‘
`Journal of Conlrolled Release, 25 ( 1993') 21-29
`© 1993 Elsevier Science Publishers B.V. All rights reserved 0l68-3659/ 93/$06.00
`
`COREL 0081 l
`
`Controlled buccal delivery of buprenorphine
`
`J .P. Cassidy, N.M. Landzert and E. Quadros
`V
`C1'ba—Geigy Corporation. Ardsley, New York, USA
`(Received 7 October 1992; accepted in revised form 13 November 1992)
`
`Buprenorphine is a potent opiate agonist-antagonist used in the treatment of both acute and chronic
`pain. Like many opiates, it has low oral bioavailability due to both presystemic metabolism in the wall
`of the gastrointestinal tract and extensive first pass metabolism. Controlled delivery of analgesics re-
`sults in good pain relief and a lower total requirement for the drug. Buccal delivery offers advantages
`in terms of accessibility, avoidance of first pass metabolism and the ability to provide controlled deliv-
`ery for extended periods of time. Buccal permeation of buprenorphine was measured in vitro and in
`vivo in the dog model using prototype non-woven and hydrogel systems. The fluxes of drug were iden-
`tical from solutions and from non-woven systems in vitro, providing a reliable way of applying a drug
`solution to the mucosa without leaking. A model is described that permits screening of potential buccal
`systems in vitro to select a system for in vivo use. In vivo, steady—state plasmalevels were obtained
`using both non-woven and hydrogel systems. Steady state was attained in 1 to 1.5 h and was maintained
`during the time of application of the system. Assuming that the flux in man is similar to that in the
`dog, controlled buccal delivery of buprenorphine would provide adequate analgesia over an extended
`period of time.
`'
`
`Key words: Buccal; Buprenorphine; Analgesia; Controlled delivery; I-Iydrogels
`
`Introduction
`
`Buprenorphine, an opiate agonist-antagonist
`with 20 to 40 times the potency of morphine [l ],
`is used in the treatment of both acute and chronic
`
`pain [2,3]. Like many opiates, it is extensively
`metabolized in both the gastrointestinal (GI)
`tract and the liver [4,5] and is therefore a poor
`' candidate for oral delivery. It is currently admin-
`istered as repeated intravenous or intramuscular
`injections and as a sublingual tablet. In the con-
`trol of pain, it has been reported that administra-
`tion of an analgesic at a constant rate results in
`
`Correspondence to: E. Quadros, Ciba-Geigy Corporation, 444
`Saw Mill River Road, Ardsley, NY 10502, USA.
`
`both optimal patient comfort and a reduced total
`amount of analgesic [6]. Controlled delivery of
`buprenorphine may therefore, offer advantages
`in pain management.
`.
`The buccal route offers several advantages for
`controlled drug delivery for extended periods of
`time. The mucosa is well supplied with both vas-
`cular and lymphatic drainage and first—pass me-
`tabolism in the liver and pre-systemic metabo-
`lism in the GI tract are avoided. The area is
`
`p
`
`obviously very accessible for placement and re-
`moval of a delivery device. Polymeric systems
`with an impermeable backing could deliver drug
`in a unidirectional fashion to the mucosa and
`avoid loss due to swallowing. The ultimate aim
`-would be to develop a small, thin, flexible device
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`
`22
`
`that would adhere to the mucosa during normal
`activities, including eating and drinking. Buccal
`delivery also offers the advantage of rapid ab-
`sorption, which would obviously be necessary in
`the control of pain, and buprenorphine is known
`to be efficacious as a sublingual tablet [7]. The
`use of a device that provides rapid, long-lasting
`and adequate pain control by noninvasive means
`could offer considerable advantages in pain
`management.
`In the present study, the buccal absorption of
`buprenorphine was assessed in vitro in modified
`Ussing chambers [8]. Three different prototype
`systems, one non-woven and two hydrogels of
`varying water content, were assessed in vitro and
`in vivo in the dog. Hydrogels have previously
`been used for the buccal delivery of diclofenac
`sodium in both the dog and man [9,l0], and
`similar fluxes were measured in both species.
