INTRODUCTION:
Buccal drug delivery consists of administration of drug through the buccal
mucosa1. Advantages
of Buccal drug delivery are, that it avoids degradation due to pH and digestive
enzymes of gastrointestinal tract, it avoids first-pass metabolism it has rapid
onset of action, ease of drug administration, easy termination and has no
stratum corneum barrier. The transport through the oral mucosa is by Transcellular
(intracellular, passing through the cell) and Paracellular (intercellular,
passing around the cell) route1. Drug’s lipid solubility, pH, drug
ionization, improved patch design, and the use of prodrugs, have all been shown
to be important in drug absorption and delivery.
Terbutaline Sulphate (TS) is widely used
for the therapeutic management of chronic as well as prophylaxis of asthma and
nocturnal asthma in particular. It is a drug of choice for the treatment of
asthma but it has several drawbacks such as short biological half-life of about
3.6 hours, it is readily metabolized in the gut wall and liver when given
orally.
It has a short duration of action, low peak
plasma level of 1.2 µg/ml and poor bioavailability of only 14.8%. These factors
necessitated formulation of buccal release drug delivery system for terbutaline
sulphate, as this route of drug administration would reduce the dosing
frequency hence better patient compliance2.
The objective of this study was to prepare mucoadhesive polymeric systems as carrier for buccal
delivery of TS using hydroxyl propyl methyl cellulose K4M (HPMC-K4M), Sodium
CMC (NaCMC), Carbopol (CP) as polymers and Glycerin as plasticizer. To evaluate
mucoadhesion and other parameters such as folding endurance, surface pH, film
thickness and percentage swelling of the prepared mucoadhesive buccal delivery
systems and to study the in-vitro release of TS through the selected buccal
patch.
EXPERIMENTAL
Terbutaline Sulphate, Glycerin
IP, hydroxyl propyl methyl cellulose K4M (HPMC-K4M), NaCMC were procured from
McW Health Care, Indore. Carbopol 934P (CP-934P) was procured from Corel Chem,
Ahmedabad. All other reagents used were of analytical grade. The raw material were analyzed as per
official monograph.
Table 1: Composition of buccal patches containing 0.4mg/cm2
of Terbutaline Sulphate.
|
Formul
ation No.
|
Composition of Buccal
Patches containing
0.4mg/cm2 of Terbutaline Sulphate.
|
|
HPMC
-K4M
|
CP
934P
|
Na
CMC
|
Glycerol (percent w/
w of polymer weight)
|
|
F1
|
2%
|
-
|
|
50%
|
|
F2
|
3%
|
-
|
|
50%
|
|
F3
|
2%
|
2%
|
|
50%
|
|
F4
|
3%
|
2%
|
|
50%
|
|
F5
|
|
|
2%
|
50%
|
|
F6
|
|
|
3%
|
50%
|
|
F7
|
|
2%
|
2%
|
50%
|
|
F8
|
|
2%
|
3%
|
50%
|
|
F9
|
1%
|
2%
|
1%
|
50%
|
|
F10
|
1%
|
3%
|
1%
|
50%
|
|
|
|
|
|
|
|
Preparation of polymeric patches:
Required quantity of polymer (Table 1) was
mixed with water and kept aside for 24 hrs for polymer hydration. The hydrated
polymeric solution was dissolved with the help of magnetic stirrer. Plasticizer
glycerol3 (Chowdhary 2000) was
added and dissolved. Air bubbles were removed by sonication. The solution was
filtered and polymeric patches were casted on aluminium4
substrate using 10ml polymeric solution. The patches were dried in
an oven for 8hrs. The dried polymeric patch was wrapped in an aluminium foil
and stored in a dessicator for further studies.
Selection of best polymer composite:
For
selecting best polymer composite, 54 polymeric patches using varied amount of
plasticizer Glycerol and polymers were prepared. Physical characteristics of
these polymeric patches were studied and best polymer composite was then
selected to it TS(TS) 0.4 mg/cm2 was added. The final composition of buccal
patches containing 0.4 mg/cm2 of TS of selected polymeric patches is
as per (Table 1).
These
polymeric patches were backed with 1% w/v ethyl cellulose backing membrane in
chloroform medium and glycerin (50% w/w of polymer) as a plasticizer. Blank
films were evaluated for various parameters such as mucoadhesive strength, %
swelling, folding endurance, surface pH and film thickness. Drug (Terbutaline
Sulphate) containing polymeric patches were evaluated for Drug content,
In-vitro release studies and stability studies.
