INTRODUCTION:
The oral route of drug administration is the most convenient and commonly used method of drug delivery. However, this route has several physiological problems, including an unpredictable gastric emptying rate that varies from person to person, a brief gastrointestinal transit time (8-12 h), and the existence of an absorption window in the upper small intestine for several drugs1,2. These difficulties have promoted researchers to design a drug delivery system can stay in the stomach for prolonged and predictable period3,4. Attempts are being made to develop a controlled drug delivery system, which can provide therapeutically effective plasma drug concentration for a longer period, thereby reducing the dosing frequency and minimizing fluctuations in plasma drug concentration at steady-state by delivering the drug in a controlled and reproducible manner5. Different methodologies have been reported in the literature to increase to increase the gastric retention of drugs, like intra-gastric floating systems, hydrodynamically balanced systems, extendable or expandable and super porous biodegradable hydrogel systems6. The floating drug delivery systems result in long lasting intra-gastric buoyancy which may not only provide a sustained site of specific therapeutic action but also may lead to a reduction in side effects and better patient compliance7.
Effervescent floating drug delivery systems generate gas (CO2) thus reduce the density of the system and remain buoyant in the stomach for a prolonged period of time and released the drug slowly at a desired rate3,8,6. Domperidone Maleate has peripheral dopamine receptor blocking properties. It increases esophageal peristalsis and increases lower oesophageal sphincter pressure, increases gastric motility and peristalsis and enhances gastroduodenal coordination, therefore, facilitating gastric emptying and decreasing small bowel transit time. It is used in symptomatic management of upper GI motility disorders associated with chronic and subacute gastritis and diabetic gastroparesis as well as in the prevention of GI symptoms associated with use of dopamine-agonists and anti-Parkinson agents. Domperidone Maleate has some side effects like Headache/migraine (1%), Abdominal crampsconstipation, diarrhoea, dizziness, dysuria, edema9,10. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in high pH environment. Effervescence production, decrease several local GIT side effects, such as gastric irritation, nausea and gastritis. This approach also reduces unwanted side effects of the drug, the tablet remain buoyanat for a long period on the gastric contents, exhibiting drug release and consistent blood levels of drug.
MATERIALS AND METHODS:
Materials:
Domperidone Maleate, HPMC K15M, HPMC K100M, Carbopol 934P were procured from Alkem Lab.Pvt.Ltd., Mumbai. Sodium bicarbonate, Citric acid, Poly vinyl pyrolidine and Talc were obtained from Samar chemicals, Nagpur.
Methods:
Effervescent Floating tablets containing Domperidone Maleate were prepared by direct compression technique using varying concentrations of different grades of polymers with sodium bicarbonate and citric acid. All the ingredients were accurately weighed and passed through different mesh sieves accordingly. Then, except Magnesium stearate all other ingredients were blended uniformly in glass morter. After sufficient mixing of drug as well as other components, Magnesium stearate was added, as post lubricant, and further mixed for additional 2-3 minutes. The tablets were compressed using tablet compression machine. The weights of the tablets were kept constant for all formulation. (Table-1).
Evaluation of Domperidone Maleate Granules:
The flow properties of granules (before compression) were characterized in terms of angle of repose11, tapped density, bulk density12, Carr’s index13 and Hausner ratio. (Table-2).
Physical evaluation of Domperidone Maleate floating tablets:
Hardness of the tablets was tested using a Monosanto hardness tester. Friability of tablets was determined in Roche friabilator. Ten tablets were selected randomly from each batch and weighed individually to check for weight variation. The results are given in table no.3.
The buoyancy lag time (BLT) and total floating time (TFT)13
On immersion of tablets of different formulations in 0.1 N HCL solutions at 37±4°C, the tablets floated, and remained buoyant without disintegration, the results of the buoyancy lag time (BLT) and total floating time (TFT) were shown in Table no.4.
