Corso di Laurea Magistrale in...
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Corso di Laurea Magistrale in Farmacia
Universita’ degli Studi di Milano
Tecnologia e Legislazione Farmaceutiche I - 9 CFU
Prof. Andrea Gazzaniga
Rilascio Modificato Orale – Ritardato/Pulsatile – Parte II
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film di EC e HPMC (75:25)
nucleo (unità singole) contenente il farmaco ed un agente idrofilo rigonfiante (polivinilalcol)
Swelling Controlled Release System (SCRS)
Morita R. et al., J. Control. Rel. 63, 297 (2000)
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&
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)
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&
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 5 229 131 (1993)
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&
film di etilcellulosa
nucleo (compresse) contenente il farmaco eduna miscela di acido citrico e sodiobicarbonato
Kroegel I. and Bodmeier R., Int. J. Pharm. 187, 175 (1999)
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- sistemi réservoir
(delayed/pulsatile release)
Sistemi orali a rilascio ritardato/pulsante
- nucleo contenente il principio attivo
- rivestimento ritardante il rilascio
• lacerazione per aumento della pressione interna
•dissoluzione e/o erosione
• aumento della permeabilità
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• aumento della permeabilità
Narisawa S. et al., Pharm. Res. 11(1), 111 (1994)
Sigmoidal Release System (SRS)
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- sistemi réservoir
(delayed/pulsatile release)
Sistemi orali a rilascio ritardato/pulsante
- nucleo contenente il principio attivo
- rivestimento ritardante il rilascio
• lacerazione per aumento della pressione interna
•dissoluzione e/o erosione
• aumento della permeabilità
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Wax mixturespray-coating in rotating pan or fluid bedat 80-90°C
Core (tablet)
Pozzi F. et al., J. Control. Rel., 31, 99 (1994)
Time-Clock® System
Stage 1 - Erosion of the wax layer [surfactants/hydrophilic agents]Stage 2 - Rapid release of the active
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Wax mixturespray-coating in rotating pan or fluid bedat 80-90°C
Core (tablet)
Pozzi F. et al., J. Control. Rel., 31, 99 (1994)
Time-Clock® System
Stage 1 - Erosion of the wax layer [surfactants/hydrophilic agents]Stage 2 - Rapid release of the active
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Salbutamol plasma profiles following oral administration of conventional
dosage form and TIME CLOCK
adapted from Pozzi F. et al., J. Control. Rel., 31, 99 (1994)
Time-Clock® System
0
5
10
15
20
0 120 240 360 480 600
Time (min)
Pla
sm
a c
on
cen
trati
on
(n
g/m
l)
conventional dosage form
Time-Clock
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Chronotopic™ System
Eur. J. Pharm. Biopharm., 40 (4) 246-250 (1994)
Oral ChronotopicTM 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
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Hydrophilic swellable polymeric layer(HPMC, different viscosity grades)
Chronotopic™ System
Gazzaniga A. et al., Eur. J. Pharm. Biopharm. 40(4), 246 (1994)
Stage 0 - Dissolution of gastric resistant filmStage 1 - Swelling/Erosion of polymeric layerStage 2 - Rapid release of the active
Drug-containing core [single/multiple unit]
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glassy rubberydrug particles
amou
ntre
leas
ed
time
Chronotopic™ System
The slow interaction polymer/fluid lead to the formation
of a gel [glassy/rubbery]
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glassy rubberydrug particles
amou
ntre
leas
ed
time
••
•••• •••• •••• •••• •••••
• •••••
no release
Chronotopic™ System
Rapid or slow release depending on core
characteristics
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glassy rubberydrug particles
amou
ntre
leas
ed
time
••
•••• •••• •••• •••• •••••
• •••••
Lag phase physical-chemical characteristicsand coating level of the retarding polymer
no releaselag phase
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Chronotopic™ System
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press-coating
spray-coating
- large-scale production implies use of special presses
- difficult core centering with consequences on coating thickness uniformity
Chronotopic™ System
How to prepare the retarding layer?
- technical obstacles to acceptable sprayability and reasonable
processing time [hydroalcoholic dispersions/viscosity]
- polymers [high viscosity HPMC] never used before as coating agents.
