Biphasic Release Characteristics Research Articles

Development and Evaluation of Drug Eluting Stent Having Biphasic Release From a Single Layer of Biodegradable Polymer

In stent restenosis is the major disadvantage of percutaneous transluminal angioplasty. To overcome this limitation, drug eluting stents were introduced. We have developed novel sirolimus eluting stent using biocompatible and biodegradable polymer matrix. Developed stent have biphasic release profile for sirolimus from a single layer of polymer matrix, having blend of slow and fast degrading polymers. Coating integrity of coated stents were evaluated after crimping and postexpansion with the help of scanning electron microscopy while thickness of coated stent was measured using destructive test method. This shows that drug-polymers bilayer was uniformly coated with the average thickness of 5.2 μms. There was no deformation after crimping and expansion of the stent. We have also measured in vitro and in vivo release profiles of sirolimus from stents which shows biphasic release characteristics, i.e., initial burst period followed by sustained release. In vitro release profile is well correlated with in vivo release in blood and arterial tissues. Developed stents showed good efficacy and safety in porcine coronary artery model.

Biphasic release of indomethacin from HPMC/pectin/calcium matrix tablet: II. Influencing variables, stability and pharmacokinetics in dogs

The pectin/calcium interaction, which is the basis for biphasic release of indomethacin from the HPMC/pectin/calcium chloride matrix tablet, is susceptible to influence of a variety of variables that is supposed to be encountered by the oral route. In this study, the effect of influencing variables on biphasic release characteristics, the stability and the pharmacokinetics of the hybrid matrix tablet were investigated. An increasing tendency of the overall release rate was observed from pH 1.2 to 7.4. The power law correlation n values increased with pH, while the release lag time or 10% release time (T0.1) decreased at pH 6.8 and 7.4. Ionic strength in the release media also influenced the biphasic release significantly at sodium chloride levels of over 0.5%. Obvious increase in overall release rate was observed at sodium chloride level of 0.9% with an n value of 1.20 and a T0.1 of 3.4h. At sodium chloride levels of over 2%, the pectin/calcium interaction was disrupted resulting in very fast release of indomethacin. Release in gradient pH media was similar to that in pH 6.8 citrate buffer. When pectinase (Pectinex Ultra SP-L) was added into the release medium in 22.2 pg/ml or over, obvious triggering on drug release was observed. The stress testing showed increased release at extreme relative humidity of 92.5%. Both accelerated testing for 6m and long-term testing for 12 m affirmed fine stability, especially in release characteristics. Pharmacokinetic study in dogs gave Tmax/Cmax of 4h/604 ng/ml and 3h/1662 ng/ml for HPMC/pectin/calcium and HPMC/pectin tablet, respectively. The plasma indomethacin level of the calcium-containing tablet was maintained at a much lower level for 3h with a MRT of 7.13 h, longer than 3.97 and 5.61 h for indomethacin crude drug and HPMC/pectin tablet, confirming delayed absorption. The AUC of the HPMC/pectin/calcium tablet was lower than that of the HPMC/pectin tablet and indomethacin crude drug showing incomplete absorption. It is concluded that the HPMC/pectin/calcium matrix tablet is potentially useful for colon-specific drug delivery.

Methylphenidate Bioavailability in Adults When an Extended-Release Multiparticulate Formulation Is Administered Sprinkled on Food or as an Intact Capsule

To determine the single-dose bioavailability of 20-mg Metadate CD (methylphenidate HCI, USP) Extended-Release Capsules sprinkled onto 1 level tablespoon (15 mL) of applesauce relative to an intact capsule under fasted conditions in healthy adults. This was a single-center, open-label, single-dose, randomized, two-way crossover study with a 6-day washout period between doses, in healthy male and female subjects (N= 26), aged 21-40 years. Plasma concentration-time data for methylphenidate were used to calculate the pharmacokinetic parameters for each treatment. The pharmacokinetic profile for Metadate CD exhibited biphasic release characteristics with a sharp initial slope and a second rising portion. For Cmax (maximum observed concentration), AUC(0-infinity) (area under the plasma concentration curve from time 0 to infinity) and AUC(0-infinity) (area under the plasma concentration curve from time 0 to the last measurable time point), the geometric least squares mean ratios and 90% confidence intervals were within the 80% to 125% confidence interval for bioequivalence. Adverse events were similar to those reported for methylphenidate. The bioavailability of methylphenidate was not altered when Metadate CD capsules were administered by sprinkling their contents onto a small amount of applesauce.

Biphasic release characteristics of dual drug-loaded alginate beads.

The dual drug-loaded alginate beads simultaneously containing drug in inner and outer layers were prepared by dropping plain (single-layered) alginate beads into CaCl2 solution. The release characteristics were evaluated in simulated gastric fluid for 2 h followed by intestinal fluids thereafter for 12 h. The surface morphology and cross section of dual drug-loaded alginate beads was also investigated using scanning electron microscope (SEM). The poorly water-soluble ibuprofen was chosen as a model drug. The surface of single-layered and dual drug-loaded alginate beads showed very crude and roughness, showing aggregated particles, surface cracks and rough crystals. The thickness of dual drug-loaded alginate beads surrounded by outer layer was ranged from about 57 to 329 microns. The distinct chasm between inner and outer layers was also observed. In case of single-layered alginate beads, the drug was not released in gastric fluid but was largely released in intestinal fluid. However, the release rate decreased as the reinforcing Eudragit polymer contents increased. When the plasticizers were added into polymer, the release rate largely decreased. The release rate of dual drug-loaded alginate beads was stable in gastric fluid for 2 h but largely increased when switched in intestinal fluid. The drug linearly released for 4 h followed by another linear release thereafter, showing a distinct biphasic release characteristics. There was a difference in the release profiles between single-layered and dual drug-loaded alginate beads due to their structural shape. However, this biphasic release profiles were modified by varying formulation compositions of inner and outer layer of alginate beads. The release rate of dual drug-loaded alginate beads slightly decreased when the outer layer was reinforced with Eudragit RS100 polymers. In case of dual drug-loaded alginate beads with polymer-reinforced outer layer only, the initial amount of drug released was low but the initial release rate (slope) was higher due to more swellable inner cores when compared to polymer-reinforced inner cores. The current dual drug-loaded alginate beads may be used to deliver the drugs in a time dependent manner.

