Nina Schroedl is Technician from the Research Center Pharmaceutical Engineering GmbH, Graz, Austria.

Nina Schroedl 

Current APIs in development are often highly active, specific and targeted drug molecules that need to be delivered precisely and in small amounts. Thus, having available reliable and robust technology to manufacture and accurately deliver small amounts of APIs or API mixtures would be an important step forward in drug development. Currently, there are few technologies available that are as precise and robust as printing. As such, using this technology to directly print drug solutions or suspensions containing APIs and excipients could significantly change the way drugs are manufactured and delivered. It would offer a straightforward way of implementing the concept of personalised medicine and, furthermore, it would make formulation — one of the most time-consuming and expensive steps in pharmaceutical development — and stability issues obsolete. Because drugs could be printed on demand, no complex formulations would have to be developed. Drugs could be delivered to pharmacies and hospitals in liquid-filled cartridges or lyophilised in containers with the solvents. 

The printing of drugs was originally proposed by the Massachusetts Institute of Technology,

  and teams from several universities are now working on similar projects including Purdue University, the New Jersey Institute of Technology and Rutgers University in cooperation with the Research Center Pharmaceutical Engineering (RCPE) GmbH.

The objective of the current research project at the RCPE is the fast and costeffective development of a printing technology for drugs that can be tailored to the age, gender or lifestyle of individual patients. This can be achieved by using printing technology that allows ultraprecise dosing of APIs onto cellulose-based edible paper carrier materials. The technique is intended to be implemented for the production of small batches in hospitals or pharmacies, and the manufacture of supplies for clinical studies. 

Using the technique could significantly reduce problems, such as drug overdosing, by individually tailoring the drug dose to the constitution, lifestyle and — potentially — to the genetic profile of the individual patient. Furthermore, by printing timerelease layers on top of a drug layer, welldefined time profiles for controlled drug delivery may also be achieved.  

The technique could also help reduce costs in the development of new pharmaceuticals; for instance, for dosing studies during phase I clinical studies, reducing lengthy development times and the problems associated with classical formulation work, as only a solution or dispersion has to be processed. Drugs could be developed faster, thus meeting the goals of the critical path initiative of the FDA, which focuses on methods to speed up pharmaceutical development. Lastly, the technique also provides interesting perspectives for low-dose and multidose drugs by providing excellent and verifiable dose accuracy and homogeneity, as well as reducing or even eliminating negative interactions of the individual APIs, as they can be printed at different positions. 

Our approach to producing personalised drugs

The method for producing personalised, individually-dosed drugs involves using an inkjettype printing technique where all of the API and related excipients required by a specific patient are directly printed onto an edible substrate of a special paper carrier. 

 shows the general principle of this approach. 

Figure 1: Schematic of the setâup.			

After printing, the paper strip may be dried and online process analysers used to verify the dosing in real time, e.g., by using UV-Vis, NIR or Raman spectroscopy. For product safety reasons, as well as to prevent counterfeiting, a 2D matrix code including the drug and patient information, with up to 200 million characters per centimetre, can be printed on the paper strip. The printed paper carrier is subsequently rolled up to minimise the size of the dosage form, and then cut and inserted into a hard gelatin capsule for oral administration. The production steps for a capsule (printing, drying, controlling, rolling and inserting in a capsule) can occur within a few seconds.  

One prerequisite for the successful application of the technique is the choice of an appropriate paper carrier material and a suitable solvent, depending on the properties of the API. High solubility of the API in the solvent is preferred to ensure high API concentrations for a faster dosing process, as well as to minimise the amount of paper substrate needed. Alternatively, suspensions of API particles in an anti-solvent can be printed. The paper carrier must not interact with the API and should be highly digestible. A paper grade with high penetration volume for fluid uptake is required to print multiple API formulations onto one paper strip. 

Currently, different solvents are used to prepare the drug solutions, depending on the solubility of the APIs, e.g., deionised water, ethanol or isopropanol. Additionally propylene glycol is added to the formulations to stabilise the dosing process and to inhibit recrystallisation of the dissolved API at the printer head. Alternative solvents and anti-solvents will be evaluated in the future. 

The printing apparatus for manufacturing the medication comprises a dropondemand technology for dosing, which is based on the piezo-electric effect. This technique is adapted from inkjet printing and is used to eject a predefined amount of a drug solution or suspension onto the carrier substrate. 

A microdrop printing device from Microdrop Technologies GmbH (Germany) has been used for the experiments.

