WO2022147189A1 - Promédicaments de varénicline - Google Patents

Promédicaments de varénicline Download PDF

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Publication number
WO2022147189A1
WO2022147189A1 PCT/US2021/065597 US2021065597W WO2022147189A1 WO 2022147189 A1 WO2022147189 A1 WO 2022147189A1 US 2021065597 W US2021065597 W US 2021065597W WO 2022147189 A1 WO2022147189 A1 WO 2022147189A1
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Prior art keywords
compound
varenicline
room temperature
pharmaceutical formulation
temperature solubility
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PCT/US2021/065597
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English (en)
Inventor
Xiaoming Chen
Shaowei Ong
David Favor
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Antares Pharma, Inc.
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Publication of WO2022147189A1 publication Critical patent/WO2022147189A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • This disclosure relates generally to varenicline prodrugs and methods of making and use thereof, including methods of treating nicotine addiction.
  • Varenicline is the first approved nicotinic receptor partial agonist. It is a partial agonist of the a4/p2 subtype of the nicotinic acetylcholine receptor. Varenicline, as the tartrate salt, is available under prescription in the US market under the trade name CHANTIX® as 0.5 mg and 1 mg equivalent to Varenicline film coated tablets.
  • Varenicline as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9, 10-tetrahy dro-6,10-methano6H- pyrazino[2,3- h][3] benzazepine, (2R,3R) -2,3- dihydroxybutanedioate (1 : 1). It is highly soluble in water.
  • Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3 • C4H6O6.
  • the disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • R 1 is selected from unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, and R 2 is methyl or hydrogen.
  • R 2 is hydrogen. In some embodiments, R 2 is methyl. In some embodiments, R 1 is a an alkyl or alkenyl group. In some embodiments, R 1 is selected from pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, O ’ — ⁇ R 1 and tridecyl. In some embodiments, in Formula I ' is an acyl group corresponding to a
  • in Formula is an acyl group
  • O corresponding to a fatty acid.
  • in Formula I is an acyl group corresponding to a fatty acid selected from the group consisting of lauric acid, linoleic acid, oleic acid, palmitic acid, palmitoleic acid, ricinoleic acid, linolenic acid, stearic acid, myristic acid, and arachidonic acid.
  • the disclosure also provides a compound of Formula 100:
  • the disclosure also provides a compound of Formula 101 :
  • the disclosure also provides a pharmaceutical formulation comprising the compound of any formula described herein, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a carrier.
  • the carrier comprises a solvent.
  • the solvent comprises an ester.
  • the solvent comprises an alcohol.
  • the solvent comprises one or more of benzyl benzoate, benzyl alcohol, and ethanol.
  • the carrier comprises an oil component.
  • the oil component comprises a vegetable oil.
  • the oil component comprises castor oil.
  • the oil component comprises sesame oil.
  • the oil component comprises cotton seed oil.
  • the oil component comprises olive oil. In some embodiments, the oil component comprises a triglyceride. In some embodiments, the oil component comprises a medium chain triglyceride. In some embodiments, the oil component comprises one or more triglyceride selected from LLL, OLL, OOL, OOO, PLL, POL, POO, or SOL. In some embodiments, the concentration of the compound in the pharmaceutical formulation is between about 2.5 mg/mL and about 250 mg/mL. In some embodiments, the amount of compound in 1 mL of pharmaceutical formulation is an amount which upon metabolization affords between about 1 mg and about 200 mg of systemically available varenicline.
  • the amount of compound in 1 mL of pharmaceutical formulation is an amount which upon metabolization affords between about 25 mg and about 150 mg of systemically available varenicline. In some embodiments, the amount of compound in 1 mL of pharmaceutical formulation is an amount which upon metabolization affords about 20 mg of systemically available varenicline, about 30 mg of systemically available varenicline, about 40 mg of systemically available varenicline, about 50 mg of systemically available varenicline, about 60 mg of systemically available varenicline, about 70 mg of systemically available varenicline, about 80 mg of systemically available varenicline, about 90 mg of systemically available varenicline, about 100 mg of systemically available varenicline, about 110 mg of systemically available varenicline, about 120 mg of systemically available varenicline, about 130 mg of systemically available varenicline, about 140 mg of systemically available varenicline, or about 150 mg of systemically available varenicline.
  • the concentration of the compound in the pharmaceutical formulation is between about 2.5 mg/g and about 250 mg/g. In some embodiments, the amount of compound in 1 g of pharmaceutical formulation is an amount which upon metabolization affords between about 1 mg and about 200 mg of systemically available varenicline. In some embodiments, the amount of compound in 1 g of pharmaceutical formulation is an amount which upon metabolization affords between about 25 mg and about 150 mg of systemically available varenicline.
  • the amount of compound in 1 g of pharmaceutical formulation is an amount which upon metabolization affords about 20 mg of systemically available varenicline, about 30 mg of systemically available varenicline, about 40 mg of systemically available varenicline, about 50 mg of systemically available varenicline, about 60 mg of systemically available varenicline, about 70 mg of systemically available varenicline, about 80 mg of systemically available varenicline, about 90 mg of systemically available varenicline, about 100 mg of systemically available varenicline, about 110 mg of systemically available varenicline, about 120 mg of systemically available varenicline, about 130 mg of systemically available varenicline, about 140 mg of systemically available varenicline, or about 150 mg of systemically available varenicline.
  • the pharmaceutical formulation further comprises one or more inactive ingredients selected from an oil, a chelating agent, an antioxidant, and a solvent.
  • the antioxidant is selected from butylated hydroxy toluene (BHT), tocopherol, butylated hydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid and salts thereof, vitamin E, niacinamide, methionine, monothioglycerol, sodium bisulfite, cysteine, dithionite sodium, gentisic acid, and glutamate monosodium.
  • the compound has Formula 100:
  • the compound has a cLogP of about 6.1.
