WO2022178018A1 - Formes galéniques unitaires liquides pour le traitement de la douleur - Google Patents

Formes galéniques unitaires liquides pour le traitement de la douleur Download PDF

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Publication number
WO2022178018A1
WO2022178018A1 PCT/US2022/016636 US2022016636W WO2022178018A1 WO 2022178018 A1 WO2022178018 A1 WO 2022178018A1 US 2022016636 W US2022016636 W US 2022016636W WO 2022178018 A1 WO2022178018 A1 WO 2022178018A1
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Prior art keywords
hours
pain
unit dosage
dosage form
liquid unit
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English (en)
Inventor
Raul Arturo TRILLO
Eric D. Lang
Tushar HINGORANI
Kumaresh Soppimath
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Nevakar Injectables Inc
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Nevakar Injectables Inc
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    • 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]
    • 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
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions

Definitions

  • the field of the invention is compositions and methods of treating pain, and especially as it relates to treatment of pain using parenteral administration of acetaminophen from a single use container to a subject in need thereof.
  • Pain management can involve the use of opioids or non-steroidal inflammatory drugs (NSAIDs) following surgery.
  • opioids or opioid-derived analgesics can lead to undesirable side effects including, for example, nausea, vomiting, constipation, and poor respiratory function.
  • NSAIDs are often used to control or reduce pain, significant side effects (e.g., gastric upset, bleeding, and ulcers) can occur, particularly when administered at relatively high dosages and/or over extended periods of time.
  • acetaminophen is a non-NSAID and non-opioid analgesic with a favorable safety profile at low dosages.
  • acetaminophen is available in an oral tablet or capsule over the counter format for mild to moderate pain.
  • dosage form often performs less desirably where the pain is more severe such as for example, with post-operative pain after surgery.
  • the acetaminophen concentration in cerebrospinal fluid after oral administration is typically significantly lower as compared to administration of the same dose by infusion.
  • Acetaminophen is also available in a liquid formulation for injection/infusion and a typical schedule of administration is infusion of 1,000 mg 4 times a day at 6 hour intervals. While such administration is common in various point-of care settings, the relatively high frequency of administration and accompanying administrative and billing generates a significant burden on personnel.
  • inventive subject matter is directed to various compositions and methods of parenteral administration of acetaminophen form a single use container at a ready-to-use concentration that does not require dilution or preparation of an injectable formulation.
  • a reduced schedule of administration e.g., 3 times per day at 8 hours intervals
  • somewhat higher concentrations e.g., about 1,300 mg
  • the invention provides a method of treating pain in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a liquid unit dosage form, wherein the liquid unit dosage form comprises acetaminophen in an amount from about 1100 mg to about 1500 mg, wherein the administration of the liquid unit dosage form is from a single use container.
  • the invention provides a method of treating pain in a subject in need thereof, the method comprising administering to the subject about 1300 mg acetaminophen in a liquid unit dosage form about every 8 hours via intravenous injection, wherein the administration of the liquid unit dosage form is from a single use container.
  • the inventors contemplate a method of treating pain in a subject in need thereof that includes a step of administering to the subject a therapeutically-effective amount of a liquid unit dosage form, wherein the liquid unit dosage form comprises acetaminophen in an amount from about 1100 mg to about 1500 mg, and wherein the administration of the liquid unit dosage form is from a single use container.
  • the liquid unit dosage form comprises acetaminophen in an amount from about 1200 mg to about 1400 mg (e.g., about 1300 mg).
  • the pain is dental pain
  • the liquid unit dosage form is administered to the subject from one to three times per day.
  • the liquid unit dosage form is administered to the subject within 24 hours prior to the subject undergoing a surgical procedure, simultaneously with the subject undergoing a surgical procedure, and/or within 24 hours after the subject has undergone a surgical procedure.
  • the administration is parenteral administration, and especially intravenous administration.
  • the liquid unit dosage form has an acetaminophen concentration of between 5-15 mg/mL (e.g., about 10 mg/mL), and/or the liquid unit dosage form has a total volume of between 100 mL and 150 mL (e.g., about 130 mL).
  • the single use container is a polymer bag, which may be packaged in an aluminized over-pouch.
  • the aluminum overwrap can optionally also contain an oxygen scavenger.
  • one exemplary method of treating pain in a subject in need thereof may include a step of administering to the subject about 1300 mg acetaminophen in a liquid unit dosage form about every 8 hours via intravenous injection, wherein the administration of the liquid unit dosage form is from a single use container.
  • the liquid unit dosage form is administered (e.g., post-operatively) at a volume of about 130 mL.
  • FIG.l is a chart that depicts the average blood plasma concentration of acetaminophen over a period of 24 hours in patients administered 1300 mg acetaminophen IV every 8 hours or 1000 mg acetaminophen IV every 6 hours.
  • the present application relates to methods for treatment of postoperative pain in a subject in need thereof. After surgery, patients can suffer from severe pain that can persist for days, weeks, or months. Postoperative pain can be managed by administering to the patient, for example, centrally-acting m-opioid analgesics or non-opioid analgesics. However, the occurrence of undesirable side effects can lead to reduced patient compliance and ineffective pain treatment.
  • the present application also describes unit dosage forms, pharmaceutical formulations, and methods of use thereof to alleviate postoperative pain by, for example, preoperatively administering the pharmaceutical formulation to the patient.
  • a pharmaceutical formulation described herein can also reduce postoperative opioid consumption by a patient who has been administered the pharmaceutical formulation.
  • Unit dosage forms of the present disclosure can be administered with less frequency compared to other forms while providing similar efficacy for relief of postoperative pain, thereby reducing administrative burden and patient treatment time as compared to traditional modes of administration.
  • Such advantage is especially beneficial in point-of-care settings such as hospital or at-home-care where nurses or other qualified medical personnel administer drugs for pain relief to a patient.
  • the present disclosure provides pharmaceutical compositions for the treatment of pain.
  • Pain can be, for example, mild, moderate, severe, or agonizing.
  • the pain of a subject can be assessed using a numeric scale, in which a patient can self-report pain on a scale from 0-10, where 0 indicates no pain, 1-3 suggests mild pain, 4-6 indicates moderate pain, and 7-10 suggests severe and disabling pain.
  • Pain of the subject can also be self-reported on a scale from 0-3, where 0 indicates no pain, 1 indicates mild pain, 2 indicates moderate pain, and 3 indicates severe pain.
  • Pain relief provided by a pharmaceutical composition or unit dosage form of the present disclosure can be evaluated using a numeric scale, in which a subject can self-report perceived pain relief on a scale from 0-4, where 0 indicates no pain relief, 1 indicates mild pain relief, 2 suggests some pain relief, 3 indicates considerable pain relief, and 4 indicates complete pain relief.
  • Pain can include, for example, angina pain, bone injury pain, central pain, chronic lower back pain, cluster headaches, dental pain, genitourinary tract- related pain including cystitis and nociceptive pain, herpes neuralgia, migraine, neuropathic pain, pain during labor and delivery, pain resulting from bums, phantom limb pain, postoperative pain, postpartum pain, surgical pain, renal colic pain, pain associated with fractures, pain associated with soft tissue injury, pain associated with would bandage changes, pain associated with joint dislocations, or visceral pain.
  • the pain is postoperative pain.
  • the pain can be chronic or acute. Postoperative pain can describe that occurs after a surgery and can be a direct or indirect result of the surgery.
  • a pharmaceutical formulation described herein can be administered to the patient during or prior to surgery to treat, for example, acute postoperative pain.
