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

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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, clindamycin 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,

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 cumulative 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 diffusivity 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 nonsteroidal 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). Benzalkonium chloride (BKC, EDA, MET, NET, NETAc and OXY were manufac- 50% aqueous solution), acetic anhydride and di- tured by reaction injection moulding according to the methylpolysiloxane (viscosity, 20 cSt.) were pur- following standard method. A standard silicone chased from Aldrich–Sigma (Poole, Dorset, UK). elastomer mix was prepared by mixing together 51.2 MED-6382 silicone elastomer base and tetrapropox- g tetrapropoxysilane and 2048.8 g MED 6382 ysilane crosslinker were supplied by Nusil Technolo- silicone elastomer base. The base consisted of a gy (Carpinteria, CA, USA). Stannous octoate was mixture of high- and low-molecular-weight hydroxy- obtained from Air Products and Chemicals (Penn- terminated silicones (Mn 5 10 000 and 2000, respec- sylvania, PA, USA). tively) and 25% (w/w) of the micronised reinforcing filler diatomaceous earth. The required amount of 2 .2. Synthesis of estradiol-3,17-diacetate drug was added to and intimately mixed with 30.0 g of the silicone mix. Stannous octoate (0.5%, w/w) Freshly distilled acetic anhydride (4.95 g, 0.048 was then added, the elastomer mixture hand-mixed mol) and anhydrous zinc chloride (0.03 g, 0.0002 for 30 s with a spatula and then injected via a mol) were added to a solution of E3A (15.02 g, disposable 60-ml plastic syringe into the stainless 0.048 mol) in 120 ml of sodium-dried and distilled steel moulds of a laboratory-scale, electrically-heated tetrahydrofuran. The solution was refluxed for 5 h IVR reaction injection moulding machine specifically before removing the solvent to yield a crude white designed for the manufacture of intravaginal rings powder. Purification by column chromatography (Technigal Division of Galen Holdings, Craigavon, 220 K. Malcolm et al. / Journal of Controlled Release 90 (2003) 217–225

T able 1 Details of HPLC assays for drugs Drug Column Mobile phase Flow-rate Det.l Retention (ml/min) (nm) (min)

CLIN Hypersil ODS BDS CH3 CN–0.02 M buffer, 1.0 210 5.29 4.63150 mm, 5 mm pH 5–water (25:44:31)

E2 Sphereclone ODS2 CH32 CN–H O (50:50) 1.5 220 2.36 4.63150 mm, 5 mm

E3A Hypersil ODS BDS CH32 CN–H O (50:50) 1.5 220 5.84 4.63150 mm, 5 mm

EDA Sphereclone ODS2 CH32 CN–H O (90:10) 1.0 220 2.96 4.63150 mm, 5 mm

MET Hypersil ODS BDS CH3 CN–0.02 M buffer, 1.0 277 2.13 4.63150 mm, 5 mm pH 5.0 (20:80)

NET Sphereclone ODS2 CH32 CN–H O (50:50) 1.5 220 2.78 4.63150 mm, 5 mm

NETA Sphereclone ODS2 CH32 CN–H O (50:50) 1.5 220 5.05 4.63150 mm, 5 mm

OXY Luna ODS CH3 CN–0.02 M buffer, 1.5 220 2.00 4.63150 mm, 5 mm pH 5.0 (45:55)

UK). The injection mixes were cured at 80 8C for 2 2 .6. Determination of drug solubility in silicone oil min producing elastomeric silicone rings weighing 10.260.1 g and having the following dimensions: Approximately 100 mg of each drug was added to 7.5 mm cross-sectional diameter, 43.0 mm internal 3.0 ml of 20 cSt poly(dimethylsiloxane) fluid. After diameter, 58.0 mm external diameter. The surface equilibration for 72 h in a shaking orbital incubator area (using equation s 5 4 p 2bc where s is surface at 37 8C, the saturated silicone solutions were filtered area, b is the cross-sectional radius and c is the at 37 8C (Nalgene cellulose acetate filters, 0.2 mm) external radius) and volumes (using v 5 2p 22bc) of and 1.0 ml of the silicone filtrate was then extracted the IVRs were calculated to be 37.4 and 7.01 cm3 , with 50 ml of the relevant mobile phase (Table 1). respectively. Drug solubilities in silicone (CSIL) were then determined using the HPLC assays already described for each drug substance (Section 2.3). 2 .5. Drug release studies

