EP2793870A2 - Transmucosal drug delivery devices for use in chronic pain relief - Google Patents
Transmucosal drug delivery devices for use in chronic pain reliefInfo
- Publication number
- EP2793870A2 EP2793870A2 EP12860757.9A EP12860757A EP2793870A2 EP 2793870 A2 EP2793870 A2 EP 2793870A2 EP 12860757 A EP12860757 A EP 12860757A EP 2793870 A2 EP2793870 A2 EP 2793870A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- subject
- buprenorphine
- pain
- buffered
- mucoadhesive
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000002193 Pain Diseases 0.000 title claims abstract description 74
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- OIJXLIIMXHRJJH-KNLIIKEYSA-N Diprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)C(C)(C)O)OC)CN2CC1CC1 OIJXLIIMXHRJJH-KNLIIKEYSA-N 0.000 description 1
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Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61K47/02—Inorganic compounds
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
Definitions
- Chronic pain is pain that persists beyond the expected healing time, if resulting from injury, and can progress from a bothersome nuisance to a profound affliction. Chronic pain can cause a marked alteration in behavior with depression and anxiety, restriction in daily activities and excessive use of medication and medical services in an afflicted individual. The treatment of chronic pain is difficult, often inadequate and associated with high economic and psychological cost.
- Buprenorphine is a partial ⁇ -opiate receptor agonist, an ORLl/nociceptin receptor agonist with high affinity and a slow dissociation rate and a ⁇ -opiate receptor antagonist.
- Buprenorphine is metabolized by the liver, via the CYP3A4 isozyme of the cytochrome P450 enzyme system, into norbuprenorphine (by N-dealkylation) and other metabolites.
- Buprenorphine has a low oral bioavailability due to very high first-pass metabolism.
- Buprenorphine is an analgesic, available commercially as Temgesic ® 0.2 mg sublingual tablets, and as Buprenex ® in a 0.3 mg/ml parenteral formulation. Buprenorphine is also available as a sublingual preparation (Subutex ) and as a sublingual abuse-resistant formulation with naloxone (Suboxone ® ). The FDA approved Suboxone/Subutex in 2002 as a treatment of opioid dependence. Sublingual buprenorphine has been used for opioid detoxification and maintenance.
- a recent open-label study used sublingual buprenorphine (Suboxone ® ) for the treatment of chronic pain to those chronic opioid users (Malinoff et ah , 2005, American Journal of Therapeutics 12, 379-384). Patients were treated with daily buprenorphine doses that ranged from 2-20 mg (mean 8 mg). The treatment lasted from 2.4 months to 16.6 months (mean 8.8 months). The article reports that patients experienced improvement in their condition and reported a decrease in their sensation of pain.
- Figure 1 is a schematic representation of the design of a clinical study for evaluating the efficacy and safety of twice daily administration of BEMA buprenorphine in subjects with chronic low back pain.
- Figure 2 is a schematic representation of disposition of subjects who participated in the clinical study to evaluate the efficacy and safety of twice daily administration of BEMA buprenorphine in subjects with chronic low back pain.
- Figure 3 is a graph showing mean change from baseline in daily pain intensity experienced by the subjects with chronic low back pain after twice daily administration of BEMA buprenorphine.
- the present teachings provide methods for treating chronic pain by administering low doses of buprenorphine twice daily (or once daily) via a mucoadhesive bioerodable drug delivery device.
- the methods and devices efficiently 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 devices comprise about 100 ⁇ g to 0.9 mg buprenorphine, and provide steady- state Cmax of plasma buprenorphine concentration in a range between about 0.1 and about 1.2 ng/mL, such that the subject is treated for chronic pain.
- the buprenorphine delivery device comprises a bioerodable mucoadhesive layer comprising a therapeutically effective amount of buprenorphine disposed in a buffered polymeric diffusion environment, wherein the polymeric diffusion environment is a buffered environment having a pH of between about 4 and about 6.
