Printable Medicines: A Microdosing Device For Producing Personalized Medicines - Pharmaceutical Technology

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Printable Medicines: A Microdosing Device For Producing Personalized Medicines
The authors describe a new method for the production of personalised medicines involving the direct printing of drug solutions or suspensions containing APIs and excipients onto edible paper carrier materials utilising ultra-precise microdrop printing technology. The approach allows ultra-precise dosing of the API according to the specific requirements of each individual patient and is suited for highly active low-dose drugs.


Pharmaceutical Technology Europe
Volume 23, Issue 1

Personalised medicine

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.5 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.6 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.7

Low-dosage forms / clinical studies

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.8,9

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

Multidosing


Figure 3: Printing of multiple APIs and time–release layers.
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 (Figure 3). 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.

Process development and approval as a carrier


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 <711> acceptance for immediate-release dosage forms, stage: S1, Q = 75 %.
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 CaCO3, Kaolin or TiO2. 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 5: Deposit of 10 droplets of a solution of 40 mg/ml Vitamin B12 in deionised water after drying.
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 Figure 4 for 5 mg Vitamin B12 on paper consisting of cellulose fibres and TiO2 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. Figure 5 shows a typical drug deposit of Vitamin B12 after drying.


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