JP6255349B2 - Transmucosal drug delivery device for use in reducing chronic pain - Google Patents

Description

  Chronic pain is pain that persists beyond the expected recovery period when it results from trauma and can progress from irritation to serious distress. Chronic pain can cause significant behavioral changes with depression and anxiety, limitations in daily activities, and overuse of drugs and medical services in affected individuals. Treatment of chronic pain is difficult, often inadequate, with high economic and mental loss.

  Buprenorphine is a partial μ-opiate receptor agonist, an ORL1 / nociceptin receptor agonist with high affinity and a slow dissociation rate, and a κ-opiate receptor antagonist. Buprenorphine is metabolized in the liver to norbuprenorphine and other metabolites by the cytochrome P450 enzyme system CYP3A4 isozyme (by N-dealkylation). Buprenorphine has low oral bioavailability due to a very high first pass metabolism.

  Buprenorphine is an analgesic and is marketed as Temgesic® 0.2 mg sublingual tablet and further as 0.3 mg / ml parenteral Buprenex®. Buprenorphine is also marketed as a sublingual formulation (Subutex®) and as a sublingual abuse-preventing formulation with naloxone (Suboxone®). The FDA approved Suboxone / Subutex as an opioid-dependent treatment in 2002. Sublingual buprenorphine has been used for opioid detoxification and management.

  In a recent open-label study, sublingual buprenorphine (Suboxone®) was used by routine opioid users for the treatment of chronic pain (Malinoff et al., 2005, American Journal of Therapeutics 12, 379-384). Patients were treated with daily buprenorphine doses ranging from 2 to 20 mg (average 8 mg). Treatment continued from 2.4 to 16.6 months (average of August). The paper reports that the patient's condition improved and their pain sensation decreased.

Malinoff et al., 2005, American Journal of Therapeutics 12, 379-384

  There remains a need for effective methods of treating chronic pain without side effects, especially for patients who are not or who have experience opioids.

  The present invention provides a method of treating chronic pain by administering a low dose of buprenorphine twice daily (or once daily) with a mucoadhesive bioerodible drug delivery device. The method and device effectively treat chronic pain without significant side effects, for example, less than 15% (preferably less than 10%, more preferably less than 5%) patients experience constipation.

The device comprises about 100 μg to 0.9 mg of buprenorphine and provides a steady state C _max of plasma buprenorphine concentration in the range of about 0.1 to about 1.2 ng / mL so that chronic pain in the subject is treated .

  In one embodiment, the buprenorphine delivery device includes a bioerodible mucoadhesive layer comprising a therapeutically effective amount of buprenorphine disposed in a buffered polymer diffusion environment, wherein the polymer diffusion environment is about 4 A buffered environment with a pH of ~ 6. In another embodiment, the buprenorphine delivery device is a polymer disposed adjacent to a mucoadhesive layer that provides a unidirectional gradient for rapid and efficient delivery of buprenorphine upon application (sticking) to a mucosal surface. Further comprising a barrier layer comprising a barrier environment, wherein the unidirectional gradient delivers buprenorphine across the buffered polymer diffusion environment upon application to the mucosal surface. In yet another embodiment, the device comprises an effective amount of buprenorphine, a mucoadhesive layer buffered to a pH of about 4.0 to about 6.0 and a backing buffered to a pH of about 4.0 to about 4.8. Including layers.

  In one embodiment, the device comprises about 120 μg to 0.9 mg buprenorphine.

  The methods and devices described herein are for treating a subject having chronic low back pain, such as moderate to severe chronic low back pain, or a subject having neuropathic or osteoarthritic pain. Can be used.

FIG. 1 is a schematic diagram of a clinical study design to assess the efficacy and safety of twice daily administration of BEMA buprenorphine in subjects with chronic low back pain. FIG. 2 is a schematic diagram of the disposal of subjects who participated in a clinical study to assess the efficacy and safety of twice daily administration of BEMA buprenorphine in subjects with chronic low back pain. FIG. 3 is a graph showing the mean change from baseline in daily pain intensity experienced by subjects with chronic low back pain after twice daily administration of BEMA buprenorphine.

  The present invention provides a method of treating chronic pain with low doses of buprenorphine. The present method of treating pain is also free of significant opioid side effects. For example, the subject is treated without experiencing severe common opioid side effects. Alternatively, the subject is treated with mild or moderate common opioid side effects or without common opioid side effects.

  The present invention also provides effective chronic pain relief by administration of buprenorphine twice daily. The present invention is surprising that a transmucosal drug delivery device comprising a low dose of buprenorphine can be administered to an opioid-experienced subject twice a day for effective management and elimination of chronic pain, such as chronic low back pain. Based at least in part on the discovery. The present invention is also based on the discovery that this treatment does not produce substantial side effects associated with opioids such as constipation and nausea.

Definitions The following definitions are provided as guidance regarding the meaning of certain terms used herein.

  As used herein, the singular terms mean “one or more” or “at least one” unless otherwise indicated. That is, a reference to any element of the invention in the singular does not exclude the possibility that there is more than one of the element.

  As used herein, the term “acute pain” refers to pain characterized by a short period of time, eg, 3-6 months. Acute pain is typically associated with tissue damage and manifests in a manner that can be easily explained and observed. For example, it can cause sweating or increased heart rate. Acute pain can also increase over time and / or occur intermittently.

  As used herein, the term “bioavailability” (bioavailability) is defined in 21 CFR Section 320.1, where the active ingredient or active moiety is absorbed from the drug product and is available at the site of action. The ratio and the degree to become are shown. The terms “bioavailability”, “absolute bioavailability” or “total bioavailability” include the amount absorbed through the oral mucosa (ie transmucosally) and through the gastrointestinal mucosa of the lower gastrointestinal tract. Shows bioavailability. In some embodiments, the transmucosal drug delivery device of the present invention provides 65% to 85% buprenorphine bioavailability. In some embodiments, the bioavailability of buprenorphine is 80%.

