3D printed implantable drug delivery devices for women's health: Formulation challenges and regulatory perspective.

Modern pharmaceutical interventions are shifting from traditional "one-size-fits-all" approaches toward tailored therapies. Following the regulatory approval of Spritam®, the first marketed drug manufactured using three-dimensional printing (3DP) technologies, there is a precedence set for the use of 3DP in the manufacture of pharmaceutical products. The involvement of 3DP technologies in pharmaceutical research has demonstrated its capabilities in enabling the customisation of characteristics such as drug dosing, release characteristics and product designs on an individualised basis. Nonetheless, research into 3DP implantable drug delivery devices lags behind that for oral devices, cell-based therapies and tissue engineering applications. The recent efforts and initiatives to address the disparity in women's health is overdue but should provide a drive for more research into this area, especially using new and emerging technologies as 3DP. Therefore, the focus of this review has been placed on the unique opportunity of formulating personalised implantable drug delivery systems using 3DP for women's health applications, particularly passive implants. An evaluation of the current landscape and key formulation challenges for achieving this is provided supplemented with critical insight into the current global regulatory status and its outlook.

Intravesical combination therapies for non-muscle invasive bladder cancer: Recent advances and future directions.

Bladder cancer is the 10th most frequently diagnosed cancer worldwide with 5-year survival rate around 70%. The current first-line treatment for non-muscle invasive bladder cancer is transurethral resection of bladder tumours followed by intravesical Mycobacterium Bovis Bacillus Calmette-Guérin (BCG) immunotherapy. However, tumor recurrence rate is still high ranging from 31% to 78% within five years. To avoid radical cystectomy, intravesical combination therapies have been developed as salvage treatments to overcome BCG failure. Recent advances in diagnostics thanks to tumor molecular profiling and in treatment such as development of immunotherapies provides more treatment options beyond BCG treatment. This also goes hand-in hand with formulation advances to deliver these new therapies where traditional drug delivery systems might not be suitable, which in turn is completed by challenges to deliver drugs via the intravesical route. In this article the aim was to provide an in-depth analysis of the current developments of intravesical combination therapies, ranging from relatively simple combinations of mixing existed intravesical therapeutic agents (immunotherapies and chemotherapies) to the combined formulations containing advanced gene therapies and targeted therapies, with special focus on therapies that have made it to the clinical trial stage. In addition, recent attempts to utilize device-assisted treatments and novel drug delivery platforms are included. This review also highlights the limitations that still need to be overcome such as the inadequate studies on newly explored drug carriers and proposes potential directions for future work to overcome BCG-failure.

Monitoring Polymorphic Phase Transitions in Flufenamic Acid Amorphous Solid Dispersions Using Hyphenated X-ray Diffraction-Differential Scanning Calorimetry.

Flufenamic acid (FFA) is a highly polymorphic drug molecule with nine crystal structures reported in the Cambridge Structural Database. This study explores the use of synchrotron X-ray powder diffraction combined with differential scanning calorimetry to study crystallization and polymorphic phase transitions upon heating FFA-polymer amorphous solid dispersions (ASDs). Ethyl cellulose (EC, 4 cp) and hydroxypropylmethylcellulose (HPMC) grades with different viscosities and substitution patterns were used to prepare dispersions with FFA at 5:1, 2:1, 1:1, and 1:5 w/w drug/polymer ratios by quench cooling. We employed a 6 cp HPMC 2910 material and two HPMC 2208 samples at 4000 and 100 000 cp. Hyphenated X-ray diffraction (XRD)-differential scanning calorimetry (DSC) studies show that the 6 and 100 000 cp HPMCs and 4 cp EC polymers can stabilize FFA form IV by inhibiting the transition to form I during heating. It appears that the polymers stabilize FFA in both amorphous and metastable forms via a combination of intermolecular interactions and viscosity effects. Increasing the polymer content of the ASD also inhibits polymorphic transitions, with drug/polymer ratios of 1:5 w/w resulting in FFA remaining amorphous during heating. The comparison of FFA ASDs prepared with different samples of HPMCs and ECs suggests that the chemical substitution of the polymer (HPMC 2208 has 19-24% methoxy groups and 4-12% hydroxypropyl groups, while HPMC 2910 has 28-30% methoxy groups and 7-12% hydroxypropyl groups) plays a more significant role in directing polymorphic transitions than the viscosity. A previously unreported polymorph of FFA was also noted during heating but its structure could not be determined.

