Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions

Definitions

• the present disclosure relates methods and compositions to treat respiratory depression, e.g., modulated by an opioid or a non-opioid agent, inflammation or infection.
• the hitman body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO ; ).
• CO carbon dioxide
• Many active agents such as opioid analgesics, through their actions on p-opioid receptor expressed on respiratory neurons hi the brainstem, may cause respiratory depression in certain situations such as overdose.
• anesthetics such as propofol can cause respiratory depression that may be life threatening.
• Respiratory depression may also be caused by non ⁇ pharmacological reasons such as inflammation or infection,
• the present disclosure is directed to methods of treatment and formulations to treat respiratory depression caused by, e.g,, opioid agents, non-opioid agents, inflammation or infection.
• the present disclosure is directed to a parenteral formulation comprising a compound of Formula (I) as disclosed herein and a pharmaceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25®C at 60% relative humidity for 2 weeks.
• an active agent includes a single active agent as well as a mixture of two or more different active agent
• excipient includes a single excipient as well as a mixture of two or more different excipients, and fee like.
• the term “about” in connection with a measured quantity refers to the normal variations in that measured quantity, as expected by one of ordinary skill in the art in making the measurement and exercising a level of care commensurate with the objective of measurement and the precision of the measuring equipment.
• the term “about” includes the recited number *10%, such that “about 10” would include from 9 io 1 1.
• active agent As used herein, the terms “active agent,” “active ingredient ” and “active pharmaceutical ingredient” refer to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for feat purpose. These terms with respect to specific agents include all pharmaceutically active agents, all pharmaceutically acceptable salts thereof complexes, stereoisomers, crystalline forms, cocrystals, ether, esters, hydrates, solvates, and mixtures thereof, where the form is pharmaceutically active.
• stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with one or more chiral centers that are not mirror images of one another (diastereomers),
• enantiomer or “enantiomeric” refers to a molecule that is nonsuperimposable on its mirror image and hence optically active wherein the enantiomer rotates the plane ofpolarized light in one direction by a certain degree, and its mirror image rotates the plane of polarized light by the same degree but in the opposite direction
• chiral center refers to a carbon atom to which four different groups are attached
• patient refers to a subject, an animal or a human, who has presented a clinical manifestation of a particular symptom or symptoms suggesting the need for treatment, who is treated prevents lively or prophy tactically for a condition, or who has been diagnosed with
• subject is inclusive of (he definition of the term “patient” and does not exclude individuals who are otherwise healthy,
• “Pharmaceutically acceptable salts'' or “salts” include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide,, hydroiodic, sulfate, hydrogen sulfate, phosphate, nitric, carbonic, sulfuric, phosphoric (including hydrogen phosphate and dihydrogen phosphate), and the like; organic acid salts such as an oxalate, a malonate, a citrate, a fumarate, a lactate, a malate, a succinate, formate, acetate, trifluoroacetate, maleate, tartrate, a gluconate, a benzoate, a salicylate, a xinafoate, a pamoate, an.
• inorganic acid salts such as hydrochloride, hydrobromide,, hydroiodic, sulfate, hydrogen sulfate, phosphate, nitric, carbonic, sulfuric
• salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; amino acid salts such as argiiiate, asparaginate, glutamate and the like; metal salts such as zinc salt, sodium salt; potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; and organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolaniine salt, triethanolamine salt, discydohexylaniine salt, N,N’-dil>enzyIethylenediamrne salt, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylgiucamme) and procaine, and the like
• These salts may be present in the form of a hydrate, a
• appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (parnoic), methanesulforiic, ethanesulfonic, benzenesulfotic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfoiiic, p- toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, p-
• disease or “diseases” or “condition” or “conditions” refers to those medical conditions that can be treated or prevented by administration to a subject of an effective amount of an active agent.
• treatment of includes the lessening of the severity of or cessation of a condition or lessening the severity of or cessation of symptoms of a condition.
• treatment or treating with respect to a condition means administration with the intent to provide a pharmacodynamics effect, regardless of the outcome.
• treatment means “having positive effect on a condition''’ and encompass reduction in the severity, amelioration, and/or alleviation, of at least one symptom of a condition; a reduction, amelioration, and/or alleviation in the severity of the conditions; delay, prevention, or inhibition of the progression of the condi tion; or a perceived improvement or benefit as a result of the treatment.
• Treatment does not require total curing of the condition.
• a composition of the present disclosure may provide improvement to a patient’s quality of life, or delay, prevent, inhibit the onset of one or more symptoms of a condition, or provide a perceived benefit.
• prevention of' and “preventing” m cludes the avoidance of the onset of a condition.
• terapéuticaally effective amount is intended to include an amount of an active agent or an amount of the combination of active agents, e.g., to treat or prevent the condition, or to treat the symptoms of the condition, in a subject.
• an effective amount is intended to include an amount of a component, or an amount of a combination of component, to achieve a certain result or property, for instance, an effective amount of a pH adjusting agent to achieve a pH of 6.0 is intended to include an amount of one or more pH adjusting agents to arrive at a pH of 6.0,
• the terms “application,” “apply ” and “applying” with respect to a disclosed topical composition, or method of using a disclosed topical composition refer to any manner of administering a topical composition to the skin of a patient which, in medical or cosmetology practice, delivers tire composition to the patient’s skin surface. Smearing, rubbing, spreading, spraying a disclosed topical composition, with or without the aid of suitable devices, on a patient’s skin are all included within the scope of the term “application ” as used herein.
• the terms “topical” or “topically” with respect to administration or application of a disclosed formulation refer to epicutaneoiis administration or application, or administration onto skin,
• parenteral admi n istration refers to a route of administration wherein the pharmaceutical dosage form is injected, e,g., to the muscle (intramuscular administration), to the vein (intravenous administration), under the skin (subcutaneous administration).
• phrases “pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms that 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 benefiVrisk ratio.
• alkyl; 5 by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e, CI -CIO means one to ten carbon atoms) and includes straight, branched chain,, or cyclic substituent: groups.
• Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl, Most preferred is (Cl- C6)alkyl, such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cyclopropylmefhy'l.
• cycloahcy 1 by itself or as part of another substituent means, unless otherwise stated, a cyclic chain hydrocarbon having the number of carbon atoms designated (i.e. C3-C6 means a cyclic group comprising a ring group consisting of three to six carbon atoms) and includes straight, branched chain or cyclic substituent groups. Examples include cyclopropyl, cyclobutyl, cyc.Iopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred is (C3- C6)cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cydohexyl.
• alkenyl; ’ employed alone or in combination with other terms means, unless otherwise staled, a stable mono-anstmiraled or di-unsaturated straight chain or branched chain hydrocarbon group having the stated number of carbon, atoms. Examples include vinyl, propenyl (or allyl), crotyl, isopentenyl, butadienyl, 1,3-pentadienyI, 1,4-pentadienyl, and the higher homologs and isomers.
• alkytiyi employed alone or in combination with other terms, means, unless otherwise stated, a stable straight chain or branched chain hydrocarbon group with a triple carbon-carbon bond, having the stated number of carbon atoms. Examples include ethynyl and propynyl, and the higher homologs and isomers.
• substituted alkyls include, but are not limited to, 2,2-difiuorpprqpyl, 2 «carboxycyclopentyl and 3-chlorqpropyl
• alkoxy employed alone or in combination with other terms means, unless otherwi se stated, an alky l group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, tor example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• oxygen atom such as, tor example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• halo or “halogen’ alone or as part of another substituent means, unless otherwise stated, a. fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.
• heteroa.lkyl by itself or in combination with another term means, unless otherwise stated, a: stable straight or branched chain alkyl group consisting of the stated 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 heteroaiom may be optionally qiiatemUed.
• the heteroatom(s) may be placed al any position of the heteroalkyl group, including between the rest of the heteroalky l group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heieroalkyl group, Examples include: —
• aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n-r2) delocalized a (pi) electrons, where n is an integer.
• aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings) wherein such rings may be attached together in a pendent maimer, such as a biphenyl, or may be fused, such as naphthalene. Examples include phenyl, anthracyl, and naphthyl. Preferred are phenyl and naphthyl, most preferred is phenyl,
• aryHCj-Cslalkyl means a functional group wherein a one to three carbon, alkylene chain is attached to an aryl group, e.g., —CILCMj-phenyl or ⁇ CH r phenyl (benzyl). Preferred is aryl-CH 3 ----- and aryl-CHCCHs)—.
• substituted aryl-(Cr C.Oalkyl” means an aryHCrGOa&yl functional group in which the aryl group is substituted. Preferred is substituted aryl(CH 2 ⁇ — .
• l-(C t --C.',)alkyl ! means a functional group wherein, a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., CHjCHi-pyridyi. Preferred is heteroaryl*(CH 2 > .
• the term “substituted heteroaryl*(Cr C.s)alkyr means a heteroaryl-(CrC;)alkyl functional group in which the heteroaryl group is substituted. Preferred is substituted heteroaryl-(CH>) — .
• heterocycle or “heterocyclyf’ or “heterocyclic” by itself or as part of another substituent means, unless otherwise stated, an unsubstituted or substituted,stable, mono- or multi-cyclic heterocyclic ring system that consists 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 qaaternized.
• the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure,
• a heterocycle may be aromatic or nan-aromatic in nature.
• the heterocycle is a heteroaryl.
• heteroaiyi or “heteroaromatic” refers to a heterocycle having aromatic character.
• a polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include telraliydroquinolme and 2,3-dihydrobenzofuryl.
• non-aromatio heterocycles include monocyclic groups such as aziridine, oxirane, ihiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, telrahydrofuran, thiophane, piperidine, 1 ,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran,
• hetetoaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidiuyl), pyridazinyl, thienyl, foryl, pyrrolyl, imidazolyl, thiazolyl.
• polycyclic heterocycles examples include indolyl (such as. but not limited to, 3-, 4-.
• substituted means (hat an atom or group of atoms has replaced hydrogen as (he substituent attached to another group.
• substituted refers io any level of substi tution, namely mono-, di-, tri ⁇ , tetra-, or penta-substitution, where such substitution is permitted.
• the substituents are independently selected, and substitution may be at any chemically accessible position. In one embodiment, the substituents vary in number between one and four. lit another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.
