1 RJPT 10 12 2017
1 RJPT 10 12 2017
1 RJPT 10 12 2017
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RESEARCH ARTICLE
ABSTRACT:
Aim: The main objective of the present work is to improve the bioavailability of curcumin by buccal route and
to study in-vitro and in-vivo drug release. Materials and Methods: The mucoadhesive buccal tablets were
formulated by direct compression method using hydrophilic polymers such as guar gum, xanthan gum, HPMC
E15 in different concentration and piperine as permeation enhancers (1%). Ethylcellulose is used as backing
layer to promote the unidirectional flow of drug in the buccal region. Curcumin has a number of beneficial
activities, such as potent antioxidant, anti-inflammatory, anticancer, anti-rheumatic and anti-diabetic. When
Curcumin is administered orally it has low bioavailability because of poor absorption, rapid GIT metabolism and
hepatic first pass metabolism. Curcumin has poor aqueous solubility and better lipid solubility, and buccal region
consist of lipid, so the absorption of curcumin can be increased by this route. Results and Discussion: The FT-
IR spectra of pure drug with different polymers showed no shift in peak, indicating absence of interaction. The
prepared formulations were evaluated for pre-compression studies such as bulk density, tapped density, angle of
repose. The post-compressions studies such as weight variation, thickness, friability, hardness, mucoadhesive
strength, drug content, swelling studies, in-vitro diffusion studies and in-vitro dissolution studies. Conclusion:
All the prepared formulations were within the standard Pharmacopoeial limit. The formulation (FX2) containing
xanthan gum showed the best dissolution (97.75%) within 4.0 hours and it follows higuchi model. The in-vivo
animal study showed the better bioavailability by buccal route when compare to oral route.
KEYWORDS: Curcumin, Xanthan gum, Guar gum, HPMC E15, Permeation enhancer, FTIR, Direct
compression, unidirectional flow.
INTRODUCTION:
The administration of pharmaceutical dosages form by
oral route is the most accessible and easy route to the
patients when compare to other dosages form like
parenteral for systemic availability of drugs but the
administration of certain pharmaceutical dosage form by
oral route have demerits like reduction in bioavailability
of dosage form due to acidic degradation and enzymatic
metabolism in stomach, degradation in alkaline pH and
metabolism by liver.1
From last few decades the interest has been increased for MATERIALS AND METHODS:
administrating the drug through buccal route for both Materials:
local and systemic affect when compare to other Curcumin and Piperine was received as gift samples
transmucosal route such as sublingual, nasal, ocular, from Novel Nutrients (Abbigere, Bangalore). Guar gum,
vaginal and rectal route. The unique character of buccal xanthan gum and HPMC E15 were purchase from
cavity is that the buccal mucosa is thin and has rich Signet chemical corporation Pvt. Ltd. Others chemicals
blood supply and lymphatic drainage that drain drug from Thermo Fisher Scientific, Mumbai. All the
directly into the systemic circulation, which ensure reagents and materials were of analytical or
reduction in absorption of drug by different pathway and pharmacopoeial grade.
lead to high bioavailability. In-case of toxicity, treatment
can be terminated.3 Methods:
Preformulation study of curcumin:8,9
Buccal tablets are small and flat, intended to be held in Preformulation study is the first step in the development
mouth between the cheek and gum or in cheek pouch, of dosage form of a drug Substance.
from where the drug content to be absorbed directly
through oral mucosa. The buccal tablets may release the • Solubility:
drug quickly or may be design to release it slowly for The solubility of Curcumin was tested in distilled water,
prolonged action, resulting better bioavailability of methanol, chloroform and acetone.
drugs due to preventing of first-pass metabolism, GIT
degradation for GIT sensitive drugs and avoiding • Melting point:
various enzymatic degradation. These tablets can be Melting point of Curcumin was determined by open
applied to different sites in the oral cavity, including the capillary method.
