INTRODUCTION:
Prolonged-release
(PR) dosage forms are formulated to control the release of drug from the dosage
forms for an extended time. The release of a drug from these systems should be at
satisfied rate, predictable with time and within the therapeutic window.
Different techniques and methods have been applied for controlling the rate of
dissolution or drug release from the dosage forms.
In
order to avoid repeated administration of immediate-release tablets, modified
release dosage forms have been produced to maintain the plasma drug
concentration in the therapeutic window, to avoid toxic concentration, to
overcome fluctuation in plasma drug levels and to reduce frequency of
administration, thus decreasing side effects1. Polymers play an
important role in the drug release. They control drug release and drug
bioavailability at the site of action by different mechanism2.
Hydroxypropyl
methyl cellulose (HPMC) and Ethylcellulose (EC) are widely used to prolong release
of a drug3,4,5. Hydroxypropyl cellulose high viscosity (HPCh) and
carboxymethyl cellulose (CMC) also control drug release for long time6,7.
Carbopol (Carbomer®) polymers can be used as matrix former for
development of controlled release matrix tablets8.
Millions
of patients worldwide take analgesics and anti-inflammatory medicines regularly
as per prescriptions of their doctors and sometimes as OTC without consulting
physicians or pharmacists. Non-steroidal antiinflammatory drugs (NSAIDS) are
used widely to relieve pain with or without inflammation, in people with both
acute and chronic musculoskeletal disorders. According to the data of the World
Health Organization on (2021), 1.71 billion of people around the world suffer
from musculoskeletal conditions9. Some medicines provide prompt
relief in sign and symptoms of pain while others provide modified or prolonged
release in management of pain like old people.
Celecoxib
is a selective NSAID, which is chemically designated as 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide
and is a diaryl substituted pyrazole. Celecoxib is practically insoluble in
water so solubility enhancer has to be incorporated10. Celecoxib
inhibit prostaglandin synthesis, primarily by inhibition of cyclooxygenase-2 at
the therapeutic concentrations. In humans, celecoxib does not inhibit
cycloxygenase-1 isoenzyme. Thus, make it a safer drug in the treatment of
osteoarthritis and rheumatoid arthritis11.
The
objectives of present research were to prepare a prolonged release matrix
tablets of celecoxib as well as to investigate the influence of different types
and concentration of polymers on drug release. To achieve these tasks, the
tablets were produced by using HPMC, Ethyl cellulose, CMC, HPCh and
Carbopol 940. In vitro drug release rates were performed in the dissolution
medium (Phosphate buffer pH 7.4) at 37 ± 0.5°C for 7-12-20 h. Since,
сelecoxib is a highly permeable drug that can be absorbed throughout the
gastrointestinal tract and dissolution in basic medium may be a rate-limiting factor
for absorption from solid dosage forms12,13. Therefore, dissolution
conducted only in the basic medium. To study the drug release kinetics,
different kinetic models were also performed.
MATERIALS
AND METHODS:
Materials:
Celecoxib
was procured from Chempfine chemicals, India. Hydroxypropyl methylcellulose
(HPMC-K100M) was procured from SUNHERE, China. Ethyl cellulose (EC-10cps) was
procured from chemist group, Peru. Hydroxypropyl cellulose high viscosity (HPCh)
was procured from Nippon Soda- Japan. Carbopol 940 was purchased from medulla-
Spain. carboxymethyl cellulose (CMC) was procured from Vega- China.
Microcrystalline cellulose (Avicel PH102) was obtained from MINGTAI- Taiwan.
Polyvinylpyrrolidone (PVP-K30). Sodium lauryl sulfate was purchased from BASF-
Syria. Lactose monohydrate was obtained from DFE pharma- Germany. Magnesium
stearate was obtained from GREVEN- Malesia. Isopropyl alcohol (IPA) and ethanol
were obtained from Merck, Germany. All other materials used were of
pharmaceutical grades.
Methods:
Preparation
of granules by wet-granulation method:
Compositions
of all tablet formulations are listed in Table 1. Six tablets formulations (F1
– F6) with different polymers (HPMC-K100M, EC-10 cps, CMC, Carbopol 940, and
HPCh) and one plain tablet formulation (F7) without polymers were
composed manually. The amount of celecoxib was 200mg per tablet.
