DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, 19(9), 1061-1081 (1993)
`
`FLOATING AND SWELLING CHARACTERISTICS OF VARIOUS
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`V.S. Gerogiannis, D.M. Rekkas, P.P. Dallas and N.H.Choulis
`University of Athens, Department of Pharmacy,
`Division of Pharmaceutical Technology,
`Panepistimioupolis 157 71, Athens, Greece
`
`ABSTRACT
`
`During the past few years, great interest was developedin the subject of
`
`floating. In the present study, the floating and swelling characteristics of
`
`several excipients used controlled release technology were examined. The
`floating behavior was evaluated with resultant weight measurements, while a
`
`gravimetric method was employedfor studying their swelling. The experiments
`
`were carried out in two different media, i.e. deionized water and simulated
`
`meal in order to monitor possible differences. The results indicated that higher
`
`molecular weight polymers and slowerrates of polymer hydration are usually
`
`followed by enhancedfloating behavior. The floating characteristics ofall
`
`evaluated excipients were improved when simulated meal medium wasused.
`
`Finally, the combination of resultant weight measurements and swelling
`
`experiments can be used to determine in vitro the buoyancy, weight and
`
`
`
`Presented at 11th Pharm. Tech. Conf., April 6-8, 1992, Manchester, U.K.
`
`1061
`
`Copyright © 1993 by Marcel Dekker, Inc.
`
`MSNExhibit 1045 - Page 1 of 21
`MSNv. Bausch - IPR2023-00016
`
`

`

`1062
`
`GEROGIANNIS ET AL.
`
`volume changes of orally administered dosage forms and to predict floating
`
`behavior.
`
`INTRODUCTION
`
`Gastrointestinal (Gl) residence time depends on manyfactors such as the
`
`density of the dosage form (1, 2, 3), the size of the dosage form (1, 3), meal
`
`intake (4, 5, 6), nature of the meal (4, 7), sleep (8), posture (9), exercise (10),
`
`etc.
`
`Many researchers (11, 12, 2, 13, 14) have suggested that a floating
`
`dosage form may either prolong GI residence time or at least prevent erratic
`
`gastric emptying during the digestive phase (1). Moreover, during the past
`
`few years, several dosage forms, like the Hydrodynamically Balanced System
`
`(HBS) (11), were designed to prolong Gl residence time dueto their floating
`
`capabilities. Under that scope, it would be useful to examine the floating and
`
`swelling characteristics of several excipients used in controlled release
`
`technology. To achievethat, resultant weight and water uptake measurements
`
`of several dosage forms, immersed in specific media, were performed, and
`
`volume changes were monitored at various time intervals.
`
`MATERIALS AND METHODS
`
`All excipients werefilled volumetrically, by a manual method, into size 2
`
`hard gelatin capsules (Capsugel AG, CH).
`
`MSNExhibit 1045 - Page 2 of 21
`MSNv.Bausch - IPR2023-00016
`
`

`

`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1063
`
`The excipients used were: Hydroxypropy!l methylcellulose (HPMC):
`
`MethocelgradesK, E and F (Colorcon, U.K.), sodium carboxymethyicellulose:
`
`CMCNa, (Aqualon, U.S.A.), hydroxypropylcellulose: HPC grade H (Nisso,
`
`Japan), Polycarbophil: Noveon AA1 (BF.Goodrich, U.S.A.) poly(ethylene) oxide:
`
`Polyox grades WSR N-750 and WSR-303 (Union Carbide, U.S.A.), sodium
`
`alginate: Protanal LF 20/200 and Protanal LF 120M (Protan Biopolymer A/S,
`
`Norway).
`
`Valrelease® capsules (Hoffmann-La Roche) were also evaluated.
`
`Test Media
`
`- Air free deionized water (D.W.) (density =0.997gr/ml)
`
`- Simulated meal medium (S.M.M.), prepared by mixing the complete
`
`nutrition product Ensure”
`
`R
`
`(Abbott Laboratories, Hellas) with the adequate
`
`amountof deionized water (5.0/4.6) (density = 1.033gr/ml).
`
`Floating Measurements
`
`The floating characteristics of the above excipients were evaluated with
`
`resultant weight measurements. Resultant Weight Force (FRW) is a vertical
`
`force and represents the vectorial sum of the buoyancy (Fg) and gravity (Fy)
`
`forces which act on an object whenit is immersed in a specific medium (15)
`
`(Equation 1).
`
`Faw = Fp - Fw => RW.g = B.g-W.g => R.W = B-W = df.V-W
`
`(1)
`
`where: g is the acceleration of gravity, df is the fluid density and V, W are the
`
`volume and the weightof the object respectively. RW was measuredin vitro.
`
`Each excipient was examinedatleast three times. The apparatus used, which
`
`MSNExhibit 1045 - Page 3 of 21
`MSNv.Bausch - IPR2023-00016
`
`

