# Regulations on excipients used in 3D printing of pediatric oral forms

M. Monteil, Noelia M. Sanchez-Ballester, Jean-Marie Devoisselle, Sylvie Bégu, I Soulairol

► To cite this version:

M. Monteil, Noelia M. Sanchez-Ballester, Jean-Marie Devoisselle, Sylvie Bégu, I Soulairol. Regulations on excipients used in 3D printing of pediatric oral forms. International Journal of Pharmaceutics, 2024, 662, pp.124402. 10.1016/j.ijpharm.2024.124402. hal-04672536

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Submitted on 19 May 2025

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# Regulations on excipients used in 3D printing of pediatric oral forms

M. Monteil<sup>a</sup>, N. M.Sanchez-Ballester<sup>a,b</sup>, J.M. Devoisselle<sup>a</sup>, S. Begu<sup>a,*</sup>, I. Soulairol<sup>a,b,**</sup>

<figure><img src="image_2.png" /></figure>

## ARTICLE INFO

### Keywords:

- Excipients

- Safety

- 3D printing

- Pediatric

- Toxicity

## ABSTRACT

A promising solution to customize oral drug formulations for the pediatric population has been found in the use of 3D printing, in particular Fused Deposition Modeling (FDM) and Semi-Solid Extrusion (SSE). Although formulation development is currently limited to research studies, the rapid advances in 3D printing warn of the need for regulation. Indeed, even if the developed formulations include pharmaceutical excipients used to produce traditional oral forms such as tablets, the quantities of excipients used must be adapted to the process. Therefore, the aim of this literature review is to provide a synthesis of the available safety data on excipients mainly used in extrusion-based 3D printing for the pediatric population. A total of 39 relevant articles were identified through two scientific databases (PubMed and Science Direct). Then, groups of the main excipients were listed including their general information (name, chemical structure and pharmaceutical use) and a synthesis of the available safety data extracted from several databases. Finally, the role of the excipients in 3D printing, the amount used in formulations and the oral dose administered per form are presented.

## 1. Introduction

Most part of the medicines (capsules, tablets) are designed to meet the needs of adult patients and are not suitable for children. In fact, treatments developed for adults cannot always be administered to the youngest patients, as the development of medicines suitable for children has its own guidelines (O'Brien et al., 2019). Despite this, off-label use remains common in pediatrics, affecting around 40% of medicines used in pediatric intensive care and up to 80% of those prescribed in neonatology (Kaguelidou et al., 2022). However, the immaturity of newborn's organs and physiological system can alter the absorption and distribution of Active Pharmaceutical Ingredient (API) and excipients.

For example, the pH of a newborn's gastric fluid is higher (1.8-6.1) than that of an adult (1.4-2.1), resulting in increased absorption of basic APIs and decreased absorption of acidic ones (Neal-Kluever et al., 2019; O'Brien et al., 2019). Similarly, intestinal transit is slower in newborns than in adults, inducing a higher absorption. The influence of the physiological variations illustrates why formulations (choice of excipient and quantity) need to be adapted to the pediatric population in order to reduce variations in pharmacokinetic parameters (O'Brien et al., 2019). For example, propylene glycol, commonly used in solid dosage forms as a humectant and preservative, can cause damage to the central nervous system if exposed to high doses, particularly in patients under 4 years of age (Kaguelidou et al., 2022; Rouaz et al., 2021). Thus,

