The invention is directed to liquid formulations containing buprenorphine, a pharmaceutically acceptable salt thereof, or a derivative thereof. The invention is further directed to liquid formulations containing buprenorphine and naloxone, pharmaceutically acceptable salts thereof or derivatives thereof. The invention is further directed to a method of treating pain or opioid dependence by administering liquid formulations containing buprenorphine or buprenorphine and naloxone, pharmaceutically acceptable salts thereof, or derivatives thereof to a patient in need thereof.
Buprenorphine is a semi-synthetic opioid and a partial μ-opioid receptor agonist and has the following structure:
Activation of the μ-opioid receptor leads to antinociception and is the pathway by which opioids such as morphine and fentanyl reduce acute and chronic pain. Buprenorphine has advantages over other opioids such as morphine and fentanyl in that it is only a partial instead of a full agonist of the opioid receptor-like receptor 1 (“ORL1”). Activation of ORL1 has been reported to weaken the analgesic effect induced by the activation of the μ-opioid receptor. Additionally, buprenorphine is an antagonist of δ- and κ-opioid receptors, whose activation has anti-analgesic and psychotomimetic effects, respectively. Buprenorphine is also useful in the management of opioid dependence. The slow binding of buprenorphine to the μ-opioid receptor along with its strong affinity allows for pain management at relatively low blood concentrations and the slow disassociation of buprenorphine from the μ-opioid receptor results in a lack of withdrawal symptoms.
Buprenorphine is currently available in transdermal patches, intravenous injection, tablet and film strip formulations. Commercially available buprenorphine formulations include Butrans® (Butrans is a registered trademark of Purdue Pharma L.P.), a 7 day transdermal patch that releases buprenorphine at 5, 10 or 20 mcg/hr, and Temgesic, a 0.2 mg sublingual tablet, are used for the treatment of chronic pain. Buprenex® (Buprenex is a registered trademark of Reckitt Benckiser Healthcare (UK) Limited) is a 0.3 mg/mL injectable solution used for the treatment of acute pain. Subutex® (Subutex is a registered trademark of Reckitt Benckiser Healthcare (UK) Limited) and Suboxone® (Suboxone is a registered trademark of Reckitt Benckiser Healthcare (UK) Limited) are tablets used in the treatment of opioid dependence. Subutex® is available in 2 mg and 8 mg sublingual doses of buprenorphine. Suboxone® contains both buprenorphine and naloxone in a 4:1 ratio. Suboxone® is available in tablet form in 2 mg and 8 mg doses. Suboxone® is also available in a sublingual film strip formulation that dissolves faster and is not lost by accidental swallowing.
Naloxone has the following structure and is synthesized from thebaine:
Naloxone is most commonly used to treat patients suffering from opioid dependence or overdose because it is a competitive μ-opioid antagonist that blocks the effects of opioids.
While there are various formulations currently available, there exists a need in the art for a liquid (i.e., sublingual or intranasal) spray formulation containing buprenorphine or buprenorphine and naloxone, pharmaceutically acceptable salts thereof, or derivatives thereof. Such a formulation should be safe, be easy to administer, have a high bioavailability, and be storage stable.
In one embodiment, the present invention is directed to a liquid formulation comprising an effective amount of buprenorphine, a pharmaceutically acceptable salt thereof, or a derivative thereof, water as a solvent, and a mixture of an alcohol and a glycol as a cosolvent.
In one embodiment, the present invention is directed to a liquid formulation comprising:
In a preferred embodiment the liquid formulation is in the form of a liquid spray.
In one embodiment, the present invention is directed to a liquid formulation comprising:
In another embodiment, the liquid formulations of the present invention are optionally, in a sublingual spray form, and are capable of producing:
In one embodiment, the present invention is directed to a liquid formulation comprising:
In one embodiment, the present invention is directed to a liquid formulation comprising:
In one embodiment, the present invention is directed to a liquid formulation comprising:
In one embodiment, the present invention is directed to a liquid formulation comprising:
In one embodiment, the present invention is directed to a liquid formulation comprising:
In one embodiment, the present invention is directed to a liquid formulation comprising:
In one embodiment, the present invention is directed to a liquid formulation comprising:
In one embodiment, the present invention is directed to a liquid formulation comprising:
In one embodiment, the present invention is directed to a liquid formulation comprising:
When the application describes the amounts of buprenorphine and naloxone, all the amounts refer to buprenorphine base and naloxone base, respectively, unless otherwise indicated.
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In certain embodiments, the liquid formulations are the liquid spray formulations.
In certain embodiments, the liquid formulations of the present invention contain naloxone in an amount that discourages improper administration of the formulations. When the naloxone containing formulations are properly administered, the naloxone is delivered at a rate that is below that which would be therapeutic. In this context, “therapeutic” refers to an amount of naloxone that would block the effects of the buprenorphine that is concurrently administered in the sublingual spray formulation. If the formulations are improperly used, however, the naloxone in the formulation could be sufficient to block the effects of buprenorphine.
In certain embodiments, the present invention is directed to methods for treating pain comprising administering a liquid formulation of the present invention to a patient.
In certain embodiments, the present invention is directed to methods for treating opioid dependence comprising administering a liquid formulation of the present invention to a patient.
In an embodiment, the present invention is directed to sublingual spray formulations wherein the Cmax (ng/mL) of buprenorphine is from 0.125±0.0203 to 1.57±0.453. In one preferred embodiment, the Cmax (ng/mL) of buprenorphine is 0.76 following sublingual administration. In another preferred embodiment, the Cmax (ng/mL) of buprenorphine is 1.38 following sublingual administration.
In yet another embodiment, the present invention is directed to sublingual spray formulations wherein the Tmax of buprenorphine is from about 0.5 to about 2.0 hours. In a preferred embodiment, the Tmax of buprenorphine is about 1.75 hours following sublingual administration.
In yet another embodiment, the present invention is directed to sublingual spray formulations wherein the Cmax (ng/mL) of buprenorphine is from about 1.2 to about 1.5. In a preferred embodiment, the Cmax (ng/mL) of buprenorphine is about 1.38 following sublingual administration.
In a further embodiment, the present invention is directed to sublingual spray formulations wherein the Tmax of buprenorphine is from about 1.2 to about 1.7 hours. In a preferred embodiment, the Tmax of buprenorphine is about 1.5 hours following sublingual administration.
In a further embodiment, the present invention is directed to sublingual spray formulations wherein the AUC0-T (ng·h/mL) of buprenorphine is from about 2 to about 6 for 0.5 mg dose, and from about 7 to about 11 for 1 mg dose.
In a further embodiment, the present invention is directed to sublingual spray formulations wherein the AUC0-∞ (ng·h/mL) of buprenorphine is from about 2 to about 6 for 0.5 mg dose, and from about 7 to about 11 for 1 mg dose.
In a further embodiment, the present invention is directed to sublingual spray formulations wherein the AUCinf (h*ng/mL) of buprenorphine is from 0.6387±0.1844 to 11.36±3.153.
In a further embodiment, the present invention is directed to sublingual spray formulations wherein the Cmax (ng/mL) of naloxone is from 4.26±2.52 to 12.0±5.38
In a further embodiment, the present invention is directed to sublingual spray formulations wherein the Tmax of naloxone is from about 1.17 to about 1.40 hours following administration.
In a further embodiment, the present invention is directed to sublingual spray formulations wherein the AUCinf (h*ng/mL) of naloxone is from 11.87±3.903 to 36.22±10.45.
In another embodiment, the present invention is directed to sublingual spray formulations wherein greater than 98% of the formulation particles are greater than 10 microns in diameter during administration.
In another embodiment, the present invention is directed to sublingual spray formulations wherein the mean Dv(10) is from about 10 to about 40 microns during administration.
In another embodiment, the present invention is directed to sublingual spray formulations wherein the mean Dv(50) is from about 30 to about 80 microns during administration.
In another embodiment, the present invention is directed to sublingual spray formulations wherein the mean Dv(90) is from about 80 to about 200 microns during administration.
In a further embodiment, the present invention is directed to sublingual spray formulations that when administered provide a spray plume ovality ratio of from about 1.1 to 2.4.
In yet another embodiment, the invention is directed to sublingual formulations that when administered provide a plume width of from about 25 to about 45 millimeters.
In a further embodiment, the invention is directed to sublingual formulations that when administered provide a plume angle of from about 30 to about 55 degrees.
In yet another embodiment, the invention is directed to sublingual formulations that when administered provide a D(4,3) of 55 to 95 microns.
In an additional embodiment, the invention is directed to sublingual formulations that when administered provide a spray span ((Dv90−Dv10)/Dv50) of from about 1.2 to about 3.3.
