embodiments, suitable pharmaceutically acceptable excipients may include plasticizers such as, but not limited to, phosphate esters; phthalates; amides; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils and hydrogenated vegetable oils, including acetylated hydrogenated cottonseed glycerides and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate, acetyl triethyl citrate, castor oil, diacetylated monoglycerides, dipropylene glycol salicylic acid glyceride, coconut oil glyceride, monoacetylated monoglycerides and diacetylated monoglycerides, nitrobenzene, carbon disulfide, fl-naphthyl salicylate, phthalyl glycolate (phthalyl glycolate), dioctyl phthalate; sorbitol, sorbitol tricitrate; sucrose octaacetate; α-tocopheryl polyethylene glycol succinate, phosphate esters; phthalates; amides; mineral oils; fatty acids and esters; fatty alcohols; and vegetable oils, fatty alcohols, including cetearyl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and myristyl alcohol; methyl rosinate, acetyl tributyl citrate, acetyl triethyl citrate, dioctyl adipate, amyl oleate, butyl ricinoleate, benzyl Benzyl esters, butyl and glycol esters of fatty acids, butyl diglycol carbonate, butyl oleate, butyl stearate, di(β-methoxyethyl adipate), dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, triethylene glycol di(β-ethylbutyrate), polyethylene glycol di(2-ethylhexanoate), diethylene glycol monolaurate, monomeric polyethylene glycol esters, hydrogenated rosin methyl ester, methoxyethyl oleate, butoxyethyl stearate, butyl phthalate glycolate (butyl phthalyl butyl glycolate), tributyrin, triethylene glycol dipelargonate, β-(p-tert-amylphenoxy)ethanol, β-(p-tert-butylphenoxy)ethanol, β-(p-tert-butylphenoxyethyl)acetate, bis(β-p-tert-butylphenoxydiethyl)ether, camphor, Cumar W-1, Cumar MH-1, Cumar V-1, diamyl phthalate, (diamylphenoxy)ethanol, diphenyl ether, industrial hydrogenated rosin alcohol, beckolin, benzenehexahydrochlonde, Clorafin 40, Piccolastic A-5, Piccalastic A-25, Flexol B-400, glycerol α-methyl α-phenyl ether, chlorinated naphthalene, HB-40, monoamyl phthalate. Nevillac 10 o-nitrobiphenyl and Paracril 26.

[0213] In certain embodiments, suitable pharmaceutically acceptable excipients may include plasticizers, such as, but not limited to, sugar alcohol plasticizers, such as isomalt, maltitol, sorbitol, xylitol, erythritol, adonitol, galactitol, pentaerythritol, or mannitol; or polyol plasticizers, such as glycerol, diglycerol, ethylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1,3-propanediol, 2-methyl-1,3-propanediol, trimethylolpropane, polyether polyols, ethanolamine; and mixtures thereof. Other exemplary plasticizers may include, but are not limited to, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols with aliphatic hydroxyl groups, ester plasticizers, glycol ethers, poly(propylene glycol), multi-block polymers, single-block polymers, citrate plasticizers, and triacetin. Such plasticizers may include 1,2-butanediol, 2,3-butanediol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitan lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyl tributyl citrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.

[0214] In certain embodiments, suitable pharmaceutically acceptable excipients can include aromatics, such as but not limited to natural and / or synthetic aromatic raw materials. For example, oil-soluble flavor oils, which may or may not be mixed with water-soluble flavor oils. Oil-soluble flavor materials are natural or natural identical essential oils, such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, clove leaves, peppermint oil, cedar oil, rosemary oil, bergamot oil, lavender oil, patchouli oil, chamomile oil, jasmine oil, tassel oil, rose oil, vetiver oil, fennel oil, anise oil, thyme oil, germanium oil, menthol and marjoram oil. Animal aromatics are, for example, musk, castoreum, aber or civet (zibet). Refined essences (Spagyric essences) are also known in the art. They are prepared by fermenting some herbs and then processing them into final products. Synthetic fragrance ingredients are, for example, synthetic essential oils, such as synthetic essential oils consisting of a single compound, such as linalool, terpineol, nerol, citronellal, benzaldehyde, cinnamaldehyde, vanillin, ethyl vanillin or methyl acetophenone. Fragrance substances can also be synthetic oil-soluble fragrance oils selected from the common group consisting of aromatic hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, and polyene derivatives. Other fragrances that can be used are catalogued and described in references and databases such as S. Arctander, Perfume and Flavor Chemicals, Vol. I and Vol. II (1960, 1969; Reprinted in 2000); Allured's Flavor and Fragrance Materials (2005); and the database maintained by the Research Institute for Fragrance Materials of the United States. www.rifm.org .

[0215] In certain embodiments, suitable pharmaceutically acceptable excipients can include perfume oils. Suitable perfume oils include mixtures of natural and synthetic aromatics. Natural aromatics are extracted from: flowers (lily, lavender, rose, jasmine, orange blossom, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (fennel, coriander, fennel, juniper), peels (bergamot, lemon, orange), roots (nutmeg, angelica, celery, cardamom, wood fragrance, iris, calamus), wood (pine, sandalwood, guaiac wood, cedar, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh (myrrh), frankincense, opoponax (opoponax)). Typical synthetic aromatic compounds are products of ester, ether, aldehyde, ketone, alcohol and hydrocarbon types. Ester fragrance compounds are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert-butylcyclohexyl acetate, linalyl acetate, dimethylbenzyl methanol acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethyl-methylphenylglycinate, allyl cyclohexylpropionate, styroyl propionate, and benzyl salicylate. Ethers include, for example, benzyl ethyl ether, aldehydes include, for example, straight-chain alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellal oxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilyral, and borgeron aldehyde, and ketones include, for example, ionone, α-isomethylionone, and methyl cedryl ketone, alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol, and terpineol, and hydrocarbons mainly include terpenes and balsams.

[0216] In certain embodiments, suitable pharmaceutically acceptable excipients may include essential oils with relatively low volatility, which are mainly used as aromatic components and are also suitable for use as spice oils, such as sage oil, chamomile oil, clove oil, melissa oil, peppermint oil, cinnamon leaf oil, linden flower oil, juniper berry oil, vetiver oil, frankincense oil, galbanum oil, labolanum oil and lavender oil. Other suitable oils include bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, alpha-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, boisambrene forte, ambroxan, indole, hedione, sandelice, lemon oil, tangerine oil, orange oil, allyl amyl glycolate, cyclovertal, lavender oil, clary sage oil, beta-damascenone, geranium oil bourbon, cyclohexyl salicylate, Vertofixcoeur, iso-E-super, Fixolide, NP, evernyl, γ-methylionone (iraldeingamma), phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide (rose oxide), romilat, irotyl, and 2-tert-butylcyclohexylethyl carbonate (floramat).

[0217] In certain embodiments, suitable pharmaceutically acceptable excipients may include preservatives. As used herein, the term "preservative" refers to an agent that prolongs the shelf life of a dosage form by delaying or preventing the deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety. Preservatives do not need to provide fatal, irreversible effects that cause partial or complete microbial cell destruction or incapacity. Bactericides, disinfectants, disinfectants, sporicides, viricides, and tuberculicides provide this irreversible mode of action, sometimes referred to as "bactericidal" effects. In contrast, preservatives can provide reversible inhibition or antibacterial effects, because if the preservative is removed, the target microorganism can resume breeding. The main difference between preservatives and disinfectants is mainly related to mode of action (preservatives prevent growth rather than killing microorganisms) and exposure time (the action time of preservatives is several days to several months, and the action time of disinfectants is at most a few minutes). Suitable preservatives include, but are not limited to, solutions of phenoxyethanol, parabens, pentanediol, and sorbic acid, and silver complexes.

[0218] In certain embodiments, suitable pharmaceutically acceptable excipients may include colorants such as, but not limited to, colors such as white, black, yellow, blue, green, pink, red, orange, purple, indigo, and brown.

[0219] In certain embodiments, suitable pharmaceutically acceptable excipients may include alkalizing agents such as, but not limited to, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate, and / or disodium phosphate.

[0220] In certain embodiments, suitable pharmaceutically acceptable excipients may include lubricants / release agents such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates, and fatty amides. Other suitable lubricants can include, but are not limited to, glyceryl behenate (Compritol™ 888), metallic stearates (e.g., magnesium stearate, calcium stearate, and sodium stearate), stearic acid, hydrogenated vegetable oils (e.g., Sterotex™), talc, waxes (such as beeswax and carnauba wax), silica, fumed silica, colloidal silicon dioxide, calcium stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride, DL-leucine, polyethylene glycol (e.g., Carbowax™ 4000 and Carbowax™ 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (Pruv™), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, microcrystalline cellulose, glycerin, propylene glycol, and combinations thereof.