All
the ingredients were weighed accurately using UniBloc analytical balance
(Sartorius TE1502S, Japan). Accurately weighed quantities of SLS and PVP-K30
were mixed uniformly in beaker, then, isopropyl alcohol (q.s) was added to make
a slurry. The slurry was then transferred to planetary mixer and gradually
accurate quantities of lactose monohydrate, MCC, half amount of celecoxib and
polymers were added into the mixer. The remaining amount of celecoxib was again added
slowly to the above mixture for making damp mass. The damp mass was passed
through 600µm size screen to make granules. Afterwards, granules were dried in
hot-air oven (JSON-050, Korea) for 30 minutes at 55°C.
Compaction
of prolonged release tablets:
The
dried granules were then transferred in a polybag. Next, 3.34% magnesium
stearate was added as a lubricant in each formulation and mixed for 5 min by tumbling.
Finally, the lubricated granules were compressed by using single punch press
with size 14mm (Erweka AR402, Germany). The compressed tablets were then
evaluated for in-vitro drug release using dissolution media with PH= 7,4.
Post-compression
studies of PR tablets:
After
compression, celecoxib PR tablets were evaluated for different tests such as
weight variation, hardness, thickness, friability, assay and dissolution by
using pharmacopeial methods14. Weight variation were assessed by
using UniBloc analytical balance (Sartorius TE1502S, Japan). Usually, a minimum
of 4kg of force is required to break a tablet, and it was set as tablet
hardness limit in the current study15,16. The tablets hardness was
determined using Erweka hardness tester (TBH 125 GmbH, Germany). The tablets
thickness was checked by using dial indicator thickness Gage 7313 Range 0-10mm,
Grad 0.01mm (Mitutoyo, Japan). The friability of compacts of each formulation
was determined using Erweka friability tester (TAR 220 GmbH, Germany). The
friability tester was operated for 100 revolutions i.e. 25 rotation/min for 4
min. Friability test was performed by taking initial and final weight of 11
tablets (≥ 6.5g) and calculated by using the following formula.
(Initial weight – Final weight)
Friability
(%) = ––––––––––––––––––––––––– × 100
Initial weight
Acceptance
criteria: % friability less than 1% is considered acceptable as per USP 41 NF
3614.
Table
1. Compositions of different celecoxib PR formulations.
|
Compositions
|
Formulation
|
|
F1
|
F2
|
F3
|
F4
|
F5
|
F6
|
F7
|
|
Celecoxib
(mg)
|
200
|
200
|
200
|
200
|
200
|
200
|
200
|
|
HPMC-K100M
(mg)
|
120
|
90
|
100
|
|
|
|
|
|
EC – 10cps (mg)
|
|
60
|
|
|
100
|
|
|
|
CMC (mg)
|
|
|
40
|
|
|
|
|
|
Carbopol – 940 (mg)
|
|
|
|
90
|
|
|
|
|
HPCh (mg)
|
|
|
|
|
|
150
|
|
|
SLS (mg)
|
40
|
40
|
40
|
40
|
40
|
40
|
40
|
|
MCC(Avicel)-PH102 (mg)
|
130
|
130
|
130
|
130
|
130
|
130
|
164
|
|
Lactose monohydrate (mg)
|
70
|
40
|
50
|
100
|
90
|
40
|
160
|
|
PVP –K30 (mg)
|
20
|
20
|
20
|
20
|
20
|
20
|
16
|
|
Mg. Stearate (mg)
|
20
|
20
|
20
|
20
|
20
|
20
|
20
|
|
Total weight tablet (mg)
|
600
|
600
|
600
|
600
|
600
|
600
|
600
|
Drug
content analysis using UV- spectrophotometric:
Initially
the maximum wavelength of celecoxib (252 nm) on spectrophotometer was
determined. Since the amount of active substance (200mg) is greater than 25% of
the tablet weight (600mg), The uniformity of dosage unit is performed for each
formulation on assaying basis according to USP 41 NF 36 depending on the weight
variation. Thirty tablets from each formulation were selected. Twenty of them
were weighed and finely powdered. A sample equivalent to the average weight of
them was taken. The absorbance of this sample was calculated at a wavelength
252nm on spectrophotometer. Standard sample was prepared by dissolving 200mg
celecoxib in a suitable solution and its absorbance was measured at a
wavelength 252nm17,18. Solvent (Ethanol 95%) and dilution factor was
the same for both sample and standard. Actual content (A) of celecoxib in sample was
calculated.
