WO2008070268A2 - Compositions pharmaceutiques - Google Patents

Compositions pharmaceutiques Download PDF

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Publication number
WO2008070268A2
WO2008070268A2 PCT/US2007/080831 US2007080831W WO2008070268A2 WO 2008070268 A2 WO2008070268 A2 WO 2008070268A2 US 2007080831 W US2007080831 W US 2007080831W WO 2008070268 A2 WO2008070268 A2 WO 2008070268A2
Authority
WO
WIPO (PCT)
Prior art keywords
agent
opioid analgesic
composition
opioid
promethazine
Prior art date
Application number
PCT/US2007/080831
Other languages
English (en)
Other versions
WO2008070268A3 (fr
Inventor
Paul Bosse
Original Assignee
Charleston Laboratories, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CA2665841A priority Critical patent/CA2665841C/fr
Priority to PL07871139T priority patent/PL2124556T3/pl
Priority to JP2009531645A priority patent/JP2010522135A/ja
Priority to SI200731562T priority patent/SI2124556T1/sl
Priority to ES07871139.7T priority patent/ES2524556T3/es
Priority to EP07871139.7A priority patent/EP2124556B1/fr
Priority to US12/444,521 priority patent/US8653066B2/en
Priority to DK07871139.7T priority patent/DK2124556T3/en
Application filed by Charleston Laboratories, Inc. filed Critical Charleston Laboratories, Inc.
Publication of WO2008070268A2 publication Critical patent/WO2008070268A2/fr
Publication of WO2008070268A3 publication Critical patent/WO2008070268A3/fr
Priority to HK10105451.9A priority patent/HK1138732A1/xx
Priority to US14/099,432 priority patent/US20140134248A1/en
Priority to US14/748,613 priority patent/US20150328210A1/en
Priority to US14/748,621 priority patent/US9427407B2/en
Priority to US14/748,614 priority patent/US9393207B2/en
Priority to US14/748,617 priority patent/US20150328212A1/en
Priority to US14/748,605 priority patent/US9402813B2/en
Priority to US14/748,609 priority patent/US9399022B2/en
Priority to US15/263,230 priority patent/US20160375013A1/en
Priority to US15/263,235 priority patent/US20160375014A1/en
Priority to US15/679,460 priority patent/US20170340627A1/en
Priority to US16/425,401 priority patent/US20200054625A1/en
Priority to US17/229,479 priority patent/US20220062276A1/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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 invention comprises methods and compositions designed to treat a subject with a drug formulation comprising multiple active agents.
  • a composition comprises, an opioid analgesic, a non-opioid analgesic agent, an agent that reduces or eliminates a adverse effect of an opioid analgesic agent and a pharmaceutically acceptable carrier or vehicle.
  • the invention also relates to methods for treating pain comprises administering to a subject in need thereof an effective amount of an opioid analgesic agent, a non-opioid analgesic agent and an agent that reduces or eliminates a adverse effect of an opioid analgesic agent.
  • the agent which reduces adverse effects is an anti-emetic agent or antihistamine.
  • the invention further relates to pharmaceutical compositions comprising from 1% to 20% by weight of an antihistamine; from 10% to 80% by weight a non-opioid analgesic; and from 1% to 20% by weight of an opioid analgesic.
  • a pharmaceutical composition comprises an opioid analgesic, a non- opioid analgesic and an antihistamine, wherein the relative ratio of said opioid analgesic, said non-opioid analgesic and said antihistamine is from 1 to 2: 40 to 45:1 to 2 respectively.
  • the invention also relates to, pharmaceutical compositions comprising an opioid analgesic, a non-opioid analgesic and an antihistamine, which is designed to provide a plasma concentration of said antihistamine at a substantially greater rate than said opioid and said non-opioid analgesic.
  • a method of treating a subject to alleviate any condition which could benefit from administering an effective amount of a pharmaceutical composition comprising an opioid analgesic, a non-opioid analgesic and an antihistamine comprising an opioid analgesic, a non-opioid analgesic and an antihistamine.
  • the condition is a adverse effect associated with administration of an opioid analgesic.
  • the invention further relates to methods for treating a subject suffering from or susceptible to pain, comprises administering to said subject a pharmaceutical composition comprising an effective amount of a first component which is a non-opioid analgesic, or a pharmaceutically acceptable salt thereof; a second component which is a non-opioid analgesic, or a pharmaceutically acceptable salt thereof; and an effective amount of a third component which is an antihistamine.
  • a pharmaceutical composition comprising an effective amount of a first component which is a non-opioid analgesic, or a pharmaceutically acceptable salt thereof; a second component which is a non-opioid analgesic, or a pharmaceutically acceptable salt thereof; and an effective amount of a third component which is an antihistamine.
  • Figure 1 illustrates the chemical structure of hydrocodone bitartrate It is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder
  • the chemical name is 4,5 ⁇ -epoxy- 3-methoxy-17-methylmorphman-6-one tartrate (1 1) hydrate (2 5)
  • Figure 3. illustrates the chemical structure of oxycodone
  • Figure 4. illustrates the chemical structure of promethazine
  • compositions comprising of multiple active agents that are useful as therapeutics that alleviate, abate or eliminate an adverse effect associated with opioid and/or non- opioid anagesic agents
  • a composition comprises an effective amount of two acttves, an effective amount of three active agents, an effective amount of four active agents, an effective amount of five active agents or more than five active agents
  • An active agent is selected from various classes of drugs, including but not limited to opioid analgesics, non-opioid analgesics, decongestant, expectorant, mucus thinning drugs, antitussives, antihistamines or a combination thereof
  • an analgesic e g , one analgesic or two, three or more analgesics
  • an adverse-effect-reducing active agent e g , an antihistamine or antiemetic
  • the opioid analgesic agent is hydrocodone or oxycodone, or a pharmaceutically acceptable salt, thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis(methylcarbamate) (each of the foregoing being an opioid analgesic agent or derivative),
  • the opioid analgesic agent is hydrocodone bitartrate or oxycodone hydrochloride
  • the pharmaceutical composition is m the form of a multi-layered tablet, such as in the form of a bi-layered tablet
  • the bi-layered tablet comprises (a) an inner, immediate-release layer that comprises the agent that reduces or eliminates a adverse effect of an opioid analgesic, and (b) an outer, controlled-release layer that comprises the agent that reduces or eliminates a adverse effect of an opioid analgesic, the opioid analgesic agent and the non-opioid an
  • a pharmaceutical composition comprising from 1 % to 20% by weight of an antihistamine, from 10% to 80% by weight a non-opioid analgesic, and from 1% to 20% by weight of an opioid analgesic
  • the composition is capable of increasing a plasma concentration of said antihistamine in about 1 minute to about 20 minutes after administration to a subject
  • the antihistamine is selected from a group consisting of promethazine, dolasetron, granisetron, ondansetron, tropisetron, palonosetron, dompe ⁇ done, drope ⁇ dol, halope ⁇ dol, chlorpromazine, prochloperazine, metocloprarmde, alizap ⁇ de, cychzine, diphenhydramine, dimenhyd ⁇ nate, meclizine, hydroxyzine, cannabis, dronabinol, nabilone, midazolam, lorazepam, hyoscine, dexamefhasone, t ⁇ methobenzamide, emctrol and propofol [0026] In one aspect of the invention, a method is provided for treating a subject in need thereof, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising an opioid analgesic agent, a non-opioid anal
  • the pharmaceutical composition can be m any form disclosed herein, such as a multi-layered tablet.(e.g., a bi-layered tablet).
  • the multi-layered tablet is a bi-layered tablet that comprises: (a) an outer, immediate-release layer that comprises an agent which reduces or eliminates a adverse effect of an opioid analgesic; and (b) an inner, controlled release layer that comprises, an opioid analgesic agent and a non-opioid analgesic agent.
  • the agent e.g., promethazine
  • the agent reducing or eliminating adverse effects is released at a substantially greater rate than an opioid or non-opioid analgesic comprised in a pharmaceutical composition of the invention, as further described herein.
  • a plasma concentration of the agent that reduces or eliminates an adverse effect of an opioid analgesic is achieved in about 1 minute to about 20 minutes, as compared to an analgesic plasma concentration provided in about 30 minutes to about 8 hours.
  • the pharmaceutical composition of the invention compnses an agent that reduces or eliminates an adverse effect which agent is released in at least about 1 minute to at least about 20 minutes.
  • such an agent is an antihistamine or antiemetic.
  • such an agent is promethazine, dolasetron, granisetron, ondansetron, tropisetron, palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, prochloperazine, metoclopramide, alizapride, cychzme, diphenhydramine, dimenhydrinate, meclizine, hydroxyzine, cannabis, dronabinol, nabilone, midazolam, lorazepam, hyoscine, dexamethasone, trimethobenzamide, emetrol or propofol
  • a pharmaceutical composition comprises an opioid analgesic agent, a non-opioid analgesic agent, and an agent useful for preventing and/or suppressing an adverse effect associated with the opioid and/or non-opioid analgesic.
