Formulation and Evaluation of Mucoadhesive Buccal Tablets of Resperidone
Dasari Nirmala, Vaddi Harika, Muvvala Sudhakar
Malla Reddy College of Pharmacy, Department of Pharmaceutics, Maisammaguda, Dhulapally,
Secunderabad - 500100 Affiliated by Osmania University.
*Corresponding Author E-mail:
ABSTRACT:
The aim of present study was to formulation and evaluation of Mucoadhesive buccal tablets of Resperidone. Mucoadhesive buccal tablets of Resperidone were prepared by direct compression method using polymers such as Karaya gum, tamarind gum, carbopol, and Sodium carboxy methyl cellulose. The Buccal tablets were evaluated for various physical, drug content uniformity, in-vitro drug release and drug- excipient interactions (FT-IR). FT-IR spectroscopic studies indicated that there were no drug-excipient interactions. The formulation F9 (containing 30mg of Carbopol) were found to be best formulation, which showed maximum drug release within 8 h. These formulations have showed good bioadhesion strength (18 gm).
KEYWORDS: Risperidone, Mucoadhesive buccal tablets, Carbopol, Karaya gum, and Sodium carboxy methyl cellulose.
INTRODUCTION:
Buccal drug delivery has several advantages over to conventional oral route, drug directly enter into systemic circulation via buccal mucosa, avoids first pass metabolism and rapid onset of action. Buccal delivery easily acceptable for patients, dosage forms can be easily applied and drug action can be terminated in emergency and unexpected side effects by removing the dosage form1. Buccal drug delivery systems are investigated by different research groups as an alternative for systemic delivery, which can be prepared as tablets, discs, gels, patches, films, sponges, or wafers. There are different mucoadhesive dosage forms currently available in the market for local or systemic drug delivery. Buccal tablets can be formulated to retain their shape, integrity, and position during application time2.
Mucoadhesion is used to define the attachment of macromolecules to the mucosal membrane. After application to the oral cavity, dosage forms may become dislodged and swallowed accidently by the patients. This may cause interruptions or reduction in drug absorption during treatment3. For this reason, it is important to provide sufficient mucoadhesion to retain the buccal tablet on the application site. Various natural, semi-synthetic, or synthetic polymers are used in buccal formulations to achieve mucoadhesion. These polymers hydrate and swell with contact to mucus layer in the epithelium. Mucin, a specific component of mucus, is a high-molecular-weight glycoprotein with negative charge on the surface. Mucoadhesion strength varies based on the physicochemical properties of the polymer, characteristics of the biological material, and contact time of the dosage form4.
Risperidone (RS) is a benzisoxazole derivative and atypical antipsychotic drug with high-affinity antagonism to 5-HT2A serotonin and D2 dopamine receptors along with histamine, α1 and α2 adrenergic receptor blockade properties. RS is primarily used in the treatment of schizophrenia and bipolar disorders as oral solution, conventional tablet, orally disintegrating tablet, and long-acting intramuscular injection. RS is practically insoluble in water at neutral pH and considered as class II (high-permeability, low-solubility) drug according to Biopharmaceutical Classification System5. RS is rapidly absorbed after oral administration but undergoes significant first-pass metabolism. Along with differences in intestinal absorption, this causes variability in plasma concentrations. Patient compliance is also a major problem in antipsychotic treatment, especially with oral route.
MATERIALS AND METHODS:
Materials:
Respirodone obtained gift samples from Aizant pharmaceuticals pvt ltd, Carbopol 934, Karaya gum, Tamarind gum, Microcrystalline cellulose, sodium CMC, Mannitol, Magnesium stearate and talc.
Methods:
Preformulation studies:
Solubility:
Solubility of Risperidone was determined in Methanol, Ethanol, 0.1N HCl, pH 7.4 and pH 6.8 phosphate buffers. Solubility studies were performed by taking excess amount of Risperidone in different beakers containing the solvents. The mixtures were shaken for 48hrs in rotary shaker. The solutions were centrifuged for 10mins at 1000rpm and supernatant were analyzed at 234nm.