  • the concentration of the compound in the formulation is from 10% to 100% of the experimentally determined mean room temperature solubility in the carrier. In some embodiments, the concentration of the compound in the formulation is from 45% to 55% of the experimentally determined mean room temperature solubility in the carrier, from 55% to 65% of the experimentally determined mean room temperature solubility in the carrier, from 65% to 75% of the experimentally determined mean room temperature solubility in the carrier, from 75% to 85% of the experimentally determined mean room temperature solubility in the carrier, or from 85% to 95% of the experimentally determined mean room temperature solubility in the carrier.
  • the carrier comprises sesame oil
  • the mean room temperature solubility of the compound in the formulation is about 27.09 mg/g or about 24.8 mg/mL.
  • the concentration of the compound in the formulation is from 10% to 100% of the mean room temperature solubility.
  • the concentration of the compound in the formulation is from 45% to 55% of the mean room temperature solubility, from 55% to 65% of the mean room temperature solubility, from 65% to 75% of the mean room temperature solubility, from 75% to 85% of the mean room temperature solubility, or from 85% to 95% of the mean room temperature solubility.
  • the carrier comprises about 36.2 %w/w castor oil and about 63.8 %w/w benzyl benzoate, and the mean room temperature solubility of the compound in the formulation is about 150.82 mg/g or about 158 mg/mL.
  • the concentration of the compound in the formulation is from 10% to 100% of the mean room temperature solubility. In some embodiments, the concentration of the compound in the formulation is from 45% to 55% of the mean room temperature solubility, from 55% to 65% of the mean room temperature solubility, from 65% to 75% of the mean room temperature solubility, from 75% to 85% of the mean room temperature solubility, or from 85% to 95% of the mean room temperature solubility.
  • the compound has Formula 101 : Formula 101.
  • the compound has a cLogP of about 7.1.
  • the concentration of the compound in the formulation is from 10% to 100% of the experimentally determined mean room temperature solubility in the carrier. In some embodiments, the concentration of the compound in the formulation is from 45% to 55% of the experimentally determined mean room temperature solubility in the carrier, from 55% to 65% of the experimentally determined mean room temperature solubility in the carrier, from 65% to 75% of the experimentally determined mean room temperature solubility in the carrier, from 75% to 85% of the experimentally determined mean room temperature solubility in the carrier, or from 85% to 95% of the experimentally determined mean room temperature solubility in the carrier.
  • the carrier comprises sesame oil
  • the mean room temperature solubility of the compound in the formulation is about 28.26 mg/g or about 25.9 mg/mL.
  • the concentration of the compound in the formulation is from 10% to 100% of the mean room temperature solubility.
  • the concentration of the compound in the formulation is from 45% to 55% of the mean room temperature solubility, from 55% to 65% of the mean room temperature solubility, from 65% to 75% of the mean room temperature solubility, from 75% to 85% of the mean room temperature solubility, or from 85% to 95% of the mean room temperature solubility.
  • the carrier comprises about 36.2 %w/w castor oil and about 63.8 %w/w benzyl benzoate, and the mean room temperature solubility of the compound in the formulation is about 156.88 mg/g or about 164 mg/mL.
  • the concentration of the compound in the formulation is from 10% to 100% of the mean room temperature solubility. In some embodiments, the concentration of the compound in the formulation is from 45% to 55% of the mean room temperature solubility, from 55% to 65% of the mean room temperature solubility, from 65% to 75% of the mean room temperature solubility, from 75% to 85% of the mean room temperature solubility, or from 85% to 95% of the mean room temperature solubility.
  • the compound has Formula 102:
  • the compound has a cLogP of about 8.0.
  • the concentration of the compound in the formulation is from 10% to 100% of the experimentally determined mean room temperature solubility in the carrier. In some embodiments, the concentration of the compound in the formulation is from 45% to 55% of the experimentally determined mean room temperature solubility in the carrier, from 55% to 65% of the experimentally determined mean room temperature solubility in the carrier, from 65% to 75% of the experimentally determined mean room temperature solubility in the carrier, from 75% to 85% of the experimentally determined mean room temperature solubility in the carrier, or from 85% to 95% of the experimentally determined mean room temperature solubility in the carrier.
  • the carrier comprises sesame oil
  • the mean room temperature solubility of the compound in the formulation is about 20.43 mg/g or about 18.7 mg/mL.
  • the concentration of the compound in the formulation is from 10% to 100% of the mean room temperature solubility.
  • the concentration of the compound in the formulation is from 45% to 55% of the mean room temperature solubility, from 55% to 65% of the mean room temperature solubility, from 65% to 75% of the mean room temperature solubility, from 75% to 85% of the mean room temperature solubility, or from 85% to 95% of the mean room temperature solubility.
  • the carrier comprises about 36.2 %w/w castor oil and about 63.8 %w/w benzyl benzoate, and the mean room temperature solubility of the compound in the formulation is about 128.03 mg/g or about 134 mg/mL.
  • the concentration of the compound in the formulation is from 10% to 100% of the mean room temperature solubility. In some embodiments, the concentration of the compound in the formulation is from 45% to 55% of the mean room temperature solubility, from 55% to 65% of the mean room temperature solubility, from 65% to 75% of the mean room temperature solubility, from 75% to 85% of the mean room temperature solubility, or from 85% to 95% of the mean room temperature solubility.
  • the disclosure also provides a method of treating nicotine addiction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any compound described herein, or a therapeutically effective amount of any pharmaceutical formulation described herein.
  • a method of treating nicotine addiction comprising administering to the subject a therapeutically effective amount of any compound described herein, or a therapeutically effective amount of any pharmaceutical formulation described herein.
  • the subject upon administration to the subject of the therapeutically effective amount of the compound, or the therapeutically effective amount of the pharmaceutical formulation, the subject experiences a reduced craving for a nicotine delivery product.
  • the subject upon administration to the subject of the therapeutically effective amount of the compound, or the therapeutically effective amount of the pharmaceutical formulation, the subject experiences a reduced pleasurable effect of a nicotine delivery product.
  • the nicotine delivery product is a cigarette or other tobacco product.
  • the nicotine delivery product is a patch-type product, a chewable or other oral delivery product, or a vaping or other inhalable product.
