Classifications

• • 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
  • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system

Definitions

• the present disclosure relates methods and compositions to treat respiratory depression modulated by a non-opioid agent.
• the human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO 2 ).
• Opioid analgesics through their actions on p-opioid receptor expressed on respiratory neurons in the brainstem, may cause respiratory depression in certain situations such as overdose.
• anesthics such as propofol can cause repiratory depression that may be fife threatening.
• the present disclosure is directed to methods of treatment and compounds to treat respiratory depression modulated by a non-opioid agent.
• the present disclosure is directed to a method of treating respiratory depression modulated by a non-opioid agent comprising administering, to a patient in need thereof, an effective amount of a compound selected from Formula (I):
• R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R 1 and R 2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- cycloheptane-l,4-diyl, propane- 1,3-diyl, butane-l,4-diyl and pentane-1,5 -diyl;
• R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, ---NR 1 R 2 , --- C(O)OR 1 , acyl, or aryl;
• R 4 is H, alkyl, or substituted, alkyl
• R 5 is H, alkyl, propargylic, substituted propargylic, homopropargylic, substituted homopropargylic, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, — OR 1 , — NRJR 2 , — C(O)ORL 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-undecane1-, 1 1-diyl and 3,6-dioxa-octane-l,8- diyl;
• R 6 is H, alkyl, substituted alkyl or alkenyl
• X is a. bond, O or NR 4 ;
• Y is N, CR 6 or C; wherein: if Y is N or CR 6 , then bond b 1 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 1 is a. single bond, and: (i) Z is CH 2 , 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.
• the compound of Formula (I) is administered via a route that is selected from oral, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal route.
• the present disclosure is directed to a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount a compound selected from Formula (I) to treat respiratory depression modulated by a non-opioid agent: wherein:
• R 1 and R. 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted het eroaryl alkyl, heteroaryl or substituted heteroaryl; or R J and R 2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- cycloheptane-l,4-diyl, propane- 1,3-diyl, butane-l,4-diyl and pentane- 1,5 -diyl;
• R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, XR 1 R 2 , ---C(O)OR 1 , 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 4 R 2 , —C(O)OR 1 , 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-undecane-1, 1 1-diyl and 3,6-dioxa ⁇ octane-l,8- diyl; R 6 is H, alkyl, substituted alkyl or alkenyl;
• X is a bond, O or NR’, and,
• Y is N, CR 6 or C; wherein: if Y is N or CR 6 , then bond b 1 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 1 is a single bond, and: (i) Z is CH 2 , bond b 2 is a single bond, and A is CH; or, (ii) Z is CH, bond b 2 is a double bond, and A is C; or a salt thereof; and a pharmaceutically acceptable excipient.
• the present disclosure is directed to a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount a compound selected from Formula (I) to treat respiratory depression modulated by a non-opioid agent, as described above, where at least one substituent selected from the group consisting of R 1 , R 2 , R 3 and R 5 is alkynyl or substituted alkynyl.
• the present disclosure is directed to a method of preparing any of the pharmaceutical compositions described herein.
• FIG. 1 is a schematic representation of the treatments and ventilatory conditions during each study period of the Example of the present disclosure
• FIG. 2 is a graph representing the estimated means hypoxic sensitivity (L/min/%) of the Example
• FIG. 3 is a graph representing the summary mean minute ventilation (L/min) of the Example
• FIG . 4 is a graph representing the summary' mean tidal volume (rnL) of the Example
• FIG. 5 is a graph representing the summary mean respiratory rate (breaths/min) of the Example
• FIG. 6 is a graph representing the summary mean end tidal CO2 (mmHg)
• FIG. 7 is a graph representing the summary' mean oxygen saturation (%)
• FIG. 8 is a graph representing the average plasma concentrations of Compound A of the Example by Propofol Dosing Interval;
• FIG. 9 is a graph representing the mean plasma Compound A concentration-time profiles following administration of Compound A of the Example (Normal Scale);
• FIG. 10 is a graph representing the mean plasma Compound A concentration-time profiles following administration of Compound A of the Example with a Logarithmic Y-axis
• 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 the 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 to 1 1.
• active agent refers to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose.
• active pharmaceutical ingredient refers to any material that is intended to produce a therapeutic, prophylactic, or other intended effect, whether or not approved by a government agency for that purpose.
• active pharmaceutically active agents include all pharmaceutically active agents, all pharmaceutically acceptable salts thereof, complexes, stereoisomers, crystalline forms, co-crystals, 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 of polarized 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.
• the term “chiral center” refers to a carbon atom to which four different groups are attached.
• the term “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 preventatively or prophylactically for a condition, or who has been diagnosed with a condition to be treated.
• the term “subject” is inclusive of the 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 ascorbate, an adipate, a cinnamte, and the like; sulfonates such as methanesulfonate, benzenesulfonate, p
• 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 (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxy ethanesulfonic, p-toluenesulfonic, sulfanilic
• 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.
• the terms “treatment” or “treating” with respect to a condition means administration with the intent to provide a pharmacodynamics effect, regardless of the outcome.
• “treatment” or “treating” 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 condition; or a perceived improvement or benefit as a result of the treatment.
• 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 includes 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 the 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 epicutaneous administration or application, or administration onto skin.
• oral delivery refers to a route of administration wherein the composition is taken through the mouth. Oral administration is a part of enteral administration, which also includes buccal (dissolved inside the cheek), sublabial (dissolved under the lip), and sublingual administration (dissolved under the tongue). In certain embodiments, oral administration includes a route of administration wherein the composition is ingested. In certain embodiments, oral administration includes a route of administration wherein the composition is inhaled. [0038] As used herein, ‘"parenteral administration” 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 benefit/risk ratio.
• alkyl 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. C1 -C10 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.
• (C1- C6)alkyl such as, but not limited to, ethyl, methyl, isopropyl, isobutyl, n-pentyl, n-hexyl and cy cl opr opy 1 m ethy 1.
• cycloalkyl by itself or as pail 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, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Most preferred is (C3- C6)cycloalkyl, such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• alkenyl means, unless otherwise stated, a stable mono-unsaturated 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-pentadienyl, 1,4-pentadienyl, and the higher homologs and isomers.
• alkynyl 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-difluoropropyl, 2-carboxy cyclopentyl and 3 -chloropropyl.
• alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1 -propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
• oxygen atom such as, for 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.
• heteroalkyl 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 (), N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
• the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
• Up to two heteroatoms may be consecutive, such as, for example, — CH 2 — NH — OCH 3 , or — CH 2 — CH 2 — S---S---CH 3 .
• heteroalkenyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di- unsaturated hydrocarbon 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 optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively.
• aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n+2) delocalized ⁇ (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 manner, such as a biphenyl, or may be fused, such as naphthalene.
• rings typically one, two or three rings
• naphthalene such as naphthalene.
• examples include phenyl, anthracyl, and naphthyl. Preferred are phenyl and naphthyl, most preferred is phenyl.
• aryl-(C 1 -C 3 )alkyl means a functional group wherein a one to three carbon alkylene chain is attached to an aryl group, e.g., — CH 2 CH 2 -phenyl or — CH 2 - phenyl (benzyl). Preferred is aryl-CH 2 — and aryl-CH(CH 3 ) — .
• substituted aryl-(C 1 - C 3 )alkyl means an aryl-(C 1 -C 3 )alkyl functional group in which the aryl group is substituted. Preferred is substituted aryl(CH 2 ) — .
• heteroaryl-(C 1 -C 3 )alkyl means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., — CH 2 CH 2 -pyridyl. Preferred is heteroaryl ⁇ (CH 2 ) — -
• substituted heteroaryl-(C 1 - C 3 )alkyl means a heteroaryl-(C 1 -C 3 )alkyl functional group in which the heteroaryl group is substituted. Preferred is substituted heteroaryl-(CH 2 ) — .
• heterocycle or “heterocyclyl” 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 sy stem 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 quaternized.
• 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 non-aromatic in nature. In one embodiment, the heterocycle is a heteroaryl.
• heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
• a polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include tetrahydroquinoline and 2,3 -dihydrobenzofuryl.
