Professional Documents
Culture Documents
May 12
_____________ 03
, 20 _____
Doctor of Philosophy
________________________________________________
in:
Pharmaceutical Sciences (Industrial Pharmacy)
________________________________________________
It is entitled:
EVALUATION OF KOLLIDON® SR FOR pH-INDEPENDENT
________________________________________________
EXTENDED RELEASE MATRIX SYSTEMS
________________________________________________
________________________________________________
________________________________________________
Approved by:
________________________
Dr. Adel Sakr, Chairperson
________________________
Dr. Hussein Al-Khalidi
________________________
Dr. Bernadette D'Souza
________________________
Dr. Ronald Millard
________________________
Dr. Apryll Stalcup
EVALUATION OF KOLLIDON® SR FOR
pH-INDEPENDENT EXTENDED RELEASE MATRIX
SYSTEMS
DOCTOR OF PHILOSOPHY
by
Committee Chair
Adel Sakr, Ph.D.
Abstract
The effects of the following formulation and process variables on tablet properties
and drug release were tested: Kollidon® SR concentration in the tablet, addition
achieve a coherent matrix, able to extend the release of the incorporated drugs.
release. Drug release followed square root of time dependent kinetics, thus
influenced by the aqueous solubility of the drug. The drug release rate was faster
for wet granulation than direct compression, thus making direct compression the
was found that Kollidon® SR was the main release controlling agent in the
was found that the two products were not bioequivalent according to the FDA
bioequivalence criteria. The tablets had higher bioavailability than the capsules
as shown by higher Cmax and AUC 0-24h. For the developed tablet formulation
the higher initial plasma concentrations correlated with the faster initial release
observed in vitro.
My gratitude to the committee members for their valuable comments and advice
My deepest gratitude to my advisor, Dr. Adel Sakr, for his constant professional,
financial and emotional support. Special thanks for giving me the chance to be
(Family), for mentoring my professional steps, for all the meetings I have
participated, for the interactions with the professional world I have had through
friendship.
To Dr. Hussein AlKhalidi for guiding me explore the ‘statistics world’ through
dissertation.
To Dr. Bernadette D’Souza, my special thanks for her major contribution in the
To Dr. Ronald Millard for sharing his knowledge and for being an academic
model.
To Dr. Apryll Stalcup for providing guidance through the Chemical Separation
Special thanks to Dr. Karl Kolter and BASF Germany for the donation of
Shadi who volunteered for the Bioequivalence study. I highly appreciate their
generous support.
To Dr. Lubna Izzatullah and Mr. Nosa Ekhator (Veterans Affair Medical Center)
To Dr. Pankaj Desai for allowing me to use some equipment in his lab, and for
Special thanks to Dr. James Ebel for the great experience of two summer
internships in the Procter & Gamble Health Care Research Center, and for his
To Dr. Ronald Shoup (BAS Analytics) for the loan of analytical equipment without
Scholarship.
and Pharmacy, Iasi, Romania, for doing such a good job in educating
generations.
and for all I have learnt from them: Julia, Laxmi, Susan, Ehab, Hamid, Hatim,
Himanshu, John, Juan, and Mohamed. Special thanks to some of them for their
true friendship.
To my Romanian friends from here and home, for being such good friends as
To my parents and my family for their love. They are the reason for what I am
1. Introduction............................................................................................ 9
1.3. Impact of the formulation and process variables on the drug release
from extended release matrix systems .................................................. 24
1.3.1. Formulation variables ............................................................................ 24
1.3.2. Process variables .................................................................................. 37
2.1. Objective................................................................................................ 52
3. Experimental ........................................................................................ 54
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3.6.1.1. Manufacture of propranolol 10mg tablets by direct compression........... 68
3.6.1.2. Manufacture of propranolol 10mg tablets by wet granulation ................ 69
3.6.1.3. Drug release profiles from propranolol 10mg matrix tablets
manufactured with Eudragit® RSPO ..................................................... 71
3.6.1.4. Testing of propranolol 10mg tablets....................................................... 71
3.6.2. Buspirone 10 mg tablets ........................................................................ 71
3.6.3. Propranolol 80 mg tablets...................................................................... 73
3.6.3.1. Manufacture of propranolol 80mg tablets with 40-60% Kollidon® SR ... 73
3.6.3.2. Testing of propranolol 80mg tablets with 40-60% Kollidon® SR............ 74
3.6.3.3. Manufacture of propranolol 80mg tablets with 70% polymer
(Kollidon® SR alone or in combination with Eudragit® L100-55)........... 74
3.6.3.4. Testing of propranolol 80mg tablets with 70% polymer
(Kollidon® SR alone or in combination with Eudragit® L100-55)........... 75
3.6.3.5. Testing of Inderal® LA capsules (reference listed drug product) ........... 76
3.6.3.6. Selection of propranolol 80mg formulation for pilot bioequivalence
study ...................................................................................................... 76
3.6.3.7. Testing of propranolol 80mg tablets for the pilot bioequivalence
study ...................................................................................................... 76
3.6.4. Pilot bioequivalence study ..................................................................... 77
3.6.4.1. Design and methodology ....................................................................... 77
3.6.4.2. Analysis of propranolol in plasma .......................................................... 81
3.6.4.3. Pharmacokinetic and statistical analysis................................................ 83
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4.1.4. Effect of dissolution medium on drug release from propranolol
10mg matrix tablets ............................................................................... 95
4.1.5. Drug release profiles from matrix tablets with Eudragit® RSPO.......... 103
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List of Figures
Figure 1. Schematic representation of a matrix release system ......................... 14
Figure 2. The fronts in a swellable HPMC matrix................................................ 22
Figure 3. Process flow chart for tablets manufactured by direct compression .... 62
Figure 4. Process flow chart for tablets manufactured by wet granulation.......... 63
Figure 5. Effect of Kollidon® SR on drug release in water from propranolol
10mg tablets manufactured by direct compression .............................. 86
Figure 6. Effect of Kollidon® SR on diffusion controlled drug release in
water from propranolol 10mg tablets manufactured by direct
compression ......................................................................................... 87
Figure 7. Effect of Kollidon® SR on drug release in water from propranolol
10mg tablets manufactured by wet granulation .................................... 90
Figure 8. Effect of Kollidon® SR on diffusion controlled drug release in
water from propranolol 10mg tablets manufactured by wet
granulation............................................................................................ 91
Figure 9. Effect of external binder on drug release in water from propranolol
10mg tablets with 30% and 50% Kollidon® SR .................................... 94
Figure 10. Effect of dissolution medium on drug release from propranolol
10mg tablets with 30% Kollidon® SR manufactured by direct
compression ......................................................................................... 96
Figure 11. Effect of dissolution medium on drug release from propranolol
10mg tablets with 30% Kollidon® SR manufactured by wet
granulation............................................................................................ 97
Figure 12. Effect of dissolution medium on drug release from propranolol
10mg tablets with 40% Kollidon® SR manufactured by direct
compression ......................................................................................... 98
Figure 13. Effect of dissolution medium on drug release from propranolol
10mg tablets with 40% Kollidon® SR manufactured by wet
granulation............................................................................................ 99
Figure 14. Effect of dissolution medium on drug release from propranolol
10mg tablets with 50% Kollidon® SR manufactured by direct
compression ....................................................................................... 100
Figure 15. Effect of dissolution medium on drug release from propranolol
10mg tablets with 50% Kollidon® SR manufactured by wet
granulation.......................................................................................... 101
Figure 16. Effect of Eudragit® RSPO on drug release in water from
propranolol 10mg tablets .................................................................... 104
Figure 17. Effect of Kollidon® SR concentration and compression force on
the hardness of buspirone 10mg tablets............................................. 106
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Figure 18. Effect of compression force on drug release from buspirone
10mg tablets with 10 - 30% Kollidon® SR .......................................... 108
Figure 19. Effect of compression force on drug release from buspirone
10mg tablets with 40 - 60% Kollidon® SR .......................................... 109
Figure 20. Effect of Kollidon® SR on drug release from buspirone 10mg
tablets ................................................................................................. 111
Figure 21. Effect of Kollidon® SR on diffusion controlled drug release from
buspirone 10mg tablets ...................................................................... 112
Figure 22. Effect of dissolution medium on drug release from buspirone
10mg tablets with 30% Kollidon® SR ................................................. 114
Figure 23. Effect of dissolution medium on drug release from buspirone
10mg tablets with 40% Kollidon® SR ................................................. 115
Figure 24. Effect of dissolution medium on drug release from buspirone
10mg tablets with 50% Kollidon® SR ................................................. 116
Figure 25. Effect of dissolution medium on drug release from buspirone
10mg tablets with 60% Kollidon® SR ................................................. 117
Figure 26. Effect of Kollidon® SR and compression force on the hardness
of propranolol 80mg tablets ................................................................ 121
Figure 27. Effect of Kollidon® SR and compression force on drug release in
water from propranolol 80mg tablets .................................................. 122
Figure 28. Effect of Kollidon® SR on diffusion controlled drug release from
propranolol 80mg tablets .................................................................... 124
Figure 29. Effect of dissolution medium on drug release from propranolol
80mg tablets ....................................................................................... 126
Figure 30. Effect of Kollidon® SR and Eudragit® L100-55 combination on
drug release in water from propranolol 80mg tablets.......................... 129
Figure 31. Effect of Kollidon® SR and Eudragit® L100-55 combination on
drug release in 0.1N HCl from propranolol 80mg tablets .................... 130
Figure 32. Effect of Kollidon® SR and Eudragit® L100-55 combination on
drug release in pH 6.8 buffer from propranolol 80mg tablets.............. 131
Figure 33. Propranolol release in water over 48 hours from tablets
manufactured with 70% Kollidon® SR................................................ 132
Figure 34. Comparison of drug release from propranolol 80 mg tablets with
60 and 70% Kollidon® SR and Inderal® LA ....................................... 134
Figure 35. Compression and ejection forces recorded during manufacturing
of propranolol 80 mg tablets with 65% Kollidon® SR ......................... 136
Figure 36. Comparison of the drug release profiles from propranolol 80mg
tablets with 65% Kollidon® SR and Inderal® LA ................................ 138
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Figure 37. Reproducibility of propranolol 80 mg tablets formulation with 65%
Kollidon® SR ...................................................................................... 140
Figure 38. Effect of storage on drug release from propranolol 80 mg tablets
– ICH long term stability conditions .................................................... 143
Figure 39. Effect of storage on drug release from propranolol 80 mg tablets
– ICH accelerated stability conditions ................................................. 144
Figure 40. Plasma levels of propranolol following administration –
subject #1 ........................................................................................... 147
Figure 41. Plasma levels of propranolol following administration –
subject #2 ........................................................................................... 148
Figure 42. Plasma levels of propranolol following administration –
subject #3 ........................................................................................... 149
Figure 43. Plasma levels of propranolol following administration –
subject #4 ........................................................................................... 150
Figure 44. Plasma levels of propranolol following administration –
subject #5 ........................................................................................... 151
Figure 45. Plasma levels of propranolol following administration –
subject #6 ........................................................................................... 152
Figure 46. Plasma levels of propranolol following administration –
subject #7 ........................................................................................... 153
Figure 47. Plasma levels of propranolol following administration –
subject #8 ........................................................................................... 154
Figure 48. Plasma levels of propranolol following administration (mean ±
SEM)................................................................................................... 155
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List of Tables
Table 1. Application of matrix for drug delivery systems..................................... 24
Table 2. Pharmacokinetic properties of propranolol ........................................... 47
Table 3. Propranolol 10mg matrix tablets formulation ........................................ 69
Table 4. Propranolol 10mg matrix tablets formulations with external binders ..... 70
Table 5. Propranolol 10mg tablets formulated with Eudragit® RSPO................. 70
Table 6. Formulation of buspirone 10mg tablets................................................. 72
Table 7. Formulation of propranolol 80mg tablets with 40-60% Kollidon® SR ... 74
Table 8. Formulation of propranolol 80mg tablets with 70% polymer ................. 75
Table 9. Stability study design ............................................................................ 77
Table 10. Analytical method for analysis of propranolol in plasma ..................... 82
Table 11. Effect of Kollidon® SR on physical properties of propranolol 10mg
tablets manufactured by direct compression ........................................ 84
Table 12. Regression parameters of the diffusion drug release curves for
propranolol 10mg tablets manufactured by direct compression............ 85
Table 13. Effect of Kollidon® SR on the physical properties of Propranolol
10mg tablets manufactured by wet granulation .................................... 89
Table 14. Regression parameters of the diffusion drug release curves for
propranolol 10mg tablets manufactured by wet granulation ................. 92
Table 15. f2 values - effect of dissolution medium on drug release from
propranolol 10mg tablets .................................................................... 102
Table 16. Physical properties of buspirone 10mg tablets ................................. 107
Table 17. f2 values - effect of compression force on drug release from
buspirone 10mg tablets ...................................................................... 110
Table 18. Regression parameters of the diffusion drug release curves for
buspirone 10mg tablets ...................................................................... 113
Table 19. f2 values – effect of dissolution medium on drug release from
buspirone 10mg tablets ...................................................................... 118
Table 20. Effect of compression force and Kollidon® SR concentration on
physical properties of propranolol 80mg tablets ................................. 119
Table 21. f2 values – effect of compression force on drug release from
propranolol 80mg tablets .................................................................... 123
Table 22. Regression parameters of the diffusion drug release curves in
water from propranolol 80mg tablets .................................................. 125
Table 23. Composition of the propranolol 80mg tablets formulation used in
the pilot bioequivalence study............................................................. 135
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Table 24. Characteristics of propranolol 80mg tablets used in the pilot
bioequivalence study .......................................................................... 137
Table 25. Drug release from the propranolol 80 mg tablets with 65%
Kollidon® SR (used for the pilot bioequivalence study) ...................... 139
Table 26. Effect of storage on the hardness of propranolol 80 mg tablets........ 142
Table 27. Pharmacokinetic parameters after administration of propranolol
80mg tablets and Inderal® LA 80mg .................................................. 157
Table 28. Results of the bioequivalence testing using WinNonlin software ...... 158
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1. Introduction
Extended release dosage forms are formulated in such manner as to make the
action and sustained-release have also been used to describe such dosage
nearly constant drug levels in plasma with reduced fluctuations via slow release
matrix.