• the substituents are independently selected from the group consisting of C « alkyl, — OH, C 5 personally 6 alkoxy, halo, amino, acetamido and nitro.
• the carbon chain may be branched, straight or cyclic, with straight being preferred.
• Certain embodiments of the instant disclosure am directed to a parenteral fonnulation coftTprising a compound of Formula (I) and a pharmaceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for 2 weeks, wherein the compound of Formula (I) is selected from:
• R’ and R 2 are independently H, alkyl, substituted alkyl, cydoalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyk phenyl, substituted phenyl, phewlalkyl, substituted phenylalkyl, aryl, substituted aryl, aryialkyt, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R !
• R 2 combine as to form a biradical selected from the group consisting of 3 ⁇ hydroxy-pentane-l,5-diyL 6-hydroxy- cycloheptane- 1 ,4-diyl, propane- 1,3-diyI, butane- 1,4-diyI and pentane- 1,5-diyl;
• R 3 is 11, alkyl, substituted alkyl, alkynyl, substituted. alkynyl, cycloalkyl, substituted cycloalky I, alkenyl, substituted alkenyl, — NR’RR — C(O)OR ! , acyl, or aryl;
• R 4 is H, alkyl, or substituted alkyl
• R s is H, alkyl, propargylic, substituted propargylic, homopropargylie, substituted homopropargylic, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, —OR’, — NR’R 2 , — C(O)OR ⁇ acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic; or R 3 and R 5 combine as to form a biradical selected from the group consisting of 3,6,9-trioxa-undecafte-l,l 1 -diyl and 3,6-dioxa-'OCtane-l,8- diyl;
• R 6 is H, alkyl, substituted alkyl or alkenyl; X is a bond, 0 or NR 4 ; and,
• Y is N, CR 6 or C; wherein: if Y is N or CR (> , then bond b* is nil and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is nil, bond ’b 2 is nil, and A is a single bond; and, if ⁇ is C, then bond b* is a single bond, and: (i) Z is CH*, bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b- is a double bond, and A is C; or a salt thereof,
• Certain embodiments of the instant disclosure are directed to a parenteral formulation comprising a compound of Formula (I) and a pharmaceutically acceptable excipient, wherein the formulaiion maintains at least 90% of the compound after accelerated storage conditions of 25”C at 60% relative humidity for 2 weeks, wherein, the compound of Formula (I) is selected from:
• R 5 and R ⁇ are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl substituted phenyl, pbenytalkyl, substituted phenylalkyd, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heieroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R. !
• R 2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-l,5-diyl, 6-hydroxy- cycloheptane-l ,4-diyl, propane- 1 ,3>diyl, butane- L4-diyl and pentane- 1 ,5-diyl;
• R 3 is H, alkyl, substituted alkyl, alkynyl. substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, — NRAR 2 , — 0(0)081, acyl, or aryl;
• R 4 is H, alkyl, or substituted alkyl
• R 5 is H, alkyl, propargylic, substituted propargylic, homopropargylic, substituted homopropargylic, substituted alkyl, cycloalkyl substituted cycloalkyl, alkenyl, substituted alkenyl, —OR 1 , — NR’R 2 , — C(O)OR ⁇ acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic; or R- 4 and R 3 combine as to form a biradical selected from the group consisting of 3,6,9-trioxa-undecaiie-l,l i ⁇ diyl.
• R 6 is H, alkyl* substituted alkyl or alkenyl
• X is a bond, Q or NR 4 ;
• ⁇ is N, CR ( * or C; wherein: if Y is N or CR 6 , then bond b ! is nil mid: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is nil bond b is nil, and A is a single bond; and, if ⁇ is C, then bond b 1 is a single bond, and: (i) Z is CH 3 , 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.
• a parenteral formulation comprising a compound of Formula (I) and a pharmaceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25 O C at 60% relative humidity for 2 weeks, wherein the compound of Formula (I) is selec ted from :
• R. 1 and R 2 are 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 heteroarylalkyi, heteroaryl or substituted heteroaryl; or R !
• R 2 combine as to form a biradical selected from the group consisting of 3-hydroxy ⁇ pentane-L5-diyl, 6-hydroxy-cycloheptane- I ,4-diyl, propane- 1 ,3- diyl, butane-l ,4-dlyl and pentane- 1 ,5-diyl;
• R ? is H, alkyl, substituted alkyl, cyclaalkyf substituted cycloalkyl, alkenyl, substituted alkenyl, — ; NR' ! R 2 , —C(O)QR ! , acyl, or aryl;
• R 4 is H, alkyl, or substituted alkyl
• R' is Fl, alkyl, substituted alkyl, cycloaikyl, substituted cycloalkyl, alkenyl, substituted alkenyl, acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic; or R 3 and R s combine as to form a biradical selected from the group consisting of 3,6,94rioxauinde£ane-l,l 1-diyl and 3,6 ⁇ dioxa ⁇ octane-I,8- diyl;
• X is a bond, 0 or NR i? ;
• Y is N , CR 6 or C; wherein: if ⁇ is N or CR 6 , then bond b* is nil and: (i) Z is H, bond b 2 is a single bond, and A is CH; or, (ii) Z is nil, bond b 2 is nil, and A is a single bond; and, if Y is C, then bond b* is a single bond, and; (i) Z is CH?, 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
• R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, or substituted alkenyl.
• R ! is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, or acyl,
• Certain embodiments of the instant disclosure are directed to A parenteral formulation comprising a compound of Form ula (I) and a pharmaceutically acceptable excipient, wherein the formulation maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for 2 weeks, wherein the compound of Formula (I) is selected from:
• R l and R. 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted .cycloalkyL alkenyl, substituted alkenyl, alkyriyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; of R J and R- combine as to form a biradical selected from the group consisting of 3 -hydroxy-pentane- 1,5- diyl, 6-hydroxy-cycloheptane- 1 ,4-diyi, propane- 13-diyk butane- 1 ,4-diyl and pentane- 1 ,5-diyl;
• R? is H, alkyl, substituted alky l, alkynyl or substituted alkynyl;
• R 4 is H, alkyl, or substituted alkyl
• R s is alkyl, propargylic, substituted propargylic, homopropargylic, or substituted homopropargylic, wherein at least one substituent selected from the group consisting of R ! , R 2 , R 3 and R 5 is alkynyl or substituted alkynyl;
• R f ' is H, alkyl, substituted alkyl or alkenyl
• X is a bond, 0 or NR 4 ;
• Y is N, CR 6 or C; wherein: if Y is N or CR 6 , then bond b E Is nil and;
• R 2 is 11, alky l or substituted alkyl, and R 5 is propargylic, substituted propargylic, homopropargylic, or substituted homopropargylic, or (ii) R 2 is H or alkynyl, and R? is alkyl, propargylic, substituted propargylic, homopropargylic, or substituted homopropargylic.
• the at least one compound of formula (I) is selected from the group consisting of (i) ⁇ is N, bond bl is nil, Z is H, bond b2 is a single bond, A is CH. and the at least one compound i s a compound of formula (Il-a) or a salt thereof
• Y is CR 6 , bond b ! is nil, Z is nil, 'bond b 2 is nil, and A is a bond, and the compound of the invention is a pyrimidine of formula (Ill-b) or a salt thereof: (Ill-b)
• Y is C
• bond b 5 is a single bond
• Z is CIL
• bond b- is a single band
• A is CH
• said at least one compound is a compound of formula (IV) or a salt thereof
• Y is C
• bond b* is a single bond
• Z is CH
• bond b 2 is a double bond
• A is C
• said at least one compound is a compound of formula (V) or a salt thereof
• the at least one compound is selected from the group consisting of: N- ('4,6-Bis-m : e ⁇ hylfimirio-[ l,.>,5
• the at least one compound is
• the salt is hydrogen sulfate or hydrochloride.
• the at least one compound is N-(4-(Methoxy(methyI)amino)-6- (propyteramo)-L3, 5 -triazin -2 «yl)propionamide or a salt thereof, in another embodiment, the salt is hydrogen sulfate or hydrochloride.
• the at least one compound is selected from the group consisting of 2- (n-Propyl)amijtK> «4-(i-propyIamino-7-metliyl «pyn'olidino[2 ⁇ -d]pyrimidme (CXXVI), 2 «(n- PropyI)amino-4-dimethyIammo-7-metbyl-pyn»lidino[2,3-d ⁇ pyrimidme (CXXVIII), 2-(n- Propyl)amino-4“tneihyhminO“7“methy1-pyrrolidino[2,3-d]pyri.midme (CXXXI), 2-(u- l > ropyl)amino*4-(i“propyl)amino ⁇ 7- ⁇ “propyl-pyrrolidmo
• the salt is hydrogen sulfate or hydrochloride.
• the at least one compound is selected from the group consisting of N- (2-Propylamino ⁇ 7I-LpyrroIo[2,3d]pyrimidm-4-yl)-O.N-dmielhy1-hydToxy1amine (CXLI).
• N «(2> (lhopen-2-yl)amino-7-methyl-pyrrolo[2,3d ; ]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine (CL-VI1I), N“(2’(Piopen-2-yl)amino-7-methyl’pyrrolo
• the compound is selected from the group consisting of O,N- dimelhyl.>N«[4>(nrpropylamin.o)-6 ⁇ (pTOp-2-ynylammo-[l,3,5' ⁇ triazin>2-y.l]-hydroxylamine; N- meihyl-'N’-n>pFopyI*N">pn ⁇ >“2 «ynyH .1 ,3,5]triazine-2,4 i 6rtriamine' a salt thereof; and any combinations thereof.
• the Compound A below is utilized in the present invention is or a pharmaceutically acceptable salt thereof such as the hydrogen sulfate salt.
• the compound of Formula (I) is selected from compounds described in United States Patent No. 9 S 162,992 and/or in United States Patent No. 9,351,972 and/or in United States Patent Application Publication No. 2015-0291597, now abandoned, the teachings of which are incorporated by reference herein in their entirety.
• the formulation maintains at least 90% of the compound after accelerated storage conditions of 25' : C at 60% relative humidity for 2 weeks.
• the fonnulaiioii maintains at least 90% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for I month.
• the lormulation maintains at least 90% of the compound alter accelerated storage conditions of 2,5%.' at 60% relative humidity for 6 weeks.