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
The present invention is directed to a liquid formulation comprising an effective amount of buprenorphine or buprenorphine and naloxone, pharmaceutically acceptable salts thereof, or derivatives thereof. The present invention further relates to a method of treating pain or opioid dependence by administering an effective amount of a liquid formulation of the present invention to a patient in need thereof.
The present invention is further directed to a liquid formulation comprising an effective amount of buprenorphine or buprenorphine and naloxone, pharmaceutically acceptable salts thereof, or derivatives thereof, a solvent, a cosolvent and an antioxidant.
Applicants developed new liquid buprenorphine and buprenorphine/naloxone formulations that unexpectedly are storage stable, safe and effective. Specifically, Applicants were surprised that the formulations were stable at high temperatures (40 degrees Celsius) for an extended period of time (see Examples 1 and 2 below). Further, Applicants unexpectedly found that the formulations provided a quick onset of action and bioavailability (as demonstrated by pharmacokinetic studies, see Example 3 below). The formulations upon administration exhibit excellent droplet size distribution, as well.
As used herein the term “patient” refers but is not limited to a person that is being treated for pain, opioid dependence or another affliction or disease that can be treated with buprenorphine.
As used herein the term “pharmaceutically acceptable” refers to ingredients that are not biologically or otherwise undesirable in a sublingual dosage form.
As used herein the term “effective amount” refers to the amount necessary to treat a patient in need thereof.
As used herein the term “liquid” refers to a sublingual, intranasal or otherwise administered through a mouth or a nose formulation.
As used herein the term “sublingual” refers to administration of a substance via the mouth in such a way that the substance is rapidly absorbed via the blood vessels under the tongue.
As used herein the term “intranasal” refers to administration of the composition to any portion of the nasal epithelium.
Pharmaceutically acceptable salts that can be used in accordance with the current invention include but are not limited to hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
In preferred embodiments the pharmaceutically acceptable salt is hydrochloride.
Derivatives of buprenorphine that can be used in accordance with the current invention include but are not limited norbuprenorphine, thenorphine, demethoxybuprenorphine and esters and diastereomers of buprenorphine.
The solvent used with the present invention is United States Pharmacopeia (“USP”) purified water.
Cosolvents that can be used in accordance with the current invention are alcohols, and glycols or a mixture thereof.
Alcohols that can be used in accordance with the current invention include but are not limited to methanol, ethanol, propyl alcohol, and butyl alcohol.
Glycols that can be used in accordance with the current invention include but are not limited to propylene glycol, butylene glycol and polyethylene glycols such as PEG 200 and PEG 400 and the like.
In preferred embodiments the cosolvent is ethanol or propylene glycol or a mixture thereof.
In more preferred embodiments the amount of cosolvent included in the formulation is from about 5% to about 90% w/w.
In other more preferred embodiments the amount of cosolvent included in the formulation is from about 2 to about 10% propylene glycol. In a most preferred embodiment the amount of cosolvent is about 5% w/w propylene glycol.
In other more preferred embodiments the amount of cosolvent included in the formulation is about 40% w/w to about 60% w/w ethanol. In a most preferred embodiment the amount of cosolvent is about 55% w/w ethanol.
In other more preferred embodiments the cosolvent is a mixture of propylene glycol at about 5% w/w and ethanol at about 55% w/w.
Solubilizers that can be used in accordance with the current invention are hydroxpropyl beta-cyclodextrin (“HPβCD”) and sulfobutylether cyclodextrin or a mixture thereof.
In preferred embodiments the solubilizer is HPβCD.
In more preferred embodiments the amount of HPβCD is from about 10% w/w to 40% w/w. In a most preferred embodiment the amount of HPβCD is about 30% w/w.
Antioxidants that can be used in accordance with the current invention include but are not limited to butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), methionine, sodium ascorbate, sodium thiosulfate and thioglycerol, cysteine hydrochloride monohydrate or a mixture thereof.
In preferred embodiments the amount of antioxidant included in the formulation is from about 0.001% to about 0.05% w/w.
In more preferred embodiments the amount of antioxidant is about 0.01% w/w of BHA.
In other more preferred embodiments the antioxidant is a mixture of about 0.01% w/w of BHA and about 0.005% w/w of BHT.
In other more preferred embodiments the antioxidant is about 0.01% w/w of sodium thiosulfate.
In other more preferred embodiments the antioxidant is about 0.02% w/w of sodium ascorbate.
Permeation enhancers that can be used in accordance with the current invention include but are not limited to menthol, Tween® 80 (Tween is a registered trademark of Uniqema Americas, LLC), sodium lauryl sulfate, glyceryl oleate, oleic acid, cetylpyridium chloride, and sodium desoxy cholate.
In preferred embodiments the amount of permeation enhancer is from about 0.001% to about 0.1% w/w.
In more preferred embodiments the amount of permeation enhancer is about 0.05% w/w of menthol.
Chelating agents that can be used in accordance with the present invention include but are not limited to ethylenediaminetetraacetic acid disodium (“disodium edetate” or edetate disodium dihydrate”).
In preferred embodiments the amount of disodium edetate is about 0.005% to about 0.01% w/w.
Formulations of the present invention may have a pH range from about 3.0 to about 7.0, preferably from about 3.5 to about 5.5 and more preferably from about 3.8 to about 5.1. pH adjustors that can be used in accordance with the present invention include but are not limited to citric acid, sodium hydroxide and a mixture thereof. In preferred embodiments the amount of citric acid is from about 2% to about 20% w/w. In more preferred embodiments the amount of citric acid is about 15%. In other more preferred embodiments the amount of citric acid is about 10%.
As used herein, all numerical values relating to amounts, weights, and the like, that are defined as “about” each particular value is plus or minus 10%. For example, the phrase “about 10% w/w” is to be understood as “9% to 11% w/w.” Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims.
As used herein “% w/w” refers to the percent weight of the total formulation.
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the present invention is directed to a sublingual spray formulation comprising:
In one embodiment, the sublingual spray formulation comprises:
In one embodiment, the sublingual spray formulation comprises:
In one embodiment, the sublingual spray formulation comprises:
In one embodiment, the sublingual spray formulation comprises:
In one embodiment, the sublingual spray formulation comprises:
an amount of buprenorphine of about 8.602% w/w;
an amount of naloxone of about 2.44% w/w;
an amount of water of about 29% w/w;
an amount of sodium thiosulfate of about 0.01% w/w; and
an amount of citric acid of about 0.0025% w/w.
In one embodiment, the sublingual spray formulation comprises:
an amount of buprenorphine of about 8.602% w/w;
an amount of naloxone of about 2.44% w/w;
an amount of water of about 29% w/w;
an amount of sodium thiosulfate of about 0.01% w/w; and
an amount of disodium edetate of about 0.005% w/w.
In one embodiment, the sublingual spray formulation comprises:
In one embodiment, the sublingual spray formulation comprises:
an amount of buprenorphine of about 8.602% w/w;
an amount of naloxone of about 2.44% w/w;
an amount of water of about 29% w/w;
an amount of sodium ascorbate of about 0.02% w/w; and
an amount of disodium edetate of about 0.005% w/w.
In one embodiment, the sublingual spray formulation comprises:
an amount of buprenorphine of about 8.39% w/w;
an amount of naloxone of about 2.37% w/w;
an amount of water of about 29% w/w;
an amount of ethanol of about 55% w/w;
an amount of propylene glycol of about 5% w/w;
an amount of sodium ascorbate of about 0.02% w/w;
an amount of disodium edetate of about 0.005% w/w; and
an amount of menthol of about 0.05% w/w.
In one embodiment, the sublingual spray formulation comprises:
an amount of buprenorphine of about 5.554% w/w;
an amount of naloxone of about 1.57% w/w;
an amount of water of about 33% w/w;
an amount of ethanol of about 55% w/w;
an amount of propylene glycol of about 5% w/w;
an amount of sodium ascorbate of about 0.02% w/w;
an amount of disodium edetate of about 0.005% w/w; and
an amount of menthol of about 0.05% w/w.
In one embodiment, the sublingual spray formulation comprises:
an amount of buprenorphine of about 2.84% w/w;
an amount of naloxone of about 0.804% w/w;
an amount of water of about 36% w/w;
an amount of ethanol of about 55% w/w;
an amount of propylene glycol of about 5% w/w;
an amount of sodium ascorbate of about 0.02% w/w;
an amount of disodium edetate of about 0.005% w/w; and
an amount of menthol of about 0.05% w/w.