  • the postoperative pain can be reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.
  • the reduction is postoperative pain can happen after about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 8 hours, about 10 hours, or about 12 hours after the surgery.
  • a pharmaceutical formulation described herein can be administered to a subject disclosed herein to treat pain.
  • the pain can be reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 99%.
  • Time between administration of a pharmaceutical composition of the disclosure and onset of pain relief can be self-reported by the subject, in which the subject is given a stopwatch and asked to press the stopwatch when the subject first perceives any pain relief.
  • the time to onset of pain relief in subjects administered a pharmaceutical composition of the disclosure can be, for example, about 0.05 hours to about 2 hours, about 0.05 hours to about 1.75 hours, about 0.05 hours to about 1.5 hours, about 0.05 hours to about 1.25 hours, about 0.05 hours to about 1 hour, about 0.05 hours to about 0.75 hours, about 0.05 hours to about 0.25 hours, about 0.1 hours to about 0.25 hours, about 0.15 hours to about 0.25 hours, about 0.1 hours to about 0.2 hours, about 0.1 hours to about 0.18 hours, about 0.14 hours to about 0.23 hours, about 0.1 hours to about 0.23 hours, about 0.15 hours to about 0.23 hours, about 0.2 hours to about 0.25 hours, or about 0.2 hours to about 0.23 hours.
  • the subject self-reports pain of 2
  • a non-opioid analgesic can include, for example, an NSAID, an anti convulsant, an anti-pyretic, acetylsalicylic acid, or acetaminophen (N-(4- hydroxy phenyl jacetamide): paracetamol; N-acetyl-para-aminophenol).
  • Acetaminophen is an anti-pyretic agent, and can be used to treat mild to moderate pain in adults and children.
  • a non-opioid analgesic in a pharmaceutical formulation described herein is acetaminophen.
  • the non-opioid analgesic can be, for example, aceclofenac, acemetacin, acetaminophen, acetylsalicylic acid, amoxiprin, azapropazone, benorilate, bromfenac, carprofen, choline magnesium salicylate, diflunisal, diclofenac, etodolac, fatelamine, fenbuprofen, flubiprofen, ibuprofen, indometacin, ketaprofen, ketorolac, lomoxicam, loxoprofen, magnesium salicylate, meclofenamic, mefenamic acid, meloxicam, metamizole, methyl salicylate, nabumetone, naproxen, oxyphenbutazone, piroxicam, phenylbutazone, sulfmprazone, sulindac, suprofen, tenoxicam, tolmet
  • compositions include, for example, acid- addition salts and base-addition salts.
  • the acid that is added to the compound to form an acid- addition salt can be an organic acid or an inorganic acid.
  • a base that is added to the compound to form a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically-acceptable salt is a metal salt.
  • a pharmaceutically- acceptable salt is an ammonium salt.
  • Metal salts can arise from the addition of an inorganic base to a compound of the present disclosure.
  • the inorganic base consists of a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.
  • a metal salt is a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, or a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound of the present disclosure.
  • the organic amine is triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N- methylmorpholine, piperidine, /V-methylpiperidine, /V-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, pyrrole, imidazole, or pyrazine.
  • an ammonium salt is atriethyl amine salt, a trimethyl amine salt, a diisopropyl amine salt, an ethanol amine salt, a diethanol amine salt, a triethanol amine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, a pyridazine salt, pyrrole salt, a pyrimidine salt, an imidazole salt, or a pyrazine salt.
  • Acid addition salts can arise from the addition of an acid to a compound of the present disclosure.
  • the acid is organic.
  • the acid is inorganic.
  • the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, saccharic acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid, or maleic acid.
  • the salt is a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, isonicotinate salt, a lactate salt, a salicylate salt, a tartrate salt, an ascorbate salt, a gentisate salt, a gluconate salt, a glucuronate salt, a saccharate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt, a succinate salt, a methanesulfonate salt, an ethanesulfonate salt, a benzenesulfonate salt, a p- toluenesulf
  • a pharmaceutical formulation of the disclosure can provide a therapeutically-effective amount of any compound disclosed herein.
  • a pharmaceutical formulation of the disclosure can provide a therapeutically-effective amount of a non-opioid analgesic.
  • the additional non-opioid analgesic is acetaminophen.
  • the disclosed formulations can contain one or more pharmaceutically-acceptable agents, which alone or in combination solubilize a compound herein or a pharmaceutically- acceptable salt thereof.
  • the pharmaceutically-acceptable agent is a buffer.
  • the pharmaceutically-acceptable agent is a citrate buffer.
  • the pharmaceutically-acceptable agent is a phosphate buffer.
  • the pharmaceutically-acceptable agent is an acetate buffer.
  • a buffer as described herein can be formed from a solution containing, for example, an acid and a conjugate base of the acid, or a base and a conjugate acid of the base.
  • the acid in a buffer described herein can be a weak acid.
  • a base in a buffer described herein can be a weak base. Any formulation described herein can contain, for example, an acid, and a conjugate base of the acid, or a base, and a conjugate acid of the base.
  • a formulation described herein can contain an isotonicity inducing agent.
  • the isotonicity inducing agent can be, for example, sodium chloride or mannitol or dextrose.
  • a compound disclosed herein or pharmaceutically-acceptable salt thereof is present in a formulation in an amount of from about 0.01 mg/mL to about 100 mg/mL, from about 0.1 mg/mL to about 1 mg/mL, from about 0.01 mg/mL to about 5 mg/mL, from about 5 mg/mL to about 10 mg/mL, from about 10 mg/mL to about 15 mg/mL, from about 15 mg/mL to about 20 mg/mL, from about 20 mg/mL to about 25 mg/mL, from about 25 mg/mL to about 30 mg/mL, from about 30 mg/mL to about 35 mg/mL, from about 35 mg/mL to about 40 mg/mL, from about 40 mg/mL to about 45 mg/mL, about 45 mg/mL to about 50 mg/mL, from about 50 mg/mL to about 55 mg/mL, from about 55 mg/mL to about 60 mg/mL, from about 60 mg/mL to about 65
  • a compound disclosed herein or pharmaceutically-acceptable salt thereof is present in a formulation in an amount of about 1 mg/mL, about 2 mg/mL, about 3 mg/mL, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, about 20 mg/mL, about 21 mg/mL about 22 mg/mL, about 23 mg/mL, about 24 mg/mL, about 25 mg/mL, about 26 mg/mL, about 27 mg/mL, about 28 mg/mL, about 29 mg/mL, about 30 mg/mL, about 31 mg/mL about 32 mg/mL,
  • the compound can be, for example, acetaminophen.
  • a pharmaceutical formulation described herein can contain, for example, acetaminophen, sodium chloride, and citric acid monohydrate.
  • the pharmaceutical formulation can be at, for example, pH 5, 5.5, or 6. In some embodiments, the pH of the pharmaceutical formulation is 5.5. In some embodiments, the pH of the pharmaceutical formulation is 6.
  • the acetaminophen can be present in the pharmaceutical formulation at a concentration of about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. In some embodiments, the acetaminophen is present in the pharmaceutical formulation at a concentration of 10 mg/mL.
  • the sodium chloride can be present in the pharmaceutical formulation at a concentration of about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 5.5 mg/mL, or about 6 mg/mL. In some embodiments, the sodium chloride is present in the pharmaceutical formulation at a concentration of 5 mg/mL. In some embodiments, the sodium chloride is present in the pharmaceutical formulation at a concentration of 4.5 mg/mL.
