Nghiên cứu bào chế viên nifedipin giải phóng kéo dài theo cơ chế bơm thẩm thấu ban tieng anh

MINISTRY OF

MINISTRY OF

EDUCATION AND TRAINING

NATIONAL DEFENSE

MILITARY MEDICAL UNIVERSITY

TRAN QUANG TRUNG

A STUDY ON THE PREPARATION OF
OSMOTIC PUMP TABLETS OF
NIFEDIPINE

PHARMACEUTICAL DOCTORAL THESIS

HANOI – YEAR 2021


MINISTRY OF

MINISTRY OF

EDUCATION AND TRAINING

NATIONAL DEFENSE

MILITARY MEDICAL UNIVERSITY

TRAN QUANG TRUNG

A STUDY ON THE PREPARATION OF
OSMOTIC PUMP TABLETS OF
NIFEDIPINE
Speciality: PHARMACEUTICAL TECHNOLOGY AND
PHARMACEUTICS
Code: 9720202

PHARMACEUTICAL DOCTORAL THESIS
FULL NAME OF SUPERVISOR:

1. Assoc. Prof. Ph.D. Trinh Van Lau
2. Prof. Ph.D. Nguyen Thanh Hai

HANOI – YEAR 2021


ACKNOWLEDGEMENT
I would like to express deep gratitude to my advisors, Assoc. Prof. Ph.D.
Trinh Van Lau and Prof. Ph.D. Nguyen Thanh Hai for their enthusiastic
guidance and wholehearted help throughout the course of this thesis.
I would also like to express my sincere thanks to Assoc. Prof.
Ph.D.Trinh Nam Trung, all my colleagues and technicians from
Pharmaceutical Training Institute under the Military Medical University for
their enthusiastic help and extending the facilities to complete this research
work.
I would extend my sincere thanks to Prof. Ph.D. Pham Thi Minh Hue
and lecturers, technicians of the Pharmaceutics Department of Hanoi
University of Pharmacy for their help and facilitation.

I would like to thank the VNU University of Medicine and Pharmacy,
National Institute of Pharmaceutical Technology, Institute of Biomedicine and
Pharmacy, National Institute of Drug Quality Control, Hanoi Quality Control
Center of Drug, Cosmetic and Food, Colorcon Vietnam company limited,
Traphaco Joint Stock Company, and Pharmaceutical Corporation Ha Tay for
the help and extending the facilities to complete this work.
I would like to thank the Board of Directors of Military Medicine
University, Prof. Ph.D. Nguyen Linh Toan, Dr. Dao Hong Duong, and the
experts of the Postgraduate Training Department for their interest and help
during the course of study and research.
I would extend my special thanks to my family members, friends, and
colleagues for their constant encouragement and for extending the facilities to
complete this research work.
Hanoi, day

month year, 2021

Tran Quang Trung


COMMITMENT

I here by declare that this is my own research work. The data and
results stated in the thesis are true and have not been published by anyone in
any project.

Author

TRAN QUANG TRUNG

TABLE OF CONTENTS
Acknowledgement
Commitment
Table of contents
List of abbreviations
List of tables
List of figures
INTRODUCTION.............................................................................................1
CHAPTER 1.REVIEW OF LITERATURE......................................................3
1.1. OVERVIEW OF NIFEDIPINE...............................................................3
1.1.1. Formula, nomenclature...................................................................3
1.1.2. Physical and chemical properties....................................................3
1.1.3. Analytical methods..........................................................................4
1.1.4. Pharmacokinetics............................................................................5
1.1.5. Pharmacological effects..................................................................5
1.1.6. Indications, dosages........................................................................5
1.1.7. Undesirable effects..........................................................................6
1.1.8. Some preparations containing nifedipine on the Vietnamese
market..............................................................................................6
1.1.9. Some studies on the extended-release drug delivery system
containing nifedipine.......................................................................7
1.2. PUSH-PULL OSMOTIC PUMP EXTENDED-RELEASE DRUG
DELIVERY SYSTEM........................................................................19
1.2.1. Structure and mechanism of drug release.....................................19
1.2.2. Advantages and disadvantages......................................................20
1.2.3. Composition..................................................................................22
1.3. EVALUATE THE BIOAVAILABILITY AND BIOEQUIVALENCE
OF PRODUCT CONTAINING NIFEDIPINE...................................26

