3D Printing in Personalized Drug Delivery

Introduction

Recently, the three-dimensional (3D) printing (3DP) process, often referred to as ‘additive manufacturing’, has gained significant attention across many disciplines. It creates physical objects by successive deposition or addition of material based on a geometrical representation.¹ The advent of 3DP and the application of this technology in the pharmaceutical sector has led to a paradigm shift in the way we approach treatment options for patients. The developments and advancements seen over the last decade indicate a bright possibility of developing patient-specific drug delivery systems, ranging from oral dosage forms to deliver small drug molecules to using biodegradable scaffolds for delivering large molecules.^2,3 The applicability of this technology extends from pre-clinical studies and development to first-in-human trials and studies, while making the process more cost-effective and less labor-intensive. However, the main benefit of 3DP is to produce medications at the point of care, in hospitals or pharmacies, that are tailored to have size, shape, dose, and release profiles specific to the needs of the patient.⁴ This is attributed to the layer-by-layer deposition of material based on the design created using computer software, such as computer-aided design (CAD) software.⁵ Personalized drug delivery is an emerging area of pharmaceutical research. It is noticed that patients with the same diseases may have different complications that require different medical regimens such as some patients using combination drug therapy have to take multiple medicines at a different time per day. Besides, the bioavailability of different patient populations can be quite different (e.g. infants, children, adults and elderly), which makes a one-size-fits-all approach dubious. Moreover, people suffering from rare diseases sometimes cannot find a drug with a suitable dose because the pharmaceutical manufacturers are not willing to produce products with limited target consumers, and they have to bear the cost of storage, transportation, waste, or other costs related to overproduction.⁶ The fairly current approval of the first 3D-printed medication, Spritam® (Apprecia Pharmaceuticals) by the US FDA in 2015, has led to an increased interest in pursuing this platform for pharmaceutical development.⁷

3D Printing Technologies

Many 3D printing techniques can be applied to assist in producing pharmaceutical products. According to the type of materials that have been used, these techniques can be simply classified as filament-based, liquid-based, and powder-based 3D printing techniques.

Filament-based 3D printing

Fused deposition modeling (FDM) or fused fi lament fabrication (FFF) which produces 3D constructs with good quality at a low cost is a widely used technique. The starting material used in the process is called a filament, which is generated using the hot-melt extrusion (HME) process (Figure 1). Active pharmaceutical ingredients (APIs), mixed with polymer powders are extruded at high temperatures, based on the thermal properties of the physical mixture. This forms a flexible, printable fi lament that is loaded into the printer. The nozzle heats up during the printing process and melts the filament, which is then easily extruded layer-by-layer like toothpaste on to the printing bed. The nozzle moves along the x and y-axis as per the design selected. This process faces a limitation of drug degradation when processing thermosensitive drugs.

Liquid-based 3D printing

Another commonly used 3D printing technique that enables printing objects with high resolution is Stereolithographic (SLA) 3DP.

This technique uses a light-sensitive polymer solution as the starting material. A chemical reaction called gelation, occurs once the compounds are exposed to ultraviolet (UV) light or projected digital light. During printing, the system will emit the light in a desired pattern leading to gelation of the polymers as per the set design. A supporting structure is needed to hold the product before the first layer is printed. Once the first layer reacts with lights, it will solidify quickly so the second layer can be attached and bonded on to the former surface. After the printing is finished, excess liquid materials and the supporting scaffold are removed. A post-printing process, including polishing, is required for improving the mechanical properties of the product. However, the SLA printing speed is slow, which makes it less efficient as compared to others.

Power-based 3D printing

Selective Laser Sintering (SLS)

Another process is the Selective Laser Sintering (SLS) process, which eliminates the pre-processing of excipients and API to form filaments as done in FDM. In this case, the starting material for printing is the physical powder mixture. Before printing, the APIs and excipients are ground into fi ne particles, mixed evenly, and spread on the printer bed. A roller will then flatten the surface of the mixture, leaving a thin layer of powder on the bed. During printing, a rotating mirror reflects a laser onto the powder in the set design pattern. The laser that hits the powder in that area bonds the powder together creating a single layer of the tablet, following which, another layer of powder feed is spread over this previous layer and the process continues until the printing is finished. The drawback of this technique is that the high energy laser could potentially cause the decomposition of the APIs.

Binder Jetting

Binder jetting, also known as “drop-on-powder” printing, is another 3DP method which also uses a physical mixture of APIs and excipients as starting materials. A powder layer is applied on the supporting bed with the help of a roller and an inkjet nozzle lays liquid binder onto powder in the designed area. This binder acts as an adhesive which holds the powder together, thus forming a tablet layer. After that, the bed lowers, and new powder is spread over the previously printed layer. This process continues till the entire object has been printed. This technique is energy-efficient since it does not require heat or laser. The main concern is that the item printed using binder jetting has poor mechanical properties due to its low resolution which is limited by the recoated powder layer thickness.⁸

Applications of 3D Printing

Using the above-mentioned 3DP techniques, pharmaceutical scientists can develop dosage forms with widely varying geometries that the user can imagine, which would, in turn, help us control the release profile of the drug from the dosage form and improve patient compliance.

