Thursday, December 16, 2010
Hydrodynamically Balanced Systems
Hydrodynamically Balanced Systems
Sheth and Tossounian developed an HBS system containing a homogeneous mixture of drug and the hydrocolloid in a capsule, which upon contact with gastric fluid acquired and maintained a bulk density of less than 1, thereby being buoyant on the gastric contents of stomach until all the drug was released. The HBS is the novel dosage form, which when in contact with gastric fluid and after dissolution of the outer exposed surface of the dosage form, forms a hydrated gel layer and maintains bulk density less than 1 g/cm 3 Thus, this system remains buoyant in the gastric fluid inside the stomach for 6 h. Conventional dosage form disintegrate completely within 60 min and are emptied totally from the stomach shortly afterward. This dosage form releases the drug through the hydrated layer by diffusion principle. This system is valuable for drugs, which are soluble at lower pH and have absorption window in the upper GIT. By varying the composition of the excipient between 20% and 75% w/w of one or more gel-forming hydrocolloids such as hydroxyethylcellulose, hydroxypropylcellulose, HPMC and sodium carboxymethylcellulose, the granules are prepared and compressed into tablets or encapsulated into capsules, which results in the desired release rate of the drug. This hydrated gel controls the rate of solvent penetration into the device and the rate of drug release from the device.
In the early 70's, Michaels first introduced floating drug delivery device with self-activated mechanism for retaining the device in the stomach, which released the drug under controlled osmotic pressure. The device was found to consist of two chambers, one for the drug reservoir and the other for the osmogen. In the stomach the gastric fluid dissolves the osmogen, which creates pressure on the drug reservoir compartment. This pressure tends to reduce the total volume of drug reservoir compartment, thereby leading to the continuous release of the drug material from the device. In another attempt, Michaels sustained the release of drug in stomach by incorporation of liquid such as ether in an inflatable chamber. In the gastric fluid, the chamber inflates and retains the drug reservoir in stomach. The drug solutes are continuously released from the reservoir into the gastric fluid. Harrigan  formulated a drug delivery device with a chamber, which contained vacuum or filled with air or harmless gas. This made the dosage form to float in gastric fluids. The fluids enter the microporous aperture, dissolve the drug and carry the drug solutes out of the drug delivery system for absorption.
Later, Mao et al.  prepared oral controlled-release system of metoprolol (M-HBS) with first-order in vitro release kinetics. The gamma scintigraphy (GS) study indicates that after oral ingestion, M-HBS was retained in human stomach for longer time (5-6 h) than the conventional metoprolol tablet (1-1.5 h). The values of t max and C max were 5.247 h and 125.1 ng/ml, respectively. Moreover, the fraction of the dose absorbed from M-HBS in vivo is well correlated with dissolution rate in vitro.
Sawicki formulated 40 mg verapamil floating tablet, which had a C max of 28.27 ng/ml, t max 3.75 h and AUC 364.65 ng/ml h, whereas the conventional tablets have 33.07 ng/ml, 1.21 h and 224.22 ng/ ml h, respectively. Thus, the formulation had higher AUC and Ke, and therefore had a sustained release pattern.
A HBS-controlled drug delivery tablet of miocamycin was developed by Diao et al The GS study after oral ingestion showed that miocamycin HBS remained in human stomach for more than 7 h, which is much longer than the conventional tablet (3-4 h). The in vitrorelease characteristics showed first-order kinetics. The serum concentration time course of miocamycin HBS exhibited typical sustained release characteristics.
Krogel et al.investigated the release behavior of the different devices as a function of HPMC viscosity grade, HPMC content, type of drug (chlorpheniramine maleate or ibuprofen), matrix weight, position of the matrix within the polymeric cylinder, addition of various fillers (lactose, dibasic calcium phosphate or microcrystalline cellulose) and agitation rate of the release medium. The drug release increased with a reduced HPMC viscosity grade, higher aqueous drug solubility, decreased HPMC content and increased surface area of the matrix. The release was fairly independent of the agitation rate, the position of the tablet within the polymeric cylinder and the length of the cylinder. With the pulsatile device, the lag time prior to the drug release could be controlled through the erosion rate of the matrix.
Wu et al. prepared a solid dispersion of nimodipine with poloxamer 188 and added excipients (HPMC and PEG 6000) to formulate floating-sustained release tablet. Increasing the HPMC content and decreasing PEG 6000 content led to decrease in nimodipine release in vitro. The optimized formulation showed gastric residence time (GRT) of 5 h under fed condition, while GRT was only 3 h under fasting condition. GRT of nimodipine conventional tablet under fed and fasting conditions was 3 and 2 h, respectively. Relative bioavailability of nimodipine floating tablet was 391.46% and GRT over twice that of nimodipine conventional tablet, which appeared to have prolonged GRT and improved bioavailability. Similarly, captopril floating tablets were prepared by Nur et al. using HPMC (4000 and 15,000 cps). With this the release profile of captopril from floating tablets could be apparently prolonged and as a result, a 24-h controlled-release dosage form of captopril could be achieved.
Furosemide (FR) is a weakly acidic drug and has a greater absorption window on the upper GIT. The bioavailability was enhanced by Ozdemir et al. by preparing an inclusion complex of FR with beta-cyclodextrin (beta-CD) in a 1:1 proportion using the kneading method. After adding the excipients, floating tablets were prepared, which showed retention time of 6 h and AUC of about 1.8 times of the conventional dosage form. Similarly, Menon ] observed around 15% increase in the bioavailability of FR by preparing monolithic modified release dosage form. Klausner et al. reported the absorption phase of levodopa (narrow absorption window) was significantly prolonged following gastroretentive dosage forms (GRDF) administration in comparison with Sinemet CR, which was solely depended on size and rigidity of the novel GRDF.
For the treatment of Helicobacter pylori-associated peptic ulcers a floating device was formulated by Yang et al. with triple drug regimen (tetracycline, metronidazole and bismuth salt). HPMC and poly (ethylene oxide) were the major rate controlling polymeric excipients. Tetracycline and metronidazole were incorporated into the core layer of the triple layer matrix for controlled delivery, while bismuth salt could be included in one of the outer layers for instant release. Results demonstrated that sustained delivery of tetracycline and metronidazole over 6-8 h could be easily achieved while the tablet remained in floating state.
Eight healthy volunteers were observed in a pharmacokinetic and hemodynamic study by Hou et al. of diltiazem floating tablet. Floating tablets showed that the t½ (6.4 ± 4.4 h) and C max (56 ± 23 ng/ml) were longer and lower than normal tablets as (2.3 ± 1.1 h and 96 ± 30 ng/ml, P < 0.01), respectively.Streubel et al. prepared floating microparticles consisting of (i) Polypropylene foam powder; (ii) verapamil HCl as model drug; and (iii) Eudragit RS, ethylcellulose (EC) or polymethyl methacrylate (PMMA) as polymers and were prepared with oil in water solvent evaporation method. The microparticles exhibited good in vitro floating behavior. The drug release rate increased with increasing drug loading and with decreasing polymer amounts