As used herein, the terms “bioequivalence” or “bioequivalency” (bioequivalence) are defined in 21 CFR Section 320.1 and are subject to similar conditions in appropriately designed studies. There should be no significant difference in the proportion and extent of active ingredient or active moiety available at the drug action site in a pharmaceutically equivalent formulation or pharmacological alternative when the same molar dose is administered in Means. The pharmacokinetic parameters C _max and AUC for bioequivalent actives fall within the range of 80% to 125% of each other.

  As used herein, the term “chronic pain” refers to pain that persists beyond the normal recovery period for trauma or disease. In one embodiment, the chronic pain is pain that lasts longer than one week. Chronic pain can be persistent or intermittent. Common causes of chronic pain include, but are not limited to, arthritis, cancer, reflex sympathetic dystrophy syndrome (RSDS), repetitive stress disorder, herpes zoster, headache, fibromyalgia, and diabetic neuropathy .

  As used herein, the term “chronic back pain” refers to a musculoskeletal disorder in which the subject experiences pain in the lumbar region or lumbar region for at least 12 weeks. In certain embodiments, the subject experiences chronic low back pain for at least 3 months.

  As used herein, the term “moderate to severe chronic low back pain” refers to, for example, an 11-point numerical rating scale (NRS, where 0 is no pain and 10 is the strongest Shows chronic low back pain characterized by a pain intensity of 5 or more.

  As used herein, the term “neuropathic pain” refers to complex chronic pain that results from damage or disease that usually occurs simultaneously with tissue damage and affects the somatosensory system. In neuropathic pain, the nerve fibers themselves can be broken, dysfunctional, or damaged. These damaged nerve fibers send false signals to other pain centers. The effects of nerve fiber damage include changes in nerve function both at the site of injury and around the injury.

  As used herein, the term “osteoarthritic pain” refers to pain resulting from osteoarthritis, degenerative joint disease and the most common types of arthritis. It involves the deterioration and loss of cartilage that covers the bone ends and cushions in normal joints. In osteoarthritis, the cartilage of the joint becomes stiff and loses its elasticity, resulting in more damage. Over time, the cartilage can be worn away and its ability to act as a shock absorber is greatly reduced. As the cartilage wears down, tendons and ligaments stretch and cause pain. As the situation gets worse, the bones can rub against each other, causing even more pain and loss of movement.

As used herein, unless otherwise specified, the term “buprenorphine” includes any pharmaceutically acceptable form of buprenorphine, including but not limited to salts, esters, and prodrugs thereof. Not. As used herein, the term “buprenorphine derivative” refers to a compound having a structure and function similar to buprenorphine. In some embodiments, the buprenorphine derivative comprises: embedded image or a pharmaceutically acceptable salt or ester thereof.

Where

Is a double bond or a single bond; R ₃ is selected from a C _1-4 alkyl group or a cycloalkyl-substituted C _1-4 alkyl group; R ₄ is selected from C _1-4 alkyl; R ₅ is —OH Or R ₄ and R _{5 taken} together form a ═O group; R ₆ is selected from —H or a C _1-4 alkyl group.

  Buprenorphine derivatives include, but are not limited to, etorphine and diprenorphine. Common buprenorphine derivatives are described in WO 2008/011194 and are incorporated herein by reference.

  As used herein, unless otherwise stated, the term “naloxone” includes any pharmaceutically acceptable form of naloxone, including but not limited to salts, esters, and prodrugs thereof. Not.

  As used herein, the term “non-parenteral” refers to a method of administration other than by direct systemic delivery of the drug. Thus, “not parenteral” excludes the use of intravenous (IV) injection, intramuscular (IM) injection, intraperitoneal (IP) injection, subcutaneous (SC) injection, etc. Includes skin, oral transmucosal administration, and administration through the gastrointestinal tract.

  As used herein, the term “mucoadhesive layer” or “polymer diffusion environment” refers to an environment that can allow a drug to flow to the mucosal surface when a gradient is created by adhesion to the mucosal surface. Show. The flow of drug being transported is proportional to the diffusivity of the environment, which takes into account the ionicity of the drug and / or the ionicity of one or more polymers contained in the environment, for example, pH It can be operated by adjusting.

  As used herein, the term “backing layer” or “barrier environment” or “non-adhesive polymer environment” refers to, for example, slowing or reducing the flow of drug from a mucoadhesive layer into the oral cavity. The environment in the form of a layer or coating or barrier layer that can be In some embodiments, the backing layer may include a second drug that is intended to dissolve in saliva. In such cases, the pH of the backing layer is adjusted to prevent the flow of drug to the mucoadhesive layer where transmucosal absorption can occur. As used herein, the term “unidirectional gradient” refers to a drug (eg, buprenorphine) that passes through the device, eg, through the polymer diffusion environment, in substantially one direction, eg, toward the oral mucosa of the subject. ) Shows the gradient that allows the flow of For example, the polymer diffusion environment can be a mucoadhesive polymer diffusion environment in the form of a layer or membrane disposed adjacent to a backing layer or membrane. When applied to the oral mucosa, a gradient is created between the mucoadhesive polymer diffusion environment and the mucosa, and the drug has a backing layer that is substantially unidirectional from the mucoadhesive polymer diffusion environment toward the mucosa. Flow until dissolved.

  As used herein, “treatment” or “treatment” of a subject is to prevent, treat, cure, reduce, alleviate, change, correct, or correct the disease or disorder, or symptoms of the disease or disorder. Administration of a drug to a subject for the purpose of remission, amelioration, improvement, stabilization or influence (eg, to reduce pain).

  The term “subject” refers to organisms such as humans, dogs, cats, and other mammals. Administration of the drug included in the device of the present invention can be carried out at a dosage and duration effective for treating the subject. In some embodiments, the subject is a human. In some embodiments, the pharmacokinetic profile of the device of the invention is similar in male and female subjects.