The era of fake medicines: Investigating counterfeit medicinal products for erectile dysfunction disguised asherbal supplements.

Sales of substandard and falsified medical products (SF) are rising rapidly everywhere around the globe. The wide and easy access to these products is an alarming issue to the global health systems and undermined the health of patients, especially with the thrive of online commerce. To tackle this threat to public health, new ways to access these products should be identified and detection technologies should be strengthened. The overarching aim of this study was to investigate if herbal supplements sold online claiming to be natural alternatives to Viagra® were amongst these SF medical products and how effective different analytical techniques are in providing information about these products. 3 products which claimed to be herbal supplements for men sexual performance were purchased from an e-commerce platform. Two products were received as unregistered generic sildenafil citrate tablets manufactured in India (and thus different to the products information on the website) while one product was received in the same packaging as shown on the website, claiming to be an herbal product. Nevertheless, all products were proven to contain sildenafil citrate, the active pharmaceutical ingredients in Viagra® after the comprehensive analytical tests. The results elucidated that the quality standards for the unregistered generic sildenafil citrate tablets were fulfilled according to the British Pharmacopeia, but the falsified product failed the quality tests and contained approximately 200 mg sildenafil citrate, which is equivalent to 2-fold of the daily maximum dose. Furthermore, physical characterisations, including powder x-ray diffraction and thermal analysis were performed and revealed that the polymorphic forms of sildenafil citrate were different, demonstrating the importance of employing thermal analysis in addition to the conventional analysis techniques for the substandard and falsified medical products. These techniques provided valuable insights into the physical form of the active ingredient in these products. What is more, the ease with which these SF products were obtained and confirmed to be misleading consumers emphasises the need for tighter regulation for e-commerce websites in line with those enforced on online pharmacies.

Clinical translation of advanced colonic drug delivery technologies.

Targeted drug delivery to the colon offers a myriad of benefits, including treatment of local diseases, direct access to unique therapeutic targets and the potential for increasing systemic drug bioavailability and efficacy. Although a range of traditional colonic delivery technologies are available, these systems exhibit inconsistent drug release due to physiological variability between and within individuals, which may be further exacerbated by underlying disease states. In recent years, significant translational and commercial advances have been made with the introduction of new technologies that incorporate independent multi-stimuli release mechanisms (pH and/or microbiota-dependent release). Harnessing these advanced technologies offers new possibilities for drug delivery via the colon, including the delivery of biopharmaceuticals, vaccines, nutrients, and microbiome therapeutics for the treatment of both local and systemic diseases. This review details the latest advances in colonic drug delivery, with an emphasis on emerging therapeutic opportunities and clinical technology translation.

Structure determination, thermal stability and dissolution rate of δ-indomethacin.

The structure solution of the δ-polymorph of indomethacin was obtained using three-dimensional electron diffraction. This form shows a significantly enhanced dissolution rate compared with the more common and better studied α- and γ-polymorphs, indicating better biopharmaceutical properties for medicinal applications. The structure was solved in non-centrosymmetric space group P21 and comprises two molecules in the asymmetric unit. Packing and molecule conformation closely resemble indomethacin methyl ester and indomethacin methanol solvate. Knowledge of the structure allowed the rational interpretation of spectroscopic IR and Raman data for δ-polymorph and a tentative interpretation for still unsolved indomethacin polymorphs. Finally, we observed a solid-solid transition from δ-polymorph to α-polymorph that can be driven by similarities in molecular conformation.

Metastable crystalline phase formation in deep eutectic systems revealed by simultaneous synchrotron XRD and DSC.