Drug and excipient compatability studies:
FT-IR Studies: To find the physical and chemical interaction or compatability between pure drug and optimized formulation using Fourier Transform Infra red Spectrometer (Brucker). FT-IR spectra of drug and physical mixture of drug and optimized formulation were recorded by placing sample in spectrometer in scanning range of 400-4000cm-1 and resolution was 1 cm-1.
Flow properties6:
Flow properties of drug and excipient mixture was performed using methods like angle of repose, carr’s index and hausner’s ratio.
Method of preparation of Resperidone buccal tablets7:
Direct compression method was used to prepare buccal tablets of Risperidone using various polymers. All the ingredients including drug, polymer and excipients were weighed accurately. The drug is throughly mixed with diluent on a butter paper with the help of a stainless steel spatula. Then all the ingredients except lubricants were mixed in the order of ascending weights and blended for 10 min. After uniform mixing of ingredients, lubricant was added and again mixed for 2 min. The prepared blend of each formulation was then compressed using a multi station tablet punching machine. (Table-1).
Post compression parameters of Buccal tablets of Risperidone8:
Hardness test:
The crushing strength (kg/cm2) of tablets was determined by using monsanto hardness tester.
Friability test:
This was determined by weighing 10 tablets after dusting, placing them in the friabilator and rotating the plastic cylinder vertically at 25rpm for 4 min. After dusting, the total remaining weight of the tablets was recorded and the percent friability was calculated (% loss in weight).
Uniformity of content:
The weight (mg) of each of 20 individual tablets was determined by dusting each tablet off and placing it in an electronic balance. The weight data from the tablets were analyzed for sample mean and percent deviation from the mean.
Table 1 Composition of buccal tablets of Respiridone
|
Ingredients (mg) |
Formulation Code |
|||||||||||
|
F1 |
F2 |
F3 |
F4 |
F5 |
F6 |
F7 |
F8 |
F9 |
F10 |
F11 |
F12 |
|
|
Risperidone |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
|
Tamarind Gum |
10 |
20 |
30 |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
|
Karaya Gum |
-- |
-- |
-- |
10 |
20 |
30 |
-- |
-- |
-- |
-- |
-- |
-- |
|
Carbopol 940 |
-- |
-- |
-- |
-- |
-- |
-- |
10 |
20 |
30 |
-- |
-- |
-- |
|
Sodium CMC |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
-- |
10 |
20 |
30 |
|
PVP K30 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
10 |
|
Mannitol |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
15 |
|
MCC |
110 |
100 |
90 |
110 |
100 |
90 |
110 |
100 |
90 |
110 |
100 |
90 |
|
Mg. sterate |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
|
Talc |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
1.5 |
|
Total weight(mg) |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
150 |
Uniformity of drug content:
Five tablets were powdered in a glass mortar and the powder equivalent to 10mg of drug is placed in a stoppered 100ml conical flask. The drug is extracted with 25ml water with vigorous shaking on a mechanical gyratory shaker (100rpm) for 2 h and filtered into 50ml volumetric flask through Whatman No.1 filter paper (Mean pore diameter 1.5µm) and more solvent is passed through the filter to produce 50ml. Aliquots of the solution are filtered through 0.22µm membrane filter disc (Millipore corporation) and analyzed for drug content by measuring the absorbance at 234 wavelength against solvent blank.
Surface pH study:
The surface pH of the buccal tablets is determined in order to investigate the possibility of any side effects in vivo. As an acidic or alkaline pH may irritate the buccal mucosa, we sought to keep the surface pH as close to neutral as possible9. A combined glass electrode is used for this purpose. The tablet is allowed to swell by keeping it in contact with 1 ml of distilled water (pH 6.8 ±0.05) for 2 h at room temperature. The pH is identified by bringing the electrode into contact with the tablet surface and allowing to equilibrate for 1 min.
Swelling Index10:
The swelling rate of the buccal tablet is evaluated by using of pH 6.8 phosphate buffer. The initial weight of the tablet is determined (w1). The tablets is placed in pH 6.8 phosphate buffer (6ml) in a petridish placed in an incubator at 37±1oC and tablet is removed at different time intervals (0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0 and 8.0 h), blotted with filter paper and reweighed (w2).