1.3.1. In vitro drug release studies..........................................................26
1.3.2. In vivo bioavailability studies........................................................29
CHAPTER 2. MATERIALS AND METHODS.............................................35
2.1. SUBJECTS............................................................................................35
2.1.1. Materials, chemicals......................................................................35
2.1.2. Equipment and tools......................................................................36
2.1.3. Reference and test product............................................................38
2.1.4. Experimental animals....................................................................38
2.1.5. Study location and duration of implementation............................38
2.2. METHODS...........................................................................................38
2.2.1. Formulation development studies.................................................38
2.2.2.Preparation methods.......................................................................42
2.2.3. Validation of preparation process of push – pull osmotic pump
tablets of 30 mg nifedipine with a batch scale of 2,000 tablets....48
2.2.4. Quality control methods................................................................49
2.2.5. Stability study methods.................................................................55
2.2.6. Bioavailability study of extended-release nifedipine tablets in
experimental dogs.........................................................................56
2.2.7. Statistical study.............................................................................66
CHAPTER 3. RESULTS.................................................................................67
3.1. DEVELOPMENT AND VALIDATION OF HIGH-PERFORMANCE
LIQUID

CHROMATOGRAPHY

METHOD

FOR

THE

DETERMINATION OF NIFEDIPINE................................................67
3.1.1. Method development............................................................67
3.1.2. Method validation.........................................................................69
3.2. FORMULATION DEVELOPMENT STUDY.....................................73
3.2.1. Assessment of the drug - excipients interaction............................73
3.2.2. Stability study of nifedipine to the light in mediums....................74


3.2.3. In vitro dissolution study of the reference product........................77
3.3. FORMULATION OF PUSH-PULL OSMOTIC PUMP TABLETS
OF NIFEDIPINE.................................................................................78
3.3.1. Formulation of core tablets...........................................................79
3.3.2. Formulation of osmotic coating....................................................84
3.3.3. Effect of the release orifice size on the drug release......................87
3.4. DEVELOPMENT AND VALIDATION OF THE PREPARATION
PROCESS OF PUSH-PULL OSMOTIC PUMP TABLETS OF
NIFEDIPINE WITH A BATCH SCALE OF 2,000 TABLETS..........90
3.4.1. Description of the preparation process of push-pull osmotic
pump tablets of 30 mg nifedipine with a batch scale of 2,000
tablets............................................................................................90
3.4.2. Validation of the preparation process of push-pull osmotic
pump tablets of 30 mg nifedipine with a batch scale of 2,000
tablets............................................................................................92
3.5.

ESTABLISHING

THE

QUALITY

STANDARD

AND

EVALUATING THE STABILITY OF PUSH-PULL OSMOTIC
PUMP NIFEDIPINE TABLETS.....................................................102
3.5.1. Establishing the quality standards of push-pull osmotic pump
tablets of nifedipine.....................................................................102
3.5.2. Stability study of push-pull osmotic pump tablets of nifedipine
.....................................................................................................104
3.6. BIOAVAILABILITY STUDY OF PUSH – PULL OSMOTIC PUMP
TABLETS OF NIFEDIPINE............................................................107
3.6.1. In vitro equivalence study...........................................................107
3.6.2. Validation of UPLC-MS/MS method for the determination of
nifedipine in dog plasma.............................................................108


3.6.3. Bioavailability study of push-pull osmotic pump tablets of 30
mg nifedipine in experimental dogs............................................123
CHAPTER 4. DISCUSSION........................................................................133
4.1. PREPARATION STUDY....................................................................133
4.1.1. Selecting the extended-release type............................................133
4.1.2. Formulation of push-pull osmotic pump tablets of nifedipine
.....................................................................................................136
4.1.3. Development of the preparation process of extended-release
nifedipine tablets.........................................................................151
4.2. ESTABLISHING THE QUALITY STANDARD AND INITIAL

EVALUATING

THE STABILITY OF EXTENDED-RELEASE

TABLETS CONTAINING 30 MG NIFEDIPINE..................................154
4.2.1. Establishing the quality standards...............................................154
4.2.2. Evaluating the stability of extended-release nifedipine tablets
.....................................................................................................155
4.3. INITIAL ASSESSMENT OF BIOAVAILABILITY..........................156
4.3.1. Development and validation of UPLC-MS/MS method for the
determination of nifedipine in dog plasma.................................156
4.3.2. Bioavailability study of extended-release tablets of 30 mg
nifedipine....................................................................................161
CONCLUSION.............................................................................................166
RECOMMENDATIONS...............................................................................168
REFERENCES..............................................................................................169
LIST OF APPENDICES