• the formulation maintains at least 90% of the compound after accelerated storage conditions of 25 C C at 60% relative humidity for 2 months.
• the formulation maintains at least 90% of the compound after accelerated storage conditions of 25 C C at 60% relative humidity for 3 months.
• the formulation maintains at least 95%, at least 99% or at least 99.5% of the corripoimd after accelerated storage conditions of 25 a C at 60% relative humidity for 2 weeks.
• the formulation maintains at least 95%, at least 99% or at least 99.5% of the compound after accelerated storage conditions of 25 ’C at 60% relative humidity for 1 month.
• the formulation maintains at least 95%, at least 99% or at least 99.5% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for 6 weeks. [0072] In certain embodiments, the formulation maintains at least 95%, at least 99% or at least 99.5% of the compound after accelerated storage conditions of 25 °C at 60% relative humidity for
• the formulation maintains at .least 95%, at least 99% or at least 99.5% of the compound after accelerated storage conditions of 25°C at 60% relative humidity for
• the total impurities is from about 0.1% to about 0.12% or about 0.10% or less, about 0.09% or less or about 0,08% or less.
• the formulation maintains at least 90% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for 2 weeks.
• the formulation maintains at least 90% of the compound after accelerated storage conditions of 40 c C at 75% relative humidity for 1 month.
• the fornndation maintains at least 90% of the compound after accelerated storage conditions of 40 r: ' € at 75% relative humidity for 6 weeks.
• the formulation maintains at least 90% of the compound after accelerated storage conditions of 40%' al 75% relative humidity for 2 months,
• the formulation maintains at least 90% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for 3 months.
• the formulation maintains at least 95%, at least 99% or at least 99.5% of the compound after accelerated storage conditions of 40 s C at 75% relative humidity for 2 weeks.
• the formulation maintains at least 95%, ai least 99% or at least 99.5% of the compound after accelerated storage conditions of 40°C at 75% relative humidity for
• the formulation maintains at least 95%, at least 99% or at least 99.5% of the compound after accelerated storage conditions of 40 e C at 75% relative humidity for 6 weeks.
• the formulation maintains at least 95%, at least 99% or at least 99.5% of the compound after accelerated storage conditions of 40°C at. 75% relative humidity for
• the formulation maintains at least 95%, at least 99% or at least 99.5% of the compound after accelerated storage conditions of 40°C at 75% relative humidi ty for
• the total impurities is from about 0.1% to about 0,40% or about 0.3.5% or less, about 0.20% or less or about 0.15% or less.
• the pH of the formulation is from about 2,5 to about 5.5,
• the pH of the formulation is from about 3,5 to about 5 5
• the pH is from about 4 to about 5.
• the pH is selected from about 4,0, about 4,5, about 4.6, about 4.8 or about 5.0.
• the concentration of the compound is from about 10 mg/mL to about 30 mg/mL
• the concentration of the compound is from about 15 mg/mL to about 25 mg/mL
• the concentration of the compound is selected from about 15 mg/mL, about 20 mg/mL or about 25 mg/m.L.
• the excipient is selected from ethanol, polyalkytene glycol, alkylene glycol, cyclodextrin, saline, ringers solution, dextrose or a combination thereof.
• the excipient is polyethylene glycol-hydroxystearate, e.g., obtained by reacting 15 moles of ethylene glycol with I mole of I 24iydro.xy stearic acid. This is commercially available as Kolliphorib HSI5 from BASF.
• the excipient comprises ethanol.
• the excipient comprises ethanol hi an amoun t of from about 1 % to about 30%, about 5% to about 25% or about 10%> to about 20%.
• the excipient comprises propylene glycol.
• die excipient comprises propylene glycol in an amount of from about 20% to about 100%, about 50% to about 95% or about 70% to about 90%, [0096] In certain embodiments, the excipient comprises polyethylene glycol.
• the excipient comprises polyethylene glycol in an amount of from about 20% to about 100%. about 50% to about 95% or about 70% to about 90%.
• the excipient comprises hydto.xypropyL]3-cyclodextrin.
• the excipient comprises hydroxi'propyl-0-cyclodextrin in an amoun t of from about 1% to about 50%, about 10% to about 40% or about 20% to about 30%.
• the formulation is suitable for intramuscular administration, [0101]
• the formulation is propylene glycol/acetate buffer in a ratio of about 75/25 to about 25/75 or about 60/40 to about 40/60 or about 50/50.
• the concentration of the active can be 10 mg/mL to about 30 mg/mL, from about 15 mg/mL to about 25 mg/mL, about 15 mg/mL, about 20 mg/mL or about 25 mg/mL.
• the pH may be from about 4.0, about 4,5, about 4,6, about 4.8 or about 5,0.
• the formulation is propylene g1yco1Zmacrogol(15)- hydroxystearate/ethanoVacelate buffer in a ratio of about 10-40/5-25/2-20/25-75 or about 25/15/10/5025 to about 25/75 or about 60/40 io about 40/60 or about 50/50.
• the concentration of the active can be 10 mg/mL to about 30 mg/mL, from about 15 mg/mL to about 25 mg/mL, about 15 mg/mL, about 20 mg/mL or about 25 mg/mL.
• the pH may be from about 4.0, about 4,5, about 4,6, about 4.8 or about 5.0,
• the present invention is directed, to a method of providing respiratory stimulation comprising administering intramuscularly a parenteral formulation as disclosed herein,
• the formulation is administered at a dosage rate of about 2,0 mg/kg to about 40 mg/kg, about 3.0 mg/kg to about 35 mg/kg, about 4.0 mg/kg to about 30 mg/kg, about 5.0 mg/kg to about 25 mg/kg, about 6,0 mg/kg to about 20 mg/kg, about 7.0 mg/kg to about 15 mg/kg, or about 8,0 mg/kg to about 10 mg/kg, In certain embodiments, the dosage rate of about 4.0 mg/kg to about 5.0 mg/kg, or about 4.8 mg/kg.
• the pharmaceutical composition is pre-mixed (e.g., an active agent is pre-mixed with one or more pharmaceutically acceptable excipients and optionally with One or more additional acti ve agents),
• the pharmaceutical composition may be contained in a glass container or in a plastic container.
• the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipien t.
• suitable pharmaceutically acceptableexcipients may vary based on the final form and route of administration of the composition.
• pharmaceutically acceptable excipients include a pharmaceutically acceptable carrier, such, as, a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound userid within the invention within or to the subject such that it may perform its intended function.
• a pharmaceutically acceptable carrier such as, a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound userid within the invention within or to the subject such that it may perform its intended function.
• a pharmaceutically acceptable carrier such as, a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound userid within the invention within or to the subject such that it may perform its intended function.
• Such constructs are carried or transported from one organ
• materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn. starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such, as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic s
• “pharmaceutically acceptable carrier” also inentes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the subject. Supplementary active compounds may also be incorporated into the compositions.
• the “pharmaceutically acceptable carrier’'’ may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical.
• compositions used in the practice of the invention are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference.
• Pharmaceutically acceptable carriers which are useful, include, but are not limited to, glycerol, water, saline, ethanol and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (.1991, Mack Publication Co., New jersey),
• the carrier may be a solvent or dispersion medium, containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
• the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required panicle size iu the case of dispersion and by the use of surfactants.
• Prevention of the action of niicrourganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlotobutanol, phenol, ascorbic acid, ihimerosal, and the like.
• isotonic agents for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol
• Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.
• the pharmaceutically acceptable carrier is not DMSO alone,
• the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, and the like.
• auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, and the like.
• preservatives useful in accordance with the invention included but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and combinations thereof.
• the composition preferably includes an antioxidant and a chelating agent which inhibit the degradation of the compound.
• Preferred antioxidants for some compounds are BHT, BHA, alpha* tocopherol and ascorbic acid in the preferred range of about 0.01 % to 0.3% and more preferably BHT in the range of 0.03% to 0.1 % by weight by total weight of the composition.
• the chelating agent is present in an amount of from 0.01% to 0.5% by weight by total weight of the composition.
• Particularly preferred chelating agents include edetate salts (e.g. disodium edetate) and citric acid in die weight range of about 0.01% to 0.20% and more preferably in the range of 0,02% to 0.10% by weight by total weight of the composition.
• the chelating agent is useful for chelating metal ions in the composition which may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are the particularly preferred antioxidant and chelating agent respectively for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art.
• Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle.
• Aqueous vehicles include, for example, water, and isotonic saline.
• Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
• Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents.
• Oily suspensions may further comprise a tiiickening agent.
• Knovm suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium oafooxymethylcellulose, methyicellutose, hydroxypropylmethylcellulose.
• Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatly acid, with a longchain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with, a partial ester derived from a fatty acid and a hexitol anhydride (e.g, polyoxyethylene stearate, heptadecaeihyleneoxycetanoL polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleale, respectively).
• naturally-occurring phosphatides such as lecithin
• condensation products of an alkylene oxide with a fatly acid, with a longchain aliphatic alcohol with a partial ester derived from a fatty acid and a hexitol, or with, a partial ester derived from a fatty acid and a
• emulsifying ageiits include, but are not limited to, lecithin, and acacia.
• preservatives include, but are not limited to, methyl, ethyl, or n-propyl parahydroxybenzoates, ascorbic- acid, and sorbic acid.
• Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
• Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol,
• Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent.
• an “oily” liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than witter.
• Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient hi the solvent.
• Aqueous solvents include, for example, water, and isotonic saline.
• Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oik fractionated vegetable oils, and mineral oils such as liquid paraffin.
• Powdered and granular formulations of a pharmaceutical preparation of the invention maybe prepared using known methods. Such formulations may be administered directly to a subject, or to prepare an aqueous or oily suspension or solution by addition of an aqueous or oily vehicle thereto. Each of these formulations may further comprise one or more of dispersing or wetting agent, a suspending agent, and a preservative. Additional excipients, such as fillers and coloring agents, may also be included in these formulations,
• a pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion.
• the oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these.
• compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
• emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate.
• the one or more additional excipients includes a pH adjusting agent, which may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, or a mixture thereof.
• a pH adjusting agent which may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sulfuric acid, phosphoric acid, nitric acid, sodium citrate, sodium acetate, magnesium hydroxide, citric acid, hydrochloric acid, or a mixture thereof.