Two major types of materials are used in the preparation of matrix devices
♦ Hydrophobic carriers:
alcohols, fatty acids, waxes - carnauba wax (Chiao and Robinson, 1995);
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♦ Hydrophilic polymers – methyl cellulose, sodium carboxy methyl cellulose,
oxide, carbopols.
• easy to manufacture
• since the drug is dispersed in the matrix system, accidental leakage of the
• the remaining matrix must be removed after the drug has been released
• the drug release rates vary with the square root of time. Release rate
decrease in effective area at the diffusion front (Qiu and Zhang, 2000).
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1.2. Mechanisms of drug release from matrix systems
A drug with slow dissolution rate will demonstrate sustaining properties, since the
release of the drug will be limited by the rate of dissolution. In principle, it would
dissolution rate of drugs that are highly water-soluble. This can be done by:
control
• incorporating the drug into a tablet with a slowly dissolving carrier – matrix
rate of diffusion from the solid surface to the bulk solution through an unstirred
dC D
= k D ⋅ A ⋅ (Cs − C ) = ⋅ A ⋅ (Cs − C ) (1)
dt h
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where:
D diffusion coefficient
Equation (1) predicts that the rate of release can be constant only if the following
• surface area
• diffusion coefficient
• concentration difference.
surface area, and this is the case for combination diffusion and dissolution
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devices to exhibit a non-zero order release rate due to an increase in diffusional
In this model, drug in the outside layer exposed to the bathing solution is
dissolved first and then diffuses out of the matrix. This process continues with the
interface between the bathing solution and the solid drug moving toward the
interior. It follows obviously that for this system to be diffusion controlled, the rate
of dissolution of drug particles within the matrix must be much faster than the
diffusion rate of dissolved drug leaving the matrix (Jantzen and Robinson, 1995).
following assumptions:
b) the diameter of the drug particles is less than the average distance of drug
c) the diffusion coefficient of drug in the matrix remains constant (no change
1995);
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f) the total amount of drug present per unit volume in the matrix is substantially
greater than the saturation solubility of the drug per unit volume in the matrix
Depleted
Drug Matrix
Zone
Solid Drug
Cs
“Ghost” Matrix dh
x=0 x=h
corresponding to the schematic in Figure 1 – page 14, the release behavior can
dM C
= C0 ⋅ dh − s (2)
dh 2
where
dh change in the thickness of the zone of matrix that has been depleted of
drug
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From diffusion theory:
Dm ⋅ Cs
dM = ⋅ dt (3)
h
When the amount of drug is in excess of the saturation concentration, (C0 >>Cs)
M = [2Cs ⋅ Dm ⋅ C0 ⋅ t ]1 / 2 (5)
That indicates that the amount of drug released is a function of square root of
time.
penetration of surrounding liquid, dissolution of drug and leaching out of the drug
through tortuous interstitial channels and pores. The volume and length of the
openings must be accounted for in the drug release from a porous or granular
matrix:
p
M = [ Ds ⋅ Ca ⋅ ⋅ (2C0 − p ⋅ Ca ) ⋅ t ]1 / 2 (6)
T
where:
t tortuosity
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p 1/ 2
M = [2 Ds ⋅ C a ⋅ C 0 ⋅ t] (7)
T
The porosity is the fraction of matrix that exists as pores or channels into which
the surrounding liquid can penetrate. It is the total porosity of the matrix after the
drug has been extracted; it consists of initial porosity due to the presence of air or
void space in the matrix before the leaching process begins as well as the
C0 C ex
p = pa + + (8)
ρ ρ ex
where ρ is the drug density and ρex and Cex are the density and the concentration
excipient is used in the formulation and initial porosity is much smaller than
C0
p= (9)
ρ
p
M = [ Ds ⋅ Ca ⋅ ⋅ (2C0 − p ⋅ Ca ) ⋅ t ]1 / 2 (10)
T
p 1/ 2
M = [2 Ds ⋅ C a ⋅ C 0 ⋅ t] (11)
T
M = k ⋅ t1 / 2 (12)
where k is a constant, so that the amount of drug released versus the square root
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this is the case, one may control the release of drug from a homogeneous matrix
• porosity
• tortuosity
• solubility of the drug (Jantzen and Robinson, 1996, Chiao and Robinson,
1995).
drug release: Fickian diffusional release and relaxation release. Diffusion is not
the only pathway by which a drug is released from the matrix; the erosion of the
matrix following polymer relaxation contributes to the overall release. The relative
For example, the release of a sparingly soluble drug from hydrophilic matrices
polymeric matrix, the polymer swells and its glass transition temperature is
lowered. At the same time, the dissolved drug diffuses through this swollen
This type of diffusion and swelling does not generally follow a Fickian diffusion
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Q = k ⋅tn (13)
and n is the diffusional exponent. It has been shown that the value of n is
For n=0.5, drug release follows a Fickian diffusion mechanism that is driven by a
For n=1 drug release occurs via the relaxational transport that is associated with
contributions from diffusion and polymer erosion (Qiu and Zhang, 2000).
Q = k1 ⋅ t n + k 2 ⋅ t 2 n (14)
where k1 and k2 are constants reflecting the relative contributions of Fickian and
relaxation mechanisms.
In the case the surface area is fixed, the value of n should be 0.5 and equation
(14) becomes:
Q = k1 ⋅ t 0.5 + k 2 ⋅ t (15)
where the first and second term represent drug release due to diffusion and
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1.2.3. Bioerodible and combination diffusion and dissolution
systems
diffusion only. In practice, the dominant mechanism for release will overshadow
both the drug and the matrix material. Drugs not only can diffuse out of the
dosage form, as with some previously described matrix systems, but also the
arises from the fact that as the polymer dissolves the diffusional path length for
the drug may change. This usually results in a moving boundary diffusion
system. Zero-order release is possible only if surface erosion occurs and surface
dissolution mechanisms. Here the drug is dispersed in the polymer, but instead
allows for the entrance of water, which causes dissolution of the drug and
diffusion out of the swollen matrix. In these systems the release rate is highly
dependent on the polymer-swelling rate and drug solubility. This system usually
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minimizes burst effects, as rapid polymer swelling occurs before drug release
With regards to swellable matrix systems, different models have been proposed
to describe the diffusion, swelling and dissolution processes involved in the drug
release mechanism (Siepman and Kranz, 2000, Siepman et al., 1999a, Siepman
et al., 1999b, Siepman et al., 1999c, Peppas and Colombo, 1997, Colombo et al.,
1999, Colombo et al., 1996, Colombo et al., 1995, Colombo et al., 1992, Wan et
al., 1995). However the key element of the drug release mechanism is the
When a matrix that contains a swellable glassy polymer comes in contact with a
solvent or swelling agent, there is an abrupt change from the glassy to the
rubbery state, which is associated with the swelling process. The individual
polymer chains, originally in the unperturbed state absorb water so that their end-
to-end distance and radius of gyration expand to a new solvated state. This is
due to the lowering of the transition temperature of the polymer (Tg), which is
system. A sharp distinction between the glassy and rubbery regions is observed
this phenomenon can activate a convective drug transport, thus increasing the
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reproducibility of the drug release. The result is an anomalous non-Fickian
transport of the drug, owing to the polymer-chain relaxation behind the swelling
position. This, in turn, creates osmotic stresses and convective transport effects.
The gel strength is important in the matrix performance and is controlled by the
tragacanth gum, do not form the gel layer quickly. Consequently, they are not
positions, where ‘front’ indicates the position in the matrix where the physical
conditions sharply change. Three fronts are present (Colombo et al., 2000), as
• the ‘swelling front’ clearly separates the rubbery region (with enough water to
lower the Tg below the experimental temperature) from the glassy region
temperature).
• the ‘erosion front’, separates the matrix from the solvent. The gel-layer
- 21 -
• the ‘diffusion front’ located between the swelling and erosion fronts, and
constituting the boundary that separates solid from dissolved drug, has been
identified.
During drug release, the diffusion front position in the gel phase is dependent on
drug solubility and loading. The diffusion front movement is also related to drug
Swelling front
Diffusion front
Erosion front
Drug release is controlled by the interaction between water, polymer and drug.
The delivery kinetics depends on the drug gradient in the gel layer. Therefore,
drug concentration and thickness of the gel layer governs the drug flux. Drug
disentanglement and mass (polymer and drug) transfer in the solvent. Initially
solvent penetration is more rapid than chain disentanglement, and a rapid build-
- 22 -
up of gel-layer thickness occurs. However, when the solvent penetrates slowly,
observed since penetration and disentanglement rates are similar. Thus gel-layer
thickness dynamics in swellable matrix tablets exhibit three distinct patterns. The
similar rate. Finally, the gel-layer thickness decreases when the entire polymer
drug-release rate, are water penetration, polymer swelling, drug dissolution and
diffusion, and matrix erosion. Drug release is controlled by drug diffusion through
- 23 -
1.3. Impact of the formulation and process variables on the
to Qiu and Zhang (2000), the following recommendations apply to matrix systems
Hydrophilic
Hydrophobic
Erodible/Degradable Erosion/enzymatic -
degradation
Qiu and Zhang, (2000)
- 24 -
Other drug properties affecting system design include drug stability in the system
and at the site of absorption, pH-dependent solubility, particle size and specific
surface area.
soluble drugs. Velasco et al. (1999) showed that for a given effective surface
area, diclofenac particle size influenced the release rate from hydroxypropyl
methyl cellulose (HPMC) tablets. The smallest particle size of drug dissolved
more easily when dissolution medium penetrated through the matrix resulting in a
greater role for diffusion. The larger particle size dissolved less readily and
therefore was more prone to erosion at the matrix surface. A similar dependence
was shown for a less soluble drug, indomethacin (Ford et al., 1995).
significantly alter the release rate of the drug. A noticeable effect was seen only
at a low drug: HPMC ratio and at a large drug particle size (above 250µm) any
was seen; in this case, rapid dissolution of the water soluble drug would leave a
For diclofenac tablets formulated with HPMC, Velasco et al. (1999) showed that
an increase in drug: polymer ratio reduced the release rate. This was because an
- 25 -
(by making it more resistant to drug diffusion and erosion) as well as the
Similar findings were reported by Rekhi et al. (1999). Diffusional release of water-
soluble drug metoprolol (primarily controlled by the gel thickness) decreased with
By varying the polymer level (Methocel® K4M 10-40%), Nellore et al. (1998)
Sung et al. (1996) demonstrated that changes in HPMC: lactose ratio can be
For Ethocel® 100 and Eudragit® RSPO matrices, Boza et al. (1999) showed that
rates due to a decrease in the total porosity of the matrices (initial porosity plus
Polymer type
preferred, especially for highly soluble drugs where a rapid rate of hydration is
- 26 -
necessary. It is important to note that an inadequate polymer hydration rate may
lead to dose dumping, due to quick penetration of gastric fluids into the tablet
In each grade, for a fixed polymer level, the viscosity of the selected polymer
different Methocel®K viscosity grades, Nellore et al. (1998) found that the higher
viscosity gel layers provided a more tortuous and resistant barrier to diffusion,
K100LV, K15, K100). The fastest release of adinazolam mesilate was achieved
for the K100LV formulation. The K4M formulation exhibited a slightly greater drug
release than K15M and K100M. Due to the lack of a significant difference in the
release profiles between K15M and K100M, the authors suggested a limiting
HPMC viscosity of 15000cP, above which if viscosity increased, the release rate
viscosity grades had slower HPMC release, but no limiting HPMC viscosity was
concentration (10%) formulations, the lag time was found to be dependent on the
viscosity grade. The increasing burst effect produced by higher viscosity grades
- 27 -
was attributed to slower swelling with increasing polymer viscosity, allowing
greater time for the dissolution of the drug (metronidazole) before the gel barrier
was established. For HPMC concentration of 20% or more, the porosity was a
less important factor in the drug release and the effect of viscosity grade was
minimized.
