Microporous and Mesoporous Materials 102 (2007) 290–298 www.elsevier.com/locate/micromeso
Low density porous carrier based conceptual drug delivery system Praveen Sher a
a,*
, Ganesh Ingavle b, Surendra Ponrathnam b, Atmaram P. Pawar
a
Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune 411038, Maharashtra State, India b Department of Polymer Science and Engineering, National Chemical Laboratory, Pune 411008, India Received 14 November 2006; received in revised form 27 December 2006; accepted 4 January 2007 Available online 14 January 2007
Abstract Chronotherapy, a new approach for treating pathological conditions, is based on circadian rhythm. Present work conceptualizes a specific technology, based on combining floating and pulsatile principles to develop drug delivery system, intended for chronotherapy in arthritis. This approach was achieved by using low density microporous polypropylene, Accurel MP 1000, as a multiparticulate carrier along with drug of choice ibuprofen. Carrier amount and solvent volume was kept invariant in designing this simple system by adsorbing drug via melting or solvent evaporation using different carrier: drug ratios. In solvent evaporation, methanol (M) and dichloromethane (DCM) were used. Drug loaded multiparticulate system was subjected to various characterization and evaluation parameters showing influence of adsorption process. Drug release study was performed in acidic environment using pH 1.2 HCl IP medium for 6 h to mimic gastric condition for evaluating gastroretention followed by basic environment using appropriate medium as phosphate buffer pH 7.2 IP for 3 h resembling transit. The release pattern showed influence of drug adsorption methods characterized by ever changing pore geometry with total release ranges in acidic medium as 10.7–27.6% and final release as 55.6–88.6%. Present drug delivery system devoid of any additives/excipients influencing drug release show distinct behaviour from other approaches/technologies in chronotherapy by (a) observing desired low drug release (11%) in acidic medium (b) overcoming the limitations of process variables caused by multiple formulation steps (c) reducing time consumption due to single step process (d) can be extended to controlled release also. 2007 Elsevier Inc. All rights reserved. Keywords: Low density porous carrier; Melt adsorption; Solvent polarity; Floating pulsatile drug delivery; Chronotherapy
1. Introduction Over the past three decades, with continuous research aiming towards underlying principle that can bring both commercial and therapeutic values to health care products, novel drug delivery systems were introduced. In solid oral dosage forms single or multiple units are primarily formulated with latter being more advantageous. Among the various materials employed in developing these systems, polymeric materials play a vital role thereby provide most important avenues for research and commercial applications. Numerous formulation techniques along with excipients are constantly discovered and exploited in modifying
*
Corresponding author. Tel.: +91 20 254 37237; fax: +91 20 2543 9383. E-mail address:
[email protected] (P. Sher).
1387-1811/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.micromeso.2007.01.001
these systems to transfer maximum benefits to patient. High end techniques experience various difficulties during formulating like coating core particles for modulating drug release with thin polymer films using a fluidized bed or centrifuge granulator for drug loading. To overcome these difficulties there has been increasing interest in the use of porous material as the drug loading core which behave as carriers [1]. Porous carriers form an integral part of various dosage forms. They are characterized by several attractive features, such as stable uniform porous structures, high surface areas, tunable pore sizes with narrow distributions, and well-defined surface properties, thus allowing them to adsorb certain kinds of drugs and release these drugs in a more reproducible and predicable manner [2]. Porous network is important in determining both natural and practical applications such as dissolution, adsorption and diffusion of drugs [3]. Porous carriers in formulations help
P. Sher et al. / Microporous and Mesoporous Materials 102 (2007) 290–298
to reduce dusting, improve flowability, influence direct compression or modify release by coating or incorporation of release modifying agents [4]. Type and extent of interaction with water characterize them as either hydrophobic or hydrophilic. Examples of pharmaceutically exploited porous carriers include porous silicon dioxide (Sylysia 550, 320), polypropylene foam powder (Accurel) [5–7], porous calcium silicate (Florite) [8], magnesium alumino metasilicate (NeusilinS2, NS2 N, US2) [9], porous ceramic [10], CaCO3 [11] to name a few. Novel drug delivery systems work on various principles by providing variable/constant drug amounts over a particular time period in our body based on the fact that physiologic parameters display constancy over a time [12]. However, a new concept which is contrary to the above popular belief, termed as