CN104125828A - Transmucosal drug delivery devices for use in chronic pain relief - Google Patents
Transmucosal drug delivery devices for use in chronic pain relief Download PDFInfo
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
Provided herein are methods for treating chronic pain by administering low doses of buprenorphine twice daily (or once daily) via a transmucosal drug delivery device. The methods and devices efficiently treat chronic pain without significant side effects.
Description
Related application
The application requires the priority of No. 61/578,755, U.S. Provisional Application that December in 2011 submits on the 21st.The full content of this application is incorporated in to this with for referencial use.
The U.S. Provisional Application 08/734,519 that the application relates on October 18th, 1996 and submits to is now No. 5,800,832, in JIUYUE, 1998 United States Patent (USP) of authorizing for 1st; No. 09/144,827, the U.S. Patent application that JIUYUE in 1998 is submitted on the 1st is now No. 6,159,498, in December, 2000 United States Patent (USP) of authorizing for 12nd; No. 11/069,089, the U.S. Patent application that on March 1st, 2005 submits to is now No. 7,579,019, the United States Patent (USP) of authorizing on August 25th, 2009; No. 11/639,408, the U.S. Patent application of December in 2006 submission on the 13rd; No. 11/817,915, the U.S. Patent application of JIUYUE in 2007 submission on the 6th; No. 13/834,306, the U.S. Patent application that on July 15th, 2011 submits to is now No. 8,147,866, the United States Patent (USP) of authorizing on April 3rd, 2012; No. 13/590,094, the U.S. Patent application of submitting on August 20th, 2012, is incorporated in this with for referencial use by its full content.
Background technology
Chronic pain is the pain (if deriving from damage) that continues the recovery time that exceedes expection, and can create disturbances to progress for deep misery from irritating.Chronic pain can cause remarkable change (with depression and anxiety), the restriction of daily routines and the abuse of medicine and medical services of the individual behavior that groans.The treatment of chronic pain is difficult, often and insufficient and be related to high economy and psychological cost.
Buprenorphine (buprenorphine) is part μ-opioid receptor agonist (partial μ-opiate receptor agonist), has ORL1/ orphanin (nociceptin) receptor stimulating agent of high-affinity and slow dissociation rate, and κ-opiate receptor antagonist.Buprenorphine is by liver, through the CYP3A4 isozyme of cytochrome P 450 Enzyme system and metabolism for removing alkyl buprenorphine (norbuprenorphine) (by N-dealkylation) and other metabolite.Buprenorphine causes oral bioavailability rate low because first pass metabolism is very high.
Buprenorphine is analgesic, can be used as
0.2mg sublingual tablet and conduct
0.3mg/ml parenteral formulation is commercially available.Buprenorphine also can be used as sublingual formulation (
) and as have naloxone the anti-abuse preparation in Sublingual (
) obtain.FDA ratified the treatment that Suboxone/Subutex relies on as opioid in 2002.Sublingual buprenorphine detoxifies and maintains for opioid.
Recent non-blind (open-label) research use Sublingual buprenorphine (
) treat the chronic pain (people such as Malinoff, 2005, American Journal of Therapeutics 12,379-384) of those chronic opioid user.Patient treats with buprenorphine dosage every day within the scope of 2-20mg (average 8mg).Treatment lasted till 16.6 months (average 8.8 months) from 2.4 months.Article reports, patient experiences is to the improvement of its patient's condition and report the reduction of its pain.
But, need to be used for the treatment of chronic pain and not relate to the effective ways of untoward reaction, particularly for not tolerance type of those opioids (opioid naive) or opioid experience type (opioid experienced) patient.
Brief description of the drawings
Fig. 1 is the schematic diagram for evaluating the effect of experimenter's administered twice every day BEMA buprenorphine and the clinical study design of safety of suffering from chronic lumbar and back pain (low back pain).
Fig. 2 participates in evaluating the schematic diagram of suffering from the effect of experimenter's administered twice every day BEMA buprenorphine of chronic lumbar and back pain and the experimenter of the clinical research of safety arrangement.
Fig. 3 be illustrate the experimenter that suffers from chronic lumbar and back pain after every day administered twice BEMA buprenorphine through going through every day pain intensity from the figure of the mean change of baseline.
Summary of the invention
This instruction provides by the method via using low dosage buprenorphine mucosa-adherent biology erosion property drug delivery device every day twice (or once a day) and treat chronic pain.Described method and apparatus is treated chronic pain effectively and non-evident effect is for example less than the patient experience constipation of 15% (be preferably less than 10%, be more preferably less than 5%).
Described device comprises the buprenorphine of approximately 100 μ g to 0.9mg, and provide approximately 0.1 and about 1.2ng/mL within the scope of stable state C
maxblood plasma buprenorphine concentration so that treatment experimenter chronic pain.
In one embodiment; buprenorphine transfer device comprises biology erosion property mucosa-adherent layer; described biology erosion property mucosa-adherent layer comprises the buprenorphine of the treatment effective dose in the polymer diffusion environment that is arranged at buffering, wherein said polymer diffusion environment is to have approximately 4 and the about buffer environment of the pH between 6.In another embodiment; buprenorphine transfer device further comprises barrier layer; described barrier layer comprises that the polymer that approaches mucosa-adherent layer configuration stops environment; thus in the time being applied to mucomembranous surface, provide unidirectional gradient to carry out effectively to transmit fast buprenorphine, wherein in the time being applied to mucomembranous surface described in unidirectional gradient make buprenorphine pass the polymer diffusion environment transmission of buffering.Also in other embodiments, described device comprises and is buffered to approximately 4.0 and the about mucosa-adherent layer of the buprenorphine containing effective dose of the pH between 6.0, and is buffered to approximately 4.0 and the about backing layer of the pH between 4.8.