[0221] In certain embodiments, suitable pharmaceutically acceptable excipients may include diluents such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, calcium hydrogen phosphate dihydrate NF, sucrose-based diluents, confectioners sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granules NF, dextrates NF (e.g., Emdex™), dextrose (e.g., Cerelose™), inositol, hydrolyzed cereal solids (such as Maltrons™ and Mor-Rex™), amylose, powdered cellulose (e.g., Elcema™), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like.

[0222] In certain embodiments, suitable pharmaceutically acceptable excipients may include oils and fats such as, but not limited to, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, coconut oil, rapeseed oil, corn oil, cottonseed oil, grapeseed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango butter, abaca oil, Mongolian 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 seed oil, walnut oil, and watermelon seed oil. Other oils and fats that may be in the filling of the PVA shell may include, but are not limited to, fish oil (ω-3), krill oil, animal or vegetable fats (e.g. in their hydrogenated form), mono-, di- and triglycerides of C12-, C14-, C16-, C18-, C20- and C22-fatty acids.

[0223] In certain embodiments, suitable pharmaceutically acceptable excipients may include plant proteins (such as sunflower protein, soy protein, cottonseed protein, peanut protein, grape seed protein), whey protein, whey protein isolate, blood protein, egg protein, acrylated protein, water-soluble polysaccharides (such as alginates, carrageenan, guar gum, agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, karaya gum, tragacanth gum), pectin), water-soluble derivatives of cellulose: alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcellulose (such as methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose), fiber Suitable water-soluble polymers include cellulose esters and hydroxyalkyl cellulose esters (such as cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose (HPMC)); carboxyalkyl cellulose, carboxyalkylalkyl cellulose, carboxyalkyl cellulose esters (such as carboxymethyl cellulose and its alkali metal salts); water-soluble synthetic polymers such as polyacrylic acid, polyacrylamide and polyacrylates, polymethacrylic acid, polymethacrylamide and polymethacrylates, polyvinyl acetate, polyvinyl alcohol, polyvinyl acetate phthalate (PVAP), polyvinyl pyrrolidone (PVP), PVY / vinyl acetate copolymers and polycrotonic acid; also suitable are phthalated gelatin, gelatin succinate, cross-linked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates having the following groups: for example tertiary amino groups 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, etc.

[0224] In certain embodiments, suitable pharmaceutically acceptable excipients may include hydrophobic materials, including but not limited to digestible long chain (C8-C 50 , 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 alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol or preferably cetearyl alcohol); fatty acids, including but not limited to mono- and di-glycerides, medium-chain triglycerides, fatty acid esters, fatty acid glycerides (mono-, di- and tri-glycerides) of medium-chain fatty acids (such as caprylic acid, capric acid, caproic acid, lauric acid, oleic acid, linoleic acid), hydrogenated fats, hydrocarbons, ordinary waxes, stearic acid, stearyl alcohol, and hydrophobic and hydrophilic materials with a hydrocarbon backbone.

[0225] In certain embodiments, suitable pharmaceutically acceptable excipients may include polyvinyl alcohol, polyvinyl pyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetate, polycarboxylic acids and salts, acetic acid, caprylic acid, oleic acid, polyamino acids or peptides, polyamides, polyacrylamides, copolymers of maleic acid / acrylic acid, polysaccharides including starch and gelatin, natural gums such as xanthan gum and carrageenan. For example, the polymer can be selected from polyacrylates and water-soluble acrylate copolymers, methylcellulose, sodium carboxymethylcellulose, dextrin, ethylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, maltodextrin, polymethacrylates and combinations thereof, or from polyvinyl alcohol, polyvinyl alcohol copolymers and hydroxypropyl methylcellulose (HPMC), methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymers, methacrylic acid / methyl acrylate / methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, PEG-35 castor oil, caprylocaproyl polyoxyethylene-8 glyceride, distearic acid glyceryl and combinations thereof.

[0226] In certain embodiments, suitable pharmaceutically acceptable excipients may include surfactants such as, but not limited to, polysorbate 80-polyoxyethylene (20) sorbitan monooleate, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, caprylocaproyl macrogol glyceride, and combinations thereof.

[0227] In certain embodiments, suitable pharmaceutically acceptable excipients may include fillers such as, but not limited to, lactose, microcrystalline cellulose, and combinations thereof.

[0228] In certain embodiments, suitable pharmaceutically acceptable excipients may include natural gums (e.g., natural plant gums). Suitable natural gums include, but are not limited to, guar gum, carob gum, konjac gum, xanthan gum, sclerotium gum, gum arabic, cellulose gum (modified or unmodified), or combinations thereof.

[0229] In certain embodiments, suitable pharmaceutically acceptable excipients may include emulsifiers such as, but not limited to, PEG-30 dipolyhydroxystearate, PEG-4 dilaurate, PEG-8 dioleate, PEG-40 sorbitan peroleate, PEG-7 glyceryl cocoate, PEG-20 almond glycerides, PEG-25 hydrogenated castor oil, glyceryl stearate (and) PEG-100 stearate, PEG-7 olive oil, PEG-8 oleate, PEG-8 laurate, PEG-60 almond glycerides, PEG-20 methyl glucose sesquistearate, PEG-40 stearate, PEG-100 stearate ...PEG-25 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-25 hydrogenated castor oil, PEG-20 G-80 sorbitan laurate, steareth-2, steareth-12, oleth-2, ceteth-2, laureth-4, oleth-10, oleth-10 / polyoxyethylene 10 oleth, 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, stearate, polyglyceryl-3-methylglucose distearate, or a combination thereof.

[0230] Further suitable emulsifiers are phosphoric acid esters and their salts, such as cetyl phosphate (Amphisol ® A), diethanolamine cetyl alcohol phosphate (Amphisol ® DEA), potassium cetyl phosphate (Amphisol ® K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glyceride phosphates and mixtures thereof. Other suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, cetearyl glucoside, lauryl glucoside, decyl glucoside, sodium stearoyl glutamate, sucrose polystearate and hydrated polyisobutylene. In addition, one or more synthetic polymers can be used as emulsifiers. For example, PVP eicosene copolymer, acrylate / C 10-3o Alkyl Acrylate Crosspolymer, Acrylates / Steareth-20 Methacrylate Copolymer, PEG-22 / Lauryl Glycol Copolymer, PEG-45 / Lauryl Glycol Copolymer and mixtures thereof.

[0231] In certain embodiments, suitable pharmaceutically acceptable excipients may include chelating agents such as, but not limited to, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).

[0232] In certain embodiments, suitable pharmaceutically acceptable excipients may include fatty alcohols such as, but not limited to, guerbet alcohols based on fatty alcohols having 6 to 18, preferably 8 to 10 carbon atoms, including cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, benzoic acid esters of C12-C15 alcohols, acetylated lanolin alcohol, and the like.

[0233] In certain embodiments, suitable pharmaceutically acceptable excipients may include esters of fatty acids, such as, but not limited to, linear C6-C 24 Fatty acids and straight chain C3-C 24 Alcohol esters, branched C6-C 13 Carboxylic acids and straight chain C6-C 24 Fatty alcohol esters, straight chain C6-C 24 Esters of fatty acids and branched alcohols (especially 2-ethylhexanol), hydroxycarboxylic acids and straight-chain or branched C6-C 22Esters of fatty alcohols (especially dioctyl malate), esters of linear and / or branched fatty acids with polyols (for example propylene glycol, dimer diol or trimer triol) and / or Guerbet alcohols, for example 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, elaiolic acid, arachidic acid, gadoleic acid, behenic acid and erucic acid and technical-grade mixtures thereof (obtained, for example, in the pressure removal of natural fats and oils, in the reduction of aldehydes from the Roelen oxidation synthesis or in the dimerization of unsaturated fatty acids) with alcohols, for example isopropanol, hexanol, octanol, 2-ethylhexanol, decanol, lauryl alcohol, isotridecanol, myristyl alcohol, cetyl alcohol, palmityl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidic acid Esters of ester oils such as linalool, linoleyl alcohol, linoleyl alcohol, tung alcohol, arachidyl alcohol, gadyl alcohol, behenyl alcohol, erucyl alcohol and brassidyl 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 aldehydes from the Roelen oxidation synthesis and as the monomer fraction in the dimerization of unsaturated fatty alcohols). Further suitable examples of ester oils are isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl erucate, erucyl erucate, 2-ethylhexyl palmitate, 2-hexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, ole ... e), erucyl erucate, cetearyl caprylate, cetyl palmitate, cetyl stearate, cetyl oleate, cetyl behenate, cetyl acetate, myristyl myristate, myristyl behenate, myristyl oleate, myristyl stearate, myristyl palmitate, myristyl lactate, propylene glycol dicaprylate / caprate, stearyl heptanoate, diisostearyl malate, octyl hydroxystearate, etc.