• non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, imidazoline, pyrazolidine, dioxolane, sulfolane, 2, 3 -dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thioniorpholine, pyran,
• heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl (such as, but not limited to, 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1 ,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
• polycyclic heterocycles include indolyl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (such as, but not limited to, 1- and 5 -isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (such as, but not limited to, 2- and 5 -quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4- benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (such as, but not limited to, 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3 -dihydrobenzofuryl, 1,2-benzisoxazolyl
• substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
• aryl, aryl-(C 1 -C 3 )alkyl and heterocyclyl groups refers to any level of substitution, 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. In 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 1-6 alkyl, —OH, C 1-6 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 are directed to methods of treating respiratory depression modulated by a non-opioid agent including administering to a patient in need thereof, an effective amount of a compound selected from Formula (I) described herein.
• the method of the present disclosure was found in certain embodiments to demonstrate efficacy against overdose of a non-opioid central depressant, such as propofol.
• the method of the present disclosure enhances the body’s ability to react to adverse changes in blood gases.
• the method of the present disclosure is capable of imparting sensitivity back into a regulatory control mechanism that is blunted at the central control point by upregulating a peripheral control point. This is different from opioid antagonists such as naloxone which reverse respiratory depression by competitively displacing opioids from the opioid receptors. That is, antagonists reverse all sequalae of opioids, including beneficial therapeutic effects.
• the method described herein restores the ability of the respiratory system to work despite the central blunting. It has also been found in certain embodiments that the dosing of the compound enhances sensitivity during exposure to anesthetic agents, but does not overtly drive hyperventilation as the patient starts to emerge. In certain embodiments, a higher dose may acutely drive breathing, whereas lower doses may modulate breathing.
• Certain embodiments of the instant disclosure are directed to methods of treating respiratory depression modulated by a non-opioid agent comprising administering, to a patient in need thereof, an effective amount of a compound selected from Formula (I):
• R 1 and R 2 are independently H , alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R J and R 2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- cycloheptane-l,4-diyl, propane- 1 ,3-diyl, butane-l,4-diyl and pentane- 1,5 -diyl;
• R 3 is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, ---NR 1 R 2 , --- C(O)OR 1 , acyl, or aryl;
• R 4 is H, alkyl, or substituted alkyl
• R 5 is H, alkyl, propargylic, substituted propargylic, hornopropargylic, substituted homopropargylic, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, — OR 1 , — NR 4 R 2 , —C(O)OR 1 , 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-undecane-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, O or NR 4 ;
• Y is N, CR 6 or C; wherein: if Y is N or CR 6 , then bond b 1 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 1 is a single bond, and: (i) Z is CH 2 , 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.
• Certain embodiments of the instant disclosure are directed to methods of treating respiratory depression modulated by a non-opioid agent comprising administering, to a patient in need thereof, an effective amount of a compound selected from Formula (I): wherein:
• R 1 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl alkyl, substituted heteroarylalkyl, heteroaryl or substituted heteroaryl; or R 1 and R 2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyl, 6-hydroxy- cycloheptane-l,4-diyl, propane- 1,3 -diyl, butane-l,4-diyl and pentane- 1,5 -diyl;
• R ? is H, alkyl, substituted alkyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, — NR 1 R 2 , — C(O)OR 1 , acyl, or aryl;
• R 4 is H, alkyl, or substituted alkyl
• R 5 is H, alkyl, propargylic, substituted propargylic, homopropargyl ic, substituted homopropargylic, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, --OR 1 , — -NR 1 R 2 , — -C(O)OR 1 , acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, or substituted heterocyclic; or R 3 and R 5 combine as to form a biradical selected from the group consisting of 3,6,9-trioxa-undecane-l,l 1-diyl and 3,6-dioxa-octane-l,8- diyl; wherein at least one substituent selected from the group consisting of R 1 , R 2 , R 3 and R 5 is alkynyl or substituted alkynyl;
• R 6 is H, alkyl, substituted alkyl or alkenyl
• X is a bond, O or NR 4 ;
• Y is N, CR 6 or C; wherein: if Y is N or CR 6 , then bond b 1 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 1 is a single bond, and: (i) Z is CH 2 , 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.
• Certain embodiments of the instant disclosure are directed to methods of treating respirator ⁇ ' depression modulated by a non-opioid agent comprising administering, to a patient in need thereof, an effective amount of a compound selected from Formula (I): wherein:
• 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 heteroarylalkyl, heteroaryl or substituted heteroaryl; or R l and R 2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5-diyi, 6-hydroxy-cycloheptane-l,4-diyl, propane-1, 3- diyl, butane- 1,4-diyl and pentane-1,5-diyl;
• R 3 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, — NR 2 R 2 , —C(O)OR 1 , acyl, or aryl;
• R 4 is H, alkyl, or substituted alkyl
• R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, OR 1 , ---NR1R2, ---C(O)OR 1 , 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-undecane-1,l 1-diyl and 3,6-dioxa-octane-l,8- diyl;
• R 6 is H, alkyl, substituted alkyl or alkenyl
• X is a bond, O or NR 4 ;
• Y is N, CR 6 or C; wherein: if Y is N or CR 6 , then bond b 1 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 1 is a single bond, and: (i) Z is CH 2 , 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 i s H, alkyl, substituted alkyl, cycloalkyl , substituted cycloalkyl, alkenyl, or substituted alkenyl.
• R 5 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, or acyl.
• Certain embodiments of the instant disclosure are directed to methods of treating respirator ⁇ ' depression modulated by a non-opioid agent comprising administering, to a patient in need thereof, an effective amount of a compound selected from Formula (I):
• R 4 and R 2 are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroaryl alkyl, heteroaryl or substituted heteroaryl; or R 4 and R 2 combine as to form a biradical selected from the group consisting of 3-hydroxy-pentane-1,5- diyl, 6-hydroxy-cycloheptane-l,4-diyl, propane- 1,3 -diyl, butane- 1,4-diyl and pentane- 1,5 -diyl;
• R 3 is H, alkyl, substituted alkyl, alkynyl or substituted alkynyl;
• R 4 is H, alkyl, or substituted alkyl
• R 5 is alkyl, propargylic, substituted propargylic, homopropargylic, or substituted homopropargylic, wherein at least one substituent selected from the group consisting of R l , R 2 , R 3 and R 5 is alkynyl or substituted alkynyl;
• R 6 is H, alkyl, substituted alkyl or alkenyl
• X is a bond, O or NR 4 , and,
• Y is N, CR 6 or C; wherein: if Y is N or CR 6 , then bond b 1 is nil and:
• R 3 is H, alkyl or substituted alkyl, and R 5 is propargylic, substituted propargylic, homopropargylic, or substituted homopropargylic, or (ii) R 3 is H or alkynyl, and R 5 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) Y is N, bond b l is nil, Z is H, bond b2 is a single bond, A is CH, and the at least one compound is a compound of formula (II-a) or a salt thereof: and
• the at least one compound of formula (I) is selected from the group consisting of: (i) Y is CR 6 , bond b 1 is nil, Z is H, bond b 2 is a single bond, A is CH, and the at least one compound is a compound of formula (Ill-a) or a salt thereof:
• Y is CR 6 , bond b 1 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:
• Y is C
• bond b 1 is a single bond
• Z is CH 2
• bond b 2 is a single bond
• A is CH
• said at least one compound is a compound of formula (IV) or a salt thereof:
• Y is C
• bond b 1 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-
• the at least one compound is 2,6-bis-(N-n-propylamino)- [l,3]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine N-(4-(Methoxy(methyl)amino)-6-
• the salt is hydrogen sulfate or hydrochloride.
• the at least one compound is N-(4-(Methoxy(methyl)amino)-6- (pr°py!amin°)-l,3,5-triazin-2-yl)propionamide or a salt thereof.
• the salt is hydrogen sulfate or hydrochloride.
• the at least one compound is selected from the group consisting of 2- (n-Propyl)amino-4-(i-propylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVI), 2-(n- Propyl)amino-4-dimethylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXVIII), 2-(n- Propyl)amino-4-methylamino-7-methyl-pyrrolidino[2,3-d]pyrimidine (CXXXI), 2-(n- Propyl)amino-4 ⁇ (i-propyl)amino ⁇ 7-i ⁇ propyl-pyrrolidino[2,3-d]pyrimidine (CXXXVI), 2,4-Bis- (n-propyl)amino-7H-pyrrolidino[2,3-d]pyrimidine (CXLIX), 2-(n-Propyl)amino-4-(i-
• the salt is hydrogen sulfate or hydrochloride.