palate, mucosa lining, and the cheek or between the lip
and the gum. Bioadhesive tablets are generally prepared • Determination of λmax:
by direct compression, but sometimes wet granulation 100 mg of Curcumin was accurately weighed and
methods are used; it required more compression pressure dissolved in 100 ml of methanol in volumetric flask.
to produce a hard tablet. In order to achieve Further the concentration was maintained to 10μg/ml
unidirectional release, multilayered tablets may be and scanned for maximum absorbance in UV/Vis double
prepared by adding and compressing the ingredients beam spectrophotometer in the range from 800 to 400
layer by layer with a hydrophobic polymeric layer as a nm, using methanol as blank.
backing membrane.4
• Compatibility study:
Curcumin is a lipophilic polyphenol compound A successful formulation depends on the careful
extracted from the rhizome of curcuma longa family selection of excipients to facilitate release of drug and
Zinigiberaceae and has wide spectrum of biological and also protect it from degradation. In the formulation drug
pharmacological activities such as potent anti-oxidant, and polymer may interact as they are in close contact
anti-inflammatory, anti-cancer, anti-rheumatic, anti- with each other, which could lead to the instability of
diabetic, hepatoprotective, anti-spasmodic, etc. However drug. Preformulation studies regarding the drug-polymer
when curcumin is administered orally it has low interaction are therefore very critical in selecting
bioavailability because of poor absorption, rapid GIT appropriate polymers. FT-IR spectroscopy was
metabolism and hepatic first pass metabolism.5 employed to ascertain the compatibility between
Curcumin and the selected polymers.
Curcumin has poor hydrophilic solubility but better
lipophilic solubility and buccal region is lipophilic in Preparation of Curcumin mucoadhesive buccal
nature, so the absorption can be increase by this route. tablets:10
Further the curcumin in combination with piperine also The tablets were prepared using compositions as given
improves the bioavailability of curcumin because in Table 1. All the ingredients were passed through sieve
piperine an alkaloid present in black pepper act as #80 and properly mixed together in an air tight plastic
permeation enhancer.6,7 container. The mixed ingredients were evaluated for pre-
compression parameters, followed by direct
compression in multi tablet punching machine. The
weight of the tablets were adjusted to 200mg and coated
with ethyl cellulose 60 mg to maintain the unidirectional
flow of drug.
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Research J. Pharm. and Tech. 10(12): December 2017
POST-COMPRESSIONAL STUDIES:11, 12 was obtained from local slaughter house and store in pH
• Weight variation test: 6.8 phosphate buffer. The experiment was performed
According USP twenty tablets were selected randomly within 2 hours of procurement of buccal mucosa. The
from each batch and weighed individually by using goat buccal mucosa was fixed in a stainless steel piece
analytical weighing balance. The average and standard with cyano acrylate adhesive in left pan and place in a
deviation were calculated. beaker. Then pH 6.8 phosphate buffer was added into
the beaker up to the upper surface of the porcine buccal
• Thickness: mucosa to maintain buccal mucosal viability during the
The tablets thickness is important for uniformity of experiment. Then the tablet was attached to the upper
tablet size. Thickness was measured using Vernier clamp of the apparatus and the beaker was raised slowly
Caliper. The average of three tablets was taken. The to establish contact between porcine buccal mucosa and
tablet thickness should be controlled within ± 5 the tablet. The pan was left undisturbed for 10 minutes
variations of a standard value. and slowly increases the weight on right pan till the
curcumin mucoadhesive buccal tablet got detached from
the goat buccal mucosa. The weight required to detach
the buccal tablet was recorded.
