Large Size Microneedle Patch to Deliver Lidocaine through Skin.

PURPOSE: Current topical treatments using lidocaine (LD) for analgesia have limited applications due to their delayed analgesic actions, resulted from slow drug permeation through skin. The aim of this study is to fabricate a large size microneedle (MN) array patch containing LD, with fast onset of action, for the treatment of acute and chronic pain. METHODS: The MN patch was developed through photolithography and tested for its mechanical characteristics. In vitro and in vivo skin permeation, plasma pharmacokinetics, histology and skin irritation testing have also been performed for the MN patches. RESULTS: The MN have a mechanical strength of 10-30 N and more than 90% of the microneedles on the patch penetrated skin. It was shown that LD permeated through skin within 5 min of patch application. Subsequently, the in vivo skin permeation study using a porcine model showed that LD administrated by the MN patch was able to achieve the therapeutic level locally within 10 min and sustained for 8 h. It shows most of the drug diffuses perpendicularly against skin, with little lateral diffusion. After skin permeation LD remains within skin and unquantifiable amount of LD was found in the plasma of the pigs. Minor skin irritations were observed after 6 h of microneedle contact. However, the skin irritations resolved within 1 day following the removal of MN patch. CONCLUSION: The large size MN patches showed fast onset and sustained delivery of LD through skin, potentially useful to increase the application scope of topical LD for pain management.

Controlled release of vancomycin from PEGylated fibrinogen polyethylene glycol diacrylate hydrogel.

Surgical site infection (SSI) is a common issue post-surgery which often prolongs hospitalization and can lead to serious complications such as sternal wound infection following cardiac surgery via median sternotomy. Controlled release of suitable antibiotics could allow maximizing drug efficacy and safety, and therefore achieving a desired therapeutic response. In this study, we have developed a vancomycin laden PEGylated fibrinogen-polyethylene glycol diacrylate (PF-PEGDA) hydrogel system that can release vancomycin at a controlled and predictable rate to be applied in SSI prevention. Two configurations were developed to study effect of the hydrogel on drug release, namely, vancomycin laden hydrogel and vancomycin solution on top of blank hydrogel. The relationship between the rigidity of the hydrogel and drug diffusion was found to comply with a universal power law, i.e., softer hydrogels result in a greater diffusion coefficient hence faster release rate. Besides, vancomycin laden hydrogels exhibited burst release, whereas the vancomycin solution on top of blank hydrogels exhibited lag release. A mathematical model was developed to simulate vancomycin permeation through the hydrogels. The permeation of vancomycin can be predicted accurately by using the mathematical model, which provided a useful tool to customize drug loading, hydrogel thickness and stiffness for personalized medication to manage SSI. To evaluate the potential of hydrogels for bone healing applications in cardiovascular medicine, we performed a proof-of-concept median sternotomy in rabbits and applied the hydrogels. The hydrogel formulations accelerated the onset of osteo-genetic processes in rabbits, demonstrating its potential to be used in human.

Form & formulation approaches for COntRollable Release in 3D printed Colonic Targeting (CORR3CT) budesonide tablet.

Inflammatory bowel disease (IBD) represents a group of chronic and debilitating inflammatory diseases affecting various parts of the gastrointestinal (GI) tract. The disease incidence and prevalence have been growing worldwide since the early 21st century and this upward trend is expected to continue. Due to a complex and variable clinical presentation across different patients, the efficacy of a one-size-fits-all commercial formulation for IBD remains limited. Here, we present the development of a novel adjustable and controllable release, 3D printed colonic targeting (CORR3CT) dosage form of budesonide, to reduce off-targeting adverse effects and to potentially replace the use of enemas, which are invasive and commonly associated with poor adherence. An in vitro Gastrointestinal Simulated System (GISS) model was employed in this study to examine the ability of the 3D printed tablets to deliver budesonide to various targeted sites along the gastrointestinal tract. CORR3CT tablet with Pill-in-pill configurations were designed, fabricated and the relationship between the 3D printed design and resultant dissolution profiles were established. The 3D printed tablets also exhibited excellent and comparable dose accuracy and quality versus commercial tablets, while enhancing the delivery of budesonide to the targeted colon region. Overall, this study has laid the foundational proof of concept demonstrating controllable targeting of oral therapeutics along the gastrointestinal tract using 3D printing technologies.