Drug content uniformity14
To evaluate a tablet potential for efficacy, the amount of drug per tablet needs to be monitored from tablet to tablet, and batch to batch. To perform the test, 20 tablets from each batch were weighed and powdered. Powder equivalent to the average weight of the tablet was accurately weighed and transferred into 100ml volumetric flask and dissolved into suitable quantity of 0.1N HCL. The prepared solution was diluted upto 100mlwith 0.1 N HCL and sonicated for 60 min. Five milliliters of the resulting solution was diluted upto 100ml with 0.1N HCl to get a conc. In the range of 15 ug/ml. A portion of the sample was filtered and analysed by U.V.Spectrophotometer at 286 nm.
In vitro Dissolution Study15
The release rate of Domperidone Maleate effervescent floating tablets was determined using United states pharmacopeia (USP) Dissolution Testing Apparatus 2 (paddle method) .The dissolution test was performed using 900 ml of 0.1 N HCL, at 37 ±4°C and 50 rpm. A sample (10 ml) of the solution was withdrawn from the dissolution apparatus hourly and the samples were replaced with fresh dissolution medium. The samples were filtered through a 0.45u membrane filter. Absorbance of these solutions was measured at 286 nm using a UV/Visible Spectrophotometer. The Cumulative Percentage drug release was plotted against time to determine the release profile. (Fig-1, 2 and 3).
Swelling Index:
The swelling of the polymers can be measured by their ability to absorb water and swell enormously. The swelling index is the ability of the polymers to swell by absorbing water. The water uptake study of the tablets was carried out by using USP dissolution apparatus type-II. The medium used was 900 ml of distilled water. The testing was carried out at rotation speed of 50 rpm. The temperature of the bath and medium was maintained at 37 ± 4°C throughout the study. The tablets were placed in the medium under rotation. The tablets were withdrawn from the medium after selected time interval, excess water removed by blotting and weighed. (Table-5). The swelling index of the tablets was given by following formula16.
Weight of swollen tablet – Initial weight of tablet
Swelling index (%) = x
100
Initial weight of tablet
Analysis of release mechanism: 17,18
Drug release mechanisms and kinetics are the two important characteristics of a drug delivery system in describing drug dissolution profile. To describe the kinetics of the drug release from effervescent floating tablet, mathematical models such as zero-order, first order, Higuchi, Hixson-Crowell and Korsmeyer-Peppas models were used. (Table-6). The criterion for selecting the most appropriate model was chosen on the basis of the goodness-or fit test.
· The zero-order kinetics (equation 1) describes the systems in which the drug release rate is independent of its concentration.
· The first order kinetics (equation 2) describes the systems in which the drug release rate is concentration dependent.
· Higuchi (equation 3) described the release of drug from an insoluble matrix as square root of time dependent process.
The Higuchi square root model also gives the drug release from a planer surface of an insoluble heterogeneous matrix by diffusion through the intragranular openings created by porosity of the matrix tablet.
· The Hixson-Crowell cube root law (equation 4) describes the drug release from systems in which there is a change in the surface area and the diameter of particle present in tablet.
· In case of Korsmeyer-Peppas model, the drug release from such devices having constant geometry will be observed till the polymer chains rearrange to equilibrium state. Korsmeyer-Peppas model (equation 5) describes the fraction released Qt/Q¥ as power function of time t for short time period.
Qt = Kot ………………………... (1)
Qt = Qo (1-e-k1t) ………………....(2)
Qt = KHÖt ................................(3)
3Ö Qo - 3Ö Qt = KHCt .....................(4)
Qt / Q∞ = Kktn ...................................................(5)
Qt - is the amount of drug release in time t
Qo - is the initial amount of the drug
F - is the fraction of drug release in time t
n - exponent value and Ko, K1, KH, KHC and Kk are release rate constants for zero-order, first-order, Higuchi, Hixson- Crowell and Korsmeyar-Peppas model rate equations respectively.
