Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
  • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • 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
  • A61K9/20—Pills, tablets, discs, rods
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

• the present inventions relate to acetaminophen compositions and methods for administering same to treat pain and other conditions for which acetaminophen administration is desired (e.g., antipyretic treatment) while minimizing multiple side effects including liver toxicity (hepatotoxicity) associated with acetaminophen.
• the present inventions are directed to solid tablets or gel capsules comprising acetaminophen and an agent that promotes glutathione production.
• the glutathione production promoter is preferably n-acetylcysteine or other mercapto-2-amino alkyl carboxylic acid having glutathione production promoting properties shown to mitigate acetaminophen-induced hepatotoxicity.
• compositions of the present invention also include an antiemetic and/or an antihistamine.
• the embodiments with an antiemetic and/or antihistamine will mitigate acetaminophen and/or opiate related nausea and vomiting (several formulations currently exist combining acetaminophen with opiates).
• the embodiments with antihistamines will also reduce itching and other histamine-based side effects known to be associated with acetaminophen and opiates.
• Antihistamines are also known to have an analgesic property improving the total analgesic effect over acetaminophen alone. Some antihistamines have sedating properties inducing sleep which can be useful in some circumstances in patients experiencing pain.
• compositions are prepared for patient self-administration in tablet or gel capsule form wherein the patients can take the medication without the need for close oversight of a medical caregiver.
• These embodiments will contain fragrances and/or physical encapsulation that will mitigate the smell and taste of the preparations improving patient compliance, as the glutathione promoters have a noxious smell and taste along with other side effects, which has thus far limited their use.
• N-acetyl-p-aminophenol also referred to generically as acetaminophen and sold under the trademark TYLENOL inter alia is one of the most common pain relievers and antipyretics sold and used in the United States and around the world. Prolonged use or ingestion of acutely elevated levels of N-acetyl-p- aminophenol can result in liver damage.
• acetaminophen includes pharmaceutically equivalent analogs of acetaminophen. Without being limited to any particular theory of biological activity, it is believed that the hepatotoxic effects of acetaminophen are related to intracellular depletion of glutathione reserves.
• N-acetylcysteine a mercapto-2-amino-alkyl carboxylic acid derivative
• Glutathione is thought to be impermeable to hepatocytes and is not an effective antidote to N-acetyl-p-aminophenol.
• Numerous studies have demonstrated that N-acetylcysteine is an effective antidote to N-acetyl-p- aminophenol-related hepatotoxicity.
• N-acetyl-p-aminophenol is available for use as an elixir or in solid form.
• N-acetyl-p-aminophenol is also commonly combined with opiates to make a more potent analgesic (e.g., a composition of hydrocodone and acetaminophen are available as Vicodin ® ).
• analgesic e.g., a composition of hydrocodone and acetaminophen are available as Vicodin ® .
• a well-documented effect of opiates is the rapid tolerance developed after only a short period of use (e.g., less than 3 days depending on the dosage). In order to maintain the same analgesic effect, patients often escalate their doses, generally doing so despite being warned against this by their physician.
• NAC administered via IV has been associated with anaphylactic shock.
• Acetaminophen at recommended doses is usually a very safe and useful drug that can effectively and safely reduce fever and pain for most patients. It is also widely available and inexpensive. Therefore, despite the large numbers of deaths and cases of liver damage requiring transplant and/or treatment associated with the use of acetaminophen, doctors continue and will likely continue to prescribe medicines containing acetaminophen and many individuals will continue to buy acetaminophen over the counter without a prescription and drink alcohol concomitantly and/or take more acetaminophen than is safe.
• antihistamines will also reduce itching and other histamine-based side effects known to be associated with acetaminophen and opiates.
• Antihistamines are also known to have an analgesic property improving the total analgesic effect over acetaminophen alone.
• Some antihistamines have sedating properties inducing sleep which can be useful in some circumstances in patients experiencing pain. There is a need to minimize and preferably eliminate the risk of liver damage from ingestion of acetaminophen, whether due solely to acetaminophen ingestion and/or concomitant use of alcohol.
• dially sulfide is well known to have a powerful noxious odor.
• DAS dially sulfide
• compositions containing an extra ingredient primarily designed to avoid the effects of overdosing and/or concomitant alcohol consumption are unlikely to appeal to most patients.
• An embodiment of the present inventions is a composition of acetaminophen combined with an agent that promotes glutathione production in a form that patients would be willing to take.
• the addition of fragrances and/or physical encapsulation by various means will mitigate the noxious smell and taste of the glutathione production promoter to the extent that patients are willing to voluntarily take the medication.
• patients threatened with the possibility of death from acetaminophen- induced-hepatotoxicity have refused to take NAC due to its noxious physical properties.
• the prior art has not addressed why a patient would take a potentially dangerous and noxious medication for simple analgesia when many have refused to take it to save their lives and/or avoid serious adverse heath effects.
• the dosage of the glutathione production promoter is low enough in preferred compositions of the present inventions that more than about 100 to 500 times the safe dosage of acetaminophen must be taken via ingestion of the composition to approach the toxic dosage of the glutathione production promoter, provided a sufficient dosage of the glutathione production promoter is administered.