  • the subject upon administration to the subject of the therapeutically effective amount of the compound, or the therapeutically effective amount of the pharmaceutical formulation, the subject experiences less side effects compared to administration of an equivalent amount of varenicline via oral dosage forms.
  • the subject is being administered an amount of compound, or corresponding formulation, which upon metabolization affords between about 1 mg and about 200 mg of systemically available varenicline.
  • the subject is being administered an amount of compound, or corresponding formulation, which upon metabolization affords between about 25 mg and about 150 mg of systemically available varenicline.
  • the subject is being administered an amount of compound, or corresponding formulation, which upon metabolization affords about 20 mg of systemically available varenicline, about 30 mg of systemically available varenicline, about 40 mg of systemically available varenicline, about 50 mg of systemically available varenicline, about 60 mg of systemically available varenicline, about 70 mg of systemically available varenicline, about 80 mg of systemically available varenicline, about 90 mg of systemically available varenicline, about 100 mg of systemically available varenicline, about 110 mg of systemically available varenicline, about 120 mg of systemically available varenicline, about 130 mg of systemically available varenicline, about 140 mg of systemically available varenicline, or about 150 mg of systemically available varenicline.
  • Figure 1 is the X H NMR of Varenicline.
  • Figure 2 is the ’H NMR of ATRS- 1901-004.
  • Figure 3 is the LC of ATRS- 1901-004.
  • Figure 4 is the MS of ATRS-1901-004.
  • Figure 5 is the ’H NMR of ATRS- 1901-005.
  • Figure 6 is the LC of ATRS- 1901-005.
  • Figure 7 is the MS of ATRS- 1901-005.
  • Figure 8 is the ’H NMR of ATRS- 1901-006.
  • Figure 9 is the LCMS of ATRS- 1901-006.
  • Figure 10 is the MS of ATRS- 1901-006.
  • Figure 11 is the chromatogram of ATRS-1901-004.
  • Figure 12 is the spectrum index plot of ATRS-1901-004.
  • Figure 13 is the chromatogram of ATRS-1901-005.
  • Figure 14 is the spectrum index plot of ATRS-1901-005.
  • Figure 15 is the chromatogram of ATRS-1901-006.
  • Figure 16 is the spectrum index plot of ATRS-1901-006.
  • Figure 17 is an overlay chromatogram of three Varenicline prodrugs.
  • Figure 18 is the overlay of three varenicline prodrugs spiked with 0.1 N NaOH.
  • Figure 19 shows physical observation of solubility screening samples of Varenicline prodrugs after shaking at room temperature, in four solvent systems as described in Table 9;
  • Figure 19A Varenicline Methoxy Acyloxy-dodecanoyl (ATRS-1901-005);
  • Figure 19B Varenicline Methoxy Acyloxy-decanoyl (ATRS-1901-004);
  • Figure 19C Varenicline Methoxy Acyloxy -tetradecanoyl (ATRS- 1901 -006).
  • the present invention is directed to prodrugs of varenicline.
  • Varenicline and related compounds and uses thereof are described in U.S. Patent Nos. 6,410,550, 6,890,927, and 7,265,119, which are incorporated in their entireties herein.
  • administer refers to (1) providing, giving, dosing, and/or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure, and/or (2) putting into, taking, or consuming by a subject, for example a mammal, including a human, according to the disclosure.
  • co-administration encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and/or their metabolites are present in the subject at the same time.
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. In some embodiments, simultaneous administration in separate compositions and administration in a composition in which both agents are present are preferred.
  • an effective amount refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment.
  • a therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc., which can readily be determined by one of ordinary skill in the art.
  • the term also applies to a dose that will induce a particular response in target cells (e.g., the reduction of platelet adhesion and/or cell migration).
  • the specific dose will vary depending on the subject to whom the dose is to be administered, the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.
  • a prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • the terms “treat,” “treatment,” and/or “treating” may refer to the management of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, and/or control the disease, disorder, pathological condition or symptom thereof.
  • control may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition).
  • the terms “prevent,” “preventing,” and/or “prevention” may refer to reducing the risk of developing a disease, disorder, or pathological condition.
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.
  • Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, phosphoric acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • cocrystal refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “physiologically compatible” carrier or carrier medium is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients.
  • the use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.
  • a “prodrug” refers to a derivative of, and/or a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo to the active compound.
  • Prodrugs include, without limitation, compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxyl or carboxylic acid group of a parent drug.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by one or three letter symbols but also include, for example, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3- methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxy methyl esters).
  • Prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of the method of the invention with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, phosphates, succinates, butyrates, pivalates, methylcarbonates, benzoates and the like.
  • free hydroxyl groups may be derivatized using groups including but not limited to hemi succinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxy carbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 115.
  • Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups.
  • Free amines can also be derivatized to amides, sulfonamides or phosphonamides. All of the stated prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities.
  • any compound that can be converted in vivo to provide the bioactive agent is a prodrug within the scope of the invention.
  • Various forms of prodrugs are well known in the art.
  • prodrugs may be designed to improve the penetration of a drug across biological membranes in order to obtain improved drug absorption, to prolong duration of action of a drug (slow release of the parent drug from a prodrug, decreased first-pass metabolism of the drug), to target the drug action (e.g., organ or tumor-targeting, lymphocyte targeting), to modify or improve aqueous solubility of a drug (e.g., i.v. preparations and eyedrops), to improve topical drug delivery (e.g., dermal and ocular drug delivery), to improve the chemical/enzymatic stability of a drug, or to decrease off-target drug effects, and more generally in order to improve the therapeutic efficacy of the compounds utilized in the invention.
  • target the drug action e.g., organ or tumor-targeting, lymphocyte targeting
  • aqueous solubility of a drug e.g., i.v. preparations and eyedrops
  • topical drug delivery e.g., dermal and ocular drug delivery
  • the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by 13 C-enriched or 14 C-enriched carbons are within the scope of this invention.
  • ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • Use of the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically from 0% to 15%, from 0% to 10%, from 0% to 5%, or the like, of the stated number or numerical range.
  • the term “about” means that amounts, sizes, formulations, parameters, shapes and other quantities and characteristics are not, and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter, shape or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such.
  • the term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step or material.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (Ci-io)alkyl or Ci-io alkyl).
  • a numerical range such as “1 to 10” refers to each integer in the given range, e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, //-butyl, isobutyl, ec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl.
  • the alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), //-propyl (Pr), 1 -methylethyl (isopropyl), //-butyl, //-pentyl, 1,1 -dimethylethyl (/-butyl) and 3 -methylhexyl.
  • an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O)tR a - (where t is 1 or 2), -OC(O)-R a , -N(R a )2, - C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)C(O)
  • the alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.
  • alkene or “alkenyl” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • alkyne refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond.
  • Alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., (C2-io)alkenyl or C2-10 alkenyl).
  • a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • the alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl and penta- 1,4-dienyl.
  • an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O)tR a - (where t is 1 or 2), -OC(O)-R a , - N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R )
  • Alkenyl-cycloalkyl refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.
  • Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e., (C3-io)cycloalkyl or C3-10 cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range - e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms.
  • cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
  • a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, acylsulfonamido, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - OR a , -SR a , -S(O)tR a - (where t is 1 or 2), -S(O)tR a - (where t is 1 or 2), -OC(O)-R a , - N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a )
  • Cycloalkyl-alkenyl refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.
  • “Acyl” refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)- C(O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality.
  • the R radical is heteroaryl or heterocycloalkyl
  • the hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, acylsulfonamido, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O)tR a - (where t is 1 or 2), -OC(O)-R a , - N(R a ) 2 , -C(O)R
  • Ester refers to, without limitation, a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon).
  • the procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • an ester group is optionally substituted by one or more substituents which independently are: alkyl, acylsulfonamido, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxamate, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -S(O)tR a - (where t is 1 or 2), -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a
  • “Ester” also refers to, without limitation, a phosphate.
  • “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.
  • “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space - /. ⁇ ., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a “racemic” mixture. The term “( ⁇ )” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.
  • the absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R-S system.
  • the stereochemistry at each chiral carbon can be specified by either (R) or (S).
  • Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line.
  • Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (5).
  • “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
  • “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization.
  • keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4- hydroxypent-3-en-2-one tautomers.
  • Another example of tautomerization is phenol-keto tautomerization.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(U7)-one tautomers.
  • “Substituted” means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxamate, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups,
  • substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • the disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • R 1 is selected from unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted heteroarylalkyl, and R 2 is alkyl, e.g., methyl, alkenyl, or hydrogen.
  • R 2 is hydrogen. In some embodiments, R 2 is methyl. In some embodiments, R 1 is a an alkyl or alkenyl group. In some embodiments, R 1 is selected from pentyl, hexyl, heptyl, octyl, nonyl, decyl,
  • O is an acyl group corresponding to a fatty acid.
  • in Formula I is an acyl group corresponding to a fatty acid selected from the group consisting of lauric acid, linoleic acid, oleic acid, palmitic acid, palmitoleic acid, ricinoleic acid, linolenic acid, stearic acid, myristic acid, and arachidonic acid.
  • the disclosure also provides a compound of Formula 100:
  • the disclosure also provides a compound of Formula 101 :
  • the disclosure also provides a compound of Formula 102:
  • the disclosure provides a compound of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • R 1 is selected from unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl, and R 2 is methyl or hydrogen.
  • R 1 is an alkyl group. In some embodiments, R 1 is an alkenyl group. In some embodiments, R 1 is selected from pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and tridecyl.
  • the disclosure also provides a compound of Formula 10, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • R 1 is selected from unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.
  • R 1 is an alkyl group. In some embodiments, R 1 is an alkenyl group. In some embodiments, R 1 is selected from pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and tridecyl.
  • the disclosure also provides a compound of Formula 20, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:
  • R 1 is selected from unsubstituted or substituted alkyl, unsubstituted or substituted heteroalkyl, unsubstituted or substituted haloalkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted alkylaryl, unsubstituted or substituted alkylheteroaryl, unsubstituted or substituted aryl, unsubstituted or substituted arylalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted heteroarylalkyl.
  • R 1 is an alkyl group. In some embodiments, R 1 is an alkenyl group. In some embodiments, R 1 is selected from pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and tridecyl.
  • ' is an acyl group corresponding to a physiologically
  • O acceptable acid is an acyl group corresponding to a fatty acid.
  • ' is an acyl group corresponding to a fatty acid selected from the group consisting of lauric acid, linoleic acid, oleic acid, palmitic acid, palmitoleic acid, ricinoleic acid, linolenic acid, stearic acid, myristic acid, and arachidonic acid.
  • Fatty acids also include myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and/or cerotic acid.
  • the disclosure also provides a compound of any one of Formula 100, 101, 102, 200, 201, and 202:
  • the disclosure also provides a pharmaceutical formulation comprising the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a carrier.
  • the carrier comprises a solvent.
  • the solvent comprises an ester.
  • the solvent comprises an alcohol.
  • the solvent comprises one or more of benzyl benzoate, benzyl alcohol, and ethanol.
  • the percentage of the solvent in the carrier is about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17% (w/w), about 18% (w/w), about 19% (w/w), about 20% (w/w), about 21% (w/w), about 22% (w/w), about 23% (w/w), about 24% (w/w), about 25% (w/w), about 26% (w/w), about 27% (w/w), about 28% (w/w), about 29% (w/w), about 30% (w/w), about 31% (w/w), about
  • the carrier comprises an oil component.
  • the oil component comprises a vegetable oil.
  • the oil component comprises castor oil.
  • the oil component comprises sesame oil.
  • the oil component comprises cotton seed oil.
  • the oil component comprises olive oil.
  • the oil component comprises a triglyceride.
  • the oil component comprises a medium chain triglyceride.