In the case of ethyl cellulose, the findings are completely different. The lower
viscosity grades of ethylcellulose are more compressible than the higher viscosity
grades, resulting in harder tablets and slower release (Katikaneni et al., 1995a,
sodium was slower for the Eudragit® based matrix (Boza et al., 1999). The
explanation was based on the chemical structure of the polymers. Ethocel® 100
has hydrophilic hydroxyl and ethoxyl groups, which make the matrix water
hydrophilic drug. Eudragit® RSPO is only slightly permeable to water due to its
low content of quaternary ammonium groups; therefore it was more suitable for
Velasco et al. (1999) found that the diclofenac sodium release rate from HPMC
tablets decreased as the polymer particle increased. Also, as the HPMC particle
size increased, the lag period decreased – the drug release occurred during the
- 28 -
initial dissolution stage, prior to the formation of the gel layer (coarse fraction of
before the gel was established. Decreasing particle size caused a smaller burst
effect and induced lag times. The explanation was based on a faster swelling of
the smaller particles that allowed a rapid establishment of the gel barrier.
Heng et al. (2001) observed significant effect of HPMC particle size on aspirin
A mean HPMC (Methocel® K15M Premium) particle size of 113µm was identified
as a critical threshold for the release of aspirin. The drug release rate increased
markedly when polymer particle size was increased above 113µm. The release
rate was much less sensitive to changes in particle size below 113µm. The
aspirin release mechanism followed first order kinetics, when mean HPMC
particle size was below 113µm. The release mechanism deviated from first order
kinetics, when the mean particle size was above 113µm. Polymer fractions with
similar mean particle size but differing size distribution were also found to
In the case of ethyl cellulose, using a constant compression force and increasing
- 29 -
dissolution rate, due to a reduction in the interparticular forces. Erosion occurred
particle sizes revealed that the porosity increased with increase in particle size
(Katiketeni et al., 1995b) and the increase in porosity resulted in a faster drug
release.
Fillers
Nellore et al. (1998) studied the effect of filler (57% of the tablet weight) on a
metoprolol formulation at 20% Methocel® K4M level. They concluded that filler
solubility had a limited effect on release rate. The release profiles showed a
decrease of about 5-7% after 6h, as the filler was changed from lactose to
soluble drugs by decreasing the tortuosity of the diffusion path of the drug, while
insoluble fillers like dicalcium phosphate dihydrate got entrapped in the matrix.
Changing the filler from 100% dicalcium phosphate dihydrate to 100% lactose
4, 6 and 12h (Rekhi et al., 1999). This was explained by dissolution of lactose
and the consequent reduction in the tortuosity and or gel strength of the polymer.
- 30 -
Similar dissolution profiles were obtained for filler concentration up to 48%. No
Ion-exchange resins
formation.
propranolol from HPMC matrix tablets containing drug without resin (Amberlite®
IRP69), drug-resin complex and drug - resin physical mixture. The fastest release
was observed for resin free tablets (in all the dissolution media). In the case of
drug-resin complex tablets, the drug was not released in water, since there were
no counterions in the medium to replace drug ions from the ion exchange resin
within the gelled matrix. The drug was released in 0.1N HCl and pH 7.4
phosphate buffer, indicating that the drug release was initiated by an ion-
through the gel layer to replace the drug, which was then released by diffusion).
A similar extended release pattern was obtained by using the physical mixture of
drug and resin, which denoted the in situ complex formation within the gelled
region. The in situ method is more advantageous with regard to simplifying the
- 31 -
The rate of drug binding to the resin increased with decreasing the resin particle
size, thus explaining the slower release and the absence of the burst phase with
As the amount of resin increased, the drug release initially decreased, leveling up
formation and release retardation was observed only in pH 7.4 buffer, but not in
Comparing different matrix materials, a rapid formation of a strong gel layer was
important for the in situ complex formation; drug release decreased in the
following order glyceryl palmitostearate > polyethylene oxide 400K > HPMC
K15M.
For different HPMC sorts, the rate of hydration influenced the release; tablets
slow rate of hydration and the disintegrating effect of the resin (resins have large
swelling ability).
Similar results were observed for sodium diclofenac and the anion exchange
resin cholestiramine.
The phenomenon was not observed in case of the non-ionic drug guaifenesin.
Surfactants
Feely and Davis (1988) characterized the ability of charged ionic surfactants to
- 32 -
(chlorphemiramine maleate and sodium alkylsulphates, sodium salicylate and
ionic interaction, resulting in a complex with low aqueous solubility, that the
release would be more dependent on the matrix erosion than diffusion. The
retarding effect was dependent upon the surfactant concentration in the matrix
environment played an important role, by altering the ionization of both the drug
and the surfactant. The ionic strength of the dissolution medium affected the
Polymeric excipients
Feely and Davis (1988) studied the effect of polymeric additives (non-ionic
release in pH 7 buffer (near zero order release), but not in an acidic medium.
This was explained by a complexation of the drug with the cationic polymer;
which was not possible below pH 3, when Na-CMC was in its un-ionized
insoluble form. As a result of the complexation, the gel erosion became the
- 33 -
No interaction occurred between sodium salicylate and Na-CMC (both anionic).
slower at pH 7, but not altered at pH 1 (when the drug was present in its
unionized form).
Overall, the effect of ionic polymers incorporated into HPMC matrices on the
resins.
Goldberg and Sakr (2003) used the drug-polymer ionic complexation approach in
(average molecular weight of less than 500,000). The weight ratio of buspirone to
anionic exchange polymer varied between 4:1 and 1:6, preferably between 2:1
and 1:4.
Takka et al. (2001) studied the effect of the addition of anionic polymers
- 34 -
propranolol hydrochloride from HPMC matrices. The interaction between
propranolol hydrochloride and anionic polymers influenced the drug release. The
HPMC: anionic polymer ratio also affected the drug release. The matrix
release tablets.
in diffusion path length and decrease in the release rate associated with HPMC
pH.
enteric polymer HPMCAS (HPMC acetate succinate). The creation of the water-
accelerate the drug release and thus compensating the effect of the reduced
However the addition of the HPMCAS to the ethylcellulose matrix reduced the
verapamil release both in 0.1N HCl and pH 6.8 buffer compared to the ethyl
cellulose solely based matrix. The authors explained this by a reduction of the
matrix pore size in case of addition of HPMCAS due to the effect of particle size
- 35 -
difference: 33µm for ethyl cellulose, 6µm for HPMCAS on compaction behavior
(larger pores in the ethyl cellulose matrix). As the release mechanism was
release rate.
In contrast to ethyl cellulose, no effect was found when adding HPMCAS to the
HPMC systems either in 0.1N HCl, or in pH 6.08 buffer. It was considered that
through the swollen polymer network and not through the water filled pores.
Thus, reduction of the initial porosity of the system was of minor significance in
drug release rate. On the other hand, due to its high molecular weight, HPMCAS
network; pre-existing cavities within the HPMC network could not accommodate
(verapamil HCl) from matrix tablets, Streubel et al. (2000) added organic acids,
tablets. Substances selected (fumaric, sorbic and adipic acid) had high acidic
strength (low pKa value) and relatively low solubility in 0.1N HCl. These acids
dissolved rather slowly and remained in the tablets during the entire period of
drug release. Independent of the pH of the dissolution medium, the pH inside the
tablet was acidic and thus the solubility of the weakly basic drug was high. In
addition, at high pH, the organic acids acted as pore formers. The release rates
- 36 -
obtained for both ethyl cellulose and HPMC matrices were pH-independent.
Among the three acids, fumaric acid showed the best results, due to the lowest
pKa value.
Compression force
It has been reported (Velasco et al., 1999) for HPMC tablets, that although the
compression force had a significant effect on tablet hardness, its effect on drug
release from HPMC tablets was minimal. It could be assumed that the variation
initial porosity, the compression force seems to have little influence on drug
release. The influence of compression force could only be observed in the lag
time (Velasco et al., 1999). Tablets made at the lowest crushing strength
(compression force 3kN) with Methocel®K4M showed an initial burst effect due
to an initial partial disintegration. Once the polymer was swollen, the dissolution
strength.
Rekhi et al. (1999) reported similar findings, i.e. changes in compression force or
crushing strength appeared to have minimal effect on drug release from HPMC
matrix tablets once a critical hardness was achieved. Increased dissolution was
- 37 -
only observed when the tablets were too soft and it was attributed to the lack of
Tablet shape
Rekhi et al. (1999) showed that the size and shape of the tablet for the matrix
system undergoing diffusion and erosion might impact the drug dissolution rate.
Modification of the surface area for metoprolol tartrate tablets formulated with
Methocel® K100LV from the standard concave shape (0.568sq. in.) to caplet
each time point. Furthermore they recommended that for maximum maintenance
The release rate of the drug (theophylline) from erodible hydrogel matrix tablets
(HPMC E50) having different geometrical shapes (compressed under the same
the matrices.
Siepman et al. (1999b) showed that varying the aspect ratio (radius/height) of the
HPMC tablets is the very easy and effective tool to modify the release rate of the
matrix system. Release rate for tablets with the same volume was higher for flat
shape (ratio = 20) than regular cylinders (ratio 2) and almost rod-shaped
- 38 -
cylinders (ratio 0.2). The reason for this phenomenon was the difference in the
surface area of the tablets. They proposed a new mathematical model that can
be applied to calculate the optimal aspect ratio and size of a cylindrical tablet to
achieve a desired profile. The model takes into account Fickian diffusion of water
in and drug out of the tablets and swelling; it does not take into account
dissolution and it cannot be applied for water insoluble drugs, which are released
Tablet size
For tablets having the same aspect ratio and drug concentration, Siepman et al.
(1999b) found that the tablet size had a very strong influence on the release rate;
within 24 hours, 99.8% was released from the small tablets, 83.1% from the
medium size and 50.9% from the large tablets. The explanation was based on
the higher surface area referred to the volume for the small tablets than for the
large ones. In addition, the diffusion pathways were much longer in large tablets
than in small ones. Thus the relative amount of drug released versus time was
much higher for small tablets. The variation of the size of the tablet was an
- 39 -
1.4. Rationale for studying Kollidon® SR as extended release
matrix excipient
monolithic drug delivery systems, the pharmaceutical industry has placed a lot of
poor compressibility of the polymer forms resulting in tablets of low hardness, the
influence of pH values or ionic strengths on the release profiles, burst effect and
These disadvantages limit the application of currently used polymers and require
Kollidon® SR was introduced to the pharmaceutical market recently, and thus its
- 40 -
1.5. Kollidon® SR - background
Povidone in a physical mixture, stabilized with 0.8% sodium lauryl sulfate and
polymerization.
Description: water white, clear solid resin, soluble in benzene and acetone,
insoluble in water or emulsion readily diluted with water (Ash and Ash, 1995).
Regulatory status: diluent in color additive mixtures for food use exempt from
in water (Ash and Ash, 1995). It has good binding properties both under dry or
wet conditions. Due to its hygroscopicity, Povidone promotes water uptake and
Manufacture
- 41 -
as binder at 0.5-20% (of the tablet weight), when the active ingredients are
The k value of the polymers should be in the range from 10-350, preferably 50-
90. To prevent particles caking together, silica (spraying aid) is added to the
dispersion before spraying. Spray drying is done in spray towers (with disks or
Physicochemical properties
Bulk density: within the range of 0.30-0.45g/ml; 0.37g/ml (Ruchatz et al., 1999);
Flowability: good flow properties with a response angle below 30° (BASF, 1999),
pH: 3.5-5.5.
- 42 -
The manufacturer generally claims for Kollidon® SR good compressibility and
drug release independent of the dissolution medium (pH and salt/ion content)
and rotation speed. Compressibility results were published for propranolol 160mg
tablets (drug: polymer 1:1). The compression force did not affect the drug release
profile. The pH-independent release was also tested for caffeine (BASF, 1999).
release kinetics; the release rates increased exponentially with the drug loading.
