Corso di Laurea Magistrale in Farmacia

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1 Universita degli Studi di Milano Corso di Laurea Magistrale in Farmacia Tecnologia e Legislazione Farmaceutiche I - 9 CFU Prof. Andrea Gazzaniga Rilascio Modificato Orale Ritardato/Pulsatile Parte II

2 Swelling Controlled Release System (SCRS) film di EC e HPMC (75:25) nucleo (unità singole) contenente il farmaco ed un agente idrofilo rigonfiante (polivinilalcol) Morita R. et al., J. Control. Rel. 63, 297 (2000)

3 film semipermeabile di cellulosa acetato & nucleo (pellets) contenente il farmaco (paracetamolo) e un agente osmoattivo (NaCl) Schultz P. and Kleinebudde P., J. Control. Rel. 47, 181 (1997)

4 film di etilcellulosa (insolubile, permeabile) & nucleo (compresse o pellets) contenente il farmaco, agenti idrofili rigonfianti (Na carbossimetilcellulosa) e osmoattivi (NaCl, sorbitolo) Amidon G.L. and Leesman G.D., US Patent (1993)

5 film di etilcellulosa & nucleo (compresse) contenente il farmaco ed una miscela di acido citrico e sodio bicarbonato Kroegel I. and Bodmeier R., Int. J. Pharm. 187, 175 (1999)

6 Sistemi orali a rilascio ritardato/pulsante (delayed/pulsatile release) - sistemi réservoir - nucleo contenente il principio attivo - rivestimento ritardante il rilascio lacerazione per aumento della pressione interna aumento della permeabilità dissoluzione e/o erosione

7 Sigmoidal Release System (SRS) Narisawa S. et al., Pharm. Res. 11(1),111 (1994) aumento della permeabilità

8 Sistemi orali a rilascio ritardato/pulsante (delayed/pulsatile release) - sistemi réservoir - nucleo contenente il principio attivo - rivestimento ritardante il rilascio lacerazione per aumento della pressione interna aumento della permeabilità dissoluzione e/o erosione

9 Time-Clock System Pozzi F. et al., J. Control. Rel., 31, 99 (1994) Wax mixture spray-coating in rotating pan or fluid bed at C Core (tablet) Stage 1 - Erosion of the wax layer [surfactants/hydrophilic agents] Stage 2 - Rapid release of the active

10 Time-Clock System Pozzi F. et al., J. Control. Rel., 31, 99 (1994) Wax mixture spray-coating in rotating pan or fluid bed at C Core (tablet) Stage 1 - Erosion of the wax layer [surfactants/hydrophilic agents] Stage 2 - Rapid release of the active

11 Plasma concentration (ng/ml) Time-Clock System adapted from Pozzi F. et al., J. Control. Rel., 31, 99 (1994) conventional dosage form Time-Clock Time (min) Salbutamol plasma profiles following oral administration of conventional dosage form and TIME CLOCK

12 Eur. J. Pharm. Biopharm., 40 (4) (1994) Oral Chronotopic TM Drug Delivery Systems: Achievement of Time and / or Site Specificity Andrea Gazzaniga *,Maria Edvige Sangalli **,Ferdinando Giordano ** - * University of Milan, Institute for Pharmaceutical Chemistry, Milan, Italy - ** University of Pavia, Department of Pharmaceutical Chemistry, Pavia, Italy

13 Gazzaniga A. et al., Eur. J. Pharm. Biopharm. 40(4), 246 (1994) Hydrophilic swellable polymeric layer (HPMC, different viscosity grades) Stage 0 - Dissolution of gastric resistant film Stage 1 - Swelling/Erosion of polymeric layer Stage 2 - Rapid release of the active Drug-containing core [single/multiple unit]

14 amount released Chronotopic System The slow interaction polymer/fluid lead to the formation of a gel [glassy/rubbery] glassy drug particles rubbery time

15 amount released Chronotopic System Rapid or slow release depending on core characteristics glassy drug particles rubbery no release time

16 amount released Lag phase physical-chemical characteristics and coating level of the retarding polymer glassy drug particles rubbery lag phase no release time