Figure 1:Comparison of in vitro dissolution profiles of B1 to B4
Figure 2:Comparison of in vitro dissolution profiles of B5 to B7
RESULTS AND DISCUSSION:
Domperidone Maleate has peripheral dopamine receptor blocking properties. It increases esophageal peristalsis and increases lower oesophageal sphincter pressure, increases gastric motility and peristalsis and enhance gastroduodenal coordination, therefore, facilitating gastric emptying and decreasing small bowel transit time. It is used in symptomatic management of upper GI motility disorders associated with chronic and subacute gastritis and diabetic gastroparesis as well as in the prevention of GI symptoms associated with use of dopamine-agonists and anti-Parkinson agents. Domperidone Maleate has some side effects like Headache/migraine (1%), Abdominal crampsconstipation, diarrhoea, dizziness, dysuria, edema. Prolonged gastric retention improves bioavailability, reduces drug waste and improves solubility for drugs that are less soluble in high pH environment. Effervescence production, decrease several local GIT side effects, such as gastric irritation, nausea and gastritis.
The effervescent floating tablets of Domperidone Maleate were formulated in ten different batches B1 to B10 by using hydrophilic polymers HPMC K100M, HPMC K15M and hydrophobic polymer Carbopol 934P along with effervescing agent Sodium bicarbonate and Citric acid. It was found that Carbopol has a negative effect on floating behavior but it was used only for the drug release retardant characteristics. All the formulations were prepared by direct compression method. The prepared tablets of all formulations were evaluated for physical characters like tablet hardness, friability, weight variation buoyancy lag time, total floating time, drug content uniformity, in-vitro drug release, swelling study and model fitting. The main aim was to optimize the formulation for 24 hours in-vitro release and total floating time to more than 24 hours.
The measured hardness of tablets of each formulation ranged between 5.0 to 5.5 Kg/Cm2. The % friability was less than 1% in all the formulations ensuring that the tablets were mechanically stable. All the tablets passed weight variation test as the % weight variation was within pharmacopoeial limits of ±5% of the weight.
Buoyancy lag time (BLT) and Total Floating time (TFT) of different formulation were noted, where B1 BLT of 130 and TFT of >10, B2 BLT of 133 and TFT of >12, B3 BLT of 125 and TFT of >8, B4 BLT of 122 and TFT of >18, B5 BLT of 104 and TFT of >22, B6 BLT of 160 and TFT of >22, B7 BLT of 145 and TFT of >24, B8 BLT of 144 and TFT of >24, B9 BLT of 140 and TFT of >24, B10 BLT of 100 and TFT of >24, with reference to buoyancy studies results it can be concluded that the batch containing HPMC polymers showed good buoyancy lag time (BLT) and total floating time (TFT). Formulation B10 containing HPMC K15M, HPMC K100M and Carbopol 934P showed good BLT of 100 sec and TFT of more than 24 hrs. (Fig.4, 5 and 6).
Domperidone Maleate release from effervescent floating tablets was studied in 0.1N HCl PH 1.2.The release profile of various formulations are shown in table no. Figure no.1 and 2.Formulation B1 released 98.00% of the drug in 10 hours. Formulation B2 released 98.75% of the drug in 12 hours. Formulation B3 released 97.03% of the drug in 8 hours. Formulation B4 released 97.26% of the drug in 18 hours. Formulation B5 released 95.32 % of the drug in 22 hours. Formulation B6 released 92.93% of the drug in 22 hours. Formulation B7 released 84.97% of the drug in 24 hours. Formulation B8 released 87.61% of the drug in 24 hours. Formulation B9 released 95.82 % of the drug in 24 hours. Formulation B10 released 97.16% of the drug in 24 hours. Thus B10 formulation was said to be optimized formulation. Swelling studies was also carried out and it was found that Combination of HPMC K15 M, HPMC K100 M and Carbopol 934P resulted in higher swelling and maintained their matrix integrity for more period of time as compared with HPMC K15 M, HPMC K100 M and Carbopol 934P alone.