  The “effective amount” of a drug required to achieve a therapeutic effect can vary depending on factors such as the age, sex, and weight of the subject. Dosage design can be adjusted to provide the optimum therapeutic response. For example, the dosage can be administered once a day, or can be divided into two separate dosages for administration twice a day. The dosage can also be reduced proportionally as indicated by the urgency of the treatment situation.

  As used herein, the term “transmucosal” refers to any route of administration through the mucosa. Examples include, but are not limited to, buccal, sublingual, nasal, intravaginal, and rectal. In one embodiment, administration is buccal. In one embodiment, administration is sublingual. As used herein, the term “direct transmucosal” refers to mucosal administration via the oral mucosa, eg, buccal and / or sublingual.

  As used herein, the term “water erodible” or “at least partially water erodible” refers to a material that exhibits water erodibility ranging from negligible to completely water erodible. The substance can be easily dissolved in water or can only be partially soluble in water over time. In addition, substances can exhibit different erosion properties in body fluids compared to water due to the more complex nature of body fluids. For example, a substance that exhibits negligible erosion in water may exhibit slight to moderate erosion in body fluids. In other cases, however, the erodibility in water and body fluids may be about the same.

  As used herein, “addiction treatment” associated with a subject includes administration to a subject of a drug intended to reduce the desire for addictive substances.

  As used herein, the term “opioid resistance” refers to a phenomenon in which a subject is less susceptible to the effects of an opioid drug as a result of prior administration of the opioid drug. “Acute tolerance” refers to resistance that develops very rapidly after either a single dose of opioid or a few doses given in a short period of time. “Chronic tolerance” refers to the observation that the effect decreases with long-term opioid administration. Relevant tolerance is best expressed by small doses of opioids at long dosing intervals and is easily corrected by behavioral or environmental intervention. Unrelated tolerance is best expressed by large doses of drug at short dosing intervals and is not corrected by behavioral or environmental intervention.

As used herein, the term “opioid resistant subject” refers to a subject currently receiving opioid therapy. In one embodiment, as identified in Table 1 below, the subject has received> 60 mg of oral morphine or another analgesic dose of opioids for a week or more per day.

  As used herein, the term “opioid experienced subject” refers to a subject currently receiving opioid therapy. In one embodiment, the subject's daily opioid use does not exceed the daily opioid dosage specified in Table 1 above.

  As used herein, the term “opioid naïve subject” refers to a subject not currently receiving opioid therapy. In one embodiment, the subject has not been exposed to the opioid for a week or longer.

  As used herein, the term “abuse” or “method of abuse” refers to using the device beyond oral transmucosal administration, for example, extracting a drug and by injection or aspiration.

  As used herein, the term “low dose of buprenorphine (small dose)” refers to a daily dose (administration of less than 1.8 mg (eg, about 200 μg to about 1800 μg, or about 240 μg to 1800 μg) of buprenorphine. ).

As used herein, the term “steady state plasma concentration” refers to a condition in which the variation in plasma drug concentration is the same or similar after each administration. The term “steady state C _max of plasma buprenorphine concentration” refers to a condition in which the maximum plasma concentration after administration of buprenorphine does not vary from dose to dose. The term “steady state C _min of plasma buprenorphine concentration” refers to a state in which the minimum plasma concentration after administration of buprenorphine does not vary from dose to dose. In one embodiment, the device used in the present invention provides a steady state C _max of plasma buprenorphine concentration within the range of about 0.1 to about 1.0 ng / mL. In another embodiment, the device used in the present invention provides a steady state C _max of plasma buprenorphine concentration within the range of about 0.1 to about 0.5 ng / mL.

  As used herein, the term “common opioid side effects” refers to side effects commonly experienced by subjects receiving opioid analgesics. These common opioid side effects include headache, constipation, nausea or vomiting, pruritus, somnolence or cognitive impairment, thirst, tolerance or dependence and urinary retention.

  The term “mild common opioid side effects” refers to side effects that do not require special treatment and do not interfere with the subject's daily activities. The term “moderate common opioid side effects” refers to side effects that cause a subject to have a low level of discomfort or anxiety and can interfere with daily activities, but is usually improved by simple therapeutic measures. The term “severe common opioid side effects” refers to side effects that interfere with normal daily activities and typically require systemic medication or other treatment.

  The term “serious constipation” refers to chronic or severe constipation associated with continued use of morphine or other opioids.

  The term “serious nausea” refers to a severe state of nausea commonly known in the art. In some embodiments, the term “serious nausea” is defined by a visual analog scale (VAS) score of 25 mm or greater on a 0-100 mm scale.

  As used herein, the term “arranged” refers to a uniform or non-uniform distribution of a component / element within another component / element.

Pain Management Certain aspects of the present invention include methods for providing pain management and / or removal to a subject in need thereof. Pain is all pain known in the art resulting from any disease, disorder, condition and / or situation and can be chronic pain or acute pain. Chronic pain can arise from many causes, including cancer, reflex sympathetic dystrophy syndrome (RSDS), and migraine. Acute pain is typically directly related to tissue damage and lasts for a relatively short period of time, such as hours to days, or 7 days. In another embodiment, the pain is prominent cancer pain.

  In some aspects, the present invention provides a method for managing or treating chronic pain in a subject. In some embodiments, the subject is opioid experienced, opioid resistant or opioid naive, as defined above. In certain embodiments, the subject is opioid resistant. In another embodiment, the subject has not responded to previous treatment with a maximum dose of a non-steroidal anti-inflammatory drug.

  In some embodiments, the chronic pain is chronic low back pain (CLBP). In some embodiments, the chronic low back pain is moderate to severe chronic low back pain. In other embodiments, the pain is neuropathic pain or osteoarthritic pain. In certain embodiments, the subject receiving treatment for moderate to severe chronic low back pain is an opioid experienced subject.