LIST OF ABBREVIATIONS
Numbe
r
1
2
3
4

Abbreviations

Full written section

ACN
OSP
AUC
AUMC

5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28

29
30

BCS
CA
CV
API
PK
VNP
DSC
EC
EOP
EtOH
EtOAc
FDA
FTIR
GC
GLI
ER
CR
PR
HPLC
SDN
HPTLC
HPMC
HQC
IPA
IS
w/w

Acetonitrile
Osmotic pressure
Area Under the Curve – time
Area under the first moment curve
(Or the curve of concentration*time versus time)
Biopharmaceutical Classification System
Cellulose acetat
Coefficient of Variation
Active Pharmaceutical Ingredient
Pharmacokinetics
Vietnamese Pharmacopoeia
Differential scanning calorimetry
Ethyl cellulose
Elementary Osmotic Pump
Ethanol
Ethylacetat
Food and Drug Administration
Fourie Transform Infrared
Gas chromatography
Glibenclamide
Extended-release
Controlled-release
Pulsatile release
High performance liquid chromatography
Solid dispersions
High performance thin layer chromatography
Hydroxy propyl methyl celulose
High quality control sample
Isopropyl alcohol
Internal standard

Weight/weight

31
32
33
34
35

SMW
MW
BDS
TDS
AVW

Weight gains of semipermeable membrane
Molecular weight
Bulk density
Tapped density
Average weight


Numbe
r
36
37
38
39
40
41
42

43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64

Abbreviations

Full written section

LC
LLOQ
LOD

LOQ
LQC
MCC
MeOH
MOTS
MQC
MS
MRT
NIF
PEG
PEO
PPOP
PVP
RSD
SCMC
SD
SEOP
SEM
BA
SLS
SOTS
SSG
UDE
BE
Tlag
UPLC-MS/MS

Liquid chromatography
Lower limit of quantification
Limit of detection

Limit of quantification
Low quality control sample
Microcrystalline cellulose
Methanol
Monolithic osmotic tablet system
Medium quality control sample
Mass Spectrometry
Mean residence time
Nifedipine
Polyethylen glycol
Polyethylen Oxid
Push – Pull Osmotic Pump
Polyvinyl Pyrrolidon
Relative standard deviation
Sodium carboxymethylcellulose
Standard deviation
Swellable elementary osmotic pump
Scanning electron microscopy
Bioavailability
Sodium lauryl sulfat
Sandwiched osmotic tablet system
Sodium starch glycolat
Undesirable effects
Bioequivalent
Lag time
Ultra performance liquid chromatography with
tandem mass spectrometric detection

65
66

67

USP
v/v
WHO

The United States Pharmacopoeia
Volume/volume
World Health Organisation


LIST OF TABLES
Table no.

Table name

Page no.

1.1.

Some preparations containing nifedipine................................................6

2.1.

List of materials and chemicals used in the study.................................35

2.2.

List of equipment for preparation and production.................................36

2.3.

List of equipment and tools for evaluation............................................37

2.4.

Parameters of mass spectrometry detector for qualitative and
quantitative

analysis

of

nifedipine

and

internal

standard

glibenclamide........................................................................................57
2.5.

Model of testing the drugs on experimental dogs.................................62

3.1.

Results of the column analysis validation.............................................68

3.2.

Mobile phase investigation results........................................................68

3.3.

Results of investigating the ratio of mobile phase components
MeOH: H2O...........................................................................................69

3.4.

Results of testing the system suitability................................................69

3.5.

Results of method precision..................................................................71

3.6.

Results of intermediate precision..........................................................71

3.7.

Results of accuracy test.........................................................................72

3.8.

Decomposition of nifedipine in pH 7.5 buffer .....................................74

3.9.

Decomposition of nifedipine in the pH 1.2 medium containing 0.5%
sodium lauryl sulfate ............................................................................75

3.10. Proportion (%) of nifedipine released from the reference tablet ..........77
3.11. Tablet samples of different polymers in the drug layer and push
layer.......................................................................................................79
3.12. The drug layer formulation of the osmotic nifedipine tablets with the
different content ratios of sodium chloride............................................81
3.13. The push layer formulation of osmotic nifedipine tablets with the
different content ratios of sodium chloride............................................83


Table no.