In one embodiment, the sublingual spray formulation comprises:
an amount of buprenorphine of about 1.42% w/w;
an amount of naloxone of about 0.402% w/w;
an amount of water of about 38% w/w;
an amount of ethanol of about 55% w/w;
an amount of propylene glycol of about 5% w/w;
an amount of sodium ascorbate of about 0.02% w/w;
an amount of disodium edetate of about 0.005% w/w; and
an amount of menthol of about 0.05% w/w.
In one embodiment, the sublingual spray formulation comprises:
In one embodiment, the spray formulation comprises:
In one embodiment, the spray formulation comprises:
The following examples are intended to illustrate the present invention and to teach one of ordinary skill in the art how to make and use the invention. They are not intended to be limiting in any way.
Method of Making the Formulations
Sublingual spray formulations were created by first degassing ethanol and USP purified water, separately. Next, the ethanol and purified water were each purged with nitrogen. Soluble excipients were then dissolved in either the ethanol or the purified water based on their solubility. Next, the solutions were combined. Active pharmaceutical ingredient/s was/were added to the final solution and mixed until dissolved.
Formulations
Stability Data
The formulations listed in Table 1 were subject to stability test at 40° C.±2° C. under 75%±5% relative humidity for six months. Stability data was collected at zero, and six months. Assay and impurities were detected using high performance liquid chromatography with an ultraviolet detector. The assay was performed at 288 nm and indicated as a % of initial concentration. For all impurities, analysis was performed at 240 nm and expressed as a % area. Amounts of particular impurities are listed in Table 2 as a percentage of the area of each formulation along with amount of total impurities.
Sublingual buprenorphine spray formulations contained less than one percent total impurities after six months at 40° C. Control and formulations 1, 3, 4, 5, 6, 8 and 9 showed significant increase in levels of individual impurities (impurity B, impurity G, bisalkyl or unspecified impurity) at the 6 month time point whereas formulations containing BHA and BHT (#2) or sodium thiosulfate (#7) showed good stability. pH also played a role in the stability of the product. These results represent sublingual buprenorphine spray formulations that would remain stable for two years at room temperature.
Method of Making the Formulations
Sublingual spray formulations were created by first degassing ethanol and USP purified water, separately. Next, the ethanol and purified water were each purged with nitrogen. Soluble excipients were then dissolved in either the ethanol or the purified water based on their solubility. Next, the solutions were combined. Buprenorphine and naloxone were added to the final solution and mixed until dissolved.
The formulations listed in Table 3 were subject to stability test at 40° C.±2° C. under 75%±5% relative humidity for three months and at ±25° C. under 60%±5% relative humidity for three months. Stability data was collected at zero, one, two and three months at 40° C. and at zero, one and three months at 25° C. Assay and impurities were detected using high performance liquid chromatography with an ultraviolet detector. Buprenorphine assay was performed at 288 nm and indicated as a % of initial concentration. For all buprenorphine impurities, analysis was performed at 240 nm and expressed as a % area. Naloxone assay was performed at 280 nm and indicated as a % of initial concentration and for all naloxone impurities, analysis was performed at 230 nm. Amounts of particular impurities are listed in Tables 4 and 5 for 40° C. and in Table 6 for 25° C. as a percentage of the area of each formulation along with amount of total impurities. Relative retention time (“RRT”) is given for each impurity.
The control formulation for the buprenorphine/naloxone sublingual spray formulation contained greater than 1% impurities of both buprenorphine and naloxone within one month at 40° C. and between about 4% and about 5% at three months.
All formulations had less than 1% total impurities at three months. Similar to the buprenorphine only formulations in Example 1, formulations containing sodium thiosulfate (#10 and #11) were exceptionally stable with no impurities after three months. Formulation #12 contains BHA and BHT as the antioxidant and had significant impurities of naloxone (0.26% total impurities). Formulation #13 contains sodium ascorbate and had no impurities of buprenorphine and 0.09% total impurities of naloxone. These results represent sublingual spray formulations that would remain stable for one year at room temperature.
The control formulation had greater than 1% impurities at three months. All formulations containing antioxidants had less than 1% total impurities at three months. Similar to the buprenorphine only formulations in Example 1, formulations containing sodium thiosulfate (#10 and #11) or a mixture of BHA and BHT (#12) were exceptionally stable with no impurities after three months. Formulation #13 which contains sodium ascorbate had no impurities of buprenorphine and 0.11% total impurities of naloxone after storage at 25° C.±2° C./75%±5% relative humidity.
A study was designed and executed to determine the pharmacokinetics of buprenorphine sublingual spray formulations of the present invention after administration in healthy volunteers under fasting conditions.
The study was a single center, single dose, open-label, 1-sequence, 2-period, ascending dose study design in twelve healthy male and female subjects. The following dose levels of the investigational product were administered under fasting conditions: Dose 1: A single 0.5 mg dose (1 spray of 100 microliters) of Buprenorphine 5 mg/mL Sublingual Spray; and Dose 2: A single 1.0 mg dose (2 sprays of 100 microliters) of Buprenorphine 5 mg/mL Sublingual Spray.
The subjects arrived at the clinical site more than 10 hours before the buprenorphine administration. The subjected were supervised overnight (while fasting) and a single 50 mg dose of naltrexone (1×50 mg tablet) was orally administered with 240 mL of water approximately 1 hour prior to the buprenorphine administration to provide blockade of the pharmacological effects of buprenorphine. Then, a single dose (0.5 mg in period 1 and 1.0 mg in period 2) of the buprenorphine formulation was sublingually administered in the morning. Subjects were allowed to leave the clinical site after the 24-hour post-dose blood draw and returned to the clinical site before the remaining blood sample. The second dose level was administered following favorable safety review. The buprenorphine administrations were separated by a wash-out of 14 calendar days. The parameters are summarized below in Table 7.
As seen in Table 7, the Cmax obtained for buprenorphine were 0.761 ng/mL and 1.38 ng/mL. The Tmax observed for buprenorphine was 1.75 and 1.50 hours following the ascending doses.
A study was designed and executed in order to compare the rate and extent of absorption and bioavailability of 1 mg buprenorphine sublingual spray formulations of the present invention with 0.3 mg (1 mL) Buprenex® (buprenorphine HCl) intramuscular injection and 0.3 mg (1 mL) Buprenex® (buprenorphine HCl) intravenous bolus injection.
This was an open-label, 3-treatment, 3-period, 6-sequence, single-dose, randomized crossover study. Eighteen healthy male and female volunteers were randomly assigned to 1 of 6 treatment sequences. Dosing occurred after an overnight fast and there was a minimum 14-day washout between the dosing in two periods. Blood samples for the measurement of the plasma concentrations of buprenorphine were collected before (pre-dose) and at 5, 10, 20, 30, and 40 minutes and at 1, 1.25, 1.5, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 144 hours after dosing. The results of this study are summarized below in Table 8.
The absolute bioavailability of buprenorphine, based on AUC(0-t) and AUC(inf), after sublingual administration was 41.03% and 42.57%, respectively.
A challenge of creating a buprenorphine sublingual spray formulation is that it must be capable of producing spray droplets that are over 10 microns in diameter. Spray droplets 10 microns or smaller could be inhaled into the lungs. The optimal particle size for sublingual spray droplets is from 20 to about 200 microns in diameter. It is desirable for the formulation to have droplet sizes near 20 because this increases the surface area and increased surface area exposure is one factor that contributes to a high bioavailability. Sublingual formulations should be able to maintain a consistent droplet size throughout its shelf life. Applicants found during testing that formulations of the present invention yielded desirable droplet sizes for sublingual administration. The testing also revealed that the formulation dose remains consistent when administered with a spray pump.
Five milligram per mL buprenorphine spray formulations of the present invention were subjected to two different storage conditions (25 and 40 degrees C.) and samples were taken at two different times (5M and 6M) for spray droplet size distribution analysis. Droplet analysis was conducted using standard laser analysis procedures known by those of skill in the art.
Droplet size distribution (Dv10, Dv50, Dv90, percent droplets less than 10 micrometers in diameter, D(4,3) and Span tested at two distances, 3 cm and 6 cm for upright and horizontal samples stored at 25 and 40 degrees C.) and spray pattern (Dmin, Dmax and ovality ratio tested at two distances, 3 cm and 6 cm for upright and horizontal samples stored at 25 and 40 degrees C.) were determined. D(4,3) refers to the volume moment mean of the particles; Dv10 refers to droplet size for which 10% of the total volume is obtained; Dv50 refers to droplet size for which 50% of the total volume is obtained; Dv90 refers to droplet size for which 90% of the total volume is obtained; Span refers to distribution span (Dv90−Dv10)/Dv50; DSD refers to droplet size distribution; the temperature listed is the storage temperature; U refers to an upright position of the spray pump; and H refers to horizontal position of the spray pump. The results of these studies can be seen below in Tables 9 to 40.