  • the oil component comprises one or more triglyceride selected from LLL, OLL, OOL, OOO, PLL, POL, POO, or SOL.
  • three letter codes can be used to refer to triglycerides, where each letter refers to a particular fatty acid.
  • Individual fatty acids, substituent fatty acids, substituted fatty acids, or fatty acid radicals can be referred to by their one letter initial, see for example The United States Pharmacopeial Convention, 2015, Sesame Oil.
  • fatty acid radicals can be designated as linoleic (L), oleic (O), palmitic (P), and stearic (S), and the common abbreviations for triglycerides are: trilinolein (LLL), l,2-dilinoleoyl-3-oleoyl-rac-glycerol (OLL), l,2-dilinoleoyl-3-palmitoyl-rac-glycerol (PLL), l,2-dioleoyl-3-linoleoyl-rac-glycerol (OOL), l-palmitoyl-2-oleoyl-3-linoleoyl-rac-glycerol (POL), triolein (000), l-linoleoyl-2- oleoyl-3-stearoyl-rac-glycerol (SOL), l,2-dioleoyl-3-palmitoyl-rac
  • a fatty acid one letter code can be underlined in order to distinguish a fatty acid radical (underlined), from a one letter code describing a different entity.
  • a fatty acid radical underlined
  • O for oleic acid
  • O oxygen
  • Triglycerides also include any triglyceride including residues of any known fatty acids, or any other shorter chain saturated or unsaturated acids.
  • Fatty acids include myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, linoelaidic acid, a-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid, and/or cerotic acid. While fatty acids are primarily present in the formulations described herein as residues part of a triglyceride, diglyceride, or monogly
  • the percentage of the oil component in the carrier is about 1% (w/w), about 2% (w/w), about 3% (w/w), about 4% (w/w), about 5% (w/w), about 6% (w/w), about 7% (w/w), about 8% (w/w), about 9% (w/w), about 10% (w/w), about 11% (w/w), about 12% (w/w), about 13% (w/w), about 14% (w/w), about 15% (w/w), about 16% (w/w), about 17% (w/w), about 18% (w/w), about 19% (w/w), about 20% (w/w), about 21% (w/w), about 22% (w/w), about 23% (w/w), about 24% (w/w), about 25% (w/w), about 26% (w/w), about
  • the concentration of the compound is between about 1 mg/mL and about 200 mg/mL of formulation.
  • the concentration of the compound ranges from 5 mg/mL to 50 mg/mL, from 25 mg/mL to 75 mg/mL, from 50 mg/mL to 100 mg/mL, from 75 mg/mL to 125 mg/mL, from 100 mg/mL to 150 mg/mL, from 125 mg/mL to 200 mg/mL, from 175 mg/mL to 250 mg/mL, from 200 mg/mL to 350 mg/mL, from 250 mg/mL to 400 mg/mL, or from 275 mg/mL to 500 mg/mL.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation ranges from 50 mg/mL to 200 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 50 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 75 mg/mL.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is about 100 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 125 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 150 mg/mL.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is about 175 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 200 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 225 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 250 mg/mL.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 1 mg/g and about 200 mg/g of formulation. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, ranges from 5 mg/g to 50 mg/g, from 25 mg/g to 75 mg/g, from 50 mg/g to 100 mg/g, from 75 mg/g to 125 mg/g, from 100 mg/g to 150 mg/g, from 125 mg/g to 200 mg/g, from 175 mg/g to 250 mg/g, from 200 mg/g to 350 mg/g, from 250 mg/g to 400 mg/g, or from 275 mg/g to 500 mg/g.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation ranges from 50 mg/g to 200 mg/g. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 50 mg/g. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 75 mg/g.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is about 100 mg/g. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 125 mg/g. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 150 mg/g.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is about 175 mg/g. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 200 mg/g. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 225 mg/g. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation, is about 250 mg/g.
  • the concentration of the compound is equal to the room temperature saturation solubility of the compound in the carrier used in the formulation.
  • the concentration of the compound is a fraction of the room temperature saturation solubility of the compound in the carrier used in the formulation, wherein the fraction can be about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 2.5 mg/mL and about 250 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 2.5 mg/mL and about 25 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 5 mg/mL and about 50 mg/mL.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 10 mg/mL and about 75 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 25 mg/mL and about 100 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 50 mg/mL and about 150 mg/mL.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 75 mg/mL and about 200 mg/mL. In some embodiments, the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 100 mg/mL and about 250 mg/mL.
  • the amount of compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in 1 mL of pharmaceutical formulation is an amount which upon metabolization affords between about 1 mg and about 200 mg of systemically available varenicline. In some embodiments, the amount of compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in 1 mL of pharmaceutical formulation is an amount which upon metabolization affords between about 25 mg and about 150 mg of systemically available varenicline.
  • the amount of compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in 1 mL of pharmaceutical formulation is an amount which upon metabolization affords about 20 mg of systemically available varenicline, about 30 mg of systemically available varenicline, about 40 mg of systemically available varenicline, about 50 mg of systemically available varenicline, about 60 mg of systemically available varenicline, about 70 mg of systemically available varenicline, about 80 mg of systemically available varenicline, about 90 mg of systemically available varenicline, about 100 mg of systemically available varenicline, about 110 mg of systemically available varenicline, about 120 mg of systemically available varenicline, about 130 mg of systemically available varenicline, about 140 mg of systemically available varenicline, or about 150 mg of systemically available varenicline.
  • the concentration of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in the pharmaceutical formulation is between about 2.5 mg/g and about 250 mg/g.
  • the amount of compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in 1 g of pharmaceutical formulation is an amount which upon metabolization affords between about 1 mg and about 200 mg of systemically available varenicline.
  • the amount of compound including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in 1 g of pharmaceutical formulation is an amount which upon metabolization affords between about 25 mg and about 150 mg of systemically available varenicline.