- the buprenorphine delivery device further comprises a barrier layer comprising a polymeric barrier environment disposed adjacent to the mucoadhesive layer to provide a unidirectional gradient upon application to a mucosal surface for the rapid and efficient delivery of buprenorphine, wherein the unidirectional gradient delivers buprenorphine across the buffered polymeric diffusion environment upon application to the mucosal surface.
- the device comprises a mucoadhesive layer comprising an effective amount of buprenorphine buffered to a pH of between about 4.0 and about 6.0, and a backing layer buffered to a pH between about 4.0 and about 4.8.
- the device comprises about 120 ⁇ g to 0.9 mg buprenorphine.
- the methods and devices disclosed therein can be used to treat a subject with chronic low back pain, such as moderate to severe chronic low back pain, or a subject with neuropathic pain or osteoarthritic pain.
- the present invention provides methods of treating chronic pain with low doses of buprenorphine.
- the present method of treating pain is also associated with lack of significant opioid adverse effects.
- the subject is treated without experiencing any severe common opioid adverse effects.
- the subject is treated experiencing mild or moderate common opioid adverse effects, or no common opioid adverse effects.
- the present invention also provides effective chronic pain relief with twice daily administration of buprenorphine.
- the present invention is based, at least in part, on the surprising discovery that a transmucosal drug delivery device containing low doses of buprenorphine can be administered twice daily to opioid experienced subjects for effective management and relief of chronic pain, such as chronic low back pain.
- the present invention is also based on the discovery that this therapy does not result in substantial side effects associated with opioids, such as constipation and nausea.
- the articles “a” and “an” mean “one or more” or “at least one,” unless otherwise indicated. That is, reference to any element of the present invention by the indefinite article “a” or “an” does not exclude the possibility that more than one of the element is present.
- the term “acute pain” refers to pain characterized by a short duration, e.g. , three to six months. Acute pain is typically associated with tissue damage, and manifests in ways that can be easily described and observed. It can, for example, cause sweating or increased heart rate. Acute pain can also increase over time, and/or occur intermittently.
- bioavailability is as defined in 21 CFR Section 320.1 and refers to the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action.
- bioavailability refers to the total bioavailability including amounts that are absorbed through the oral mucosal membrane ⁇ i.e. , transmucosally) and through the GI mucosa of the lower GI tract.
- the transmucosal drug delivery devices of the present invention provide bioavailability of buprenorphine of between 65% and 85%. In some embodiments, the bioavailability of buprenorphine is 80%.
- bioequivalence or “bioequivalent” is as defined in 21 CFR Section 320.1, and means the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
- the pharmacokinetic parameters C max and AUC for bioequivalent actives fall within the 80%-125% range of each other.
- chronic pain refers to pain which persists beyond the usual recovery period for an injury or illness. In one embodiment, chronic pain is the pain that lasts longer than one week. Chronic pain can be constant or intermittent. Common causes of chronic pain include, but are not limited to, arthritis, cancer, Reflex Sympathetic Dystrophy Syndrome (RSDS), repetitive stress injuries, shingles, headaches, fibromyalgia, and diabetic neuropathy.
- RSDS Reflex Sympathetic Dystrophy Syndrome
- chronic low back pain refers to a muscoskeletal disorder, wherein the subject experiences pain in the lumbar, or low back region for at least 12 weeks. In a specific embodiment, a subject experiences chronic low back pain for at least 3 months.
- moderate to severe chronic low back pain refers to the chronic low back pain characterized, e.g. , by pain intensity of > 5 on an 11 -point Numerical Rating Scale (NRS, wherein 0 represents no pain and 10 represents the worst pain imaginable).
- neuropathic pain refers to a complex, chronic pain that usually is accompanied by tissue injury and results from lesions or diseases affecting the somatosensory system. With neuropathic pain, the nerve fibers themselves may be damaged, dysfunctional or injured. These damaged nerve fibers send incorrect signals to other pain centers. The impact of nerve fiber injury includes a change in nerve function both at the site of injury and areas around the injury. As used herein, the term “osteoarthritic pain” refers to pain resulting from
- osteoarthritis a degenerative joint disease and the most common type of arthritis. It is associated with the degradation and loss of a cartilage that covers and cushions the ends of bones in normal joints. Osteoarthritis causes the cartilage in a joint to become stiff and lose its elasticity, making it more susceptible to damage. Over time, the cartilage may wear away in some areas, greatly decreasing its ability to act as a shock absorber. As the cartilage wears away, tendons and ligaments stretch, causing pain. If the condition worsens, the bones could rub against each other, causing even more pain and loss of movement.