`

`1064
`
`GEROGIANNIS ET AL.
`
`1. Balance
`
`2. Interface
`
`3. Water-bath
`
`4. Test medium
`S. Computer
`6. Printer
`
`Figure 1: The resultant weight measurement
`
`apparatus.
`
`is shown in Figure 1, was based on the one developed recently by
`
`Timmermans and Moes(16,17,18). The most important difference was that
`
`the balance (Mettler AE200) was connected through an RS 232C interface to
`
`a Personal Computer and the recorder was substituted by a printer. Thus, at
`
`any time an exact indication (gr) of the RW vaiue was available. The
`
`MSNExhibit 1045 - Page 4 of 21
`MSNv.Bausch - IPR2023-00016
`
`

`

`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1065
`
`apparatus wasvalidated through comparison of theoretical and experimental
`
`data for spherical objects. The difference between the mean experimental and
`
`the mean theoretical value of RW was not greater than 0.87%. A standard
`
`deviation (SD) of less than 0.0042 was calculated between five subsequent
`
`measurements.
`
`Swelling Measurements
`
`A gravimetric method (19, 20, 21, 22) was considered to be the most
`
`suitable in order to study the swelling behavior of the excipients.
`
`The
`
`capsules, containing the excipients, were kept in USP dissolution baskets
`
`without rotation. The wet weight of the swollen dosage form was recordedat
`
`specific time intervals. Swelling characteristics were expressed in terms of
`
`water uptake (WU) (%) (22, 23) according to the equation 2:
`
`(W of swollen form - initial W of the form)
`WU (%) = wnn---22-nnennnncenseccnnnnesneneenannnenn x100
`initial W of the form
`
`(2)
`
`RESULTS AND DISCUSSION
`
`The selected excipients are polymeric materials that can absorb a
`
`significant amount of water (more than 20% of their dry weight), while
`
`maintaining a distinct three-dimmensional structure. As a result, they conform
`
`to the definition of hydrogels provided by Gehrkeet al, (24). When a dosage
`
`form is immersedin a specific medium and after the dissolution of the gelatin
`
`capsule, an outer gel layer is formed, accompanied by an increase ofits
`
`volume. The process of erosion, due to dissolution of the gel formed or to
`
`MSN Exhibit 1045 - Page 5 of 21
`MSNv.Bausch - IPR2023-00016
`
`

`

`1066
`
`GEROGIANNIS ET AL.
`
`deaggregation (20), and the creation of new gel layers affect both the volume
`
`and the weight of the dosage form.
`
`The RW force which is responsible for floating depends on both the
`
`weight and the buoyancy forces, as shown in equation 1. Water uptake and,
`
`consequently, weight gain should be compensated by adequate swelling in
`
`order to keep the dosage form at buoyant state. RW data for each dosage
`
`form were plotted versus time. Representative graphs are shownin Figures 2
`
`and 3.
`
`In all cases RW decreasedin a step-like pattern, due to the periodic
`
`release of air bubbles created by the substitution of air, enclosed in pores of
`
`the formulation, by the test medium. Such a phenomenon does not take
`
`place in the case of Valrelease (Figure 2),which maybe due to the
`
`compression of the capsule contents. This observation is in aggreementwith
`
`previous findings of Timmermans et al
`
`(16,17,18).
`
`In each graph,
`
`the
`
`horizontal zero baseline represents the measurement obtained by the
`
`apparatus when no dosage form was immersed. The point where an RW
`
`graph crosses the zero baseline indicates the Maximum Floating Time (MFT),
`
`namely, the time period a dosage form remains at buoyant state, when
`
`immersed in a specific medium. An additional criterion applied in the
`
`evaluation of excipients was the Area Under the Curve (AUC), i.e. the area
`
`between the RW curve andthe zero baseline. These data are summarized in
`
`Table 1.
`
`According to Table 1, it can be derived that different viscosity grades of
`
`the same polymerdisplay significant differences both in AUC and MFT values.
`
`MSNExhibit 1045 - Page 6 of 21
`MSNv. Bausch - IPR2023-00016
`
`