The swelling index is calculated by the formula:
Swelling index = 100 (w2-w1) / w1.
Mucoadhesion strength:
The mucoadhesive forces of the tablets were determined by means of mucoadhesion measuring device. The sheep buccal mucosa was cut into stripes/pieces and washed with buffer solution. At time of testing a section of sheep buccal mucosa was secured keeping the mucosal side, out of the upper glass vial using rubber band and aluminum cap. The diameter of each exposed mucosal membrane was 1cm. The vial with sheep buccal mucosa secured at 37oC for 10 min. the one vial with section of sheep buccal mucosa and another vial were fixed on height adjustable pan. To a lower vial a tablet was paced on adhesive side facing downward. The height of the lower vial was adjusted so that tablet could adhere to the sheep of buccal mucosa on the upper vial. A consant force was applied on the upper vial for 2 mins, after which it was removed and the upper vial was then connected to the balance. Then the weight on right side pan was slowly added in a increment of 0.5g, till the two vials just separated from each other the total weight (gm) required to detach two vials was taken as a measure of mucoadhesive strength. From this mucoadhesive strength, the force of adhesive was calculated11.
In vitro drug release study12:
The prepared buccal tablets were subjected to in vitro dissolution. Dissolution test was carried out using USP type 2 paddle method. The stirring rate was 50 RPM, pH 6.8 phosphate buffer was used as dissolution medium and dissolution medium was maintained at 37±0.5oC. Samples of 5ml were withdrawn at regular intervals of time, filtered and replace with 5ml of fresh dissolution medium, dilutions were made wherever necessary and were analyzed for Risperidone at 234nm by using UV-visible spectrophotometer.
Release kinetics13:
In the present study, data of the in vitro release were fitted to different equations and kinetic models to explain the release kinetics of Risperidone from the buccal tablets. The kinetic models used were Zero order equation, First order, Higuchi release and Korsmeyer-Peppas models.
RESULTS AND DISCUSSION:
Precompression studies:
Solubility:
It was determined as per standard procedure
Table 2 Results of solubility of Risperidone in various solvents
|
Solvent |
Solubility (µg/ml) |
|
0.1N HCl |
0.196 |
|
6.8pH buffer |
0.497 |
|
7.4pH buffer |
0.268 |
|
Methanol |
1.398 |
|
Ethanol |
1.056 |
Fig 1: Graphical Representation of Risperidone solubility studies
Solubility studies revealed that Risperidone was found to be more soluble in 6.8pH buffer compared to other buffers.
Drug-Excipient compatibility studies:
Fig 2: FTIR spectrum of pure Risperidone
Fig 3: FTIR spectrum of optimized resperidone buccal tablets
The FT-IR spectra of pure drug and with excipients were presented in fig 2 and 3 respectively. Pure Resperidone exhibited characteristic peak of C-H aromatic stretching at 2921.31cm-1, C=O stretching at 1679.38 cm-1, C-F stretching at 1018.99 cm-1, and C-N stretching at 1263.32 cm-1. The spectrum of Respiridone with excipients was shown characteristic peak of C-H aromatic stretching at 2925.17 cm-1, C=0 stretching at 1732.72, C-F stretching at 1083.04 cm-1 , C-N stretching at 1326.75 cm-1. Hence there was no considerable change in shifting of functional groups of Resperidone formulation with excipients revealed that Resperidone was compatable with all excipients of mucoadhesive buccal tablets.