In one embodiment, described device comprises the buprenorphine of approximately 120 μ g to 0.9mg.
Method and apparatus disclosed herein can be used for treatment to be suffered from for example moderate of chronic lumbar and back pain and, to the experimenter of severe chronic lumbar and back pain, or suffers from the experimenter of neuropathic pain or osteoarthritis pain.
Detailed description of the invention
The invention provides the method with low dosage buprenorphine treatment chronic pain.The method of this treatment pain does not also relate to obvious opioid untoward reaction.For example, experimenter receives treatment and without the common opioid untoward reaction of successive what severe.Or experimenter receives treatment experience slightly or the common opioid untoward reaction of moderate, or without common opioid untoward reaction.
The present invention also provides the effective chronic pain alleviation of administered twice buprenorphine every day.The present invention at least part of based on following unexpected discovery: contain low dosage buprenorphine across mucosal drug transfer device can every day administered twice to there being the experimenter who takes opioid experience effectively to control and relieve chronic pain, as chronic lumbar and back pain.The present invention is also based on finding that this treatment does not cause the substantial side effects relevant to opioid as constipation and feels sick.
Definition
About the implication of some term used herein, provide following definition as instructing.
As used herein, article " one " (a and an) refers to " one or more " or " at least one ", except as otherwise noted., about do not got rid of the probability existing more than a kind of element by the represented arbitrary element of the present invention of indefinite article " one ".
As used herein, it is short that term " acute pain " refers to be characterized as the persistent period, for example the pain of three to six months.Acute pain is typically relevant to tissue injury, and shows in the mode that can easily describe and observe.For example, can cause that perspire or heart rate increase.Acute pain also can strengthen in time, and/or intermittently occurs.
As used herein, term " bioavailability " defines as institute in 21 CFR 320.1 joints, and refers to that active component or active part are from medicine absorption and in the available speed of site of action and degree.Term " bioavailability ", " definitely bioavailability " or " total bioavailability " refer to comprise by total bioavailability of the amount of oral mucosa (, across mucosa) and the GI mucosa absorption by XiaGI road.In certain embodiments, the bioavailability that the buprenorphine between 65% and 85% is provided across mucosal drug transfer device of the present invention.In certain embodiments, the bioavailability of buprenorphine is 80%.
As used herein, term " bioequivalence " or " bioequivalent " be as definition in Section 320.1 of 21 CFR, and the active component in medicament equivalent (pharmaceutical equivalents) and medicament succedaneum (pharmaceutical alternatives) or active part becomes available speed at drug effect position and degree does not exist significant difference while referring to use with identical molar dose under condition of similarity in the research of suitably design.The pharmacokinetic parameter C of bioequivalence activity
maxfall into respectively within the scope of 80%-125% with AUC.
As used herein, term " chronic pain " refers to outside injury or normal convalescent period of disease still lasting pain.In one embodiment, chronic pain is to continue to exceed the pain of one week.Chronic pain can be to continue or intermittence.The common cause of chronic pain is including, but not limited to, arthritis, cancer, reflex sympathetic dystrophy syndrome (RSDS), repeated stress damage (repetitive stress injuries), herpes zoster, headache, fibromyalgia and diabetic neuropathy.
As used herein, term " chronic lumbar and back pain " refers to flesh skeleton (muscoskeletal) disease, and wherein experimenter experiences at least 12 weeks of pain in waist or region, back.In specific embodiment, experimenter experiences chronic lumbar and back pain at least 3 months.
As used herein, term " moderate is to severe chronic lumbar and back pain " refers to chronic lumbar and back pain, it is characterized in that for example 11 digital equal interval scale (11-point Numerical Rating Scale, NRS, wherein 0 indicate without pain and 10 represent the most serious conceivable pain) pain intensity >=5.
As used herein, term " neuropathic pain " refers to conventionally be attended by tissue injury and by affecting the pathological changes of somatosensory system or the complicated chronic pain that disease causes.The in the situation that of neuropathic pain, nerve fiber itself may damage, dysfunction or damage.The nerve fiber of these damages is transmitted incorrect signal to other pain center.The impact of nerve fiber damage is included in the variation of function of nervous system in damage location and damage peripheral region.
As used herein, term " osteoarthritis pain " refers to the pain being caused by the arthritis of osteoarthritis, osteoarthritis and common type.This is relevant with disappearance to the degeneration of the cartilage of the end of covering in natural joint and buffering bone.Osteoarthritis makes the cartilage in joint become stiff and loses its elasticity, makes it more responsive to damaging.As time goes by, cartilage can, in some regions wear, significantly reduce the ability that it serves as buffer.Due to cartilage wearing and tearing, tendon and ligament tension, cause pain.If the patient's condition worsens, the mutual friction of bone possibility phase, causes pain and LOM even more.
Except as otherwise noted, otherwise as used herein term " buprenorphine " comprises any pharmaceutically acceptable form of buprenorphine, including, but not limited to its salt, ester and prodrug.As used herein, term " buprenorphine derivatives " refers to have the compound with buprenorphine analog structure and function.In certain embodiments, buprenorphine derivatives comprises those of following formula:
Or its pharmaceutically-acceptable salts or ester, wherein
for two keys or singly-bound; R
3be selected from-C
1-4the C of alkyl or cycloalkyl-replacement
1-4alkyl; R
4be selected from-C
1-4alkyl; R
5wei – OH, or R
4and R
5formation=O base together; And R
6xuan Zi – H or-C
1-4alkyl.
Buprenorphine derivatives includes, but not limited to etorphine and dipropyl promise phenanthrene.General buprenorphine derivatives is recorded in No. 2008/011194, international application published WO, is introduced into herein as a reference.