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Chronotopic™ Systempress-coating Methocel ® K100 LV
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Chronotopic™ System
limitations in the design flexibility owing to the large amount of coating needed
press-coating Methocel ® K100 LV
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0
40
80
% released
0 120 240 360 480 600
time (min)
Release profile of Verapamil.HCl from Methocel® K100 LV press-coated systems with150% weight gain – 177.6 mg/cm2 coating polymer amount [tablet cores 60 mg]
Chronotopic™ System
limitations in the design flexibility owing to the large amount of coating needed
press-coating Methocel ® K100 LV
Adapted from Gazzaniga A. et al.- Eur.J. Pharm. Biopharm. 40(4), 246 (1994)
quite difficult to avoid the relatively and undesired long
diffusion phase
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Chronotopic™ Systemspray-coating hydroalcoholic dispersions Methocel ®K15M
Polymer 5 % W/W in Ethanol/Water mixture (84/6 w/w)
Large scale production limitations due to the use of organic solvents
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Chronotopic™ Systemspray-coating hydroalcoholic dispersions Methocel ®K15M
0 100 200 300 400
0
20
40
60
80
100
tablet core
7,6 mg/cm 2
15,2 mg/cm 2
22,8 mg/cm 2
30,4 mg/cm 2
time (min)
% r
elea
sed
Release profiles of indomethacin from uncoated cores (4 mm diameter, 20 mg model drug) andsystems spray-coated [rotating pan] with increasing amounts, mg/cm2, 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)
Polymer 5 % W/W in Ethanol/Water mixture (84/6 w/w)
Large scale production limitations due to the use of organic solvents
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Relationship between applied polymer amount and lag time for high viscosity HPMC spray-coatedunits [rotating pan, hydro-alcoholic dispersion of Methocel K15M- 5% w/w]
0 10 20 30 400
100
200
300 Lag time (min)
Applied polymer amount (mg/cm 2)
Chronotopic™ Systemspray-coating hydroalcoholic dispersions Methocel ®K15M
Adapted from Gazzaniga A. et al.- Eur.J. Pharm. Biopharm. 40(4), 246 (1994)
Polymer 5 % W/W in Ethanol/Water mixture (84/6 w/w)
Large scale production limitations due to the use of organic solvents
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Chronotopic™ System
systematic study to select the most convenient HPMC aqueous coating systems
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 issuehow to switch to aqueous solvents ?
Spray–coating with aqueous solutions of different HPMC viscosity grade
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SEM photomicrographs of cross-sectioned systems coated withMethocel®E5 (top), E50 (middle) and K4M (bottom) aqueoussolutions at 16, 8 and 2% w/v, respectively (magnification 47x)
Spray–coating with aqueous solutions of different HPMC viscosity grade
Chronotopic™ System
M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004)
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Release profiles obtained from uncoated cores and systems coated (w.g. 20%) withMethocel® E5, E50 and K4M aqueous solutions at 16, 8 and 2% w/v, respectively
Spray–coating with aqueous solutions of different HPMC viscosity grade
Chronotopic™ System
M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004)
0
25
50
75
100
0 30 60 90 120 150
time (min)
dru
g re
leas
ed (
%)
uncoated
Methocel ® E5
Methocel ® E50
Methocel ® K4M
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-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
Spray–coating with aqueous solutions of different HPMC viscosity grade
Chronotopic™ System
… Methocel E50 … was selected for further studies since it
affords the best balanceamong:
finally
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corew.g. 22%w.g. 35%w.g. 50%w.g. 58%w.g. 73%w.g. 92%w.g. 115%w.g. 142%
27024021018015012090603000
20
40
60
80
100
time (min)
% released
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 amountof low viscosity HPMC (Methocel® E50)
Spray–coating with aqueous solutions of Methocel ® E 50
Chronotopic™ System
A. Gazzaniga et al., STP Pharma Sci., 5, 83 (1995)
fine tuning of lag time
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14012010080604020000
30
60
90
120
150
180
210
weight gain (%)
Lag time (min)
Relationship between weight gain and lag time for low viscosity HPMC(Methocel® E50)-coated units (fluid bed).
Spray–coating with aqueous solutions of Methocel ® E 50
Chronotopic™ System
A. Gazzaniga et al., STP Pharma Sci., 5, 83 (1995)
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Relationship between weight gain and layer thickness for Methocel® E50 caoted-units.
0.0
0.4
0.8
1.2
thickness (mm)
0 50 100 150
weight gain (%)
Spray–coating with aqueous solutions of Methocel ® E 50
Chronotopic™ System
A. Gazzaniga et al., STP Pharma Sci., 5, 83 (1995)
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Release profiles of acetaminophenobtained from Methocel® E50-coatedsystems at different pH (weight gain:
20% - coating thickness 277 µm).
pH=1.5
0
20
40
60
80
100
0 20 40 60 80
100 % released
pH=11.5
0
20
40
60
80
0 15 30 45 60 75 90
time (min)time (min)
pH=7.5
0
20
40
60
80
100
0 20 40 60 80
% released
% released
time (min)
Spray–coating with aqueous solutions of Methocel ® E 50
Chronotopic™ System
M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004)
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t10% as a function of the medium ionic strength for Methocel®E50-coated systems (weightgain 20%, coating thickness 277 µm) - bars represent s.d.