In addition, the formulations were tested for plume geometry including width and angle using standard procedures known by those of skill in the art. This testing showed that the spray pattern and plume were acceptable for formulations of the present invention. The results of these studies can be seen below in Tables 41 and 42.
Formulations #15, #16 and #17 are used in the clinical trial listed as Example 8 for acute pain indication, whereas formulations #14, #15, #16, #17 and #18 will be used in chronic pain indication.
Formulations #14, #15, #16, #17 and #18 represent 0.0625 mg, 0.125 mg, 0.25 mg, 0.5 mg and 1 mg doses, respectively. (Equivalent to buprenorphine base).
Buprenorphine formulations of Table 43 were all stable upon preparation.
Buprenorphine/naloxone formulations of Table 44 were all stable upon preparation.
This was a multicenter, randomized, double-blind, multiple-dose, placebo-controlled study evaluating the efficacy and safety of three dosing regimens of Buprenorphine Sublingual Spray (0.5 mg (formulation #17) three times daily (“tid”), 0.25 mg (formulation #16) tid, or 0.125 mg (formulation #15) tid), and/or matching placebo in subjects with moderate to severe postoperative pain after bunionectomy. 322 subjects were randomized. 298 subjects completed the study, and 24 discontinued for various reasons (9 to lack of efficacy; 14 due to nausea and emesis; and 1 for non-related hypotension); and one lost to follow-up.
The study lasted four months and comprised 4 periods: The Screening Period (Days −28 to −1), the Surgical Period (Day 0), the Treatment Period (48 hours; Days 1 to 3) and the Follow-up Period (Days 5 to 9).
The measurements of pain intensity and pain relied were conducted at Time 0 (i.e., at 5, 15, 30, and 45 minutes, and 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12, 16, 20, 24, 32, 40, and 48 hours).
As agreed with the U.S. Food and Drug Administration (“FDA”), the primary efficacy endpoint in this study was the Summed Pain Intensity Difference relative to baseline over a period of 48 hours (SPID-48). The patient assessment of pain intensity utilized a numeric pain scale (11-point scale with 0=no pain to 10=worst possible pain).
The secondary variables were as follows:
The disposition of subjects is depicted in the flow chart in
Results
The primary efficacy endpoint was statistically significant at all doses studied. The Buprenorphine Sublingual Spray 0.5 mg tid demonstrated the largest reduction in SPID-48 and was statistically significant to placebo (p<0.0001). The 0.25 mg tid and 0.125 mg tid doses also demonstrated statistically significant reductions in SPID-48 (p=0.0108 and p=0.0120, respectively). All treatments were generally well tolerated.
Table 45 below describes NRS SPID over 0 to 48 hours (NRS SPID-48) for intention-to-treat (ITT) population.
aLeast square means, standard errors(SE), confidence interval(CI) and p-values are from an ANCOVA model with factors for treatment, site and baseline pain intensity.
Table 46 below describes NRS SPID over 0 to 24 hours (NRS SPID-24) for ITT population.
aLeast square means, standard errors(SE), confidence interval(CI) and p-values are from an ANCOVA model with factors for treatment, site and baseline pain intensity.
Table 47 below describes NRS SPID over 0 to 8 hours (NRS SPID-8) for ITT population.
aLeast square means, standard errors(SE), confidence interval(CI) and p-values are from an ANCOVA model with factors for treatment, site and baseline pain intensity.
Table 48 below describes NRS SPID over 0 to 4 hours (NRS SPID-4) for ITT population.
aLeast square means, standard errors(SE), confidence interval(CI) and p-values are from an ANCOVA model with factors for treatment, site and baseline pain intensity.
Table 49 shows time of onset analgesia for investigator initiated trials (IIT) population.
aPercentile estimates and confidence intervals (CI) are from a Kaplan-Meier analysis.
bP-value from a log-rank test of each treatment arm vs. placebo
Table 50 is a representation of mean pain intensity differences by timepoint.
The conclusions are as follows:
The largest pain reduction (NRS SPID-48) was observed for the 0.5 mg TID BSS group.
Statistically significantly larger reductions in NRS SPID-48 compared to placebo for the 0.5 mg TID BSS p-value: <0.0001. The largest reduction in NRS SPID-48 compared to placebo was observed for the 0.5 mg TID BSS treatment group.
Largest pain reductions (NRS SPID-4, NRS SPID-8, and NRS SPID-24) were observed for 0.5 mg TID BSS group (p-value: <0.0001). Secondary time points at 4, 8 and 24 hours SPID were all statistically significantly different.
Objective
The primary objective of this study was to compare the bioavailability of a test formulation of Buprenorphine-Naloxone Sublingual (SL) spray, 6.5 mg/1.63 mg (1 spray) to that of a single dose of Suboxone® (buprenorphine and naloxone) sublingual film, 12 mg/3 mg, under fasted conditions. The secondary objective was to evaluate the safety and tolerability of Buprenorphine-Naloxone SL spray.
Study Design
This was a single-dose, open-label, randomized, two-period, two-treatment crossover study. Fifty-six healthy subjects were enrolled. Subjects who successfully completed the screening process checked into the research center the evening before first dose. Subjects who continued to meet inclusion/exclusion criteria the morning of dose were assigned a subject number, based on the order in which they successfully completed the screening process and procedures as outlined in the study protocol. Subjects were randomly assigned to a treatment sequence and received two separate single-dose administrations of study medication, one treatment per period, according to the randomization schedule. Dosing days were separated by a washout period of at least 14 days.
Subjects received each of the treatments listed below during the two treatment periods:
Treatment A: Test Product
Buprenorphine Naloxone SL spray, 6.5 mg/1.63 mg
Dose=1 sublingual spray (total dose 6.5 mg/1.63 mg)
Treatment B: Reference Product
Suboxone® (buprenorphine and naloxone) sublingual film, 12 mg/3 mg
Dose=1×12 mg/3 mg sublingual film
Clinical Procedures Summary
During each study period, 6 mL blood samples were obtained for buprenorphine, norbuprenorphine, and unconjugated naloxone analysis before and after each dose at selected times through 144 hours after dose administration. A total of 34 pharmacokinetic (PK) blood samples were collected from each subject for buprenorphine, norbuprenorphine, and unconjugated naloxone, 17 samples in each study period. In addition, 6 mL blood samples were obtained for total naloxone analysis before and after each dose at selected times through 72 hours after dose administration. A total of 28 PK blood samples were collected from each subject for naloxone analysis, 14 samples in each study period.
Blood samples (1×6 mL) for buprenorphine, norbuprenorphine, and unconjugated naloxone analysis were collected at 0 (predose), and at 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, and 144 hours.
Blood samples (1×6 mL) for total naloxone analysis were collected at 0 (predose), and at 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, and 72 hours.
Plasma samples were analyzed for buprenorphine, norbuprenorphine, unconjugated naloxone, and total naloxone by Worldwide Clinical Trials (WCT) using validated LC-MS-MS procedures. The methods were validated for ranges of 20.0 to 10,000 pg/mL for buprenorphine and norbuprenorphine and 2.00 to 1000 pg/mL for unconjugated naloxone, based on the analysis of 1.00 mL of human EDTA plasma, and 0.0500 to 50.0 ng/mL for total naloxone, based on the analysis of 0.200 mL of human EDTA plasma. Data were stored in Watson Laboratory Information Management System (LIMS; Version 7.2.0.03, Thermo Fisher Scientific).
Concentration-time data were analyzed using noncompartmental methods in Phoenix™ WinNonlin® (Version 6.3, Pharsight Corporation). Concentration-time data that were below the limit of quantification (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”. Actual sample times were used in the pharmacokinetic analysis. The linear trapezoidal method was used to calculation the area under the curve (AUC).
The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λz), terminal half-life (T1/2), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), area under the plasma concentration time curve from time-zero extrapolated to infinity (AUCinf), the percent of AUCinf based on extrapolation (AUCextrap), last quantifiable plasma concentration (Clast), and time of the last quantifiable plasma concentration (Tlast). In addition, partial AUCs AUC0-72, AUC0-96, AUC0-120, and AUC0-144 were estimated for buprenorphine and unconjugated naloxone to provide information regarding systemic exposure at different times during the extended pharmacokinetic sampling interval.
Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-test procedure at the 5% significance level were applied to the log-transformed pharmacokinetic exposure parameters, Cmax, AUClast, and AUCinf for buprenorphine, norbuprenorphine, unconjugated naloxone, and total naloxone. The ratio of the geometric means (Insys Sublingual Spray-Test/Suboxone Sublingual Film-Reference) was reported along with the 90% confidence interval about the ratio. For informational purposes, AUC0-72, AUC0-96, AUC0-120, and AUC0-144 for buprenorphine and unconjugated naloxone were compared across treatments using an analogous statistical method.