Except as otherwise noted, otherwise as used herein term " naloxone ", comprise any pharmaceutically acceptable form of naloxone, including, but not limited to its salt, ester and prodrug.
As used herein, " parenteral is outer " refers to the method for application except the direct systemic delivery of pharmaceuticals.Similarly, " parenteral outer " do not comprise and use intravenous (IV) injection, intramuscular (IM) injection, intraperitoneal (IP) injection, subcutaneous (SC) injection etc. to use pharmaceuticals, but generally comprise percutaneous, oral transmucosal is used He Jing GI road and is used.
As used herein, term " mucosa-adherent layer " or " polymer diffusion environment " refer to by adhering to while producing gradient and can make pharmaceuticals to the mobile environment of mucomembranous surface with mucomembranous surface.Flowing of the pharmaceuticals of carrying is proportional relevant to environment diffusibility, considers the ionic nature of pharmaceuticals and/or is contained in a kind of polymer in environment or the ionic nature of multiple polymers, can be by for example regulating pH to control.
As used herein, term " backing layer " or " stopping environment " or " non-adhesive polymer environment " refer to the environment existing from the form on the mucosa-adherent layer layer mobile to oral cavity or coating or barrier layer for example can slow down or reduce pharmaceuticals.In certain embodiments, backing layer can comprise the second pharmaceuticals for being dissolved in saliva.In this case, regulate the pH of backing layer, to stop pharmaceuticals moving to the mucosa-adherent laminar flow that cross-film absorption can occur.As used herein, term " unidirectional gradient " refers to allow pharmaceuticals (for example, buprenorphine) substantially to flow through device (for example, by polymer diffusion environment) along a direction to arrive for example gradient of experimenter's mucosa.For example, polymer diffusion environment can be to be configured to the mucosa-adherent polymer diffusion environment close to the layer of backing layer or film or the form of film.In the time of oral mucosal use, between mucosa-adherent polymer diffusion environment and mucosa, produce gradient, pharmaceuticals flow to mucosa along a direction substantially from mucosa-adherent polymer diffusion environment, until backing layer dissolves.
As used herein, experimenter's verb " treatment " or noun " treatment " comprise in order to prevent, to cure, cure, alleviate, alleviate, change, remedy, improve, promote, stable or affect disease or disease, or the object of the symptom of disease or disease (for example, easing the pain) and medicine is used to experimenter.
Term " experimenter " refers to live organism for example people, Canis familiaris L., cat and other mammals.The using of pharmaceuticals being contained in apparatus of the present invention can be carried out under effective treatment experimenter's dosage and duration.In certain embodiments, experimenter behaves.In certain embodiments, the pharmacokinetics collection of illustrative plates of device of the present invention for male be similar with female subject.
" effective dose " that reach the required medicine of therapeutic effect can change according to factors such as such as experimenter's age, sex and body weight.Scalable dosage is to provide best treatment response.For example, dosage can once-a-day administration, maybe can be divided into twice independently dosage for administered twice every day.Also can reduce pro rata dosage according to the instruction of emergency treatment situation.
As used herein, term " across mucosa " refers to any route of administration via mucosa.Example including, but not limited to oral cavity, Sublingual, nose, vagina and rectum.In one embodiment, use as oral cavity.In one embodiment, use as Sublingual.As used herein, term " directly across mucosa " refers to the mucosal administration via oral mucosa, for example oral cavity and/or Sublingual.
As used herein, the material of term " water erosion property (water erodable) " or " water erosion property at least in part " the water erosion property within the scope of referring to show from insignificant water erosion property to complete water erosion property.Described material can be easy to be dissolved in water or can only partly be insoluble in for a long time in water.In addition,, due to the more complicated character of body fluid, described material and water ratio can show different erosion property in body fluid.For example, the insignificant material of the erosion property in water can show the slightly body fluid erosion property to moderate.But in other situation, the erosion property in water and body fluid can be unanimous on the whole.
As used herein, " addiction therapy " relevant to experimenter comprises reducing craving for for object is to experimenter's drug administration addicted substance.
As used herein, term " opioid toleration " refers to wherein make experimenter to the more insensitive phenomenon of opioid drug owing to using opioid drug early stage.What " acute tolerance " described is to develop very fast toleration after the opioid of single dose or several dosage is provided in a short time.What " chronic toleration " described is the situation that chronic administration opioid produces less effect.Associated toleration 25 (associative tolerance) the most often shows as the low dosage opioid at interval between long administration, and easily adjusts by behavior or environment intervention.Dereferenced toleration the most often shows as the high dose medicament at interval between short administration, and does not adjust by behavior or environment intervention.
As used herein, before term " opioid toleration experimenter " feeling the pulse with the finger-tip, accept the experimenter that opioid is treated.In one embodiment, as shown in table 1 below, the another kind of opioid that experimenter is taking oral Morphine/sky of >60mg or pain relieving (equianalgesic) dosage such as taking is more than 1 week.
Table 1.
| Opioid | Oral dose such as pain relieving such as grade roughly |
| Morphine | 60mg |
| Tramadol | 300mg |
| Hydromorphone | 12mg |
| Oxycodone | 30mg |
| Hydrocodone | 30mg |
| Oxymorphone | 20mg |
| Codeine | 400mg |
As used herein, before term " opioid experience type experimenter " feeling the pulse with the finger-tip, accept the experimenter that opioid is treated.In one embodiment, experimenter's opioid routine use is no more than opioid daily dose as shown in Table 1.
As used herein, before term " not tolerance type of opioid experimenter " feeling the pulse with the finger-tip, do not accept the experimenter that opioid is treated.In one embodiment, experimenter was not exposed to opioid more than 1 week.
