Br. J. clin. Pharmac. (1985), 19, 151S-162S In vitro and in vivo deconvolution assessment of drug release kinetics from oxprenolol Oros preparations F. LANGENBUCHER & J. MYSICKA Pharmaceutical Development, Ciba-Geigy Ltd, Basle, Switzerland 1 The relationship between in vitro and in vivo drug release from Oros systems has been examined by analysing plasma concentration data from two pharmacokinetic studies, using a numerical deconvolution technique. This method generates an input profile by comparing the response with that achieved following an instantaneous reference unit dose. The approach is conceptually simple and does not require compartmental pharmacokinetic modelling or curve fitting. 2 In the analysis of the first study, the plasma profile following intravenous dosing was used as the reference function, allowing the combined release/absorption process to be calculated; for the second, an oral bolus was used, the result of the deconvolution therefore indicating the in vivo dissolution rate of the Oros systems. 3 The in vivo release from Oros in most volunteers followed the same pattern as that measured in vitro; only after 6-8 h was the decline in the in vivo release rate somewhat greater than expected. 4 In a few individuals the cumulative absorption profile reached an early plateau level which coincided, on some but not all occasions, with the premature excretion of the Oros system from the body. The amount of drug in recovered systems agreed reasonably with the prediction of the deconvolution analysis. Keywords oxprenolol Oros preparations drug release kinetics Introduction The primary objective in the design of a drug delivery system for once-daily administration is to maintain effective blood concentrations throughout the dosage interval. In practice this is achieved by developing systems with extended durations of constant drug release (Theeuwes, 1975; Theeuwes et al., 1985). However, the success of this approach depends on the uniformity of the absorption kinetics throughout the gastrointestinal (GI) tract, since any change in the degree of first-pass metabolism, or poor absorption in certain segments of the gut, will significantly affect drug entry into the systemic circulation. Since routine measurements of drug uptake in different regions of the GI tract are difficult to perform, it is desirable to develop techniques to assess in 151S vivo absorption rates, in man, by the analysis of easily obtainable data. With the advent of controlled-release systems which maintain drug delivery for extended periods in comparison with conventional formulations, the characterization of the absorption process simply in terms of AUC, tmax, and Cmax values is clearly inadequate. The technique of linear systems analysis allows the study of time functions, such as plasma concentration data, without making any but the most general assumptions regarding the data. In particular, no compartmental pharmacokinetic model is assumed and curve fitting is not necessary, the actual data points being used in the calculation. Either an intravenous or oral bolus dose can be used to generate the weight-
152S F. Langenbucher & J. Mysicka ing function, allowing the estimation of either the combined release/absorption process or the pure release step in vivo (Hanano, 1967; Cutler, 1981; Langenbucher, 1982). The application of linear systems theory to the analysis of plasma profiles for Oros drug delivery systems is considered in the present paper. The plasma concentration data were generated in two pharmacokinetic studies, one comparing two 16/26 oxprenolol Oros systems, with intravenous dosing as a reference, the other comparing full- and half-strength Oros systems, using a conventional tablet formulation to provide the reference plasma profile. Methods Table 1 summarizes the materials used in the two studies (I and II). The purpose of study I was to compare the plasma profiles for 'prototype' and a 'clinical' preparation of Oros 16/ 26, with an intravenous bolus dose as reference (Bradbrook et al., 1985). Eight healthy male volunteers participated in this open, crossover study, and the plasma concentrations