[0234] In certain embodiments, suitable pharmaceutically acceptable excipients may include other adjuvants such as, but not limited to, diethylhexyl 2,6-naphthalene dicarboxylate, di-n-butyl adipate, di(2-ethylhexyl) adipate, di(2-ethylhexyl) succinate, and diisotridecyl acelaat, and glycol esters such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2-ethylhexanoate), propylene glycol diisostearate, propylene glycol dipelargonate, butylene glycol diisostearate, and neopentyl glycol dioctanoate. 24Esters of fatty alcohols and / or Guerbet alcohols with saturated and / or unsaturated aromatic carboxylic acids, especially benzoic acid, C2-C 12 Esters of dicarboxylic acids with straight-chain or branched alcohols having 1 to 22 carbon atoms or polyols having 2 to 10 carbon atoms and 2 to 6 hydroxyl groups.

[0235] In certain embodiments, suitable pharmaceutically acceptable excipients may include natural or synthetic triglycerides (including glycerides and derivatives), such as but not limited to C6-C 18 Fatty acids, di- or triglycerides modified by reaction with other alcohols (caprylic / capric triglyceride, wheat germ glyceride, etc.). Fatty acid esters of polyglycerol (polyglycerol-n, such as 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 oil, olive oil, hydrogenated tallow, almond oil, hazelnut oil, borage oil, etc. Additional suitable excipients include waxes, including esters of long-chain acids and alcohols and compounds with waxy properties, such as carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ozokerite, Japan wax, paraffin, microcrystalline wax, ceresin, cetearyl alcohol ester wax, synthetic beeswax, etc. There are also hydrophilic waxes, such as cetearyl alcohol or partial glycerides.

[0236] In certain embodiments, suitable pharmaceutically acceptable excipients may include pearlescent waxes such as, but not limited to, alkylene glycol esters, especially ethylene glycol distearate; fatty acid alkanolamides, especially coconut fatty acid diethanolamide; partial glycerides, especially stearic acid monoglyceride; esters of polyvalent, unsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having 6 to 22 carbon atoms, especially long-chain esters of tartaric acid; fatty substances (e.g., fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers and fatty carbonates) having a total of at least 24 carbon atoms, especially lauryl ether 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 hydroxyl groups, and mixtures thereof.

[0237] In certain embodiments, suitable pharmaceutically 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.

[0238] In certain embodiments, suitable pharmaceutically acceptable excipients may include silicone or siloxane (organically substituted polysiloxane), such as but not limited to dimethylpolysiloxane, methylphenylpolysiloxane, cyclic silicone and amino, fatty acid, alcohol, polyether, epoxy, fluorine, glycoside and / or alkyl modified silicone compounds, which may be in liquid or resin form at room temperature. Straight chain polysiloxane, dimethicone (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluid, cyclopentasiloxane volatiles (Dow Corning 345 fluid), phenyltrimethicone (Dow Corning 556 fluid). Also suitable is simethicone, which is a mixture of dimethicone and hydrogenated silicate having an average chain length of 200 to 300 dimethylsiloxane units. A detailed survey of suitable volatile silicones by Todd et al. can be found elsewhere in Cosm. Toil. 91, 27 (1976).

[0239] In certain embodiments, suitable pharmaceutically 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, etc. Alkyl phosphates or phosphate esters, acid phosphates, diethanolamine phosphate, potassium cetyl phosphate. Ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acylates. Straight-chain fatty alcohols having 8 to 22 carbon atoms, branched by 2 to 30 mol of ethylene oxide and / or 0 to 5 mol of propylene oxide with fatty acids having 12 to 22 carbon atoms and alkylphenols having 8 to 15 carbon atoms in the alkyl group. Fatty alcohol polyglycol ethers such as laureth-n, cetearyl alcohol polyether-n, steareth-n, oleth-n. Fatty acid polyglycol ethers, such as PEG-n stearate, PEG-n oleate, PEG-n coconut oil ester. Glycerol monoesters and polyol esters. C12-C22 fatty acid monoesters and diesters of the addition product of 1 to 30 mol ethylene oxide and polyol. Fatty acid and polyglycerol esters, such as glyceryl monostearate, diisostearyl polyglycerol-3-diisostearate, polyglycerol-3-diisostearate, triglycerol diisostearate, polyglycerol-2-sesquiisostearate or polyglycerol dimer acid ester (polyglyceryl dimerate). Mixtures from compounds of multiple these material classes are also suitable. Fatty acid polyglycol esters such as diethylene glycol monostearate, fatty acids and polyethylene glycol esters, fatty acids and sucrose esters such as sucrose fatty acid esters (sucro ester), glycerol and sucrose esters such as sucrose glyceride (sucro glyceride). Sorbitol and sorbitan, sorbitan monoesters and diesters of saturated and unsaturated fatty acids having 6 to 22 carbon atoms, and ethylene oxide addition products. Polysorbate-n series, sorbitan esters, such as sesquiisostearate, sorbitan, PEG-(6)-isostearate sorbitan, PEG-(10)-sorbitan laurate, PEG-17-dioleate sorbitan. Glucose derivatives, C8-C22 alkyl mono- and oligosaccharides and ethoxylated analogs preferably with glucose 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 tetrapropylene sulfonates, sodium lauryl sulfate, ammonium lauryl sulfate and ethanolamine lauryl sulfate, lauryl ether sulfate, sodium laureth sulfate, sulfosuccinates, acetyl isothiocyanate, alkanolamide sulfates, taurine, methyl taurine, imidazole sulfate. Polysiloxane / polyalkyl / polyether copolymers and derivatives, dimethicone, copolyol, silicone polyethylene oxide copolymers, silicone glycol copolymers. Propoxylated or POE-n ethers (Meroxapols), Polaxamers or poly(oxyethylene) m-block-poly(oxypropylene) n-block (oxyethylene). Zwitterionic surfactants with 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-hydroxyethylimidazolines, each having 8 to 18 carbon atoms in the alkyl or acyl group, and cocoacylaminoethylhydroxyethylcarboxymethylglycinate, N-alkylbetaines, N-alkylaminobetaines, alkylimidazolines, alkylpeptides, lipoaminoacides, self-emulsifying bases and compounds as described in KF DePolo, A shorttextbook of cosmetology, Chapter 8, Tables 8-7, pages 250-251.

[0240] Suitable nonionic matrices 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 PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and stearyl polyglucoside. PEG-7 and Steareth-10, Cetearyl Alcohol and Steareth-7 and Steareth-10, Glyceryl Stearate and PEG-75 Stearate, Propylene Glycol Ceteth-3 Acetate, Propylene Glycol Isoceteth-3 Acetate, Cetearyl Alcohol and Ceteth-12 and Oleth-12, PEG-6 Stearate and PEG-32 Stearate, PEG-6 Stearate and Ceteth-20 and Steareth-20, PEG-6 Stearate and Ceteth-20 and Glyceryl Stearate and Steareth-20, Glyceryl Stearate and Ceteareth-20.

[0241] Suitable anionic alkaline bases include, but are not limited to, PEG-2 stearate SE, glyceryl stearate SE, propylene glycol stearate. Anionic acidic bases such as cetearyl alcohol and sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, tri(laureth-4) phosphate and ethylene glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl sulfate. Cationic acidic bases such as cetearyl alcohol and cetrimonium bromide.

[0242] In certain embodiments, suitable pharmaceutically acceptable excipients may include adjuvants and additives such as, but not limited to, surfactants, super-fatting agents, consistency regulators, thickeners, polymers, stabilizers, biologically active ingredients, swelling agents, further UV photoprotective factors, antioxidants, hydrotropic agents, preservatives, self-tanning agents, solubilizers, fragrance oils, colorants, antibacterial agents, and the like.

[0243] In certain embodiments, suitable pharmaceutically acceptable excipients may include refatting agents such as, but not limited to, lanolin and lecithin, and polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides, and fatty acid alkanolamides, the latter also acting as foam stabilizers.

[0244] In certain embodiments, suitable pharmaceutically acceptable excipients may include surfactants such as, but not limited to, fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and / or di-alkyl sulfosuccinates, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurates, fatty acid glutamates, α-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.

[0245] In certain embodiments, suitable pharmaceutically acceptable excipients may include consistency regulators / thickeners and rheology modifiers such as, but not limited to, silicon dioxide, magnesium silicate, aluminum silicate, polysaccharides or their derivatives, for example, hyaluronic acid, xanthan gum, guar gum, agar, alginates, carrageenan, gellan gum, pectin or modified celluloses such as hydroxycellulose, hydroxypropyl methylcellulose. In addition, homopolymers of polyacrylates or reticulated acrylic acid and polyacrylamides, carbomers (CARBOPOL types 980, 981, 1382, ETD 2001, ETD2020, ULTREZ 10) or the SALCARE series, 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 isodecanol crosspolymer), PEMULEN TR-1 (acrylates / C10-30 alkyl acrylate crosspolymer), LUVIGEL EM (sodium acrylates copolymer), ACULYN 28 (acrylic acid esters / vinyl isodecanol crosspolymer), (Acrylates / Beheneth-25 Methacrylate Copolymer), etc.