  • the citric acid monohydrate can be present in the pharmaceutical formulation at a concentration of about 2 mg/mL, about 2.05 mg/mL, about 2.1 mg/mL, about 2.101 mg/mL, about 2.102 mg/mL, about 2.103 mg/mL, about 2.014 mg/mL, about 2.105 mg/mL, about 2.11 mg/mL, about 2.15 mg/mL, or about 2.2 mg/mL. In some embodiments, the citric acid monohydrate is present in the pharmaceutical formulation at a concentration of 2.101 mg/mL.
  • a pharmaceutical formulation described herein can contain, for example, acetaminophen, sodium chloride, and acetic acid.
  • the pharmaceutical formulation can be at, for example, pH 5, 5.5, or 6. In some embodiments, the pH of the pharmaceutical formulation is 5.5.
  • the acetaminophen can be present in the pharmaceutical formulation at a concentration of about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. In some embodiments, the acetaminophen is present in the pharmaceutical formulation at a concentration of 10 mg/mL.
  • the sodium chloride can be present in the pharmaceutical formulation at a concentration of about 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 5.5 mg/mL, or about 6 mg/mL. In some embodiments, the sodium chloride is present in the pharmaceutical formulation at a concentration of 5 mg/mL.
  • the acetic acid can be present in the pharmaceutical formulation at a concentration of about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, or about 1 mg/mL. In some embodiments, the acetic acid is present in the pharmaceutical formulation at a concentration of 0.6 mg/mL.
  • a pharmaceutical formulation described herein can contain, for example, acetaminophen, sodium chloride, and citric acid.
  • the pharmaceutical formulation can be at, for example, pH 5, 5.5, or 6. In some embodiments, the pH of the pharmaceutical formulation is 6.
  • the acetaminophen can be present in the pharmaceutical formulation at a concentration of about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, or about 10 mg/mL. In some embodiments, the acetaminophen is present in the pharmaceutical formulation at a concentration of 10 mg/mL.
  • the sodium chloride can be present in the pharmaceutical formulation at a concentration of about 3.5 mg/mL, 4 mg/mL, about 4.5 mg/mL, about 5 mg/mL, about 5.5 mg/mL, about 6 mg/mL, about 6.5 mg/mL, about 7 mg/mL or about 7.5 mg/mL. In some embodiments, the sodium chloride is present in the pharmaceutical formulation at a concentration of 5.5 mg/mL.
  • the citric acid can be present in the pharmaceutical formulation at a concentration of aboutl mg/mL, about 0.1 mg/mL, 0.2 mg/mL, 0.3 mg/mL, 0.4mg/mL, 0.5 mg/mL, 0.6 mg/mL, 0.7 mg/mL, 0.8 mg/mL, 0.9 mg/mL, 1 mg/mL,
  • the citric acid is present in the pharmaceutical formulation at a concentration of
  • Sodium chloride can be a present in a pharmaceutical formulation described herein at a concentration of about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.1 mg/mL, about 1.2 mg/mL, about 1.3 mg/mL, about 1.4 mg/mL, about 1.5 mg/mL, about 1.6 mg/mL, about 1.7 mg/mL, about 1.8 mg/mL, about 1.9 mg/mL, about 2 mg/mL, about 2.1 mg/mL, about 2.2 mg/mL, about 2.3 mg/mL, about 2.4 mg/mL, about 2.5 mg/mL, about 2.6 mg/mL, about 2.7 mg/mL, about 2.8 mg/mL, about 2.9 mg/mL, about
  • Sodium chloride can be present in a pharmaceutical formulation described herein at a concentration from about 0.1 mg/mL to about 0.5 mg/mL, about 0.2 mg/mL to about 0.6 mg/mL, about 0.3 mg/mL to about 0.7 mg/mL, about 0.4 mg/mL to about 0.8 mg/mL, about 0.5 mg/mL to about 1 mg/mL, about 0.6 mg/mL to about 1.1 mg/mL, about 0.7 mg/mL to about
  • 1-Histidine can be present in a pharmaceutical formulation described herein at a concentration from about 0.1 mg/mL to about 6 mg/mL.
  • Citric acid monohydrate or sodium dihydrogen phosphate can be present in a pharmaceutical formulation described herein at a concentration from about 0.1 mg/mL to about 6 mg/mL.
  • Acetic acid can be present in a pharmaceutical formulation described herein at a concentration of about 0.1 mg/mL to about 5 mg/mL.
  • a pharmaceutical agent that is disclosed herein can be made more soluble in a formulation by the addition of an additive or agent.
  • the improvement of solubility of the formulation can increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75% about 80%, about 85%, about 90%, about 95%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, about 225%, about 250%, about 275%, about 300%, about 325%, about 350%, about 375%, about 400%, about 450%, or about 500%.
  • compositions described herein can be used, stored, tested, analyzed or assayed at any suitable temperature.
  • temperatures include about 0 °C, about 1 °C, about 2 °C, about 3 °C, about 4 °C, about 5 °C, about 6 °C, about 7 °C, about 8 °C, about 9 °C, about 10 °C, about 11 °C, about 12 °C, about 13 °C, about 14 °C, about 15 °C, about 16 °C, about 17 °C, about 18 °C, about 19 °C, about 20 °C, about 21 °C, about 22
  • compositions described herein can be used, stored, tested, analyzed or assayed at room temperature.
  • the room temperature can be, for example, about 20.0 °C, about 20.1 °C, about 20.2 °C, about 20.3 °C, about 20.4 °C, about 20.5 °C, about 20.6 °C, about 20.7 °C, about 20.8 °C, about 20.9 °C, about 21.0 °C, about 21.1 °C, about 21.2 °C, about 21.3 °C, about21.4 °C, about21.5 °C, about21.6 °C, about21.7 °C, about21.8 °C, about21.9 °C, about 22.0 °C, about 22.1 °C, about 22.2 °C, about 22.3 °C, about 22.4 °C, about 22.5 °C, about 22.6 °C, about 22.7 °C, about 22.8 °C, about 22.9 °C, about 23.0 °C, about
  • a liquid unit dosage form described herein can be administered to the patient one time a day, two times a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day. In some embodiments, the liquid unit dosage form is administered to the patient three times per day.
  • a liquid unit dosage form described herein can be administered four times a day at 1300 mg every 8 hours or 1000 mg every 6 hours or 650 mg every 4 hours.
  • a dosage administered herein can be adjusted based upon a patient’s weight.
  • the liquid unit dosage form can be administered from a container or vessel, which can be sealed.
  • the container or vessel can maintain the sterility of, or reduce the likelihood of contamination of, the pharmaceutical formulation.
  • a liquid unit dosage form described herein can be formulated as, for example, a single use dosage or a multiple use dosage.
  • the container or vessel can be, for example, a glass vial, an ampoule, or a plastic flexible container.
  • the plastic flexible container can be made of, for example, PVC (polyvinyl chloride), or polypropylene.
  • a container can be a prefilled syringe.
  • a container can be a glass vial.
  • a liquid unit dosage form disclosed herein is administered to the patient from one single use container.
  • the single use container is a glass vial.
  • the single use container is a polymer bag.
  • the polymer bag is a polypropylene bag.
  • the liquid unit dosage form comprises about 10 mg/mL acetaminophen and is about 130 mL in volume.
  • the bag, such as a polypropylene bag can be further packaged in an aluminum or aluminized over-pouch.