`Preliminary results of the current studies have
`been presented [ 1 1,12].
`
`Materials and Methods
`
`Materials
`
`.
`
`Buprenorphine hydrochloride was obtained
`from Diosynth (Bensenville, IL) and was used
`without further purification. Radioimmunoas—
`say (RIA) kits were purchased from Diagnostic
`Products Corporation (Los Angeles, CA). t-Bu-
`tyl peroctoate was from Pennwalt, Buffalo, NY,
`2-hydroxyethyl methacrylate
`(HEMA, Lot
`#64622) was obtained from Polysciences, Inc.,
`Warrington, PA, and rnonomerzmacromer mix
`. was kindly supplied by Dr. K. F. Mueller‘ofCen—
`tral Research, Ciba-Geigy Corporation, Ardsley,
`NY. All other reagents were of HPLC or analyt-
`ical grade and were used as purchased.
`
`Methods
`
`Analytical methodology
`
`HPLC. Buprenorphine was quantitated by re-
`verse phase high performance liquid chromato-
`graphy (HPLC) on a C-18 column (3 cm, 3 ,urn
`particle size; Perkin-Elmer, Norwalk, CT) with
`
`fluorescence detection using an excitation wave-
`length of 213 nm and a 360 nm emission cut-off
`filter. The mobile phase (60/40 acetonitri1e/
`0.01M KH2PO4, 0.01% TEA, adjusted to pH 3
`with phosphoric acid) was pumped isocratically
`at a flow rate of 1.5 ml/min. Standards were
`made up in the same solution as the samples
`being assayed. The standard curve was linear over
`the concentration range 25 ng/ml to 20 ,ug/ml,
`using an injection volume of 15 pl.
`
`RIA. Buprenorphine in Tris-phosphate saline
`[13] was measured using a modification of a
`commercially available kit. Briefly, 50 pl of sam-
`ple (or standard) was incubated with 100 [ll of
`[mllbuprenorphine and 100 pl of antiserum at
`room temperature for 1 h. Separation of anti-
`body—bound from free buprenorphine was ac-
`complished by the addition of a second antibody
`(goat anti-rabbit gamma-globulin), and centrif-
`ugation at 25°C ( 1500 Xg for 30 min). The ‘pel-
`let, containing antibody-bound material, was
`counted using a gamma counter (Minaxi Gamma
`Model 5000, Packard Instrument Company,
`Downers Grove, IL). The amount of buprenor-
`phine was calculated from the standard curve
`which ranged from 0.05 to 15 ng/ml. Samples
`were assayed undiluted or at a dilution of 1 :5 or
`1:20. The assay was validated at all dilutions
`studied and stability of buprenorphine was con-
`firmed in buffer stored at —70°C for up to 21
`days prior to analysis.
`
`Solubility ofbuprenorphine hydrochloride
`The solubility of buprenorphine HCl was de-
`termined by the addition of excess drug to either
`phosphate buffers [ 14,15 ] or physiological buffer
`(Tris-phosphate saline) with initial pH values
`between 4 and V8. The vials were capped, vor-
`texed and placed in a shaking water bath at 25 °C
`for 24 h. 1.5 ml of solution was removed, centri-
`fuged in a microfuge (Model 235B, Fisher Sci-
`entific, Springfield, NJ) at l5000Xg for 2 min
`at room temperature and diluted for deterrnina—
`tion of buprenorphine by HPLC. The pH of the
`solutions was measured to give the final pH of
`the solutions.