A study by Martinez et.al. shows that changing the surface area (SA) to volume (V) ratio of the dosage form while modifying its shape would help alter the release kinetics and tailor medications specific to a patient. SLA printing was used to create tablets with various shapes like cube, sphere, pyramid, torus, etc., of which torus was found to be the ideal delivery platform to achieve zero-order release (Figure 2).9 Also, by just modifying a single process parameter in the 3D-printer, it is possible to modify the release profile of the tablet. A recent study by Thakkar et.al. demonstrated a simple yet effective method to alter the performance dynamics of drug release for Ibuprofen, a BCS Class II drug from the HPMC-AS polymer matrix of a 3D-printed tablet by modifying the in-fill density of the printed tablet without changing any formulation parameters. Changing the in-fill density from 20% to 80% allowed flexibility to achieve a fast complete and controlled release, respectively. This study shows that without changing the formulation composition, the dosage form can be modified for the patient based on needs by sole manipulation of the printing process parameters.² Further, the robustness of using HME along with FDM to provide a versatile platform for personalized drug development while adhering to the regulatory expectations was proved by Zhang et.al. using Design of Experiment (DoE). Controlling and modifying the printing parameters (infill density, shell thickness, and layer height) showcased the platforms ability to develop customized dosage forms which is the end goal for point-of-care delivery.¹⁰ Use of FDM for printing dosage forms involves the use of high temperature to process the fi laments obtained using HME. Processing thermosensitive drugs using this platform becomes difficult due to the degradation associated with increased temperatures. As a result, a different 3DP technology such as SLS provides another novel processing platform. A study by Davis et.al. showed for the first time, a 21-fold improvement in Ritonavir solubility, a BCS class IV and thermosensitive drug by developing an ASD in a single step using the SLS-3DP process. This application of SLS-3DP to develop patient-specific, controlled release formulations in a single-step process directly from the powder blend could provide a huge leap in delivering tailored medications at the point-of-care by eliminating the extensive formulation steps involved in other processes.¹¹ The development of medications using 3DP would be highly beneficial for delivering accurate dosages to the pediatric and geriatric populations, given the pharmacokinetic differences as compared to the conventional “one size fits all” marketed medications. The pediatric population ranging from pre-term neonates to adolescents, put forward a range of challenges concerning delivery of medications, ranging from dose accuracy to excipient safety. Even though oral administration is the preferred route, most of the formulations are extemporaneously prepared due to a lack of appropriate dosage forms. Januskaite et.al. conducted a study with 368 pediatric patients, aged 4 to 11, to determine their preference for the printed medication based on visual inspection followed by the type of dosage forms. The study showed that the same drug was preferred by the participants when printed using digital light processing (DLP) as compared to those printed using SLS, SSE, or FDM. However, the preference changed to the same drug printed as chewable tablets printed using SSE. Thus, this study gives an idea that the dosage form can be modified based on the preferences of the patient of interest, which would, in turn, increase patient compliance and improve adherence to the treatment regimen. These precisely designed and produced tablets also hold an advantage over the administration of oral liquids such as syrups and emulsions, which are associated with drawbacks such as dosing errors, formulation instability, and storage concerns.¹²

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Geriatric patients show a high rate of failure to follow the treatment regimen due to the complex regimen consisting of multiple drugs with multiple dosing in one single day. Developing a formulation of a single pill that consists of more than one drug (termed as “Polypill”) with each drug component having its specific release profile would help improve adherence to the regimen and in turn improve quality of life for the elderly population in the long run. These pills can be designed to have once a day dosing or even a further extended-release, depending on the needs of the patient (Figure 3). One such study projects the use of a combination of FDM and SSE to deliver multiple drugs in one single dosage form. The polypill developed by Khaled et.al. showed a complex cardiovascular treatment regimen by incorporating a compartment for the fast or immediate release of aspirin and hydrochlorothiazide along with additional compartments including atenolol, ramipril, and pravastatin for their sustained release.