  • a unit dosage form described herein can be supplied, stored, or delivered in a vial, tube, container, bag, or vessel that is, for example, about 0.5 mL, about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL, about 6 mL, about 7 mL, about 8 mL, about 9 mL, about 10 mL, about 11 mL, about 12 mL, about 13 mL, about 14 mL, about 15 mL, about 16 mL, about 17 mL, about 18 mL, about 19 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, about 90 mL, about 100 mL, about 110 mL, about 120 mL, about 130 mL, about 140 mL, about 150
  • a pharmaceutical formulation described herein can be stored as a liquid in an aliquot having a total volume of between about 1 and about 1500 mL, between about 110 and 140 mL, between about 80 mL and about 120 mL, between about 90 mL and about 110 mL, between about 120 mL and about 140 mL, between about 90 mL and about 140 mL, between about 1 and about 250 mL, between about 1 and about 200 mL, between about 1 and about 150 mL, between about 1 and about 125 mL, between about 1 and about 120 mL, between about 1 and about 110 mL, between about 1 and about 100 mL, between about 1 and about 90 mL, between about 1 and about 80 mL, between about 1 and about 70 mL, between about 1 and about 60 mL, between about 1 and about 50 mL, between about 1 and about 40 mL, between about 1 and about 30 mL, between about 1 and about 20 mL, between about 1 and about
  • therapeutically-effective amounts of the compounds described herein are administered in pharmaceutical compositions to a subject having a disease or condition to be treated.
  • a therapeutically-effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors.
  • Subjects can be, for example, humans, elderly adults, adults, adolescents, pre-adolescents, children, toddlers, infants, or neonates.
  • a subject can be a patient.
  • compositions described herein can be formulated in any suitable volume.
  • the formulation volume can be, for example, about 0.1 mL, about 0.2 mL, about 0.3 mL, about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1 mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5 mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2 mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, about 3 mL, about 3.1 mL, about 3.2 mL, about 3.3 mL, about 3.4
  • the formulation volume can be, for example, about 0.1 mL to about 1500 mL, such as about 100 mL to about 1500 mL, about 20 mL to about 150 mL, about 40 mL to about 150 mL, about 60 mL to about 150 mL, about 80 mL to about 150 mL, about 100 mL to about 150 mL, about 110 mL to about 140 mL, about 120 mL to about 150 mL, about 120 mL to about 140 mL, about 80 mL to about 140 mL, about 80 mL to about 130 mL, about 90 mL to about 120 mL, or about 90 mL to about 110 mL.
  • a therapeutically-effective amount of a compound described herein can be present in a composition described herein at a mass of, for example, about 0.01 pg, about 0.05 pg, about 0.1 pg, about 0.15 pg, about 0.2 pg, about 0.25 pg, about 0.3 pg, about 0.35 pg, about 0.4 pg, about 0.5 pg, about 0.6 pg, about 0.7 pg, about 0.8 pg, about 0.9 pg, about 1 pg, about 2 pg, about 3 pg, about 4 pg, about 5 pg, about 10 pg, about 15 pg, about 20 pg, about 25 pg, about 30 pg, about 35 pg, about 40 pg, about 45 pg, about 50 pg, about 60 pg, about 70 pg, about 80 pg, about 90 pg, about 100 pg, about 125 pg,
  • a therapeutically-effective amount of a compound described herein can be present in a composition described herein at a mass of, for example, about 0.01 pg to about 20 mg, about 0.01 pg to about 1 mg, about 0.01 pg to about 100 pg, about 0.01 pg to about 10 pg, about 0.1 pg to about 10 pg, about 1 pg to about 10 pg, about 500 pg, to about 1 mg, about 1 mg to about 20 mg, about 1 mg to about 10 mg, about 1 mg to about 5 mg, about 1 mg to about 2 mg, about 5 mg to about 20 mg, about 10 mg to about
  • the compound is acetaminophen.
  • a therapeutically-effective amount of a compound described herein can be present in a composition described herein at a concentration of, for example, about 0.001 mg/mL, about 0.002 mg/mL, about 0.003 mg/mL, about 0.004 mg/mL, about 0.005 mg/mL, about 0.006 mg/mL, about 0.007 mg/mL, about 0.008 mg/mL, about 0.009 mg/mL, about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.25 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 mg/mL, about
  • a therapeutically-effective amount of a compound described herein can be present in a composition described herein at a concentration of, for example, from about 0.1 mg/mL to about 20 mg/mL, from about 0.1 mg/mL to about 50 mg/mL, from about 0.25 mg/mL to about 6 mg/mL, from about 1 mg/mL to about 20 mg/mL, from about 2 mg/mL to about 20 mg/mL, from about 5 mg/mL to about 15 mg/mL, from about 8 mg/mL to about 12 mg/mL, from about 9 mg/mL to about 11 mg/mL, from about 9.5 mg/mL to about 10.5 mg/mL, from about 9.9 mg/mL to about 10.1 mg/mL, from about 3 mg/mL to about 6 mg/mL, from about 3.5 mg/mL to about 5.5 mg/mL, from about 4 mg/mL to about 5 mg/mL, or from about 4.4 mg/mL to about 4.6 mg/mL.
  • a therapeutically-effective amount of a compound described herein can be present in a composition described herein at a concentration of, for example, at least about 0.5 mg/mL, at least about 1 mg/mL, at least about 1.5 mg/mL, at least about 3 mg/mL, or at least about 5 mg/mL.
  • the therapeutically-effective amount of acetaminophen can be at least about 8 mg/mL, at least about 10 mg/mL, at least about 15 mg/mL, or at least about 20 mg/mL.
  • the compound is acetaminophen.
  • a therapeutically-effective amount of a compound described herein can be a dose based on the body mass of the subject, for example, about 0.5 mg/kg, about 1 mg/kg, about 1.25 mg/kg, about 1.5 mg/kg, about 1.75 mg/kg, about 2 mg/kg, about 2.25 mg/kg, about 2.5 mg/kg, about 2.75 mg/kg, about 3 mg/kg, about 3.25 mg/kg, about 3.5 mg/kg, about 3.75 mg/kg, about 4 mg/kg, about 4.25 mg/kg, about 4.5 mg/kg, about 4.75 mg/kg, about 5 mg/kg, about 5.25 mg/kg, about 5.5 mg/kg, about 5.75 mg/kg, about 6 mg/kg, about 6.25 mg/kg, about 6.5 mg/kg, about 6.75 mg/kg, about 7 mg/kg, about 7.25 mg/kg, about 7.5 mg/kg, about 7.75 mg/kg, about 8 mg/kg, about 8.25 mg/kg, about 8.5 mg/kg, about 8.75 mg/kg
  • a therapeutically-effective amount of a compound described herein can be a dose based on the body mass of the subject, for example, about 0.5 mg/kg to about 50 mg/kg, about 0.5 mg/kg to about 1 mg/kg, about 1 mg/kg to about 5 mg/kg, about 5 mg/kg to about 10 mg/kg, about 10 mg/kg to about 15 mg/kg, about 15 mg/kg to about 20 mg/kg, about 20 mg/kg to about 25 mg/kg, about 25 mg/kg to about 30 mg/kg, about 30 mg/kg to about 35 mg/kg, about 35 mg/kg to about 40 mg/kg, about 40 mg/kg to about 45 mg/kg, or about 45 mg/kg to about 50 mg/kg.
  • compositions described herein can be formulated at any suitable pH.
  • the pH can be, for example, about 2, about 2.05, about 2.1, about 2.15, about 2.2, about 2.25, about 2.3, about 2.35, about 2.4, about 2.45, about 2.5, about 2.55, about 2.6, about 2.65, about
  • compositions described herein can be formulated at any suitable pH.