`V
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`Buprenorphineflux across buccal mucosa in vitro
`Male New Zealand White rabbits (2-4 kg)
`were sacrificed by carbon dioxide inhalation and
`beagle dogs of either sex (7-11 kg) were sacri-
`ficed by an intravenous overdose of Nembutal®
`and exsanguination. All animal experimentation
`was performed according to protocols approved
`by Ciba-Geigy’s Animal Care Committee. Buc-
`cal tissue was removed by blunt dissection, sep-
`arated from underlying muscle, rinsed in buffer
`and mounted in modified Ussing chambers
`(WPI, Sarasota, FL). Equilibration was ‘in 10 ml
`Krebs-Henseleit buffer [16], containing 10 mM
`glucose. The pH was maintained at 7.4 by bub-
`bling with 95% 02/ 5% CO2 and the temperature
`was maintained at 37°C by water-jacketing. The
`tissue was equilibrated for 30-60 min before drug
`donor solution was added to the mucosal side and
`fresh buffer was added to the serosal side. Sam-
`
`ples (0.5 ml) were taken at intervals from the
`serosal side and the volume replaced with buffer.
`Samples were assayed for buprenorphine con-
`tent by RIA or HPLC. Due to the low solubility
`of buprenorphine at neutral pH, some flux stud-
`ies were performed at pH 4 using Tris—phosphate
`saline buffer. To monitor tissue viability, tran-
`sepithelial potential difference and short-circuit
`current were measured by salt bridges of 2% agar
`in Krebs-Henseleit buffer in contact with Ag/
`AgCl electrodes connected to a voltage current
`clamp (DVC—1000, WPI, Sarasota, FL) via a
`preamplifier.
`
`Preparation ofhydrogel discs
`The hydrogels were prepared by copolymeri-
`zation of HEMA with a macromer synthesized
`by the reaction of polytetramethylene glycol
`(Polymeg®) with isophorone diisocyanate in a
`1:2
`ratio
`[17].
`Both
`90:10
`(mono-
`mer:macromer, wt/wt) and 80: 20.hydrogel sys-
`tems were assessed. 90:10 and 80:20 hydrogels
`were prepared by the addition of HEMA to a
`70:30 monomer:macromer mixture. After de-
`gassing for 30 min, 0.2 wt% of t-butyl peroctoate
`was added as initiator. The solution was placed
`between two ‘Mylar®-covered glass plates with the
`appropriate Teflon“) spacer around the perime-
`ter. The polymer was crosslinked by placing the
`
`23
`
`mold at 80° C for 1 h. After cooling, the polymer
`was removed and washed with 5 changes of 8 l of
`distilled water. Discs were punched from the
`water-washed polymer, and remaining mono-
`mer was removed by Soxhlet extraction in
`ethanol overnight. The extracted discs were dried
`in a vacuum oven at 45 ° C for 24 h.
`
`.
`
`For drug loading, the dried discs were weighed,
`placed in a solution of buprenorphine HCl (15
`wt% in 70% ethanol/ 30% 0.01 M KHZPO4, pH
`4) and stirred at 45 °C for 72 h. The loaded sys-
`tems were removed, rinsed briefly in 70% ethanol
`and dried for 48 h at room temperature in a vac-
`uum desiccator. Before use, the systems were
`placed in a 95% humidity chamber for 48 h at
`room temperature.
`
`Dissolution testing
`The release profiles of the systems were deter-
`mined using dried discs in a standard dissolution
`apparatus with stainless steel baskets (Vander-
`kamp 600, Van-Kel Industries, Chatham, NJ).
`Dissolution was determined in 500 ml of dis-
`
`tilled water at 32°C. At various time intervals,
`0.8 ml of the solution was withdrawn from the
`reservoir and assayed for buprenorphine content
`by HPLC.
`
`Systems application in vitro
`‘ The fluxes of buprenorphine across canine
`buccal mucosa were measured from both non-
`
`woven and hydrogel discs in vitro. Buprenor-
`phine (220 pl of 10 mg/ml buprenorphine hy-
`drochloride in 10 mM KH2PO4) was pipetted
`onto the surface of the non-woven material. The
`system was applied to -the buccal mucosa and
`mounted in the Ussing chamber. Hydrogel discs,
`prepared as described above, were applied to the
`mucosal surface, backed with Parafilm® and I
`mounted in the Ussing chamber. In all experi-
`ments, the total exposed surface area was 1 cm2.