Flow properties of powder blend:
Table 3. Results of flow properties of Resperidone buccal tablets
|
Code |
Angle of Repose |
Bulk Density (g/ml) |
Tapped Density (g/ml) |
Carr’s Index. (%) |
Hausner’s ratio |
|
F1 |
27065±0.1 |
0.796±0.2 |
0.917±0.3 |
13.20±0.09 |
1.15±0.05 |
|
F2 |
28064±0.3 |
0.789±0.09 |
0.905±0.2 |
12.82±0.1 |
1.15±0.03 |
|
F3 |
27015±0.2 |
0.759±0.3 |
0.913±0.1 |
16.87±0.3 |
1.20±0.02 |
|
F4 |
30025±0.1 |
0.794±0.3 |
0.905±0.09 |
12.27±0.2 |
1.14±0.01 |
|
F5 |
31045±0.5 |
0.785±0.2 |
0.913±01 |
14.02±0.2 |
1.16±0.04 |
|
F6 |
29026±0.2 |
0.789±0.1 |
0.905±0.2 |
12.82±0.1 |
1.15±0.03 |
|
F7 |
28036±0.09 |
0.769±0.3 |
0.911±0.1 |
15.59±0.2 |
1.18±0.01 |
|
F8 |
27045±0.1 |
0.785±0.2 |
0.908±0.4 |
13.55±0.09 |
1.16±0.02 |
|
F9 |
27069±0.3 |
0.748±0.3 |
0.896±0.09 |
16.52±0.3 |
1.20±0.01 |
|
F10 |
28015±0.5 |
0.786±0.1 |
0.904±0.1 |
13.05±0.4 |
1.15±005 |
|
F11 |
28036±0.4 |
0.753±0.5 |
0.873±0.2 |
13.75±0.5 |
1.16±0.04 |
|
F12 |
29054±0.09 |
0.789±0.2 |
0.896±0.3 |
11.94±0.3 |
1.14±0.02 |
Table 4: Results of post compression parameters of Risperidone buccal tablets
|
Formulation code |
Hardness (kg/cm2) |
Thickness (mm) |
Weight variation (%) |
Friability (%) |
% Drug content |
|
F1 |
4.84±0.11 |
2.16±0.14 |
2.54±0.21 |
0.54±0.03 |
96.42±0.13 |
|
F2 |
4.52±0.31 |
2.25±0.23 |
2.64±0.12 |
0.56±0.04 |
96.25±0.21 |
|
F3 |
4.62±0.22 |
2.54±0.32 |
3.12±0.21 |
0.65±0.01 |
98.15±0.43 |
|
F4 |
4.58±0.51 |
2.85±0.34 |
2.54±031 |
0.25±0.02 |
97.02±0.65 |
|
F5 |
5.02±0.09 |
2.02±0.21 |
2.63±0.28 |
0.31±0.01 |
95.35±0.32 |
|
F6 |
4.56±0.21 |
2.03±0.23 |
2.58±037 |
0.24±0.05 |
98.46±0.23 |
|
F7 |
4.28±0.25 |
2.63±0.32 |
2.36±0.42 |
0.25±0.03 |
96.38±0.32 |
|
F8 |
4.62±0.32 |
2.15±0.43 |
3.58±0.36 |
0.38±0.03 |
95.02±0.12 |
|
F9 |
4.24±0.16 |
2.24±0.54 |
3.47±0.24 |
0.12±0.02 |
97.42±0.34 |
|
F10 |
4.06±0.31 |
2.36±0.45 |
3.12±0.18 |
0.05±0.01 |
98.06±0.45 |
|
F11 |
4.32±0.42 |
2.52±032 |
2.06±0.12 |
0.46±0.06 |
99.36±0.32 |
|
F12 |
4.28±0.21 |
2.36±0.21 |
2.48±0.31 |
0.53±0.05 |
98.75±0.21 |
The angle of repose of all formulations was found to be in the range of 27015±0.2 to 31045±0.5, which indicates powder blends showed good flow property. The bulk density of all formulations was found to be in the range of 0.748±0.3 to 0.796±0.2g/cm3.The tapped density was found to be in the range of 0.873±0.2 to 0.917±0.3g/cm,3 which are within the acceptable limits. The Carr’s index of all formulations was found to be in the range of 11.94±0.3 to 16.87±0.3. It shows that good flow property. The Hausners ratio of all formulations was found to be in the range of 1.14±002 to 1.20±0.05, which indicates that powder blend shows good flow property.