  • the amount of compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, in 1 g of pharmaceutical formulation is an amount which upon metabolization affords about 20 mg of systemically available varenicline, about 30 mg of systemically available varenicline, about 40 mg of systemically available varenicline, about 50 mg of systemically available varenicline, about 60 mg of systemically available varenicline, about 70 mg of systemically available varenicline, about 80 mg of systemically available varenicline, about 90 mg of systemically available varenicline, about 100 mg of systemically available varenicline, about 110 mg of systemically available varenicline, about 120 mg of systemically available varenicline, about 130 mg of systemically available varenicline, about 140 mg of systemically available varenicline, or about 150 mg of systemically available varenicline.
  • the pharmaceutical formulation includes one or more inactive ingredients selected from an oil, a chelating agent, an antioxidant, and a solvent.
  • the antioxidant is selected from butylated hydroxy toluene (BHT), tocopherol, butylated hydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid and salts thereof, vitamin E, niacinamide, methionine, monothioglycerol, sodium bisulfite, cysteine, dithionite sodium, gentisic acid, and glutamate monosodium.
  • the concentration of an inactive ingredient ranges from 0.001% to 0.025%, from 0.015% to 0.05%, from 0.035% to 0.075%, from 0.05% to 0.085%, from 0.06% to 0.095%, or from 0.075% to 0.1%. In some embodiments, the concentration of an inactive ingredient ranges from 0.075% to 0.15%, from 0.1% to 0.25%, or from 0.15% to 0.5%. In some embodiments, the concentration of an inactive ingredient ranges from 0.01% to 0.1%.
  • the concentration of an inactive ingredient ranges from 0.001 mg/mL to 1 mg/mL, from 0.025 mg/mL to 0.5 mg/mL, from 0.035 mg/mL to 0.75 mg/mL, from 0.05 mg/mL to 1.5 mg/mL, or from 0.1 mg/mL to 5 mg/mL. In some embodiments, the concentration of an inactive ingredient ranges from 0.01% to 1%, from 0.025% to 2.5%, from 0.1% to 10%. In some embodiments, the concentration of an inactive ingredient ranges from 0.001% to 5%.
  • the concentration of the compound is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005% ⁇ 0.0004%, 0.0003%, 0.0002% or 0.000
  • the concentration of the compound including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, described herein is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%,
  • the concentration of the compound including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, described herein is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12% or about 1% to about 10% w/w, w/v, or v/v of the pharmaceutical formulations described herein.
  • the concentration of the compound including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, described herein is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v, or v/v of the pharmaceutical formulations described herein.
  • the amount of each of the active and/or inactive pharmaceutical ingredients provided in the pharmaceutical compositions of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g,
  • the amount of each of the active and/or inactive pharmaceutical ingredients provided in the pharmaceutical compositions of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g,
  • Each of the active pharmaceutical ingredients according to the invention is effective over a wide dosage range.
  • dosages independently range from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used.
  • Effective dosages from 50 to 200 mg per week are also examples of dosages that may be used.
  • the effective weekly dosage is about 50 mg.
  • the effective weekly dosage is about 100 mg.
  • the effective weekly dosage is about 150 mg.
  • the effective weekly dosage is about 200 mg.
  • the effective weekly dosage is about 250 mg.
  • the exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.
  • the clinically-established dosages of the compound including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, may also be used if appropriate.
  • a pharmaceutical composition for injection containing an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, such as the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, and a pharmaceutical excipient suitable for injection.
  • active pharmaceutical ingredient or combination of active pharmaceutical ingredients such as the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, and a pharmaceutical excipient suitable for injection.
  • Aqueous solutions in saline are also conventionally used for injection.
  • Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal preservatives or preservative agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.
  • Sterile injectable solutions are prepared by incorporating an active pharmaceutical ingredient or combination of active pharmaceutical ingredients in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • certain desirable methods of preparation are vacuumdrying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Administration of an active pharmaceutical ingredient or combination of active pharmaceutical ingredients or a pharmaceutical composition thereof can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intradermal, intravascular, intraperitoneal or infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation.
  • the active pharmaceutical ingredient or combination of active pharmaceutical ingredients can also be administered intraadiposally or intrathecally.
  • kits include an active pharmaceutical ingredient or combination of active pharmaceutical ingredients, either alone or in combination in suitable packaging, and written material that can include instructions for use, discussion of clinical studies and listing of side effects.
  • kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials.
  • the kit may further contain another active pharmaceutical ingredient.
  • an active pharmaceutical ingredient or combination of active pharmaceutical ingredients are provided as separate compositions in separate containers within the kit. In selected embodiments, an active pharmaceutical ingredient or combination of active pharmaceutical ingredients are provided as a single composition within a container in the kit.
  • Suitable packaging and additional articles for use e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like
  • Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in selected embodiments, be marketed directly to the consumer.
  • the invention provides a kit including a composition including a therapeutically effective amount of an active pharmaceutical ingredient (e.g., the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof) or combination of active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.
  • an active pharmaceutical ingredient e.g., the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof
  • active pharmaceutical ingredients e.g., the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof.
  • active pharmaceutical ingredient e.g., the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or
  • the invention provides for a kit including a composition including a therapeutically effective amount of the compound, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, alone or in combination with active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug in an oil, optionally combined with an antioxidant, in a prefilled syringe (PFS) or vial.
  • PFS prefilled syringe
  • the prefilled syringe or the vial are transparent.
  • the kit includes suitable packaging for protecting the prefilled syringe or vial from light. In some embodiments this includes an autoinjector. In other embodiments, this includes an autoinjector with a viewing window to allow inspection of the drug prior to injection. In yet other embodiments, the autoinjector is in a carton to prevent light access to the drug.
  • the prefilled syringe or the vial may include one dose or multiple doses.
  • a prefilled syringe or vial including multiple doses is bigger, i.e., has a larger volume than a prefilled syringe or vial including only one dose.
  • the surface area to the volume ratio of a prefilled syringe or vial gets smaller as the prefilled syringe or vial gets larger in volume.
  • kits may include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider and/or the patient.
  • information may instruct the user to keep the prefilled syringe or prefilled syringe and autoinjector in a carton to protect the pharmaceutical ingredients from light.