Mucoadhesive Strength:
The apparatus used was a modification of the apparatus
applied by Parodi et.al 5. The device was mainly composed of a
two-arm balance. The left arm of the balance was replaced by small copper
lamina vertically suspended through a wire. At the same side, a movable
platform was maintained in the bottom in order to fix the model mucosal
membrane. The fabricated balance described above was used for the mucoadhesion
studies. The bovine cheek pouch, excised and washed was fixed to the movable
platform. The mucoadhesive patch of 3 x 3 cm² was fixed to the copper lamina
using double adhesive tape. The exposed patch surface was moistened with 1 ml
of isotonic phosphate buffer pH 6.6 for 30 seconds for initial hydration and
swelling. The platform was then raised upward until the hydrated patch was
brought into the contact with the mucosal surface. A preload of 20 g was
placed over the stainless steel lamina for 3 minutes as initial pressure.
Weights were then slowly increased on the right pan, till the patch detaches
from the mucosal membrane. The weight required to detach the patch from the
mucosa give the mucoadhesive strength of the mucoadhesive patch. The procedure
is repeated for 5 times for each patch and mean value of the 5-trials was taken
for each set of formulation. After each measurement the tissue was gently and
thoroughly washed with isotonic phosphate buffer pH 6.6 and left for 5 minutes
before taking reading.
Percentage Swelling:
The film swelling studies were conducted using
distilled water. A wire mesh of dimension 4cm x 4cm was prepared. The buccal
patch of equal weights (100mg) was kept on the wire mesh and the wire mesh
along with buccal patch was immersed Petri dish containing 15 ml of water. The
films were taken out after 5, 10, 30, and 60 min intervals5. The
mesh was shaken mildly to remove any water present. Further excess water
present on the mesh and film was removed with filter paper and the film along
with the mesh was weighed accurately. The Wet weight of the film was determined
by using parameter (wet weight = weight of the mesh along with wet film – wt.
of the mesh) increase in the wt. The percentage swelling was calculated using
the formula
Folding
Endurance:
The folding endurance of the patches was
determined by repeatedly folding one patch at the same place till the patch
broke or folded up to 300 times6, which is considered satisfactory
to reveal good film properties. The number of times the film could be folded at
the same place without breaking gave the value of folding endurance. The
procedure is repeated for 5 times for each patch
Surface pH:
The surface pH of the patches was
determined because acidic or alkaline pH is bound to cause irritation to the
buccal mucosa7. Buccal patches were left
to swell for 2 h on
Table 3: Evaluation of TS buccal patches.
|
Formulation
|
Mean % Drug Content (±SEM)
|
|
F1
|
99.91 (± 0.348)
|
|
F2
|
99.63 (± 0.512)
|
|
F3
|
100.14 (0.415)
|
|
F4
|
99.51 (± 0.334)
|
|
F5
|
99.96 (± 0.475
|
|
F6
|
100.48 (± 0.415)
|
|
F7
|
100.54 (± 0.298)
|
|
F8
|
99.94 (± 0.417)
|
|
F9
|
99.67 (± 0.214)
|
|
F10
|
100.14 (± 0.198)
|
the surface of an agar plate,
prepared by dissolving 2% (m/V) agar in warmed isotonic phosphate buffer of pH
6.75 under stirring and then pouring the solution into a Petri dish till
gelling at room temperature8. The surface pH was measured by means
of a pH paper placed on the surface of the swollen patch and by bringing the swollen patch in contact
with pH electrode and after equilibrating it for 1min.The
mean of five readings was recorded.
Film Thickness:
The residual moisture was removed from the
buccal patches by storing them in desiccators for 1 week9.
Thickness was measured using screw guage10 at 4 corners and the
centre of the film11 and the average was calculated.
Calibration Curve:
Absorbance of TS between 10mg/ml to 100mg/ml
was determined at 278 nm using UV spectrophotometeric method. The calibration
curve was constructed by plotting absorbance v/s concentration12.
Drug Content:
The medicated patch of known weight / dimension 2cm x
2cm was extracted with 100 ml water by shaking. The solution was filtered and
the amt of TSin the patch was measured spectrophotometerically at lmax 278 nm.
In-Vitro Release Study:
In-vitro studies were performed by Franz Diffusion cell13
using distilled water14 as dissolution medium and cellophane
(cellulose acetate) pore size 0.2µ as diffusion membrane. Studies were carried
out using 1cm x 1cm buccal patch. The distilled water present in receptor
chamber was maintained at a temperature of 370C ± 20C and
was constantly stirred by temperature controlled magnetic stirrer13.
Aliquots of 1ml were withdrawn from the diffusion cell
at 15min, 30 min, 1 hr, 2 hrs, 3 hrs, 4 hrs, and thereafter every 1 hr till the
results were constant or till the erosion of patch took place7. Sink
condition were maintain. The absorbance of the samples collected was measured
at 278 nm within 30 minutes of the release. The readings were recorded in
triplicate for each batch. Average % release at various time were determined
using PCP- Disso software.
