Each effect can be varying with time according to the rates of production and dissipation of gas bubbles. The formation of gas bubbles starts with the beginning of the hydration process. Although the reduction of the diffusion path reduces the surface area available for drug transport, the continuing development of carbon dioxide bubbles contributes also to expand the matrix volume and to decrease the coherence of hydroxypropylmethylcellulose matrices. This second effect of carbon dioxide bubbles overrules in a second part of the release process, facilitating drug transport and increasing the cumulative drug released over that showed by pure hydroxypropylmethylcellulose matrices³.

The drug bioavailability of pharmaceutical dosage forms is influenced by various factors. One of the important factors is the gastric residence time of these dosage forms⁴. The gastric emptying process from the stomach to small intestine generally lasts from a few minutes to 12h. This variability leads to an unpredictable bioavailability of an orally administered dosage form. Furthermore, the relatively short gastric emptying time can result in an incomplete release of drug from the drug delivery system, leading to a diminshed efficacy of the administered dose⁵. Therefore, an effective control of the placement of a delivery system in a specific region of the gastrointestinal (GI) tract offers numerous advantages, especially for the drugs with specific absorption site in the gastrointestinal tract or the drugs with stability problem. These considerations have led to the development of the controlled release dosage forms that possess gastric retention capability. Floating Drug Delivery System (FDDS) is one of the gastroretentive dosage form that prolong Gastro Retentive Time (GRT) to obtain sufficient drug bioavailability^6-9. The system basically floats in the gastric fluid because of its lower bulk density compared to that of the aqueous medium. Floating Drug Delivery System is desirable for drugs with an absorption window in the stomach or in the upper small intestine such as furosemide and theophylline^7,10,11. It is also useful for drug that act locally in the proximal part of gastrointestinal tract such as antibiotic administration for Helicobacter Pylori eradication in the treatment of peptic ulcer^9,12-14, for drugs that are unstable in the intestinal fluid such as captopril^7,15,16, and for drugs that exhibit poor solubility in the intestinal tract such as diazepam¹⁷ and verapamil¹⁸.

Metoclopramide Hydrochloride was a drug of choice because of its high aqueous solubility, pharmacokinetic properties of variable bioavailability (50%), short plasma half life, and therapeutic interest. It is recommended for use as a potent antiemetic agent in various types of vomiting¹⁹(e.g., it is the antiemetic of choice for chemotherapy induced emesis). Metoclopramide Hydrochloride is a procainamide derivative with effects based on at least two mechanisms: first it acts in the central nervous system as an antagonist at D2 dopamine receptors; and second Metoclopramide Hydrochloride has an agonistic effect on the cholinergic systems in the stomach and gut²⁰. The result is improved gastroduodenal coordination. High doses of Metoclopramide Hydrochloride inhibit the effect of dopaminergic D₂receptors at lower doses. Because the activity of Metoclopramide Hydrochloride is dose dependent, it is important to control the quantity of drug released from the dosage form²¹.

It is evident the importance of swelling behaviour on drug release and the effect of polymers on it. The aim of this work is the evaluation of effect of percentage of polymer on the floating matrix tablet of Metoclopramide Hydrochloride and its effect on floating, Hydration behaviour and release profile of the drug from hydroxypropylmethylcellulose matrices.

MATERIALS AND METHODS:

Materials:

Metoclopramide Hydrochloride was received as a gift sample from Vaikunth Chemicals (P) Ltd. Ankleshwar, Gujarat. Hydroxypropylmethylcellulose (HPMC E50 LV; viscosity 35-65 cps) and calcium carbonate were procured from Loba Chemicals Pvt. Ltd. All other chemicals used were of analytical reagent grade, available commercially and used as such without further processing.

Methods:

Drug polymer interaction study:

The Drug polymer interaction study of metoclopramide hydrochloride with hydroxypropyl methylcellulose was done with visual inspection and DSC.

There were not any physical changes found in solid mixture of drug and polymer suggesting no interaction between drug and polymer. The observation was further confirmed by DSC study (Figure: 1, 2, 3) which gives no peaks other than drug and polymer, which show the corresponding melting point of the drug and polymer and indicating there is no any interaction between drug and polymer used.