Post compression parameters of Risperidone buccal tablets:
The hardness of the tablets was found to be in the range of 4.06±0.31 to 5.02±0.09Kg/cm2. It was within the range of monograph specification. Friability of the tablets was found to be less than 1% and it was within the range of standard specification. Weight variation values of all the tablets was found to be in the range of 2.48±0.31 to 3.58±0.36, it revealed that percentage of weight variation within in the acceptable limits. The drug content estimations showed the values in the range of 95.02±0.12 to 99.36±0.32% which reflects good uniformity in drug content among the formulations F1 to F12 and indicates these values were within specified range as per USP (±15% of label claim was acceptable).
Table 5 Results of Surface pH, Swelling Index and Mucoadhesive strength of Risperidone buccal tablets:
|
Formulation code |
Surface pH |
SI (%) |
Mucoadhesive sterngth (gm) |
|
F1 |
6.4±0.12 |
20.53±0.21 |
4±0.02 |
|
F2 |
6.5±0.25 |
26.35±0.34 |
6±0.04 |
|
F3 |
6.3±0.33 |
39.54±0.54 |
9±0.01 |
|
F4 |
6.5±0.14 |
29.54±0.45 |
6±0.03 |
|
F5 |
6.4±0.28 |
38.26±0.21 |
8±0.02 |
|
F6 |
6.8±0.32 |
42.36±0.32 |
12±005 |
|
F7 |
6.7±0.32 |
39.65±0.18 |
7±0.06 |
|
F8 |
6.5±0.23 |
50.26±0.24 |
11±0.01 |
|
F9 |
6.8±0.43 |
59.35±043 |
18±0.09 |
|
F10 |
6.5±0.12 |
20.54±0.43 |
5±0.03 |
|
F11 |
6.8±0.23 |
29.36±0.21 |
10±0.05 |
|
F12 |
6.7±032 |
38.45±0.21 |
12±0.03 |
The surface pH was determined in order to investigate the possibility of any side effects, in the oral cavity as acidic or alkaline pH is bound to cause irritation to the buccal mucosa. Surface pH of all formulations was found to be in the range of 6.3 to 6.8. Hence it is assumed that these formulations cause no irritation in the oral cavity.
The swelling profile of different batches of the tablets is shown in Table 7. These profiles indicate the uptake of water into the tablet matrix, producing an increase in weight. The swelling state of the polymer (in the formulation) was reported to be crucial for its bioadhesive behavior. Adhesion occurs shortly after the beginning of swelling but the bond formed between mucosal layer and polymer is not very strong. The adhesion will increase with the degree of hydration until a point where over-hydration leads to an abrupt drop in adhesive strength due to disentanglement at the polymer/tissue interface. In formulations maximum swelling was seen with the formulation containing higher concentration of Carbopol. Results indicated that as the concentration of polymers increases the swelling index increases.
The mucoadhesion of all the buccal tablets of varying ratios of polymers were tested and weight required to pull off the formulation from the mucous tissue is recorded as mucoadhesion strength in grams and results are given in Table 7 The mucoadhesivity of buccal tablets was found to be maximum in case of formulation F9 i.e. 30mg of Carbopol.
Fig 4: in vitro drug release profiles of Resperidone buccal tablets
All the 12 formulations of Risperidone buccal tablets were subjected to dissolution studies.
Formulations F1, F2, F3 containing the Tamarind gum as polymer. F1 formulation containing 10mg of Tamarind gum shows 95.34% drug release at the end of 3hrs. Where as F2 formulation containing 20mg of Tamarind gum shows 98.05% drug release at the end of 4hrs. While the F3 formulation containing 30mg of Tamarind gum shows 95.25% drug release at the end of 5hrs. As the concentration of polymer increasing drug release time is increased. So further trails were performed using Karaya gum with same proportions.
Formulations F4, F5, F6 containing the Karaya gum as polymer. F4 formulation containing 10mg of Karaya gum shows 97.68% drug release at the end of 4hrs. Where as F2 formulation containing 20mg of Karaya gum shows 96.22% drug release at the end of 6hrs. While the F3 formulation containing 30mg of Karaya gum shows 98.42% drug release at the end of 7hrs. As the concentration of polymer increasing drug release time is increased. So further trails were performed using Carbopol with same proportions.
