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Poornima et al: Design and Preclinical Evaluation of Gastroretentive Floating Tablets of Quetiapine Fumerate 4121

Research Paper

Design and Preclinical Evaluation of Gastroretentive Floating Tablets of Quetiapine Fumerate

P. Poornima1*, K. Abbulu2 and K. Mukkanti1 1Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad-500085, Telangana, India; and 2CMR College of Pharmacy, Kandlakoya (V), Medchal Road, Hyderabad-501401, Telangana, India.

Received February 26, 2018; accepted March 23, 2018

ABSTRACT The present study was focused on gastro-retentive tablets of quetiapine fumarate using hydrophilic polymers HPMC K250 PH PRM, HPMC K750 PH PRM and HPMC K1500 PH PRM as release retarding agents. WSR 301 was chosen as resin, sodium bicarbonate was used as effervescent agents. FTIR studies revealed that there is no interaction between the drug and polymers used for the formulation. The tablets were prepared by direct compression method and the release rate was found to decrease with proportional increase in the ratio of polymer to drug. Quetiapine fumarate is absorbed well from stomach and therefore is a very good drug to be formulated into gastro retentive floating dosage form. In-vitro release profile of quetiapine fumarate and marketed product

when compared, the optimized formulation F19 showed drug release of 98.65% within 24 h whereas 96.78% of the drug was released from the marketed product within 1h. The optimized formulation remained stable when subjected to accelerated stability studies. In vivo radiographic studies of quetiapine fumarate optimized formulation (F19) supported the expectations in prolonging the gastric residence time in the fasted state in beagle dogs. C

max and AUC values of

optimized formulation were found to be significantly higher than of marketed product. In conclusion, gastro-retention can be a promising approach to enhance bioavailability of quetiapine fumarate with narrow absorption window in upper GIT.

KEYWORDS: Quetiapine; Floating tablets; HPMC; Schizophrenia; Radiographic studies; Bioavailability.

Introduction Oral route is the most common route of administering

the drug owing to the ease of formulation, low cost, convenient for the patient and simple regulatory approval process. Based on the requirement, formulations can be changed from immediate release to extended release by using several polymers (Whitehead et al., 1996). Gastro-retentive floating dosage forms are continuously researched and developed as the stomach is a major absorption zone. The gastric emptying time which varies from 2-3 h is a disadvantage for gastro-retentive dosage forms. Based on the formulation type and physiological condition of the patient, the gastric emptying process can vary from a few minutes to 12 h also. This variation may lead to unpredictable bioavailability and times to achieve peak plasma levels (Mojaverian et al., 1988). In addition, the relatively brief gastric emptying time in humans, through the stomach or upper part of the intestine (major absorption zone), can result in incomplete drug release from the drug delivery system, leading to reduced overall efficacy of the drug. Some drugs like quetiapine fumarate exhibit region-specific absorption in different regions of the intestine because of different pH conditions, various enzymes and endogenous components like bile (Deshpande et al., 1996).

Some of the common approaches used to increase the gastric residence time of pharmaceutical dosage forms include floating systems, swelling and expanding systems, bioadhesive systems, unfolding and modified-shape systems, and high-density systems. Floating drug delivery systems have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time (Hwang et al., 1998). Whilst the system remains afloat, the drug is released at a desired rate from the system (Grubel, 1987). Following drug release, the residual system is emptied from the stomach. This results in an increased gastric retention time and a better control of the fluctuations in plasma drug concentration. However, besides a minimal gastric content needed to allow the proper achievement of the buoyancy retention principle, a minimal level of floating force is also required to keep the dosage form reliably buoyant on the surface of the meal. (Desai and Bolton, 1993).

In this study we sought to prepare and evaluate gastro-retentive tablets of quetiapine fumarate using hydrophilic polymers HPMC K250 PH PRM, HPMC K750 PH PRM and HPMC K1500 PH PRM as release retarding agents.