Preferences of Healthcare Professionals on 3D-Printed Tablets: A Pilot Study.

An inaugural study was performed to understand the perceptions of healthcare professionals toward the potential benefits of 3D printing in Singapore. This study sought to increase awareness of 3D printing applications for viable clinical applications and to elucidate the current gaps in therapy where 3D printing could play a role. A common example would be the use of 3D printing to manufacture polypills, thereby reducing the daily pill burden of patients and possibly improving medication adherence. A qualitative descriptive survey with a single-centered cross-sectional design was performed at Tan Tock Seng Hospital, a tertiary referral hospital with 1700 beds. This study had a total of 55 respondents comprising doctors and pharmacists. Most of the respondents viewed the 3D printing of oral dosage forms favorably and agreed about the potential advantages this technology could offer. More than 60% of the respondents were also willing to prescribe 3D printed tablets to patients. Respondents' concerns were grouped into three main categories: formulation considerations, manufacturing processes, and administrative issues. Viewed in its entirety, this study provides a valuable starting point for understanding the perceptions of healthcare professionals in adopting 3D printing technology.

A 3D printed human upper respiratory tract model for particulate deposition profiling.

Pulmonary route is the main route of drug delivery for patients with asthma and chronic obstructive pulmonary diseases, offering several advantages over the oral route. Determining the amount of drug deposited onto various parts of the respiratory tract allows for a good correlation to clinical efficacy of inhalation drug devices. However, current in vitro cascade impactors measure only the aerodynamic particle size distribution, which does not truly represent the in vivo deposition pattern in human respiratory tract. In this study, a human upper respiratory tract model was fabricated using a 3D printer and subsequently characterized for its dimensional accuracy, surface finishing and air leaking. The effects of using a spacer and/or various airflow rates were also investigated. To assess this in vitro model, the deposition pattern of a model drug, namely, salbutamol sulphate, was tested. The resultant deposition pattern of salbutamol sulphate from a metered dose inhaler at 15 L per minute with the spacer, showed no significant difference from that of a published radiological in vivo study performed in adult humans. In addition, it was also found that the deposition pattern of salbutamol at 35 L per minute was comparable to the results of another published study in human. This in vitro model, showing reasonable in vitro-in vivo correlation, may provide opportunities for personalized medicine in special populations or disease states.

High resolution photopolymer for 3D printing of personalised microneedle for transdermal delivery of anti-wrinkle small peptide.

Acetyl-hexapeptide 3 (AHP-3) has good efficacy and safety profile as an anti-wrinkle small peptide. However, its skin permeation is poor due to its hydrophilicity and large molecular weight. 3D printing of personalised microneedles (MN), that contour to the skin surface, offers an attractive alternative for delivery for AHP-3. However, commercially available photocurable resin for 3D printing are not suitable for fabrication of drug loaded delivery systems. In this study, two liquid monomers, namely, polyethylene glycol diacrylate (PEGDA) and vinyl pyrrolidone (VP), were investigated at various proportions, for critical parameters such as mechanical strength of final polymer, rate of polymerisation, rate of swelling of final polymer, 3D printing resolution and safety profile of final polymer. The optimal resin, based on the above parameters, was that of ratio 7 VP: 3 PEGDA in weight. Drug loading into the optimal resin demonstrated that AHP-3 remained stable throughout the fabrication process and there was no effect on the physical properties of final polymer. Using a 3D scanned face model, a personalised MN patch was designed using computer aided design (CAD) software and subsequently fabricated using a Digital Light Processing (DLP) 3D printer, with the optimal resin. In vitro characterisation of fabricated MN patch demonstrated the ability to penetrate human cadaver dermatomed skin and the MN remained intact after compression. The final polymer also had minimal cytotoxicity to human dermal fibroblast. Therefore, personalised MN patch fabricated using the photopolymer can potentially be a novel approach to augment transdermal delivery of AHP-3 for effective wrinkle management.

3D printing of four-in-one oral polypill with multiple release profiles for personalized delivery of caffeine and vitamin B analogues.

