Intestine-Specific, Oral Delivery of Captopril/Montmorillonite: Formulation and Release Kinetics
© Madurai et al. 2010
Received: 3 July 2010
Accepted: 5 August 2010
Published: 27 August 2010
The intercalation of captopril (CP) into the interlayers of montmorillonite (MMT) affords an intestine-selective drug delivery system that has a captopril-loading capacity of up to ca. 14 %w/w and which exhibits near-zero-order release kinetics.
Captopril (CP; 1-[(2s)-3-mercapto-2-methyl propionyl]-L- proline), an orally active inhibitor of angiotensin-converting enzyme (ACE) [1, 2], is in many countries the medication of choice for the management of hypertension and is often used to treat some types of congestive heart failure [3–6]. CP contains a reactive thiol group, which is postulated to bind to the Zn2+ of the angiotensin-converting enzyme  and which forms the disulfide linkages with thiol-containing residues of plasma proteins that are responsible for the extensive tissue binding of the drug . Owing to its pKa (3.7 at 25°C), CP is highly soluble in water at acidic pH (125–160 mg/ml at pH 1.9). At pH > pKa, the amidic linkage of the molecule becomes increasingly susceptible to hydrolysis; under basic conditions, the drug exhibits a pseudo-first-order degradation reaction [9, 10].
In man, CP reduces plasma angiotensin II and aldosterone levels, increases plasma renin activity and produces a significant decrease in blood pressure in hypertensive patients . It blocks the enzyme system that causes the relaxation of artery walls, reducing blood pressure, decreasing symptoms of cystinuria and reducing rheumatoid arthritis symptoms. The duration of the antihypertensive action of a single oral dosing of CP is 6–8 h, with the implication that clinical administration requires the daily dose of 37.5–75.0 mg to be taken at 8-h intervals . The metabolic products of CP include a disulfide dimer of CP, a CP-cysteine disulfide and mixed disulfides with endogenous thio compounds . In efforts to reduce the frequency of administration, several attempts have been made to design sustained release formulations. These have included coated tablets [14–16], beadlets , hydrophobic tablets , pulsatile delivery systems , microcapsules , semisolid matrix systems , floating tablets and capsules , and bioadhesive polymers .
An evolving approach to controlled drug delivery involves the use of nanoclays with well-defined morphologies. Montmorillonite (MMT), a swelling clay mineral, is one such material that has shown considerable promise as a carrier in controlled drug delivery. Since the mineral is comprised of alternating negatively charged alumino-silicate layers with exchangeable counter ions positioned between each layer , the capability of the material to act as a controlled delivery vehicle is rationalized in terms of the potential for drug molecules to become adsorbed onto the hydrated alumino-silicate layers, which in aqueous media exist as dispersions of individual platelet. This paper describes an attempt to assess the suitability of MMT to act as a matrix for the controlled release of CP by evaluating intercalation data from three methods (solution, melt and grinding) and by considering the characteristics of CP release.
Materials and Methods
Preparation of CP-MMT Systems
Optimization of Clay Colloidal Dispersion
Solution Intercalation Method
To improve the cation exchange capacity (CEC) of the clay, MMT-K10 was treated with sodium chloride and the resultant Na-MMT dispersions were washed with deionised water (centrifugation) until a AgNO3 test confirmed that all chloride had been removed . CP (1.382, 2.765, 3.456 and 4.417 mM) was added to separate vessels containing the 5 %w/w Na-MMT aqueous dispersion (100 cm3) and maintained (stirring) at 50°C for 4 h. To remove any free drug, the intercalated particles were collected following repeated (4×; replacing the deionized water after each cycle) centrifugation (4,000 rpm, 20 min) of the dispersion. The isolated CP-MMT powder was dried in a vacuum oven, ground and stored in a desiccator. To assess the improvement in cation exchange capacity following treatment with sodium, samples of MMT were subjected to an identical procedure and used as controls.
Melt Intercalation Method
A mixture of MMT and CP (10:9 w/w) was heated (2°C/min) to the melting point of CP and maintained at that temperature for 6 h. The cooled (room temperature) residue was washed (3×) with deionised water and dried (room temperature) before use.
Grinding Intercalation Method
A mixture of MMT and CP (10:9 w/w) was ground finely (ca. 30 min) using a pestle and mortar, washed (deionised water, 3×) and dried (desiccator) before use.
In Vitro Drug Release
The simulated gastric fluid was a buffer solution (pH 1.2) that had been prepared by mixing 250 ml of aqueous HCl (0.2 M) with 147 ml of aqueous KCl (0.2 M). The simulated intestinal fluid was a buffer solution (pH 7.4) that had been prepared by mixing 250 ml of aqueous KH2PO4 (0.1 M) and 195.5 ml of aqueous NaOH (0.1 M) .
The drug release study was performed in a constant temperature bath (37°C) fitted with a rotating round-bottomed flask (100 rpm) by suspending a dialysis membrane bag containing 20 ml of CP-MMT dispersion in 900 ml of dissolution media. At specified time intervals, an aliquot (5 ml) of the dissolution medium was removed and the concentration of CP was determined by UV absorption measurements, respectively, at 205 and 217 nm for the acidic and basic buffers.
Drug Release Kinetics
To assess the kinetics of CP release, in vitro drug release data were fitted into established mathematical models.
where, Q o = initial amount of drug, Q t = cumulative amount of drug release at time t, K o = zero-order rate constant and t = time in h.
where, K1 = first-order rate constant.
where, Q = cumulative drug release at time t and K H = constant reflective of the design variables of the system.
Where, Mt/M∞ = fraction of drug released at time t, K = rate constant and n = release exponent.
Values of n between 0.5 and 1.0 are indicative of anomalous, non-Fickian, kinetics .
The concentration of CP was determined from calibration plots of absorbance (SHIMADZU UV 240 Spectrophotometer; quartz cell path length = 1 cm) at 205 nm or at 217 nm for the molecule in acidic or alkaline buffer, respectively. Infrared spectra (KBr disks) were recorded using a PERKIN-ELMER Spectrum RX1, FTIR V.2.00 spectrophotometer. X-ray diffraction (XRD) patterns were recorded using a SIEMENS D-500 variable angle diffractometer (CuKα source, λ = 1.5405 A°; 1–60°). Thermogravimetric determinations (37–800°C, 10°C/min; TA instruments TGA Q50) were carried out under nitrogen.
Results and Discussion
Basal spacings of CP-MMT systems, as determined by XRD
Drug loaded amount (mmol/g)
Interlayer distance (nm)
CP-MMT by solution
CP Release Profiles
Drug release profiles of CP-MMT systems
Drugloaded amount (mmol/g of clay)
Drug release rate (%) at
Drug Release Kinetics
Parameters for CP release at pH 1.2
Parameters for CP release at pH 7.4
CP has been confirmed to successfully intercalate into the interlayers of MMT. The maximum percentage of intercalated CP was determined as ca. 14 %w/w. In vitro release experiments have shown that the release of CP from the MMT matrix is sensitive to the pH of the dissolution media. The CP release rate in simulated intestinal fluid (pH 7.4) is significantly higher than that in simulated gastric fluid (pH 1.2) and exhibits near-zero-order release kinetics.
One of the authors (JWS) is grateful to CSIR for funding as a Project Assistant in the NWP-035 project.
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