International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 11 • Issue 3 • May – June 2018MS ID: IJPSN-2-16-18-POORNIMA

4121

4122 Int J Pharm Sci Nanotech Vol 11; Issue 3 • May− June 2018

Materials and Methods Materials

Quetiapine Fumarate was procured from MSN Labs Ltd. Hyderabad. HPMC K250 PRM, HPMC K750 PRM, HPMC K1500 PRM, and Polyox WSR 301 were obtained from Granules India Ltd, Hyderabad. Sodium bicarbonate, avicel pH 102, PVP K 30, talc and magnesium stearate were procured from SD Fine Ltd, Mumbai and all other chemicals used were of analytical grade.

Methods Formulation method: Accurately weighed quantities

of polymers and MCC were taken in a mortar and mixed geometrically, to this required quantity of quetiapine fumarate was added and mixed slightly with pestle (Lin et al., 2002). Accurately weighed quantity of sodium bicarbonate was taken separately in a mortar and powdered with pestle. The powder is passed through sieve no 40 and mixed with the drug blend which is also passed through sieve no 40. The whole mixture was collected in a plastic bag and mixed for 3 minutes (Martindale). To this magnesium stearate was added and mixed for 5 minutes, later talc was added and mixed for 2 minutes (Rama Rao et al., 2014). The mixture equivalent to 400 mg was compressed into tablets with 10 mm round concave punches at a hardness of 6 kg/cm2.

Evaluation of floating matrix tablets of quetiapine fumarate: Evaluation parameters like weight variation, thickness, hardness, friability (Nasrin et al., 2008), In vitro buoyancy studies (Penners et al., 1997) and drug content (Phuapradit W and Bolton S 1991) was performed according to the reported methods.

In vitro drug release studies: The in vitro drug release study was performed for the single & multiple-unit tablets using USP Type II dissolution apparatus using 900mL of 0.1N HCl at a temperature of 37±0.5ºC at 50 rpm. 5 mL of sample was collected at 0, 2, 4, 6, 8, 12, 16, 20, 24 hours and the same volume of fresh media was replenished. The drug content in the samples was estimated using UV visible spectrophotometer at 231 nm (Phuapradit, 1989).

Drug-excipient compatibility studies Fourier transform infrared spectroscopy (FTIR): The

spectral analysis can be used to identify the functional groups in the pure drug and drug-excipient compatibility. Pure quetiapine fumarate FTIR spectra, physical mixtures and optimized formulation were recorded by using FTIR (SHIMADZU). Weighed quantity of KBr and drug-excipients were taken in the ratio 100:1 and mixed by mortar. The samples were made into pellet by the application of pressure (Małgorzata et al., 2016). Then the FTIR spectras were recorded in the wavelength region between 4000 and 400cm−1.

Stability studies: Stability testing was conducted at 40°C ± 2°C/75% RH ± 5% RH for 3 months using stability chamber (Thermo Lab, Mumbai). Samples were withdrawn at predetermined intervals 0, 30, 60 and 90 days period according to ICH guidelines (Tyagi et al.,

2014). Various in vitro parameters like percentage yield, entrapment efficiency and in vitro release studies were evaluated.

Tablet preparation for in vivo radiographic studies: The quetiapine fumarate tablets of 400 mg in weight were prepared for in vivo radiographic studies in beagle dogs. To make the tablets X-ray opaque the incorporation of BaSO4 was necessary. For in vivo radiographic studies 60mg of BaSO4 (15%) was taken, 60mg of quetiapine fumarate was replaced with BaSO4. The amount of the X-ray opaque material in these tablets was sufficient to ensure visibility by X-ray. The analyses confirmed that these tablets were like the tablets for in vitro testing, i.e. the mechanical strength, floating properties, controlled drug release. (Singh et al., 2009).

Quetiapine fumarate in vivo radiographic studies: Three healthy beagle dogs, weighing approximately 16 kg, were used throughout the study. In each experiment, animals were fasted for 24 h and the first radiograph was made to ensure the absence of radiopaque material in the stomach. The dogs swallowed one of the tablets and immediately afterwards drank 100 mL of water. During the experiment the dogs were not allowed to eat, but water was available ad libitum. The study protocol was approved by institutional animal ethics committee with No. 1292/ac/09/CPCSEA/ 21/A. For radiographic imaging the animal was positioned in a right lateral or ventrodorsal recumbency. After the determined time intervals standard lateral and ventrodorsal radiographs of the abdomen were taken using an X-ray machine (General Electric Corporation, USA). The distance between the source of X-rays and the object was the same for all imaging. This allowed us to see the tablet in the body of stomach. At different time intervals of 0.5, 3, 4 and 6 h post-administration of tablets, the dogs were exposed to abdominal X-ray imaging. (Baumgartner et al., 2000).