`
`Buccal absorption in vivo
`Beagles (7-11 1(8) of either sex were fasted
`overnight and had free access to water until the .
`time of experimentation. They were anesthe-
`tized with sodium pentobarbital (approximately
`25 mg/ kg) via a 22 G Abbocath® in the cephalic
`
`.
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`24
`
`vein and additional doses were administered to
`
`maintain anesthesia during the course of the ex-
`periment. Cannula patency was maintained with
`an i.v. drip of sterile lactated Ringers (1 ml/
`min). Blood samples (3 ml) were drawn into
`heparinized Monoject® syringes and plasma, ob-
`tained following centrifugation (2000><g for 10
`min), was placed in microfuge tubes and frozen
`in a dry ice-ethanol bath. Samples were stored
`for up to 3 weeks at —70°C.
`To determine the i.v. pharmacokinetics of bu-
`prenorphine, a 0.30 mg bolus of buprenorphine
`HCl in 1.5 ml of lactated Ringers solution was
`injected through a second catheter placed in the
`saphenous vein. The bolus was followed by 5 ml
`of lactated Ringers to insure injection of the total
`dose. Plasma samples were obtained over a 4 h
`period and assayed for buprenorphine content by
`RIA. The fit of the plasma profile to a biexpo—
`nential equation was modelled using R-Strip
`(Micromath, Inc.) with a y2 weighting, and
`pharmacokinetic parameters were determined for
`each animal.
`
`To determine buccal delivery of buprenor-
`phine, beagles were anesthetized as described
`above, and a zero time blood sample was taken.
`The inner cheek was blotted drywith gauze, the
`appropriate device(s) was placed on the cheek
`and the area coveredby an impermeable backing
`membrane held in place by a peripheral adhesive
`(Super Polygrip, Dentco, Inc., Jersey City, NJ).
`The device was left in position for 2 to 4 h. Blood
`samplesiwere taken at intervals during the appli-
`cation of the device and after its removal. All
`
`plasma samples were assayed for buprenorphine
`content by RIA. Results are expressed as the
`mean i 1 SEM.
`
`Results
`
`Solubility of buprenorphine hydrochloride-
`
`At the end of the 24 h incubation period all
`vials contained undissolved material which was
`removed by centrifugation. The solubility of bu-
`prenorphine was highly pH dependent with the
`highest solubility seen at low pH ( 17.3 mg/ml at
`
`pH 4.2). The solubility at neutral pH was con-
`siderably lower (52 pg/ml at pH 7.3) (Fig. l).
`Essentially, similar solubilities were measured in
`USP, phosphate, and physiological (TPS) buff-
`ers, except at pH 4.2 when the solubility was con-
`siderably lower in TPS (4.2 mg/ml).
`»
`
`Buprenorphine flux across buccal mucosa in vitro
`
`The flux of buprenorphine in vitro was mea-
`sured across buccal mucosa obtained from both
`
`rabbit and dog. The donor solutions were at sat-
`uration (4.3 mg/ml) in TPS buffer, adjusted to
`pH 4 with isotonic citric acid. Steady—state fluxes
`were calculated by linear regression using the
`asymptotic region of the cumulative amount /
`time curve and the time lag (to steady-state) was
`determined from the intercept on the abscissa.
`The steady-state fluxes and time lags were
`4.2 :0.6 pg/cmz/h and 2.7 ‘:01 h (n=6) in the
`rabbit and 22.3 : 6.0 ttg/cmz/h and 1.6 i 0.4 h
`(n :4) in the dog, respectively. In the rabbit,
`steady-state flux was linearly related to donor
`concentration over the range 0.04 to 4.3 mg/ml
`(Fig. 2, r=0.998 ). The addition of sodium azide
`(10 mM ), a metabolic inhibitor, to the mucosal
`solution at the same time as the drug caused the
`abolition of the transepithelial potential differ-
`ence and an approximately 10-fold increase in the
`flux of buprenorphine,’ with no attainment of
`steady—state within the experimental time period.