The phase behaviour of various deep eutectic systems was analysed using concurrent synchrotron powder X-ray diffraction and differential scanning calorimetry. Deep eutectic systems containing the pharmaceuticals metacetamol, 2-ethoxybenzamide or benzamide as binary mixtures with phenol revealed new crystalline phases melting either before or with crystals of phenol, highlighting their lower stabilities. Furthermore, in the phenol : 2-ethoxybenzamide system it was shown that multiple metastable phases can form, highlighting the potential for the separation of a hierarchy of crystal structures with differing stabilities from eutectic systems. Through these experiments, we strengthen the idea that eutectic systems can be described by understanding the formation and stabilities of metastable co-crystalline structures. These novel results lead to a deeper understanding of the structure and thermodynamics of deep eutectic solvents, with relevance for analagous systems across materials science.

Mechanistic In Situ and Ex Situ Studies of Phase Transformations in Molecular Co-Crystals.

Co-crystallisation is widely explored as a route to improve the physical properties of pharmaceutical active ingredients, but little is known about the fundamental mechanisms of the process. Herein, we apply a hyphenated differential scanning calorimetry-X-ray diffraction technique to mimic the commercial hot melt extrusion process, and explore the heat-induced synthesis of a series of new co-crystals containing isonicotinamide. These comprise a 1:1 co-crystal with 4-hydroxybenzoic acid, 2:1 and 1:2 systems with 4-hydroxyphenylacetic acid and a 1:1 crystal with 3,4-dihydroxyphenylactic acid. The formation of co-crystals during heating is complex mechanistically. In addition to co-crystallisation, conversions between polymorphs of the co-former starting materials and co-crystal products are also observed. A subsequent study exploring the use of inkjet printing and milling to generate co-crystals revealed that the synthetic approach has a major effect on the co-crystal species and polymorphs produced.

Solid-state epimerisation and disproportionation of pilocarpine HCl: Why we need a 5-stage approach to validate melting point measurements for heat-sensitive drugs.

Melting points for new drugs are reported in regulatory documents, e.g. investigational brochures, and frequently in published research; however, the authors do not typically consider that heat-induced degradation can affect the melting point measurement. Applying a single heating rate is not adequate, and thus many melting points in the literature and regulatory documentation are not valid. Our aim was to validate a five-stage approach for the melting point measurement of heat-sensitive drugs. These stages are; (1) observe melting; (2) record mass loss; (3) measure melting points at different heating rates; (4) characterise degradation and (5) test for potential isomerisation. Applying this approach to pilocarpine HCl illustrated the sensitivity of a melting point to thermal degradation. Due to salt disproportionation & loss of HCl gas, pilocarpine's melting point decreased by 14 °C when the heating rate was lowered from 20 to 1 °C/min. Epimerization occurred before melting was reached. Increasing the heating rate diminished disproportionation; however, this did not remove epimerization. Thus, the melting point of pilocarpine HCl of 205.5 ± 0.4 °C measured at 20 °C/min represents the melt of a racemic mixture containing inactive isopilocarpine. Heating above the melting point accelerated degradation, a rate of 5 °C/min recovered just 38 ± 1% of pilocarpine. Such data predicted a shelf-life of 6.6 years. Pilocarpine successfully validated the multistage approach by providing new knowledge concerning its thermal stability. Our 5-stage approach must be applied to all new drugs especially if their formulation requires heat. For example, thermal stability is an infrequently considered pre-requisite in the emerging field of 3D printing.

Solid lipid nanoparticles self-assembled from spray dried microparticles.

We report the self-assembly of drug-loaded solid lipid nanoparticles (SLNs) from spray dried microparticles comprising poly(vinylpyrrolidone) (PVP) loaded with glyceryl tristearate (GTS) and either indomethacin (IMC) or 5-fluorouracil (5-FU). When the spray dried microparticles are added to water, the PVP matrix dissolves and the GTS and drug self-assemble into SLNs. The SLNs provide a non-toxic delivery platform for both hydrophobic (IMC) and hydrophilic (5-FU) drugs. They show extended release profiles over more than 24 h, and in permeation studies the drug cargo is seen to accumulate inside cancer cells. This overcomes major issues with achieving local intestinal delivery of these active ingredients, in that IMC permeates well and thus will enter the systemic circulation and potentially lead to side effects, while 5-FU remains in the lumen of the small intestine and will be secreted without having any therapeutic benefit. The SLN formulations are as effective as the pure drugs in terms of their ability to induce cell death. Our approach represents a new and simple route to the fabrication of SLNs: by assembling these from spray-dried microparticles on demand, we can circumvent the low storage stability which plagues SLN formulations.