The increase in compressional force from 20kN to 60kN caused a slight linear
dissolution rate along with an increase in tablet hardness was noticed for tablets
with high level of Kollidon® SR (>37%) prepared without diluents or with 15%
Such changes were not observed for tablets stored at 25°C/ 60%RH or cured at
- 43 -
Rock et al. (2000) evaluated different additives: diacetyl-tartaric acid diglyceride
ester, pectin, stearic acid and methyl hydroxyethyl cellulose for optimization of
caffeine release from Kollidon® SR -based matrix tablets. Stearic acid retarded
the initial drug release in acidic medium due to its hydrophobic character, but
methyl hydroxyethyl cellulose and pectin reduced the initial drug release and
Flick et al. (2000) showed the applicability of Kollidon® SR in hot melt technology
using acetaminophen.
In 2001, BASF filled a DMF (drug master file) for this product with the FDA (FDA
- 44 -
1.6. Propranolol extended release formulations
(Isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride
(1:20), soluble in 0.1 N HCl: 220 mg/ml and in pH 7.4 phosphate buffer: 254
antagonist, which interacts with beta1 and beta2 receptors with equal affinity,
and does not block alpha-adrenergic receptors (Goodman and Gilman, 2001).
Brocks, 2001). The absorption takes place from both the proximal and distal
intestine, making it a good candidate for extended release dosage forms (Buch
and 23% (Cid et al., 1986, Walle et al., 1986). Propranolol binds (90% of the
resulting in higher free fraction of S(-) propranolol in plasma. The age and gender
- 45 -
of the patients do not appear to have a substantial effect on the protein binding of
propranolol enantiomers (Mehvar and Brocks, 2001). Peak effect occurs after 1-2
hours and can vary up to seven fold after oral administration due to individual
dose), the metabolism being overall stereoselective for the less active R(+)
(Buch and Barr, 1998, Mehvar and Brocks, 2001). The metabolism is affected by
genetic polymorphism for both CYP1A and CYP2D6 isozymes in the liver
(Mehvar and Brocks, 2001). The biologic half-life is approximately four hours
No conclusive results were reported for the effect of the input rate on the ratio of
which is x100 times more potent than the R(+) enantiomer (Mehvar and Brocks,
2001).
reduce patient compliance and thus therapeutic efficacy (Serlin et al., 1983).
Several extended release systems have been developed in order to enable daily
- 46 -
There are some reported problems associated with propranolol extended release
and higher first pass effect or sometimes due to an underestimation of the area
under the plasma concentration-time curve due to limited blood sampling or low
analytical sensitivity (Nace and Wood, 1987). However similar bioavailability for
ER and conventional products has been reported (Bottini et al., 1983, Dunn et
al., 1985).
1987).
- 47 -
The apparent elimination half-life of ER propranolol formulations ranges from 8 to
McAinsh et al., 1978, Serlin et al., 1983, Garg et al., 1987, Lalonde et al., 1987).
obtained with conventional propranolol given in divided doses and correlated well
- 48 -
Takahashi et al. (1990) showed no significant differences in the hepatic
and naphthoxylactic acid after the administration of the two products were
administration was about one third that of the conventional preparation (Drummer
et al., 1981). Garg et al. (1987) showed that area under the curve and the peak
concentration was lower for two propranolol long-acting formulations (80mg and
160mg) than for the conventional tablets; in addition the elimination half-life was
longer (9 hours) for the extended release products than for conventional
single dose and 54% for steady state compared to the regular tablet formulation
capsules (single dose in the morning) and Inderal® conventional formulation (two
doses: morning and evening) were similar despite prolonged absorption time for
- 49 -
release preparations produced a smoother drug serum level profile with lower
and delayed peak times. At steady state, all regimens ensured relatively
The bioavailability of Inderal® LA (80, 160 and 240mg once daily for 4 days) was
For different extended release formulations, the peak blood level and AUC
decreased as the dissolution time increased and the half-lives were inversely
An attempt to develop plastic matrix tablets was done in 1974 by Grundy et al.
Pevikon D-42-P (polyvinyl chloride, 273 mg). The formulation had a satisfactory
in vitro release profile (50% of the dose in 3 hours, at 100rpm). However, when
administered in dogs, the in vivo release profile was unsatisfactory (the drug was
not completely released from the matrix) (Grundy et al., 1974). Single entity
- 50 -
extended release formulations of propranolol were therefore abandoned in favor
of multiparticulate systems.
All the propranolol extended release formulations currently in use in the United
States are capsules (Electronic Orange Book, 2002). Therefore, this research
The reference listed product, Inderal® LA, consists of hard gelatin capsules
- 51 -
2. Objective, hypothesis and specific aims
2.1. Objective
2.2. Hypothesis
Studying the effect of the following variables on the tablet properties and in vitro
♦ Formulation variables:
• polymer concentration
♦ Process variables:
• compression force.
♦ Dissolution medium.
- 52 -
Evaluation for one developed tablet formulation of its bioequivalence to an
- 53 -
3. Experimental
Darmstadt, Germany)
USA)
Ethyl acetate HPLC grade (Fisher Scientific, Fair Lawn NJ, USA)
date 07/2003)
Germany)
o-Phosphoric acid 85% HPLC grade (Fisher Scientific, Fair Lawn NJ, USA)
- 54 -
Polyvinyl acetate and Povidone based excipient, Kollidon® SR (BASF,
Ludwigshafen, Germany)
Germany)
Sodium phosphate dibasic anhydrous (Fisher Chemicals, Fair Lawn NJ, USA)
BD Vacutainer Lithium Heparin 5ml (Becton Dickinson, Franklin Lakes NJ, USA)
Clear glass threaded vials 1.5dr. (Fisher Scientific, Pittsburgh PA, USA)
Full flow filters 35µm (VanKel Technology Group, Carry NC, USA)
Glass inserts 250µl for HPLC vials (Agilent Technologies, Palo Alto CA, USA)
High-density polyethylene bottles 60cc, 90cc (Selco Inc., Anaheim CA, USA)
- 55 -
Luer Adapter Venoject (Terumo Corp., Tokyo, Japan)
4.6mm Inertsil ODS-3 5µm (Metachem Technologies Inc., Torrance CA, USA)
Millipore swinnex disks filter holders 25mm (Millipore Corp., Bedford MA, USA)
Polypropylene conical tubes 15ml (Becton Dickinson, Franklin Lakes NJ, USA)
Polypropylene flat top microcentrifuge tubes 2ml (Fisher Scientific, Pittsburgh PA,
USA)
Terumo Syringes 2ml, 5ml, 10ml (Terumo Medical Corp., Elkton MD, USA)
- 56 -
3.2. Equipment
HPLC Beckman System Gold 126 Solvent Module with 507e Autosampler
(Beckman Coulter, Fullerton CA, USA) and Waters 474 Scanning Fluorescence
Dissolution Tester VK7000 (VanKel Technology Group, Carry, NC, USA) coupled
IN, USA)
ReactiTherm III TM with Heating Stirring Module Reacti Vap TM III (Pierce,
Rotary tablet press Manesty D3B (Manesty Machines Ltd., Liverpool, UK)
Ultra Low Temperature Freezer Sanyo (Sanyo Electric Biomedical Co. Osaka,
Japan)
- 57 -
Tumbling Mixer Turbula T2G (Glen Mills Inc., Maywood NJ, USA)
Software
SAS software systems for Windows Release 8.02 (SAS Institute Inc, Cary NC,
USA)
- 58 -
3.3. Tablet composition
8-[4-[4-(2-Pyrimidinyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione
microcrystalline cellulose (Emcocel® 90M) in ratio 1:1 was used as tablet filler.
- 59 -
This ratio was selected based on literature data (Sakr et al., 1988, Sakr et al.,
Eudragit® L100-55 was added to some propranolol 80mg formulations to see the
effect of the addition of an enteric polymer on the drug release (section 3.6.3.4 –
page 75).
- 60 -
3.4. Tablet manufacture
to the process flow presented in Figure 3 – page 62 and Figure 4 – page 63,
weighed.
• The screened powder was transfered into the turbula mixer jar and mixed for
5 minutes.
screened through screen #35, added to the turbula jar and mixed for 10
minutes.
and mixed with the powder in the turbula jar for additional 3 minutes.
• The powder was compressed into tablets using an instrumented tablet press
and tablets were collected during compression for in-process testing (weight
and hardness).
- 61 -
Drug Mixing
Kollidon® SR 5 Minutes
(sieve #35)
- 62 -
Drug Mixing
Kollidon® SR 5 Minutes
(sieve #35)
(Turbula Mixer)
Mixing
Fillers 10 Minutes
(sieve #35)
- 63 -
Wet Granulation - Process flow:
weighed.
• The screened powder was transferred into the turbula mixer jar and mixed for
5 minutes.
accurately weighed, screened through screen #35, added to the turbula jar
• The powder mixture was transferred to the planetary mixer and granulated
• The wet mass was passed through a #12 sieve and the resulting granules
were placed on trays for drying into the oven at 40°C to a moisture content of
1.5%.
and Aerosil® 200 were accurately weighed and then mixed in the turbula jar
• The mixture was compressed into tablets using an instrumented tablet press
and tablets were collected during compression for in-process testing (weight
and hardness).
- 64 -
3.5. Tablet testing
Tablet weight variation - twenty tablets from each batch were individually
weighed and the average weight and relative standard variation were reported.
micrometer and the average thickness and relative standard variation were
reported.
Hardness - was determined for 10 tablets (of known weight and thickness) of
each batch; the average hardness and relative standard variation were reported.
<905> for content uniformity. The batch meets the USP requirements if the
amount of the active ingredient in each of the 10 tested tablets lies within the
range of 85% to 115% of the label claim and RSD is less than or equal to 6%.
According to the USP criteria, if one of these conditions is not met, additional 20
tablets need to be tested. Not more than 1 unit of the 30 tested should be outside
the range of 85% and 115% of the label claim and no unit outside the range of
75% to 125% of label claim; also RSD should not exceed 7.8%.
In vitro drug release was performed for the manufactured tablets according to the
- 65 -
0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours. The release was calculated
using a standard solution. The drug release was tested in different dissolution
media: distilled water, 0.1N HCl and USP 25 pH=6.8 phosphate buffer. The pH
range (pH = 1.2 – 6.8) was chosen to reflect the physiologic conditions of the
gastrointestinal tract.
propranolol 80mg tablet batches were tested according to the USP dissolution
monograph (apparatus 1, 100rpm, 900ml, first 1.5 hours pH 1.2 buffer, then pH
6.8 buffer). Additional sampling times (1.5 and 14 hours) were included in
similarity was assessed using the FDA recommended approach (f2 similarity
n
f 2 = 50 ⋅ log{[1 + (1 / n)∑ (Rt − Tt ) 2 ] − 0.5 ⋅ 100} (16)
t =1
where Rt and Tt are the cumulative percentage dissolved at each of the selected
two profiles, with emphasis on the larger difference among all the time-points.
- 66 -
The transformation is such that the f2 equation takes values less or equal to 100.
When the two profiles are identical, f2=100. An average difference of 10% at all
measured time points results in an f2 value of 50 (Shah et al., 1998). FDA has
two dissolution profiles. To use mean data for extended release products, the
less than 10% (FDA, 1997b). The average difference at any dissolution sampling
point should not be greater than 15% between the tested and reference products
(FDA, 1997a). Because f2 values are sensitive to the number of dissolution time
points, for extended release products only one point past the plateau of the
The dissolution profiles were fitted using the Higuchi model (for drug release up
to 60%) and the R2 was reported. For the dissolution profiles, which confirmed
this diffusion model, the slopes of the curves were used to compare the release
rates.
- 67 -
3.6. Experimental design and methodology
release excipient for high dose drug matrix tablets manufactured by direct
compression method (BASF, 1999, Pathan and Jalil, 2000, Rock et al., 2000).
drug extended release systems, using propranolol HCl (10mg) as a model drug.
A full factorial design was applied to study the effect of polymer concentration
(10-50% w/w of the tablet weight) and the method of manufacture (direct
compression and wet granulation) on tablet properties and drug release. Tablets
page 68, section 3.6.1.2 – page 69). For the wet granulation technology, the
investigated.
- 68 -
Table 3. Propranolol 10mg matrix tablets formulation
(Formulations 6-9, Table 4 – page 70) and the tablets were compressed to a
- 69 -
Table 4. Propranolol 10mg matrix tablets formulations with external binders
- 70 -
3.6.1.3. Drug release profiles from propranolol 10mg matrix tablets
manufactured with Eudragit® RSPO
Kollidon® SR was replaced in direct compression with a polymethacrylate
polymer, Eudragit® RSPO at 30, 40 and 50% concentration levels and the drug
The effect of dissolution medium on drug release was tested for the formulations
with 30, 40 and 50% Kollidon® SR. The release profiles in three different
dissolution media, distilled water, USP pH 6.8 phosphate buffer and 0.1N
Hydrochloric acid (method A – section 3.5, page 65) were compared using the
Buspirone HCl was selected as model drug in this set of experiments, based on
Buspirone HCl has a short and variable biological half-life (2-3 hours), and high
- 71 -
first pass metabolism (Sakr and Andheria, 2001, Mahmood and Sahajwalla,
1999).
three levels of compression force (1000, 2000, 3000lbs) and six levels of polymer
concentration (10-60%) was used. Also a control batch without the polymer was
manufactured.
