Minitablet: A Novel Approach for Oral Extended Release
Shyamala Bhasakran and Preethi Sudheer*
Department of Pharmaceutics, East Point College of
pharmacy, Bidsrshalli, Virgo Nagar Post,
Bangalore-560049, India.
ABSTRACT
The present study is carried out to compare matrix
tablets and mini tablets of Diltiazem hydrochloride.
Matrix tablets and mini-matrix tablets containing Diltiazem
hydrochloride have been prepared by wet granulation technique. The hydrophilic
matrix was formed with chitosan together with the
additives. Preparation, the swelling and erosion behavior, in-vitro release
profiles and release kinetics and mechanism of release are discussed.
Comparison of all the parameters of matrix and mini matrix tablets is
discussed. The result shows that mini
matrix tablets shows more extended release profile in comparison with the
matrix tablets under similar conditions.
KEYWORDS:
matrix tablets, chitosan,
minitablets, Diltiazem
hydrochloride.
INTRODUCTION
Matrix technologies have often proven popular because
of the simplicity of the manufacturing processes required, level of
reproducibility, stability of the raw materials, dosage form as well as ease of
scale up operation, validation and favorable in-vitro in-vivo correlation. One
of the least complicated approaches to the manufacture of sustained release
dosage forms involves the direct compression of blends of the drug with
retardant materials and additives to form a tablet in which the drug is
embedded in the matrix core of retardant. Alternatively the retardant drug
blends may be granulated prior to compression.
Matrix dissolution devices are prepared by compressing
the drug with a slowly soluble polymer carrier in to a tablet form. There are
two general method of preparing drug wax particles: congealing method in which
the drug is mixed with a wax material and either spray – congealed or congealed
and screened. 1
Multiparticulate systems are multiple unit oral dosage forms consisting
of a multiplicity of small discrete units, each exhibiting some desired
characteristics2. They
form a major role in the design of solid dosage form processes because of their
unique properties and flexibility found in their manufacture, so hydrophilic
polymer matrix systems are widely used in oral controlled drug delivery to
obtain a desirable drug release profile, cost-effectiveness, and also have
broad regulatory acceptance.3
The administration of multiparticulate
matrix system filled in to hard gelatin capsules offers several advantages over
conventional single-unit matrix formulations like less risk of dose dumping,
less inter- intra subject variability, higher degree of dispersion thus
minimizing risk of high local drug concentration.3
Minitablets are tablets with diameter equal to or less than 2-4mm.
They are made by ordinary reciprocating or rotary tableting
machines. Due to the manufacturing process, defined sizes and strength can be
easily produced and variability with in a batch is small.
Because
of their uniform size and smooth surface, low porosity and high attainable
strength, minitablets can be coated more reproducibly
than usual pellets or granules. Minimatrix tablets
show an extended release over a longer period of time in comparison with the
matrix tablets5,6.
Diltiazem
Hydrochloride is a calcium ion cellular influx inhibitor (slow calcium channel
blocker or calcium antagonist). It acts mainly by blocking the Ca2+ entry
through voltage sensitive calcium channels. Diltiazem
hydrochloride is well absorbed from the gastrointestinal tract and is subject
to an extensive first-pass effect, giving an absolute bioavailability (compared
to intravenous administration) of about 40%. Plasma half-life following single
or multiple drug administration is approximately 3.0 to 4.5 hours7.
Hence it is a suitable candidate for a sustained release formulation.
Chitosan (C
6 H 11 O 4 N) n is a principal
derivative of chitin. Chitin is the most abundant polysaccharide in nature. Its
sugar backbone consists of units of 1, 4 linked glucosamine with a high degree
of N- acetylation. Chitosan
is nontoxic and easily bioabsorbable with gel forming
ability at low pH 8. Chitosan has antacid
and antiulcer activities that prevents or weakens drug irritation in the
stomach. Chitosan matrix formulations appear to float
and gradually swell in acid media. The cationic character along with the
presence of reactive functional group in chitosan,
has given it possibilities for utilization in controlled release technologies. Chitosan combines unique physicochemical characteristics
like in-vivo biodegradability, biocompatibility and antimicrobial action 9,10.
