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
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
• • 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
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

• the present invention is directed to oral, therapeutically effective pharmaceutical compositions of buprenorphine and it pharmaceutically acceptable salts and the use thereof, including delayed onset and controlled release dosage forms.
• the present invention is also directed delayed onset, rapid release dosage forms and delayed onset, extended release dosage forms of oral buprenorphine which provide robust efficacy and reduced potential for abuse and misuse.
• opioid analgesics are administered by a wide variety of routes and methods, including oral, oro-transmucosal, buccal, sublingual, via NG-tubes, rectal, intranasal, inhalational, topical, transdermal, intravenous, subcutaneous, intramuscular, epidural and intrathecal, the oral route is by far the most preferred route for most patients and medical settings.
• drugs need to be administered by a non-oral route.
• reasons for the use of non-oral routes are lack of therapeutic effect, lack of a consistent, reliable or robust effects, the need for rapid onset of effect, contraindications to oral drug administration, reduced safety by the oral route and the lack of availability of the oral route (for example due to GI obstruction, nausea, vomiting, GI obstruction, obtundation or coma).
• Nonlimiting examples of agents used include nonsteroidal anti-inflammatory agents (NSAIDs), e.g., aspirin, ibuprofen, ketoprofen, diclofenac; opioids, e.g., morphine, hydromorphone, hydrocodone, oxycodone, tramadol, and codeine; cyclooxygenase-2 (COX-2) selective NSAIDs, e.g., celecoxib, valdecoxib, etoricoxib, lumiracoxib, and rofecoxib; acetaminophen; tricyclic antidepressants, e.g., amitriptyline, desipramine, nortriptyline; non-tricyclic antidepressants, e.g., doxepin, duloxetine, paroxetine, venlafaxine; antie
• NSAIDs nonsteroidal anti-inflammatory agents
• opioids e.g., morphine, hydromorphone
• Morphine-6-glucuronide accumulation has been implicated in increasing levels of nausea and sedation in patients with renal impairment (Babul and Darke, Clin Pharm Ther, 1993;54:286-92).
• the principal metabolite of hydromorphone, hydromorphone-3-glucuronide can accumulate in patients with renal impairment and has been found to be more neurotoxic than morphine-3-glucuronide (Babul and Darke, Pain, 1992;51:260-61; Hagen et al., J Clin Pharmacol, 1995;35:38-45; Babul et al., J Pain Symptom Manage, 1995; 10: 184-86; Wright et al., Life Sci, 1998;63:401- 11; Wright et al., Life Sci, 2001;69:409-20.).
• An important goal of analgesic therapy in chronic pain is to achieve continuous relief of pain. Regular administration of an analgesic is generally required to ensure that the next dose is given before the effects of the previous dose have worn off.
• analgesic sometimes referred to as around the clock, scheduled or time contingent analgesia
• chronic pain to also cover many acute pain states where the pain lasts longer than a few hours or a few days (e.g., pain after surgery, trauma, etc).
• MS Contin ® extended release morphine
• the first tier for mild to moderate pain, consists of NSAIDs and acetaminophen with or without adjuvant medications.
• treatment progresses to the second tier, in which a weak opioid, such as codeine or hydrocodone, is added to the NSAID with or without an adjuvant drug.”
• a weak opioid such as codeine or hydrocodone
• treatment progresses to the third tier: substitution of the "weak” opioid for a "strong” opioid (i.e., one more readily titrated to doses with greater analgesic efficacy).
• the latter category includes morphine, hydromorphone, methadone, fentanyl, and levorphanol, all full opioid agonists at the morphine or mu receptor.”
• the AHRQ report further notes that "if pain relief is not achieved at the maximum recommended dose of a particular NSAID or opioid, it should be discontinued and another drug from the same class tried before abandoning that class. Case series indicate that on an individual basis, other drugs from the same class may prove more effective or be better tolerated.”
• Cancer Pain Management (Guideline No. 9, AHCPR Publication No. 94-0592, March 1994) states: "It is usually advisable to observe the patient's response to several different opioids, sequentially, before switching routes of administration or trying an anesthetic, neurosurgical, or other invasive approach to relieve persistent pain. For example, patients who experience dose-limiting sedation, nausea, or mental clouding on oral morphine should be switched to an equianalgesic dose of hydromorphone or fentanyl. The dose of the second opioid should then be adjusted. Sequential analgesic trials should be based on regular assessments of pain, with continuous attention to antineoplastic and noninvasive nonpharmacologic therapies".
• opioid analgesics A number of oral immediate release formulations of opioid analgesics have been described in the art, including codeine, hydrocodone, hydromorphone, isomethadone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene, tapentadol, tramadol, or their pharmaceutically acceptable salts.
• a number of oral extended release formulations of opioid analgesics have been developed or commercialized, including morphine, hydromorphone, oxycodone, hydrocodone and oxymorphone.
• Buprenorphine or [5 ⁇ ,7 ⁇ (S)]-17-(Cyclopropylmethyl)- ⁇ -(l,l-dimethylethyl)-4,5- epoxy-18,19-dihydo-3-hydroxy-6-methoxy- ⁇ -methyl-6,14-ethenomo ⁇ hinan-7-methanol or it pharmaceutically acceptable salts have been used for the treatment of a variety of medical conditions, including pain and opioid addiction disorders. It is a semi-synthetic opioid first derived in 1966 from thebaine, an alkaloid from the poppy Papaver somniferum.
• buprenorphine is a Schedule III narcotic. According to the Drug
• DEA Enforcement Administration
• a Schedule III drug has a low potential for abuse relative to the drugs or other substances in Schedule II, II or I.
• morphine, fentanyl, meperidine, methadone, oxycodone and hydromorphone the most commonly used opioids are all Schedule II opioids.
• Schedule II Prescriptions for Schedule II controlled substances cannot be refilled. A new prescription must be issued. Prescriptions for Schedules III controlled substances may be refilled up to five times in six months. Additionally, prescriptions for Schedule II controlled substances must be written and be signed by the practitioner. Prescriptions for Schedules III may by written, oral or transmitted by fax.
• Buprenorphine is a partial agonist at the mu ( ⁇ )-opioid receptor. There is greater resistance on the part of physicians and patients to the use of the more potent and full opioid analgesics for non-cancer pain. There is also a greater risk of drug abuse and drug diversion with the full opioid agonists, such as morphine, fentanyl, meperidine, methadone, oxycodone and hydromorphone. Because of the intrinsic activity profile of buprenorphine, it has been classified as a partial opioid agonist at the mu-opioid receptor. Similar to its affinity at the mu receptor, buprenorphine also has a high affinity for the kappa-opioid receptor.
• the partial agonist properties of buprenorphine at the mu receptor together with its high affinity and slow dissociation from the receptor, give rise to its unique pharmacological profile when compared with full mu-opioid agonists such as morphine, including: (i) the ceiling effect in buprenorphine 's opioid receptor activity which provides a greater margin of safety (e.g., ceiling effect on respiratory depression) than full agonists such as morphine and methadone; (ii) the potential to block the effects of a full opioid agonist taken after administration of adequate doses of buprenorphine; (iii) the potential to antagonize the effects of a full mu opioid agonist and cause a precipitated withdrawal in opioid- dependent patients according to their level of dependence and the dose and time since the last administration of the full mu agonist; and (iv) the low intrinsic activity at the opioid receptor which provides significantly reduced
• buprenorphine may provide a safer alternative to the full opioid agonists, both in terms of opioid effects and in terms of the risk of physical dependence, addiction and drug diversion.
• buprenorphine has lower risk of abuse, it does carry a real risk of drug addiction, drug diversion and drug abuse.
• an opioid to have appeal as an abusable drug among recreational drug users or addicts, it must produce rapid onset of euphoric or psychic effects.
• a temporal relationship between drug ingestion and the appearance of discernible euphoric or psychic effects is essential to its abuse and high "street value" among recreational drug users and addicts.
• many opioid when given orally to recreational drug users or addicts, many opioid produce measureable euphoric or psychic effects soon after administration, usually within 15 to 120 minutes.
• the applicant has found a novel way to deter or minimize the abuse of oral buprenorphine among recreational drug users and drug addicts breaking the temporal relationship between drug ingestion and the rapid appearance of discernible euphoric or psychic effects by delaying the release of the buprenorphine.
• oral buprenorphine provides is more tolerable and provides fewer side effects than sublingual buprenorphine.
• oral delivery of delayed onset, ileal delivery, and colonic delivery dosage buprenorphine provides significantly more robust therapeutic effects that oral immediate release buprenorphine dosage forms which are released into the stomach.
• Buprenorphine has been commercially available as a parenteral formulation for intravenous and intramuscular use. According to the FDA's Orange Book, parenteral buprenorphine was approved prior to January 1, 1982. Buprenorphine has been widely reported to have very poor oral bioavailability and is believed to be ineffective when given orally. For this reason, pharmaceutical companies have made elaborate efforts to develop alternative non-invasive methods of delivering buprenorphine into systemic circulation. Foremost among these methods is the sublingual delivery of buprenorphine for the treatment of pain (sublingual buprenorphine [Temgesic ® ] was approved in the U.K. in 1992). This approach has provided only modest efficacy and has been a commercially failure in a number of countries.
• Major disadvantages with sublingual administration of buprenorphine include but are not limited to: (i) highly variable pharmacokinetics and pharmacodynamics; (ii) variability of patient's ability to adhere to the instructions about oral retention of drug; (iii) the development of a depot of buprenorphine on in the oral tissue; (iv) an unpleasant taste and after-taste; (v) a sensation of "gagging"; (vi) durability of a robust effect over the course of 24 hours; and (vii) increased risk of drug abuse through tampering of the dosage form and subsequent intravenous, intranasal and inhalational use.
• the sublingual formulation has also been repeatedly been shown to be unstable and susceptible to degradation.
• Methods to deal with this degradation have included use of antioxidants (e.g., ascorbic acid, vitamin E, tocopherol, butylated hydroxytoluene, alpha- lipoic acid, sodium metabisulfite, butylated hydroxyanisole, ascorbyl palmitate, hypophosphorous acid, monothioglycerol, potassium metabisulfite, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium sulfite, sodium thiosulfate, sulfur dioxide, tocopherol, or tocopherols excipient), and use of chelating agents (e.g., edetic acid, edetate calcium disodium, edetate disodium or malic acid).
• antioxidants e.g., ascorbic acid, vitamin E, tocopherol, butylated hydroxytoluene, alpha- lipo
• Buprenorphine active pharmaceutical ingredient has also been shown to be subject to oxidative degradation under stress conditions, with degradation producing both known and unknown byproducts.
• addition of antioxidants and chelating agents to the dosage form can adversely influence the stability, potency and use of other excipients, adversely influence safety of the patient through iatrogenic or idiosyncratic reactions, adversely influence the safety of workers handling the excipients, adversely influence the efficiency of co-ingested drugs, and interact with the GI environment in a manner that is adverse to the efficiency of the dosage form (see Rowe, Sheskey and Quinn, Handbook of Pharmaceutical Excipients, 6 edition, Pharmaceutical Press; APhA Publications; 2009).
• buprenorphine Another limitation with the sublingual route is the high peak concentration of buprenorphine. Both peak concentrations of opioids and the rate of rise in concentrations have variously been implicated in the causation of various opioid side effects such as nausea, drowsiness, dizziness and (acute) cognitive impairment. Orally administered buprenorphine can be formulated to provide significantly lower peak concentrations than sublingual buprenorphine. Such an effect is also desirable in opioid dependent individuals to minimize the "rush" or euphoric effect of high peak concentrations.
• Oral formulations of buprenorphine, with their differential opioid receptor binding and clinical effects have the potential to be a drug of choice in opioid rotation regimens in patients with suboptimal efficacy and/or safety on other orally available opioids (e.g., oxycodone, morphine, oxymorphone, hydrocodone), thereby providing an effective strategic intervention for such patients (Hagen and Babul, Cancer 1997;79: 1428-37).
• opioids e.g., oxycodone, morphine, oxymorphone, hydrocodone
• Two transdermal formulations of buprenorphine have been commercialized in some countries, including the U.K., for the treatment of pain.
• One formulation is designed for application to the skin about twice a week (Transtec ® ) and another formulation is designed for administration once-a-week (BuTrans ® ).
• Major disadvantages with transdermal administration of buprenorphine include but are not limited to: (i) cost of goods; (ii) wide inter-and intra-individual variability if rate and extent of absorption; (iii) delay with onset of clinically meaningful therapeutic effect; (iv) poor skin adhesion over sweaty and hairy skin and in tropical climatic zones; (v) cutaneous adverse reactions to buprenorphine and/or its adhesives and other excipients; (vi) reduce flexibility in dose titration in relation to changing clinical status; (vii) the potential for variable absorption in the presence of pronounced fever; (viii) formation of a skin depot of buprenorphine, despite removal of the patch; and (ix) poor adhesion during vigorous physical activity, bathing or water sports .
• Addicts and recreational drug also abuse of transdermal opioids through tampering and extraction of drug for subsequent oral ingestion, snorting, inhalation or intravenous injection.
• Such tampering has been known to include extraction of the active substance from the transdermal reservoir or matrix by needle aspiration, oral ingestion of the active substance from the transdermal system, and solvent extraction of the active substance from the transdermal system.
• Transdermal buprenorphine dosage forms are not yet available in the USA; therefore it is difficult to fully predict their likely patterns of abuse.
• transdermal forms of the opioid fentanyl have been widely available in the USA for a considerable period of time.
• Transdermal fentanyl has been an important addition to the therapeutic armamentarium for the treatment of pain.
• fentanyl patch has involved a variety of methods including steeping the patch in hot water ("fentanyl tea bag”); inhalation of patch contents; solvent extraction, followed by intravenous use; needle aspiration, followed by intravenous use; mechanical extraction, followed by intravenous use; solvent extraction, followed by oral, mL;, nasal and inhalation use; mechanical extraction, followed by oral, mL;, nasal and inhalation use; transdermal application of the contents of the tampered patch; combustion of the patch, followed by inhalation; and a combination of the above methods.
• the dosage form of the invention also provides pharmaceutical compositions and methods to improve treatment compliance and to deter episodic, occasional, or intermittent use in subjects requiring chronic buprenorphine therapy around the clock or on a time contingent basis by rendering the dosage form therapeutically ineffective or suboptimally effective when taken episodically, intermittently, or occasionally.
• the dosage form of the invention also provides pharmaceutical compositions and methods to deter the abuse and misuse of the dosage form by recreational drug users of opioids and opioid addicts by rendering the dosage form devoid of or substantially devoid of euphoria, pleasurable, drug liking or other mood alerting effects when taken on an as needed basis.
• the oral route of administration i.e., oral ingestion
• oral ingestion is the most widely used and most widely preferred method of drug administration. It is simple, reliable and readily accessible. Under most conditions of use, particularly outside the hospital setting, it is the recommended method of drug administration. Even in settings of skilled nursing care, where there are technical and human resources to initiate and manage parenteral therapy, the goal is to rapidly transition patients from parenteral medications to oral medications.
• Some generally cited exceptions to the use of the oral route include: (i) drugs with poor oral bioavailability; (ii) drugs requiring a rapid onset of effect; (iii) where venous access already exists (e.g., in the peri-operative or intensive care setting); (iii) where the oral route provides unreliable or inconsistent clinical effects.
• buprenorphine can provide acceptable pharmacokinetics, pharmacodynamics, clinical efficacy and safety.
• Administration of buprenorphine by the oral route provides significantly greater flexibility in dosage form design, clinical utility and patient acceptability.
• buprenorphine is classified as a Schedule III drug.
• Schedule III drugs have lower potential for abuse than the drugs in Schedules I and II (e.g., fentanyl, codeine, hydrocodone, hydromorphone, methadone, meperidine, morphine, oxycodone, and oxymorphone).
• sustained release drugs are the standard of care for the management of many chronic conditions and sustained release opioids are the standard of care for the management of chronic pain
• an orally effective buprenorphine with its reduced abuse potential compared with Schedule II opioids, has the potential to provide fewer interruptions in sleep, reduced dependence on caregivers, improved compliance, enhanced quality of life outcomes, and increased control over the management of their pain.
• such formulations can provide more constant plasma concentrations and clinical effects, less frequent peak to trough fluctuations and fewer side effects, compared with sublingual buprenorphine.
• oral sustained release buprenorphine can provide similar attributes as seen in patients with pain and has the potential to become the standard of care.
• oral immediate and sustained release buprenorphine may be associated with reduced peak to trough fluctuation in concentrations and clinical effects, such as drug craving.
• dosage forms have a reduced potential for abuse and diversion than sublingual formulations of buprenorphine which are designed to rapidly dissolve in the oral cavity, thereby reducing subsequent intravenous, intranasal and inhalational abuse.
• the stability of the active drug in the acidic media of the stomach is important. Furthermore, impurities produced through degradation of the drug substance can have adverse safety consequences. Since the safety (e.g. toxicology, mutagenicity and carcinogenicity) of almost all impurities are not evaluated during drug development, regulatory authorities put strict limits on individual and total impurities, on the assumption that lesser (and fewer) the impurities, the lower the potential risk to patients. Buprenorphine has been found to degrade upon stress degradation in acid and H 2 O 2 (oxidation), each producing impurities which are known to the applicant (oxidative stress) and impurities which are unknown to the applicant (oxidative stress and acid stressed).
• the applicant has found that the behavior of oral buprenorphine dosage forms incorporating certain widely used controlled release material shows unexpected deterioration in the dissolution rate of buprenorphine under acidic conditions (increase in release at pH 1.2), providing a rationale in some embodiments of the invention for protection of the dosage form from the acid media of the stomach and release from the dosage form at some point distal to the stomach.
• sublingual buprenorphine has primarily been evaluated in opioid tolerant and opioid dependent subjects. In such subjects, the incidence of opioid related side effects is known to be much lower than in subjects who are opioid naive or who are not opioid tolerant. Despite this, sublingual buprenorphine can produce side effects in opioid tolerant and opioid dependent patients, including nausea, vomiting, constipation, and cognitive impairment. In non-addicts receiving opioids under the care of physicians highly experienced in pain management in the controlled setting of an analgesic clinical trial (where treatment dropout rates should be low), approximately 20 to 40% of subjects discontinue treatment within a few days to a few weeks of initiation due to side effects.
• opioid side effects are a substantial deterrent to initiating opioid therapy and they add to patient suffering and the cost of therapy (e.g., drugs to treat the side effects, additional physician visits, etc).
• drugs to treat the side effects, additional physician visits, etc e.g., drugs to treat the side effects, additional physician visits, etc.
• Buprenorphine has a long elimination half-life, particularly when measured using optimized venous sampling times and sensitive bioanalytical methods. According to the prescribing information for sublingual buprenorphine (Suboxone ® and Subutex ® ), "bupreno ⁇ hine has a mean elimination half-life from plasma of 37 h". The elimination half- life of its principal metabolite, norbuprenorphine, is even longer, at approximately 57 hours (Kuhlman et al, Addiction 1998; 93:549-559). In addition, buprenorphine has a high affinity and slow dissociation from the ⁇ -opioid receptor.
• a pharmaceutically acceptable dosage form of oral bupreno ⁇ hine for the treatment of bupreno ⁇ hine responsive conditions, including pain and opioid addiction disorders beyond its now discovered short duration of action at a controlled rate over an extended period of time appears to be lacking in the pharmaceutical and medical arts.
• the need exists to provide a novel therapeutic composition comprising oral buprenorphine, the need exists to provide a novel dosage form comprising oral buprenorphine, and the need to provide a novel method of administering buprenorphine to a patient in need of buprenorphine therapy.
• the invention provides an oral, relatively easy mode and manner of buprenorphine administration in comparison with sublingual, transdermal, intranasal and parenteral administration.
• a widely used commercially available sublingual formulation of contains buprenorphine in combination with naloxone in an optimized ratio of 4 parts buprenorphine base to 1 part naloxone base (Suboxone ® ). Contrary to this ratio, in some embodiments, the orally administered buprenorphine pharmaceutical compositions of the invention are optimized with a significantly lower amount of naloxone base relative to buprenorphine base to provide an optimal balance of efficacy and safety and abuse deterrence.
• the present invention is directed at oral buprenorphine pharmaceutical compositions and methods for the treatment of pain, addiction disorders, dyspnea and cough. [90] The present invention is also directed at oral pharmaceutical compositions of buprenorphine and their use for the treatment of other buprenorphine or opioid responsive medical conditions. [91] In some preferred embodiments, the oral pharmaceutical compositions of the invention are delayed onset dosage forms of buprenorphine. [92] In some preferred embodiments, the oral pharmaceutical compositions of the invention are modified release (e.g., controlled release, delayed onset, extended release, sustained release, slow release) dosage forms of buprenorphine.
• the oral pharmaceutical compositions of the invention are delayed onset, rapid release dosage forms of buprenorphine.
• the oral pharmaceutical compositions of the invention are delayed onset, extended release dosage forms of buprenorphine.
• the oral pharmaceutical compositions of the invention are delayed onset, pulsatile release dosage forms of buprenorphine.
• the oral pharmaceutical compositions of the invention are delayed onset, rapid release; delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; or jejunal release; or ileal release; or ileo-colonic release; or colonic release.
• the oral pharmaceutical compositions of the invention comprise immediate release buprenorphine.
• the present invention also provides advantages in that equivalent, or higher doses of buprenorphine may be used with better efficacy and/or fewer side effects observed than with sublingual formulations.
• oral buprenorphine formulations of the present invention may include the same amount or up to 5-fold higher daily maximum doses of sublingual buprenorphine. However, even with these higher doses, formulations of the present invention achieve better efficacy and fewer side effects.
• the present invention is directed at oral pharmaceutical composition for the treatment of pain, opioid dependence, addiction disorders and other buprenorphine and opioid responsive medical conditions comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine, or a mixture thereof, said dosage form not intended to provide significant oro-mucosal, lingual, sublingual or buccal absorption, said dosage form not intended for oro-mucosal, lingual, sublingual or buccal administration.
• the present invention is directed at oral pharmaceutical compositions of buprenorphine which are stable without the need to incorporate antioxidants or chelating agents into the dosage form to provide stability to the buprenorphine API.
• the present invention is directed at oral pharmaceutical compositions of buprenorphine which are stable without the need for antioxidants or chelating agents in direct or substantial contact with the buprenorphine API.
• the present invention is directed at pharmaceutical compositions of buprenorphine which are pharmaceutically and therapeutically robust when given orally and which release the buprenorphine distal to the stomach, duodenum, jejunum or ileum.
• oral administration of buprenorphine in a dosage form that provides controlled release; or extended release; or sustained release; or modified release; or delayed onset, rapid release; or delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; or jejunal release; or ileal release; or ileo-colonic release; or colonic release of buprenorphine provides a significantly more robust therapeutic effects than following oral immediate release dosage forms.
• oral dosage forms of the invention provide robust stability without the need for anti-oxidants or chelating agents to stabilize the buprenorphine.
• oral dosage forms of the invention that provide controlled release; extended release; sustained release; modified release; delayed onset, rapid release; delayed onset, extended release; delayed onset, pulsatile release; duodenal release; jejunal release; ileal release; ileo-colonic release; or colonic release of buprenorphine are highly stable without the need for anti-oxidants or chelating agents to stabilize the buprenorphine.
• buprenorphine has a long elimination half-life, and high affinity and slow dissociation from the ⁇ -opioid receptor which provide good therapeutic outcomes when given once-a-day, once every two days and thrice weekly in immediate release form by the sublingual route
• oral administration of an immediate release form of buprenorphine unexpectedly provides a duration of therapeutic effect less than about 24 hours, or less than about 18 hours, or less than about 16 hours, or less than about 14 hours, or less than about 12 hours, or less than about 9 hours, or less than about 8 hours, or less than about 7 hours, or less than about 6 hours.
• such an unexpectedly short duration of provides a basis for a controlled release, delayed onset, extended release, or delayed onset, pulsatile release, buprenorphine oral dosage form of the invention and methods for the treatment of pain, opioid dependence, addiction disorders, cough, dyspnea and other buprenorphine responsive medical conditions which result in a prolonged duration (e.g., equal to or more than about 6, 7, 8, 9, 10, 12, 14, 16, 18 or 22, 23 or 24 hours) of therapeutic effect (e.g., pain relief).
• a prolonged duration e.g., equal to or more than about 6, 7, 8, 9, 10, 12, 14, 16, 18 or 22, 23 or 24 hours
• therapeutic effect e.g., pain relief
• the controlled release, delayed onset, extended release, or delayed onset, pulsatile release duodenal release, jejunal release, ileal release, ileo-colonic release or colonic release buprenorphine oral dosage form of the invention provide a sufficiently prolonged duration of therapeutic effect so that it may be administered about every 36 hours, or about every 48 hours or about every 60 hours, or about every 72 hours or about every 84 hours.
• the oral pharmaceutical compositions of the invention provide greater dose proportional bioavailability over a 2, 3, 4, 5, 6, 7, 8, 9, 10 and 15-fold dose range than sublingual or nasal formulations of buprenorphine.
• the commercially available sublingual formulation of buprenorphine in combination with naloxone contain an optimized ratio of 4 parts buprenorphine base to 1 part naloxone base (Suboxone ® )
• the dosage form of the invention is optimized with a lower amount of naloxone base relative to buprenorphine base to provide an optimal balance of efficacy, safety and abuse deterrence (e.g., well tolerated when taken orally as prescribed, and aversive when abused without placing the illicit drug user at serious risk).
• the ratio of buprenorphine to naloxone in the oral dosage form of the invention i.e., lower amount of naloxone base relative to buprenorphine base
• the ratio of buprenorphine to naloxone in the oral dosage form of the invention i.e., lower amount of naloxone base relative to buprenorphine base
• efficacy can be improved (e.g., reduced potential for pain and positive urine samples for illicit drugs)
• pharmacokinetics and absorption profile of buprenorphine can be improved (e.g., reduced hypermotility and more reproducible gastrointestinal transit time), particularly for dosage forms of the invention which are controlled release; delayed onset, rapid release; delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; r jejunal release; or ileal release; or ileo-colonic release; or colonic release).
• the ratio of buprenorphine base to naloxone base is more than about: 6:1, 7:1, 8:1, 9:1, 10: 1, 12: 1, 14:1, 16:1, 18: 1, 20:1, 22:1, 24: 1, 26:1, 28:1, or 30:1.
• the ratio of naloxone may be replaced with naltrexone, and the buprenorphine base to naltrexone base ratio is more than about: 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 12: 1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, 30:1; 35:1; 40:1; 45:1 50:1 ; 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85: 1 or 90:1.
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naloxone, where the ratio of systemic exposure to naloxone as measured by the area under the plasma naloxone concentration-time curve from time 0 to 48 hours or 0 to infinity (AUC 0-48 or AUC 0- i nf ) after single dose administration of lingual, sublingual or buccal buprenorphine to the oral buprenorphine dosage form of the invention is at least about 2:1, 3: 1, 4;1, 5: 1, 6: 1, 7:1, 8: 1, 9: 1, 10:1, 12:1, 14: 1, 16:1, 18:1, 20:1, 22:1, 24: 1, 26:1, 28:1, or 30: 1, after the same amount of naloxone is administered.
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naloxone, where the ratio of systemic exposure to naloxone as measured by the area under the plasma naloxone concentration-time curve from time 0 to 48 hours or 0 to infinity (AUQM 8 or AUCo-i nf ) after single dose administration of lingual, sublingual or buccal naltrexone to the oral buprenorphine dosage form of the invention comprising naloxone is at least about 2: 1, 3:1, 4;1, 5: 1, 6:1, 7:1, 8: 1, 9:1, 10: 1, 12:1, 14:1, 16:1, 18:1, 20:1, 22: 1, 24:1, 26:1, 28:1, or 30:1, after the same amount of naloxone is administered.
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naltrexone, where the ratio of systemic exposure to naltrexone as measured by the area under the plasma naloxone concentration-time curve from time 0 to 48 hours or 0 to infinity (AUCo -48 or AUCo-i nf ) after single dose administration of lingual, sublingual or buccal buprenorphine comprising naltrexone to the oral buprenorphine dosage form of the invention comprising naltrexone is at least about 2: 1, 3:1, 4;1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, or 30:1, after the same amount of naltrexone is administered.
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naltrexone, where the ratio of systemic exposure to naltrexone as measured by the area under the plasma naloxone concentration-time curve from time 0 to 48 hours or 0 to infinity (AUCo -48 or AUCo-i nf ) after single dose administration of lingual, sublingual or buccal naltrexone to the oral buprenorphine dosage form of the invention comprising naltrexone is at least about 2:1, 3:1, 4;1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12: 1, 14: 1, 16:1, 18: 1, 20: 1, 22:1, 24:1, 26:1, 28:1, or 30:1, after the same amount of naltrexone is administered.
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naloxone, where the ratio of peak plasma naloxone concentration (C max ) after single dose administration of lingual, sublingual or buccal buprenorphine to the oral buprenorphine dosage form of the invention is at least about 2:1, 3: 1, 4;1, 5:1, 6: 1, 7:1, 8:1, 9: 1, 10: 1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24: 1, 26: 1, 28:1, or 30:1, after the same amount of naloxone is administered.
• C max peak plasma naloxone concentration
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naloxone, where the ratio of peak plasma naloxone concentration (C max ) after single dose administration of lingual, sublingual or buccal naltrexone to the oral buprenorphine dosage form of the invention comprising naloxone is at least about 2:1, 3:1, 4;1, 5: 1, 6:1, 7: 1, 8:1, 9:1, 10:1, 12: 1, 14: 1, 16: 1, 18: 1, 20:1, 22: 1, 24: 1, 26: 1, 28: 1, or 30: 1, after the same amount of naloxone is administered.
• C max peak plasma naloxone concentration
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naltrexone, where the ratio of peak plasma naltrexone concentration (C max ) after single dose administration of lingual, subungual or buccal buprenorphine comprising naltrexone to the oral buprenorphine dosage form of the invention comprising naltrexone is at least about 2:1, 3: 1, 4;1, 5:1, 6:1, 7: 1, 8: 1, 9: 1, 10: 1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, or 30:1, after the same amount of naltrexone is administered.
• C max peak plasma naltrexone concentration
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naltrexone, where the ratio of peak plasma naltrexone concentration (C max ) after single dose administration of lingual, sublingual or buccal naltrexone to the oral buprenorphine dosage form of the invention comprising naltrexone is at least about 2:1, 3:1, 4;1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 12:1, 14:1, 16:1, 18:1, 20:1, 22:1, 24:1, 26:1, 28:1, or 30:1, after the same amount of naltrexone is administered.
• C max peak plasma naltrexone concentration
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naloxone, where the systemic exposure to naloxone as measured by the area under the plasma naloxone concentration-time curve from time 0 to 48 hours or 0 to infinity (AUCo -48 or AUCo- mf ) after single dose administration, for each mg of naloxone in the oral dosage form, is less than about: 400 pg.hr/mL, 350 pg.hr/mL, 300 pg.hr/mL, 250 pg.hr/mL, 200 pg.hr/mL, or 150 pg.hr/mL, or 100 pg.hr/mL, 75 pg.hr/mL, or 50 pg.hr/mL, or 40 pg.hr/mL, or 30 pg.hr/mL, or 25 pg.hr/mL, or 20
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naltrexone, where the systemic exposure to naltrexone as measured by the area under the plasma naltrexone concentration-time curve from time 0 to 48 hours or 0 to infinity (AUCo -48 or AUCo-inf) after single dose administration, for each mg of naltrexone in the oral dosage form, is less than about: 400 pg.hr/mL, 350 pg.hr/mL, 300 pg.hr/mL, 250 pg.hr/mL, 200 pg.hr/mL, or 150 pg.hr/mL, or 100 pg.hr/mL, 75 pg.hr/mL, or 50 pg.hr/mL, or 40 pg.hr/mL, or 30 pg.hr/mL, or 25 pg.hr/mL,
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naloxone, where the peak plasma naloxone concentration (C max ) after single dose administration, for each mg of naloxone in the oral dosage form, is less than about: 80 pg/mL, 70 pg/mL, 60 pg/mL, 50 pg/mL, 40 pg/mL, or 30 pg/mL, or 20 pg/mL, 10 pg/mL, or 8 pg/mL, or 6 pg/mL, or 5 pg/mL, or 3 pg/mL, or 2 pg/mL, or 1 pg/mL.
• C max peak plasma naloxone concentration
• the present invention is directed to oral pharmaceutical compositions of buprenorphine comprising naltrexone, where the peak plasma naltrexone concentration (Cm 3x ) after single dose administration, for each mg of naltrexone in the oral dosage form, is less than about: 80 pg/mL, 70 pg/mL, 60 pg/mL, 50 pg/mL, 40 pg/mL, or 30 pg/mL, or 20 pg/mL, 10 pg/mL, or 8 pg/mL, or 6 pg/mL, or 5 pg/mL, or 3 pg/mL, or 2 pg/mL, or 1 pg/mL.
• the oral buprenorphine dosage forms of the invention comprising naloxone or naltrexone in the amounts, ratios or exposure level in the specifications are therapeutically effective and without unacceptable side effects in most or substantially all subjects taking it as medically prescribed
• the oral buprenorphine dosage form of the invention comprises naltrexone or naloxone, said dosage having a buprenorphine base to naltrexone base or naloxone base ratio of more than about: 6:1 to about 12:1.
• the oral buprenorphine dosage form of the invention comprises naltrexone or naloxone, said dosage form providing an AUC 0-48 or AUCo- inf after single dose administration, for each mg of naltrexone base or naloxone base in the oral dosage form of less than about 300 pg.hr/mL or less than about 100 pg.hr/mL.
• the oral buprenorphine dosage form of the invention comprises naltrexone or naloxone, said dosage form providing a naltrexone or naloxone Cmax after single dose administration for each mg of naltrexone base or naloxone base in the oral dosage of less than about 50 pg/mL or less than about 10 pg/mL.
• the oral buprenorphine dosage forms of the invention comprising naloxone or naltrexone in the amounts, ratios or exposure level in the specifications are abuse deterrent in some, most, substantially all or all recreational opioid users and opioid abusers when the dosage form is tampered with and the contents (buprenorphine plus naloxone or buprenorphine plus naltrexone) are injected.
• the invention provides an oral dosage form for the treatment of buprenorphine responsive conditions requiring chronic buprenorphine therapy which is designed to improve treatment compliance and deter episodic, occasional, intermittent, periodic, as needed, or PRN use of the dosage form by rendering the dosage form therapeutically ineffective or suboptimally effective when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release when given orally.
• the invention provides an oral dosage form for the treatment of buprenorphine responsive conditions requiring around the clock or time contingent buprenorphine therapy which is designed to improve treatment compliance and deter episodic, occasional, intermittent, periodic, as needed, or PRN use of the dosage form by rendering the dosage form therapeutically ineffective or suboptimally effective when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release when given orally.
• the invention provides an oral dosage form of buprenorphine which is therapeutically effective but which deters the abuse and misuse of the dosage form by rendering the dosage devoid of or substantially devoid of euphoria, pleasurable effects, drug liking and mood alerting effects when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release when given orally.
• the invention provides an oral dosage form of buprenorphine which is therapeutically effective but which deters the abuse and misuse of the dosage form by delaying or substantially delaying euphoria, pleasurable effects, drug liking and mood alerting effects when taken regularly or when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release when given orally.
