Polysorbate enhanced progesterone loaded drug diffusion from macromolecular fibrous patches for applications in obstetrics and gynaecology

Progesterone, a steroidal hormone, is used as pharmacotherapy in the clinical practice of obstetrics and gynaecology. There are however considerable bioavailability issues with the currently available formulation. Widening the range of progesterone formulations will increase the usefulness of this drug in a variety of clinical interventions. We undertook this study to create an ideal transdermal progesterone patch, which requires a reliable system to host and release drugs sustainably. This study investigates the use of a combined fatty acid, polysorbate 80 in distilled water or ethanol, with the well-known polymer polyvinylpyrrolidone (PVP). The rheology of the polymer solutions was investigated with incremental changes in either PVP or polysorbate. For each polymer solution, electrospinning was used to create fibre systems, which were characterised by scanning electron microscopy. The optimal polymer solution consisted of 2 g of PVP in 20 ml of ethanol with 4 ml of polysorbate. Performance analysis was completed by carrying out two drug release studies: direct submersion of fibres in PBS and transdermal drug delivery of fibres across a cellulose acetate membrane using Franz Diffusion Cells. The results have shown that the polysorbate loaded fibre systems reached near 100% drug release (over two weeks) and nearly 5 times faster than the fibres without polysorbate. This confirms the penetrative enhancing capabilities of polysorbate widely presented in literature. Kinetic release studies and geometric models were also used to observe the experimental behaviour compared to expectations. Experimental results closely fit both the Makoid Banakar model and the Geometric Equation

Using pressurised gyration to generate mucoadhesive progesterone-loaded fibres for drug delivery applications

This work explores the prospects of polymeric micro and nanofibres as drug delivery systems intended to facilitate transport of progesterone across vaginal mucosa by mucoadhesion. These fibres, due to their physical attributes, ability to improve drug solubility and high adsorption efficiency may be adapted for improved trans-mucosal drug delivery. Mucoadhesion on the other hand is being explored for improved dosage form residence times, targeting and therapeutic efficacy. Notwithstanding the potential utility of mucoadhesion and nanofibres, generating substantial amounts of mucoadhesive fibres is fraught with many challenges. In this work, pressurised gyration, a novel approach combining centrifugal force and pressure was used to produce fibres from combinations of polyethylene oxide (PEO), carboxymethyl cellulose sodium (CMC), sodium alginate and polyacrylic acid; polymers with inherent mucoadhesive properties. Nanofibres generated were characterised using scanning electron microscopy, infra-red and x-ray diffraction analyses to determine their morphology, size distribution and molecular composition. Furthermore, they were assessed by texture analyser and atomic force microscope for mucoadhesive performance after which PEO/CMC blends were selected for drug (progesterone) loading. The progesterone-loaded fibres were assessed, mainly for drug release and mucoadhesion. A new methodology based on classical mucoadhesion theories, where atomic force microscopy was used to map interfacial roughness and voids in adhering surfaces was developed for quantifying mucoadhesive properties of systems produced. In conclusion, this work has demonstrated the possibility of generating drug-loaded fibres as potential constructs for developing vaginal dosage forms for improved performance facilitated by mucoadhesion. Furthermore, a new approach to quantifying mucoadhesion between fibres and mucosa by AFM was developed, with outcome correlating favourably with forces required to detach interacting surfaces measured by texture analyser

An Inexpensive, Portable Device for Point-of-Need Generation of Silver-Nanoparticle Doped Cellulose Acetate Nanofibers for Advanced Wound Dressing

This short communication describes the design and assembly of a new, miniaturized electrospinner to produce nanofibers at the site of need for drug delivery and wound dressing applications. The portable apparatus would eliminate the storage and transportation concerns with regards to the delicate nature of drug‐loaded nanofibers, thereby preserving product integrity at the site of use. Furthermore, the setup features a smaller size, a cheaper price, and components that are readily obtainable off‐the‐shelf, compared to those of available devices that are custom‐built and more expensive, making it desirable and accessible for other users in the field. As a proof‐of‐concept for wound care, the device is successfully used to electrospin three types of nanofibers comprised of pure cellulose acetate (CA), and CA respectively doped with 0.75 and 1.5 wt% silver nanoparticles. The miniaturized device is useful on account of the popularity of electrospinning as well as the potential to minimize wound infection due to the reduced manipulation of both the dressing and the wound from product generation to the point of need. Work is in progress to further develop the portable device and compare its product performance with traditional wound dressing materials for clinical translation