Data from 50 subjects who completed at least one study period were included in the pharmacokinetic and statistical analyses. Mean concentration-time data are shown in Tables 51 through 54. Results of the pharmacokinetic and statistical analyses are shown below in Tables 55 through 64.
Buprenorphine
Overall, the pharmacokinetic profile of buprenorphine after the administration of Buprenorphine Naloxone SL spray, 6.5 mg/1.63 mg was similar to that after the administration of Suboxone Sublingual Film 12 mg/3 mg. From the mean buprenorphine concentration-time profiles, the concentrations achieved after the Sublingual Spray were comparable to those after Suboxone, even though a much lower Sublingual Spray dose was administered (6.5 mg in Sublingual Spray vs. 12 mg in Suboxone). At early time points and through approximately 24 hours, the mean buprenorphine concentration-time profiles were practically superimposable for the two treatments; at latter time points, minor differences were noted, with the mean buprenorphine concentrations after the Sublingual Spray being slightly lower than those after Suboxone. These trends were reflected in the derived pharmacokinetic parameters. No appreciable differences were noted in the mean buprenorphine Cmax across treatments (5670±1590 pg/mL after Sublingual Spray, 6210±3110 pg/mL after Suboxone). No appreciable differences were noted in the mean±SD buprenorphine AUC0-72, AUC0-96, AUC0-144, AUClast, and AUCinf. For example, mean AUClast was 46660±12980 h*pg/mL after Sublingual Spray and 56100±21460 h*pg/mL after Suboxone. Due to the extended pharmacokinetic sampling interval used in this study, AUC to the last quantifiable sample (AUClast) provided a reasonable estimate of the overall systemic exposure (AUCinf, extrapolated to infinity). Mean AUCs values were 48790±13810 h*pg/mL after Sublingual Spray and 59240±22500 h*pg/mL after Suboxone. On average, only 4.27 to 5.28% of AUCinf was based on extrapolation.
It should be noted that some degree of pharmacokinetic variability was observed, in particular for Suboxone relative to that for the Sublingual Spray; the intersubject variability (CV %) for Cmax and AUCs ranged from 27.81 to 28.31% for the Sublingual Spray and 37.98 to 50.02% for Suboxone. It was also noted that a differential location shift existed between the mean and median AUC values for Suboxone; the mean AUClast and AUCinf values for Suboxone were higher than the median, suggesting that the data were skewed toward the upper range. The differential distribution of the AUCinf values between the two treatments may have contributed to the ANOVA results for this metric (discussed below).
From the statistical analysis log-transformed pharmacokinetic parameters using an ANOVA model, the geometric mean ratios (90% confidence interval) for buprenorphine Cmax, AUClast, and AUCinf were 96.01% (88.29, 104.42%), 86.11% (80.44, 92.18%), and 85.19% (79.64, 91.12%), respectively. The ANOVA results for buprenorphine AUC0-72, AUC0-96, AUC0-120, and AUC0-144 were 88.40% (82.59, 94.62%), 87.37% (81.68, 93.46%), 86.75% (81.12, 92.77%), and 86.31% (80.72, 92.29%), respectively. Hence, based on actual data over the 144-hour sampling interval (and over truncated intervals through 72, 96, 120 and 144 hours), bioequivalence criteria were met for buprenorphine in comparisons of the Sublingual Spray to Suboxone. The lower 90% confidence interval for the extrapolated AUC (AUCinf) was 79.64%, 0.36% below the standard bioequivalence limit (80.00%) using the two one-sided tests procedure.
Norbuprenorphine
Exposure to norbuprenorphine differed across treatments. Based on mean estimates of Cmax and AUCs, exposure to norbuprenorphine was 2- to 2.6-fold lower after the Sublingual Spray relative to Suboxone, possibly due to increased direct absorption into systemic circulation and lower presystemic, first-pass metabolism for the Sublingual Spray.
Unconjugated Naloxone
Overall, the pharmacokinetic profile of unconjugated naloxone after the administration of Buprenorphine Naloxone SL spray, 6.5 mg/1.63 mg was similar to that after the administration of Suboxone Sublingual Film 12 mg/3 mg. Based on mean estimates of Cmax and AUCs, exposure to unconjugated naloxone was comparable across treatments. Mean Cmax was 379±211 pg/mL after Sublingual Spray and 356±149 pg/mL after Suboxone; mean AUClast was 887.6±445.4 h*pg/mL after Sublingual Spray and 942.0±430.1 h*pg/mL after Suboxone. AUCinf were similar to AUClast values; due to the relatively short T1/2 of unconjugated naloxone (approximately 3 to 4 hours), only 2.18 to 2.41% of AUCinf was based on extrapolation.
From the statistical analysis log-transformed pharmacokinetic parameters using an ANOVA model, the geometric mean ratios (90% confidence interval) for unconjugated naloxone Cmax, AUClast, and AUCinf were 103.72% (93.78, 114.71%), 94.95% (86.93, 103.72%), and 94.69% (86.79, 103.31%), respectively. The ANOVA results for unconjugated naloxone AUC0-72, AUC0-96, AUC0-120, and AUC0-144 were comparable to those for AUClast and AUCinf. Hence, bioequivalence criteria were met for all pharmacokinetic metrics considered in the analysis.
Total Naloxone
Exposure to total naloxone differed across treatments. Based on mean estimates of Cmax and AUCs, exposure to total naloxone was approximately 2-fold lower after the Sublingual Spray relative to Suboxone, possibly due to increased direct absorption into systemic circulation and lower presystemic, first-pass metabolism/glucuronidation for the Sublingual Spray.
Conclusions
Overall, the pharmacokinetic profile of buprenorphine after the administration of Buprenorphine Naloxone SL spray, 6.5 mg/1.63 mg was similar to that after the administration of Suboxone Sublingual Film 12 mg/3 mg. No significant differences in Cmax and AUCs over the 144-hour pharmacokinetic sampling period were observed and bioequivalence criteria (90% confidence intervals within 80.00-125.00%) were met for the AUC at 72 hours (82.6%-94.6%), 96 hours (81.7%-93.5%), 120 hours (81.1%-92.8%), and 144 hours (80.7%-92.3%) postdose. The lower 90% confidence interval for the extrapolated AUC (AUCinf) was 79.64%, 0.36% below the bioequivalence limit of 80.00%. Therefore, based on data acquired over an extended sampling period (144 hours or 6 days), Buprenorphine Naloxone SL spray, 6.5 mg/1.63 mg is considered essentially bioequivalent to Sublingual Film 12 mg/3 mg.
The pharmacokinetic profile of unconjugated naloxone after the administration of Buprenorphine Naloxone SL spray, 6.5 mg/1.63 mg was similar to that after the administration of Suboxone Sublingual Film 12 mg/3 mg. No significant differences in Cmax and AUCs were observed and bioequivalence criteria (90% confidence intervals within 80.00-125.00%) were met for all pharmacokinetic metrics considered in the analysis.
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
The primary objective of this study was to compare the bioavailability of a test formulation of Buprenorphine-Naloxone Sublingual (SL) spray, 2.2 mg/0.55 mg (1 spray) to that of a single dose of Suboxone (buprenorphine and naloxone) sublingual film, 4 mg/1 mg, under fasted conditions. The secondary objective was to evaluate the safety and tolerability of Buprenorphine-Naloxone SL spray.
This was a single-dose, open-label, randomized, two-period, two-treatment crossover study. Fifty-six healthy subjects were enrolled. Subjects who successfully completed the screening process checked into the research center the evening before first dose. Subjects who continued to meet inclusion/exclusion criteria the morning of dose were assigned a subject number, based on the order in which they successfully completed the screening process and procedures as outlined in the study protocol. Subjects were randomly assigned to a treatment sequence and received two separate single-dose administrations of study medication, one treatment per period, according to the randomization schedule. Dosing days were separated by a washout period of at least 14 days.
Subjects received each of the treatments listed below during the two treatment periods:
Treatment A: Test Product
Buprenorphine Naloxone SL spray, 2.2 mg/0.55 mg
Dose=1 sublingual spray (total dose 2.2 mg/0.55 mg)
Treatment B: Reference Product
Dose=1×4 mg/1 mg sublingual film
During each study period, 6 mL blood samples were obtained for buprenorphine, norbuprenorphine, and unconjugated naloxone analysis before and after each dose at selected times through 168 hours after dose administration. A total of 36 pharmacokinetic (PK) blood samples were collected from each subject for buprenorphine, norbuprenorphine, and unconjugated naloxone, 18 samples in each study period. In addition, 6 mL blood samples were obtained for total naloxone analysis before and after each dose at selected times through 72 hours after dose administration. A total of 28 PK blood samples were collected from each subject for naloxone analysis, 14 samples in each study period.