Formulation strategies designed to maintain the biphasic release characteristics of liquid-filled capsules

Formulation strategies have been developed to prevent the intermixing and consequent loss of biphasic release characteristics during prolonged storage of a drug delivery system (HALO TM) comprising liquid-filled capsules containing a rapid-release phase of oleic acid and propranolol base, and a sustained-release phase of an erodible matrix of the above. In one approach, a hydrophilic Gelucire ® phase barrier was inserted between the rapid and sustained-release formulation components, while in an alternative approach, a hydrophobic Gelucire ® was added to the rapid-release phase, solidifying it at temperatures below 37°C. Maintenance of the biphasic dissolution characteristics at pH 6.8, and acid resistance of the enteric coat were monitored by sensitive and discriminating dissolution methods at a variety of storage temperatures for up to 2 years. The importance of retaining the biphasic release characteristics of the formulation to ensure the greatly enhanced bioavailability of lipophilic drugs administered using the HALO TM delivery system is discussed.

An in vitro assessment of liquid-filled capill® potato starch capsules with biphasic release characteristics

This paper describes the first use of liquid-filled Capill® potato starch capsules formulated for biphasic release and reports the development of dissolution methods suitable for assessment of drug release from this type of dosage vehicle. The liquid filling of Capill® capsules was made possible by overcoming the problem of incomplete sealing of the Capill® cap and body which initially resulted in leakage of liquid capsule contents. This was achieved by modification of the formulation to incorporate a thermosoftening agent which remained solid below 30°C, but melted at 37°C. The use of enteric-coated liquid-filled Capill® capsules formulated for biphasic release required further development of the dissolution method to incorporate a dissolution medium containing bile acids at a concentration of 14 mM to produce a similar release profile to that seen from enteric-coated hard gelatin capsules containing the same formulation. The concentration of bile salts used is in agreement with the acceptable range previously validated for use with enteric-coated hard gelatin capsules whilst also remaining within the physiological levels of bile acids found in vivo.

Development and validation of an in vitro dissolution method for a floating dosage form with biphasic release characteristics

The present study describes the development of a dissolution method for a floating dosage form using HALO TM-propranolol capsules containing propranolol base dissolved in oleic acid. A modified paddle dissolution method in which the paddle blades were set to the surface of the dissolution medium was shown to be effective for assessing HALO TM-propranolol capsules, characterised by having both rapid release and sustained release properties. The standard paddle or basket methods described in the British Pharmacopoeia (1993) were unable to provide either sufficient mixing of the dissolution medium to disperse the oily rapid release material or sufficient mechanical erosion of the sustained release component of the formulation. Further studies showed that the modified paddle method resulted in reproducible biphasic-release dissolution profiles when paddle speeds were increased from 70 to 100 rpm and the dissolution medium pH varied from pH 6.0 to 8.0. Dissolution performance was adversely affected by temperatures below 36.8° C but unaffected up to a temperature of 37.5° C. Increasing the bile acid concentration in the dissolution medium from 7 to 14 mM did not alter the dissolution profile. The physiological implications of these results are discussed.

A study of enteric-coated liquid-filled hard gelatin capsules with biphasic release characteristics

Studies were carried out using enteric-coated, liquid-filled hard gelatin capsules with biphasic rapid and sustained release characteristics, containing 80 mg of propranolol in a novel HALO ™ drug delivery formulation designed to avoid hepatic first-pass metabolism. The disintegration at pH 1.0 of HALO ™-propranolol capsules, coated with different levels (3–12 mg/cm 2) of enteric polymer (methacrylic acid copolymer, type A USP/NF) was visually assessed using the disintegration test for enteric-coated capsules described in the BP 1988. Quantification of propranolol release, at pH 1.0, from enteric-coated capsules was carried out using a dissolution procedure based on the USP XXII method. The results of the study showed that significant release of propranolol (> 10%) could take place at low coating levels (3 mg/cm 2) without visible breakdown of the enteric coat. In a further study, enteric-coated HALO ™-propranolol capsules coated with 4 mg/cm 2 of enteric polymer were stored under a variety of conditions for up to 18 months. Dissolution and disintegration studies showed that under conditions of low temperature storage (4°C) HALO ™-propranolol capsules released significant amounts ( > 10%) of propranolol at pH 1.0 without visible breakdown of the enteric coat. Dissolution studies carried out at pH 6.8 following acid challenge demonstrated that inadequate enteric protection greatly affected the subsequent sustained-release dissolution profile of HALO ™-propranolol capsules. The present investigation demonstrates the importance of ensuring a sufficient enteric-coating level for oral dosage vehicles to maintain post gastric dissolution characteristics and illustrates the need for a reliable means of assessing enteric coat performance in vitro.