• the at least one compound is selected from the group consisting of: N- (2-Propylamino-7H”pyrrolo[2,3d]pyrimidin-4-yl)-O,N-dimethyl-hydroxylamine (CXLI), N-(2- (Propen-2-yl)amino-7-methyl-pyrrolo[2,3d]pyrimidin-4-yl)-N,O-dimethyl-hydroxylamine
• the compound is selected from the group consisting of O,N- dimethyl-N”[4-(n-propylamino)-6-(prop-2-ynylamino-[l,3,5]triazin-2-yl]-hydroxylamine; N ⁇ methyl-N'-n-propyl-N"-prop-2”ynyl-[l,3 5]triazine-2,4,6-triamine; a salt thereof; and any combinations thereof.
• the Compound A below is utilized in the present invention is or a pharmaceutically acceptable salt thereof.
• the compound of Formula (I) is selected from compounds described in United States Patent No. 9,162,992 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 non-opioid agent is a central nervous system depressant.
• the central nervous system depressant is a surgical anesthetic.
• the surgical anesthetic is propofol, fospropofol, ketamine, thiopental, methohexital, etomidate, sevoflurane, isoflurane, desflurane or a pharmaceutically acceptable salt thereof.
• the patient exhibits a restored ventilatory' sufficiency.
• the patient exhibits restored ventilator sufficiency under normal sedation, under low sedation or under high sedation.
• the patient exhibits restored ventilator sufficiency under overdose.
• the patient shows increased ventilatory responsiveness.
• the patient shows increased ventilatory responsiveness to hypoxemic events.
• the patient show's increased ventilatory responsiveness to hypercapnic events.
• ventilatory' degradation in the patient is avoided or minimized.
• ventilatory' degradation in the patient is avoided or minimized during periods of hypercapnia.
• the administration route is selected from oral, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal route.
• the therapeutic effect is not decreased.
• the anesthetic effect is maintained.
• the anesthetic effect is not decreased.
• the patient exhibits an improvement in hypoxia
• the patient exhibits an improvement in hyperercapnia.
• the improvement is at least 5%, at least 10% atleast 15%, at least 20% or at least 25%.
• the patient exhibits an improvement in minute ventilation.
• the patient has a positive ventilator response under normocapnic and mild hypercapnic conditions during normoxia.
• the patient maintains ventilator response under normocapnic and mild hypercapnic conditions during normoxia.
• the patient does not exhibit a side effect or experience a clinically significant side effect as measured by one or more of reported adverse events, physical examinations, vital signs, 12- lead ECGs, clinical laboratory test results and Columbia-Suicide Severity Rating Scale (C-SSRS) responses.
• C-SSRS Columbia-Suicide Severity Rating Scale
• the patient does not exhibit clinically significant change in cardiovascular response.
• the patient exhibits a therapeutic effect as measured by Hypoxic sensiti vi ty (A Ventilation/ A S aturati on) .
• the patient exhibits a therapeutic effect as measured by tidal volume (VT).
• VT tidal volume
• the patient exhibits a therapeutic effect as measured by respiratory rate (breaths/min).
• the patient exhibits a therapeutic effect as measured by minute ventilation (VE).
• VE minute ventilation
• the patient exhibits a therapeutic effect as measured by transcutaneous CO 2 measurement and/or end-tidal CO 2 (mmHg).
• the patient exhibits a therapeutic effect as measured by transcutaneous hemogiobin saturation (SpO 2 in %).
• the patient exhibits a therapeutic effect as measured by arterial blood gases.
• the therapeutic effect is measured by BIS.
• the patient exhibits a therapeutic effect as measured by hemodynamic parameters from arterial line monitoring.
• the change is at least 5%, at least 10% at least 15%, at least 20% or at. least. 25%.
• the administration is intravenously.
• the compound of formula (I) is administered at a rate of from about 0.10 mg/kg/hour to about 10 mg/kg/hour.
• the compound of formula (I) is administered at a rate of from about 0.50 mg/kg/hour to about 5 mg/kg/hour.
• the compound of formula (I) is administered at a rate of from about 0.40 mg/kg/hour to about 1.0 mg/kg/hour.
• the compound of formula (I) is administered at a rate of about 0.40 mg/kg/hour.
• the compound of formula (I) is administered at a rate of about 1.0 mg/kg/hour.
• the invention further comprises administering a loading dose.
• the loading dose is from about 0.50 mg/kg/hour to about 5 mg/kg/hour.
• the loading dose is from about 1.0 mg/kg/hour to about 3.0 mg/kg/hour.
• the loading dose is about 2.0 mg/kg/hour.
• the total time of administration is from about 5 minutes to about 24 hours.
• the total time is from about 30 minutes to about 6 hours or from about 1 hour to about 3 hours.
• the loading dose is administered as a bolus.
• the loading dose is administered for a time of less than 1 hour, less than 45 minutes, less than 30 minutes, less than 25 minutes, less than about 10 minutes, about 10 minutes or about 20 minutes.
• administration may be selected from oral, intravenous (e.g., continuous infusion or bolus injection), nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael (e.g., intratracheal instillation or intratracheal inhalation), otic, intraocular, or intrathecal route.
• intravenous e.g., continuous infusion or bolus injection
• nasal, inhalational topical
• buccal rectal
• pleural pleural
• peritoneal vaginal
• intramuscular subcutaneous
• transdermal epidural
• intratrachael e.g., intratracheal instillation or intratracheal inhalation
• otic intraocular, or intrathecal route.
• Non- limiting exemplary’ suitable pulmonary administration may be with a metered dose inhaler, nebulizer, soft mist inhaler, a high efficiency nebulizer, ultrasonic nebulizer, dry' powder inhaler, a continuous positive airway pressure (CPAP) machine, a bilevel positive airway pressure machine (BiPAP), or a ventilator.
• a metered dose inhaler nebulizer, soft mist inhaler, a high efficiency nebulizer, ultrasonic nebulizer, dry' powder inhaler, a continuous positive airway pressure (CPAP) machine, a bilevel positive airway pressure machine (BiPAP), or a ventilator.
• CPAP continuous positive airway pressure
• BiPAP bilevel positive airway pressure machine
• the terminal half-life is about 1 to about 15 hours, about 2 to about 14 hours, about 3 to about 13 hours, about 4 to about 12 hours, about 4 to about 11 hours, about 5 to about 10 hours, about 6 to about 9 hours, or about 7 to about 8 hours.
• the compound of formula (I) is administered at a rate of about. 0.40 mg/kg/hour, and the terminal half-life is about 2 to about 8 hours, about 3 to about 7 hours, about 3.2 to about 6.7 hours, about 3.4 to about. 6.5 hours, about 3.6 to about 6.3 hours, about 3.8 to about 6.1 hours, about 4.0 to about 5.9 hours, about 4.2 to about 5.7 hours, about 4.4 to about 5.5 hours, about 4.6 to about 5.3 hours, or about 4.8 to about 5.1 hours.
• the compound of formula (I) is administered at a rate of about 1.0 mg/kg/hour, and the terminal half-life is about 3 to about 9 hours, about 3.3 to about 8.7 hours, about 3.6 to about. 8.2 hours, about 3.8 to about 8.0 hours, about 4.0 to about 7.8 hours, about 4.2 to about 7.6 hours, about 4.4 to about 7.4 hours, about 4.6 to about 7.2 hours, about 4.8 to about 7.0 hours, about 5.0 to about 6.8 hours, about. 5.2 to about. 6.6 hours, about 5.4 to about 6.4 hours, about 5.6 to about 6.2 hours, or about 5.8 to about 6.0 hours.
• plasma concentration of the compound of formula (I) increases over time.
• the time to maximum plasma concentration (t max ) is about 2 to about. 8 hours, about 3 to about 5 hours, about 3.2 to about 4.7 hours, about 3.5 to about 4.5 hours, or about 3.8 to 4.2 hours.
• the mean peak plasma concentration (C max ) is about 200 to about 2500 ng/niL, about 500 to about 2000 ng/mL, or about 1000 to about 1500 ng/niL.
• the compound of formula (I) is administered at a rate of about 2.0 mg/kg/hr for 20 minutes followed by 1.1 mg/kg/hour for 250 minutes, and has a mean peak plasma concentration (C max ) of about 500 to about 2500 ng/mL, about 1000 to about 2000 ng/mL, about 1050 to about.