Personalized supplementation has found recent momentum with an estimated global market size of USD 1.6 billion in 2019 and an expected CAGR of 8.5% between 2020 and 2028. Alongside this rising trend, a simple, accurate, inexpensive and flexible method to produce personalized dosage forms of a wide variety of supplements would be beneficial to both the industry players and individual consumers. Here, we present a 3D printing method to fabricate a four-in-one oral polypill with multiple release profiles for personalized delivery of caffeine and vitamin B analogues. The 3D printable formulations were fabricated and optimized from existing FDA GRAS excipients based on their viscosity, shear thinning properties, recovery of paste and mechanical strength. In the polypill, vitamin B analogues and caffeine were used as the model dietary ingredients. We performed a standard 2 stage USP in vitro dissolution test of the polypill, and demonstrated that vitamin B1, B3 and B6 could be immediately released within 30 min, while caffeine could be slowly released over a period of 4 h. This demonstrated the ability dietary supplement containing different ingredients with varying release profiles, all within a single polypill. Throughout the formulation and 3D printing process, there were no detectable changes to the dietary ingredients nor any interactions with the excipients. This method serves as an intriguing complement to traditional manufacturing of oral tablets, especially when flexibility in design, dose, volume and release profiles of each dietary ingredient is required, as exemplified in personalized supplementation.

Geometrical optimisation of a personalised microneedle eye patch for transdermal delivery of anti-wrinkle small peptide.

Acetyl-hexapeptide-3 (AHP-3) is a small peptide with good anti-wrinkle efficacy and safety profile. However, due to its hydrophilicity and high molecular weight, its skin permeation is generally poor. An innovative microneedle (MN) patch such as the curved, flexible or personalised MN patch is a viable avenue to deliver AHP-3. However, the well-researched geometrical relationship of MN on a flat MN patch cannot be assumed for these novel MN patches due to a complex mix of axial and shear forces. In this study, 3D printing was used for the fabrication of various MN patches with different MN geometries and curvatures. Both mechanical strength and skin penetration efficiency were used to determine the optimal MN geometry. The optimal MN geometry was then applied to the fabrication of a personalized MN patch (PMNP) for anti-wrinkle therapy, via 3D printing. In all, the general principles of MN geometrical effects on mechanical strength and skin penetration efficiency for a curved and a flat MN patch were similar. A MN height of 800 µm, tip diameter of 100 µm, interspacing of 800 µm and base diameter of 400 µm was observed to be the optimal MN geometry across all curvatures. In vitro skin permeation study demonstrated enhanced transdermal delivery of AHP-3 using the fabricated PMNP. Therefore, PMNP with optimized MN geometry can potentially be a novel approach to augment transdermal delivery of AHP-3 for effective wrinkle management.

A miniaturized device for biomembrane permeation analysis.

Transdermal drug delivery is widely investigated as an alternative drug administration route to oral delivery and hypodermic injections. Owing to the availability of human skin samples, in vitro tests are used to predict the in vivo delivery of transdermal drugs. The most widely used validation method is skin permeation using diffusion cells. Traditional diffusion cells, however, are capacious and often require large amounts of skin sample and drugs, which is undesirable, given the scarcity of new drug entities and the limitation of skin sample supply. In this study, we fabricated miniaturized multichannel devices (MCDs) by 3D printing, to minimize the use of skin and drug samples. The MCDs were compared with conventional static diffusion cells and achieved comparable drug permeation profiles. The finite element method-based simulation revealed the efficient carry-off of permeated ingredients by the multichannel devices, and a critical role of distance between the buffer stream and skin sample in determining the flow velocity inside the chamber. The results support these devices as qualified alternatives to Franz cells for in vitro permeation studies using biomembranes, with reduced use of skin and drug samples.

Enhanced Skin Permeation of Anti-wrinkle Peptides via Molecular Modification.

Wrinkles can have a negative effect on quality of life and Botox is one of the most effective and common treatments. Argireline (Arg0), a mimetic of Botox, has been found to be safer than Botox and effective in reducing wrinkles, with efficacies up to 48% upon 4 weeks of twice daily treatment. However, the skin permeation of Arg0 is poor, due to its large molecular weight and hydrophilicity. Arg0 exists in zwitterionic form and this charged state hindered its skin permeation. Chemical modification of the peptide structure to reduce the formation of zwitterions may result in increased skin permeability. We investigated a total of 4 peptide analogues (Arg0, Arg1, Arg2, Arg3), in terms of skin permeation and wrinkle reduction. The 4 peptides were dissolved in various propylene glycol and water co-solvents. Enhanced human skin permeation was demonstrated by both Arg2 and Arg3 in vitro. On the other hand, the abilities of the 4 analogues to reduce wrinkle formation were also compared using primary human dental pulp stem cells derived neurons. By measuring the inhibition of glutamate release from the neurons in vitro, it was shown that Arg3 was the most effective, followed by Arg1, Arg0 and Arg2.

