MAILLART I had to live in the desert before I could understand the full value of grass in a green ditch."
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CLOTHES = CONDITION X STYLE
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LOGIC FNS FROM PRE REGD DATA IN YR MIND
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HUMN - SMALL OUTCROP OF NATR-
SHOW GRACEFULNESS AND GRATEFULNESS TO EVERYBODY AND EVERYTHING
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WESTECH NOT V BUT PLUS EASTMED
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3D printing, paediatric medicines
Lack of age-appropriate commercially available drugs hinders adequate pharmacotherapy in children. The European Union Paediatric Regulation (EC No1901/2006) and the establishment of the EU Paediatric Committee PDCO (2007) were aimed to stimulate research into the use of medicines in children and to lead to the authorisation of more medicines among all age groups. Since then, we have seen indeed an increase in the number of authorised medicines for children.1 But progress has been slow, as is expressed by the fact that 47.7% of all oral medicines on the 2019 WHO Essential Medicines List for Children do not have an age-appropriate dosage form registered by the European Medicines Agency (EMA).2 In our comprehensive paediatric care hospital, we see that more than half of oral drugs need to be manipulated somehow, for instance, by crushing, splitting or dissolving adult-dosed tablets, before they can be administered to children. The drugs that need to be manipulated represent a broad range of therapeutic subgroups like antiepileptics, corticosteroids, antihypertensives, immunosuppressants and antiarrhythmic drugs. For example, the class Ic antiarrhythmic drug flecainide has no authorised paediatric formulation in the EU. The adult oral product is a flecainide tablet with a minimum strength of 50 mg. To achieve the correct dose for the child (sometimes as low as a few milligrams in small children), flecainide tablets are split, suspensions are compounded, or bad tasting intravenous liquids are given orally using a syringe. Manipulating medication in such way inevitably leads to serious medication errors sooner or later.3 We want to stress the importance to continuously promote the development of suitable palatable paediatric dosage forms. Catalysing the integration of three-dimensional (3D) printing technology in medicines’ development can support this purpose.
3D-printing technology
3D-printing technology is a fast developing novel method to formulate personalised medicine. This manufacturing technique uses computer-aided design software and a 3D printer to print materials, layer by layer, in a precise manner. By loading these materials with an active pharmaceutical ingredient (API), it is possible to create solid pharmaceutical preparations in a desired shape or form suitable for the specific patient. To print pharmaceutical dosage forms, there are different techniques with corresponding starting materials: ranging from powders normally used in tablets, to polymers such as Soluplus or polyethylene glycol and even chocolate. Powders can be sintered with a laser or agglomerated with a binder solution (mainly consisting of polymers such as pregelatinised starch or povidone). Semisolid materials can be extruded through a nozzle, forming spaghetti-like strands. These 3D-printing techniques can lead to a variety of dosage forms such as (mini)tablets, orodispersible films or chewable soft dosage forms.4 Depending on the technique, the starting material and the printing resolution, objects with different visual appearances can be printed. The appearance of medicines influences children’s visual perception and acceptance. Januskaite et al compared tablets printed with four different techniques. These tablets were rated visually by 368 children in terms of visual appearance, familiarity, perceived taste and texture.5 Once told that one of the tablets was chewable, the majority of the children favoured the chewable printed tablet. With the flexibility 3D printing offers, it is possible to address individual preferences with regard to palatability, which is a vital characteristic for a child’s acceptance of and compliance to (chronic) medication.