As used herein, term " abuse " or " abuse mode " refer to except oral across mucosal administration for example by extracting medicine and injection or the use of smelling the device of suction.
As used herein, term " low dosage buprenorphine " refers to be less than 1.8mg, and (for example, approximately 200 μ g are to the daily dose of approximately 1800 μ g or approximately 240 μ g to 1800 μ buprenorphine g).
As used herein, term " Cpss " refers to wherein fluctuation same or analogous state after each dosage of plasma drug level.Term " the stable state C of blood plasma buprenorphine concentration
max" refer to that wherein dose does not have different state terms " the stable state C of blood plasma buprenorphine concentration from the post dose maximal plasma concentration of the buprenorphine of another dose
min" refer to dose wherein and another dose buprenorphine rear-dosage minimum plasma concentration do not have different states.The stable state C of blood plasma buprenorphine concentration is provided for device of the present invention in one embodiment,
maxapproximately 0.1 and about 1.0ng/mL between.The stable state C of I blood plasma buprenorphine concentration is provided for device of the present invention in another embodiment,
maxapproximately 0.1 and about 0.5ng/mL between.
As used herein, term " common opioid untoward reaction " refers to take the untoward reaction that the experimenter of opioid analgesic generally experiences.These common opioid untoward reaction comprise headache, constipation, n or V, pruritus, drowsiness or cognitive disorder, xerostomia, tolerance or dependence and urine retention etc.
The untoward reaction that term " slight common opioid untoward reaction " refers to not need particular treatment and do not disturb experimenter's daily routines.Term " the common opioid untoward reaction of moderate " refers to that experimenter produces low-level inconvenience or worry and can disturb daily routines, but the untoward reaction conventionally improving by simple treatment measure.Term " the common opioid untoward reaction of severe " refers to hinder daily routines and typically needs the untoward reaction of systemic medication treatment or other treatment.
Term " significance constipation " refers to the chronic or severe constipation relevant to continuous use morphine or other opioid.
Term " significance is felt sick " refers to nauseating critical conditions well known in the art.In some embodiments, term " significance is felt sick " is limited by Visual analogue scale (VAS) mark that is more than or equal to 25mm in 0 to 100mm scale.
As used herein, term " configuration " refers to element even or non-uniform Distribution each other.
Pain control (Pain Management)
Some aspect of the present invention comprises the method that pain control and/or alleviation are provided to the experimenter who has needs.Described pain can be known in the art, any pain being caused by any disease, disease, the patient's condition and/or situation, and can be chronic pain or acute pain.Chronic pain can be caused by the multiple source that comprises cancer, sympathetic reflex dystrophy syndrome (RSDS) and migraine etc.Acute pain is typically directly related with tissue injury, and continues the relatively short time, and for example a few hours are to a couple of days, or as many as 7 days.In other embodiments, pain is breakthrough cancer pain (breakthrough cancer pain).
In some respects, the invention provides the method for controlling or treating experimenter's chronic pain.In some embodiments, experimenter is opioid experience type as above, opioid tolerance type or not tolerance type of opioid.In specific embodiment, experimenter is opioid tolerance type.In another embodiment, experimenter not yet makes response to the treatment of maximal dose NSAID (non-steroidal anti-inflammatory drug) before.
In some embodiments, chronic pain is chronic lumbar and back pain (CLBP).In some embodiments, chronic lumbar and back pain is that moderate is to severe chronic lumbar and back pain.In other embodiments, pain is neuropathic pain or osteoarthritis pain.In specific embodiment, the experimenter that treat moderate or severe chronic lumbar and back pain is opioid experience type experimenter.
Also find to be at present associated across low incidence rate or the shortage of using the common opioid untoward reaction that low dosage buprenorphine is relevant to opioid analgesic mucosal drug transfer device every day twice (or once a day) via of the present invention.In one embodiment, untoward reaction is for feeling sick.In another embodiment, untoward reaction is constipation.
Using and administration (dosing) of buprenorphine
In some embodiments, of the present invention across mucosal drug transfer device (as BEMA buprenorphine) once a day or every day administered twice.In some embodiments, total daily dose of administration of buprenorphine between 200 μ g and 1800 μ g, for example 200 μ g, 220 μ g, 240 μ g, 280 μ g, 300 μ g, 320 μ g, 350 μ g, 360 μ g, 400 μ g, 450 μ g, 480 μ g, 500 μ g, 550 μ g, 600 μ g, 620 μ g, 650 μ g, 700 μ g, 720 μ g, 750 μ g, 800 μ g, 860 μ g, 900 μ g, 960 μ g, 1000 μ g, 1100 μ g, 1200 μ g, 1250 μ g, 1300 μ g, 1400 μ g, 1500 μ g, 1600 μ g and 1800 μ g.
In some embodiments, of the present inventionly comprise low dosage buprenorphine across mucosal drug transfer device.In one embodiment, the low dosage that is included in the buprenorphine in device is defined as the dosage of approximately 100 μ g to the buprenorphine of approximately 900 μ g.In some embodiments, the low dosage that is included in the buprenorphine in mucosa-adherent device of the present invention is 100 μ g, 110 μ g, 120 μ g, 140 μ g, 150 μ g, 160 μ g, 175 μ g, 180 μ g, 200 μ g, 225 μ g, 240 μ g, 250 μ g, 275 μ g, 300 μ g, 310 μ g, 325 μ g, 350 μ g, 360 μ g, 375 μ g, 400 μ g, 430 μ g, 450 μ g, 480 μ g, 500 μ g, 550 μ g, 600 μ g, 625 μ g, 650 μ g, 700 μ g, 750 μ g, 800 μ g, 900 μ g, 1000 μ g, 1200 μ g, 1250 μ g, 1300 μ g, 1400 μ g, 1500 μ g, 1600 μ g and 1800 μ g.
