Physicochemical considerations in the formulation development of silicone elastomer vaginal rings releasing 5-nitroimidazole drugs for the treatment of bacterial vaginosis.

Bacterial vaginosis (BV) is a common dysbiosis of the human vaginal microbiota characterized by depletion of hydrogen peroxide and lactic acid-producing Lactobacillus bacteria and an overgrowth of certain facultative anaerobic bacteria. Although short-term cure rates following treatment with frontline antibiotics (most notably oral metronidazole (MNZ), clindamycin vaginal cream, and MNZ vaginal gel) are generally high, longer-term recurrence rates are an issue. The development of vaginal formulations offering continuous/sustained administration of antibiotic drugs over one or more weeks might prove useful in reducing recurrence. Here, we report the manufacture and preclinical testing of matrix-type vaginal rings offering sustained release of four 5-nitroimidazole antimicrobial drugs either being used clinically or having potential in treatment of BV - MNZ, tinidazole (TNZ), secnidazole (SNZ) and ornidazole (ONZ). All four drugs showed good compatibility with a medical-grade addition-cure silicone elastomer based upon thermal analysis experiments, and matrix-type rings containing 250 mg (3.125 %w/w) of each drug were successfully manufactured by reaction injection molding. 28-day in vitro drug release studies demonstrated root-time kinetics, with daily release rates of 25, 22, 9 and 6 mg/day½ for SNZ, ONZ, MNZ and TNZ, respectively. The rank order of drug release from rings correlated with the simple molecular permeability parameter S/V, where S is the measured drug solubility in silicone fluid and V is the drug molecular volume. The relative merits of SNZ and ONZ over MNZ (the current reference treatment) are discussed. The data support development of vaginal rings for sustained release of 5-nitroimidazole compounds for treatment of BV.

Orthodontists' perceptions of the need for orthognathic surgery in patients with Class II Division 1 malocclusion based on extraoral examinations.

INTRODUCTION: The purpose of this study was to establish the influence of soft-tissue profile values on the decision of orthodontists to recommend orthognathic surgery for patients with Class II Division 1 malocclusion. METHODS: A questionnaire containing 40 profile photographs of adults with Class II Division 1 malocclusion was sent to all 256 consultant orthodontists in the United Kingdom asking for a "yes" or "no" response to the question: "Based on the profile view of this patient, would you treat this patient using an orthognathic surgical approach?" A soft-tissue analysis was carried out on each photograph, and multi-level logistic regression was used to investigate factors that affect the decision to recommend surgery. RESULTS: The response rate was high: 208 of 256 questionnaires (81.3%). Intraexaminer reliability of the photographic analysis method with a Bland-Altman plot showed good (95% CI) limits of agreement for each measurement. Consultants who carried out more orthognathic surgery treatment were more likely to recommend surgery. Secondary analysis with a logistic regression model indicated that 80% of the consultants would recommend surgery if B-point was more than or equal to -14.1 mm posterior to the true vertical through subnasale (95% CI, -29.9 to -10.9 mm), the facial profile angle was less than or equal to 148.9° (95% CI, 6.7° to 151.1°), pogonion to true vertical through subnasale was more than or equal to -12.0 mm (95% CI, -48.7 to -8.6 mm). CONCLUSIONS: The facial profile angle and the positions of soft-tissue pogonion and B-point are useful clinical guides for planning treatment for adults with Class II Division 1 malocclusion.

Dapivirine-releasing vaginal rings produced by plastic freeforming additive manufacturing.

Here we report the first use of an additive manufacturing (AM) technique based on high pressure material jetting of molten thermoplastic for the fabrication of dapivirine (DPV) loaded vaginal rings (VRs). The VRs are compared to those produced conventionally using injection molding (IM). VRs (outer diameter 54.0 mm, cross-sectional diameter 4.0 mm) were manufactured by either injection molding or Arburg Plastic Freeforming (APF) - a proprietary droplet deposition modelling (DDM) process, using medical grade thermoplastic polyurethanes (TPUs) loaded with 10% w/w DPV. This unique DDM process was used to produce rings of 100, 50 and 10% matrix infill density. DDM printed VRs with 10% density (57-62 mg drug load) exhibited up to seven-fold increase in DPV release compared to injection molded rings containing 190-194 mg DPV. This work has shown that DDM using the APF technique can be used to manufacture drug delivery devices of varying geometries, densities and surface areas to give precise levels of control over the drug release kinetics. This work presents a new opportunity to increase the release of poorly water-soluble compounds or to achieve desired dosing levels using lower drug loadings than those required using conventional thermoplastic processing techniques.

In vitro release testing methods for drug-releasing vaginal rings.

