Controlling Drug Release Through Osmotic Systems - Pharmaceutical Technology

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Controlling Drug Release Through Osmotic Systems
Osmotic systems offer versatility for delivering drugs with varied properties and dosage requirements.

Pharmaceutical Technology
Volume 37, Issue 7, pp. 40-44

Asymmetric membrane capsules in application
An asymmetric membrane capsule for controlled release of terbutaline sulfate was recently described by Gobade et al. (29). The drug is a beta agonist used in the treatment of asthma. The oral dosage regimen of terbutaline sulfate is 5 mg twice or three times daily. The plasma half-life is approximately 3–4 hours. The asymmetric membrane was prepared using ethyl cellulose as the polymer and sorbitol as the pore-forming agent. Dissolution studies showed that the formulation provided zero-order drug release over a 12-hour period.

Philip and Pathak developed a nondisintegrating, controlled-release, asymmetric membrane capsule of ketoprofen and evaluated the in vitro and in vivo correlation of the formulation (30). Ketoprofen is a nonsteroidal anti-inflammatory drug, used in treatment of rheumatoid arthritis, osteoarthritis, and musculoskeletal disorders. Multiple dosing is required to achieve and maintain therapeutic concentration because of its short half-life (4.2 h) and poor solubility. The asymmetric membrane capsule was made of ethyl cellulose and glycerol. Sodium chloride was used as an osmotic agent and citric acid as a solubilizer. The formulation provided controlled release of ketoprofen and the half-life of the drug was prolonged for more than 16 hours. In vivo pharmacokinetic studies showed excellent level A correlation (r2 > 0.99), demonstrating that the in vitro drug-release profile of ketoprofen from the asymmetric membrane capsule could be used to accurately predict the in vivo performance.

A double-membrane system of cefadroxil using ethyl cellulose as the inner membrane and cellulose acetate phthalate as the outer membrane has been developed by Philip et al. (31). The asymmetric membrane in a membrane capsule was prepared on glass pins using a two-step phase-inversion process. The first step was to form a nondisintegrating, asymmetric membrane capsule and the second step involved formation of a pH-sensitive, disintegrating, asymmetric membrane formed over the nondisintegrating membrane. This double-membrane formulation was able to delay the release of cefadroxil for the first two hours in the gastric medium and provide controlled release in the intestinal medium for an extended 12-hour period. Drug release was independent of pH and agitation intensity and followed zero-order release kinetics.

More recently, Garg et al. reported on the development of asymmetric membrane capsules with two compartments for simultaneous delivery of two poorly soluble antihypertensive drugs, atenolol and amlodipine (32). Scanning electron microscopy showed a dense outer region and a porous inner region of the asymmetric membrane before dissolution. Pore size of the outer and inner layers increased after dissolution. Buffering agents were used to increase the solubility of atenolol and amlodipine. The formulation followed zero-order release kinetics, which was not affected by the agitation intensity of the dissolution fluid. Drug release was dependent on the diffusion rate of the drug across the membrane and the osmotic pressure. The effect of membrane thickness on dissolution fluid entering the asymmetric membrane capsule showed that as the membrane thickness increased, the volume of dissolution fluid entering into the system decreased.

A gastroretentive asymmetric membrane capsule of famotidine was recently developed by Guan et al. (33). The drug is used for the treatment of duodenal, gastric and peptic ulcers. It has a relatively short half-life (3 h) and a low bioavailability (45–50%). Increasing gastric residence time would allow the drug to penetrate through the gastric mucus layer and produce a more pronounced effect. Polyethylene oxide was used as floating agent in the formulation. Pharmacokinetic studies in beagle dogs showed that the gastroretentive asymmetric membrane capsule displayed complete drug delivery with zero-order release kinetics and a 12-hour floating time. The system had the ability to prolong drug action, minimize dosing frequency, and reduce the average peak plasma concentration.

Chauhan et al. also reported on the design of a floating asymmetric membrane capsule for site-specific delivery of ranitidine in a controlled manner (34). Ranitidine was given 150 mg twice daily or 300 mg once daily as an oral dosage form. Dosing has to be increased to 150 mg 4–5 times a day for the treatment of endoscopically diagnosed erosive esophagitis. The conventional formulations could only inhibit acid secretion for up to 5 hours, hence, requiring frequent dosing, which would cause fluctuations of drug levels in the plasma. The aim was to develop a buoyant asymmetric capsule with density less than the gastric fluid for controlled release of ranitidine in the gastric cavity. The capsule shell was prepared by the phase-inversion process wherein the polymeric membrane was precipitated on glass pins by dipping them in a solution of cellulose acetate followed by quenching. The solubility of ranitidine was suppressed by the ion effect, using optimized coated sodium chloride crystals as a formulation component. Drug release with zero-order kinetics was achieved and the asymmetric membrane capsule demonstrated floating ability for up to 12 hours.

Osmotic systems will continue to play an important role in controlled-release drug delivery for decades to come. Today, there is available a wide range of osmotic drug-delivery systems that can be adapted to various drug properties and dosage requirements. The area of controlled-release remains a challenge, but advances in technology promise bright prospects for the future of healthcare.


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