• Hardness test:
The hardness of the tablet indicates the ability of a tablet • Drug content:14
to withstand mechanical shocks while handling. It is Five tablets from each formulation were taken, crushed
measured by using Monsanto hardness tester. It is and mixed. From the mixture 100mg equivalent of
expressed in kg/cm2. The average of six tablets was mixture was extracted thoroughly with in pH 6.8
taken according to USP guidelines from each phosphate buffer and 3% tween 80 (Tween 80 is use as a
formulation. surfactant to enhance the solubility of curcumin).The
amount of drug present in each extract was determined
• Friability test: using UV/Vis spectrophotometer at 424.4nm against
It indicates the loss in weight of tablets in containers blank.
during transportation. Roche friabilator was used. 20
tablets were weighed and initial weight was recorded Absorbance x 1 x Dilution factor
Percentage drug content = ----------------------------------------x 100%
and place in Roche friabilator and rotates at 25 rpm for 4 Slope x 1000 x Dose
minutes. The tablets were removed and again weighed,
final weight was recorded. It is calculated by using the • Swelling studies:13
equation. The curcumin mucoadhesive buccal tablets were
weighed accurately (initial weight) and placed in a Petri
Initial weight of the tablets – Final weight of the tablets
% Friability =---------------------------------------------------------- X 100
dish containing 5ml of pH 6.8 phosphate buffer,
Initial weight of the tablets temperature was maintained at 37±0.5oC. At the end of 3
hr the tablets were removed from the Petri dish and
• Mucoadhesion strength:13 swollen tablets were reweighed (final weight). The
The mucoadhesive strength of tablet was measured in swelling index was calculated according to the formula.
modified double beam physical balance by using goat Final weight – Initial weight
buccal mucosal membrane. The apparatus consist of a Swelling index (%) =---------------------------------- X 100
double beam physical balance. The goat buccal mucosa Initial weight
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Research J. Pharm. and Tech. 10(12): December 2017
• In-vivo study:15,16
Three healthy albino rabbits weighing about 1.5 to 2.5 Graph 1: Calibration Curve of Curcumin at 424.4nm
kg were selected, marked and fasted for overnight. All
the animals were administered with the oral dose of The regression co-efficient of Curcumin was found to be
curcumin as a standard drug and the time was noted. 0.999 and the slope value was found to be 0.1383, which
Then 0.5 ml of blood was withdrawn from the marginal showed linearity between absorbance and concentration.
ear vein at an interval of 0, 1, 2, 4, 8 and 16 hours.
FTIR Compatibility study:
The serum was separated and curcumin was estimated The compatibility studies of drug and polymers were
by using HPLC. After the washout period of 7 days done by FTIR. All the characteristic peaks of Curcumin
again the same rabbits were administered with prepared were present in the spectrum of drug and polymer
curcumin mucoadhesive formulation. Rabbits were mixture, indicating compatibility between drug and
anaesthetized (Ketamine hydrochloride) and the polymer as shown in table 3.
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Research J. Pharm. and Tech. 10(12): December 2017
Figure 1: FT-IR spectrum of curcumin Figure 3: FT-IR spectrum curcumin + Xanthan gum
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Research J. Pharm. and Tech. 10(12): December 2017
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Research J. Pharm. and Tech. 10(12): December 2017
