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Transcript of DESIGN AND EVALUATION OF ENTERIC COATED MICROPOROUS ... · PDF file trolled delivery systems...

  • Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 69 No. 6 pp. 1125ñ1136, 2012 ISSN 0001-6837 Polish Pharmaceutical Society

    Psychosis, an abnormal condition of the mind, is a generic psychiatric term for a mental state which may occur throughout the day or may precipitate at any time (1). Treatment of psychosis may require continuous supply of drug to the brain. Conventional formulations may require high dosing frequency to maintain the drug within therapeutic plasma level for prolonged duration. Increased dos- ing frequency for psychotic may cause poor patient compliance, which remains a challenge to the phar- maceutical scientists. One useful approach to improve compliance is to dispense the drugs in con- trolled delivery systems like osmotic pump that releases the drugs in a controlled manner within therapeutic concentrations over a prolonged period of time and may also minimize the risk of emer- gence of potential toxicity (2).

    Microporous osmotic pump tablet (MOPT) works on the principle of osmosis, where the drug moiety moves from its higher concentration to lower concentration area until equilibrium at both sides (3, 4). The MOPT generally consists of a compartment containing drug and osmotic agents (osmogen) cov- ered with a microporous membrane (MPM) embed- ded with in situ micropores former. Water leachable

    polymers are present in MPM which get dissolved when it comes in contact with release media, creat- ing in situ micropore formation generating osmotic pressure within MOPT to release the drug in con- trolled manner (5). The advantages of MOPT, that holds a prominent place among controlled release systems, are pH independent drug release, reduced adverse reactions, improved safety profile, enhance- ment of activity duration for drugs exhibiting short half-life and good in vitro-in vivo correlation without need of mechanical drilling contrary to EOPT since the micro pores are formed in situ (6, 7).

    Quetiapine fumarate (QTF), a BCS class II drug, was chosen as a model drug. The dose of QTF was 25ñ50 mg twice to thrice in a day, then the dose was gradually increased up to 400 mg per day owing to its shorter plasma half life (6ñ8 h) (8). QTF shows pH dependent solubility ñ it is highly soluble in acidic environment, moderately soluble in water and in basic environment (9). For osmotic system, the solubility of drug should be within 50ñ300 mg/mL to attain zero order release rate (5). Thus, core needs to have sufficient osmotic pressure to deliver the drug outside. The moderate aqueous solubility of QTF is insufficient to generate very high osmotic





    Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, Varanasi-221005, India

    Abstract: The present work investigates the feasibility of the design of an enteric coated microporous osmotic pump tablet (ECMOPT) to prolong the drug release of an antipsychotic drug, quetiapine fumarate (QTF). The ECMOPT consisted of an osmotic core coated with a microporous membrane (MPM) made up of cellulose acetate and PEG 4000 as in situ micropore former. The effect of formulation variables such as concentration of sodium chloride, types of pore former (PEG 400, PEG 4000 and PEG 6000), coat thickness (100 and 200 µm) of MPM were evaluated for drug release characteristics. The FTIR, DSC and XRD analyses were carried out to characterize physico-chemical changes of powder blend and final formulation. SEM images have confirmed in situ micropores formation in MPM. A zero order release was obtained for QTF. The formulations were found to be stable up to 3 months when tested for stability at 40OC/75% RH.

    Keywords: enteric coating, microporous membrane, osmotic pump tablet, polyethylene glycol, quetiapine fumarate


    * Corresponding author: e-mail:; phone: +91-542-26702748, fax: +91-542-2368428


    pressure within the core compartment of tablet to deliver the drug by osmosis. Our system consists of a core tablet containing the drug, diluents, pH mod- ulator, osmotic agent further coated with cellulose acetate (CA) containing in situ micropore former and a final enteric coat. Citric acid has been chosen as pH modulator expecting to increase the solubility by decreasing the pH and exerting osmotic pressure within the core compartment (10). Further, to increase the release of QTF from MOPT, sodium chloride was chosen as osmotic agent, because it could generate high osmotic pressure gradient to deliver poorly or moderately soluble drugs (5). The core tablet is coated with microporous membrane (MPM; 2% w/v cellulose acetate in acetone contain- ing PEG 4000 as pore former) to form MOPT. To design and fabrication of ECMOPT, a MOPT may further be coated with enteric coating polymer (HPMCP 5.5) (Fig. 1).