(0.185 x 0.426 in) of label claim 10 mg Buspirone (tablet weight 160.0mg), under
3 – page 62.
- 72 -
The physical properties of the tablets and the drug release in water, 0.1N HCl
as matrix former for propranolol 80mg tablets (high dose), knowing that the
polymer concentration (40, 50 and 60%) (Table 7 – page 74) and compression
according to the process flow chart presented in Figure 3 – page 62, using bisect
- 73 -
Table 7. Formulation of propranolol 80mg tablets with 40-60% Kollidon® SR
0.1N HCl and pH 6.8 buffer (method A – section 3.5, page 65). The released
increasing the polymer level up to 70% of the tablet weight and/or partial
(Table 8 – page 75). As a result of increasing the polymer level, tablet weight had
- 74 -
The objective was to study the effect of addition of an enteric polymer on drug
release and to modify the release to be close / similar to the USP requirements
compression, using bisect capsule shaped punches (0.220 x 0.500 in) to a target
page 62).
(method A – section 3.5, page 65) and according to the USP method for
propranolol extended release capsules (method B – section 3.5, page 65). The
- 75 -
determine the mechanism of drug release. A model independent approach using
page 65). This step was necessary because the reference listed product served
the developed matrix tablet formulations with 60 and 70% Kollidon® SR were
- 76 -
Effect of storage on tablet physical properties and drug release
Propranolol 80mg tablets with 65% Kollidon® SR were stored in HDPE bottles in
the presence of desiccant under different storage conditions (FDA, 2001 ICH
Q1A, FDA, 1997 ICH Q1C). At predetermined time points, the tablets were
sampled and tested for physical properties and drug release (Table 9 – page 77).
matrix tablets and reference listed drug product Inderal® LA 80mg were
- 77 -
According to the 21 CFR 320.31 b., the study did not require an IND submission
hydrochloride) and the dose did not exceed the maximum single dose specified
in the labeling of the drug product that is the subject of an approved new drug
with the Food and Drug Administration - Office of Generic Drugs was submitted
The pilot study was conducted in compliance with the requirements for IRB
review and informed consent (21 CFR parts 56 and 50, respectively) and with the
requirements concerning the promotion and sale of drug (21 CFR 312.7). The
study did not invoke 21 CFR 50.24. It was performed under medical supervision
Cincinnati.
Ten volunteers underwent a screening procedure 2-6 days prior to the first
testing period and 8 subjects who met inclusion criteria, provided written consent
were enrolled in the study and randomized to one of the two dosing sequences
(SAS software).
Inclusion Criteria
inclusive
- 78 -
• Subjects must be on no chronic medications (prescription or OTC) and must
be medication-free for a period of at least one week prior to the first test day
• Subjects must be off any investigational drug for a period of at least 3 months
Exclusion Criteria
alcoholism.
screening
- 79 -
• Subjects unable and/or unlikely to comprehend and follow the study protocol.
Screening examinations
• Safety examination – ECG before the treatment, blood pressure, pulse and
temperature
renal profiles.
Treatments
innovator product).
Methodology
Subjects were admitted as outpatients in the morning (7.30 am) of the first day of
each period and after the insertion of the catheter, they received a single dose of
the drug (test or reference product) at 8.00am (0 hour of the test). Subjects were
in the facility until 8.00pm (after the 12-hour blood sample was withdrawn).
Subjects returned the second day of each period at 8.00 am and 2.00pm for the
Meals and Food Restrictions. Subjects fasted for at least 12 hours prior to the
dose administration. Prior to and during each study phase subjects were allowed
water as desired except for one hour before and after drug administration.
Subjects received lunch at 1.00pm. Subjects abstained from alcohol for 24 hours
- 80 -
prior to each study period and until after the last sample from each period was
collected. Use of tobacco and caffeine was not allowed for 24 hours prior to each
study period and until after the last sample from each period was collected.
Subject monitoring. The blood pressure and pulse rate were monitored prior to
dosing and at the sampling times. The treatment effects on blood pressure and
pulse rate at every time point were tested by one-way ANOVA. Subjects had
their weight measurements taken and recorded at each period. Subjects were
Blood samples
During each period, 12 venous blood samples were taken from the antecubital
transferred to the labeled tubes and promptly frozen. The samples were stored at
Braza et al., 2000, Rekhi et al., 1995). The method parameters are presented in
- 81 -
To 1.0ml spiked plasma or sample, 0.1ml 1M NaOH, 0.1 ml Pronethalol 600ng/ml
(internal standard) and 5ml ethyl acetate were added. The mixture was vortexed
for 15sec and then centrifuged at 3000 rpm for 3 minutes. 4ml of the supernatant
nitrogen steam. The residue was reconstituted in 0.5ml mobile phase, vortexed
10, 20, 40, 100ng/ml. Calibration curves were generated by plotting the ratio of
two components. The calibration curve was considered linear for values of the
- 82 -
Accuracy. Three concentrations within the linearity range (2, 20, 100ng/ml) were
20, 100ng/ml). For inter-day variability, the samples were prepared and injected
under the concentration time curves from 0-24h (AUC 0-24h) and 0-∞ (AUC 0-∞)
for each subject and formulation (WinNonlin). The resulting data were statistically
The bioequivalence of the two formulations was tested using the following model
- 83 -
4. Results and Discussions
Kollidon® SR, (10, 20, 30, 40 and 50% of tablet weight) – section 3.6.1.1, page
68. Tablets were uniform in weight and thickness and their hardness increased
84).
- 84 -
It was found that increasing polymer concentration up to 40%, significantly
decreased the drug release rate in water, sustaining the release of the highly
water soluble drug incorporated at low dose for a longer period of time
(dissolution data for all the experimental batches were reproducible n=6,
RSD<3% and hence only the average values were plotted). There was no
significant difference between the formulations containing 40% and 50% of the
The regression parameters of the drug release curves for formulations with 30-
50% polymer content are indicated in Table 12 – page 85 and the plot of percent
drug released versus square root of time is illustrated in Figure 6 – page 87. The
high correlation coefficient (above 0.99) obtained indicates a square root of time
dependent release kinetics. Thus, as the data fitted the Higuchi model, it
Table 12. Regression parameters of the diffusion drug release curves for
propranolol 10mg tablets manufactured by direct compression
- 85 -
110
100
90
80
70
10% KSR
60
%released
20% KSR
30% KSR
50 40% KSR
50% KSR
40
30
20
10
0
0 4 8 12 16 20 24
time (hr)
- 86 -
110
100
90
80
70
%released
60
30% KSR
40% KSR
50
50% KSR
40
30
20
10
0
0 1 2 3 4
√t (√hr)
- 87 -
It is suggested that the main driving force for the drug release in case of water-
soluble drug like propranolol hydrochloride from the matrix tablets is the
infiltration of release medium. As the tablet is introduced into the medium, water
penetrates into the matrix and povidone leaches out to form pores through which
the drug may diffuse out. Also, as observed in Figure 6 – page 87, as the
polymer level in the formulation is increased, drug diffusion is slowed due to the
lower porosity and higher tortuosity of the matrix. Thus polyvinylacetate, which is
a very plastic material, produces a coherent matrix, sustaining the drug release
from the tablet matrix. Similarly, Ruchatz et al 1999 reported that caffeine was
released from Kollidon® SR matrix tablets by diffusion over more than 16 hours.
The matrix remained intact during the dissolution test due to the water-insoluble
polyvinylacetate.
using distilled water as granulating medium, was studied (section 3.6.1.2 – page
- 88 -
Table 13. Effect of Kollidon® SR on the physical properties of Propranolol
10mg tablets manufactured by wet granulation
- 89 -
110
100
90
80
70
%released
60
10% KSR
50 20% KSR
30% KSR
40 40% KSR
50% KSR
30
20
10
0
0 2 4 6 8 10 12
time (hr)
- 90 -
110
100
90
80
70
%released
60
30% KSR
40% KSR
50
50% KSR
40
30
20
10
0
0 1 2 3 4
√t (√hr)
- 91 -
The drug release in water is shown in Figure 7 – page 90 and the Higuchi plots in
By comparing the slopes of Higuchi plots as an indicator for release rate, it can
be seen that wet granulation (Table 14 – page 92) produced a faster release than
Table 14. Regression parameters of the diffusion drug release curves for
propranolol 10mg tablets manufactured by wet granulation
faster rate of drug release from the matrix. The regression parameters for
Higuchi model are presented in Table 14 – page 92 and the change in release
profiles is indicated by the varying slope values for the square root of time plots.
particles, leading to a faster channeling action. The lower tortuosity and higher
- 92 -
water penetration due to an increase in the volume of povidone at 50% polymer
content, could also lead to a faster drug release rate. As Kollidon® SR was not
studied before for wet granulation applications, no literature data were available
The effect of the addition of an external binder in the granulating medium, on the
drug release rate from formulations containing 30 and 50% Kollidon® SR content
was evaluated and the release profiles are as shown in Figure 9 – page 94. The
No significant change in drug release profiles (f2 >50) was observed at 30%
binder did not slow the release as expected. None of the two binders used could
the other hydrophilic components from the tablets (reduced interaction caused by
exposure of the polymer during the wet granulation process) (Mulye and Turco,
1994). The results indicated that Kollidon® SR was primarily controlling the drug
release rate.
- 93 -
110
100
90
80
70
%released
40
50% KSR / water
20
10
0
0 2 4 6 8 10 12
time (hr)
- 94 -
4.1.4. Effect of dissolution medium on drug release from propranolol
Drug release from tablets with 30, 40 and 50% Kollidon® SR was tested in three
different dissolution media: distilled water, USP pH 6.8 phosphate buffer and
On applying the similarity factor, f2, to compare the dissolution in 0.1N HCl or pH
6.8 buffer to the release in water, values of above 50 were obtained indicating
Drug release from matrix systems is influenced by the aqueous solubility of the
drug and matrix behavior at different pH. Propranolol has a pKa=9.5 (Avdeef et
al., 2000) and an acceptable solubility over the physiologic pH range: 220 mg/ml
in 0.1 N HCl and 254 mg/ml in pH 7.4 phosphate buffer (Siepmann and Kranz,
substances and its solubility and hydration are not influenced by pH. As a result,
the drug release was pH-independent and it was concluded that Kollidon® SR is
tablets, on the condition that drug solubility does not drastically change with the
pH.
- 95 -
110
100
90
80
70
60
% released
water
50 0.1N HCl
pH 6.8 buffer
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 96 -
110
100
90
80
70
% released
60
water
0.1N HCl
50
pH 6.8 buffer
40
30
20
10
0
0 2 4 6 8 10 12
time (hr)
- 97 -
110
100
90
80
70
% released
60
water
50 0.1N HCl
pH 6.8 buffer
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 98 -
110
100
90
80
70
% released
60
50 water
0.1N HCl
40 pH 6.8 buffer
30
20
10
0
0 2 4 6 8 10 12
time (hr)
- 99 -
110
100
90
80
70
60
% released
water
0.1N HCl
50
pH 6.8 buffer
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 100 -
110
100
90
80
70
% released
60
water
50
0.1N HCl
pH 6.8 buffer
40
30
20
10
0
0 2 4 6 8 10 12
time (hr)
- 101 -
Table 15. f2 values - effect of dissolution medium on drug release from
propranolol 10mg tablets
- 102 -
4.1.5. Drug release profiles from matrix tablets with Eudragit® RSPO
polymer, Eudragit® RSPO. Tablets with 30, 40 and 50% polymer levels were
manufactured and the drug release profiles in distilled water were compared. The
drug release was faster (Figure 16 – page 104), with about 80-100% of
propranolol released in the first 1-2 hours, which was attributed to a rapid and
complete erosion of the matrix (disintegration time for all Eudragit® RSPO
formulations tested was less that 10 minutes). This was a result of a low
- 103 -
110
100
90
80
70
60
%released
30
20
10
0
0 2 4 6 8 10 12
time (hr)
- 104 -
4.2. Buspirone 10mg tablets
Buspirone tablets were found uniform in weight and thickness and had high
mechanical strength, even under the lowest applied compression force (Table 16
significantly increased the hardness of the tablets, but further increase above
2000lbs did not significantly change the hardness of the tablets with 40 - 60%
Increasing the compression force from 1000lbs to 2000 lbs reduced the release
rate in water, but compression forces above 2000 lbs did not significantly change
the drug release profile f2>50 (Figure 17 - Figure 19, pages 106 - 109; Table 17
– page 110).