  • the pH can be, for example, from about 2 to about 2.2, about 2.05 to about 2.25, about 2.1 to about 2.3, about 2.15 to about 2.35, about 2.2 to about 2.4, about 2.25 to about 2.45, about 2.3 to about 2.5, about 2.35 to about 2.55, about 2.4 to about 2.6, about 2.45 to about 2.65, about 2.5 to about 2.7, about 2.55 to about 2.75, about 2.6 to about 2.8, about 2.65 to about 2.85, about 2.7 to about 2.9, about 2.75 to about 2.95, about 2.8 to about 3, about 2.85 to about 3.05, about 2.9 to about 3.1, about 2.95 to about 3.15, about 3 to about 3.2, about 3.05 to about 3.25, about 3.1 to about 3.3, about 3.15 to about 3.35, about 3.2 to about 3.4, about 3.25 to about 3.45, about 3.3 to about 3.5, about 3.35 to about 3.55, about 3.4 to about 3.6, about 3.
  • the pH of a pharmaceutical formulation described herein is about 4 to about 7. In some embodiments, the pH of a pharmaceutical formulation described herein is about 4 to about 6. In some embodiments, the pH of a pharmaceutical formulation described herein is about 5 to about 6. In some embodiments, the pH of a pharmaceutical formulation described herein is about 5.5 to about 6. In some embodiments, the pH of a pharmaceutical formulation described herein is 5.5. In some embodiments, the pH of a pharmaceutical formulation described herein is 6.
  • a pharmaceutical composition of the disclosure can be a combination of any pharmaceutical compounds described herein with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can be administered by therapeutically-effective routes, for example, oral, intravenous, subcutaneous, intramuscular, subdermal, transdermal, or parenteral administration.
  • a pharmaceutical formulation described herein can be administered as an intravenous infusion.
  • compositions can be formulated for intravenous administration as injectable formulations.
  • the pharmaceutical formulations can be in a form suitable for parenteral injection as a sterile suspension, solution, or emulsion in oily or aqueous vehicles, and can contain formulation agents such as suspending, stabilizing, and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • Suspensions of the active compounds can be prepared as oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use.
  • compositions described herein can be packaged as a kit.
  • a kit includes written instructions on the administration or use of the composition.
  • the written material can be, for example, a label.
  • the written material can suggest conditions methods of administration.
  • the instructions provide the subject and the supervising physician with the best guidance for achieving the optimal clinical outcome from the administration of the therapy.
  • the label can be approved by a regulatory agency, for example the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), or other regulatory agencies.
  • FDA U.S. Food and Drug Administration
  • EMA European Medicines Agency
  • a method of manufacture for a pharmaceutical composition described herein can involve manufacturing in a manufacturing tank.
  • the manufacturing tank can contain water that has been, for example, deoxygenated.
  • the deoxygenation of the water in the manufacturing tank can occur, via, for example, sparging using nitrogen, argon, or helium.
  • the sparging can reduce the amount of oxygen in the water to about 0.01 ppm, about 0.02 ppm, about 0.03 ppm, about 0.04 ppm, about 0.05 ppm, about 0.1 ppm, about 0.15 ppm, about 0.2 ppm, about 0.25 ppm, about 0.3 ppm, about 0.35 ppm, about 0.4 ppm, about 0.45 ppm, about 0.5 ppm, about 0.6 ppm, about 0.7 ppm, about 0.8 ppm, about 0.9 ppm, about 1 ppm, about 1.5 ppm, or about 2 ppm.
  • Non-limiting examples of pharmaceutically-acceptable excipients can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), each of which is incorporated by reference in its entirety.
  • the pharmaceutical composition provided herein comprises a buffer as an excipient.
  • buffers include potassium phosphate, sodium phosphate, phosphate buffer, citrate buffer, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2 -hydroxy ethyl- 1- piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS), and piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), citric acid monohydrate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, or any combination thereof.
  • the pharmaceutical composition provided herein comprises an alcohol as an excipient.
  • alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, lactitol, or any combination thereof.
  • PEG polyethylene glycol
  • PEGs with molecular weights ranging from about 300 g/mol to about 10,000,000 g/mol can be used.
  • Non-limiting examples of PEGs include PEG 200, PEG 300, PEG 400, PEG 540, PEG 550, PEG 600, PEG 1000, PEG 1450, PEG 1500, PEG 2000, PEG 3000, PEG 3350, PEG 4000, PEG 4600, PEG 6000, PEG 8000, PEG 10,000, and PEG 20,000.
  • compositions described herein include, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxy toluene, chlorobutanol, dehydroacetic acid, ethylenediamine, ethyl vanillin, glycerin, hypophosphorous acid, phenol, phenylethyl alcohol, phenylmercuric nitrate, potassium benzoate, potassium metabisulfite, potassium sorbate, sodium bisulfite, sodium metabisulfite, sorbic acid, thimerasol, acetic acid, aluminum monostearate, boric acid, calcium hydroxide, calcium stearate, calcium sulfate, calcium tetrachloride, cellulose acetate phthalate, microcrystalline celluose, chloroform, citric acid, edetic acid, and ethylcellulose.
  • benzalkonium chloride benzethon
  • the pharmaceutical composition provided herein comprises an aprotic solvent as an excipient.
  • aprotic solvents include perfluorohexane, a,a,a-trifluorotoluene, pentane, hexane, cyclohexane, methylcyclohexane, decalin, dioxane, carbon tetrachloride, freon-11, benzene, toluene, carbon disulfide, diisopropyl ether, diethyl ether, t-butyl methyl ether, ethyl acetate, 1,2-dimethoxy ethane, 2- methoxyethyl ether, tetrahydrofuran, methylene chloride, pyridine, 2-butanone, acetone, N- methylpyrrolidinone, nitromethane, dimethylformamide, acetonitrile, sulfolane
  • the amount of the excipient in a pharmaceutical composition described herein can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900%, or about 1000% by mass of a compound in the pharmaceutical formulation.
  • the amount of the excipient in a pharmaceutical composition described herein can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55% about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% by mass or by volume of the unit dosage form.
  • the addition of an excipient can change the viscosity of a pharmaceutical composition described herein.
  • the use of an excipient can increase or decrease the viscosity of a fluid by at least 0.001 Pascal-second (Pa.s), at least 0.001 Pa.s, at least 0.0009 Pa.s, at least 0.0008 Pa.s, at least 0.0007 Pa.s, at least 0.0006 Pa.s, at least 0.0005 Pa.s, at least 0.0004 Pa.s, at least 0.0003 Pa.s, at least 0.0002 Pa.s, at least 0.0001 Pa.s, at least 0.00005 Pa.s, or at least 0.00001 Pa.s.
  • Pa.s Pascal-second
  • the addition of an excipient to a pharmaceutical composition described herein can increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%.
  • the addition of an excipient to a pharmaceutical composition described herein can increase or decrease the viscosity of the composition by no greater than 5%, no greater than 10%, no greater than 15%, no greater than 20%, no greater than 25%, no greater than 30%, no greater than 35%, no greater than 40%, no greater than 45%, no greater than 50%, no greater than 55%, no greater than 60%, no greater than 65%, no greater than 70%, no greater than 75%, no greater than 80%, no greater than 85%, no greater than 90%, no greater than 95%, or no greater than 99%.
  • a dose can be modulated to achieve a desired pharmacokinetic or pharmacodynamics profile, such as a desired or effective blood profile, as described herein.