Track-and-trace: Novel anti-counterfeit measures for 3D printed personalized drug products using smart material inks.

Printing technologies have been forecast to initiate a new era of personalised medicine in pharmaceuticals. To facilitate integration, a non-destructive and robust method of product authenticity is required. This study reports, for the first time, the interface between 3D printing and 2D inkjet printing technologies in order to fabricate a drug-loaded 3D printed tablet (printlet) with a unique track-and-trace measure in a single step process. In particular, quick response (QR) codes and data matrices were printed onto the surface of polymeric-based printlets for scanning using a smartphone device, and were designed to encode tailored information pertaining to the drug product, patient and prescriber. Moreover, a novel anti-counterfeit strategy was designed, which involved the deposition of a unique combination of material inks for detection using Raman spectroscopy. The inks were characterised for printability by measuring surface tension, viscosity and density, and each was successfully detected on the 3D printed tablet post-printing. Overall, this novel approach will enable an enhanced transparency and tracking of 3D printed medicines across the supply chain, leading to a safer treatment pathway for patients.

Polymorphic Phase Transitions in Carbamazepine and 10,11-Dihydrocarbamazepine.

Temperature-induced phase transitions in carbamazepine (CBZ) and 10,11-dihydrocarbamazepine (DHC) were studied by simultaneous differential scanning calorimetry-X-ray diffraction in this work. The transitions generally involve a transitional melt phase which is quickly followed by recrystallisation. The expansions of the unit cell as a function of temperature could be quantified and allow us to determine a directional order of stability in relation to the lattice constants. Dihydrocarbamazepine form II undergoes a conversion to form I by a localised melt phase. Carbamazepine (CBZ) form IV converts to form I at 182 °C, again by a localised intermediate melt phase. CBZ form II converted to form I at 119 °C by a pathway that appears to have included some melting, and form III underwent a part melt-recrystallisation and a part sublimation-recrystallisation to form I.

Sustained antimicrobial activity and reduced toxicity of oxidative biocides through biodegradable microparticles.

The spread of antibiotic-resistant pathogens requires new treatments. Small molecule precursor compounds that produce oxidative biocides with well-established antimicrobial properties could provide a range of new therapeutic products to combat resistant infections. The aim of this study was to investigate a novel biomaterials-based approach for the manufacture, targeted delivery and controlled release of a peroxygen donor (sodium percarbonate) combined with an acetyl donor (tetraacetylethylenediamine) to deliver local antimicrobial activity via a dynamic equilibrium mixture of hydrogen peroxide and peracetic acid. Entrapment of the pre-cursor compounds into hierarchically structured degradable microparticles was achieved using an innovative dry manufacturing process involving thermally induced phase separation (TIPS) that circumvented compound decomposition associated with conventional microparticle manufacture. The microparticles provided controlled release of hydrogen peroxide and peracetic acid that led to rapid and sustained killing of multiple drug-resistant organisms (methicillin-resistant Staphylococcus aureus and carbapenem-resistant Escherichia coli) without associated cytotoxicity in vitro nor intracutaneous reactivity in vivo. The results from this study demonstrate for the first time that microparticles loaded with acetyl and peroxygen donors retain their antimicrobial activity whilst eliciting no host toxicity. In doing so, it overcomes the detrimental effects that have prevented oxidative biocides from being used as alternatives to conventional antibiotics. STATEMENT OF SIGNIFICANCE: The manuscript explores a novel approach to utilize the antimicrobial activity of oxidative species for sustained killing of multiple drug-resistant organisms without causing collateral tissue damage. The results demonstrate, for the first time, the ability to load pre-cursor compounds into porous polymeric structures that results in their release and conversion into oxidative species in a controlled manner. Until now, the use of oxidative species has not been considered as a candidate therapeutic replacement for conventional antibiotics due to difficulties associated with handling during manufacture and controlling sustained release without causing undesirable tissue damage. The ultimate impact of the research could be the creation of new materials-based anti-infective chemotherapeutic agents that have minimal potential for giving rise to antimicrobial resistance.