  Administration of low doses of buprenorphine with the transmucosal drug delivery device of the present invention twice a day (or once a day) is associated with low incidence or absence of common opioid side effects associated with opioid analgesics. It is also known now. In one embodiment, the side effect is nausea. In another embodiment, the side effect is constipation.

Administration and Dosing of Buprenorphine In some embodiments, the transmucosal drug delivery device of the present invention (eg, BEMA buprenorphine) is administered once daily or twice daily. In some embodiments, the total daily dosage of buprenorphine administered is 200 μg to 1800 μg, such as 200 μg, 220 μg, 240 μg, 280 μg, 300 μg, 320 μg, 350 μg, 360 μg, 400 μg, 450 μg, 480 μg, 500 μg, 550 μg, 600 μg, 620 μg, 650 μg, 700 μg, 720 μg, 750 μg, 800 μg, 860 μg, 900 μg, 960 μg, 1000 μg, 1100 μg, 1200 μg, 1250 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg and 1800 μg.

  In some embodiments, the transmucosal drug delivery device of the present invention comprises a low dose of buprenorphine. In one embodiment, the low dose of buprenorphine included in the device is defined as a dose of about 100 μg to about 900 μg of buprenorphine. In some embodiments, the low dose of buprenorphine included in the mucoadhesive devices of the invention is 100 μg, 110 μg, 120 μg, 140 μg, 150 μg, 160 μg, 175 μg, 180 μg, 200 μg, 225 μg, 240 μg, 250 μg, 275 μg, 300μg, 310μg, 325μg, 350μg, 360μg, 375μg, 400μg, 430μg, 450μg, 480μg, 500μg, 550μg, 600μg, 625μg, 650μg, 700μg, 750μg, 800μg, 900μg, 1000μg, 1200μg, 1250μg, 1300μg, 1400g 1600 μg and 1800 μg.

Preparation of transmucosal drug delivery device transmucosal drug delivery device, for example, a U.S. Patent Application Serial No. 08 / 734,519, filed October 18, 1996, U.S. Pat., Issued September 1, 1998 No. 5,800,832; U.S. Patent Application No. 09 / 144,827 filed on September 1, 1998; U.S. Patent No. 6,159,498 issued on December 12, 2000; filed on March 1, 2005 U.S. Patent Application No. 11 / 069,089, U.S. Patent No. 7,579,019 issued on August 25, 2009; U.S. Patent Application No. 11 / 639,408 filed on Dec. 13, 2006. Published as U.S. Patent Application Publication No. 2007/0148097; U.S. Patent Application No. 11 / 817,915 filed on September 6, 2007, published as U.S. Patent Application Publication No. 2010/0015183; 2011 U.S. Patent Application No. 13 / 834,306 filed on July 15, US Patent No. 8,147,866 issued on April 3, 2012; U.S. Patent filed on August 20, 2012 Application 13 / 590,094; U.S. Patent Application No. 12 / 537,571, filed August 7, 2009, published as U.S. Patent Application Publication No. 2011/0033541; and filed August 7, 2009 No. 12 / 537,580, previously described in U.S. Patent Application published as U.S. Patent Application Publication No. 2011/0033542, the entire contents of these applications are hereby incorporated by reference. Incorporated into.

i. Mucoadhesive Layer In some embodiments, the device of the invention adheres to the mucosal surface of a subject within about 5 seconds after application (sticking). In some embodiments, the device of the invention includes an opioid agonist. In some embodiments, the devices of the present invention include a bioerodible or water erodible mucoadhesive layer and the opioid agonist is included in the mucoadhesive layer. In one embodiment, the opioid agonist is buprenorphine. The dose of buprenorphine that can be incorporated into the devices of the invention depends on the desired therapeutic dose to be administered and can range from about 20 μg to about 20 mg, or from about 120 μg to about 2000 μg of buprenorphine.

ii. Backing layer In some embodiments, the device further comprises at least one additional non-adhesive polymer environment, eg, a backing layer. This layer, eg, the backing layer, is positioned adjacent to the mucoadhesive polymer diffusion environment and functions to facilitate delivery of the opioid agonist, such as buprenorphine, to the mucosa. This additional layer may comprise a polymer in the same or different combination as the mucoadhesive or non-adhesive polymer diffusion environment.

  In some embodiments, the backing layer includes an additional drug, such as an opioid antagonist, to make the device of the invention resistant to abuse. In some embodiments, the opioid antagonist is naloxone. The dosage of naloxone that can be incorporated into the backing layer of the device of the present invention can range from about 2.5 μg to about 5 mg of naloxone. In some embodiments, the amount of buprenorphine and the amount of naloxone disposed in the device are present in a ratio selected such that the effect of buprenorphine is counteracted by naloxone when the mixture is injected (infusion) or aspirated. To do. In some embodiments, the amount of buprenorphine and the amount of naloxone disposed in the device are present in a ratio of 4: 1 w / w.

  The invention is further understood by the following examples. However, it will be appreciated by those skilled in the art that the details of the particular experiment are merely illustrative and are not meant to limit the invention described herein and as defined by the appended claims. Can be easily understood.

Example 1. Preparation of the Device of the Invention A transmucosal device is constructed in the form of a rectangular disk with rounded corners, with one or both sides of the cheek being yellow. Buprenorphine is present in the mucoadhesive layer and is placed in contact with the buccal mucosa (inner cheek). As the disc erodes in the mouth, the drug is delivered into the mucosa. The non-adhesive backing layer controls the erosion rate of the disc and dissolves in saliva and minimizes the amount of buprenorphine that is finally swallowed in a path of less absorption that undergoes first pass metabolism. The mucoadhesive polymer diffusion layer and backing layer are bonded together and do not delaminate during or after application.