• the invention provides a method of improving treatment compliance and deterring episodic, occasional, intermittent, periodic, as needed, or PRN use of the dosage form in subjects requiring around the clock, scheduled or time contingent oral buprenorphine therapy by rendering the dosage form therapeutically ineffective or suboptimally effective when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form therapeutically effective in a substantial number of subjects when taken around the clock, on scheduled basis or on time contingent basis, comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release when given orally.
• the invention provides a method of improving treatment compliance and deterring episodic, occasional, intermittent, periodic, as needed, or PRN use of the dosage form in subjects requiring chronic or prolonged oral buprenorphine therapy by rendering the dosage form therapeutically ineffective or suboptimally effective when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form therapeutically effective in a substantial number of subjects when taken around the clock, on scheduled basis or on time contingent basis, comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release when given orally.
• the invention provides a method of deterring abuse and misuse of oral buprenorphine by rendering the dosage form devoid of or substantially devoid of euphoria, pleasurable effects, drug liking and mood alerting effects when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release when given orally.
• the invention provides a method of deterring abuse and misuse of oral buprenorphine by delaying or substantially delaying or reducing euphoria, pleasurable effects, drug liking and mood alerting effects when taken regularly or when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release when given orally.
• the invention provides an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release, said dosage form providing less side effects than sublingual buprenorphine, said side effects measured after single dose administration to opioid naive subjects.
• the invention provides an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release, said dosage form providing less side effects than oral immediate release buprenorphine, said side effects measured after single dose administration to opioid naive subjects.
• the invention provides a method for reducing side effects, comprising administering an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing less side effects than sublingual buprenorphine, said side effects measured after single dose administration to opioid naive subjects.
• the invention provides a method for reducing side effects, comprising administering an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing less side effects than oral immediate release buprenorphine, said side effects measured after single dose administration to opioid naive subjects.
• the present invention is directed to oral pharmaceutical compositions of buprenorphine which provide one or more of the following (i) efficacy or improved efficacy by the oral route; (ii) improved safety by the oral route; (iii) improved efficiency of the dosage form; (iv) improved dose proportional extent of absorption; (v) reduced variability in absorption; and (vi) reduced potential for misuse, abuse, addiction and drug diversion.
• the pharmaceutical compositions and methods of the invention achieve their objectives at least in part through delivery of some, most, substantially all or all of the drug into the lower segments of the gastrointestinal tract (e.g., delayed onset, rapid release; or delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; or jejunal release; or ileal release; or ileo-colonic release; or colonic release) through time-controlled, pH-controlled, pressure- controlled, enzyme-controlled and hydration controlled.
• some, most, substantially all or all of the drug e.g., delayed onset, rapid release; or delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; or jejunal release; or ileal release; or ileo-colonic release; or colonic release
• the oral pharmaceutical compositions of buprenorphine of the present invention improve the clinical efficacy, safety, tolerability, abuse resistance, improved dose proportional extent of absorption, predictability of clinical response, reproducibility of clinical response, efficiency, and/or pharmacokinetics, said effect achieved through targeted gastrointestinal delivery, availability, release, disintegration, dissolution, metabolism and/or absorption, said targeted delivery achieved at least in part through delivery of some, most, substantially all or all of the drug in lower segments of the gastrointestinal tract (e.g., delayed onset, rapid release; or delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; or jejunal release; or ileal release; or ileo-colonic release; or colonic release) by incorporation of materials into the dosage form to provide time-controlled, diffusion- controlled pH-controlled, pressure-controlled, osmotic pressure controlled and/or enzyme controlled delivery or release.
• the oral controlled release; or delayed onset, rapid release; or delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; or jejunal release; or ileal release; or ileo-colonic release; or colonic release pharmaceutical compositions of buprenorphine result in one or more or all of the following benefits or characteristics when given at equal doses compared with immediate release oral dosage forms: increased dose proportional extent of absorption; increased peak concentration (C max ); increased time to peak concentration (t max ); reduced variability in extent of absorption (% coefficient of variation for AUCo-i nf or AUCo-O; reduced apparent oral clearance; lower norbuprenorphine to buprenorpbine AUCo-i nf ratio; improved clinical efficacy; improved safety; reduced side effects 0.5, 1, 2, 3, 4 5, 6, 7 and/or 8 hours after oral ingestion of the dose; reduced abuse potential in drug abusers and recreational drug users; reduced abuse potential in subjects using the drug in accordance with
• the oral controlled release; or delayed onset, rapid release; or delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; or jejunal release; or ileal release; or ileo-colonic release; or colonic release pharmaceutical compositions of buprenorphine start to liberate or deliver some, a lot, most, substantially all or all of the buprenorphine in the dosage form upon reaching the duodenum, terminal ileum, ileo-cecal junction, ascending colon, transverse colon or descending colon.
• compositions containing buprenorphine have been abused in a variety of settings, including: (i) patients with an addiction disorder who are prescribed buprenorphine for opioid maintenance therapy but who are using it in excess doses or by an unapproved route; (ii) patients with an addiction disorder who obtain it from illicit sources; (iii) patients with pain who have a pre-existing addiction disorder; (iv) patients with pain who have developed an addiction disorder following initiation of buprenorphine or opioid therapy; (v) recreational drug users.
• Abused opioid analgesics may be ingested whole, crushed and ingested, crushed or vaporized and snorted or injected intravenously after attempted extraction of the active pharmaceutical ingredient.
• the manipulation of pharmaceutical dosage forms of opioids has been documented for many decades. For instance, pentazocine (Talwin ® ), a synthetic opioid was crushed, extracted and injected intravenously by drug addicts.
• the abuse of pharmaceutical grade opioids in finished dosage forms is in its intact form (i.e., the dosage form has not been physically manipulated or tampered with to alter its absorption profile) and taken by the usual route of administration for that dosage form.
• many recreational drug users and patients with an addiction disorder will not use an abusable drug intended to be taken by the oral route by any other route (e.g., intravenously after extraction and filtration, or by inhalation), nor will they physically manipulate or tamper the dosage form prior to oral ingestion, in order to "distinguish” themselves and their use from "junkies' and "real addicts”.
• opioid abuse by the oral route involves immediate release drugs (i.e., drugs that have not been designed with material to delay the liberation and absorption of the opioid from the dosage form) or drugs in which such material has been tampered.
• immediate release opioids generally provide meaningful plasma concentrations, an onset of therapeutic effect (e.g., pain relief or blunting of opioid withdrawal symptoms), and in the case of use by recreational drug users or addicts, an onset of euphoric or psychic within about 15 to about 180 minutes or within about 15 to about 120 minutes or within about 15 to about 90 minutes.
• opioid produce perceptible or meaningful euphoric or psychic effects soon after administration, usually within about 15 to about 180 minutes or within about 15 to about 120 minutes or within about 15 to about 90 minutes, even when taken in an untampered form.
• Extended release opioids generally provide peak plasma concentrations soon after ingestion, for example, approximately 1.5 hours after MS Contin ® and approximately 2 to 3 hours after OxyContin . Although their peak plasma concentration is generally somewhat later than oral immediate release opioid analgesics, the 12 or 24-hour supply of opioid contained in one tablet or capsule, means that their plasma concentration after ingestion is generally similar to that provided by a 4 to 6 hourly dose of an immediate release formulation. Other extended release opioids with delayed time to peak concentrations continue to provide meaningful plasma concentrations soon aftre ingestion, even if the maximum concentration is delayed.
• the dosage form of the invention will provide discernible euphoric or psychic effects at a later time by delaying the time to attainment of pharmacologically discernible or meaningful plasma concentrations or by providing a lower C max and/or later t max than oral, immediate release dosage forms containing the same drug and oral, extended release dosage forms containing the same drug. Consequently, in some embodiments, the dosage forms of the invention will have a lower propensity for abuse and misuse.
• the buprenorphine dosage forms of the invention have a reduced potential for abuse and misuse, including: (a) drug abuse in individuals with a history of drug abuse or recreational drug use; (b) drug abuse in individuals with no prior history of drug abuse or recreational drug use; (c) iatrogenic addiction, euphoria, or pleasurable effects in individuals who take the dosage form in accordance with the instructions of the clinician, approved prescribing information or approved package insert; (d) drug diversion; (e) pharmaceutical company liability; (f) pharmacy break-ins, prescription forgeries, doctor shopping; (g) illicit (street) availability and price; and/or (g) mood altering effects, said reduced potential abuse and misuse resulting in some embodiments at least in part from introducing a substantial lag period between oral ingestion of the buprenorphine and the appearance of detectable plasma concentrations, or clinically meaningful plasma concentrations, or pharmacologically meaningful plasma concentrations; or pharmacologically discernible plasma concentrations, or plasma concentrations associated
• the present invention is directed to oral dosage forms of buprenorphine for the treatment of buprenorphine responsive conditions requiring chronic buprenorphine therapy
• the dosage form is designed to improve treatment compliance and deter episodic, occasional, intermittent, periodic, as needed, or PRN use by rendering the dosage form therapeutically ineffective or suboptimally effective when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorpbine release.
• said dosage form improves compliance or deters episodic, occasional, intermittent, periodic, as needed, or PRN use by more than about 1%, or 2%, or 3%, or 5%, or 7%, or 10%, or 12%, or 15%, or 18%, or 20%, or 25%, or 30%, or 35%, or 40%, or 50%, or 60%, or 70%, or 100%.
• the present invention is directed to oral dosage forms of buprenorphine for the treatment of buprenorphine responsive conditions around the clock or time contingent buprenorphine therapy
• the dosage form is designed to improve treatment compliance and deter episodic, occasional, intermittent, periodic, as needed, or PRN use by rendering the dosage form therapeutically ineffective or suboptimally effective when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release.
• said dosage form improves compliance or deters episodic, occasional, intermittent, periodic, as needed, or PRN use by more than about 1%, or 2%, or 3%, or 5%, or 7%, or 10%, or 12%, or 15%, or 18%, or 20%, or 25%, or 30%, or 35%, or 40%, or 50%, or 60%, or 70%, or 100%.
• the present invention is directed at oral buprenorphine dosage forms which are therapeutically effective but which deter the abuse and misuse of the dosage form by recreational drug users of opioids and opioid addicts by rendering the dosage devoid of or substantially devoid of euphoria, pleasurable, drug liking or other mood alerting effects when taken episodically, intermittently, occasionally, periodically, on an as needed basis, or PRN, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release.
• said dosage form reduces euphoria, pleasurable, drug liking or other mood alerting effects by more than about 1%, or 2%, or 3%, or 5%, or 7%, or 10%, or 12%, or 15%, or 18%, or 20%, or 25%, or 30%, or 35%, or 40%, or 50%, or 60%, or 70%, or 100%.
• the present invention is directed at oral buprenorphine dosage forms which are therapeutically effective but which deter the abuse and misuse of the dosage form by recreational drug users of opioids and opioid addicts by rendering the dosage devoid of or substantially devoid of the instant gratification from euphoria, pleasurable, drug liking or other mood alerting effects sought by recreational drug users of opioids and opioid addicts, said dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release.
• said dosage form reduces the instant gratification from euphoria, pleasurable, drug liking or other mood alerting effects by more than about 1%, or 2%, or 3%, or 5%, or 7%, or 10%, or 12%, or 15%, or 18%, or 20%, or 25%, or 30%, or 35%, or 40%, or 50%, or 60%, or 70%, or 100%.
• the orally administered buprenorphine dosage forms of the invention have a reduced potential for abuse and misuse, including frequency, duration or magnitude of euphoria, sedation, drug liking, fatigue, cognitive impairment, motor impairment and CNS impairment.
• the orally administered buprenorphine dosage forms of the invention have a reduced street value, or a reduced frequency, duration or magnitude of sedation, drug liking fatigue, cognitive impairment, motor impairment and CNS impairment when assessed 0.5, or 1, or 1.5, or 2, or 2.5 or 3, or 4, or 5 or 6, or 7 or 8 hours after ingestion of the initial dose, or a subsequent dose by recreational drug users, drug addicts, or opioid naive healthy subjects.
• the orally administered buprenorphine dosage forms of the invention have a reduced street value, or a reduced frequency, duration or magnitude of nausea, vomiting, sedation, drug liking fatigue, cognitive impairment, motor impairment, CNS impairment and other side effects, when assessed 0.5, or 1, or 1.5, or 2, or 2.5 or 3, or 4, or 5 or 6, or 7 or 8 hours after ingestion of the initial dose, or a subsequent dose by recreational drug users, drug addicts, or opioid naive healthy subjects, when compared with the an oral immediate release solid or solution dosage form of buprenorphine, or a sublingual (or buccal or mucoretentive) dosage form, or an oral extended release dosage form of buprenorphine.
• said oral immediate release solid or solution dosage form or said sublingual (or buccal or mucoretentive) dosage form of buprenorphine is administered at about the same dose, or at ⁇ about 90%, or ⁇ about 80%, or ⁇ about 75%, at ⁇ about 70%, or ⁇ about 60%, or ⁇ about 50%, or ⁇ about 45%, or ⁇ about 40%, or ⁇ about 35%, at ⁇ about 30%, or ⁇ about 25%, or ⁇ about 20%, or ⁇ about 15% of the dose of orally administered buprenorphine of the invention.
• said minimal dose increase is required in less than 1%, 2%, 3%, 4%,.5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 18%, 20%, 25%, 30%, 35%, or 40%, or 50% of subjects.
• This is in sharp contrast to other opioids, including other controlled release or extended release opioids for the treatment of chronic condition which require lower initial doses to attain an optimal balance between therapeutic outcome (e.g., pain relief) and side effects, and gradual dose increases after the subject has developed improved tolerability to the opioid.
• self-titrating means that following first administration (or following initiation of therapy) at the recommended or approved starting dose, or the recommended or approved usual dose, the oral dosage form of the invention requires minimal or no dose increases or upward dose adjustments over the first few days, first few weeks or first few months of treatment for a chronic condition.
• no dose increase is required during the first month of treatment in about 90% of the subjects.
• less than 1 in 100, or less than 1 in 70, or less than 1 in 50, or less than 1 in 40, or less than 1 in 30, or less than 1 in 20, or less than 1 in 15, or less than 1 in 12 or, less than 1 in 10, or less than 1 in 9, or less than 1 in 8, or less than 1 in 7, or less than 1 in 6, or less than 1 in 5, or less than 1 in 4 subjects requires a dose increase during the first month of treatment.
• the number of dose changes required to reach adequate or optimal therapeutic outcomes e.g., pain relief and tolerability of side effects
• oral buprenorphine dosage forms of the invention e.g., controlled release, extended release, sustained release, modified release, delayed onset, rapid release or delayed onset, extended release, or delayed onset, pulsatile release, duodenal release, jejunal release, ileal release, ileo- colonic release, or colonic release dosage forms
• the present invention discloses that the dose range required to control pain with oral buprenorphine dosage forms of the invention in about 90% of subjects is less than or substantially less than the 8-fold dose range required with morphine, thereby providing several potential benefits, including more efficient titration process (adjusting the subject's dosage to provide acceptable pain relief without unacceptable side effects), more therapeutically and cost efficient control of symptoms, faster control of symptoms, reduced cost of goods, reduced need for dose titration, reduced need for additional visits to the clinician, reduced need for a wider range of dosage strengths and reduced pharmacy inventory.
• the dose range of oral buprenorphine dosage forms of the invention is at least about 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70% or 75% less than oral morphine.
• the present invention discloses that the dose range required to control pain with oral buprenorphine dosage forms of the invention in about 90% of subjects is less than or substantially less than the 4-fold dose range required with oxycodone, thereby providing several potential benefits, including more efficient titration process (adjusting the subject's dosage to provide acceptable pain relief without unacceptable side effects), more therapeutically and cost efficient control of symptoms, faster control of symptoms, reduced cost of goods, reduced need for dose titration, reduced need for additional visits to the clinician, reduced need for a wider range of dosage strengths and reduced pharmacy inventory.
• the dose range of oral buprenorphine dosage forms of the invention is at least about 5%, 7%, 10%, 12%, 15%, 17%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% less than oral oxycodone.
• dose range required to control pain in about 90% of subjects with oral buprenorphine dosage forms of the invention is about 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold or 4 fold, or not more than about 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold or 4 fold.
• dose range required to control pain in about 90% of subjects with controlled release; or extended release; or sustained release; or modified release; or delayed onset, rapid release; or delayed onset, extended release; or delayed onset, pulsatile release dosage forms of oral buprenorphine is about 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold or 4 fold, or not more than about 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold or 4 fold.
• dose range required to control pain in about 90% of subjects with duodenal release, jejunal release, ileal release, ileo-colonic release, or colonic release dosage forms of oral buprenorphine is about 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold or 4 fold, or not more than about 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold or 4 fold.
• said delayed onset dosage form is limited to compositions that deliver or release drug distal to the jejunum (i.e., ileal release, ileo-colonic release or colonic release).
• oral buprenorphine daily dose range required to control pain in about 90% of subjects is 2.5 mg to 15 mg, or 2.5 mg to 12.5 mg, or 2.5 mg to 10 mg, or 5 mg to 30 mg, or 5 mg to 25 mg, or 5 mg to 20 mg, or 5 mg to 15 mg, or 7.5 mg to 25 mg, or 7.5 mg to 20 mg, or 7.5 mg to 15 mg, or 10 mg to 50 mg, or 10 mg to 40 mg, or 10 mg to 35 mg, or 10 mg to 30 mg, or 10 mg to 25 mg, or 10 mg to 20 mg.
• the oral buprenorphine daily dose range required to control pain in about 90% of subjects is 5 mg to 20 mg or 5 mg to 15 mg, or 10 mg to 40 mg or 10 mg to 30 mg.
• oral buprenorphine daily dose range required to control pain in about 90% of subjects in some embodiments of the invention is less than or substantially less than the 8-fold dose range seen with morphine which is the prototype opioid agonist
• some patients will require doses that exceed or far exceed the dose range required to control pain in a substantial majority of subjects (e.g., 5, 10, 15 or 20 fold higher than the dose range required to control pain in about 90% of subjects ), due to a variety of pharmacokinetic and pharmacodynamic factors known in the art.
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 60 pg/mL to about 1800 pg/ml after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 dosing intervals
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml from a mean of about 2.5 hours to about 5 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml measured from a mean of about 8 to about 15 hours after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 60
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 60 pg/mL to about 1800 pg/ml from a mean of about 2.5 hours to about 5 hours after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 dosing intervals
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 60 pg/mL to about 1800 pg/ml from a mean of about 2.5 hours to about 5 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml measured from a mean of about 8
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 single dosing interval
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml from a mean of about 3.5 hours to about 18 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml from a mean of about 20 to about 28 hours after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 60
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml from a mean of about 3.5 hours to about 18 hours after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 single dosing interval
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml from a mean of about 3.5 hours to about 18 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml from a mean of about 20 to about 28 hours after repeated oral administration every
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 30 pg/mL to about 2700 pg/ml after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 dosing intervals
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml from a mean of about 2.5 hours to about 5 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml measured from a mean of about 8 to about 15 hours after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 30 pg/mL to about 2700 pg/ml from a mean of about 2.5 hours to about 5 hours after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 dosing intervals
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 30 pg/mL to about 2700 pg/ml from a mean of about 2.5 hours to about 5 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml measured from a mean of about 8 to about
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 single dosing interval
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml from a mean of about 3.5 hours to about 18 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml from a mean of about 20 to about 28 hours after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml from a mean of about 3.5 hours to about 18 hours after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 single dosing interval
• the dosage form provides a method for reducing the range in daily dosages required to control pain in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml from a mean of about 3.5 hours to about 18 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml from a mean of about 20 to about 28 hours after repeated oral administration every 24 hours
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 60 pg/mL to about 1800 pg/ml after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 dosing intervals
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml from a mean of about 2.5 hours to about 5 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml measured from a mean of about 8 to about 15 hours after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 60 pg/mL to about 1800 pg/ml from a mean of about 2.5 hours to about 5 hours after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 dosing
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 60 pg/mL to about 1800 pg/ml from a mean of about 2.5 hours to about 5 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 p
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 single dosing interval
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml from a mean of about 3.5 hours to about 18 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml from a mean of about 20 to about 28 hours after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml from a mean of about 3.5 hours to about 18 hours after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 single dosing interval
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 10 mg to about 40 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 3200 pg.hr/mL to about 190,000 pg.hr/mL, a mean maximum plasma concentration of buprenorphine from about 60 pg/mL to about 1800 pg/ml from a mean of about 3.5 hours to about 18 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml from a mean
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 30 pg/mL to about 2700 pg/ml after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 dosing intervals
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml from a mean of about 2.5 hours to about 5 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml measured from a mean of about 8 to about 15 hours after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo- 24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 30 pg/mL to about 2700 pg/ml from a mean of about 2.5 hours to about 5 hours after repeated oral administration every 12 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo- 24 a dosing
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over two consecutive dosing intervals (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, a mean maximum plasma concentration of buprenorphine from the first of the two consecutive doses from about 30 pg/mL to about 2700 pg/ml from a mean of about 2.5 hours to about 5 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 single dosing interval
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml from a mean of about 3.5 hours to about 18 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml from a mean of about 20 to about 28 hours after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, and a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml from a mean of about 3.5 hours to about 18 hours after repeated oral administration every 24 hours to steady-state conditions, said dosage form providing extended release or delayed onset, extended release.
• AUCo -24 single dosing interval
• the dosage form provides a method for reducing the number of dose adjustments or dose titrations required to control pain over the first month of treatment in substantially all human patients, comprising administering a modified release oral buprenorphine comprising from about 5 mg to about 60 mg of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, which provides a mean a systemic exposure of buprenorphine as assessed by the mean buprenorphine area under the plasma concentration time curve over a single dosing interval (AUCo -24 ) from about 1600 pg.hr/mL to about 285,000 pg.hr/mL, a mean maximum plasma concentration of buprenorphine from about 30 pg/mL to about 2700 pg/ml from a mean of about 3.5 hours to about 18 hours, and a mean minimum plasma concentration of buprenorphine of about 30 pg/mL to about 900 pg/ml from a mean of
• the improved therapeutic effect will reduce the street supply of the drug for misuse, abuse and tampering (e.g., use of the oral dosage form by the intravenous, inhalational, intranasal after tampering the dosage form). Underscoring its concerns about drug abuse, recently, the U.S.
• a major challenge with the administration of more than one drug concurrently or in close proximity to each other is the occurrence of increased adverse effects from the combined and simultaneous high plasma concentrations of more than one drug producing the same or similar side effects through additive, super-additive or synergistic effects.
• buprenorphine may be used in conjunction with other drugs for the treatment of the same or different condition or side effect.
• Such other drugs can produce similar or the same side effects as buprenorphine, including sedation, nausea, vomiting, and fatigue.
• using an alternative concomitant drug is not a practical option.
• the present invention provides oral pharmaceutical compositions and methods to reduce the frequency, duration or magnitude of side effects from such concurrent, allowing for the advantageous use of drugs with similar or the same side effects as buprenorphine.
• Buprenorphine is widely believed by ineffective and inappropriate to give orally, resulting in the need to: (i) administer the opioid by the parenteral route, with all of its sterility, cost, route accessibility to patients, and technical challenges; (ii) administer the drug by the transdermal route, with all of its cost and technical challenges; (iii) administer a sublingual dosage form with its lack of dose proportional bioavailability, limited dose range and higher potential for tampering and abuse.
• the oral dosage from delivers most, substantially all or all of the buprenorphine into the lower segments of the gastrointestinal tract (e.g., delayed onset, rapid release; or delayed onset, extended release; or delayed onset, pulsatile release; or duodenal release; or jejunal release; or ileal release; or ileo-colonic release; or colonic release) and the dosage form is best suited under certain conditions for the treatment of signs and symptoms which do not require a rapid onset of effect from "one of, intermittent or episodic use of the dosage form or which are not administered as a single dose, or an intermittent dose or for episodic use.
• the dosage form of the present invention delivers most, substantially all or all of the buprenorphine into the lower segments of the gastrointestinal tract, it would usually be impractical to use the dosage form as a meaningful pharmacologic response may take unacceptably long to manifest itself. In some embodiments, this delay in onset of effect with single-doses, intermittent doses or episodic use contributes to providing a buprenorphine dosage form with lower abuse potential.
• the present invention makes it medically and pharmacologically feasible for the first time to administer buprenorphine by the oral route.
• the invention deals with this issue in the following way: (i) for oral buprenorphine formulations whose release is delayed but subsequently immediate upon arriving at the target site in the lower segments of the gastrointestinal tract, the current dose would provide a therapeutic effect until the next dose of the invention reaches the target site; (ii) for oral buprenorphine formulations whose release is delayed but when initiated it is subsequently further retarded at the target site(s) in the lower segments of the gastrointestinal tract (e.g., controlled release, extended release or sustained release), the current dose would provide a therapeutic effect until the next dose of the invention reaches the target site.
• the current dose would provide a therapeutic effect until the next dose of the invention reaches the target site.
• the only potential “therapeutic gap” of relates to the delay with therapeutic effect with the initial or first dose of the drug. This may be dealt with by using the dosage form of the drug in conventional or immediate release form on a one time basis, or by use of an alternate drug with the same or similar therapeutic effect or by limiting such dosage forms to individuals requiring repeated or multiple dose therapy, time contingent therapy, treatment lasting more than a few days, or chronic therapy, or by excluding individuals requiring single doses, rapid onset of effect with the initial dose, intermittent dosing, episodic dosing.
• This potential "therapeutic gap” also provides for some of the abuse deterrent properties of the invention.
• the dosage form of the invention is a modified release oral formulation which, after an initial in vivo lag period lasting at least about 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 or 12 hours during which there is little or no release of buprenorphine, rapidly releases (e.g., over a period of less than about 5, 10, 15, 30, or 45 minutes, or 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours) most, substantially all or all of the buprenorphine in vivo.
• the dosage form of the invention is a modified release oral formulation which, after an initial in vivo lag period lasting at least about 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 or 12 hours during which there is little or no release of buprenorphine, gradually or slowly releases (e.g., over a period of about 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28, 30, 36 or 40 hours) most, substantially all or all of the buprenorphine in vivo, said product characteristics observed after administration of some, most or substantially all or all doses.
• the dosage form of the invention is a modified release oral formulation which, after ingestion is characterized by little or no release of the buprenorphine in the stomach, said dosage form releases most, substantially all or all of the buprenorphine from the dosage form in the duodenum, jejunum, ileum and/or colon, over a period of less than about 5, 10, 15, 30, or 45 minutes, or 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours.
• the dosage form of the invention is a modified release oral formulation which, after ingestion is characterized by little or no release of the buprenorphine in the stomach or duodenum, said dosage form releases most, substantially all or all of the buprenorphine from the dosage form upon arrival in the jejunum, ileum and/or colon, over a period of less than about 5, 10, 15, 30, or 45 minutes, or 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours.
• the dosage form of the invention is a modified release oral formulation which, after ingestion is characterized by little or no release of the buprenorphine in the stomach, duodenum or jejunum, said dosage form releases most, substantially all or all of the buprenorphine from the dosage form upon arrival in the ileum and/or colon, over a period of less than about 5, 10, 15, 30, or 45 minutes, or 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours.
• the dosage form of the invention is a modified release oral formulation which, after ingestion is characterized by little or no release of the buprenorphine in the stomach, duodenum, jejunum or ileum, said dosage form releases most, substantially all or all of the buprenorphine from the dosage form upon arrival in the colon, over a period of less than about 5, 10, 15, 30, or 45 minutes, or 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours.
• the dosage form of the invention is a modified release oral formulation which, after ingestion is characterized by little or no release of the buprenorphine in the stomach, said dosage form releases most, substantially all or all of the buprenorphine from the dosage form in the duodenum, jejunum, ileum and/or colon gradually over a period of not less than about 7, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28, 30, 36 or 40 hours.
• the dosage form of the invention is a modified release oral formulation which, after ingestion is characterized by little or no release of the buprenorphine in the stomach or duodenum, said dosage form releases most, substantially all or all of the buprenorphine from the dosage form upon arrival in the jejunum, ileum and/or colon gradually over a period of not less than about 7, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28, 30, 36 or 40 hours.
• the dosage form of the invention is a modified release oral formulation which, after ingestion is characterized by little or no release of the buprenorphine in the stomach, duodenum or jejunum, said dosage form releases most, substantially all or all of the buprenorphine from the dosage form upon arrival in the ileum and/or colon gradually over a period of not less than about 7, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28, 30, 36 or 40 hours.
• the dosage form of the invention is a modified release oral formulation which, after ingestion is characterized by little or no release of the buprenorphine in the stomach, duodenum, jejunum or ileum, said dosage form releases most, substantially all or all of the buprenorphine from the dosage form upon arrival in the colon gradually over a period of not less than about 7, 8, 10, 12, 14, 16, 18, 20, 21, 22, 23, 24, 28, 30, 36 or 40 hours.
• the described in vitro or in vivo (including gastrointestinal tract and systemic) release characteristics, specifications and claims of the dosage forms of the invention are observed after some, or most, or substantially all, or all administered or ingested doses.
• the described pharmacokinetic and pharmacodynamic characteristics, specifications and claims of the dosage forms of the invention are observed after some, or most, or substantially all, or all administered or ingested doses.
• the described in vitro or in vivo (including gastrointestinal tract and systemic) release characteristics, specifications and claims of the dosage forms of the invention are observed after first administration.
• the described pharmacokinetic and pharmacodynamic characteristics, specifications and claims of the dosage forms of the invention are observed after first administration.
• the described in vitro or in vivo (including gastrointestinal tract and systemic) release characteristics, specifications and claims of the dosage forms of the invention are observed after repeated or multiple administration.
• the described pharmacokinetic and pharmacodynamic characteristics, specifications and claims of the dosage forms of the invention are observed after repeated or multiple administrations.
• the oral modified release buprenorphine dosage form is enteric coated, or sequestered so as to release little or no buprenorphine in the stomach, or stomach and duodenum, or stomach, duodenum and jejunum, or stomach, duodenum, jejunum and ileum, or stomach, duodenum, jejunum, ileum and ileo-cecal junction.
• the oral modified release buprenorphine dosage form provides an oral pharmaceutical composition and method of treating a buprenorphine responsive medical condition, said treatment (i) achieving the same therapeutic objectives with a reduced dose of buprenorphine; (ii) providing improved dose proportional extent of absorption; (iii) a more consistent clinical effect; (iv) a more consistent pharmacokinetic effect; (v) more consistent extent of oral absorption; (vi) greater efficacy; (vii) reduced frequency, duration and/or magnitude of side effects; (viii) reduced frequency, duration and/or magnitude of side effects at or for up to 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 hours after the first dose; (ix) reduced frequency, duration and/or magnitude of nausea, vomiting and/or drowsiness; (x) reduced potential for drug abuse, drug diversion, drug liking, and mood altering effects; (xi) reduced potential for euphoria, drug liking, and mood altering effects; (xii) more efficient clinical
• the oral modified release buprenorphine dosage form demonstrate increased efficacy of at least about 1%, 2%, 3%, 4%, 5%, 6%, or 8%, 10%, 12%, 15%, 20%, 30%, or 40%, when compared with oral immediate release dosage forms.
• the oral modified release buprenorphine dosage form demonstrate reduced euphoria, drug liking, mood altering effects, nausea, vomiting, blurred vision, fatigue and/or drowsiness of at least about 1%, 2%, 3%, 4%, 5%, 6%, or 8%, 10%, 12%, 15%, 20%, 30%, or 40%, when compared with oral immediate release dosage forms.
• the oral modified release buprenorphine dosage form demonstrate reduced euphoria, drug liking, mood altering effects, nausea, vomiting, blurred vision, fatigue and/or drowsiness of at least about 1%, 2%, 3%, 4%, 5%, 6%, or 8%, 10%, 12%, 15%, 20%, 30%, or 40%, when compared with sublingual, buccal or mucoretentive dosage forms.
• the dosage form of the invention is an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release.
• the dosage form of the invention is an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release, said delayed release rendering said dosage form abuse resistant.
• the dosage form of the invention is an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release, said dosage form abuse resistant compared with sublingual buprenorphine.
• said modified release dose is at least about 20%, or 30%, or 40%, or 50%, or 60%, or 75%, or 100%, or 150%, or 200%, or 250%, or 300%, or 350%, or 400%, or 450%, or 500%, or 700%, or 1000% greater than said sublingual dose.
• the dosage form of the invention is an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release, said dosage form abuse resistant compared with oral immediate release buprenorphine.
• said modified release dose is at least about 20%, or 30%, or 40%, or 50%, or 60%, or 75%, or 100%, or 150%, or 200%, or 250%, or 300%, or 350%, or 400%, or 450%, or 500%, or 700%, or 1000% greater than said oral immediate release dose.
• the dosage form of the invention is an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release, said dosage form abuse resistant compared with oral dosage forms of buprenorphine suitable for pulsatile release but without a delay in release of the initial pulse.
• said modified release dose is at least about 20%, or 30%, or 40%, or 50%, or 60%, or 75%, or 100%, or 150%, or 200%, or 250%, or 300%, or 350%, or 400%, or 450%, or 500%, or 700%, or 1000% greater than said oral pulsatile dose.
• the dosage form of the invention is an oral dosage form comprising: (i) a therapeutically effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a mixture thereof, and (ii) controlled release material to render said dosage form suitable for modified release, said dosage form providing delayed onset of buprenorphine release, said dosage form abuse resistant compared with oral dosage forms of buprenorphine suitable for modified release but without delayed release.
• said modified release dose with delayed onset is at least about 10%, 20%, or 30%, or 40%, or 50%, or 60%, or 75%, or 100%, or 150%, or 200%, or 250%, or 300%, greater than said comparator dose of modified release without delayed onset.
• the controlled release material of the oral dosage form of the invention further comprises material to render said composition resistant or substantially resistant to dissolution in the stomach, or in the duodenum, or in the jejunum, or in the ileum, or in the small intestine, or in the stomach and duodenum, or in the stomach, duodenum and jejunum, or in the stomach, duodenum, jejunum and terminal ileum, in the stomach and small intestine, or before it reaches the ileo-cecal junction, or until it crosses the ileo-cecal junction or until it reaches the colon.
• the controlled release material of the oral dosage form of the invention further comprises an overcoat material or an embedded material to render said composition resistant or substantially resistant to dissolution in the stomach, or in the duodenum, or in the jejunum, or in the ileum, or in the small intestine, or in the stomach and duodenum, or in the stomach, duodenum and jejunum, or in the stomach, duodenum, jejunum and terminal ileum, in the stomach and small intestine, or before it reaches the ileocecal junction, or until it crosses the ileo-cecal junction or until it reaches the colon.
• said overcoat is additionally incorporated into or applied over immediate release dosage forms, and controlled release matrix dosage forms, including controlled porosity osmotic dosage forms, push pull osmotic dosage forms.
• oral As used herein with respect to the buprenorphine dosage form of the invention, the term “oral”, “oral dosage form”, “oral pharmaceutical dosage form”, “oral administration”, “oral compositions” “oral pharmaceutical compositions”, “oral tablets”, “oral capsules”, “orally ingested”, “orally”, “oral route” and the like all refer to any method of administration through the mouth for rapid deposit of the dosage form into the stomach or alimentary canal.