• the composition may include one or more additional excipients, such as, without limitations, carbohydrates, antioxidants, chelating agents, low- molecular weight proteins, high-molecular weight polymers, gel-forming agents, stabilizers, additives, wetting agents, emulsifying agents, surfactant and/or dispersing agents, alkalizing agents, coloring agents, synthetic dies, fillers, diluents, mineral oxides, preservatives, or a mixture thereof.
• additional excipients such as, without limitations, carbohydrates, antioxidants, chelating agents, low- molecular weight proteins, high-molecular weight polymers, gel-forming agents, stabilizers, additives, wetting agents, emulsifying agents, surfactant and/or dispersing agents, alkalizing agents, coloring agents, synthetic dies, fillers, diluents, mineral oxides, preservatives, or a mixture thereof.
• the composition further includes an antioxidant.
• the antioxidant may include irivalent phosphorous like e.g phosphite, phenolic antioxidants, hydroxylamines, lactones such as substituted benzofuranones.
• Hindered phenols, thiosynergists and/or hindered amines are useful for the long-term stability for polymers, whereas the following antioxidants are suitable for use also in situation where the active substance is subject to oxidation: acids (ascorbic acid, erythorbic acid, etidrouic acid, gallic acid, hypophosphorous acid, ntirdihydroguairetic acid, propionic- acid etc.), phenols (e.g, BHA, BHT.
• suitable antioxidants may include, without limitations, statically hindered phenols, aryl amines, thioureas, thiocarbamates, phosphites, thloether esters, and combinations of the foregoing.
• Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols, inchiding but not limited to, l ⁇ -dMert-bmyl ⁇ methylphenol, 2 -tert- butyl ⁇ 4 t 6-di-methylphenoh 2,6-di-tert-biityI-4-ethylphenol, S ⁇ h-di-terl-butyl-d-n-butyipheiio],
• malonates including but notlimited to, dioctadecyk2,2 «b»(3,5-di4ert ⁇ buly1r2-hydroxybenzjd)ma1onaie, di «ociadecyb2-('3- t®rt !
• 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 oxides, polypropylene oxides) polyethylenes, polypropylenes, polyvinyl chlorides, polycarbonates, polystyrenes, polyacrylaies, polycaprolactone, polymethacrylaies copolymers thereof, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, crosscarmellose sodium, or a mixture thereof), giidants, lubricants, absorption enhancers, surfactants, binders, softeners, plasticizers (e.g., lecithin, hydrogenated vegetable oils, glycerol ester, lanolin, methyl ester, pentaerythrito, binders, softeners
• suitable pharmaceutically acceptable excipients may include polyvinylpyrrolidone, natural and. synthetic gums, polyvinyl alcohol, com starch, hydrophilic and hydrophobic materials such as sustained release polymers, acrylic resins, protein-derived materials, waxes, shellacs, and solid or semi-solid oils such, as hydrogenated castor oil and hydrogenated vegetable oil.
• the controlled release materials can be, e.g., alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers (e.g., acrylic add and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly( acrylic acid).
• alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers (e.g., acrylic add and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly( acrylic acid).
• hydroxyalkylcelluloses e.g., hydroxypropylmethylcelluiose
• carijoxyalkylcelluloses e.g., hydroxypropylmethylcelluiose
• Waxes include, e.g., natural and synthetic waxes, laity acids, fatty alcohols, and mixtures of the same (e.g., beeswax, carnauba wax, stearic acid and stearyl alcohol).
• suitable pharmaceutically acceptable excipients may include gelling agents, such as and without limitation, sugars or sugar derived alcohols, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives (such as microcrystalline cellulose, sodium caboxymethyl cellulose, methyteellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose esler-ethers, cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetates, cellulose diacetales, cellulose iriacetates, cellulose acetate propionates, cellulose acetate butyrates, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,
• gelling agents such as and
• acacia gum arable, pullulan gum, dextrin, gellan gum, agar gum, tarn gum, karaya, guar gum, we lan gum, rhamsaa gum, locust bean gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, the carbomers and carbopols, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, mixed surfactanVwetting agent systems, emulsifiers, other polymeric materials, and mixtures thereof.
• suitable pharmaceutically acceptable excipients may include hydrophilic excipients, such as without limitations, water, low molecular weight polyols, such as, polyethylene glycol, polypropylene glycol or a combination thereof Examples of other suitable hydrophilic. carriers include, without limitations, polyoxyethylene derivatives of a sorbitan ester, 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.
• hydrophilic excipients such as without limitations, water, low molecular weight polyols, such as, polyethylene glycol, polypropylene glycol or a combination thereof
• suitable hydrophilic. carriers include, without limitations, polyoxyethylene derivatives of a sorbitan ester, such as sorbitan monolaurate (Polysorbate 20), Polysorbate 80, Polysorbate 60, polyoxyethylene 20
• Exemplary low molecular weight polyols include, without limitations, those having a number average molecular weight of from any of about 200 Dalton, about 400 Dal ton , about 600 Dalton, about 800 Dalton, or about 1000 Dalton to any of about 2000 Dalton, about 3000 Dalton, about 4000 Dalton, about 5000 Dalton, about 6000 Da, or about 7000 Da, or any sub-range or single value therein (for instance, polyethylene glycol 400, polyethylene glycol 600, or the like).
• suitable pharmaceutically acceptable excipients may include plasticizers, such as, but not be limited to, sugar alcohol plasticizer such as triacetin, isomalt, maltitol, xylitol, erythritol, adonitol, dulcitol, pentaeryfhrilol, or mannitol; or polyol plasticizer such as diglycerin, ethylene glycol, diethylene glycol, triethyleneglycol, tetraethylene glycol, dipropylene glycol, a polyethylene glycol up to 10,000: MW, neopentyl glycol, propylene glycol, 1 ,3-propanediol, 2-methyl-l,3-propanediol, trimethylolpropane, a polyether polyol, ethanol amines; and mixtures thereof.
• sugar alcohol plasticizer such as triacetin, isomalt, maltitol, xylitol, erythri
• plasticizers may also include, without limitations, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls* ester-type plasticizers, glycol ethers, polypropylene glycol), multi-block polymers, single block polymers, citrate ester-type plasticizers, and triacetin.
• plasticizers may include 1,2-butylene glycol, 2,3-butylene.
• suitable pharmaceutically acceptable excipients may include plasticizer such as, without limitations, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; faty alcohols, vegetable oils and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glyceride and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate, acetyl triethyl citrate, Castor oil, diacetylated.
• plasticizer such as, without limitations, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; faty alcohols, vegetable oils and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glyceride and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate, acetyl triethyl citrate, Castor oil, diacetylated.
• suitable pharmaceutically acceptable excipients may include plasticizer such as, without limitations, sugar alcohol plasticizer such as isomalt, maltitol, sorbitol xylitol, erythritol, adonitol, dulcitol pentaerythritol, or mannitol; or polyol plasticizer such as glycerin, diglycerin, ethylene glycol, diethylene glycol, triethyleneglycol, tetraethylene glycol, dipropylene glycol, a polyethylene glycol up to 10,000 MW, neopentyl glycol, propylene glycol, 1 ,3-propanediol, 2-methyl-l ,3 ⁇ propanediol, trimethylolpropane, a polyether polyol, ethanol amines; and mixtures thereof.
• sugar alcohol plasticizer such as isomalt, maltitol, sorbitol xylitol, erythrito
• plasticizers may include, without limitations, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols having aliphatic hydroxyls, ester-type plasticizers, glycol ethers, polypropylene glycol), multi-block polymers, single block polymers, citrate ester-type plasticizers, and triacetin.
• plasticizers may include 1,2-bntylene glycol 2,3-butylene glycol, styrene glycol, manopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol nionoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyllributyicitmte, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.
• suitable pharmaceutically acceptable excipients may include fragrances such as, without limitations, natural and/or synthetic fragrance raw materials.
• fragrances such as, without limitations, natural and/or synthetic fragrance raw materials.
• oil soluble perfume oils which may or may not be in mixture with water soluble perfume oils.
• Oil soluble perfume materials are natural, or natural-identical essential oils such as orange oil, lavender oil, pine oil, eucalyptus oil, lemon oil, dove leaf, peppermint oil, cedarwood oil, rosemary' oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil.
• An animal fragrance is for example musk, castoream. aber or zibet, Spagyric- essences are also known in the art. They are made by fermenting certain herbs that are then processed to the final product.
• Synthetic fragrance ingredients are for example synthetic essential oils such as composed of single compounds such as linalol, terpineol, nerol, citronellal, benzaldehyde, cinnamon aldehyde, vanillin, ethylvanillin, or methylacetophenone.
• the fragrance materials may also be synthetic oil soluble perfume oils selected from the usual group consisting of fragrant hydrocarbons, alcohols, ketones, aldehydes, ethers, esters, polyene derivatives.
• fragrances that may be used are catalogued and described in references and databases such as S. Arclander, Perfume and Flavor Chemicals, Volumes I and 11 (1960, 1969; reprint 2000) ; Allured's Flavor and Fragrance Materials (2005); and database maintained by the Research Institute for Fragrance Materials at www ; riftmorg.
• suitable pharmaceutically acceptable excipients may include a perfume oil.
• suitable perfume oils include mixtures of natural and synthetic fragrances. Natural fragrances are extracts from flowers (lily; lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (aniseed, coriander, cumin, juniper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, cahnus), woods (pinewood, sandalwood, guaiac wood, cedarwood, rosewood), herbs and grasses (tarragon, lemongrass, sage, thyme), needles and branches (spruce, fir, pine, dwarf-pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax).
• Typical synthetic fragrance compounds are products of the ester, ether, aldehyde, ketone, alcohol and hydrocarbon type.
• Fragrance compounds of the ester type are, for example, benzyl acetate, phenoxyethyl isobutyrate, p-tert- butylcyclohexyl acetate, linalyl acetate, dimethylbenzylcarbinyl acetate, phenylethyl acetate, linalyl benzoate, benzyl formate, ethyl-methylphenyl glycinate, allyl cyclohexylpropibnate, styrallyl propionate and benzyl salicylate.
• the ethers include, for example, benzyl ethyl ether
• the aldehydes include, for example, the linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial and bourgeonal
• the ketones include, for example, the ionones, u-isomethylionone and methyl cedtyl ketone
• the alcohols include anethole, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol and terpineol
• the hydrocarbons include mainly the terpenes and balsams.