  • An adverse effect of an opioid and/or non-opioid analgesic includes but is not limited to nausea, vomiting, other gastric upsets, skin rashes, allergic reactions such as swelling, difficulty breathing, closing of throat, abdominal pain, unusual bleeding or bruising and skin rashes or skm rashes.
  • an averse effect(s) reduced or eliminated is associated with an opioid analgesic including but not limited to nausea, vomiting, constipation or a combination thereof
  • the opioid analgesic agent is, for example, hydrocodone, oxycodone or fentanyl
  • the non-opioid analgesic agent is, for example, acetaminophen, ibuprofen, ketaprofen, naproxen, or aspirin
  • the agent useful for preventing and/or suppressing a adverse effect is, for example, an antihistamine such as promethazine
  • a composition comprises an analgesic agent, an antitussive agent, and an agent useful for preventing and/or suppressing a adverse effect of the analgesic agent and/or the antitussive agent.
  • an antitussive is also an analgesic.
  • the composition comprises acetaminophen, hydrocodone or oxycodone;
  • the antitussive agent is, for example, dikasetron, domperidone, meclizine, dronabinol, a benzodiazepine, an anticholinergic, hydrocodone or oxycodone,
  • the agent useful for preventing and/or suppressing adverse effect is, for example, an antihistamine such as promethazine.
  • Another embodiment of the invention is directed to a pharmaceutical composition, comprising an opioid analgesic agent, an non-opioid analgesic agent, and an antiemetic agent.
  • the opioid analgesic agent is, for example, hydrocodone, oxycodone;
  • the non-opioid analgesic agent is, for example, acetaminophen, ibuprofen, ketaprofen, naproxen, or aspirin
  • the antiemetic agent is, for example 5-HT 3 receptor antagonists, a dopamine antagonist, an antihistamine, a cannabinoid, benzodiazepines, an anticholinergic, wherein all or less than all of the total amount of the antimetic agent is formulated for immediate release WSGR Docket No 35681-701 601
  • Another embodiment of this invention is directed to methods for the treatment of pam, comprising administering an effective amount of an opioid analgesic agent, a non-opioid analgesic agent and an agent useful for preventing and/or suppressing, reducing or eliminating a adverse effect of the opioid analgesic agent to a subject in need thereof.
  • the methods allow for use of analgesics in populations at risk of adverse effect such as nausea, vomiting, other gastric upsets, skin rashes, allergic reactions such as swelling, difficulty breathing, closing of throat, abdominal pain, unusual bleeding or bruising and skin rashes.
  • the opioid analgesics include, for example, hydrocodone, hydrocodone bitartrate, pharmaceutically acceptable salts and complexes of hydrocodone, oxycodone, oxycodone HCi, pharmaceutically acceptable salts and complexes of oxycodone.
  • the non-opioid analgesics include, for example, acetaminophen, lbuprofen, ketapiofen, naproxen, or aspirin.
  • the agents are useful for reducing or eliminating adverse effectadverse effects, such as, for example, promethazine, promethazine analogue, pharmaceutically acceptable salts and complexes of promethazine, or combinations of these compounds.
  • the pharmaceutical composition comprises an opioid analgesic, a non-opioid analgesic and an antihistamine, wherein said composition provides a plasma concentration of said antihistamine at a substantially greater rate than said opioid and said non-opioid analgesic.
  • the antihistamine is formulated for immediate-release.
  • the opioid analgesic and/or the non-opioid analgesic is/are formulated for controlled-release.
  • the composition is capable of increasing a plasma concentration of said antihistamine immediately after administration to a subject. In this embodiment increased a plasma concentration of said antihistamine occurs from about 1 minute to about 20 minutes after administration
  • Another aspect of the invention comprises a method of treating a subject to alleviate pain, comprising administering an effective amount of a pharmaceutical composition comprising an opioid analgesic, a non- opioid analgesic and an antihistamine
  • a pharmaceutical composition comprising an opioid analgesic, a non- opioid analgesic and an antihistamine
  • the antihistamine is formulated for immediate release.
  • a dosage form of the invention provides an increased plasma concentration of said antihistamine occurs from about 1 minute to about 20 minutes after administration, such as about 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 mm, 16 mm, 17 mm, 18mm, 19 min, 20 min, 21 min, 22 min, 23mm, 24 mm, 25 min.
  • the release rate occurs at substantially faster as compared to release rates for the analgesic agents.
  • the antihistamine e g., promethazin dolasetron, gramsetron, ondansetron, tropisetron, palonosetron, domperidone, dropendol, halopendol, chlorprornazine, prochloperazme, metoclopramide, alizap ⁇ de, cyclizine, diphenhydramine, dimenhydrinate, meclizine, hydroxyzine, cannabis, dronabinol, nabilone, midazolam, lorazepam, hyoscine, dexamethasone, trimethobenzamide, emetrol and propofol) is released and a plasma concentration of an antihistamine is provided before release of the opioid and/or non-opioid analgesic.
  • the antihistamine e g., promethazin dolasetron, gramsetron, ondansetron, tropisetron, palonosetron, domperidone, dropendol,
  • a dosage form of the invention provides a plasma concentration of said opioid analgesic and/or said non-opioid analgesic occurs from about 1 hour to about 4 hours after administration, such as about lhr, 1.2 hrs, 1.4hrs, 1.6 hrs, 1.8 hrs, 2.0hrs, 2.2 hrs, 2.4 hrs, 2.6 hrs, 2.8 hrs, 3.0 hrs, 3.2 hrs, 3.4 hrs, 3.6 hrs, 3.8 hrs, 4.0 hrs, 5.0 hrs, 6.0 hrs, 7.0 hrs, 8.0 hrs, 9.0 hrs, 10.0 hrs, 11.0 hrs, 12.0 hrs, 13.0 hrs, 14.0 hrs, 15.0 hrs, 16.0 hrs, 17.0 hrs, 18.0 hrs, 19.0 hrs, 20.0 hrs, 21.0 hrs, 22.0 hrs, 23 0 hrs, or 24.0 hrs.
  • the opioid or non-opioid analgesic are present from about 1 hour to 24 hour, 1 day to 30 days, including but not limited to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 12, 13, 14, 15, 16, 17, 18, 19, 20, WSGR Docket No 35681-701 601
  • Another aspect of the invention comprises a method of treating a subject to alleviate a condition comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an opioid analgesic, a non-opioid analgesic and an antihistamine.
  • the antihistamine is formulated for immediate release.
  • a plasma concentration of said antihistamine occurs from about 1 minute to about
  • a plasma concentration of an opioid analgesic and/or non-opioid analgesic is achieved from about 1 hour to about 8 hours after administration.
  • subjects receiving opioid analgesics and acetaminophen concomitantly with, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants is given a reduced dosage of one or more agents to prevent or ameliorate any additive effects, such as CNS depression.
  • the dosage of one or more of the agents is adjusted according to the severity of the pain and the response of the subject.
  • pain management can be of a primary concern to the subject's quality of life.
  • adjustments are made to the amounts or time release characteristics of the components in a composition, comprising an opioid analgesic, a non-opioid analgesic and an antihistamine.
  • the adjustments are designed to provide pain relief to a subject with tolerance to opioid analgesics.
  • the amount of the opioid analgesic may be increased in the composition to be adminstered to a subject.
  • the time release characteristics of the opioid analgesic may be adjusted so as to change the ratio of immediate-release opioid analgesic to controlled-release opioid analgesic.
  • the pharmaceutical compositions comprises 1 hydrocodone in a dosage range of between about 1.0 mg to about 15 mg or oxycodone in a dosage range of between about
  • the pharmaceutical compositions comprise about 7.5 mg of hydrocodone, about 325 mg of acetaminophen, and about 12.5 mg of promethazine.
  • the pharmaceutical compositions comprise about 7.5 mg of oxycodone, about 325 mg of acetaminophen, and about 12.5 mg of promethazine.
  • the pharmaceutical compositions comprise an effective amount of hydrocodone or oxycodone HCl, an effective amount of acetaminophen, and an effective amount of promethazine in a single, oral pill or tablet form having dosage levels that can be safely doubled for combating severe pain
  • the agents are formulated as oral dosage forms, inhalations, nasal sprays, patches, absorbing gels, liquids, liquid tannates, suppositories, injections, LV. drips, other delivery methods, or a combination thereof to treat subjects.
  • the agents are formulated as single oral dosage forms such as tablets, capsules, cachets, soft gelatin capsules, hard gelatin capsules, extended release capsules, tannate tablets, oral disintegrating tablets, multi-layer tablets, beads, liquids, oral suspensions, chewable lozenges, oral solutions, oral syrups, sterile packaged powder including pharmaceuttcally-acceptable excipients, other oral dosage forms, or a combination thereof
  • the pharmaceutical compositions comprise an agent in immediate release, quick release, controlled release, sustained release, extended release, other release formulations or patterns, or a combination thereof.