• the oral dosage form of the invention is usually ingested intact, although it may be ingested un-intact or tampered (e.g., crushed) and usually with the aid of water or a beverage to hasten passage through the mouth.
• oral dosage forms are buprenorphine dosage forms and pharmaceutical compositions administered by the lingual, sublingual, oro-mucosal, transmucosal and buccal routes.
• Lingual, sublingual, oro-mucosal, transmucosal and buccal routes of administration are intended to provide absorption or substantial absorption of the drug in the oral cavity (i.e., the mouth) through rapid or slow dissolution in the oral cavity and/or through prolonged residence in the oral cavity (i.e., oral cavity residence time beyond the usual time associated with oral ingestion of drug intended to be deposited into the stomach or alimentary canal).
• Such formulations and their method of administration are well known in the art and may under certain conditions include lozenges, transmucosal films, buccal products, mucoretentive products, orally disintegrating tablets, fast dissolving tablets, fast dispersing tablets, fast disintegrating dosage forms, provided they are intended for absorption or substantial absorption of the drug in the oral cavity (i.e., the mouth) through rapid or slow dissolution in the oral cavity and/or through longer residence in the oral cavity (i.e., oral cavity residence beyond the usual time associated with oral ingestion of drug intended to be deposited into the stomach).
• controlled release material As used herein, "controlled release material”, “controlled release means”, and
• material to provide controlled release means an in vitro or in vivo release rate controlling excipient or material incorporated in the dosage form whose function or primary function is to modify release (e.g, onset of release, rate of release, duration of release) of an active drug (e.g., buprenorphine) from a dosage form or a portion (i.e., cause the dosage form to release in other than an immediate release fashion).
• an active drug e.g., buprenorphine
• the controlled release material functions to provide one or more of the following: (1) delay in the onset of release; (2) delay in the rate of release; (3) delay in the duration of release; (4) prolonged or extended duration of release; (5) pulsatile release; (6) delay in the onset of therapeutic effect; (7) delay in onset of side effects; (8) delay in the onset of psychic or mood altering effects; (9) reduced abuse liability; (10) prolonged or extended duration of therapeutic effect; or (11) more robust therapeutic effect; (12) a pharmacokinetic profile consistent with dosage forms which are controlled release, extended release, sustained release, delayed onset, rapid release or delayed onset, extended release, or delayed onset, pulsatile release, or modified release, or slow release or prolonged release; (13) a pharmacodynamic profile consistent with dosage forms which are controlled release, extended release, sustained release, delayed onset, rapid release or delayed onset, extended release, or delayed onset, pulsatile release, or modified release, or slow release or prolonged release; (13) a pharmacodynamic profile consistent with dosage forms which are controlled release,
• incorporation of controlled release material into the dosage form can provide for one or more of the following: (1) delay in release (for up to about 0.5, 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, 11 or 12 hours), where the onset of first release or first substantial release is delayed but after start of said release, most, substantially all, or all of the active drug is rapidly released or liberated from the dosage form; (2) delay in release (for up to about 0.5, 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, 11 or 12 hours), where the onset of first release or first substantial release is delayed but after start of said release, the active drug is rapidly released or liberated from the dosage form; (3) a delay in release, where, (a) the onset of first release or first substantial release is delayed until a specified or preferred time after oral ingestion (e.g., for up to
• modified release formulations, dosages, dosage forms, compositions, drugs, tablets, capsules or pharmaceutical compositions mean pharmaceutical preparations which release an active ingredient from a dosage form or a portion thereof in other than an immediate release fashion.
• Modified release pharmaceutical compositions are made by incorporating a controlled release material in the dosage form.
• Modified release dosage forms are sometimes designed to accomplish pharmaceutical, pharmacokinetic, pharmacodynamic, therapeutic or convenience objectives not offered by conventional dosage forms such as a solution or an immediate release dosage form.
• modified release includes "delayed onset” (or “delayed release”) and "controlled release”.
• controlled release formulations, dosages, dosage forms, compositions, drugs, tablets, capsules or pharmaceutical compositions mean pharmaceutical preparations which release an active ingredient from a dosage form or a portion thereof over an extended period of time (over a period of time greater than 4 or 6 hours, more preferably for periods of up to about 12 hours or up to about 24 hours, or longer.), either with an initial delay in release (e.g., a delay of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours) or without an initial delay in release.
• an initial delay in release e.g., a delay of 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours
• “delayed onset” and “delayed release” formulations, dosages, dosage forms, compositions, drugs, tablets, capsules or pharmaceutical compositions mean pharmaceutical preparations which release begin the first release of an active ingredient from a dosage form or a portion thereof (i) at time other than immediately following oral administration; and/or (ii) after a lag period lasting from minutes to hours (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours); and/or (iii) upon reaching the desired or target GI anatomic location distal to the stomach (e.g., distal to the duodenum, jejunum, ileum, ileo-cecal junction or colon) or GI environment (e.g., pH at the point of release, osmotic pressure at the point of release, hydration, microbial flora).
• minutes to hours e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5,
• delayed onset, rapid release means dosage forms which after a desired lag period post-ingestion (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours), rapidly releases (i.e, over about 0.05, 0.1, 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 hours, preferably over less than about 1 or 2 hours) substantially all or all the active drug from the dosage form.
• a desired lag period post-ingestion e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours
• rapidly releases i.e, over about 0.05, 0.1, 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 hours, preferably over less than about 1 or 2 hours
• delayed onset, pulsatile release means dosage forms which after a desired lag period post-ingestion (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours), rapidly releases (i.e, over about 0.05, 0.1, 0.125, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5 hours, preferably over less than about 1 or 2 hours) some of the active drug from the dosage form in "pulses” at the desired time intervals (e.g, about every 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 or 24 hours), each pulse releasing a portion of the active drug in the dosage form.
• a desired lag period post-ingestion e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours
• delayed onset, extended release means dosage forms which after a desired lag period post-ingestion (e.g., 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 hours), slowly release the active drug from the dosage form over an extended period of time (e.g., over about 4, 4.5, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, or 30 hours).
• delayed release and “delayed onset” include dosage forms which are delayed onset, rapid release; delayed onset, pulsatile release; and delayed onset.
• one or more, or substantially all, or all of the embodiments and specifications showing benefit or a difference for modified release delayed onset dosage forms of oral buprenorphine e.g., delayed onset, rapid release; delayed onset, pulsatile release; delayed onset, extended release
• immediate release oral buprenorphine e.g., delayed onset, rapid release; delayed onset, pulsatile release; delayed onset, extended release
• immediate release oral buprenorphine e.g., delayed onset, rapid release; delayed onset, pulsatile release; delayed onset, extended release
• one or more, or substantially all, or all of the embodiments and specifications showing benefit or a difference for modified release delayed onset dosage forms of oral buprenorphine e.g., delayed onset, rapid release; delayed onset, pulsatile release; delayed onset, extended release
• modified release delayed onset dosage forms of oral buprenorphine e.g., delayed onset, rapid release; delayed onset, pulsatile release; delayed onset, extended release
• the phrase “sublingual”, “buccal”, “lingual” or “oromucosal” may be substituted with "controlled release", “extended release” or "pulsatile release”, provided said controlled release, extended release or pulsatile release dosage forms are not delayed onset dosage forms.
• controlled release dosage forms of the present invention releases buprenorphine from the oral dosage form at a slower rate than immediate release formulations.
• extended release dosage forms and delayed onset, extended release dosage forms release buprenorphine at such a rate that plasma concentrations and/or therapeutic effects are maintained within the therapeutic range (above the minimum effective therapeutic concentration) but below toxic levels for intended duration (e.g., over a period of about 1 to about 170 hours, preferably over a period of time indicative of a Q3H, Q4H, Q6H, Q8H, Q12H, Q16H, Q18H, Q24H, Q36H, Q48H or Q72H administration, more preferably over a period of time indicative of a Q12H, Q24H or Q48H administration).
• the extended release formulations of the present invention provide therapeutic effects for a duration that is longer or substantially longer than the duration of meaningful or detectable plasma concentrations of buprenorphine.
• immediate release forms When applied to the present invention, present invention, the term “immediate release”, “immediate release dosage forms”, “immediate release composition”, “immediate release tablet”, “immediate release capsule”, “immediate release formulation”, immediate release forms” and the like is a dosage form which is formulated to release the active drug from the dosage form immediately (i.e., without an attempt to delay or prolong the release of the active drug from the dosage form as is the case, for example, with extended release dosage forms) or a dosage form which allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug).
• Immediate release dosage forms may be in any form, including tablet, capsule, solution, suspension, powder, micronized, granulated etc.
• immediate release refers to oral dosage forms.
• an available parenteral formulation of buprenorphine or a salt thereof may be used orally, or a solution of buprenorphine or a salt thereof may be prepared or an immediate release tablet may be prepared, or a sublingual or buccal formulation may be given orally for the purpose of in vivo testing requiring immediate release buprenorphine.
• an immediate release formulation of buprenorphine may be prepared by encapsulating liquid or uncompressed solid buprenorphine, or by compressing buprenorphine into tablet form without excipients or material that impart a delay or retardation to its release.
• Immediate release dosage forms generally disintegrate in ⁇ about 0.5 hours or ⁇ about 1 hour, and generally substantially or completely dissolve in ⁇ about 0.25, or ⁇ about 0.5, or ⁇ about 0.75, or ⁇ about 1 or ⁇ about 1.25, or ⁇ about 1.5, or ⁇ about 1.75, or ⁇ about 2 hours, when measured by the recommended or appropriate USP compendial methods (for example some dosage forms may be tested by USP Basket Method or USP Paddle Method at 100 rpm in 900 mL of water at 37 0 C).
• the oral controlled release formulations disclosed herein and the oral immediate release control formulations are dose proportional.
• the pharmacokinetic parameters e.g., AUC and C max
• the pharmacokinetic parameters of a particular dose can be inferred from the parameters of a different dose of the same formulation.
• duodenal release and duodenal delivery are interchangeable and refer to in vivo release of all, substantially all or most buprenorphine from the dosage form into the portion of gastrointestinal tract distal to the stomach.
• duodenal release or duodenal delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form rapidly upon reaching the portion of gastrointestinal tract distal to the stomach.
• duodenal release and duodenal delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form slowly (e.g., sustained release or extended release) upon reaching the portion of gastrointestinal tract distal to the stomach.
• jejunal release and “jejunal delivery” are interchangeable, and refer to in vivo release of all, substantially all or most buprenorphine from the dosage form into the portion of gastrointestinal tract distal to the duodenum.
• jejunal release or “jejunal delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form rapidly upon reaching the portion of gastrointestinal tract distal to the duodenum.
• duodenal release and duodenal delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form slowly (e.g., sustained release or extended release) upon reaching the portion of gastrointestinal tract distal to the duodenum.
• ileal release and ileal delivery are interchangeable and refer to in vivo release of all, substantially all or most buprenorphine from the dosage form into the portion of gastrointestinal tract distal to the jejunum.
• ileal release or ileal delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form rapidly upon reaching the portion of gastrointestinal tract distal to the jejunum.
• ileal release and ileal delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form slowly (e.g., sustained release or extended release) upon reaching the portion of gastrointestinal tract distal to the jejunum.
• ileo- colonic release and “ileo-colonic delivery” are interchangeable and are interchangeable and refer to in vivo release of all, substantially all or most buprenorphine from the dosage form into the portion of gastrointestinal tract distal to the jejunum and/or distal to the ileum.
• ileo-colonic release or ileo-colonic delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form rapidly upon reaching the portion of gastrointestinal tract distal to the jejunum.
• ileo-colonic release and ileo-colonic delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form slowly (e.g., sustained release or extended release) upon reaching the portion of gastrointestinal tract distal to the jejunum.
• colonic release and colonic delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form rapidly upon reaching the portion of gastrointestinal tract distal to the ileum.
• colonic release and colonic delivery dosage forms of the invention provide in vivo release of all, substantially all or most buprenorphine from the dosage form slowly (e.g., sustained release or extended release) upon reaching the portion of gastrointestinal tract distal to the ileum.
• the dosage form provides an oral pharmaceutical composition for the treatment of a buprenorphine responsive medical condition comprising a therapeutically effective amount of buprenorphine or pharmaceutically acceptable salts thereof or mixture thereof; said dosage form providing an in-vitro buprenorphine release rate, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL of distilled water at 37 0 C which is substantially pH dependent in that a difference, at 1, or 1.5, or 2, or 2.5, or 3 hours, between the amount of buprenorphine released at a pH of ⁇ 0.5, or ⁇ 1, or ⁇ 1.5, or ⁇ 2, or ⁇ 2.5, or ⁇ 3, or ⁇ 3.5, or ⁇ 4, or ⁇ 4.5, or ⁇ 5, or ⁇ 5.5 and an amount released at a pH of or >5.8, or >6, or >6.2, or >6.4, or>6.6, or >6.8, or >7, or >7.1, or >7.2, or>7.3, or >7.
• the dosage form provides an oral pharmaceutical composition for the treatment of a buprenorphine responsive medical condition comprising a therapeutically effective amount of buprenorphine or pharmaceutically acceptable salts thereof or mixture thereof; said dosage form providing duodenal delivery, jejunal delivery, ileal delivery, ileo-colonic delivery or colonic delivery; said dosage form providing an in-vitro buprenorphine release rate, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL of distilled water at 37 0 C which is substantially pH dependent in that a difference, at 1, or 1.5, or 2, or 2.5, or 3 hours, between the amount of buprenorphine released at a pH of ⁇ 0.5, or ⁇ 1, or ⁇ 1.5, or ⁇ 2, or ⁇ 2.5, or ⁇ 3, or ⁇ 3.5, or ⁇ 4, or ⁇ 4.5, or ⁇ 5, or ⁇ 5.5 and an amount released at a pH of >5.8, or >6, or >6.2, or >
• the dosage form provides an oral pharmaceutical composition for the treatment of a buprenorphine responsive medical condition comprising a therapeutically effective amount of buprenorphine or pharmaceutically acceptable salts thereof or mixture thereof, and a controlled release material; said dosage form providing an in-vitro buprenorphine release rate, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL of distilled water at 37 0 C which is substantially pH dependent in that a difference, at 1, or 1.5, or 2, or 2.5, or 3 hours, between the amount of buprenorphine released at a pH of ⁇ 0.5, or ⁇ 1, or ⁇ 1.5, or ⁇ 2, or ⁇ 2.5, or ⁇ 3, or ⁇ 3.5, or ⁇ 4, or ⁇ 4.5, or ⁇ 5, or ⁇ 5.5 and an amount released at a pH of >5.8, or >6, or >6.2, or >6.4, or >6.6, or >6.8, or >7, or >7.1, or >7.2, or >
• the dosage form provides an oral pharmaceutical composition for the treatment of a buprenorphine responsive medical condition comprising a therapeutically effective amount of buprenorphine or pharmaceutically acceptable salts thereof or mixture thereof, and a controlled release material; said dosage form providing duodenal delivery, jejunal delivery, ileal delivery, ileo-colonic delivery or colonic delivery; said dosage form providing an in-vitro buprenorphine release rate, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL of distilled water at 37 0 C which is substantially pH dependent in that a difference, at 1, or 1.5, or 2, or 2.5, or 3 hours, between the amount of buprenorphine released at a pH of ⁇ 0.5, or ⁇ 1, or ⁇ 1.5, or ⁇ 2, or ⁇ 2.5, or ⁇ 3, or ⁇ 3.5, or ⁇ 4, or ⁇ 4.5, or ⁇ 5, or ⁇ 5.5 and an amount released at a pH of >5.8, or >
• pH adjustments of the dissolution media may be achieved by adjustment as required with hydrochloric acid or sodium hydroxide.
• pH adjustments of the dissolution media may be achieved with other pharmaceutical excipients, including acids, bases and buffers known in the art.
• the foregoing dosage forms in (l) to (l l l) also incorporate a controlled release material and/or provide duodenal delivery, jejunal delivery, ileal delivery, ileo-colonic delivery or colonic delivery.
• the foregoing in-vitro release rate of buprenorphine in (1) to (111) are achieved when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL distilled water at 37 0 C at a pH of between 4.5 and 8 at 37 0 C.
• a controlled release material means that the dosage may or may not be require one or more controlled release material to achieve some, most, substantially all or all of the objectives, specifications or claims of the invention.
• the dosage form provides an oral pharmaceutical composition for the treatment of a buprenorphine responsive medical condition comprising a therapeutically effective amount of buprenorphine or pharmaceutically acceptable salts thereof or mixture thereof, and optionally a controlled release material, said buprenorphine given alone or in combination with another drug in the same dosage form or in a different dosage form to treat the same or a different condition or to treat side effects of buprenorphine or to deter abuse of the buprenorphine.
• a buprenorphine responsive medical condition comprising a therapeutically effective amount of buprenorphine or pharmaceutically acceptable salts thereof or mixture thereof, and optionally a controlled release material, said buprenorphine given alone or in combination with another drug in the same dosage form or in a different dosage form to treat the same or a different condition or to treat side effects of buprenorphine or to deter abuse of the buprenorphine.
• the dosage form provides a pharmaceutical dosage form for the treatment of a buprenorphine responsive medical condition comprising a therapeutically effective amount of buprenorphine or pharmaceutically acceptable salts thereof or mixture thereof, said dosage form resistant or substantially resistant to dissolution and/or absorption in the stomach, and/or in the duodenum, and/or in the jejunum, and/or in the ileum, or in the small intestine, or in the stomach and duodenum, or in the stomach, duodenum and jejunum, or in the stomach, duodenum, jejunum and terminal ileum, or in the stomach and small intestine, or before it reaches the ileo-cecal junction, or until it crosses the ileo-cecal junction, or until it reaches the colon; said buprenorphine in the dosage form released rapidly or slowly upon reaching a the desired anatomic region of the GI tract (e.g., ileum or colon) or upon reaching the desired gastrointestinal conditions conducive to
• the oral buprenorphine dosage form is substantially non- releasable in the stomach and small intestine, or substantially non-releasable in the stomach and duodenum, or substantially non-releasable in the stomach, duodenum and jejunum, or substantially non-releasable in the stomach, duodenum, jejunum and terminal ileum, or substantially non-releasable until it reaches the ileum, or substantially non-releasable until it reaches the colon.
• the oral buprenorphine dosage form is substantially non- releasable until up to about 1, or 1.5, 2, or 2.25, or 2.5, or 2.75, or 3, or 3.25, or 3.5, or 3.75, or 4, or 4.25, or 4.5, or 4.75, or 5, or 5.25, or 5.5, or 5.75, or 6, or 6.25, or 6.5, or 7.75, or 7, or 7.25, or 7.5, or 7.75, or 8, or 8.25, or 8.5, or 8.75, or 9, or 9.25, or 9.5, or 9.75, or 10, or 10.25, or 10.5, or 10.75, or 11, or 11.25, or 1.5, or 11.75, or 12, or 14, or 16, or 18, or 20 hours after oral ingestion of the oral dosage form.
• said dosage form is substantially non-releasable until up to about 2.5, or 2.75, or 3, or 3.25, or 3.5, or 3.75, or 4, or 4.25, or 4.5, or 4.75, or 5, or 5.25, or 5.5, or 5.75, or 6, or 6.25, or 6.5, or 7.75, or 7 hours after oral ingestion of the oral dosage form.
• the oral buprenorphine dosage form includes a coated capsule or tablet wherein the coating comprises material which dissolves at a pH > 5, or > 5.5, or > 5.7, or > 6, or > 6.2, or > 6.4, or > 6.6, or > 6.8, > 7, or > 7.2.
• the oral buprenorphine dosage form includes material incorporated in dosage form, wherein the material substantially resists dissolution for at least about 1, or 1.5, or 2, or 2.5, or 3, or 3.25, or 3.5, or 3.75, or 4, or 4.25, or 4.5, or 4.75, or 5, or 5.25, or 5.5, or 5.75, or 6, or 6.25, or 6.5, or 7.75, or 7 31 hours at a pH of about ⁇ 5, or ⁇ 5.5, or ⁇ 5.7, or ⁇ 6, or ⁇ 6.2, or ⁇ 6.4, or ⁇ 6.6, or ⁇ 6.8, ⁇ 7, or ⁇ 7.2.
• the oral buprenorphine dosage form is coated with or includes incorporated one or more of the following: (i) cellulose acetate trimellitiate (CAT); (ii) hydroxypropylmethyl cellulose phthalate (HPMCP); (iii) polyvinyl acetate phthalate (PVAP); (iv) shellac; (v) a copolymer of methacrylic acid and methylmethacrylate; (vi) a material which is redox-sensitive; (vii)an azopolymer or a disulphide polymer; (viii) a material which is degraded by enzymes or bacteria present in the colon; (ix) a copolymer of methacrylic acid and methylmethacrylate to which has been added during polymerization the monomer methyl acrylate; (x) a cellulose ester; (xi) polyvinyl acetate phthalate.
• CAT cellulose acetate trimellitiate
• HPMCP hydroxypropyl
• the dosage form consists of a coated capsule wherein the coating is applied separately to empty capsule body and cap. In some embodiments, the dosage form consists of a coated capsule filled with a caplet or tablet.
• the dosage form is coated with a film or incorporates material which makes the dosage form: (i) is non-dissolving at pH ⁇ 3 to 4 and dissolving at pH>5; or (ii) non-dissolving at pH ⁇ 3 to 4 and dissolving at pH>5.5; or (iii) non-dissolving at pH ⁇ 3 to 4 and dissolving at pH>6; or (iv) non-dissolving at pH ⁇ 3 to 4.5 and dissolving at pH>6; or (v) non-dissolving at pH ⁇ 3 to 4 and dissolving at pH>6.5; or (vi) non-dissolving at pH ⁇ 3 to 4.5, and dissolving at pH>6.5; or (vii) non-dissolving at pH ⁇ 3 to 4 and dissolving at pH>7; or (viii) non-dissolving at pH ⁇ 3 to 4.5 and dissolving at pH>7; or (ix) is non-dissolving at pH ⁇ 3 to 5 and
• the oral buprenorphine dosage form is non-dissolving or substantially non-dissolving at pH ⁇ 5.5, or at pH ⁇ 6.0, or at pH ⁇ 6.2, or at pH ⁇ 6.5, or at pH ⁇ 6.8, or at pH ⁇ 7.0, when measured by USP Basket Method or USP Paddle Method at 100 rpm in 900 mL of water at 37 0 C (adjusted to the required pH with hydrochloric acid or sodium hydroxide) for up to about 2, 2.5, 3, 3.5, 4, 4.5, or 5.
• the oral buprenorphine dosage form is non-releasing or substantially non-releasing at pH ⁇ 5.5, or at pH ⁇ 6.0, or at pH ⁇ 6.2, or at pH ⁇ 6.5, or at pH ⁇ 6.8, or at pH ⁇ 7.0, when measured by USP Basket Method or USP Paddle Method at 100 rpm in 900 mL of water at 37 0 C (adjusted to the required pH with hydrochloric acid or sodium hydroxide) for up to about 2, 2.5, 3, 3.5, 4, 4.5, or 5.
• the oral buprenorphine dosage form is non-releasing or substantially non-releasing for up to about 2, 2.5, 3, 3.5, 4, 4.5, or 5 hours following ingestion.
• the oral buprenorphine dosage form comprises material which is non-dissolving or substantially non-dissolving at a particular pH or range of pH and is dissolving or substantially dissolving at another pH or another range of pH, said material commingled with the buprenorphine API or with the granulation containing buprenorphine API.
• the oral buprenorphine dosage form comprises material which is non-dissolving or substantially non-dissolving at a particular pH or range of pH and is dissolving or substantially dissolving at another pH or another range of pH, said material commingled with the buprenorphine API or with the granulation containing buprenorpbine API, in addition to being coated on the dosage form.
• the specifications regarding coating of the dosage form of the invention with controlled release material or pH sensitive material are also applicable to dosage forms where said material is commingled with the buprenorphine API or with the granulation containing buprenorphine API, instead of or in addition to coating the dosage form.
• the specifications regarding coating of the dosage form of the invention with controlled release material or pH sensitive material are also applicable to dosage forms where is the coating is applied to multiparticulate matrices or to subunits of the dosage form e.g., beads incorporating drug), instead of or in addition to coating the dosage form.
• the dosage form consists of a coated capsule wherein the coating is applied to capsules having a sealing on the gap between capsule body and cap.
• the dosage form consists of a coated capsule containing a buprenorphine, wherein the capsule is coated with a material selected from the group comprising cellulose acetate trimellitiate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, shellac, and a copolymer of methacrylic acid and ethyl acrylate, azopolymers, disulphide polymers and amylose.
• the oral buprenorphine dosage form has a buprenorphine Tmax that exceeds its dosing frequency.
• the buprenorphine Tmax ratio of the oral buprenorphine dosage form of the invention to buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule or given sublingually or bucally is > 1.25, or > 1.5, or > 1.75, or > 2, or > 2.5, or > 3, or > 3.5, or > 4, or > 4.5, or > 5, or > 5.5, or ⁇ 6, or > 6.5, or > 7, or ⁇ 7.5, or > 8, or > 8.5, or > 9, or > 9.5, or > 10, or > 10.5, or > 12, or ⁇ 14, or > 16, or ⁇ 18, or ⁇ 20.
• the norbuprenorphine Tmax ratio of the oral buprenorphine dosage form of the invention to buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule or given sublingually or bucally is > 1.25, or > 1.5, or > 1.75, or > 2, or > 2.5, or > 3, or > 3.5, or > 4, or > 4.5, or > 5, or > 5.5, or ⁇ 6, or ⁇ 6.5, or > 7, or > 7.5, or > 8, or > 8.5, or > 9, or > 9.5, or > 10, or > 10.5, or > 12, or ⁇ 14, or > 16, or ⁇ 18, or > 20.
• the buprenorphine Cmax ratio after buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule, or given sublingually or bucally, to the oral buprenorphine dosage form of the invention given orally is > 1.1, or > 1.2, or > 1.3, or > 1.5, or > 1.5, or ⁇ 1.6, or ⁇ 1.7, or > 1.8, or ⁇ 1.9, or ⁇ 2, or ⁇ 2.2, or ⁇ 2.5, or > 3, or ⁇ 3.5, or ⁇ 4, or ⁇ 4.5, or ⁇ 5, or ⁇ 5.5, or > 6, or ⁇ 6.5, or ⁇ 7, or ⁇ 7.5, or ⁇ 8, or ⁇ 8.5, or ⁇ 9, or ⁇ 9.5, or ⁇ 10, or > 10.5, or ⁇ 12, or ⁇ 14, or > 16, or
• the norbuprenorphine Cmax ratio of buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule, or given sublingually or bucally, to the oral buprenorphine dosage form of the invention given orally is > 1.1, or > 1.2, or > 1.3, or > 1.5, or > 1.5, or > 1.6, or ⁇ 1.7, or > 1.8, or ⁇ 1.9, or
• the buprenorphine AUCo -24 ratio of the oral buprenorphine dosage form of the invention to buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule is ⁇ 1.1, or > 1.2, or > 1.3, or > 1.5, or ⁇ 1.5, or > 1.6, or > 1.7, or > 1.8, or > 1.9, or > 2, or ⁇ 2.2, or > 2.5, or ⁇ 3.
• the buprenorphine AUC 0- j n f ratio of the oral buprenorphine dosage form of the invention to buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule is > 1.1, or > 1.2, or > 1.3, or > 1.5, or ⁇ 1.5, or > 1.6, or > 1.7, or > 1.8, or > 1.9, or > 2, or >2.2, or ⁇ 2.5, or > 3.
• the norbuprenorphine AUCo- 24 ratio of the oral buprenorphine dosage form of the invention to buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule is > 1.1, or > 1.2, or > 1.3, or > 1.5, or ⁇ 1.5, or ⁇ 1.6, or ⁇ 1.7, or ⁇ 1.8, or ⁇ 1.9, or ⁇ 2, or ⁇ 2.2, or ⁇ 2.5, or ⁇ 3.
• the norbuprenorphine AUCo-inf ratio of the oral buprenorphine dosage form of the invention to buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule is ⁇ 1.1, or ⁇ 1.2, or ⁇ 1.3, or ⁇ 1.5, or ⁇ 1.5, or ⁇ 1.6, or ⁇ 1.7, or > 1.8, or ⁇ 1.9, or > 2, or ⁇ 2.2, or ⁇ 2.5, or ⁇ 3.
• the apparent oral clearance ratio of buprenorphine given orally as a conventional solution, suspension, immediate release tablet or capsule, to the oral buprenorphine dosage form of the invention given orally is ⁇ 1.1, or ⁇ 1.2, or ⁇ 1.3, or ⁇ 1.4, or ⁇ 1.5.
• the oral modified release buprenorphine dosage form releases less than about 0.1%, or 0.5%, or 1%, or 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or 12%, or 14%, or 15%, or 16%, or 17%, or 18%, or 20% of buprenorphine in vitro from the dosage form when measured at about 1, 1.5, 2, 2.5, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 10.5, 11, 11.5, or 12 hours, said in vitro release measured by the USP Basket or Paddle Method at 100 rpm in 100 to 900 mL in one or more of the following: (a) water at 37 0 C at a pH of 4.5, adjusted with HCl; (b) water at 37 0
• said in vitro dissolution is measured by the USP Apparatus III (Reciprocating Cylinder) Method instead of the Basket or Paddle Method.
• the dosage form releases less than about 0.1%, or 0.5%, or 1%, or 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10 of buprenorphine in vitro from the dosage form when measured at about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 hours.
• the oral modified release buprenorphine dosage form releases
• the oral modified release buprenorphine dosage form releases
• buprenorphine in vivo from the dosage form for at least about 1 hour, or at least about 1.5 hours, or at least about 2 hours, or at least about 2.5 hours, or at least about 3 hours, or at least about 3.25 hours, or at least about 3.5 hours, or at least about 3.75 hours, or at least about 4 hours, or at least about 4.25 hours, or at least about 4.5 hours, or at least about 4.75 hours, or at least about 5 hours, or at least about 5.25 hours, or at least about 5.5 hours, or at least about 5.75 hours, or at least about 6 hours, or at least about 6.25 hours,
• the time after oral ingestion is at least about 2 hours, or at least about 2.5 hours, or at least about 3 hours, or at least about 3.5 hours, or at least about 4 hours, or at least about 4.5 hours, or at least about 5 hours, or at least about 5.5 hours, or at least about 6 hours, or at least about 6.5 hours, or at least about 7 hours.
• the oral modified release buprenorphine dosage form releases
• buprenorphine in vivo from the dosage form when the average measured or expected gastrointestinal pH is less than about 3.5, or is less than about 4, or is less than about 4.5, or is less than about 5, or less than about 5.2, or less than about 5.4, or less than about 5.6, or less than about 5.8, or less than about 6, or less than about 6.2, or less than about 6.4, or less than about 6.5, or less than about 6.6, or less than about 6.7, or less than about 6.8, or less than about 6.9, or less than about 7, or less than about 7.1, or less than about 7.2, or
• the dosage form releases 0%, or less than about 0.1%, or 0.5%, or 1%, or 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or 12%, or 14%, or 15%, or 16%, or 17%, or 18%, or 20% or 25% or 28% or 30% or 35% of buprenorphine in vivo when the measured or expected gastrointestinal pH is less than about 5, or less than about 5.5, or less than about 6, or less than about 6.5, or less than about 6.8, or less than about 7, or less than about 7.2, or less than about 7.5. Most preferably, said release is measured at about 2 hours, or about 2.5 hours, or about 3 hours, or 4 hours or 4.5 hours or 5 hours, or 5.5 hours or 6 hours or 6.5 hours or 7 hours.
• the targeted gastrointestinal delivery of the buprenorphine from the oral modified release buprenorphine dosage form into the lower segments of the gastrointestinal tract can be achieved through a variety of approaches, including but limited to incorporation of material or processes to achieve one or more of the following: time- controlled, pH-controlled, pressure-controlled, enzyme-controlled and hydration-controlled. Since the gastrointestinal tract is a complex, variable and highly dynamic environment and further complicated by the volume, content and location of food and beverages, in some embodiments, incorporation of material to achieve more than one of the above approaches is preferred.
• the targeted gastrointestinal delivery of the buprenorphine from the oral modified release buprenorphine dosage form into the lower segments of the gastrointestinal tract can be achieved through encapsulation of the buprenorphine, preferably with excipients or functional excipients, said capsule incorporating, coated with or overcoated with material or processes to achieve targeted gastrointestinal delivery.
• the oral modified release buprenorphine dosage form is coated with a material or incorporates material which is non-dissolving or substantially resistant to dissolution, each when measured by USP Basket Method or USP Paddle Method at 100 rpm in 900 mL of water at 37 0 C (adjusted to the required pH with hydrochloric acid or sodium hydroxide) at about pH 2, pH 2.2, pH 2.4, pH 2.6, pH 2.8, pH 3, pH 3.2, pH 3.4, pH 3.6, pH 3.8, pH 4, pH 4.2, pH 4.4, pH 4.6, pH 4.8, pH 5, pH 5.2, pH 5.4, pH 5.6, pH 5.8, pH 6, pH 6.2, pH 6.4, pH 6.6, pH 6.8, pH 7, pH 7.2, pH 7.4, for up to about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4,
• the oral modified release buprenorphine dosage form is coated with a material or incorporates material which is non-releasing or substantially non-releasing, each when measured by USP Basket Method or USP Paddle Method at 100 rpm in 900 mL of water at 37 0 C (adjusted to the required pH with hydrochloric acid or sodium hydroxide) at about pH 2, pH 2.2, pH 2.4, pH 2.6, pH 2.8, pH 3, pH 3.2, pH 3.4, pH 3.6, pH 3.8, pH 4, pH 4.2, pH 4.4, pH 4.6, pH 4.8, pH 5, pH 5.2, pH 5.4, pH 5.6, pH 5.8, pH 6, pH 6.2, pH 6.4, pH
• the oral modified release buprenorphine dosage form is coated with a material or incorporates material which is non-dissolving or substantially non- dissolving at one pH but dissolving or substantially dissolving at another pH for up to about 0.5, 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, 14, 16, 18, or 20 hours; said one pH being ⁇ 2, or ⁇ 2.1, or ⁇ 2.2, or ⁇ 2.3, or ⁇ 2.4, or ⁇ 2.5, or ⁇ 2.6, or ⁇ 2.7, or ⁇ 2.8, or ⁇ 2.9, or ⁇ 3, or ⁇ 3.1, or ⁇ 3.2, or ⁇ 3.3, or ⁇ 3.4, or ⁇ 3.5, or ⁇
• the oral modified release buprenorphine dosage form is coated with a material or incorporates material which is non-releasing or substantially non-releasing at one pH but releasing or substantially releasing at another pH for up to about 0.5, 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, 14, 16, 18, or 20 hours; said one pH being ⁇ 2, or ⁇ 2.1, or ⁇ 2.2, or ⁇ 2.3, or ⁇ 2.4, or ⁇ 2.5, or ⁇ 2.6, or ⁇
• the oral modified release buprenorphine dosage form is non- bioavailable or substantially non-bioavailable for up to about 0.5, 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, 14, 16, 18, or 20 hours after oral ingestion (e.g., the dosage form releases 0%, or less than about 0.1%, or 0.5%, or 1%, or 1.5%, or 2%, or 2.5%, or 3%, or 3.5%, or 4%, or 4.5%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or 12%, or 14%, or 15%, or 16%, or 17%, or 18%, or 20% or 25% or 28% or 30% or 35% of buprenorphine in vivo when assessed up to the specified time).