A Portable Device for the Generation of Drug-Loaded Three-Compartmental Fibers Containing Metronidazole and Iodine for Topical Application

The use of combination therapies for the treatment of a range of conditions is now well established, with the component drugs usually being delivered either as distinct medicaments or combination products that contain physical mixes of the two active ingredients. There is, however, a compelling argument for the development of compartmentalised systems whereby the release, stability and incorporation environment of the different drugs may be tailored. Here we outline the development of polymeric fine fiber systems whereby two drugs used for the treatment of wounds may be separately incorporated. Fibers were delivered using a newly developed handheld electrospinning device that allows treatment at the site of need. Crucially, the delivery system is portable and may be used for the administration of drug-loaded fibers directly into the wound in situ, thereby potentially allowing domiciliary or site-of-trauma administration. The three-layered fiber developed in this study has polyethylene glycol as the outermost layer, serving as a structural support for the inner layers. The inner layers comprised iodine complexed with polyvinylpyrrolidone (PVP) and metronidazole dispersed in polycaprolactone (PCL) as a slow release core. The systems were characterized in terms of structure and architecture using scanning electron microscopy, transmission electron microscopy, attenuated total reflection Fourier transform infrared spectroscopy and diffractometry. As antibacterial creams are still used for managing infected wounds, the performance of our trilayered fiber was studied in comparison with creams containing similar active drugs. Drug release was measured by UV analysis, while antimicrobial efficiency was measured using agar diffusion and suspension methods. It was found that the trilayered systems, averaging 3.16 µm in diameter, released more drug over the study period and were confirmed by the microbacterial studies to be more effective against P. aeruginosa, a bacterium commonly implicated in infected wounds. Overall, the portable system has been shown to be capable of not only incorporating the two drugs in distinct layers but also of delivering adequate amounts of drugs for a more effective antibacterial activity. The portability of the device and its ability to generate distinct layers of multiple active ingredients make it promising for further development for wound healing applications in terms of both practical applicability and antimicrobial efficacy

Application of nanotechnology for the development of microbicides

The vaginal route is increasingly being considered for both local and systemic delivery of drugs, especially those unsuitable for oral administration. One of the opportunities offered by this route but yet to be fully utilised is the administration of microbicides. Microbicides have an unprecedented potential for mitigating the global burden from HIV infection as heterosexual contact accounts for most of the new infections occurring in sub-Saharan Africa, the region with the highest prevalent rates. Decades of efforts and massive investment of resources into developing an ideal microbicide have resulted in disappointing outcomes, as attested by several clinical trials assessing the suitability of those formulated so far. The highly complex and multi-level biochemical interactions that must occur among the virus, host cells and the drug for transmission to be halted means that a less sophisticated approach to formulating a microbicide e.g. conventional gels, etc may have to give way for a different formulation approach. Nanotechnology has been identified to offer prospects for fabricating structures with high capability of disrupting HIV transmission. In this review, predominant challenges seen in microbicide development have been highlighted and possible ways of surmounting them suggested. Furthermore, formulations utilising some of these highly promising nanostructures such as liposomes, nanofibres and nanoparticles have been discussed. A perspective on how a tripartite collaboration among governments and their agencies, the pharmaceutical industry and academic scientists to facilitate the development of an ideal microbicide in a timely manner has also been briefly deliberated