  • a composition of the invention comprises three active agents each of which is selected from a decongestant, an antitussive, an expectorant, a mucus thinning drugs, an analgesic and an antihistamine.
  • an agent is an antitussive such as, e.g , codeine, dihydrocodeme, hydrocodone, dextromethorphan and a pharmaceutically acceptable salt thereof; another agent is a decongestant such as, e.g., phenylephrine, pseudoephednne and a pharmaceutically acceptable salt thereof, and another agent is an expectorant.
  • an active agent may fit into more than one category (e.g , hydrocodone is an antitussive and opioid analgesic).
  • a composition of the invention comprises an effective amount of an opioid analgesic (e.g., hydrocodone or oxycodone), a non-opioid analgesic (e.g., acetaminophen or ibuprofen), and an antihistamine (e.g., promethazine).
  • an opioid analgesic e.g., hydrocodone or oxycodone
  • a non-opioid analgesic e.g., acetaminophen or ibuprofen
  • an antihistamine e.g., promethazine
  • the composition comprises an effective amount of hydrocodone, acetaminophen and promethazine.
  • the composition comprises an effective amount of oxycodone, acetaminophen and promethazine.
  • composition of the invention can be administered using one or more different dosage forms which are further described herem.
  • a composition of the invention is administered in various dosage forms.
  • a composition comprising multiple active agents can be administered in solid, gel, patch or liquid form.
  • dosage forms are further desc ⁇ bed herem. Examples of such dosage forms are known, such as tablet forms disclosed in US Patent Nos: 3048526, 3108046, 4786505, 4919939, 4950484; gel forms disclosed in US Patent Nos.
  • a composition of the invention is administered at various dosages and/or has various release rates (e.g., controlled release or immediate release)
  • immediate release refers to the release of an active agent substantially immediately upon administration.
  • immediate release results in dissolution of an agent within 1-20 minutes after entering the stomach. Dissolution can of all or less than all of the active. For example, dissolution of 100% of an agent ( antihistamine or antiemetic) can occur in the prescribed time.
  • dissolution of less than all of the agent can occur in about 1 minute to about 20 minutes (e.g., dissolution of about 70%, about 75%, about 80%, about 85%, about about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about about 99%, about 99.5% or 99 9% of an agent).
  • dissolution of about 70%, about 75%, about 80%, about 85%, about about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about about 99%, about 99.5% or 99 9% of an agent WSGR Docket No 35681-701 601
  • immediate release occurs when there is dissolution of an agent withm 1-20 minutes after administration. In another embodiment, immediate release results m substantially complete dissolution within about 1 hour following administration
  • immediate release occurs when there is dissolution of an agent within 1-20 minutes after administration Dissolution can be in a subject's stomach and/or intestine In another embodiment, immediate release results in complete or less than complete dissolution within about 1 hour following administration to a subject In another embodiment, immediate release results in complete or less than complete dissolution within about 1 hour following rectal administration Immediate release components can also be referred to as instant release When used in association with the dissolution profiles discussed herein, the term "immediate release" refers to wherein all or less than all of the total amount of a dosage form is dissolved In some embodiments, immediate release is through inhalation, such that dissolution occurs in a subject's lungs, as further described herem Dissolution of less than all of an active includes but is not limited to dissolution of about 50%, 60%, 70%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, 99 1%, 992%, 9935, 994%, 99 5%, 996%, 99 7%, 99 8% or 99
  • controlled-release results in substantially complete dissolution after at least 1 hour following rectal administration
  • controlled release compositions allow delivery of an agent to a subject over an extended period of tune according to a predetermined profile
  • Such release rates can provide therapeutically effective levels of agent for an extended period of time and thereby provide a longer period of pharmacologic or diagnostic response as compared with conventional rapid release dosage forms
  • Such longer periods of response provide for many inherent benefits that are not achieved with immediate release dosages
  • controlled release formulations can be preferred over conventional short-acting formulations
  • the term "controlled-release" refers to wherein all or less than all of the total amount of a dosage form, made according to the present invention, delivers an active agent over a pe ⁇ od of time greater than 1 hour [0064]
  • the compositions of the present invention can be dosed at a substantially lower daily dosage level than conventional immediate release products At comparable daily dosage levels, the controlled release oral solid
  • the analgesics are opioid or non-opioid analgesics (e.g , hydrocodone or oxycodone and acetaminophen).
  • the active agent which reduces adverse effects of such analgesics is promethazine.
  • a pharmaceutical composition of the invention by reducing adverse effects associated with an opioid and/or non-opioid analgesic allows for higher dosages for said analgesics m the pharmaceutical composition.
  • a pharmaceutical composition of the invention comprising an opioid analgesic, a non-opioid analgesic and promethazine, will reduce the adverse effects (e.g. nausea, vomiting) associated with the analgesic, thus allowing for increased dosages to be administered.
  • administration would be through a single composition.
  • the analgesic agent of the multidrug composition comprises, an opioid analgesic such as hydrocodone, oxycodone, morphine, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol, codeine, dezocine, fentanyl, hydromorphone, levomethadyl acetate, levorphanol, meperidine, methadone, morphine sulfate, nalbuphine, oxycodone, oxymorphone, pentazocine, propoxyphene, remifentanil, sufentanil, or tramadol; and an opioid an antagonists such as nalmefene, naloxone, or naltrexone.
  • an opioid analgesic such as hydrocodone, oxycodone, morphine, diamorphine, codeine, pethidine, alfentanil, buprenorphine, butorphanol,
  • compositions of the invention can further comprise antitussives such as codeine or dextromethorphan.
  • a composition of the invention comprises an opioid and non-opioid analgesic such as: codeme/acetaminophen, codeine/aspirin, hydrocodone/acetaminophen, hydrocodone/ ⁇ buprofen, oxycodone/acetaminophen, oxycodone/aspirin, or propoxyphene/aspirin or acetaminophen.
  • a composition comprises an analgesic and an active agent useful for reducing or eliminating adverse effects, such as an antihistamine (e.g., promethazine) and/or an antiemetic, as desc ⁇ bed herein.
  • an antihistamine e.g., promethazine
  • an antiemetic as desc ⁇ bed herein.
  • the composition comprises an opioid, a non-opioid analgesic, and an antihistamine (e.g., promethazine).
  • a composition comprises an opioid and/or non-opioid analgesic and promethazine.
  • the composition further comprises an anti-emetic.
  • one or more additional adverse-effect-reducing active agents can be administered separately (concurrently, before, after, administration of a multi-drug composition).
  • any of the compositions of the invention can comprise a non-opioid analgesic o ⁇ an opioid analgesics.
  • non-opioid analgesics useful in the compositions of the invention include but are not limited to acetaminophen; a non-steroidal anti-inflammatory drug (NSAID) such as a salicylate (including, for example, amoxiprin, beno ⁇ late, choline magnesium salicylate, diflunisal, dispatchlamine, methyl salicylate, magnesium salicylate), an arylalkanoic acid (including, for example, diclofenac, aceclofenac, acemetacin, bromfenac, etodolac, indometacin, nabumetone, sulindac, tolmetin), a profen (including, for example, lbuprofen, carprofen, fenbuprofen, flubiprofen, ketaprofen, ketorolac, loxoprofen, naproxen, suprofen), a fenamic acid (including, for example me
  • NSAID
  • Each agent is useful as its free base, where applicable or its pharmaceutically acceptable salt, prodrug, analog and complex.
  • Pharmaceutically acceptable salts include bitartrate, bitartrate hydrate, hydrochloride, p-toluenesulfonate, phosphate, sulfate, trifluoroacetate, bitartrate hemipentahydrate, WSGR Docket ND.
  • the agent is hydrocodone, a pharmaceutically acceptable salt or its fhiosemicarbazone, p-nitrophenylhydrazone, o- methyloxime, semicarbazone, or bis(methylcarbamate).
  • the agent is oxycodone, a pharmaceutically acceptable salt or its thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis(methylcarbamate).
  • the agent is acetaminophen, a pharmaceutically acceptable salt or its thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, semicarbazone, or bis(methylcarbamate).
  • an agent is promethazine, a pharmaceutically acceptable salt or its thiosemicarbazone, p-nitrophenylhydrazone, o-methyloxime, strigicarbazone, or bis(methylcarbamate).
  • the agent useful for treating a subject, such as by preventing or alleviating an adverse effect includes, for example, an antihistamine including a histamine agonist and an antagonist which is classified according to receptor subtype.
  • Hl agonists or partial agonists include 2-(m-fluorophenyl)-histamine
  • Hl antagonists include chlorpheniramine, scopolamine, mepyramine, terfenadine, astemizole, and triprolidine.