were measured by gas-liquid chromatography with metoprolol as internal standard; individual values are given in Table 2. Study II was a comparison of oxprenolol Oros 16/26 with the half-strength 8/13 form; a conventional 4 mg tablet served as the reference formulation (Ciba-Geigy Ltd, unpublished data). Nine healthy volunteers participated in a three-way crossover design; plasma concentrations were measured by means of a double radioisotope derivative (DRID) technique, and individual values are listed in Table 3. As indicated in Table 3, some of the values were adjusted prior to further mathematical analysis to remove obvious inconsistencies, e.g. non-zero values measured before dosing, etc. Table 1 Identification of the materials used in the bioavailability studies In both studies the time of bowel movements and recovery of the Oros system and, where possible, the drug content of the excreted system, were recorded. Theoretical and in vitro release The Oros systems contain 26 (or 13) mg of oxprenolol succinate and are designed to release drug at an initial, zero-order rate of 16 (or 8) mg/h. The release rate begins to decline when all the solid drug in the system is dissolved. For the existing oxprenolol systems this occurs when approximately 5% of the total content has been delivered, at roughly 8 h after dosing. By 12 h, approximately 65% of the drug is released; by 24 h this value increases to 85% of the total content. The theoretical Oros profile is shown in Figure 1, together with the measured in vitro release curves for each oxprenolol Oros preparation investigated, and for the conventional rapid-release tablet formulation. The curves represent means of either three or six individual Oros profiles, obtained by means of a flow-through dissolution method (Langenbucher & Rettig, 1977). The conventional tablet was tested at the standard flow rate of 16 ml/min, a pulsation of 13/min, and a 22.6 mm inner diameter cell. For the Oros systems the testing conditions were modified to avoid mechanical pumping on the softened shell. Under the revised conditions, pulsation was completely damped, and a flow rate of 4 ml/min was used to reduce the total volume of dissolution fluid used during the extended testing time. However, by using a smaller cell of diameter 12. mm, the same flow velocity was maintained. In all cases, the dissolution medium was a ph 1.3 buffer during the first hour, and a ph 7.5 buffer thereafter. Number of Amount of hydrochloride Code Preparation units administered Study A Oxprenolol succinate Oros 16/26 Prototype 1 242 mga) I B Oxprenolol succinate Oros 16/26 Clinical 1 242 mga) I C Iv. bolus injection 2 ml 2 mg I D Oxprenolol succinate Oros 16/26 1 242 mga) II E Oxprenolol succinate Oros 8/13 1 121 mga) II F Trasicor 4 tablets 3 12 mg II a) 26 mg of oxprenolol succinate corresponds to 242 mg of hydrochloride, 13 mg to 121 mg
Drug release kinetics from oxprenolol Oros Table 2 Plasma oxprenolol hydrochloride concentrations (ng/ml) after administration of Oros A, Oros B, and i.v. C. Data from Study I (Bradbrook et al.. 1985). 1 3 4 6 8 12 15 2 24 28 32 34 3 4 68 12 15 2 24 28 32 34 Time (h).83.167.333.5 9 3 4 6 8 12 Subjects 1 2 3 4 5 6 7 8 Oros A 146 13 27 17 54 218 112 124 83 6 3 96 72 271 158-215 164 168 172 221 13 247 227 284 186 129 12 24 141 252 165 152 17 99 25 135 14 26 136 179 142 114 61 17 13 182 145 315 136 18 9 122 97 12 1 215 137 99 161 92 98 88 54 81 87 74 141 82 64 24 65 65-63 92 29 3 11 41 17-11 71 7 7 16 - - 53 -- - 42 Oros B 33 94 18 63 27 32 11 227 138 58 72 36 112 162 274 366 213 271 155 56 246 157 237 331 219 264 166 11 26 99 213 274 244 24 136 1 31 73 149 113 212 14 131 113 197 69 114 19 182 18 115 115 189 62 297 12 111 93 71 221 42 21-83 88 61 5 18 34 135 39 86 47 6 77 6 8 15 5 17 23-37 46 9 - z 44 - I.v. C 634 564 847 426 391 52 59 52 387 468 511 344 265 354 355 428 312 389 441 36 249 265 291 34 298 318 346 217 189 213 252 316 24 252 241 172 12 122 173 23 15 16 97 122 9 67 92 13 65 52 46 72 54 33 53 7 35 29 26 39 27 16 29 38 13 6 15 7 5 1 5 _ 153S Deconvolution ofplasma responses unit response, or weighting function of the body system, as observed after intravenous or oral The input functions from each Oros system bolus dosing, and I(t) either the combined were computed by means of numerical decon- release/absorption or the release time function. volution represented by the expression: To allow the comparison of data following l(t) = R(t) ll W(t) (1) different doses of oxprenolol, all plasma data were linearly adjusted to a common dosage where R(t) denotes the response (plasma con- level of 24 mg hydrochloride salt. Deconvolucentration) after Oros administration, W(t) the tion according to equation (1) was computed by