`

`
`
`IZJOLe8ed-SPOTHaNUXANSW
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`91000-€707UdI-Yosneg“ANSW
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`1067
`
`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
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`

`

`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1069
`
`Table 1: Area Under the Curve (AUC) and Maximum Floating Time
`
`(MFT) derived from Resultant Weight measurements of
`
`dosage forms. Parentheses indicate SD.
`
`
`
`[aetiecetwe[ewe|were[|
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`>8
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`:
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` Methocel K 100M
`
`
`
`
`Methocel K 100M CR
`
`Methocel K 100M CR
`
`Methocel E 4M
`
`Methocel E 4M
`
`Methocel E 10M CR
`
`Methocel F4M
`
`CMC Na
`
`HPC H
`
`Noveon AA1
`
`Polyox 750
`
`Polyox 303
`
`Polyox 303
`
`Protanal LF 20/200
`
`Protanal LF 120M
`
`Protanal LF 120M
`
`Valrelease
`
`Valrelease
`
`
`
`
`
`
`
`
`
`
`Deionized Water
`W
`-M.M.: Simulated Meal Medium
`
`MSN Exhibit 1045 - Page 9 of 21
`MSNv. Bausch - IPR2023-00016
`
`

`

`1070
`
`GEROGIANNIS ET AL.
`
`Particularly, Methocel K 100M displays better floating capabilities compared
`
`to Methocel K 4M (46.7% greater AUC, 34.3% longer MFT). According to the
`
`product's information pamphlet (25), Methocel K 100M has greater Molecular
`
`Weight (MW) than Methocel K 4M. The same was observedin the case of
`
`Polyox polymers (Table 1).
`
`Polyox 303 (M.W. 7.000.000) shows 618.3%
`
`greater AUC and more than 479% longer MFT compared to Polyox 750 (M.W.:
`
`300.000). From the above observations, it can be concludedthat as the M.W.
`
`of these polymersincreases,their floating characteristics are enhanced.
`
`Chemical substitution of Methocel polymers seemsto affect the floating
`
`characteristics as well. According to the product's information pamphlet (25)
`
`the differences in chemical substitution result in different rates of hydration.
`
`The lowest percentage of the hydrophobic substituent (methoxyl group) and
`
`the highest amount of hydrophilic (hydroxylpropoxyl) substitution give to
`
`MethocelK series the fastest rate of hydration compared to E andFseries.
`
`The findings displayed on Table 1 indicate that there might be somekind of
`
`correlation between the rate of hydration and floating characteristics among
`
`polymersof the sameviscosity grade. Methocel K 4M, for instance, which has
`
`the fastest rate of hydration displays 21.9% smaller AUC and 16.4% shorter
`
`_MFT compared to Methocel E 4M, whichis the next fastest. Methocel K 4M
`
`also shows 29.5% and 35% smaller AUC and MFT values respectively when
`
`compared to F 4M, which has the slowest rate of hydration.
`
`It should be
`
`mentioned, however, that the above explanation contradicts with previously
`
`conducted research (26) which indicated that the rates of hydration between
`
`HPMCseries are not significantly different.
`
`MSN Exhibit 1045 - Page 10 of 21
`MSNv. Bausch - IPR2023-00016
`
`

`

`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1071
`
`From Table 1,
`
`it can be concluded that Methocel K 100M (90% passed
`
`through a 40 meshscreen) exhibits more than 13.3% longer MFT and 9.5%
`
`larger AUC compared to Methocel K 100MCR (99% passes through an 100
`
`meshscreen). A similar effect of particle size is also observed in the caseof
`
`sodium alginate. Protanal LF 120M (99% passes through 120 meshscreen)
`
`displays 10.1% and 32.3% larger AUC and MFT values respectively (Table 1)
`
`compared to Protanal LF 20/200 (99% passes through a 200 meshscreen).
`
`Although the polymer’s particle size seems to have someeffect on floating
`
`behavior, the differences were not found significantly different ( t test,
`
`p< 0.01).
`|
`The floating behavior of the various dosage forms depends upon the
`
`medium used as well
`
`(Table 1).
`
`This has also been suggested by
`
`Timmermans et al (16,17,18). Dosage forms displayed larger AUCs and
`
`longer MFTs when immersed in SMM. The higher density of SMM compared
`
`to DW leads to higher buoyancy values for the same dosage form volume.
`
`Moreover, this effect may be attributed to the presence of fatty substances
`
`which delay water uptake. Excluding Methocel K 100M CR which showed
`
`similar AUC in both DW and SMM, therest of excipients displayed an at least
`
`10% higher AUC when immersed in SMM compared to DW. All excipients
`
`increasedtheir MFT for at least 18% in SMM.
`
`It should also be mentionedthat
`
`all members of MethocelK series under evaluation remained buoyant for more
`
`than 8 hours when the test medium was SMM.
`
`Swelling measurements were performed separately in orderto collect data
`
`on the weight increase of the various forms over time and also to examineif
`
`MSNExhibit 1045 - Page 11 of 21
`MSNv. Bausch - IPR2023-00016
`
`