• the oral modified release buprenorphine dosage form is coated with a material or incorporates material which renders the dosage form non-bioavailable or substantially non-bioavailable for up to about 0.5, 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, 14, 16, 18, or 20 hours.
• said dosage form is non-bioavailable or substantially non-bioavailable for up to about 2 hours, or about 2.5 hours, or about 3 hours, or 4 hours or 4.5 hours or 5 hours, or 5.5 hours or 6 hours or 6.5 hours or 7 hours.
• oral formulation which provides a sustained duration of therapeutic effect.
• oral formulations which provide therapeutic effects for up to about 30 minutes. In other preferred embodiments, the oral formulations provide therapeutic effects for up to about 1 hour, or up to about 2 hours, or up to about 4 hours, or up to about 6 hours, or up to about 8 hours, or up to about 10 hours, or up to about 12 hours, or up to about 16 hours, or up to about
• the invention comprises an oral pharmaceutical composition for the treatment of diseases and disorders comprising a therapeutically effective amount of a buprenorphine or a pharmaceutically acceptable salt thereof or a mixture thereof.
• said dosing regimen associated with reduced side effects, improved tolerability, improved efficiency of therapeutic response, reduced breakthrough symptoms (e.g., breakthrough pain) and reduced treatment discontinuation due to side effects.
• opioids e.g., opioids described for oral administration in the FDA's Orange Book. Goodman & Gilman's The Pharmacological Basis of Therapeutics (Brunton, Lazo and Parker, eds, 11th ed., McGraw Hill (2005); Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, Fifth Ed., American, Pain Society (2003); Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No. 35, AHRQ Publication No. 02-E002, October 2001; Carr et al.
• extended release opioids e.g., MS Contin ® , Kadian ® , Avinza ® , Ultram ® ER, Opana ® ER, Palladone ® , Jurnista ®.
• the present invention is directed at oral pharmaceutical composition for the treatment of pain, opioid dependence, addiction disorders, cough, dyspnea, restless leg syndrome and other buprenorphine responsive medical conditions comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine, or a mixture thereof.
• the present invention relates to oral buprenorphine pharmaceutical compositions and methods for the treatment of pain, including acute pain, chronic pain, cancer pain, neuropathic pain, cough, dyspnea, acute herpes zoster, visceral pain and breakthrough pain.
• the present invention relates to oral buprenorphine pharmaceutical compositions and methods for the treatment of acute and chronic cough, including iatrogenic cough, postinfectious cough, cough secondary to asthma, COPD, lung cancer, gastroesophageal reflux disease, respiratory bacterial and viral infections, and upper airway cough syndrome.
• the present invention relates to oral buprenorphine pharmaceutical compositions and methods for the treatment of urinary incontinence.
• the present invention relates to oral buprenorphine pharmaceutical compositions and methods for the treatment of restless leg syndrome.
• the present invention also relates to oral buprenorphine pharmaceutical compositions and methods for the treatment of addiction disorders.
• the present invention relates to oral buprenorphine pharmaceutical compositions and methods for the treatment of conditions other than pain and addiction disorders amenable to treatment with buprenorphine.
• an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine which produces less moderate to severe sedation or drowsiness than after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• an immediate release dosage form e.g., solution, suspension, tablet or capsule
• an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine which produces less moderate to severe nausea than after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• an immediate release dosage form e.g., solution, suspension, tablet or capsule
• an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine which produces less dizziness than after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• an immediate release dosage form e.g., solution, suspension, tablet or capsule
• an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine which produces less dry mouth than after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• an immediate release dosage form e.g., solution, suspension, tablet or capsule
• an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine which has less abuse potential than an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally (e.g., produces lower abuse scores for "drug effects", “drug liking”, “coasting”, “take again”, as defined herein).
• an immediate release dosage form e.g., solution, suspension, tablet or capsule
• an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine which produces less neurologic, cognitive, motor and psychomotor impairment than an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally (e.g., produces lower impairment scores for "critical tracking task", “stop signal task” and “Tower of London” (TOL), as defined herein).
• an immediate release dosage form e.g., solution, suspension, tablet or capsule
• bioavailable formulations for oral administration suitable for up to every 1, 2, 4, 6, 8, 12, 24 , 36, 48 hour and 72 hour administration.
• one or more or all of the specifications, embodiments and claims of the invention applicable to a human subject are also applicable to other mammals.
• the invention comprises pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof wherein all the specifications of the invention applicable to the treatment of pain and addiction disorders are also applicable to the treatment of medical conditions other than pain and addiction disorders.
• the invention provides oral buprenorphine formulations which when evaluated versus other buprenorphine dosage forms in fasted healthy subjects provide a relative mean C ⁇ whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects.
• the invention provides oral buprenorphine formulations which when evaluated versus other buprenorphine dosage forms in fasted healthy subjects provide a relative mean AUCo -1 whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects.
• the invention provides oral buprenorphine formulations which when evaluated versus other buprenorphine dosage forms in fasted healthy subjects provide a relative mean AUCo- mf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects.
• buprenorphine dosage forms which are administered by the lingual, sublingual, oro-mucosal, transmucosal and buccal routes.
• Lingual, sublingual, oro-mucosal, transmucosal and buccal routes are intended to provide absorption or substantial absorption of the drug in the oral cavity (i.e., the mouth) through rapid or slow dissolution in the oral cavity and/or through longer residence in the oral cavity (i.e., oral cavity residence beyond the usual time associated with oral ingestion of drug intended to be deposited into the stomach).
• Such formulations and their method of administration are well known in the art and include lozenges, transmucosal films, buccal products, mucoretentive products, orally disintegrating tablets, fast dissolving tablets, fast dispersing tablets, fast disintegrating dosage forms, provided they are administered for absorption or substantial absorption of the drug in the oral cavity (i.e., the mouth) through rapid or slow dissolution in the oral cavity and/or through longer residence in the oral cavity (i.e., oral cavity residence beyond the usual time associated with oral ingestion of drug intended to be deposited into the stomach).
• the dosage form of oral buprenorphine releases substantially more buprenorphine into systemic circulation during the first half of the intended dosing frequency than during the second half of the intended dosing frequency.
• the dosage form of oral buprenorphine releases at least as much buprenorphine into systemic circulation during the first one-third of the intended dosing frequency as during the remainder of the intended dosing frequency.
• the dosage form of oral buprenorphine releases substantially more buprenorphine into systemic circulation during the first one-third of the intended dosing frequency than during the remainder of the intended dosing frequency.
• the invention comprises an oral pharmaceutical composition for the prevention or treatment of pain comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• the oral dosage form of the present invention comprises a matrix which includes a sustained release material and buprenorphine or a pharmaceutically acceptable salt thereof.
• the matrix is compressed into a tablet and may be optionally overcoated with a coating that in addition to the sustained release material of the matrix may control the release of the buprenorphine or pharmaceutically acceptable salt thereof from the formulation, such that blood levels of active ingredient are maintained within the therapeutic range over an extended period of time.
• the matrix is encapsulated.
• the sustained release oral dosage form of the present invention comprises a plurality of pharmaceutically acceptable sustained release matrices comprising buprenorphine, the dosage form maintaining the blood plasma levels of buprenorphine within the therapeutic range over an extended period of time when administered to patients.
• the dosage form of the invention comprises oral buprenorphine formulated to release the buprenorphine from the dosage form or to initiate the release of the buprenorphine from the dosage form after a certain specific amount of time post-oral ingestion, or at an approximately specific anatomic location in the gastrointestinal tract, or when the dosage form is in contact with specific gastrointestinal conditions (e.g., pH range, osmolality, electrolyte content, food content, pressure, time since first ingestion, osmotic pressure in the dosage form, osmotic pressure in the gastrointestinal tract, hydration, etc), said dosage form suitable for providing an orally effective therapeutic for a short, intermediate or extended duration of effect, said dosage form providing a rapid or delayed onset of clinical effect.
• specific gastrointestinal conditions e.g., pH range, osmolality, electrolyte content, food content, pressure, time since first ingestion, osmotic pressure in the dosage form, osmotic pressure in the gastrointestinal tract, hydration, etc
• the sustained release oral dosage form of the present invention is an osmotic dosage form which comprises a single layer or bilayer core comprising buprenorphine; an expandable polymer; a semipermeable membrane surrounding the core; and a passageway disposed in the semipermeable membrane for sustained release of the buprenorphine or pharmaceutically acceptable salt thereof, such that blood levels of active ingredient are maintained within the therapeutic range over an extended period of time when administered to patients.
• Other oral osmotic delivery systems may be used for the oral administration of buprenorphine.
• the oral buprenorphine is interdispersed and are not isolated from each other in two distinct layers.
• the oral buprenorphine is in the form of multiparticulates.
• the oral buprenorphine is dispersed in a matrix
• the oral buprenorphine is in the form of multiparticulates can be dispersed in a matrix or contained in a capsule.
• the oral buprenorphine is in the form of multiparticulates can be dispersed in a matrix and compressed into a tablet.
• the oral buprenorphine is in a matrix that is in the form of pellets.
• the oral buprenorphine is in coated beads.
• the dosage form of the invention comprises a compressed tablet, compressed capsule or uncompressed capsule. In other embodiments, the dosage form comprises a liquid fill capsule.
• the oral dosage in immediate or sustained release form provides therapeutic effects that persist despite the low or undectable buprenorphine concentrations.
• the dosage form of the invention comprises an oral formulation (e.g., tablet or capsule) which is coated to prevent substantial direct contact of buprenorphine with oral cavity (e.g. tongue, oral mucosa), oropharyngeal mucosal surface, esophagus or stomach.
• the dosage form of the invention comprises an oral formulation which is coated with a film or polymer.
• the dosage form of the invention comprises buprenorphine in an enteric coating.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said therapeutically effective amount in a reservoir comprising: (i) buprenorphine or a pharmaceutically acceptable salt of buprenorphine, or a mixture thereof; (ii) a membrane layer, said membrane being substantially permeable to buprenorphine; wherein the dosage form substantially releases the buprenorphine from the dosage form to render said dosage form suitable for extended release to a human patient.
• the dosage form provides an oral pharmaceutical composition comprising a plurality of pharmaceutically acceptable beads coated with a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine, or a mixture thereof; and overcoated with controlled release material to render said dosage form suitable for extended release oral administration to a human patient.
• the dosage form provides an oral pharmaceutical composition comprising (i) a drug layer comprising a therapeutically effective amount of buprenorphine; and (ii) a displacement layer comprising an osmopolymer; and (b) a semipermeable wall surrounding the bilayer core having a passageway disposed therein for the release of said buprenorphine or a pharmaceutically acceptable salt thereof; said dosage form suitable for extended release oral administration to a human patient.
• the oral dosage form is a controlled release material suitable for extended release in a human patient of the dosage form comprises a matrix.
• the said matrix is a plurality of multiparticulate matrices.
• the multiparticulates are compressed into a tablet.
• the multiparticulates are disposed in a pharmaceutically acceptable capsule.
• the controlled release material of the oral dosage form of the invention is selected from the group consisting of hydrophobic polymers, hydrophilic polymers, gums, protein derived materials, waxes, shellac, oils, fats and mixtures thereof.
• the controlled release material of the oral dosage form of the invention is selected from the group consisting of polyethylene oxide, polyvinyl alcohol, hydroxypropyl methyl cellulose, a carbomer and mixtures thereof.
• the oral dosage form comprises a plurality of pharmaceutically acceptable beads coated with drug and overcoated with controlled release material.
• the oral dosage form comprises (i) a drug layer
• a displacement layer comprising an osmopolymer; and (b) a semipermeable wall surrounding the bilayer core having a passageway disposed therein for the release of said drug.
• the oral dosage form comprises a compressed tablet, compressed capsule or uncompressed capsule. In some preferred embodiments, the oral dosage form comprises a liquid fill capsule.
• the in vivo pharmacokinetic parameters of the specifications, embodiments and claims are derived or determined under fed conditions. In other preferred embodiments, the in vivo pharmacokinetic parameters are derived or determined under fasted conditions.
• the present invention excludes immediate release dosage forms.
• the present invention excludes dosage forms devoid or material to render the dosage form as modified release, delayed release, extended release or controlled release.
• the oral dosage forms of buprenorphine exclude pharmaceutical compositions buprenorphine which when coated or encapsulated with any excipient where the coated or encapsulated particle is less than about 130 ⁇ m, or 200 ⁇ m, or 250 ⁇ m, or 400 ⁇ m, or 1000 ⁇ m, or 2000 ⁇ m, or 3000 ⁇ m, or 3500 ⁇ m.
• the oral dosage forms of buprenorphine exclude oral pharmaceutical compositions of buprenorphine which contain polyvinyl alcohol, or polyvinylpyrrolidone, or block copolymers of propylene oxide or ethylene oxide, or polyethylene glycol or tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine.
• the oral dosage forms of buprenorphine exclude oral pharmaceutical compositions of buprenorphine where the buprenorphine is encapsulated by polyvinyl alcohol, or polyvinylpyrrolidone, or block copolymers of propylene oxide or ethylene oxide, or polyethylene glycol or tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine.
• the oral dosage forms of buprenorphine exclude oral pharmaceutical compositions of buprenorphine where the buprenorphine is encapsulated by polyvinyl alcohol, or polyvinylpyrrolidone, or block copolymers of propylene oxide or ethylene oxide, or polyethylene glycol or tetrafunctional block copolymers derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine, said encapsulated particles having a particle of less than about 3000 ⁇ m, or 3500 ⁇ m.
• the oral dosage forms of buprenorphine exclude pharmaceutical compositions buprenorphine which are encapsulated with polyethylene glycol.
• the oral dosage forms of buprenorphine exclude pharmaceutical compositions buprenorphine which are encapsulated with polyethylene glycol, where the buprenorphine content of the composition is between about 2 parts in 1000 to about 4 parts in 100, or between about 1.5 parts in 1000 to about 4.5 parts or 5 parts in 100.
• the oral dosage form of the invention exclude oral immediate release forms of buprenorphine.
• the oral dosage form of the invention excludes oral immediate release dosage forms of buprenorphine which have been modified to enhance the solubility or bioavailability of the buprenorphine in the upper GI tract (e.g., by use of certain excipients or by physical manipulation of the buprenorphine or granulation), using methods well know in the art, including complexation (e.g., with cyclodextrins), or particle size reduction (e.g., micronization), or lipid suspensions, solutions, emulsions, microemulsions, or mixed micelles, or self-emulsifying drug delivery systems (SEDDS), or self-microemulsifying drug delivery systems (SMEDDS), or thixotropic vehicles, or surfactants, or solid dispersions, or liposomes, or co-solvents, or solvation.
• complexation e.g., with cyclodextr
• the oral dosage form of the invention excludes oral dosage forms of buprenorphine which have been modified to enhance the bioavailability of the buprenorphine in the upper GI tract.
• the oral dosage forms of buprenorphine are limited to controlled release buprenorphine. In some embodiments of the invention, the oral dosage forms of buprenorphine are limited to controlled release buprenorphine which are matrix or monolithic matrix formulations. In some embodiments of the invention, the oral dosage forms of buprenorphine exclude multiparticulate matrix controlled release buprenorphine formulations.
• the oral dosage forms of buprenorphine excludes controlled release buprenorphine formulations where the buprenorphine is in controlled release multiparticulates or controlled release microparticulates, where the buprenorphine is not entirely coated with polymer.
• the oral dosage forms of buprenorphine excludes controlled release buprenorphine formulations where the controlled release buprenorphine multiparticulates or microparticulates are less than about 130 ⁇ m, or 140 ⁇ m, or 150 ⁇ m, or 160 ⁇ m, or 180 ⁇ m, or 200 ⁇ m, or 250 ⁇ m, or 300 ⁇ m, or 350 ⁇ m, or 400 ⁇ m, or 450 ⁇ m, or 500 ⁇ m, or 550 ⁇ m, or 600 ⁇ m, or 650 ⁇ m.
• the oral dosage forms of buprenorphine are limited to controlled release buprenorphine which provide first release or first therapeutically beneficial release of buprenorphine not until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to controlled release buprenorphine which are overcoated with a pH sensitive material which dissolve at a pH ⁇ 4, or pH ⁇ 4.5, or pH, ⁇ 5, or pH ⁇ 5.5, or pH ⁇ 6, or pH ⁇ 6.5, or pH ⁇ 6.8, or pH ⁇ 7, or pH ⁇ 7.2.
• the oral dosage form of the invention excludes oral controlled release dosage forms of buprenorphine which have been modified to enhance the solubility or bioavailability of the buprenorphine in the upper GI tract through complexation (e.g., with cyclodextrins), or particle size reduction (e.g., micronization), or lipid suspensions, solutions, emulsions, microemulsions, mixed micelles, or self-emulsifying drug delivery systems (SEDDS), or self-microemulsifying drug delivery systems (SMEDDS), or thixotropic vehicles, or surfactants, or solid dispersions, or liposomes, or co-solvents, or solvation.
• complexation e.g., with cyclodextrins
• particle size reduction e.g., micronization
• lipid suspensions solutions, emulsions, microemulsions, mixed micelles, or self-emulsifying drug delivery systems (SEDDS), or self-microemuls
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provides an onset of therapeutic effect not before about 1, 1,5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours following first ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provides quantifiable or therapeutic or substantial plasma concentrations not before about 1, 1,5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours following first ingestion. In some embodiments of the invention, the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide quantifiable, or substantial plasma concentrations or therapeutic plasma concentrations not before about 1, 1,5, 2, 2.5 3, 3.5, 4, 4.5, 5, 5.5 or 6 hours following first ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which are osmotic delivery dosage forms (e.g., push pull osmotic pumps, monolithic osmotic delivery systems and controlled porosity osmotic pumps).
• osmotic delivery dosage forms e.g., push pull osmotic pumps, monolithic osmotic delivery systems and controlled porosity osmotic pumps.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which are osmotic delivery dosage forms, overcoated with a pH sensitive material which dissolve at a pH ⁇ 4, or pH ⁇ 4.5, or pH, ⁇ 5, or pH ⁇ 5.5, or pH ⁇ 6, or pH ⁇ 6.5, or pH ⁇ 6.8, or pH ⁇ 7, or pH ⁇ 7.2.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide release of all, substantially all, or most of the buprenorphine only at pH > 4, or pH >4.5, or pH, > 5, or pH > 5.5, or pH > 6, or pH > 6.5, or pH > 7, or pH > 7.5, or pH > 7.8 upon dissolution using the USP Paddle Method for 2 hours at 37 0 C at 100 rpm in 900 mL distilled water adjusted for pH.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide release of all, substantially all, or most of the buprenorphine distal to the stomach, distal to the duodenum, distal to the jejunum, distal to the ileum, or distal to the ileo-cecal junction.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide release of all, substantially all, or most of the buprenorphine at least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which begin the release of all, substantially all, most, or some of the buprenorphine at least about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide the intended therapeutic effect not until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide all, substantially all, most, or some of the intended therapeutic effect not until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which begin to provide all, substantially all, most, or some of the intended therapeutic effect not until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide a psychic effect in recreational drug or opioid users and drug or opioid abusers not until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine provide a psychic effect in recreational drug or opioid users and drug or opioid abusers not until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which begin to provide a psychic effect in recreational drug or opioid users and drug or opioid abusers not until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which result in little or no nausea, or little or no sedation until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which result in little or no nausea, or little or no sedation until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which result in little or no nausea, or little or no sedation until about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 hours after first oral ingestion, preferably at least about 2, 2.5, 3, 3.5, or 4 hours after first oral ingestion.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide all, substantially all, most, or some of the release of buprenorphine from the dosage form distal to the stomach, or distal to the duodenum, or distal to the jejunum, or distal to the ileum, or distal to the ileo-cecal junction, or in the colon.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which begins to provide all, substantially all, most, or some of the release of buprenorphine from the dosage form distal to the stomach, or distal to the duodenum, or distal to the jejunum, or distal to the ileum, or distal to the ileo-cecal junction, or in the colon.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide release of buprenorphine from the dosage form in the duodenum and jejunum, or in the duodenum, jejunum and ileum, or in duodenum, jejunum, ileum and colon.
• the oral dosage forms of buprenorpbine are limited to modified release buprenorphine which provide release of buprenorphine from the dosage form in the ileum and colon.
• the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide release of buprenorphine from the dosage form in the ileo-colonic region. In some embodiments of the invention, the oral dosage forms of buprenorphine are limited to modified release buprenorphine which provide release of buprenorphine from the dosage form in the colon.
• the oral dosage forms of buprenorphine are limited to buprenorphine without an additional therapeutic agent (e.g., acetaminophen, COX- 2 inhibitor, NSAID, methadone) incorporated in the dosage form or given concurrently with the dosage form of the invention.
• the oral dosage forms of buprenorphine are limited to buprenorphine without an additional therapeutic agent to treat the same medical condition or to enhance the effect of the buprenorphine which is incorporated in the dosage form or given concurrently with the dosage form of the invention.
• the invention excludes oral buprenorphine pharmaceutical compositions which provide a more rapid onset of action of buprenorphine compared with sublingual buprenorphine, or orally ingested buprenorphine active pharmaceutical ingredient (API), or oral buprenorphine made using conventional excipients.
• the invention excludes oral controlled-release formulations buprenorphine pharmaceutical compositions which a more rapid onset of action compared with sublingual buprenorphine, buccal buprenorphine, or oral buprenorpbine API or oral immediate release buprenorphine.
• the invention excludes oral buprenorphine pharmaceutical compositions for the treatment of acute pain. In some embodiments, the invention excludes oral buprenorphine pharmaceutical compositions for the treatment of addiction disorders.
• the invention excludes oral buprenorphine pharmaceutical compositions which provide more rapid (or “improved") dissolution of the buprenorphine when compared with sublingual buprenorphine, or orally ingested buprenorphine active pharmaceutical ingredient (e.g., uncompressed powder in a capsule), or oral immediate release buprenorphine made using conventional excipients.
• oral buprenorphine pharmaceutical compositions which provide more rapid (or “improved") dissolution of the buprenorphine when compared with sublingual buprenorphine, or orally ingested buprenorphine active pharmaceutical ingredient (e.g., uncompressed powder in a capsule), or oral immediate release buprenorphine made using conventional excipients.
• the invention excludes oral buprenorphine pharmaceutical compositions which provide greater than 65%, or greater than 75%, or greater than 85% release of buprenorphine form the dosage form when measured by USP Paddle Method at 50 or 100 rpm in 900 mL of 0.1 N HCl buffer (at any pH between 1.6 and 3) at 37 0 C after 45 minutes.
• the invention excludes oral buprenorphine pharmaceutical compositions which provide greater than about 50%, or about 60% or about 70%, or about 80% release of buprenorphine form the dosage form when measured by USP Paddle Method at 50 or 100 rpm in 900 mL of pH 6.8 buffer at 37 0 C after 60 minutes.
• the oral dosage form of buprenorphine contains an antioxidant in a molar ratio between antioxidant and buprenorphine greater than 3:1. In some embodiments of the invention, the oral dosage forms of buprenorphine exclude oral pharmaceutical compositions buprenorphine which contain an antioxidant in any amount. In some embodiments of the invention, the oral dosage form contains an antioxidant which is sequestered or substantially sequestered in the push layer of the dosage form. In some embodiments of the invention, the oral dosage form contains no antioxidant in the buprenorphine containing pull layer or reservoir but does contain an antioxidant in the push layer of the dosage form.
• the oral dosage form contains an antioxidant which is not commingled or interspersed with the buprenorphine. In some embodiments of the invention, the oral dosage form contains an antioxidant which is not in contact or substantial contact with the buprenorphine. In some embodiments of the invention, the oral dosage form contains an antioxidant which does not provide anti-oxidant properties to the buprenorphine or protect the buprenorphine from oxidation by virtue of being in a separate compartment (e.g., push layer of an osmotic delivery system), said antioxidant protecting other excipients in the separate compartment (e.g., push layer) from oxidation.
• a separate compartment e.g., push layer of an osmotic delivery system
• the oral dosage forms of buprenorphine is devoid of antioxidants selected from the group comprising ascorbic acid, or vitamin E, or tocopherol, or sodium metabisulf ⁇ te, or butylated hydroxyanisole, or butylated hydroxytoluene, or alpha-lipoic acid, and mixtures thereof.
• the oral dosage forms of buprenorphine is devoid of antioxidants selected from the group comprising ascorbic acid, or ascorbyl palmitate, or butylated hydroxyanisole, or butylated hydroxytoluene, or hypophosphorous acid, or monothioglycerol, or potassium metabisulfite, or propyl gallate, or sodium bisulfite, or sodium formaldehyde sulfoxylate, or sodium metabisulf ⁇ te, or sodium sulfite, or sodium thiosulfate, or sulfur dioxide, or tocopherol, or tocopherols excipient and mixtures thereof.
• antioxidants selected from the group comprising ascorbic acid, or ascorbyl palmitate, or butylated hydroxyanisole, or butylated hydroxytoluene, or hypophosphorous acid, or monothioglycerol, or potassium metabisulfite, or propyl gallate, or sodium bisulfite, or sodium formaldehyde s
• the oral dosage forms of buprenorphine are devoid of antioxidants. In some embodiments of the invention, the oral dosage forms of buprenorphine do not contain antioxidants in a molar ratio between antioxidant and buprenorphine from 1:1 to 3:1 or in a molar ratio of antioxidant and buprenorphine ranging which is less than 1:1. In some embodiments, the foregoing limitation in amount or any use of antioxidant refers to ascorbic acid, or vitamin E, or tocopherol, or sodium metabisulfite, or butylated hydroxyanisole, or butylated hydroxytoluene, or alpha-lipoic acid, and mixtures thereof.
• the oral dosage forms of buprenorphine include magnesium.
• the oral dosage forms of buprenorphine exclude chelating agents.
• the foregoing limitation in any use of chelating agent refers to is limited, said chelating agent is edetic acid, or malic acid, and mixtures thereof.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of pain.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of chronic pain.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of neuropathic pain.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of cancer pain.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of pain, excluding acute pain.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of pain, excluding acute postsurgical pain.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of pain which is unresponsive to other oral formulations of opioid analgesics, particularly full or pure mu opioid agonists.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of pain which is unresponsive to other oral formulations of pure or full mu-opioid receptor agonists.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended for the treatment of pain which is unresponsive to sublingual buprenorphine.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended for the treatment of pain which is unresponsive to transdermal buprenorphine.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of pain in patients with an addiction disorder or at significant risk of an addiction disorder.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of addiction disorders.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of opioid addiction disorders.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment of addiction disorders unresponsive to methadone.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for treatment unresponsive to sublingual, lingual, or buccal buprenorphine.
• the dosage form provides an oral extended release pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for treatment unresponsive to oral immediate release buprenorphine.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; said dosage form intended solely for the treatment unresponsive to buprenorphine dosage forms intended to be significantly absorbed through the oral cavity oral mucosa (e.g., lozenges, orally disintegrating tablets, fast dissolving tablets, effervescent tablets, buccal dosage forms, sublingual dosage forms, lingual dosage forms or muco-retentive dosage forms),
• kits of the dosage forms including kits for titration disclosed herein.
• the invention in another aspect, relates to a method for prevention or treatment of pain, cough, dyspnea, opioid addiction disorders, restless leg syndrome, acute herpes zoster, visceral pain, breakthrough pain, opioid dependence and urinary incontinence, comprising oral administration of a dosage form containing buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• the invention in another aspect, relates to a method for prevention or treatment of buprenorphine responsive or opioid responsive medical conditions, comprising oral administration of a dosage form containing buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said dosing regimen associated with reduced side effects, improved tolerability, improved efficiency of therapeutic response, reduced breakthrough symptoms (e.g., breakthrough pain) and reduced treatment discontinuation due to side effects.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; optionally, an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said dosing regimen associated with reduced side effects, improved tolerability, improved efficiency of therapeutic response, reduced breakthrough symptoms (e.g., breakthrough pain) and reduced treatment discontinuation due to side effects.
• a therapeutically effective amount of buprenorphine optionally, an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient
• said dosage form administered at a prespecif ⁇ ed dosing regimen
• said dosing regimen associated with reduced side effects, improved tolerability, improved efficiency of therapeutic response, reduced breakthrough symptoms (e.g., breakthrough pain) and reduced treatment discontinuation due to side effects
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for oral immediate release in a human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said dosing regimen associated with reduced side effects, improved tolerability, improved efficiency of therapeutic response, reduced breakthrough symptoms (e.g., breakthrough pain) and reduced treatment discontinuation due to side effects.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; optionally; said dosage form intended to treat pediatric patients; said dosage form administered at a prespecif ⁇ ed dosing regimen; said dosing regimen as provided herein, except that the dose or total daily dose (as applicable) is multiplied by the ratio obtained from the child's weight in kilograms divided by 70 kilograms.
• plasma Ti ag refers to a time period from first administration (or first dosing) of buprenorphine to the occurrence of first of two consecutive plasma buprenorphine concentrations of not less than 50 pg/mL per mg of administered buprenorphine base, provided that the second consecutive buprenorphine plasma concentration is obtained not more than 10 minutes and not less than 30 minutes after the first plasma buprenorphine concentration.
• the plasma T ⁇ ag of the oral buprenorphine dosage form is more than about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 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 or 12 hours.
• the plasma Ti ag of the oral buprenorphine dosage form is more than about 1.5, 2, 2.25, 2.5, 2.75, 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 or 12 hours, more preferably, more than about 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 5.5, or 6 hours.
• the plasma Ti ag of the oral buprenorphine dosage form is more than about 1.5, 2, 2.25, 2.5, 2.75, 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 or 12 hours, more preferably, more than about 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 4.5, 5, 5.5, or 6 hours.
• T ⁇ ag(X) refers to the time from the start of dissolution testing to the first attainment of an in-vitro release of about 5% by weight of the active drug from the dosage form rate when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL of dissolution media at 37 0 C, where "( X )" is the pH of the dissolution media.
• the T ⁇ ag (5.o), Ti ag (5.5), Ti ag (6.8) Ti ag (7.o), and Ti ag ( 7 .2) of the oral buprenorphine dosage form is more than about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, or 4 hours, preferably more than about 2, 2.25, 2.5, 2.75, or 3 hours .
• the oral dosage form of the invention incorporates controlled release material, the Ti ag (5.o), Ti ag (5.5), Ti ag ( 6 . 8 ) Ti ag ( 7 .o), and T
• the oral buprenorphine dosage form is more than about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, or 4 hours, preferably more than about 2, 2.25, 2.5, 2.75, or 3 hours.
• the Ti ag ( 72 ) of the oral buprenorphine dosage form is more than about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.5, or 4 hours, preferably more than about 2, 2.25, 2.5, 2.75, or 3 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form releasing or delivering buprenorphine at a controlled rate of release of about 0.05 mg/hr, or 0.1 mg/hr, or 0.2 mg/hr, or 0.3 mg/hr, or 0.4 mg/hr, or 0.5 mg/hr, or 0.6 mg/hr, or 0.7 mg/hr, or 0.8 mg/hr, or 0.9 mg/hr, or 1 mg/hr, or 1.1 mg/hr, or 1.2 mg/hr, or 1.3 mg/hr, or 1.4 mg/hr, or 1.5 mg/hr, or 1.6 mg/hr, or 1.7 mg/hr, or 1.8 mg/hr, or 2 mg/hr, or 2.2 mg/hr, or 2.3 mg/hr, or 2.4 mg/hr, or 2.5 mg/hr, or 2.6 mg/hr, or 2.7
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for extended release in a human patient, said dosage form releasing or delivering buprenorphine at a controlled rate of release of about 0.1 mg/hr, or 0.2 mg/hr, or 0.3 mg/hr, or 0.4 mg/hr, or 0.5 mg/hr, or 0.6 mg/hr, or 0.7 mg/hr, or 0.8 mg/hr, or 0.9 mg/hr, or 1 mg/hr, or 1.1 mg/hr, or 1.2 mg/hr, or 1.3 mg/hr, or 1.4 mg/hr, or 1.5 mg/hr, or 1.6 mg/hr, or 1.7 mg/hr, or 1.8 mg/hr, or 2 mg/hr, or 2.2 mg/hr, or 2.3 mg/hr, or 2.4 mg/hr, or 2.5 mg/hr, or
• the oral buprenorphine dosage form incorporates a controlled release material to render said dosage form suitable for extended release in a human patient
• said dosage form releases or delivers buprenorphine at a controlled rate of release of 0.22 mg/hr to 2.5 mg/hr, more preferably, 0.22 mg/hr to 1.8 mg/hr, or 0.22 mg/hr to 1.7 mg/hr.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form releasing or delivering buprenorphine at a controlled rate of release of about 0.1 mg/hr to about 8 mg/hr, or about 0.2 mg/hr to about 8 mg/hr, or about 0.3 mg/hr to about 8 mg/hr, or about 0.4 mg/hr to about 8 mg/hr, or 0.5 mg/hr to about 8 mg/hr, or 0.6 mg/hr to about 8 mg/hr, or about 0.7 mg/hr to about 8 mg/hr, or about 0.8 mg/hr to about 8 mg/hr, or about 0.9 mg/hr to about 8 mg/hr, or about 1 mg/hr to about 8 mg/hr, or about 1.2 mg/hr to about 8 mg/hr, or about 1.4 mg/hr to about 8 mg/hr, or 1.5 mg/hr to about 8 mg/
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for extended release in a human patient, said dosage form releasing or delivering buprenorphine at a controlled rate of release of about 0.1 mg/hr to about 8 mg/hr, or about 0.2 mg/hr to about 8 mg/hr, or about 0.3 mg/hr to about 8 mg/hr, or about 0.4 mg/hr to about 8 mg/hr, or 0.5 mg/hr to about 8 mg/hr, or 0.6 mg/hr to about 8 mg/hr, or about 0.7 mg/hr to about 8 mg/hr, or about 0.8 mg/hr to about 8 mg/hr, or about 0.9 mg/hr to about 8 mg/hr, or about 1 mg/hr to about 8 mg/hr, or about 1.2 mg/hr to about 8 mg/hr, or about 1.4 mg/hr to
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for extended release in a human patient, said dosage form releasing or delivering buprenorphine at a controlled rate of release of about 0.1 mg/hr to about 6 mg/hr, or about 0.2 mg/hr to about 6 mg/hr, or about 0.3 mg/hr to about 6 mg/hr, or about 0.4 mg/hr to about 6 mg/hr, or 0.5 mg/hr to about 6 mg/hr, or 0.6 mg/hr to about 6 mg/hr, or about 0.7 mg/hr to about 6 mg/hr, or about 0.8 mg/hr to about 6 mg/hr, or about 0.9 mg/hr to about 6 mg/hr, or about 1 mg/hr to about 6 mg/hr, or about 1.2 mg/hr to about 6 mg/hr, or about 1.4 mg/hr to
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for extended release in a human patient, said dosage form releasing or delivering buprenorphine at a controlled rate of release of about 0.1 mg/hr to about 4 mg/hr, or about 0.2 mg/hr to about 4 mg/hr, or about 0.3 mg/hr to about 4 mg/hr, or about 0.4 mg/hr to about 4 mg/hr, or 0.5 mg/hr to about 4 mg/hr, or 0.6 mg/hr to about 4 mg/hr, or about 0.7 mg/hr to about 4 mg/hr, or about 0.8 mg/hr to about 4 mg/hr, or about 0.9 mg/hr to about 4 mg/hr, or about 1 mg/hr to about 4 mg/hr, or about 1.2 mg/hr to about 4 mg/hr, or about 1.4 mg/hr to
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for extended release in a human patient, said dosage form releasing or delivering buprenorphine at a controlled rate of release of about 0.1 mg/hr to about 3 mg/hr, or about 0.2 mg/hr to about 3 mg/hr, or about 0.3 mg/hr to about
• 3 mg/hr or about 0.4 mg/hr to about 3 mg/hr, or 0.5 mg/hr to about 3 mg/hr, or 0.6 mg/hr to about 3 mg/hr, or about 0.7 mg/hr to about 3 mg/hr, or about 0.8 mg/hr to about 3 mg/hr, or about 0.9 mg/hr to about 3 mg/hr, or about 1 mg/hr to about 3 mg/hr, or about 1.2 mg/hr to about 3 mg/hr, or about 1.4 mg/hr to about 3 mg/hr, or 1.5 mg/hr to about 3 mg/hr, or 1.6 mg/hr to about 3 mg/hr, or about 1.8 mg/hr to about 3 mg/hr, or about 2 mg/hr to about 3 mg/hr.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for extended release in a human patient, said dosage form releasing or delivering buprenorphine at a controlled rate of release of about 0.1 mg/hr to about 4 mg/hr, or about 0.2 mg/hr to about 4 mg/hr, or about 0.3 mg/hr to about
• 4 mg/hr or about 0.4 mg/hr to about 4 mg/hr, or 0.5 mg/hr to about 4 mg/hr, or 0.6 mg/hr to about 4 mg/hr, or about 0.7 mg/hr to about 4 mg/hr, or about 0.8 mg/hr to about 4 mg/hr, or about 0.9 mg/hr to about 4 mg/hr, or about 1 mg/hr to about 4 mg/hr, or about 1.2 mg/hr to about 4 mg/hr, or about 1.4 mg/hr to about 4 mg/hr, or 1.5 mg/hr to about 4 mg/hr, or 1.6 mg/hr to about 4 mg/hr, or about 1.8 mg/hr to about 4 mg/hr, or about 2 mg/hr to about 4 mg/hr.