Blood samples (1×6 mL) for buprenorphine, norbuprenorphine, and unconjugated naloxone analysis were collected at 0 (predose), and at 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, 72, 96, 120, 144, and 168 hours post dose (18 time points).
Blood samples (1×6 mL) for total naloxone analysis were collected in Vacutainer tubes containing K2-EDTA as a preservative at 0 (predose), and at 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 36, 48, and 72 hours (14 time points).
Bioanalytical Summary
Plasma samples were analyzed for buprenorphine, norbuprenorphine, unconjugated naloxone, and total naloxone by Worldwide Clinical Trials (WCT) using validated LC-MS-MS procedures. The methods were validated for ranges of 20.0 to 10,000 pg/mL for buprenorphine and norbuprenorphine and 2.00 to 1000 pg/mL for unconjugated naloxone, based on the analysis of 1.00 mL of human EDTA plasma, and 0.0500 to 50.0 ng/mL for total naloxone, based on the analysis of 0.200 mL of human EDTA plasma. Data were stored in Watson Laboratory Information Management System (LIMS; Version 7.2.0.03, Thermo Fisher Scientific). Details of the method validation and sample analysis procedure are provided in the Method Validation Report and Bioanalytical Report sections.
Concentration-time data were analyzed using noncompartmental methods in Phoenix™ WinNonlin® (Version 6.3, Pharsight Corporation). Concentration-time data that were below the limit of quantification (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero.
The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λz), terminal half-life (T1/2), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), area under the plasma concentration time curve from time-zero extrapolated to infinity (AUCinf).
Analysis of variance (ANOVA) and the Schuirmann's two one-sided t-test procedure at the 5% significance level were applied to the log-transformed pharmacokinetic exposure parameters, Cmax, AUClast, and AUCinf. The 90% confidence interval for the ratio of the geometric means (Test/Reference) was calculated. Bioequivalence was declared if the lower and upper confidence intervals of the log-transformed parameters were within 80% to 125%.
Data from 52 subjects who completed at least one study period were included in the pharmacokinetic analysis. Data from 50 subjects who completed both study periods were included in the statistical analysis. Mean concentration-time data are shown in Tables 65 through 68. Results of the pharmacokinetic and statistical analyses are shown below in Tables 69 through 76.
Buprenorphine exposure, based on ln(AUClast) and ln(AUCinf), was comparable across treatments and the 90% confidence intervals were within the accepted of 80% to 125% limits for demonstrating similar bioavailability between Buprenorphine Naloxone SL spray, 2.2 mg/0.55 mg and Suboxone sublingual film, 4 mg/1 mg. Buprenorphine Cmax was approximately 27% higher after the administration of Buprenorphine Naloxone SL spray, 2.2 mg/0.55 mg compared to that after Suboxone sublingual film, 4 mg/1 mg.
Peak and overall systemic exposure to unconjugated naloxone, based on ln(Cmax), ln(AUClast), and ln(AUCinf), was approximately 31 to 66% higher after the administration of Buprenorphine Naloxone SL spray, 2.2 mg/0.55 mg compared to that after Suboxone sublingual film, 4 mg/1 mg.
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean tor the Test Product (Test) and Reference Product (Ret) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for the Test Product (Test) and Reference Product (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
Formulations #15, #16 and #17 are used in the clinical trial listed as Example 8 for acute pain indication, whereas formulations #14, #15, #16, #17 and #18 will be used in chronic pain indication.
Formulations #26, #27, #28, #29 and #30 represent 0.0625 mg, 0.125 mg, 0.25 mg, 0.5 mg and 1 mg doses, respectively.
Buprenorphine formulations of Table 77 were all stable upon preparation.
The buprenorphine formulations described in Example 11, Table 77 of the instant specification were used. For formulations #27, #28 and #29 were administered as a 0.125 mg, a 0.25 mg and a 0.5 mg dose. Further, 8 mg buprenorphine tablet and 0.3 mg Buprenex® IV injections were administered.
Specifically, this was an open-label, randomized, parallel group study in healthy adult subjects. 60 subjects were divided evenly into 5 cohorts and the subject of each cohort received one of the following treatments:
Blood samples (1×6 mL) were collected for the quantitation of buprenorphine and norbuprenorphine at each predefined time points. The predose blood samples were collected within 60 minutes prior to the first dose of study drug. Plasma samples were analyzed using validated LC/MS/MS assays.
The following pharmacokinetic parameters were estimated from the buprenorphine and norbuprenorphine plasma concentration-time data using noncompartmental methods: areas under the curve from time 0 to the last measured concentration (AUClast), to tau (AUC0-tau), to 24 hours (AUC0-24), and to infinity (AUCinf), maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), the time prior to the first measurable (non-zero) concentration (Tlag), elimination rate constant (λz), elimination half-life (t½), and dose-normalized AUCs and Cmax. Additional pharmacokinetic parameters were calculated, as appropriate. Pharmacokinetic analyses were performed using Phoenix™ WinNonlin® (Version 6.3 or higher, Pharsight Corporation). Arithmetic means, standard deviations, minimum, median, maximum, and coefficients of variation were reported. Additionally, geometric means and geometric CV % was reported for Cmax and AUCs.
an = 8
an = 10
After administration of Buprenorphine Sublingual Spray 0.125 to 0.5 mg Q8 h, buprenorphine was detected in systemic circulation with a mean Tlag of 0.0694 to 0.0833 hour, which was earlier than the mean Tlag observed after administration of Buprenorphine Sublingual Tablet 8 mg QD (0.174 hour).
Exposure to buprenorphine and norbuprenorphine after administration of Buprenorphine Sublingual Spray between 0.125 and 0.5 mg Q8 h was lower than that after Buprenorphine Sublingual Tablet 8 mg QD.
Ratios of the geometric means (Buprenorphine Sublingual Spray/Buprenorphine Sublingual Tablet) for buprenorphine Cmax and AUCs ranged from 6.52% (Cmax, 0.125 mg Sublingual Spray) to 54.10% (AUClast, 0.5 mg Sublingual Spray). Ratios of the geometric means (Buprenorphine Sublingual Spray/Buprenorphine Sublingual Tablet) for norbuprenorphine ranged from 2.34% (AUClast, 0.125 mg Sublingual Spray) to 14.95% (AUClast, 0.5 mg Sublingual Spray).
The geometric mean ratios for AUC0-24 were as follows:
The geometric mean ratios (Buprenorphine Sublingual Spray/Buprenorphine Sublingual Tablet) for dose-normalized buprenorphine parameters ranged from 139.14% (Cmax/D0-24, 0.125 mg Sublingual Spray) to 293.97% (AUCinf/D0-24, 0.25 mg Sublingual Spray). Based on dose-normalized AUCinf (AUCinf/D0-24) the bioavailability of Buprenorphine Sublingual Spray relative to Buprenorphine Sublingual Tablet was 288%, 294%, and 253% for 0.5, 0.25, and 0.125 mg, respectively.
Exposure to buprenorphine after Buprenorphine Sublingual Spray between 0.125 and 0.5 mg Q8 h was lower than that after Buprenex® IV 0.3 mg Q6 h. Ratios of the geometric means (Buprenorphine Sublingual Spray/Buprenex® IV) for the primary buprenorphine parameters (Cmax, AUC0-24, AUClast, and AUCinf) ranged from 1.16% (Cmax, 0.125 mg Sublingual Spray) to 60.18% (AUCinf, 0.5 mg Sublingual Spray). Due to the lack of first pass metabolism after IV administration, the geometric mean ratios (Buprenorphine Sublingual Spray/Buprenex® IV) for norbuprenorphine were higher than observed for the parent drug and ranged from 30.26% (AUClast, 0.125 mg Sublingual Spray) to 193.44% (AUClast, 0.5 mg Sublingual Spray). The geometric mean ratios for AUC0-24 were as follows:
Buprenorphine AUC0-24: 49%, 25%, and 11% for 0.5, 0.25, and 0.125 mg Buprenorphine Sublingual Spray Q8 h, respectively, compared to Buprenex® IV 0.3 mg Q6 h.
Norbuprenorphine AUC0-24: 115%, 78%, and 38% for 0.5, 0.25, and 0.125 mg Buprenorphine Sublingual Spray Q8 h, respectively, compared to Buprenex® IV 0.3 mg Q6 h.