`

`1072
`
`GEROGIANNIS ET AL.
`
`there is any correlation with the previous findings on the floating behavior of
`
`excipients. Water Uptake (%) (Equation 2) data were plotted versus time
`
`(Figures 4, 5). The above graphs express the swelling behavior of a range of
`
`excipients both in DW and SMM. It should be pointed out that such data alone
`
`cannot provide accurate information on floating characteristics, which is
`
`depicted by the fact that dosage forms such as Polyox 303 and Valrelease,
`
`with radically different WU profiles, display both excellent floating behavior.
`
`To investigate further the previous findings Buoyancy (B) has been also
`
`estimated. Based on Equation 1, B can be caiculated by adding RW and the
`
`weight (W) of the dosage form at a specific time point. Both B and W data
`
`were plotted versus the square root of time. Then regression analysis was
`
`performed.
`
`In all cases, regressionlines for B versus the square rootof time
`
`displayed greater intercept and smaller slope values compared to W versus
`
`the square rootof time lines. At the point where the regressionlines of B and
`
`W cross eachother, i.e. when B equals W, the dosage form starts sinking
`
`(Figure 6). Therefore,
`
`that point represents MFT, and,
`
`thus the above
`
`regression equations can be applied effectively in calculating mathematically
`
`MFT. Additionally, the volume (V) of a dosage form can be calculated by
`
`dividing B by the test medium density.
`
`Since the volume of orally
`
`administered dosage forms could influence GI residence time (27) the above
`
`measurements can be very useful. The calculated volumes at various time
`
`points of several dosage forms, after immersion in a specific medium, are
`
`shownin Table 2. According to this Table, Polyox 303 acquires after eight
`
`MSN Exhibit 1045 - Page 12 of 21
`MSNv. Bausch - IPR2023-00016
`
`

`

`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1073
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`IZJOPIa8ed-SPOTHGIUXANSIN
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`1074
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`GEROGIANNIS ET AL.
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`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
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`Aouphonge
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`

`1076
`
`GEROGIANNIS ET AL.
`
`Table 2: Volume of several excipients filled in size 2 hard
`
`gelatin capsules after immersion
`
`in a particular
`
`medium. Bars indicate SD.
`
`
`Time (HR)
`
`
`
`Volume (ML)
`
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`Polyox 303
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`Valrelease
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`Valrelease
`
`
`
`
`: Deionized Water
`W.
`-M.M.: Simulated Meal Medium
`
`MSNExhibit 1045 - Page 16 of 21
`MSNv. Bausch - IPR2023-00016
`
`

`

`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1077
`
`Table 3: Slopes
`
`of the
`
`regression lines of Weight
`
`(Slope W)
`
`and Volume (Slope V)
`
`versus
`
`the
`
`square
`
`root
`
`of time,
`
`for excipients filled in size 2 hard gelatin capsules.
`
`Parentheses indicate SD.
`
`Dosage Form
`
`Medium
`
`Slope W
`
`Slope V
`
`
`SlopeW
`
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`
`
`
`
`
`PistonsBnewor|p.w.[outere.ea)|oveoenm|19
`
`
`
`Pretyerses[nm[oweoer|ose?won|a8|
`
`: Deionized Water
`D.W.
`S.M.M.: Simulated Meal Medium
`
`hours of immersion in DW thelargerV, 8.7 times greater comparedtoitsinitial
`
`V. Moreover,
`
`the measurment of V helps identifying which of the two
`
`processes-weight gain or volume expansion- is more important for a particular
`
`excipient. For that purpose, W and V were plotted versus the squareroot of
`
`time and regression analysis was performed for the first eight hours. The
`
`slopes of these regression lines, for some of the excipients used, are shown
`
`MSNExhibit 1045 - Page 17 of 21
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`