  • Pharmacokinetic and pharmacodynamic data can be obtained by various experimental techniques. Appropriate pharmacokinetic and pharmacodynamic profile components describing a particular composition can vary due to variations in drug metabolism in human subjects. Pharmacokinetic and pharmacodynamic profiles can be based on the determination of the mean parameters of a group of subjects. The group of subjects includes any reasonable number of subjects suitable for determining a representative mean, for example, 5 subjects, 10 subjects, 15 subjects, 20 subjects, 25 subjects, 30 subjects, 35 subjects, or more. The mean is determined, for example, by calculating the average of all subject's measurements for each parameter measured. A dose can be modulated to achieve a desired pharmacokinetic or pharmacodynamics profile, such as a desired or effective blood profile, as described herein.
  • the pharmacodynamic parameters can be any parameters suitable for describing compositions described herein.
  • the pharmacodynamic profile can be obtained at a time after dosing of, for example, about zero minutes, about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, about 40 minutes, about 41 minutes, about 42 minutes, about 43 minutes, about 44 minutes, about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51
  • the pharmacokinetic parameters can be any parameters suitable for describing a compound disclosed herein.
  • the Cmax can be, for example, not less than about 1 ng/mL; not less than about 5 ng/mL; not less than about 10 ng/mL; not less than about 15 ng/mL; not less than about 20 ng/mL; not less than about 25 ng/mL; not less than about 50 ng/mL; not less than about 75 ng/mL; not less than about 100 ng/mL; not less than about 200 ng/mL; not less than about 300 ng/mL; not less than about 400 ng/mL; not less than about 500 ng/mL; not less than about 600 ng/mL; not less than about 700 ng/mL; not less than about 800 ng/mL; not less than about 900 ng/mL; not less than about 1000 ng/mL; not less than about 1250 ng/mL; not less than about 1500 ng/mL
  • the Cmax can be, for example, about 1 ng/mL to about 5,000 ng/mL; about 1 ng/mL to about 4,500 ng/mL; about 1 ng/mL to about 4,000 ng/mL; about 1 ng/mL to about 3,500 ng/mL; about 1 ng/mL to about 3,000 ng/mL; about 1 ng/mL to about 2,500 ng/mL; about 1 ng/mL to about 2,000 ng/mL; about 1 ng/mL to about 1,500 ng/mL; about 1 ng/mL to about 1,000 ng/mL; about 1 ng/mL to about 900 ng/mL; about 1 ng/mL to about 800 ng/mL; about 1 ng/mL to about 700 ng/mL; about 1 ng/mL to about 600 ng/mL; about 1 ng/mL to about 500 ng/mL; about 1 ng/mL to about 450
  • the Tmax of a compound described herein can be, for example, not greater than about 0.5 hours, not greater than about 1 hours, not greater than about 1.5 hours, not greater than about 2 hours, not greater than about 2.5 hours, not greater than about 3 hours, not greater than about 3.5 hours, not greater than about 4 hours, not greater than about 4.5 hours, not greater than about 5 hours, or any other Tmax appropriate for describing a pharmacokinetic profile of a compound described herein.
  • the Tmax can be, for example, about 0.1 hours to about 24 hours; about 0.1 hours to about 0.5 hours; about 0.5 hours to about 1 hour; about 1 hour to about 1.5 hours; about 1.5 hours to about 2 hour; about 2 hours to about 2.5 hours; about 2.5 hours to about 3 hours; about 3 hours to about 3.5 hours; about 3.5 hours to about 4 hours; about 4 hours to about 4.5 hours; about 4.5 hours to about 5 hours; about 5 hours to about 5.5 hours; about 5.5 hours to about 6 hours; about 6 hours to about 6.5 hours; about 6.5 hours to about 7 hours; about 7 hours to about 7.5 hours; about 7.5 hours to about 8 hours; about 8 hours to about 8.5 hours; about 8.5 hours to about 9 hours; about 9 hours to about 9.5 hours; about
  • the AUC(O-inf) or AUC(last) of a compound described herein can be, for example, not less than about 1 ng*hr/mL. not less than about 5 ng*hr/mL. not less than about 10 ng*hr/mL. not less than about 20 ng*hr/mL. not less than about 30 ng*hr/mL. not less than about 40 ng*hr/mL. not less than about 50 ng*hr/mL. not less than about 100 ng*hr/mL. not less than about 150 ng*hr/mL. not less than about 200 ng*hr/mL. not less than about 250 ng*hr/mL.
  • the AUC(O-inf) of a compound can be, for example, about 1 ng*hr/niL to about 10,000 ng*hr/niL; about 1 ng*hr/niL to about 10 ng*hr/niL; about 10 ng*hr/niL to about 25 ng*hr/niL; about 25 ng*hr/niL to about 50 ng*hr/niL; about 50 ng*hr/niL to about 100 ng*hr/niL; about 100 ng*hr/niL to about 200 ng*hr/niL; about 200 ng*hr/niL to about 300 ng*hr/niL; about 300 ng*hr/niL to about 400 ng*hr/niL; about 400 ng*hr/niL to about 500 ng*hr/niL; about 500 ng*hr/niL to about 600 ng*hr
  • the plasma concentration of a compound described herein can be, for example, not less than about 1 ng/mL, not less than about 5 ng/mL, not less than about 10 ng/mL, not less than about 15 ng/mL, not less than about 20 ng/mL, not less than about 25 ng/mL, not less than about 50 ng/mL, not less than about 75 ng/mL, not less than about 100 ng/mL, not less than about 150 ng/mL, not less than about 200 ng/mL, not less than about 300 ng/mL, not less than about 400 ng/mL, not less than about 500 ng/mL, not less than about 600 ng/mL, not less than about 700 ng/mL, not less than about 800 ng/mL, not less than about 900 ng/mL, not less than about 1000 ng/mL, not less than about 1200 ng/mL, or any other plasma concentration of a compound described herein.
  • the plasma concentration can be, for example, about 1 ng/mL to about 2,000 ng/mL; about 1 ng/mL to about 5 ng/mL; about 5 ng/mL to about 10 ng/mL; about 10 ng/mL to about 25 ng/mL; about 25 ng/mL to about 50 ng/mL; about 50 ng/mL to about 75 ng/mL; about 75 ng/mL to about 100 ng/mL; about 100 ng/mL to about 150 ng/mL; about 150 ng/mL to about 200 ng/mL; about 200 ng/mL to about 250 ng/mL; about 250 ng/mL to about 300 ng/mL; about 300 ng/mL to about 350 ng/mL; about 350 ng/mL to about 400 ng/mL; about 400 ng/mL to about 450 ng/mL; about 450 ng/mL to about 500 ng/mL; about 500
  • the pharmacodynamic parameters can be any parameters suitable for describing compositions of the disclosure.
  • the pharmacodynamic profile can demonstrate an increased pain tolerance in a subject who has been administered a pharmaceutical formulation described herein.
  • a pharmaceutical composition described herein When administered via intravenous injection, can exert an effect at a level of at least about 50%, at least about 70%, at least about 80%, or at least about 90% within less than about, for example, one hour or two hours of the administration.
  • a pharmaceutical composition described herein can remain effective at a level of at least about 50%, at least about 70%, at least about 80%, or at least about 90% for at least about 1 hour, at least about 2 hours, at least about 3 hours, or at least about 6 hours after the administration.
  • a pharmaceutical formulation described herein can be administered to a subject about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, about 10 minutes, about 11 minutes, about 12 minutes, about 13 minutes, about 14 minutes, about 15 minutes, about 16 minutes, about 17 minutes, about 18 minutes, about 19 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about
  • a pharmaceutical formulation described herein can be administered to a patient at the same time as when the surgery begins.