154S F. Langenbucher & J. Mysicka Table 3 Plasma oxprenolol hydrochloride concentrations (ng/ml) after administration of Oros D, Oros E, and Trasicor tablet F. Data from Study II (on file, Ciba-Geigy Ltd). Subjects Time (h) 1 2 3 4 5 6 7 8 9 Oros D 5b 2b lb lb 1 21 1 26 24 16 5 7 2 9 2 162 88 151 18 95 42 56 85 17 3 368 263 397 487 211 127 171 182 23 4 379 264 48 47 168 11 148 15 225 6 429 249 252 511 23 83 183 144 212 9 32 17 278 438 274 38 111 132 86 12 231 17 56 23 27 58 73 112 152 15 23 18 14 11 25 4 84 3 147 2 116 18 4 37 12 17 36 2 53 24 116 13 19 113 2 42 6 44 27 59 12 13 99 8 28 69 3 59 11 6 53 158a 9 44 36 7 3 2 3 26 2 1 17 Oros E 3b 2b lb 1 8 26 1 27 3 9 2 44 54 69 253 15 16 22 58 18 3 177 118 152 463 65 36 71 86 73 4 176 137 13 552 79 52 72 111 85 6 22 153 144 59 1 26 83 81 79 9 18 77 111 545 141 41 45 16 43 12 1 69 6 548 86 35 52 89 38 15 112 65 71 679 79 27 44 44 4 2 99 32 54 32 54 9 9 23 28 24 75 33 46 256 41 17 17 28 4 27 21 42 79 199 49 15 9 21 35 3 5 18 8 1 2 2 5 6 13 36 16 42 9 1 3 1 4 Tablet F 6 12 4 2 3.5 719 681 551 871 76C 44 663 196 337 1 138 751 957 1258 439 295 472 526 52 1.5 166 561 871 1223 66 228 382 43 434 2 852 54 836 1196 565 216 298 433 335 2.5 693 349 595 93 517 145 229 32 278 3 61 296 377 84 389 115 236 234 259 4 385 171 265 616 276 7 146 125 192 6 176 62 74 36 22 21 54 44 77 9 48 13 11 169 74 1 12 9 15 12 22 4 8 85 38 2 5 3 2 15 13 3 3 46 17 2 5 2 3 24 4 4 4 4 2 6 a - value replaced by 5 b - value replaced by c - replaced by interpolated value of 22 means of the CONVOL computer program manner similar to that of the point-area method (Langenbucher, 1982). A common time step of (Vaughan & Dennis, 1978) but is conceptually.83 h (5 min) for study I, and.5 h for study more simple. Figure 2 illustrates a typical result II, was chosen as being the most suitable for of the linear interpolation used to generate analysing the plasma concentration data. In equidistant time-points of R(t) and W(t), and both cases the trapezoid algorithm of Stepanek the cumulative input function (absorption or (1976) was employed, which functions in a release) from the deconvolution analysis.
Instability in the calculation due to the generation of negative input values was minimized by replacing the calculated negative input value with zero (Kiwada et al., 1977). This results in a stepwise appearance of the cumulative input curve (see Figure 2). No obvious systematic bias results from this procedure. Results and discussion In vitro drug release The in vitro release of all four Oros preparations, shown in Figure 1, is close to that predicted theoretically with the addition of a lag time of.5-1 h. This delay probably reflects the time taken for the system to generate sufficient osmotic pressure to initiate drug release. Thereafter, the release rate from all the systems closely followed the theoretical curve with the exception of preparation E, which seemed to release drug at a slower than expected rate. As expected, drug release from the conventional tablet F was very rapid, with a mean dissolution time of about.4 h. In contrast the mean release time of the Oros preparations was between 1 and 14 h. Since this difference was considerable, the use of the conventional plasma data as the response function to a unit oral dose in the deconvolution analysis of Oros data in study II was considered justifiable. 