Table name

Page no.

3.14. The coating formulation of tablets with the different content ratios of
plasticizer to cellulose acetate ..............................................................84
3.15. The coating formulation of tablets with the content ratio of
plasticizer to cellulose acetate of 10%..................................................86
3.16. The formulation of a batch of 2,000 tablets..........................................90
3.17. The particle size distribution of NIF raw material powder.....................92
3.18. The nifedipine content uniformity when dry blending the drug layer
in a batch scale of 2,000 tablets.............................................................93
3.19. The density of the push layer powder after dry blending in a batch
scale of 2,000 tablets ............................................................................93
3.20. Loss on drying of the drug layer granules with different drying times

in a batch scale of 2,000 tablets.............................................................95
3.21. Loss on drying of the push layer granules with different drying times
in a batch scale of 2,000 tablets.............................................................95
3.22. The particle size distribution of the drug layer granules after final
blending in a batch scale of 2,000 tablets..............................................95
3.23. Properties of the drug layer granules after final blending in a batch
scale of 2,000 tablets.............................................................................96
3.24. The particle size distribution of the push layer granules after final
blending in a batch scale of 2,000 tablets..............................................96
3.25. Properties of the push layer granules after final blending in a batch
scale of 2,000 tablets.............................................................................96
3.26. Properties of tablets at all the stages with tableting speed 1 (2.5 rpm)
in a batch scale of 2,000 tablets.............................................................97
3.27. Properties of tablets at all the stages with tableting speed 2 (5 rpm)
in a batch scale of 2,000 tablets.............................................................97
3.28. Properties of tablets at all the stages with tableting speed 3 (10 rpm)
in a batch scale of 2,000 tablets.............................................................98


Table no.

Table name

Page no.

3.29. The effect of some parameters of the coating process on the
uniformity of coating weight ................................................................99
3.30. Investigation results of the parameters for drilling the drug release
orifice..................................................................................................100
3.31. Granule properties of the push and the drug layers in a batch scale of

2,000 tablets........................................................................................101
3.32. Properties of core tablet and osmotic tablet in a batch scale

of

2,000 tablets........................................................................................101
3.33. he mass uniformity of three batches of the coated tablets...................102
3.34. The dissolution results of three study batches ....................................103
3.35. Nifedipine content (%) of the three study batches..............................103
3.36. Several quality standards which proposed for the extended-release
tablet containing 30 mg nifedipine......................................................104
3.37. Nifedipine content (%) of three batches stored under the accelerated
conditions ...........................................................................................105
3.38. Nifedipine content (%) of three batches stored under the real
conditions............................................................................................105
3.39. Impurity content (%) of three batches stored under the accelerated
conditions for three months ................................................................106
3.40. Impurity content (%) of three batches stored under the accelerated
conditions for six months ...................................................................106
3.41. Impurity content (%) of three batches stored under the real
conditions for twelve months..............................................................106
3.42. Percentage of nifedipine released from the test product and the
reference product in three dissolution media .....................................108
3.43. Test results of the UPLC-MS/MS system suitability..........................109
3.44. Effect of blank samples at the retention time of nifedipine and
internal standard of glibenclamide......................................................110


Table no.

Table name

Page no.

3.45. Accuracy of standard samples.............................................................112
3.46. The peak area response of zero samples compared with the LLOQ
sample..................................................................................................113
3.47. The determination results of the LLOQ value of the method.............114
3.48. The investigation results of accuracy and intra-day precision............115
3.49. The investigation results of accuracy and inter-day precision............115
3.50. The investigation results of recovery percentage of NIF and GLI......117
3.51. The evaluation results of matrix effect................................................118
3.52. The evaluation results of carry-over....................................................119
3.53. The stability of the working solutions of internal standard.................119
3.54. The stability of plasma samples after three freeze-thaw cycles..........120
3.55. The stability of plasma samples at room temperature for 5 hours......121
3.56. The stability of the post-process samples in auto-sampler..................122
3.57. The long-term stability of plasma samples..........................................122
3.58. Nifedipine concentration in dog plasma after taking a single dose of
the test product (T) .............................................................................123
3.59. Nifedipine concentration in dog plasma after taking a single dose of
Adalat LA 30 mg reference product (R) .............................................124
3.60. The pharmacokinetic parameters of the test product ..........................126
3.61. The pharmacokinetic parameters of the reference product ................127
3.62. The analysis of variance with the dependent variable of ln[Cmax].......128
3.63. The analysis of variance with the dependent variable of ln[AUC0-∞]
.............................................................................................................129
3.64. The analysis of variance with the dependent variable of ln[MRT].....130
3.65. The comparison of Tmax value as per the non-parametric
statistical method.................................................................................131

LIST OF FIGURES
Figure no.