The steroid-containing rings were individually 3 . Results and discussion placed in stoppered 250-ml conical flasks containing 100 ml of a 1% (w/w) aqueous BKC solution. For The solid, micronised, pharmaceutical grade drugs CLIN, MET and OXY release experiments, 100 ml employed in this study were incorporated into the of 0.02 M phosphate buffer, pH 5.0, was employed. silicone elastomer base at various loadings and cured The release mediums were selected to maintain sink at an elevated temperature produce IVRs containing conditions over a 24-h release period. The flasks a homogeneous dispersion of the drug within the were shaken for 14 days in an orbital incubator matrix environment of the crosslinked silicone elas- (Sanyo Gallenkamp Model IOX400.XX2.C, 60 rpm, tomer. The rings thus displayed typical matrix-type, 37 8C, 32 mm orbit diameter) with samples taken and diffusion-controlled release characteristics where release medium replaced fully every 24 h. Release mean daily drug release was proportional to drug studies were performed in triplicate. concentration, as exemplified in Fig. 2 for norethis- K. Malcolm et al. / Journal of Controlled Release 90 (2003) 217–225 221

Fig. 3. Cumulative release per unit area (Q) versus root time Fig. 2. Fourteen-day daily release profiles of norethisterone from profile for norethisterone matrix-type intravaginal rings of various matrix-type intravaginal rings of various drug loadings. j, 50 mg; drug loadings. j 50 mg; ♦, 125 mg; m, 250 mg; d, 500 mg; *, ♦, 125 mg; m, 250 mg; d, 500 mg; *, 1000 mg. 1000 mg. terone-loaded IVRs. Similar matrix-type release pro- of the drugs investigated. The trend in increasing files were obtained for the other drug-loaded IVRs. release rates was CLIN,E2,NET,MET,E3A, The release profiles are characterized by an initial NETAc,EDA,OXY. Entirely similar trends were burst followed by a gently decreasing daily release. observed for the other drug loadings. The standard deviation for each mean daily release Acetylating the 3-hydroxyl and 17-hydroxyl data point (n53) is smaller than the height of the groups of E2 and NET, respectively, provided sig- plot symbols (coefficient of variance ,2%) and error nificantly faster release rates than the corresponding 1/2 bars have therefore been omitted. This high degree parent steroid. For E3A, the Q/t flux rate was of reproducibility in in vitro studies is typical for some 7 times greater that for E2, while NETAc IVRs produced in our laboratory, which are manu- provided a 4.5-fold enhancement over NET. A factured by reaction injection moulding on a labora- further increase in the flux rate is observed for EDA. tory-scale ring making machine using precision-en- The trend in release amongst the structurally-similar gineered stainless steel moulds identical to those steroids seems to relate to the number of hydroxyl used in the commercial manufacturing process. groups within the steroids-E2, NET, E3A, NETAc According to the Higuchi equation [Eq. (1)], and EDA have 2, 1, 1, 0 and 0 hydroxyl groups, diffusion-controlled release from matrix-type IVRs 1/2 should produce linear Q versus t cumulative T able 2 release profiles having a gradient equal to Flux rates of drugs from 250- and 1000-mg loaded matrix-type 0.5 [DCSIL SIL(2A 2 C SIL)] , as exemplified for intravaginal rings norethisterone IVRs in Fig. 3. IVRs loaded with the Drug Q/t1/2 (mg cm22 t2 /2 ) other drug substances displayed entirely similar 250 mg IVR 1000 mg IVR profiles. The linear correlation coefficient, r 2, for the 14-day Q/t1/2 profiles was .0.995 for each IVR CLIN 0.063 0.138 formulation except the 50 mg NETAc and 50 mg E2 0.120 0.269 E3A 0.847 1.778 EDA rings where drug exhaustion of the matrix was EDA 1.117 2.326 2 evident beyond day 10. However, r .0.997 over 10 MET 0.278 0.658 day release profiles for these rings. The cumulative NET 0.252 0.535 release flux rates (Q/t1/2) for the 250- and 1000-mg NETAc 1.139 2.255 drug-loaded rings are presented in Table 2 for each OXY 3.069 6.893 222 K. Malcolm et al. / Journal of Controlled Release 90 (2003) 217–225

