Pharmaceutical Technology: Controlled Drug Release, Volume 2

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17 Formulation of silicone matrix systems for long-term constant release of peptides Matthais Hoth Parmazeutische Technologie, Universität Bonn, D-Bonn, FRG Hans P.Merkle Eidgenössiche Technische Hochschule, Pharmazeutisches Institut, CH-Zürich, Switzerland SUMMARY Theoretically, release of drug through the water-filled pores of matrix systems is expected to show a square-root-of-time dependence, with a time exponent of 0.5 and hence continual declining release rates. However, there have been many research groups finding remarkable deviations. The aim of this work was to investigate factors which lead to deviations from the t 1/2 law and may be helpful for the development of matrix systems with constant drug release. Matrices of polydimethylsiloxane (PDMS) were prepared incorporating varying amounts of different porebuilding, water-soluble hydrogels. The hydrophilic model drug was Gly-Tyr. The following factors influencing the long-term release profiles were found: (i) total matrix loading, (ii) its dissolution rate and (ii) the viscosity of the pore-building hydrogel. A proper choice of conditions lead to release profiles with time exponents up to 0.8 for at time period of several weeks. INTRODUCTION Long-term controlled release of drugs from inert matrices has been subject of numerous scientific investigations (e.g. refs. [1–7]). The easily manufactured release systems may be applied as subcutaneous implants in humans and for veterinary use. They are helpful in many other areas too, for instance in agriculture [8].
184 CH. 17] SILICON MATRIX SYSTEMS FOR LONG-TERM CONSTANT RELEASE OF PEPTIDES THEORY As for long-term release a comparatively high drug dose is required, drug concentration in the device will in most cases far exceed matrix solubility. Theoretical considerations may therefore be reduced to suspension-type matrix systems [9,10]. Dealing with the release of a peptide, or generally hydrophilic, water-soluble drugs, drug release will occur by pore diffusion. The pores may be part of the matrix itself or they may be formed in situ, as drug particles are leached out by the penetrating aqueous medium [11]. Provided that (i) water penetration and drug dissolution are much faster than pore diffusion and (ii) matrix pores are only built in situ, while (iii) matrix diffusion be negligible, time-dependent release is described by. (1) where M is the amount of drug released, F is the surface in contact with release medium, A, the drug concentration in matrix (matrix loading), ε the porosity of the matrix, C s the drug solubility in matrix pores, τ the tortuosity factor of matrix pores and D the diffusion coefficient of drug in matrix pores. Unfortunately, the t 1/2 dependence described by equation (1) is inconvenient especially for longterm drug delivery as release rates decline with time. On the other hand, there are numerous publications on matrix-type release systems showing remarkable deviations from the expected t 1/2 law (Table 1). Deviations are mainly observed when water-soluble drugs are delivered. It may further be noticed that presumably most of the corresponding experiments are based on the use of PDMS as the matrix polymer. As indicated by Table 1, in many cases matrix swelling is suggested to be the reason for the unexpected release profiles. Di Colo et al. [15] showed that water uptake into the matrix may indeed have a strong influence on release kinetics. MATERIALS, METHODS The following materials were used: Matrix polymer: PDMS (Silastic ® 382 Medical Grade Elastomer, Dow Corning Corp., Midland, MI); Matrix embedding: PDMS (Silastic ® MDX-4–4210 Medical Grade Elastomer, Dow Corning Corp., Midland, MI); Pore-building, hydrophilic excipient: hydroxyethylcellulose (HEC), viscosity grades of 2% aqueous solution 300, 6000, 30000 mPas, (Natrosol ® 250 G, H, M, Hercules BV, Den Haag, The Netherlands); Pore building, hydrophilic excipient: bovine serum albumin (Sigma Chemical Company, St. Louis, MO) of high and low dissolution rates (the dissolution rate of the product could be reduced by special treatment); Model drug: Gly-Tyr (Fluka AG, Buchs, Switzerland). <strong>Drug</strong> and excipients were sieved to obtain a particle size between 45 and 90 µm. The model drug Gly-Tyr and excipient were thoroughly dispersed in Silastic ® 382 plus curing agent. Dispersions were quickly transferred to a mould. After curing (24 h, 40°C), a sheet of 1.5 mm thickness was
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PHARMACEUTICAL TECHNOLOGY Controlle
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3 TABLET MACHINE INSTRUMENTATION IN
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First published in 1991 by ELLIS HO
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1 Influence of drug solubility in t
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CH. 1] INFLUENCE OF DRUG SOLUBILITY
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CH. 6] CONTROLLED RELEASE MATRIX TA
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7 A new ibuprofen pulsed release or
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CH. 7] A NEW IBUPROFEN PULSED RELEA
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90 CH. 8] TOPICAL RELEASE AND PERME
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118 CH. 10] CONTROLLED DELIVERY OF
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126 CH. 11] THE EFFECT OF FOOD ON G
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128 CH. 11] THE EFFECT OF FOOD ON G
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Pharmaceutical Technology: Controlled Drug Release, Volume 2

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