Stability Studies:
The TS patches were subjected to
accelerated stability testing. Patches were packed in glass Petri dishes lined
with aluminium foil and kept in an incubator maintained at 400C ± 20C
and 75±5% relative humidity15 for 6 months. After initial readings
changes in drug content were investigated after 3 months and 6 months.
RESULTS AND DISCUSSIONS:
TS, polymers and plasticizers were found to comply
with pharmacopoeial standards.
Polymeric patches F1 to F10 with different polymeric
composition (Table 1) were evaluated for their physical properties. It is
evident from the results that mucoadhesive strength of the polymeric patches
increase in concentration of Carbopol. HPMC-CP, NaCMC-CP had more mucoadhesive
strength than plain HPMC, NaCMC patches. F10 having highest conc. of CP (3%)
had highest mucoadhesive strength of 5.29 (± 0.006)g while F5 had lowest
mucoadhesive strength of 2.25 (± 0.006) g (Table 2), this results corroborates
with results of Ayyapan et. al 16 and LiC et. al 17. In
general it was observed that any rise in the amount of hydrophilic polymer
increased mucoadhesion.
The percent swelling index determined at intervals of
5, 10, 30 and 60 minutes increased with an increase in the hydrophilic polymer
concentration. Higher the polymer content greater was the %swelling observed,
HPMC-NaCMC-CP combination patches showed greater % swelling than CP-HPMC and
CP-NaCMC followed by HPMC and NaCMC showed lowest %
|
Formulation
|
Mean % Drug Content
Estimation after 3 months
at 75±5%
RH and
400C ± 20C (± SEM)
|
Mean % Drug ContentEstimation after 6months at 75±5% RHand 400C
± 20C (± SEM)
|
|
F1
|
99.12± 0.412
|
99.27 ± 0.574
|
|
F2
|
99.45± 0.318
|
99.17± 0.349
|
|
F3
|
99.26± 0.537
|
99.28± 0.275
|
|
F4
|
99.37± 0.253
|
99.36± 0.593
|
|
F5
|
99.17± 0.236
|
99.46± 0.239
|
|
F6
|
99.39± 0.467
|
99.37± 0.164
|
|
F7
|
99.22± 0.523
|
99.46± 0.942
|
|
F8
|
99.34± 0.783
|
98.09± 0.528
|
|
F9
|
99.59± 0.219
|
98.17± 0.836
|
|
F10
|
99.71± 0.263
|
98.92± 0.947
|
swelling (Table 2). Thus %swelling showed a direct
relationship with mucoadhesive strength, higher the %swelling of the polymer
patch greater the mucoadhesive strength. Similar findings have been reported in
literature for Carbopol and HPMC patches by Ayyapan
et.al16, Vijayaraghavan et.al18. The general trend
in the folding endurance studies suggested that HPMC- NaCMC -CP > CP- NaCMC
> CP-HPMC > NaCMC > HPMC. The maximum folding endurance was observed
for F10 polymeric patch 142 (± 0.11) (Table 2).
The surface pH of the film was found to be in the
neutral range of 6.52 to 7.24 (Table 2)
The mean film thickness of the buccal polymeric
patches increases with an increase in the amount of polymer. The F10
formulation i.e. HPMC-NaCMC-CP had maximum thickness 0.72 (±0.08)mm. (Table 2)
After incorporation of the TS (0.4mg/ cm²) in the
selected polymeric buccal patches, the drug content was found to be
uniform.(Table 3).
Absorbance of TS at concentration between 10mg/ml to 100mg/ml was determined and calibration curve of TS
constructed at 278nm showed a linear relationship with
coefficient of correlation r=0.9943, slope=0.0059 and constant =0.0081.
The In vitro release study of TS showed decrease in
percent release with an increase in the amount of polymer with F1 containing 1%
HPMC patches showed maximum release than F2 while F3 containing 1% NaCMC
patches showed maximum release than F4 containing 2% NaCMC Also the patches
containing HPMC and NaCMC alone showed faster release than when it is in
combination with CP (Table 4). These findings corroborates with the studies of
Ayyapan et.al16 and Soliman et.al19
HPMC-NaCMC-CP (F9-F10) patches showed increases the in
vitro release of TS with increase in Carbopol 934 as CP is more hydrophilic so
it swells rapidly17 thus an increase in the concentration of CP
increases the rate of release (Table 4).
The release mechanism of TS from various buccal
patches prepared was studied. This data was then treated to PCP Disso V2
software. The best fit model for F1, F2, F3, F7, F9 and F10 buccal patches was
zero order whereas F4 buccal patches showed the release mechanism
corresponding to Hixson-Crowell, while F5, F6 and F8 showed matrix type release
mechanism.