`
`
`
`solimimy(mg/ml)
`
`9
`
`Phosphate
`
`A
`
`LJSP«
`
`O
`
`TPS
`
`l. Solubility of buprenorphine hydrochloride in phos-
`Fig.
`phate, USP phosphate and physiological (TPS) buffers.
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`M,
`°° 8exp(——D[2n+l]27tZt/L2)
`A_4;=1—,.;o
`.
`(2n+l)27t2
`
`(18)
`
`where: M,=tota1 amount of drug released at time
`t, Mm =tota1 drugloaded into hydrogel, D= drug
`diffusion coefficient,
`and L=thickness of
`hydrogel.
`The diffusion coefiicient for buprenorphine
`can be calculated using an early time approxi-
`mation of the above equation:
`
`This equation is accurate to within 1% for M, /
`Moo < 0.6.
`The diffusion coefficients for buprenorphine
`were 6.6:0.72><1O‘5 and 2.2:0.14>< 10"
`cmz/h for the 90: 10 and 80 2 20 hydrogels,
`respectively.
`
`Flux from systems in vitro
`
`Steady-state flux across dog buccal mucosa
`from a solution of buprenorphine (10 mg/ ml in
`10 mM KHZPO4, pH 4) was 87.1 : 30.3 ,ug/cm2/
`h with a time lag of l.3:0.33 h, n=7 (Fig. 4).
`The
`permeability
`coefficient
`' was
`2.42 : 0.84>< 10‘6 cm /s. The steady—state flux
`from the same solution loaded onto a non-woven
`
`chamber was 78.7 :26.4 pg/cm’/h with a time
`
`Janlug/cm‘/hr)
`
`Donor concentration (mg/ml)
`
`Fig. 2. Relationship between donor concentration and steady-
`state flux of buprenorphine across rabbit buccal mucosa in
`vitro. The number of experiments was between 4 and 6.
`
`‘U
`0 .II
`A’0..
`-ou
`2a.0
`ill
`
`-0- 90:10
`ma
`-6- some
`n-3
`—-|— Non- woven
`
`0.50
`
`1.00
`
`1.50
`
`2.00
`
`2.50
`
`Square root of time
`
`00
`
`.00
`
`Fig. 3. Dissolution of buprenorphine from non-woven and
`hydrogel systems as a function of the square root of time in
`' hours.
`
`500
`
`Dissolution of buprenorphine from systems
`
`The hydrogel discs were 1.9 cm2 and 0.138 mm
`thick. The release profiles of buprenorphine from
`90: 10 and 80:20 hydrogel discs were linear with
`the square root of time for l and 2 h, respectively
`(Fig. 3). The release rates were 432 1 25 and
`173 i 5 pg/cmz/h’ ‘/2 for the 90:10 and 80: 20
`discs, respectively (n: 3, for each system).
`Drug release from these monoliths that are ini-
`tially swelled with water may be described by the
`equation:
`
`
`
`Bupronorphina(un/cm‘)
`
`*0“ 10 mg/ml
`n-10
`‘- 0 '=- Non-woven
`
`Fig. 4. Cumulative flux of buprenorphine across dog buccal
`mucosa from a solution of 10 mg/ml (n: 10) andvfrom 220
`pl of a 10 mg/ ml solution loaded on to a non-woven system
`( I1 = 1 0 )-
`'
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`
`26
`
`lag of 0.95:0.24 h, n: ll (Fig. 4). There was
`no significant difference between the flux from
`solution‘ or from the non-woven device, suggest-
`ing that the use of non-woven systems in vivo
`would be equivalent to the application of a solu-
`tion to the buccal mucosa without the associated
`
`problems of leakage and clamping of the device
`in place. Although there was a fairly large varia-
`tion in the fluxes among animals, the flux across
`tissue from a single animal was much more re-
`producible. Paired experiments were performed
`using solutions, 90: 10 and 80: 20 hydrogel discs
`on buccal mucosa from 4 dogs in vitro in Ussing
`chambers (Fig. 5). The steady-state fluxes were
`65.0: 19.0, 20.8 : 3.1 and 10.4: 2.4 /lg/C1112/h
`with time lags of l.8:0.15,
`l.4:0.21 and
`2.1 : 0.12 h, respectively.