• suitable pharmaceutically acceptable excipients may include essential oils of relatively low volatility, which are mostly used as aroma components, are also suitable as perfume oils, e.g. sage oil, chamomile oil, oil of cloves, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, jumper berry oil, vetiver oil, olibanum oil, galbanum oil, labolanum oil and lavandin oil.
• perfume oils e.g. sage oil, chamomile oil, oil of cloves, melissa oil, mint oil, cinnamon leaf oil, linden blossom oil, jumper berry oil, vetiver oil, olibanum oil, galbanum oil, labolanum oil and lavandin oil.
• oils include bergamot oil, dihydromyrcenol, lilial, lyrai, citronellol, phenylethyl alcohol, n-hexyleinnainaldehyde, geraniol, benzylacetone, cyclamen aldehyde, linalool, boisambrene forte, am broxau, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cyclovertai, lavandin oil, clary sage oil, 0-damasco.ne, geranium oil bourbon, cyciohexyi salicylate, Vertofix coeirr, jso-E-siiper, Fixolide NP, evernyi, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose
• suitable pharmaceutically acceptable excipients may include preservatives
• Sterilants, sanitizers, disinfectants, sporicides, viracides and luberculocidai agents provide such an irreversible mode of action, sometimes referred to as “bactericidal” action.
• a preservative can provide an inhibitory or bacteriostatic action that is reversible, in that the target microbes can resume multiplication if the preservative is removed.
• the principal differences between a preservative and. a sanitizer primarily involve mode of action (a preservative prevents growth rather than killing microorganisms) and. exposure time (a preservative has days to months to act whereas a sanitizer has at most a few minutes to act).
• Suitable preservatives include, without limitations, phenoxyethanol, a solution of paraben, penianediol and sorbic ac id, as well as silver complexes.
• suitable pharmaceutically acceptable excipients may include coloring agents, such as, without limitations, colors such as e.g., white, black, yellow, blue, green, pink,, red, orange, violet, indigo, and brown,
• suitable pharmaceutically acceptable excipients may include alkalizing agent(s), such as, without limitations, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate and/or disodium phosphate.
• alkalizing agent(s) such as, without limitations, magnesium oxide, ammonium hydroxide, sodium hydroxide, sodium carbonate, sodium citrate, trisodium phosphate and/or disodium phosphate.
• suitable pharmaceutically acceptable excipients may include lifericant(s)/re lease ageni(s) such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatly amine acetates and fatty amides.
• lifericant(s)/re lease ageni(s) such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatly amine acetates and fatty amides.
• Suitable lubricants may include, but not be limited to, glyceryl behenate (CornpritolTM 888), metallic stearates (e.g., magnesium, calcium and sodium stearates), stearic acid, hydrogenated vegetable oils (e.g., SterotexTM), talc, waxes such as beeswax and carnauba wax, silica, fumed silica, colloidal silica, calcium: stearate, long chain fatty alcohols, boric acid, sodium benzoate and sodium acetate, sodium chloride,, DL-Leudne, polyethylene glycols (e,g., t CarbowaxTM 4000 and CarbowaxTM 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate.
• glyceryl behenate CornpritolTM 888
• metallic stearates e.g., magnesium, calcium and sodium stearates
• suitable pharmaceutically acceptable excipients may include diluents such as, but not limited to, lactose USP, lactose US? (anhydrous), lactose IJSP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, dibasic calcium phosphate dihydrate NF, sucrose-based diluents, confectioner’s sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate trihydrate granular NF, dextrates NF (e.g,, EmdexTM), dextrose (e.g, CereloseTM), inositol, hydrolyzed cereal solids such as the MaltronsTM and Mor-RexTM, amylose, powdered cellulose (e.g,, ElcemaTM), calcium carbonate, glycine
• suitable pharmaceutically acceptable excipients may include oils and fats such as, but not be limited to, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, coconut oil, colza oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, hemp oil, hydroxylated lecithin, lecithin, linseed oil, macadamia oil, mango better, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, and watermelon seed oil.
• oils and fats such as, but not be limited to, almond oil, argan oil, avocado oil, canola oil, cashew oil, castor oil, cocoa butter, coconut oil, colza oil, corn oil, cottons
• Other oil find fats that may be in the fill of the EVA shell may include, but not be limited to, fish oil (omega-3), crill oil, animal or vegetable fats, e.g., in their hydrogenated form, mono-, di-, and tri-glycerides with C12-, C14-, C16-, C18-, C20- and C22-fatiy acids,
• suitable pharmaceutically acceptable excipients may include vegetable proteins such as sunflower protein, soybean proteins, cotton seed proteins, peanut proteins, grape seed proteins, whey proteins, whey prolein isolates, blood proteins, egg proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar- agar, xanthan gum, gellan gum, gum arable and related gums (gum ghatti, gum karaya, gum tragancanth), pectin, water-soluble derivatives of cellulose: alkylcelluloses hydroxyalkyicelluloses and hydroxyalkylalkylcelluloses* such as methylcelluloseose, hydroxymeiliylcellulose, hydroxyethylceUulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hytkoxypropylmelhylcellulose, hydroxybutylmethykeihiiose, cellulose esters
• suitable pharmaceutically acceptable excipients may include a hydrophobic material, including, but not limited to, digestible, long chain (C 3 -C 5ti , especially C u - C ⁇ h substituted or unsubslituted hydrocarbons, such as natural or synthetic waxes (such as beeswax, glycowax, castor wax and carnauba wax), fatty alcohols (such as lauryl, myristyl, stearyl.
• a hydrophobic material including, but not limited to, digestible, long chain (C 3 -C 5ti , especially C u - C ⁇ h substituted or unsubslituted hydrocarbons, such as natural or synthetic waxes (such as beeswax, glycowax, castor wax and carnauba wax), fatty alcohols (such as lauryl, myristyl, stearyl.
• cetyl or preferably cetostearyl alcohol fatty acids, including, but not limited to, mono-diglyceride of medium chain fatty acids (such as caprylic, capric, caproic, lauric, oleic, linoleic), medium chain triglycerides, fatty acid esters, fatly acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones.
• mono-diglyceride of medium chain fatty acids such as caprylic, capric, caproic, lauric, oleic, linoleic
• medium chain triglycerides such as caprylic, capric, caproic, lauric, oleic, linoleic
• medium chain triglycerides such as caprylic, capric, caproic, lauric, o
• suitable pharmaceutically acceptable excipients may include polyvinyl alcohols, polyvinyl pyrrolidone, polyalkylene oxides, polyacrylic acid, cellulose, cellulose ethers, cellulose esters, cellulose amides, polyvinyl acetates, polycarboxylic acids and salts, acetic acid, caprylic acid, oleic acid, polyanrinoacids or peptides, polyamides, polyacrylamide, copolymers of maleic/acrylic acids, polysaccharides including starch and gelatin, natural gums such as xanthan, and carrageenans.
• polymers can be selected from polyacrylates and water-soluble acrylate copolymers, methylcellulose, carboxymethylcellulose sodium, dextrin, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl, methylcellulose, maltodextrin, polymethacrylates, and combinations thereof, or selected from polyvinyl alcohols, polyvinyl alcohol copolymers and hydroxypropyl methyl cellulose (IIPMC), methacrylic acidZmethyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/metbyl.
• IIPMC hydroxypropyl methyl cellulose
• suitable pharmaceutically acceptable excipients may include high HLB surfactants such as, without limitations, polysorbate 80-polyoxy ethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil. polyoxyl 35 castor oil, caprylocaproyl macrogol glycerides, and combinations thereof
• suitable pharmaceutically acceptable excipients may include fillers such as, without limitations, lactose,, microcrystalline cellulose, and combinations thereof.
• suitable pharmaceutically acceptable excipients may include natural gums (e.g., a natural plant gum). Suitable natural gums include, without, limitations, guar gum, carob gum, konjac gum, xanthan gum, sclerotium gum, acacia gum, cellulose gum (modified or not), or a combination thereof
• suitable pharmaceutically acceptable excipients may include emulsifiers such as, without limitations, PEG- 30 Dipolyhydroxystearate, PEG-4 Dilaurate, PEG-8 Dioleate, PEG-40 Sorbitan Peroleate, PEG-7 Glyceryl Cocoate, PEG-20 Almond Glycerides, PEG-25 Hydrogenated Castor Oil, Glyceryl Stearate (and) PEG-100 Stearate , PEG-7 Olivate, PEG- 8 Oleate, PEG-8 Laurate, PEG-60 Almond Glycerides, PEG-20 Methyl Glucose Sesquistearate, PEG -40 Stearate, PEG-100 Stearate, PEG-80 Sorbitan Laurate, Stearelh-2, Steareth-12, Oleth-2, Ceteth-2, Laureth-4, Oleth-lO, Oleth-lOZPolyoxyl 10 Oleyl Ether, Ceteth- 10,
• emulsifiers are phosphate esters and the salts thereof such as cetyl phosphate (Amphisol* A), diethanolamine cetyl phosphate (AmphisoFDEA), potassium cetyl phosphate (Amphisoi ⁇ K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glycerides phosphate and mixtures thereof,
• Further suitable emulsifiers are sorbitan oleate, sorbitan sesquioleate, sorbitan isostearate, sorbitan trioleate, Cetearyl Glucoside, Lauryl Glucoside, Decyl Glucoside, Sodium Stearoyl Glutamate, Sucrose Polystearate and Hydrated Polyisobutene.
• one or more synthetic polymers may be used as an emulsifier.
• PVP eicosene copolymer acrylates/Cio-sO alkyl acrylate crosspolymer, acrylates/steareth-20 methacrylate copolymer, PEG-22/dodecyl glycol copolymer, PEG- 45, ''dodecyl glycol copolymer, and mixtures thereof
• suitable pharmaceutically acceptable excipients may include chelating agents such as, without limitations, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepattaacetic acid (DTPA), N-(hydroxyethyi)-ethylenediamiiietriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).
• chelating agents such as, without limitations, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepattaacetic acid (DTPA), N-(hydroxyethyi)-ethylenediamiiietriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).