The geometric mean ratios (Buprenorphine Sublingual Spray/Buprenex® IV) for the primary dosenormalized buprenorphine parameters ranged from 3.70% (Cmax/D0-24, 0.125 mg Sublingual Spray) to 49.16% (AUCinf/D0-24, 0.25 mg Sublingual Spray). Based on dose-normalized AUCinf (AUCinf/D0-24) the absolute bioavailability of Buprenorphine Sublingual Spray was 48%, 49%, and 42% for 0.5, 0.25, and 0.125 mg, respectively. Thus, relative to dosage buprenorphine sublingual sprays of the present invention have a higher bioavailability than both sublingual tablets and IV injections.
The buprenorphine formulations described in Example 11, Table 77 of the instant specification were used. For formulations #27, #28 and #29 were administered as a 0.125 mg, a 0.25 mg and a 0.5 mg dose. Further, 8 mg buprenorphine tablet and 0.3 mg Buprenex® IV injections were administered.
Specifically, this was an open-label, randomized, parallel group study in healthy adult subjects. 60 subjects were divided evenly into 5 cohorts and the subject of each cohort received one of the following treatments:
Blood samples (1×6 mL) were collected for the quantitation of buprenorphine and norbuprenorphine at each pre-specified time point. The predose blood samples were collected within 60 minutes prior to the first dose of study drug. Plasma samples were analyzed using validated LC/MS/MS assays. The following pharmacokinetic parameters were estimated from the buprenorphine and norbuprenorphine plasma concentration-time data using noncompartmental methods: areas under the curve from time 0 to the last measured concentration (AUClast), to tau (AUC0-tau), to 24 hours (AUC0-24), and to infinity (AUCinf), maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), the time prior to the first measurable (non-zero) concentration (Tlag), elimination rate constant (λz), elimination half-life (t½), dose-normalized AUCs and Cmax, and accumulation ratios with respect to trough concentration, Cmax, and AUC0-tau.
an = 5;
bn = 8;
cn = 7
After administration of Buprenorphine Sublingual Spray, concentrations increased with dose and peak buprenorphine concentrations were observed at a median Tmax between 1.50 and 2.00 h, similar to the time to reach maximum buprenorphine concentration after administration of Buprenorphine Sublingual Tablet.
On Day 1 and Day 6, exposure to buprenorphine after administration of Buprenorphine Sublingual Spray between 0.125 and 0.5 mg Q8 h was lower than that after Buprenex IV 0.3 mg Q6 h. Exposure to norbuprenorphine was lower than that after Buprenex IV 0.3 mg Q6 h only for Buprenorphine Sublingual Spray 0.125 and 0.25 mg Q8 h. The geometric mean ratios for AUC0-24 were:
Based on dose-normalized AUCinf on Day 6, the absolute bioavailability of Buprenorphine Sublingual Spray was 46%, 49%, and 40% for 0.5, 0.25, and 0.125 mg, respectively.
On Day 1 and Day 6, exposure to buprenorphine and norbuprenorphine after administration of Buprenorphine Sublingual Spray between 0.125 and 0.5 mg Q8 h was lower than that after Buprenorphine Sublingual Tablet 8 mg QD. The geometric mean ratios for AUC0-24 were:
Based on dose-normalized AUCinf on Day 6, the bioavailability of Buprenorphine Sublingual Spray relative to Buprenorphine Sublingual Tablet was 460%, 491%, and 405% for 0.5, 0.25, and 0.125 mg, respectively.
During dosing of Buprenorphine Sublingual Spray Q8 h over 6 days, accumulation of buprenorphine in systemic circulation was slightly higher than the accumulation observed after Buprenex IV 0.3 mg Q6 h and Buprenorphine Sublingual Tablet 8 mg QD. The metabolite-to-parent ratios after Buprenorphine Sublingual Spray Q8 h were higher than observed after Buprenex IV 0.3 mg Q6 h but lower than observed after Buprenorphine Sublingual Tablet 8 mg QD. During dosing of Buprenorphine Sublingual Spray Q8 h, steady state buprenorphine concentrations were achieved between Day 3 and Day 5, approximately the same time as for Buprenex IV 0.3 mg Q6 h and Buprenorphine Sublingual Tablet 8 mg QD. Trough concentrations of norbuprenorphine on Day 5 and Day 6 were similar. Buprenorphine exposure is proportional to dose for Buprenorphine Sublingual Spray between 0.25 and 0.5 mg, for both single administration and after multiple dosing Q8 h.
The buprenorphine formulations described in Example 11, Table 77 of the instant specification were used. For formulations #26, #27, #28, #29 and #30 were administered as a 0.0625 mg, 0.125 mg, a 0.25 mg, a 0.5 and a 1.0 mg dose.
Specifically, a single dose, open-label, randomized, parallel group study to compare the bioavailability of five single doses of Buprenorphine Sublingual Spray. 30 subjects were divided evenly into 5 cohorts and the subjects of each cohort received one of the following treatments:
0.0625 mg, 1 spray, administered sublingually;
0.125 mg, 1 spray, administered sublingually;
0.25 mg, 1 spray, administered sublingually;
0.5 mg, 1 spray, administered sublingually; and
1.0 mg, 1 spray, administered sublingually.
Blood samples (1×6 mL) for buprenorphine and norbuprenorphine analyses were collected in Vacutainer tubes containing K2-EDTA at 0 hour (predose), 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, and 144 hours post dose (19 time points) for quantification of buprenorphine and norbuprenorphine. Subjects who experienced emesis within 2 hours of administration of the study drug were not included in the pharmacokinetic and statistical analyses.
Single-dose pharmacokinetic parameters for buprenorphine and norbuprenorphine were calculated using non-compartmental techniques in Phoenix™ WinNonlin® (Version 6.3, Pharsight Corporation). Concentration-time data that were below the limit of quantification (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”. Actual sample times were used for all pharmacokinetic and statistical analyses. The linear log trapezoidal method was used to calculate the area under the curve (AUC).
The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λz), terminal half-life (t½), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), area under the plasma concentration time curve from time-zero extrapolated to infinity (AUCinf), the percent of AUCinf based on extrapolation (AUCextrap), last quantifiable plasma concentration (Clast), and time of the last quantifiable plasma concentration (Tlast).
After single dose administrations of Buprenorphine Sublingual Spray, maximum buprenorphine exposure occurred between 1.25 h and 1.75 h postdose. Mean dose-normalized buprenorphine Cmax values were similar across treatments, ranging from 1.54 ng/mL/mg (Treatment C; 0.25 mg) to 2.01 ng/mL/mg (Treatment A; 0.0625 mg). Mean dose-normalized buprenorphine AUClast and AUCinf values were similar across treatments as well, ranging from 8.368 h*ng/mL/mg (Treatment B; 0.125 mg) to 10.68 h*ng/mL/mg (Treatment E; 1.0 mg) for AUClast/Dose and from 9.011 h*ng/mL/mg (Treatment B; 0.125 mg) to 11.36 h*ng/mL/mg (Treatment E; 1.0 mg) for AUCinf/Dose. From the analysis of dose proportionality for buprenorphine, the slopes ranged from 0.9154 (Cmax) to 1.0721 (AUClast), suggesting that the increase in maximum and total buprenorphine exposure was dose-proportional from 0.0625 mg to 1.0 mg.
After single dose administrations of Buprenorphine Sublingual Spray, maximum norbuprenorphine exposure occurred between 2.00 h and 3.75 h postdose. Mean dose-normalized norbuprenorphine Cmax values decreased with an increase in dose, ranging from 0.147 ng/mL/mg (Treatment C; 0.25 mg) to 0.0990 ng/mL/mg (Treatment E; 1.0 mg). Mean dose-normalized norbuprenorphine AUClast values increased with an increase in dose, ranging from 3.042 h*ng/mL/mg (Treatment C; 0.25 mg) to 5.345 h*ng/mL/mg (Treatment E; 1.0 mg). From the analysis of dose proportionality for norbuprenorphine, the slope for Cmax was 0.6418, indicating that norbuprenorphine Cmax increased in a less than proportional manner with an increase in dose from 0.25 mg to 1.0 mg. The slope for AUClast was 1.8594, suggesting that norbuprenorphine AUClast increased in a greater than proportional manner with an increase in dose from 0.25 mg to 1.0 mg.
The buprenorphine formulations described in Example 11, Table 77 of the instant specification were used. For formulation #29 was administered as a 0.5 mg dose.