• 1950 ng/mL about 1100 to about 1900 ng/mL, about 1 150 to about 1850 ng/mL, about 1200 to about 1800 ng/mL, about 1250 ng/mL to about 1750 ng/mL, about 1300 ng/mL to about 1700 ng/mL, about 1350 to about 1650 ng/mL, or about 1400 ng/mL to about 1500 ng/mL.
• the compound of formula (I) has a mean Al of about 1000 to about 15,000 ng*h/mL, about 2000 to about 12,500 ng*h/mL, about 3000 to about 10,000 ng*h/mL. or about 5000 to about 8000 ng*h/mL.
• the compound of formula (I) is administered at a rate of about 2.0 mg/kg/hr for 20 minutes followed by 1.1 mg/kg/hour for 250 minutes and has a mean ( ⁇ SD) AUC inf of about 5000 to about 15,000 ng*h/mL, about 6200 to about 1 1,000 ng*h/mL, about 6300 to about 10,900 ng*h/mL, about 6400 to about 10,800 ng*h/mL, about 6500 to about 10.700 ng*h/mL, about 6600 to about.
• a geometric mean C av30-3270min (average arterial plasma concentration during 30-270 min) is about 200 ng/mL to about 2000 ng/mL, 250 ng/mL to about. 1800 ng/mL, about 300 ng/mL to about 1500 ng/mL, or about 350 ng/mL to about 1200 ng/mL.
• the compound of formula (I) is administered at a rate of about 2.0 mg/kg/hr for 20 minutes followed by 1.1 mg/kg/hour for 250 minutes and has a geometric mean C av30-3270min (average arterial plasma concentration during 30-270 min) of about 800 ng/mL to about 1800 ng/mL, about 900 ng/mL to about 1600 ng/mL, about 1000 ng/mL to about 1500 ng/mL, about 1050 to about 1450 ng/mL, about 1100 to about 1400 ng/mL, about 1150 to about 1350 ng/mL, or about 1200 to about 1300 ng/mL.
• C av30-3270min average arterial plasma concentration during 30-270 min
• the compound of formula (I) is administered at a rate of about 2.0 mg/kg/hr for 20 minutes followed by 0.4 mg/kg/hour for 250 minutes and has a geometric mean C av30-3270min (average arterial plasma concentration during 30-270 min) of about 200 ng/mL to about 800 ng/mL, about 250 ng/mL to about 600 ng/mL about 300 ng/mL to about 400 ng/mL, about 310 to about 390 ng/mL, about 320 to about 380 ng/mL, about 330 to about 370 ng/mL, or about 340 to about 360 ng/mL.
• C av30-3270min average arterial plasma concentration during 30-270 min
• the compound of formula (I) is administered at a rate of about 2.0 mg/kg/hr for 20 minutes followed by 0.4 mg/kg/hour for 250 minutes and has a mean C max of about 200 to about 800 ng/mL about 375 to about 550 ng/mL, about 400 to about 525 ng/mL, or about 425 to about 500 ng/mL.
• the compound of formula (I) is administered at a rate of about 2.0 mg/kg/hr for 20 minutes followed by 0.4 mg/kg/hour for 250 minutes and has a mean AUC inf of about 1000 to about 4000 ng*h/mL, about 1500 to about 3500 ng*h/mL, about 2000 to about 3300 ng*h/mL, about 2200 to about 3000 ng*h/mL, or about 2500 to about 2800 ng*h/mL.
• the average concentration (e.g., Cmax) at a time period (e.g., Tmax of the compound of formula (I) increases with increasing dosing of the surgical anesthetic.
• the increase is at least about 5%, at least about 10%, at least about 25%, at least about 35%, at least about 45%, or about 5% to about 50%, or about 10% to about 40% or about 15% to about 35%.
• a mean minute ventilation increases during hypoxic measurement.
• the mean minute ventilation may increase by at least about 5%, at least about 10%, at least about 25%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 125%, at least about 150%, or at least about 200%, or any value therein.
• the mean minute ventilation may increase by about 5% to about 200%, about 15% to about 175%, about. 25 % to about 150%, about 50% to about 125%, or about 75% to about 100%.
• a mean tidal volume increases during hypoxic measurements.
• the mean tidal volume may increase by at least about 5%, at least about 10%, at least about 25%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 125%, at least about 150%, or at least about 200%, or any value therein.
• the mean tidal volume may increase by about 5% to about 200%, about 15% to about 175%, about 25 % to about 150%, about 50% to about 125%, or about 75% to about 100%.
• a respiratory rate increases during hypoxic measurements.
• the respiratory rate may increase by at least about. 5%, at least about 10%, at. least about 25%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 125%, at least about 150%, or at least about 200%, or any value therein.
• the respiratory rate may increase by about. 5% to about 200%, about 15% to about 175%, about. 25 % to about 150%, about 50% to about 125%, or about 75% to about 100%.
• the instant disclosure is directed to a pharmaceutical composition
• a pharmaceutical composition comprising an effective amount a compound selected from Formula (I) as disclosed herein to treat respiratory depression modulated by a non-opioid agent.
• the active agent(s) in the pharmaceutical composition is/are lyophilized.
• 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 active 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 excipient. Suitable pharmaceutically acceptable excipients may vary based on the final form and route of administration of the composition.
• Routes of administration of any of the compositions of the invention include inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, intraperitoneal, intrathoracic, intrapleural and topical administration.
• inhalational e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra
• compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
• 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 useful 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 useful 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 useful 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 hvdroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic acid,
• “pharmaceutically acceptable carrier” also includes 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 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 particle size in the case of dispersion and by the use of surfactants.
• Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
• 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 earner 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, flavoring and/or aromatic substances and the like.
• auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances 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 the 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.
• 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 thickening agent.
• suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose.
• Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain 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, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively).
• Known emulsifying agents include, but are not limited to, lecithin, and acacia.
• Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid.
• Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin.
• Known thickening agents for oily suspensions include, for example, beeswax, hard paraffin, and cetyl alcohol.
• 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 water.
• 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 in the solvent.
• Aqueous solvents include, for example, water, and isotonic saline.
• Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin.
• Powdered and granular formulations of a pharmaceutical preparation of the invention may be prepared using known methods. Such formulations may be administered directly to a subject, used, for example, to form tablets, to fill capsules, 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 sweetening, flavoring, or 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.
• emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents.
• 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 trivalent 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, etidronic acid, gallic acid, hypophosphorous acid, nordihydroguairetic acid, propionic acid etc.), phenols (e.g.
• vitamin E tocopherol, D-a-tocopherol, DL-a-tocopherol, tocopherol
• suitable antioxidants may include, without limitations, sterically hindered phenols, aryl amines, thioureas, thiocarbamates, phosphites, thioether esters, and combinations of the foregoing.
• Other suitable examples of antioxidants include, but are not limited to, alkylated monophenols, including but not limited to, 2,6-di-tert-butyl-4-methylphenol, 2-tert- butyl-4,6 ⁇ di-methylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-butyl-4-n-butylphenol,
• hydroquinones and alkylated hydroquinones including but not limited to, 2,6-di-tert-hutyl-4-methoxyphenol, 2,5-di-tert-butylhydroquinone, 2,5-di-tort- amylhydroquinone, 2,6-diphenyl-4-octadecyloxyphenol, 2,6-di-tert-butylhydroquinone, 2,5-di- tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4-hydroxyanisole, 3,5-di-tert-butyl-4- hydroxyphenyl stearate, bis(3,5-di-tert-butyl-4-hydroxyphenyl) adipate, tocopherols, including but not limited to, a-tocopherol, p-tocopherol, y-to
• ene glycol di ethylene glycol, tri ethylene glycol, pentaerythritol, tri s(hydroxyethyl)i socyanurate, N,N'-bis(hydroxyethyl)oxamide, 3-thiaundecanol, 3 -thiapentadecanol, trimethylhexanediol, trimethylolpropane, 4-hydroxymethyl-l-phospha-2,6,7-trioxabicyclo[2.2.2]octane, amides of 6- (3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid e.g.