In vivo Study Animal preparation: Twelve New Zealand white

rabbits of either sex rabbits were (weighing 2-3 kg) selected for this study, all the animals were healthy during the period of the experiment. Animals were maintained at room temperature 250C, RH 45% and 12 h alternate light and dark cycle with 100 % fresh air exchange in animal rooms, uninterrupted power and water supply and rabbits were fed with standard diet and water ad libitum. The protocol of animal study was approved by the institutional animal ethics committee with No: 1292/ac/09/CPCSEA/ 21/A

In vivo study design (Kadivar et al., 2015): Rabbits were randomly divided into two groups each group contains six animals. The group A rabbits were fed with quetiapine fumarate optimized formulation, group B fed with marketed product with equivalent dose to animal body weight. Blood samples (approximately 0.5mL) were obtained with syringes by marginal ear vein at 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 20 and 24 h post doses. During collection, blood sample have been mixed thoroughly with heparin in order to prevent blood clotting. Plasma

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Fig. 7. FTIR spectrum of quetiapine fumarate optimized formulation (F19).

Drug - excipient compatibility studies

FTIR spectra of quetiapine fumarate showed peaks of 3410, 2941, 1629, 1530, 1400 and 1060 cm-1due to –OH stretching, C-H stretching, C=O stretching, N-H bending, C-H bend in plane and C-C stretching respectively. FTIR Spectra of HPMC K1500 PH PRM showed peaks of 2929, 1462, 1163, 1022, 947 and 850 cm–1 due to C-H stretching, O-H stretching and C-C stretching respectively. FTIR spectra of optimized formulation showed both characteristics peaks of drug and polymer indicating no drug-polymer interaction.

Stability Studies

There were no changes observed in percentage drug content, In vitro drug release studies and floating lag time during storage of the quetiapine fumarate optimized formulation F19 for 6 months.

In vivo Radiographic Studies of Quetiapine Fumarate Optimized Formulation (F19)

The behaviour of the optimized formulation of quetiapine fumarate tablet in the dog stomach was observed in real time using a radiographic imaging technique. On radiographic images made 0.5 h after the administration, the tablets were observed in the animal’s stomach. In the next picture taken at 1.5 h significant changes were detected, the tablet had altered its position and turned around. This provided evidence that the tablets did not adhere to the gastric mucous, but, on the contrary, floated on the gastric fluid. Additionally, the swelling of the tablet is visualized very well together with the white dry core and translucent swelling layer around it. As the swelling continued, but the results have

shown that the mean gastric residence time for the developed floating tablets was 240 min ± 60. The comparison of gastric motility and stomach emptying between humans and dogs shows no big differences. Therefore, it might be speculated that experimentally proven increased GRT in beagle dogs can be compared to known literature data for humans.

Bioavailability Parameters

Mean plasma concentration profiles of prepared quetiapine fumarate optimized formulation and marketed product are presented in Fig. 9. Quetiapine fumarate optimized formulation exhibited as sustained release in vivo when compared with marketed tablet. All the pharmacokinetics parameters displayed in Table 4. In this study in rabbits, prolonged drug absorption was achieved with the test formulation. The average peak concentration of the test formulation was significantly higher than that of the reference (454±30.21ng/mL for the test formulation versus 385±91.25ng/mL for the reference). In order to estimate the amount of drug absorbed from the test formulation, the relative bioavailability was calculated from the AUC of the reference and test formulations (8226.25±38.12ng. h/mL for the reference product versus 9325±28.14ng. h/mL for the test formulation). The results indicated that the test formulation could increase the bioavailability of quetiapine fumarate in rabbits effectively. In this study, the quetiapine fumarate floating tablet produce higher bioavailability than that of a marketed product, this overall increase in bioavailability and increased gastric residence time, caused by flotation of dosage form in the stomach.