The
remaining ten tablets were weighed individually. Actual content of celecoxib in
each of ten tablets was calculated by using the following formula: 
i = Wi*
i:
individual estimated contents of each tested unit from ten tablets, Wi: individual weight of
each tested
unit from ten tablets, A: actual content of celecoxib, obtained using an
appropriate analytical method. (A
[90- 110%],
weight of sample.
In-vitro
dissolution studies:
PR
tablets were subjected to in-vitro drug release study, using USP type-II paddle
apparatus (Erweka DT 128 Light, Germany) at 50rpm in 900mL of sodium dihydrogen
phosphate buffer (pH 7.4) with 1% SLS. The dissolution medium was maintained at
37 ± 0.50 °C. Test was carried out for 7, 12, 20 h, and test specimens were
withdrawn after every 1, 2, 4 h. Volume of each withdrawn sample was replaced by
equal volume of fresh dissolution medium. Samples after filtration and suitable
dilution were subjected to the UV- spectrophotometric determination (Shimadzu
UV1800 [2UV/33], Japan) at a wavelength of 252nm19. The amount of
drug released from the samples was calculated in percentage. The mean drug
release percentage with standard deviation values vs time was plotted.
Drug
release kinetic studies:
The
release pattern of prolonged release dosage form is regulated by several
mechanisms such as dissolution of drug, erosion of matrix, and combination of
these processes20. There are different kinetic models such as Zero
order, First order, Higuchi and Korsmeyer–Peppas.
The
main objective of the prolonged release drug delivery system is to achieve a
cost effective and efficient extended-release system to deliver drugs at a
constant rate21. Prolonged release celecoxib tablets were compressed
using different hydrophilic and hydrophobic polymers by using wet granulation
method. The PR tablets were developed using HPMC K100M, EC (10-cps), CMC, HPCh
and Carbopol 940 in various concentrations. The MCC and PVP-K30 were used in a
fixed quantity in all formulations except F9 i.e. 21.66% and 3.33%,
respectively. The use of hydrophilic and hydrophobic polymers is very common to
obtain a prolonged release system22. Previously, HPMC of different
viscosity grade (i.e. K4M, K15M and K100 M), acrylic and methacrylic acid
copolymers were used as matrix formers for prolonged release systems23.
Celecoxib is practically insoluble in water, so solubility enhancer has to be
add. Polyvinyl pyrrolidone (PVP) is also known as Povidone, is used as a
solubilizer in oral and parenteral formulations and has been shown to enhance
dissolution of poorly soluble drugs from solid-dosage forms24. Sodium lauryl
sulphate (SLS) and Polyvinyl pyrrolidone (PVP) both were used in all the formulations
as a dispersing and solubilizing agent. Microcrystalline cellulose (MCC) by
concentrations (20- 90%) is used in pharmaceuticals as a binder and diluent for
oral tablets and capsules formulations25. Carboxymethyl Cellulose
(CMC) dissolves in hot water as well as in cold water. Pre-mix of CMC Powder
with other HPMC can increase dissolving and dispersing speed of less soluble
drug. CMC is not a very effective retarding agent for drug release; hence, it
is not used as alone polymer in the current study26. Previously,
different research studies used only HMPC and EC as a retarding-agents in the
formulations, while, in the current study we have used five different polymers.
Post
compression evaluation of tablets:
The
average weight of compressed celecoxib tablets was found to be 596.65±10.99 – 607.8±7.61mg.
The average weight results were found within the prescribed limit of ±5%14.
Hardness of all formulations were found satisfactory and the values were
observed to be 8.89± 0.57 –12.19±0.95kg/cm2. The average thickness
of all formulations was observed in the ranges of 4.62 ± 0.03 – 4.99±0.03mm.
The results of friability test of all formulations (F1 – F7) were less than 1%.
Drug
content analysis:
Celecoxib
content in each tablet formulation was determined by using assay with
spectrophotometric method. Mean percentage assay of celecoxib tablet
formulations was found in the range of 100.076 –104.28%. All the results were found
within the pharmacopoeial limits of 90–110% (UPS41/NF36).