`
`Buprenorphine pharmacokinetics in the dog
`
`Representative plasma levels of buprenor-
`phine following an intravenous bolus of 0.3 mg
`of buprenorphine hydrochloride are shown in
`Fig. 6. The pharmacokinetic parameters deter-
`mined for each dog are shown in Table l. The
`experimental data were fitted to a biexponential
`rate equation to give the following mean param-
`eter values:
`
`C(t)= 79.2e<-5-“>'+7.5e,<-0-33)’
`
`where C(t) is the plasma concentration
`
`
`
`Bupreinorphine(ua/cm‘)
`
`_
`
`In D
`
`Fig. 5. Cumulative flux of buprenorphine across dog buccal‘
`mucosa from solution (10 mg/ml), 90: 10 and 80:20 hydro-
`gel discs, rt: 4.
`'
`
`,,¢<7449 - I-o I-652 in nu» » I745 - ma l~c\J3? e um
`
`
`
`
`
`PlasmabuprenorphineIna/ml)
`
`Time (hr)
`
`Fig. 6. Representative plasma profile of buprenorphine fol-
`lovidng administration ofa 0.3 mg intravenous bolus. The data
`points were fitted to the curve shown by the dotted line using
`the equation in the figure.
`
`ml at time t (h) after dosing. The mean clear-
`ance value was 144: 10 ml/ min and the total
`volume of distribution was 26.3 :2.3 1 (n=6).
`These values are similar to those reported in the
`literature [19].
`
`Buccal absorption in vivo
`
`Plasma buprenorphine levels following buccal
`application of one and three 1 cm2 non-woven *
`devices are shown in Fig. 7. Steady-state levels
`(C,,) were calculated from the linear portions of
`the cumulative area under the plasma concentra-
`tion time curves '(AUC) versus time plots and
`the time lag to steady-state was the intercept on
`the abscissa (Fig. 8). The steady-state plasma
`levels were 8.2: l.l (n=6), 1.6:0.06 (n=3)
`and 1.5 ng/ml (n=2) during the application of
`three 1 cm’ discs, four 0.5 cm? discs and onel
`cm? disc, respectively. Steady-state flux (J55, was
`calculated from the following equation
`
`J5.
`
`_ C55 X Clearance
`A
`
`where A = area in cm2
`
`The steady-state fluxes were 22.0: 3.4 ug/
`cm’/h (n= 6 )‘ from three 1 cm: devices, 7.0 : 0.3
`from four 0.5 cm2 discs and 12.7 ;1g/ cmz/h from
`a single ICII12 device. The steady-state flux of bu-
`prenorphine from the smaller (0.5 cm2) devices
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`
`TABLE I
`
`Pharrnacokinetic parameters for an intravenousbolus of buprenorphine hydrochloride (300 ug)
`
`Parameter
`
`Dog No.
`
`616567
`
`991911
`
`99267
`
`996971
`
`581216
`
`487945
`
`Weight (kg)
`Sex
`A (ng/ml)
`01 (I171)
`B (ng/ml)
`3 (h“)
`Clearance‘ (ml/min)
`Vdz (I)
`
`9.5
`
`F
`74.5
`6.9
`7.5
`0.33
`15]
`27.5
`
`10.5
`
`F
`156.3
`3.1
`9.5
`0.37
`110
`18.0
`
`10.2
`
`F
`64.8
`4.1
`8.9
`0.33
`116
`21.1
`
`10.2
`
`F
`
`66.4.