• suitable pharmaceutically acceptable excipients may include .fatly alcohols, such as, without limitations guerbel alcohols based on fatty alcohols having from 6 to 18, preferably from 8 to 10 carbon atoms including cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, benzoate of C12-C15 alcohols, acetylated lanolin alcohol, etc.
• guerbel alcohols based on fatty alcohols having from 6 to 18, preferably from 8 to 10 carbon atoms including cetyl alcohol, stearyl alcohol, cetearyl alcohol, oleyl alcohol, octyldodecanol, benzoate of C12-C15 alcohols, acetylated lanolin alcohol, etc.
• suitable pharmaceutically acceptable excipients may include esters of fatty acids, such, as, without limitations esters of linear C «-C u laity acids with linear Cr Cu alcohols, esters of branched Q-C ⁇ carboxyl acids with linear Q-C24 fatty alcohols, esters of linear Q-C 24 fatty acids with branched alcohols, especially 2-ethylhexanok esters of hydroxycarboxylic acids with linear or branched C ⁇ , ⁇ C 22 fatty alcohols, especially dioctyl malates, esters of linear and/or branched fatty acids with polyhydric alcohols (for example propylene glycol, dimer diol or irimer 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,
• esters of fatty acids such
• ester oils are isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl isostearate, isopropyl oleate, n-butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, iso- nonylstearate, isononyl isouonanoate, 2-eth.yIhexylpalmi.tate, 2-hexyllaurate, 2- hexyldecylstearate, 2-octyldodecyIpalmitate, oieyloleate, oleylenicate, erucyloleate, erucyferucate, cetearyl octanoate, cetyl palmitate, cetyl stearate, cetyl oleate, cetyl behenate, cetyl
• suitable pharmaceutically acceptable excipients may include other adjuvants, such as, without limitations, diethylhexyl 2,6-naphthaIate, di-n-butyl adipate, di(2- eihylhexyD-adipate, di(2-ethyl hexyl)>succmaie and diisotridecylvestat, and also diol esters, such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2- ethylhexanoate), propylene glycol diisosieatate, propylene glycol, dipelargonate, butanediol diisostearate and neopentyl glycol dicaprylate.
• adjuvants such as, without limitations, diethylhexyl 2,6-naphthaIate, di-n-butyl adipate, di(2- ei
• suitable pharmaceutically acceptable excipients may include natural or synthetic triglycerides (including: glyceryl esters and derivatives), such as, without limitations, di- or triglycerides, based on C 6 -C 6f; .fatty acids, modified by reaction with other alcohols (caprylic/capric triglyceride, wheat germ glycerides, etc.), Faty acid esters of polyglycerin (polyglyceryl-n such as polyglyceryl-4 caprate, polyglyceryl-2 isostearate, etc.
• natural or synthetic triglycerides including: glyceryl esters and derivatives
• glyceryl esters and derivatives such as, without limitations, di- or triglycerides, based on C 6 -C 6f; .fatty acids, modified by reaction with other alcohols (caprylic/capric triglyceride, wheat germ glycerides, etc.), Faty acid esters of polyglycerin (poly
• castor oil hydrogenated vegetable oil, sweet almond oil, wheal germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea buter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borage oil, etc.
• waxes including esters of long-chain acids arid alcohols as well as compounds having wax-like properties, e.g., carnauba wax, beeswax (white or yellow), ianolin wax, candelilla wax, ozokerite, japan wax, paraffin wax, microcrystalllne wax, ceresin, cetearyl esters wax, synthetic beeswax, etc.
• hydrophilic waxes as Cetearyl Alcohol or partial glycerides.
• suitable pharmaceutically acceptable excipients may include pearfescent waxes, such as, without limitations, alkylene glycol esters, especially ethylene glycol distearate; fatty acid alkanolamides, especially coco faty acid diethanolamide; partial glycerides, especially stearic acid monoglyceride; esters of polyvalent, tmsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having from.
• pearfescent waxes such as, without limitations, alkylene glycol esters, especially ethylene glycol distearate; fatty acid alkanolamides, especially coco faty acid diethanolamide; partial glycerides, especially stearic acid monoglyceride; esters of polyvalent, tmsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having from.
• fatty substances for example fatty alcohols, faty ketones, faty aldehydes, faty ethers and fatty carbonates, which in total have at least 24 carbon atoms, especially lauryl and disteatyl ether; taty acids, such as stearic acid, hydroxystearic acid or behenic acid, ringopening products of olefin epoxides having from 12 to 22 carbon atoms with fatly alcohols having from 12 to 22 carbon atoms and/or polyols having from 2 to 15 carbon atoms and from 2 to 10 hydroxy groups, and mixtures thereof.
• fatty substances for example fatty alcohols, faty ketones, faty aldehydes, faty ethers and fatty carbonates, which in total have at least 24 carbon atoms, especially lauryl and disteatyl ether
• taty acids such as stearic acid, hydroxystearic acid or behenic acid, ringopening products of olefin
• suitable pharmaceutically acceptable excipients may include hydrocarbon, oils, such as, without limitations, mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline wax, paraffinic and isoparaffinic compounds, hydrogenated isoparafTmic molecules as polydecenes and polybmene, hydrogenated polyisobuiene, squalane, isohexadecane, isododeeaue and others from plant and animal, kingdom.
• oils such as, without limitations, mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline wax, paraffinic and isoparaffinic compounds, hydrogenated isoparafTmic molecules as polydecenes and polybmene, hydrogenated polyisobuiene, squalane, isohexadecane, isododeeaue and others from plant and animal, kingdom.
• suitable pharmaceutically acceptable excipients may include silicones or siloxanes (orgaaosubstituted polysiloxane), such as, without limitations, dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic silicones, and also amino-, fatty acid-, alcohol-, polyetber-, epoxy-, fluorine-, glycoside- and/br alkyl-modified silicone compounds, which at room temperature may be in either liquid or resinous form.
• silicones or siloxanes orgaaosubstituted polysiloxane
• Linear polysiloxanes dimethicone (Dow Coming 200 fluid, Rhodia Mirasil DM), dimethicoaol, cyclic silicone fluids, cyclopentasiloxan.es volatiles (Dow Corning 345 -fluid), phenyltrimethicone (Dow Coming 556 fluid).
• simethicones are mixtures of dimethicones having an average chain length of from 200 to 300 dimethylsiloxane units with hydrogenated silicates.
• a detailed survey by Todd et al. of suitable volatile silicones may in addition be found in Cosm. Toil. 91 , 27 (1976).
• suitable pharmaceutically acceptable excipients may include emulsifiers, such as, without limitations , carboxylic acids and their salts: alkaline soap of sodium, potassium and arnmonimn, metallic soap of calcium or magnesium, organic basis soap such as Lauric, palmitic, stearic and oleic acid etc. Alkyl phosphates or phosphoric acid esters, acid phosphate, diethanolamine phosphate, potassium cetyl phosphate. Ethoxylated carboxylic acids or polyethylene glycol esters, PEG-n acylates.
• Linear fatty alcohols having from 8 to 22 carbon atoms, branched front 2 to 30 mol of ethylene oxide and/or from 0 to 5 mol propylene oxide with fatty acids having from 12 to 22 carbon atoms and with, alkylphenols having from 8 to 15 carbon atoms in the alky l group.
• Fatty alcohol polyglycol ether such as laureth-n, ceteareth-n, steareth-n, oleth-n.
• Fatty acid polyglycolether such as PEG-n stearate, PEG-n oleate, PEG-n cocoate.
• Monoglycerides and polyol esters Monoglycerides and polyol esters.
• Fatty acid and polyglycerol ester such as monostearate glycerol, diisostearoyl polyglyceryl-3-diisostearates, polyglyceryl-3-diisostearates, triglyceryl diisostearaies, polyglyceryl-2-ses ⁇ iisostearates or polyglyceryl dimerates. Mixtures of compounds from a plurality of those substance classes are also suitable.
• Fatty acid polyglycolesters such as monostearate diethylene glycol, fatty acid and polyethylene glycol esters, fatty acid and saccharose esters such as sucro esters, glycerol and saccharose esters such as sucro glycerides.
• Sorbitol and sorbitan sorbitan mono- and di-esters of saturated and unsaturated fatty acids having from 6 to 22 carbon atoms and ethylene oxide addition products.
• Polysorbate-n series, sorbitan esters such as sesquiisostearate, sorbitan, PEG-(6) ⁇ isostearate sorbitan, PEG-(I O)- sorbitan laurate, PEG47-dioieate sorbitan.
• Glucose derivatives C8-C22 alkyl-moao and oligoglycosides and ethoxylated analogues with glucose being preferred as the sugar component.
• O/W emulsifiers such as methyl gluceth-20 sesquistearate, sorbitan stearate/sucrose cocoate, methyl glucose sesquistearate, cetearyl alcohol/cetearyl glucoside.
• W/O emulsifiers such as methyl glucose dioleate/methyl glucose isostearate.
• Sulfates and sulfonated derivatives dialkylsalfosuccinates, dioctyl succinate, alkyl lauryl sulfonate, linear sulfonated paraffins, sulfonated tetrapropyene sulfonate, sodium lauryl sulfates, ammonium and ethanolamine lauryl sulfates, lauryl ether sulfates, sodium laureth sulfates, sulfosuccinates, acetyl isothionates, alkanolamide sulfates, taurines, methyl taurines, imidazole sulfates.
• Zwitterionic surfactants that carry at least one quaternary ammonium group and at least one carboxylate and/or sulfonate group in the molecule.
• Zwitterionic surfactants that are especially suitable are betaines, such as N-alkyl-N,N-dimethylainmoninm glycinates, cocoalkyldimedtylainmonium glycinate, N-acylaminopropyl-N,N-dimethyiamiTioniuni glycinates, cocoacylaminopropyldimeihylammoniutn glycinate and 2-alkyl-3-carboxymethyl-3- hydroxyethylim idazoiines each having from 8 to 18 carbon atoms in the alkyl or acyl group and also cocoacylaminoethylhydroxyethylcarboxymethylgiycinate, N-alkyl betaine, N - alkylaminobetaines.
