2) United States Patent Rashid et al. (54) POLYVINYLPYRROLIDONE-CONTAINING ACETAMINOPHEN LIQUID FORMULATIONS (75) Inventors: Abdul Rashid, Livingston, NI (US); ‘Zhang Julia Zhang, Scotch Plains, NI (US); Minh Tran, Secaucus, NJ (US) Dabai Guo, Belle Mead, NI (US) (73) Assignee: Enspire Group LLC, South Paine NI(US) (4) Notice: Subject to any diteluimer the tem of this patent is extended or adjusted under 35 USC. 184(b) by 171 days. (21) Appl. Nos 19434267 (22) Filed: Mar. 29,2012 « Prior Publication Data $ 201300261189 Al Oet.3, 2013 GI) mee AGIK 31167 (2006.01) (2) US.CL AGIK 31/167 201301) usp 514/630; 424/500 (58) Field of Classification Search crc AGIK 31/167 usp 434/400, 514/630 See pplication ile for complete search history. References Cited US. PATENT DOCUMENTS SO7LGH A 12901 Yostal. EMIS6 A ‘$1992 Coapman 'US008969416B2 (10) Patent No. 4s) Date of Patent: US 8,969,416 B2 Mar. 3, 2015 sus4928 S4on907 A 1011992 Kawasaki ta 41995, Blaeetal 111996 Dhabhar SS08301 A + 41996. Shelley a sp04st S508 A * 41995 Dhabhar 144629 G410,030 A 122600. Ohonneian eal 8788731 BL Sam.cox Be Beeman Al soto Al 2004 Aneret a 42006 Waranis $2003. Waranis otal 72007 Dasee ta. 12011 Modi eta FOREIGN PATENT DOCUMENTS wo owns aL 22003 wo 200906614 92 52009 OTHER PUBLICATIONS Foltmsnn el, “Drag Delivery Technology 2am. 2008, vol 8(6) pp. 2227, * cited by examiner Primary Examiner — Johann R Rieter Assistant Examiner — Yanahi Zhang (V4) Attorney, Agent, or Firm —Fox Rothschild LLP; Fianming Jimmy Heo on ABSTRACT A pharmaceutical formulation contains 10-60% by wei inophen as the only active ingredient and a solvent ‘system for dissolving the eetaminophen The formulation is free of any ionizing agent and its solvent system includes ‘water, polyethylene glycol, and polyvinylpyrotidone that is 2.50% by weight and hat @ molecular weight of 2,000 to 1,500,000. Albo disclosed is another acetaminophen form- lation containing polyvinylpyrTolidoneas high as 25-S0% by weight 28 Claims, No DrawingsUS 8,969,416 B2 1 POLYVINYLPYRROLIDONE-CONTAINING ACETAMINOPHEN LIQUID FORMULATIONS. BACKGROUND Acetaminophen is an overthe-counter dnig commonly used to relieve headaches and reduce fever ‘A ighly concentrated solution of acetaminophen allows 3 high dose of acetaminophen (eg, 325 mg) to be formulated Jn a compact oral dosage form for easy swallowing. I¢ also ‘enhances the bioavailability of acetaminophen, However, ‘acetaminophen tends to degrade or recrystallize in such a solution “There is a need to develop an acetaminophen liquid formu lation in a highly concentrated solution suitable fora compact dosage form. SUMMARY, ‘This invention is based on an unexpected discovery of a way to enhance the solubility of acetaminophen in liquid Tormuation, “Accordingly one aspect of this invention relates tow phar maceutical formulation containing acetaminophen 8s the ‘only active ingredient and a solvent system fr dissolving the ‘acetaminophen. The acetaminophen is 10-60% (eg, 15-40% ‘0r20-35%) by Weight of the formulation. Thesolveat system, ‘nadaltion to water nd polyethylene glycol, further inctudes polyvinylpyrrolidone tht is 2-80% (e., §-30% or 10-25%) by weight, ako of the formulation, and has molecular ‘weight of 2.000 to 1,500,000 (e-. 2,000 to 62,000, 2.000 10 4,000, or 4.000 to 18,000). Note thatthe formulation i ree oF ‘any’ionizing agents aamely, «compound capable of ionizing ‘an active ingredient, acetaminophen here in a soltion ‘The above-described pharmaceutical formulation ean fur- ther contain propylene glyco in its solvent system, Another aspect of this invention relates to a similar scetaminophen fomulation that is not necessarily free of ‘another active ingredient o° free ofan ionizing agent. Api, the acetaminophen is 10-60% (e., 15-40% or 20-3596) by weight. Likely, dhe solvent system, in addition to water and polyethylene glyco, further inchudes polyvinylpyrolidone ‘and, optionally. propylene glycol. The polyvinylpyrrofidone has a molecular weight of 2,000 to 1,500,000 (eg. 2.000 10 £62,000, 2,000 to 4,000, 04,000 to 18,000). lis content in this armulation is 25-50% (eg. 25 10 35%) by weight Also within the scope of this