  • a pharmaceutical formulation described herein can be administered to a patient during a surgery.
  • a pharmaceutical formulation described herein can be administered to a patient right after a surgery is ended.
  • a pharmaceutical formulation described herein can be administered one or more times prior to, during, or after, surgery for a patient.
  • a pharmaceutical formulation described herein can be administered to a patient one time a day, two times a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, or ten times a day.
  • a pharmaceutical formulation described herein can be administered to a patient every 1 hours, every 2 hours, every 3 hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every 8 hours, every 9 hours, every 10 hours, every 11 hours, or every 12 hours.
  • compositions that provide advantages in stability, administration, efficacy, and modulation of formulation viscosity.
  • Any embodiments disclosed herein can be used in conjunction or individually.
  • any pharmaceutically-acceptable excipient, method, technique, solvent, or compound disclosed herein can be used together with any other pharmaceutically-acceptable excipient, method, technique, solvent, or compound disclosed herein to achieve any therapeutic result.
  • Compounds, excipients, and other formulation components can be present at any amount, ratio, or percentage disclosed herein in any such formulation, and any such combination can be used therapeutically for any purpose described herein and to provide any viscosity described herein.
  • Time to perceptible pain relief confirmed (FPR-C): The time to perceptible pain relief confirmed can be used to assess time to self-reported onset of pain relief, in which a subject is given a stopwatch and asked to press the stopwatch when the subject first perceives any pain relief.
  • Pain Intensity Difference Rating Changes in patient evaluation of pain relief can be expressed as the Pain Intensity Difference Rating (PID), which can be calculated by taking the subtraction of baseline PI evaluated before Dose 1 administration from reported PI at different time points after administration of Dose 1.
  • Time to Treatment Failure can be used to assess the period of time between administration of Dose 1 to administration of a rescue medication or subject withdrawal from the study for any reason. Subjects that did not withdraw from the study or take a rescue medication can be excluded.
  • a randomized, double-blind, single-site, placebo-controlled, parallel-group study was conducted to assess similarities in safety, tolerability, efficacy, and pharmacokinetics of 1300 mg of injectable acetaminophen given in three doses, each 8 hours apart, relative to placebo, and 1000 mg of injectable acetaminophen given in four doses, each 6 hours apart, relative to placebo over a 24-hour period in patients experiencing moderate to severe postsurgical pain within 7 hours following surgical removal of 2 or more molars.
  • doses can be spaced apart significantly more than 6 hours with only a moderate increase of drug concentration per administration.
  • administration of the acetaminophen could be spaced to 8 hours, which conveniently reduces daily administration from 4 to 3 times per day, thereby substantially reducing administrative burden and patient treatment time.
  • the therapeutic effect as measured in the pain scores indicated below was substantially the same as compared with 4 times daily acetaminophen infusion of 1,000 mg each.
  • Patients who met the randomization criteria post-surgical pain of moderate to severe on the 4-point Categorical Pain Intensity scale, and at least a score of 5 on the 11 -point (0-10) pain intensity numerical pain rating scale (PINPRS) at baseline within 7 hours of last stitch from dental extractions) were randomly assigned to one of three treatment groups in a 2:2:1 ratio of active to active to placebo treatments.
  • PINPRS pain intensity numerical pain rating scale
  • NPRS and PR were collected prior to each use of rescue (if applicable).
  • Time to perceptible pain relief and time to meaningful pain relief were collected using the double-stopwatch methodology as follows: For each randomized patient, two stopwatches were started immediately upon initiation of the first study dose infusion.
  • the first stopwatch was given to each patient with the instructions to stop the watch when they first perceive pain relief to occur (time to perceptible rebel). Once the first stopwatch was stopped, the second stopwatch was given to the patient with the instruction to stop the watch when they are first experiencing meaningful pain relief (time to meaningful rebel). Time to perceptible pain relief was confirmed only if the patient experienced meaningful relief.
  • Rescue medication was one ibuprofen 200 mg tablet taken orally with at least 4 ounces of water. Prior to each dose of rescue medication, 11-point Pain Intensity (via 0-10 Numerical Pain Rating Scale) and Pain Relief (via 5-Point Categorical Pain Relief Assessment) measurements were performed. For statistical purposes, pain assessments performed after any dose of rescue were censored and imputed. Any subject requiring additional rescue medication was eligible to again receive ibuprofen 200 mg, and their data was similarly censored and imputed. Pain scores and safety data continued to be collected for the 24- hour observation period. Rescue medication did not exceed ibuprofen 200 mg q3h or 2400 mg in a 24-hour period. Patient Global Evaluation of the study medication was collected at Hour 24.25 or at the time of patient withdrawal (if applicable), whichever occurred first, using a 0-4 rating scale: (0) poor, (1) fair, (2) good, (3) very good, and (4) excellent.
  • TOTPAR24 The sum of pain relief from 0 to 24 hours (TOTPAR24) based on a 5-point Likert scale is summarized in TABLE 5.
  • TOTPAR24 was analyzed using an ANCOVA model with treatment group as a fixed effect and baseline PI-NPRS as a covariate.
  • the upper limit of one-sided 90% Cl was + ⁇ .
  • the Evaluable Population included all randomized patients who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and (2) were administered Dose 1. The number of subjects censored were 6 in High Dose IVAPAP group, 8 in Low Dose IVAPAP group, and 15 in IV placebo group.
  • the pain intensity difference rating (PID) at different timepoints after Dose 1 administration is summarized in TABLE 11.
  • the Pain intensity difference was calculated from the scores reported on the 0-10 PI-NRS at each observation time after Dose 1 administration. Pain intensity was collected at 0.5, 0.75, 1, 1.25, 1.75, and 2.25 hours ( ⁇ 5 minutes), 3.25, 4.25,
  • the Evaluable Population included all randomized patients who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and (2) were administered Dose 1.
  • the Evaluable Population included all randomized patients who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and (2) were administered Dose 1.
  • the Evaluable Population included all randomized patients who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and (2) were administered Dose 1.
  • the time to treatment failure for each cohort is summarized in TABLE 14.
  • the time to treatment failure is defined as time to first dose of rescue medication after Dose 1 or withdrawal from the study for any reason. If a subject did not take rescue medication or withdraw from the study prior to 24 hours, the subject was censored at 24 hours.
  • the Evaluable Population included all randomized patients who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and (2) were administered Dose 1. The number of subjects censored were 31 in High Dose IV APAP group, 32 in Low Dose IV APAP group and 6 in IV Placebo group.
  • An initial baseline PK blood sample was collected at least 5 minutes before administration of Dose 1 of study medication. The time of initiation of Dose 1 was designated as TO. After administration of Dose 1, samples were drawn at 0.25 hr. ⁇ 3 min (end of infusion), 0.5 hr. ⁇ 3 min, 0.75 hr. ⁇ 3 min, 1 hr. ⁇ 5 min, 2 hr. ⁇ 5min , 4 hr. ⁇ 5 min, 6 hr.- 5 min (prior to the next planned infusion), 6.25 hr. ⁇ 3 min (end of the infusion), 8hr. - 5 min (prior to the next scheduled infusion), 8.25 hr.
  • the mean area under the plasma concentration-time curve from time of administration to 24 hours after dosing (AUC 0-24h) observed for each cohort is summarized in TABLE 16.
  • the Area Under the Plasma Concentration-Time Curve (AUC) is a measure of the plasma concentration of the drug over time used to characterize drug absorption.