(a) (b)

(c) (d)

Fig. 8. Intragastric behavior of the BaSO4 loaded optimized quetiapine fumarate floating tablets (F19) represented by typical radiographic images after definite time intervals (the tablet is pointed by ring). (a) after 0.5 h (b) after 3 h (c) after 4.5 h and (d) after 6 h of tablet administration.

Fig. 9. Plasma concentrations at different time intervals for quetiapine fumarate optimized formulation and marketed product.


TABLE 1

Composition of floating matrix tablets of quetiapine fumarate with HPMC K250 PH PRM.

Ingredients (weight in mg)

Formulations

F1 F2 F3 F4 F5 F6 F7

Quetiapine fumarate*

230.4 230.4 230.4 230.4 230.4 230.4 230.4

HPMC K250 PH PRM

65 70 75 80 85 90 95

WSR 301 13.6 13.6 13.6 13.6 13.6 13.6 13.6

Sodium bicarbonate 22 24 26 28 30 32 34

Avicel pH 102 53 46 39 32 25 18 11

PVP K 30 12 12 12 12 12 12 12

Talc 2 2 2 2 2 2 2

Magnesium stearate 2 2 2 2 2 2 2

Total weight 400 400 400 400 400 400 400

Quetiapine Fumarate* is equivalent to 200mg of quetiapine

TABLE 2



Formulations

F8 F9 F10 F11 F12 F13 F14

Quetiapine fumarate*

230.4 230.4 230.4 230.4 230.4 230.4 230.4

HPMC K750 PH PRM

65 70 75 80 85 90 95

WSR 301 13.6 13.6 13.6 13.6 13.6 13.6 13.6

Sodium bicarbonate

22 24 26 28 30 32 34

Avicel pH 102

53 46 39 32 25 18 11

PVP K 30 12 12 12 12 12 12 12

Talc 2 2 2 2 2 2 2


Total weight 400 400 400 400 400 400 400

Quetiapine fumarate* is equivalent to 200mg of Quetiapine

TABLE 3



Formulations

F15 F16 F17 F18 F19 F20 F21

Quetiapine fumarate* 230.4 230.4 230.4 230.4 230.4 230.4 230.4

HPMC K1500 PH PRM

65 70 75 80 85 90 95

WSR 301 13.6 13.6 13.6 13.6 13.6 13.6 13.6

Sodium bicarbonate 22 24 26 28 30 32 34

Avicel pH 102 53 46 39 32 25 18 11

PVP K 30 12 12 12 12 12 12 12

Talc 2 2 2 2 2 2 2


Total weight 400 400 400 400 400 400 400 Quetiapine fumarate* is equivalent to 200mg of quetiapine

TABLE 4

Comparison of pharmacokinetic parameters of quetiapine fumarate optimized formulation and marketed product.

Parameters Quetiapine fumarate

optimized formulation (F19)Marketed product

Cmax(ng/ml) 454 ± 30.21 385±91.25AUC0-t(ng. h/ml) 8176 ± 56.44 7597±44.26AUC0-∞ (ng. h/ml) 9325 ± 28.14 8226.25±38.12Tmax (h) 4.00 ± 1.23 3.50±0.24t1/2 (h) 9.053 ± 0.519 8.164 ± 0.01Kel (h–1) 0.051 ± 0.016 0.084 ± 0.018

Conclusions

In the present work, it can be concluded that the quetiapine fumarate floating tablets can be an innovative and promising approach for the delivery of quetiapine fumarate as extended drug release over 24 h which is the best formulation for the treatment of Schizophrenia with only one oral tablet a day thus minimizing the side effects with low drug dose, which improves patient compliance. In vivo radiographic studies of quetiapine fumarate optimized formulation (F19) supported the expectations in prolonging the gastric residence time in the fasted state in beagle dogs. The mean gastric residence time for the tested tablets was 240 min ±60. Cmax and AUC values of optimized formulation were found to be significantly higher than of marketed product. Hence, gastroretention can be a promising approach to enhance bioavailability of quetiapine fumarate with narrow absorption window in upper GIT. These results are encouraging, because a longer gastric residence time is an important condition for higher bioavailability of the drugs included in the prolonged or controlled release dosage form.

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Address correspondence to: P. Poornima, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500085, Telangana, India. Mob: +91-9490551723 E-mail: [email protected]

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