invention is the use of the above-described pharmaceutical formulations forthe mama- Tacture of medicameats that alleviate pain of rece fever, “The details of one of more embodiments of the invention ‘are set forth in the accompanying description below. Other features, objects, and advantages of the invention will be apparent from the description and the claims DETAILED DESCRIPTION This invention provides a liquid pharmaceutical formu tion that contains acetaminophen ata high concentration. The formulation is suitable for preparing various oral dosage orm, soft gl capsule suspension, solution, syrup, 1Wo- picce hard shell eapstle, and nasaloral spray. See Modern Pharmaceutics, Volume’ 121(2004), edited by Gilbert S. Banker and Christopher T. Rhodes, and references cited therein. In particular, it may be used to prepare soft gels ‘containing «high dose of acetaminophen in stable solution, ‘eg, 250:my or 325 mg acetaminophen per soft ge. 0 o 2 The pharmaceutical formulation ofthis invention acetaminophen and a solvent system for dissolving the ‘acetaminophen. "The acetaminophen can be the only active ingredient inthe ‘oemulation, The formulation ean further eontainone.oe more ther active ingredients that can be co-dissolved with Acetaminophen in the solvent system of this invention ‘The acetaminophen ca be either in its freeform or in aay pharmaceutically acceptable salt form. ‘The acetaminoplien can be dissolved in the solvent system at an unexpectedly high conceatration, ep, 10-60%, 15-40%, oF 20-35% by Weight. “The solvent system inthis invention coatainspolyvinylpyr- rolidane, polyethylene glyeol, and water. Optionally, it also includes other solvents suchas propylene glycol, polysorbate 80 (i.e, Tween 80), and sugar aleohol (eg. glycerol and sorbitol. Polyvinylpyeroidone, also known as Polyviddone or Povi- done, isa water-soluble polymer, Polyviny}pyrolidone used inthis invention hasan molecular weight inthe range of2,000 10 1,500,000 e.2, 2,000 0 62,000, 2,000 104,000, 4,000 10 18,000, o 6,000 to 15.000, Polyvinylpyreolidne products are commonly graded by K. values. The K value isn index Tor correlating relative i cosity with the average degree of polymerization. See Cel lose ‘Chem. 1932, 13, 60. The K value is ealeulated by the folowing formuls EUS bas macy usoamene le nat ‘pg: Relative viscosity of aqueous polyvinylpyerotidone soliton to water e: Content of polyvinyipyrmlidane in an aqueous polyvinylpytrolidone solution (6). Polyvinylpyrrolidone used inthe formulation basa K value ‘1210 90,¢4., 12,15, 17,25, 0730, olyvinylpyrolidone is ‘signated as Povidone inthe United States Pharmacopeial Convention ("USP"), Polyvinylpysotidone. products are commercially available and generally include K values in their trade names, ¢., Polyvinylpysrolidone KIT oF Povie done K17, There ate correlations between K values and molecular wweighis. For example, polyvinylpyrrlidone K12 las a ‘molecular weight of 2,000 fo 4,000, K15 6,000 to 15,000, 17 4,000 wo 18.000, K30-40,000 1 62,000, and K90 1,000, (00 1,500,000, Polyvinylpyertidone products rom differ cent vendors may have different average molecu Weights, ‘whieh typically fll into the ranges cited above, Polyvinylpyreoldone herein refers oa single product oF 3 mixture of several products. For example, it can be poly aylpyrolidone K12, KIS, K17, K25, K30, K60, KOO, ‘mixture thereof. Tite amount of polyvinylpyrolidone is 2.50%, 530%, oF 10-25% by weight ofthe fomnulation. Polyvinylpsreolidone enhances, in unexpected manners, the solubility of eetaminophen in the solvent system eon: taining polyvinylpyrmlidone, polyethylene glycol, water, ‘and optionally propylene glycol or other components Polyethylene leo, also known as “PEG,” has formula of B(OCH,CHL),OH, wherein a is 4 or greater. A number generally follows the name PEG to indicate its average ‘molecular weight, For example, PEG-400 has an average ‘molecular weight of about 400. See Cosmetic Ingredient Dietionary, 3d Fd (1982), pages 201-03; Merck Index, 10th Fd, (1983), page 1092, Polyetiylene glycol used inthisinventionisa clear viseous liquid ora white solid at room temperature, and ean bed