Customizable drug tablets with constant release profiles via 3D printing technology.

Medicine should ideally be personalized as each individual has his/her own unique biological, physical, and medical dispositions. Medicine can be personalized by customizing drug tablets with the specific drug dosages, release durations, and combinations of multiple drugs. This study presents a method for fabricating drug tablets with customizable dosages, durations, and combinations of multiple drugs by using the 3D printing technology. The method focuses on fabricating customizable drug tablets with a very simple structure for delivering the constant release profile due to its importance in treatment (i.e., the drug may produce side effects if too much is released andmay not have therapeutic value is too little is released). The method is simple: it involves first printing a template using the 3D printer and fabricating the drug tablet via the template. The tablets are customized by varying the amount of excipient used, the height of the tablet, and the numberand amount of drugs used. Three different common drugs (i.e., paracetamol, phenylephrine HCl and diphenhydramine HCl) and FDA-approved excipients are studied. The simplicity of the structure of the tablet and method via templating allows the fabrication of these fully customizable drug tablets to be easily performed, low-cost, efficient, and safe for consumption. These features enable the customizable tablets to be made widely accessible to the public; hence, the concept of personalized medicine can be realized.

On-demand fully customizable drug tablets via 3D printing technology for personalized medicine.

Personalized medicine should ideally be prescribed to every individual because of the unique characteristics (e.g., biological, physical, and medical) of each individual. It is, however, challenging to provide personalized medicine for the mass population of specific individuals effectively and efficiently. This manuscript describes a method of fabricating fully customizable drug tablets for personalized medicine by the 3D printing technology. This method involves the versatile fabrication of the tablets via the specifically designed 3D printed molds of different shapes and sizes, and an intuitive 1-dimensional release of drug that relates the shape of the drug-containing matrix to the release profile. The customization includes all the aspects of varying dosage, duration, release profiles, and combination of multiple drugs. In particular, it has previously been technically difficult to devise a single platform that fabricates carriers that release drug with any desired type of release profiles. This method of fabricating fully customizable tablets is simple, inexpensive, and efficient. Detailed selection and investigation of the materials ensured that the tablet and the method of fabrication are safe (e.g., biocompatible, FDA-approved ingredients used) and other desirable features (e.g., sustained release and high dosage) are achieved. These desirable characteristics of the method thus allow fully customizable drug tablets to be fabricated efficiently on the spot after the diagnosis of individual patients; at the same time, the method can be made widely accessible to the mass population. Hence, the concept of personalized medicine can truly be realized.

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.

Polymeric Microneedle Array Fabrication by Photolithography.

This manuscript describes the fabrication of polymeric microneedle (MN) arrays by photolithography. It involves a simple mold-free process by using a photomask consisting of embedded micro-lenses. Embedded micro-lenses were found to influence MN geometry (sharpness). Robust MN arrays with tip diameters ranging between 41.5 µm ± 8.4 µm and 71.6 µm ± 13.7 µm, with two different lengths (1,336 µm ± 193 µm and 957 µm ± 171 µm) were fabricated. These MN arrays may provide potential applications in delivery of low molecular and macromolecular therapeutic agents through skin.

Direct microneedle array fabrication off a photomask to deliver collagen through skin.

PURPOSE: To fabricate microneedle arrays directly off a photomask using a simple photolithographical approach and evaluate their potential for delivering collagen. METHODS: A simple photolithographical approach was developed by using photomask consisting of embedded micro-lenses that govern microneedle geometry in a mould free process. Microneedle length was controlled by use of simple glass scaffolds as well as addition of backing layer. The fabricated arrays were tested for their mechanical properties by using a force gauge as well as insertion into human skin with trypan blue staining. Microneedle arrays were then evaluated for the delivery of fluorescent collagen, which was evaluated using a confocal laser scanning microscope. RESULTS: Microneedles with sharp tips ranging between 41.5 ± 8.4 µm and 71.6 ± 13.7 µm as well as of two different lengths of 1336 ± 193 µm and 957 ± 171 µm were fabricated by using the photomasks. The microneedles were robust and resisted fracture forces up to 25 N. They were also shown to penetrate cadaver human skin samples with ease; especially microneedle arrays with shorter length of 957 µm penetrated up to 72% of needles. The needles were shown to enhance permeation of collagen through cadaver rat skin, as compared to passive diffusion of collagen. CONCLUSIONS: A simple and mould free approach of fabricating polymeric microneedle array is proposed. The fabricated microneedle arrays enhance collagen permeation through skin.

Microneedle integrated transdermal patch for fast onset and sustained delivery of lidocaine.

Lidocaine as an analgesic is of particular interest in both acute and chronic pain conditions and is used via injections or transdermal patches. While injections are associated with problems such as patient incompliance, topical administration of lidocaine using patches is less efficient due to variability of drug absorption among individuals, slower drug permeation through the skin, and hence a resultant undesirable delay in analgesic effects. To address this clinical problem, we developed a microneedle integrated transdermal patch (MITP), using a photolithography based process, in which microneedles create micrometer-sized channels in the skin to deliver lidocaine rapidly, while the reservoir patch holding the bulk of the drug enables higher drug loading and carries on to release the drug for prolonged periods. We demonstrated a new approach of drug delivery using microneedles, where drugs diffuse out of microneedles through the porous channels left by dissolving drug particles. MITP was shown to be able to encapsulate up to 70 mg of lidocaine. In vitro permeation through rat skin demonstrated that MITP delivered a significantly higher amount of lidocaine than a commercial patch and with a faster onset of drug permeation.