  • the invention provides a kit including (1) a composition including a therapeutically effective amount of an active pharmaceutical ingredient (e.g., a varenicline prodrug) or combination of active pharmaceutical ingredients or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and (2) a diagnostic test for determining whether a patient is in need of a varenicline prodrug administration.
  • an active pharmaceutical ingredient e.g., a varenicline prodrug
  • a diagnostic test for determining whether a patient is in need of a varenicline prodrug administration.
  • the amounts of the pharmaceutical compositions administered using the methods herein, such as the dosages of varenicline prodrug, will be dependent on the subject, e.g., human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the active pharmaceutical ingredients and the discretion of the prescribing physician. Dosage in the range of 0.1 to 100 mg per week for administration to a human may be adequate to achieve an effective therapeutic level. At times, dosages of 0.5 to 100 mg per week over several weeks may be required to achieve the desired therapeutic level. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • the dosage of the pharmaceutical compositions and active pharmaceutical ingredients may be provided in units of mg/kg of body mass or in mg/m 2 of body surface area.
  • a pharmaceutical composition or active pharmaceutical ingredient is administered in multiple doses.
  • a pharmaceutical composition is administered in multiple doses. Dosing may be once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, a pharmaceutical composition is administered about once per day to about 6 times per day. In some embodiments, a pharmaceutical composition is administered once daily, while in other embodiments, a pharmaceutical composition is administered twice daily, and in other embodiments a pharmaceutical composition is administered three times daily.
  • a pharmaceutical composition is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 day(s). Other embodiments require the pharmaceutical composition is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 week(s). In some embodiments, a pharmaceutical composition is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day(s). In some embodiments, a pharmaceutical composition is administered chronically on an ongoing basis - e.g., for the treatment of chronic effects. In some embodiments, the administration of a pharmaceutical composition continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.
  • an effective dosage of an active pharmaceutical ingredient disclosed herein is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 50 mg to 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 50 mg to about 100 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg.
  • an effective dosage of an active pharmaceutical ingredient disclosed herein is less than about 25 mg, less than about 50 mg, less than about 75 mg, less than about 100 mg, less than about 125 mg, less than about 150 mg, less than about 175 mg, less than about 200 mg, less than about 225 mg, or less than about 250 mg. In some embodiments, an effective dosage of an active pharmaceutical ingredient disclosed herein is greater than about 25 mg, greater than about 50 mg, greater than about 75 mg, greater than about 100 mg, greater than about 125 mg, greater than about 150 mg, greater than about 175 mg, greater than about 200 mg, greater than about 225 mg, or greater than about 250 mg.
  • an effective dosage of an active pharmaceutical ingredient disclosed herein is in the range of about 0.01 mg/kg to about 200 mg/kg, or about 0.1 to 100 mg/kg, or about 1 to 50 mg/kg.
  • an active pharmaceutical ingredient is administered at a dosage of 10 to 200 mg BID, including 50, 60, 70, 80, 90, 100, 150, or 200 mg BID.
  • an active pharmaceutical ingredient is administered at a dosage of 10 to 500 mg BID, including 1, 5, 10, 15, 25, 50, 75, 100, 150, 200, 300, 400, or 500 mg BID.
  • dosage levels below the lower limit of the aforesaid ranges may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g., by dividing such larger doses into several small doses for administration throughout the day.
  • the dosage actually administered will depend upon the condition being treated, the age, health and weight of the recipient, the type of concurrent treatment, if any, and the frequency of treatment.
  • the effective dosage amount may be determined by one skilled in the art on the basis of routine empirical activity testing to measure the bioactivity of the compound(s) in a bioassay, and thus establish the appropriate dosage to be administered.
  • An effective amount of the combination of the active pharmaceutical ingredient may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, intradermally, orally, topically, or as an inhalant.
  • compositions described herein further include controlled- release, sustained release, or extended-release therapeutic dosage forms for administration of the compounds described herein, which involves incorporation of the compounds into a suitable delivery system in the formation of certain compositions.
  • This dosage form controls release of the compound(s) in such a manner that an effective concentration of the compound(s) in the bloodstream may be maintained over an extended period of time, with the concentration in the blood remaining relatively constant, to improve therapeutic results and/or minimize side effects.
  • a controlled-release system would provide minimum peak to trough fluctuations in blood plasma levels of the compound.
  • the disclosure provides a method of treating nicotine addiction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein, including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, or a therapeutically effective amount of a pharmaceutical formulation described herein.
  • a therapeutically effective amount of a compound described herein including without limitation the compound of any one of Formulas I, 10, 20, 100, 101, 102, 200, 201, or 202, or pharmaceutically acceptable salts thereof, or a therapeutically effective amount of a pharmaceutical formulation described herein.
  • the subject upon administration to the subject of the therapeutically effective amount of the compound, or the therapeutically effective amount of the pharmaceutical formulation, the subject experiences a reduced craving for a nicotine delivery product.
  • the subject upon administration to the subject of the therapeutically effective amount of the compound, or the therapeutically effective amount of the pharmaceutical formulation, the subject experiences a reduced pleasurable effect of a nicotine delivery product
  • the subject upon administration to the subject of the therapeutically effective amount of the compound, or the therapeutically effective amount of the pharmaceutical formulation, experiences less side effects compared to administration of an equivalent amount of varenicline via oral dosage forms.
  • varenicline e.g., Chantix
  • common side effects of varenicline include nausea (may persist for several months), stomach pain, indigestion, constipation, gas, vomiting, headaches, weakness, tiredness, unusual dreams, sleep problems (insomnia), headache, dry mouth, or unpleasant taste in mouth.
  • nausea is the most common adverse reaction (up to 30% incidence rate); also the most common adverse reactions (>5% and twice the rate seen in placebo treated patients) were nausea, abnormal (e.g., vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.
  • Example 2 Solubility Screening of three Varenicline prodrugs in oil based vehicles
  • the aim of this study is to evaluate the in-vitro saturation solubilities of three prodrugs of Varenicline at room temperature.