Abbreviations: ADI, administrable daily intake; ADME, administration distribution metabolism elimination; API, active pharmaceutical ingredient; bPMMA, basic butylated methacrylate copolymer; bw, Body weight; CMC-Na, carboxymethylcellulose sodium; DSC, differential scanning calorimetry; EFSA, european food safety authority; EMA, european medicine agency; EUPFI, european pediatric formulation initiative; FDA IID, food and drug administration inactive ingredient database; FDM, fused deposition material; GRAS, generally recognized as safe; HME, hot-melt extrusion; HMW, high molecular weight; HPC, hydroxypropyl cellulose; HPMC, hydroxypropylmethyl cellulose = hypromellose; HPMCAS, hydroxypropylmethyl cellulose acetate succinate; LD50, median lethal dose; LMW, low molecular weight; MA, marketing authorization; MC, methylcellulose; MCC, microcrystalline cellulose; MFI, melt flow index; MOS, margin of safety; MPL, maximum permitted level; MW, molecular weight; NOAEL, no observed adverse effect level; PAM, pressure assisted microsyringe; PEG, poly(ethylene) glycol; PEO, polyethylene oxide; Ph. Eur., europaean pharmacopoeia; PPI, pediatric plan of investigation; PRISMA, preferred reporting items for systematic reviews and *meta*-analyses; PVA, poly(vinyl alcohol); PVP, poly(vinylpyrrolidone) = povidone; PVPP, crospovidone; ODF, orodispersible dosage forms; SD, silicon dioxide; SLS, selective laser sintering; SSE, Semi-solid extrusion; STEP, safety and toxicity of excipients for paediatrics; TDI, tolerable daily intake; TDLo, toxic dose low; Tg, glass transition; Tm, melting point; WHO, world health organization; Wt%, weight percentage; 3DP, three-dimensional printing.

<footnote><sup>a</sup> ICGM, Univ Montpellier, CNRS, ENSCM, Montpellier, France</footnote>

<footnote><sup>b</sup> Department of Pharmacy, Nîmes University Hospital, Nîmes, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>** Corresponding author at: ICGM, Univ Montpellier, CNRS, ENSCM, Montpellier, France.</footnote>

<footnote>E-mail addresses: sylvie.begu@umontpellier.fr (S. Begu), ian.soulairol@montpellier.fr (I. Soulairol).</footnote>
the choice of excipients depends not only on the population (adult or pediatric) but also on the age of the patient. Indeed, the pediatric population cannot be reduced to a single group, but is divided into several subcategories: neonates, infants (28 days-23 months), children (2-11 years) and adolescents (12-16 years). Then, the medicine, through its API and excipient concentration must be adapted to each patient category (Belayneh et al., 2020). As a result, the development of targeted population medicines remains challenging and, from an industry perspective, adopting a patient-centered approach for such a small target group is costly (Hanning et al., 2016).

To improve the safety of medicines for children, European Medicine Agency (EMA) has published guidelines for each age group with the following information:

1. Have dosages adapted to the weight of the child,

2. Have a concentration or dose adapted to the volumes to be administered,

3. Allow for a limited number of daily doses,

4. Not contain potentially dangerous excipients, especially in neonates or for chronic use,

5. Be acceptable in terms of palatability,

6. Be easy for the caregiver or family to administer. (European Medicine Agency (EMA), 2018)

With all these specifications to be considered, developing pediatric medicines is a challenge. The APIs and excipients (nature and concentration) must comply with the safety regulations of EMA, while the medicine has to be easily administrated to children. The choice of excipient therefore also depends on the final form of the medicine, which adds further requirements. An ideal pediatric formulation should meet all of these requirements (long term storage, swallowability) and offer flexibility in dosing (Bracken et al., 2022; O'Brien et al., 2019). For young patients, oral liquid formulations may be preferred as they are easy to swallow and allow dose flexibility. However, the use of concentrated liquids forms can lead to errors in volume measurement (i. e. 1 ml instead of 0.1 ml) (Smith et al., 2022). Liquid dosage forms also present stability issues requiring the addition of excipients such as preservatives at concentrations that may not be appropriate for children.

Contrary to liquid forms, solid medicines are often preferred by the pharmaceutical industry due to their lower manufacturing costs and their long-term stability. However, the acceptability of solid oral forms, such as tablets, depends on several criteria such as swallowability, amount of water needed for the intake and palatability. Thus, conventional oral solid forms are limited for the pediatric population, as most children are not able to take tablets regularly before the age of 8-10 years old. In order to facilitate the administration and the dose adjustment, there are tablet designed to be broken or crushed, however, dose flexibility is still limited (Mfoafo et al., 2021; Smith et al., 2022). All these constraints make the development of customized solid formulations a challenge.