3D printed drug delivery and testing systems - a passing fad or the future?

The US Food and Drug Administration approval of the first 3D printed tablet in 2015 has ignited growing interest in 3D printing, or additive manufacturing (AM), for drug delivery and testing systems. Beyond just a novel method for rapid prototyping, AM provides key advantages over traditional manufacturing of drug delivery and testing systems. These includes the ability to fabricate complex geometries to achieve variable drug release kinetics; ease of personalising pharmacotherapy for patient and lowering the cost for fabricating personalised dosages. Furthermore, AM allows fabrication of complex and micron-sized tissue scaffolds and models for drug testing systems that closely resemble in vivo conditions. However, there are several limitations such as regulatory concerns that may impede the progression to market. Here, we provide an overview of the advantages of AM drug delivery and testing, as compared to traditional manufacturing techniques. Also, we discuss the key challenges and future directions for AM enabled pharmaceutical applications.

Author Correction: Enhanced Skin Permeation of Anti-wrinkle Peptides via Molecular Modification.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Formulation, characterization and evaluation of mRNA-loaded dissolvable polymeric microneedles (RNApatch).

In this paper, we report a proof of concept study on the fabrication, characterization and therapeutic evaluation of in vitro transcribed messenger RNA (mRNA) loaded in a dissolving microneedle patch (RNApatch). We show that low molecular weight polyvinylpyrrolidone (PVP) can directly be used without further purification for RNApatch fabrication with no detectable mRNA degradation. Physical and functional integrity of mRNA stored within the RNApatch are completely preserved for at least 2 weeks under ambient conditions. While the loading of mRNA into RNApatch is limited by the solubility of mRNA in concentrated PVP solution, mechanical strength of RNApatch is not compromised by the presence of mRNA. RNApatch can mediate in vivo transgene expression of mRNA encoding luciferase for up to 72 hours and transfection efficiency and kinetics mediated by RNApatch compares favorably to subcutaneous injection. Interestingly, mRNA transfection efficiency does not correlate with contact surface area but instead increases with deeper delivery depths. In an E.G7-OVA immunotherapy model, RNApatch induces slightly higher cellular and humoral immune responses compared to subcutaneous injection. In conclusion, RNApatch is a viable delivery platform for mRNA and represents an attractive option with significant translation potential for the delivery of mRNA therapeutics.

Three-dimensional printing of a microneedle array on personalized curved surfaces for dual-pronged treatment of trigger finger.

The hand function of patients who suffer from trigger finger can be impaired by the use of traditional splints. There is also a risk of systemic side effects with oral non-steroidal anti-inflammatory drugs (NSAIDs) used for pain relief. Microneedle-assisted transdermal drug delivery offers an attractive alternative for local delivery of NSAIDs. However, traditional microneedle arrays fabricated on flat surfaces are unable to deliver drugs effectively across the undulating skin surface of affected finger(s). In this study, using 3D printing, a dual-function microneedle array has been fabricated on personalized curved surfaces (microneedle splint) for drug delivery and splinting of the affected finger. The novel microneedle splint was assessed for its physical characteristics and the microneedles were shown to withstand up to twice the average thumb force without fracturing. An average skin penetration efficiency of 64% on dermatomed human cadaver skin was achieved and the final microneedle splint showed biocompatibility with human dermal cell lines. A significantly higher amount of diclofenac permeated through the skin by 0.5 h with the use of the microneedle splint as compared to intact skin. The fabricated microneedle splint can thus be a potential new approach to treat trigger finger via personalized splinting without affecting normal hand function.

Squid suckerin microneedle arrays for tunable drug release.