polar molecule in the hydrophobic silicone elastomer. Values of Q 2 /t, obtained by squaring the line gradients from the Q versus t1/2 plots (Fig. 3), were

then plotted against (2A 2 CSIL), producing a straight-line correlation of gradient DCSIL SIL accord- 2 ing to Eq. (1). The linear Q /t versus (2A 2 CSIL) plot for the NET rings is presented in Fig. 4. Matrix IVRs containing the other drug substances produced 2 similar straight-line Q /t versus (2A 2 CSIL) plots 2 (r .0.993), the gradient product DCSIL SIL of which are presented in Table 3. The trend in increasing

magnitude of the DCSIL SIL values (CLIN,E2, NET,MET,E3A,NETAc,EDA,OXY) reflects Fig. 4. Linear relationship between Q 2 /t and (2A 2 C ) for the trend observed for increasing release flux rates SIL 1/2 norethisterone matrix-type intravaginal rings, with line gradient Q/t (Table 2). equal to DCSIL SIL, according to the Higuchi equation. Having arrived at an experimentally derived value for the product of the diffusion coefficient and the solubility of the drug in silicone elastomer, a value respectively. Based on the previous discussion de- for the diffusion coefficient may be easily calculated scribing the parameters influencing release of drugs if the solubility of the drug in silicone can be from silicone systems, the increases in drug release measured. Several methods for determining the rate as a result of mono- or diacetylation can be silicone solubility of compounds have been reported attributed to an increase in the drug solubility in the in the literature, including (i) the use of a low- silicone elastomer (CSIL) and/or an increase in the molecular-weight/low-viscosity silicone oil as a silicone elastomer diffusion coefficient (DSIL). It is surrogate for silicone elastomer [10,18,19,26,27], (ii) likely that the former proposition is correct since the differential scanning calorimetry [28], (iii) dynamic rate of molecular diffusion, and thus release, is mechanical analysis [19], and (iv) diffusion of drug expected to be slower for the larger acetylated from a saturated drug solution into a thin film of derivatives. silicone elastomer [16]. The silicone oil method was It is also interesting to note that the relatively adopted in this study owing to its simplicity. The small molecular weight/size of MET did not trans- solubility of each drug in silicone oil at 37 8C(CSIL) late into the fastest release rate, suggesting that its is presented in Table 3. The trend in increasing release rate from the silicone IVR might be largely solubility is E2.MET.CLIN.NET.E3A. determined by the limited solubility of this relatively NETAc.EDA.OXY. It is apparent that the differ-

T able 3 Physicochemical, intravaginal ring release, silicone diffusion and silicone solubility characteristics of drugs