- 105 -
25
20
0% KSR
15 10% KSR
20% KSR
Hardness (kP)
30% KSR
40% KSR
50% KSR
60% KSR
10
0
0 1000 2000 3000 4000
Compression force (lbs)
- 106 -
Table 16. Physical properties of buspirone 10mg tablets
- 107 -
110
100
90
80
70
60
%released
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 108 -
110
100
90
80
70
60
%released
50
40
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 109 -
Table 17. f2 values - effect of compression force on drug release from
buspirone 10mg tablets
Consequently, further testing was carried out for tablets compressed at 2000 lbs.
slowed down due to the lower porosity and higher tortuosity of the matrix.
The release of drug dispersed in the matrix systems fitted the Higuchi model
21 – page 112).
- 110 -
110
100
90
80
70
60
%released
50
40
KSR 0%
KSR10%
30
KSR20%
KSR30%
20 KSR40%
KSR50%
KSR60%
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 111 -
110
100
90
80
70
60
%released
50
40
30% KSR
30
40% KSR
50% KSR
20 60% KSR
10
0
0 1 2 3 4 5
√t (√hr)
- 112 -
Table 18. Regression parameters of the diffusion drug release curves for
buspirone 10mg tablets
10mg tablets
polymer level in the three dissolution media varied (Table 19 – page 118); the
fastest release was obtained in 0.1N HCl and the slowest in pH 6.8 phosphate
buffer (Figure 22 - Figure 25, pages 114 - 117). This was attributed to the pH-
- 113 -
110
100
90
80
70
60
%released
50 0.1N HCl
water
40
pH 6.8
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 114 -
110
100
90
80
70
60
%released
50
0.1N HCl
40
water
pH 6.8
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 115 -
110
100
90
80
70
60
%released
50
0.1N HCl
40
water
pH 6.8
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 116 -
110
100
90
80
70
60
%released
50
40
0.1N HCl
30
water
pH 6.8
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 117 -
Table 19. f2 values – effect of dissolution medium on drug release from
buspirone 10mg tablets
necessary for a coherent matrix, able to extend the drug release. Considering
this previous finding and the higher drug dose to be used (80mg) the minimum
which may occur during manufacturing. The resultant tablets were uniform in
- 118 -
Table 20. Effect of compression force and Kollidon® SR concentration on
physical properties of propranolol 80mg tablets
40% KSR
50% KSR
60% KSR
A change in the drug release due to variation in the compression force during the
assure that minor changes in the formulation and process variables that may
occur during the manufacturing process will not result in alteration of the product
performance.
- 119 -
For tablet formulations containing 40 - 60% Kollidon® SR, it was observed that
while changes in the compression forces from 1000 to 2000 lbs produced an
page 123), further increase to 3000 lbs did not affect the drug release profiles
compression force above 2000 lbs and this represented a definite advantage of
these formulations.
Release profiles of the tablets that were formulated with 40-60% Kollidon® SR
and compressed under 2000 lbs are shown in Figure 28 – page 124. It was found
that the drug release was faster at 40% polymer levels, and further increase from
- 120 -
25
20
15
40% KSR
Hardness (kP)
50% KSR
60% KSR
10
0
0 1000 2000 3000 4000
Compression force (lbs)
- 121 -
110
100
90
80
70
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 122 -
Table 21. f2 values – effect of compression force on drug release from
propranolol 80mg tablets
drug delivery systems are placed in contact with a dissolution medium, the
release of the drug must be preceded by the drug dissolution in water filled pores
and by diffusion through the water filled channels. The geometry and the
structure of the pore network are important to the drug release process (Gurny et
considered to give a coherent matrix in which the drug is dispersed and the
tortuosity of the tablets. At lower polymer levels, the diffusion occurred faster due
to lower porosity of the matrix, while increasing the polymer concentration led to
a slower release until the matrix achieved its maximum tortuosity and minimum
porosity. All the tablets remained intact during the 24-hour dissolution test.
- 123 -
110
100
90
80
70
%released
60
40% KSR
50 50% KSR
60% KSR
40
30
20
10
0
0 1 2 3 4
√t (√hr)
- 124 -
Table 22. Regression parameters of the diffusion drug release curves in
water from propranolol 80mg tablets
80mg tablets
Drug release from matrix systems is influenced by the aqueous solubility of the
drug and matrix behavior at different pH. Propranolol has a pKa=9.5 (Avdeef et
al., 2000) and an acceptable solubility over the physiologic pH range: 220 mg/ml
in 0.1 N HCl and 254 mg/ml in pH 7.4 phosphate buffer (Siepmann and Kranz,
imposable release curves in pH 6.8 buffer and 0.1N HCl (Figure 29 – page 126)
and f2 values greater that 50 (66.51, 73.38 and 64.95 for Kollidon® SR 40%,
50% and respectively 60%). This confirmed the findings in case of propranolol
- 125 -
110
100
90
80
70
60
%released
50
40% KSR 0.1N HCl
40% KSR pH 6.8
40 50% KSR 0.1N HCl
50% KSR pH 6.8
60% KSR 0.1N HCl
30
60% KSR pH 6.8
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 126 -
4.3.3. Effect of Kollidon® SR – Eudragit® L100-55 combination on
(Streubel et al., 2000). In acidic medium, the enteric polymer is insoluble and
acts as a part of the matrix thus contributes to the retardation of the drug release.
In buffer media, the enteric polymer dissolves and loosens the matrix structure,
thus increasing the porosity and permeability of the dosage form and
with Eudragit® L100-55, while keeping constant the total matrix forming agent
expected, the release rates in water and 0.1N HCl were slightly reduced (Figure
30 – page 129, Figure 31 – page 130). This was because Eudragit® L100-55 is
polymer due to the polyvinylacetate network (Streubel et al., 2000) and also in
cationic drug - anionic polymer interaction (Takka et al., 2001, Streubel et al.,
- 127 -
A 48-hour dissolution test was performed in distilled water for the formulation
propranol at the end of the first 24 hours was still present in the matrix. 100% of
the label claim was released at the end of the 48-hour interval, compared to 7%
- 128 -
110
100
90
80
70
60
%released
50
40
30
20 70%KSR
65%KSR+ 5%Eudragit
10 60%KSR+ 10%Eudragit
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 129 -
110
100
90
80
70
60
%released
50
40
30
20 70%KSR
65%KSR+ 5%Eudragit
10 60%KSR+ 10%Eudragit
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 130 -
110
100
90
80
70
60
%released
50
40
30
20 70%KSR
65%KSR+ 5%Eudragit
10 60%KSR+ 10%Eudragit
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 131 -
110
100
90
80
70
%released
60
50
40
30
20
10
0
0 4 8 12 16 20 24 28 32 36 40 44 48
time (hr)
- 132 -
4.3.4. Comparison of the propranolol 80 mg tablet formulations with
Currently all extended release propranolol products available in the United States
are capsules and Inderal® LA is the reference listed product (RLD, innovator).
method (method B – section 3.5, page 65) for propranolol 80mg tablets with 60
and 70% Kollidon® SR and the reference listed capsule product (Figure 34 –
page 134), it was found that the initial release was faster for the tablets than for
the capsules, while at the later dissolution stages the release profile for the
innovator product was intermediate to the tablet profiles. Thus, it was decided to
- 133 -
110
100
90
80
70
%released
60
50
40
70%KSR
30 60%KSR
Inderal LA
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 134 -
The composition of the selected formulation (65% Kollidon® SR) is presented in
- 135 -
Compression Force [lb]
Average: 1967.17 lb
St. Dev. 113.87 lb
Rel. SD 5.79 %
1967.17
1934.57
1901.96
2108.46
2206.28
1978.04
1858.49
1880.23
1847.62
1988.91
115.02
115.02
109.97
108.11
116.22
114.75
111.16
111.30
108.64
109.30
- 136 -
The resulting tablets were uniform in weight, thickness and hardness and passed
the USP criteria for the Content Uniformity (Table 24 – page 137).
Compared to the reference-listed product, the drug release from the matrix
tablets was faster in the initial stage (Figure 36 – page 138). This can be
(multiparticulate versus monolithic system). The burst effect observed with the
tablets could be explained by the propranolol trapped on the surface of the matrix
common reported phenomenon for matrix systems (Krajacic and Tucker, 2003,
Huang and Brazel, 2001, Bodea and Leucuta, 1997). During the buffer stage, the
developed product met the USP requirements for propranolol release (Table 25 –
page 139) and was similar to the innovator product, as determined with the
- 137 -
110
100
90
80
70
%released
60
50
40
30
65%KSR
Inderal LA
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
Figure 36. Comparison of the drug release profiles from propranolol 80mg
tablets with 65% Kollidon® SR and Inderal® LA
- 138 -
Table 25. Drug release from the propranolol 80 mg tablets with 65%
Kollidon® SR (used for the pilot bioequivalence study)
4 49.64% 35-60%
8 63.23% 55-80%
14 77.74% 70-95%
24 91.22% 81-110%
The formulation was robust and reproducible, as shown by the drug release
This formulation was used in the pilot bioequivalence study and was tested for
- 139 -
110
100
90
80
70
60
% released
50
40
batch 1
batch 2
30 batch 3
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 140 -
4.3.5. Effect of storage conditions on propranolol 80 mg tablets
Propranolol 80 mg tablets with 65% Kollidon® SR were tested to see the effect of
physical properties and drug release (method B – section 3.5, page 65).
No change in the dissolution profile was observed for tablets stored under long-
dissolution profile was observed for tablets stored at 40°C/75% RH for more than
3 months. The reduction in the dissolution rate continued after six months, the
time period recommended for conducting accelerated stability studies; it was also
observed at nine months testing point. The change in the dissolution profile
observed just in case of the tablets stored under accelerated conditions could be
published data. Shao et al. (2001) observed a reduction in the dissolution rate for
- 141 -
The change in the dissolution rate of propranolol tablets was accompanied by an
increase in tablet hardness. The increase in hardness was significantly higher for
9 months 16.97±0.59 * ND
(*) significantly different from the initial at 0.05 level (Tukey procedure)
(**) significantly different from the long term conditions at 0.05 level (Tukey
procedure)
ND – could not be determined (above the hardness tester maximum capacity);
tablets were plastically deformed.
- 142 -
110
100
90
80
70
60
%released
50
initial
1 month
40
3 months
6 months
30 9 months
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 143 -
110
100
90
80
70
60
%released
50
40
initial
30 1 month
3 months
6 months
20 9 months
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
time (hr)
- 144 -
4.4. Evaluation of bioequivalence of propranolol 80 mg matrix
> 0.99).
theoretical values for three concentrations within the linearity range (2, 20,
The intra- and inter-day variability determined by using three replicate analyses
of spiked plasma at three different concentrations (2, 20, 100ng/ml) were 9.60,
Subjects enrolled in the study had their body weight recorded each period and
their vital signs were monitored at each blood drawing (Appendix 2 – page 197).
It was found that at each time point the treatment effects on blood pressure and
procedure. No significant adverse effects were reported during and post - study.
- 145 -
4.4.3. Pharmacokinetic and statistical analysis
fasting study was performed for propranolol 80mg developed tablets and the
reference listed product Inderal® LA (FDA, 2002). The single dose study is
bioequivalence, i.e. release of the drug substance from the product into the
systemic circulation. The multiple dose study is not recommended by the FDA
even in the instances where nonlinear kinetics is present. The parent drug
propranolol was measured in plasma (rather than the metabolites) because the
matrix tablets and Inderal® LA are graphically displayed for each subject in
Figure 40 - Figure 47, pages 147 - 154. The mean results are shown in Figure 48
page 155.
- 146 -
70
Inderal LA 80mg
50
Propranolol (ng/ml)
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 147 -
70
Inderal LA 80mg
50
Propranolol (ng/ml)
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 148 -
70
Inderal LA 80mg
50
Propranolol (ng/ml)
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 149 -
70
Inderal LA 80mg
50
Propranolol (ng/ml)
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 150 -
70
Inderal LA 80mg
50
Propranolol (ng/ml)
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 151 -
70
Inderal LA 80mg
50
Propranolol (ng/ml)
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 152 -
70 Inderal LA 80mg
60
50
Propranolol (ng/ml)
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 153 -
70
Inderal LA 80mg
50
Propranolol (ng/ml)
40
30
20
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 154 -
Propranolol 80 mg tablets
40
Inderal LA 80 mg
35
30
25
Propranolol (ng/ml)
20
15
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
time (hr)
- 155 -
A good agreement was found between the in vitro drug release and propranolol
plasma concentration for the first twelve hours post-dosing, as may be seen in
Figure 5 – page 86 and Figure 48 – page 155. The developed matrix tablets
which had faster initial release produced higher plasma concentrations compared
those of McAinsh et al. (1981) who reported for different extended release
propranolol formulations that the peak blood level and AUC decreased as the
dissolution was slower. McAinsh et al. (1981) explained the lowering of the
metabolism of propranolol.