  This system consists of a fluid container, a flexible tube connecting the container with a capillary and a drop-generating electric element. The end of the capillary is formed as an orifice, where specific amounts of fluid are ejected. The capillary of the microdosing device is surrounded by a piezoelectric element, which is deformed when an electric voltage pulse is applied. This deformation leads to a compression of the capillary and, subsequently, to the ejection of a fluid droplet with an exactly defined volume (

). Dropondemand technology enables the generation of single droplets in the range of 30–500 pl. The formation of one single droplet takes about 200 µs and the maximum drop rate can be set to 2000 Hz.

  The volume of the droplets depends on the electric voltage pulse level, the geometry of the nozzle and fluid properties, such as surface tension, dynamic viscosity and contact angle.

Figure 2: Principle of the microdrop printing device using the piezoelectric effect.			

Droplets of different fluids were analysed with a video camera and image analytical tools, which showed that the size of an ejected water droplet (surface tension of 72.75 mN/m and viscosity of 1 mPa∙s) is about 80 µm for a nozzle with a diameter of 70 µm. Ethanol droplets with a considerably lower surface tension of 22.55 mN/m and a similar viscosity of 1.2 mPa∙s have a size of 65 µm. The ejection velocity for most liquids is approximately 1 m/s.			

Temperature adjustment elements are installed for heating or cooling the fluid container and the capillary, and for equilibrating the fluid flow properties before ejection; thus, constant printing conditions are guaranteed. The printing of larger amounts of the drug solution/suspension is realised by ejecting a defined number of droplets. The final dosage of the medication can be calculated from the concentration of the liquid, the droplet size and the number of droplets. This printing method provides an efficient way of manufacturing drugs with target dosages in the range of 1–20 mg of API. 

The drying of the printed paper strip after completion of the dosing process will be performed using IR-dryers or air dryers. Heat-sensitive drugs should not be exposed to temperatures exceeding 50 °C, which can be compensated by an elongated drying time. To control the quality of the final dosage form and the performance of the process, the application of an NIR or UV–Vissensor is envisioned to be an appropriate tool to measure API content on the paper strip and to ensure that the amount of residual solvent does not exceed a predefined value. 

Major advantages of the technique include the fact that most steps downstream of the API synthesis can be eliminated. In fact, after the final purification and/or crystallisation, the drug solution or suspension, including further printing additives, can be filled in cartridges. Alternatively, in case of limited drug stability in solution, a dry powder can be provided with an appropriate solvent in a twocompartment container. These prepacked drug containers are delivered to pharmacies or care providers, effectively eliminating most steps in association with powder processing, such as blending, milling, sieving, granulation, compaction and coating of solid forms. 

Potential limitations of the technique may involve the production of high-dose dosage forms because of the limited capacity of paper substrates for fluid uptake and the solubility limit of many APIs, which may prevent the dosing of highly concentrated formulations. However, solvent optimisation could offer a solution. Furthermore, the actual setup is not intended for the mass production of dosage forms with a high throughput, such as seen in conventional tablet presses.  

The main advantages and limitations of the presented technique for the production of personalised drugs are listed in

Table 1: Main advantages and limitations of the presented microdosing technique for the preparation of personalised oral dosage forms.			

Personalised medicine summarises concepts and methods that aim to achieve an individualised therapy specifically tailored to the requirements and needs of an individual patient. Conventional dosage forms, such as tablets or capsules, provide predefined contents of the APIs. As a consequence, many patients, particularly women, children and elderly persons, may be confronted with under- or overdosage, which can lead to reduced or counter-productive effects. In the proposed concept, factors such as age, weight, height, race and gender-related aspects of the individual patients can be considered and translated in precisely tailored oral delivery forms. 

For example, in paediatric healthcare, medications with the appropriate dosage are often not commercially available and only exist for a minority of drugs. To overcome this, the common practice is to cut tablets originally produced for adults into smaller portions to acquire lower dosages for children. However, this is imprecise because tablets cannot be split accurately, resulting in deviations of up to 40% from the required dosage.

  Another practice to prepare drugs for children is the conversion of a commercially available solid medication (tablet or capsule) into a liquid dosage form by dissolution of the solid in a solvent. This procedure is challenging and creates a lot of uncertainties — interactions with excipients, increased toxicity, decreased efficacy or instability of the medication are just some of the shortcomings of this practice.  