• 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, polyacrylates, polycaprolactone, polymethacrylates copolymers thereof, and mixtures thereof), liposomes, disintegrants (e.g., polyvinylpyrrolidone, sodium starch glycolate, crosscarmellose sodium, or a mixture thereof), glidants, lubricants, absorption enhancers, surfactants, binders, softeners, plasticizers (e.g., lecithin, hydrogenated vegetable oils, glycerol ester, lanolin, methyl ester, pentaeiythritol este
• polyalkylene oxides
• suitable pharmaceutically acceptable excipients may include polyvinylpyrrolidone, natural and synthetic gums, polyvinyl alcohol, corn 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 acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid) (anhydride), methyl methacrylate, polymethacrylate, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), glycidyl methacrylate copolymers, and mixtures of any of the foregoing), and cellulose ethers,
• Waxes include, e.g., natural and synthetic waxes, fatty 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 microciystalline cellulose, sodium caboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, cellulose acylates, cellulose diacylates, cellulose triacylates, cellulose acetates, cellulose diacetates, cellulose triacetates, cellulose acetate propionates, cellulose acetate butyrates, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, hydroxy propyl
• 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.
• hydrophilic carriers examples 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
• Exemplary low molecular weight polyols include, without limitations, those having a number average molecular weight of from any of about 200 Dalton, about 400 Dalton, 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, pentaerythritol, 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-methy 1 -1,3 -propanediol, trimethylolpropane, a polyether polyol, ethanol amines; and mixtures thereof
• plasticizers such as, but not be limited to, sugar alcohol plasticizer such as triacetin, isomalt, maltitol,
• plasticizers may include 1,2-butylene glycol, 2,3 -butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributylcitrate, triethyl citrate, glyceryl monostearate, polysorbate 80, acetyl triethyl citrate, tributyl citrate and allyl glycolate, and mixtures thereof.
• suitable pharmaceutically acceptable excipients may include plasticizer such as, without limitations, phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; fatty 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 monoglycerides, dipropylene glycol salicylate glycerin, glyceryl cocoate, mono- and di-acetylated monoglycerides, nitrobenzene, carbon disulfide, fl-naphtyl salicylate, phthalyl glycolate, diocyl phthalate; sorbitol, sorbitol glyceryl tricitrate; sucrose octaacetate;
• plasticizer such as, without limitations
• 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
• plasticizers may include, without limitations, low molecular weight polymers, oligomers, copolymers, oils
• plasticizers may include 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, monopropylene glycol monoisopropyl ether, propylene glycol monoethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether, sorbitol lactate, ethyl lactate, butyl lactate, ethyl glycolate, dibutyl sebacate, acetyltributylcitrate, 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, clove leaf, peppermint oil, cedarwood oil, rosemary' oil, bergamot oil, lavandin oil, patchouli oil, chamomile oil, jasmine oil, spike oil, rose oil, Vetiver oil, fennel oil, anise oil, thyme oil, germanium oil, menthol, and marjoram oil.
• An animal fragrance is for example musk, castoreum, 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, citronella!, benzaldehyde, cinnamon aldehyde, vanillin, ethylvanillin, or methyl acetophenone.
• 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. Arctander, Perfume and Flavor Chemicals, Volumes I and II (1960, 1969; reprint 2000); Allured’s Flavor and Fragrance Materials (2005); and database maintained by the Research Institute for Fragrance Materials at www 7 . rifm.org.
• 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, jumper), fruit peels (bergamot, lemon, orange), roots (mace, angelica, celery, cardamom, costus, iris, calmus), 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 cyclohexylpropionate, styrallyl propionate and benzyl salicylate.
• the ethers include, for example, benzyl ethyl ether
• the aldehydes include, for example, the linear alkanals having 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxy citronellal, lilial and bourgeonal
• the ketones include, for example, the ionones, a-isomethylionone and methyl cedryl 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, juniper 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, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labolanum oil and lavandin oil.
• oils include bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, a-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, boisambrene forte, ambroxan, indole, hedione, sandelice, lemon oil, mandarin oil, orange oil, allyl amyl glycolate, cy clovertai, lavandin oil, clary sage oil, p-damascone, geranium oil bourbon, cyclohexyl salicylate, Vertofix asphalt, iso-E-super, Fixolide NP, evernyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romilat,
• suitable pharmaceutically acceptable excipients may include preservatives.
• preservative refers to an agent that extends the storage life of the dosage form by retarding or preventing deterioration of flavor, odor, color, texture, appearance, therapeutic value, or safety.
• a preservative need not provide a lethal, irreversible action resulting in partial or complete microbial cell destruction or incapacitation.
• Sterilants, sanitizers, disinfectants, sporicides, viracides and tuberculocidal 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, pentanediol and sorbic acid, 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, without limitations, “flavor extract” obtained by extracting a part of a raw material, e.g., animal or plant material, often by using a solvent such as ethanol or water; natural essences obtained by extracting essential oils from the blossoms, fruit, roots, etc., or from the whole plants.
• Additional exemplary flavoring agents for the compositions described herein may include, but not be limited to, menthol, spearmint, and cinnamon, coffee beans, other flavors or fragrances such as fruit flavors (e.g., cherry', orange, grape, etc.), quaternary' ammonium bases.
• flavors e.g., cherry', orange, grape, etc.
• quaternary' ammonium bases e.g., quaternary' ammonium bases.
• the effect of flavors may be enhanced using flavor enhancers like tartaric acid, citric acid, vanillin, or the like.
• suitable pharmaceutically acceptable excipients may include sweetening agents such as, without limitations, one or more artificial sweeteners, one or more natural sweeteners, or a combination thereof.
• Artificial sweeteners include, e.g., acesulfame and its various salts such as the potassium salt (available as Sunett®), alitame, aspartame (available as NutraSweet® and Equal®), salt of aspartame-acesulfame (available as Twinsweet®), neohesperidin dihydrochalcone, naringin dihydrochalcone, dihydrochalcone compounds, neotame, sodium cyclamate, saccharin and its various salts such as the sodium salt (available as SweefN Low®), stevia, chloro derivatives of sucrose such as sucralose (available as Kaltame® and Splenda®), and mogrosides.
• Natural sweeteners include, e.g., glucose, dextrose, invert sugar, fructose, sucrose, glycyrrhizin; monoammonium glycyrrhizinate (sold under the trade name MagnaSweet®); Stevia rebaudiana (Stevioside), natural intensive sweeteners, such as Lo Han Kuo, polyols such as sorbitol, mannitol, xylitol, erythritol, and the like.
• 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 lubricant(s)/release agent(s) such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates and fatty amides.
• lubricant(s)/release agent(s) such as, but not limited to, fatty acids and their salts, fatty alcohols, fatty esters, fatty amines, fatty amine acetates and fatty amides.
• Suitable lubricants may include, but not be limited to, glyceryl behenate (CompritolTM 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-Leucine, polyethylene glycols (e.g., CarbowaxTM 4000 and CarbowaxTM 6000), sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, sodium stearyl fumarate (PruvTM), magnesium lauryl sulfate, stearic acid, stearyl alcohol, mineral oil, paraffin, micro crystalline cellulose,
• suitable pharmaceutically acceptable excipients may include diluents such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate, microcrystalline cellulose NF, 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..).
• diluents such as, but not limited to, lactose USP, lactose USP (anhydrous), lactose USP (spray dried), starch USP, directly compressible starch, mannitol USP, sorbitol
• CereloseTM inositol, hydrolyzed cereal solids such as the MaltronsTM and Mor-RexTM, amylose, powdered cellulose (e.g., ElcemaTM), calcium carbonate, glycine, bentonite, polyvinylpyrrolidone, and the like.
• 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 butter, manila oil, mongongo nut oil, olive oil, palm kernel oil, palm oil, peanut oil, pecan oil, perilla oil, pine nut oil, pistachio oil, poppy seed oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, shea butter, soybean oil, sunflower oil, walnut oil, and watermelon seed oil.