  • Further antagonists include the ethanolamines carbinoxamine, dimenhydrmate, diphenhydramine, and doxylamine; the ethylaminediamines pyrilamine and tripelennamine; the piperazine derivatives dydroxyzine, cyclizine, fexofenadine and meclizine; the alkylamines brompheniramine and chlorpheniramine; and miscellaneous antagonists cyproheptadine, loratadine, cetrizine.
  • H2 agonists include dimaprit, impromidine, and amthamine; and H2 antagonists
  • H3 agonists include R-alpha-methylhistamine, lmetit, and immepip and H3 antagonists include thioperamide, iodophenpropit, and clobenpropit; and H4 agonists include clobenpropit, imetit, and clozapine and H4 antagonists include thioperamide.
  • the agent useful for preventing or suppressing a adverse effect can also include an Hl blocker, such as azelastine, brompheniramine, buclizine, carbinoxamine, cetrizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratidine, dimenhydrinate, diphenhydramine, emedastine, fexofenadine, hydroxyzine, ketotifen, levocabastine, loratadine, meclizine, olopatadine, phenindamine, and promoathazine.
  • Hl blocker such as azelastine, brompheniramine, buclizine, carbinoxamine, cetrizine, chlorpheniramine, clemastine, cyclizine, cyproheptadine, desloratidine, dimenhydrinate, diphenhydramine, emedastine, fexofenadine, hydroxyzine, keto
  • the promethazine is formulated for immediate release, controlled-release, delayed release or a combination thereof (e.g., some dosage amount for immediate release some dosage controlled/delayed release),
  • the compositions can comprise an antiemetic agent including, for example, promethazine, dolasetron, granisetron, ondansetron, tiopisetron, palonosetron, domperidone, droperidol, haloperidol, chlorpromazine, prochloperazine, metoclopiamide, alizapride, cyclizine, diphenhydramine, dimenhydrinate, meclizine, hydroxyzine, cannabis, dronabinol, nabilone, midazolam, lorazepam, hyoscine, dexamethasone, trimethobenzamide, emetrol, propofol, or the like.
  • an antiemetic agent including, for example, promethazine, dolasetron, granisetron, ondan
  • the composition can comprise an antitussive agent including, for example, dextromethorphan, noscapine, ethyl morphine, codeine, camphor, menthol, theobromine, guaifenesin, or the like.
  • an antitussive agent including, for example, dextromethorphan, noscapine, ethyl morphine, codeine, camphor, menthol, theobromine, guaifenesin, or the like.
  • a composition comprises at least two analgesics; and one antihistamine or antiemetic.
  • a composition comprises hydrocodone, WSGR Docket No 35681 701 601 acetaminophen and promethazine
  • a composition comprises oxycodone, acetaminophen and promethazine [0080] Administration
  • One aspect of the present invention provides a method for preventing an adverse effect such as nausea, vomiting other gastric upsets, skin rashes, allergic reactions such as swelling, difficulty breathing, closing of throat, abdominal pam, unusual bleeding or bruising and skin rashes in a subject receiving or in need of opioid analgesic therapy by the administration of acetaminophen or other non-opiod analgesic and promethazine or other antihistamine with the chosen opioid analgesics
  • the invention provides methods for treating pain, comprising administering to a subject in need thereof an effective amount of an opioid analgesic agent, a non-opioid analgesic agent and an agent that reduces side affects of the opioid analgesic agent
  • the non-opioid analgesic agent is acetaminophen
  • the agent that reduces a adverse effect is promethazine
  • the administration can continue for only a relatively short time in the case of an acute condition requiring opioid therapy or for long periods in the
  • a method for treating a subject comprising administering a pharmaceutical composition comprising an effective amount of a first agent which is a non-opioid analgesic, or a pharmaceutically acceptable salt thereof, an effective amount of a second agent which is an opioid analgesic, or a pharmaceutically acceptable salt thereof, and an effective amount of a third component which is an antihistamine
  • the at least one adverse effect is selected from the group consisting of nausea, vomiting, other gastric upsets, skin rashes, allergic reactions such as swelling, difficulty breathing, closing of throat, abdominal pam, unusual bleeding or bruising and skm rashes
  • the non-opioid analgesic is acetaminophen or analogue thereof
  • the antihistamine is promethazine
  • the opioid analgesic is hydrocodone
  • the opioid analgesic is oxycodone
  • the present invention provides for a method for preventing a adverse effect such as nausea, vomiting, and a skin rash in a subject receiving or in need of opioid therapy by the administration WSGR Docket No 35681-701 601 of acetaminophen or analogue thereof and promethazine with the opioid analgesic
  • the opioid analgesic is hydrocodone.
  • the opioid analgesic is oxycodone.
  • administration of a composition comprising a non-opioid analgesic and an antihistamine enhances the reduction or elimination of adverse effects associated with an opioid analgesic.
  • addition of promethazine and acetaminophen/ibuprofen reduces or eliminates an adverse effect associated with an opioid analgesic in a synergistic manner.
  • composition of the invention would result in treatment of the subject which includes elimination or reduction of an adverse effect associated with analgesics (e.g., opioids) and enhance the beneficial uses of such analgesics
  • analgesics e.g., opioids
  • Such an adverse effect can otherwise render administration of certain analgesics intolerable, due to for example vomiting, nausea, and skin rashes. Therefore, various embodiments of the methods of the invention are directed to target populations of subjects that are susceptible to such an adverse effect(s), thus allowing such subjects to benefit from the pain-alleviating effects of analgesic-based pain relief, administration of which would otherwise be intolerable
  • composition of the invention comprises multiple active agents at the same or different dosages.
  • the analgesic components may vary in dosages as further described herein, and the antihistamine or antiemetic dosage can be adjusted according to the particular analgesics used.
  • an opioid analgesic present m a composition of the invention is at a dose of 1.0 mg to about 20 mg, including but not limited to 1.0 mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6 0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5mg, 9.0 mg, 9.5 mg, 10 0, 10 5 mg, 11 0 mg, 12.0 mg, 12.5 mg, 13.0 mg, 13.5mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg, 19 mg, 19.5 mg or 20 mg.
  • a non-opioid analgesic is present at a doses of 200 mg to about 600 mg, including but not limited to 200 mg, 225 mg, 250 mg, 275 mg, 300 mg,
  • an antiemetic or antihistamine component of a multi-drug composition of the invention is present at a dose of 0 5 mg to about 60 mg of promethazine, including but not limited to 0.5 mg, 1 0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg, 9,0 mg, 9.5 mg, 10 mg, 10 5 mg, 11 mg, 11.5 mg, 12.0 mg,
  • a composition of the invention comprises hydrocodone, a pharmaceutically acceptable salt or its thiosemicarbazone, p-mtrophenylhydrazone, o-methyloxime, sernicarbazone, or bis(methylcarbamate) (each of the foregoing being a hydrocodone agent or derivative);; acetaminophen; and promethazine.
  • the hydrocodone agent is present in a range of about 1.0 mg to about 20 mg, including but not limited to l .O mg, 1.5 mg, 2.5 mg, 3.0 mg, 4.0 rng, 5.0 mg, 6.0 mg, 6.5 mg, 7.0 mg, WSGR Docket No 35681-701 601
  • the acetaminophen is rn a range of about 200 mg to about 600 mg, including but not limited to 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg
  • the promethazine is between about 0 5 mg to about 60 mg, including but not limited to 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2 5 mg, 3.0 mg, 3.5 mg, 4 0 mg, 4.5 mg, 5 0 mg
  • a composition of the invention comprises hydrocodone, acetaminophen and promethazine, wherein the composition comprises the respective agents rn a ratio of about (1 to 2). (40 to 45):(1 to 2), such as about 1 :40:1, 1:40:1.1, 1.40 1.2, 1:40 1 3, 1 40 1.4, 1.40.1.5, 1 40 1 6, 1:40:1 7, 1 40:1.8, 1-40:1 9, 1 40:2, 1.1:40:1, 1.2:40.1, 1.3:40 1, 1.4:40 1, 1.5:40:1, 1.640.1, 1.7.40.1, 1 8.40.1, 1 9:40:1, 2.40:1, 1:41 1, 1 41.1.1, 1.41:1.2, 1 41 1.3, 1.41.1.4, 1 41 1.5, 1.41 1.6, 1 41.1.7, 1.41.1.8,
  • the ratio of amounts for each active agent is (I)- (43 33)-(l .67) for hydrocodone, acetaminophen and promethazine, respectively
  • the pharmaceutical composition comprises oxycodone, a pharmaceutically acceptable salt or Us thiosemicarbazone, p-mtr ⁇ phenylhydrazone, o-methyloxime, semicarbazone, or bis(methylcarbamate) (each of the foregoing being a hydrocodone agent or derivative),; acetaminophen; and promethazine
  • the oxycodone agent is present in a range of about 1 mg to about 200 mg, including but not limited to 1 0 mg, 1 5 mg, 2.5 mg, 3 0 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5mg, 9.0 mg, 9.5 mg, 100, 10.5 mg, l l.O mg, 12.0 mg, 12.5 mg, 13.0 mg, 13 5mg, 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5
  • the pharmaceutical composition provides promethazine at 12 5 mg
  • a composition of the invention comprises oxycodone, acetaminophen and promethazine, wherein the composition comprises the agents in a ratio of about (1 to 2): (40 to 45) (1 to 2), respectively
  • the ratio of amounts for each active agent is (1): (43.33):(1.67) for oxycodone, acetaminophen and promethazine, respectively
  • a pharmaceutical composition of the invention comprises an antihistamine (e.g., promethazine) at a lower dosage than that which the antihistamine is administered alone.