To overcome these drawn-backs, new products are being developed using conventional methods, such as orodispersible tablets, films or chewable formulations. Orodispersible forms are designed to disintegrate and be absorbed in the oral cavity, but do not allow flexible dosing. Chewable formulations avoid swallowing, making them more acceptable to children over the age of two. Yet, depending on children's ability to chew, drug release and therapeutic effect may change, resulting in pharmacokinetics variability (Mfoafo et al., 2021). The still remaining limitations on the development of more adapted patient medicines can be overcome by the use of 3D printing. 3D printing is an additive manufacturing process that builds 3D objects by depositing material layer by layer. The advantages of 3D printing technology include low production costs, time savings, high flexibility with local control of material composition and microstructure, and negligible variability among printed objects. Since its conception, 3D printing has been democratized in many industries such as automotive, aerospace, food or

health (printing prosthetics). In recent years, research has also focused on using this technology to print personalized medicines leading to an increasing number of scientific articles on pediatric 3D printing (Fig. 1).

3D printing includes several techniques such as extrusion-based printing, inkjet, binder jet or selective laser sintering (SLS). Among them, two extrusion-based printing are mainly used in pharmaceutical applications, Fused Deposition Modelling (FDM) and Semi-Solid Extrusion (SSE). In FDM, a filament material is heated and extruded through a nozzle and the layers of molten material are deposited into the desired product and solidify. While SSE, also known as pressure assisted micro syringe (PAM), is based on the deposition of a gel or paste at room temperature or low temperature (40 °C). A more detailed presentation of these two techniques and the parameters to be considered for their use in the preparation of pharmaceutical forms is explained in the section below.

## 2. Extrusion based 3D printing and choice of excipients

### 2.1. Hot melt extrusion coupled with fused deposition modeling

FDM is a very attractive platform for small-scale individualizing for solid dosage forms because the printers are affordable and there is no need of finishing steps. There are several publications on the development of personalized medicine forms using Hot Melt Extrusion (HME) coupled with FDM, as HME is very interesting to produce filament for FDM 3D printing (Maniruzzaman and Pawar, 2021).

HME coupled with FDM is based on two heating steps, thus the excipients need to be thermally stable. Also, in order to avoid the thermal degradation of the API, a polymer with a low melting temperature or the addition of plasticizer to reduce the process temperature would be required (Hoffmann et al., 2022; Palekar et al., 2019).

In the printer head, two feed gears exert significant mechanical forces on the filaments, which must therefore be neither too soft (bending) nor too hard (breaking). Different parameters can be used to characterize the mechanical properties of the filaments (Young's modulus, tensile strength or brittleness) in order to develop a screening method to assess the brittleness and thus the printability of the polymers used in FDM (Nasereddin et al., 2018).

### 2.2. Semi-solid extrusion

SSE consists of printing of an ink or gel at low temperatures (room temperature up to 40 °C). SSE formulations are mainly composed of a binding agent and other excipients such as filler depending on the targeted printed object: orodispersible dosage forms (ODF) (Suárez-González et al., 2021), chocolate-based medicine (Karavasili et al., 2020), gums (Tagami et al., 2021), films (Elbadawi et al., 2021), tablets (Gorkem Buyukgoz et al., 2020) or cereal-based forms (Karavasili et al., 2022). The printability of the form depends on the viscosity of the ink. A high viscosity leads to a semi-solid ink requiring high pressure for extrusion, with a risk of nozzle clogging. While a low viscosity inks will easily leak from the nozzle and become difficult to deposit. Consequently, the choice of excipients and the development of the formulations are carried out based on rheological studies with viscosity, yield stress or flow index measurement (Chachlioutaki et al., 2022; Karavasili et al., 2020; Tagami et al., 2021).