`

`1078
`
`GEROGIANNIS ET AL.
`
`in Table 3.
`
`In all cases, the slopes of W increase versus the square root of
`
`time were larger than those of V increase. The slower rate of V increase
`
`compared to W increase indicates that after a particular time point, V
`
`expansion can not generate a buoyancy force substantial enough to
`
`counteract W increases.
`
`It should also be mentioned that the slopes of both
`
`W and V are decreased in SMM compared to DW.
`
`In orderto investigate
`
`further the above findings, the ratio of the slope of W over the slope of
`
`V(slopeW/slopeV), versus the root of time was calculated. This ratio seems
`
`to correlate with the floating behavior of the excipients. More specifically, the
`
`lower the value of the ratio, the better the floating characteristics. As a
`
`consequence,
`
`the floating behavior of an excipient can be predicted by
`
`monitoring W and V over a time period.
`
`CONCLUSION
`
`Resultant Weight measurements of excipients, widely used in controlled
`
`release technology, show that higher molecular weight polymers and slower
`
`rates of polymer hydration are usually followed by enhanced floating behavior.
`
`Therefore, the selection of high molecular weight and less hydrophilic grades
`
`of polymers seem to improve floating characteristics. The floating behavior of
`
`all evaluated excipients was enhanced when simulated meal medium was
`
`usedinstead ofdistilled water. The resultant weight measurements combined
`
`with swelling experiments can be used to determinein vitro the buoyancy and
`
`volume changesversustime of various orally administered dosage forms. The
`
`MSN Exhibit 1045 - Page 18 of 21
`MSNv. Bausch - IPR2023-00016
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`

`

`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1079
`
`slopes of weight, volume and buoyancy of dosage forms versus the square
`
`root of time provide important information on their behavior, when immersed
`
`in a specific medium, and can be effectively applied to predict floating
`
`behavior.
`
`REFERENCES
`
`1. Timmermans, J., Van Gansbeke, B., Oth, M., Franz, M. and Moes, A.J.,
`Gastric residence time of floating vs non-floating matrices correlated with in
`vitro measuredsize and resultant-force kinetics. 16th International Symposium
`on controlled release of bioactive materials. Proccedings of the symposium
`(August 6-9 1989) p.60.
`
`2. Sugito, K., Ogata, H., Goto, H., Noguchi, M., Kogure, T., Takano, M.,
`Maruyama, Y. and Sasaki, Y., Gastrointestinal transit of non-disintegrating
`solid formulations in humans.
`Int. J. Pharm. 60, 89 (1990).
`
`3. Esposito, P., Sandefer, E., Digenis, G.A. and Carli, F., Effect of size and
`density on gastric residence of non swellable dosage forms.
`10th
`Pharmaceutical Technology Conference. Proceedings of the Symposium,
`April 16-18, 1991, p.121.
`
`4. Davis, S.S., Khosla, R., Wilson, C.G. and Washington, N., Gastrointestinal
`transit of a controlled-release pellet formulation of tiaprofenic acid and the
`effect of food. Int. J. Pharm., 35, 253 (1987).
`
`5. Sangekar, S., Vadino, W.A., Chandry,I., Parr, A., Beinn, R. and Digenis,G.,
`Evaluation of the effect of food and specific gravity of tablets on gastric
`retention time.
`Int. J. Pharm. 35, 187 (1987).
`
`6. Khosla, R. and Davis, S.S., The effect of tablet size on the gastric emptying
`of non-disintegrating tablets, Int. J. Pharm. 62, R9 (1990).
`
`7. Khosla, R., Feely, L.C. and Davis, S.S., Gastrointestinal transit of non-
`disintegrating tablets in fed subjects,Int. J. Pharm. 53, 107 (1989).
`
`8.Coupe, A.J., Davis, S.S., Evans, D.F. and Wilding, I.R., The effect of sleep
`on the gastrointestinal transit of pharmaceutical dosage forms,Int. J. Pharm.
`78, 69 (1992).
`
`MSNExhibit 1045 - Page 19 of 21
`MSNv. Bausch - IPR2023-00016
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`