[0246] In certain embodiments, suitable pharmaceutically acceptable excipients can include polymers, such as but not limited to anions, zwitterions, amphoterics and nonionic polymers. For example, it is necessary to consider 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 polyacrylic acid crosslinked with polyol, 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 and optionally derivatized cellulose ethers and silicones. In addition, the polymer described in EP 1093796 (page 3-8, paragraph 17-68) can be used.

[0247] In certain embodiments, suitable pharmaceutically acceptable excipients may include antioxidants such as, but not limited to, amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives, imidazoles (e.g., urocanic acid) and their derivatives, peptides (e.g., D,L-carnosine, D-carnosine, L-carnosine and its derivatives (e.g., anserine)), carotenoids, carotenes, lycopene and its derivatives, chlorogenic acid and its derivatives, lipoic acid and its derivatives (e.g., dihydrolipoic acid), gold thioglucose, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine and its sugar esters, N-acetyl esters, methyl esters, ethyl esters, propyl esters, amyl esters, butyl esters, lauryl esters, palmitoyl esters, oleyl esters, linoleyl esters, cholesterol esters and glycerides) and salts thereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and its derivatives (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts), and sulfoximine compounds (e.g., buthionine sulfoximine, homocysteine ​​sulfoximine, buthionine sulfone, pentathionine sulfoximine, hexathionine sulfoximine, heptathionine sulfoximine), and (metal) chelators (e.g., hydroxy fatty acids, palmitic acid, phytic acid, lactoferrin), hydroxy acids (e.g., citric acid, lactic acid, malic acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EDDS, EGTA and its derivatives, unsaturated fatty acids and their derivatives (e.g., linolenic acid, linoleic acid, oleic acid), folic acid and its derivatives, ubiquinone and ubiquinol and their derivatives, vitamin C and its derivatives (e.g., ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate), tocopherol and its derivatives (e.g., vitamin E acetate), vitamin A and its derivatives (e.g., vitamin A palmitate), and coniferyl benzoate of benzoin resin, rutinic acid and its derivatives, glycosyl rutin, ferulic acid, furfurylidene glycosides Sugar alcohols, 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, such as the disodium salt), selenium and its derivatives (such as methionine selenium), stilbene and its derivatives (such as stilbene oxide, trans-stilbene oxide) and derivatives (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids) of those active ingredients mentioned which are suitable according to the invention. Mention may also be made of HALS (= “hindered amine light stabilizer”) compounds.

[0248] In certain embodiments, suitable pharmaceutically acceptable excipients may include hydrotropes, such as, but not limited to, ethoxylated or non-ethoxylated monohydric alcohols, dihydric alcohols or polyhydric alcohols with fewer carbon atoms or their ethers (e.g., ethanol, isopropanol, 1,2-dipropylene glycol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monobutyl ether, diethylene glycol monomethyl ether; diethylene glycol monoethyl ether, diethylene glycol monobutyl ether and similar products). The polyhydric alcohols considered for this purpose preferably have 2 to 15 carbon atoms and at least two hydroxyls. The polyhydric alcohol may further contain other functional groups, especially amino groups, and / or may be modified with nitrogen. Typical examples are as follows: glycerol, alkylene glycols, such as ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol and polyethylene glycols having an average molecular weight of 100 to 1000 daltons; technical oligoglycerol mixtures having an intrinsic degree of condensation of 1.5 to 10, such as technical diglycerol mixtures having a diglycerol content of 40 to 50% by weight; methylol compounds, such as, in particular, trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol and dipentaerythritol; lower alkyl-glucosides, especially those having 1 to 8 carbon atoms in the alkyl group, such as methyl glucoside 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 sucrose; amino sugars, such as glucosamine; diolamines, such as diethanolamine or 2-amino-1,3-propanediol.

[0249] In certain embodiments, suitable pharmaceutically acceptable excipients may include preservatives such as, but not limited to, methylparaben, ethylparaben, propylparaben, butylparaben, benzalkonium chloride, 2-bromo-2-nitro-propane-1,3-diol, dehydroacetic acid, diazolidinyl urea, 2-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, pages 210-219.

[0250] In certain embodiments, suitable pharmaceutically acceptable excipients may include bacteriostatic agents such as, but not limited to, 2,4,4′-trichloro-2′-hydroxydiphenyl ether, chlorhexidine (1,6-bis(4-chlorophenyl-biguanidino)hexane), or TCC (3,4,4′-trichlorocarbanilide). A large number of aromatic substances and ethereal oils also have antimicrobial properties. Typical examples are the active ingredients eugenol, menthol, and thymol in clove oil, peppermint oil, and thyme oil. A natural deodorant of interest is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol) present in lemon flower oil. Glyceryl monolaurate has also been shown to be a bacteriostatic agent.

[0251] In certain embodiments, the pharmaceutical compositions described herein may include (alone or cumulatively) a pharmaceutically acceptable excipient in a concentration range of about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% to about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 99% by weight, based on the total weight of the composition, or any sub-range or individual value therein.

[0252] Preparation method

[0253] In certain embodiments, the present disclosure relates to a method of preparing any nasal composition described herein. In certain embodiments, the method comprises combining a therapeutically effective amount of a compound disclosed herein with one or more nasal pharmaceutically acceptable excipients and containing the formulation in a container or device suitable for nasal delivery.

[0254] Additional Active Agents and Embodiments

[0255] In certain embodiments, the present invention relates to a method of treating an opioid overdose or prophylactically treating an opioid overdose, comprising administering to a patient in need thereof an opioid receptor antagonist and a respiratory stimulant (e.g., of Formula I)

[0256] In another aspect, the invention relates to a nasal 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 is in an effective amount to treat or prophylactically treat opioid overdose in a patient in need thereof.

[0257] In certain embodiments, the invention relates to a method of treating opioid withdrawal symptoms or prophylactically treating opioid withdrawal symptoms comprising administering to a patient in need thereof an opioid receptor antagonist and a respiratory stimulant (eg, of Formula I).

[0258] In another aspect, the invention relates to a nasal 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 is in an effective amount to treat or prophylactically treat opioid withdrawal symptoms in a patient in need thereof.

[0259] In a specific aspect, the opioid antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, and pharmaceutically acceptable salts thereof.

[0260] In one aspect, the weight ratio of antagonist to respiratory stimulant can be about 1:9 to about 9:1, about 1:7 to about 7:1, about 1:5 to about 5:1, or about 1:3 to about 3:1.

[0261] In some aspects of the nasal formulation, the pharmaceutical composition of the respiratory irritant and optionally the antagonist includes one or more excipients selected from water, NaCl, benzalkonium chloride, sodium edetate, disodium edetate, and hydrochloric acid.

[0262] In some aspects of the nasal formulation, the pharmaceutical composition further comprises water, NaCl, benzalkonium chloride, disodium edetate, and hydrochloric acid.

[0263] In some aspects of the nasal formulation, the pharmaceutical composition further comprises: an isotonicity agent; a preservative; a stabilizer; an amount of an acid sufficient to achieve a pH of 3.5-5.5; and an amount of water.

[0264] In some aspects of the nasal formulation, the pharmaceutical composition comprises: about 0.2 mg to about 1.2 mg of an isotonic 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 amount of an acid sufficient to achieve a pH of 3.5-5.5; and an amount of water.

[0265] In some aspects of the nasal formulation, the isotonicity agent is NaCl; the preservative is benzalkonium chloride; the stabilizer is disodium edetate; and the acid is hydrochloric acid.

[0266] In some aspects of the nasal formulation, the pharmaceutical composition comprises: about 0.74 mg NaCI; about 0.01 mg benzalkonium chloride; about 0.2 mg edetate disodium; an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5; and an amount of water.

[0267] In one aspect 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 aspects, the therapeutically effective amount is equivalent to an amount selected from about 2 mg naloxone hydrochloride, about 4 mg naloxone hydrochloride, and about 8 mg naloxone hydrochloride.

[0268] In some aspects of the nasal formulation, the amount of naloxone is equivalent to about 2 mg of naloxone hydrochloride. In some aspects of the nasal formulation, the amount of naloxone is equivalent to about 4 mg of naloxone hydrochloride. In some aspects of the nasal formulation, the amount of naloxone is equivalent to about 8 mg of naloxone hydrochloride. In some aspects of the nasal formulation, the amount of naloxone is equivalent to about 3.4 mg of naloxone hydrochloride.