  • an antihistamine or antiemetic e.g , promethazine
  • a dosage that is effective in reducing adverse affects associated with the opioid analgesic and/or non-opioid analgesic but is at a relative low enough dosage (e.g , given the subject's weight) to prevent sedation associated with the antihistamine/antiemetic.
  • a pharmaceutical composition of the invention comprises 6-8 mg of hydrocodone (such as about 6.0 mg, 6.1 mg, 62 mg, 6.3 mg, 6.4 mg, 6.5 mg, 6.6 mg, 6.7 mg, 6.8 mg, 6.9 mg, 7.0 mg,
  • acetaminophen such as about 310 mg, 315 mg, 320mg, or 325 mg
  • promethazine such as WSGR Docket No 35681-701 601 about 10 mg, 10 5 mg, 11 0 mg, 11 5 mg, 12 0 mg, 12 5 mg, 13 0, mg, 13 5 mg, 14 0 mg, 14 5 mg, or 15 mg.
  • the hydrocodone and the acetaminophen can be formulated using conventional technologies to provide for an extended time release over a desired dosage interval.
  • a composition of the invention comprises from 1% to 20% by weight of an antihistamine (such as 1%, 1.5%, 2%, 2.5%, 3%, 3 5%, 4%, 4 5%, 5%, 5.5%, 6%, 6 5%, 7%, 7.5%, 8%, 8 5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16 5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, or 20%); from 10% to 80% by weight a non-opioid analgesic (such as
  • a composition of the invention comprises 6-8 mg of oxycodone HCl (such as about 7 5mg), 31O-33Omg of acetaminophen (such as about 325 mg), and 6-8mg of promethazine (such as about
  • the oxycodone HCl and the acetaminophen can be formulated using conventional technologies to provide for an extended time release over a desired dosage interval AU or some of the promethazine is formulated for immediate release Therefore, in one embodiment, administration of a composition of the invention comprising such a promethazine active agent can result m reduced, abated or eliminated adverse effects associated with the oxycodone HCl and/or acetaminophen. Reduced, abated or eliminated adverse effects include but are not limited to including nausea, vomiting, other gastric upsets, skin rashes, allergic reactions such as swelling, difficulty breathing, closing of throat, abdominal pam, unusual bleeding or bruising or any combination thereof.
  • the dosages and concentrations of active agents in the compositions may be varied as desired, as further described herein Depending on the subject andVor condition being treated and on the administration route, the active agent in a composition can generally be administered in dosages of 0.01 mg to 500 mg V/kg body weight per day, e g about 20 mg/day for an average person. The dosage can be adjusted based on the mode of administration. A typical dosage may be one administration daily, or multiple administrations daily.
  • dosage for one or a combination of agents can be from 0.01 to 5mg, 1 to 10 mg, 5 to 20 mg, 10 to 50 mg, 20 to 100 mg, 50 to 150mg, 100 to WSGR Docket No 35681 701 601
  • the active agents are formulated to be administered through oral dosage forms (e g , tablets, capsules, gels), inhalations, nasal sprays, patches, absorbing gels, liquids, liquid tannates, suppositories, injections, I V drips, other delivery methods, or a combination thereof to treat subjects
  • Administration may be performed m a variety of ways, including, but not limited to orally, subcutaneous Iy, intravenously, rntranasalty, lntraotically, transdermally, topically (e.g , gels, salves, lotions, creams, etc.), rntraperitoneally, intramuscularly, rn
  • the active agents can be mixed with a suitable pharmaceutically acceptable carrier
  • the resulting composition can be a solid, a half-solid, a solution, suspension, or an emulsion
  • Such compositions can be prepared according to methods known to those skilled in the art
  • the forms of the resulting compositions can depend upon a variety of factors, including the intended mode of administration and the solubility of the compounds in the selected carrier or vehicle
  • the effective concentration of analgesics is sufficient for lessening or alleviating pain
  • the components of the present compositions are at least one opioid analgesic agent (e g , hydrocodone/oxycodone), one non-opioid analgesic agent (e.g , acetaminophen), and one antihistamine
  • compositions suitable for nasal inhalation by oxygen aerosolization administration comprise hydrocodone or oxycodone, acetaminophen, and promethazine
  • an antihistamine e g , promethazine
  • the agents of the present invention can also be administered as a self-propelled dosage unit in aerosol form suitable for inhalation therapy Suitable means for employing the aerosol inhalation therapy technique are desc ⁇ bed, for example, in U S Pat No 6,913,768 to Couch et al , incorporated herein by reference in its entirety.
  • the agent can be suspended in an inert propellant such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane, together with a co-solvent such as ethanol, together with other medications such as albuterol, together with flavoring mate ⁇ als and stabilizers
  • an inert propellant such as a mixture of dichlorodifluoromethane and dichlorotetrafluoroethane
  • a co-solvent such as ethanol
  • other medications such as albuterol
  • albuterol together with flavoring mate ⁇ als and stabilizers
  • the agents useful for a self-propelled dosage unit in aerosol form administration are hydrocodone or oxycodone, acetaminophen, and promethazine WSGR Docket No 35681-701 601
  • compositions and methods of the present invention can also be administered as nasal spray/drop compositions, which can conveniently and safely be applied to subjects to effectively treat pain with reduced adverse effects
  • compositions may further comprise a water soluble polymer such as polyvinylpyrrolidone, together with other medications such as sumatriptan, together with bioadhesive material
  • a composition for nasal spray or drop administration are hydrocodone or oxycodone agent, acetaminophen, and promethazine
  • compositions of the present invention can also be administered topically to the skin of a subject
  • the agents can be mixed with a pharmaceutically acceptable carrier or a base which is suitable for topical application to skin to form a dermatological composition
  • Suitable examples of earner or base include, but not limited to, water, glycols, alcohols, lotions, creams, gels, emulsions, and sprays
  • a dermatological composition comprising an analgesic agent can be integrated into a topical dressing, medicated tape, dermal patch absorbing gel and cleansing tissues
  • the dermatological composition comprises hydrocodone or oxycodone, acetaminophen, and promethazine
  • compositions of the present invention can also be in liquid or liquid tannate form
  • the liquid formulations can comprise, for example, an agent in water-m-solution and/or suspension form, and a vehicle comprising polyethoxylated castor oil, alcohol and/or a polyoxyethylated sorbitan mono-oleate with or without flavoring
  • Each dosage form comprises an effective amount of an active agent and can optionally comprise pharmaceutically inert agents, such as conventional excipients, vehicles, fillers, binders, disentegrants, solvents, solubilrzing agents, sweeteners, coloring agents and any other inactive agents that can be mcluded in pharmaceutical dosage forms for oral administration Examples of such vehicles and additives can be found in Remington's Pharmaceutical Sciences, 17th edition (1985) Therefore, in one embodiment a liquid composition of the invention comprises an opioid analgesic (e g , hydrocodone or oxycodone), a non-opioid analgesic (e g , aceta
  • compositions of the present invention can also b ⁇ administered in injection-ready stable liquids for injection or I V drip
  • saline or other injection-ready liquid can be mixed with an opioid analgesic (e g , hydrocodone or oxycodone), a non-opioid analgesic (e g , acetaminophen) and an antihistamine (e g , promethazine)
  • opioid analgesic e g , hydrocodone or oxycodone
  • non-opioid analgesic e g , acetaminophen
  • an antihistamine e g , promethazine
  • a composition is in one or more dosage form
  • a composition can be administered in a solid or liquid form
  • solid dosage forms include but are not limited to discrete units in capsules or tablets, as a powder or granule, or present in a tablet conventionally formed by compression molding
  • Such compressed tablets may be prepared by compressing in a suitable machine the three or more agents and a pharmaceutically acceptable carrier
  • the molded tablets can be optionally coated or scored, having indicia inscribed thereon and can be so WSGR Docket No 35681 701 601 formulated as to cause immediate, substantially immediate, slow, or controlled release of the hydrocodone and/or the acetaminophen
  • dosage forms of the invention can comprise acceptable carriers or salts known in the art, such as those described in the Handbook of Pharmaceutical Excipients, American Pharmaceutical Association (1986), incorporated by reference herein [00113]
  • the components are mixed with a pharmaceutical excipient to form a solid pre formulation composition comprising a homo
  • compositions can be formulated, in the case of capsules or tablets, to be swallowed whole, for example with water
  • side-effect-reducing agent such as an antihistamine or antiemetic to abate common symptoms of nausea and vomiting are believed beneficial in that promethazine or the like will eliminate or minimize the amount of discomfort
  • side-effect-reducing agent such as an antihistamine or antiemetic to abate common symptoms of nausea and vomiting are believed beneficial in that promethazine or the like will eliminate or minimize the amount of discomfort
  • Adverse effects reduced or eliminated include but are not limited to nausea, vomiting, other gastric upsets, skin rashes, allergic reactions such as swelling, difficulty breathing, closing of throat abdominal pain, unusual bleeding or bruising
  • the dosage forms of the present invention can be manufactured using processes that are well known to those of skill m the art
  • the agents can be dispersed uniformly in one or more excipients, for example, using high shear granulation, low shear granulation, fluid bed granulation, or by blending for direct compression
  • Excipients include diluents, binders, disintegrants, dispersants, lubricants, ghdants, stabilizers, surfactants and colorants
  • Diluents also termed "fillers” can be used to increase the bulk of a tablet so that a practical size is provided for compression
  • Non-lirmtmg examples of diluents include lactose, cellulose, micro crystalline cellulose, man
  • Lubricants can also facilitate tablet manufacture, non-limiting examples thereof include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol Disintegrants can facilitate tablet disintegration after administration, and non-limiting examples thereof include starches, algmic acid, crosslinked polymers such as, e g , crosslinked polyvinylpyrrolidone, croscarmellose sodium, potassium or sodium starch glycolate, clays, celluloses, starches, gums and the like WSGR Docket No 35681-701.601
  • Non-limitmg examples of suitable glidants include silicon dioxide, talc and the like.