• the oral buprenorphine dosage form incorporates a controlled release material to render it as extended release suitable for dosing every 6 hours
• said dosage form releases or delivers buprenorphine at a controlled rate of release for a period of about 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours.
• the oral buprenorphine dosage form incorporates a controlled release material to render it as extended release suitable for dosing every 8 hours
• said dosage form releases or delivers buprenorpbine at a controlled rate of release for a period of about 4, 5, 6, 7, 8, 9, 10 or 12 hours.
• the oral buprenorphine dosage form incorporates a controlled release material to render it as extended release suitable for dosing every 12 hours
• said dosage form releases or delivers buprenorphine at a controlled rate of release for a period of about 7, 8, 9, 10, 11, 12, 14, 16 or 18 hours.
• the oral buprenorphine dosage form incorporates a controlled release material to render it as extended release suitable for dosing every 24 hours
• said dosage form releases or delivers buprenorphine at a controlled rate of release for a period of about 12, 14, 16, 18, 20, 22, 24, 26 or 30 hours.
• the oral buprenorphine dosage form incorporates a controlled release material to render it delayed onset (e.g., release or delivery of drug distal to the stomach, duodenum, or ileum) and where said delayed onset dosage form is intended to provide rapid release or burst release upon reaching the target GI anatomic location or GI environment, or at a desired time after oral ingestion (e.g., 2 to 6 hours), the dosage form releases or delivers buprenorphine in less than about 15, 30, 60, 90, 120, 160, 180 or 240 minutes, preferably in less than about 15, 30, 60, 90, or 120 minutes.
• a controlled release material e.g., release or delivery of drug distal to the stomach, duodenum, or ileum
• the delayed onset dosage form is intended to provide rapid release or burst release upon reaching the target GI anatomic location or GI environment, or at a desired time after oral ingestion (e.g., 2 to 6 hours)
• the dosage form releases or delivers buprenorphine in
• controlled rate of release refers to the release or delivery of the active drug from the oral dosage form of the invention at rate per unit time over an extended period of time, or any time period over thirty-minutes up to thirty hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose of about 10 mg to about 20 mg for about 4 to about 10 days, then about 22 mg to about 40 mg for about 4 to about 10 days, and then about 50 mg to 600 mg for at least 1 day and optionally thereafter; or a dose of about 5 mg to about 20 mg for about 2 to about 7 days, then about 22 mg to about 60 mg for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 20 mg for about 1 to about 7 days, then about 5 mg to about 40 mg for at least 1 day and optionally thereafter; or a dose of about 10 mg to about 20 mg for about 2 to about 7 days, then about 22 mg to about 40 mg for at least 1 day and optionally thereafter;
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose of about 1 mg to about 5 mg for about 4 to about 10 days, then about 6 mg to about 10 mg for about 4 to about 10 days, and then about 12 mg to 200 for at least 1 day and optionally thereafter; or a dose of about 5 mg to about 20 mg for about 2 to about 7 days, then about 22 mg to about 60 mg for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 20 mg for about 1 to about 7 days, then about 5 mg to about 40 mg for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 8 mg for about 2 to about 7 days, then about 10 mg to about 15 mg for about 2 to about 7 days, and then about 16 mg to 200 for at least 1 day and optional
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose of about 1 mg to about 5 mg for about 2 to about 4 days, then about 6 mg to about 10 mg for about 2 to about 4 days, and then about 12 mg to 200 for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 8 mg for about 1 to about 4 days, then about 10 mg to about 15 mg for about 1 to about 4 days, and then about 16 mg to 200 for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 5 mg for about 1 to about 4 days, then about 6 mg to about 10 mg for about 1 to about 4 days, and then about 12 mg to 200 for at least 1 day and optionally thereafter; or about 5 mg to about 8 mg for about 2 to about 4 days, then about 10 mg to about 20 mg for about 2 to about 4 days, and
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a total daily dose of a dose of about 10 mg to about 20 mg for about 4 to about 10 days, then about 22 mg to about 40 mg for about 4 to about 10 days, and then about 50 mg to 600 mg for at least 1 day and optionally thereafter; or a dose of about 5 mg to about 20 mg for about 2 to about 7 days, then about 22 mg to about 60 mg for at least
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a total daily dose of about 1 mg to about 5 mg for about 4 to about 10 days, then about 6 mg to about 10 mg for about 4 to about 10 days, and then about 12 mg to 200 for at least 1 day and optionally thereafter; or a dose of about 5 mg to about 20 mg for about 2 to about 7 days, then about 22 mg to about 60 mg for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 8 mg for about 2 to about 7 days, then about 10 mg to about 15 mg for about 2 to about 7 days, and then about 16 mg to 200 for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 5 mg for about 2 to about 7 days, then about 6 mg to about 10 mg for about 2 to about
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a total daily dose of about 1 mg to about 5 mg for about 1 to about 4 days, then about 6 mg to about 10 mg for about 1 to about 4 days, and then about 12 mg to 200 for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 8 mg for about 1 to about 4 days, then about 10 mg to about 15 mg for about 1 to about 4 days, and then about 16 mg to 200 for at least 1 day and optionally thereafter; or a dose of about 2 mg to about 5 mg for about 1 to about 4 days, then about 6 mg to about 10 mg for about 1 to about 4 days, and then about 12 mg to 200 for at least 1 day and optionally thereafter; or about 5 mg to about 8 mg for about 1 to about 4 days, then about 10 mg to about 20 mg for about 1 to
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; optionally; said dosage form intended to treat pediatric patients; said dosage form administered at a prespecified dosing regimen; said dosing regimen providing a mean buprenorphine and norbuprenorphine area under the plasma concentration time curve (AUC) as provided herein, except that the AUC is multiplied by the ratio obtained from the child's weight in kilograms divided by 70 kilograms.
• AUC plasma concentration time curve
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 15000 pg.hr/mL for about 1 to about 10 days, then about 5000 pg.hr/mL to about 40000 pg.hr/mL for at least 1 day and optionally thereafter; or about 5000 pg.hr/mL to about 20000 pg.hr/mL for about 1 to about 10 days, then about 7500 pg.hr/mL to about 80000 pg.
• AUCo -24 mean bu
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 15000 pg.hr/mL for about 1 to about 10 days, then about 5000 pg.hr/mL to about 40000 pg.hr/mL for at least 1 day and optionally thereafter; or about 5000 pg.hr/mL to about 20000 pg.hr/mL for about 1 to about 10 days, then about 7500 pg.hr/mL to about 80000 pg.hr/mL
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 15000 pg.hr/mL for about 1 to about 10 days, then about 5000 pg.hr/mL to about 40000 pg.hr/mL for at least 1 day and optionally thereafter; or about 5000 pg.hr/mL to about 20000 pg.hr/mL for about 1 to about 10 days, then about 7500 pg.hr/mL to about 80000 pg.h
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 15000 pg.hr/mL for about 1 to about 10 days, then about 5000 pg.hr/mL to about 40000 pg.hr/mL for at least 1 day and optionally thereafter; or about 5000 pg.hr/mL to about 20000 pg.hr/mL for about 1 to about 10 days, then about 7500 pg.hr/mL to about 80000 pg.hr
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 15000 pg.hr/mL for about 1 to about 10 days, then about 5000 pg.hr/mL to about 40000 pg.hr/mL for at least 1 day and optionally thereafter; or about 5000 pg.hr/mL to about 20000 pg.hr/mL for about 1 to about 10 days, then about 7500 pg.hr/mL to about 80000 pg.h
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 15000 pg.hr/mL for about 1 to about 10 days, then about 5000 pg.hr/mL to about 40000 pg.hr/mL for at least 1 day and optionally thereafter; or about 5000 pg.hr/mL to about 20000 pg.hr/mL for about 1 to about 10 days, then about 7500 pg.hr/mL to about 80000 pg
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 4 to about 10 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 4 to about 10 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -24 of about 2500 pg.hr/mL to about 7
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 4 to about 10 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 4 to about 10 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -24 of about 2500 pg.hr/mL to
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 2 to about 7 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 2 to about 7 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUC 0-24 of about 2500 pg.hr/mL
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 2 to about 7 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 2 to about 7 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -24 of about 2500 pg.hr/mL to
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 1 to about 4 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 1 to about 4 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -24 of about 2500 pg.hr/mL
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to 24 hours post-dose (AUCo -24 ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 1 to about 4 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 1 to about 4 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -24 of about 2500 pg.hr/mL to
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to infinity (AUCo- mf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 4 to about 10 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 4 to about 10 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo-i nf of about 2500 pg.hr/m
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to infinity (AUCo -inf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 4 to about 10 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 4 to about 10 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo- mf of about 2500 pg.hr/mL to about 7500
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to infinity (AUCo- mf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 2 to about 7 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 2 to about 7 days, and then about 5000 pg.hr/niL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -mf of about 2500 pg.hr/mL to about
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to infinity (AUCo-i nf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 2 to about 7 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 2 to about 7 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUC 0- i nf of about 2500 pg.hr/
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to infinity (AUCo- mf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 1 to about 4 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 1 to about 4 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -inf of about 2500 pg.hr/mL to about 7
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean buprenorphine area under the plasma concentration time curve to infinity (AUCo- mf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 1 to about 4 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 1 to about 4 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo- mf of about 2500 pg.hr/mL to about 7500
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to infinity (AUCo -mf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 4 to about 10 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 4 to about 10 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo- mf of about 2500 pg.hr/m
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to infinity (AUCo-i nf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 4 to about 10 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 4 to about 10 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUC 0- i nf of about 2500 pg.hr/mL
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to infinity (AUCo- mf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 2 to about 7 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 2 to about 7 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUC 0-mf of about 2500 pg.hr/mL to about 7
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecified dosing regimen; said dosage form administered at a prespecii ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to infinity (AUCo -mf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 2 to about 7 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 2 to about 7 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -inf of about 2500 pg.hr/m
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; an oral controlled release material to render said dosage form suitable for extended release, or delayed onset, extended release or delayed onset, rapid release or delayed onset, pulsatile release human patient; said dosage form administered at a prespecified dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to infinity (AUCo-i nf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 1 to about 4 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 1 to about 4 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo-i nf of about 2500 pg.hr/mL
• the oral controlled release material is optional.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form suitable for immediate release in a human patient; said dosage form administered at a prespecif ⁇ ed dosing regimen; said dosage form administered at a prespecif ⁇ ed dosing regimen; said regimen comprising administering a dose which provides a mean norbuprenorphine area under the plasma concentration time curve to infinity (AUCo- mf ) of about 1000 pg.hr/mL to about 5000 pg.hr/mL for about 1 to about 4 days, then about 2500 pg.hr/mL to about 7500 pg.hr/mL for about 1 to about 4 days, and then about 5000 pg.hr/mL to about 500,000 pg.hr/mL for at least 1 day and optionally thereafter; or an AUCo -inf of about 2500 pg.hr
• the dosage form containing buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof is an extended release form.
• Oral, extended release buprenorphine has several distinct advantages over oral immediate release opioids and over sublingual, lingual and buccal dosage forms, including fewer interruptions in sleep, reduced dependence on caregivers, improved compliance, enhanced quality of life outcomes, and increased control over the management of then- malady (e.g., pain).
• such formulations can provide more constant plasma concentrations and clinical effects, less frequent peak to trough fluctuations and fewer side effects.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof; optionally, a controlled release material to render said dosage form suitable for up to every 24 hour (once- a-day) administration to a human patient; said dosage form providing at least 10% of the steady state concentration of buprenorphine and norbuprenorphine after administration of one dose at its intended dosing frequency.
• the dosage form provides at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90% of the steady state therapeutic concentration of buprenorphine after administration of one dose or two doses at their intended dosing frequency.
• the invention provides a method of providing relief in a human patient suffering from pain comprising a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• the invention provides a method of providing relief in a human patient suffering from cough, dyspnea, opioid addiction disorders, restless leg syndrome, acute herpes zoster, visceral pain, breakthrough pain, opioid dependence and urinary incontinence comprising a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• the invention provides a method of providing relief in a human patient suffering from a buprenorphine responsive medical condition comprising a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for three times a day administration (or about every eight hours administration).
• the oral pharmaceutical composition provides a therapeutic effect for about 1, 2, 3, 4, 5, or 6 hours.
• the oral pharmaceutical composition is used on a time contingent basis.
• the oral pharmaceutical composition is used on a pain contingent basis.
• the QID or Q6H oral pharmaceutical composition provides a therapeutic effect for about 6 hours.
• the TID or Q8H oral pharmaceutical composition provides a therapeutic effect for about 8 hours.
• the Q4H or Q4H PRN oral pharmaceutical composition provides a C max of buprenorphine and norbuprenorphine at about 1 to about 4 hours.
• the Q4H or Q4H PRN oral pharmaceutical composition provides a C m j n of buprenorphine and norbuprenorphine at about 3 to 6 hours.
• the Q4H or Q4H PRN oral pharmaceutical composition provides a mean buprenorphine AUCo-mf after first administration or AUC 0-4 at steady state of about 50 pg.hr/mL to about 20,000 pg.hr/mL.
• the Q4H or Q4H PRN oral pharmaceutical composition provides a mean of buprenorphine and norbuprenorphine C ⁇ Cmax ratio of 0.05 to about 1.25.
• the Q4H or Q4H PRN oral pharmaceutical composition provides a buprenorphine and norbuprenorphine percent fluctuation of less than
• the Q4H or Q4H PRN oral pharmaceutical composition provides of buprenorphine and norbuprenorphine W 50 of 0.5 to about 3.5 hours.
• the Q4H or Q4H PRN oral pharmaceutical composition provides a HVD of buprenorphine and norbuprenorphine of 0.75 to about 3.75 hours.
• the Q4H or Q4H PRN oral pharmaceutical composition provides an AI of buprenorphine and norbuprenorphine of not more than 4.0.
• the Q6H or Q6H PRN oral pharmaceutical composition provides a C max of buprenorphine and norbuprenorphine at about 1 to about 6 hours.
• the Q6H or Q6H PRN oral pharmaceutical composition provides a C m i n of buprenorphine and norbuprenorphine at about 3 to 8 hours.
• the Q6H or Q6H PRN oral pharmaceutical composition provides a mean buprenorphine AUCo- mf after first administration or AUC 0-4 at steady state of about 50 pg.hr/mL to about 20,000 pg.hr/mL.
• the Q6H or Q6H PRN oral pharmaceutical composition provides a mean of buprenorphine and norbuprenorphine CyCmax ratio of 0.05 to about 1.25.
• the Q6H or Q6H PRN oral pharmaceutical composition provides a buprenorphine and norbuprenorphine percent fluctuation of less than
• the Q6H or Q6H PRN oral pharmaceutical composition provides of buprenorphine and norbuprenorphine W 5 o of 1.0 to about 5 hours.
• the Q6H or Q6H PRN oral pharmaceutical composition provides a HVD of buprenorphine and norbuprenorphine of 1.25 to about 5.5 hours.
• the Q6H or Q6H PRN oral pharmaceutical composition provides an AI of buprenorphine and norbuprenorphine of not more than 4.0.
• the TID or Q8H oral pharmaceutical composition provides a C m3x of buprenorphine and norbuprenorphine at about 1 to about 6 hours. [573] In some preferred embodiments, the TID or Q8H oral pharmaceutical composition provides a C m j n of buprenorphine and norbuprenorphine at about 6 to 10 hours.
• the TID or Q8H oral pharmaceutical composition provides a mean buprenorphine AUC 0 .j n f after first administration or AUCo -8 at steady state of about 125 pg.hr/mL to about 150,000 pg.hr/mL, or about 125 pg.hr/mL to about 100,000 pg.hr/mL, or about 125 pg.hr/mL to about 75,000 pg.hr/mL, or about 125 pg.hr/mL to about 50,000 pg.hr/mL, or about 125 pg.hr/mL to about 30,000 pg.hr/mL, or about 125 pg.hr/mL to about 20,000 pg.hr/mL, or
• the TID or Q8H oral pharmaceutical composition provides a mean of buprenorphine and norbuprenorphine C 8 /Cmax ratio of 0.05 to about 1.25.
• the TID or Q8H oral pharmaceutical composition provides an buprenorphine and norbuprenorphine percent fluctuation of less than 400%.
• the TID or Q8H oral pharmaceutical composition provides of buprenorphine and norbuprenorphine W 50 of 1.5 to about 6.5 hours.
• the TID or Q8H oral pharmaceutical composition provides a HVD of buprenorphine and norbuprenorphine of 2 to about 7 hours.
• the TID or Q8H oral pharmaceutical composition provides an AI of buprenorphine and norbuprenorphine of not more than 4.0.
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage from providing a C m3x of buprenorphine and norbuprenorphine from about 200 pg/mL to about 40,000 pg/mL.
• the dosage form provides a C max of buprenorphine and norbuprenorphine of about 400 pg/mL to about 40,000 pg/mL, or about 600 pg/mL to about 40,000 pg/mL or about 800 pg/mL to about 40,000 pg/mL, or about 1000 pg/mL to about 40,000 pg/mL or about 2000 pg/mL to about 40,000 pg/mL, or about 3000 pg/mL to about 40,000 pg/mL or about 4000 pg/mL to about 40,000 pg/mL or about 5000 pg/mL to about 40,000 pg/mL, or about 6000 pg/mL to about 40,000 pg/mL or about 7000 pg/mL to about 40,000 pg/mL, or about 8000 pg/mL to about 40,000 pg/mL or about 200 pg
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage from providing a C 13x of buprenorphine and/or norbuprenorphine from about 20 pg/mL to about 6000 pg/mL.
• the dosage form provides a C max of buprenorphine and norbuprenorphine of about 40 pg/mL to about 6000 pg/mL, or about 50 pg/mL to about 6000 pg/mL, or about 75 pg/mL to about 6000 pg/mL, or about 100 pg/mL to about 6000 pg/mL, or about 125 pg/mL to about 6000 pg/mL, or about 150 pg/mL to about 6000 pg/mL, or about 175 pg/mL to about 6000 pg/mL, or about 200 pg/mL to about 6000 pg/mL, or about 225 pg/mL to about 6000 pg/mL, or about 250 pg/mL to about 6000 pg/mL, or about 300 pg/mL to about 6000 pg/mL, or about 350
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage from providing a C max of buprenorphine and norbuprenorphine occurring from a mean of about 0.25 to about 30 hours.
• the dosage form provides a Cmax of buprenorphine and norbuprenorphine occurring from a mean of about 0.5 to about 30 hours, or from a mean of about 1 to about 30 hours, or about 1 to about 26 hours, or about 1 to about 24 hours, or about 1 to about 20 hours, or about 1 to about 18 hours, or about 1 to about 16 hours, or about 1 to about 14 hours, or about 1 to about 12 hours, or about 1 to about 10 hours, or about 1 to about 8 hours, or about 1 to about 6 hours, or about 1 to about 4 hours, or about 1 to about 3 hours, or about 2 to about 30 hours, or about 4 to about 30 hours, or about 4 to about 24 hours, or about 6 to about 24 hours, or about 8 to about 24 hours, or about 10 to about 20 hours, or about 12 to about 24 hours, or about 18 to about 24 hours, or about 2 to about 12 hours, or about 3 to about 12 hours, or about 3 to about 8 hours, or about 4 to about 10 hours, or about 4 to about 12 hours, or about 1 to
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; a controlled release material to render said dosage form suitable for extended release in a human patient.
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage from providing a C m i n of buprenorphine and norbuprenorphine of about 0 pg/mL to about 20,000 pg/mL or 1 pg/mL to about 20,000 pg/mL.
• the dosage form provides a C m j n of buprenorphine and norbuprenorphine of less than about 20,000 pg/mL, or less than about 18,000 pg/mL, or less than about 16,000 pg/mL, or less than about 15,000 pg/mL, or less than about 14,000 pg/mL, or less than about 12,000 pg/mL, or less than about 10,000 pg/mL, or less than about 9,000 pg/mL, or less than about 8,000 pg/mL, or less than about 7,000 pg/mL, or less than about 6,000 pg/mL, or less than about 5,000 pg/mL, or less than about 4,000 pg/mL, or less than about 3,000 pg/mL, or less than about 2,000 pg/mL, or less than about 1,000 pg/mL, [585]
• the invention comprises an oral
• the dosage form provides a C m j n of buprenorphine and norbuprenorphine of less than about 2500 pg/mL, or less than about 2000 pg/mL, or less than about 1800 pg/mL, or less than about 1600 pg/mL, or less than about 1800 pg/mL, or less than about 1500 pg/mL, or less than about 1400 pg/mL, or less than about 1200 pg/mL, or less than about 1100 pg/mL, or less than about 1000 pg/mL, or less than about 900 pg/mL, or less than about 800 pg/mL, or less than about 700 pg/mL, or less than about 600 pg/mL, or less than about 500 pg/mL, or less than about 400 pg/mL, or less than about 300 pg/mL, or less than about 250 pg/mL,
• the aforementioned C m i n being achieved with oral pharmaceutical compositions comprising a controlled release material to render said dosage form extended release, or delayed onset, extended release, or delayed onset, rapid release, or delayed onset, pulsatile release.
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage from providing a C m i n of buprenorphine and norbuprenorphine measured from a mean of about 0.5 to about 30 hours.
• the dosage form provides a C m j n of buprenorphine and norbuprenorphine measured from a mean of about 0.5 to about 28 hours, or about 1 to about 28 hours, or about 1 to 24 hours, or about 1 to about 20 hours, or about 1 to about 18 hours, or about 1 to about 16 hours, or about 1 to about 12 hours, or about 1 to 10 hours, or about 1 to about 8 hours, or about 1 to about 6 hours, or about 1 to about 4 hours, about 2 to about 24 hours, or about 3 to 24 hours, or about 4 to about 24 hours, or about 6 to about 24 hours, or about 8 to about 24 hours, about 2 to about 12 hours, or about 3 to 10 hours, or about 3 to about 8 hours, or about 4 to about 8 hours, or about 6 to about 10 hours.
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form providing a systemic exposure as assessed by the mean of buprenorphine and norbuprenorphine area under the plasma concentration time curves to 24 hours post-dose (AUCo-24) of about 500 pg.hr/mL to about 500,000 pg.hr/mL.
• the dosage form provides an AUCo -24 of buprenorphine and norbuprenorphine of about 50 pg.hr/mL to about 475000 pg.hr/mL, or about 500 pg.hr/mL to about 450000 pg.hr/mL, or about 500 pg.hr/mL to about 425000 pg.hr/mL, or about 500 pg.hr/mL to about 400000 pg.hr/mL, or about 500 pg.hr/mL to about 375000 pg.hr/mL, or about 500 pg.hr/mL to about 350000 pg.hr/mL, or about 500 pg.hr/mL to about 325000 pg.hr/mL, or about 500 pg.hr/mL to about 300000 pg.hr/mL, or about 500 pg.hr/mL to about 275000
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form providing a systemic exposure as assessed by the mean of buprenorphine and norbuprenorphine area under the plasma concentration time curves to infinity (AUCo-i nf ) of about 500 pg.hr/mL to about 500,000 pg.hr/mL.
• the dosage form provides an AUCo-i nf of buprenorphine and norbuprenorphine of about 50 pg.hr/mL to about 475000 pg.hr/mL, or about 500 pg.hr/mL to about 450000 pg.hr/mL, or about 500 pg.hr/mL to about 425000 pg.hr/mL, or about 500 pg.hr/mL to about 400000 pg.hr/mL, or about 500 pg.hr/mL to about 375000 pg.hr/mL, or about 500 pg.hr/mL to about 350000 pg.hr/mL, or about 500 pg.hr/mL to about 325000 pg.hr/mL, or about 500 pg.hr/mL to about 300000 pg.hr/mL, or about 500 pg.hr/mL to about 500 pg
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form providing a systemic exposure as assessed by the mean of buprenorphine and norbuprenorphine area under the plasma concentration time curves to 24 hours post-dose (AUCo -24 ) of about 50 pg.hr/mL to about 80000 pg.hr/mL.
• the dosage form provides an AUCo -24 of buprenorphine and norbuprenorphine of about 50 pg.hr/mL to about 70000 pg.hr/mL, or about 50 pg.hr/mL to about 60000 pg.hr/mL, or about 50 pg.hr/mL to about 50000 pg.hr/mL, or about 50 pg.hr/mL to about 40000 pg.hr/mL, or about 50 pg.hr/mL to about 30000 pg.hr/mL, or about 50 pg.hr/mL to about 25000 pg.hr/mL, or about 50 pg.hr/mL to about 20000 pg.hr/mL, or about 50 pg.hr/mL to about 18000 pg.hr/mL, or about 50 pg.hr/mL to about 15000
• the aforementioned AUCo -24 being achieved with oral pharmaceutical compositions comprising a controlled release material to render said dosage form extended release, or delayed onset, extended release, or delayed onset, rapid release, or delayed onset, pulsatile release.
• the invention comprises an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form providing a systemic exposure as assessed by the mean buprenorphine and norbuprenorphine area under the plasma concentration time curve to infinity (AUCo-i nf ) of about 50 pg.hr/mL to about 80000 pg.hr/mL.
• the dosage form provides an AUCo-i nf of buprenorphine and norbuprenorphine of about 50 pg.hr/mL to about 70000 pg.hr/mL, or about 50 pg.hr/mL to about 60000 pg.hr/mL, or about 50 pg.hr/mL to about 50000 pg.hr/mL, or about 50 pg.hr/mL to about 40000 pg.hr/mL, or about 50 pg.hr/mL to about 30000 pg.hr/mL, or about 50 pg.hr/mL to about 25000 pg.hr/mL, or about 50 pg.hr/mL to about 20000 pg.hr/mL, or about 50 pg.hr/mL to about 18000 pg.hr/mL, or about 50 pg.hr/mL to
• the aforementioned AUCo -inf being achieved with oral pharmaceutical compositions comprising a controlled release material to render said dosage form extended release, or delayed onset, extended release, or delayed onset, rapid release, or delayed onset, pulsatile release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form providing a systemic exposure as assessed by the mean buprenorpbine and norbuprenorphine area under the plasma concentration time curve (AUCo -24 ) of up to 80000 pg.hr/mL, or up to 70000 pg.hr/mL, or up to 60000 pg.hr/mL, or up to 50000 pg.hr/mL, or up to 40000 pg.hr/mL, or up to 38000 pg.hr/mL, or up to 35000 pg.hr/mL, or up to 33000 pg.hr/mL, or up to 31000 pg.hr/mL, or up to 30000 pg.hr/mL, or up to 29000 pg.hr/mL, or up to 28000 pg.hr/mL
• AUCo -24 plasma concentration
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form providing at least 80% of the steady state therapeutic concentration of buprenorphine and norbuprenorphine after administration of ⁇ three doses at their intended dosing frequency.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form after administration to a human patient providing a C min /C m ax ratio of buprenorphine and norbuprenorphine of 0.1 to about 1.25.
• the dosage form provides a C m1n ZC m3x ratio of buprenorphine and norbuprenorphine of about 0.1 to about 1.15, about 0.1 to about 1.19, about 0.1 to about 1, about 0.1 to about 0.9, about 0.1 to about 0.85, or about 0.1 to about 0.8, or about 0.1 to about 0.7, or about 0.1 to about 0.6, or about 0.1 to about 0.5, or about 0.1 to about 0.4, or about 0.1 to about 0.3, or about 0.2 to about 1.0, or about 0.25 to about 1.25, or about 0.25 to about 1.25, or about 0.4 to about 1.25, or about 0.5 to about 1.25, or about 0.65 to about 1.25, or about 0.75 to about 1.25, or about 0.2 to about 0.9, or about 0.3 to about 0.9, or about 0.3 to about 0.8, or about 0.4 to about 0.8, or about 0.4 to about 0.7, or about 0.4 to about 0.6.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form after administration to a human patient providing a percent fluctuation of buprenorphine and norbuprenorphine of less than 400%.
• the dosage form provides a percent fluctuation of buprenorphine and norbuprenorphine of less than 350%, or less than 300%, or less than 250%, or less than 200%, or less than 150%, or less than 100%, or less than 75%, or less than 50%, or less than 25%.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form after administration to a human patient providing a W 50 of buprenorphine and norbuprenorphine of about 1 to about 6 hours for each 6 hour time period of intended dosing frequency and intended duration of action.
• the dosage form provides a W 50 of buprenorphine and norbuprenorphine for each 6 hour time period of intended dosing frequency and intended duration of action of about 1 to about 5 hours, or about 1 to about 4 hours, or about 1 to about 3 hours, or about 1 to about 2 hours, or 2 to about 6 hours, or about 3 to about 6 hours, or about 4 to about 6 hours, or about 2 to about 4 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form after administration to a human patient providing a HVD of buprenorphine and norbuprenorphine of about 1.5 to about 6 hours for each 6 hour time period of intended dosing frequency and intended duration of action.
• the dosage form provides a HVD of buprenorphine and norbuprenorphine for each 6 hour time period of intended dosing frequency and intended duration of action of about 1.5 to about 5 hours, or about 1.5 to about 4 hours, or about 1.5 to about 3 hours, or about 1.5 to about 2 hours, or 2 to about 6 hours, or about 3 to about 6 hours, or about 4 to about 6 hours, or about 2 to about 4 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form after administration to a human patient providing an AI of buprenorphine and norbuprenorphine of not more than 4.0.
• the dosage form provides an AI of buprenorphine and norbuprenorphine of not more than about 3.5, or not more than about 3.0, or not more than about 2.5, or not more than about 2, or not more than about 1.75, or not more than about 1.5, or not more than about 1.25, or not more than about 1, or not more than about 0.75, or not more than about 0.5, or not more than about 0.25.
• the in vivo pharmacokinetic parameters of the specifications, embodiments and claims are achieved with oral pharmaceutical compositions comprising a controlled release material to render said dosage form suitable for extended release.
• the specifications and claims are achieved with oral pharmaceutical compositions comprising a controlled release material to render said dosage form suitable for extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; and a controlled release material with gastroretentive properties to render said dosage form suitable for extended release oral administration to a human patient.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; and a controlled release material with osmotic release to render said dosage form suitable for extended release oral administration to a human patient.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; and a controlled release material with zero-order or pseudo-zero-order release to render said dosage form suitable for extended release oral administration to a human patient.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and a controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a percent fluctuation of buprenorphine and norbuprenorphine of less than 400%.
• a controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a
• the dosage form provides a percent fluctuation of buprenorphine and norbuprenorphine of less than about 375%, or less than about 350%, or less than about 325%, or less than about 300%, or less than about 275%, or less than about 250%, or less than about 225%, or less than about 200%, or less than about 175%, or less than about 150%, or less than about 125%, or less than about 100%, or less than about 75%, or less than about 50%, or less than about 25%.
• the aforementioned percent fluctuation being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient, providing an AI of buprenorphine and norbuprenorphine of not more than 4.0.
• the dosage form provides an AI of buprenorphine and norbuprenorphine of not more than about 3.75, or not more than about 3:5, or not more than about 3.25, or not more than about 3, or not more than about 2.75, or not more than about 2.5, or not more than about 2, or not more than about 1.5, not more than about 1.25, or not more than about 1, or not more than about 0.75.
• the aforementioned AI ratio being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a mean buprenorphine and norbuprenorphine C max of about 20 pg/mL to about 2000 pg/mL.
• the dosage form provides a mean buprenorphine and norbuprenorphine C max of about 20 pg/mL to 1800 pg/mL, or about 20 pg/mL to 1600 pg/mL, or about 20 pg/mL to 1500 pg/mL, or about 20 pg/mL to 1400 pg/mL, or about 20 pg/mL to 1200 pg/mL, or about 20 pg/mL to 1100 pg/mL, or about 20 pg/mL to 1000 pg/mL, or about 20 pg/mL to 900 pg/mL, or about 20 pg/mL to 800 pg/mL, or about 20 pg/mL to 700 pg/mL, or about 20 pg/mL to 600 pg/mL, or about 20 pg/mL to 500 pg/mL, or about 20 pg/mL, or
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a mean buprenorphine and norbuprenorphine Cmax of less than about 4000 pg/mL, or less than about 3000 pg/mL, or less than about 2000 pg/mL.
• the dosage form provides a mean buprenorphine and norbuprenorphine C max of less than about 1800 pg/mL, or less than about 1700 pg/mL, or less than about 1600 pg/mL, or less than about 1500 pg/mL, or less than about 1400 pg/mL, or less than about 1200 pg/mL, or less than about 100 pg/mL, or less than about 900 pg/mL, or less than about 800 pg/mL, or less than about 700 pg/mL, or less than about 600 pg/mL, or less than about 500 pg/mL, or less than about 400 pg/mL, or less than about 300 pg/mL, or less than about 200 pg/mL, or less than about 100 pg/mL, or less than about 50 pg/mL.
