Formulations of 4-Methyl-5-(Pyrazin-2-yl)-3H-1,2-Dithiole-3-Thione, Taste-Modified Formulations, and Methods of Making and Using Same

Abstract

This disclosure provides, among other things, compositions comprising quantities of oltipraz crystals, as well as method of making such compositions, and method of treating patients using such compositions. Taste-modified compositions also are provided.

1 . A composition comprising a quantity of crystals of 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiole-3-thione having an intensity averaged, mean hydrodynamic diameter (Z-average) (“MHD”) of from 30 to 2000 nm, as measured by dynamic light scattering at 25° C. on a suspension of the crystals in water at a concentration of 0.01 to 0.1 mg of crystals per mL of water. 
     
     
         2 . A composition comprising a quantity of crystals according to  claim 1  wherein the MHD is from about 30 to about 1200 nm, preferably from about 100 to about 600 nm, more preferably from about 150 to about 450 nm. 
     
     
         3 . A composition comprising a quantity of crystals according to  claim 1 , wherein the polydispersity index (PdI) of the crystals, defined as PdI=(σ/d) 2 , wherein σ is the standard deviation and d is the mean hydrodynamic diameter (Z-average) of the crystals, is from about 0.10 to about 0.60, preferably from about 0.1 to about 0.45, more preferably from about 0.1 to about 0.35. 
     
     
         4 . A composition comprising a quantity of crystals according to  claim 1 , wherein the solubility of the crystals in water at 20° C. is from about 3.5 to about 8 μg/ml, preferably from about 4.5 to about 7 μg/ml, more preferably from about 5 to about 6.5 μg/ml. 
     
     
         5 . A composition comprising crystals according to  claim 4  and a stabilizing agent, wherein preferably the stabilizing agent comprises:
 i) a polymeric stabilizing agent selected from an acrylate- and alkenyl ether-based co-polymer (e.g., Carbopol® type polymers such as Carbopol 974P NF), polyvinylpyrrolidine (e.g., PVP K15 or K30), a cellulosic polymer such as a cationic hydroxyethyl cellulose (e.g., in the Polymer JR family), hydroxypropylcellulose (HPC e.g. HPC EF typically having a molecular weight of about 80 kDa), hydroxypropyl methylcellulose (HPMC e.g. HMPC E3 typically having viscosity of about 3 cP at 2% in water), hydroxypropyl methylcellulose acetate succinate, HPMCAS, a copovidone (e.g., PVP-VA64), poly(ethylene oxide), a poloxamer (e.g., a poly(propylene oxide) and poly(ethylene oxide) copolymer), an acrylamide polymer, or poly(ethyl acrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2 (“EUDRAGIT® RL”); and/or 
 ii) a surfactant selected from sodium isostearate, cetyl alcohol, polysorbates (Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 80), steareth-10 (Brij 76), sodium dodecyl sulfate (sodium lauryl sulfate), lauryl dimethyl amine oxide, cetyltrimethylammonium bromide (CTAB), polyethoxylated alcohols, polyoxyethylene sorbitan, octoxynol, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide (HTAB), polyoxyl 10 lauryl ether, bile salts (such as sodium deoxycholate or sodium cholate), polyoxyl castor oil, nonylphenol ethoxylate, cyclodextrins, lecithin, dimethicone copolyol, lauramide DEA, cocamide DEA, cocamide MEA, oleyl betaine, cocamidopropyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, dicetyl phosphate (dihexadecyl phosphate), ceteareth-10 phosphate, methylbenzethonium chloride, dicetyl phosphate, ceteth-10 phosphate, ceteth-20, Brij S10 (polyethylene glycol octadecyl ether, average M n -711), PEG-20 phytosterol, Poloxamers such as Poloxamer 188 and Poloxamer 407 (e.g., “Pluronic F-68”), polyoxyethylene glycol alkyl ethers (e.g., octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, and polyethylene glycol alkyl ethers such as Brij® Detergents), polyoxypropylene glycol alkyl ethers, glucoside alkyl ethers (e.g., decyl glucoside, lauryl glucoside, or octyl glucoside), polyoxyethylene glycol alkylphenol ethers (e.g. Triton X-100, Nonoxyol-9), glycerol alkyl esters, polyoxyethylene glycol sorbitan alkyl esters (e.g., polysorbates), sorbitan alkyl esters, cocamides, and polyoxyethylene (20) sorbitan monooleate (polysorbate 80, also known as “Tween 80”). 
 
