Local Drug Delivery Strategies for Cancer Treatment: Gels, Nanoparticles, Polymeric Films, Rods, and Wafers

Critical factors in the release of drugs from sustained release hydrophilic matrices

In addition to a number of highly soluble drugs, most new chemical entities under development are poorly water-soluble drugs generally characterized by an insufficient dissolution rate and a small absorption window, leading to the low bioavailability. Controlled-release (CR) formulations have several potential advantages over conventional dosage forms, such as providing a uniform and prolonged therapeutic effect to improve patient compliance, reducing the frequency of dosing, minimizing the number of side effects, and reducing the strength of the required dose while increasing the effectiveness of the drug. Solid dispersions (SD) can be used to enhance the dissolution rate of poorly water-soluble drugs and to sustain the drug release by choosing an appropriate carrier. Thus, a CR-SD comprises both functions of SD and CR for poorly water-soluble drugs. Such CR dosage forms containing SD provide an immediately available dose for an immediate action followed by a gradual and continuous release of subsequent doses to maintain the plasma concentration of poorly water-soluble drugs over an extended period of time. This review aims to summarize all currently known aspects of controlled release systems containing solid dispersions, focusing on the preparation methods, mechanisms of action and characterization of physicochemical properties of the system.

Controlled Release Systems Containing Solid Dispersions: Strategies and Mechanisms

Characterization of poly(vinyl acetate) based floating matrix tablets.

A new plant gum, Okra (extracted from the pods of Hibiscus esculentus), has been evaluated as a controlled-release agent in modified release matrices, in comparison with sodium carboxymethyl cellulose (NaCMC) and hydroxypropylmethyl cellulose (HPMC), using Paracetamol as a model drug. Tablets were produced by direct compression and the in-vitro drug release was assessed in conditions mimicking the gastro intestinal system, for 6 h. Okra gum matrices provided a controlled-release of Paracetamol for more than 6 h and the release rates followed time-independent kinetics. The release rates were dependent on the concentration of the drug present in the matrix. The addition of tablet excipients, lactose and Avicel, altered the dissolution profile and the release kinetics. Okra gum compared favourably with NaCMC, and a combination of Okra gum and NaCMC, or on further addition of HPMC resulted in near zeroorder release of paracetamol from the matrix tablet. The results indicate that Okra gum matrices could be useful in the formulation of sustained-release tablets for up to 6 h.

Matrix properties of a new plant gum in controlled drug delivery.

Purpose: The present study was under- taken to investigate the effect of plastic, hydrophilic and hydrophobic types of polymers and their content level on the release profile of drug from matrix systems. As the physico-chemical nature of the active ingredients influence the drug retarding ability of these polymers, three different drugs were used to evaluate their comparative release char- acteristics in similar matrices. Methods: Matrix tablets of theophylline, diclofenac sodium and diltiazem HCl using Kollidon SR, Carnauba wax and Hydroxypropyl methylcel- lulose (HPMC-15cps) were prepared separately by direct compression process. The USP Basket method was selected to perform the dissolution test carried out in 250 ml 0.1N HCl for first two hours and 1000 ml phosphate buffer of pH 6.8 for ten hours. Results: Statistically signif- icant differences were found among the drug release pro- file from different classes of polymeric matrices. The release kinetics was found to be governed by the type and content of polymer in the matrix system. Higher polymeric content (75%) in the matrix decreased the release rate of drug because of increased tortuosity and decreased poros- ity. At lower polymeric level (25%), the rate and extent of drug release was elevated. Carnauba wax was found to cause the strongest retardation of drug. On the otherhand, highest drug release was from HPMC matrices while Kolli- don SR gave an intermediate release profile between these two polymers. Release rate was also found to be the func- tion of physico-chemical nature of drug molecule. Theo- phylline and diltiazem HCl, being soluble in nature, released faster than diclofenac sodium from all matrix sys- tems. The release mechanism was explored and explained with biexponential equation. Release profile showed a ten- dency to follow zero-order kinetics from HPMC matrix systems whereas Fickian (Case I) transport was predomi- nant mechanism of drug release from Kollidon SR matrix system. The mean dissolution time (MDT) was calculated for all the formulations and the highest MDT value was obtained with Carnauba wax for all the drugs under inves- tigation. Conclusions: The results generated in this study showed that the profile and kinetics of drug release were functions of polymer type, polymer level and physico- chemical nature of drug. A controlled plasma level profile of drug can be obtained by judicious combination of poly- mers and modulation of polymer content in the matrix system.

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Comparative evaluation of plastic, hydrophobic and hydrophilic polymers as matrices for controlled-release drug delivery.