• the aforementioned C max being achieved with oral pharmaceutical composition
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a mean buprenorphine and norbuprenorphine C m i n of about 1 pg/mL to about 1000 pg/mL.
• the dosage form provides a mean buprenorphine and norbupreno ⁇ hine C min of about 1 pg/mL to 950 pg/mL, or about 1 pg/mL to 900 pg/mL, or about 1 pg/mL to 850 pg/mL, or about 1 pg/mL to 800 pg/mL, or about 1 pg/mL to 750 pg/mL, or about 1 pg/mL to 700 pg/mL, or about 1 pg/mL to 650 pg/mL, or about 1 pg/mL to 600 pg/mL, or about 1 pg/mL to 550 pg/mL, or about 1 pg/mL to 500 pg/mL, or about 1 pg/mL to 450 pg/mL, or about 1 pg/mL to 400 pg/mL, or about
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a mean buprenorpbine and norbupreno ⁇ hine C min of less than about 1000 pg/mL.
• the dosage form provides a mean bupreno ⁇ hine and norbupreno ⁇ hine C min of less than about 900 pg/mL, or less than about 800 pg/mL, or less than about 700 pg/mL, or less than about 600 pg/mL, or less than about 500 pg/mL, or less than about 400 pg/mL, or less than about 300 pg/mL, or less than about 200 pg/mL, or less than about 100 pg/mL, or less than about 90 pg/mL, or less than about 80 pg/mL, or less than about 70 pg/mL, or less than about 60 pg/mL, or less than about 50 pg/mL, or less than about 40 pg/mL, or less than about 30 pg/mL, or less than about 20 pg/mL, or less than about 10 pg/mL, or less than about 5 p
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a mean buprenorphine and norbuprenorphine C n ii n of greater than about 600 pg/mL, or greater than about 500 pg/mL, or greater than about 400 pg/mL, or greater than about 300 pg/mL, or greater than about 200 pg/mL, or greater than about 100 pg/mL, or greater than about 90 pg/mL, or greater than about 80 pg/mL, or greater
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a greater than about 60%, 65%, 70%, 75%, 80%, 85%, 90% , 95%, or 100% of the total absorbed dose into systemic circulation (as measured by bioavailability) during the first half of the intended dosing frequency.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a greater than about 60%, 65%, 70%, 75%, 80%, 85%, 90% , 95%, or 100% of the total absorbed dose into systemic circulation (as measured by bioavailability) during the second half of the intended dosing frequency.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% , 95%, or 100% of the total absorbed dose into systemic circulation (as measured by bioavailability) during the first one-third of the intended dosing frequency.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% , 95%, or 100% of the total absorbed dose into systemic circulation (as measured by bioavailability) during the last one-third of the intended dosing frequency.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% , 95%, or 100% of the total absorbed dose into systemic circulation (as measured by bioavailability) during the first one-quarter of the intended dosing frequency.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form after administration to a human patient providing a greater than about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% , 95%, or 100% of the total absorbed dose into systemic circulation (as measured by bioavailability) during the last one-quarter of the intended dosing frequency.
• the aforementioned embodiments which provide a greater amount of the total absorbed dose into systemic circulation (as measured by bioavailability) during the first half, first one-third or first one quarter of the intended dosing frequency result in reduced frequency or duration of buprenorphine related side effects.
• the aforementioned embodiments which provide a greater amount of the total absorbed dose into systemic circulation (as measured by bioavailability) during the second half, last one-third or last one quarter of the intended dosing frequency result in reduced frequency or duration of buprenorphine related side effects.
• the dosage form comprises a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine, or a mixture thereof, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, wherein the in vivo specifications, including pharmacokinetic specifications achieved with oral pharmaceutical compositions which are devoid of a controlled release material to render said dosage form extended release.
• the dosage form comprises a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine, or a mixture thereof, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, wherein the in vitro specifications, including dissolution rate specifications achieved with oral pharmaceutical compositions which are devoid of a controlled release material to render said dosage form extended release.
• birenorphine and norbuprenorphine mean buprenorphine alone and norbuprenorphine alone and not a summation of the two.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorpbine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN), once-a-day (QD, Q24H or Q24H PRN), once every two days (Q2D, Q48H or Q48H PRN), once every three days (Q3D, Q72H or Q72H PRN), once every four days, once every five days, and up to once every week (QWeekly, Q168H or Q168H PRN) administration to a human patient.
• Q6H or Q6H PRN three times-a-day
• Q8H or Q8H PRN twice-a-day
• Q12H or Q12H PRN once-a-day
• QD, Q24H or Q24H PRN once every two days
• the specifications of the invention including in vitro specifications (e.g., dissolution rates) and in vivo specifications (e.g., pharmacodynamic measures) are applicable to dosage forms having dosing frequency (scheduled or PRN) that exceeds 24 hours for up to once-a-week (e.g., the dosage form is suitable once every two days (Q2D, Q48H or Q48H PRN), once every three days (Q3D, Q72H or Q72H PRN), once every four days, once every five days, and up to once every week (Q Weekly, Q168H or Q168H PRN) administration to a human patient).
• in vitro specifications e.g., dissolution rates
• in vivo specifications e.g., pharmacodynamic measures
• the dosage form is suitable once every two days (Q2D, Q48H or Q48H PRN), once every three days (Q3D, Q72H or Q72H PRN), once every four days, once every five days, and up to once every week (Q Weekly, Q
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN), once-a-day (QD, Q24H or Q24H PRN), once every two days (Q2D, Q48H or Q48H PRN), once every three days (Q3D, Q72H or Q72H PRN), once every four days, once every five days, and up to once every week (QWeekly, Q168H or Q168H PRN) administration to a human patient, wherein the in-vitro release rate is substantially independent of pH in that a difference, at any given time, between an amount of buprenorphine released at one pH and an amount released at any other pH, when measured in- vitro using the USP Basket or Paddle Method of USP Drug Release test
• Pharmacopeia (2003) at 100 rpm in 900 ml aqueous buffer is no greater than about 30%. In other preferred embodiments, said difference is no greater than about 25%, or 20%, or 18%, or 15%, or 12%, or 10%, or 8%, or 5%.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, wherein the buprenorphine and norbuprenorphine C max is substantially independent of food intake in that a difference, at any given time, between the C m a x of buprenorphine administered in fasted state and the C m3x of buprenorphine and norbuprenorphine administered in fed state (using a standardized meal) is no greater than about 30%. In other preferred embodiments, said difference is no greater than about 25%, or 20%, or 18%, or 15%, or 12%, or 10%, or 8%, or 5%.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, wherein the buprenorphine and norbuprenorphine C max is substantially independent of food intake in that a difference, at any given time, between the C max of buprenorphine and norbuprenorphine administered in fasted state and the C m3x of buprenorphine administered after a standardized high fat meal is no greater than about 30%.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, wherein the buprenorphine and norbuprenorphine C max is substantially independent of alcohol intake in that a difference, at any given time, between the C max of buprenorphine and norbuprenorpbine administered with about 30 to about 24 mL of a 40% ethanol solution and the C max of buprenorphine administered without concurrent alcohol (i.e., in an alcohol free state)
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, wherein the AUCo -I2 , AUCo -24 and AUCo- mf after single- dose administration are substantially independent of food intake in that a difference, at any given time, between the said AUC of buprenorphine and norbuprenorphine when the dosage form administered in fasted state and the said AUC of buprenorphine and norbuprenorphine when the dosage form is administered in fed state (using a standardized meal) is no greater than about 30%. In other preferred embodiments, said difference is no greater than about 25%, or 20%,
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, wherein the buprenorphine and norbuprenorphine AUCo -I2, AUCo -24 and AUCo-inf is substantially independent of food intake in that a difference, at any given time, between the said AUC when administered in fasted state and the AUC when administered after a standardized high fat meal is no greater than about 30%. In other preferred embodiments, said difference is no greater than about 25%, or 20%, or 18%, or 15%, or 12%, or 10%, or 8%, or 5%.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, wherein the buprenorphine and norbuprenorphine AUCo -I , AUCo -2 , and AUCo ⁇ is substantially independent of alcohol intake in that a difference, at any given time, between the said AUC when administered with about 30 to about 24 mL of a 40% ethanol solution and the said AUC when administered without concurrent alcohol (i.e., in an alcohol free state) is no greater than about 30%. In other preferred embodiments, said difference is no greater than about 25%, or 20%, or 18%, or 15%, or 12%, or 10%, or
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient, said dosage form after administration to a human patient providing a C max of buprenorphine and norbuprenorphine at 0.75 to about 7 hours; and said dosage form providing a therapeutic effect for at least about 8 hours.
• Q8H or Q8H PRN three times-a-day
• the dosage form provides a C ma ⁇ of buprenorphine and norbuprenorphine at about 0.75 to about 6.5 hours or about 0.75 to about 6 hours, or about 0.75 to about 5 hours, or about 0.75 to about 4 hours, or about 0.75 to about 3.5 hours, or about 0.75 to about 3 hours, or 0.75 to about 2.5 hours, or about 0.75 to about 2 hours, or about 0.75 to about 1.5 hours, or about 1 to about 7 hours, or about 1.5 to about 7 hours, or about 2 to about 7 hours, or about 2.5 to about 7 hours, or 3 to about 7 hours, or about 3.5 to about 7 hours, or about 4 to about 7 hours, or about 4.5 to about 7 hours, or about 5 to about 6 hours, or about 5.5 to about 7 hours, or about 2 to about 6, or about 2.5 to about 5.5 hours, or about 3 to about 5 hours, or about 3 to about 6.
• the aforementioned C max being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient, said dosage form after administration to a human patient providing a C min of buprenorphine and norbuprenorphine at about 6 to about 10 hours; and said dosage form providing a therapeutic effect for at least about 8 hours.
• Q8H or Q8H PRN three times-a-day
• the dosage form provides a C m1n of buprenorphine and norbuprenorphine at about 6 to about 9 hours, or about 6 to about 8.5 hours, or about 6 to about 8 hours, or about 6 to about 7.5 hours, or about 6 to about 7 hours, or about 6.5 to about 10 hours, or about 7 to about 10 hours, or about 8 to about 10 hours, or about 8 hours.
• the aforementioned C m j n being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient, said dosage form after administration to a human patient providing a mean buprenorphine and norbuprenorphine AUCo-i nf after first administration or AUCo- 8 at steady state of about 125 pg.hr/mL to about 40000 pg.hr/mL; and said dosage form providing a therapeutic effect for at least about 8 hours.
• Q8H or Q8H PRN three times-a-day
• the dosage form provides a mean buprenorphine and norbuprenorphine AUCo- i nf after first administration or AUC 0-8 at steady state of about 125 pg.hr/mL to about 35000 pg.hr/mL, or about 125 pg.hr/mL to about 30000 pg.hr/mL, or about 125 pg.hr/mL to about 28000 pg.hr/mL, or about 125 pg.hr/mL to about 25000 pg.hr/mL, or about 125 pg.hr/mL to about 22000 pg.hr/mL, or about 125 pg.hr/mL to about 20000 pg.hr/mL, or about 125 pg.hr/mL to about 18000 pg.hr/mL, or about 125 pg.hr/mL to about 15000
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient, said dosage form after administration to a human patient providing a C 8 /C ma ⁇ ratio of buprenorphine and norbuprenorphine 0.1 to about 1.25; and said dosage form providing a therapeutic effect for at least about 8 hours.
• Q8H or Q8H PRN three times-a-day
• the dosage form provides a Cg/C ma ⁇ ratio of buprenorphine and norbuprenorphine of about 0.1 to about 1, or about 0.1 to about 0.8, or about 0.1 to about 0.75, or about 0.1 to about 0.6, or 0.1 to about 0.5, or about 0.1 to about 0.4, or about 0.1 to about 0.35, or about 0.25 to about 0.95, or about 0.4 to about 0.95, or about 0.5 to about 0.95, or about 0.65 to about 0.95, or about 0.75 to about 0.95, or about 0.3 to about 0.8, or about 0.4 to about 0.75, or about 0.5 to about 0.75.
• the aforementioned C 8 /C max ratio being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient, said dosage form after administration to a human patient, providing a W 50 of buprenorphine and norbuprenorphine of 1 to about 7 hours; and said dosage form providing a therapeutic effect for at least about 8 hours.
• a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient, said dosage form after administration to a human patient, providing a W 50 of buprenorphine and norbuprenorphine of 1 to about 7 hours; and said dosage form providing a therapeutic effect for at least about 8 hours.
• the dosage form provides a W50 of buprenorphine and norbuprenorphine of about 1 to about 6 hours, or about 1 to about 5 hours, or about 1 to about 5.5 hours, or about 1 to about 5 hours, or 1 to about 4.5 hours, or about 1 to about 4 hours, or about 1 to about 3.5 hours, or about 1 to about 3 hours, or about 1 to about 2.5 hours, or about 1 to about 2 hours, or about 1.5 to about 7 hours, or about 2 to about 6 hours, or 2 to about 5.5 hours, or about 2 to about 5 hours, or about 2 to about 4.5 hours, or about 2 to about 4 hours, or about 2 to about 3.5 hours, or about 2.5 to about 6.5 hours, or about 2.5 to about 6 hours, or about 2.5 to about 5 hours, or about 2.5 to about 4.5 hours, or 3 to about 6.5 hours, or about 3 to about 6 hours, or about 3 to about 5 hours, or about 3 to about 6.5 hours.
• the aforementioned W 50 ratio being achieved with oral pharmaceutical composition
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient, said dosage form after administration to a human patient, providing a HVD of buprenorphine and norbuprenorphine of 1.5 to about 7 hours; and said dosage form providing a therapeutic effect for at least about 8 hours.
• a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient, said dosage form after administration to a human patient, providing a HVD of buprenorphine and norbuprenorphine of 1.5 to about 7 hours; and said dosage form providing a therapeutic effect for at least about 8 hours.
• the dosage form provides a HVD of buprenorphine and norbuprenorphine of about 1.5 to about 6 hours, or about 1.5 to about 5 hours, or about 1.5 to about 5.5 hours, or about 1.5 to about 5 hours, or 1.5 to about 4.5 hours, or about 1.5 to about 4 hours, or about 1.5 to about 3.5 hours, or about 1.5 to about 3 hours, or about 1.5 to about 2.5 hours, or about 1.5 to about 2 hours, or about 1.5 to about 7 hours, or about 2 to about 6 hours, or 2 to about 5.5 hours, or about 2 to about 5 hours, or about 2 to about 4.5 hours, or about 2 to about 4 hours, or about 2 to about 3.5 hours, or about 2.5 to about 6.5 hours, or about 2.5 to about 6 hours, or about 2.5 to about 5 hours, or about 2.5 to about 4.5 hours, or 3 to about 6.5 hours, or about 3 to about 6 hours, or about 3 to about 5 hours, or about 3 to about 6.5 hours.
• the aforementioned HVD ratio being achieved with oral
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, and, optionally, controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient; said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of from 0% to about 47.5% at 1 hour, from about 10% to about 65% at 2 hours, from about 10% to about 90% at 4 hours, from about 15% to about 95% at 6 hours, and greater than about 65% at 8 hours.
• the dosage form provides said an in-vitro release rate of from 0% to about 40% at 1 hour, from about 5% to about 60% at 2 hours, from about 10% to about 70% at 4 hours, from about 15% to about 90% at 6 hours, and greater than about 50% at 8 hours.
• some of the dissolution rate specifications of buprenorphine referred to herein are obtained following pretreatment of the dosage form using the USP Basket or Paddle Method at 100 rpm in 900 mL distilled water at a pH of ⁇ 4.5, ⁇ 5, or ⁇ 5.5 for two hours at 37 °C before a switch to an aqueous buffer at 37 0 C at a pH > 6, or > 6.8 or a pH > 7 (instead of the aqueous buffer at a pH of between 1.6 and 7.2), whereupon the clock is reset to time equal to 0.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, and, optionally, controlled release material to render said dosage form suitable for three times-a-day (Q8H or Q8H PRN) administration to a human patient; said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of from 0% to about 47.5% at 1 hour, from about 10% to about 65% at 2 hours, from about 15% to about 70% at 4 hours, from about 25% to about 80% at 6 hours, and greater than about 65% at 8 hours; said in-vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of buprenorphine released at one pH and an amount released at any other pH, when measured in-vitro using the USP Basket or Paddle
• said pH independent in-vitro release rate is from 0% to about 47.5% at 1 hour, from about 10% to about 65% at 2 hours, from about 10% to about 90% at 4 hours, from about 15% to about 95% at 6 hours, and greater than about 65% at 8 hours or from 0% to about 40% at 1 hour, from about 5% to about 60% at 2 hours, from about 10% to about 70% at 4 hours, from about 15% to about 90% at 6 hours, and greater than about 50% at 8 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form after administration to a human patient providing a C max of buprenorphine and norbuprenorphine at 2 to about 10 hours; and said dosage form providing a therapeutic effect for at least about 12 hours.
• the dosage form provides a C max of buprenorphine and norbuprenorphine at about 2 to about 8 hour or about 2 to about 6 hours, or about 2 to about 5 hours, or about 2 to about 7 hours, or about 2 to about 4.5 hours, or about 2 to about 4 hours, or 2 to about 3.5 hours, or about 2 to about 3 hours, or about 3 to about 10 hours, or about 3.5 to about 10 hours, or about 4 to about 10 hours, or about 4.5 to about 10 hours, or about 5 to about 10 hours, or 5 to about 10 hours, or about 6 to about 10 hours, or about 3 to about 8 hours, or about 3 to about 7 hours, or about 3 to about 6 hours, or about 4 to about 8 hours, or about 4 to about 6.
• the aforementioned C m3x being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form after administration to a human patient providing a C m i n of buprenorphine and norbuprenorphine at about 10 to about 14 hours; and said dosage form providing a therapeutic effect for at least about 12 hours.
• the dosage form provides a C m i n of buprenorphine and norbuprenorphine at about 10 to about 13 hours, or about 10 to about 12.5 hours, or about 10 to about 12 hours, or about 10 to about 11.5 hours, or about 10 to about 11 hours, or about 10.5 to about 14 hours, or about 1 1 to about 14 hours, or about 12 to about 14 hours.
• the aforementioned C m i n being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form after administration to a human patient providing a mean buprenorphine and norbuprenorphine AUCo-i nf after first administration or AUCo -I2 at steady state of about 125 pg.hr/mL to about 250000 pg.hr/mL; and said dosage form providing a therapeutic effect for at least about 12 hours.
• the dosage form provides a mean buprenorphine and norbuprenorphine AUCo-i nf after first administration or AUC 0-I2 at steady state of about 125 pg.hr/mL to about 200000 pg.hr/mL, or about 125 pg.hr/mL to about 150000 pg.hr/mL, or about 125 pg.hr/mL to about 100000 pg.hr/mL, or about 125 pg.hr/mL to about 50000 pg.hr/mL, or about 125 pg.hr/mL to about 22000 pg.hr/mL, or about 125 pg.hr/mL to about 20000 pg.hr/mL, or about 125 pg.hr/mL to about 18000 pg.hr/mL, or about 125 pg.hr/mL to about 15000
• the aforementioned AUC being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form after administration to a human patient providing a Ci 2 /C max ratio of buprenorphine and norbuprenorphine 0.1 to about 1.25; and said dosage form providing a therapeutic effect for at least about 12 hours.
• the dosage form provides a Ci 2 /C max ratio of buprenorphine and norbuprenorphine of about 0.1 to about 1, or about 0.1 to about 0.8, or about 0.1 to about 0.75, or about 0.1 to about 0.6, or 0.1 to about 0.5, or about 0.1 to about 0.4, or about 0.1 to about 0.35, or about 0.25 to about 0.95, or about 0.4 to about 0.95, or about 0.5 to about 0.95, or about 0.65 to about 0.95, or about 0.75 to about 0.95, or about 0.3 to about 0.8, or about 0.4 to about 0.75, or about 0.5 to about 0.75.
• the aforementioned C] 2 /C max ratio being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form after administration to a human patient, providing a W 50 of buprenorphine and norbuprenorphine of 2 to about 11 hours; and said dosage form providing a therapeutic effect for at least about 12 hours.
• the dosage form provides a W 50 of buprenorphine and norbuprenorphine of about 2 to about 10 hours, or about 2 to about 9 hours, or about 2 to about 9 hours, or about 2 to about 8 hours, or 2 to about 7 hours, or about 2 to about 6 hours, or about 2 to about 5 hours, or about 2 to about 4 hours, or about 3 to about 10 hours, or about 4 to about 10 hours, or about 5 to about 10 hours, or about 6 to about 10 hours, or 7 to about 10 hours, or about 3 to about 8 hours, or about 4 to about 8 hours, or about 4 to about 7 hours, or about 3 to about 6 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form after administration to a human patient, providing a HVD of buprenorphine and norbuprenorphine of 1.5 to about 10 hours; and said dosage form providing a therapeutic effect for at least about 12 hours.
• the dosage form provides an HVD of buprenorpbine and norbuprenorphine of about 1.5 to about
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, and, optionally, controlled release material to render said dosage form suitable for twice-a-day administration to a human patient; said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of from 0% to about 47.5% at 1 hour, from about 10% to about 65% at 2 hours, from about 15% to about 70% at 4 hours, from about 25% to about 77.5% at 6 hours, from about 35% to about 87.5% at 9 hours, and greater than about 65% at 12 hours.
• the dosage form provides said an in-vitro release rate of from 0% to about 40% at 1 hour, from about 5% to about 55% at 2 hours, from about 10% to about 60% at 4 hours, from about 15% to about 70% at 6 hours, from about 25% to about 80% at 9 hours, and greater than about 50% at 12 hours
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, and, optionally, controlled release material to render said dosage form suitable for twice-a-day administration to a human patient; said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 °C of from 0% to about 47.5% at 1 hour, from about 10% to about 65% at 2 hours, from about 15% to about 70% at 4 hours, from about 25% to about 77.5% at 6 hours, from about 35% to about 87.5% at 9 hours, and greater than about 65% at 12 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, and, optionally, controlled release material to render said dosage form suitable for twice-a-day administration to a human patient; said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of from 0% to about 47.5% at 1 hour, from about 10% to about 65% at 2 hours, from about 15% to about 70% at 4 hours, from about 25% to about 77.5% at 6 hours, from about 35% to about 87.5% at 9 hours, and greater than about 65% at 12 hours; said in-vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of buprenorphine released at one pH and an amount released at any other pH, when measured in-vitro using the USP
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for once-a-day administration to a human patient, said dosage form after administration to a human patient providing a C max of buprenorphine and norbuprenorphine at about 3 to about 20 hours; and said dosage form providing a therapeutic effect for at least about 24 hours.
• the dosage form provides a Cmax at about 3 to about 18 hours, or about 3 to about 15 hours, or about 3 to about 12 hours, or at about 3 to about 10 hours, or at about 3 to about 8 hours, or at about 3 to about 7 hours, or at about 3 to about 7 hours, or about 4 to about 20 hours, or about 5 to about 20 hours, or about 6 to about 20 hours, or at about 8 to about 20 hours, or at about 10 to about 20 hours, or at about 12 to about 20 hours, or at about 14 to about 20 hours, or about 18 to about 20 hours, or about 4 to about 18 hours, or about 4 to about 16 hours, or at about 4 to about 12 hours, or at about 4 to about 8 hours, or at about 4 to about 10 hours, or at about 3 to about 6 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for once-a-day administration to a human patient, said dosage form after administration to a human patient providing a C m i n of buprenorphine and norbuprenorphine at about 20 to about 28 hours; and said dosage form providing a therapeutic effect for at least about 24 hours.
• the dosage form provides a C m j n at about 20 to about 26 hours, or about 20 to about 27 hours, or about 20 to about 25 hours, or about 20 to about 24 hours, or about 20 to about 23 hours, or about 21 to about 28 hours, or about 22 to about 28 hours, or about 23 to about 28 hours, or about 23.5 to about 28 hours, or about 22 to 26 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage form providing a therapeutic effect longer than would be expected based on the prevailing plasma concentrations. For example, under normal circumstances, many drugs provide duration of effect that is at least partly correlated with or dependent on the prevailing plasma concentrations of drug. In some preferred embodiments of the invention, the dosage form provides persistent therapeutic effects despite short lived, low or negligible prevailing plasma concentrations.
• the dosage form provides sustained therapeutic effects of up to about 4, or about 6, or about 8, or about 12, or about 18 or about 20 or about 24 hours despite being administered in immediate release form.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage from providing a Cmax of buprenorphine and norbuprenorphine from about 0.25 hours to about 30 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine; said dosage from providing a C m i n of buprenorphine and norbuprenorphine from about 1 hour to about 30 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for once-a-day administration to a human patient, said dosage form after administration to a human patient providing a buprenorphine and norbuprenorphine mean AUCo.i nf after first administration or AUCo -24 at steady state of about 2250 pg.hr/mL to about 500000 pg.hr/mL; and said dosage form providing a therapeutic effect for at least about 24 hours.
• the dosage form provides a mean buprenorphine and norbuprenorphine AUCo- mf after first administration or AUCo -24 at steady state of about 250 pg.hr/mL to about 350000 pg.hr/mL, or about 250 pg.hr/mL to about 250000 pg.hr/mL, or about 250 pg.hr/mL to about 150000 pg.hr/mL, or about 250 pg.hr/mL to about 100000 pg.hr/mL, or about 250 pg.hr/mL to about 50000 pg.hr/mL, or about 250 pg.hr/mL to about 25000 pg.hr/mL, or about 250 pg.hr/mL to about 20000 pg.hr/mL, or about 250 pg.hr/mL to about 18000 pg.hr/mL, or
• the aforementioned AUCo-i nf being achieved with oral pharmaceutical compositions comprising a controlled release material to render said dosage form extended release, or delayed onset, extended release, or delayed onset, rapid release, or delayed onset, pulsatile release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for once-a-day administration to a human patient, said dosage form after administration to a human patient providing a buprenorphine and norbuprenorphine mean AUCo-i nf after first administration or AUCo -24 at steady state of not more than about 80000 pg.hr/mL; and said dosage form providing a therapeutic effect for at least about 24 hours.
• the dosage form provides a mean buprenorphine and norbuprenorphine AUCo- mf after first administration or AUCo -24 at steady state of not more than about 70000 pg.hr/mL, or not more than about 60000 pg.hr/mL, or not more than about 50000 pg.hr/mL, or not more than about 40000 pg.hr/mL, or not more than about 30000 pg.hr/mL, or not more than about 25000 pg.hr/mL, or not more than about 20000 pg.hr/mL, or not more than about 18000 pg.hr/mL, or not more than about 15000 pg.hr/mL, or not more than about 14000 pg.hr/mL, or not more than about 12000 pg.hr/mL, or not more than about 11000 pg.hr/mL, or not more than about
• the aforementioned AUCo-i nf being achieved with oral pharmaceutical compositions comprising a controlled release material to render said dosage form extended release, or delayed onset, extended release, or delayed onset, rapid release, or delayed onset, pulsatile release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and controlled release material to render said dosage form suitable for once-a-day administration to a human patient, said dosage form after administration to a human patient providing a C 16 ZC 24 ratio of buprenorphine and norbuprenorphine 0.1 to about 1.25; and said dosage form providing a therapeutic effect for at least about 24 hours.
• the dosage form provides a CWC 24 ratio of buprenorphine and norbuprenorphine of about 0.1 to about 1, or about 0.1 to about 0.8, or about 0.1 to about 0.75, or about 0.1 to about 0.6, or 0.1 to about 0.5, or about 0.1 to about 0.4, or about 0.1 to about 0.35, or about 0.25 to about 0.95, or about 0.4 to about 0.95, or about 0.5 to about 0.95, or about 0.65 to about 0.95, or about 0.75 to about 0.95, or about 0.3 to about 0.8, or about 0.4 to about 0.75, or about 0.5 to about 0.75.
• the aforementioned Ci 6 ZC 24 ratio being achieved with oral pharmaceutical compositions devoid of a controlled release material to render said dosage form extended release.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for once-a-day administration to a human patient, said dosage form after administration to a human patient, providing a W 50 of buprenorphine and norbuprenorphine of 4 to about 22 hours; and said dosage form providing a therapeutic effect for at least about 24 hours.
• the dosage form provides a W 50 of buprenorphine and norbuprenorphine of about 4 to about 20 hours, or about 4 to about 19 hours, or about 4 to about 18 hours, or 4 to about 16 hours, or 4 to about 14 hours, or about 4 to about 12 hours, or about 4 to about 10 hours, or about 4 to about 8 hours, or about 6 to about 20 hours, or about 8 to about 20 hours, or about 10 to about 20 hours, or about 12 to about 20 hours, or 14 to about 20 hours, or about 6 to about 16 hours, or about 8 to about 16 hours, or about 8 to about 14 hours, or about 6 to about 12 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine and, optionally, controlled release material to render said dosage form suitable for once-a-day administration to a human patient, said dosage form after administration to a human patient, providing a HVD of buprenorphine and norbuprenorphine of 3 to about 20 hours; and said dosage form providing a therapeutic effect for at least about 24 hours.
• the dosage form provides an HVD of buprenorphine and norbuprenorphine of about 3 to about 18 hours, or about 3 to 16 hours, or about 3 to about 14 hours, or about 3 to 12 hours, or about 3 to about 10 hours, or about 3 to about 8 hours, or about 4 to about 20 hours, or about 6 to 20 hours, or about 8 to about 20 hours, or about 10 to 20 hours, or about 12 to about 20 hours, or about 16 to 20 hours, about 6 to about 16 hours, or about 8 to 16 hours, or about 10 to about 14 hours, or about 6 to 12 hours, or about 6 to about 16 hours, or about 10 to about 16 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, and, optionally, controlled release material to render said dosage form suitable for once-a-day administration to a human patient; said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of from 0% to about 30% at 1 hour, from about 10% to about 65% at 4 hours, from about 20% to about 70% at 8 hours, from about 25% to about 80% at 12 hours, from about 35% to about 95% at 18 hours, and greater than about 65% at 24 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, and, optionally, controlled release material to render said dosage form suitable for once-a-day administration to a human patient; said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of from 0% to about 30% at 1 hour, from about 10% to about 65% at 4 hours, from about 20% to about 70% at 8 hours, from about 25% to about 80% at 12 hours, from about 35% to about 95% at 18 hours, and greater than about 65% at 24 hours; said in-vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of buprenorphine released at one pH and an amount released at any other pH, when measured in-vitro using the USP Basket or Paddle Method of
• the oral dosage form of the invention provides an in- vitro release of from about 2% to about 50% by weight of the buprenorphine or a pharmaceutically acceptable salt of buprenorphine from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) at 37 0 C.
• SGF Simulated Gastric Fluid
• said dosage form provides an in-vitro release rate by weight of the buprenorphine or a pharmaceutically acceptable salt of buprenorphine from the dosage form at one hour from about 2% to about 45%, or from about 2% to about 60%, or from about 5% to about 40%, or from about 5% to about 60%, or from about 10% to about 70%, or from about 10% to about 80%, or from about 15% to about 90%, or from about 60 to about 100%, or from about 80 to about 100%, or greater than about 1%, or greater than about 5%, or greater than about 15%, or greater than about 40%, or greater than about 60%, or greater than about 80%, or greater than about 90%, or greater than about 95%.
• the oral dosage form of the invention provides at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100% lower variability in buprenorphine C max (as defined by the coefficient of variation or CV.) than after the sublingual dosage form of buprenorphine, each given according to its intended route and method of administration.
• the oral dosage form of the invention provides at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100% lower variability in buprenorphine T max (as defined by the coefficient of variation or CV.) than after the sublingual dosage form of buprenorphine, each given according to its intended route and method of administration.
• the oral dosage form of the invention provides at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100% lower variability in the buprenorphine AUCo -24 , or AUCoo ⁇ , or AUCo -48 , or AUCo -72 (as defined by the coefficient of variation or CV.) than after the sublingual dosage form of buprenorphine, each given according to its intended route and method of administration.
• the oral dosage form of the invention provides a ratio of mean AUCo ⁇ 8 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100%, or 120%, or 140%, or 150%, or 170%, or 200%, or 230%, or 250%, or 270%, or 300% greater than said ratio after the same amount of sublingual dosage form of buprenorphine, each given according to its intended route and method of administration.
• the oral dosage form of the invention provides a time to 75% mean C max of buprenorphine after the first dose which is at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100%, or 120%, or 140%, or 150%, or 170%, or 200%, or 230%, or 250%, or 270%, or 300% or 400%, or 500%, or 600%, or 700%, or 1000% longer than said time to mean C max after the same amount of sublingual dosage form of buprenorphine, each given according to its intended route and method of administration.
• the oral dosage form of the invention provides a mean T max of buprenorphine after the first dose which is at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100%, or 120%, or 140%, or 150%, or 170%, or 200%, or 230%, or 250%, or 270%, or 300% or 400%, or 500%, or 600%, or 700%, or 1000% longer than said T max after the same amount of sublingual dosage form of buprenorpbine, each given according to its intended route and method of administration.
• the oral dosage form of the invention provides a mean C max of buprenorphine which is at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100%, or 120%, or 140%, or 150%, or 170%, or 200%, or 230%, or 250%, or 270%, or 300% less than said C max after the same amount of sublingual dosage form of buprenorphine, each given according to its intended route and method of administration.
• the oral dosage form of the invention provides a mean C m a X ratio of norbuprenorphine to buprenorphine which is at least about 5%, or 10%, or 15%, or 20%, or 30% or 40%, or 50% or 60%, or 70%, or 80%, or 100%, or 120%, or 140%, or 150%, or 170%, or 200%, or 230%, or 250%, or 270%, or 300% greater than said C max ratio after the same amount of sublingual dosage form of buprenorphine, each given according to its intended route and method of administration.
• the oral dosage form of the invention provides a time to 75% mean C m3x of buprenorphine which is about 100% to about 2000% of the time to 75% mean C max after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a controlled release dosage form of the invention provides a time to mean C max of buprenorphine which is at least about 1.25, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 12 fold greater than the time to mean C m a x after the same amount of an oral immediate release buprenorphine solution.
• the oral dosage form of the invention provides a time to mean C max of buprenorphine which is at least about 1.25, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 12 fold greater than the time to mean C max after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• the oral dosage form of the invention provides a mean C max of buprenorphine which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than the mean C m3x after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book
• an immediate release dosage form e.g., solution, suspension, tablet or capsule
• the oral dosage form of the invention provides a ratio of mean AUCo -I4 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% greater than the said ratio after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given according to its intended route of administration.
• the oral dosage form of the invention provides a ratio of mean AUCo -24 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% greater than the said ratio after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given according to its intended route of administration.
• the oral dosage form of the invention provides a ratio of mean AUCo -36 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% greater than the said ratio after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given according to its intended route of administration.
• the oral dosage form of the invention provides a ratio of mean AUQM 8 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% greater than the said ratio after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given according to its intended route of administration.
• the oral dosage form of the invention provides a ratio of mean AUCo -6O of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% greater than the said ratio after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given according to its intended route of administration.
• the oral immediate release and oral extended release dosage forms provide a ratio of mean AUCo -24 , or AUCo -36 , or AUCo -48 , or AUCo -72 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% greater than the said ratio after the transdermal buprenorphine, each given according to its intended route and method of administration.