In
this study, matrix and mini-matrix tablets of Diltiazem
hydrochloride were prepared by the wet granulation method using varying
concentrations of chitosan for extending drug
release. The mini tablets prepared were encapsulated in hard gelatin capsules
to give multiple unit dosage forms. The production of mini matrices and the
dosing flexibility are quiet simple. These have several advantages like uniform
plasma levels and reproducible bioavailability11,12.
MATERIALS
AND METHODS:
Materials:
Diltiazem hydrochloride was a
gift sample obtained from Micro Labs, India, Chitosan
was from CIFT, Cochin, Kerala, Dicalcium phosphate (Encompress- Lobachemie, Mumbai,
India), Starch ( Merck), Magnesium stearate and talc
(Lobachemie, Mumbai) were purchased.
PREPARATION
OF TABLETS:
MATRIX
TABLETS:
Granules
for the matrix and mini-matrix tablets were prepared by wet granulation
technique.
An
accurately weighed quantity of Diltiazem
hydrochloride (90 mg for each tablet) was mixed thoroughly with the required
quantities of the polymer chitosan. The chitosan was used in various concentrations of 1%, 2%, 4%,
6% and 8 %.( F1, F2, F3, F4, F5). To this the diluent dicalcium
phosphate was added .The drug and the excipients were well-blended and
granulated using starch paste (4 %) as the binder solution. The compositions of
different formulations are given in the Table1. The granules obtained were
sieved through sieve No.16 and allowed to dry in the hot air oven at 500 for
one hour. The dried granules were then sieved over sieve No. 22 / 44 and mixed
well with talc and magnesium stearate before
compression.
The
granules were evaluated for the following propeties.
Fixed
funnel method was used to determine the angle of repose.
The
angle of repose was then calculated using the formula
tan θ
= h / r, where
θ
- is the angle of repose
h -
is the height of the conical pile
r -
is the radius of the base of the conical pile
The
results are reported in Table 2.
Bulk
Density and Percent compressibility:
Bulk
Density =Weight of granules/ volume occupied
by granules
The
percent compressibility was then calculated from initial bulk density and
tapped density using the equation:
%
compressibility = Tapped
bulk density – Initial bulk density/tapped bulk densityx100
The
results are reported in Table 2
Compression of tablet:
The
dried granules were lubricated using 1% (w/w) each of magnesium stearate and talc. Lubricated granules (150 mg) of the
containing 90 mg of the drug were compressed into matrix tablets on 6mm punches
on a CIP 10 station machine where only one compression station was kept active.
The
matrix tablets prepared were subjected to further optimization studies. The
design selected was two levels two factor factorial design to study the effect
of polymer concentration and level of hardness on the drug release rate. The
cube graph of optimization is shown in figure 1.
MINI MATRIX TABLETS:
Preparation of Mini matrix Tablets:
Granules
for preparation of mini-matrix tablets were prepared by the wet granulation
technique.
Wet granulation Method:
Accurately
weighed quantities of diltiazem hydrochloride (15 mg
for each tablet) was mixed thoroughly with the required quantities of the
polymer chitosan of 6% (on the basis of the previous
experiments of matrix tablets as shown in table No.1. which proved that desired
drug release profile of the drug was shown by tablets containing 6% of chitosan ). To this dicalcium
phosphate was added as the diluent. The drug and the excipients were
well-blended and granulated using starch paste (4%) as the binder solution. The
composition of formulation is given in the Table No.3. The granules obtained
were sieved through sieve No.16 and allowed to dry in the hot air oven at 500
C. The dried granules were then sieved over sieve No. 22 / 44 and mixed well
with talc and magnesium stearate before compression.