Figure: 1 DSC curve of Metoclopramide Hydrochloride

Figure: 2 DSC curve of Hydroxypropylmethylcellulose

Figure: 3 DSC curve of Metoclopramide HCl + Hydroxypropyl methylcellulose

Preparation of floating matrix tablet of Metoclopramide Hydrochloride:

Floating matrix tablets containing metoclopramide hydrochloride were prepared by wet granulation technique using varying concentrations of polymer with calcium carbonate.

Polymers and Metoclopramide Hydrochloride were mixed homogenously using glass mortar and pestle. Starch paste was used as granulating agent. Granules were prepared by passing the wet coherent mass through a # 16 sieve. The granules were dried in hot air oven at a temperature of 60⁰C. Dried granules were sieved through # 20/44 sieves and mixed with calcium carbonate and citric acid used as gas generating agent and lubricated with magnesium stearate and talc 4-5 minutes before compression.

Lubricated granules were compressed into tablets using single punch tablet machine to obtain tablets of desired specifications.

Composition of Metoclopramide Hydrochloride matrix tablet powder for wet granulation is given in Table: 1.

Table: 1 Composition of Metoclopramide Hydrochloride matrix tablet powder for wet granulation

Ingredients	Quantity (mg) present in floating matrix tablet
Ingredients	F1	F2	F3
Metoclopramide Hydrochloride	30	30	30
Hydroxypropylmethylcellulose	80	100	120
Microcrystalline cellulose	41	21	1
Calcium carbonate	30	30	30
Citric acid	6	6	6
Mg-stearate	1	1	1
Talc	2	2	2
Starch paste	q.s.	q.s.	q.s.

Weight variation and hardness:

Weight variation test was done according to USP and hardness was measured with Monsanto hardness tester.

Buoyancy/ Floating test:

The time between introduction of dosage form and its buoyancy on the simulated gastric fluid and the time during which the dosage form remained buoyant were measured. The time taken for dosage form to emerge on surface of medium called Floating Lag time (FLT) and total duration of floatation i.e. as long the dosage form remains buoyant is called Total Floating Time (TFT).

Tablet density:

Tablet density is an important parameter for floating tablets. The tablet will float only if its density is less than that of gastric fluids (1.004). Density (d) was determined using the relationship d = m/v where v = πr²h.

Swelling study:

The swelling of the polymers can be measured by their ability to absorb water and swell. The swelling property of the formulation was determined by the reported method. For each formulation one tablet was weighed and placed in beaker containing the standard set of condition as specified for the determination of in vitro drug release. The medium was maintained at 37 ± 0.5ºC throughout the study. After a selected time interval the tablet was removed blotted to remove excess water and weighed swollen weight of each tablet was determined.

The Swelling Index (SI) was calculated using formula SI = [(W_t-W_o)/ W_o) x 100] where W_t = Weight of tablet at time t and W_o = Weight of tablet before placing in beaker containing specified media.

In vitro release Study:

Drug release studies were done by using USP XXIV basket dissolution apparatus (Electrolab-tablet dissolution tester USP-TDT-06P) at 100 rpm. The dissolution medium consisted of 0.1 N Hydrochloric acid (900ml), maintained at 37^oC ± 0.5^oC. An aliquot (5ml) was withdrawn at specified time intervals, filtered through Wattman filter paper and drug content was determined by UV-Visible spectrophotometer at 309nm for 0.1 N Hydrochloric acid medium. It was made clear that none of the ingredients used in the matrix formulations interfered with the assay. The release studies were conducted in triplicate.

RESULTS AND DISCUSSIONS:

Weight variation and assay:

The percentage weight variation of each tablet from average weight was less than 5% which proved good uniformity. The assays for drug content were found uniform among different batches of floating tablets and ranged between 90% and 110%.

Hardness:

The hardness of all formulas was kept at 4-6 kg/cm².

Buoyancy/ Floating test:

The tablet Floating Lag Time (FLT) was found to be less than 8m and Total Floating Time (TFT) more than 12h for all the formulations.