Drug-releasing vaginal rings are torus-shaped devices, generally fabricated from thermoplastic polymers or silicone elastomers, used to administer pharmaceutical drugs to the human vagina for periods typically ranging from three weeks to twelve months. One of the most important product performance tests for vaginal rings is the in vitro release test. Although it has been fifty years since a vaginal ring device was first described in the scientific literature, and despite seven drug-releasing vaginal rings having been approved for market, there is no universally accepted method for testing in vitro drug release, and only one non-compendial shaking incubator method (for the estradiol-releasing ring Estring®) is described in the US Food and Drug Administration's Dissolution Methods Database. Here, for the first time, we critically review the diverse range of test methods that have been described in the scientific literature for testing in vitro release of drug-releasing vaginal rings. Issues around in vitro-in vivo correlation and modelling of in vitro release data are also discussed.

Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers.

With a dapivirine-releasing vaginal ring having successfully completed late-stage clinical testing for HIV prevention and currently undergoing regulatory review, there is now growing interest in next-generation multipurpose prevention technologies that seek to combine antiretroviral and contraceptive drugs within a single product. Here, we focus on ongoing efforts to develop a silicone elastomer vaginal ring releasing both dapivirine and levonorgestrel. Specifically, we evaluate various strategies aimed at both better understanding and reducing the tendency of levonorgestrel to bind with the elastomer, including: (i) formulation and post-manufacturing strategies aimed at reducing the extent of levonorgestrel reaction with addition-cure silicone elastomers; (ii) evaluation of a simple silicone system to model the complex elastomer; (iii) use of model compounds representing the enone and ethinyl moieties of levonorgestrel to probe the mode of addition of levonorgestrel to addition-cure silicone elastomers; and (iv) solution and solid-state 13C NMR analysis to probe the structural features of the levonorgestrel-silicone system. The results demonstrate that both the enone and ethinyl groups within levonorgestrel undergo hydrosilylation reactions with the hydrosiloxane groups in the silicone elastomer leading to covalent binding. The results also highlight potential strategies for further optimising the dapivirine + levonorgestrel silicone vaginal ring formulation to ensure that the levonorgestrel is available for release.

Intravaginal rings for continuous low-dose administration of cervical ripening agents.

Intravaginal rings (VRs) have been widely reported for administration of pharmaceutical drugs - most notably estrogens, progestogens and antiretrovirals - to the vagina for clinical benefit. Here, for the first time, we describe the design, manufacture and preclinical testing of VRs for sustained/controlled release of the cervical ripening agents isosorbide mononitrate (ISMN) and misoprostol (MP), either singly or in combination. Matrix-type silicone elastomer VRs containing ISMN showed declining daily release rates, ranging from 31 to 168 mg (Day 1) to 3-25 mg (Day 11). Novel orifice-type rings, in which a MP-containing silicone elastomer core is partially exposed to the external environment by overmolding with a non-medicated silicone elastomer sheath containing orifices, provided relatively constant daily MP release rates over 14 days (∼20 or 60 µg/day depending on the formulation type). Combination VRs offered simultaneous release of both ISMN and MP over 14 days, with an almost constant MP release rate (60 µg/day) and steadily declining daily ISMN release (295 mg on Day 1 and 24 mg on Day 11). The VR design can be readily tailored to provide sustained or controlled release of ISMN and MP at rates potentially useful for cervical ripening.

Solid state 13C NMR spectroscopy provides direct evidence for reaction between ethinyl estradiol and a silicone elastomer vaginal ring drug delivery system.

Steroid molecules have a long history of incorporation into silicone elastomer materials for controlled release drug delivery applications. Previously, based on in vitro release testing and drug content analysis, we demonstrated indirectly that the contraceptive progestin levonorgestrel (LNG) chemically and irreversibly binds to addition cure silicone elastomers, presumably via a hydrosilylation reaction between the levonorgestrel ethynyl group and the hydrosilane groups in the poly(dimethylsiloxane-co-methylhydrosiloxane) crosslinker of the silicone elastomer. Here, for the first time, we report that solid state 13C nuclear magnetic resonance (NMR) spectroscopy provides direct evidence for the irreversible binding of ethinyl estradiol (EE) - an estrogenic steroid molecule also containing an ethynyl functional group - to an addition cure silicone elastomer. By preparing silicone elastomer samples containing 13C-labelled EE, signals in the NMR spectra could readily be assigned to both the free and bound EE. Additional depolymerisation studies, performed on an addition cure silicone elastomer system from which the unbound EE fraction was completely extracted, further confirmed the presence of bound EE through the formation of coloured reaction mixtures resulting from the reaction of bound EE and trifluoroacetic acid (TFA). These methods will be particularly useful in the ongoing development of new steroid-releasing silicone drug delivery devices, including various vaginal ring devices for contraception, HIV prevention and multipurpose prevention technology applications.

Packing Polymorphism of Dapivirine and Its Impact on the Performance of a Dapivirine-Releasing Silicone Elastomer Vaginal Ring.