Table
– 1: Composition of matrix formulations (mg/tablet)
|
|
Formulation
Code |
||||
|
|
F1 |
F2 |
F3 |
F4 |
F5 |
|
Diltiazem
HCl (drug) |
90.00 |
90.00 |
90
.00 |
90.00 |
90.00 |
|
Chitosan
(polymer) |
01.50 |
03.00 |
06.00 |
09.00 |
12.00 |
|
Dicalcium
phosphate |
48.50 |
46.50 |
44.50 |
40.50 |
37.50 |
|
Starch
paste |
06.00 |
06.00 |
06.00 |
06.00 |
04.00 |
|
Talc |
01.50 |
01.50 |
01.50 |
01.50 |
01.50 |
|
Magnesium
stearate |
01.50 |
01.50 |
01.50 |
01.50 |
01.50 |
Weight
of each tablet =150mg
Table
– 2: Evaluation of granules for matrix tablets
|
Formulation
Code |
Angle
of Repose (θ) |
Bulk
density (g/cm3) |
% Compressibility |
|
F1 |
25.06 |
0.632 |
4.74.. |
|
F2 |
25.45 |
0.658 |
4.97 |
|
F3 |
25.99 |
0.695 |
4.87 |
|
F4 |
26.57 |
0.703 |
4.28 |
|
F5 |
26.83 |
0.714 |
4.58 |
The
granules were evaluated for the properties as such as angle of
repose, bulk density and percent compressibility
as per the procedures followed for matrix tablets.
Compression of tablet:
The
dried granules were lubricated using 1% w/w each of magnesium stearate and talc. Mini matrix tablets were prepared by
compressing 50 mg of the lubricated granules containing 15 mg of the drug on 4
mm punches on a CIP 10 station machine where only one compression station was
kept active.
Filling in to capsule shell:
Six
such mini matrix tablets amounting to a total of 90 mg of the drug were filled
in to a capsule of size 3 to form the multi unit dosage form.
Table
– 3: Composition of Minimatrix Tablets
|
Materials
Used |
Mg
per tablet |
|
Diltiazem
HCl (drug) |
15.00 |
|
Chitosan
(polymer) |
03.00 |
|
Dicalcium
phosphate |
28.50 |
|
Starch
paste |
02.00 |
|
Talc |
00.50 |
|
Magnesium
stearate |
00.50 |
Total
weight of each mini tablet =50mg
EVALUAION OF TABLETS:
Size (Diameter), Thickness and shape
Diameter
and thickness was measured using screw gauge. Ten tablets from each formulation
were selected and the diameter and the crown thickness were measured. Results
are reported in Table 4.
Friability:
Ten
tablets were weighed and placed in Roche Friabilator,
which was then operated for 100 revolutions at 25 rpm. The tablets were then
dusted and weighed. The difference in two weights represents friability
Friability
= Initial weight – Final weight / Initial weight X 100 Results are reported in
Table 4.
|
Formulation code |
Thickness (mm) |
Hardness ( kg/cm2) |
Friability (%) |
Drug Content (mg) |
|
F1 |
4.10 |
4.50 |
0.90 |
90.99 |
|
F2 |
4.15 |
4.80 |
0.85 |
90.05 |
|
F3 |
4.10 |
5.20 |
0.74 |
90.60 |
|
F4 |
4.10 |
5.50 |
0.70 |
89.85 |
|
F5 |
4.15 |
5.50 |
0.70 |
89.60 |
Fig: 2 In- vitro
dissolution profile of the tablets with varied polymer concentration.
Fig.3 Higuchi’s first order plot of dissolution.
Fig 4.
Comparative Dissolution profile of 6% matrix tablet with the marketed product
Fig.5. Comparative
dissolution Profiles of Matrix tablets and Minimatrix
tablets containing 6% chitosan
Hardness:
Monsanto
hardness tester was used to determine the hardness. The tablet was placed
between the two plungers containing a compressible spring. The pressure
required for the tablet to just crack was noted directly on the scale attached
to the spring.
Drug Content:
Ten
tablets of each formulation were weighed and powdered. The quantity equivalent
to 90 mg of diltiazem
hydrochloride was transferred to a 100 ml volumetric flask and extracted with
distilled water and the absorbance was measured at 237 nm after filtration and
suitable dilution and the drug content was then determined. .Results are
reported in Table 4
INVITRO RELEASE STUDIES:
Procedure:
The
in vitro release studies of the matrix
tablets and mini-matrix tablets were
carried out using USP Type II dissolution test apparatus (USP 21 XXI/ XXII,
Model: T.P.T. –0.6N) using 900 ml of Phosphate buffer pH 7.4 as the dissolution medium. The temperature
was maintained at 37± 10 C and the speed was maintained at 100 rpm. One matrix tablet or one capsule containing
90 mg of the drug was placed in the dissolution medium.