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18 How to prepare the retarding layer? spray-coating press-coating - polymers [high viscosity HPMC] never used before as coating agents. - technical obstacles to acceptable sprayability and reasonable processing time [hydroalcoholic dispersions/viscosity] - large-scale production implies use of special presses - difficult core centering with consequences on coating thickness uniformity

19 press-coating Methocel K100 LV

20 press-coating Methocel K100 LV limitations in the design flexibility owing to the large amount of coating needed

21 Adapted from Gazzaniga A. et al.- Eur.J. Pharm. Biopharm. 40(4), 246 (1994) press-coating Methocel K100 LV limitations in the design flexibility owing to the large amount of coating needed % released quite difficult to avoid the relatively and undesired long diffusion phase 0 time (min) Release profile of Verapamil.HCl from Methocel K100 LV press-coated systems with 150% weight gain mg/cm 2 coating polymer amount [tablet cores 60 mg]

22 Polymer 5 % W/W in Ethanol/Water mixture (84/6 w/w) spray-coating hydroalcoholic dispersions Methocel K15M Large scale production limitations due to the use of organic solvents

23 % released Chronotopic System Polymer 5 % W/W in Ethanol/Water mixture (84/6 w/w) spray-coating hydroalcoholic dispersions Methocel K15M Large scale production limitations due to the use of organic solvents tablet core 7,6 mg/cm ,2 mg/cm 2 22,8 mg/cm 2 30,4 mg/cm time (min) Release profiles of indomethacin from uncoated cores (4 mm diameter, 20 mg model drug) and systems spray-coated [rotating pan] with increasing amounts, mg/cm 2, of high viscosity HPMC - [hydro-alcoholic dispersion of Methocel K15M - 5% w/w] Adapted from Gazzaniga A. et al.- Eur.J. Pharm. Biopharm. 40(4), 246 (1994)

24 Adapted from Gazzaniga A. et al.- Eur.J. Pharm. Biopharm. 40(4), 246 (1994) Chronotopic System Polymer 5 % W/W in Ethanol/Water mixture (84/6 w/w) spray-coating hydroalcoholic dispersions Methocel K15M Large scale production limitations due to the use of organic solvents 300 Lag time (min) Applied polymer amount (mg/cm 2 ) Relationship between applied polymer amount and lag time for high viscosity HPMC spray-coated units [rotating pan, hydro-alcoholic dispersion of Methocel K15M- 5% w/w]

25 Spray coating with aqueous solutions of different HPMC viscosity grade Comparative evaluation of different HPMC viscosity grades, Methocel E5, E50 and K4M, in terms of process feasibility and performances as coating agents in aqueous solution unsolved issue how to switch to aqueous solvents? systematic study to select the most convenient HPMC aqueous coating systems

26 Spray coating with aqueous solutions of different HPMC viscosity grade M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004) SEM photomicrographs of cross-sectioned systems coated with Methocel E5 (top), E50 (middle) and K4M (bottom) aqueous solutions at 16, 8 and 2% w/v, respectively (magnification 47x)

27 drug released (%) Spray coating with aqueous solutions of different HPMC viscosity grade M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004) uncoated Methocel E5 Methocel E50 Methocel K4M 0 time (min) Release profiles obtained from uncoated cores and systems coated (w.g. 20%) with Methocel E5, E50 and K4M aqueous solutions at 16, 8 and 2% w/v, respectively

28 Spray coating with aqueous solutions of different HPMC viscosity grade finally Methocel E50 was selected for further studies since it affords the best balance among: -process time necessary for spray-coating -ability to delay drug release -final dimensions of the coated units -possibility of finely tuning the lag phase duration

29 Spray coating with aqueous solutions of Methocel E 50 A. Gazzaniga et al., STP Pharma Sci., 5, 83 (1995) fine tuning of lag time 100 % released core w.g. 22% w.g. 35% w.g. 50% w.g. 58% w.g. 73% w.g. 92% w.g. 115% w.g. 142% time (min) Release profiles of a tracer substance from uncoated cores (6.7 mm diameter, 180 mg weight, 2.3% methyl-4-hydroxybenzoate ) and cores coated with increasing amount of low viscosity HPMC (Methocel E50)

30 Spray coating with aqueous solutions of Methocel E 50 A. Gazzaniga et al., STP Pharma Sci., 5, 83 (1995) 210 Lag time (min) weight gain (%) 140 Relationship between weight gain and lag time for low viscosity HPMC (Methocel E50)-coated units (fluid bed).