Specifically, a single dose, open-label, randomized, five-period, crossover study to compare the bioavailability of single doses of Buprenorphine Sublingual Spray under various conditions. Each dose of study treatment was separated by a washout period of 7 days. 15 subjects were divided evenly into 5 cohorts and the subjects of each cohort received treatments under the following conditions according to the order in Table 92:
A=Subject given cold water approximately 1 minute before study treatment;
B=Subject given hot water approximately 1 minute before study treatment;
C=Subject given no pretreatment beverage (the reference treatment);
D=Subject given low pH beverage approximately 1 minute before study treatment; and
E=Subject given high pH beverage approximately 1 minute before study treatment.
In each study period, blood samples were collected for the quantitation of buprenorphine and norbuprenorphine at 0 (predose), at 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, and 144 hours post dose (16 time points).
Single-dose pharmacokinetic parameters for buprenorphine and norbuprenorphine were calculated using non-compartmental techniques in Phoenix™ WinNonlin® (Version 6.4, Pharsight Corporation). Concentration-time data that were below the limit of quantification (BLQ) were treated as zero in the data summarization and descriptive statistics. In the pharmacokinetic analysis, BLQ concentrations were treated as zero from time-zero up to the time at which the first quantifiable concentration was observed; embedded and/or terminal BLQ concentrations were treated as “missing”. Actual sample times were used for all pharmacokinetic and statistical analyses. The linear log trapezoidal method was used to calculate the area under the curve (AUC).
The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λz), terminal half-life (t½), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), area under the plasma concentration time curve from time-zero extrapolated to infinity (AUC0-inf), the percent of AUCinf based on extrapolation (AUCextrap), last quantifiable plasma concentration (Clast), and time of the last quantifiable plasma concentration (Tlast).
aGeometric Mean for Buprenorphine Sublingual Spray, 0.5 mg, Pre-treated with Cold Water (A), Pre treated with Hot Water (B), without Pre-treatment (C), Pre-treated with a Low pH Beverage (D), and Pre-treated with a High pH Beverage (E) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for Buprenorphine Sublingual Spray, 0.5 mg, Pre-treated with Cold Water (A), Pre treated with Hot Water (B), without Pre-treatment (C), Pre-treated with a Low pH Beverage (D), and Pre-treated with a High pH Beverage (E) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
Pretreatment with cold water (Treatment A) or hot water (Treatment B) did not alter maximum and total buprenorphine exposure after single dose administration of Buprenorphine Sublingual Spray (0.5 mg); the 90% confidence intervals for Cmax, AUClast, and AUCinf were contained entirely within the 80%-125% interval for both conditions.
Pretreatment with a low pH beverage (Treatment D) reduced maximum buprenorphine exposure by approximately 10% and the lower bound of the 90% confidence interval for Cmax fell slightly below the 80%-125% interval (79.78%). Pretreatment with a low pH beverage did not alter total buprenorphine exposure after single dose administration of Buprenorphine Sublingual Spray (0.5 mg); the 90% confidence intervals for AUClast and AUCinf were contained entirely within the 80%-125% interval for both conditions.
Pretreatment with a high pH beverage (Treatment E) did not alter maximum and total buprenorphine exposure after single dose administration of Buprenorphine Sublingual Spray (0.5 mg); the 90% confidence intervals for Cmax, AUClast, and AUCinf were contained entirely within the 80%-125% interval.
Pretreatment with cold water (Treatment A) did not alter maximum and total norbuprenorphine exposure after single dose administration of Buprenorphine Sublingual Spray (0.5 mg); the 90% confidence intervals for Cmax and AUClast, were contained entirely within the 80%-125% interval for both conditions.
Pretreatment with hot water (Treatment B) did not alter maximum norbuprenorphine exposure after single dose administration of Buprenorphine Sublingual Spray (0.5 mg); the 90% confidence intervals for Cmax were contained entirely within the 80%-125% interval for both conditions. Pretreatment with hot water (Treatment B) increased total norbuprenorphine exposure by approximately 15% and the upper bound of the 90% confidence interval for AUClast fell above the 80%-125% interval (136.42%).
Pretreatment with a low pH beverage (Treatment D) or a high pH beverage (Treatment E) did not alter maximum norbuprenorphine exposure after single dose administration of Buprenorphine Sublingual Spray (0.5 mg); the 90% confidence intervals for Cmax were contained entirely within the 80%-125% interval for both conditions.
Pretreatment with a low pH beverage (Treatment D) or a high pH beverage (Treatment E) reduced total norbuprenorphine exposure by approximately 7% and 12%, respectively (0.5 mg) and the lower bounds of the 90% confidence intervals for AUClast fell below the 80%-125% interval (77.62% and 74.04%, respectively).
The buprenorphine formulations described in Example 11, Table 77 of the instant specification were used. For formulation #29 and #30 was administered as a 0.5 mg dose and 1.0 mg dose.
Specifically, a single dose, open-label, two-period, two-treatment, ascending study to compare the bioavailability of ascending doses of Buprenorphine Sublingual Spray. Each dose of study treatment was separated by a washout period of 14 days. 20 subjects received 0.5 mg spray in period 1 and a 1.0 mg spray in period 2.
Each dose of buprenorphine sublingual spray (0.5 mg and 1.0 mg) was delivered as a single 100-μL spray developed by Insys Therapeutics, Inc. USA for investigational use only.
Each dose was administered following a 10-hour overnight fast. No food was allowed until 4 hours after dose administration. No water was consumed from 1 hour prior through 1 hour after dose. Meals were the same and scheduled at approximately the same times relative to dose for each study period. For each period, subjects were confined before dosing to ensure adherence to the 10-hour fast, and remained confined through the end of procedures for each period. In each study period, blood samples were collected for the quantitation of buprenorphine and norbuprenorphine at 0 (predose), at 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, 72, 96, 120, and 144 hours post dose (16 time points).
Plasma samples were analyzed by WCT using validated LC-MS-MS procedures. The methods were validated for ranges of 0.0125 to 2.50 ng/mL for buprenorphine and 0.0200 to 4.00 ng/mL for norbuprenorphine, based on the analysis of 0.500 mL of human EDTA plasma. Data were stored in Watson Laboratory Information Management System™ (LIMS; Version 7.2.0.03, Thermo Fisher Scientific).
The following pharmacokinetic parameters were calculated: peak concentration in plasma (Cmax), time to peak concentration (Tmax), elimination rate constant (λz), terminal half-life (t½), area under the concentration-time curve from time-zero to the time of the last quantifiable concentration (AUClast), area under the plasma concentration time curve from time-zero extrapolated to infinity (AUC0-inf), the percent of AUCinf based on extrapolation (AUCextrap), last quantifiable plasma concentration (Clast), and time of the last quantifiable plasma concentration (Tlast).
aGeometric Mean for 0.5 mg Buprenorphine (Test) and 1.0 mg Buprenorphine (Ref) based on Least Squares Mean of log-transformed parameter values
bRatio(%) = Geometric Mean (Test)/Geometric Mean (Ref)
c90% Confidence Interval
aGeometric Mean for 0.5 mg Buprenorphine (Test) and 1.0 mg Buprenorphine (Ref) based on Least Squares Mean of log-transformed parameter values
bc Mean (Test)/Geometric Mean (Ref)
ce Interval
Results
The first quantifiable buprenorphine concentrations were observed at the 0.08-hour sample time for the 1.0 mg buprenorphine sublingual spray (Treatment B) and at 0.17 hour sample time for the 0.5 mg buprenorphine sublingual spray (Treatment A). The highest mean plasma concentrations were 0.612±0.159 ng/mL for the 0.5 mg buprenorphine sublingual spray (Treatment A) and 1.14±0.338 ng/mL for the 1.0 mg buprenorphine sublingual spray (Treatment B), both at 2.00 h. Quantifiable buprenorphine concentrations were observed throughout the 48.00 hour sampling interval for most subjects.
The first quantifiable norbuprenorphine concentrations were observed at the 0.25-hour sample time for the 1.0 mg buprenorphine sublingual spray (Treatment B) and at 0.50-hour sample time for the 0.5 mg buprenorphine sublingual spray (Treatment A). The highest mean plasma concentrations were 0.0547±0.0353 ng/mL at 2.00 h for the 0.5 mg buprenorphine sublingual spray (Treatment A) and 0.102±0.0556 ng/mL at 4.00 h for the 1.0 mg buprenorphine sublingual spray (Treatment B) h. Quantifiable norbuprenorphine concentrations were observed throughout the 48.00 hour sampling interval for some subjects.
Number | Date | Country | |
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61875837 | Sep 2013 | US |
Number | Date | Country | |
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Parent | 15336547 | Oct 2016 | US |
Child | 15887655 | US | |
Parent | 14923630 | Oct 2015 | US |
Child | 15336547 | US | |
Parent | 14469063 | Aug 2014 | US |
Child | 14923630 | US |