• the composition of the present invention comprises acetaminophen combined with at least one mercapto-2-amino alkyl carboxylic acid having glutathione production promoting properties, wherein, a mammal will have substantially none or reduced hepatotoxic effects after consuming a sufficient amount of the composition to ingest an amount of acetaminophen sufficient to cause hepatotoxic effects in the absence of the mercapto-2-amino alkyl carboxylic acid.
• the preferred glutathione producing agent is N- acetylcysteine ("NAC”), and is compounded in pill or capsule form with acetaminophen.
• NAC is compounded with standard dosages of acetaminophen that are currently available (e.g., 325 or 650 mg acetaminophen), wherein the composition of the present invention comprises acetaminophen and NAC.
• a glutathione production promoting agent such as NAC
• the dosage of NAC is automatically increased, thus concomitantly minimizing or avoiding hepatotoxicity.
• compositions of the present inventions can be administered so that more than about 4 grams of acetaminophen can be delivered per day to a healthy adult mammal (e.g., human) weighing at least 100 pounds without irreparable hepatic toxicity effects.
• all acetaminophen tablets and capsules containing an opioid or other substance that is subject to abuse must contain a sufficient amount of N-acetylcysteine to prevent hepatoxicity, preferrably at dosages of 4 grams of acetaminophen per day.
• prescribing literature will be modified to reflect the assumption that patients will exceed recommended dosages of acetaminophen when combined with an opioid or other addictive agent. Under such an assumption, it becomes appropriate to require the addition of a prophylactic agent to prevent hepatotoxicity to acetaminophen compositions, and that medical insurance cover the additional cost. Patient compliance is enhanced by reducing the noxious odor and taste of the prophylactic agent(s). Further, the additional costs of the prophylactic agent(s) may be more than offset by the cost savings in reducing the number of patients requiring treatment for hepatotoxicity.
• acetaminophen is combined with at least one compound from the group consisting of NAC, methionine, and cysteine.
• the composition comprises at least one active agent selected from the group consisting of a narcotic drug (e.g., codeine, hydrocodone), an anti-emetic drug, an antihistamine drug, and an anti- inflammatory drug.
• a narcotic drug e.g., codeine, hydrocodone
• Antihistamines also act as anti-emetics, anti-pruritics, soporifics, and mild analgesics. These mitigate the known side effects of acetaminophen, and/or glutathione promoters, and/or opiates. Mitigation of these side effects will also increase patient compliance.
• Antihistamines and anti-inflammatories analgesic effects will make for a more effective analgesic.
• Embodiments of the present inventions can include various combinations of various classes of drugs may, for example: acetaminophen can be combined with NAC and optionally DAS 1 and also be combined with stimulants such as caffeine, Antihistamines (H1 and H2 blockers), NSAID's, proton-pump inhibitors, laxatives, antiemetics, opiates and other analgesics, anxiolytics, muscle relaxants.
• stimulants such as caffeine, Antihistamines (H1 and H2 blockers), NSAID's, proton-pump inhibitors, laxatives, antiemetics, opiates and other analgesics, anxiolytics, muscle relaxants.
• Exemplary members of each the forgoing classes of drugs include but are not limited to: 1 ) for antihepatoxic effects, drugs with a sulfhydryl moiety, such as NAC, Methionine, L-cysteine; 2) stimulants and drugs with CNS stimulating effects, such as caffeine, theophylline, dextroamphetamine, amphetamine, methamphetamine, atomoxetine, dexmethylphenidate, methylphenidate, modafinil, phentermine, and sibutramine;
• antihistamines that have an H1 -blockers effect, such as desloratidine, fexofenadine, loratidine, azatidine, cetirizine, chlorfeniramine, clemastine, cyproheptadine, dexchlorpheniramine, diphenhydramine, hydroxyzine, promethazine;
• antihistamines that have an H2-blocker effect and/or antacid effect, such as: cimetidine, famotidine, nizatidine, ranitidine; 5) antinflamtory drugs such as nonsteroidal antiflamatory drugs, aspirin, diflunisal, salsalate, trilisate, flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, diclofenac, etodolac, indomethacin, ketorolac, nabumetone, sulindac, tolmetin, meclofenamate, meloxicam, piroxicam, celecoxib;.
• antinflamtory drugs such as nonsteroidal antiflamatory drugs, aspirin, diflunisal, salsalate, trilisate, flurbiprofen, ibuprofen, ketoprofen, naproxen, oxaprozin, diclofenac, etodo
• proton-pump inhibitors and/or antacids such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, or any other drug with proton-pump inhibitor or antacid effects;
• Laxatives such as bisacodyl, cascara, docusate calcium, docusate sodium, magnesium citrate, magnesium hydroxide, sennosides, polyethylene glycol, senna, and sorbitol;
• Drugs with 5-HT3-blocker effects such as antiemetics that are 5-HT3- blockers, and other 5-HT3-blockers, such as dolasetron, granisetron, ondansetron, and palonosetron,.