Gender studies have found that there can also be quite large differences between male and female patients in both drug efficacy and adverse drug reaction (ADR) because of differences in body weight, body composition, metabolising enzymes or hormone concentrations. These factors can influence the pharmacokinetics and pharmacodynamics of medications, such as antidepressants or other drugs.

  An adjustment of the dosage — on a daily basis — depending on the sex of the patient is, therefore, crucial. Also the consideration of female test persons in clinical studies is important for the development of personalised drugs; an FDA regulation from 1998 demands equal male and female representation in clinical trials to change dosing guidelines.

The suitability for the formulation and precise dosing of low-dose APIs with a content of less than 2 mg or 2% w/w is another advantage of the new technique. In powder dosing, a homogeneous distribution of APIs and excipients is a prerequisite for manufacturing tablets or capsules. However, this is accomplished only with significant efforts and associated costs because of the intricacies of powder blending and/or segregation effects. In contrast to powders, liquid formulations and suspensions can be mixed with proven technology, providing much better dose homogeneity and accuracy compared with powder dosing, particularly for drug products with a low therapeutic dose range.

Highly accurate, low-dose liquid printing can also be beneficial for use in clinical trials, such as during dosing studies because it can eliminate extensive formulation studies, which are usually undesirable because of the limited amount of drug substance available during the early stages of development.

  As such, direct microdosing (i.e., printing) of APIcontaining solutions or suspensions can significantly reduce costs and development time. 

Another aspect of our novel approach is the possibility of applying multiple drugs or APIs using barrier coatings for separating the single deposits printed on the paper carrier (

). One benefit of these barrier coatings is the ability to control drug release by applying time-release layers such as Eudragit, PVP or methacrylates. In addition, single deposits of different drugs can be separated by applying dedicated coating barriers. The numbers of individual dosage forms taken per day can, therefore, be reduced, leading to higher patient compliance and less sources of human error. 

Figure 3: Printing of multiple APIs and timeârelease layers.			

Process development and approval as a carrier

In our work, various aspects of the process have been studied, including drop generation, impact of the drops on the carrier surface, wicking of the solution into the carrier structure, drying and crystallisation/precipitation of the drug substance, and the suitability of various paper materials as carriers for drugs. The main components of paper are cellulose fibers and pigments, such as CaCO

. In our study, papers with defined properties were produced from different fibers and excipients to investigate the interaction of the paper grades with different APIs and to meet general pharmaceutical criteria of drug excipients. Our results indicate that, for the model substances chosen (Vitamin B6, Vitamin B12 and folic acid), neither the printing procedure nor contact with the paper has a major effect on the properties and conditions of the API. 

Figure 4: Dissolution profile of 5 mg Vitamin B12 printed on paper of cellulose fibers and TiO2 as the filler - n=6 according to USP  acceptance for immediate-release dosage forms,stage: S1, Q = 75 %.			

Furthermore, disintegration tests with water and 0.1 normal HCl solution showed an almost complete decomposition of the selected paper after a few minutes, i.e., the dissolution of the fiber network into single fibers and dispersed excipients. An example dissolution profile of Vitamin B12, used as a model drug, is illustrated in 

 for 5 mg Vitamin B12 on paper consisting of cellulose fibres and TiO

 as the filler. The dissolution profile showed an immediate release of the vitamin from the paper, as expected for an immediate-release formulation. Detailed scientific reports focusing on the specific aspects of the process will be published elsewhere. 

 shows a typical drug deposit of Vitamin B12 after drying.				

Figure 5: Deposit of 10 droplets of a solution of 40 mg/ml Vitamin B12 in deionised water after drying.			

We present a method for manufacturing a medication using microdrop printing technology, which offers new possibilities in the fields of personalised medicine, the production of lowdosage forms, including process verification, documentation and labelling, and the individual adjustment of the medication with respect to multidosing and controlled drug release. The system has already been extensively tested, provides an innovative mechanism to prevent counterfeit medications and seems to be suitable for the formulation of highly potent and active drug substances.									

 is Senior Researcher from the Research Center Pharmaceutical Engineering GmbH, Graz, Austria. 

 is Junior Researcher from the Research Center Pharmaceutical Engineering GmbH, Graz, Austria. 

 is Technician from the Research Center Pharmaceutical Engineering GmbH, Graz, Austria. 

 is R&D Manager from Dr. Franz Feurstein GmbH, Traun, Austria. 

 is Professor from the Institute for Paper, Pulp and Fibre Technology, Graz University of Technology, Graz, Austria. 

Articles

The authors describe a new method for the production of personalised medicines utilising ultra-precise microdrop printing technology.