- buprenorphine includes any pharmaceutically acceptable form of buprenorphine, including, but not limited to, salts, esters, and prodrugs thereof.
- buprenorphine derivative refers to compounds having similar structure and function to buprenorphine. In some embodiments, buprenorphine derivatives include those of the following formula:
- R3 is selected from a -C 1-4 alkyl group or a cycloalkyl- substituted-Ci ⁇ alkyl group
- R 4 is selected from a -C 1-4 alkyl
- R 6 is selected from -H or a -C 1-4 alkyl group.
- Buprenorphine derivatives include, but are not limited to, etorphine and
- diprenorphine diprenorphine.
- General buprenorphine derivatives are described in International Application Publication No. WO 2008/011194, which is hereby incorporated by reference.
- naloxone includes any pharmaceutically acceptable form of naloxone, including, but not limited to, salts, esters, and prodrugs thereof.
- non-parenteral refers to modes of administration other than by direct systemic delivery of the medicament.
- non-parenteral excludes the use of intravenous (IV) injection, intramuscular (IM) injection, Intraperitoneal (IP) injection, subcutaneous (SC) injection, etc. for administration of the medicament and includes transdermal, oral transmucosal administration, and administration via the GI tract, generally.
- the term "mucoadhesive layer” or "polymeric diffusion environment” refers to an environment capable of allowing flux of a medicament to a mucosal surface upon creation of a gradient by adhesion to a mucosal surface.
- the flux of a transported medicament is proportionally related to the diffusivity of the environment which can be manipulated by, e.g. , adjusting the pH, taking into account the ionic nature of the medicament and/or the ionic nature of the polymer or polymers included in the environment.
- the term “backing layer” or “barrier environment” or “non-adhesive polymeric environment” refers to an environment in the form of, e.g. , a layer or coating or barrier layer, capable of slowing, or reducing flux of a medicament from the mucoadhesive layer into the oral cavity.
- the backing layer may contain a second medicament intended for dissolution in the saliva.
- the pH of the backing layer is adjusted, such that it impedes flux of the medicament toward the mucoadhesive layer where transmucosal absorption may occur.
- the term “unidirectional gradient” refers to a gradient which allows for the flux of a medicament (e.g.
- the device e.g. , through a polymeric diffusion environment, in substantially one direction, e.g. , to the oral mucosa of a subject.
- the polymeric diffusion environment may be a mucoadhesive polymeric diffusion environment in the form of a layer or film disposed adjacent to a backing layer or film.
- a gradient is created between the mucoadhesive polymeric diffusion environment and the mucosa, and the medicament flows from the mucoadhesive polymeric diffusion environment, substantially in one direction towards the mucosa, until the backing layer dissolves.
- treating or “treatment” of a subject includes the administration of a drug to a subject with the purpose of preventing, curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder (e.g. , to alleviate pain).
- subject refers to living organisms such as humans, dogs, cats, and other mammals.
- Administration of the medicaments included in the devices of the present invention can be carried out at dosages and for periods of time effective for treatment of a subject.
- the subject is a human.
- the pharmacokinetic profiles of the devices of the present invention are similar for male and female subjects.
- an "effective amount" of a drug necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, the dosage may be administered once daily, or may be divided into two individual dosages for twice daily administration. The dose may also be proportionally reduced as indicated by the exigencies of the therapeutic situation.
- transmucosal refers to any route of administration via a mucosal membrane. Examples include, but are not limited to, buccal, sublingual, nasal, vaginal, and rectal. In one embodiment, the administration is buccal. In one embodiment, the administration is sublingual. As used herein, the term “direct transmucosal” refers to mucosal administration via the oral mucosa, e.g. , buccal and/or sublingual.
