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Influence of Silicone Elastomer Solubility and Diffusivity on the in Vitro Release of Drugs from Intravaginal Rings

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Influence of Silicone Elastomer Solubility and Diffusivity on the in Vitro Release of Drugs from Intravaginal Rings Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings Malcolm, K., Woolfson, D., McAuley, L., Russell, J., Tallon, P., & Craig, D. (2003). Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings. DOI: 10.1016/S0168- 3659(03)00178-0 Published in: Journal of Controlled Release Document Version: Publisher's PDF, also known as Version of record Queen's University Belfast - Research Portal: Link to publication record in Queen's University Belfast Research Portal General rights Copyright for the publications made accessible via the Queen's University Belfast Research Portal is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The Research Portal is Queen's institutional repository that provides access to Queen's research output. Every effort has been made to ensure that content in the Research Portal does not infringe any person's rights, or applicable UK laws. If you discover content in the Research Portal that you believe breaches copyright or violates any law, please contact [email protected]. Download date:09. Sep. 2018 Journal of Controlled Release 90 (2003) 217–225 www.elsevier.com/locate/jconrel I nfluence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings Karl Malcolm* , David Woolfson, Julie Russell, Paul Tallon, Liam McAuley, Duncan Craig School of Pharmacy, Queen’s University of Belfast,97Lisburn Road, Belfast, Northern Ireland, BT97BL UK Received 17 January 2003; accepted 1 April 2003 Abstract The in vitro release characteristics of eight low-molecular-weight drugs (clindamycin, 17b-estradiol, 17b-estradiol-3- acetate, 17b-estradiol diacetate, metronidazole, norethisterone, norethisterone acetate and oxybutynin) from silicone matrix- type intravaginal rings of various drug loadings have been evaluated under sink conditions. Through modelling of the release data using the Higuchi equation, and determination of the silicone solubility of the drugs, the apparent silicone elastomer diffusion coefficients of the drugs have been calculated. Furthermore, in an attempt to develop a quantitative model for predicting release rates of new drug substances from these vaginal ring devices, it has been observed that linear relationships exist between the log of the silicone solubility of the drug (mg ml21 ) and the reciprocal of its melting point (K21 ) (y 5 3.558x 2 9.620, R 5 0.77), and also between the log of the diffusion coefficient (cm2 s21 ) and the molecular weight of the drug molecule (g mol21 ) (y 520.0068x 2 4.0738, R 5 0.95). Given that the silicone solubility and silicone diffusion coefficient are the major parameters influencing the permeation of drugs through silicone elastomers, it is now possible to predict through use of the appropriate mathematical equations both matrix-type and reservoir-type intravaginal ring release rates simply from a knowledge of drug melting temperature and molecular weight. 2003 Elsevier Science B.V. All rights reserved. Keywords: Silicone; Intravaginal ring; Drug delivery; Diffusion coefficient; Solubility Abbreviations: BKC, benzalkonium chloride; CLIN, clin- damycin free base; E2, 17b-estradiol; E3A, 17b-estradiol-3-ace- 1 . Introduction tate; EDA, 17b-estradiol-3,17-diacetate; IVR, intravaginal ring; MET, metronidazole; NET, norethisterone; NETAc, norethis- Intravaginal rings (IVRs) are elastomeric drug terone acetate; OXY, oxybutynin free base; A, drug loading per 23 23 delivery devices specifically designed to provide unit volume (mg cm ); CSIL, solubility in silicone oil (mg cm ); 2 21 controlled and sustained released of substances to the DSIL, apparent silicone diffusion coefficient (cm s ); log Ko/w, log of the octanol–water partition coefficient; Q, cumulative vagina of the human female for either local or release per unit area (mg cm22 ); R, gas constant (J K21 mol21 ); systemic effect (Fig. 1) [1–4]. Since the IVR con- T , drug melting temperature (K); DH , drug lattice dissociation mdcept was first established in 1970 [5–7], most of the energy (J mol21 ) *Corresponding author. Tel.: 144-28-9027-2319; fax: 144-28- research has focused on the development of steroid- 9024-7794. releasing rings, for either contraceptive [1–9] or E-mail address: [email protected] (K. Malcolm). hormone replacement therapies [10–14]. As a result, 0168-3659/03/$ – see front matter 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0168-3659(03)00178-0 218 K. Malcolm et al. / Journal of Controlled Release 90 (2003) 217–225 steroids which permits relatively rapid molecular diffusion. Specifically, drug release has been shown to depend primarily on the silicone elastomer dif- fusivity (DSIL) and the silicone elastomer solubility (CSIL) of the drug molecule, as described by cumula- tive release Eqs. (1) and (2) for matrix and reservoir- type