• betaines such as N-alkyl-N,N-dimethylainmoninm glycinates, cocoalkyldimedtylainmonium glyc
• Suitable nonionic bases include, without limitations, PEG-6 beeswax (and) PEG-6 stearate (and.) polyglycery’1-2 -isostearate, glyceryl stearate (and) PEG- 100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polygIyceryl-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 ceteareih-20, cetearyl alcohol and PEG-40 castor oil, cetearyl alcohol and PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and steareih-7 and steareth
• Suitable anionic alkaline bases includes, without limitations, PEG-2 stearate SE, glyceryl stearate SB, propylene glycol stearate.
• Anionic acid bases such as cetearyl Alcohol and Sodium cetearyl sulfate, cetearyl. alcohol arid sodium lauryl sulfate, irtlaneih-4 phosphate and glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl Sulfate, Cationic acid bases such as cetearyl alcohol and cetrimonium bromide.
• suitable pharmaceutically acceptable excipients may include adjuvants and additives, such as, without limitations, surfectams, super-tatting agents, consistency regulators, thickeners, polymers, stabilizers, biogenic active ingredients, swelling agents, further UV light-protective factors, antioxidants, hydrotropic agents, preservatives, self-tanning agents, solubilizers, perfume oils, colorants, bacteria-inhibiling agents and the like.
• adjuvants and additives such as, without limitations, surfectams, super-tatting agents, consistency regulators, thickeners, polymers, stabilizers, biogenic active ingredients, swelling agents, further UV light-protective factors, antioxidants, hydrotropic agents, preservatives, self-tanning agents, solubilizers, perfume oils, colorants, bacteria-inhibiling agents and the like.
• suitable pharmaceutically acceptable excipients may include super-fatting agents, such as, without limitations, lanolin and lecithin and also polyethoxylated or acetylated lanolin and lecithin derivatives, polyol faty acid esters, monoglycerides and faty acidalkanolamides, the latter simultaneously acting as foam stabilizers,
• suitable pharmaceutically acceptable excipients may include surfactants, such as, without limitations, fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and/or di-alkyl sulfosuccinates, fatty acid isethionates, fluty acid sarcosinates, fatty acid taurides.
• surfactants such as, without limitations, fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and/or di-alkyl sulfosuccinates, fatty acid isethionates, fluty acid sarcosinates, fatty acid taurides.
• suitable pharmaceutically acceptable excipients may include consistency regulators/thickeners and rheology modifiers, such as, without limitations, silicium dioxide, magnesium silicates, aluminium silicates, polysaccharides or derivatives thereof for example hyaluronic acid, xanthau gum, guar-guar, agar-agar, alginates, carrageenan, gellan, pectines, or modified cellulose such as hydroxycellulose, hydroxypropylmethylcellulose.
• consistency regulators/thickeners and rheology modifiers such as, without limitations, silicium dioxide, magnesium silicates, aluminium silicates, polysaccharides or derivatives thereof for example hyaluronic acid, xanthau gum, guar-guar, agar-agar, alginates, carrageenan, gellan, pectines, or modified cellulose such as hydroxycellulose, hydroxypropylmethylcellulose.
• polyacrylates or homopolymer of reticulated acrylic acids and polyacrylamides carbomer (CARBOPOL types 980, 981, 1382, ETD 2001, ETD2020, ULTREZ 10) or SALCARE range such as SALCARE SC80 (steareth-10 allyl ether/acrylates copolymer), Salcare SC81 (acrylates copolymer), Salcare SC91 and Salcare AST (sodium acrylates copc/lymer/PPG-1 trideceth-6), SEPIGEL 305 (polyacrylamide/lauretfir?), SIMULGEL NS and SIMULGEL EG (hydroxyethyl acrylate/sodium.
• SALCARE SC80 steareth-10 allyl ether/acrylates copolymer
• Salcare SC81 acrylates copolymer
• Salcare SC91 and Salcare AST sodium acrylates copc/lymer/PPG-1 trideceth-6
• SEPIGEL 305 polyacrylamide/lauretfir?
• acryloyldimethyl laurate copolymer acryloyldimethyl laurate copolymer
• STABILEN 30 acrylates/vinyl isodecanoate crosspolymer
• PEMULEN TR-1 acrylates/C 10-30 alkyl acrylate crosspolymer
• LUVIGEL EM sodium acrylates copolymer
• ACULYN 28 acrylates/beheneth-25 methacrylate copolymer
• suitable pharmaceutically acceptable excipients may include polymers, such as, without limitations, an anionic, zwitterionic, amphoteric and non-ionic polymers there come into consideration, for example, vinyl acetate/croionic acid copolymers, viaylpyrrolidone/vinyl acrylate copolymers, vinyl acetate/butyl maleate/isoboniyl acrylate copolymers, methyl vinyl ether/maleic anhydride copolymers and esters thereof, uncrosslinked polyacrylic acids and polyacrylic acids crosslinked with polyols, acrylamidopropyl- trhnethylammonium chloride/acrylate copolymers, octyl acrylamide/methyl methacrylate-tert- butylaminoethyl methacryIate/2-hydroxypropyl methacrylate copolymers, -polyvinylpyrrolidone, vinylpyrrolidoneMn
• suitable pharmaceutically acceptable excipients may inrissa antioxidants, such as, without limitations amino acids (e.g. glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles (e.g. urocanic acid) and derivatives thereof, peptides, such as D,L ⁇ earnosine, D-caruosine, L*catnosite and derivatives thereof (e.g. anserine), carotinoids, carotenes, lycopene and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (e.g.
• amino acids e.g. glycine, histidine, tyrosine, tryptophan
• imidazoles e.g. urocanic acid
• peptides such as D,L ⁇ earnosine, D-caruosine, L*catnosite and derivatives thereof (e.g. anserine)
• carotinoids carotenes
• thiols e.g. thioredoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl, lauryl, palmitoyl, oleyl, linoleyl, cholesteryl and glyceryl esters thereof
• salts hereof, dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and also sulfoximine compounds (e.g.
• liiiolenic acid linoleic acid, oleic acid
• folic acid and derivatives thereof ubiquinone and ubiquinol and derivatives thereof
• vitamin C and derivatives e.g. ascorbyl palmitate, magnesium ascorbyl phosphate, ascorbyl acetate
• tocopherols and derivatives e.g. vitamin E acetate
• vitamin A and derivatives e.g.
• vitamin A palmitate and also coniferyl benzoate of benzoin resin, ratinic acid and derivatives thereof, glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine, butyl 'hydroxytoluene, butyl hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof superoxide dismutase, N-
• stilbene and derivatives thereof e.g. stilbene oxide, trans-stilbene oxide
• derivatives suitable according to the invention salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids
• suitable pharmaceutically acceptable excipients may include hydrotropic agents, such as, without limitations, ethoxylated or non-ethoxylaled mono-alcohols, diols or polyols with a low number of carbon atoms or their ethers (e.g, ethanol, isopropanol, 1 ,2- dipropanediol, propylene glycol, glycerin, ethylene glycol, ethylene glycol mouoethylether, ethylene glycol monobutylether, propylene glycol monomethylether, propylene glycol moaoettrylether, propylene glycol monobutylether, diethylene glycol monomethylether; diethylene glycol monoethyleiher, diethylene glycol monobutylether and similar products).
• hydrotropic agents such as, without limitations, ethoxylated or non-ethoxylaled mono-alcohols, diols or polyols with a low number of carbon atoms or their ethers
• the polyols that come into consideration for that purpose have preferably from 2 to 15 carbon atoms and at least two hydroxy groups.
• the polyols may also contain further functional groups, especially amino groups, and/or may be modified with nitrogen.
• Typical examples are as follows: glycerol, alkylene glycols, for example ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol and also polyethylene glycols having an average molecular weight of from 100 io 1000 Dalton; technical oligoglycerol mixtures having an intrinsic degree of condensation of from 1 ,5 to 10, for example technical diglycerol mixtures having a diglycerol content of from 40 to 50% by weight; methylol compounds, such as, especially, trimethylolethane, trimethylolpfopane, trimethylolbutane, pentaerythritol and dipentaerythritol; lower alkylglucosides, especially those having from 1
• suitable pharmaceutically acceptable excipients may include preservatives, such as, without limitations, Methyl-, Ethyl-, Propyl-, Butyl-parabens, Benzalkonium chloride, 2-Bromo-2 ⁇ nit.ro-propane ⁇ I 5 3-dioI, Dehydroacetic acid, IJiazolidinyl Urea, 2-Dichloro ⁇ benxyl alcohol, D.M.DM hydantoin, Formaldehyde solution, Methyldibromoglutanitrile, Phenoxyethanol, Sodium Hydroxymethylglycinate, Imidazolidhiyl Urea, Triclostm and further substance classes listed in the following reference: K. F. DePolo-A short textbook of cosmetology, Chapter 7, Table 7-2, 7-3, 7-4 and 7-5, p 210-219.
• preservatives such as, without limitations, Methyl-, Ethyl-, Propyl-, Butyl
• suitable pharmaceutically acceptable excipients may include bacteria-inhibiting agents, such as, without limitations, 2 x 4 > 4'-trichforo-2'-hydroxydiphenyl ether, chlorhexidine (.1 ,6-di(4-chloropheny1-biguanido)hexane) or TCC (3,4,4'-trichlorocarbanilide).
• bacteria-inhibiting agents such as, without limitations, 2 x 4 > 4'-trichforo-2'-hydroxydiphenyl ether, chlorhexidine (.1 ,6-di(4-chloropheny1-biguanido)hexane) or TCC (3,4,4'-trichlorocarbanilide).
• chlorhexidine .1 ,6-di(4-chloropheny1-biguanido)hexane
• TCC 3,4,4'-trichlorocarbanilide
• Typical examples are the active ingredients eugenol, menthol and thymol in clove oil, mint oil and thyme oil,
• a natural deodorizutg agentof interest is the terpene alcohol farnesol (3,7,11 -trim efby 1-2 ,6,10- dodecatr.ien- l.--ol), which is present in lime blossom oil.
• Glycerol monolaurate has also proved to be a bacteriostatic agent.
• pharmaceutically acceptable excipients may be included (individually or cumulatively) in the pharmaceutical compositions described herein in a concentration ranging from any of about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, or about 50 wt% to any of about 55 wl%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, or about 99 wt%, or any sub-range or single value therein based on the total weigh t of the composition.
• formulations disclosed herein can be utilized for the treatment of a breathing control disorder or disease that is intrinsic or caused, by external factors such as drug overdose (e.g.,, an opioid stidi as oxycodone, morphine, hydrocodone, heroin or fentanyl or an agent such as propofol).