     
     
         6 . A composition according to  claim 5  further comprising a bulking agent, wherein preferably the bulking agent is selected from polyvinylpyrrolidones (e.g., PVP K30 and PVP-VA64), cellulosic polymers such as HPC, HPMC, HPMC E3, Trehalose, and Dextrans such as Dextran 10 or Dextran 40. 
     
     
         7 . A composition according to  claim 5  which is in liquid form, wherein the composition preferably comprises water and/or a non-aqueous solvent. 
     
     
         8 . A composition according to  claim 5  which is in dry form, wherein the composition substantially excludes water and any non-aqueous solvent. 
     
     
         9 . A liquid composition according to  claim 7  wherein the composition does not comprise a bulking agent, and wherein:
 the composition comprises between about 1 to about 40 wt % of oltipraz crystals, based on the weight of the liquid composition; 
 the non-solvent components in the composition typically comprise from about 1 to about 70 wt % oltipraz crystals; and 
 the composition comprises (i) from about 5 to about 40 wt % (based on the weight of solid components in the composition) of one or more of acrylate- and alkenyl ether-based co-polymers, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, a copovidone such as PVP-VA64, and a polymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) from about 10 to about 20 wt % % (based on the weight of solid components in the composition) of one or more of sodium lauryl sulfate, a poloxamer such as Pluronic F-68 and polysorbate 80. 
 
     
     
         10 . A liquid composition according to  claim 9  wherein:
 the composition comprises between about 7 to about 10 wt % of oltipraz crystals, based on the weight of the liquid composition; 
 the non-solvent components in the composition typically comprise from about 55 to about 58 wt % oltipraz crystals; 
 the composition comprises (i) from about 25 to about 30 wt % (based on the weight of solid components in the composition) of one or more of a copovidone such as PVP-VA64 and a polymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) from about 14 to about 15 wt % % (based on the weight of solid components in the composition) of polysorbate 80 (Tween 80); 
 the liquid solvent is water; and 
 the composition optionally comprises 0.1 to 1 wt % simethicone based on the non-solvent components in the composition. 
 
     
     
         11 . A liquid composition according to  claim 7  comprising a bulking agent wherein:
 i) the concentration of oltipraz crystals in the liquid is from about 0.1 to about 10 wt % based on the weight of the liquid composition; 
 ii) the non-solvent components in the composition typically comprise from about 0.5 to about 25 wt % oltipraz crystals; 
 iii) the composition comprises (i) from about 5 to about 40 wt % (based on the weight of solid components excluding bulking agents in the composition) of one or more of acrylate- and alkenyl ether-based co-polymers, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, a copovidone such as PVP-VA64, and a polymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) from about 10 to about 20 wt % % (based on the weight of solid components excluding bulking agents in the composition) of one or more of sodium lauryl sulfate, a poloxamer such as Pluronic F-68 and polysorbate 80; and 
 iv) the composition comprises from about 1 to about 40 wt % (based on the overall weight of the composition) of a bulking agent selected from polyvinylpyrrolidones (e.g., PVP K30 and PVP-VA64), cellulosic polymers such as HPC, HPMC, HPMC E3, Trehalose, Dextrans (such as Dextran 10 or Dextran 40), PVP-VA64 and HPC EF. 
 
     
     
         12 . A liquid composition according to  claim 11  wherein:
 i) the concentration of oltipraz crystals in the liquid is from about 2 to about 5 wt % based on the weight of the liquid composition; 
 ii) the non-solvent components in the composition typically comprise from about 10 to about 18 wt % oltipraz crystals; 
 iii) the composition comprises (i) from about 25 to about 30 wt % (based on the weight of solid components excluding bulking agents in the composition) of one or more of a copovidone such as PVP-VA64 and a polymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) from about 14 to about 15 wt % % (based on the weight of solid components excluding bulking agents in the composition) of polysorbate 80 (Tween 80); 
 iv) the composition comprises from about 15 to about 25 wt % (based on the overall weight of the composition) of a bulking agent which is PVP-VA64; 
 v) the liquid solvent is water; and 
 vi) the composition optionally comprises 0.1 to 1 wt % simethicone based on the non-solvent components (excluding the bulking agent) in the composition. 
 