- water erodable or “at least partially water erodable” refers to a substance that exhibits a water erodability ranging from negligible to completely water erodable.
- the substance may readily dissolve in water or may only partially dissolve in water with difficulty over a long period of time.
- the substance may exhibit a differing erodability in body fluids compared with water because of the more complex nature of body fluids.
- a substance that is negligibly erodable in water may show an erodability in body fluids that is slight to moderate.
- the erodability in water and body fluid may be approximately the same.
- addiction therapy as related to a subject includes the administration of a drug to a subject with the purpose of reducing the cravings for the addictive substance.
- opioid tolerance refers to the phenomenon in which a subject is less susceptible to the effect of an opioid drug as a consequence of its prior administration.
- acute tolerance describes tolerance that develops very rapidly following either a single dose or a few doses of opioids given over a short period of time.
- Chronic tolerance describes the observation that opioid administration over a longer period of time produces reduced effects.
- Associative tolerance is best expressed with low doses of opioids at long interdose intervals and is readily modified by behavioral or environmental interventions.
- Nonas sociative tolerance is best expressed with high doses of drugs at short interdose intervals and is not modified by behavioral or environmental interventions.
- opioid tolerant subject refers to a subject currently receiving opioid therapy. In one embodiment, the subject is taking >60 mg oral opioid therapy.
- opioid experienced subject refers to a subject currently receiving opioid therapy.
- the subject's daily use of opioids does not exceed the daily doses of opioids as specified in the Table 1 above.
- opioid naive subject refers to a subject who is not currently receiving opioid therapy. In one embodiment, the subject has not been exposed to opioids for 1 week or longer.
- abusive or “abusive manner” refers to uses of the devices beyond oral transmucosal administration such as by extracting the drug and injecting or snorting.
- the term "low dose of buprenorphine” refers to the daily dose less than 1.8 mg (e.g. , about 200 ⁇ g to about 1800 ⁇ g, or about 240 ⁇ g to 1800 ⁇ g) of buprenorphine.
- the term “steady-state plasma concentration” refers to the state, wherein the fluctuation in plasma drug concentrations are the same or similar after each dose.
- the term “steady-state C max of plasma buprenorphine concentration” refers to the state, wherein the post dose maximum plasma concentration of buprenorphine does not differ from one dose to another.
- steady-state C m i n of plasma buprenorphine concentration refers to the state, wherein the post-dose minimum plasma concentration of buprenorphine does not differ from one dose to another.
- the devices used in the present invention provide steady-state C max of plasma buprenorphine concentration in a range between about 0.1 and about 1.0 ng/mL. In another embodiment, the devices used in the present invention provide steady-state C max of plasma buprenorphine concentration in a range between about 0.1 and about 0.5 ng/mL.
- common opioid adverse effects refers to adverse effects commonly experienced by the subjects taking opioid analgesics. These common opioid adverse effects include, among others, headache, constipation, nausea or vomiting, pruritus, somnolence or cognitive impairment, dry mouth, tolerance or dependence and urinary retention.
- migraine common opioid adverse effects refers to adverse effects that do not require a special treatment and do not interfere with the subject's daily activities.
- moderate common opioid adverse effects refers to adverse effects that introduce a low level of inconvenience or concern to the subjects and could interfere with daily activities, but are usually ameliorated by simple therapeutic measures.
- severe common opioid adverse effects refers to adverse effects that interrupt usual daily activity and typically require systemic drug therapy or other treatment.
- significant constipation refers to chronic or severe constipation associated with the continuous use of morphine or other opioids.
- significant nausea refers to a severe condition of nausea that is commonly known in the art.
- the term “significant nausea” is defined with a visual analog scale (VAS) score of greater than or equal to 25 mm on a 0 to 100 mm scale.
- VAS visual analog scale
- disposed refers to the uniform or non-uniform distribution of an element within another.
- Certain aspects of the present invention include methods for providing pain management and/or relief to a subject in need thereof.
- the pain can be any pain known in the art, caused by any disease, disorder, condition and/or circumstance and can be chronic pain or acute pain.