Table 6: In-vitro drug release studies of Curcumin mucoadhesive buccal tablet (FG1 –FX2)
SL. No Time (min) Cumulative % drug release
FG1 FG2 FG3 FG4 FX1 FX2
1 0 0 0 0 0 0 0
2 30 25.72±0.92 26.53±0.64 11.07±0.29 19.21±0.12 15.630±0.38 14.17±0.64
3 60 64.00±0.67 38.35±0.55 24.94±0.87 23.01±0.25 50.950±0.87 32.69±0.81
4 90 72.42±0.37 49.08±0.01 29.52±0.19 32.84±0.14 65.87±0.19 47.67±0.73
5 120 96.67±0.19 65.14±0.06 59.95±0.45 38.29±0.16 78.08±0.45 69.65±0.69
6 150 - 81.79±0.62 65.21±0.65 44.58±0.38 82.29±0.65 71.68±0.65
7 180 - 93.91±0.95 71.82±0.55 49.60±0.65 95.24±0.56 91.81±0.21
8 210 - - 78.13±0.37 56.28±0.75 - 92.80±0.37
9 240 - - 80.86±0.19 62.35±0.81 - 97.75±0.89
Table 7: In-vitro drug release studies of Curcumin mucoadhesive buccal tablet (FX3 –FH4)
SL. Time Cumulative % drug release
No (min) FX3 FX4 FH1 FH2 FH3 FH4
1 0 0 0 0 0 0 0
2 30 25.23±0.52 15.14±0.52 11.07±0.13 4.572±0.58 3.10±0.56 3.10±0.68
3 60 30.12±0.95 24.80±0.18 16.88±0.25 12.41±0.36 9.21±0.42 6.81±0.82
4 90 37.69±0.81 29.05±0.94 21.58±0.52 19.72±0.26 15.57±0.36 13.59±0.35
5 120 45.63±0.68 35.95±0.71 29.27±0.84 24.92±0.58 19.61±0.25 14.16±0.58
6 150 56.57±0.18 45.03±0.61 32.39±0032 27.36±0.59 23.17±0.31 19.67±0.42
7 180 64.11±0.75 51.20±0.29 38.32±0.35 33.11±0.71 25.11±0.62 20.76±0.61
8 210 71.86±0.89 59.87±0.37 44.78±0.42 35.26±0.62 26.39±0.41 22.52±0.41
9 240 79.82±0.68 64.47±0.68 49.30±0.60 41.04±0.44 28.18±0.0.61 24.12±0.37
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Research J. Pharm. and Tech. 10(12): December 2017
Stability Study:
The stability studies for best formulations FX2 was
carried out for 90 days at 40 ± 2 °C /75% ± 5% RH.
There was no significant change in colour and odour,
hardness, drug content and %CDR. 90 days of stability
studies revealed that; there was no any significant
degradation of the drug. The results found to be
satisfactory.
CONCLUSION:
The mucoadhesive buccal tablets of Curcumin were
prepared by direct compression method using various
hydrophilic polymers such as guar gum, Xanthan gum,
Graph No.04: Diffusion study of curcumin mucoadhesive buccal HPMC E15 and ethylcellulose is used as backing layer
tablet for maintaining the unidirectional flow of drug. The
formulation FX2 containing Xanthan gum showed the
In-vivo study: 97.75±0.89 % of drug release within 4 hours so it is
The in-vivo study of curcumin mucoadhesive buccal consider as best formulation. The optimized formulation
tablet was performed for the best formulation FX2. The (FX2) was subject for ex-vivo diffusion study and the
Cmax was found to be 0.049μg/ml from oral route and percentage release of drug was found to be 89.86±1.132
0.098μg/ml from buccal route as shown in table 9. % within 270 minutes. Then in-vivo study was
performed using 3 albino rabbits for 24 hours and the
Table 9: Data showing the pharmacokinetic parameters of
Curcumin by oral and buccal route. bioavailability of curcumin was found to be increased by
Pharmaceutical Parameters Curcumin (1.42 mg/kg) buccal route when compared to oral route.
Oral route Buccal route
Cmax (μ g / m l ) 0.049 0.098 REFERENCES:
Tmax (hrs) 2.0 4.0 1. Naga Raju K, Velmurugan S, Deepika B, Vinushitha S. Formulation and in-
AUC (μ g / m l / h r ) 1.560 3.693 vitro evaluation of buccal tablets of metoprolol tartrate. Int J Pharm Pharm
AUMC (μ g / m l / h r ) 3.978 8.897 Sci 2011;3(2):239-46.
T1/2 1.89 3.27 2. Ajeet, Singh B, Juneja R. Recent findings in concern to buccal patches: a
review.Int J Curr Pharm Res 2012;3(3):12-7.
MRT (hr) 18.021 20.045 3. Reddy KA, Venugopal K. Formulation and in-vitro evaluation of buccal
tablets of piroxicam. Int J Chem Sci 2012;10(1):399-412.