Figure name

Page no.

1.1.

Structure of push-pull osmotic pump....................................................19

1.2.

Mechanism of drug release from a push pull osmotic pump................20

2.1.

Preparation process flow diagram for extended-release nifedipine
tablets....................................................................................................46

3.1.

The ultraviolet absorption spectrum of standard nifedipine solution
of 150 µg/mL........................................................................................67

3.2.

The calibration curve of nifedipine in mobile phase of MeOH:H2O

...............................................................................................................70

3.3.

Graph showing the decomposition of nifedipine in pH 7.5 medium
...............................................................................................................75

3.4.

Graph showing the decomposition of nifedipine in pH 1.2 medium
containing 0.5% sodium lauryl sulfate..................................................76

3.5.

Release graph of Adalat LA reference product.....................................77

3.6.

Percentage of nifedipine released from the tablet samples of
different polymers in the drug layer and push layer and the reference
product ..................................................................................................80

3.7.

Percentage of nifedipine released from the tablet samples with the
different content ratios of sodium chloride in the drug layer and
reference product ..................................................................................81

3.8.

Percentage of nifedipine released from the tablet samples with the
different content ratios of sodium chloride in the push layer and
reference product ..................................................................................83

3.9.

Percentage of nifedipine released from the coated tablets with the
different content ratios of PEG 4000 plasticizer ..................................84


3.10. Percentage of nifedipine released from the tablet samples of the
different semipermeable membrane thickness .....................................86

Figure no.

Figure name

Page no.

3.11. Percentage of nifedipine released from the tablet samples with the
coating thickness of 10%, 12%, and the different orifice size (n = 6)
...............................................................................................................87
3.12. Chromatogram of blank samples of plasma........................................109
3.13. Chromatogram of a spiked sample containing the reference standard
of nifedipine and internal standard of glibenclamide at LLOQ
concentration of 0.5 ng/ml and concentration of 40 ng/mL,
respectively..........................................................................................110
3.14. A plot showing the correlation of the peak area ratio of nifedipine to
glibenclamide versus nifedipine concentration in plasma on different
days (a _ 1.12.2019, b _2.12.2019, c _ 3.12.2019, d _ 4.12.2019, e _

7.12.2019)............................................................................................112
3.15. The curve of average drug concentration over time of 6 dogs after
taking a single dose of the test product and reference product...........125


1
INTRODUCTION
In recent years, the trend of focusing on research in the field of
pharmaceuticals in order to improve the quality of the drug dosage form and
launch new preparations from active pharmaceutical ingredients has been
growing. On the basis of innovation in order to improve the quality of
conventional dosage forms of the drug, many generations of new dosage
forms have been brought to the market. The extended-release drug appeared
in the 1950s [1], and up to now, it is strongly developed with many
preeminent properties.
Osmotic pump extended-release drug (or controlled-release drug,
gastrointestinal therapeutic system) has attracted great attention from
researchers during the past 30 years. This is because they release the drug at a
rate that is independent of the pH and hydrodynamics of the external
dissolution medium [2], and they have an excellent in vitro/in vivo correlation
[3]. They also prevent peak-valley fluctuations, reduce dosage frequency,
improve patient compliance and offer many benefits compared to sustainedrelease

matrix-type

drug

delivery

systems,

especially

for

active

pharmaceutical ingredients with poor water solubility, many undesirable
effects.
Nifedipine, a calcium channel blocker, is the first dihydropyridine drug
to be clinically used to treat coronary venous insufficiency in 1969 [4]. It is
widely used in the treatment of angina, hypertension, other vascular disorders
and is well tolerated [5], [6], [7]. NIF is rapidly and completely absorbed
from the gastrointestinal tract after oral administration. However, NIF is
insoluble in water, has a short elimination haft-life of 2-4 hours [8]. Its
immediate release dosage forms and sustained-release matrix dosage forms
are rarely indicated in clinical at the moment due to theirs many undesirable


2
effects, and unstable plasma concentrations leading to difficulties in
controlling clinical hypertension and angina attacks. Osmotic pump extendedrelease tablets of nifedipine have not been comprehensively researched and
produced in Vietnam, leading to ineffective use of this active pharmaceutical
ingredient.
From the fact above, the thesis: “A study on the preparation of
osmotic pump tablets of nifedipine” was conducted with the following
goals:
1. To formulate and prepare the push- pull osmotic pump tablets containing
30 mg nifedipine with a batch scale of 2,000 tablets with in vitro release
profile extended up to 24 hours.