Drug Melting mw DCSIL SIL C SIL(37 8C) D SILlog D SIL substance point (8C) (g mol21 ) (mg cm21 day21 ) (mg cm232 ) (cm s212 ) (cm s21 ) CLIN 142 425 0.00008 0.009 1.0331028 26.99 E2 175 272 0.00038 0.004 1.1031026 25.96 E3A 137 314 0.01715 0.237 8.3831027 26.08 EDA 125 356 0.02976 1.310 2.6331027 26.58 MET 159 171 0.00246 0.006 4.7531026 25.32 NET 203 298 0.00151 0.015 1.1731026 25.93 NETAc 161 340 0.02829 0.655 5.0031027 26.30 OXY 57 357 0.21764 11.249 2.2431027 26.65 K. Malcolm et al. / Journal of Controlled Release 90 (2003) 217–225 223 ences observed in the IVR release characteristics of the various steroids (Table 2) are largely attributed to the differing silicone solubilities of these compounds. Clearly, acetylation of the hydroxyl groups of E2 and NET enhances silicone elastomer solubility. The relatively polar metronidazole and clindamycin (log Ko/w 0.0 and 2.0, respectively, compared with higher values of 3.9, 4.0, 5.0, 3.0, 4.0 and 4.0 for E2, E3A, EDA, NET, NETAc and OXY, respectively [29–31]) and the presence of two free hydroxyl groups in E2 contribute to their limited solubility in the hydrophobic silicone. Interestingly, the results suggest that acetylating metronidazole at its free hydroxyl group may produce a pro-drug with signiﬁcantly enhanced silicone solubility and hence increased release rate compared to metronidazole Fig. 5. Linear relationship between the logarithm of the silicone itself, a pro-drug approach that has already been solubility and the reciprocal of the drug melting temperature. successfully adopted in the development of Galen Holdings’ estradiol-3-acetate IVR [10,18]. The dramatic differences observed in the silicone surface for temporary Langmuir adsorption and solubilities of the drug molecules can be attributed to creating a more tortuous diffusion pathway [33–35]. the variations in chemical structure/functionality. The diffusion coefﬁcient values range from 131028 According to the theory described earlier, the disso- to 5310262 cm s21 and are similar to those reported lution of a drug crystal in a polymer composition can for other diffusants in silicone elastomer systems be considered to consist of a dissociation step [36–39]. The diffusion process can be considered as followed by a dissolution step. The former requires a a ‘jumping’ mechanism wherein a solubilised penet- dissociation energy and is dependent upon the melt- rant molecule spends long periods of time (up to 1 ing temperature of the drug, according to Eq. (3) ns) located within a pocket of free volume (a void) [20,32] within the polymer structure before a temporary DH channel opens up with a neighbouring pocket. If the log C 5 constant 1 ]]d] (3) penetrant has a suitable velocity it may jump be- p 2.303RT m tween the two pockets of free volume via the where Cp is the mole fraction solubility of the drug, channel. The channel then closes and the permeant is DHd is the drug lattice dissociation energy, R is the entrapped within a different void. It is the rate and gas constant, and Tm is the drug melting temperature. distance of this jumping motion that governs the rate The exponential relationship between the silicone of diffusion [40,41]. Intuitively, the molecular size/ solubility and the reciprocal of the melting point for volume of the diffusant is likely to be an important the drugs of this study is demonstrated in Fig. 5. factor in this diffusional process. Accordingly, a

From the values of DCSIL SILand C SIL (Table 3), linear relationship (R50.952) between the log of the the apparent silicone diffusion coefficients (DSIL) of apparent silicone diffusion coefficient (Table 3) and the drugs in silicone have been calculated (Table 3). the relative molecular weight for each drug substance The silicone diffusion coefficient is described as was observed (Fig. 6). Importantly, the graph allows ‘apparent’ in recognition of the fact that the diffu- the diffusion coefficient of any drug in MED-6382 sional process does not take place though a pure silicone elastomer to be predicted with a reasonable silicone polymer; the silicone elastomer base used to degree of accuracy based solely on a knowledge of manufacture the IVRs includes a diatomaceous earth its molecular weight. (Of course, the diffusion reinforcing filler which is known to influence the rate coefficient will vary for other silicone elastomer of diffusion of the permeating species by providing a formulations, which may have different degrees of 224 K. Malcolm et al. / Journal of Controlled Release 90 (2003) 217–225