• 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, cotton
• oil and fats that may be in the fill of the PVA 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-fatty 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 protein isolates, blood proteins, egg proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar- agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragancanth), pectin, water-soluble derivatives of cellulose: alkylcelluloses hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as methylcelluloseose, hy droxym ethyl cellul ose, hydroxy ethyl cel 1 ulose, hy droxypropy 1 cell ul ose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethyl
• suitable pharmaceutically acceptable excipients may include a hydrophobic material, including, but not limited to, digestible, long chain (C 8 -C 50 , especially C 42 - C 40 ), substituted or unsubstituted hydrocarbons, such as natural or synthetic waxes (such as beeswax, glycowax, castor wax and carnauba wax), fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, 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, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and
• 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, polyaminoacids 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, methyl cellulose, 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 (HPMC), methacrylic acid/methyl methacrylate, methacrylic acid/ethyl acrylate copolymers, methacrylic acid/methyl acrylate/methyl methacrylate copolymers, shellac, hydroxypropyl methylcellulose phthalate, hydroxyl propyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose trimellitate, cellulose acetate phthalates, polyvinyl acetate phthalates, PEG-35 castor oil, caprylocaproyl polyoxyl-8 glycerides,
• suitable pharmaceutically acceptable excipients may include high HLB surfactants such as, without limitations, polysorbate 80-polyoxyethylene (20) sorbitan monooleate, polyoxyl 40 hydrogenated castor oil, polyoxyl 35 castor oil, capryl ocaproyl 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, Steareth-2, Steareth-12, Oleth-2, Ceteth-2, Laureth-4, Oleth-10, Oleth-10/Polyoxyl 10 Oleyl Ether, Ceteth- 10, lsosteareth
• emulsifiers
• emulsifiers are phosphate esters and the salts thereof such as cetyl phosphate (Amphisol® A), diethanolamine cetyl phosphate (Amphisol ® DEA), potassium cetyl phosphate (Amphisol® K), sodium cetearyl sulfate, sodium glyceryl oleate phosphate, hydrogenated vegetable glycerides phosphate and mixtures thereof.
• 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-30 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), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).
• chelating agents such as, without limitations, disodium ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), N-(hydroxyethyl)-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA).
• suitable pharmaceutically acceptable excipients may include fatty alcohols, such as, without limitations guerbet 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, octyl dodecanol, benzoate of C12-C15 alcohols, acetylated lanolin alcohol, etc.
• fatty alcohols such as, without limitations guerbet 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, octyl dodecanol, 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 6 - C 24 fatty acids with linear C 3 - C 24 alcohols, esters of branched C 6 -C 13 carboxyl acids with linear C 6 -C 24 fatty alcohols, esters of linear C 6 -C 24 fatty acids with branched alcohols, especially 2-ethylhexanol, esters of hydroxycarboxylic acids with linear or branched C 6 -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 turner triol) and/or Guerbet alcohols, for example caproic acid, caprylic acid, 2-ethylhexanoic acid, capric acid, lauric acid, isotridecanoic acid, myristic acid, palmitic acid, palm
• 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- nonyl stearate, isononyl isononanoate, 2-ethylhexylpalmitate, 2-hexyllaurate, 2- hexyldecylstearate, 2-octyldodecylpalmitate, oleyloleate, oleylerucate, erucyloleate, erucyl erucate, 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-naphthalate, di-n-butyl adipate, dim- ethyl hexyl )-adipate, di(2-ethyl hexyl)-succinate and diisotridecylvestat, and also diol esters, such as ethylene glycol dioleate, ethylene glycol diisotridecanoate, propylene glycol di(2- ethylhexanoate), propylene glycol diisostearate, propylene glycol dipelargonate, butanediol diisostearate and neopentyl glycol dicapiylate.
• other adjuvants such as, without limitations, diethylhexyl 2,6-naphthalate, di-n-butyl adipate, dim- ethyl hexyl )
• suitable pharmaceutically acceptable excipients may include natural or synthetic triglycerides (including glyceryl esters and derivatives), such as, without limitations, di- or triglycerides, based on Cg-Cis fatty acids, modified by reaction with other alcohols (caprylic/capric triglyceride, wheat germ glycerides, etc.). Fatty acid esters of polyglycerin (polyglyceryl-n such as polyglyceryl-4 caprate, polyglyceryl-2 isostearate, etc.
• castor oil hydrogenated vegetable oil, sweet almond oil, wheat germ oil, sesame oil, hydrogenated cottonseed oil, coconut oil, avocado oil, corn oil, hydrogenated castor oil, shea butter, cocoa butter, soybean oil, mink oil, sunflower oil, safflower oil, macadamia nut oil, olive oil, hydrogenated tallow, apricot kernel oil, hazelnut oil, borage oil, etc.
• waxes including esters of long-chain acids and alcohols as well as compounds having wax-like properties, e.g., carnauba wax, beeswax (white or yellow), lanolin wax, candelilla wax, ozokerite, japan wax, paraffin wax, microcrystalline wax, ceresin, cetearyl esters wax, synthetic beeswax, etc.
• hydrophilic waxes as Cetearyl Alcohol or partial glycerides.
• suitable pharmaceutically acceptable excipients may include pearl escent waxes, such as, without limitations, alkylene glycol esters, especially ethylene glycol distearate; fatty acid alkanolamides, especially coco fatty acid diethanolamide; partial glycerides, especially stearic acid monoglyceride; esters of polyvalent, unsubstituted or hydroxy-substituted carboxylic acids with fatty alcohols having from 6 to 22 carbon atoms, especially long-chained esters of tartaric acid; fatty substances, for example fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers and fatty carbonates, which in total have at least 24 carbon atoms, especially lauryl and di stearyl ether; fatty acids, such as stearic acid, hydroxystearic acid or behenic acid, ring- opening products of olefin epoxides having from 12 to 22 carbon atoms with fatty
• 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 isoparaffinic molecules as polydecenes and polybutene, hydrogenated poly isobutene, squalane, isohexadecane, isododecane and others from plant and animal kingdom.
• hydrocarbon oils such as, without limitations, mineral oil (light or heavy), petrolatum (yellow or white), microcrystalline wax, paraffinic and isoparaffinic compounds, hydrogenated isoparaffinic molecules as polydecenes and polybutene, hydrogenated poly isobutene, squalane, isohexadecane, isododecane and others from plant and animal kingdom.
• suitable pharmaceutically acceptable excipients may include silicones or siloxanes (organosubstituted polysiloxane), such as, without limitations, dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic silicones, and also amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside- and/or alkyl-modified silicone compounds, which at room temperature may be in either liquid or resinous form.
• silicones or siloxanes organosubstituted polysiloxane
• suitable pharmaceutically acceptable excipients may include silicones or siloxanes (organosubstituted polysiloxane), such as, without limitations, dimethylpolysiloxanes, methylphenylpolysiloxanes, cyclic silicones, and also amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside- and/or alkyl-modified silicone compounds, which at
• Linear polysiloxanes dimethicone (Dow Corning 200 fluid, Rhodia Mirasil DM), dimethiconol, cyclic silicone fluids, cyclopentasiloxanes volatiles (Dow Corning 345 fluid), phenyltrimethicone (Dow Corning 556 fluid).
• simethicones are mixtures of dimethi cones 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 ammonium, 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.
• emulsifiers such as, without limitations, carboxylic acids and their salts: alkaline soap of sodium, potassium and ammonium, 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.
• Linear fatty alcohols having from 8 to 22 carbon atoms, branched from 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 alkyl group.
• Fatty alcohol polyglycol ether such as laureth-n, ceteareth-n, steareth-n, oleth-n.
• Fatty acid polyglycol ether 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, poly glyceryl-3 -diisostearates, triglyceryl diisostearates, polyglyceryl-2-sesquiisostearates 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-(10)- sorbitan laurate, PEG-17-dioleate sorbitan.
• Glucose derivatives C8-C22 alkyl-mono and oligo- glycosides 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/m ethyl glucose isostearate.
• Sulfates and sulfonated derivatives dialkylsulfosuccinates, 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.
• Propoxylated or POE-n ethers (Meroxapols), Polaxamers or poly(oxy ethyl ene)m-bl ock-poly(oxypropyl ene)n- block(oxyethylene).
• Zwitterionic surfactants that cany 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-dimethylammonium glycinates, cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium glycinates, cocoacylaminopropyldimethylammonium glycinate and 2-alkyl-3-carboxymethyl-3- hydroxy ethylimidazolines each having from 8 to 18 carbon atoms in the alkyl or acyl group and also cocoacylaminoethylhydroxyethylcarboxymethylglycinate, N-alkyl betaine, N- alkylaminobetaines.