  • Stabilizers can inhibit or retard drug decomposition reactions, including oxidative reactions.
  • Surfactants can also included and can be anionic, cationic, amphoteric or nonionic.
  • the tablets can also comprise nontoxic auxiliary substances such as pH buffering agents, preservatives, e.g., antioxidants, wetting or emulsifying agents, solubilizing agents, coating agents, flavoring agents, and the like.
  • Extended or controlled-release formulations can comprise one or more combination of excipients that slow the release of the agents by coating oi temporarily bonding or decreasing their solubility of the active agents.
  • excipients include cellulose ethers such as hydroxypropylmethylcellulose (e.g., Methocel K4M), polyvinylacetate-based excipients such as, e.g., Kollidon SR, and polymers and copolymers based on methacrylates and methacrylic acid such as, e g., Eudragit NE 30D
  • the analgesic agents e g., hydrocodone oi oxycodone, and acetaminophen
  • the promethazine is formulated for immediate release.
  • all agents are formulated for extended or controlled-release.
  • Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include all such carriers known to those skilled in the art to be suitable for the particular mode of administration.
  • the analgesics and promethazine can also be administered with other components that do not impair the desired action, or with components that supplement the desired action, or have another action.
  • a composition can comprise additional (e.g., a fourth, fifth, sixth, etc ) addition active compounds.
  • the composition comprises three or more active agents wherein at least one active agent is in immediate release form.
  • the immediate-release form is included in an amount that is effective to shorten the time to its maximum concentration hi the blood
  • certain immediate-release pharmaceutical preparations are taught in United States Patent Publication US 2005/0147710A1 entitled, "Powder Compaction and Enrobing" which is incorporated herein in its entirety by reference.
  • the component in immediate-release form is a component that reduces abates or eliminates and/or suppresses a adverse effect associated with one or more opioid analgesics.
  • the immediate-release active can be an antihistamine or antiemetic, which reduces, abates or eliminates an adverse effect associated with opioid and/or non-opioid analgesics described herein.
  • the analgesic formulation comp ⁇ ses an opioid and non-opioid analgesic (e.g., hydrocodone or oxycodone and acetaminophen, respectively) and an antihistamine (e.g., promethazine).
  • all or less than all of the total amount of the antiemetic or antihistamine agent is formulated in immediate -release form, as described herein.
  • a variety of known methods and materials may be used to bring about the immediate release. For instance, placement of the agent along an exte ⁇ or of a tablet (e.g., coating the exterior or formulating the outer layer with the agent) and/or combined with forming a tablet by compressing the powder using low compaction can produce immediate-release of the agent from the composition.
  • an effective amount of the promethazine in immediate-release form may be coated onto a substrate. For example, where the extended release of one or more analgesics from a formulation is due to a controlled-release coating, an immediate-release layer comprising promethazine can WSGR Docket No 35681-701 601 overcoat the controlled-release coating.
  • the immediate-release layer of promethazine can be coated onto the surface of a substrate wherein hydiocodone and/or oxycodone is incorporated in a controlled release matrix.
  • a plurality of controlled-release substrates comprising an effective unit dose of an analgesic (e g., multiparticulate systems including pellets, spheres, beads and the like) are incorporated into a hard gelatin capsule
  • the side-effect-reducing compound can be incorporated into the gelatin capsule via inclusion of an amount of immediate-release promethazine as a powder or granulate within the capsule.
  • the gelatin capsule itself can be coated with an immediate-release layer of promethazine.
  • the composition comp ⁇ ses three or more active agents wherein at least one active agent is in controlled-release form.
  • the controlled-release form can be in an amount that is effective to protect the agent from rapid elimination from the body.
  • compositions comprise one or more earners that protect the agents against rapid elimination from the body, such as time-release formulations or coatings.
  • Such carriers include controlled-release formulations, including, for example, microencapsulated delivery systems.
  • the active agents can be included m the pharmaceutically acceptable carrier in amounts sufficient to treat a subject's pain, with reduced adverse effects.
  • compositions are in oral-dosage form and comprise a matrix that includes, for example, a controlled-release material and an analgesic such as hydrocodone or a pharmaceutically acceptable salt thereof.
  • the matrix is compressible into a tablet and can be optionally overcoated with a coating that can control the release of the analgesics including hydrocodone or pharmaceutically acceptable salt thereof from the composition.
  • blood levels of analgesics are maintained within a therapeutic range over an extended period of time.
  • the matrix is encapsulated.
  • Tablets or capsules containing a composition of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action
  • the tablet or capsule can contain an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an ente ⁇ c layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • the capsule can also have micro drilled holes.
  • a coating comprising a side-effect-reducing compound such as promethazine, in immediate release form can be added to the outside of a controlled-release tablet core to produce a final dosage form.
  • a WSOR Docket No. 35681-701.601 coating can be prepared by admixing a compound like promethazine with polyvinylpyrrolidone (PVP) 29/32 or hydroxypropyl methylcellulose (HPMC) and water/isopropyl alcohol and triethyl acetate.
  • PVP polyvinylpyrrolidone
  • HPMC hydroxypropyl methylcellulose
  • Such an immediate-release coating can be spray coated onto the tablet cores.
  • the immediate-release coating can also be applied using a press-coating process with a blend consisting of 80% by weight promethazine and 20% by weight of lactose and hydroxypropyl methylcellulose type 2910. Press-coating techniques are known in the art and are described in U.S. Pat. No. 6,372,254 to Ting et al., incorporated herein by reference in its entirety.
  • the immediate-release or controlled- release dosage forms of the present invention can also take the form of a bi- layered tablet, which comprises a first layer and a second layer.
  • the first layer comprises a first drug selected from analgesics, antitussives, antihistamines, antiemetics.
  • the second layer comprises a second drug selected from analgesics, antitussives, antihistamines, antiemetics.
  • the second drug is the same as or different from the first drug.
  • the bi-layered tablet can provide a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 70% of the period (e.g., 12 hours) within which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug.
  • the first layer is an immediate release layer and/ or the second layer is a controlled-release layer.
  • both layers can comprise an opioid analgesic such as hydrocodone or oxycodone; a non-opioid analgesic such as acetaminophen,; and a compound, such as promethazine, to reduce or suppress adverse effects.
  • opioid analgesic such as hydrocodone or oxycodone
  • non-opioid analgesic such as acetaminophen
  • a compound such as promethazine
  • the first layer comprises promethazine and the second layer comprises hydrocodone or oxycodone.
  • the first or second layer can further comprise acetaminophen.
  • the components are released from a multi-layered tablet that comprises a first layer and a second layer.
  • the first layer comprises a first drug which is selected from analgesics, antitussives, antihistamines, antiemetics.
  • the second layer comprises a second drug which is selected from analgesics, antitussives, antihistamines, antiemetics.
  • the second drug can be the same as or different from the first drug.
  • the second drug can have a plasma half-life that differs from the plasma half-life of the first drug by at least about 2 hours.
  • the first layer is an immediate-release layer and/or the second layer is a controlled release layer.