2
ml of the sample was collected in each case at regular time interval and
filtered and analyzed after suitable dilution with the phosphate buffer 7.4 pH by measuring the absorbance at 237 nm using buffer as
blank. The results were recorded and the cumulative percentage drug release was
calculated and plotted against time in minutes.
Also release data was compared with a sustained release marketed product
of Diltiazem hydrochloride containing 90 mg of the
drug. The results are presented in the tables 6-10. The comparative dissolution
profiles of formulations F1- F5 are given in Figure 2. Higuchi’s plots
were constructed and are given in
Figure 3.
Comparative Studies of Matrix, Mini
matrix Tablets:
The
matrix tablets and mini matrix tablets of Diltiazem
hydrochloride and 6 % of chitosan polymer were
compared for their physico- chemical characteristics,
in vitro release profile and stability.
Dissolution Studies:
Data Analysis:
A simple relationship which described drug release from
a polymeric system13.
M
t/ M = kt n
Where
Mt / M is the fraction of the
drug released, t is the release time, k is the kinetic constant incorporating
structural and geometric characteristics of the release device and n is the
release exponent indicative of the mechanism of release. These equations can be
used to analyze the first 60 % of a release curve where the release is related
to tn.
It
was shown that two competing release mechanism, a Fickian
diffusional release and a case-II relaxational
release, are the limits of this phenomenon. Fickian diffusional release occurs by usual molecular diffusion of
the drug due to a chemical potential gradient. Case –II relaxational
release is the drug transport mechanism associated with the stresses and
transition states in hydrophilic glassy polymers which swell in water or
biological fluids. This term also includes polymer disentanglement and erosion.
The value of exponent for case-II transport mechanism is twice that of pure Fickian diffusional mechanism 14.
Compatibility Studies:
Differential Scanning Colorimetry:
Instrument
DS Calorimeter (Mettler Toledo Model DSC 821)
equipped with a monitor and a computerized thermal analysis system 40-1 printer
(chromatopac L-R 6A) was used. The instrument was
calibrated with standard indium and operated at an ampere range of 8 mj / sec. DSC graphs of pure drug diltiazem
hydrochloride and the formulations (matrix tablets and mini matrix tablets)
were obtained.
Samples
were heated hermetically in flat bottomed aluminium
cells. These samples when heated over a temperature of 40- 3400 C in an
atmosphere of nitrogen (50ml/min) at a constant rate of 100 C/min.
FTIR ANALYSIS:
FT-IR
spectra of Diltiazem hydrochloride, the polymer chitosan and the formulations were taken after making
potassium bromide discs with small amount of the sample, to detect drug- excipients
interaction.
RESULTS
AND DISCUSSION:
Matrix
tablets and mini matrix tablets containing Diltiazem
hydrochloride and excipients were well formed and no problems were experienced.
Matrix tablets were prepared by
wet granulation method using various polymer concentrations of chitosan polymer and drug Diltiazem
hydrochloride. The granules showed a bulk density of 0.632 –0.714 g/ cm3.
The angle of repose was found to be between 25.06° to 26.83 °, indicating that they have good flow
properties. The hardness of the tablets varied from 4.5- 6.0 kg / cm2
and the friability was between 0.7 – 0.9 %. The drug content ranged from
99.5 - 100 % of the label claim for all the formulations. In case of mini
matrix tablets, the granules showed a bulk density of 0.732 g/cm3.
The angle of repose was found to be between 24.26. Thus the granules shows low
angle of repose and they have good flow properties.
The in-vitro dissolution studies performed showed a release
profile ranging from 62 % - 100 %. The in-vitro studies showed that lower
concentration of the polymer showed no controlled release due to the
disintegrating property of the polymer. Tablets containing lower polymer
concentrations, F1 and F2 showed a rapid release profile of the drug which was
not desirable. The polymer concentration of 4 % in formulation F3 showed a
controlled release of 92 % at six hours but showed an initial burst effect may
be due to the disintegrating property of the polymer at lower concentration. 6
% of chitosan showed the release of 80 % in six hours
in a controlled manner with no burst effect and the formulation F5 containing 8
% of chitosan showed a still further controlled
release of 62 % by the end of six hours which was not a desirable one. Thus
polymer concentration of 6 % shows the optimum release characteristics.
Optimization studies concluded that 6 % of chitosan
can give desirable extended release characteristics of the drug.