1 9 8 _% 7 6 C, 5 o 4 a 3 2 1 F Drug release kinetics from oxprenolol Oros Deconvolution with intravenous data (study I) The results of the deconvolution of Oros A and B with the intravenous bolus C are shown in Figure 3. The curves represent the fraction of drug which has entered the systemic circulation at a given time. Essentially the same result was obtained using Wagner-Nelson or Loo- Riegelman analysis (Bradbrook et al., 1985). However, these methods require that a particular compartmental model is chosen, whilst the present analysis is free of any compartmental assumptions and relies only on the linearity and time-invariance of the body system. In the majority of the cases, plateau values in the cumulative absorption plots coincided with expulsion of the system from the body, although this was not verified in all cases. A clear exception is subject 1 after treatment B, where the computed input function indicates that absorption stopped at approximately 6 h but the Oros system was not recovered during the observation period. Similarly, in the case of subject 6, deconvolution of the plasma concentration data indicated that absorption ceased at 7-9 h but the system was not recovered until 25.4 h after dosing. In this particular example, the amount absorbed was estimated to be 18% of the administered dose but the residual drug in the expelled system indicated that nearly 9% was released. In this same individual, the degree of absorption after the alternative Oros 2 4 6 8 1 12 14 16 18 2 22 24 Time (h) Figure 1 In vitro oxprenolol release from conventional tablet (F) and four Oros preparations (Ao, BA, Do, and Eo). All curves represent mean values of either three or six single determinations, obtained with the flow-through dissolution method. Actual in vitro (-) and theoretical (---) release profile for oxprenolol succinate Oros system. E 155S
156S F. Langenbucher & J. Mysicka l J. SSm* o..62 * *- * c a).4 ) co._ CU co.2 L'- * tn.t E CD e)2 - C ) - C.) co al) Co co. S Tablet en - Om ṯ A It h&ak- * AA AAA A o * a, AA ama Oros -OOO OOOOihBIaab &AA*AAAIIA~,&i~A,A 6 12 18 24 3 Time (h) Figure 2 Cumulative fraction of drug released (upper graph), computed by numerical deconvolution (.5 h time step) of the plasma response to an Oros system with an oral bolus weighting function (lower graph). The final plateau represents the relative bioavailability of Oros with respect to the tablet.
Drug release kinetics from oxprenolol Oros 157S.8[ Subject 1 Subject 2 ar ) -. L- a) m coi c._ cj co.6.4.2.8 _ Subject 3.6..4..2[.8.8.6.4.2 ti - u- ni.6-.4 _.2 _ ui Subject 5 Subject 7.53 1, ~~~~~.24.45.45.46 =.39.45.2 s, 1 6 12 18 24 3 Time (h) Subject 4.43..9.39 Subject 6,,"~~~~~. 'x -.45.36.84 _6-.18 Subject 8..54 I 2I 3 6 12 18 24 3 U- Figure 3 Individual time functions of the fraction absorbed, obtained by deconvolution of the plasma concentration data for Oros A (-) and B ) using i.v. data as the weighting function. The values given with each curve indicate the cumulative amount reaching the circulation after 32 h. recovered from faeces, x = achievement of a plateau level in the deconvolution profile. = system
158S F. Langenbucher & J. Mysicka 1 9 8 _ 7 ~ Oros A 6 s - 4-3 -. w 2 4 8 11t2 14 1 2 22 242 9 7 - a.~~~~~~~~~~~~~~~~~~~7 7 23 4~~~~~~~~~~~~~~ (3~ ~ ~ ~ ~ h 1 2 4 6 8 1.612 14 1l6 186 2 222:42 fls@3 Time (h) Figure 4 Combined plots of fraction of drug absorbed from Oros A and B as a function of time. The plateau phases for individual profiles have been omitted for clarity. The solid curve shows the in vitro release profile, multiplied by an assumed first-pass factor of 6%.
Drug release kinetics from oxprenolol Oros 159S.8.6.4.2F Subject 1.73 Subject 2 84 /e - -.64. 8 Subject 3.76. 6- - -- 1 O. 4--.43..2 - ' -. Subject 4 K.41 a) CO) co CO) c n- Subject 5.81.6[.4[.2 I-J! I -.4 'O.. -.-, -.99,e.83 Subject 6.62.54 LL..8.6[.4[.21 Subject 7.57.53 /~~~~~~~~~~~~~~~~~~~~~~~~~~~r Time (h) Figure 5 Individual time functions of the fraction absorbed obtained by deconvolution of the plasma concentration data for Oros D (-) and E (---) using tablet F data as the weighting function. The values given with each curve indicate the cumulative amount reaching the circulation after 32 h. * = system recovered from faeces, x = achievement of a plateau level in the deconvolution profile, T = residual drug fraction recovered.