Across the drug delivery device of mucosa
Being recorded in advance the U.S. Provisional Application 08/734,519 of submitting on October 18th, 1996 for example across the drug delivery device of mucosa, is now No. 5,800,832, in JIUYUE, 1998 United States Patent (USP) of authorizing for 1st; No. 09/144,827, the U.S. Patent application that JIUYUE in 1998 is submitted on the 1st is now No. 6,159,498, in December, 2000 United States Patent (USP) of authorizing for 12nd; No. 11/069,089, the U.S. Patent application that on March 1st, 2005 submits to is now No. 7,579,019, the United States Patent (USP) of authorizing on August 25th, 2009; No. 11/639,408, the U.S. Patent application of December in 2006 submission on the 13rd; No. 11/817,915, the U.S. Patent application of JIUYUE in 2007 submission on the 6th; No. 13/834,306, the U.S. Patent application that on July 15th, 2011 submits to is now No. 8,147,866, the United States Patent (USP) of authorizing on April 3rd, 2012; No. 13/590,094, the U.S. Patent application of submitting on August 20th, 2012, is incorporated in this with for referencial use by its full content.
i. mucosa-adherent layer
In some embodiments, in after application approximately 5 seconds of device of the present invention, adhere to experimenter's mucomembranous surface.In some embodiments, the inventive system comprises opioid agonist.In some embodiments, the inventive system comprises biology erosion property or water erosion property mucosa-adherent layer, and opioid agonist is included in mucosa-adherent layer.In one embodiment, opioid agonist is buprenorphine.The dosage that can be incorporated to the buprenorphine in apparatus of the present invention depend on the expectation therapeutic dose that will use and can approximately 20 μ g to about 20mg or at approximately 120 μ g to the buprenorphine of approximately 2000 μ g.
ii. backing layer
In some embodiments, described device further comprises the non-adhesive polymer environment that at least one is other, for example backing layer.This layer is close to mucosa-adherent polymer diffusion environment configurations, and for example backing layer plays and promotes opioid agonist if buprenorphine is to the transmission of mucosa.The combination that this other layer can comprise identical or different polymer is as mucosa-adherent polymer diffusion environment or non-adhesive polymer diffusion environment.
In some embodiments, backing layer comprises other medicine, and for example opioid antagonists provides device of the present invention in case abuse property.In some embodiments, opioid antagonists is naloxone.The dosage that can be incorporated to the naloxone in the backing layer of apparatus of the present invention can be at approximately 2.5 μ g to the scope of about 5mg naloxone.In some embodiments, be disposed at the amount of the buprenorphine in device and the amount of naloxone so that the selection percentage that the effect of buprenorphine is offset by naloxone exists (if injection or suction mixture).In some embodiments, be disposed at the amount of the buprenorphine in device and the amount of naloxone exists with the ratio of 4:1w/w.
Embodiment
Will be further understood that the present invention by following examples.But, one of ordinary skill in the art will readily recognize that specific experiment details described herein is only not intended to limit the present invention for illustrative, the present invention by after claim limited.
The preparation of embodiment 1. apparatus of the present invention
Taking CD, there is fillet the formal construction of rectangle across mucosa device (one or both sides of offside frame (cheek) as yellow).Buprenorphine is present in mucosa-adherent layer, and this side will contact and place with buccal mucosa (buccal mucosa) (in offside frame).In the time that dish corrodes in mouth, drug delivery is also passed to mucosa to mucosa.The erosion rate of non-adhesive backing layer console panel, and minimize the amount that buprenorphine is dissolved in saliva and finally swallows, the approach that the absorption causing due to first pass metabolism reduces.Mucosa-adherent polymer diffusion layer and backing layer combine and not during applying or application after layering.
The present invention who comprises desired amount buprenorphine passes through to mix pure water across the mucosa-adherent layer of mucosa device, propylene glycol (approximately 4.6% total preparation, dry weight), sodium benzoate (approximately 0.5% total preparation, dry weight), methyl hydroxybenzoate (approximately 0.9% total preparation, dry weight), propylparaben (approximately 0.2% total preparation, dry weight), Vitamin E acetate (approximately 0.06% total preparation, dry weight), citric acid (approximately 0.5% total preparation, dry weight), yellow iron oxide (approximately 0.5% total preparation, dry weight), sodium dihydrogen phosphate (approximately 3.4% total preparation, dry weight) prepare.Mentioned component continuous adding is to mixer.After components dissolved, add buprenorphine HCl (approximately 1.3% total preparation, dry weight), and container is heated to 120 °F to 130 °F.After dissolving, polymeric blends (hydroxypropyl cellulose (approximately 6.8% total preparation, dry weight), hydroxyethyl-cellulose (approximately 20.3% total preparation, dry weight), polycarbophil (approximately 6.3% total preparation, dry weight) and carboxymethyl cellulose (approximately 54.3% total preparation, dry weight)) be added into container, and be stirred to dispersion.Subsequently, remove heat from mixer.As last interpolation step, add tertiary sodium phosphate and sodium hydroxide and regulate blend to the pH expecting.Blend mixes several hours under vacuum.The mixture storage of each preparation is ensconced in the container of sealing gland until it is for being coated with operation.