2. To establish a quality standard and initially evaluate the stability of
extended-release tablets containing 30 mg nifedipine.
3. To initially evaluate the bioavailability of extended-release tablets
containing 30 mg nifedipine in experimental dogs.

CHAPTER 1.
REVIEW OF LITERATURE
1.1. OVERVIEW OF NIFEDIPINE
1.1.1. Formula, nomenclature


3
- Molecular formula: C17H18N2O6
- Molecular weight (MW): 346.3
- Structural formula:
H3C

H3C

H
N

CH3

O

O
O

CH3

O
NO2

*Source: Vietnamese Ministry of Health (2017) [9]

-Nomenclature:

dimethyl

2,6-dimethyl-4-(2-nitrophenyl)-1,4-

dihydropyridine-3,5-dicarboxylate.
1.1.2. Physical and chemical properties
- A yellow crystalline powder, practically insoluble in water. Melting point:
171 – 175oC. At 20oC, nifedipine (NIF) is freely soluble in acetone 250g/l, in
methylene chloride 160g/l, in chloroform 140g/l, soluble in ethyl acetate
50g/l, in methanol (MeOH) 26g/l. At 37oC, the solubility in buffer solutions of
different pH-values can be given as: pH 4 - 0.0058 g/l, pH 7 - 0.0056 g/l, pH
9 - 0.0078 g/l, pH 13 - 0.006 g/l [10].
- According to the Biopharmaceutics Classification System (BCS), NIF is a
typical class II compound with high permeability and low solubility leading to
a low oral bioavailability (BA), although NIF is rapidly absorbed from the
gastrointestinal tract. Therefore, the formulation of extended-release (ER) NIF
tablets not only focuses on prolonging drug release but also needs to improve
solubility and absorption in the gastrointestinal tract.
- Stability to light and temperature: NIF is unstable to light in solid form and
extremely unstable to light in dissolved state in solution [11]. The

4
photostability of nifedipine is influenced by the intensity and wavelength of
light exposure [11]. Under the influence of daylight and certain wavelengths
of artificial light, NIF is converted into a nitrosophenylpyridine derivative.
When exposed to UV light leads to the formation of a nitrophenylpyridine
derivative. Therefore, all experimental work with nifedipine solutions, such as
a dissolution test with the extended-release drug form under test for several
hours, should be performed in the dark or under the light of wavelength
greater than 450 nm, preferably under red light (wavelength 630 – 760nm).
Yellow light of sodium lamp can also be used (wavelength 589 nm). NIF
should not be stored at a temperature above 25oC.
1.1.3. Analytical methods
Determination of NIF in raw materials and preparations :
- Chemical method [12].
- UV spectrophotometry method: NIF has two absorption peaks of 236 nm
and 350 nm. This method is used to determine the active ingredient in tablets
[13] and the rate of drug release from capsules [14], GPKD tablets [15], [16],
[17]. In addition, a colored derivative of NIF can be made for spectroscopy in
the visible region [18], [19].
- High-performance liquid chromatography (HPLC) method: determination of
NIF in raw materials,capsules, GPKD tablets [14], determination of NIF in
tablets [20].
In addition, NIF can be determined in biological fluids by methods
such as: HPLC, gas chromatography [21], [22], [23], [24].
1.1.4. Pharmacokinetics
NIF is rapidly absorbed from the gastrointestinal tract; however, NIF
has low bioavailability (45-75%)due to undergoing extensive hepatic firstpass metabolism [5]. The percentage of NIF bound to plasma proteins is high,
about 92 to 98% (92-98%) [5]. It is almost entirely metabolized in the liver to