• betaines such as N-alkyl-N,N-dimethylammonium glycinates, cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N,N-dimethylammonium
• Suitable nonionic bases include, without limitations, PEG-6 beeswax (and) PEG-6 stearate (and) polyglyceryl-2-isostearate, glyceryl stearate (and) PEG-100 stearate, PEG-5 glyceryl stearate, sorbitan oleate (and) polyglyceryl-3 ricinoleate, sorbitan stearate and sucrose cocoate, glyceryl stearate and laureth-23, cetearyl alcohol and ceteth-20, cetearyl alcohol and polysorbate 60 and PEG-150 and stearate-20, cetearyl alcohol and cetearyl polyglucoside, cetearyl alcohol and ceteareth-20, cetearyl alcohol and PEG-40 castor oil, cetearyl alcohol and PEG-40 castor oil and sodium cetearyl sulfate, stearyl alcohol and steareth-7 and steareth-10, ceteary
• Suitable anionic alkaline bases includes, without limitations, PEG-2 stearate SE, glyceryl stearate SE, propylene glycol stearate.
• Anionic acid bases such as cetearyl Alcohol and Sodium cetearyl sulfate, cetearyl alcohol and sodium lauryl sulfate, trilaneth-4 phosphate and glycol stearate and PEG-2 stearate, glyceryl stearate and sodium lauryl Sulfate.
• Cationic acid bases such as cetearyl alcohol and cetrimonium bromide.
• suitable pharmaceutically acceptable excipients may include adjuvants and additives, such as, without limitations, surfactants, super-fatting 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-inhibiting agents and the like.
• adjuvants and additives such as, without limitations, surfactants, super-fatting 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-inhibiting 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 fatty acid esters, monoglycerides and fatty acid alkanol amides, the latter simultaneously acting as foam stabilizers.
• super-fatting agents such as, without limitations, lanolin and lecithin and also polyethoxylated or acetylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides and fatty acid alkanol amides, 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, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, .alpha. -olefin sulfonates, ethercarboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkylamidobetaines and/or protein fatty acid condensation products, the latter preferably being based on wheat proteins.
• surfactants such as, without limitations, fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and/or di-alkyl sulfosuccinates, fatty acid isethionates, fatty acid sarcosinates,
• 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, xanthan gum, guar-guar, agar-agar, alginates, carrageenan , gellan, pectines, or modified cellulose such as hydroxy cellulose, 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, xanthan gum, guar-guar, agar-agar, alginates, carrageenan , gellan, pectines, or modified cellulose such as hydroxy cellulose, hydroxypropylmethylcellulose.
• polyacrylates or homopolymer of reticulated acrylic acids and polyacrylamides carbomer (CARBOPOL types 980, 981, 1382, ETD 2001, ETD2020, ULTREZ 10) or SALCARE range
• SALCARE SC80 steareth-10 allyl ether/acrylates copolymer
• Salcare SC81 acrylates copolymer
• Salcare SC91 and Salcare AST sodium acrylates copolymer/PPG-1 trideceth-6
• SEPIGEL 305 polyacrylamide/laureth-7
• SIMULGEL NS and SIMULGEL EG hydroxy ethyl acrylate/ sodium acryloyldimethyl taurate 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
• 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/crotonic acid copolymers, vinylpyrrolidone/vinyl acrylate copolymers, vinyl acetate/butyl maleate/isobomyl acrylate copolymers, methyl vinyl ether/maleic anhydride copolymers and esters thereof, uncrosslinked polyacrylic acids and polyacrylic acids crosslinked with polyols, aery I amidopropyl - trimethylammonium chloride/acrylate copolymers, octyl acrylamide/methyl methacrylate-tert- butylaminoethyl methacrylate/2-hydroxypropyl methacrylate copolymers, polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymers,
• suitable pharmaceutically acceptable excipients may include 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-carnosine, D-carnosine, L-camosine and derivatives thereof (e.g. anserine), carotinoids, carotenes, lycopene and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (e.g.
• 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-carnosine, D-carnosine, L-camosine and derivatives thereof (e.g. anserine), ca
• 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 thereof dilauryl thiodi propionate, distearyl thiodipropionate, thiodi propionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and also sulfoximine compounds (e.g.
• buthionine sulfoximines homocysteine sulfoximine, buthionine sulfones, penta-, hexa-, hepta-thionine sulfoximine
• metal chelating agents e.g. hydroxy fatty acids, palmitic acid phytic acid, lactoferrin), hydroxy acids (e.g. citric acid, lactic acid, malic acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, HDDS, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (e.g.
• 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, rutinic acid and derivatives thereof, glycosylrutin, ferulic acid, furfurylidene glucitol, carnosine, butyl hydroxy toluene, butyl hydroxyanisole, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof superoxide dismutase, N-[3-(3,5-di-tert-butyl-4- hydroxyphenyl)propionyl]sulfanilic acid (and salts thereof, for example the disodium salts), selenium and derivatives thereof (e.g.
• suitable pharmaceutically acceptable excipients may include hydrotropic agents, such as, without limitations, ethoxylated or non-ethoxylated 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 monoethyl ether, ethylene glycol monobutylether, propylene glycol monomethylether, propylene glycol monoethylether, propylene glycol monobutylether, diethylene glycol monomethylether; diethylene glycol monoethylether, diethylene glycol monobutylether and similar products).
• 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 to 1000 Dalton; technical oligoglycerol mixtures having an intrinsic degree of condensation of from 1.5 to 10, for example technical di glycerol mixtures having a di glycerol content of from 40 to 50% by weight, methylol compounds, such as, especially, trimethylolethane, trimethylolpropane, trimethylolbutane, pentaerythritol and dipentaerythritol; lower alkyl- glucosides, especially those having from 1 to 8 carbon atoms in the alkyl radical, for example methyl and butyl glucoside; sugar alcohols having from 5 to 12 carbon atoms, for example sorbitol or mannitol; sugars having from 5 to 12 carbon
• suitable pharmaceutically acceptable excipients may include preservatives, such as, without limitations, Methyl-, Ethyl-, Propyl-, Butyl-parabens, Benzalkonium chloride, 2-Bromo-2-nitro-propane-l,3-diol, Dehydroacetic acid, Diazolidinyl Urea, 2-Di chloro-benzyl alcohol, DMDM hydantoin, Formaldehyde solution, Methyldibromoglutanitrile, Phenoxyethanol, Sodium Hydroxymethyl glycinate, Imidazolidinyl Urea, Triclosan 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-parabens, Benzalkon
• suitable pharmaceutically acceptable excipients may include bacteria-inhibiting agents, such as, without limitations, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, chlorhexidine (l,6-di(4-chlorophenyl-biguanido)hexane) or TCC (3,4,4'-trichlorocarbanilide).
• bacteria-inhibiting agents such as, without limitations, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, chlorhexidine (l,6-di(4-chlorophenyl-biguanido)hexane) or TCC (3,4,4'-trichlorocarbanilide).
• a large number of aromatic substances and ethereal oils also have antimicrobial properties. Typical examples are the active ingredients eugenol, menthol and thymol in clove oil, mint oil and thyme oil.
• a natural deodorizing agent of interest is the terpene alcohol farnesol (3,7,1 l-trimethyl-2,6, 10- dodecatrien-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 wt%, about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, or about 99 wt%, or any sub-range or single value therein based on the total weight of the composition.
• the instant disclosure is directed 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 or more pharmaceutically acceptable excipients.
• 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, an enteric 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.
• a customized release profile for the active agent such as, without limitations, an immediate release profile, a controlled release profile, a delayed release profile, an enteric release profile, a zero order release profile, a first order release profile, a pulsatile release profile, a targeted release in a certain location within the body (such as a target location within the gastrointestinal tract), and the like.
• the study is a 3-period, randomized, placebo-controlled, double-blind, crossover study in healthy subjects.
• the primary objective of the study was to determine the safety and tolerability of Compound A in healthy participants after low and high doses of Compound A under hypoxic and hypercapnic conditions in conjunction withlow and high doses of propofol.
• Another primary objective of the study was to determine the ventilatory response of low and high doses of Compound A under hypoxic and hypercapnic conditions in conjunction with low and high doses of propofol.
• a secondary objective of the study was to determine the cardiovascular response oflow and high doses of Compound A during hypoxic and hypercapnic conditions in conjunction with low and high doses of propofol. Another secondary?
• the study was a randomized, double-blinded, placebo-controlled, three-way crossover study to assess the safety, tolerability, respiratory? PD, and PK of Compound A in healthy male and female participants. Subjects were initially screened up to 6 weeks prior to randomization. Following successful initial medical screening, they were scheduled for the study and receive a randomization number.