[0269] In some aspects of the nasal formulation, the amount of naloxone is about 2.2 mg to about 13.2 mg of naloxone hydrochloride dihydrate. In some aspects of the nasal formulation, the amount of naloxone is about 4.4 mg to about 11 mg of naloxone hydrochloride dihydrate. In some aspects, 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 aspects of the nasal formulation, the amount of naloxone is about 2.2 mg of naloxone hydrochloride dihydrate. In some aspects of the nasal formulation, the amount of naloxone is about 4.4 mg of naloxone hydrochloride dihydrate. In some aspects of the nasal formulation, the amount of naloxone is about 8.8 mg of naloxone hydrochloride dihydrate.

[0270] In some aspects of the nasal formulation, the pharmaceutical composition comprises: about 0.2 mg to about 1.2 mg of an isotonic 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 amount of an acid sufficient to achieve a pH of 3.5-5.5; and an amount of water.

[0271] In some aspects of the nasal formulation, the isotonicity agent is NaCl; the preservative is benzalkonium chloride; the stabilizer is disodium edetate; and the acid is hydrochloric acid.

[0272] In some aspects of the nasal formulation, the pharmaceutical composition comprises: about 0.74 mg NaCl; about 0.01 mg benzalkonium chloride; about 0.2 mg edetate disodium; an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5; and an amount of water.

[0273] The drug of abuse used to treat the overdose subject can be an opioid, such as morphine; codeine; thebaine; oripavine; diacetylmorphine; 2,4-dinitrophenylmorphine; methylenedioxydimethamphetamine; chlomaltrexamine; dihydromorphine; hydromorphol; nicomorphine; dipropionylmorphine; desomomorphine; acetylpropionylmorphine; methyldesorphine; N-phenylethylnormorphine; 14-hydroxydihydrocodeine (RAM -318); 7,8-dihydro-14-hydroxy-N-phenylethylnormorphine (RAM-378); dibenzoylmorphine; diacetyldihydromorphine; dibenzoylmorphine; 6-monoacetylcodeine (6-MAC); acetyldihydrocodeine; dihydrocodeine; nalbuphine; nicotinylcodeine; nicotinyldihydrocodeine (nicodicodeine); oxidized morphine; 1-iodomorphine; morphine-6-uronide (M6G); 6-monoacetylmorphine (6- MAM); norcodeine; normorphine; morphine-N-oxide (genomorphine); dextromorphan (DXA); cypromethazolol; dihydroisocodeine; pholcodine; myrophine; 14-cinnamoyloxycodeinone; 14-ethoxymethoprene; 14-methoxymethoprene; 14-phenylpropoxymethoprene (PPOM); 7-spiroindanyloxymorphone; acetylmorphone; codeinone; conorphone; codeine Ketone oxime; hydrocodone acetate; methopone; N-phenylethyl-14-ethoxymethopone; morphone; benzylmorphine; methylcodeine bromide; ethylmorphine; isocodeine; hydromorphone; hydrocodone; oxycodone; oxymorphone; valorone; semone; chloromorphine; ethylmorphine; buprenorphine; fentanyl; alpha-methylfentanyl; alfentanil; sufentanil; remifentanil; carfentanil; hydroxymethylfentanyl; pethidine; ketobemidone; desmethylprodine (MPPP); allylprodine; prodin; 1-methyl-4-phenyl-4-propionyloxypiperidine (PEPAP); propoxyphene; dextropropoxyphene; dextromorphamide; bezitamide; pirithramide; levorphanol; methadone; dipipanone; levoracetylmethadone (LAAM); diphenoxin; diphenoxylate; loperamide; dezocine; pentazocine; phenazocine; dihydroetorphine; etorphine; butorphanol; nalbuphine; levomethorphan; levophenmorphan; norlevorphanol; oxymorphan; Phenorphan; furethylnorlevorphanol; zolphanol; butorphanol; cyprodime; drotibanol; 7-PET; acetorphine; BU-48; ciprenorphine; norbuprenorphine; lefetamine; meptazinol; mitragynine; tilidine; tramadol; tapentadol; dextropropoxyphene; endorphins; enkephalins; dynorphins; and endomorphins.In some embodiments, the opioid is oxymorphone. In other embodiments, the opioid is oxycodone. The above list of opioids also includes pharmaceutically acceptable salts thereof.

[0274] In a specific aspect, the respiratory irritant may be selected from the group consisting of doxapram, almitrine, a compound of formula I, and pharmaceutically acceptable salts thereof.

[0275] Device

[0276] In certain embodiments, a nasal drug delivery device comprising a pharmaceutical composition described herein is provided. The benefits of nasal delivery include needle-free, systemic drug delivery, especially when rapid absorption and onset of action are required. In addition, nasal delivery may help solve problems associated with low bioavailability, slow absorption, drug degradation, and gastrointestinal adverse events (AEs), and avoid first-pass metabolism in the liver.

[0277] Liquid nasal preparations may be aqueous solutions, suspensions or emulsions. In certain spray pump systems, an antimicrobial preservative may be included to maintain microbial stability.

[0278] In certain embodiments, the nasal formulations disclosed herein may be in a metered spray pump.

[0279] The pump can deliver, for example, 0.05 ml to about 0.5 mL or about 0.1 mL. In certain embodiments, the preparation includes a preservative, and in other embodiments, the preparation does not include a preservative. In certain embodiments, the spray pump of the present invention replaces the liquid ejected with air, and therefore includes a preservative to prevent contamination. In other embodiments, the system uses a collapsible bag, a movable piston or compressed gas to compensate for the volume of liquid ejected. The solution with a collapsible bag and a movable piston that compensates for the volume of liquid ejected provides another advantage, that is, they can be inverted and ejected without air being sucked into the dip tube and endangering the risk of subsequent ejection. This may be useful for some patients who are bedridden and suggest products that bow their heads for use. Another method is to filter the air that replaces the liquid ejected by a sterile air filter. In addition, some systems have a ball valve at the top to prevent the liquid in the applicator top from being contaminated.

[0280] In certain embodiments, metered dose spray pumps require priming and a degree of overfilling to maintain dosage consistency for the labeled number of doses. In other embodiments, single-dose or dual-dose spray devices are preferred.

[0281] In certain embodiments, the system is terminally sterilized. The product can be filled and sealed in a controlled environment to minimize the microbial and particle content of the product during the process and help ensure the success of the subsequent sterilization process. In certain embodiments, the product in the final container is then sterilized, such as by heating or irradiation. In aseptic processing, the drug, container, and closure can first be subjected to appropriate sterilization methods separately and then put together.

[0282] Pharmacodynamics

[0283] In some embodiments, following treatment comprising delivery of a therapeutically effective amount of a respiratory stimulant and, optionally, an antagonist, the patient is free of respiratory depression for at least about half an hour, 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.

[0284] In some embodiments, the device is a bi-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 wherein the therapeutically effective amount is delivered substantially by actuating the device a first time into a first nostril of a patient and actuating the device a second time into the same nostril or a second nostril of the patient.

[0285] In certain embodiments having two agents, each formulation in a bi-dose device may be combined in two reservoirs, while in other embodiments, each active agent is separate in each reservoir.

[0286] In some embodiments, upon nasal delivery of a 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 drainage to the nasopharynx or externally.

[0287] Example

[0288] Specific embodiments of the present invention will now be described with reference to the following examples. It should be understood that these examples are disclosed only to illustrate the present invention and should not be used to limit the scope of the present invention in any way.

[0289] Stability studies

[0290] The formulation was prepared using the formulation shown in Table 1. The formulation included the hydrogen sulfate salt of Compound A as the active agent (N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine):

[0291]

[0292] Table 1

[0293]

[0294] The stability of the samples in Table 1 was tested after 4 weeks at 25° C. and 40° C. The results are shown in Table 2. It should be noted that the concentrations in Table 2 are concentrations after filtration.

[0295] Table 2

[0296]

[0297] Another embodiment with a concentration of 15 mg / mL was prepared and stability was tested at 40°C and 60°C over the course of 2 weeks. The 15 mg / mL concentration was prepared using 50% polyethylene glycol at a pH of 4.0 and 5.0. The results of the stability study are shown in Tables 3-5.