The floating lag time may be explained as a result of the time required for dissolution medium to penetrate the matrix and develop the swollen layer for entrapment of carbon dioxide generated in situ. The tablet mass decreased progressively due to liberation of carbon dioxide and release of drug from the matrix. On the other hand, as solvent front penetrated the glassy polymer layer the, the swelling of hydroxypropylmethylcellulose caused an increase in volume of the tablet. The combined effect is a net reduction in density of the tablets, which prolongs the duration of floatation beyond 12h.

Tablet density:

The tablet density was found to be uniform among different batches of floating tablets and ranged from 0.92 to 0.98 g/cm².

The tablet density is less than gastric fluid both before and after ingestion so the tablets float on the surface of the gastric fluid for as long as 12-13h.

Swelling study:

The matrices hydration volume increases at the beginning, attains a maximum and then declines. The matrices behavior can be ascribed to a natural hydration process. Hydrophilic matrices in contact with water swell and increase their volume due to water diffusion through the matrix. The polymer chains continue the hydration process and the matrix gain more water. The increasing water content dilutes the matrix until a disentanglement concentration is attained. At this point, the polymer molecules are released from the matrix, diffusing to the bulk of the dissolution medium. Then, the matrix volume decreases slowly because of polymer dissolution. Polymeric matrices experiences simultaneous swelling and polymer dissolution and diffusion. The swelling behavior of matrices is shown in Figure 4.

Figure: 4 Swelling behavior of all formulations.

It is evident from Figure 1 that swelling of matrices increases with increase in polymer concentration. Maximum swelling is seen in the formulation F3 which contains 30 mg metoclopramide hydrochloride and 120 mg of hydroxypropylmethylcellulose.

In vitro release study:

Increasing polymer contents produce decreasing drug release rates. The effect of polymer content is attributed to an increasing tortuosity and length of the diffusion path through the matrix as the polymer content increases. This can be seen in Figure 5, for matrices containing different quantities of polymer and a fixed metoclopramide hydrochloride quantity of 30 mg/tablet.

Increasing polymer proportions decrease the values of the release constant (k) while increase the values of the exponent indicative of the release mechanism predominantly controlled by diffusion toward a mechanism with a little more emphasis on relaxation, erosion and polymer dissolution as the drug release rate is restricted. This has been attributed to greater extension or exercise of hydration and dissolution of the polymeric matrix as the drug release is subject to limitation²². The increasing release restriction given by increasing hydroxypropylmethylcellulose proportions modifies the release mechanism from diffusion toward a relaxation and erosion controlled process. Every restriction of drug release is associated with an extended time of matrix exposition to dissolution medium to release a given quantity of the drug. Consequently, every release restriction in metoclopramide hydrochloride/ hydroxypropylmethylcellulose system is associated to a higher degree of matrix hydration before a given quantity of the drug is released. It means a greater contribution of matrix relaxation and erosion processes to predominate release mechanism. Moreover, by increasing water content the diffusion coefficient of the drug increases substantially²³.

The drug release data were explored for the type of release mechanism followed. Release kinetic study of all formulation (F1 to F3) was studied for different kinetic equation (zero order, first order, Higuchi equation). The best fit with higher correlation (r²> 0.979) was found with the Higuchi equation for all the formulations, which means that release of Metoclopramide HCl from the matrix system was in sustained manner. Release kinetic study was again verified by putting the values of release data in Modern Biopharmaceutic software MB-V6 and found that all the sustained release formulations follows Higuchi model. Hence we can state that release of Metoclopramide HCl from the matrix system was mainly due to diffusion mechanism.

In controlled or sustained release formulation, diffusion, swelling and erosion are the three most important rate controlling mechanisms followed. The drug release from the polymeric system is mostly by the diffusion and is best described by Fickian diffusion. But in case of formulations containing swelling polymers, other processes in addition to diffusion play an important role in exploring the drug release mechanism. These processes include relaxation of polymer chains, imbibitions of water causing polymers to swell and changing them to initial glassy to rubbery state due to swelling, considerable volume expansion, take place leading to moving diffusion and boundaries complicating the solution of Fick’s second law of diffusion (Siepmann and Peppas, 2001). So the release data were further treated by Korsmeyer-Peppas model. This model is a generalization of the observation that superposes two apparently independent mechanism of drug transport. Fickian diffusion and a case II transport describes drug release from a swelling polymer. When n takes the value 0.5 it indicates diffusion-controlled drug release and the value 1.0 indicates swelling-controlled drug release. Values of n between 0.5 and 1.0 can be regarded as an indicator for the both phenomenon (anomalous or Non Fickian transport).