chronotherapy has been introduced. Chronotherapy considered as a drug delivery regime is based on the circadian rhythms. Circadian rhythms by definition are endogenous in nature, driven by oscillatory or clocks and persist under free running conditions. In humans these rhythms affect the heart rate, body temperature, blood flow properties and various other body functions thereby expressing its influence over a particular pathological condition, as already cited in literature. Numerous studies conducted give convincing evidence that pharmacokinetics, drug efficacy and side effects can be modified by following therapy based on circadian time i.e. timing the drug application within the given time. These timings, when correlated with specific pathological disorder, point towards time specificity for delivering higher amounts of drug instantly to achieve maximum drug effect [13–17]. Morning stiffness associated with pain at the time of awakening is a diagnostic criterion of the rheumatoid arthritis and these clinical circadian symptoms are supposed to be outcome of altered functioning of hypothalamic–pitutary–adrenocortical axis [18,19]. Chronopharmacotherapy has been recommended for rheumatoid arthritis to ensure that the highest blood levels of the drug coincide with peak pain and stiffness [20]. This easily leads to serious drawbacks considering the patient compliance as well as the choice and characteristics of dosage form. In order to nullify this ‘ideally’ a dosage form that can be administered at night (before sleep) so as to release maximum drug in early morning would be a promising chronotherapeutic system. In our previous communication we were successful in developing this ‘ideal’ system using new concept by applying floating and pulsatile principles together in formulating a multiparticulate system using hydrogels with non-steroidal anti inflammatory drug (NSAID) [21]. In these formulations floating time contributed two major significances as (a) ensuring the retention of the dosage form in stomach for extended period (b) simultaneous least release during this period resembling lag phase suited for these types of drugs to avoid gastric irritation. Various methods based on different approaches [22–27] and technologies like OROS, CONTIN, CEFORM, TIMERx [28], etc. have been developed for chronother-
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apy. These systems are mostly formulated by using various polymers in combination or alone, multiple coatings, excipients and above all numerous process parameters assisted by various equipments to achieve desired drug release profile. These lead to various process variables and also time consumption which are always a source of concern. These concerns also hold true for our developed approach of combining floating and pulsatile principle to formulate delivery system for chronotherapy using NSAID with hydrogels. The objective of this study was to develop an excipients free multiparticulate drug delivery system intended for chronotherapy using our approach wherein a higher amount of drug would be available after an initial lower release, thus delivering a time-dependent amount of drug in the body. The technology for the development of such a system was based on the use of low density porous material to overcome/limit the variations of above described systems. Ibuprofen, categorized as NSAID, was selected as model drug because it is used in the treatment of arthritis which shows circadian variation. One step drug loading process was done by two different techniques as melt and solvent evaporation. Methanol and dichloromethane were selected as solvents. Non-loaded and drug loaded microparticles were characterized for practical yield, drug content, surface morphology by scanning electron microscopy (SEM), for crystallinity by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD), for porosity by BET method, interaction by FTIR, thermogravimetric analysis (TGA). We presumed 6 h as the maximum gastric floating time to evaluate the concept of floating followed by 3 h in basic medium for developing intended drug delivery system. 2. Experimental 2.1. Preparation of drug loaded beads Ibuprofen was loaded onto the porous beads by melt and solvent evaporation. Accurel MP 1000 microparticles selected were sieved in the range of 250–350 lm in order to get a narrower range for uniform distribution of the particles. For solvent evaporation different amounts of drug dissolved in 3 ml of both the solvents were taken in a beaker followed by the addition of 100 mg of Accurel MP 1000, stirred very gently externally at intervals, till the solvent evaporated under ambient conditions. In melt method, the drug was melted in a beaker using a cryostatic bath, Hakke Germany, for maintaining a constant temperature (73 C) and Accurel MP 1000 was dispersed into it with mild stirring and then allowed to cool to ambient temperature. A series of samples were made by varying the drug to Accurel MP 1000 as shown in Table 1. Accurel MP 1000, a generous gift from Membrana Germany, are low density polypropylene microporous carrier polymer powder with a characteristic size