     
     
         13 . A dry composition according to  claim 8  comprising a bulking agent, wherein:
 i) the percentage of oltipraz in the composition (i.e. the drug loading) is from about 12 to about 20 wt %; 
 ii) the composition comprises (i) from about 5 to about 40 wt % (based on the weight of solid components excluding bulking agents in the composition) of one or more of acrylate- and alkenyl ether-based co-polymers, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl methylcellulose, a copovidone such as PVP-VA64, and a polymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) from about 10 to about 20 wt % % (based on the weight of solid components excluding bulking agents in the composition) of one or more of sodium lauryl sulfate, a poloxamer such as Pluronic F-68 and polysorbate 80; and 
 iii) the composition comprises from about 40 to about 90 wt % (based on the overall weight of the composition) of a bulking agent selected from polyvinylpyrrolidones (e.g., PVP K30 and PVP-VA64), cellulosic polymers such as HPC, HPMC, HPMC E3, Trehalose, Dextrans (such as Dextran 10 or Dextran 40), PVP-VA64 and HPC EF. 
 
     
     
         14 . A dry composition according to  claim 13 , wherein:
 i) the percentage of oltipraz in the composition (i.e. the drug loading) is from about 15 to about 17 wt %;   ii) the composition comprises (i) from about 25 to about 30 wt % (based on the weight of solid components excluding bulking agents in the composition) of one or more of a copovidone such as PVP-VA64 and a polymethacrylate-based copolymer such as EUDRAGIT® RL; and/or (ii) from about 14 to about 15 wt % % (based on the weight of solid components excluding bulking agents in the composition) of polysorbate 80 (Tween 80); and   iii) the composition comprises from about 70 to about 78 wt % (based on the overall weight of the composition) of a bulking agent which is PVP-VA64; and   iv) the composition optionally comprises 0.1 to 1 wt % simethicone based on the weight of solid components excluding bulking agents in the composition.   
     
     
         15 . A suspension of crystals according to  claim 14  in aqueous solution wherein the ratio of the crystals or the composition to the solution is from 1:10 to 1:200. 
     
     
         16 . A suspension according to  claim 15  wherein the weight ratio of the dry composition to liquid is from about 1:10 to about 1:200, the suspension comprising:
 i) From about 0.0005 to about 0.005 wt % of a mint or menthol flavor (based on the overall weight of the suspension); and/or 
 ii) From about 0.05 to about 0.5 wt % of a fruit flavor (based on the overall weight of the suspension); and/or 
 iii) From about 0.1 to about 1.5 mg/mL of a sweetener e.g. one or more sweetener selected from monosoccharides, disaccharides, oligosaccharides, alcohols and high-potency sweeteners; and/or 
 iv) From about 0.01 to about 0.05% wt % of a cooling/freshening agent such as a Physcool® flavouring; and optionally 
 v) From about 0.05 to about 5 mg/mL of a preservative such as potassium sorbate. 
 
     
     
         17 . A suspension according to  claim 15  wherein the weight ratio of the dry composition to liquid is from about 1:30 to about 1:100, the suspension comprising:
 i) From about 0.0007 to about 0.003 wt % (e.g. from about 0.0009 to about 0.001 wt %) of a mint or menthol flavor (based on the overall weight of the suspension); and/or 
 ii) From about 0.1 to about 0.4 wt % (e.g. from about 0.2 to about 0.3 wt %) of a fruit flavor such as a berry flavor (based on the overall weight of the suspension); and/or 
 iii) From about 0.5 to about 1 mg/mL (e.g. about 0.5 mg/mL) of a sweetener selected from aspartame, saccharin, neotame, acesulfame potassium, xylitol, sorbitol, mannitol, sucrose, fructose, glucose, maltose, lactose, xylose and curalose, most often sucralose; and/or 
 iv) From about 0.01 to about 0.05% wt % (e.g. about 0.025%) of a cooling/freshening agent such as a Physcool® flavouring; and optionally 
 v) From about 0.1 to about 1 mg/mL (e.g. about 0.5 mg/mL) of a preservative such as potassium sorbate. 
 
     
     
         18 . A pharmaceutical composition comprising a suspension according to  claim 15 , wherein:
 i) the composition is in liquid dosage form and comprises at least one pharmaceutically acceptable diluent, adjuvant; suspending agent and/or carrier; or   ii) the composition is in dry dosage form and comprises at least one pharmaceutically acceptable additive, lubricant, excipient or diluent.   
     
     
         19 . A pharmaceutical composition according to  claim 18  for oral, topical, rectal, or colonic administration or for administration by inhalation, preferably for oral administration. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . A kit comprising:
 i) the composition of crystals according to  claim 1 ; and   ii) either (A) a device for oral administration of the crystals, composition, suspension, pharmaceutical composition or crystals, composition, suspension or pharmaceutical composition for use; or (B) an inhaler device for administration of the crystals, composition, suspension, pharmaceutical composition or crystals, composition, suspension or pharmaceutical composition for use by inhalation.   
     
     
         23 - 25 . (canceled)