solved in water and many organie solvents. ts molecularUS 8,969,416 B2 3 weight ean be between 200 sand 800, preferably 400, The solvent system may comtain a single polyethylene glycol product of # mixture of 1Wo of more polyethylene glycol products, Propylene glycol, a clear viscous liquid, has the formula HOCH,CHOHCH, It is miscible with water and can be ‘optionally included in the solvent system described above. The term ionizing agent” herein refers a compound tat ‘can react with acetaminophen inthe solvent system to form fcetaminophen ons, Examples of an ionizing agent include both organic and inorganic bases capable of accepting hydro- zen ions or donating electron pairs. Alkali or alkaine-curth metal salts or hydroxides are commonly used ionizing agents to increase the solubility of acetaminophen, An ionizing agent can be added tothe formulation 1 boost the solubility of acetaminophen in the solvent system. Hovs ‘ever it cam undesirably accelerate the degradation of acta open. Thus. aa acetaminophen formation having an ion izing agent might be less stable. Based on the required shell life of « formulation, « person shilled in dhe art can easily ‘decide whether or not tb include an ionizing agent in the ormullaton, In the formulation of thisiventon tat does not include an ionizing agent, acetaminophen is dissolved at an unexpectedly high concentration in the solvent system, ‘which, as pointed out above, contains polyvinylpymolidone, polyethylene alyeol, and water. ‘The tem “dissolving” herein means “evenly dispersing ‘acetaminophen as molecules inthe solvent system containing polyvinyipyrrolidone, polyethylene glycol, and water for at Feast tree days, as judged by the naked eye or by a magnify- ing optical device based on two criteria: (i) transparence of the solution, and Gi) no formation of solid precipitation.” “The transitional phrase “consisting essentially ofr "con= sists essentially of” as used herein mits the seope ofa claim to the specified materials o steps and those that do not mate- rially affect the basie and novel characteristics ofthe claimed ‘Unexpectedly, polyvinyipyrrotidone continues to enhance the solubility of acetaminophen when present inthe above- described solvent system at 225% by weight, coneary tothe belief that polyvinylpyrmlidane beyond 20% by weight ‘ceases to further enhance the solubility af acetaminophen. The formulations ofthis invention can further contain 3 preserving agent, a stabilizing ant, a wetting agent, a taste masking agent, o a coloring substance. ‘Below isa general procedure thatean bese to prepare the Jormulaton ofthis invention: Polyethylene glycol (e-, PEG-400), water, polyvinylpyr rolidone, dd one or more optional solveats (eg. propylene alyeo!) or other agents (eg, sodium acetate) are mixed! at an ‘levated temperate to form a clear solvent system. The acetaminophen is then dissolved in the solvent system. The resulting solution can further be procested. eg. deaerated and sterilized. The dissolution of sectaminophen in the for- ‘lation can be determined visually based on bot ranspar- ‘ence ofthe solution and lack of sold precipitation. Further, the dissolved acetaminophen in the formulation can be assayed by analytical methods, such as thin layer chromatog- raphy andlor high performance liquid ehromatography. ‘A person skilled in the art can determine without undve ‘experimentation the order of adding polyvinylpymotidone, polyethylene glycol, water, and other component, if any. their relative amounts, and the mixingiissolving temper tures to form the solvent system and to dissolve acetami- rnophen- Indeed, skilled arisan can make adjustments ofthe above to abtnin desired concentration of acetaminophen ia the system, 0 o 4 The spevific examples below are to be construed as merely itlstative, and not limitative ofthe remainder of the diselo- ‘rein any way whatsoever. Without further elaboration, tis believed that one skilled in the at ean, based om the desrip- tion herein, uilize the present invention to is fllest extent All publications eted herein are incorporated by reference in thei enti, EXAMPLE 1 Polyethylene glycol 400 (575 mg) and