Backing layer is by adding mixer by pure water, then order is added sodium benzoate (approximately 0.5% total preparation, dry weight), methyl hydroxybenzoate (approximately 0.4% total preparation, dry weight), propylparaben (approximately 0.1% total preparation, dry weight), citric acid (approximately 0.5% total preparation, dry weight), prepared by Vitamin E acetate (approximately 0.05% total preparation, dry weight), saccharin sodium (approximately 0.5% total preparation, dry weight).Subsequently, add polymer hydroxypropyl cellulose (approximately 63% total preparation, dry weight) and hydroxyethyl-cellulose (approximately 32% total preparation, dry weight) and stir at the temperature between approximately 120 °F and 130 °F, until dispersed.In the time being cooled to room temperature, titanium dioxide (approximately 2.5% total preparation, dry weight) and Oleum menthae (approximately 0.8% total preparation, dry weight) are then added into container and stir.The mixture storage of preparation is ensconced in sealing gland container until it is ready for coating operation.
Layer is cast continuously in St.Gobain polyester liner.First, backing layer uses blade (knife-on-a-blade) rubbing method.Then backing layer is solidified and is dried to 95 DEG C at approximately 65 DEG C in continuous oven.The coating replacing for twice obtains the thick backing layer of about 8mil (203 to 213 microns) after being dried.Subsequently, mucosa-adherent polymer diffusion environment is cast on backing layer, solidifies and is dried to 95 DEG C at approximately 65 DEG C in stove.Then by device by osculating method (kiss-cut) cross cutting (die-cut) and remove from casting plane.
The double-blind study of embodiment 2. placebo is evaluated the effect of BEMA buprenorphine in the experimenter who suffers from moderate or severe chronic lumbar and back pain
The double blind random that carries out the placebo in 12-week exits research (withdrawal study) and evaluates via strengthening effect and the safety of the buprenorphine across twice transmission mucosal drug transfer device every day (BEMA buprenorphine) absorbing in the experimenter who suffers from moderate or severe chronic lumbar and back pain.This research is also related to the scope of alignment degree to the effective BEMA buprenorphine of severe chronic lumbar and back pain dosage that limit.
i. research design
This research by continuing random, the double blinding of the as many as cumulative phase of non-blind dose titration (titration period) and 12 weeks subsequently of 4 weeks, the treatment of placebo forms.Experimenter is in the initial screening phase (14 to-1 days) and until proceed their current pain therapies during before 0/1 day of non-blind cumulative phase of dose titration 12 to 24 hours.Estimate evaluation is carried out at non-blind dose titration on the 0th day, within the 1st day, gets the first dosage of drugs at non-blind dose titration.
In the non-cumulative phase of blind dose titration, experimenter approximately uses BEMA buprenorphine for every 12 hours, and until find consistent dose (, provide significant pain relief and well tolerance dosage) as many as during 4 weeks in interval carry out dose titration.The titration order of BEMA buprenorphine is shown in following table 4.The experimenter that can not find consistent dose stops research.
Table 4.BEMA buprenorphine titration scheme
| Research natural law | Titration order-BEM buprenorphine low dosage (Q12 hour) |
| 1 | A |
| 7 (± 3 days) | 2×A |
| 14 (± 3 days) | 3×A |
| 21 (± 3 days) | 4×A |
The experimenter who identifies consistent dose and get this dosage at least 12 times in the end 7 days enters the 12-double-blind treatment phase in week, and wherein the experimenter of half accepts BEMA placebo, and half continues to accept the BEMA buprenorphine of consistent dose.Each experimenter continues 19 weeks to the participation of whole research.Illustrating in Fig. 1 of research design is shown.
ii. for the population of subjects of this research
As aforementioned definitions in the application, select to comprise that experimenter is under study for action not tolerance type of opioid or opioid experience type.Opioid experience type experimenter be the oral daily dose of take≤60mg morphine or etc. the opioid 1 week that allows of the another kind of AD experimenter above.Not tolerance type of opioid experimenter does not take any opioid more than 1 week.
Amount to 334 experimenters and enter research, wherein 332 experimenters enter the 4-non-cumulative phase of blind dose titration in week.Because 97 experimenters stopped intervening in the non-cumulative phase of blind titration, thereby 235 experimenters of total continue to enter the 12-double-blind treatment phase.In the experimenter that 117 are accepted BEMA buprenorphine, 28 stop intervening, and 89 experimenters complete research.In the experimenter that 118 are accepted placebo, 37 stop intervening, and 8 experimenters complete research.Experimenter during research disposes and is summarized in Fig. 2, and the population characteristic that participates in research is summarized in following table 5:
Table 5. Research Group feature
the pain relieving effect of iii.BEMA buprenorphine
Carry out to evaluate every day pain relieving effect by making experimenter be recorded in their average pain intensity in the past 24 hours on the scale of 0-10, wherein 0 indicates without pain, and 10 represent the most serious conceivable pain (the digital equal interval scale of 11-point, NRS).The double-blind treatment phase from baseline (CBL) to final observe every day pain intensity mean change be shown in following table 6-12.Table 6-8 represents the mean change data of different subject group, and table 9-12 represents the mean change data by the subject group of various dose buprenorphine processing.
Table 6. average every day of pain intensity-all experimenters
Table 7. average every day of pain intensity-opioid experience type experimenter
In not tolerance type of table 8. experimenter opioid average every day pain intensity
As shown in table 7, BEMA buprenorphine compared with placebo average every day pain score from the variation of baseline opioid experience type colony close to statistical significantly.
