The Development of a Floating Drug-Delivery System for Metronidazole - Pharmaceutical Technology

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

The Development of a Floating Drug-Delivery System for Metronidazole
The authors developed a metronidazole-based floating drug-delivery system to investigate the effect of rate-controlling polymers on release pattern and duration of buoyancy in matrix tablets.


Pharmaceutical Technology
pp. 41-44

Sustained-release dosage forms enable prolonged action of a drug in the body. Much research has focused on overcoming the short residence times and unpredictable gastric emptying times of drugs in sustained-release oral drug-delivery systems (1). A floating drug-delivery system floats in the gastric juice without affecting the gastric emptying rate. It forms a cohesive gel barrier that serves as a reservoir and releases the drug over the desired period of time. This technique helps increase a drug's gastric residence time and reduces the variability in bioavailability (2, 3).

Metronidazole is used as an antibiotic, amebicide, and antiprotozoal, and as a gel preparation for dermatological conditions (4–8). The drug has a wide therapeutic index for sustained-release administration (5). For example, a sustained-release oral dosage form of metronidazole is an effective antibiotic because it is locally active in the gastric mucosa (9). The prolonged effect of locally active metronidazole increases its clinical efficacy at eradicating Helicobacter pylori (10). Oral, sustained-release metronidazole has several advantages for treating H. pylori locally through systemic absorption (11).

Metronidazole was chosen as a model drug to develop a sustained-release floating matrix tablet because it has a half life of 6–8 h. Methocel K15M CR (hydroxypropyl methylcellulose, Dow Chemical) is beneficial in controlling drug release in a floating formulation, but Carbomer 934P (carboxy polymethylene–prop-2-enoic acid, ChemIndustry) enables more floating time than Methocel K15M CR and hydroxypropyl cellulose (HPC) (12).

Materials

Metronidazole BP was obtained from Aarti Drugs. Methocel K15M CR with a molecular weight of 10–1,500 kDa, HPC, and Carbomer 934P were obtained from Eskayef Pharmaceuticals. ChemIndustry provided 1-ethenylpyrrolidin-2-one (povidone). Sodium bicarbonate, citric acid, lactose, and magnesium stearate were provided by Wiechers and Helm.

Methods

Preparation of standard curve. A standard curve of metronidazole hydrochloride was constructed by serially diluting an aqueous solution of the drug to obtain the concentration in the range of 1–20 g/mL using simulated gastric fluid without enzymes and phosphate buffer as the diluents. The spectrophotometric analysis was performed using a Shimadzu spectrophotometer at the absorbance of 278 nm against a blank for each solution. The measured absorbance, plotted against the respective concentration of the standard solutions, appeared as a straight line.

Preparation of tablets. Metronidazole tablets were prepared using rate-controlling polymers and other gas-generating excipients. Each formulation contained 400 mg of metronidazole, 100 mg of sodium bicarbonate as a gas-generating agent, 30 mg of citric acid, 70 mg of povidone, and 160 mg of lactose.


Table I: Properties of tablets containing Methocel K15M CR, hydroxypropyl cellulose (HPC), and Carbomer 934P in a metronidazole-based tablet formulation.
Polymers and excipients with various concentrations (see Table I) were mixed together by pestle carefully for 20 min. Next, 1.5% (w/w) of magnesium stearate was rubbed with the punch and die as lubricant. Each tablet was 50% (w/w) metronidazole powder. Tablets were prepared by direct compression using a 13-mm die and flat-faced punch (KBR Press). Sufficient compression load was applied to produce tablets with a hardness of 6–17 kg.

A 32 randomized full-factorial design was used to design the formulations. Three factors were evaluated in this study at three levels and tested in nine possible formulations. The amounts of polymers were determined as independent variables, and percentage release as a dependent variable.


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
FDASIA was signed into law two years ago. Where has the most progress been made in implementation?
Reducing drug shortages
Breakthrough designations
Protecting the supply chain
Expedited reviews of drug submissions
More stakeholder involvement
Reducing drug shortages
27%
Breakthrough designations
9%
Protecting the supply chain
41%
Expedited reviews of drug submissions
9%
More stakeholder involvement
14%
View Results
Jim Miller Outsourcing Outlook Jim Miller Health Systems Raise the Bar on Reimbursing New Drugs
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerThe Mainstreaming of Continuous Flow API Synthesis
Jill Wechsler Regulatory Watch Jill Wechsler Industry Seeks Clearer Standards for Track and Trace
Siegfried Schmitt Ask the Expert Siegfried SchmittData Integrity
Sandoz Wins Biosimilar Filing Race
NIH Translational Research Partnership Yields Promising Therapy
Clusters set to benefit from improved funding climate but IP rights are even more critical
Supplier Audit Program Marks Progress
FDA, Drug Companies Struggle with Compassionate Use Requests
Source: Pharmaceutical Technology,
Click here