The
matrix tablets formulated were white in colour, with
a concave shape and a glossy appearance. They were medium sized with a diameter
of 6mm enabling it to be swallowed easily by the patients.
The
mini matrix tablets prepared were flat shaped with a yellowish tint. They were
micro tablets with a diameter of 4 mm that makes it quite small compared to
that of the matrix tablets. They gave a good aesthetic appearance especially
after they were filled in to a capsule shell, preferably transparent or
slightly colored which enables dose adjustment as well as ease of handling by
the patients. The capsule containing tablets shows an innovative drug delivery
system. The capsule also increases the patient compliance by increasing the
palatability of the bitter tasting drug.
Both
matrix and mini matrix tablets were punched at a hardness of 6 kg/cm2.
There was not much loss in all matrix tablets and mini matrix tablets when
friability test was carried out. Both showed good flow property since the angle
of repose is within the limits.
It
was observed that matrix tablets showed an extended release for 6 hours. About
82 % was released at the end of six hours. But in the case of mini matrix
tablets a better extended release was seen for a period of 24 hours. The reason
for this may be due to the fact that, in case of mini matrix tablets, a better
force transmission occurs due to less material between the punches with
decreasing tablet height, resulting in the greater overall pressure15. Thus
they may have higher mechanical strength. All the dosage form showed non- fickian diffusion as the n
values were between 0.45 and 0.89.
The
DSC studies prove that there is no adverse drug - polymer interaction in the
formulations.
FTIR spectra of pure chitosan
and pure Diltiazem hydrochloride mixture of drug and
polymer in ratio 1:1 showed that physical mixtures did not differ from that of
the drug alone in the area of the main spectral bands of the drug or polymer.
No change in band was observed in any spectra of the formulations also.
REFERENCES:
1.
Alfonso R. Gennaro (2005) Remington: science and practice of pharmacy,
2.
Bechgard, H.., Nielsen, G.H. (1978) Controlled release multiple
units and single unit doses- A Literature review. Drug Development and
Industrial Pharmacy. 4, 53-67.
3.
Reddy, K. R. et
al. (2003) Once-Daily Sustained-Release Matrix Tablets of Nicorandil:
Formulation and In Vitro Evaluation. AAPS PharmSciTech.
4 (4) 61.
4.
Follonier, N., Doelker,E. (1992) Biopharmaceutical comparison of oral multiple
unit and single unit sustained release dosage forms. STP Pharma
Sciences. 2, 141-158.
5.
Lennartz, P., Mielck,
J. (1998) Mini tabletting: Improving the compactability of paracetamol powder mixtures.
International Journal of Pharmaceutics. 173, 75-85.
6.
De Brabander, C. et al.
(2000). Matrix mini-tablets based on starch/ microcrystalline wax
mixtures. International Journal of Pharmaceutics. 199, 115-203.
7.
William
Martindale, (2002). The complete drug reference, pharmaceutical press,
8.
Chitosan: A unique polysaccharide for drug delivery. Drug
Development and Industrial Pharmacy, 24, 979-993.
9.
Chawla, V., Dureja, H., (2000). Chitosan- Preparation and Properties- a Review. STP Pharma. 2, 34-56.
10. Kristyl, J. Et al. (1999). Hydrocolloids and gels of chitosan as drug carriers. International journal of Pharmaceutics., 99, 13-19.
11. Lin, S.Y. et al.
(1985). Preparation of prolonged release tablet of aspirin with chitosan. Chemical Pharmacy Bulletin..
12. Graffner, C. et al. (1986). Inter and Intra subject variation
of erythromycin absorption from single-unit and multiple unit enteric coated
products. Biopharm., Drug Dispose, 163-171.
13. Korsemeyer, R.W. et al.
(1983). Mechanisms of solute release from porous hydrophilic polymers.
International Journal of Pharmaceutics. 15, 25-35.
14. Sinclair, G.W., Peppas, N.A.,
(1984). Analysis of nonfickian transport in polymers
using simplified exponential expressions. J. Memb.
Sci., 17, 329-331.
15.
Received on 15.10.2009
Accepted on 17.11.2009
© A&V Publication all right reserved
Research Journal of Pharmaceutical
Dosage Forms and Technology.
1(3): Nov. – Dec. 2009, 263-268