Microneedles are increasingly used in transdermal delivery of therapeutic agents due to the elimination of first-pass metabolism, simplicity of operation, and lack of pain, which collectively lead to improved patient compliance. However, microneedles are still met by challenges with regard to the choice of biocompatible materials and the control of drug release profiles. Herein, we tackle these limitations by producing microneedles from a biocompatible robust biopolymer, namely squid sucker ring teeth (SRT) proteins (suckerins), using a soft lithography method. Taking advantage of the modular sequence design of suckerins leading to their self-assembly into ß-sheet enriched structures, suckerin microneedles display an accurate replication of their templates with robust mechanical properties, endowing them with a high skin penetration capability. Critically, the ß-sheet content in the microneedles can be modulated by varying the solvent conditions, which allows tuning of the mechanical response, and in turn the drug release rates by more than one order of magnitude. In vitro skin permeation studies of suckerin microneedles using human cadaver skin samples suggest a fast onset and enhanced skin permeation of drugs compared to flat patches. The skin permeation can also be tailored 10-fold by applying hydrogen bond disruptor solutions. As a proof-of-concept, the anti-bacterial drug kanamycin is encapsulated within the microneedles, leading to efficient anti-bacterial activity and offering an additional benefit to further minimize the risk of infections caused by microneedle-based drug delivery systems. Lastly, suckerin microneedles are found to be biocompatible in cell culture studies, opening the door to further clinical applications.

Effectiveness of a multidisciplinary home-based medication review program in reducing healthcare utilization among older adult Singaporeans.

AIM: The study aimed to: (i) evaluate the effectiveness of a multidisciplinary home-based medication review (HBMR) program in reducing hospital admissions and emergency department (ED) visits, cost of hospital admissions and length of stay (LOS); and (ii) determine the prevalence of drug-related problems (DRP) in elderly Singaporeans. METHODS: A retrospective observational study was carried out at an academic medical center in Singapore. Patients referred between 1 March 2011 and 31 December 2012 were included. Frequency of hospital admissions and ED visits, cost of hospital admissions, and LOS 6 months before and after HBMR, number of DRP, their categories, and their outcomes (i.e. resolved/ unresolved) were recorded. RESULTS: The analysis included 107 patients with a mean (SD) age of 75.6 years (7.6 years). HBMR resulted in a 41% reduction in risk for hospital admissions (Incidence rate ratio 0.59, 95% CI 0.47-0.73, P < 0.001). The same magnitude of reduction was observed for ED visits. The mean (SD) cost of hospital admissions reduced from $16 957.77 ($16 118.35) before HBMR to $7488.76 ($12 773.40) after (P < 0.001). Among 62 patients with hospital admissions before and after HBMR, the mean (SD) LOS decreased from 26.5 days (22.4 days) to 17.6 days (17.8 days; P = 0.010). The team identified 525 DRP from 1353 medications reviewed. Of these, 34 (6.7%) and 174 (34.1%) were resolved with and without physician involvement, respectively. The most common DRP identified were failure to receive drug (n = 163, 31.0%) and untreated indication (n = 140, 26.7%). CONCLUSIONS: The multidisciplinary HBMR program was associated with reduced ED visits, hospital admissions, LOS and costs in older adult Singaporeans with multiple DRP. Geriatr Gerontol Int 2017; 17: 302-307.

Three-Dimensional Printing of Carbamazepine Sustained-Release Scaffold.

Carbamazepine is the first-line anti-epileptic drug for focal seizures and generalized tonic-clonic seizures. Although sustained-release formulations exist, an initial burst of drug release is still present and this results in side effects. Zero-order release formulations reduce fluctuations in serum drug concentrations, thereby reducing side effects. Three-dimensional printing can potentially fabricate zero-order release formulations with complex geometries. 3D printed scaffolds with varying hole positions (side and top/bottom), number of holes (4, 8, and 12), and hole diameters (1, 1.5, and 2 mm) were designed. Dissolution tests and high performance liquid chromatography analysis were conducted. Good correlations in the linear release profiles of all carbamazepine-containing scaffolds with side holes (R(2) of at least 0.91) were observed. Increasing the hole diameters (1, 1.5, and 2 mm) resulted in increased rate of drug release in the scaffolds with 4 holes (0.0048, 0.0065, and 0.0074 mg/min) and 12 holes (0.0021, 0.0050, and 0.0092 mg/min), and the initial amount of carbamazepine released in the scaffolds with 8 holes (0.4348, 0.7246, and 1.0246 mg) and 12 holes (0.1995, 0.8598, and 1.4366 mg). The ultimate goal of this research is to improve the compliance of patients through a dosage form that provides a zero-order drug release profile for anti-epileptic drugs, so as to achieve therapeutic doses and minimize side effects.