Amine bridges grafted mesoporous silica, as a prolonged/controlled drug release system for the enhanced therapeutic effect of short life drugs.

Hybrid mesoporous silica SBA-15, with surface incorporated cross-linked long hydrophobic organic bridges was synthesized using stepwise synthesis. The synthesized materials were characterized by elemental analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, nitrogen adsorption, X-rays diffraction, thermogravimetry and scanning and transmission electron microscopy. The functionalized material showed highly ordered mesoporous network with a surface area of 629.0m2g-1. The incorporation of long hydrophobic amine chains on silica surface resulted in high drug loading capacity (21% Mass/Mass) and prolonged release of ibuprofen up till 75.5h. The preliminary investigations suggests that the synthesized materials could be proposed as controlled release devices to prolong the therapeutic effect of short life drugs such as ibuprofen to increase its efficacy and to reduce frequent dosage.

Simultaneous Differential Scanning Calorimetry-Synchrotron X-ray Powder Diffraction: A Powerful Technique for Physical Form Characterization in Pharmaceutical Materials.

We report a powerful new technique: hyphenating synchrotron X-ray powder diffraction (XRD) with differential scanning calorimetry (DSC). This is achieved with a simple modification to a standard laboratory DSC instrument, in contrast to previous reports which have involved extensive and complex modifications to a DSC to mount it in the synchrotron beam. The high-energy X-rays of the synchrotron permit the recording of powder diffraction patterns in as little as 2 s, meaning that thermally induced phase changes can be accurately quantified and additional insight on the nature of phase transitions obtained. Such detailed knowledge cannot be gained from existing laboratory XRD instruments, since much longer collection times are required. We demonstrate the power of our approach with two model systems, glutaric acid and sulfathiazole, both of which show enantiotropic polymorphism. The phase transformations between the low and high temperature polymorphs are revealed to be direct solid-solid processes, and sequential refinement against the diffraction patterns obtained permits phase fractions at each temperature to be calculated and unit cell parameters to be accurately quantified as a function of temperature. The combination of XRD and DSC has further allowed us to identify mixtures of phases which appeared phase-pure by DSC.

Stabilisation of metastable polymorphs: the case of paracetamol form III.

The design of a melt synthesis of the first air-stable formulation of the metastable form III of paracetamol is derived from thermo-spectroscopic and thermo-diffraction experiments. Melt crystallisation in the presence of ß-1,4-saccharides produces form III selectively and the excipients appear to act as stabilising 'active' templates of the metastable polymorph.

Amorphous Formulation and in Vitro Performance Testing of Instantly Disintegrating Buccal Tablets for the Emergency Delivery of Naloxone.

The aim of this study was to develop a freeze-dried buccal tablet for the rapid delivery of naloxone in opioid overdose. The tablet composition was optimized to produce an amorphous matrix, which was confirmed by the absence of peaks associated with crystallinity observed by differential scanning calorimetry and powder X-ray diffraction. Tablets with high gelatin content lacked adequate porosity. Mannitol was added to the formulation to bridge and intercalate gelatin's tight polymer aggregates, however sodium bicarbonate was also required to prevent crystallization within the tablets. A linear reduction in mannitol's recrystallization enthalpy was observed with increasing sodium bicarbonate concentration (ΔrecryH = -20.3[NaHCO3] + 220.9; r(2) = 0.9, n = 18). The minimum sodium bicarbonate concentration for full inhibition of mannitol crystallization was 10.9% w/w. Freeze-dried tablets with lower amounts of sodium bicarbonate possessed a crystalline fraction that PXRD identified as mannitol hemihydrate from the unique peak at 9.7° 2θ. Mannitol's greater affinity for both ions and residual water rather than its affinity for self-association was the mechanism for the inhibition of crystallization observed here. The optimized tablet (composition mannitol 24% w/w (4.26 mg), gelatin 65% w/w (11.7 mg), sodium bicarbonate 11% w/w (1.98 mg), and naloxone 800 µg) formed predominantly amorphous tablets that disintegrated in less than 10 s. Optimized tablets were chemically and physically stable over 9 months storage at 25 °C. As speed of drug liberation is the critical performance attribute for a solid dosage form designed to deliver drug in an emergency, a novel imaging based in vitro disintegration assay for buccal tablets was developed. The assay was optimized with regard to conditions in the buccal cavity: i.e., temperature 33-37 °C, volume of medium (0.1-0.7 mL), and use of mucin-containing biorelevant medium. The disintegration assay was sensitive to temperature, medium volume, and medium composition; naloxone tablet disintegration was extremely rapid, with full disintegration ranging from 5 to 20 s. In conclusion, rapidly disintegrating tablets have been developed which are suitable for proof-of-concept clinical trial in humans to determine the pharmacokinetics of naloxone delivered via the buccal route.