Table 9. with the buprenorphine of A μ g every day dosage treatment experimenter's average every day of pain intensity
Table 10. with the buprenorphine of 2 × A μ g every day dosage treatment experimenter's average every day of pain intensity
Table 11. with the buprenorphine of 3 × A μ g every day dosage treatment experimenter's average every day of pain intensity
Table 12. with the buprenorphine of 4 × A μ g every day dosage treatment experimenter's average every day of pain intensity
In Fig. 3, draw be all experimenters every day pain intensity from the mean change of baseline; All experimenters accept the BEMA buprenorphine of 2 × A μ g, 3 × A μ g or 4 × A μ g; All opioid experience type experimenters; Accept the BEMA buprenorphine of 2 × A μ g, 3 × A μ g or 4 × A μ g with all opioid experience type experimenters.
iv. the incidence rate of adverse events
All experimenters' adverse events (AE) in Record analysis.AE is defined as patient or the clinical research experimenter's of administration of drugs any unsuitable medical events, and needn't have cause effect relation with this treatment.The two the sum of adverse events of the non-blind titration of record and double-blind treatment phase is listed in the table below in 13
The adverse events (TEAE) occurring in the total treatment of table 13.
The intensity of AE is divided into slightly as follows, moderate or severe:
Slight: of short duration, do not need special treatment and do not disturb the AE of experimenter's daily routines.
Moderate: cause the low-level inconvenience of experimenter or worry and can disturb daily routines, but the AE conventionally improving by simple treatment measure.
Severe: the daily routines that interrupt experimenter also typically need the untoward reaction AE of systemic medication treatment or other treatment.
Following table 14 is illustrated in the experimenter's of the experience TEAE of cumulative phase of non-blind titration that comprises 330 experimenters number and percentage, and all TEAE are characterised in that event intensity and the relation with drugs.Following table 15 illustrates the double-blind treatment phase and comprises the class likelihood data of 117 experimenters' buprenorphine treatment group.The maximum intensity that each event once recorded and the medicine relation under this intensity are for classifying adverse events." medicine relevant " classification be shown " R " and be included in " probably " or investigator's evaluation relation " possibility " and medicine under adverse events." non-medicine is relevant " classification is shown " NR ".
Table 14. is in TEAE and the medicine relation of non-event intensity of cumulative phase of blind titration.
Table 15. is in TEAE and the medicine relation of double-blind treatment phase event intensity.
The pharmacokinetic parameters of embodiment 3.BEMA buprenorphine
The pharmacokinetic parameters that is not used in the BEMA buprenorphine for the treatment of chronic pain is determined in independent multiple dose research.The buprenorphine dosage that BEMA buprenorphine comprises 2 × A μ g and 4 × A μ g.Each dosage administered twice every day 3 days, continuous acquisition blood sample.The pharmacokinetic parameters of selecting is shown in following table 16.
Table 16. comprises the pharmacokinetic parameters of the BEMA buprenorphine oral mucosa (Buccal Films) of the selection of 1 × A μ g, 2 × A μ g, 3 × A μ g and 4 × A μ g buprenorphine.
| Pharmacokinetic parameters (meansigma methods) | 1×Aμg | 2×Aμg | 3×Aμg | 4×Aμg |
| T max(hr) | 2.90 | 2.61 | 2.00 | 2.20 |
| C max(ng/mL) | 0.0766 | 0.156 | 0.216 | 0.364 |
| C min(ng/mL) | 0.0157 | 0.0371 | 0.0558 | 0.0862 |
| C avg(ng/mL) | 0.0409 | 0.0805 | 0.113 | 0.195 |
| AUC 0-τ(hr*ng/mL) | 0.4903 | 0.9658 | 1.358 | 2.343 |
| AUC Eventually(hr*ng/mL) | 0.4085 | 0.7902 | 1.111 | 5.033 |
T
maxrefer to and reach blood plasma buprenorphine concentration stable state C
maxtime.
C
maxrefer to the blood plasma Cmax in stable state.
C
minrefer to the blood plasma Cmin in stable state.
C
avgrefer to the blood plasma mean concentration in stable state.
AUC
0-τrefer to from time m-zero plasma concentration time graph by dosing interval area.
AUC
eventuallyrefer to from time m-zero in the time to final quantitative concentrations the area under Cot curve.
Claims (20)
1. treat a method for chronic pain, described method comprises:
To there being the experimenter who needs to use mucosa-adherent biology erosion property drug delivery device, wherein
Described device administered twice every day, wherein said device comprises the buprenorphine of approximately 100 μ g to about 0.9mg; With
Described device provide approximately 0.1 and about 1.2ng/mL between scope in the stable state C of blood plasma buprenorphine concentration
max, to treat described experimenter's chronic pain.
2. method according to claim 1, wherein said device once-a-day administration.
3. method according to claim 1 and 2, wherein said chronic pain is chronic lumbar and back pain.
4. according to the method described in aforementioned claim any one, wherein said chronic lumbar and back pain is that moderate is to severe chronic lumbar and back pain.
5. according to the method described in aforementioned claim any one, wherein said experimenter receives treatment and without the common opioid untoward reaction of successive what severe.
6. according to the method described in aforementioned claim any one, wherein said experimenter receives treatment, and experience is slight or the common opioid untoward reaction of moderate, or without common opioid untoward reaction.
7. according to the method described in aforementioned claim any one, wherein said patient receives treatment without significance constipation.
8. according to the method described in aforementioned claim any one, wherein said experimenter receives treatment and feels sick without significance.
9. according to the method described in aforementioned claim any one, wherein said experimenter is not tolerance type of opioid.
10. according to the method described in aforementioned claim any one, wherein said experimenter is opioid experience type.
11. according to the method described in aforementioned claim any one, wherein be applied to the freely 200 μ g of total daily dose choosing of described experimenter's buprenorphine, 220 μ g, 240 μ g, 280 μ g, 300 μ g, 320 μ g, 350 μ g, 360 μ g, 400 μ g, 450 μ g, 480 μ g, 500 μ g, 550 μ g, 600 μ g, 620 μ g, 650 μ g, 700 μ g, 720 μ g, 750 μ g, 800 μ g, 860 μ g, 900 μ g, 960 μ g, 1000 μ g, 1100 μ g, 1200 μ g, 1250 μ g, 1300 μ g, 1400 μ g, 1500 μ g, the group of the buprenorphine composition of 1600 μ g and 1800 μ g.