  • both die first layer and the second layer can comprise an opioid analgesic such as hydrocodone or oxycodone; a non-opioid analgesic such as acetaminophen; and compound to reduce or suppress adverse effects such as promethazine.
  • the first layer comprises promethazine and the second layer comprises hydrocodone or oxycodone.
  • the first or second layer can further comprise acetaminophen.
  • the immediate-release or controlled release dosage forms of the present invention can also take the form of pharmaceutical particles manufactured by a variety of methods, including but not limited to high-pressure homogenization, wet or dry ball milling, or small particle precipitation (nGimat's NanoSpray SM ).
  • Other methods to make a suitable powder formulation are the preparation of a solution of active ingredients and excipients, followed by precipitation, filtration, and pulverization, or followed by removal of the solvent by WSGR Docket No 35681-701 601 freeze-drying, followed by pulverization of the powder to the desired particle size.
  • the pharmaceutical particles are manufactured to a final size of 3-1000 uM, such as at most 3, 4, 5, 6, 7, 8, 9,10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000 uM.
  • the pharmaceutical particles are manufactured to a final size of 10-500 uM embodiment the pharmaceutical particles are manufactured to a final size of 50-
  • the pharmaceutical particles are manufactured to a final size of 100-800 uM.
  • These dosage forms can include immediate-release particles in combination with controlled-release particles rn a ratio sufficient useful for delivering the desired dosages of active agents.
  • the immediate- release particles can comprise about 12.5 mg of promethazine
  • the controlled-release particles can comprise about 7.5 mg of hydrocodone (or 7.5 mg of oxycodone) and about 325 mg of acetaminophen.
  • the components are released from a multi-layered tablet that comprise at least a first layer, a second layer and a third layer.
  • the layers containing an agent such as an opioid analgesic, a non-opioid analgesic and an antihistamine
  • the layers containing an agent can be optionally separated by one or more layers of inert materials.
  • the layers containing an agent have similar rates of release, e.g. all are immediate release or all are controlled-release.
  • the layers have different rates of release.
  • at least one layer is an immediate release layer and at least one layer is a controlled release layer.
  • the multilayer tablet comprises at least three layers, each of which contains a different agent, such as: layer one contains promethazine; layer two comprises hydrocodone or oxycodone; and layer three comprises acetaminophen
  • layer one contains promethazine
  • layer two comprises hydrocodone or oxycodone
  • layer three comprises acetaminophen
  • the promethazine layer may be designed for immediate-release, while the other two layers may be designed for controlled-release.
  • composition comprising an opioid analgesic agent, a non-opioid analgesic agent and an antihistamine agent is administered to a subject.
  • the antihistamine component can be formulated for immediate release or a controlled release which is faster than the release of the opioid analgesic agent and, optionally, the non-opioid analgesic agent.
  • the composition comprises hydrocodone or oxycodone, acetaminophen and promethazine
  • compositions comprising an opioid analgesic agent, a non-opioid analgesic agent and an antihistamine agent is administered to a subject; wherein the amounts and release rates of the opioid analgesic agent and the antihistamine agent are effective to reduce at least one side affect of opioid treatment in a subject.
  • the composition comprises hydrocodone or oxycodone, acetaminophen and promethazine.
  • Additives [00143]
  • the present compositions can further comprise suitable additives, including, but not limited to, diluents, binders, surfactants, lubricants, glidants, coating materials, plasticizers, coloring agents, flavoring agents, or pharmaceutically inert materials.
  • diluents include, for example, cellulose; cellulose derivatives such as microcrystalline cellulose and the like, starch; starch de ⁇ vatives such as corn starch, cyclodextrin and the like; sugar; sugar alcohol such as lactose, D-mannitol and the like; inorganic diluents such as dried aluminum hydroxide gel, precipitated calcium carbonate, magnesium alummometasilicate, dibasic calcium phosphate and the like.
  • binders include, for example, hydroxypropylcellulose, methylcellulose, hydroxypropylrnethylcellulose, povidone, dextrin, pullulane, hydroxypropyl starch, polyvinyl alcohol, scacia, agar, gelatin, tragacanth, macrogol and the like.
  • surfactants include, for example, sucrose esters of fatty acids, polyoxyl stearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan sesqmoleate, sorbitan trioleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, lauromacrogol and the like
  • lubricants include, for example, stearic acid, calcium stearate, magnesium stearate, talc and
  • glidants include, for example, dried aluminium hydroxide gel, magnesium silicate and the
  • coating materials include, for example, hydroxypropylmethyl cellulose 2910, aminoalkyl rnethacrylate copolymer E, polyvinylacetal diethylaminoacetate, macrogol 6000, titanium oxide and the like
  • plasticizers include, for example, tnethyl citrate, tnacetin, macrogol 6000 and the like
  • Analgesic Composition A [00151] Agents mg/Tablet [00152] Hydrocodone Bitartrate 7 5 mg [00153] Acetaminophen 325 mg [00154] Promethazine 12 5 mg
  • Example 1 The composition of Example 1 is orally administered with water to a subject having a tendency to exhibit adverse effects of gastric upset, nausea, vomiting, or skin rash Such subjects, upon taking the composition set forth in Example 1 would receive a therapeutically effective amount of promethazine in then blood stream The promethazine would reduce the adverse effects that such a target population would otherwise exhibit
  • the dosage form is a bi-layered tablet, in which the first layer is an immediate-release layer comprising 12 5 mg of promethazine hydrochloride and the second layer is a controlled-release layer comprising 12 5 mg of promethazine hydrochloride, 15 mg of hydrocodone bitartrate, and 325 mg of acetaminophen
  • Analgesic Composition B [00159] Agents mg/Tablet [00160] Oxycodone HCl 7 5 mg or 5 mg
  • Example 3 The composition of Example 3 is orally administered with water to a subject having a tendency to exhibit adverse effects of gastric upset, nausea, vomiting, or skm rash Such subjects, upon taking the composition set forth m Example 3 would receive a therapeutically effective amount of promethazine which will reduce the adverse effects that such a target population would otherwise exhibit WSGR Docket No 35681-701.601
  • the dosage form is a bi-layered tablet, m which the first layer is an immediate-release layer comprising 12.5 mg of promethazine hydrochloride, and the second layer is a controlled-release layer comprising 12.5 mg of promethazine hydrochloride, 15 mg of oxycodone HCl, and 325 mg of acetaminophen.

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  • Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques qui comportent des quantités efficaces d'analgésique pour traiter un sujet, y compris pour réduire ou éliminer un effet indésirable associé à l'analgésique.