4. Inampudi A, Adimoolam S, Bhosale R, Vantoor BNS. Formulation and
Drug Release Kinetic: evaluation of vanlafaxine hydrochloride mucoadhesive buccal tablets. Int
The data obtained from in-vitro dissolution studies were Res J Pharm 2012;3(1):226-31.
fitted in different models viz. zero order, first order, 5. Yan H, Yuan Y, Xi Z, Kun Z, Shaohua C, Zhiyun D. Curcumin,
Inflammation and chronic diseases: how are they linked? Mol
Higuchi and Korsmeyer- Peppa’s equation, the result 2015;20:9183-9213.
were shown in table 8.It was observed that the highest 6. Preetha A, Kunnumakkara AB, Newman RA, Aggarwal BB. Bioavailability
of curcumin: Problems and promises. Mol Pharm 2007;4(6):807-18.
correlation of best formulation FX2 was found for 7. Maheswaran A, Mullaicharam AR. Pharmacological effect of curcumin. Int
Higuchi model (R2=0.9597), which indicates the drug J nutrients pharmacology neurological diseases 2012;2(2):92-99.
8. Prasad VK, Chandrashekhar LB, Rohini YN, Suchita AP. Development and
release would be by diffusion process. validation of UV Spectrophotometric method for the estimation of
Curcumin in cream formulation. Pharma meth 2013;4:43-5.
Table 10: Mathematical modelling and drug release 9. Vishal VH, Deepika RN, Sonali KM. Development and validation of UV
Formulation KINETIC MODULES Spectrophotometric method for the estimation of curcumin in bulk and
pharmaceutical formulation. World J Pharm Pharma Sci 2015;4(5):1456-
Code Zero Higuchi’ Korsmeyer First
63.
order s -Peppa’s Order 10. Lachmann/Liebermann’s. The theory and practical of industrial pharmacy,
R2 R2 R2 R2 fourth edition 2013. Page 451-452.
FG1 0.9409 0.9634 0.9512 0.8598 11. Barhate SD, Patel KM, Lokhande GS. Formulation and evaluation of
FG2 0.9691 0.9919 0.9826 0.9614 buccoadhesive tablet of atenolol. Der Pharmacia Lettre 2011;3(2):34-8.
12. Bhaskar U, Rudragouda P, Ravindra B, Swati M, Siddramesh B, Dhananjay
FG3 0.9100 0.9607 0.9532 0.9808
A. Formulation and in-vitro evaluation of mucoadhesive buccal tablets of
FG4 0.8867 0.7425 0.4913 0.6192 Furosemide. World J Pharm Pharm Sci 2012;1(3):1041-63.
FX1 0.9173 0.9557 0.9861 0.0551 13. Chaudhari VA, Sarode SM, Sathe BS, Vadnere GP. Formulation and
FX2 0.9584 0.9597 0.7370 0.0693 evaluation of mucoadhesive buccal tablet of Flurbiprofen. World J Pharm
FX3 0.896 0.9901 0.9815 0.7783 Pharma Sci 2014;3(5):945-62
14. Latheeshjlal L, Sunil A., Abdhul M, Vaidya MJ. Formulation and
FX4 0.9839 0.9626 0.9977 0.1307
Development of Buccal Drug Delivery System containing Curcumin. Int J
FH1 0.9880 0.9085 0.9986 0.1890 Pharm Tech Res 2011;3(1):37-41.
FH2 0.9806 0.9453 0.9577 0.2102 15. Shivanand K, Raju SA, Nizamuddin S, Jayakar B. In-vivo bioavailability
FH3 0.9463 0.9454 0.9232 0.2414 studies of sumatriptan succinate buccal tablets. DARU J Pharm Sci
FH4 0.9584 0.9380 0.9239 0.2512 2011;19(3):224-30.
16. Acholu PK, Yajaman S, Jayaveera KN. Ex-vivo and in-vivo evaluation of
formulated novel felodipine core in cup buccal tablets. Asian J Biomed
Pharm Sci2014;4(38):35-40.
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