12. according to the method described in aforementioned claim any one, and wherein said device comprises:
Biology erosion property mucosa-adherent layer, it comprises the buprenorphine of the effective dose in the polymer diffusion environment that is arranged at buffering, wherein said polymer diffusion environment is to have approximately 4 and the about buffer environment of the pH between 6.
13. according to the method described in aforementioned claim any one, and wherein said mucosa-adherent biology erosion property drug delivery device further comprises barrier layer, and described barrier layer comprises:
Polymer is stopped to environment approaches described mucosa-adherent layer configuration, thereby the fast effectively transmission of unidirectional gradient for buprenorphine is provided in the time being applied to mucomembranous surface,
Wherein said unidirectional gradient polymer diffusion environment through described buffering in the time being applied to described mucomembranous surface transmits buprenorphine.
14. 1 kinds of treatments suffer from the method for moderate to the experimenter of severe chronic lumbar and back pain, and it comprises:
Oral mucosa surface to described experimenter administered twice every day mucosa-adherent biology erosion property drug delivery device to described experimenter, described device comprises:
Biology erosion property mucosa-adherent layer, it comprises the buprenorphine of the effective dose in the polymer diffusion environment that is arranged at buffering, wherein said polymer diffusion environment is to have approximately 4 and the about buffer environment of the pH between 6;
The total daily dose that is wherein applied to described experimenter's buprenorphine is effective for treatment moderate or severe chronic lumbar and back pain.
15. methods according to claim 14, wherein said device further comprises and is buffered to approximately 4.0 and the about backing layer of the pH between 4.8.
16. 1 kinds of treatments suffer from the experimenter's of neuropathic pain method, and described method comprises:
Oral mucosa surface to described experimenter administered twice every day mucosa-adherent biology erosion property drug delivery device to described experimenter is to treat described experimenter's neuropathic pain, and described device comprises:
Biology erosion property mucosa-adherent layer, it comprises the buprenorphine of the effective dose in the polymer diffusion environment that is arranged at buffering, wherein said polymer diffusion environment is to have approximately 4 and the about buffer environment of the pH between 6.
17. methods according to claim 16, wherein said device further comprises and is buffered to approximately 4.0 and the about backing layer of the pH between 4.8.
18. 1 kinds of treatments suffer from the experimenter's of osteoarthritis pain method, and it comprises:
Oral mucosa surface to described experimenter administered twice every day mucosa-adherent biology erosion property drug delivery device to described experimenter is to treat described experimenter's osteoarthritis pain, and described device comprises:
Biology erosion property mucosa-adherent layer, it comprises the buprenorphine of the effective dose in the polymer diffusion environment that is arranged at buffering, wherein said polymer diffusion environment is to have approximately 4 and the about buffer environment of the pH between 6.
19. methods according to claim 18, wherein said device further comprises and is buffered to approximately 4.0 and the about backing layer between 4.8.
20. according to the method described in claim 1-11 any one, and wherein said device comprises:
Be buffered to approximately 4.0 and the about mucosa-adherent layer that comprises effective dose buprenorphine of the pH between 6.0; With
Be buffered to approximately 4.0 and the about backing layer of the pH between 4.8.
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| US5800832A (en) | 1996-10-18 | 1998-09-01 | Virotex Corporation | Bioerodable film for delivery of pharmaceutical compounds to mucosal surfaces |
| DE19652188C2 (en) * | 1996-12-16 | 2002-02-14 | Lohmann Therapie Syst Lts | Flat drug preparation for application and release of buprenorphine or a pharmacologically comparable substance in the oral cavity and process for its preparation |
| US5968547A (en) * | 1997-02-24 | 1999-10-19 | Euro-Celtique, S.A. | Method of providing sustained analgesia with buprenorphine |
| DE19960154A1 (en) * | 1999-12-14 | 2001-07-12 | Lohmann Therapie Syst Lts | Flat pharmaceutical preparation for transmucosal administration of oxycodone or a comparable active ingredient in the oral cavity, for use in pain therapy and addiction therapy |
| SI2517710T1 (en) * | 2000-02-08 | 2015-07-31 | Euro-Celtique S.A. | Tamper-resistant oral opioid agonist formulations |
| CA2445346C (en) | 2001-04-27 | 2010-04-06 | Ajinomoto Co., Inc. | N-substituted pyrazole-o-glycoside derivatives and therapeutic agent for diabetes containing the same |
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| US20060281775A1 (en) * | 2005-06-14 | 2006-12-14 | Applied Pharmacy Services, Inc. | Two-component pharmaceutical composition for the treatment of pain |
| BRPI0619806A2 (en) | 2005-12-13 | 2011-10-18 | Biodelivery Sciences Int Inc | abuse resistant transmucosal drug delivery device |
| CA2649107A1 (en) | 2006-04-12 | 2007-10-25 | Spinal Motion, Inc. | Posterior spinal device and method |
| EP1897543A1 (en) * | 2006-08-30 | 2008-03-12 | Euro-Celtique S.A. | Buprenorphine- wafer for drug substitution therapy |
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| CA2728912C (en) * | 2008-06-23 | 2018-04-10 | Biodelivery Sciences International, Inc. | Multidirectional mucosal delivery devices and methods of use |
| US8475832B2 (en) | 2009-08-07 | 2013-07-02 | Rb Pharmaceuticals Limited | Sublingual and buccal film compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101511337A (en) * | 2006-07-21 | 2009-08-19 | 生物递送科学国际公司 | Transmucosal delivery devices with enhanced uptake |
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