developed that will allow the prediction of daily flux rates for any new drug substance based solely on a knowledge of the molecular weight and melting temperature of the drug. Specifically, linear relationships were observed between the experimentally determined silicone diffusion coefficient and the drug molecular weight, and between the log of the experimentally determined silicone solubility and reciprocal melting temperature of the drug. The results will enable researchers to evaluate the potential of releasing new drug entities at therapeutic amounts from core and matrix type IVR devices.

A cknowledgements Fig. 6. Linear relationship between the logarithm of the silicone diffusion coefficient and the drug molecular weight. This work was supported by the European Re- gional Development Fund, the European Social Fund crosslinking and different amounts and types of filler and Galen Holdings plc. incorporated.) For maximum permeation rates in silicone intravaginal rings, small and hydrophobic drugs work best. However, the study clearly demonstrates that R eferences small, hydrophilic drug molecules, such as metronidazole, or relatively large hydrophobic drugs, [1] R.K. Malcolm, The intravaginal ring, in: M. Rathbone (Ed.), Modified-Release Drug Delivery Technology, Marcel such as oxybutynin, may be released effectively from Dekker, New York, 2003, pp. 775–790. a silicone IVR device and in potentially therapeutic [2] A.D. Woolfson, R.K. Malcolm, R. Gallagher, Drug delivery amounts. It is only when both physicochemical by the intravaginal route, Crit. Rev. Ther. Drug Carrier Syst. parameters, silicone solubility of the drug and its 17 (2000) 509–555. molecular size, are nonoptimal that release is par- [3] R. Lipp, Novel drug delivery systems for steroidal hormones, Exp. Opin. Ther. Pat. 11 (2001) 1291–1299. ticularly poor, such as with clindamycin. Of course, [4] D.R. Mishell, Vaginal contraceptive rings, Ann. Med. 25 the potency of the drug and the required vaginal (1993) 191–197. concentration required for therapy will also play a [5] G.W. Duncan, Medicated devices and methods, US Pat. major role in determining whether a particular 3545439, December 8, 1970. release rate is suitable or not. To this end, the results [6] D.R. Mishell, M. Talas, A.F. Parlow, D.L. Moyer, Contra- ception by means of a silastic vaginal ring impregnated with of the study will be particularly useful in evaluating medroxyprogesterone acetate, Am. J. Obstet. Gynecol. 107 the potential of delivering new drugs from matrix or (1970) 100–107. reservoir IVR devices, since it provides a model for [7] D.R. Mishell, M.E. Lumkin, Contraceptive effects of varying the prediction of silicone solubility and silicone doses of progestogen in silastic vaginal rings, Fertil. Steril. diffusion coefficient from which daily flux rates may 21 (1970) 99–103. [8]V . Brache, F. Avarez-Sanchez, A. Faundes, T. Jackanicz, be calculated. D.R. Mishell, P. Lahteenmaki, Progestin-only contraceptive rings, Steroids 65 (2000) 687–691. [9] T.M. Jackanicz, Vaginal ring steroid releasing systems, in: 4 . Conclusions G.I. Zatuchni et al. (Ed.), Long-Acting Contraceptive Deliv- ery Systems, Harper Row, Philadelphia, 1983, pp. 201–212. [10] A.D. Woolfson, G.R.E. Elliott, C.A. Gilligan, C.M. Pas- The in vitro controlled release of eight drug smore, Design of an intravaginal ring for the controlled molecules from matrix-type silicone intravaginal delivery of 17b-estradiol as its 3-acetate ester, J. Control. rings have been investigated and a qualitative model Rel. 61 (1999) 319–328. K. Malcolm et al. / Journal of Controlled Release 90 (2003) 217–225 225

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