A silicone elastomer vaginal ring providing sustained release over 28 days of the anti-retroviral microbicide dapivirine has recently completed phase III clinical testing and showed moderate protection against HIV acquisition. In support of the product licensure program, we report the impact of dapivirine packing polymorphism on the thermal and solubility characteristics of dapivirine and on the in vitro performance of the 25 mg dapivirine ring product. This is the first time that polymorphism has been reported for a drug-releasing vaginal ring product. Thermal, particle size, powder X-ray diffraction, and thermodynamic solubility analyses of dapivirine polymorphic forms I and IV, both of which are persistent at room temperature and with form I being the thermodynamically stable form, were conducted for both micronized and non-micronized materials. No significant differences in solubility between DPV forms I and IV were observed in media commonly used for in vitro release testing. Matrix-type silicone elastomer vaginal rings were manufactured and the impact of dapivirine polymorphism on key in vitro parameters (compression and tensile behavior; content assay; in vitro release; residual content assay) was investigated. The data demonstrate that dapivirine packing polymorphism has no significant impact on in vitro performance of the 25 mg dapivirine vaginal ring.

Controlling levonorgestrel binding and release in a multi-purpose prevention technology vaginal ring device.

Despite a long history of incorporating steroids into silicone elastomers for drug delivery applications, little is presently known about the propensity for irreversible drug binding in these systems. In this study, the ability of the contraceptive progestin levonorgestrel to bind chemically with hydrosilane groups in addition-cure silicone elastomers has been thoroughly investigated. Cure time, cure temperature, levonorgestrel particle size, initial levonorgestrel loading and silicone elastomer type were demonstrated to be key parameters impacting the extent of levonorgestrel binding, each through their influence on the solubility of levonorgestrel in the silicone elastomer. Understanding and overcoming this levonorgestrel binding phenomenon is critical for the ongoing development of a number of drug delivery products, including a multi-purpose technology vaginal ring device offering simultaneous release of levonorgestrel and dapivirine - a lead candidate antiretroviral microbicide - for combination HIV prevention and hormonal contraception.

A novel scalable manufacturing process for the production of hydrogel-forming microneedle arrays.

A novel manufacturing process for fabricating microneedle arrays (MN) has been designed and evaluated. The prototype is able to successfully produce 14×14 MN arrays and is easily capable of scale-up, enabling the transition from laboratory to industry and subsequent commercialisation. The method requires the custom design of metal MN master templates to produce silicone MN moulds using an injection moulding process. The MN arrays produced using this novel method was compared with centrifugation, the traditional method of producing aqueous hydrogel-forming MN arrays. The results proved that there was negligible difference between either methods, with each producing MN arrays with comparable quality. Both types of MN arrays can be successfully inserted in a skin simulant. In both cases the insertion depth was approximately 60% of the needle length and the height reduction after insertion was in both cases approximately 3%.

A temperature-monitoring vaginal ring for measuring adherence.

BACKGROUND: Product adherence is a pivotal issue in the development of effective vaginal microbicides to reduce sexual transmission of HIV. To date, the six Phase III studies of vaginal gel products have relied primarily on self-reporting of adherence. Accurate and reliable methods for monitoring user adherence to microbicide-releasing vaginal rings have yet to be established. METHODS: A silicone elastomer vaginal ring prototype containing an embedded, miniature temperature logger has been developed and tested in vitro and in cynomolgus macaques for its potential to continuously monitor environmental temperature and accurately determine episodes of ring insertion and removal. RESULTS: In vitro studies demonstrated that DST nano-T temperature loggers encapsulated in medical grade silicone elastomer were able to accurately and continuously measure environmental temperature. The devices responded quickly to temperature changes despite being embedded in different thickness of silicone elastomer. Prototype vaginal rings measured higher temperatures compared with a subcutaneously implanted device, showed high sensitivity to diurnal fluctuations in vaginal temperature, and accurately detected periods of ring removal when tested in macaques. CONCLUSIONS: Vaginal rings containing embedded temperature loggers may be useful in the assessment of product adherence in late-stage clinical trials.

A silicone elastomer vaginal ring for HIV prevention containing two microbicides with different mechanisms of action.

Vaginal rings are currently being developed for the long-term (at least 30 days) continuous delivery of microbicides against human immunodeficiency virus (HIV). Research to date has mostly focused on devices containing a single antiretroviral compound, exemplified by the 25mg dapivirine ring currently being evaluated in a Phase III clinical study. However, there is a strong clinical rationale for combining antiretrovirals with different mechanisms of action in a bid to increase breadth of protection and limit the emergence of resistant strains. Here we report the development of a combination antiretroviral silicone elastomer matrix-type vaginal ring for simultaneous controlled release of dapivirine, a non-nucleoside reverse transcriptase inhibitor, and maraviroc, a CCR5-targeted HIV-1 entry inhibitor. Vaginal rings loaded with 25mg dapivirine and various quantities of maraviroc (50-400mg) were manufactured and in vitro release assessed. The 25mg dapivirine and 100mg maraviroc formulation was selected for further study. A 24-month pharmaceutical stability evaluation was conducted, indicating good product stability in terms of in vitro release, content assay, mechanical properties and related substances. This combination ring product has now progressed to Phase I clinical testing.