`

`1080
`
`GEROGIANNIS ET AL.
`
`9. Moore, J.G., Patz, F.L., Christian, P.E., Greenberg, E. and Alazraki, N.P.,
`Effect of body posture on radionuclide measurements of gastric emptying.
`Dig. Dis. Sci., 33, 1592 (1988).
`
`10. Moore, J.G., Datz, F.L., Christian, P.E., Exercise increases solid meal
`gastric emptying rates in man, Dig. Dis. Sci., 35, 428 (1990).
`
`11. Sheth, P.R. and Tossounian, J., The Hydrodynamically Balanced System
`(HBS™). a novel drug delivery system for oral use. Drug Dev. Ind. Pharm. 10
`(2), 313 (1984).
`
`12. Ingani, H.M., Timmermans, J. and Moes, A.J., Conception and in vivo
`investigation of peroral sustained release dosage forms with enhanced
`gastrointestinal transit.
`Int. J. Pharm. 35, 157 (1987).
`
`13. Babu, V.B.M. and Khar, R.K., In vitro and in vivo studies of sustained-
`release floating dosage forms containing salbutamol sulfate, Pharmazie 45,
`268 (1990).
`
`14. Fell, J., Methods of delaying Gl transit! Oral sustained and controlled
`release drug delivery systems. European continuing Education College.
`Bologna,Italy, April 15 1991. Proceedings of the course, 1991, p.p. 45-57.
`
`15. Cromer, A.H., Physics for the life sciences, 2nd Ed. Int. Student Edition
`McGraw-Hill Intern. Book Co., Tokyo, Japan, 1981, p. 134-153.
`
`16. Timmermans, J. and Moes, A.J., How well do floating dosage formsfloat?
`Int. J. Pharm. 62, 207 (1990).
`
`17. Timmermans, J. and Moes, A.J., Measuring the resultant weight of an
`immersed test materlal: |. Validation of an apparatus and a method dedicated
`to pharmaceutical applications. Acta Pharm. Technol. 36 (3), 171 (1990).
`
`18. Timmermans, J. and Moes, A.J., Measuring the resultant weight of an
`immersed test material:
`Il. Examples of Kinetic determinations applied to
`monilithic dosage forms. Acta Pharm. Technol. 36 (8), 176 (1990).
`
`19. Golomb, G., Fisher, P. and Rahamim, E., The relationship between drug
`release rate, particle size and swelling of silicone matrices, J. Controlled
`Release, 12, 121 (1990).
`
`20. Malamataris, S., Hatzipantou, P. and Tsiri, K., Swelling and erosion of a
`sustained release matrix system comprising hydrophobic and hydrophilic (gel
`foming) parts, 18th International Symposium on Controlled release of bioactive
`materials. Proceedings of the Symposium (July 8-11, 1991) p.163.
`
`MSN Exhibit 1045 - Page 20 of 21
`MSNv. Bausch - IPR2023-00016
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`

`

`EXCIPIENTS USED IN CONTROLLED RELEASE TECHNOLOGY
`
`1081
`
`21. Harsh, D.C. and Gehrke, S.H., Controlling the swelling characteristics of
`temperature sensitive cellulose ether hydrogels, J. Controlled Release, 17, 175
`(1991).
`
`22. Shukla, P.G., Rajagopalan, N., Bhaskar, C. and Sivaram, S., Crosslinked
`starch-urea formaldehyde (St-UF) as a hydrophilic matrix for encapsulation:
`studies in swelling and release of carbofuran, Int. J. Pharm. 15, 153 (1991).
`
`23. Stoy, A.V. and Climent, K.C., Hydrogels: specialty plastics for biomedical
`and pharmaceutical applications. May 29 and 30, 1991, Basel, Switzerland.
`Technomic Publishing A.G. Proceedings of the course, 1991.
`
`24. Gehrke, S.H. and Lee, P.I. Specialized drug delivery systems, Chapter8,
`Marcel Dekker, Inc., New York, 1990.
`
`25. Methocel Product Information, Dow Chemical Co., Michigan U.S.A.
`
`26. Mitchell, K., Sogo, T., Ford, J., Armstrong, D., Elliot, P., Rostron, C.B. and
`Hogan, J., The influence of cellulose ether substitution type on water uptake
`and dissolution of propranolol hydrochloride, J. Pharm. Pharmacol. 42, 124
`(1990).
`
`27. Dressman, J.B., Current trends in oral controlled release dosage form
`research. 16th International Symposium on Controlled release of bioactive
`materials. Proceedings of the Symposium, Chicago,Illinois, U.S.A., August
`6-9, 1989, p.11.
`
`MSN Exhibit 1045 - Page 21 of 21
`MSNv. Bausch - IPR2023-00016
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`