• the oral immediate release and oral extended release dosage forms provide a ratio of mean AUC 0-I2 , or AUCo -24 , or AUC O-48 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% greater than the said ratio after intranasal buprenorphine, each given according to its intended route and method of administration.
• the oral immediate release and oral extended release dosage forms provides a ratio of mean AUCo -24 , or AUCo -36 , or AUCo -48 , or AUCo -72 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% greater than the said ratio after a sublingual formulation of buprenorphine, each given according to its intended route and method of administration.
• the oral extended release dosage form provides a ratio of mean AUCo -24 , or AUCo -36 , or AUCo -48 , or AUCo -72 of norbuprenorphine to buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% less than the said ratio after the same amount of an oral immediate release formulation of buprenorphine.
• the oral extended release dosage form provides a mean extent of absorption (as measured by AUCo -24 , ° r AUCo -36 , or AUCo -48 , or AUCo -72 ) of buprenorphine after the first dose which is at least about 5%, 10%, 15%, 20%, 30%, or 40% greater than the said ratio after the same amount of an oral immediate release formulation of buprenorphine.
• norbuprenorphine to buprenorphine for oral extended release buprenorphine after the first dose is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% less than the said ratio after the first dose of the same amount of an oral immediate release formulation of buprenorphine.
• the oral dosage form of the invention provides a mean drowsiness score in buprenorphine and opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than the mean drowsiness score after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• the oral dosage form of the invention provides a mean nausea score which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than the mean nausea score after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a mean nausea score which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than the mean nausea score after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• the oral dosage form of the invention provides a mean driving simulation impairment score in buprenorphine and opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than the mean driving simulation impairment score after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a mean driving simulation impairment score in buprenorphine and opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than the mean driving simulation impairment score after the same amount of a commercially available immediate release sublingual formulation of buprenorphine listed
• the oral dosage form of the invention provides a mean number needed to harm (NNH) due to moderate to severe sedation or drowsiness in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• NNH mean number needed to harm
• the oral dosage form of the invention provides a mean number needed to harm (NNH) due to moderate or severe nausea in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• NNH mean number needed to harm
• the oral dosage form of the invention provides a mean number needed to harm (NNH) due to dizziness in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• NNH mean number needed to harm
• the oral dosage form of the invention provides a mean number needed to harm (NNH) due to dry mouth in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• NNH mean number needed to harm
• the oral dosage form of the invention provides a mean "drug effects" score in opioid abusers or recreational opioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a mean "drug effects" score in opioid abusers or recreational opioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e
• the oral dosage form of the invention provides a mean "drug liking" score in opioid abusers or recreational opioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a mean "drug liking" score in opioid abusers or recreational opioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e
• the oral dosage form of the invention provides a mean "take again" score in opioid abusers or recreational opioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a mean "take again" score in opioid abusers or recreational opioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g
• the oral dosage form of the invention provides a mean "coasting" score in opioid abusers or recreational opioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a mean "coasting" score in opioid abusers or recreational opioid users which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g
• the oral dosage form of the invention provides a mean "critical tracking task" impairment score in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a mean "critical tracking task" impairment score in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g
• the oral dosage form of the invention provides a mean "stop signal task" impairment score in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• a mean "stop signal task" impairment score in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g
• the oral dosage form of the invention provides a mean "Tower of London” (TOL) impairment score in opioid naive subjects which is at least about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 120%, 140%, 150%, 180%, 200%, 230%, 260%, or 300% lower than said score after an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally.
• TOL Total of London impairment score
• the oral dosage form of the invention provides a mean ratio of street price at about 1, or 2, or 3, or 4 or 5, or 6 hours post-dose, after administration of an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally to the dosage form of the invention is > 1.10, > 1.15, or > 1.25, or > 1.5, or > 1.75, or > 2, or > 2.5, or > 3, or > 3.5, or > 4, or > 4.5, or > 5, or > 5.5, or > 6, or > 6.5, or > 7, or > 7.5, or > 8, or > 8.5, or > 9, or > 9.5, or > 10, where "street price" is based the price recreational drug users or drug addicts would be prepared to pay after consuming said buprenorphine by the intended method of use or by any method of use.
• an immediate release dosage form e.g., solution, suspension, tablet or capsule
• the oral dosage form of the invention provides a mean ratio of street price at about 1, or 2, or 3, or 4 or 5, or 6 hours post-dose, after administration of an equal amount or dose of commercially available immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book or an immediate release dosage form (e.g., solution, suspension, tablet or capsule) given orally to the dosage form of the invention is > 1.10, > 1.15, or > 1.25, or > 1.5, or > 1.75, or > 2, or > 2.5, or > 3, or > 3.5, or > 4, or > 4.5, or > 5, or > 5.5, or > 6, or > 6.5, or > 7, or > 7.5, or > 8, or > 8.5, or > 9, or > 9.5, or > 10, where "street price" is based the price recreational drug users or drug addicts would be prepared to pay after consuming said buprenorphine by the intended method of use or by any method of use, and where said buprenorphine use is followed about 0.5 to 1.5
• the oral dosage form of the invention provides a relative mean C max whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given to according to its intended route of administration.
• the oral dosage form of the invention provides a relative mean C max whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with other available buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean C max under single-dose fasted test conditions in healthy subjects which is statistically significantly different, when compared with immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given to according to its intended route of administration.
• the oral dosage form of the invention provides a relative mean C max under single-dose fasted test conditions in healthy subjects which is statistically significantly different, when compared with oral ingestion of a conventional solution, suspension, immediate release tablet or capsule.
• the oral dosage form of the invention provides a relative mean C max whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with intranasal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean C max whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with transdermal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean C max whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with buccal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean C max whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release oral buprenorphine.
• the oral dosage form of the invention provides a relative mean C max whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release oral buprenorphine solution.
• the oral dosage form of the invention provides a relative mean AUCo ⁇ , or AUC 0-8 , or AUCo -I2 , or AUCo -24 , or AUCo -1 , or AUC 0- , nf , under single-dose fasted test conditions in healthy subjects which is statistically significantly different, when compared with immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given to according to its intended route of administration.
• the oral dosage form of the invention provides a relative mean AUC 0- 6, or AUC 0-8 , or AUCo -I2 , or AUC 0-24 , or AUCo - ⁇ , or AUCo -inf , under single-dose fasted test conditions in healthy subjects which is statistically significantly different, when compared with oral ingestion of a conventional solution, suspension, immediate release tablet or capsule.
• the oral dosage form of the invention provides a relative mean AUCo - ⁇ whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book.
• the oral dosage form of the invention provides a relative mean AUC 0-1 whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given to according to its intended route of administration.
• the oral dosage form of the invention provides a relative mean AUCo -1 whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with other available buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean AUCo -1 whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with intranasal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean AUCo - ⁇ whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with transdermal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean AUCo -1 whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with buccal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean AUCo - ⁇ whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release oral buprenorphine.
• the oral dosage form of the invention provides a relative mean AUCo - ⁇ whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release oral buprenorphine solution.
• the oral dosage form of the invention provides a relative mean AUCo- mf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book.
• the oral dosage form of the invention provides a relative mean AUCo-i nf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release sublingual formulation of buprenorphine listed in FDA's Orange Book, each given to according to its intended route of administration.
• the oral dosage form of the invention provides a relative mean AUCo-i nf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with other available buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean AUCo- mf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with intranasal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean AUCo-i nf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with transdermal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean AUCo-i nf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with buccal dosage forms of buprenorphine dosage forms.
• the oral dosage form of the invention provides a relative mean AUCo-i nf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release oral buprenorphine.
• the oral dosage form of the invention provides a relative mean AUCo-i nf whose 90% confidence interval is outside the 80.00% to 125.00, under single-dose fasted test conditions in healthy subjects, when compared with immediate release oral buprenorphine solution.
• the dosage from maintains a plasma buprenorphine and norbuprenorphine concentration within 50% Of C m3x for about 1 to about 9 hours, or about
• the dosage from maintains a plasma buprenorphine and norbuprenorphine concentration within 50% of C max for about 1 to about 9 hours, or about 2 to about 9 hours, or about 3 to about 9 hours, or about 4 to about 9 hours, or about 5 to about 9 hours, or about 6 to about 9 hours, or about 1 to about 8 hours, or about 2 to about 8 hours, or about 3 to about 8 hours, or about 4 to about 8 hours, or about 5 to about 8 hours, or about 6 to about 8 hours, or about 2 to about 7 hours, or about 2 to about 6 hours, or about 2 to about 5 hours, or about 2 to about 4 hours, or about 1 to about 4 hours, or about 1 to about 3 hours, or about 2 to about 6 hours, or about 3 to about 5 hours during a 12 hour dosing interval.
• the dosage from maintains a plasma buprenorphine and norbuprenorphine concentration within 50% of C ma ⁇ for about 1 to about 20 hours, or about 1 to about 18 hours or about 1 to about 16 hours, or about 1 to about 14 hours or about 1 to about 10 hours, or about 1 to about 8 hours or about 1 to about 6 hours, or about 1 to about 5 hours or about 2 to about 20 hours, or about 4 to about 20 hours or about 4 to about 18 hours, or about 5 to about 18 hours or about 6 to about 18 hours, or about 7 to about 18 hours or about 8 to about 18 hours, or about 10 to about 18 hours or about 12 to about 18 hours, or about 14 to about 18 hours or about 4 to about 16 hours, or about 4 to about 12 hours or about 4 to about 10 hours, or about 4 to about 8 hours or about 5 to about 15 hours, or about 5 to about 10 hours or about 6 to about 18 hours, or about 6 to about 12 hours or about 6 to about 10 hours, or about 8 to about 18 hours or about 8 to about
• the dosage from maintains a plasma buprenorphine and norbuprenorphine concentration within 50% of C max for about 1 to about 20 hours, or about 1 to about 18 hours or about 1 to about 16 hours, or about 1 to about 14 hours or about 1 to about 10 hours, or about 1 to about 8 hours or about 1 to about 6 hours, or about 1 to about 5 hours or about 2 to about 20 hours, or about 4 to about 20 hours or about 4 to about 18 hours, or about 5 to about 18 hours or about 6 to about 18 hours, or about 7 to about 18 hours or about 8 to about 18 hours, or about 10 to about 18 hours or about 12 to about 18 hours, or about 14 to about 18 hours or about 4 to about 16 hours, or about 4 to about 12 hours or about 4 to about 10 hours, or about 4 to about 8 hours or about 5 to about 15 hours, or about 5 to about 10 hours or about 6 to about 18 hours, or about 6 to about 12 hours or about 6 to about 10 hours, or about 8 to about 18 hours or about 8 to about 16 hours
• the oral pharmaceutical composition of buprenorphine or a pharmaceutically dosage from provides a buprenorphine T max greater than about 0.25 hours, or greater than about 0.5 hours, or greater than about 0.75 hours, or greater than about 1 hour, or greater than about 1.5 hours, or greater than about 2 hours, or greater than about 2.5 hours, or greater than about 3 hours, or greater than about 3.5 hours, or greater than about 4 hours, or greater than about 4.5 hours, or greater than about 5 hours, or greater than about 6 hours, or greater than about 8 hours, or greater than about 10 hours, or greater than about 12 hours, or greater than about 14 hours, or greater than about 16 hours, or greater than about 17 hours, or greater than about 18 hours, or greater than about 20 hours, or greater than about 22 hours, or greater than about 24 hours.
• the oral pharmaceutical composition of buprenorphine or a pharmaceutically dosage from provides a buprenorphine T max of about 0.25 to about 8 hours, about 0.5 to about 30 hours, or about 0.5 to about 26 hours, or about 0.5 to about 22 hours, or about 0.5 to about 20 hours, or about 0.5 to about 18 hours, or about 0.5 to about 16 hours, or about 0.5 to about 14 hours, or about 0.5 to about 12 hours, or about 0.5 to about 10 hours, or about 0.5 to about 9 hours, or about 0.5 to about 8 hours, or about 0.5 to about 7 hours, or about 0.5 to about 6 hours, or about 0.5 to about 5 hours, or about 0.5 to about 4 hours, or about 0.5 to about 3 hours, or about 0.5 to about 2 hours, or about 0.5 to about 1 hour, or about 1 to about 30 hours, or about 2 to about 30 hours, or about 3 to about 30 hours, or about 4 to about 30 hours, or about 5 to about 30 hours, or about 6 to about 30
• the oral pharmaceutical composition of buprenorphine or a pharmaceutically dosage from provides a norbuprenorphine T max greater than about 0.25 hours, or greater than about 0.5 hours, or greater than about 0.75 hours, or greater than about 1 hour, or greater than about 1.5 hours, or greater than about 2 hours, or greater than about 2.5 hours, or greater than about 3 hours, or greater than about 3.5 hours, or greater than about 4 hours, or greater than about 4.5 hours, or greater than about 5 hours, or greater than about 6 hours, or greater than about 8 hours, or greater than about 10 hours, or greater than about 12 hours, or greater than about 14 hours, or greater than about 16 hours, or greater than about 17 hours, or greater than about 18 hours, or greater than about 20 hours, or greater than about 22 hours, or greater than about 24 hours.
• the oral pharmaceutical composition of buprenorphine or a pharmaceutically dosage from provides a norbuprenorphine T max of about 0.25 to about 8 hours, about 0.5 to about 30 hours, or about 0.5 to about 26 hours, or about 0.5 to about 22 hours, or about 0.5 to about 20 hours, or about 0.5 to about 18 hours, or about 0.5 to about 16 hours, or about 0.5 to about 14 hours, or about 0.5 to about 12 hours, or about 0.5 to about 10 hours, or about 0.5 to about 9 hours, or about 0.5 to about 8 hours, or about 0.5 to about 7 hours, or about 0.5 to about 6 hours, or about 0.5 to about 5 hours, or about 0.5 to about 4 hours, or about 0.5 to about 3 hours, or about 0.5 to about 2 hours, or about 0.5 to about 1 hour, or about 1 to about 30 hours, or about 2 to about 30 hours, or about 3 to about 30 hours, or about 4 to about 30 hours, or about 5 to about 30 hours, or about 6 to about
• the oral dosage form of the invention provides a mean in vivo extent of absorption of buprenorphine from 0 to 4 hours which is at least 20% of the mean in vivo extent of absorption from to 0 to 12 hours, wherein the mean in vivo extent of absorption is the area under the plasma or serum buprenorphine concentration time curve from the time of drug administration to the specified time point.
• the oral dosage form of the invention provides a mean in vivo extent of absorption of buprenorphine from 0 to 8 hours which is at least 20% of the mean in vivo extent of absorption from to 0 to 24 hours, wherein the mean in vivo extent of absorption is the area under the plasma or serum buprenorphine concentration time curve from the time of drug administration to the specified time point.
• the oral dosage form of the invention provides a mean in vivo extent of absorption of buprenorphine and norbuprenorphine over the dosing interval (e.g., from 0 to 12 hours or from 0 to 24 hours) which is at least 40% of the mean in vivo extent of absorption from to 0 to infinity, wherein the mean in vivo extent of absorption is the area under the plasma or serum buprenorphine and norbuprenorphine concentration time curves (AUC) from the time of drug administration to the specified time point and where AUC infinity is the sum of AUC from time "0" to time "t" (the last quantifiable time point which has been sampled) plus the extrapolated AUC from the last quantifiable sampling time point to infinity.
• AUC concentration time curves
• the oral buprenorphine dosage form provides a mean in vivo extent of absorption of buprenorphine or norbuprenorphine from about 0 to about 2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, or about 0 to about 5 hours, or about 0 to about 6 hours, which is ⁇ about 1% of the mean in vivo extent of absorption from to 0 to 12 hours, wherein the mean in vivo extent of absorption is the area under the plasma or serum buprenorphine or norbuprenorphine concentration time curve from the time of drug administration to the specified time point.
• said in vivo extent of absorption from about 0 to about 2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, or about 0 to about 5 hours, or about 0 to about 6 hours is ⁇ about 2%, or ⁇ about 3%, or ⁇ about 4%, or ⁇ about 5%, or ⁇ about 6%, or ⁇ about 7%, or ⁇ about 8%, or ⁇ about 9%, or ⁇ about 10%, or ⁇ about 12%, or ⁇ about 14%, or ⁇ about 15%, or ⁇ about 16%, or ⁇ about 18%, or ⁇ about 20%, or ⁇ about 25%, or ⁇ about 30%, or ⁇ about 35% of the mean in vivo extent of absorption from to 0 to 12 hours.
• the oral buprenorphine dosage form provides a mean in vivo extent of absorption of buprenorphine or norbuprenorphine from about 0 to about 2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, or about 0 to about 5 hours, or about 0 to about 6 hours, which is ⁇ about 1% of the mean in vivo extent of absorption from to 0 to 24 hours, wherein the mean in vivo extent of absorption is the area under the plasma or serum buprenorphine or norbuprenorphine concentration time curve from the time of drug administration to the specified time point.
• said in vivo extent of absorption from about 0 to about 2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, or about 0 to about 5 hours, or about 0 to about 6 hours is ⁇ about 2%, or ⁇ about 3%, or ⁇ about 4%, or ⁇ about 5%, or ⁇ about 6%, or ⁇ about 7%, or ⁇ about 8%, or ⁇ about 9%, or ⁇ about 10%, or ⁇ about 12%, or ⁇ about 14%, or ⁇ about 15%, or ⁇ about 16%, or ⁇ about 18%, or ⁇ about 20%, or ⁇ about 25%, or ⁇ about 30%, or ⁇ about 35% of the mean in vivo extent of absorption from to 0 to 24 hours.
• the oral buprenorphine dosage form provides a mean in vivo extent of absorption of buprenorphine or norbuprenorphine from about 0 to about 7 hours, or about 0 to about 8 hours, or about 0 to about 9 hours, or about 0 to about 10 hours, which is ⁇ about 1% of the mean in vivo extent of absorption from to 0 to 24 hours, wherein the mean in vivo extent of absorption is the area under the plasma or serum buprenorphine or norbuprenorphine concentration time curve from the time of drug administration to the specified time point.
• said in vivo extent of absorption from about 0 to about 7 hours, or about 0 to about 8 hours, or about 0 to about 9 hours, or about 0 to about 10 hours is ⁇ about 2%, or ⁇ about 3%, or ⁇ about 4%, or ⁇ about 5%, or ⁇ about 6%, or ⁇ about 7%, or ⁇ about 8%, or ⁇ about 9%, or ⁇ about 10%, or ⁇ about 12%, or ⁇ about 14%, or
• the oral buprenorphine dosage form provides a mean in vivo extent of absorption of buprenorphine or norbuprenorphine from about 0 to about 2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, or about 0 to about 5 hours, or about 0 to about 6 hours, or about 0 to about 7 hours, or about 0 to about 8 hours, or about 0 to about 9 hours, or about 0 to about 10 hours, which is ⁇ about 1% of the mean in vivo extent of absorption from to 0 to 36 hours, wherein the mean in vivo extent of absorption is the area under the plasma or serum buprenorphine or norbuprenorphine concentration time curve from the time of drug administration to the specified time point.
• said in vivo extent of absorption from about 0 to about 2 hours, or about 0 to about 3 hours, or about 0 to about 4 hours, or about 0 to about 5 hours, or about 0 to about 6 hours, or about 0 to about 7 hours, or about 0 to about 8 hours, or about 0 to about 9 hours, or about 0 to about 10 hours is ⁇ about 2%, or ⁇ about 3%, or ⁇ about 4%, or ⁇ about 5%, or ⁇ about 6%, or ⁇ about 7%, or ⁇ about 8%, or ⁇ about 9%, or ⁇ about 10%, or ⁇ about 12%, or ⁇ about 14%, or
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine of less than 5% at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) at 37 0 C.
• SGF Simulated Gastric Fluid
• said release rate from 2% to about 50% at one hour, or from 5% to about 40% at one hour, or from 5% to about 40% at one hour, or from 5% to about 45% at one hour, or from 10% to about 40% at one hour, or from 20% to about 40% at one hour, or from 1% to about 40% at one hour, or from 1% to about 60% at one hour, or from 1% to about 80% at one hour, or from 1% to about 90% at one hour, or from 1% to about 100% at one hour, or greater than about 1 % at one hour, or greater than about 5 % at one hour, or greater than about 10% at one hour, or greater than about 20% at one hour, or greater than about 30% at one hour, or greater than about 40% at one hour, or greater than about 50% at one hour, or greater than about 60% at one hour, or greater than about 70% at one hour, or greater than about 80% at one hour, or greater than about 90% at one hour.
• the oral dosage form of the invention provides an in- vitro release of between 0% to about 50% by weight of the buprenorphine or a pharmaceutically acceptable salt of buprenorphine from the dosage form at one hour when measured by the USP Basket or Paddle Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) at 37 0 C.
• SGF Simulated Gastric Fluid
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of more than about 40% at 10 minutes, more than about 60% at 20 minutes and more than about 80% at 30 minutes
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 °C of between 0% to about 80% at 0.5 hours, and greater than about 40% at 1 hour.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 90% at 0.5 hours, and greater than about 60% at 1 hour.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 °C of between 5% to about 90% at 10 minutes, and greater than about 60% at 20 minutes.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 5% to about 100% at 10 minutes, and greater than about 60% at 30 minutes.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 100% at 0.5 hours, and greater than about 70% at 1 hour.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 90% at 1 hour, and greater than about 40% at 2 hours.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 90% at 1 hour, and greater than about 70% at 2 hours.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 50% at 1 hour, and greater than about 30% at 2 hours.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 30% at 1 hour, and greater than about 25% at 2 hours.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 100% at 0.5 hours, and greater than about 60% at 1 hour.
• the oral dosage form of the invention provides an in- vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Method at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 100% at 1 hour, and greater than about 60% at 2 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing a mean in vitro controlled release rate of buprenorphine of 0.15 mg per hour to 35.0 mg per hour.
• said release rate is about 0.20 mg per hour to about 8.33 mg per hour, more preferably 0.42 mg per hour to 4.2 mg per hour, and most preferably 0.2 mg per hour to 2.5 mg per hour.
• the oral dosage form provides a therapeutic effect for about 6, 8, 12 or 24 hours and provide said release rate of about 0.20 mg per hour to about 8.33 mg per hour, more preferably 0.42 mg per hour to 4.2 mg per hour, and most preferably 0.2 mg per hour to 2.5 mg per hour.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 40% at 1 hour, from about 5% to about 60% at 2 hours, from about 10% to about 75% at 4 hours, from about 20% to about 75% at 6 hours, from about 30% to about 80% at 9 hours, and greater than about 70% at 12 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 1% and about 45% at 1 hour, between about 5% and about 70% at 2 hours, between about 10% and about 90% at 4 hours, between about 20% and about 90% at 8 hours, greater than about 60% at 12 hours, greater than about 80% at 18 hours, and greater than about 85% at 24 hours.
• Q6H or Q6H PRN three
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 5% and about 60% at 1 hour, between about 12.5% and about 80% at 2 hours, between about 25% and about 95% at 4 hours, between about 45% and about 100% at 8 hours, greater than about 55% at 12 hours, greater than about 65% at 18 hours, and greater than about 70% at 24 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% and about 40% at 1 hour, between about 0% and about 70% at 2 hours, between about 5% and about 95% at 4 hours, between about 12.5% and about 100% at 8 hours, between about 20% and about 100% at 12 hours, between about 35% and about 100% at 16 hours, between about 55% and about 100%
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% and about 60% at 1 hour, between about 0% and about 75% at 2 hours, between about 5% and about 95% at 4 hours, between about 12.5% and about 100% at 8 hours, between about 15% and about 100% at 12 hours, between about 25% to about 100% at 16 hours, between about 30% and about 100% hours
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release from the dosage form at one hour when measured by the USP Basket or Paddle Methods at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) at 37 0 C of between 0% to about 50% by weight of buprenorphine.
• SGF Simulated Gastric Fluid
• said release rate is between 0% to about 1%, or 0% to about 3%, or 0% to about 5%, or 0% to about 10%, or 0% to about 15%, or 0% to about 20%, 0% to about 30%, or 0% to about 40%, or 0% to about 60%, or 0% to about 70%, or 0% to about 80%, or 0% to about 90%, 0% to about 100%.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release from the dosage form at one hour when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% and about 60% at 1 hour, between about 0% and about 80% at 2 hours, between about 3% and about 95% at 4 hours and between about 10% and about 100% at 8 hours.
• said release rate is between 0% and about 10% at 1 hour, between about 0% and about 20% at 2 hours, between about 2% and about 80% at 4 hours and between about 5% and about 100% at 8 hours; or between 0% and about 20% at 1 hour, between about 0% and about 40% at 2 hours, between about 0% and about 80% at 4 hours and between about 2% and about 100% at 8 hours; or between 0% and about 40% at 1 hour, between about 0% and about 60% at 2 hours, between about 5% and about 85% at 4 hours and between about 5% and about 90% at 8 hours and greater than 20% at 12 hours; or between 0% and about 50% at 1 hour, between about 0% and about 50% at 2 hours, between about 10% and about 90% at 4 hours and between about 15% and about 90% at 8 hours and greater than 30% at 12 hours; or between 0% and about 70% at 1 hour, between about 0% and about 70% at 2 hours, between about 10% and about 75% at 4 hours and between about 15% and about 90% at 8 hours and greater than 30% at 12 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release from the dosage form at one hour when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 10% and about 65% at 1 hour, between about 20% and about 75% at 2 hours, between about 30% and about 95% at 4 hours and between about 40% and about 100% at 8 hours.
• said release rate is between 2% and about 70% at 1 hour, between about 5% and about 80% at 2 hours, between about 10% and about 90% at 4 hours and between about 20% and about 100% at 8 hours; or between 5% and about 60% at 1 hour, between about 10% and about 75% at 2 hours, between about 15% and about 85% at 4 hours and between about 30% and about 100% at 8 hours; or between 20% and about 70% at 1 hour, between about 20% and about 75% at 2 hours, between about 20% and about 90% at 4 hours and between about 40% and about 100% at 8 hours; or between 30% and about 80% at 1 hour, between about 40% and about 85% at 2 hours, between about 40% and about 90% at 4 hours and between about 60% and about 100% at 8 hours; or between 1% and about 20% at 1 hour, between about 5% and about 20% at 2 hours, between about 10% and about 40% at 4 hours and between about 20% and about 40% at 8 hours and greater than 40% at 12 hours.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 47.5% at 1 hour, from about 10% to about 65% at 2 hours, from about 15% to about 70% at 4 hours, from about 25% to about 77.5% at 6 hours, from about 35% to about 87.5% at 9 hours, and greater than about 65% at 12 hours.
• said release rate is between 0% to about 30% at 1 hour, from about 5% to about 45% at 2 hours, from about 10% to about 60% at 4 hours, from about 15% to about 70% at 6 hours, from about 25% to about 80% at 9 hours, and greater than about 50% at 12 hours; or between 0% to about 20% at 1 hour, from about 2% to about 35% at 2 hours, from about 5% to about 50% at 4 hours, from about 10% to about 60% at 6 hours, from about 15% to about 70% at 9 hours, and greater than about 40% at 12 hours; or between 0% to about 10% at 1 hour, from about 1% to about 30% at 2 hours, from about 5% to about 40% at 4 hours, from about 10% to about 60% at 6 hours, from about 15% to about 70% at 9 hours, and greater than about 40% at 12 hours; or between 0% to about 5% at 1 hour, from about 0% to about 10% at 2 hours, from about 2% to about 20% at 4 hours, from about 5% to about 30% at 6 hours, from about 10% to about 40% at 9 hours, and greater than about 50% at 12 hours
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 5% and about 50% at 1 hour, between about 10% and about 75% at 2 hours, between about 20% and about 95% at 4 hours, between about 40% and about 100% at 8 hours, greater than about 50% at 12 hours, greater than about 70% at 18 hours, and greater than about 80% at 24 hours.
• Q6H or Q6H PRN three times
• said release rate is between 2% and about 50% at 1 hour, between about 5% and about 75% at 2 hours, between about 15% and about 75% at 4 hours, between about 30% and about 90% at 8 hours, greater than about 40% at 12 hours, greater than about 60% at 18 hours, and greater than about 70% at 24 hours; or between 1% and about 40% at 1 hour, between about 2% and about 60% at 2 hours, between about 10% and about 65% at 4 hours, between about 20% and about 80% at 8 hours, greater than about 30% at 12 hours, greater than about 40% at 18 hours, and greater than about 60% at 24 hours; or between 5% and about 60% at 1 hour, between about 15% and about 80% at 2 hours, between about 25% and about 95% at 4 hours, between about 45% and about 100% at 8 hours, greater than about 60% at 12 hours, greater than about 80% at 18 hours, and greater than about 90% at 24 hours; or between 10% and about 65% at 1 hour, between about 20% and about 85% at 2 hours, between about 30% and about 100% at 4 hours, between about 60% and about 100% at 4 hours, between
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 30% at 1 hour, from about 10% to about 65% at 4 hours, from about 20% to about 70% at 8 hours, from about 25% to about 80% at 12 hours, from about 35% to about 95% at 18 hours, and greater than about 65% at 24 hours.
• said release rate is between 0% to about 20% at 1 hour, from about 5% to about 50% at 4 hours, from about 10% to about 60% at 8 hours, from about 15% to about 70% at 12 hours, from about 25% to about 90% at 18 hours, and greater than about 55% at 24 hours; or between 0% to about 10% at 1 hour, from about 5% to about 40% at 4 hours, from about 8% to about 50% at 8 hours, from about 10% to about 60% at 12 hours, from about 22% to about 80% at 18 hours, and greater than about 45% at 24 hours; or between 0% to about 35% at 1 hour, from about 15% to about 70% at 4 hours, from about 25% to about 75% at 8 hours, from about 30% to about 85% at 12 hours, from about 40% to about 100% at 18 hours, and greater than about 75% at 24 hours; or between 0% to about 40% at 1 hour, from about 20% to about 70% at 4 hours, from about 30% to about 80% at 8 hours, from about 35% to about 90% at 12 hours, from about 45% to about 100% at 18 hours, and
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% and about 50% at 1 hour, between about 0% and about 75% at 2 hours, between about 3% and about 95% at 4 hours, between about 10% and about 100% at 8 hours, between about 25% and about 100% at 12 hours, between about 30% and about 100% at 16 hours, between about 50% and about 100% at 24 hours
• said release rate is between 0% and about 40% at 1 hour, between about 0% and about 65% at 2 hours, between about 2% and about 85% at 4 hours, between about 8% and about 90% at 8 hours, between about 20% and about 95% at 12 hours, between about 25% and about 95% at 16 hours, between about 40% and about 90% at 24 hours, and greater than about 70% at 36 hours; or between 0% and about 30% at 1 hour, between about 0% and about 50% at 2 hours, between about 1% and about 75% at 4 hours, between about 5% and about 80% at 8 hours, between about 10% and about 85% at 12 hours, between about 15% and about 90% at 16 hours, between about 30% and about 80% at 24 hours, and greater than about 70% at 36 hours; or between 0% and about 60% at 1 hour, between about 0% and about 80% at 2 hours, between about 5% and about 100% at 4 hours, between about 15% and about 100% at 8 hours, between about 35% and about 100% at 12 hours, between about 40% and about 100% at 16 hours, between about 60% and about 100% at
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 20% and about 50% at 1 hour, between about 40% and about 75% at 2 hours, between about 60% and about 95% at 4 hours, between about 80% and about 100% at 8 hours and between about 90% and about 100% at 12 hours.
• said release rate is between 15% and about 45% at 1 hour, between about 35% and about 70% at 2 hours, between about 55% and about 90% at 4 hours, between about 75% and about 90% at 8 hours and between about 80% and about 95% at 12 hours; or between 10% and about 40% at 1 hour, between about 30% and about 65% at 2 hours, between about 50% and about 85% at 4 hours, between about 70% and about 85% at 8 hours and between about 75% and about 90% at 12 hours; or between 5% and about 35% at 1 hour, between about 25% and about 60% at 2 hours, between about 45% and about 80% at 4 hours, between about 65% and about 80% at 8 hours and between about 70% and about 85% at 12 hours; or between 25% and about 55% at 1 hour, between about 45% and about 80% at 2 hours, between about 65% and about 95% at 4 hours, between about 85% and about 100% at 8 hours and between about 95% and about 100% at 12 hours; or between 30% and about 60% at 1 hour, between about 50% and about 80% at 2 hours, between 30% and about 60% at
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% and about 50% at 1 hour, between about 0% and about 75% at 2 hours, between about 10% and about 95% at 4 hours, between about 35% and about 100% at 8 hours, between about 55% and about 100% at 12 hours, between about 70% to about 100% at 16 hours, and greater than about 90% at 24 hours.
• said release rate is between 0% and about 40% at 1 hour, between about 0% and about 65% at 2 hours, between about 8% and about 85% at 4 hours, between about 30% and about 90% at 8 hours, between about 45% and about 100% at 12 hours, between about 60% to about 100% at 16 hours, and greater than about 80% at 24 hours; or between 0% and about 30% at 1 hour, between about 0% and about 55% at 2 hours, between about 5% and about 75% at 4 hours, between about 20% and about 80% at 8 hours, between about 35% and about 100% at 12 hours, between about 50% to about 100% at 16 hours, and greater than about 70% at 24 hours; or between 0% and about 20% at 1 hour, between about 0% and about 45% at 2 hours, between about 5% and about 65% at 4 hours, between about 10% and about 70% at 8 hours, between about 25% and about 80% at 12 hours, between about 40% to about 100% at 16 hours, and greater than about 60% at 24 hours; or between 0% and about 60% at 1 hour, between about 0% and about 80%
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% and about 30% at 1 hour, between about 0% and about 45% at 2 hours, between about 3% and about 55% at 4 hours, between about 10% and about 65% at 8 hours, between about 20% and about 75% at 12 hours, between about 30% to about 88% at 16 hours, between about 50% and about 100% hours at 24
• said release rate is between 0% and about 25% at 1 hour, between about 0% and about 40% at 2 hours, between about 2% and about 50% at 4 hours, between about 8% and about 60% at 8 hours, between about 10% and about 70% at 12 hours, between about 25% to about 80% at 16 hours, between about 45% and about 100% hours at 24 hours and greater than 75% at 36 hours; or between 0% and about 20% at 1 hour, between about 0% and about 35% at 2 hours, between about 1% and about 45% at 4 hours, between about 5% and about 55% at 8 hours, between about 8% and about 65% at 12 hours, between about 20% to about 75% at 16 hours, between about 40% and about 100% hours at 24 hours and greater than 70% at 36 hours; or between 0% and about 15% at 1 hour, between about 0% and about 30% at 2 hours, between about 0% and about 40% at 4 hours, between about 5% and about 50% at 8 hours, between about 8% and about 60% at 12 hours, between about 15% to about 70% at 16 hours, between about 35% and about 100% hours
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 °C of between 0% and about 50% at 1 hour, between about 0% and about 75% at 2 hours, between about 3% and about 95% at 4 hours, between about 10% and about 100% at 8 hours, between about 20% and about 100% at 12 hours, between about 30% to about 100% at 16 hours, between about 50% and about 100% hours at 24 hours and greater
• said release rate is between 0% and about 45% at 1 hour, between about 0% and about 70% at 2 hours, between about 3% and about 90% at 4 hours, between about 8% and about 100% at 8 hours, between about 15% and about 100% at 12 hours, between about 25% to about 100% at 16 hours, between about 45% and about 100% hours at 24 hours and greater than 80% at 36 hours; or between 0% and about 40% at 1 hour, between about 0% and about 65% at 2 hours, between about 0% and about 80% at 4 hours, between about 5% and about 80% at 8 hours, between about 10% and about 90% at 12 hours, between about 20% to about 100% at 16 hours, between about 40% and about 100% hours at 24 hours and greater than 70% at 36 hours; or between 0% and about 35% at 1 hour, between about 0% and about 60% at 2 hours, between about 0% and about 70% at 4 hours, between about 3% and about 70% at 8 hours, between about 5% and about 80% at 12 hours, between about 15% to about 100% at 16 hours, between about 30% and about 100% hours at 24
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing an in-vitro release rate by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 15% and about 25% at 1 hour, between about 25% and about 35% at 2 hours, between about 30% and about 45% at 4 hours, between about 40% and about 60% at 8 hours, between about 55% and about 70% at 12 hours and between about 60% to about 75% at 16 hours.