Linear regression analysis and model fitting showed that all formulation followed korsmeyer-peppas model which had higher value of correlation coefficient, r². The release exponent value of all formulations (F1-F3) varies from 0.618 to 0.689, indicates Non-Fickian release or anomalous transport.

Therefore, the most probable mechanism that the release patterns of all formulations followed was non-fickian diffusion or anomalous diffusion²⁴ wherein the drug release mechanism is controlled by both diffusion as well as polymer relaxation process. Since no lag time was observed in the dissolution of any of the developed formulations, it may be inferred that the swellable polymers could not turn into gel immediately in contact with dissolution fluid, thereby giving an initial higher release rate from the tablets. However, once the gel barrier is established around the tablet, the rate of gel barrier progression became the rate-limiting factor by modulating the drug diffusibility. The rate of drug permeation out of the matrix is supposed to be proportional to the rate of solvent entry and broadening of the diffusion path length due to swelling of the matrix as a result of polymer hydration and subsequent strand relaxation. That this mechanism was operative throughout the dissolution period for all the formulations is evident from the closeness of R² values to 1, as also from the straightness of the dissolution curves.

It can be resolved from the graph obtained that F2 gives steady and desired release profile of metoclopramide hydrochloride from the hydrophilic matrices. Thus we can conclude that hydroxypropylmethylcellulose (100 mg) and metoclopramide hydrochloride (30 mg) are better than other formulations for the development of floating matrix tablet of metoclopramide hydrochloride for the sustained delivery of drug for a period of 12h.

Figure: 5 Effect of polymer content on release profile of 30 mg metoclopramide hydrochloride from different formulations.

CONCLUSION

Floating matrix tablet of an antiemetic drug metoclopramide hydrochloride can be developed as an approach to increase gastric residence time and thereby improve its bioavailability. The drug release rate from the hydrophilic matrices depends majorly on the percentage of polymer used for development of floating matrix tablet. Among the different polymer percentage used for the development of floating matrices F2 with 50% of hydroxyl propylmethylcellulose and 15% of metoclopramide hydrochloride gave better sustained drug release in comparison to other prepared formulation. All of the formulations floated for a period of more than 12h. Formulated floating tablets best fitted to Korsemeyer-Peppas model and Higuchi equation. Release of metoclopramide hydrochloride from the matrix system was in sustained manner. The release patterns of all formulations followed was non-fickian diffusion or anomalous diffusion wherein the drug release mechanism is controlled by both diffusion as well as polymer relaxation process.

REFERENCES:

1. Srimornsak P, Thirawong N, Korkerd K. Swelling and release behavior of alginate-based matrix tablets. Eur. J. Pharm. Biopharm. 2007; 66: 435-450.

2. Cedilo R, Hernandez L, Villafucrte RL. Effect of added Pharmatose DCL11 on the sustained release of Metronidazole from Methocel K4M and Carbopol 971 NF floating matrices. Drug Dev. Ind. Pharm. 2006; 32: 955-965.

3. Gutierrez SPE, Hernandez LA, Villafuerte RL. Effect of sodium bicarbonate on the properties of Metronidazole floating tablets made of Methocel K4M and Carbopol 971 NF. Drug Dev. Ind. Pharm. 2008; 34: 171-180.

4. Desai S, Bolton S. A floating controlled-release drug delivery systems: in vitro-in vivo evaluation. Pharm. Res. 1993; 10: 1321-1325.

5. Chueh HR, Zia H, Rhodes CT. Optimization of sotalol floating and bioadhesive extended release tablet formulations. Drug Dev. Ind. Pharm. 1995; 21(15): 1725-1747.