  The mucoadhesive layer of the transmucosal device of the present invention containing the desired dose of buprenorphine comprises purified water, propylene glycol (about 4.6% of the total formulation by dry weight), sodium benzoate (by dry weight, of the total formulation). About 0.5%), methylparaben (by dry weight, about 0.9% of the total formulation), propylparaben (by dry weight, about 0.2% of the total formulation), vitamin E acetate (by dry weight, about 0.06% of the total formulation) Citric acid (dry weight, about 0.5% of the total formulation), yellow iron oxide (dry weight, about 0.5% of the total formulation), monobasic sodium phosphate (dry weight, about 3.4% of the total formulation) It is prepared by mixing. The above ingredients are added sequentially to the mixing vessel. After the ingredients were dissolved, buprenorphine HCl (about 1.3% of the total formulation by dry weight) was added and the container was heated to 120 ° F. to 130 ° F. After dissolution, the polymer mixture (hydroxypropylcellulose (dry weight, about 6.8% of total formulation), hydroxyethylcellulose (dry weight, about 20.3% of total formulation), polycarbophil (dry weight, about 6.3% of total formulation) %), And carboxymethylcellulose (by dry weight, about 54.3% of the total formulation) are added to the vessel and stirred until dispersed, then heat is removed from the mixing vessel. Sodium acid and sodium hydroxide are added to adjust the mixture to the desired pH, the mixture is mixed under vacuum for several hours, and each prepared mixture is stored in an airtight container until used in a coating operation.

  The backing layer adds purified water to the mixing vessel, followed by sodium benzoate (dry weight, about 0.5% of total formulation), methylparaben (dry weight, about 0.4% of total formulation), propylparaben (dry weight). About 0.1% of the total formulation), citric acid (dry weight, about 0.5% of the total formulation), vitamin E acetate (dry weight, about 0.05% of the total formulation), saccharin sodium (dry weight, total formulation) Of about 0.5%) is added sequentially. Thereafter, a polymer mixture of hydroxypropylcellulose (dry weight, about 63% of the total formulation) and hydroxyethylcellulose (dry weight, about 32% of the total formulation) is added and at a temperature of about 120 ° F. to 130 ° F. Stir until evenly dispersed. Cool to room temperature, and then add titanium dioxide (dry weight, about 2.5% of total formulation) and peppermint oil (dry weight, about 0.8% of total formulation) to the container and stir. The prepared mixture is stored in an airtight container until ready for use in the coating operation.

  The layer is continuously cast on a St. Gobain polyester liner. First, the backing layer is cast using a knife-on-blade coating method. Thereafter, the backing layer is cured in a continuous oven at about 65 ° C. to 95 ° C. and dried. After repeated coating and drying twice, a backing layer about 8 mils (203-213 μm) thick is obtained. A mucoadhesive polymer diffusion environment is then cast on the backing layer, cured in an oven at about 65 ° C. to 95 ° C., and dried. Thereafter, the device is punched out by a kiss cutting method and removed from the casting surface.

Example 2 A placebo-controlled, double-blind study to assess the efficacy of BEMA buprenorphine in subjects with moderate to severe chronic low back pain
By a transmucosal drug delivery device with enhanced uptake (BEMA buprenorphine) in subjects with moderate to severe chronic low back pain in a 12-week, placebo-controlled, double-blind randomized withdrawal study The efficacy and safety of buprenorphine delivered twice a day were evaluated. The study was also designed to define a range of effective BEMA buprenorphine doses for the management of moderate to severe chronic low back pain.

i. The study design study consisted of an open-label dose titration period lasting 4 weeks, followed by a 12-week randomized, double-blind, placebo-controlled treatment period. Subjects continued their current pain treatment for up to 12-24 hours prior to 0/1 day of the initial qualification period (-14 to -1 days) and the open label dose escalation period. Pre-dose assessments were performed on the open-label escalation period day 0, and the first dose of study drug was performed on the open-label escalation period day 1.

During an open-label escalation period, subjects are administered BEMA buprenorphine approximately every 12 hours and are medicated until a stable dose (ie, a dose that provides significant pain relief and is well tolerated) is known Volume adjustment was performed at intervals over a period of up to 4 weeks. The increasing order of BEMA buprenorphine is illustrated in Table 4 below. Subjects who were unable to find a stable dose were discontinued from the study.

  A subject who has confirmed a stable dose and has received that dose at least 12 times over the last 7 days will participate in a double-blind treatment period for 12 weeks, where the subject's Half received a BEMA placebo and half continued to receive BEMA buprenorphine at a stabilized dose. Participation of each subject in the entire study lasted 19 weeks. A schematic diagram showing the study design is shown in FIG.

ii. Subjects selected for inclusion in the subject subject population studies used in the study were opioid naive or opioid experience as defined herein above. Opioid experienced subjects were subjects who received morphine at an oral dosage of 60 mg or less per day or another acceptable opioid at an iso-analgesic dosage for one week or longer. The opioid naïve subjects had not received any opioid for a week or longer.

A total of 334 subjects participated in the study, of which 332 subjects participated in a 4-week open-label dose escalation period. 97 subjects discontinued treatment during the open-label escalation period, and a total of 235 subjects continued a 12-week double-blind treatment period. Of the 117 subjects who received BEMA buprenorphine, 28 discontinued treatment and 89 subjects completed the study. Of the 118 subjects who received placebo, 37 discontinued treatment and 81 subjects completed the study. The disposal of the subject under study is summarized in Figure 2, and the characteristics of the target population participating in the study are summarized in Table 5 below.

iii. Analgesic efficacy of BEMA buprenorphine Analgesic efficacy was assessed daily by having subjects record their average pain intensity on a scale of 0 to 10 over the past 24 hours. Here, 0 indicates no pain and 10 indicates the strongest pain (11-point numerical rating scale, NRS). Tables 6-12 below show the mean change from baseline (CBL) in daily pain intensity relative to the final diagnosis during the double-blind treatment period. Tables 6-8 show the average values of the change data of different subject groups, and Tables 9-12 show the average values of the change data of the subject groups treated with different doses of buprenorphine.