TS buccal patches stored at 75% relative humidity and
40 ±2ºC for 24 weeks were found to be stable (Table 5)
CONCLUSION:
From the studies it may
be finally concluded that amongst the various polymer composites HPMC, NaCMC,
CP-HPMC, CP- NaCMC and CP-HPMC- NaCMC studied, CP-HPMC- NaCMC mucoadhesive
patches using 50% glycerol w/w of polymer weight demonstrated good potential as
carrier systems for buccal delivery of TS
ACKNOWLEDGEMENTS:
The authors are thankful to McW Health Care, Indore for providing gift samples and to the management of Maharashtra Institute of
Pharmacy for providing necessary facilities to carry out this work.
REFERENCES:
1. Shojaei A. H., Buccal mucosa as a route for
systemic drug delivery, Journal of Pharmacy and Pharmaceutical Sciences, 1998,
1(1), 15-30.
2. Rathore RPS*, Chauhan C S, Naruka P S,
Tanwar Y S , Chauhan L S, Transdermal formulation of Terbutaline Sulphate,
Priory Lodge Education Limited, April 2006, www.priory.com
3. Chowdhary K. P. R. and Shrinivas
L., Mucoadhesive drug delivery Systems: a review of Current Status, Indian
Drugs, 2000, 37(9), 400-406.
4. Mitra A. K, Alur H. H., Johnston, Peptides and Protein- Buccal
Absorption, Encyclopedia of Pharmaceutical technology, Marcel Dekker Inc.,
2002, 2081-2093.
5. Noha Adel Nafee, Nabila
Ahmed Boraie, Fatma Ahmed Ismail and Lobna Mohamed, Design and characterization of
mucoadhesive buccal patches containing cetylpyridinium chloride, Acta Pharma,
2003, 53,199-212.
6. Panigrahi L, Pattinaik S, Ghosal SK, Design and
characterization of mucoadhesive buccal patches of diclofenac sodium, Indian
Journal of Pharmaceutical Sciences, 2005, 67(3), 319-325.
7. Javed Ali, Roop K. Khar, Alka
Ahuja, Effect of
polymer loading on drug Release and bioadhesion of Buccoadhesive Carriers for
local drug delivery of Triamicinolone Acetomide, Eastern Pharmacists, 1999,
XLII (503), 115- 119.
8. Khanna R, Agarwal SP, Ahuja A, Preparation and evaluation of
muco-adhesive buccal films of clotrimazole for oral candida infection, Indian
Journal of Pharmaceutical Sciences , 1997, 59(6), 299-305.
9. Ilango R, Kavimani S,
Mullaicharam AR, Jayakar B, In-vitro studies on buccal strips of glibenclamide using
chitosan, Indian Journal of Pharmaceutical Sciences , 1997, 59(5),
232-235.
10. Pavankumar GV, Ramakrishna V,
William GJ, Konde A,
Formulation and evaluation of buccal films of salbutamol sulphate, Indian Journal
of Pharmaceutical Sciences , 2005, 67(2), 160-164.
11. Khoda, Y., Kobayashi, H.,
Baba,Y.,Yuasa, H., Ozeki, T., Kanaya,Y., Sagara, E.,. Controlled release of lidocaine
hydrochloride from buccal mucosa-adhesive films with solid dispersion,
International Journal of Pharmaceutics, 1997, 158, 147–155.
12.
Beckett A.H. and
Stenlake J. B., Practical
Pharmaceutical Chemistry, Fourth Edition, Part two, CBS Publishers and
Distributors, 275-288.
13. Hiraku Onishi , Osamu Sakata,
Kosuke Masuda, Yoshiharu Machida, Novel Mucoadhesive Oral Patch Containing Diazepam, 2005, 31(7),
607 – 613.
14.
Narasimha Murthy
and Shobha Rani Hiremath, Formulation And Evaluation Of Controlled Release Transdermal Patches of
Theophylline - Salbutamol Sulphate, The Internet Journal of Pharmacology,
2001, 1(1), 69-72.
15.
ICH Guidelines, ICH Topic Q 1 A (R2), Stability Testing of
new Drug Substances and Products, Step 5, 2736- 99.
16. Ayyapan T, Kasture P.V., Development and in-vitro
evaluation of a buccoadhesive of Ondansetron HCl Tablet formulation, Indian
Drugs, 2006, 43(2), 111-153.
17. Li C, Bhatt PP, Johnston TP, Evaluation of a mucoadhesive
buccal patch for delivery of peptides: in vitro screening of bioadhesion, Drug Development
and Industrial Pharmacy, 1998, 24(10), 919-926.
18. Vijayaraghavan C, Ravi T. K., Buccal Delivery of Nifedipine
using a novel natural mucoadhesive polymer as an excipient in buccal Tablets,
Indian Drugs, 2004, 41(3).
19. Soliman Mohammadi-Samani, Rahim
Bahri-Najafi and Golamhosein Yousefi, Formulation and in vitro evaluation of prednisolone buccoadhesive
tablets, II Farmaco, April 2005, 60(4), 339-344.