6. Whitehead L, Fell JT, Collett JH, Sharma HL, Smith AM. Floating dosage forms: an in vivo study demonstrating prolonged gastric retention. J. Control. Release. 1998; 55: 3-12.

7. Singh BN, Kim KH. Floating drug delivery systems: an approach to oral controlled drug delivery via gastric retention. J. Control. Release. 2000; 63: 235-239.

8. Arora S, Ali J, Ahuja A, Khar RK, Baboota S. Floating drug delivery systems: a review. AAPS Pharm Sci. Technol. 2005; 6(3): 372-386.

9. Bardonnet PL, Faivre V, Pugh WJ, Piffaretti JC, Falson F. Gastroretentive dosage forms: overview and special case of Helicobacter Pylori. J. Control. Release. 2006; 111: 1-18.

10. Rouge N, Buri P, Doelker E. Drug absorption sites in the gastrointestinal tract and dosage forms for site-specific delivery. Int. J. Pharm. 1996; 136: 117-139.

11. Sato Y, Kawashima Y, Takeuchi H, Yamamoto H. In vitro and in vivo evaluation of riboflavin-containing microballoons for a floating controlled drug delivery system in healthy humans. Int. J. Pharm. 2004; 275: 97-107.

12. Cooreman MP, Krausgrill P, Hengels KJ. Local gastric and serum amoxicillin concentrations after different oral application forms. Antimicrob. Agents Chemother. 1993; 37: 1506-1509.

13. Yang L, Eshraghi J, Fassihi R. A new intragastric delivery system for the treatment of Helicobacter Pylori associated gastric ulcer: in vitro evaluation. J. Control. Release. 1999; 57: 215-222.

14. Umamaheshwari RB, Jain S, Bhadra D, Jain NK. Floating microspheres bearing acetohydroxamic acid for the treatment of Helicobacter Pylori. J. Pharm. Pharmacol. 2003; 55: 1607-1613.

15. Seta Y, Higuchi F, Kawahara Y, Nishimura K, Okada R. Design and preparation of captopril sustained-release dosage forms and their biopharmaceutical properties. Int. J. Pharm. 1988; 41: 245-254.

16. Jain SK, Awasthi AM, Jain NK, Agrawal GP. Calcium silicate based microspheres of repaglinide for gastroretentive floating drug delivery: preparation and in vitro charactrization. J. Control. Release. 2005; 107: 300-309.

17. Wurster DE, Alkhamis KA, Matheson LE. Prediction of the adsorption of diazepam by activated carbon in aqueous media. J. Pharm. Sci. 2003; 92: 2008-2016.

18. Munday DL. Film coated pellets containing verapamil hydrochloride: enhanced dissolution into neutral medium. Drug. Dev. Ind. Pharm. 2003; 29: 575-583.

19. Breura ED, et. al. Comparison of the efficacy, safety, and pharmacokinetics of controlled release and immediate release metoclopramide for the management of chronic nausea in patients with advanced cancer. Cancer. 1994; 74: 3204-3211.

20. Albibi R, Mc Callum RW. Metoclopramide: Pharmacology and clinical applications. Ann. Intern. Med. 1983; 98: 85-95 .

21. Frutos P, Pabon C, Lastres JL, Frutos G. In vitro release of Metoclopramide from hydrophobic matrix tablets. Influence of hydrodynamic conditions on kinetic release parameters. Chem. Pharm. Bull. 2001; 49(10): 1267-1271.

22. Gonzalez MI, Robles VL. Effect of varying the restriction degree of 4-aminopyrimidine release from HPMC matrices on the mechanism controlling the process. Int. J. Pharm. 2003; 257: 253-264.

23. Siepmann J, Streubel A, Peppas NA. Understanding and predicting drug delivery from hydrophlic matrix tablets using the “sequential layer” model. Pharm. Res. 2002; 19: 306-314.e

24. Kim, Chemg J. Controlled release dosage form design, Lancaster: Technomic Pub; Basel. 2000.

Received on 01.04.2010

Accepted on 17.08.2010

Research Journal of Pharmaceutical Dosage Forms and Technology. 2(5): Sept. - Oct. 2010, 329-334