5
inactive metabolites. NIF is mainly excreted in the urine (80%), and the
remainder in feces and bile (20%) [5], [7].
1.1.5. Pharmacological effects
NIF mainly has anti-hypertensive effects, in addition to anti-angina
effects and treatment of Raynaud’s disease [5].
The mechanism of action of NIF is to selectively inhibit the inflow of
calcium ions into the cell by interacting specifically with the calcium channel
in the cell membrane without altering the ionic concentration of calcium in
the blood.Due to the decrease in the concentration of calcium in cells, it has
the effect of dilating the arteries, arterioles and can reduce the heart rate [7].
NIF has a relatively selective effect on vascular smooth muscle, less effect on
cardiomyocytes. Therefore, at therapeutic doses, the drug does not directly
affect cardiac contractility and impulse conduction.
1.1.6. Indications, dosages
1.1.6.1. Indications:
- The prophylaxis of angina, especially when a vasospastic element is present,
as in Prinzmetal’s angina.
- The treatment of hypertension.
- The treatment of Raynaud’s syndrome.
1.1.6.2. Administration
- Controlled-release preparation of NIF may be given in doses of 20 mg twice
daily or 30 mg, 60mg, 90 mg once daily.
Doses of NIF are dependent upon the preparation used, which can be
gradually increased depending on the patient’s response and tolerance until
the best control of blood pressure.They may need to be reduced in the elderly
or those with impaired liver function [7].
1.1.7. Undesirable effects
The undesirable effects usually occur in the early stages of drug
administration and gradually decrease after a few weeks or after the adjustment

6
of therapeutic doses. Usually, the tablet forms have a less undesirable effect than
the capsule form. Short-acting and fast-acting capsules can cause excessive
hypotension and reflex tachycardia, which can lead to ischemia of the heart
muscle or brain. In addition, common symptoms are headache, fatigue,
dizziness, hot flushes, palpitations, nausea, diarrhea or constipation.
1.1.8. Some preparations containing nifedipine on the Vietnamese market
Table 1.1.Some preparations containing nifedipine
Number Name of the
medicine
1
Adalat
2

3

4
5
6

Dosage forms

Content

Producer

Soft capsule
10mg NIF

Osmotic pump
20mg, 30mg,
Adalat LA
extended60mg NIF
release tablet
Bayer Pharma
AG
Sustainedrelease matrix
Adalat retard
20mg NIF
type film coated
tablet
Nifedipine
ExtendedHasan –
Hasan 20
release film
20mg NIF
Dermapharm
Retard
coated tablet
(Vietnam)
Nifedipine
Film coated
10mg NIF
STADA-VN J.V
STADA
tablet
ControlledVellpharm
Avensa LA
30mg, 60mg NIF

release tablet
(Vietnam)
* Source: following Drug Administration of Vietnam (2020)[25]

1.1.9. Some studies on the extended-release drug delivery system
containing nifedipine
1.1.9.1. Studies affecting the physical and chemical properties of nifedipine
Kanagale P. et al. [26] developed a solid dispersion (SDN) to serve as a
basis for the preparation of the elementary osmotic pump (EOP) system to
deliver the drug with poor water solubility of NIF in a zero-order fashion over
an extended period of time. SDNs were prepared by a hot-melt technique


7
using Poloxamer-188 at various ratios of drug and polymer (1:1, 1:5, and
1:10, on a weight basis) and investigated for solubility study. Core tablets
using SDN were prepared, coated with cellulose acetate (CA)

and

polyethylene glycol (PEG) 400, and manually drilled to create a delivery
orifice. The osmotic pump system was found to deliver NIF at a zero-order
rate for 20 hours. The drug release from the developed formulation was
independent of pH and agitational intensity.
Pham Thi Minh Hue [15] developed an SDN to serve as a basis for the
preparation of sustained-release matrix type tablets of NIF with action
extended up to 12 hours.The author has researched to improve the solubility
and dissolution rate of NIF by SDN preparation technique with PEG,
polyvinyl pyrrolidone (PVP), and hydroxy propyl methyl cellulose (HPMC)
carriers. Investigation of the effect of carrier ratio, carrier MW, SDN

fabrication method on the dissolution rate and solubility of NIF was
performed. The results showed that: SDN with PVP carrier made by the
solvent method has the ability to improve the solubility and dissolution rate of
NIF more than that and is used in the preparation of long-acting NIF tablets.
Misra M. et al. [27] had researched to prepare solid selfmicroemulsifying drug delivery systems serving as a basis for the preparation
of extended-release osmotic pump tablet of NIF with in vitro release profile
extended up to 12 hours. Self-microemulsifying drug delivery systems of NIF
were prepared by the author to improve the solubility of NIF before being
used to prepare an osmotic pump tablet. Research on the preparation of
osmotic pump tablets of NIF was conducted by granulating excipients: silicon
dioxide, lactose, mannitol, PVP, citric acid and sodium bicarbonate with the
prepared molten self emulsifying base of NIF mentioned above. Prepared
tablets were evaluated for particle size, solid-state properties, and release
profile. The effect of orifice size and amount of plasticizers on drug release