[0298] Table 3: Results at initial time point

[0299] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG300 at 40°C, pH 4.0 14.14 3.89 RRT 0.70-0.71 = 0.08 0.08 50% PEG300 at 40°C, pH 5.0 14.57 4.9 RRT 0.70-0.71 = <0.05 <0.05

[0300] Table 4: Results at 1 week

[0301] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG300 at 40°C, pH 4.0 14 3.87 RRT 0.70-0.71 = 0.13 0.13 50% PEG300 at 60°C pH 4.0 13.8 3.74 RRT 0.61-.062 = 0.43RRT 0.70-0.71 = 0.6RRT 0.81 = 0.06RRT 0.90 = 0.15RRT 0.93-0.94 = 0.1RRT 1.16-1.18 = 0.1 1.43 50% PEG300 at 40°C, pH 5.0 13.91 4.92 RRT 0.70-0.71 = 0.06 0.06 50% PEG300 at 60°C, pH 5.0 14.45 4.7 RRT 0.61-.062 = 0.6RRT 0.70-0.71 = 0.22RRT 0.81 = 0.09RRT 0.90 = 0.13RRT 0.93-0.94 = 0.09RRT 1.16-1.18 = 0.09 1.23

[0302] Table 5: Results at 2 weeks

[0303] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG300 at 40°C, pH 4.0 14.26 3.97 RRT 0.66-0.67 = 0.05RRT 0.76= 0.2 0.25 50% PEG300 at 60°C pH 4.0 13.9 3.77 RRT 0.66-0.67 = 0.42RRT0.70-0.71 = 0.14RRT 0.76 =0.73RRT 0.85 = 0.07RRT 0.93-0.94 = 0.44RRT 0.96 =0.11RRT 1.16-1.18 = 0.1 2.01 50% PEG300 at 40°C, pH 5.0 14.51 5.02 RRT 0.66-0.67 = 0.08RRT 0.76= 0.08 0.16 50% PEG300 at 60°C, pH 5.0 14.34 4.69 RRT 0.66-0.67 = 0.61RRT 0.76= 0.37RRT 0.85 = 0.11RRT0.93-0.94 = 0.31RRT 0.96 =0.11RRT 0.97 = 0.12RRT 1.16-1.18 = 0.1RRT 1.22 = 0.05 1.77

[0304] Another embodiment was prepared with a concentration of 25 mg / mL and stability was tested at 40°C and 60°C over the course of 2 weeks. The 25 mg / mL concentration was prepared using 50% polyethylene glycol at a pH of 4.0 and 5.0. The results of the stability studies are shown in Tables 6-8.

[0305] Table 6: Results at initial time point

[0306] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG300 at 40°C, pH 4.0 22.97 4.01 RRT 0.70-0.71 = 0.06 0.06 50% PEG300 at 40°C, pH 5.0 23.87 4.86 RRT 0.70-0.71 = 0.05 0.05

[0307] Table 7: Results at 1 week

[0308] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG300 at 40°C, pH 4.0 22.28 4.03 RRT 0.70-0.71 = 0.13 0.13 50% PEG300 at 60°C pH 4.0 21.99 3.87 RRT 0.61-.062 = 0.32RRT 0.70-0.71 = 0.36RRT 0.81 = 0.05RRT 0.90 = 0.14RRT0.93-0.94 = 0.08RRT 1.16-1.18 = 0.09 1.04 50% PEG300 at 40°C, pH 5.0 22.91 4.88 RRT 0.70-0.71 = 0.07 0.07 50% PEG300 at 60°C, pH 5.0 22.76 4.64 RRT 0.61-.062 = 0.66RRT 0.70-0.71 = 0.29RRT 0.81 = 0.1RRT 0.90 = 0.2RRT0.93-0.94 = 0.11RRT 1.16-1.18 = 0.12 1.48

[0309] Table 8: Results at 2 weeks

[0310] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG300 at 40°C, pH 4.0 23.17 4.05 RRT 0.76 = 0.18 0.18 50% PEG300 at 60°C pH 4.0 22.39 4 RRT 0.66-0.67 = 0.36RRT 0.70-0.71 = 0.11RRT 0.76 = 0.97RRT0.85 = 0.06RRT 0.93-0.94 =0.37RRT 0.97 = 0.12RRT 1.16-1.18 = 0.12RRT 1. 22 = 0.07 2.17 50% PEG300 at 40°C, pH 5.0 21.75 4.72 RRT 0.66-0.67 = 0.08RRT 0.81 =0.07 0.15 50% PEG300 at 60°C, pH 5.0 23.37 4.65 RRT 0.66-0.67 = 0.6RRT 0.70-0.71 = 0.05RRT 0.76 = 0.38RRT0.85 = 0.11RRT 0.93-0.94 =0.39RRT 0.96 = 0.06RRT 0.97 =0.15RRT 1.16-1.18 = 0.15RRT1.22 = 0.09 1.96

[0311] In addition, stability tests were performed using different excipients at a concentration of 50 mg / mL at a pH of 5.0. The results of the stability tests are shown in Tables 9-11 below.

[0312] Table 9: Results at initial time point

[0313] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG30010% EtOH at 40°C 47.34 4.98 RRT 0.70-0.71 = 0.07 0.07 50% PEG30015% glycerol at 40℃ 41.17 4.86 RRT 0.70-0.71 = 0.07 0.07 50% PEG30010% DMA 47.03 4.86 RRT 0.70-0.71 = 0.06 0.06 50% PG 45.33 4.86 RRT 0.70-0.71 = 0.06 0.06 80% PG 45.63 5.09 RRT 0.70-0.71 = 0.06 0.06

[0314] Table 10: Results at 1 week

[0315] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG300 10% EtOH at 40°C 48.17 4.54 RRT 0.76 = 0.11 0.11 50% PEG300 10% EtOH at 60°C 47.13 4.51 RRT 0.66-0.67 = 0.22RRT 0.76 = 0.3RRT 0.93 = 0.07RRT 0.97 = 0.09RRT 1.18 =0.1RRT 1.22 = 0.09 0.88 50% PEG30015% glycerol at 40℃ 43.67 4.84 RRT 0.76 = 0.09 0.09 50% PEG30015% glycerol at 60℃ 42.78 4.65 RRT 0.66-0.67 = 0.32RRT 0.76 = 0.33RRT 0.78 = 0.07RRT 0.85 = 0.07RRT 0.93 =0.17RRT 0.97 = 0.1RRT 1.18 = 0.11RRT 1.22 = 0.16 1.26 50% PEG30010% DMA at 40℃ 48.42 4.77 RRT 0.76 = 0.1 .1 50% PEG30010% DMA at 60℃ 46.9 4.82 RRT 0.66-0.67 = 0.36RRT 0.76 = 0.27RRT 0.85 = 0.07RRT 0.93 = 0.19RRT 0.97 =0.1RRT 1.18 = 0.12RRT 1.22 = 0.15 1.26 50% PG at 40℃ 46.3 4.84 RRT 0.76 = 0.07 0.07 50% PG at 60℃ 46.57 4.84 RRT 0.76 = 0.21RRT 0.89 = 0.07 0.28 80% PG at 40℃ 46.5 5.12 RRT 0.76 = 0.07 0.07 80% PG at 60℃ 46.69 5.07 RRT 0.76 = 0.07RRT 0.89 = 0.12RRT 0.90 = 0.06 0.25

[0316] Table 11: Results at 2 weeks

[0317] sample Determination (mg / mL) pH Presence of impurities Total impurities 50% PEG300 10% EtOH at 40°C 48.27 4.41 RRT 0.66-0.67 = <0.05 RRT0.76 = 0.16 0.16 50% PEG300 10% EtOH at 60°C 47.07 4.63 RRT 0.66-0.67 = 0.24RRT0.76 = 0.92RRT 0.78 = <0.05RRT 0.85 = 0.05RRT 0.89= <0.05RRT 0.90 = <0.05RRT0.93 = 0.15RRT 0.96 = <0.05RRT 0.97 = 0.12RRT 1.18= 0.13RRT 1.22 = 0.1 1.7 50% PEG30015% glycerol at 40℃ 44.14 4.74 RRT 0.66-0.67 = 0.06RRT0.76 = 0.12 0.18 50% PEG30015% glycerol at 60℃ 41.77 4.69 RRT 0.66-0.67 = 0.41RRT0.76 = 0.4RRT 0.78 =0.13RRT 0.85 = 0.11RRT 0.89= <0.05RRT 0.90 = <0.05RRT0.93 = 0.33RRT 0.96 =0.05RRT 0.97 = 0.17RRT 1.18= 0.17RRT 1.22 = 0.15 1.93 50% PEG30010% DMA at 40℃ 48.46 4.68 RRT 0.66-0.67 = 0.07RRT0.76 = 0.14 0.21 50% PEG30010% DMA at 60℃ 47.08 4.88 RRT 0.66-0.67 = 0.4RRT 0.76= 0.54RRT 0.78 = <0.05RRT0.85 = 0.08RRT 0.89 = <0.05RRT 0.90 = <0.05RRT0.93 = 0.27RRT 0.96 =0.05RRT 0.97 = 0.15RRT 1.18= 0.16RRT 1.22 = 0.15 1.79 50% PG at 40℃ 47.1 4.74 RRT 0.66-0.67 = <0.05 RRT0.76 = 0.09 0.09 50% PG at 60℃ 46.83 4.79 RRT 0.66-0.67 = <0.05RRT0.76 = 0.42RRT 0.78 = <0.05RRT 0.85 = <0.05RRT0.89 = 0.14RRT 0.90 =0.08RRT 0.93 = <0.05RRT0.96 = <0.05RRT 0.97 = <0.05RRT 1.18 = <0.05RRT1.22 = <0.05 0.65 80% PG at 40℃ 46.91 5.06 RRT 0.66-0.67 = <0.05 RRT0.76 = 0.08 0.08 80% PG at 60℃ 47.2 5.05 RRT 0.66-0.67 = <0.05RRT0.76 = 0.26RRT 0.78 = <0.05RRT 0.85 = 0.22RRT 0.89= 0.12RRT 0.90 = <0.05RRT0.93 = <0.05RRT 0.96 = <0.05RRT 0.97 = <0.05RRT1.18 = <0.05RRT 1.22 = <0.05 0.6

[0318] Solubility of formulations as a function of pH

[0319] pH solubility studies were performed to assess the feasibility of formulating compounds of formula (I) as simple buffered solutions at a reasonable pH for use in nasal formulations.