31 Spray coating with aqueous solutions of Methocel E 50 A. Gazzaniga et al., STP Pharma Sci., 5, 83 (1995) 1.2 thickness (mm) weight gain (%) Relationship between weight gain and layer thickness for Methocel E50 caoted-units.

32 Spray coating with aqueous solutions of Methocel E 50 M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004) % released 100 % released ph=1.5 time (min) ph=11.5 time (min) % released ph=7.5 time (min) Release profiles of acetaminophen obtained from Methocel E50-coated systems at different ph (weight gain: 20% - coating thickness 277 µm).

33 Spray coating with aqueous solutions of Methocel E 50 M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004) 120 Lag timet 10 % (min) ionic strength-independent lag phase in the physiological range ionic strength t 10% as a function of the medium ionic strength for Methocel E50-coated systems (weight gain 20%, coating thickness 277 µm) - bars represent s.d.

34 Spray coating with aqueous solutions of Methocel E 50 M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004) 120 Lag timet 10 % (min) ionic strength-independent lag phase in the physiological range ionic strength t 10% as a function of the medium ionic strength for Methocel E50-coated systems (weight gain 20%, coating thickness 277 µm) - bars represent s.d.

35 there was still room for improvement in process time spray-coating top spray fluid bed equipment tangential spray-coating powder layering rotor insert progressive decrease in process time

36 Tablets coated by spray-coating, top-spray fluid bed (thickness 475 µm, amount 49 mg/cm 2 ) Tablets coated by spray-coating, rotary tangential fluid bed (thickness 375 µm, amount 48 mg/cm 2 ) Tablets coated by powder layering, rotary tangential fluid bed (thickness 1020 µm, amount 48 mg/cm 2 ) 60 Lag time (min) <2 hours 13 hours 6 hours layer thickness ~ 450 µm, ~ 50 mg/cm 2 ) Weight gain (%) progressive decrease in process time

37 pellets large units design flexibility

38 Chronotopic System in vivo study on Antipyrine-containing units Model drug: Disintegrating core: Retarding layer: Spraying equipment: Volunteers: Sampling Antipyrine (50 mg) 6 mm, 158 mg Methocel E50 (thickness 325, 575 and 1020 µm) Fluid bed (Uniglatt, Glatt GmbH) 4 healthy male (age 36-45, weight 70-80Kg) Antipyrine was quantified in saliva by HPLC saliva and blood concentrations of Antipyrine are known to be consistent

39 Adapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001) HPMC coated units drug released (%) F F25 F50 F100 time (h) In vitro release profiles of antipyrine from uncoated cores (formulation F) and units coated with different amounts of HPMC (formulations F25, F50 and F100, coating thickness 325, 575 and 1020 µm); paddle, SIF, C, 100 rpm, mean of 6 replicates.

40 Adapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001) 1.8 saliva concentration (µg/ml) HPMC coated units saliva concentration (µg/ml) time (h) F F25 F50 F time (h) Average antipyrine saliva levels after oral administration of uncoated cores (formulation F) and units coated with differing amounts of HPMC (formulations F25, F50 and F100, coating thickness 325, 575 and 1020 µm).

41 Adapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001) Relationship between in vivo t 10% (time to 10% C max ) and coating thickness for formulations F25, F50 and F100 [coating thickness 325, 575 and 1020 µm] HPMC coated units in vivo lag time T 10% (min) y = 0,2812x - 58,195 R 2 = 0,9993 coating thickness (µm)

42 Adapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001) HPMC coated units 4 in vivo lag time T 10% (hours) 2 0 in vitro lag time T 10% (hours) Relationship between in vivo and in vitro lag time for systems coated with Methocel E50 up to 325, 575 and 1020 µm layer thickness.