    QTF is gastric irritant in nature. Among vari- ous approaches, enteric coating of formulation with pH dependent solubility is most commonly employed approach to check the release of drug in the stomach. Phthalate derivatives (HPMCP 5.5) are most commonly used coating materials which get dissolved at pH 5.5 and thus drug is exposed to duo- denal pH (> 5.5) (11). The present study was aimed towards the development of ECMOPT of QTF and to deliver a constant, predetermined amount of drug in solution form, over fixed span of time in the intes- tine and independent of the external environmental conditions. On extensive literature survey, no report has been found in the area of ECMOPT based oral drug delivery systems for QTF. The excipients used for the manufacturing of ECMOPT are GRAS (gen- erally regarded as safe) within their IIG limits (acceptable safety limits from FDA).


    Materials QTF was kindly procured from Jubilant Life

    Sciences (New Delhi, India) as a gift sample.

    HPMCP 5.5 was obtained from Ranbaxy (New Delhi, India) as a gift sample. The following chemi- cals and excipients were purchased from commer- cial sources and used as received: cellulose acetate (39.8% acetylation), polyvinyl pyrrolidone (PVP), mannitol, microcrystalline cellulose (MCC; Avicel PH101) and talc from Central Drug House (New Delhi, India). Acetone (AR grade) was purchased from Qualigens Chemicals (Mumbai, India). Dibutyl phthalate and PEG 400, 4000 and 6000 were purchased from S.D. Fine Chemicals (Mumbai, India).

    Drug ñ excipient compatibility studies Fourier Transform Infrared (FT-IR) spectroscopy

    Infrared spectra were recorded on FT-IR instrument (Shimadzu, Japan) equipped with tem- perature controlled high sensitivity DLATGS detec- tor. Samples were prepared and compressed with KBr on Minipress (Jasco, Japan) to form discs. The compressed discs were scanned over 400 to 4000 cm-1 and characteristic peaks were recorded and evaluated (12).

    X-ray diffraction (X-RD) Powder X-ray diffraction (PXRD) patterns of

    QTF and physical mixture were collected in trans- mission using an X-ray diffractometer (Rigaku, Japan) with Cu-rotating anode (radiation; λ = 1.54 nm) generated at 18 kW. Powder diffractometer operating on Bragg-Brentano geometry was fitted with a curved crystal graphite monochromator in the diffraction beam from the range of 20ñ40O (2θ). The powder was packed into the rotating sample holder (13).

    Differential scanning calorimetry (DSC) The physical state of drug in the optimized for-

    mulation was determined by measuring the thermo- grams by differential scanning calorimetry (Shimadzu DSC-50, Japan). The instrument was cal- ibrated with 5 mg of indium at a heating rate of 10OC/min. The thermal behavior was studied by

    Figure 1. Schematic diagram describing stepwise mechanism of pore formation and drug release from ECMOPT composed of MOPT, sur- rounded by enteric coating layer. Diagram also describing the release of enteric coating after it comes in contact to release media (pH > 5.5) followed by in situ micropores formation in MPM layer

  • Design and evaluation of enteric coated microporous osmotic pump... 1127

    heating 4ñ8 mg of the QTF and physical mixture of QTF and excipients at a rate of 10OC/min from 50 to 220OC in a hermetically sealed pan with a pinhole in the lid under a nitrogen purge of 20 mL/min with an empty pan as a reference (14).

    Preparation of core tablets Core tablets of QTF were prepared by wet

    granulation method. Different compositions (Table 1) of drug and excipients (except talc) were passed through no. 60 sieves and mixed together for 10 min in a glass bottle. The blend was granulated using 5% w/v solution of PVP in acetone and wet mass was passed through no. 36 mesh sieve. Granules were dried in oven at 50OC for 2 h. Dried granules were lubricated with talc (passed through no. 60 mesh sieve). Lubricated blend was compressed with aver- age weight of 300 mg on a single station tablet punching machine (Cadmach, Ahmedabad, India) fitted with 8 mm round standard concave punch (12).

    Fabrication of microporous osmotic pump tablet (MOPT)

    MOPT tablets were prepared by coating core tablets with a mixture of cellulose acetate (2% w/v), PEG 4000 (30% w/w of cellulose acetate) and ace- tone to form MPM. Conventional laboratory coating pan (Scientific Instruments, New Delhi, India) fitted with three baffles placed at angle of 120O having outer diameter of 10 cm was used. Coating process was optimized (50 tablets/batch) with the following conditions: preheating temperature, 50OC; preheat- ing time, 30 min; inlet temperature, 48ñ50OC; outlet temperature, 38ñ40OC;