`5.6
`6.2
`0.37
`173
`23.4
`
`10.2
`M
`59.3
`4.9
`6.8
`0.31
`I48
`28.5
`
`lI.8
`
`F
`
`53.7
`5.8
`6.2
`0.29
`I63
`34.0
`
`Mean i SEM
`
`10.4 :0.3
`
`79.2 il5.7
`5.9 i0.6
`7.5 ‘:06
`O.33i0.0l
`144
`‘:10
`26.3 i2.3
`
`cumulativeAUG"(nghr/ml)
`
`‘‘l'“ 80:20 3X1
`
`—'9—' 80:20 1K3.75
`
`‘Clearance =
`
`Dose
`Area under curve
`Clearance
`Terminal half life'.
`
`2Vd=
`
`5D
`
`5o
`
`.54:Q..
`O:0_
`Q.:D
`
`IEnS3
`
`.
`
`Time (hr) -
`
`Fig. 7. Plasma levels of buprenorphine obtained after appli-
`cation of one or three 1 cm’ non-woven buccal devices. The
`single device was applied for 3 h and the three devices for
`4 h.
`
`Fig. 8. Cumulative AUC versus time curves following the ap-
`plication of non-woven and hydrogel systems to canine buc-
`cal mucosa.
`
`was significantly lower than that from three 1 cmz
`devices (p< 0.01 ), when expressed on the basis
`of area.
`
`Using the 80: 20 hydrogels, steady-state plasma
`levels of3.7 :06 ng/ml (n=3) and 1.6 :0.4 ng/
`ml (n=3) were achieved following application
`of one 3.75 cm’ and three 1 cm2 discs, respec-
`tively (Fig. 9). The time-lags to steady-state were
`0.9 i 0.4 and 0.7 i 0.1 h, respectively. The steady-
`state fluxes were 8.6 i 0.9 and 4.8 i 0.7 ,ug/cm2/
`h from one 3.75 cm2 and three 1 cm2 discs, re-
`spectively. The flux from three 1 cmz hydrogel
`
`discs was significantly lower than that from three
`1 cm2 non-woven discs (p<0.01 ) and the time
`lag to steady-state was significantly longer (0.7
`vs. 0.3 h, p<_0.01 ). Using the higher water con-
`tent hydrogels of various sizes (0.5 to_ 3.75 cm’)
`steady-state plasma levels were not achieved and
`considerable variation was seen. The flux data are
`summarized in Table 2.
`
`Discussion
`
`The solubility of buprenorphine hydrochlo-
`ride was highly pH dependent, with an exponen-
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`PlasmabuprenorphineIna/ml)
`
`-9- tx3.75::rn’
`n-3
`
`Fig. 9. Plasma levels of buprenorphine following the buccal
`application of 80: 20 hydrogel discs. The time ofapplication
`for the 3.75 cm2 disc was 4 hours and for the three 1 cm:
`discs. 3.5 hours.
`
`TABLE 2
`
`In vivo fluxes ofbuprenorphine from prototype systems in the dog
`
`Flux
`(#s/cm’/ hr)
`
`Steady-state plasma
`concent ration (ng/ml)
`
`22.0ir3.4
`7.01-0.3
`12.7
`
`8.2i1.1
`l_6ir0.06
`1.5
`
`System‘
`
`Non-woven
`3><1cm1
`4X0.5cm’
`lxl cm:
`
`80:20 hydrogels
`I X 3.75 cm’
`3 X 1 cm1
`
`‘Number ofsystems >< area of system.
`Results are the mean 1'1 SEM.
`
`tial increase in solubility as the pH decreased. Its
`behavior in solution was similar to that reported
`for fentanyl and sufentanil, which are also weakly
`basic narcotic analgesics [20]. The presence of
`salts at a physiological concentration decreased
`the solubility from 17.3 mg/ml in phosphate
`buffer to 4.2 mg/ml.