Mucoadhesion of Progesterone-Loaded Drug Delivery Nanofiber Constructs

Mucoadhesive delivery systems have attracted remarkable interest recently, especially for their potential to prolong dosage form resident times at sites of application such as the vagina or nasal cavity, thereby improving convenience and compliance as a result of less frequent dosage. Mucoadhesive capabilities need to be routinely quantified during the development of these systems. This is however logistically challenging due to difficulties in obtaining and preparing viable mucosa tissues for experiments. Utilizing artificial membranes as a suitable alternative for quicker and easier analyses of mucoadhesion of these systems is currently being explored. In this study, the mucoadhesive interactions between progesterone-loaded fibers (with varying carboxymethyl cellulose (CMC) content) and either artificial (cellulose acetate) or mucosa membranes are investigated by texture analysis and results across models are compared. Mucoadhesion to artificial membrane was about 10 times that of mucosa, though statistically significant (p = 0.027) association between the 2 data sets was observed. Furthermore, a hypothesis relating fiber–mucosa interfacial roughness (and unfilled void spaces on mucosa) to mucoadhesion, deduced from some classical mucoadhesion theories, was tested to determine its validity. Points of interaction between the fiber and mucosa membrane were examined using atomic force microscopy (AFM) to determine the depths of interpenetration and unfilled voids/roughness, features crucial to mucoadhesion according to the diffusion and mechanical theories of mucoadhesion. A Kendall’s tau and Goodman–Kruskal’s gamma tests established a monotonic relationship between detaching forces and roughness, significant with p-values of 0.014 and 0.027, respectively. A similar relationship between CMC concentration and interfacial roughness was also confirmed. We conclude that AFM analysis of surface geometry following mucoadhesion can be explored for quantifying mucoadhesion as data from interfacial images correlates significantly with corresponding detaching forces, a well-established function of mucoadhesion

Macromol. Mater. Eng. 3/2018

Bacterial cellulose blended polymeric fibrous bandages made in a novel way, from a solution subjected to gyration under pressure to directly weave the bandages. The products show cellular attraction, mechanical and swelling properties in preliminary tests and heralds a very promising new route for the manufacture of wound care bandages. This is reported by Esra Altun, Mehmet Onur Aydogdu, Fatma Koc, Maryam Crabbe‐Mann, Francis Brako, Rupy Kaur‐Matharu, Gunes Ozen, Serap Erdem Kuruca, Ursula Edirisinghe, Oguzhan Gunduz, and Mohan Edirisinghein

Novel Making of Bacterial Cellulose Blended Polymeric Fiber Bandages

Bacterial cellulose (BC) is a very promising biological material. However, at present its utilization is limited by difficulties in shape forming it. In this Communication, it is shown how this can be overcome by blending it with poly(methylmethacrylate) (PMMA) polymer. BC:PMMA fibers are produced by pressurized gyration of blended BC:PMMA solutions. Subsequently, BC:PMMA bandage‐like scaffolds are generated with different blends. The products are investigated to determine their morphological and chemical features. Cell culture and proliferation tests are performed to obtain information on biocompatibility of the scaffolds

The development of progesterone-loaded nanofibers using pressurized gyration: A novel approach to vaginal delivery for the prevention of pre-term birth

Recent evidence has continued to support the applicability of progesterone in preventing preterm birth, hence the development of an appropriate vaginal delivery system for this drug would be of considerable interest. Here, we describe the development of progesterone-loaded bioadhesive nanofibers using pressurized gyration for potential incorporation into a vaginal insert, with a particular view to addressing the challenges of incorporating a poorly water-soluble drug into a hydrophilic nanofiber carrier. Polyethylene oxide and carboxymethyl cellulose were chosen as polymers to develop the carrier systems, based on previous evidence of their yielding mucoadhesive nanofibers using the pressurized gyration technique. The fabrication parameters such as solvent system, initial drug loading and polymer composition were varied to facilitate optimisation of fiber structure and efficiency of drug incorporation. Such studies resulted in the formation of nanofibers with satisfactory surface appearance, diameters in the region of 400 nm and loading of up to 25% progesterone. Thermal and spectroscopic analyses indicated that the drug was incorporated in a nanocrystalline state. Release from the drug-loaded fibers indicated comparable rates of progesterone dissolution to that of Cyclogest, a commercially available progesterone pessary, allowing release over a period of hours. Overall, the study has shown that pressurized gyration may produce bioadhesive progesterone-loaded nanofibers which have satisfactory loading of a poorly water-soluble drug as well as having suitable structural and release properties. The technique is also capable of producing fibers at a yield commensurate with practical applicability, hence we believe that the approach shows considerable promise for the development of progesterone dosage forms for vaginal application