Spray–coating with aqueous solutions of Methocel ® E 50
Chronotopic™ System
M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004)
0
40
80
120
0 0.1 0.2 0.3 0.4
ionic strength
ionic strength-independent lag phase
t10 % (min)Lag time
in the physiological range 0.01-0.166
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t10% as a function of the medium ionic strength for Methocel®E50-coated systems (weightgain 20%, coating thickness 277 µm) - bars represent s.d.
Spray–coating with aqueous solutions of Methocel ® E 50
Chronotopic™ System
M.E. Sangalli et al., Eur. J. Pharm. Sci. 22, 469 (2004)
0
40
80
120
0 0.1 0.2 0.3 0.4
ionic strength
ionic strength-independent lag phase
t10 % (min)Lag time
in the physiological range 0.01-0.166
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top spray fluid bed equipment
tangential spray-coating
rotor insertpowder layering
spray-coating
Chronotopic™ System
… there was still room for improvement in process time…
progressive decrease in process time
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Tablets coated by spray-coating, top-spray fluid bed (thickness 475 µm, amount 49 mg/cm2)
Tablets coated by powder layering, rotary tangential fluid bed (thickness 1020 µm, amount 48 mg/cm2)
Tablets coated by spray-coating, rotary tangential fluid bed (thickness 375 µm, amount 48 mg/cm2)
0
20
40
60
0 10 20 30 40 50 60
<2 hours13 hours
6 hours
Lag time (min)
Chronotopic™ System
Weight gain (%)
layer thickness ~ 450 µm, ~ 50 mg/cm2)
progressive decrease in process time
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Chronotopic™ System
… pellets large units … design flexibility
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Chronotopic™ System
Model drug: Antipyrine (50 mg)
Disintegrating core: 6 mm, 158 mg
Retarding layer: Methocel®E50 (thickness 325, 575 and 1020 µm)
Spraying equipment: Fluid bed (Uniglatt, Glatt GmbH)
Volunteers: 4 healthy male (age 36-45, weight 70-80Kg)
Sampling Antipyrine was quantified in saliva by HPLC
in vivo study on Antipyrine-containing units
Chronotopic™ System
saliva and blood concentrations of Antipyrine are known to be consistent
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0
20
40
60
80
100
0 2 4 6 8 10 12 14
F
F25
F50
F100
time (h)
drug released (%)
In vitro release profiles of antipyrine from uncoated cores (formulation F) and unitscoated with different amounts of HPMC (formulations F25, F50 and F100, coatingthickness 325, 575 and 1020 µm); paddle, SIF, 370.5°C, 100 rpm, mean of 6 replicates.
HPMC coated units
Chronotopic™ SystemAdapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)
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0.0
0.3
0.6
0.9
1.2
1.5
1.8
0 2 4 6
time (h)
saliva concentration (µg/ml)
F
F25
F50
F100
0.0
0.3
0.6
0.9
1.2
1.5
1.8
0 8 16 24 32 40 48time (h)
saliva concentration (µg/ml)
Average antipyrine saliva levels after oral administration of uncoated cores(formulation F) and units coated with differing amounts of HPMC (formulationsF25, F50 and F100, coating thickness 325, 575 and 1020 µm).
HPMC coated units
Chronotopic™ SystemAdapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)
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Relationship between in vivo t10% (time to 10% Cmax) and coating thickness for formulations F25, F50 and
F100 [coating thickness 325, 575 and 1020 µm]
HPMC coated units
Chronotopic™ SystemAdapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)
y = 0,2812x - 58,195
R 2 = 0,9993
0
60
120
180
240
300
360
0 200 400 600 800 1000 1200
coating thickness (µm)
in vivo lag time T10% (min)
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Relationship between in vivo and in vitro lag time for systems coated withMethocel®E50 up to 325, 575 and 1020 µm layer thickness.
HPMC coated units
Chronotopic™ SystemAdapted from Sangalli M.E. et al., J. Control. Release 73, 103 (2001)
0
2
4
0 2 4
in vivo lag time T10% (hours)
in vitro lag time T10% (hours)