- Chronic pain can arise from many sources including, cancer, Reflex Sympathetic Dystrophy Syndrome (RSDS), and migraine.
- RSDS Reflex Sympathetic Dystrophy Syndrome
- Acute pain is typically directly related to tissue damage, and lasts for a relatively short amount of time, e.g., hours to days, or up to 7 days.
- the pain is breakthrough cancer pain.
- the present invention provides methods of managing or treating chronic pain in a subject.
- the subject is opioid experienced, opioid tolerant or opioid naive, as defined above.
- the subject is opioid tolerant.
- the subject has not responded to previous treatment with the maximal doses of non-steroidal anti-inflammatory drugs.
- the chronic pain is chronic lower back pain (CLBP).
- the chronic lower back pain is moderate to severe chronic lower back pain.
- the pain is neuropathic pain or osteoarthritic pain.
- the subject to be treated for moderate to severe chronic low back pain is an opioid experienced subject.
- twice daily (or once daily) administration of low doses of buprenorphine via transmucosal drug delivery devices of the present invention is associated with low incidence or absence of common opioid adverse effects associated with opioid analgesics.
- the adverse effect is nausea.
- the adverse effect is constipation.
- transmucosal drug delivery devices of the present invention are administered once daily or twice daily.
- the total daily dose of buprenorphine administered is between 200 ⁇ g and 1800 ⁇ ⁇ , e.g.
- the transmucosal drug delivery devices of the present invention comprise low doses of buprenorphine.
- the low dose of buprenorphine contained in the devices is defined as the dose of about 100 ⁇ g to about 900 ⁇ g of buprenorphine.
- the low dose of buprenorphine comprised in the mucoadhesive device of the invention is 100 ⁇ g, 110 ⁇ g, 120 ⁇ g, 140 ⁇ g, 150 ⁇ g, 160 ⁇ g, 175 ⁇ ⁇ , 180 ⁇ ⁇ , 200 ⁇ ⁇ , 225 ⁇ ⁇ , 240 ⁇ ⁇ , 250 ⁇ ⁇ , 275 ⁇ ⁇ , 300 ⁇ ⁇ , 310 ⁇ ⁇ , 325 ⁇ ⁇ , 350 ⁇ ⁇ , 360 ⁇ ⁇ , 375 ⁇ ⁇ , 400 ⁇ ⁇ , 430 ⁇ ⁇ , 450 ⁇ ⁇ , 480 ⁇ ⁇ , 500 ⁇ ⁇ , 550 ⁇ ⁇ , 600 ⁇ ⁇ , 625 ⁇ ⁇ , 650 ⁇ ⁇ , 700 ⁇ g, 750 ⁇ g, 800 ⁇ g, 900 ⁇ g, 1000 ⁇ g,
- the devices of the present invention adhere to a mucosal surface of the subject within about 5 seconds following application.
- the devices of the present invention comprise an opioid agonist.
- the devices of the present invention include a bioerodable- or water-erodable mucoadhesive layer, and the opioid agonist is comprised in the mucoadhesive layer.
- the opioid agonist is buprenorphine. The dose of buprenorphine that can be incorporated into the device of the present invention depends on the desired treatment dosage to be
- the device further comprises at least one additional non- adhesive polymeric environment, e.g. , a backing layer.
- This layer is disposed adjacent to the mucoadhesive polymeric diffusion environment, e.g. , a backing layer, functions to facilitate the delivery of the opioid agonist, such as buprenorphine, to the mucosa.
- This additional layer may comprise the same or a different combination of polymers as the mucoadhesive polymeric diffusion environment or the non- adhesive polymeric diffusion environment.
- the backing layer includes an additional medicament, such as an opioid antagonist, to render the device of the invention abuse-resistant.
- the opioid antagonist is naloxone.
- the dose of naloxone that can be incorporated into the backing layer of the device of the present invention can range from about 2.5 ⁇ g to about 5 mg of naloxone.
- the amount of buprenorphine and the amount of naloxone disposed in the device are present in a ratio chosen such that the effect of buprenorphine is negated by naloxone if the mixture is injected or snorted.