Controllable degradation kinetics of POSS nanoparticle-integrated poly(ε-caprolactone urea)urethane elastomers for tissue engineering applications.

Biodegradable elastomers are a popular choice for tissue engineering scaffolds, particularly in mechanically challenging settings (e.g. the skin). As the optimal rate of scaffold degradation depends on the tissue type to be regenerated, next-generation scaffolds must demonstrate tuneable degradation patterns. Previous investigations mainly focussed on the integration of more or less hydrolysable components to modulate degradation rates. In this study, however, the objective was to develop and synthesize a family of novel biodegradable polyurethanes (PUs) based on a poly(ε-caprolactone urea)urethane backbone integrating polyhedral oligomeric silsesquioxane (POSS-PCLU) with varying amounts of hard segments (24%, 28% and 33% (w/v)) in order to investigate the influence of hard segment chemistry on the degradation rate and profile. PUs lacking POSS nanoparticles served to prove the important function of POSS in maintaining the mechanical structures of the PU scaffolds before, during and after degradation. Mechanical testing of degraded samples revealed hard segment-dependent modulation of the materials' viscoelastic properties, which was attributable to (i) degradation-induced changes in the PU crystallinity and (ii) either the presence or absence of POSS. In conclusion, this study presents a facile method of controlling degradation profiles of PU scaffolds used in tissue engineering applications.

Fabrication of controlled-release budesonide tablets via desktop (FDM) 3D printing.

The aim of this work was to explore the feasibility of using fused deposition modelling (FDM) 3D printing (3DP) technology with hot melt extrusion (HME) and fluid bed coating to fabricate modified-release budesonide dosage forms. Budesonide was sucessfully loaded into polyvinyl alcohol filaments using HME. The filaments were engineered into capsule-shaped tablets (caplets) containing 9mg budesonide using a FDM 3D printer; the caplets were then overcoated with a layer of enteric polymer. The final printed formulation was tested in a dynamic dissolution bicarbonate buffer system, and two commercial budesonide products, Cortiment® (Uceris®) and Entocort®, were also investigated for comparison. Budesonide release from the Entocort® formulation was rapid in conditions of the upper small intestine while release from the Cortiment® product was more delayed and very slow. In contrast, the new 3D printed caplet formulation started to release in the mid-small intestine but release then continued in a sustained manner throughout the distal intestine and colon. This work has demonstrated the potential of combining FDM 3DP with established pharmaceutical processes, including HME and film coating, to fabricate modified release oral dosage forms.

3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics.

Three dimensional printing (3D printing) was used to fabricate novel oral drug delivery devices with specialized design configurations. Each device was loaded with multiple actives, with the intent of applying this process to the production of personalized medicines tailored at the point of dispensing or use. A filament extruder was used to obtain drug-loaded--paracetamol (acetaminophen) or caffeine--filaments of poly(vinyl alcohol) with characteristics suitable for use in fused-deposition modeling 3D printing. A multinozzle 3D printer enabled fabrication of capsule-shaped solid devices containing the drug with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different to the drug in the adjacent layers, and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least-squares component matching to produce false color representations of distribution of the drugs was used. This clearly showed a definitive separation between the drug layers of paracetamol and caffeine. Drug release tests in biorelevant bicarbonate media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both paracetamol and caffeine was simultaneous and independent of drug solubility. With the DuoCaplet design, it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device; the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.