As shown in Table 7, the change from baseline in the average daily pain score for BEMA buprenorphine compared to placebo is almost statistically significant in the opioid-experienced population.

  The graph in FIG. 3 shows all subjects: 2 × Aμg, 3 × Aμg or 4 × Aμg, all subjects receiving BEMA buprenorphine; all opioid experienced subjects; and 2 × Aμg, 3 × Aμg or 4 × Aμg BEMA Average of change from baseline in daily pain intensity for all opioid experienced subjects receiving buprenorphine.

iv. The occurrence of adverse events (AEs) was recorded in all subjects in the study. AE is defined as any adverse medical occurrence in a patient receiving a pharmaceutical product or clinical study subject, which is not necessarily causally related to this treatment. The total number of adverse events recorded in both the open-label escalation period and the double-blind treatment period are listed in Table 13 below.

  AE intensity was characterized as mild, moderate, or severe as follows.

  Mild: A temporary AE that did not require special treatment and did not interfere with the subject's daily activities.

  Moderate: An AE that causes a low level of discomfort or anxiety to a subject and can interfere with daily activities, but is usually improved by simple therapeutic measures.

  Severe: An AE that interferes with the subject's normal daily activities and typically required systemic medication or other treatment.

Table 14 below shows the number and percent of subjects who experienced TEAE during an open-label escalation period involving 330 subjects, all TEAEs characterized by event intensity and relationship to study drug. Table 15 below shows similar data for the buprenorphine treatment group with 117 subjects in the double-blind treatment period. The highest recorded intensity at each event and the drug relationship at that intensity was used to classify adverse events. The “drug-related” classification is described as “R” and includes adverse events that have a “presumably” or “probably” relationship assessed by researchers for drugs. The “non-drug related” classification is described as “NR”.

本発明の実施形態として、例えば以下を挙げることができる。
(1) 慢性疼痛を治療する方法であって、治療を必要とする被検体に粘膜付着性生体侵食性薬物送達デバイスを投与することを含んでおり、
デバイスは１日に２回投与され、ここで、デバイスは約100μg〜約0.9mgのブプレノルフィンを含み、
デバイスが、被検体の慢性疼痛が治療されるように、約0.1〜約1.2ng/mLの範囲の血漿中ブプレノルフィン濃度の定常状態C _max を提供する、前記方法。
(2) デバイスが１日に１回投与される、(1)に記載の方法。
(3) 慢性疼痛が慢性的な腰痛である、(1)又は(2)に記載の方法。
(4) 慢性的な腰痛が中等度から重度の慢性的な腰痛である、(1)〜(3)のいずれかに記載の方法。
(5) 被検体がいずれの重度の共通したオピオイド副作用を経験することなく治療される、(1)〜(4)のいずれかに記載の方法。
(6) 被検体が軽度のもしくは中等度の共通したオピオイド副作用を経験して、又は共通したオピオイド副作用を経験しないで治療される、(1)〜(5)のいずれかに記載の方法。
(7) 患者が重大な便秘症がなく治療される、(1)〜(6)のいずれかに記載の方法。
(8) 被検体が重大な吐き気がなく治療される、(1)〜(7)のいずれかに記載の方法。
(9) 被検体がオピオイド未経験である、(1)〜(8)のいずれかに記載の方法。
(10) 被検体がオピオイド経験である、(1)〜(9)のいずれかに記載の方法。
(11) 被検体に投与されるブプレノルフィンの1日の総投薬量が、200μg、220μg、240μg、280μg、300μg、320μg、350μg、360μg、400μg、450μg、480μg、500μg、550μg、600μg、620μg、650μg、700μg、720μg、750μg、800μg、860μg、900μg、960μg、1000μg、1100μg、1200μg、1250μg、1300μg、1400μg、1500μg、1600μg及び1800μgのブプレノルフィンからなる群より選択される、(1)〜(10)のいずれかに記載の方法。
(12) デバイスが緩衝されたポリマー拡散環境に配置された有効量のブプレノルフィンを含む生体侵食性粘膜付着性層を含み、ここで、ポリマー拡散環境が約4〜約6のpHを有する緩衝された環境である、(1)〜(11)のいずれかに記載の方法。
(13) 粘膜付着性生体侵食性薬物送達デバイスが、粘膜表面へ適用された際にブプレノルフィンの迅速で効率的な送達のための一方向勾配を与えるように粘膜付着性層に隣接して配置されたポリマーバリア環境を含むバリア層を更に含み、ここで、一方向勾配は粘膜表面へ適用された際に緩衝されたポリマー拡散環境を横切ってブプレノルフィンを送達する、(1)〜(12)のいずれかに記載の方法。
(14) 被験体に対して、１日に２回の粘膜付着性生体侵食性薬物送達デバイスを被検体の口腔粘膜表面に投与する工程であって、デバイスが
緩衝されたポリマー拡散環境に配置された有効量のブプレノルフィンを含む生体侵食性粘膜付着性層、ここで、ポリマー拡散環境が約4〜約6のpHを有する緩衝された環境である、を含み、
被験体に投与されるブプレノルフィンの1日の総投薬量が中等度から重度の慢性的な腰痛を治療するのに有効である前記工程、
を含む中等度から重度の慢性的な腰痛を有する被験体を治療する方法。
(15) デバイスが約4.0〜約4.8のpHに緩衝されたバッキング層を更に含む、(14)に記載の方法。
(16) 方法が
被検体の神経障害性疼痛が治療されるように、被験体に対して、１日に２回の粘膜付着性生体侵食性薬物送達デバイスを被検体の口腔粘膜表面に投与する工程であって、デバイスが
緩衝されたポリマー拡散環境に配置された有効量のブプレノルフィンを含む生体侵食性粘膜付着性層、ここで、ポリマー拡散環境が約4〜約6のpHを有する緩衝された環境である、を含む前記工程、
を含む神経障害性疼痛を有する被験体を治療する方法。
(17) デバイスが約4.0〜約4.8のpHに緩衝されたバッキング層を更に含む、(16)に記載の方法。
(18) 被検体の骨関節炎性疼痛が治療されるように、被験体に対して、１日に２回の粘膜付着性生体侵食性薬物送達デバイスを被検体の口腔粘膜表面に投与する工程であって、デバイスが
緩衝されたポリマー拡散環境に配置された有効量のブプレノルフィンを含む生体侵食性粘膜付着性層、ここで、ポリマー拡散環境が約4〜約6のpHを有する緩衝された環境である、を含む前記工程、
を含む骨関節炎性疼痛を有する被験体を治療する方法。
(19) デバイスが約4.0〜約4.8のpHに緩衝されたバッキング層を更に含む、(18)に記載の方法。
(20) デバイスが
約4.0〜約6.0のpHに緩衝された有効量のブプレノルフィンを含む粘膜付着性層；及び
約4.0〜約4.8のpHに緩衝されたバッキング層
を含む、(1)〜(11)のいずれかに記載の方法。 Example 3. Pharmacokinetic profile of BEMA buprenorphine The pharmacokinetic parameters of BEMA buprenorphine dosage used in the treatment of chronic pain were measured in separate, multiple dosage studies. BEMA buprenorphine contained buprenorphine dosages of 2 × A μg and 4 × A μg. Each dose was administered twice a day for 3 days and serial blood samples were collected. Selected pharmacokinetic parameters are shown in Table 16 below.