[0320] Methods: A solution of a compound having formula (I) and H2SO4 at a concentration of about 107 mg / mL in 100 mM citric acid at pH 2.5 was prepared. Approximately 150 µL aliquots of this solution were transferred to 6 individual glass HPLC vials. Each aliquot was titrated with 6N sodium hydroxide to a different pH value ranging from 3-5.5 as shown in Table 12. All samples, including the solution at pH 2.5, were shaken overnight at room temperature using a rotary shaker. After shaking, the samples were visually assessed for the presence of precipitate and then filtered through a 0.45 µm syringe tip filter (4 mm diameter) at 3000 rpm for 20 min. The final pH of the filtrate was measured. The filtrate was then diluted appropriately and analyzed for the compound having formula (I).H2SO4 concentration using an HPLC assay.

[0321] Results: The pH values, appearance of the samples before and after shaking overnight, and the concentrations of the samples 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), so the concentration values ​​for these samples do not represent saturated solubility values.

[0322] Table 12. pH solubility results

[0323] Target pH Initial pH Final pH after shaking and filtration Appearance after vibration <![CDATA[Concentration of Compound A.H2SO4 (mg / mL)]]> 2.5 2.51 2.42 clear solution 104.1 3.0 3.05 3.00 clear solution 99.8 3.5 3.51 3.51 clear solution 101.6 4.0 4.00 3.79 Sediment 20.8 4.5 4.55 4.37 Sediment 3.46 5.0 4.93 4.52 Sediment 2.73 5.5 5.63 5.02 Sediment 0.99

[0324] Stability with pH changes

[0325] Compounds with formula (I) have been evaluated 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 becomes insufficient for an expected product concentration higher than about pH 3.6. At such a low pH, the stability of the drug in solution may be a problem. The purpose of this experiment is to evaluate the stability of the drug as it changes with pH.

[0326] In such experiments, a key consideration is the concentration of the drug and buffer used. Buffers are used because if the pH changes significantly during the experiment, the data is meaningless. However, it is desirable to keep the buffer at 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 confusion of the data with solubility limits (i.e., precipitation of the drug from solution).

[0327] Method: Buffer solutions containing about 10 mM each of citric acid and glycine were prepared in the pH range of 2-6 by titrating 250 mL of a single stock solution containing both buffers with 1N NaOH / 1N HCl and removing 50 mL aliquots at the predetermined pH values. A 1 mg / mL solution was prepared in a pH 2-5 buffer by dissolving about 25 mg of the compound of formula (I).H2SO4 in about 23 mL of a given buffer, adjusting the pH to the target, and making up the volume to 25.0 mL in a volumetric flask. Similarly, a pH 6 solution was prepared using 6.68 mg of the compound of formula (I).H2SO4, but at a lower drug concentration of 0.25 mg / mL.

[0328] Each buffer solution was filtered through a 0.2 µm polyethersulfone syringe filter into a volumetric flask that had been previously rinsed with 70% ethanol and dried in a laminar flow hood. After filtration, each buffer solution was divided into 10 aliquots (9 aliquots of 2.5 mL each and 1 aliquot of 2 mL) in 5 mL serum vials that had been previously rinsed with 70% ethanol and dried in a laminar flow hood. Filtration and aliquot preparation were performed in a laminar flow hood. A 2 mL aliquot of each buffer solution was used for T0 analysis (HPLC assay and related substances). Of the nine 2.5 mL aliquots, three aliquots were each stored at 40°C and 60°C, two aliquots were stored at 25°C, and one aliquot was stored at -70°C. After 1, 2, and 4 weeks of storage, the physical appearance, pH, assay, and related substances of the samples stored at 40°C and 60°C were evaluated. When necessary, samples at 25°C and -70°C were analyzed as controls.

[0329] result: The pH stability data are shown in Table 13. All samples remained clear, colorless, and particle-free for up to 4 weeks at 40°C and 60°C. The pH values ​​of all samples remained relatively constant for up to 4 weeks at both storage temperatures. Both the assay and impurity data indicated that the stability of the solutions at pH 2 was significantly poorer than the rest of the pH values ​​evaluated. No specific trends were observed in the pH 3-6 range. The pH stability curve at 60°C was Figure 1 The (impurity %) is shown in FIG.

[0330] Table 13. pH stability

[0331]

[0332] nd = Not Detected

[0333] Stability with pH changes – narrow pH range

[0334] The pH stability studies described above showed that the compound was unstable at pH 2.0 but more stable at higher pH values. Therefore, the stability of the compound was evaluated in the pH 2-3.6 range.

[0335] Method: Buffer solutions containing approximately 10 mM each of citric acid and glycine were prepared in the pH range of 2-3.6 by titrating 250 mL of a single stock solution containing both buffers with 1 N NaOH / 1 N HCl and removing 50 mL aliquots at the predetermined pH values. A 1 mg / mL solution was prepared in the buffer by dissolving approximately 25 mg of compound in approximately 23 mL of a given buffer, adjusting the pH to the target, and making up the volume to 25.0 mL in a volumetric flask.

[0336] Each buffer solution was filtered through a 0.2 μm polyethersulfone syringe filter into a volumetric flask previously 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 previously rinsed with 70% ethanol and dried in a laminar flow hood. Filtration and aliquot preparation were performed in a laminar flow hood. Of the nine aliquots, three aliquots were each stored at 40°C and 60°C, two aliquots were stored at 25°C, and one aliquot was used for T0 testing. The pH, assays, and related substances of the samples were evaluated at T0 and after 1 week, 2 weeks, and 4 weeks of storage at 40°C and 60°C. When necessary, samples at 25°C were analyzed as controls. The results are shown in Tables 14 and Figure 2 shown.

[0337] The most striking result of this study was that the impurity levels decreased significantly with increasing pH over the entire pH range studied during storage at 40°C and 60°C. This means that within the pH range where aqueous formulations are feasible, any increase in the pH of the formulation leads to an improvement in stability.

[0338] Table 14. pH stability of Compound A – narrow pH range

[0339]

[0340] nd = Not Detected

[0341] Drug substance stability

[0342] Method: Approximately 100 mg of API (Batch No. 009MSB058) were each stored in sealed Type I glass vials at 40° C. and 60° C. The samples were analyzed for appearance and percent purity at T0 and after 1, 2, and 4 weeks of storage.

[0343] Results: As shown in Table 15, the API was quite stable over 4 weeks even at 60°C. Visually, there was no sign of degradation (i.e., discoloration, etc.).

[0344] Table 15. Drug Substance Stability

[0345]

[0346] nd = Not Detected

[0347] Simple prototype stability

[0348] Experiments were performed to determine the stability of the API in a simple formulation prototype. A solution of the API as a free base was prepared at a concentration of 25 mg / mL, which corresponds to 35 mg / mL of the compound having formula (I). H2SO4.

[0349] Methods: A total of 9 prototypes were prepared, including simple buffer solutions, co-solvent systems, and non-aqueous solutions, as shown in Table 16.

[0350] Table 16. Compound A prototypes used for stability evaluation

[0351] prototype# illustrate 1 35 mg / mL of the compound of formula (I). 50 mM citrate containing H2SO4, pH 3.0 2 35 mg / mL of the compound of formula (I). 50% v / v PEG-400 in H2SO4 in water 3 35 mg / mL of the compound of formula (I). A 50% v / v aqueous solution of PEG-400 in H2SO4, adjusted to pH 4.4 with 1N NaOH 4 30 mg / mL of the compound of formula (I). 100% PEG-400 in H2SO4 5 35 mg / mL of the compound of formula (I). 100% propylene glycol containing H2SO4 6 35 mg / mL of the compound of formula (I). 50% v / v PEG-400 acetate solution in H2SO4 (about 40 mM sodium acetate and about 100 mM sodium hydroxide) 7 35 mg / mL of the compound of formula (I). 50% v / v propylene glycol acetate solution (about 40 mM sodium acetate and about 100 mM sodium hydroxide) containing H2SO4 8 35 mg / mL of the compound of formula (I). Acetate solution containing H2SO4 v / v PEG-400 (about 40 mM ammonium acetate and about 100 mM ammonium hydroxide) 9 35 mg / mL of the compound of formula (I). 70% v / v propylene glycol acetate solution containing H2SO4 (about 40 mM ammonium acetate and about 100 mM ammonium hydroxide)

[0352] Prototypes 6, 7, and 8 resulted in significant precipitation during preparation and were therefore not evaluated further. The remaining prototypes were stored in serum vials at 2°C-8°C, room temperature, 40°C, and 60°C. Samples stored at 2°C-8°C and room temperature were analyzed at selected time points.