Real-World Impact of Setting a Narrow International Normalized Ratio Target Range in the Management of Older Adult Patients on Warfarin.

INTRODUCTION: Elderly patients intrinsically have higher bleeding risks, deterring clinicians from prescribing them oral anticoagulants. Setting a narrow international normalized ratio (INR) target range might potentially mitigate some of these risks. This study sought to compare the outcomes of elderly patients who were assigned to either a narrow INR target range or the conventional INR target range in a real-world environment. METHODS: This was a retrospective cohort study with the primary and secondary outcomes being the mean percentage time above INR 3.0 and the mean percentage time below INR 2.0 and the incidents of bleeding and thromboembolism associated with oral anticoagulant therapy, respectively. Patients and health care workers managing them had no prior knowledge of this study. RESULTS: Data of 150 patients with a narrow INR target range (2.0-2.5) and 164 patients with a conventional INR target range (2.0-3.0) were collected and analyzed. The narrow INR group had significantly higher underlying risks of bleeding than the conventional INR group. Patients in the narrow INR group had a significantly lower percentage time above INR 3.0 but no significant difference in the percentage time below INR 2.0. Adjusted incidence rate ratio (IRR) for bleeding events was significantly lower for the narrow INR group, while the adjusted IRR for thromboembolic events between both groups was similar. CONCLUSION: Patients assigned to a narrow INR target range in real-world practice spent a significantly lower amount of time below an INR of 3.0 compared to conventional INR target range with lower incidents of bleeding complications and no increase in subtherapeutic INRs.

Adherence to premixed insulin in a prefilled pen compared with a vial/syringe in people with diabetes in Singapore.

BACKGROUND: The real-world clinical effectiveness of exogenous insulin is limited by nonadherence. Various insulin delivery systems have been developed to help improve adherence, with prefilled pens gaining popularity among adult Singaporeans with diabetes. However, adherence to insulin in people with diabetes in Singapore and most of Asia has not been studied. OBJECTIVES: This study aimed to compare adherence to premixed insulin formulated in a prefilled pen versus a vial/syringe and to identify predictors of adherence in 955 patients managed at the outpatient clinics of the largest acute care hospital in Singapore. METHODS: In this retrospective longitudinal study, electronic medical and pharmacy refill records were used to determine adherence to insulin over 24 months, measured in terms of compliance and persistence. Compliance is expressed as the medication possession ratio (used as continuous and categorical variables), and persistence is reported as a dichotomous variable with a permissible refill gap of 30 days before discontinuation of therapy is considered. Multivariate linear or logistic regression analysis was used to identify predictors of adherence. RESULTS: Compared with prefilled pen users, vial/syringe users were older (mean [SD] age, 64.1 [10.6] vs 62.4 [11.9] years; P = 0.032), and more were undergoing polypharmacy (69.6% vs 54.1%; P < 0.001). The mean (SD) medication possession ratio was comparable in vial/syringe versus prefilled pen users (83.8% [26.9%] vs 86.0% [23.2%]; P = 0.266). Prefilled pen users were more persistent with therapy compared with vial/syringe users (odds ratio = 1.36; 95% CI, 1.01-1.86) after adjusting for sociodemographic and clinical covariates. Median time to discontinuation of therapy was comparable (vial/syringe vs prefilled pen: 409 vs 532 days; P = 0.076). Being managed by an endocrinologist and not receiving government subsidies were significant predictors of persistence. CONCLUSIONS: Compared with other studies that found strong associations between adherence and insulin devices, the findings of this study suggest that persistence but not compliance varies by insulin device. The willingness to pay for health care, in addition to affordability, may affect insulin therapy adherence. Patients with uncontrolled diabetes due to suspected nonadherence may benefit from referral to a multidisciplinary care team comprising endocrinologists, diabetes nurse educators, dietitians, and allied health professionals. These findings are applicable to outpatients with similar demographic features managed at other acute care hospitals in Singapore. The impact of insulin devices on glycemic control needs to be investigated in future larger studies.