16S F. Langenbucher & J. Mysicka O'%' 2. Oro D.2.9 4 a L. Oroc E Figure 6 Combined plots of fraction of drug release from Oros D and E as a function of time. The plateau phases for individual profiles have been omitted for clarity. The solid curve shows the in vitro release profile. system (84%) was higher than expected from previous studies, but no obvious explanation for this finding presents itself. When using an intravenous reference dose, incomplete or delayed release from the dosage form cannot be distinguished from reduced absorption or loss due to first-pass metabolism. In one study (Mason & Winer, 1977), the fraction of oxprenolol reaching the systemic circulation after oral dosing was found to be about 6% with a range from 41 to 75% in six subjects. Figure 4 shows the absorption profiles for all the subjects in study I compared with the in vitro release scaled by a factor of.6 (solid curve), i.e. assuming a constant first-pass factor of 6% throughout the absorption period. For clarity, the curves were truncated when a plateau value was reached, and the profile for
subject 6 after treatment B was omitted. Accepting that the assumption concerning the extent of the first-pass effect may not be valid for all subjects, the results of the deconvolution analysis indicate that the release/absorption rate was slower than the scaled in vitro rate, but there were no obvious differences between the two Oros preparations. Deconvolution with oral data (study II) The results of the deconvolution of Oros D and E, weighted using the bolus data for the conventional tablet F, are shown in Figure 5. Data from subject 4 following treatment E were excluded, as there was some doubt as to the dosage given. The calculated profiles in this figure represent the fraction of total drug released from the dosage form into the gastrointestinal lumen at a given time. Again, no assumptions other than linearity and timeinvariance of the body system are made. However, since the absorption process itself is now part of the body system, it must also behave in a linear and time-invariant fashion. In particular, the extent of first-pass loss (both in the gut wall and liver) is assumed to remain constant throughout the gastrointestinal tract. The computed release curves depicted in Figure 5 indicate that the in vivo rates of drug release from the Oros systems correspond reasonably well with the in vitro dissolution profiles. Where the system could be recovered from the faeces, the residual drug content was, in most cases, similar to the amount predicted from the plateau value of the deconvolution profile. Thus the analysis- of plasma_ profiles using the deconvolution approach provides a valid insight into both the in vivo rate of release and extent of drug absorption. Deconvolution of the plasma level data in study II has identified a number of interesting effects which warrant further consideration. In subject 3 after treatment D, for example, the profile indicates that release stopped at approximately 8 h, although no bowel movement was recorded at this time and the system was not expelled. A similar effect occurred after treatment D in subject 4. In both cases it seems Drug release kinetics from oxprenolol Oros 161S that the system stopped releasing drug at these points, although an alternative explanation is that the drug was released but not absorbed from the gut lumen. The last observation, however, conflicts with the results reported by Antonin et al. (1985), who showed that oxprenolol was similarly absorbed in the small intestine and in two regions of the colon. No explanation can be advanced to explain the high calculated total release from formulation E in subject 8. Figure 6 summarized the results of the deconvolution analysis in study II with the anomalous curves omitted for clarity. Both in vitro dissolution and in vivo release curves showed an initial delay of approximately 1 h. During the next 6 h, in vivo release closely followed the theoretical and measured in vitro release profile. Thereafter, in most cases, in vivo release seemed to decline more rapidly than expected, with the slowest rate being approximately 6% of the in vitro value. This reduction exceeds the technical variability in Oros release and may reflect changes in system performance in response to the different luminal environments, or an increase in the degree of first-pass metabolism as the system travels down the gastrointestinal tract. In conclusion, the present analysis showed that the calculated in vivo performance of the Oros systems is in reasonable agreement with that assessed by in vitro dissolution methods. The assumptions of linearity and time-invariance necessary for the calculation do not appear to restrict significantly the use of the deconvolution technique, which has the potential to indicate both the rate and extent of absorption from the gastrointestinal tract. The results suggest that drug release and absorption from Oros systems occurs throughout the gastrointestinal tract for up to 32 h, although in some instances premature excretion of the system occurred with a consequent reduction in bioavailability. The overall release rate calculated using an oral reference dose shows greater variability in vivo than indicated by in vitro tests, ranging from 6 to 1% of both the theoretical and measured in vitro release behaviour. References Antonin, K.-H., Bieck, P., Scheurlen, M., Jedrychowski, M. & Malchow, H. (1985). Oxprenolol absorption in man after single bolus dosing into two segments of the colon compared with that after oral dosing. Br. J. clin. Pharmac., 19, 137S-142S. Bradbrook, I. D., John, V. A., Morrison, P. J., Rogers, H. J. & Spector, R. G. (1985). Pharmacokinetic investigation of the absorption ot oxprenolol from Oros delivery systems: comparison of in vivo and in vitro drug release. Br. J. clin. Pharmac., 19, 163S-169S.
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