8
was also studied. The results showed that: self-emulsifying osmotic pump
tablet has not only provided improvement in solubility of NIF by selfemulsifying effect but also controlled-release due to the EOP system. Drug
release studies revealed that the release of NIF from prepared tablets was
followed a zero order release profile for 12 hours, independent of agitational
intensity with a cumulative release of 83.85%.
Nguyen Ngoc Chien et al. [28] fabricated an SDN containing NIF to
serve as a basis for the preparation of pulsatile-release tablets of NIF with a
lag time (Tlag) of 6 hours. The author has researched to improve the solubility
and dissolution rate of NIF through the fabrication of SDN with PVP carrier
at various ratios of NIF and PVP of 1:1, 1:2, and 1:3 (on a weight basis). The
SDN was prepared by dissolving NIF and PVP in MeOH with the ratio of NIF
and MeOH of 1:50 and adding 5% sodium laurylsulfate (SLS), spray drying
in BUCHI machine with parameters: air speed of 95%, the working

temperature of 70oC, pump speed of 7 rpm. The results showed that: the
solubility of NIF from SDN was significantly improved compared to the raw
material and SDN with the ratio of PVP and NIF of 1: 1 and 5% SLS used in
the preparation of pulsatile-release NIF tablets. Core tablets using SDN were
prepared by wet granulation method with excipients: starch, lactose, sodium
starch glycolate (SSG); then mixed the sieved granules with SDN and
lubricants. Core tablets were coated with a release-controlled layer by the
double compression coating method. Prepared tablets were tested for
dissolution for the first 1 hour in HCl 0.1N pH 1.2 medium and the following
hours in pH 6.8 buffer medium. The results showed that tablets have a T lagof 6
hours and complete release of drug within 1 hour after lag phase.
1.1.9.2. Study on preparation of sustained-release matrix-type drug delivery
system
a. Extended-release tablet dosage form


9
Akhtar S. et al. [29] had researched to prepare sustained-release matrix
tablet of NIF by direct compression method. The author has formulated and
optimized sustained-release matrix tablets of NIF using different grades of
HPMC (HPMC - K100 and HPMC - K4). The tablet formulations were
evaluated for physicochemical properties, buoyancy lag time, total floating
time, and in vitro drug release. The results indicated that optimized
formulation included NIF.HCl, HPMC K100, lactose, talc, magnesium
stearate on immersion in a 0.1N HCl solution at pH 1.2 and 6.8 pH phosphate
buffer at 37 ± 0.5oC, tablets immediately and remain buoyant up to 12 hours
without disintegration. Drug release from formulations was found to follow
Higuchi kinetics. In vitro data obtained for matrix tablets of NIF showed
prolonged drug release.
Barzegar-Jalali M. et al. [30] had researched to prepare sustained-release

matrix tablets of NIF hydrochloride employing HPMC and EC as hydrophilic
polymers. The direct compression method was used to prepare sustainedrelease matrix tablets of NIF. Drug content uniformity, friability tests were
performed, and the in vitro drug release profiles were compared with the
reference product (Procardia), benefiting similarity factor (f 2) and difference
factor (f1). The results showed that in all formulations, content uniformity
was in the acceptable range. Most of the prepared formulations passed the
friability test. Formulation containing HPMC and EC in the ratio of 88.5:5
showed acceptable dissolution properties compared to the reference
formulation. The best fitted kinetic models for the prepared matrix tablets and
Procardia were zero-order and Weibull models, respectively.
Thakare V.M. et al. [31] had researched to prepare a sustained-release
bilayer tablet of NIF in which one layer was immediate release as the initial
dose and the second layer was maintenance dose. Bilayer tablets were
prepared by wet granulation technique for immediate release layer using NIF,