- the amount of buprenorphine and the amount of naloxone disposed in the device are present in a 4:1 w/w ratio.
- Transmucosal devices are configured in the form of a disc, rectangular in shape with round corners, yellow on one or both sides of the cheek).
- Buprenorphine is present in the mucoadhesive layer, and this side is to be placed in contact with the buccal mucosa (inside the cheek).
- the drug is delivered into and across the mucosa as the disc erodes in the mouth.
- the non-adhesive, backing layer controls the rate erosion of the disc, and minimizes the amount of buprenorphine dissolved in saliva and ultimately swallowed, a pathway of lower absorption due first pass metabolism.
- the mucoadhesive polymeric diffusion layer and the backing layer are bonded together and do not delaminate during or after application.
- the mucoadhesive layer for the transmucosal devices of the present invention comprising the desired dosage of buprenorphine is prepared by mixing purified water, propylene glycol (about 4.6% total formulation, by dry weight), sodium benzoate (about 0.5% total formulation, by dry weight), methylparaben (about 0.9% total formulation, by dry weight), propylparaben (about 0.2% total formulation, by dry weight), vitamin E acetate (about 0.06% total formulation, by dry weight), citric acid (about 0.5% total formulation, by dry weight), yellow iron oxide (about 0.5% total formulation, by dry weight), monobasic sodium phosphate (about 3.4% total formulation, by dry weight).
- the above ingredients are added sequentially to a mixing vessel.
- buprenorphine HC1 (about 1.3% total formulation, by dry weight) is added, and the vessel was heated to 120 °F to 130 °F.
- the polymer mixture hydroxypropyl cellulose (about 6.8% total formulation, by dry weight), hydroxyethyl cellulose (about 20.3% total formulation, by dry weight), polycarbophil (about 6.3% total formulation, by dry weight), and carboxy methyl cellulose (about 54.3% total formulation, by dry weight)
- the polymer mixture hydroxypropyl cellulose (about 6.8% total formulation, by dry weight), hydroxyethyl cellulose (about 20.3% total formulation, by dry weight), polycarbophil (about 6.3% total formulation, by dry weight), and carboxy methyl cellulose (about 54.3% total formulation, by dry weight)
- tribasic sodium phosphate and sodium hydroxide are added to adjust the blend to a desired pH.
- the blend is mixed under vacuum for a few hours. Each prepared mixture is stored in an air-sealed vessel until its use in the coating operation.
- the backing layer is prepared by adding purified water to a mixing vessel followed by sequential addition of sodium benzoate (about 0.5% total formulation, by dry weight), methylparaben (about 0.4% total formulation, by dry weight), propylparaben (about 0.1% total formulation, by dry weight), citric acid (about 0.5% total formulation, by dry weight), vitamin E acetate (about 0.05% total formulation, by dry weight), sodium saccharin (about 0.5% total formulation, by dry weight). Subsequently, a mixture of the polymers
- hydroxypropyl cellulose about 63% total formulation, by dry weight
- hydroxyethyl cellulose about 32% total formulation, by dry weight
- titanium dioxide about 2.5% total formulation, by dry weight
- peppermint oil about 0.8% total formulation, by dry weight
- the layers are cast in series onto a St. Gobain polyester liner.
- the backing layer is cast using a knife-on- a-blade coating method.
- the backing layer is then cured in a continuous oven at about 65 °C to 95 °C and dried. After two coating and drying iterations, an approximately 8 mil (203 to 213 micrometers) thick backing layer is obtained.
- the mucoadhesive polymeric diffusion environment is cast onto the backing layer, cured in an oven at about 65 °C to 95 °C and dried.
- the devices are then die-cut by kiss-cut method and removed from the casting surface.