devices, respectively [10,16,18–20] ]]]]]] Q 5œDSIL(2A 2 C SIL)Ct SIL (1) DC Q 5?]]SIL SIL] t (2) hsheath where Q is the cumulative amount of drug released per unit area of device (mg cm22 ), A is the drug 23 loading (mg cm ), CSIL is the solubility of the drug 23 in silicone elastomer (mg cm ), DSIL is the dif- fusivity of the drug in the elastomer (cm2 day21 ), hsheath is the thickness of the sheath layer (cm) and t is the time (days). However, the IVR platform might also be effectively employed to deliver nonsteroidal molecules, having the requisite physicochemical characteristics, for a range of other therapies within women’s healthcare. Yet, to date, the only nonsteroi- dal drugs evaluated for IVR administration are oxybutynin for the treatment of urinary incontinence [21,22], nonoxynol-9 as a potential anti-HIV vaginal microbicide [23], and bromocryptine mesylate for the treatment of hyperprolactinaemia [24]. The pre- conception still persists that silicone IVRs are only suitable for the administration of steroidal molecules Fig. 1. (A) Silicone intravaginal ring; (B) X-ray image showing for contraceptive and hormone replacement position of silicone intravaginal ring positioned in the human therapies. female. Although a significant body of work has been published to date on the development, application three steroidal IVR products have now reached the and clinical testing of IVRs, no attempt has yet been market: Estring (17b-estradiol; Pharmacia and Up- made to develop a model for predicting drug release john), Menoring (17b-estradiol-3-acetate; Galen rates. In fact, only a small number of publications Holdings), and Nuvaring (etonogestrel and ethinyl have been reported in the scientific literature which estradiol; Organon). Much of the IVR literature focus on the major parameters influencing IVR relates to crosslinked poly(dimethylsiloxane), or release rates, namely polymer solubility and dif- silicone devices, although other elastomeric poly- fusivity [10,14,16,18,19,25]. Such a model would be mers have been employed in recent years e.g. a particularly useful tool in evaluating the potential poly(ethylene–co-vinyl acetate) and styrene– for new drug substances to be effectively released butadiene block copolymers [15–17]. Silicone, in from a silicone IVR device. Necessarily, any predic- particular, lends itself well to the release of steroid tive model should be based on real IVR release data, molecules, a consequence of the relatively high and is likely to be based on certain physicochemical solubility of steroids in the hydrophobic silicone and properties of the drug substances themselves. In the relatively low molecular weight/volume of the order to elucidate the relative importance of these K. Malcolm et al. / Journal of Controlled Release 90 (2003) 217–225 219 physicochemical parameters, the solid drugs of this (silica gel, eluent. ethyl acetate–hexane, 25:75) study were selected to represent permeants having a yielded 16.04 g of estradiol-3,17-diacetate (94% range of molecular size and hydrophilic/lipophilic yield, m.p. 120–121 8C). The chemical structure was characteristics. In this study, the solubility and confirmed by13 C-NMR, FT-IR and HPLC. 13 C- diffusivity factors influencing the controlled release NMR: C=O signals, 169.38 and 170.36 ppm (cf. of a range of steroidal and nonsteroidal molecules E3A, 169.40 ppm); FT-IR: C=O peaks, 1733.9 and from silicone IVRs have been determined, and a 1766.5 cm21 (cf. E3A, 1734.0 ppm). model has been developed that will allow qualitative assessment of the potential to release new drug 2 .3. High-performance liquid chromatographic substances from silicone IVR devices. analysis HPLC assays were developed to quantify in vitro 2 . Materials and methods drug release from the IVRs (Section 2.5) and to measure the solubility of the drugs in poly(di- 2 .1. Materials methylsiloxane) fluid (Section 2.6). Details of the HPLC assays are summarized in Table 1 for each 17b-Estradiol (E2) was obtained from Schering drug. The HPLC instrumentation (Shimadzu, Kyoto, Health (West Sussex, UK). 17b-Estradiol-3-acetate Japan) consisted of a model SIL-10AXL autoin- (E3A) was synthesized under GMP conditions by jector, a model SCL-10A system controller, a model Irotech (Cork, Ireland). Metronidazole (MET) was LC-10AT solvent delivery module, a model FCV- supplied by Mediolast Spa (Milan, Italy). Norethis- 10AL low-pressure gradient-flow valve, a model GT- terone (NET) and norethisterone acetate (NETAc) 154 degassing unit, and a model SPD-10A UV–Vis were supplied by Galen Holdings (Larne, Northern detector. Injection volumes were 10 ml. Ireland, UK). Clindamycin (CLIN) was obtained from Lek (Ljubljana, Slovenia). Oxybutynin free- 2 .4. Preparation of matrix-type intravaginal rings base was supplied by Orgamol (Evionnaz, Switzer- land). HPLC grade tetrahydrofuran, ethyl acetate and Matrix rings containing various drug loadings (50, GPR grade hexane were purchased from LabScan 125, 250, 500 and 1000 mg) of CLIN, E2, E3A, (Dublin, Ireland).
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