[0353] Results: Tables 17 to 22 provide the data. The aqueous buffered formulation (Prototype #1) was found to be stable at room temperature and under refrigeration, but some degradation was observed under accelerated conditions. A very small amount of precipitate, described as one or two snowflake-like particles, has been observed after 2 weeks at 60°C and after 8 weeks at 40°C. Since the appearance of this precipitate coincided with a substantial decrease in the major impurity peak during storage at 60°C, the possibility of insolubility of the degradant is being investigated.

[0354] Prototype #2 was not stable in 50% PEG / 50% water without pH adjustment. The instability may be due to the low pH of the formulation. The drug was found to be more stable in Prototype #3 with the same 50% PEG base, but also containing enough sodium hydroxide to bring the apparent pH to about 4.5. Similarly, good stability was observed in Prototype #9, 70% propylene glycol / 30% water with ammonium acetate buffer to bring the apparent pH to about 5.3. Good stability was also observed in simple solutions of salts in PEG or propylene glycol, probably due to the absence of water as a reactant.

[0355] Table 17. Stability of Prototype #1

[0356]

[0357] Table 18. Stability of Prototype #2

[0358]

[0359] Table 19. Stability of Compound A Formulation Prototype #3

[0360]

[0361] Table 20. Stability of Prototype #4

[0362]

[0363] Table 21. Stability of Prototype #5

[0364]

[0365] Table 22. Stability of prototype #9

[0366]

[0367] The formulation as disclosed above is placed in a suitable nasal dropper, nasal spray, nebulizer, atomizer or other device suitable for nasal administration.

[0368] It is clear from the narrow range pH stability study that even in the upper part of the studied range, stability will also significantly improve with the increase of pH. The upper limit of pH is limited by drug solubility, so the reduction of drug concentration required to be dissolved will allow the product to be formulated at a higher pH, which will improve the stability of the product. Specifically, halving the concentration increases the pH of the formulation by about 0.3 units, and as can be seen in Table 6, the pH increase of 0.3 units significantly improves the stability of the formulation. Based on this consideration, it was decided to reduce the concentration of compound 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 provided in Table 23.

[0369] Table 23. Final formulation

[0370]

[0371] For simplicity of explanation, the embodiment of the method of the present disclosure is depicted and described as a series of actions. However, actions according to the present disclosure may occur in various orders and / or simultaneously, and occur together with other actions not presented and described herein. In addition, all exemplified actions may not be required to implement the method according to the disclosed subject matter. In addition, those skilled in the art will understand and appreciate that the method may alternatively be represented as a series of interrelated states by state diagrams or events.

[0372] In the foregoing description, many specific details, such as specific materials, dimensions, process parameters, etc., are set forth to provide a thorough understanding of the present invention. Specific features, structures, materials or characteristics can be combined in any suitable manner in one or more embodiments. The words "embodiment" or "exemplary" are used herein to indicate use as examples, instances or illustrations. Any aspect or design described herein as "example (embodiment)" or "exemplary" need not be interpreted as being more preferred or more advantageous than other aspects or designs. On the contrary, the use of the words "example (embodiment)" or "exemplary" is intended to provide concepts in a specific manner. As used in this application, the term "or" is intended to represent an inclusive "or", not an exclusive "or". That is, unless otherwise specified or clear from the context, "X includes A or B" is intended to represent any natural inclusive arrangement. That is, if X includes A; X includes B; or X includes both A and B, then "X includes A or B" is satisfied in any of the foregoing cases. References to "embodiment", "certain embodiments" or "one embodiment" throughout this patent specification mean that specific features, structures or characteristics described in conjunction with the embodiment are included in at least one embodiment. Thus, the appearances of the phrases "an embodiment," "certain embodiments," or "one embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

[0373] The present invention has been described with reference to specific exemplary embodiments of the present invention. Therefore, the description and the accompanying drawings are to be considered in an illustrative rather than a restrictive sense. Various modifications of the present invention, except those shown and described herein, will be apparent to those skilled in the art and are intended to fall within the scope of the appended claims.

Claims

1. A nasal formulation comprising about 0.01% w / w to about 10% w / w of a compound of formula (I) and a pharmaceutically acceptable excipient, wherein the compound of formula (I) is selected from: ， in: R 1 and R 2 R is independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl, or substituted heteroaryl; or R 1 and R 2 Combined to form a dibasic group selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy-cycloheptane-1,4-diyl, propane-1,3-diyl, butane-1,4-diyl and pentane-1,5-diyl; R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —NR 1 R 2 ,—C(O)OR 1 , acyl or aryl; R 4 is H, alkyl or substituted alkyl; R 5 is H, alkyl, propargyl, substituted propargyl, homopropargyl, substituted homopropargyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —OR 1 ,—NR 1 R 2 ,—C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic; or R 3 and R 5 Combined to form a dibasic group selected from the group consisting of 3,6,9-trioxa-undecane-1,11-diyl and 3,6-dioxa-octane-1,8-diyl; R 6 is H, alkyl, substituted alkyl or alkenyl; X is a bond, O or NR 4 ;and, Y is N, CR 6 or C; where: The compound Y is N or CR 6 , then key b 1 is empty, and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is empty, bond b 2 is empty, and A is a single bond; and, If Y is C, then key b 1 is a single bond, and: (i) Z is CH2, bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof; wherein the formulation is contained in a nasal delivery device.

2. The nasal formulation of claim 1, wherein the pharmaceutically acceptable excipient comprises a liquid.

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

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

5. The nasal formulation of claim 1, wherein the pharmaceutically acceptable excipient is a collection of particles.

6. The nasal formulation of claim 1, wherein the compound of formula (I) is dispersed in each particle.

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

8. The nasal formulation of claim 1, wherein the pharmaceutically acceptable excipient is a cream, an ointment or a gel.

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

10. The nasal formulation of any preceding claim, wherein the pH of the formulation is from about 3.5 to about 5.

5.

11. The nasal formulation of claim 17, wherein the pH is about 4 to about 5.

12. The nasal formulation of claim 18, wherein the pH is selected from about 4.0, about 4.5, or about 5.

0.

13. The nasal formulation of any preceding claim, wherein the concentration of the compound is from about 1 mg / mL to about 100 mg / mL.

14. The nasal formulation of any preceding claim, wherein the excipient is selected from water, ethanol, polyalkylene glycol, alkylene glycol, cyclodextrin, saline, Ringer's solution, dextrose, polyethylene glycol-hydroxystearate, or combinations thereof.

15. The nasal formulation of claim 13, wherein the excipient comprises ethanol.

16. The nasal formulation of claim 14, wherein the excipient comprises ethanol in an amount of about 1% to about 30%, about 5% to about 25%, or about 10% to about 20%.

17. The nasal formulation of claim 13, wherein the excipient comprises propylene glycol.

18. The nasal formulation of claim 16, wherein 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%.

19. The nasal formulation of claim 13, wherein the excipient comprises polyethylene glycol.

20. The nasal formulation of claim 18, wherein 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%.

21. The nasal formulation of claim 13, wherein the excipient comprises hydroxypropyl-β-cyclodextrin.

22. The nasal formulation of claim 20, wherein the excipient comprises hydroxypropyl-β-cyclodextrin in an amount from about 1% to about 50%, from about 10% to about 40%, or from about 20% to about 30%.

23. The nasal formulation of claim 1, further comprising a buffer solution.

24. The nasal formulation of claim 23, wherein the buffer solution comprises citric acid, glycine, citrate, or acetate.

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

26. The nasal formulation of claim 1, wherein the compound is the hydrogen sulfate salt of N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-O,N-dimethyl-hydroxylamine.

27. A method of providing respiratory stimulation comprising intranasally administering the nasal formulation of any one of claims 1 to 26.

28. A method of treating respiratory depression comprising nasally administering a formulation as claimed in any one of claims 1 to 26.

29. The method of claim 28, wherein the respiratory depression is caused by an opioid agent.

30. The method of claim 28, wherein the respiratory depression is caused by a non-opioid agent.

31. The method of claim 28, wherein the respiratory depression is caused by inflammation.

32. The method of claim 28, wherein the respiratory depression is caused by an infection.

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