Besides the benefits described above, 3D printing offers the option to print (extreme) low dosages in an accurate way and to adjust the dose easily by varying infill ratio (0% for a hollow object–100% for a solid object), tablet size or API-concentration in the starting material. Risky manipulations by nurses, pharmacy staff or caregivers can thus be avoided. Printing of multiple APIs in a single oral formulation forming a so-called ‘poly-pill’ will become optional, which is beneficial for children who need to take multiple medicines. Furthermore, dissolution rates can be tuned with 3D printing, either by varying the infill ratio or by using carrier materials with, for example, an extended solubility rate. Combining such carriers gives the opportunity to tailored dissolution profiles in one single tablet. Tailored dissolution profiles can be used in personalising, for example, ADHD (attention deficit hyperactivity disorder) therapy with methylphenidate, when the release profile is adjusted to the daily schedule of each child.4 6
The advantages of 3D printing are endorsed by a group of healthcare professionals. Rautamo et al interviewed a paediatric focus group of physicians, nurses and pharmacists that were new to the concept of 3D-printed medicine. This group considered many positive aspects of the technique that could benefit drug treatment in children and could improve adherence to medications. The professionals also expressed their concerns which were mostly associated with medication safety.7 Although printing medicines directly based on an electronic prescription by a clinician can be an improvement in the medication process, questions arise about responsibilities and validation of computerised systems. Next to that, the quality of the printed product like dose accuracy and shelf-life must be ensured. These concerns should be resolved by all parties working in the field of 3D printing, including regulatory authorities, the pharmaceutical industry and researchers.6
Suitable candidate APIs for 3D-printed paediatric medicines
The recent technological advancements will lead to great opportunities at our disposal in the coming years. Optimal use of 3D-printing technology in the clinic or at home will depend on which type of APIs for paediatric use will benefit the most from this technique. We suggest to focus first on development of medication that currently lacks suitable oral formulations for paediatric use. In our opinion, these are as follows: drugs to treat specific metabolic diseases during childhood (eg, enzyme deficiencies), drugs that need to be dosed very low (eg, hormones in endocrinology) and drugs for which dosing is frequently adjusted based on increasing bodyweight of the growing child or individual pharmacokinetic parameters (eg, antiepileptic drugs, cardiovascular drugs and immunosuppressive agents). Second, distasteful oral solutions and suspensions, or tablets that are too large to swallow, are candidates for 3D printing. Third, currently available paediatric formulations could be improved. Printed tablets with (individualised) sustained release profiles of some drugs (eg, methylphenidate) could contribute to more stable therapeutic levels over the day, leading to an increase of therapeutic effect and safety of APIs with a narrow therapeutic window. Last, frequently used combinations of medications could be printed in a poly-pill.
Clinical trial with 3D-printed tablets in a paediatric population
To date, only one clinical trial with 3D-printed drugs in a paediatric population was published. Goyanes et al studied the use of 3D printing for manufacturing chewable isoleucine supplements in a hospital setting for the treatment of four children (3–16 years) with maple syrup urine disease (MSUD), a rare metabolic disorder. Treatment of MSUD involves oral supplementation of the amino acid isoleucine. The dose administration normally requires practitioners to prepare extemporaneous formulations due to the lack of suitable commercial products. Administration of the printed isoleucine tablets led to well-controlled serum levels that were closer to the target value with less variability than the serum levels after administration of standard-care handmade isoleucine capsules.8 With regard to the printed isoleucine tablets, the authors showed that the patients had different preferences in terms of flavour and colour, but acceptability was overall high.8 This outcome supports the overall idea that 3D printing is a suitable flexible manufacturing method and can replace hazardous manipulation. However, the significance of the technique is ideally studied in a larger population.
Conclusion
The pace of innovation in the field of 3D printing of drugs has accelerated in the last decade. We expect that new 3D-printed drugs will be introduced in the paediatric clinic in the coming years. Clinical implementation should be facilitated and knowledge gaps should be overcome in order to provide every child the benefit of this new manufacturing method. Major attributes of 3D printing like taste-masking, flexible shape and dosing seem par excellence applicable for personalising children’s medication. The possibilities to create attractive child-friendly dosage forms and additional possibilities to fully personalise each child’s daily medication seem infinite. Through 3D printing, the expansion of options for child-tailored pharmacotherapy truly will be boosted.
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