Formulations F7, F8, F9 containing the Carbopol as polymer. F7 formulation containing 10mg of Carbopol shows 95.02% drug release at the end of 6hrs. Where as F8 formulation containing 20mg of Carbopol shows 96.25% drug release at the end of 7hrs. While the F9 formulation containing 30mg of Carbopol shows 97.24% drug release at the end of 8hrs. As the concentration of polymer increasing drug release time is increased.
Formulations F10, F11, F12 containing the Sodium CMC as polymer. F10 formulation containing 10mg of Sodium CMC shows 98.92% drug release at the end of 4hrs. Where as F11 formulation containing 20mg of Sodium CMC shows 98.46% drug release at the end of 5hrs. While the F12 formulation containing 30mg of Sodium CMC shows 96.24% drug release at the end of 6hrs. As the concentration of polymer increasing drug release time is increased.
Among all the 9 formulations F9 formulation is optimized, as it shows maximum drug release at the end of 8hrs which suits the buccal drug delivery system criteria as per our studies.
Table 6: Results of release kinetics of Resperidone mucoadhesive buccal tablets
|
R2 values |
n values |
||||
|
Formulation |
Zero order |
First order |
Higuchi |
Korsmeyer - Peppas |
Korsmeyer- Peppas (n) |
|
F9 |
0.928 |
0.863 |
0.994 |
0.432 |
0.938 |
The invitro dissolution data for best formulation F9 were fitted in different kinetic models i.e, zero order, first order, Higuchi and korsemeyer-peppas equation. Optimized formulation F9 shows R2 value 0.928. As its value nearer to the ‘1’ it is conformed as it follows the zero order release. The mechanism of drug release is further confirmed by the korsmeyer and peppas plot, if n = 0.45 it is called Case I or Fickian diffusion, 0.45 < n < 0.89 is for anomalous behavior or non-Fickian transport, n = 0.89 for case II transport and n > 0.89 for Super case II transport.
The ‘n’ value is 0.938 for the optimised formulation (F9) i.e., n value was n > 0.89 this indicates Super case II transport. The release kinetics for the optimized formula are shown in table.
CONCLUSION:
Risperidone is an antipsychotic medicine. The bioavailability of oral Risperidone is reduced due to extensive hepatic metabolism. Since buccal route by passes first-pass effect. Therefore, it is selected as suitable drug for the design of Buccal drug delivery system with a view of improve its oral bioavailability and patient compliance.
In the present study, an attempt was made to prepare buccal tablets of Risperidone in order to overcome bioavailability problems, to reduce dose dependent side effects.
Buccal tablets containing drug was prepared by direct compression method by using combinations of polymers (Tamarind gum, Carbopol, Karaya gum and Sodium CMC). Estimation of Risperidone was carried out spectrophotometrically at 234 nm.
The Buccal tablets were evaluated for physical parameters like appearance, hardness, thickness, weight variation, friability, swelling index, and surface pH; biological parameter-mucoadhesive strength; and other parameters such as drug content uniformity, in-vitro release, drug excipient interactions (IR)
The Buccal tablets prepared by direct compression were found to be of uniform thickness and weight, smooth appearance with uniform drug content, good hardness and mucoadhesive strength. An increase in polymer concentration brought in an increase in mucoadhesive strength. The maximum mucoadhesive strength is shown by formulation F9 (30mg carbopol) is approximately 18 gm.IR spectroscopic studies indicated that there are no drug- excipients interactions.
Among all the 9 formulations F9 formulation is optimized, as it shows maximum drug release at the end of 8hrs which suits the buccal drug delivery system criteria as per our studies.
Optimized formulation (F9) displayed that it follows zero order release kinetics and drug release follows super case II transport mechanism.
Hence by the above results we can formulate Risperidone buccal tablets using Carbopol as mucoadhesive polymer.
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Received on 12.08.2021 Modified on 30.08.2021
Accepted on 29.09.2021 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Tech. 2022; 12(1):13-19.
DOI: 10.52711/2231-5713.2022.00003