  • the prodrugs of Varenicline included in this study are: Varenicline Methoxy Acyloxy-decanoyl (ATRS- 1901-004), Varenicline Methoxy Acyloxy - dodecanoyl (ATRS- 1901-005) and Varenicline Methoxy Acyloxy-tetradecanoyl (ATRS-1901- 006).
  • Varenicline is the first approved nicotinic receptor partial agonist. It is a partial agonist of the a4/p2 subtype of the nicotinic acetylcholine receptor. Varenicline, as the tartrate salt, is available under prescription in the US market under the trade name CHANTIX® as 0.5 mg and 1 mg equivalent to Varenicline film coated tablets.
  • Varenicline as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9, 10-tetrahy dro-6,10-methano6H- pyrazino[2,3- h][3] benzazepine, (2R,3R) -2,3- dihydroxybutanedioate (1 : 1). It is highly soluble in water.
  • Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3 • C4H6O6.
  • Varenicline Methoxy Acyloxy-decanoyl (ATRS-1901- 004), Varenicline Methoxy Acyloxy-dodecanoyl (ATRS- 1901-005) and Varenicline Methoxy Acyloxy-tetradecanoyl (ATRS-1901-006) in Tables 1, 2 and 3 respectively.
  • Table 1 Information on Varenicline Methoxy Acyloxy-decanoyl.
  • Table 2 Information on Varenicline Methoxy Acyloxy-dodecanoyl.
  • Table 3 Information on Varenicline Methoxy Acyloxy-tetradecanoyl.
  • Analytical method for HPLC analysis the following HPLC methods for analysis of Varenicline prodrugs were developed.
  • Table 5 includes the HPLC method for ATRS- 1901-004 and ATRS- 1901-005 and
  • Table 6 includes the HPLC method for ATRS- 1901-006.
  • Table 5 HPLC method for ATRS-1901-004 and ATRS-1901-005.
  • Table 6 HPLC method for ATRS-1901-006.
  • Figures 11, 13 and 15 show ATRS- 1901-004, ATRS-1901-005 and ATRS-1901-006 respectively on chromatogram by HPLC methods disclosed in Tables 5 and 6 and Figures 12, 14 and 16 show UV absorption spectrum of ATRS- 1901-004, ATRS-1901-005 and ATRS-1901- 006 respectively.
  • the Spectrum Index plots show PDA spectrums of three varenicline prodrugs included in the solubility screening. All prodrugs show maximum absorption at 238 nm and 321 nm. Solubility screening in present study uses a co-solvent system of Castor oil and Benzyl benzoate. Based on previous investigations performed at Tara, Benzyl benzoate shows maximum absorption at 230 nm. Wavelength 321 nm was chosen as final detection wavelength to avoid absorption of benzyl benzoate peak on chromatogram which may interfere with other adjacent varenicline prodrugs peaks during analysis.
  • Table 7 lists the ingredients used in the solubility screening.
  • Table 9 shows composition of solubility screening samples of Varenicline prodrugs. All the samples were prepared in duplicates. The proposed procedure detailed the amounts of vehicle (175 mg) and Varenicline prodrugs (75 mg) to be taken in preparation of solubility screening samples. It was observed, as a separate test, on preparing samples that amount of vehicle weighed may not be enough to create supernatant which can be separated from the undissolved solute. Also, all the esters may have different physical flow properties. After saturation solubility is achieved, if the undissolved portion of any ester have lumps, it may interfere during centrifugation and result in inaccurate analysis. Therefore the amount of vehicle taken was increased.
  • Example 3 Scheme of in vivo metabolism of ATRS-1901-005, a Varenicline Methoxy Acyloxy Carbamate Prodrug
  • any compound described herein is a prodrug of varenicline, and can be metabolized as follows: While certain embodiments of the present invention have been described and/or exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. The present invention is, therefore, not limited to the particular embodiments described and/or exemplified, but is capable of considerable variation and modification without departure from the scope and spirit of the appended claims.

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Abstract

La divulgation concerne des promédicaments de varénicline, ainsi que des formulations pharmaceutiques et des méthodes d'utilisation associées.
PCT/US2021/065597 2020-12-30 2021-12-30 Promédicaments de varénicline WO2022147189A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024050516A3 (fr) * 2022-09-02 2024-04-11 Spacerx Llc Composés apparentés à la varénicline et méthodes de traitement de maladies et d'états pathologiques comprenant un trouble de consommation de tabac

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US6858624B2 (en) * 2001-11-30 2005-02-22 Pfizer, Inc. Aryl fused azapolycyclic compounds
US20070275973A1 (en) * 1997-12-31 2007-11-29 Pfizer Inc Aryl fused azapolycyclic compounds
US20110224437A1 (en) * 2008-09-01 2011-09-15 Actavis Group Ptc Ehf Process for preparing varenicline, varenicline intermediates, and pharmaceutically acceptable salts thereof
US20200276113A1 (en) * 2016-01-08 2020-09-03 Ctc Bio, Inc. Taste-masked and orally administered pharmaceutical preparation containing varenicline or pharmaceutically acceptable salt thereof

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Publication number Priority date Publication date Assignee Title
US20070275973A1 (en) * 1997-12-31 2007-11-29 Pfizer Inc Aryl fused azapolycyclic compounds
US6858624B2 (en) * 2001-11-30 2005-02-22 Pfizer, Inc. Aryl fused azapolycyclic compounds
US20110224437A1 (en) * 2008-09-01 2011-09-15 Actavis Group Ptc Ehf Process for preparing varenicline, varenicline intermediates, and pharmaceutically acceptable salts thereof
US20200276113A1 (en) * 2016-01-08 2020-09-03 Ctc Bio, Inc. Taste-masked and orally administered pharmaceutical preparation containing varenicline or pharmaceutically acceptable salt thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024050516A3 (fr) * 2022-09-02 2024-04-11 Spacerx Llc Composés apparentés à la varénicline et méthodes de traitement de maladies et d'états pathologiques comprenant un trouble de consommation de tabac

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