  • An ANOVA analysis of daily drug exposure was performed.
  • the PK Evaluable Population included all randomized subjects who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and (2) were administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate PK parameters. Subjects with positive pre-dose concentrations were excluded.
  • Geometric LS mean, GMR (1300 mg IV q8hr / 1000 mg IV q6hr), 80% Cl, 90% Cl and p-value were obtained from an ANOVA model with treatment group as a fixed effect.
  • AUC(O-infmity) is the area under the plasma concentration-time curve from time zero to infinite time.
  • Half-life (t 1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration.
  • the PK Evaluable Population included all randomized subjects who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and; (2) were administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate PK parameters.
  • Cmax The mean maximum observed plasma concentration (Cmax) last dose observed for each cohort is summarized in TABLE 18.
  • the PK Evaluable Population included all randomized subjects who, as documented prior to the breaking of the study blind: (1) met all the inclusion and exclusion criteria and (2) were administered Dose 1 resulting in an adequate number of quantifiable concentrations to calculate PK parameters.
  • Embodiment 1 A method of treating pain in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a liquid unit dosage form, wherein the liquid unit dosage form comprises acetaminophen in an amount from about 1100 mg to about 1500 mg, wherein the administration of the liquid unit dosage form is from a single use container.
  • Embodiment 2 The method of embodiment 1, wherein the liquid unit dosage form comprises acetaminophen in an amount from about 1200 mg to about 1400 mg.
  • Embodiment 3 The method of any one of embodiments 1-2, wherein the liquid unit dosage form comprises acetaminophen in an amount of about 1300 mg.
  • Embodiment 4 The method of any one of embodiments 1-3, wherein the pain is dental pain.
  • Embodiment 5 The method of any one of embodiments 1-4, wherein the liquid unit dosage form is administered to the subject from one to three times per day.
  • Embodiment 6 The method of any one of embodiments 1-5, wherein the liquid unit dosage form is administered to the subject three times per day.
  • Embodiment 7 The method of any one of embodiments 1-6, wherein the liquid unit dosage form is administered to the subject within 24 hours prior to the subject undergoing a surgical procedure.
  • Embodiment 8 The method of any one of embodiments 1-6, wherein the liquid unit dosage form is administered to the subject simultaneously with the subject undergoing a surgical procedure.
  • Embodiment 9 The method of any one of embodiments 1-6, wherein the liquid unit dosage form is administered to the subject within 24 hours after the subject has undergone a surgical procedure.
  • Embodiment 10 The method of any one of embodiments 1-9, wherein the administration is parenteral administration.
  • Embodiment 11 The method of any one of embodiments 1-9, wherein the administration is intravenous.
  • Embodiment 12 A method of treating pain in a subject in need thereof, the method comprising administering to the subject about 1300 mg acetaminophen in a liquid unit dosage form about every 8 hours via intravenous injection, wherein the administration of the liquid unit dosage form is from a single use container.
  • Embodiment 100 A pharmaceutical composition comprising, in a liquid unit dosage form, acetaminophen in an amount from about 1100 mg to about 1500 mg, wherein the pharmaceutical composition is formulated for packaging in a single use container.
  • Embodiment 101 The pharmaceutical composition of embodiment 100, wherein the liquid unit dosage form further comprises water.
  • Embodiment 102 The pharmaceutical composition of any one of embodiments 100-101, wherein the liquid unit dosage form further comprises a pH-adjusting agent.
  • Embodiment 103 The pharmaceutical composition of any one of embodiments 100-102, wherein the acetaminophen is present in the liquid unit dosage form in an amount from about 2 mg/mL to about 20 mg/mL.
  • Embodiment 104 The pharmaceutical composition of any one of embodiments 100-103, wherein the acetaminophen is present in the liquid unit dosage form in an amount from about 8 mg/mL to about 12 mg/mL.
  • Embodiment 105 The pharmaceutical composition of any one of embodiments 100-104, wherein the liquid unit dosage form further comprises an acid, a conjugate base of the acid, or both the acid and conjugate base of the acid.
  • Embodiment 106 The pharmaceutical composition of any one of embodiments 100-105, wherein the liquid unit dosage form has a pH of about 4 to about 7.
  • Embodiment 107 The pharmaceutical composition of any one of embodiments 100-106, wherein the liquid unit dosage form has a pH of about 5.
  • Embodiment 108 The pharmaceutical composition of any one of embodiments 100-106, wherein the liquid unit dosage form has a pH of about 5.5.
  • Embodiment 109 The pharmaceutical composition of any one of embodiments 100-106, wherein the liquid unit dosage form has a pH of about 6.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.
  • administering refers to both direct and indirect administration of the pharmaceutical composition or drug, wherein direct administration of the pharmaceutical composition or drug is typically performed by a health care professional (e.g., physician, nurse, etc.), and wherein indirect administration includes a step of providing or making available the pharmaceutical composition or drug to the health care professional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.).
  • a health care professional e.g., physician, nurse, etc.
  • indirect administration includes a step of providing or making available the pharmaceutical composition or drug to the health care professional for direct administration (e.g., via injection, infusion, oral delivery, topical delivery, etc.).
  • the terms “prognosing” or “predicting” a condition, a susceptibility for development of a disease, or a response to an intended treatment is meant to cover the act of predicting or the prediction (but not treatment or diagnosis ol) the condition, susceptibility and/or response, including the rate of progression, improvement, and/or duration of the condition in a subject.

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Abstract

L'invention concerne des compositions, des formes galéniques unitaires de celles-ci, ainsi que des méthodes d'utilisation de celles-ci pour le traitement de la douleur. Les compositions pharmaceutiques peuvent contenir un analgésique non opioïde et peuvent être administrées avant une opération chirurgicale en vue de réduire la douleur postopératoire.
PCT/US2022/016636 2021-02-19 2022-02-16 Formes galéniques unitaires liquides pour le traitement de la douleur Ceased WO2022178018A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009098716A2 (fr) * 2008-01-17 2009-08-13 Aptuit Laurus Private Limited Compositions pharmaceutiques aqueuses stables
US20130096201A1 (en) * 2010-06-30 2013-04-18 Ketan R. Patel Pharmaceutical Compositions Comprising Paracetamol and Process for Preparing The Same
WO2020043587A1 (fr) * 2018-08-28 2020-03-05 GSK Consumer Healthcare S.A. Suspensions liquides de paracétamol
EP3656377A1 (fr) * 2014-07-18 2020-05-27 Hyloris Pharmaceuticals sa Formulation aqueuse comprenant du paracétamol et de l'ibuprofène
US20200230091A1 (en) * 2017-10-03 2020-07-23 Nevakar Inc. Acetaminophen pregabalin combinations and methods of treating pain

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009098716A2 (fr) * 2008-01-17 2009-08-13 Aptuit Laurus Private Limited Compositions pharmaceutiques aqueuses stables
US20130096201A1 (en) * 2010-06-30 2013-04-18 Ketan R. Patel Pharmaceutical Compositions Comprising Paracetamol and Process for Preparing The Same
EP3656377A1 (fr) * 2014-07-18 2020-05-27 Hyloris Pharmaceuticals sa Formulation aqueuse comprenant du paracétamol et de l'ibuprofène
US20200230091A1 (en) * 2017-10-03 2020-07-23 Nevakar Inc. Acetaminophen pregabalin combinations and methods of treating pain
WO2020043587A1 (fr) * 2018-08-28 2020-03-05 GSK Consumer Healthcare S.A. Suspensions liquides de paracétamol

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