Polymeric films of Eudragit RS 100 were prepared by solvent casting method to explore the possibilities of using this polymer in transdermal therapeutic system (TTS). Naproxen was used as a model drug and incorporated in two different percent loading (8.3 % w/w and 20.8 % w/w of films). Effects of two plasticizers ( PEG 1500 and PEG 4000) and two release modifiers ( PVA and HPMC 15cps) on in vitro drug release from naproxen loaded eudragit RS films were assessed. Drug release was found to be a function of drug load, PEG molecular weight and physico-chemical property of the release modifiers incorporated. At low drug load, highest amount of drug was released from flims containing PEG 1500 (more than 95%). However, a burst release was evident in case of all the experimental batches except that loaded with HPMC 15 cps. With this formulation, more than 75 % of active principle was released after 8 hours while only 12 % of naproxen was liberated in the first hour of dissolution. Increasing drug load, increased the rate and extent of drug release from eudragit RS films; however this effect was minimized when PEG 4000 was used as release modifier. For PEG 1500 loaded films, drug release was decreased with increasing drug concentration in the TTS. Inclusion of PEG in eudragit RS films caused the drug to be released by diffusion (Fickian) kinetics whereas PVA and HPMC containing formulations released drug by diffusion mechanism coupled with erosion. Key words: Naproxen sodium, Eudragit RS 100, Controlled release.

Dhaka Univ. J. Pharm. Sci. Vol.3(1-2) 2004

The full text is of this article is available at the Dhaka Univ. J. Pharm. Sci. website

Controlled Release of Naproxen Sodium from Eudragit RS 100 Transdermal Film

The aim of the current study was to formulate Fexofenadine hydrochloride loaded sustained release microspheres using HPMC K100 M CR, a release retardant hydrophilic polymer by solvent evaporation method. The effect of different drug loading on drug content, drug encapsulation efficiency and release of drug was monitored. The studies on in vitro release mechanism were performed using USP paddle method with 900 ml of phosphate buffer (pH 6.8) for 10 h at 100 rpm. The mechanism of the drug release was determined by fitting in vitro release data to various release kinetic models such as the zero order, first order, Higuchi, Hixson Crowell and Korsemeyer–Peppas model and finding R2 values for the release profile corresponding to each model. The results confirm that the release rate of the drug from the microspheres is highly affected by the drug to polymer ratio. The study finds that Higuchi release kinetics, Korsmeyer–Peppas release kinetics and Hixson–Crowell release kinetics were the major release mechanism. The release mechanism was found to be non-Fickian with increase of polymer content. Scanning electron microscopic technique was performed to obtain the morphological changes due to different drug loading. Differential scanning calorimetry and Fourier transform infra-red spectroscopy was performed to determine any interaction of drug with the polymer. A statistically significant variation in release rate was observed for variation in the amount of HPMC K100 M CR. In the present study, a series of sustained release formulations of Fexofenadine hydrochloride were developed with different drug loading so that these formulations could further be evaluated from the in vivo studies. The formulations were found to be stable and reproducible.

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Design, characterization and in vitro evaluation of HPMC K100 M CR loaded Fexofenadine HCl microspheres.

Digital watermarking system is a paramount for safeguarding valuable resources and information. Digital watermarks are generally imperceptible to the human eye and ear. Digital watermark can be used in video, audio and digital images for a wide variety of applications such as copy prevention right management, authentication and filtering of internet content. The proposed system is able to protect copyright or owner identification of digital media, such as audio, image, video, or text. The system permutated the watermark and embed the permutated watermark into the wavelet coefficients of the original image by using a key. The key is randomly generated and used to select the locations in the wavelet domain in which to embed the permutated watermark. Finally, the system combines the concept of cryptography and digital watermarking techniques to implement a more secure digital watermarking system.

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An Approach of Digital Image Copyright Protection by Using Watermarking Technology

Diclofenac sodium loaded agarose beads were prepared and release profile of Diclofenac Sodium was investigated. Beads were prepared by dropping a hot aqueous agar solution into a beaker of chilled Paraffin oil and water. Water was made acidic to the pH of 1.65 using concentrated hydrochloric acid to reduce the prior diffusion of Diclofenac sodium into preparatory vehicle. Upon drying, the beads shrank and their dimensions were changed. In-vitro drug dissolution studies were carried out in distilled water. The release profile was found to be a function of polymer load and electrolytes incorporation into the beads. Increasing the polymer load decreased the rate and extent of drug release due to increased thickness and reduced the porosity of the system. Incorporation of mono & divalent metal salts by abating the amount of agarose in the formulations increased the release rate of the drug.

 Key words: Diclofenac Na, Agarose bead, Electrolyte

Dhaka Univ. J. Pharm. Sci. Vol.4(2) 2005

The full text is of this article is available at the Dhaka Univ. J. Pharm. Sci. website

Md. Selim Reza

Papers

Comparative evaluation of plastic, hydrophobic and hydrophilic polymers as matrices for controlled-release drug delivery.

Controlled Release of Naproxen Sodium from Eudragit RS 100 Transdermal Film

Design, characterization and in vitro evaluation of HPMC K100 M CR loaded Fexofenadine HCl microspheres.

An Approach of Digital Image Copyright Protection by Using Watermarking Technology

Effect of Electrolytes on Release of Diclofenac Sodium from Agarose Beads