- Example 2 Placebo-controlled, Double-blind Study to Evaluate the Efficacy of BEMA Buprenorphine in Subjects with Moderate to Severe Chronic Low Back Pain
- a 12-week, placebo-controlled, double-blind randomized withdrawal study was conducted to evaluate the efficacy and safety of buprenorphine delivered twice daily via transmucosal drug delivery device with enhanced uptake (BEMA buprenorphine) in subjects with moderate to severe chronic low back pain. The study was also designed to define the range of BEMA Buprenorphine doses effective for management of moderate to severe chronic lower back pain. i. Study Design
- the study consisted of an open-label dose titration period lasting up to 4 weeks, followed by a randomized, double-blind, placebo-controlled treatment period of 12 weeks. The subjects continued on their current pain therapy during the initial screening period (days -14 to -1) and until 12 to 24 hours prior to Day 0/1 of the open-label dose titration period. Predose assessments were performed on open-label titration period Day 0 and the first dose of study drug was taken on open-label titration period Day 1.
- BEMA Buprenorphine During the open-label titration period, the subjects were administered BEMA Buprenorphine approximately every 12 hours, and dose adjustments were performed at intervals over a period of up to 4 weeks until a stabilized dose was found (i. e. , the dose that provided meaningful pain relief and was well tolerated).
- the titration sequence of BEMA Buprenorphine is illustrated in the Table 4 below. The subjects for whom a stabilized dose could not be found were discontinued from the study.
- opioid naive or opioid experienced The subjects who were selected for the inclusion in the study were opioid naive or opioid experienced, as defined earlier in this application.
- Opioid experienced subjects were subjects taking ⁇ 60 mg oral daily dose of morphine or equianalgesic dose of another allowed opioid for 1 week or longer.
- Opioid naive subjects were not taking any opioids for 1 week or longer.
- Analgesic efficacy was assessed daily by having the subject record their average pain intensity over the past 24 hours on a scale of 0 to 10, where 0 represents no pain and 10 represents the worst pain imaginable (11-point Numerical Rating Scale, NRS).
- the mean change in daily pain intensity from baseline (CBL) to final visit during double blind treatment period is presented in Tables 6-12 below.
- Tables 6-8 present the mean change data for different subject groups, and Tables 9-12 present the mean change data for the subject groups treated with different doses of buprenorphine.
- Table 9 Average daily pain intensity in subjects treated with the daily dose of A ug of buprenorphine
- Table 10 Average daily pain intensity in subjects treated with the daily dose of 2xA g of buprenorphine
- Graphed in Figure 3 is the mean change from baseline in daily pain intensity for all subjects; all subjects receiving 2xA ⁇ g, 3xA ⁇ g, or 4xA ⁇ g, BEMA Buprenorphine; all opioid experienced subjects; and all opioid experienced subjects receiving 2xA ⁇ g, 3xA ⁇ g, or 4xA ⁇ g BEMA Buprenorphine.
- AE Adverse events
- the intensity of AEs was characterized as mild, moderate, or severe as follows:
- Moderate AEs that introduced a low level of inconvenience or concern to the subject and could interfere with daily activities, but were usually ameliorated by simple therapeutic measures.
- Severe AEs that interrupted a subject's usual daily activity and typically required systemic drug therapy or other treatment.
- Table 14 shows the number and percent of subjects who experienced TEAEs during the open label titration period involving 330 subjects, with all TEAEs characterized by event intensity and relationship to the study drug.
- Table 15 shows analogous data for the double blind treatment period and buprenorphine treatment group involving 117 subjects. The maximum intensity ever recorded for each event and the drug relationship at that intensity were used to categorize adverse events.
- Drug-related category is listed as “R” and includes adverse events with investigator-assessed relation to drug of "probably” or “possibly”.
- “Non drug-related” category is listed as "NR".
- BEMA Buprenorphine contained buprenorphine doses of 2xA ⁇ g, and 4xA ⁇ g. Each dose was administered twice daily for 3 days with serial blood samples collected. Selected pharmacokinetic parameters are shown in the Table 16 below.
- ⁇ refers to the time to reach the steady-state of plasma buprenorphine concentration.
- C avg refers to the average concentration in plasma in steady-state.
- X refers to the area under the plasma concentration time curve from time-zero through the dosing interval
- AUC refers to the area under the concentration-time curve from time-zero to the time of the last quantifiable concentration.
Abstract
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