The calculated AUC0-24h, AUC0-∞ and Cmax for each subject are presented in
Testing the AUC0-24h, AUC 0-∞ and Cmax by non-parametric Wilcoxon two-
carry over (residual) effect (p= p=0.8852, p=0.8852 and p=1.000 respectively).
for variable XOVERDIF proved that the period did not significantly affect the
responses, i.e. AUC 0-24h, AUC 0-∞ and Cmax (p=0.6650, p=1.000, respectively
p=0.3123).
- 156 -
Table 27. Pharmacokinetic parameters after administration of propranolol
80mg tablets and Inderal® LA 80mg
AUC 0-24h AUC 0-∞ Cmax AUC 0-24h AUC 0-∞ Cmax
Analysis of variance was carried out to test for the treatment effect. The
treatment effect was not significant with regard to AUC 0-24h and 0-∞ (p=0.1070,
24 hour- and total drug exposure. Analysis of Cmax showed significant difference
According to the FDA two products are considered bioequivalent if the 90%
confidence interval for the ratio of the averages (population geometric means) of
the measures for the test and reference (Cmax, AUC) falls within a BE limit,
usually 80-125% for the ratio of the product averages (FDA 2001). By applying
- 157 -
this criterion, the two products tested (propranolol 80mg matrix tablets and
Inderal® LA) were not bioequivalent with regards to Cmax, AUC0-24h, AUC 0-∞
(Table 28 – page 158). The tablets produced higher Cmax and 24-hour drug
Thus, Cmax was higher for the tablets than the capsules as tested by both
ANOVA and FDA criterion for bioequivalence. Testing by ANOVA for the area
under the curve did not show a significant treatment effect, while testing
according to the FDA criterion revealed that the two products were not
the drug (Bottini et al., 1983, Flouvat et al., 1989, Lalonde et al., 1987, Perucca
- 158 -
et al., 1984). As the study could not be performed on a larger number of subjects
sample size (6-9 subjects) was used in other studies on the bioavailability /
Lalonde et al., 1987, Perucca et al., 1984, Rekhi et al., 1996). To account for the
It is concluded that according to the FDA criteria the two products were not
bioequivalent and the tablets had higher bioavailability as shown by Cmax and
AUC 0-24h than the capsules. This conclusion applies for the mean results and
for each subject. The initial faster release observed in vitro in case of the
- 159 -
5. Conclusions
matrix, able to extend the release of the incorporated drugs. Increasing the
and a slower drug release. Drug release followed square root of time dependent
The drug release rate was faster for wet granulation than for direct compression,
conditions, but not under long term conditions. Based on this finding, the
- 160 -
The developed propranolol 80mg extended release formulation was found to
have higher bioavailability than the reference listed product capsules, as shown
by higher Cmax and AUC 0-24h. For the developed tablet formulation, the higher
initial plasma concentration was correlated with the faster initial release observed
in vitro. Thus, according to the FDA bioequivalence criteria, the two products
- 161 -
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Nellore, R.V., Rekhi, G.S., Hussain, A.S., Tillman, L.G., Augsburger, L.L., 1998.
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Pharmacokinetic and pharmacodynamic studies with a new controlled
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Rock, T.C., Steenpaß, T., Ruchatz, F., Kolter, K., 2000. Methods to reduce the
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7. Appendix 1
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Research Protocol - page 1
To:
UCMC Institutional Review Board Chairperson
From:
Principal Investigator Bernadette D’Souza, M.D.
Associate Director of Clinical Affairs, Associate Professor
Bernadette.Dsouza@med.va.gov
Phone (513) 475-6326
Fax (513) 475-6379
Mail Location 116A
Department of Veterans Affairs, Medical Center
Mental Health Care Line
3200 Vine Street, Cincinnati OH 45220
06/11/2001
Revised 11/07/01
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Research Protocol - page 2
RESEARCH PROTOCOL
OUTLINE
A. Specific aims 3
B. Significance 3
Background Information 4
C. Preliminary Studies 7
D. Experimental Design and Methods 9
1. Subjects 9
a. Criteria for subject selection 9
Inclusion Criteria 9
Exclusion Criteria 9
b. Screening examinations 10
2. Source of subject population 10
3. Research Protocol 11
a. Methodology 11
• Study design 11
• Products studied 11
• Drug assignment 11
• Study visits 12
• Screening 12
• Study test days 12
• Drug administration 12
• Blood samples 13
• Meals and food restrictions 13
• Subject monitoring 13
b. Analysis 14
• Method of analysis 14
• Pharmacokinetic and statistical analysis 14
c. Setting and laboratory facilities 14
E. Human subjects 15
1. Recruitment 15
2. Risks and benefits 15
3. Payment 15
4. Subject costs 15
5. Consent form 15
F. Estimated period of time to complete the study 16
Study schedule 16
G. Funding 16
H. References 17
J. Consent form 19
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Research Protocol - page 3
RESEARCH PROTOCOL
A. Specific aims
B. Significance
All the Propranolol extended release formulations currently in use are hard
gelatin capsules, containing small spheroids each containing Propranolol
hydrochloride dispersed in an insoluble matrix. The drug containing spheroids
are in turn coated with a semipermeable membrane, which allow drug to diffuse
at a controlled rate.
This study is an attempt to formulate and deliver Propranolol as directly
compressed extended release tablets. The drug is homogenously dispersed
through the Polyvinylacetate-Povidone matrix and the drug release follows the
diffusional mechanism (Jantzen, Robinson 1996, Draganoiu et al, 2001).
Compared to capsule manufacturing (spheronization followed by coating) the
tablet manufacturing technology by direct compression is easier and more
efficient. The in vitro dissolution test conducted for tablet in different media
should provide an extended release of the drug over 24 hours.
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Research Protocol - page 4
Background Information
Propranolol is almost completely absorbed from the gastrointestinal tract, but it is
subjected to an extensive and highly variable hepatic first pass metabolism, with
a reported systemic bioavailability between 15 and 23% (Cid et al, 1986, Walle et
al, 1986). Peak effect occurs after 1-2 hours and can vary up to seven fold after
oral administration due to individual variations in hepatic metabolic activity
(Shand et al, 1970). The biologic half-life is approximately four hours.
Due to relatively short plasma half-life, Propranolol conventional tablets are
administrated at 6 to 8 hours intervals. Such frequent drug administration may
reduce patient compliance and thus therapeutic efficacy (Serlin et al, 1983).
Several sustained release systems have been developed in order to enable daily
administration of the drug and a 24 hours maintained beta-adrenoceptor
blockade.
In a crossover single oral dose study (Takahashi et al, 1990) on healthy subjects
who received 60 mg Propranolol as sustained release capsules (Inderal LA) or
as conventional tablets, significant differences (parallel decreases for Inderal
LA release compared to conventional tablets) were observed in area under the
curve of Propranolol hydrochloride, Propranolol glucuronide and naphtoxylactic
acid and in the amounts of all metabolites excreted in urine. Therefore it was
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Research Protocol - page 5
Garg et al (1987) showed that for two Propranolol long-acting formulation (80mg
and 160mg) the area under the curve and the peak concentration were
significantly less compared to the conventional tablets; in addition the elimination
half-life was longer (9 hours) than for conventional Propranolol (4hours).
In a crossover study on healthy subjects with Propranolol 160mg daily for 7 days
mean bioavailability of sustained release capsules relative to regular tablet
formulation was 52% for single doses and 54% for steady state (Straka et al,
1987).
For one-day therapy with sustained release Duranol capsules (single dose in
the morning) and Inderal conventional formulation (two doses morning and
evening) it was found that the relative bioavailabilities were similar despite
prolonged absorption time for the sustained action capsules (Bottini et al, 1983)
The bioavailability of Inderal LA (80, 160 and 240mg once daily for 4 days) was
proportional to the dose administrated as sustained action capsules. Steady state
was attained after 2 doses. (Dvornik et al, 1983)
For different sustained release formulation, the peak blood level and AUC
decrease as the dissolution time increase; the half-life are inversely proportional
to the dissolution rate. The lowering of the systemic bioavailability as the
dissolution time increases is thought to be due to an increased metabolism of
Propranolol (McAinsh et al, 1981)
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Research Protocol - page 6
An attempt to develop plastic matrix tablets was done in 1974 by Grundy et al.
The matrix consisted on Propranolol 125 mg embedded in an insoluble matrix of
Pevikon D-42-P (polyvinyl chloride, 273 mg). The formulation had a satisfactory
in vitro release profile (50% of the dose in 3 hours, at 100rpm). However when
administered in dogs, the in vivo release profile was unsatisfactory (the drug was
not completely released from the matrix) (Grundy et al, 1974). Single entity
extended release formulations of Propranolol were therefore abandoned in favor
of multiparticulate systems.
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Research Protocol - page 7
C. Preliminary Studies
The dissolution test is the best in vitro predictor for in vivo product performance.
Among the dissolution test specifications, the dissolution profile comparison
seems to be more precise than single point estimate approach to characterize
the drug product (O’Hara et al, 1998). For extended release formulation FDA
recommends that the dissolution profile should be evaluated by using a
multipoint profile, with adequate sampling at different time points (for example at
1, 2 and 4 hours and every two hours after, until either 80% of the drug is release
or an asymptote is reached). The regulatory accepted method for comparison of
the dissolution profiles is a model independent mathematical approach described
by Moore and Flanner (1996), which is know as f2 (similarity factor) equation.
n
f 2 = 50 ⋅ log{[1 + (1 / n)∑ (Rt − Tt ) 2 ] − 0.5 ⋅ 100}
t =1
Where Rt and Tt are the cumulative percentage dissolved at each of the selected
n time points of the reference and test product respectively.
Factor f2 is inversely proportional to the average squared difference between the
two profiles, with emphasis on the larger difference among all the time-points.
The transformation is such that the f2 equation takes values less or equal to 100.
The value of f2 is 100 when the test and reference mean profiles are identical.
The factor f2 measures the closeness between the two profiles.
When the two profiles are identical, f2=100. An average difference of 10% at all
measured time points results in an f2 value of 50 (Shah et al, 1998). FDA has set
a public standard of f2 value between 50-100 to indicate similarity between two
dissolution profiles.
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Research Protocol - page 8
100
90
80
70
60
50
Inderal LA cps 0.1N HCl
40
Inderal LA cps pH 6.8
30 Propranolol Tb 0.1N HCl
20 Propranolol Tb pH 6.8
10
0
0 2 4 6 8 10 12 14 16 18 20 22 24
The dissolution profiles in 0.1N HCl for the two formulations are almost super
imposable. The similarity is confirmed by f2 values at all tested points greater
than 50.
In case of using pH 6.8 USP phosphate buffer as dissolution medium, the
dissolution profiles meet the FDA criteria for similarity (f2 values greater than 50
at all tested points). For the developed tablet formulation the release is slighter
slower than for the marketed product. This difference of in vitro release should be
tested for in vivo significance, knowing that in some cases formulation with
significantly different in vitro release rates exhibit equal bioavailability (Sakr,
Andheria 2001)
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Research Protocol - page 9
1. Subjects
Inclusion Criteria
Exclusion Criteria
Screening examinations:
Routine physical examination and medical history
Safety examination – ECG before the treatment, blood pressure, pulse and
temperature
Laboratory examination – complete blood count with differential, hepatic and
renal profiles
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Research Protocol - page 11
3. Research Protocol
a. Methodology
Study design
This study will be a cross-over single-dose two-period open-label study which will
compare the absorption of Propranolol from two dosage forms: Propranolol 80mg
extended release capsules (InderalLA) and Propranolol 80mg extended release
tablets, administrated oral, under fasting conditions.
Subjects will undergo a screening procedure 2-6 days prior to the first test day. If
all inclusion and exclusion criteria are met, subjects will be randomized to one of
the two dosing sequence. Subjects will report to the outpatient facility in the
morning of the first day of each period and will receive a single dose of the drug
(capsule or tablet).
Products studied
A) Propranolol ER tablet formulation - test product (Industrial Pharmacy
Laboratory, UC)
B) Propranolol ER capsule formulation – reference product (Inderal LA,
Manufacturer Ayerst Laboratories Inc., lot # 9010268, expiration date 07/2003)
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Research Protocol - page 12
Study visits
Screening
Routine physical examination and medical history; body weight will be recorded
Vital signs – blood pressure (100-140 mm Hg systolic /70-90 mm Hg diastolic),
pulse 60-100 beats/min
Electrocardiogram before the treatment
Laboratory examination – complete blood count with differential, hepatic and
renal profiles
Period 1 Day 1
Day2
Time between periods: One week
Period 2 Day 1
Day 2
Subjects will be admitted in the morning (7.30 am) of the first day of each period
and after the insertion of the catheter, they will receive a single dose of the drug
(treatment A or B) at 8am (0 hour of the test). Subjects will be in the facility until
8pm (after the 12 hours blood sample is withdrawn). Subjects will return the
second day of each period at 7.30 am for the 24h and 30h blood sample
withdrawal. There will be 2 test periods separated by one-week washout.