Examples of the present invention include the following.
(1) A method of treating chronic pain, comprising administering a mucoadhesive bioerodible drug delivery device to a subject in need of treatment,
The device is administered twice a day, wherein the device comprises from about 100 μg to about 0.9 mg buprenorphine,
The method, wherein the device provides a steady state C _max of plasma buprenorphine concentration in the range of about 0.1 to about 1.2 ng / mL such that chronic pain in the subject is treated .
(2) The method according to (1), wherein the device is administered once a day.
(3) The method according to (1) or (2), wherein the chronic pain is chronic low back pain.
(4) The method according to any one of (1) to (3), wherein the chronic back pain is moderate to severe chronic back pain.
(5) The method according to any one of (1) to (4), wherein the subject is treated without experiencing any severe common opioid side effects.
(6) The method according to any one of (1) to (5), wherein the subject is treated with mild or moderate common opioid side effects, or without experiencing common opioid side effects.
(7) The method according to any one of (1) to (6), wherein the patient is treated without significant constipation.
(8) The method according to any one of (1) to (7), wherein the subject is treated without significant nausea.
(9) The method according to any one of (1) to (8), wherein the subject is inexperienced in opioids.
(10) The method according to any one of (1) to (9), wherein the subject has an opioid experience.
(11) The total daily dose of buprenorphine administered to the subject is 200 μg, 220 μg, 240 μg, 280 μg, 300 μg, 320 μg, 350 μg, 360 μg, 400 μg, 450 μg, 480 μg, 500 μg, 550 μg, 600 μg, 620 μg, 650 μg 700 μg, 720 μg, 750 μg, 800 μg, 860 μg, 900 μg, 960 μg, 1000 μg, 1100 μg, 1200 μg, 1250 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg and 1800 μg of buprenorphine, (1) to (10) The method according to any one.
(12) The device includes a bioerodible mucoadhesive layer comprising an effective amount of buprenorphine disposed in a buffered polymer diffusion environment, wherein the polymer diffusion environment has a pH of about 4 to about 6 The method according to any one of (1) to (11), which is an environment.
(13) A mucoadhesive bioerodible drug delivery device is placed adjacent to the mucoadhesive layer to provide a unidirectional gradient for rapid and efficient delivery of buprenorphine when applied to the mucosal surface. A barrier layer comprising a polymer barrier environment, wherein the unidirectional gradient delivers buprenorphine across the buffered polymer diffusion environment when applied to the mucosal surface. The method of crab.
(14) A step of administering to a subject a mucoadhesive bioerodible drug delivery device twice a day to the oral mucosal surface of a subject, the device comprising:
A bioerodible mucoadhesive layer comprising an effective amount of buprenorphine disposed in a buffered polymer diffusion environment, wherein the polymer diffusion environment is a buffered environment having a pH of about 4 to about 6,
The step wherein the total daily dosage of buprenorphine administered to the subject is effective to treat moderate to severe chronic low back pain;
A method of treating a subject having moderate to severe chronic low back pain.
(15) The method of (14), wherein the device further comprises a backing layer buffered to a pH of about 4.0 to about 4.8.
(16) Method is
Administering a mucoadhesive bioerodible drug delivery device to a subject twice a day to the oral mucosal surface of a subject so that the subject's neuropathic pain is treated; Device
A bioerodible mucoadhesive layer comprising an effective amount of buprenorphine disposed in a buffered polymer diffusion environment, wherein the polymer diffusion environment is a buffered environment having a pH of about 4 to about 6 Process,
A method of treating a subject having neuropathic pain comprising:
(17) The method of (16), wherein the device further comprises a backing layer buffered to a pH of about 4.0 to about 4.8.
(18) In the step of administering to the subject's oral mucosal surface twice a day a mucoadhesive bioerodible drug delivery device to the subject so that the subject's osteoarthritic pain is treated And the device is
A bioerodible mucoadhesive layer comprising an effective amount of buprenorphine disposed in a buffered polymer diffusion environment, wherein the polymer diffusion environment is a buffered environment having a pH of about 4 to about 6 Process,
A method of treating a subject having osteoarthritic pain comprising:
(19) The method of (18), wherein the device further comprises a backing layer buffered to a pH of about 4.0 to about 4.8.
(20) Device is
A mucoadhesive layer comprising an effective amount of buprenorphine buffered to a pH of about 4.0 to about 6.0; and
Backing layer buffered to a pH of about 4.0 to about 4.8
The method according to any one of (1) to (11), comprising:

Claims (31)

A mucoadhesive bioerodible drug delivery device for treating chronic pain, wherein the device is administered once or twice a day, wherein the device receives from about 100 μg to about 0.9 mg of buprenorphine. Including
The device provides a steady state C _max of plasma buprenorphine concentration in the range of about 0.156 to about 0.364 ng / mL so that chronic pain in the subject is treated;
The subject is an opioid experience subject,
The subject being treated experiences mild or moderate common opioid side effects, or does not experience common opioid side effects,
The mucoadhesive bioerodible drug delivery device.   The mucoadhesive bioerodible drug delivery device according to claim 1, wherein the chronic pain is chronic low back pain.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein the chronic back pain is moderate to severe chronic back pain.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein the subject is treated without significant constipation.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein the subject is treated without significant nausea.   The total daily dose of buprenorphine administered to the subject is 200 μg, 220 μg, 240 μg, 280 μg, 300 μg, 320 μg, 350 μg, 360 μg, 400 μg, 450 μg, 480 μg, 500 μg, 550 μg, 600 μg, 620 μg, 650 μg, 700 μg, The mucoadhesive bioerosion according to claim 1, selected from the group consisting of 720 μg, 750 μg, 800 μg, 860 μg, 900 μg, 960 μg, 1000 μg, 1100 μg, 1200 μg, 1250 μg, 1300 μg, 1400 μg, 1500 μg, 1600 μg and 1800 μg buprenorphine. Sex drug delivery device.   The device includes a bioerodible mucoadhesive layer comprising an effective amount of buprenorphine disposed in a buffered polymer diffusion environment, where the polymer diffusion environment is a buffered environment having a pH of about 4 to about 6. The mucoadhesive bioerodible drug delivery device of claim 1.   A polymer barrier positioned adjacent to the mucoadhesive layer so that the mucoadhesive bioerodible drug delivery device provides a unidirectional gradient for rapid and efficient delivery of buprenorphine when applied to the mucosal surface The mucoadhesive bioerodible of claim 1 further comprising a barrier layer comprising an environment, wherein the unidirectional gradient delivers buprenorphine across the buffered polymer diffusion environment when applied to the mucosal surface. Drug delivery device. A mucoadhesive bioerodible drug delivery device for treating a subject having moderate to severe chronic low back pain, wherein the device is administered to the oral mucosal surface of the subject twice a day,
Device
Providing a steady state C _max of plasma buprenorphine concentration in the range of about 0.156 to about 0.364 ng / mL ;
A bioerodible mucoadhesive layer comprising an effective amount of buprenorphine disposed in a buffered polymer diffusion environment, wherein the polymer diffusion environment is a buffered environment having a pH of about 4 to about 6,
The total daily dose of buprenorphine administered to the subject is effective to treat moderate to severe chronic low back pain,
The subject is an opioid experience subject,
The subject being treated experiences mild or moderate common opioid side effects, or does not experience common opioid side effects,
The mucoadhesive bioerodible drug delivery device.   The mucoadhesive bioerodible drug delivery device of claim 9, wherein the device further comprises a backing layer buffered to a pH of about 4.0 to about 4.8.   The mucoadhesive bioerodible drug delivery device according to claim 1, wherein the chronic pain is neuropathic pain.   12. The mucoadhesive bioerodible drug delivery device of claim 11, wherein the device further comprises a backing layer buffered to a pH of about 4.0 to about 4.8.   The mucoadhesive bioerodible drug delivery device according to claim 1, wherein the chronic pain is osteoarthritic pain.   14. The mucoadhesive bioerodible drug delivery device of claim 13, wherein the device further comprises a backing layer buffered to a pH of about 4.0 to about 4.8. The mucoadhesive property of claim 1, wherein the device comprises a mucoadhesive layer comprising an effective amount of buprenorphine buffered to a pH of about 4.0 to about 6.0; and a backing layer buffered to a pH of about 4.0 to about 4.8. Bioerodible drug delivery device.   The mucoadhesive bioerosion according to claim 1, wherein the total daily dose of buprenorphine administered to the subject is selected from the group consisting of 100 μg, 110 μg, 120 μg, 140 μg, 150 μg, 160 μg, 175 μg and 180 μg. Sex drug delivery device.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein the total daily dosage of buprenorphine administered to the subject ranges from 20 μg to about 20 mg. The mucoadhesive bioerodible drug delivery device of claim 1, wherein the steady state C _max of plasma buprenorphine concentration is in the range of about 0.1 to about 0.5 ng / mL. The mucoadhesive bioerodible drug delivery device of claim 1, wherein the steady state T _{max of} buprenorphine is in the range of about 2.00 to about 2.90 h. The mucoadhesive bioerodible drug delivery device of claim 1, wherein the C _{avg of} buprenorphine is in the range of about 0.0157 to about 0.0862 ng / mL. The mucoadhesive bioerodible drug delivery device of claim 1, wherein the steady state AUC _{last of} buprenorphine is in the range of about 0.4085 to about 5.033 hr ^* ng / mL.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein about 7.9% of subjects experience a drug-related headache as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein about 9-32% of subjects experience nausea as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1 wherein about 6-5% of subjects experience vomiting as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein about 2.6-12% of subjects experience a headache as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein about 6-11% of subjects experience constipation as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein about 2.4-7% of subjects experience drug-related mild or moderate headache as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein about 3-7% of subjects experience drug-related mild or moderate dizziness as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein about 2.6-27.9% of subjects experience drug-related mild or moderate nausea as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1, wherein about 1.5 to 8.5% of subjects experience drug-related mild or moderate constipation as an adverse event (TEAE) caused by treatment.   The mucoadhesive bioerodible drug delivery device of claim 1 wherein about 0.9 to 3% of subjects experience drug-related mild or moderate vomiting as an adverse event (TEAE) caused by treatment.

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