• Each assessment period (i.e., “run”) consists of a hypoxia/hyperoxic exposure at normocapnia followed by one the same sequence at hypercapnia.
• a total of 12 participants completed all treatments as planned per protocol. The participants received the following treatments in random order during the dosing periods:
• Subjects were admitted to study site on Day -1 for pre-dose activities and eligibility was reassessed and stayed overnight. On each dosing day (Day 1), subjects were transferred to a special unit at study site in the morning (or early afternoon) after a minimum 8 hour overnight fasting. After placement of the respiratory and cardiovascular monitoring/assessment devices including an arterial line, subjects assumed the semi-recumbent position and sufficient time was allowed for subjects to resume a normal breathing pattern. After completion of baseline evaluations, all measurements were performed as per the schedule of assessments.
• subjects Upon completion of all measurements on the dosing day, subjects were monitored overnight and assessed the next morning (at least 12 hours post study treatments) prior to discharge (Day 2). Subjects were not immediately discharged in cases where prolonged care is required (e.g., due to adverse event, residual sedation etc.) and were treated as necessary.
• the investigational product was prepared as follows: Compound A 10 mg/mL was supplied as 50-mL vials (batch number B210239). Infusion bags at a fixed concentration of Compound A ⁇ 0.8 mg/mL in Ringer’s lactate were prepared for dosing by the LUMC trial pharmacy per the pharmacy manual. Compound A was administered intravenously based on participant weight for a period of 270 minutes. Investigational product was dispensed for each participant according to the randomisation list.
• a loading dose was administered at 2.0 mg/kg/h for 10 (for low dose) or 20 minutes (for high dose) for both the low and high dose followed by continuous infusion of the following for 250- 260 minutes, so that the total infusion time is 270 minutes:
• Propofol was administered over a 155-minute period per dosing/treatment session, composed of two 70- minute low/high dosing regimens separated by a 15-minute transition dose. Propofol was infused from a 10 mg/ml preparation as follows:
• Propofol 10 mg/niL for injection was provided as a sterile product ready for infusion (batch numbers 16QF1624 and 16QG1950).
• Compound A solution was colorless and its identity (prior to dilution and when mixed for injection) is similar to sterile normal saline solution or Ringer’s lactate.
• PD and safety reports Performed after completion of all the treatments and procedures for the first 6 subjects of the study.
• the data (i.e., PD and safety reports) supporting interim analysis will be archived. Analysis will include blinded safety (AEs, BP, ECG) (unblinded if necessary) and PD parameters will include ventilatory' measurements and ETCO?. PD will be unblinded for treatment but not subject. Dosing of the last 6 subjects is not dependent on the interim analysis and will proceed in parallel.
• the primary PD endpoint was hypoxic sensitivity which was analyzed with a mixed model analysis of variance with the fixed factors treatment, condition and treatment by condition, and the random factors participant, participant by treatment and participant by condition (combination of propofol condition and ventilatory condition).
• the BIS was analyzed with a mixed model analysis of covariance with the fixed factors treatment, time, treatment by time, and the random factors participant, participant by treatment and participant by time and the pre-value as covariate.
• the general treatment effect and specific contrasts were reported with the estimated difference and the 95% confidence interval, the least, square mean estimates, and the p- value.
• the individual Compound A and propofol plasma concentrations were listed and plotted in panel plots for each Compound A treatment period using both a linear and log y-axis.
• the individual plasma Compound A and propofol concentrations were summarised by Compound A treatment period and time, and were also presented graphically as mean over time, with standard deviation as error bars. Summary/ statistics were provided including all plasma concentration samples irrespective of the sampling time.
• the individual PK parameters were summarised per treatment and propofol treatment interval and were presented graphically as boxplots.
• hypoxic sensitivity was the primary PD outcome measure of the study.
• Hypoxic sensitivity is the marker of carotid body activity. In all participants, breathing increased during the hypoxic measurements. This was generally more profound during hy percapnia than during normocapnia.
• minute ventilation increased from 8.1 L/min to 30.3 L/min during the first hypoxic measurement under hypercapnic conditions and increased from 6.3 L/min to 15.0 L/min during the hypoxic/hypercapnic measurement during the propofol high dose administration.
• minute ventilation increased from 8.5 L/min to 38.8 L/min during the first hypoxic measurement under hypercapnic conditions and increased from 8.4 L/min to 27.4 L/min during the hypoxic/hypercapnic measurement during the propofol high dose administration thereby maintaining a similar increase to pre-propofol levels after placebo treatment. Minute ventilation did not increase during treatment with Compound A when participants were not exposed to hypoxia.
• Minute ventilation was a composite of tidal volume in mL per breath (Fig. 4) and respiratoiy rate in breaths per minute (Fig. 5). For these two parameters, the same trend was observed as for minute ventilation, thereby indicating that the increase in ventilation was a result both the increased volume of breath as well as the increased number of breaths drawn per minute. For respiratory rate, a difference between Compound A high dose compared to placebo and Compound A low' dose could be observed during propofol infusion at pre-hypoxic timepoints.
• the ETCO 2 (Fig. 6) was increased after the first hypoxic measurement of each propofol dosing interval in order to perform another hypoxic measurement at hypercapnia. Values recorded for Compound A low' dose w'ere comparable to placebo treatment. However, at both pre-hypoxic timepoints as well as during hypoxia and hypercapnia, the values recorded for Compound A high dose were lower compared to placebo. Although no statistical analysis was defined for ETCO 2 in the statistical analysis plan, the difference between treatments was evidence from the summary graph in Fig. 6.
• the oxygen saturation SpO 2 was also measured and shown in Fig. 7.
• the SpO 2 remained above 96.4% at all pre-hypoxic baseline timepoints for all three treatments.
• SpO 2 ranged 80.4-84.3%, 81.2-83.7%, 80.4-84.2% for placebo, Compound A low and high dose, respectively.
• the SpO 2 was steered during measurements by the investigator-controlled inhaled gas mix, this did not regard an independent variable but rather a confirmation that the measurements were performed per protocol.
• the highest individual C max reached with the Compound A high dose was 2600 ng/mL, the highest individual AUC inf reached with the Compound A high dose was 13763 ng*h/mL.
• the average Compound A concentrations increased with increasing propofol dosing intervals i.e., no propofol 30-100min, low propofol 115-185min, and high propofol 200-270min: the average concentrations for Compound A low dose were 323.41, 359.75, and 427.54 ng/mL, respectively, and for Compound A high dose these were 971.79, 1206,27, and 1412,28 ng/mL, respectively.
• Geometric mean C av30-3270min average arterial plasma ENA-001 concentration during 30-270min
• Compound A low and high dose were 366.40 and 1161.69 ng/mL, respectively.
• the increase was not considered related to the propofol dose but rather to the fact that steady state had not been reached.
• the infusion regimens in the current study were designed to maintain stable Compound A and propofol (low and high dose) concentrations during the respective dosing intervals.
• the PK of Compound A showed dose proportionality over the investigated dosing range, and exposure levels were in the targeted range, based on PK modelling that was performed in preparation of this study. Low levels of inter-individual variability in the C max , distribution, and elimination phase w'ere observed.
• Compound A did not reach steady state and concentrations increased during continuous infusion until infusion was stopped. Plasma concentration differences were not reflected in safety parameters and the ventilatory/ response of Compound A was evident throughout the treatment period. No apparent effect of propofol on Compound A concentrations w-ere observed.
• the propofol dosing regimen was designed to simulate infusion with a target-controlled infusion pump, targeting plasma concentration of 600 and 1200 ng/mL during the propofol low' and high dose, respectively. Plasma concentrations during the low dose infusion were similar to the targeted concentration, but the high dose resulted in plasma concentrations exceeding those targeted. Dose proportionality of propofol PK over the investigated dosing range was not apparent, with relatively higher plasma concentrations recorded during the high dose infusion. It must be noted that despite these higher propofol plasma concentrations, the effect of Compound A on ventilation was significant.
• Compound A is safe and well tolerated in healthy participants at the two dose levels administered in the study. Treatment with Compound A increased hypoxic sensitivity compared to placebo, both with and without co-administration of clinically relevant plasma concentrations of propofol. Administration of Compound A did not impact the level of the propofol -induced sedation, as measured by the BIS.
• 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 to the same embodiment.

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