• Q6H or Q6H PRN three times-a-day
• said release rate is between 10% and about 20% at 1 hour, between about 20% and about 30% at 2 hours, between about 25% and about 40% at 4 hours, between about 30% and about 50% at 8 hours, between about 50% and about 65% at 12 hours and between about 55% to about 65% at 16 hours; or between 5% and about 15% at 1 hour, between about 15% and about 25% at 2 hours, between about 20% and about 35% at 4 hours, between about 25% and about 45% at 8 hours, between about 45% and about 60% at 12 hours and between about 50% to about 60% at 16 hours; or between 15% and about 30% at 1 hour, between about 20% and about 40% at 2 hours, between about 20% and about 50% at 4 hours, between about 30% and about 70% at 8 hours, between about 60% and about 80% at 12 hours and between about 70% to about 90% at 16 hours; or between 0% and about 50% at 1 hour, between about 5% and about 50% at 2 hours, between about 5% and about 70% at 4 hours, between about 10% and about 80% at 8 hours, between about 20% and about 100% at 12 hours and between about 40% to
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said in-vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of said buprenorphine released at one pH and an amount released at any other pH, when measured in-vitro using the USP Basket or Paddle Methods of USP Drug Release test of U.S.
• Pharmacopeia (2003) at 100 rpm in 900 ml aqueous buffer is no greater than 30%.
• the difference, at any given time, between an amount of buprenorphine released at one pH and an amount released at any other pH using the aforementioned methods is no greater than 50%, or no greater than 40%, or no greater than 35%, or no greater than 25%, or no greater than 20%, or no greater than 15%, or no greater than 10%, or no greater than 5%.
• pH independent dissolution and release can work against the objectives of the some oral dosage forms of buprenorphine (delayed onset, rapid release or delayed onset, extended release, or delayed onset, pulsatile release) which are intended to provide delivery or release of the dosage form in the proximal to the stomach, duodenum, or ileum (i.e., duodenal release, jejunal release, ileal release, ileo-colonic release or colonic release).
• certain controlled release material used to achieve delayed onset, duodenal release, jejunal release, ileal release, ileo-colonic release or colonic release exploit the pH difference in the GI tract to achieve some or all of its objectives.
• the in-vitro release rate is substantially dependent on pH in that the amount of buprenorphine released at an undesirable pH (e.g., pH 1.2) and the amount released at a desirable pH (e.g., depending on the controlled release material and delivery and release objectives, pH 5.5, 6, 6.5, 7, 7.2, 7.4), when measured in-vitro at 1.5 or 2 hours using the USP Basket or Paddle Method of USP Drug Release test of U.S.
• an undesirable pH e.g., pH 1.2
• a desirable pH e.g., depending on the controlled release material and delivery and release objectives, pH 5.5, 6, 6.5, 7, 7.2, 7.4
• the in-vitro release rate difference is greater than about 35%, or 40%, or 45%, or 50%, or 55%, or 60% or 70%, or 80%, with the release rate higher at the desirable pH compared with the undesirable pH.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said in- vitro release rate being substantially independent of pH in that a difference, at any given time, between an amount of said buprenorphine released at one pH and an amount released at any other pH, when measured in-vitro using the USP Basket or Paddle Methods of USP Drug Release test of U.S.
• Pharmacopeia (2003) at 100 rpm in 900 ml aqueous buffer is no greater than 30%.
• the difference, at any given time, between an amount of buprenorphine released at one pH and an amount released at any other pH using the aforementioned methods is no greater than 50%, or no greater than 40%, or no greater than 35%, or no greater than 25%, or no greater than 20%, or no greater than 15%, or no greater than 10%, or no greater than 5%.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage form providing in-vitro release rates by weight of between 0% to about 50% by weight of buprenorphine from the dosage form at one hour when measured by the USP Basket or Paddle Methods at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) at 37 0 C.
• SGF Simulated Gastric Fluid
• said release rate at one hour is between 0% to about 10% by weight, or 0% to about 20% by weight, or is between 0% to about 30% by weight, or 0% to about 40% by weight, or between 0% to about 60% by weight, or 0% to about 70% by weight, or 0% to about 80% by weight, or 0% to about 90% by weight, or 10% to about 50% by weight, or 10% to about 60% by weight, or 10% to about 70% by weight, or 10% to about 90% by weight, or 10% to about 100% by weight, or 30% to about 100% by weight, or 50% to about 100% by weight.
• the dosage form provides an oral pharmaceutical composition comprising a therapeutically effective amount of buprenorphine, said dosage form suitable for four times-a-day (Q6H or Q6H PRN), three times-a-day (Q8H or Q8H PRN), twice-a-day (Q12H or Q12H PRN) or once-a-day (QD, Q24H or Q24H PRN) administration to a human patient, said dosage forms providing in-vitro release rates by weight of buprenorphine, when measured by the USP Basket or Paddle Methods at 100 rpm in 900 mL aqueous buffer at a pH of between 1.6 and 7.2 at 37 0 C of between 0% to about 80% at 0.5 hours, and greater than about 40% at 1 hour.
• said release rate is between 0% to about 40% at 0.5 hours, and greater than about 60% at 1 hour; or between 0% to about 20% at 0.5 hours, and greater than about 40% at 1 hour; or between 0% to about 20% at 0.5 hours, and greater than about 20% at 1 hour; or between 0% to about 90% at 0.5 hours, and greater than about 60% at 1 hour; or between 0% to about 100% at 0.5 hours, and greater than about 60% at 1 hour; or between 0% to about 90% at 1 hour, and greater than about 40% at 2 hours; or between 0% to about 100% at 1 hour, and greater than about 60% at 2 hours; or between 0% to about 60% at 1 hour, and greater than about 40% at 2 hours; or between 0% to about 40% at 1 hour, and greater than about 30% at 2 hours; or between 0% to about 50% at 1 hour, and greater than about 40% at 2 hours; or between 0% to about 30% at 1 hour, and greater than about 20% at 2 hours; or between 0% and about 50% at 1 hour, between about 0% and about 80% at 2
• the dosage forms of the invention contains one or more substances in sufficient quantity to render said dosage form controlled release, such that: (i) in-vitro release rate of buprenorphine by weight of any commercially available sublingual formulations of buprenorphine at the time of this invention (e.g., as listed in the FDA's Orange Book, the EMEA website, Martindale: The Complete Drug Reference, 35th Edition, Pharmaceutical Press) compared with in-vitro release rate by weight of buprenorphine from the dosage form of the invention is at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% faster, or at least 100% faster, or at least 200% faster, or at least 300% faster, or at least 400% faster, or at least 500% faster, or at least 600% faster, or at least 700% faster, or at least 800% faster, or at least 100
• the oral dosage form is a controlled release material suitable for extended release oral administration to a human patient of the dosage form comprises a matrix.
• the said matrix is a plurality of multiparticulate matrices.
• the multiparticulates are compressed into a tablet.
• the multiparticulates are disposed in a pharmaceutically acceptable capsule.
• the in vivo pharmacokinetic parameters of the specifications and claims are derived or determined from first administration. In other preferred embodiments, the in vivo pharmacokinetic parameters are derived or determined from steady state administration.
• the in vivo pharmacokinetic parameters of the specifications and claims are derived or determined under fed conditions. In other preferred embodiments, the in vivo pharmacokinetic parameters are derived or determined under fasted conditions.
• the in vivo pharmacokinetic parameters of the specifications and claims are derived or determined from an individual subject. In other preferred embodiments, the in vivo pharmacokinetic parameters are derived or determined from a population of subjects.
• the in vivo specifications and claims of the invention are measured, reported, observed or achieved after administration of some or most doses of the invention. In other preferred embodiments, the in vivo specifications and claims of the invention are measured, reported, observed or achieved after administration of substantially all or all doses of the invention.
• BMI Body Mass Index
• Also disclosed are methods for the targeted release of buprenorphine from the dosage form into the duodenum, jejunum, ileum and colon to provide a therapeutic effect comprising administering a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• methods for the treatment of opioid dependence or addiction disorders in a human patient suffering comprising administering a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• the addiction disorder is an opioid addiction disorder or a poly- substance abuse disorder.
• Also disclosed are methods for resisting, deterring, minimizing or preventing drug abuse, drug diversion and drug addiction in a human patient comprising administering a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• Also disclosed are methods for the treatment of medical conditions amenable to treatment with buprenorphine in patients who are at higher risk for nausea, vomiting, sedation or other opioid agonist side effects or who have a prior history of said side effects on other opioids comprising administering a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• Also disclosed are methods for the treatment of medical conditions amenable to treatment with buprenorphine in patients who are at higher risk for nausea, vomiting, sedation or other side effects with sublingual buprenorphine or oral immediate release buprenorphine comprising administering a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• Also disclosed are methods for the treatment of dyspnea, cough and COPD comprising administering a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• Also disclosed are methods for the treatment of medical conditions amenable to treatment with buprenorphine or opioid agonists in a human patient who also suffers from an addiction disorder, who is at risk or increased risk for addiction or who may be prone to drug diversion into illicit channels comprising administering a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• Also disclosed are methods for the treatment of medical conditions amenable to treatment with buprenorphine or opioid agonists in a human patient suffering comprising administering a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• Also disclosed are methods for preventing and treating pain in a human patient comprising administering a therapeutically effective amount of oral buprenorpbine or a pharmaceutically acceptable salt of buprenorphine or a mixture thereof.
• All pain states are contemplated by this invention, regardless of etiology, mechanisms, duration, prior treatment response and anatomic location, including acute pain, inflammatory pain, chronic pain, cancer pain, visceral pain and neuropathic pain.
• kits for providing relief in a human patient suffering from neuropathic and chronic pain comprising a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt buprenorphine or a mixture thereof.
• the dosage form of the invention is intended for the treatment of neuropathic pain, peripheral neuropathic pain, central neuropathic pain, chronic pain, osteoarthritis, back pain, cancer pain, and chronic inflammatory pain.
• Also disclosed are methods of providing relief in a human patient suffering from acute pain comprising a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt buprenorphine or a mixture thereof.
• Also disclosed are methods of providing relief in a human patient suffering from an addiction disorder comprising a therapeutically effective amount of oral buprenorphine or a pharmaceutically acceptable salt buprenorphine or a mixture thereof.
• kits for use in treating or preventing the pain with the oral administration of buprenorphine or a pharmaceutically acceptable salt of buprenorphine, or a mixture thereof for a subject in need of such treatment comprising: (i) a dosage form of the invention; (ii) a container for the dosage form; and optionally, any of (iii) to (vi): (iii) a container for individual units of the dosage form (e.g., individual tablets or capsules in blisters); (iv) educational instructions in any media about various medical conditions, their etiology, pathophysiology, consequences and treatment, including information on the potential for abuse and diversion and methods for prevention of same and information on the proper use and disposal of the medication; (v) containers or bags for the safe disposal of any used or remaining unused dosage form, preferably child proof and flushable; (vi) tamper evident and child proof packaging for the kit and its contents.
• the amount of buprenorphine in the oral dosage form will vary depending on variety of physiologic, pharmacologic, pharmacokinetic, pharmaceutical and physicochemical factors, including: (i) the choice of buprenorphine as the base, pharmaceutically acceptable salt or mixtures therof; (ii) the nature of the oral dosage form (e.g, immediate release or extended release); (iii) the anatomical location of the pain relieving target; (iv) the intensity and intractability of the pain; (v) the contribution of different mechanism to the initiation, propagation, summation and maintenance of the pain; (vi) the absorption, metabolism, distribution and excretion of orally administered buprenorphine in healthy subjects and in patients with various diseases and disorders, including renal and hepatic impairment; (vii) the presence of comorbid pathology; (viii) the patient's risk of iatrogenic side effects; (ix) the tolerability of the dose, including the patient's propensity for buprenorphin
• the amount of buprenorphine in the dosage form is about
• the amount of buprenorphine in the dosage form is about 0.1 mg to 1000 mg. In other embodiments, the amount of buprenorphine in the dosage form is about 0.5 mg to about 500 mg or about 1 mg to about 200 mg, or 2 mg to about 100 mg or 1 mg to about 60 mg.
• the maximum dose of oral buprenorphine exceeds the maximum approved dose of sublingual buprenorphine by at least about 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%, or 100%, or 120%, or 140%, or 160%, or 180%, or 200%, or 220%, or 240%, or 260%, or 280%, or 300%, or 320%, or 340%, or 360%, or 380%, or 400%, or 450%, or 500%, or 550%, or 600%, or 650%, or 700%.
• the minimum dose of oral buprenorphine exceeds the minimum approved dose of sublingual buprenorphine by at least about 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%, or 100%, or 120%, or 140%, or 160%, or 180%, or 200%, or 220%, or 240%, or 260%, or 280%, or 300%, or 320%, or 340%, or 360%, or 380%, or 400%, or 450%, or 500%, or 550%, or 600%, or 650%, or 700%.
• the average dose of oral buprenorphine exceeds the average dose of sublingual buprenorphine by at least about 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%, or 100%, or 120%, or 140%, or 160%, or 180%, or 200%, or 220%, or 240%, or 260%, or 280%, or 300%, or 320%, or 340%, or 360%, or 380%, or 400%, or 450%, or 500%, or 550%, or 600%, or 650%, or 700%.
• the induction (where appropriate) or maintenance dose of oral buprenorphine exceeds the approved induction (where appropriate) or maintenance dose of sublingual buprenorphine by at least about 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%, or 100%, or 120%, or 140%, or 160%, or 180%, or 200%, or 220%, or 240%, or 260%, or 280%, or 300%, or 320%, or 340%, or 360%, or 380%, or 400%, or 450%, or 500%, or 550%, or 600%, or 650%, or 700%.
• the induction (where appropriate) dose, maintenance dose, minimum dose, average doe and/or maximum dose of oral buprenorphine exceeds the corresponding dose sublingual buprenorphine by at least about 5%, or 10%, or 15%, or 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 80%, or 90%, or 100%, or 120%, or 140%, or 160%, or 180%, or 200%, or 220%, or 240%, or 260%, or 280%, or 300%, or 320%, or 340%, or 360%, or 380%, or 400%, or 450%, or 500%, or 550%, or 600%, or 650%, or 700%.
• the dose of oral buprenorphine is at least about 2 mg, or 3 mg, or 4 mg, or 5 mg, or 6 mg, or 7 mg, or 8 mg, or 9 mg, or 10 mg or 11 mg, or 12 mg, or 13 mg, or 14 mg, or 15 mg, or 16 mg, or 17 mg, or 18 mg, or 19 mg, or 20 mg, or 21 mg, or 22 mg, or 23 mg, or 24 mg, or 25 mg, or 26 mg, or 27 mg, or 28 mg, or 29 mg, or 30 mg, or 32 mg, or 34 mg, or 35 mg, or 36 mg, or 38 mg, or 40 mg, or 45 mg, or 50 mg, or 55 mg, or 60 mg, or 65 mg, or 70 mg.
• the amount of buprenorphine base in the dosage form is not less than 10 mg, or not less than about 10 mg, or 11 mg, or 12 mg, or 13 mg or 14 mg, or 15 mg, or 16 mg, or 17 mg, or 18 mg, or 19 mg, or 20 mg, or 21 mg, or 22 mg, or 23 mg, or 24 mg, or 25 mg, or 26 mg, or 27 mg, or 28 mg, or 29 mg, or 30 mg.
• the amount of buprenorphine hydrochloride in the dosage form is not less than 10 mg, or not less than about 10 mg, or 11 mg, or 12 mg, or 13 mg or 14 mg, or 15 mg, or 16 mg, or 17 mg, or 18 mg, or 19 mg, or 20 mg, or 21 mg, or 22 mg, or 23 mg, or 24 mg, or 25 mg, or 26 mg, or 27 mg, or 28 mg, or 29 mg, or 30 mg.
• the amount of any pharmaceutically acceptable salt of buprenorphine in the dosage form is not less than 10 mg, or not less than about 10 mg, or 11 mg, or 12 mg, or 13 mg or 14 mg, or 15 mg, or 16 mg, or 17 mg, or 18 mg, or 19 mg, or 20 mg, or 21 mg, or 22 mg, or 23 mg, or 24 mg, or 25 mg, or 26 mg, or 27 mg, or 28 mg, or 29 mg, or 30 mg.
• the daily dose of buprenorphine or its pharmaceutically acceptable salt in the dosage form is not less than 40 mg, or 50 mg or 60 mg or 65 mg.
• the invention is also directed to methods of preparing the dosage forms disclosed herein.
• the invention is also directed to a process for the preparation and manufacture of the dosage form.
• the invention is also directed to methods of treating buprenorphine responsive medical conditions comprising administering a therapeutically effective amount of oral buprenorphine in a dosage form of the invention, or pharmaceutically acceptable salts thereof or mixtures thereof.
• the invention is also directed to methods of treating pain, chronic pain, neuropathic pain, opioid dependence, dyspnea, cough and addiction disorders comprising administering a therapeutically effective amount of oral buprenorphine in a dosage form of the invention, or pharmaceutically acceptable salts thereof or mixtures thereof.
• the invention is also directed to methods of treating buprenorphine responsive medical conditions with reduced risk of drug abuse, drug misuse, and drug diversion comprising administering a therapeutically effective amount of oral buprenorphine in a dosage form of the invention, or pharmaceutically acceptable salts thereof or mixtures thereof.
• the invention is also directed to methods of improving treatment compliance and deter episodic, occasional, intermittent, periodic, as needed, or PRN use of the dosage form when treating buprenorphine responsive medical conditions requiring more than few days of therapy to more than a few weeks of therapy or chronic therapy comprising administering a therapeutically effective amount of oral buprenorphine in a dosage form of the invention, or pharmaceutically acceptable salts thereof or mixtures thereof.
• the buprenorphine in the dosage form is combined with one or more other drugs for the treatment of the same medical condition as the buprenorphine or for the treatment of a different medical condition.
• All modes of coadministration are contemplated, including via an oral, subcutaneous, direct intravenous, slow intravenous infusion, continuous intravenous infusion, intravenous or epidural patient controlled analgesia (PCA and PCEA), intramuscular, intrathecal, epidural, intracisternal, intramuscular, intraperitoneal, transdermal, topical, transmucosal, buccal, sublingual, inhalation, intranasal, epidural, intra-atricular, intranasal, rectal or ocular routes.
• PCA and PCEA patient controlled analgesia
• first administration means administration of a dose of the present invention at the initiation of therapy to an individual patient or a patient population.
• steady state means that the amount of the drug reaching the system is approximately the same as the amount of the drug leaving the system.
• the patient's body eliminates the drug at approximately the same rate that the drug becomes available to the patient's system through absorption into the blood stream.
• AUC 0 . mean the area under the plasma drug concentration-time curve from time zero to the intended dosing frequency of the dosage form after a single administration (e.g., 8 hours, 12 hours or 24 hours) and to the end of the dosing interval after repeated dosing or at steady-state, respectively;
• AUCo-i nf means area under the plasma drug concentration-time curve from time zero to infinity;
• AUCo -6 means area under the plasma drug concentration- time curve from time zero to 6 hours after dosing;
• AUCo -8 means area under the plasma drug concentration-time curve from time zero to 8 hours after dosing;
• AUCo -I2 means area under the plasma drug concentration-time curve from time zero to 12 hours after dosing;
• AUCo -24 means area under the plasma drug concentration-time curve
• Pharmacokinetic parameters of the invention are be computed from single dose (i.e., first administration) and steady state pharmacokinetic studies conducted in an individual subject or in a population of subjects in the fasted or fed states.
• the AI and percent of steady state computations requires both single dose (i.e., first administration) and steady state pharmacokinetic assessment.
• an effective amount of buprenorphine in immediate release form is included in the controlled release unit dose buprenorphine formulation to be administered.
• the immediate release form of the buprenorphine is preferably included in an amount which is effective to shorten the time to C max of the buprenorphine in the blood (e.g., plasma).
• an effective amount of the buprenorphine in immediate release form may be coated onto the substrates of the present invention. For example, where the extended release buprenorphine from the formulation is due to a controlled release coating, the immediate release layer would be overcoated on top of the controlled release coating.
• the immediate release layer maybe coated onto the surface of substrates wherein the buprenorphine is incorporated in a controlled release matrix.
• the immediate release portion of the buprenorphine dose may be incorporated into the gelatin capsule via inclusion of the sufficient amount of immediate release buprenorphine as a powder or granulate within the capsule.
• the gelatin capsule itself may be coated with an immediate release layer of the buprenorphine.
• a patient in reference to pharmacokinetic parameters means that the discussion (or claim) is directed to the pharmacokinetic parameters of an individual patient or subject.
• any one or all of the above in- vivo parameters are achieved after a first administration (often referred to as "single dose administration") of the dosage form to a human patient or a population of human patients.
• any one or all of the above in- vivo parameters are achieved after steady state administration of the dosage form to a human patient or a population of human patients.
• USP Paddle or Basket Method is the Paddle and Basket Method described, e.g., in specified in the United States Pharmacopeia, USP-28 NF-23 (2005), published by the United States Pharmacopeial Convention, Inc, herein incorporated by reference.
• pH-dependent for purposes of the present invention is defined as having characteristics (e.g., dissolution) which vary according to environmental pH.
• pH-independent for purposes of the present invention is defined as having characteristics (e.g., dissolution) which are substantially unaffected by pH.
• pH-dependent for purposes of the present invention is defined as having characteristics (e.g., dissolution) which are substantially affected by pH.
• bioavailability is defined for purposes of the present invention as the extent to which the drug (e.g., buprenorphine) is absorbed from the unit dosage forms.
• All oral pharmaceutical dosage forms of the invention are contemplated, including oral suspensions, tablets, capsules, effervescent tablets, effervescent powders, powders, solutions, powders for reconstitution, oral gastroretentive tablets and capsules, administered as immediate release, modified release, enteric coated, sustained release, controlled release, pulsatile release and extended release dosage form.
• the dosage form comprises one or more of the following: modified release or enteric coated or sustained release or controlled release or pulsatile release or extended release.
• the dosage form comprises only one of the following: modified release or enteric coated or sustained release or controlled release or pulsatile release or extended release. In some preferred embodiments of the invention, the dosage form specifically excludes one or more of the following: modified release or enteric coated or sustained release or controlled release or pulsatile release or extended release. [828] In some embodiments, the invention specifically excludes oral immediate release dosage forms. [829] In some preferred embodiments of the invention, the dosage form of the invention is controlled release, extended release, sustained release, modified release, or delayed onset. [830] In some preferred embodiments of the invention, the dosage form of the invention is delayed onset, rapid release or delayed onset, extended release, or delayed onset, pulsatile release.
• the dosage form of the invention is delayed onset, duodenal delivery, jejunal delivery, ileal delivery, ileo-colonic delivery, colonic delivery
• the controlled release material of the dosage form may function to provide duodenal delivery, jejunal delivery, ileal delivery, ileo-colonic delivery or colonic delivery.
• the controlled release material of the dosage form may function to provide delayed onset, rapid release or delayed onset, extended release, or delayed onset, pulsatile release
• the dosage form does not substantially disintegrate or dissolve in the oral cavity upon residence for up to about 0.5, 1, 2,
• the dosage form does not substantially adhere to the buccal mucosa upon contact for up to about 0.5, 1, 2, 3, 4, 5, 7 or
• the dosage form excludes pharmaceutical excipients and ingredients which are intended to provide taste masking properties to minimize the bitter taste of buprenorphine.
• the dosage form upon prolonged residence in the oral cavity or prolonged oromucosal or buccal contact (e.g., for up to about 0.5, 1, 2, 3, 4, 5, 7 or 10 minutes) is not absorbed or substantially absorbed into the systemic circulation.
• the dosage form includes taste aversive agents (e.g., bittering agents) in sequestered or unsequestered form to deter sublingual, oromucosal or buccal use of the dosage form.
• taste aversive agents e.g., bittering agents
• the taste aversive agents is coated on the oral dosage form and then overcoated with material which prevents or minimizes the bitter sensation upon normal oral ingestion but which does not protect against an aversive taste upon prolonged residence in the oral cavity (e.g., upon sublingual, oromucosal or buccal use).
• the taste aversive agent is not sequestered in the sense that it is readily released in the GI tract upon oral ingestion, where it is devoid of taste aversive effects.
• a wide variety of pharmaceutical excipients known in the art may be used to provide the desired outer coating to the dosage form.
• the taste aversive agents e.g., bittering agent
• the oral dosage form which prevents or minimizes the bitter sensation upon normal oral ingestion but which does not protect against an aversive taste upon prolonged residence in the oral cavity (e.g., upon sublingual, oromucosal or buccal use). In this manner the taste aversive agent may be sequestered or unsequestered.
• the taste aversive agents e.g., bittering agent
• the taste aversive agents is incorporated into the inside walls of the capsule shell which prevents or minimizes the bitter sensation upon normal oral ingestion but which does not protect against an aversive taste upon prolonged residence in the oral cavity (e.g., upon sublingual, oromucosal or buccal use).
• the dosage form excludes sugar, or other natural or artificial sweeteners.
• the dosage form excludes pharmaceutical excipients and ingredients known in the art or intended to produce or enhance disintegration or dissolution in the oral cavity.
• the dosage form excludes pharmaceutical excipients and ingredients known in the art or intended to produce effervescence within the oral cavity.
• the dosage form excludes pharmaceutical excipients and ingredients known in the art or intended to enhance the transmucosal, lingual or sublingual absorption of buprenorphine.
• the dosage form is non-releasable or substantially non-releasable until (i) after a particular time following oral ingestion, when the dosage form can be anticipated to have reached the duodenum, jejum, ileum, ileo-cecal junction, cecum, or colon; (ii) the dosage form has come in contact or substantial contact or sustained contact with a desired gastrointestinal pH environment (e.g., pH > 3, or pH > 3.5, or pH > 4, or pH >4.5, or pH, > 5, or pH > 5.5, or pH > 6, or pH > 7, or pH > 7.5, or pH > 7.8); (iii) the dosage form has come in contact with desired microbial flora (e.g., colonic microbial flora).
• desired microbial flora e.g., colonic microbial flora
• agonist means a ligand that binds to a receptor and alters the receptor state resulting in a biological response.
• Conventional agonists increase receptor activity, whereas inverse agonists reduce it (See Neubig et al, IUPHAR Committee on Receptor Nomenclature and Classification, Pharmacol Rev, 2003; Howlett et al., MoI Pharmacol, 1988).
• opioid agonist means a molecule that causes a specific physiologic, pathophysiologic or pharmacologic effect after binding to an opioid receptor.
• an "antagonist” is a drug or ligand that reduces the action of another drug or ligand, generally an agonist. Many antagonists act at the same receptor macromolecule as the agonist. (See Neubig et al, IUPHAR Committee on Receptor Nomenclature and Classification, Pharmacol Rev, 2003; Howlett et al., MoI Pharmacol, 1988).
• receptor means a molecule within a cell, on a cell surface, on a membrane, in tissue, in fluid or otherwise found in humans that serve as a recognition or binding site to cause specific physiologic, pathophysiologic or pharmacologic effects.
• the term “receptor” also means a cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells. Combination of a hormone, neurotransmitter, drug, ligand, or intracellular messenger with its receptor(s) initiates a change in cell function (Neubig et al, IUPHAR Committee on Receptor Nomenclature and Classification, Pharmacol Rev, 2003).
• opioid receptor includes mu ( ⁇ ), delta ( ⁇ ) and kappa (K) opioid receptors, their subtypes and splice variants such as mui, mu 2 , delta], delta 2 , kappai, kappa 2 and kappa 3 , etc.
• Opioid antagonists are known or readily determined by individuals who practice the art.
• the opioid antagonists useful for the present invention may be selected from the group consisting of naltrexone, methylnaltrexone, nalbuphine, naloxone, nalmefene, cyclazocine, cyclorphan, oxilorphan nalorphine, nalorphine dinicotinate, nalmefene, nadide and levallorphan.
• the invention allows for the use of lower doses of buprenorphine by virtue of the inclusion or co-administration of an additional drug for the prevention or treatment of pain.
• an additional drug for the prevention or treatment of pain.
• buprenorphine means buprenorphine base, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, and hydrates, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixtures thereof.
• the dosage form comprises buprenorphine base or their pharmaceutically acceptable salts, or mixtures thereof.
• the dosage form comprises buprenorphine base or buprenorphine HCl, or mixtures thereof.
• buprenorphine or a pharmaceutically acceptable salt of buprenorphine, or prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs and hydrates thereof, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixtures thereof.
• any salt may be use.
• the salt is the hydrochloride salt of buprenorphine.
• Some of the drugs disclosed herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
• the present invention is also meant to encompass all such possible forms as well as their racemic and resolved forms and mixtures thereof.
• the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended to include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present invention as well.
• stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms is space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).
• chiral center refers to a carbon atom to which four different groups are attached.
• enantiomer or “enantiomeric” refers to a molecule that is nonsuperimposeable on its mirror image and hence optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image rotates the plane of polarized light in the opposite direction.
• racemic refers to a mixture of equal parts of enantiomers and which is optically inactive.
• resolution refers to the separation or concentration or depletion of one of the two enantiomeric forms of a molecule.
• the "NNH” or “number needed to harm” is a measure that indicates how many patients would require a specific treatment to cause harm in one patient.
• the "NNH or “number needed to harm” is a measure that includes: (i) how many opioid naive healthy subjects would require treatment to cause moderate or severe sedation (or drowsiness) in one subject, where moderate to severe sedation or drowsiness is defined as a VAS score of > 50 mm on a 100 mm scale bounded on the left by "no sedation or drowsiness” and on the right by "extreme sedation or drowsiness”; ( ⁇ ) how many opioid naive healthy subjects would require treatment to cause moderate or severe nausea in one subject, where moderate to severe nausea is defined as a VAS score of > 50 mm on a 100 mm scale bounded on the left by "no nausea” and on the right by "extreme nausea”; (iii) how many opioid naive
• This questionnaire can be used to examine the overall drug effects, preferably in drug abusers and recreational drug users.
• the "take again” questionnaire assesses whether subjects would take the drug again if given the opportunity. The patient is asked “If given an opportunity, would you take this drug again? (circle one: YES or NO). This questionnaire can be used to examine the overall desirability of the drug experience, preferably in drug abusers and recreational drug users.
• VAS visual analog scale
• the "critical tracking task” measures the patient's ability to control a displayed error signal in a first-order compensatory tracking task.
• the error is displayed as a horizontal deviation of a cursor from the midpoint on a horizontal, linear scale.
• Compensatory joystick movements correct the error by returning the cursor to the midpoint.
• the frequency at which the patient loses the control is the critical frequency.
• the critical tracking task measures the psychomotor control during a closed loop operation. It is a laboratory analog to on-the-road tracking performance.
• the "stop signal task” measures motor impulsivity, which is defined as the inability to inhibit an activated or pre-cued response leading to errors of commission.
• the task requires patients to make quick key responses to visual go signals, i.e. the letters ABCD presented one at a time in the middle of the screen, and to inhibit any response when a visual stop signal, i.e. "*" in one of the four corners of the screen, is presented at predefined delays.
• the main dependent variable is the stop reaction time on stop signal trials that represents the estimated mean time required to inhibit a response.
• the "Tower of London” is a decision-making task that measures executive function and planning.
• the task consists of computer generated images of begin- and end- arrangements of three colored balls on three sticks.
• the subject's task is to determine as quickly as possible, whether the end-arrangement can be accomplished by "moving" the balls in two to five steps from the beginning arrangement by pushing the corresponding number coded button.
• the total number of correct decisions is the main performance measure.
• the dosage form of the invention, one or more or all of the specifications and claims applicable to the prevention and treatment of pain or addiction disorders is also applicable to the prevention or treatment of any other disease or disorder that responds to opioid agonists or to buprenorphine.
• the oral pharmaceutical dosage forms of buprenorphine are used to treat pain, cough, dyspnea, opioid addiction disorders, restless leg syndrome, acute herpes zoster, visceral pain, breakthrough pain, opioid dependence and urinary incontinence.
• peripheral neuropathic pain e.g., acute and chronic inflammatory demeyelinating polyradiculopathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome (CRPS) Type I and Type II, entrapment neuropathies (e.g., carpal tunnel syndrome), HIV sensory neuropathy, iatrogenic neuralgias (e.g., postthoracotomy pain, postmastectomy pain), idiopathic sensory neuropathy, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, radiculopathy (e.g., cervical thoracic, lumbosacral), sciatica, acute he ⁇ es zoster pain, temporomandibular joint disorder pain and postradiation plexopathy; and (ii) central neuropathic pain, e.g., compressive myelopathy from spinal
• acute pain refers to self-limiting pain that subsides over time and usually lasting less that about 30 days and more preferably lasting less than about 21 days. Acute pain does not include chronic conditions such as chronic neuropathy, chronic neuropathic pain and chronic cancer and non-cancer pain.
• neuropathic pain is pain initiated or caused by a primary lesion or dysfunction of the nervous system and includes (i) peripheral neuropathic pain and (ii) central neuropathic pain.
• chronic pain includes all non-neuropathic pain usually lasting more than 30 days, including inflammatory pain, non-inflammatory pain, muscle pain, joint pain, fascia pain, visceral pain, bone pain and idiopathic pain.
• analgesic effectiveness is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of pain, along with a tolerable level of side effects, as determined by the human patient.
• addiction and “addiction disorder” is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over medication use, compulsive use, continued use despite harm, and craving (Sloan and Babul, Expert Opinion on Drug Delivery 2006;3:489-97).
• the pharmaceutical composition of the present invention is in some embodiments intended to treat addiction disorder, particularly opioid addiction disorder and poly-substance abuse involving opioids.
• the dosage form of the invention is intended to reduce or eliminate the craving or desire for opioids and the antisocial, medically harmful and potentially criminal behavior of the patient with the addiction disorder.
• the use of sublingual buprenorphine for the treatment of addiction disorder has been well established in the literature.
• therapeutic effectiveness is defined for purposes of the present invention as a satisfactory prevention, reduction in or elimination of signs and symptoms of the medical disorder, disease or syndrome (e.g., pain, addiction disorder), along with a tolerable level of side effects, as determined by the human patient.

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