• drug overdose e.g., an opioid stidi as oxycodone, morphine, hydrocodone, heroin or fentanyl or an agent such as propofol.
• the disorder or disease in certain embodiments can be selected from respiratory depression, sleep apnea, apnea of prematurity, obesity-hypoventilation syndrome, primary alveolar hypoventilation syndrome, dyspnea, altitude sickness, hypoxia, hypercapnia and chronic obstructive pulmonary disease (COPD), wherein the respiratory depression may be caused by an anesthetic, a sedative, an anxiolytic agent, a hypnotic agent, alcohol or a narcotic.
• COPD chronic obstructive pulmonary disease
• the patient or subject is farther administered a composition comprising at least one additional compound useful for treating said breathing disorder or disease such as acetazolamide, almitrine, theophylline, caffeine, methyl progesterone, a serotinergic modulator, a cannabinoid and an ampakme.
• the formulation is administered in conjunction with the use of a mechamcal ventilation device or positive airway pressure device on the subject or after the discontinuation of such a device.
• the formulations disclosed herein may be used to treat a disease, or condition modulated by large-conductance potassium channels such as a neurological disorder such as epilepsy, paroxysmal dyskinesia, or schizophrenia; a cardiac disorder such as cardiac ischemia or cardiac hypoxia; or a cerebral disorder such as cerebral ischemia or cerebral hypoxia.
• a neurological disorder such as epilepsy, paroxysmal dyskinesia, or schizophrenia
• a cardiac disorder such as cardiac ischemia or cardiac hypoxia
• a cerebral disorder such as cerebral ischemia or cerebral hypoxia.
• the subject is a mammal.
• the mammal is a human.
• the formiilaiion disclosed herein may be administered to the patient or subject by an inhalational, topical, oral, buccal, rectal, vaginal, intramuscular, subcutaneous, transdermal, intrathecal, or intravenous route.
• the instant, disclosure is direc ted to a method of preparing any of the compositions described herein.
• the method includes combining a therapeutically effective amount of the compounds disclosed herein with one ar more p h arm aceut i cal ly acceptab I e exc ipienis,
• compositions described herein may be formulated to have a customized release profile for the active agent, such as, without limitations, an immediate release profile, a controlled release profile, a delayed release profile, a zero order release profile, a first order release profile, a pulsatile release profile, a targeted release in a certain location within the body (such as a target location within the gastrointestinal tract), and the like,
• the active agent (N-(4,6 ⁇ Bi8-n-propylamino-
• the solubility of the drug becomes inadequate for the intended product concentration above about pH 3.6,
• the drug product will be diluted prior to infusion and then intravenously infused slowly, arid such a low pH is unlikely to present a safely or patient comfort issue, but stability of the drug tn solution could be an issue at such a low pH.
• the purpose of this experiment was to assess the stability of the drug: as a function of pH.
• a key consideration in such an experiment is the concentration of drug and buffer used.
• Use of a buffer is essential since the data is meaningless if the pH shifts dramatically during the experiment.
• Buffer strength can be minimized by keeping, the drug concentration low. Keeping the drag concentration low also minimizes confounding the data with solubility limits (i.e. the drug precipitating out of solution).
• Buffer solutions containing - 1 OmM each of citric acid and glycine in the pH range 2-6 were prepared by titrating 25QmL of a single stock con taining both buffer agents with IN NaOH/lN HC1 and removing 50mL aliquots at predetermined pH values.
• Solutions at lmg/mL were prepared in buffers of pH 2-5 by dissolving -25mg of Compounds having the active agent (N-(4,6-Bis-u-ptopy lanrmo-[ 1 ,3,5 [triazin-2-y l)-0,N-dimetbyl-hydtoxylamine) H 2 SO 4 in ⁇ 23mL of a given buffer, adjusting the pH to the target and making up the volume to 25,0mL in a volumetric flask.
• the active agent N-(4,6-Bis-u-ptopy lanrmo-[ 1 ,3,5 [triazin-2-y l)-0,N-dimetbyl-hydtoxylamine
• the solution at pH 6 was prepared similarly but at a lower drug concentration of 0.25.mgZmL using 6.68mg of Compounds having the acti ve agent (H «(4,6-Bis-n-propylamino- [ 1 ,3 ,5 )triazin“2-yl)-0,N-dimethyl-hydroxy lamine) H2SO4.
• each of the buffered solutions were filtered through a 0.2pm polyether sulfone syringe filter into a volumetric flask, which had been previously rinsed w ith 70% ethanol and dried in a laminar flow hood. Following filtration, each buffered solution, was split into 10 aliquots (9 aliquots of 2.5mL each and 1 aliquot Of 2mL) in 5mL serum vials previously rinsed with 70% ethanol and dried in a laminar How hood. Filtration and preparation of aliquots were performed in a laminar flow hood. The 2mL aliquot of each buffered solution was submitted for TO analysis (HPLC assay and related substances).
• Buffer solutions containing ⁇ 10mM each of citric acid and glycine in the pH range 2-3.6 were prepared by titrating 250mL of a single stock containing both buffer agents with IN NaOH/lN HC1 and removing 50mL aliquots at predetermined pH values. Solutions at Irng/rnL were prepared in the buffers by dissolving --25mg of compound in ⁇ 23mL of a given buffer, adjusting the pH to the target and making up (he volume to 25.0mL in a volumetric flask,
• each of the buff ered solutions was filtered through a 0.2pm polyether sulfone syringefilter into a volumetric .flask previously rinsed with 70% ethanol and dried in a laminar flow hood. Following filtration, each buffered solution was split into 9 aliquots in 5mL serum vials previously rinsed wi th 7t)% ethanol and dried in a laminar flow hood. Filtration and preparation of aliquots were performed in a laminar flow hood. Of the nine aliquots, three aliquots were stored at each 4O' ;t C and 60 ,;: C, two aliquots were stored at 25*C and one aliquot was submitted for TO testing.
• Prototypes 6, 7 and 8 resulted in significant precipitation during preparation and hence were not evaluated further,
• the remaining prototypes were stored at 2-8°C, RT, 4(FC and 60°C in serum vials. Samples stored at 2- ⁇ °C and RT were analyzed at selected timepoints.
• Prototype #2 was unstable in, 50% PEG/50% water without pH adjustment. The instability was presumably due to the low pH of this formulation.
• the drug was found to be much more stable in Prototype #3 , which has the same 50% P.EG base but also contains sufficient sodium hydroxide to bring the apparent pH up to about 4.5, Similarly, good stability was seen in Prototype #9, 70%> propylene glycol/3()% water with ammonium acetate buffer to bring the apparent pH to about 5.3, Good stability was also seen in simple solutions of the salt in PEG or propylene glycol, presumably due to the absence of water as a reactant.
• minipigs received a single IV bolus (1-2 minutes) administration of the Compound ha ving Formula (1) (N> ⁇ 4,6 «Bis ⁇ u-p.topylammo-
• minipigs for IM administration, minipigs (n ::: 3) received a single IM administration of Compound having Formula (1) (N ⁇ (4J>-Bis-B-propylanT!Bo ⁇ fl.
• the mean dose for IV dose Group I was 4,79 */- 0,012 mg/kg.
• the mean dose for IM dose Group 2 was 4,82 +/- 0,036 mg/kg.
• the mean dose for IM dose Group 3 was 4.79 +/- 0.033 mg/kg, All through groups nominal doses were 4.8 mg/kg, These does were based on the nominal concentrations of the Compound having Formula (I) (N-(4,6»Bis-ni>ropyiamino4l,3 ? 5]triazm-2- yif-OjN-dirnethyl-hydroxylamine) in the dose formulations (purity, water, and salt content corrected).
• minipigs (n-3) received a single IV bolus (1-2 minutes) administration of Compound having Formula (I) (N-(4,6-Bis-n“propylamino'’[ 1,3,5 ]triazin-2’yl)- O 5 N-dimettyl-hydroxylamine) via a Vascular access port (VAP) in the jugular vein.
• VAP Vascular access port
• IM administrations mimpigs (n ⁇ 3) received a single IM administration of each IM formulation via the lateral neck muscle (behind the ear).
• blood samples were collected at 8 timepoints; 0.083, 0.167, 0.25, 0,5, I, 2, 4 and 24 hours post dose.
• Table 26 includes the Plasma Concentration Descriptive Statistics of Compound having Formula (I) (N- (4,6-Bis-n-propyIaminO’l 1 ,3,5]triazm-2-yl)-O,N’dimethyl-hydroxyiamine).
• Table 27 illustrates the plasma concentration pharmacokinetic parameters of Compound having Formula (I) (N-(4,6- Bis ⁇ n ⁇ propylaniino ⁇
• the pharmacokinetic parameters for Dose Events 1 , 2, and 3 are presented in Table 29. Following IV dosing, the was 0.083 hour for Group I. Following IM dosing, the was 0.5 hoar for Group 2 (50/50 Propylene Glycol/Aceiate buffer at pH 4.8) and 1 hour for Group 3 (25/15/10/50 Propylene Glycol/Kolhphor HSl5/Ethanol/Acetate buffer at pH 4.6). The T sz? values were 3.0 hours for IV Group 1 and 3.2 hours and 2,7 hours for IM Groups 2 and 3, respectively.
• the C ⁇ , x was 2820 ng/niL and the ALIC ⁇ was 2313 hr*ng/niL.
• the C max was 466 ng/mL and the AUC ⁇ was 2617 hr*ng/mL for Group 2
• the C ;ijas ' was 601 ng/mL and the AUCw was 2711 hrtig/niL for Group 3.
• C ws was higher for IV dosing than for IM dosing whereas AUC ⁇ . was higher for IM dosing than for IV
• the term “or” is intended to mean an inclusive “or” rather than an exclusive “or” That is, unless specified otherwise, or clear from context, “X. includes A or B” is intended to mean any of the natural inclusive permutations. That is, if X includes A; X includes B; or X includes both A and B, then “X includes A or B” is satisfied under any of the foregoing instances.
• Reference throughout this specification to “an embodiment”, “certain embodiments”, or “one embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase “an embodiment”, “certain embodiments”, or “one embodiment” in various places throughout this specification are not necessarily all referring io the same embodiment.

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