propylene glyco! (64.5 mg) were mixed with stirring at 250-350 epm. The ‘mixture was slowly heated to 17025¢ F. Subsequenty, poly ‘inylpyrrolidonie K17 (115.0 mg) wa ada to te mitre ot the same temperature. After the mixture turned into clear solution with constant string, water (80 S mg) and aeetami ‘nophen (325 mg) were then added. The acetaminophen-con- ‘aining solution was further sired a 170e5° F for 45 min- ‘utes until it became clear. The clear acetaminophen solution ‘was thea removed from the heat source and deserted in a vacuum desiccator (a vacuum between 26 10 30 inches of ‘mereury) at room temperature for 20-30 minutes, The sol tion, containing acetaminophen ia an amount as high as 28.3% by weight, was visually evaluated. Unexpectedly it ‘remained clear for 3 days (indeed, for more than eight months) despite the high aeetaminophen concentration. EXAMPLE2 Polyethylene glyeo! 400 (575 mg) and propylene glyco! (64.5 mg) were mixed with stirring at 250-350 epm. The ‘mixture Was slowly heated to 1705" F. Subsequealy, poly vinylpyetolidone K30 (115.0 mg) was added to the mixture at the same temperature. After the mixture turned into clear solution with constant string, water (80 S mg) and aeetami ‘nophen (325 mg) were then added. The acetaminophen-con- ‘aining solution was further sired at 17025° F. for 45 min- ‘les until it became clear. The clear acetaminophen solution ‘was thea removed from the heat source and deserted in a vacuum desiccator (a vacuum between 26 10 30 inches of ‘mercury at room temperature for 20-30 minutes, The sol tion, containing acetaminophen in an amount as high as 28.3% by weight, was visually evalvated. Unexpectedly it remained clea for 3 days despite the high acctaminophen ceoncentation EXAMPLE 3 Polyethylene glycol 400 (575 mg) and propylene glycol (54.5 mg) were mixed with stirring at 250-850 apa. The ‘mixture was slowly heated to 17025° F. Subsequently, poly Vinylpyrtolidone K12 230.0 mg) was add to the mixture at the same temperature, Afer the mixture turned info a clear solution with constant string, water (80.5 mg) and acetami ‘nophen (325 mg) were then added. The aeetaminophen-com- ‘aining solution was further sired at 17085° F for 48 min- ‘les until it became clear. The clear acetaminophen solution ‘was thea removed from the heat source and deaerated in vacuum desiccator (a vacuum between 26 10 30 inches of mercury) at room temperature for 20-30 minutes. The solu- tion, containing acetaminophen ia an amount as high as 25.7% by weight, was visually evalvated. Unexpectedly it remained clear for 3 days despite the high acetaminophen concentation OTHER EMBODIMENTS All of the features disclosed in this specification may be combined in any combination, Bal eate diselosed i thisUS 8,969,416 B2 5 specification may be replaced by an alterative feature serv- ing the same, equivalent, or similar purpose. Thus, unless ‘expressly sated otherwise, each feature disclosed is only aa ‘example ofa generic series of equivalent or similar Features, ‘From theabove deseription, one skilledintheart can easily s sscerain the essential characteristic ofthe present invention, and without departing fom the spirit and seope thereof, can take various changes and modifications ofthe invention to adapitto various usoges andl conditions. Thus, other embod tents ae also within the claims. What i claimed is 1. A liguid pharmaceutical formulation consisting essen- tially of soetaminophen as the only active ingredient and @ solvent system fordissolving he acetaminophen, wherein the acetaminophen is 10-60% by weight ofthe formulation, the folvent system consists esseatilly of water, polyethylene _alycol, propylene glycol, and polyvinypyrrlidane, the poly Vinylpystolidone having a molecular weight of2000 (0 1,500, ‘000 std being 2-50% by wight ofthe formulation, and the Jormulation is fre of any ionizing agent, wherein the formu- Jation remains clear fora least 3 days at room temperature ‘and the water is about 6.36-7.0%% by weight of the formula 2, The liquid pharmaceutical formulation of claim 1, ‘wherein the acetaminophen i 15-40% by weight of the for: rnulation, and the polyvinylpyrtotidane, has a. molecular weight of 2.000 to 62,000 and is $-30%% by weight of the formulation 13. The liquid phamnoceutical formulation of claim 1, “wherein the polyvinylpyrlidane has a molecular weight of 2,000 to 4,000. 