Altering the ratios of the excipients used in the development of this formulation can further help tailor the dosage form as per the patient’s needs. Such a method of using multiple 3DP techniques can help incorporate a wide range of drugs, which would be difficult to do using conventional approaches.¹³ 3DP can not only be used for altering the release profiles but can also be used to develop modified dosage forms to alter the mechanisms for prolonging the residence time in the body. Chai et.al. demonstrated the development of an intragastric drug delivery device that will enable a higher retention time in the stomach as a result of the hollow structure which allows it to float on the gastric fluid. This would enable delivering a tailored single dose to the patient, thus reducing the dosing frequency.¹⁴ A study was conducted by Li et. al., wherein thermal extrusion was used to manufacture rapid-release puerarin tablets without the use of a solvent. This method showed the combined advantages of using the FDM method and semi-solid extrusion method. The tablets showed complete release within 7.5 min and they were able to modify the release by altering the ratio of drug and polymer matrix used, which was PEG 4000.¹⁵

Besides, the 3DP technique can also be devoted to the treatment of cancer via individualized local chemotherapy. Wang et al. utilized SLA 3DP to print biodegradable implants which were loaded with anticancer drugs to treat osteosarcoma. Compared with traditional chemotherapy, this platform overcomes the issues of invasive side effects on normal cells and insufficient drug concentration in cancer cells owing to non-specific drug delivery. The model of the implant was designed after performing an immunohistochemical examination and micro-computed tomography (CT). The blank implant, printed with poly L-lactic acid (PLLA), is then soaked in the chemotherapy regimen solution (namely, doxorubicin, ifosfamide, methotrexate, and cisplatin in a small amount of dichloromethane, which escapes rapidly on its exposure to open-air conditions following further drying in a desiccator). The results of in-vitro characterization show that this PLLA implant is biodegradable with high efficiency and biosafety showing a promising drug delivery platform for anti-cancer therapy.¹⁶

Another novel application of 3D printing is its use for transdermal delivery. Biocompatible polymeric microneedle arrays were built using SLA and then coated by cisplatin formulations using the inkjetting technique. This microneedle shows an improved penetration with 80% depth and a rapid drug release rate of up to 80% to 90% within an hour. The histopathology analysis proves that this drug-loaded microneedle has enhanced tumor suppression and elimination effect. This study demonstrates the potential of 3D printed microneedle mediated drug delivery for cancer treatment.17 3DP can not only be used to develop dosage forms for delivery of drugs through the conventional routes, but it has also been used to develop novel methods to deliver drugs and aid in patient recovery after surgeries. In one such study, Wu et.al. developed a first of its kind, anti-cancer drug-loaded calcium phosphate cement (CPC) scaffold to decrease the relapse and resurgence of bone cancer post-surgery. The CPC scaffold, printed using semi-solid extrusion was allowed to set and then was coated with the 5-Fluorouracil solution, showed complete drug release in the first 2 hours and also exhibited cell killing ability. This successfully developed scaffold can be used as a novel bone graft material while also delivering personalized medication for the treatment of bone cancers.¹⁸

Conclusion

The market growth of Spritam^® and the promising future potential of 3DP for use in the pharmaceutical sector has led to a surge in the research carried out in this area with rapid progress being made each day. There still is a need to overcome the gaps to catapult this technology to a widely used platform at the point-of-care and aforementioned facilities while bridging academic research to the industry and developing regulatory guidelines for the same. The incorporation of real-time evaluation and in-line quality control would propel 3DP to a more flexible and robust stage. 3DP as a technology to improve the current healthcare and pharmaceutical sector is only limited to the creative genius of the scientist.

References

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Author Biographies

Vineet R. Kulkarni graduated with a Bachelor’s degree in Pharmacy from the University of Mumbai in India and received his Master’s degree in Pharmaceutical Sciences from Virginia Commonwealth University, USA where he was also recognized with the ‘M.S. Scholarly Excellence Award’. His work at UT Austin involves developing a process and technology for faster and efficient manufacturing of novel drug delivery systems. [email protected] LinkedIn: https://www.linkedin.com/in/vineetkulkarni-97/

Anqi Lu is a first-year Ph.D. student with Maniruzzaman Group. She has received her Bachelor’s degree in Pharmaceutical Analysis from Shenyang Pharmaceutical University, China, and obtained her Masters’ degree in Pharmaceutics from the University of Minnesota. Her current research project at UT Austin is focused on 3D printable oral formulations and process optimization. [email protected] LinkedIn: https://www.linkedin.com/in/anqi-lu-37a23b11a/

Dr. Mo Maniruzzaman is currently an Assistant Professor in Pharmaceutics and Drug Delivery at College of Pharmacy, The University of Texas (UT) at Austin and leads the newly established state-of-the-art ‘Pharmaceutical Engineering and 3D Printing (PharmE3D)’ Labs. Dr. Mo has extensive research experience in pharmaceutical drug delivery, additive manufacturing (e.g. 3D printing), medical implants, and pharmaceutical formulations. He sits on the Editorial Board of AAPS PharmSciTech, Current Drug Delivery. [email protected] Webpage: https://sites.utexas.edu/maniruzzaman/LinkedIn: https://www.linkedin.com/in/mo-maniruzzaman-63a09342/