PCT/US2007/080831 2006-10-09 2007-10-09 Compositions pharmaceutiques WO2008070268A2 (fr)

Priority Applications (21)

Application Number Priority Date Filing Date Title
PL07871139T PL2124556T3 (pl) 2006-10-09 2007-10-09 Kompozycje farmaceutyczne
JP2009531645A JP2010522135A (ja) 2006-10-09 2007-10-09 医薬組成物
SI200731562T SI2124556T1 (sl) 2006-10-09 2007-10-09 Farmacevtske sestave
ES07871139.7T ES2524556T3 (es) 2006-10-09 2007-10-09 Composiciones farmacéuticas
EP07871139.7A EP2124556B1 (fr) 2006-10-09 2007-10-09 Compositions pharmaceutiques
CA2665841A CA2665841C (fr) 2006-10-09 2007-10-09 Compositions pharmaceutiques
US12/444,521 US8653066B2 (en) 2006-10-09 2007-10-09 Pharmaceutical compositions
DK07871139.7T DK2124556T3 (en) 2006-10-09 2007-10-09 Pharmaceutical compositions
HK10105451.9A HK1138732A1 (en) 2006-10-09 2010-06-02 Pharmaceutical compositions
US14/099,432 US20140134248A1 (en) 2006-10-09 2013-12-06 Pharmaceutical compositions
US14/748,609 US9399022B2 (en) 2006-10-09 2015-06-24 Pharmaceutical compositions
US14/748,613 US20150328210A1 (en) 2006-10-09 2015-06-24 Pharmaceutical compositions
US14/748,605 US9402813B2 (en) 2006-10-09 2015-06-24 Pharmaceutical compositions
US14/748,621 US9427407B2 (en) 2006-10-09 2015-06-24 Pharmaceutical compositions
US14/748,614 US9393207B2 (en) 2006-10-09 2015-06-24 Pharmaceutical compositions
US14/748,617 US20150328212A1 (en) 2006-10-09 2015-06-24 Pharmaceutical compositions
US15/263,230 US20160375013A1 (en) 2006-10-09 2016-09-12 Pharmaceutical compositions
US15/263,235 US20160375014A1 (en) 2006-10-09 2016-09-12 Pharmaceutical compositions
US15/679,460 US20170340627A1 (en) 2006-10-09 2017-08-17 Pharmaceutical compositions
US16/425,401 US20200054625A1 (en) 2006-10-09 2019-05-29 Pharmaceutical Compositions
US17/229,479 US20220062276A1 (en) 2006-10-09 2021-04-13 Pharmaceutical compositions

Applications Claiming Priority (6)

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US85045106P 2006-10-09 2006-10-09
US60/850,451 2006-10-09
US95256307P 2007-04-03 2007-04-03
US60/952,563 2007-04-03
US94837507P 2007-07-06 2007-07-06
US60/948,375 2007-07-06

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US12/444,521 A-371-Of-International US8653066B2 (en) 2006-10-09 2007-10-09 Pharmaceutical compositions
US14/099,432 Continuation US20140134248A1 (en) 2006-10-09 2013-12-06 Pharmaceutical compositions

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EP2240022A2 (fr) * 2008-01-09 2010-10-20 Charleston Laboratories, Inc. Compositions pharmaceutiques
US7906541B2 (en) 2008-11-07 2011-03-15 Universite Paul Cezanne-Aix Marseille Iii Process to prepare new substituted 1H-benzo[d]imidazol-2(3H)-ones, new intermediates and their use as BACE 1 inhibitors
WO2011063164A2 (fr) * 2009-11-18 2011-05-26 Steady Sleep Rx Co., Inc. Médicaments de cannabinoïde à libération prolongée
EP2451274A1 (fr) * 2009-07-08 2012-05-16 Charleston Laboratories Inc. Compositions pharmaceutiques
US8653066B2 (en) 2006-10-09 2014-02-18 Charleston Laboratories, Inc. Pharmaceutical compositions
WO2015157738A1 (fr) * 2014-04-10 2015-10-15 Charleston Laboratories, Inc. Compositions pharmaceutiques
WO2015157509A1 (fr) * 2014-04-10 2015-10-15 The Trustees Of The University Of Pennsylvania Compositions et methodes de traitement de maladies associées aux recepteurs des opioides
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
WO2017066488A1 (fr) * 2015-10-13 2017-04-20 Charleston Laboratories, Inc. Traitement de la douleur à l'aide d'une composition comprenant un opioïde et un antiémétique
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10179109B2 (en) 2016-03-04 2019-01-15 Charleston Laboratories, Inc. Pharmaceutical compositions comprising 5HT receptor agonist and antiemetic particulates
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EP3468558A4 (fr) * 2016-06-10 2019-11-20 Charleston Laboratories, Inc. Compositions pharmaceutiques comprenant un analgésique opioïde et un antiémétique pour traiter la douleur
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US11324727B2 (en) 2020-07-15 2022-05-10 Schabar Research Associates, Llc Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn
US11331307B2 (en) 2020-07-15 2022-05-17 Schabar Research Associates, Llc Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

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US8653066B2 (en) 2006-10-09 2014-02-18 Charleston Laboratories, Inc. Pharmaceutical compositions
US9427407B2 (en) 2006-10-09 2016-08-30 Locl Pharma, Inc. Pharmaceutical compositions
US9402813B2 (en) 2006-10-09 2016-08-02 Locl Pharma, Inc. Pharmaceutical compositions
US9399022B2 (en) 2006-10-09 2016-07-26 Locl Pharma, Inc. Pharmaceutical compositions
US9393207B2 (en) 2006-10-09 2016-07-19 Locl Pharma, Inc. Pharmaceutical compositions
US9387177B2 (en) 2008-01-09 2016-07-12 Locl Pharma, Inc. Pharmaceutical compositions
US9226901B2 (en) 2008-01-09 2016-01-05 Locl Pharma, Inc. Pharmaceutical compositions
US9789104B2 (en) 2008-01-09 2017-10-17 Locl Pharma, Inc. Pharmaceutical compositions
US8124126B2 (en) 2008-01-09 2012-02-28 Charleston Laboratories, Inc. Pharmaceutical compositions
US9789105B2 (en) 2008-01-09 2017-10-17 Locl Pharma, Inc. Pharmaceutical compositions
US9775837B2 (en) 2008-01-09 2017-10-03 Charleston Laboratories, Inc. Pharmaceutical compositions
US10064856B2 (en) 2008-01-09 2018-09-04 Local Pharma, Inc. Pharmaceutical compositions
US9498444B2 (en) 2008-01-09 2016-11-22 Locl Pharma, Inc. Pharmaceutical compositions
US9198867B2 (en) 2008-01-09 2015-12-01 Charleston Laboratories, Inc. Pharmaceutical compositions
EP2240022A4 (fr) * 2008-01-09 2012-04-25 Charleston Lab Inc Compositions pharmaceutiques
EP2240022A2 (fr) * 2008-01-09 2010-10-20 Charleston Laboratories, Inc. Compositions pharmaceutiques
US9855264B2 (en) 2008-01-09 2018-01-02 Locl Pharma, Inc. Pharmaceutical compositions
US7906541B2 (en) 2008-11-07 2011-03-15 Universite Paul Cezanne-Aix Marseille Iii Process to prepare new substituted 1H-benzo[d]imidazol-2(3H)-ones, new intermediates and their use as BACE 1 inhibitors
US9226918B2 (en) 2008-12-04 2016-01-05 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for treating or preventing narcotic withdrawal symptoms
WO2010065930A1 (fr) * 2008-12-04 2010-06-10 The Board Of Trustees Of The Leland Stanford Junior University Méthodes et compositions de traitement prophylactique ou thérapeutique de symptômes de manque après arrêt de prise de narcotiques
US9526704B2 (en) 2009-07-08 2016-12-27 Locl Pharma, Inc. Pharmaceutical compositions for treating or preventing pain
US9433625B2 (en) 2009-07-08 2016-09-06 Locl Pharma, Inc. Pharmaceutical compositions for treating or preventing pain
US10532030B2 (en) 2009-07-08 2020-01-14 Locl Pharma, Inc. Pharmaceutical compositions for treating or preventing pain
US10016368B2 (en) 2009-07-08 2018-07-10 Locl Pharma, Inc. Pharmaceutical compositions for treating or preventing pain
EP3311667A1 (fr) * 2009-07-08 2018-04-25 Charleston Laboratories, Inc. Compositions pharmaceutiques
US8728522B2 (en) 2009-07-08 2014-05-20 Charleston Laboratories, Inc. Pharmaceutical compositions for treating or preventing pain
EP2451274A4 (fr) * 2009-07-08 2014-04-02 Charleston Lab Inc Compositions pharmaceutiques
EP2451274A1 (fr) * 2009-07-08 2012-05-16 Charleston Laboratories Inc. Compositions pharmaceutiques
WO2011063164A2 (fr) * 2009-11-18 2011-05-26 Steady Sleep Rx Co., Inc. Médicaments de cannabinoïde à libération prolongée
WO2011063164A3 (fr) * 2009-11-18 2011-10-06 Steady Sleep Rx Co., Inc. Médicaments de cannabinoïde à libération prolongée
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
GB2541571A (en) * 2014-04-10 2017-02-22 Charleston Laboratories Inc Pharmaceutical compositions
CN106413717A (zh) * 2014-04-10 2017-02-15 查尔斯顿实验室公司 药物组合物
WO2015157509A1 (fr) * 2014-04-10 2015-10-15 The Trustees Of The University Of Pennsylvania Compositions et methodes de traitement de maladies associées aux recepteurs des opioides
WO2015157738A1 (fr) * 2014-04-10 2015-10-15 Charleston Laboratories, Inc. Compositions pharmaceutiques
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
WO2017066488A1 (fr) * 2015-10-13 2017-04-20 Charleston Laboratories, Inc. Traitement de la douleur à l'aide d'une composition comprenant un opioïde et un antiémétique
US10772840B2 (en) 2016-03-04 2020-09-15 Charleston Laboratories, Inc. Sumatriptan promethazine pharmaceutical compositions
US10179109B2 (en) 2016-03-04 2019-01-15 Charleston Laboratories, Inc. Pharmaceutical compositions comprising 5HT receptor agonist and antiemetic particulates
EP3468558A4 (fr) * 2016-06-10 2019-11-20 Charleston Laboratories, Inc. Compositions pharmaceutiques comprenant un analgésique opioïde et un antiémétique pour traiter la douleur
US11324727B2 (en) 2020-07-15 2022-05-10 Schabar Research Associates, Llc Unit oral dose compositions composed of naproxen sodium and famotidine for the treatment of acute pain and the reduction of the severity of heartburn and/or the risk of heartburn
US11331307B2 (en) 2020-07-15 2022-05-17 Schabar Research Associates, Llc Unit oral dose compositions composed of ibuprofen and famotidine for the treatment of acute pain and the reduction of the severity and/or risk of heartburn
US11977085B1 (en) 2023-09-05 2024-05-07 Elan Ehrlich Date rape drug detection device and method of using same

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CA2918576C (fr) 2019-01-08
WO2008070268A3 (fr) 2008-11-27
PT2124556E (pt) 2014-12-03

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