Effect of microneedle geometry and supporting substrate on microneedle array penetration into skin.

Microneedles are being fast recognized as a useful alternative to injections in delivering drugs, vaccines, and cosmetics transdermally. Owing to skin's inherent elastic properties, microneedles require an optimal geometry for skin penetration. In vitro studies, using rat skin to characterize microneedle penetration in vivo, require substrates with suitable mechanical properties to mimic human skin's subcutaneous tissues. We tested the effect of these two parameters on microneedle penetration. Geometry in terms of center-to-center spacing of needles was investigated for its effect on skin penetration, when placed on substrates of different hardness. Both hard (clay) and soft (polydimethylsiloxane, PDMS) substrates underneath rat skin and full-thickness pig skin were used as animal models and human skins were used as references. It was observed that there was an increase in percentage penetration with an increase in needle spacing. Microneedle penetration with PDMS as a support under stretched rat skin correlated better with that on full-thickness human skin, while penetration observed was higher when clay was used as a substrate. We showed optimal geometries for efficient penetration together with recommendation for a substrate that could better mimic the mechanical properties of human subcutaneous tissues, when using microneedles fabricated from poly(ethylene glycol)-based materials.

A simple method of microneedle array fabrication for transdermal drug delivery.

The outermost layer of skin, stratum corneum, being lipophilic limits the passive transport of hydrophilic and large molecular weight drugs. Microfabrication technology has been adapted to fabricate micron scale needles, which are minimally invasive, yet able to deliver the drugs across this barrier layer. In this study, we fabricated microneedles from a biocompatible polymer, namely, poly (ethylene glycol) diacrylate. A simple lithographical approach was developed for microneedle array fabrication. Several factors including polymerization time, ultraviolet light intensity and distance from light source were studied for their effects on microneedle formation. The microneedle length and tip diameter can be controlled by varying these factors. The microneedles were shown to be able to penetrate cadaver pig skin. Model drug rhodamine B was encapsulated in the range of 50 µg to 450 µg per microneedle array. The fabricated microneedles containing rhodamine B increased the permeability by four times than the control. Altogether, we demonstrated that the microneedle arrays can be fabricated through a simple single-step process and needles were mechanically strong to penetrate skin, increasing the permeability of encapsulated drug through skin.

A miniaturized flow-through cell to evaluate skin permeation of endoxifen.

Endoxifen, an anti-estrogenic agent, has been recently implicated in the use of breast cancer. Its physicochemical properties make it a good candidate for transdermal delivery. However, as an investigative drug, its limited supply makes it difficult to conduct extensive pre-formulation studies. To address this issue, a miniaturized flow-through diffusion cell has been fabricated that utilized minimal amounts of the drug for in vitro skin permeation studies. The novel flow-through cells have been validated against horizontal diffusion cells and shown to cause no noticeable damage to the applied skin, as observed by histological sectioning. The cells were also demonstrated to be useful in search of suitable enhancers for endoxifen. Endoxifen permeation using permeation enhancers was tested by using this new device and limonene was found to achieve highest flux, attaining the requirement for clinical applications. The fabricated cells can thus be useful in carrying out pre-formulation studies for expensive, new drug entities, both in industrial as well as academic research.

Protein encapsulation in polymeric microneedles by photolithography.

BACKGROUND: Recent interest in biocompatible polymeric microneedles for the delivery of biomolecules has propelled considerable interest in fabrication of microneedles. It is important that the fabrication process is feasible for drug encapsulation and compatible with the stability of the drug in question. Moreover, drug encapsulation may offer the advantage of higher drug loading compared with other technologies, such as drug coating. METHODS AND RESULTS: In this study, we encapsulated a model protein drug, namely, bovine serum albumin, in polymeric microneedles by photolithography. Drug distribution within the microneedle array was found to be uniform. The encapsulated protein retained its primary, secondary, and tertiary structural characteristics. In vitro release of the encapsulated protein showed that almost all of the drug was released into phosphate buffered saline within 6 hours. The in vitro permeation profile of encapsulated bovine serum albumin through rat skin was also tested and shown to resemble the in vitro release profile, with an initial release burst followed by a slow release phase. The cytotoxicity of the microneedles without bovine serum albumin was tested in three different cell lines. High cell viabilities were observed, demonstrating the innocuous nature of the microneedles. CONCLUSION: The microneedle array can potentially serve as a useful drug carrier for proteins, peptides, and vaccines.

Clinical therapeutics for phenylketonuria.

Phenylketonuria was amongst the first of the metabolic disorders to be characterised, exhibiting an inborn error in phenylalanine metabolism due to a functional deficit of the enzyme phenylalanine hydroxylase. It affects around 700,000 people around the globe. Mutations in the gene coding for hepatic phenylalanine hydroxylase cause this deficiency resulting in elevated plasma phenylalanine concentrations, leading to cognitive impairment, neuromotor disorders and related behavioural symptoms. Inception of low phenylalanine diet in the 1950s marked a revolution in the management of phenylketonuria and has since been a vital element of all therapeutic regimens. However, compliance to dietary therapy has been found difficult and newer supplement approaches are being examined. The current development of gene therapy and enzyme replacement therapeutics may offer promising alternatives for the management of phenylketonuria. This review outlines the pathological basis of phenylketonuria, various treatment regimes, their associated challenges and the future prospects of each approach. Briefly, novel drug delivery systems which can potentially deliver therapeutic strategies in phenylketonuria have been discussed.