`The permeation of buprenorphine through
`rabbit buccal mucosa in vitro was linearly re-
`lated to the donor concentration over the range
`0.04 to 4.3 mg/ml, which is supportive of pas-
`sive dilfusion as the mechanism of transport. The
`permeability of canine buccal mucosa was about
`seven-fold greater than that of the rabbit, with
`
`permeability coefficients of '1 4.4 and 2.7x 10-7
`cm / s, respectively. The relative permeability was
`similar to that reported for CGS 16617, a highly
`hydrophilic angiotensin converting enzyme in-
`hibitor [8]. The addition of sodium azide, an
`uncoupler of oxidative phosphorylation,
`re-
`sulted in significantly increased flux of bupren-
`orphine across rabbit buccal mucosa. Azide
`abolishes the spontaneous transepithelial poten-
`tial difference and the barrier properties of buc-
`cal mucosa from a variety of species [8 ]. The flux
`of buprenorphine was the same from a 10 mg/
`ml donor in free solution or loaded onto a non-
`
`woven chamber, suggesting that the non-woven
`chamber in vivo would be equivalent to the ap-
`plication of a drug solution to the mucosa. The
`use of cups containing solutions has been asso-
`ciated with leakage and the problems of clamp-
`ing a cup securely in position without it moving
`or compromising the blood supply to the area.
`The application of non-woven systems to the
`buccal mucosa for 3 to 4 h resulted in steady-state
`plasma levels which were maintained until the
`removal of the systems. The slower decline in
`plasma levels compared to the rapid fall after an
`intravenous dose suggests the presence of a de-
`pot in the buccal mucosa. The lower flux from
`smaller systems even when corrected for area may
`reflect an edge effect which maybe due to poor
`contact with the tissue. The 80: 20 hydrogel sys-
`tems also produced steady-state plasma levels
`with a similar slow decline after system removal
`(Fig. 9), but the flux was significantly lower than
`that obtained during the application of non-
`woven systemsof the same size. The higher water
`content hydrogels gave rise to much more erratic
`plasma levels and steady-state was not achieved.
`
`Conclusions
`
`Steady-state plasma levels of buprenorphine
`were obtained in the dog usingtwo different pro-
`totype systems, one non-woven and the other a
`hydrogel. The lag times were less than 1 h in both
`cases which would therefore provide rapid deliv-
`ery of this analgesic. Good analgesic effect was
`obtained in man with sublingual buprenorphine
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`following a similar delay in absorption [7]. The
`dog has been reported to be a good model for man
`[9,10] and extrapolation of these results to man
`suggests that the buccal route of delivery of bu-
`prenorphine would be feasible and would offer
`an excellent treatment modality for pain relief.
`
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`
`R.C. Heel, R.N. Brodgen, '1‘.M. Speight and GS. Avery,
`Buprenorphine: a new strong analgesic, Curr. Ther. 5
`(1979) 29-33.
`P.J.Q. Watson, H.J. McQuay, R.E.S. Bullingharn, M.C.
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`aesth. 54 (1982) 37-43.
`H. Adriaensen, B. Mattelaer and H. Vanmeenen, A long-
`term open, clinical and pharmacokinetic assessment of
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`D. Brewster, M.J. Humphrey and M.A. McLeavy, Bili-
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`
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`
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`U. S. Phannacopeia (1985) pp. 1419-1420.
`Geigy Scientific Tables, Vol. 3 (1984) C. Lentner, Ed.
`Ciba-Geigy, Limited, Basle, pp. 58-60.
`H.A. Krebs and K. Henseleit, Untersuchugen uber.die
`Harnstoffbildung im Tierkorper, Hoppe-Seylcr’s Z.
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`W.R. Good and K.F. Mueller, A new family of mono-
`, lithic hydrogels for controlled release application, Con-
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`S.D. Roy and G.L. Flynn, Solubility behavior of nar-
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`tanil, Pharm. Res. 6 (1989) 147-151.
`
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