• Opiates and other analgesics such as buprenophine, butorphanol, nalbuphine, pentazocine, codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene, hydrocodone, dihydrcodeine, nalmefene, naloxone, tramadol, and ziconotide;
• Anxiolytics such as bromazepam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, flurazepam, estazolam, lorazepam, temazepam, alprazolam, oxazepam, triazolam, buspironechloral hydrate, diphenhydramine, eszoclipone, ramelteon, zaleplon, Zolpidem, and zipiclone; and
• Muscle relaxants such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, dantrolene, diazepam, metaxalone, methocarbamol, orphenadrine, and tizanidine.
• drugs may have more than one of the 12 effects listed above and/or belong to more than one class of drugs listed above, regardless of how these drugs might otherwise be classified in the art and/or any particular mechanism of action.
• Preferred embodiments of the present invention comprise acetaminophen, NAC and at least one of an antihistamine and an antiemetic.
• the compositions, with or without the addition of a fragrance of the present invention are in solid pill or capsule form, wherein the noxious odor and taste of NAC can be minimized and nausea offset by the presence of an antiemetic.
• Coatings designed to break down after swallowing may be included in some formulations.
• the present invention also provides for an adjunctive composition to prevent hepatotoxicity, and other related side effects.
• a patient taking a liquid elixir of acetaminophen or a liquid medicine such as cold medications containing acetaminophen would not want to include in medication the liguid form of NAC due to the noxious odor and possible emesis that can create related health complications.
• Patients may also be prescribed or purchase acetaminophen containing pills that contain nothing to offset possible hepatotoxic effects.
• the present invention provides a method for preventing hepatoxicity in patients taking acetaminophen via providing sufficient dosages of NAC in solid pill or capsule form at or near the time of each dosage of acetaminophen given.
• the tablet is preferably formulated to reduce the odor of NAC, such as by coating, use of masking agents, or compounding with compounds that offset or absorb the NAC odor.
• the solid form of NAC is combined with an antiemetic and/or an antihistamine.
• Vicodin is a well known trademark, which will also be referred to herein by "vicodin”
• Vicodin is a well known trademark, which will also be referred to herein by "vicodin”
• the patient must seek a refill in only a week; often doctors refilling such prescriptions give a stern advisory about taking too many pills and the dangers of Tylenol / acetaminophen.
• the patient sought prescriptions from other physicians and took 30 Vicodin tablets each day.
• NAC n-acetylcysteine
• NAC prophylactic NAC
• all rats in the study are given the LD50 dose of acetaminophen (determined by the dosage of acetaminophen that causes 50% of the test subjects to expire after a predetermined period of time).
• acetaminophen with an agent that has glutathione production promoting properties reduces or avoids hepatoxicity.
• an agent that has glutathione production promoting properties is coadministered in pill or capsule form with acetaminophen.
• n-acetylcysteine is combined with acetaminophen in formulations made in accordance with Table I below.
• N-acetylcysteine has adverse side effects at large dosages
• a very large amount of an acetaminophen-containing composition of the present invention would have to be consumed to approach the toxic level of N- acetylcysteine; however, in order to consume such a large quantity of the present invention other ingredients would cause noticeable effects encouraging the user to stop taking more.
• an agent could be added that is not noticeable at low doses but causes vomiting only at high dosages.
• agents that offset the euphoria of addictive drugs may also be used to discourage abuse as are kown to those of skill in the art.
• a sufficient amount of n-acetylcysteine or other agent that counters the hepatotoxic effects of acetaminophen is added to that amount of acetaminophen, with the mix then divided into standard aliquots sufficient to meet the needs of a patient.
• compositions of the present inventions would make an ideal medication for pulmonary conditions in addition to its usefulness for treatment of fever and painful bodily injuries.
• exemplary embodiments and uses of the present inventions have been described. Alternative embodiments, descriptions and terms are contemplated. While exemplary embodiments of the present invention have been set forth above, it is to be understood that the pioneer inventions disclosed herein may be made and used otherwise than as specifically described.

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• Chemical Kinetics & Catalysis (AREA)
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• Pain & Pain Management (AREA)
• Gastroenterology & Hepatology (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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• 2007
  • 2007-12-07 US US11/952,556 patent/US20080139654A1/en not_active Abandoned
  • 2007-12-08 AU AU2007332812A patent/AU2007332812A1/en not_active Abandoned
  • 2007-12-08 BR BRPI0721216-0A2A patent/BRPI0721216A2/pt not_active Application Discontinuation
  • 2007-12-08 WO PCT/US2007/025167 patent/WO2008073344A1/en not_active Ceased
  • 2007-12-08 CA CA002671490A patent/CA2671490A1/en not_active Abandoned
  • 2007-12-08 MX MX2009006177A patent/MX2009006177A/es not_active Application Discontinuation
  • 2007-12-08 KR KR1020097011839A patent/KR20090089867A/ko not_active Withdrawn
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  • 2007-12-08 EP EP07853309A patent/EP2094253A4/en not_active Withdrawn
  • 2007-12-08 CN CNA2007800389520A patent/CN101588797A/zh active Pending
  • 2007-12-08 JP JP2009540327A patent/JP2010513229A/ja not_active Withdrawn
• 2009
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