Drug Administration
Treatment A: Propranolol 80mg ER tablet (1 tablet) oral at 0 hour with 240ml of
room temperature water
Treatment B Propranolol 80mgER capsule (1 capsule) oral at 0 hour with 240ml
of room temperature water
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Research Protocol - page 13
Blood samples:
During each period, 12 venous blood samples will be taken in heparinized
vacutainers as follows:
Day 1 - at 0 (predose), and at 1, 2, 3, 4, 5, 6, 8, 10, 12h (using catheter hep-lock)
after drug administration
Day 2 - at 24, 30h (by direct venipuncture) after drug administration (Singh,
Jambhekar, 1996).
The plasma will be separated, transferred to the labeled tubes and promptly
frozen. The samples will be stored frozen at –20C, until analyzed.
Meals and Food Restrictions: Subjects shall fast for at least 12 hours prior to the
dose administration. Prior to and during each study phase subjects are allowed
to water as desired except for one hour before and after drug administration After
drug administration, subjects will receive lunch at 1pm. Subjects should abstain
from alcohol, for 24 hours prior to each study period and until after the last
sample from each period is collected (alcohol increases plasma clearance rate).
Abuse of tobacco, caffeine is not allowed for 24 hours prior to each study period
and until after the last sample from each period is collected.
Subject monitoring
The blood pressure and pulse rate will be monitored prior to dosing and at the
sampling times.
Subjects will have their weight measurements taken and recorded at check-in,
each period.
Subjects will be advised to avoid the use of prescription and OTC medications
and alcohol
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Research Protocol - page 14
Method of analysis: All Propranolol samples obtained from the test and reference
product will be analyzed by the same HPLC method coupled with fluorescence or
UV detection. The measurement of only the Propranolol concentration is
performed, assuming that the concentration-time profile of the parent drug is
more sensitive to changes in formulation than a metabolite (FDA Guidance on
Bioequivalence). The validation, linearity and sensitivity of the method will be
conducted before the study is started.
The study will be sponsored by the University of Cincinnati and conducted at the
Veterans Affairs Medical center (VAMC), Outpatient Clinic facilities.
The screening procedure will be conducted at the investigator’s office and
laboratory at the VAMC.
The Propranolol plasma analysis will be performed in the laboratories of the
College of Pharmacy
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E. Human subjects
1. Recruitment
Advertisement for study enrollment will be posted in the News Record and on
boards within the East Campus (see attached advertisement). Healthy volunteers
responding to the advertisement will be recruited, after explaining the purpose
and protocol of the study and given the informed consent. A screening procedure
will be done before enrolment in the study.
4. Subject costs:
Funds are not available to cover the costs of any ongoing medical care and the
subjects remain responsible for the cost of non-research related care. Tests,
procedures and other costs incurred solely for purposes of research will be the
financial responsibility of the sponsor.
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Study schedule
G. Funding
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Research Protocol - page 17
REFERENCES
Bottini, P. B.; Caulfield, E. M.; Devane, J. G.; Geoghegan, E. J.; Panoz, D. E. 1983.
Comparative oral bioavailability of conventional Propranolol tablets and a new controlled
absorption Propranolol capsule. Drug Dev. Ind. Pharm. (9) 1475-1493
Cid, E.; Mella, F.; Lucchini, L.; Carcamo, M.; Monasterio, J., 1986. Plasma
concentrations and bioavailability of Propranolol by oral, rectal and intravenous
administration in man. Biopharm. Drug Disp (7) 559-566
Draganoiu, E., Andheria, M., Sakr, A. Evaluation of a New Polyvinyl acetate/ Povidone
Excipient for Matrix Sustained Release Dosage Forms. Accepted for publication in
Pharm. Ind.
Drummer, O. H.; McNeil, J.; Pritchard, E.; Louis, W. J. 1981. Combined high
performance liquid chromatographic procedure for measuring 4-hydroxyPropranolol and
Propranolol in plasma: pharmacokinetic measurements following conventional and slow-
release Propranolol administration. J. Pharm. Sci. (70) 1030-1032
Dvornik, D.; Kraml, M.; Dubuc, J.; Coelho, J.; Novello, L. A.; et al. 1983. Relationship
between plasma Propranolol concentrations and dose of long-acting Propranolol
(Inderal LA). Curr. Ther. Res. (34) 595-605
Frishman, W.H., Jorde, U. 2000 β-Adrenergic Blockers in Oparil, S., Weber, M.A.
Hypertension: A Companion to Brenner and rector’s The Kindey, pp.590-594, W.B.
Saunders Company
Garg, D.G., Jallad, N.S., Mishriki, A., Chalavarya, G., Kraml, M. et al 1987. Comparative
Pharmacodynamics and Pharmacokinetics of Conventional and Long-Acting Propranolol
J. Clin. Pharmacol. (27) 390-396
Grundy, R. U., McAinsh, J., Taylor, D.C. 1974 The effect of food on the in vivo release of
Propranolol from a PVC matrix tablet in dog, J.Pharm. Pharmacol. (26 Suppl.), 65P
Jantzen, G.M., Robinson, J.R. Sustained and Controlled Release Drug Delivery Systems
in Banker, G.S., Rhodes, C. (eds.) Modern Pharmaceutics, 3rd ed., pp 575-610, Marcel
Dekker (1996).
Moller, H. 1983. Release in vitro and in vivo and bioavailability of Propranolol from
sustained release formulations. Acta Pharm. Technol. (29) 287-294
Moore, J.W., Flanner, H.H., 1996. Mathematical Comparison of curves with an emphasis
on in vitro dissolution profiles. Pharm. Tech. 20(6), 64-74.
O’Hara, T, Dunne, A, Butler, J., Devane, J., 1998. A review of methods used to compare
dissolution profile data. Pharm. Sci. Tech. Today. (5) 214-223.
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Research Protocol - page 18
Perucca, E.; Grimaldi, R.; Gatti, G.; Caravaggi, M.; Frigo, G. M. et al. 1984.
Pharmacokinetic and pharmacodynamic studies with a new controlled release
formulation of Propranolol in normal volunteers: comparison with other commercially
available formulations. Br. J. Clin. Pharm. (18) 37-43
Rekhi, G.S., Jambhekar, S.S. 1996. Bioavailability and In-vitro-/in-vivo Correlation for
Propranolol Hydrochloride Extended-release Bead Products Prepared Using Aqueous
Polymeric Dispersions. J. Pharm. Pharmacol. (48) 1276-1284
Serlin. M.J., Orme, M. L’E., MacIver, M., Sibeon, R.G., Breckenridge, A.M. 1983. The
Pharmacodynamics and pharmacokinetics of conventional and long-acting Propranolol
in patients with moderate hypertension. Br. J. Clin. Pharm. (15) 519-527
Shah, V.P., Tsong, Y., Sathe, P., 1998. In vitro dissolution profile comparison - statistics
and analysis of the similarity factor, f2. Pharm. Res. (15) 889-896.
Shand, D.G., Nuckolls, E.M., Oates, J.A. 1970. Plasma Propranolol levels in adults with
observations in four children. Clin. Pharm. Ther. (11) 112-120
Straka, R. J.; Lalonde, R. L.; Pieper, J. A.; Bottorff, M. B.; Mirvis, D. M. 1987. Nonlinear
pharmacokinetics of unbound Propranolol after oral administration. J. Pharm. Sci. (76)
521-524
Takahashi, H.; Ogata, H.; Warabioka, R.; Kashiwada, K.; Someya, K.; et al 1990.
Decreased absorption as a possible cause for the lower bioavailability of a sustained-
release Propranolol. J. Pharm. Sci. (79) 212-215
Walle, T.; Walle, U. K.; Olanoff, L. S.; Conradi, E. C. 1986. Partial metabolic clearances
as determinants of the oral bioavailability of Propranolol. Br. J. Clin. Pharm. (22) 317-323
***FDA 1997 Guidance for Industry Modified Release Solid Oral Dosage Forms Scale-
Up and Postaproval Changes: Chemistry, Manufacturing, and Controls, In Vitro
Dissolution Testing and In Vivo Bioequivalence Documentation. Guidance for Industry.
US Department of Health and Human Services Food and Drug Administration Center for
Drug Evaluation and Research, Center for Biologics Evaluation and Research.
***FDA 1997 Guidance for Industry Extended Release Solid Oral Dosage Forms
Development, Evaluation And Application Of In Vitro-In Vivo Correlation.
US Department of Health and Human Services, Food and Drug Administration, Center
for Drug Evaluation and Research.
*** Martindale - The Extra Pharmacopoeia 32nd Ed. The Royal Pharmaceutical Society
London, 1999
*** United States Pharmacopeia&National Formulary 24th Ed. The United States
Pharmacopeial Convention, Inc., 1999.
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INTRODUCTION
Before agreeing to participate in this study, it is important that the following
explanation of the proposed procedures be read. It describes the purpose,
procedures, benefits, risks, discomforts and precautions of the study. It also
describes alternative procedure available and the right to withdraw from the study
at any time. I have been told that no guarantee or assurance can be made as to
the results. I have also been told that refusal to participate in this study will not
influence standard treatment available to me.
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PURPOSE
The purpose of this research study is to evaluate how a new preparation of an
extended release Propranolol tablet behaves in the body when taken by healthy
volunteers who are under fasting conditions and to compare the blood
concentrations of Propranolol when taken as a once-a-day tablet versus a
marketed once-a-day capsule. Propranolol is a beta-adrenergic blocker that is
currently used for the treatment of high blood pressure, anginal chest pain, some
types of heart beat irregularities, and post heart attacks. It is approved for use in
the United States
DURATION
My participation in this study will last for approximately 14days.
PROCEDURE
I have been told that during the course of the study, the following will occur:
Initially a physician will take my medical history, perform a physical examination,
check my body weight and record my electrocardiogram. For testing purposes,
approximately two teaspoons of blood will be drawn from a vein in my arm. The
results of my tests and physical examination will be kept confidential and
disclosed only as required by law. All procedures will be completed within a
seven day timeframe to determine my eligibility for the study.
The study consists of two periods separated by one week. On Day One of each
period I will come to the outpatient facility at 7.30 am and I will remain there for at
least 12 hours after dosing. Because this study is performed under fasting
conditions, I will be required not to eat anything after 8 pm of the evening before
the test day. I will be able to eat lunch at 1 pm on Day One. I may drink water as
desired except within one hour before and after receiving the study medication.
A catheter with a lock (hep-lock) will be inserted into a vein in my arm before the
drug administration and will be kept at site for 12 hours after administration.
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EXCLUSION
I should not participate in this study if any of the following apply to me:
I am under 18 or over 65 years of age.
I have a medical condition (hematological, renal, hepatic, gastrointestinal,
endocrine, pulmonary, dermatological, oncological or neurological, alcoholism),
requiring medical treatment, medications or care
I have a history of cardiovascular disease
I take concomitant drugs
I am allergic to Propranolol
I am a pregnant or lactating woman
I have participated in another drug study or any other study using the same drug
within the last three months.
RISKS / DISCOMFORTS
I have been told that the study described above may involve certain risks and
discomforts, as well as the possibility for unforeseen risks. The 80 mg daily dose
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PREGNANCY
If I am a woman of childbearing potential, I will not participate in this research
study unless I have a negative pregnancy test and am using an approved form of
birth control. I agree to inform the investigator immediately if: 1) I have any
reason to suspect pregnancy; 2) I find that circumstances have changed and that
there is now a risk of becoming pregnant; or 3) I have stopped using the
approved form of birth control.
BENEFITS
I have been told that I will receive no payment from my participation in this study,
but my participation may help health care practitioners better understand the
release and absorption of the study drugs after administration. I will also receive
educational materials up to a value of $200.
ALTERNATIVES
The study will evaluate the rate of absorption of the studied drugs in healthy
volunteers and it is not intended for treatment of a medical condition. As such,
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NEW FINDINGS
I have been told that I will receive any new information during the course of the
study concerning significant findings that may affect my willingness to continue
participating in the study.
CONFIDENTIALITY
Every effort will be made to maintain the confidentiality of my study records.
Agents of the United States Food and Drug Administration, representatives of the
UCMB – IRB, the investigator and coinvestigators or sponsor will be allowed to
inspect sections of my medical and research records related to this study. The
data from the study may be published; however I will not be identified by name.
My identity will remain confidential unless disclosure is required by law.
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PAYMENT TO PARTICIPANTS
I have been told that I will be compensated for my participation in this study with
educational materials up to a value of $200
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LEGAL RIGHTS
Nothing in this consent form waives any legal rights I may have nor does it
release the investigator, the sponsor, the institution or its agents from liability for
negligence.
Revised 11/07/01
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8. Appendix 2
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Subjects monitoring during the pilot bioequivalence study - period 2 (blood
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