4. The pharmaceutical formulation of claim 2, wherein the ‘acetaminophen is 20-85% by weight of the formulation and inylpyrolidone is 10-25% by weight ofthe fom ', The pharmaceutical formulation of elaim 2, wherein the polyvinylpyrrolidone has a molecular weight of 2,000 0 $4,000, 6. The pharmaceutical formulation of laim S, wherein the scetaminophen is 20-35% by weight and the polyvinylpyr= rolidone is 10-25% by weight ofthe formulation 7. The pharmaceutical formulation of claim 2, wherein the polyvinylpyerlidone has a molecular weight of 4000 to 18,000, 8, The pharmaceutical formulation of claim 6, wherein the scetaminopen is 20-35% by weight of the formelation and ihe polyvinylpyreolidone is 10-25% by weight ofthe formu- 9, The pharmaceutical formulation of laim 2, wherein the polyvinylpyrrolidone has a molecular weight of 6.000 t0 15,000, 10. The pharmaceutical formulation of claim 9, wherein the acetaminophen is 20.35% by weight of the formulation ‘and the polyvinylpyrrolidone is 10-25% by weight of the formulation. 11. The pharmaceutical formulation of claim 2, wherein the polyethylene glycol has a moteculae weight of 200-800 12, The pharmaceutical formulation of claim 11, wherein the polyvinylpymolidone has a molecular weight of 2,000 10 44.000, 0 6 13, The pharmaceutical formulation of elim 12, wherein the acetaminophen is 20-35% by weight of the formulation and the polyialpyoidone is 10-25% by weight ofthe 14, The pharmaceutical formulation of claim 11, wherein the polyvinylpyrrolidone has a molecular weight of 4,000 10 18,000. 18, The pharmaceutical formulation of claim 14, wherein the acetaminophen is 20-35% by weight of the formulation an he poysnypyoidone i 10-25% by weight of the ‘ormulation 16, The pharmaceutical formulation of claim 11, wherein the polyvinylpyerolidone has a molecular weight of 6.000 t0 17, The pharmaceutical formulation of elim 16, wherein the acetaminophen is 20-35% by weight of the fomaulation and the polyvinylpyrolidone is 10-25% by weight of the Tormlation, 18, The pharmaceutical formulation of elsim 3, wherein the acetaminophen is 15-40% by weight of the formulation and the polyvinylpyrlidone is 530% by weight of the for sation 19. The pharmaceutical formulation of claim 3, wherein the acetaminophen is 20-35% by weight of the formulation and the polyvinylpyrrolidone is 10-25% by weight of the Tormlation, 20, The pharmaceutical formulation of claim 3, wherein the polyethylene glycol hus a molecular weight of 200-80. 21, The pharmaceutical formulation of claim 20, wherein the acetaminophen is 15-40% hy weight of the fomnuation and the polyvinylpyrlidone is 5-30% by weight ofthe fore ‘ulation 22. The phamaceutcal formolaton of claim 20, wherein the acetaminophen is 20-35% by weight of the fomaulation and the polyvinylpyrolidone is 10-25% by weight of the Tormulation, 23. The pharmaceutical formulation of claim 1, wherein the polyethylene glycol has a molecular weight of 400, ‘24.4 method of preparing guid pharmaceutical form Jation of claim 1, which method comprises: (@) string polyethylene glycol and propylene glyco! to ‘obtain @ mixture, the polyethylene glyeo! having an average molecular weight of 200-800; (beating the mixture toa temperature OF 170=5°F. with stirring to obtain a heated mitre (©)adding polyvinylpyrolidone to the heated mixture with string atthe same temperature to obtain a clear sol tion; (aking purified water to the lear solution with sising athe same temperature to obtain an aqueous solution (6) adding acetaminophen to the aqueos solution with stirring at the same temperature to obtain an aeetami nophen solution; (O stirring the acetaminophen sotuion atthe same tem- ‘erature to obtain a clear acetaminophen solution, and (g)coolingtoambient temperature and deaerating the clear ‘setatninophen solution. 25. The pharmaceutical formulation of claim 1, wherein the waters about 636% or 7.00% by weight ofthe farmula- sie,