In-vitro
drug release studies:
Figure
1 shows- in-vitro drug release profiles in sodium dihydrogen phosphate buffer
(pH 7.4) with 1% SLS for all formulations. The samples were withdrawn after
every period of time (1, 2, 3, 4, 6, 7, 8, 9, 10, 12, 16 and 20h). It was found
that formulation F1 (HPMCK100M) extended drug release up to 16 h, and it
released more than 90% of its content within 20h. Formulations F2 (HPMCK100M
and EC) and F3 (HPMCK100M and CMC) released 81, 47% - 86,56% within 20h
respectively.
Figure
1. Drug release profile for all formulations at pH= 7.4
Formulation
F4 (Carbopol-940) released 92,28% of its content within 12h. Formulation F6
(HPCh) released about half of its active ingredient content 53,56%
within 20 hours, so the release lasted more than a day. At the same time,
formulation F5 (EC-10cps) released 90,38% within 16h. Standard formulation F7
(without polymer) released maximum drug within 7h. However, using these polymers
in higher concentration ranges might be effective in controlling drug release for
a longer time. The rate controlling step in such type of polymers is their
liquid penetration into the matrices which requires addition of wetting agents
like isopropyl alcohol and water, and results in prolonged drug dissolution and
diffusion27,28. Similarly, Carbopol 940 is also a hydrophobic
polymer and it prolongs the drug release. However, in the previous study
formulation containing carbopol 940 extended drug release up to 12 h.
Kinetic
models such as First order, Zero order, Higuchi and Korsmeyer-peppas were
applied to interpret the release kinetics of celecoxib from the PR tablets
formulations (F1, F2, F3, F4, F5 and F6) and plain standard tablet formulation
(F7). We used Microsoft excel for the dissolution data profile comparison and
modeling. The correlation coefficient (r2) values obtained from
different kinetics models recommended that one of these models may be followed
by the formulations. Higher correlation coefficient (r2) values show
that the formulations appear to fit this model better as in some previous
studies29.
Table
3. Drug release kinetics.
|
Formulation
|
correlation coefficient r2
|
release exponent n
|
|
r2 0
|
r2 1
|
r2 higuchi
|
r2 korsmeyer
|
|
F1
|
0.8626
|
0.9262
|
0.9316
|
0.7953
|
1.3396
|
|
F2
|
0.8276
|
0.9534
|
0.9178
|
0.7851
|
1.3716
|
|
F3
|
0.9869
|
0.8998
|
0.9173
|
0.9589
|
1.5162
|
|
F4
|
0.9801
|
0.8682
|
0.9425
|
0.9662
|
1.6581
|
|
F5
|
0.8612
|
0.9017
|
0.9081
|
0.7959
|
1.5359
|
|
F6
|
0.9859
|
0.9714
|
0.944
|
0.9802
|
1.4558
|
|
F7 std
|
0.9759
|
0.9044
|
0.9601
|
0.909
|
1.7944
|
Formulation
(F1) containing HPMC–K100M as a matrix former showed drug release with highest
correlation coefficient (r2) values obtained when higuchi-order
model was applied (r2 = 0.9316), as shown in Table 3. Formulation
(F2) containing HPMC–K100M and EC showed the highest correlation coefficient (r2)
values when first-order model was applied (r2 = 0.9534).
Formulations F3, F4, F6 and F7 were best fitted to zero order kinetic and r2
values were observed in the ranges of (0.9759 -0.9869). Whereas, formulation
(F5) containing EC was fitted to higuchi-order model and r2 =
0.9081.
The
release exponent values for all formulations (n ˃ 0,89) refers to
erosion-controlled rate release (Case II relaxation release).
CONCLUSIONS:
On
the basis of the current study results, it can be concluded that celecoxib
prolonged release matrix tablets were successfully prepared using different
polymers by wet-granulation technique. The formulations F1, F2, F3 retarded the
release of drug up to 16 h. Formulation F4 controlled drug release for 12h. At
the same time, formulation F5 extended drug released for 16h. All formulations
except F6 were found to be good due to satisfactory quality attributes. Drug
release data of formulations F3, F4, F6, F7 were explained by zero order
kinetic model. F1 and F5 followed Higuchi model. Whereas, F2 followed first order
kinetic model. Thus, HPMC and ethyl cellulose can be used as excellent rate
controlling agents for poorly soluble drug celecoxib. This study has
established that prolonged release celecoxib tablets formulation of can be a
good alternative choice for the treatment of osteoarthritis and rheumatoid
arthritis.
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