Therefore, combining the specification of both children and 3D printing is challenging. Thus, the objective of this review is first to explore the excipients mainly used in the development of 3D printed oral dosage forms for pediatric population. To achieve that an overview of the role of these excipients in 3D printing with a particular focus on the amount used per printed form is presented. Then, research on the available safety data of these excipients for oral administration is displayed. Finally, the potential toxicity of the developed printed forms is discussed pointing out the lack of information on most of the currently used excipients.
<figure><img src="image_3.png" /><figcaption>Fig. 1. Evolution of the number of pediatric 3D printing articles per year.</figcaption></figure>

**3. State-of-the-art study strategy**

Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement criteria (PRISMA) used to perform systematic reviews, two bibliography methods were employed to get a maximum of articles directly related to the subject: systematic research and top-down bibliography. Research strategy is schematically represented in Fig. 2.

A total of 39 articles were collected from the Pubmed and Science-Direct databases, and 1 article was added from the top-down bibliographic approach. The systematic search ended in April 2024. The formulations presented in the reviewed articles were classified

according to the type of printing technique (Fig. 3). As extrusion-based 3D printing is predominantly represented in the reviewed articles, this work will focus on the excipients most commonly used in the research articles using FMD and SSE.

Among the considered research articles, 106 formulations for pediatric solid oral dosage forms were considered with 58% for FDM printing and 42% for SSE printing. Formulations with the same excipients in different proportions were not included in the calculation to prevent overrepresentation.

The excipients used in the reviewed articles have been listed and the most commonly used were presented, based on their frequency of use in

<figure><img src="image_4.png" /><figcaption>Fig. 2. Flow chart indicating the number of articles found through the different phases of the systematic review according to the PRISMA statement.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>Fig. 3. Number of research articles on pediatric oral solid form per 3D printing techniques.</figcaption></figure>

the 106 formulations (Fig. 4). It was noted that the same types of excipients are used in both printing methods with the exception of glycerin, which was only used in one article on SSE to develop three different formulations (Yang et al., 2020), making it therefore less representative. It has to be noted that although water is listed as an excipient, it was not covered in this review. In view of the recurrence of excipients used regardless of the method of counting (article or formula), the next part of this review will focus on the excipients presented in these graphs.

In this review, each excipient will be covered in three sections organized as follows. The first part describes excipient's properties, mainly based on the Handbook of pharmaceutical excipients (Sheskey et al., 2020) and on the European Pharmacopeia (Ph. Eur.) (Eu. Ph. 11.3, 2023). The second part, entitled “Safety information on the excipient”, summarizes the available clinical studies, the reported Acceptable Daily Intake (ADI) and other indicative limits for excipient oral uses. The STEP (Safety and Toxicity of Excipients for Paediatrics) database and other studies were consulted to collect and regroup the data. As information was not always available, the research also relied on reports from the European Food Safety Authority (EFSA) to estimate exposure doses and the No Observed Adverse Effect Level (NOAEL) for food additives. In addition, animal toxicology studies and other indicators were

considered to complete the missing information. For example, the LD50 (the amount of material administered at one time that causes the death of half of a group of animals tested) is used to assess acute toxicity (Nutrition, 2020). After presenting the data collected, a pediatric daily oral dose, expressed in mg/kg/day body weight (bw), was defined for each excipient. Finally, the third part “Excipient in 3D printing” is dedicated to describe the role of these excipients in extrusion-based 3D printing. In this section, the number of excipients used in the presented formulations was calculated (when the data was available) in order to estimate the mass administered per printed form. These values were compared with the pediatric daily oral threshold taken as a reference from the literature to verify that excipient's dose did not exceed the recommendations. As the daily intake dose depends on the age and the body weight of the patient, curves showing the evolution of a child's weight as a function of age were used as reference. Curves for female patient's was took as reference as their average weight is lower than that of boys. This choice was made to set a stricter limit and thus limit the risks (“Growth Charts – Clinical Growth Charts,” 2022).

<figure><img src="image_6.png" /><figcaption>Fig. 4. Graphical representation of the excipients or groups of excipients mainly used in FDM and SSE 3D printings in the formulations presented in the reviewed articles.* Mainly used in SSE.</figcaption></figure>
# 4. Main excipients used in extrusion-based 3D printing

The following part will be dedicated to the excipients mainly used in the reviewed articles. It is interesting to highlight that most of them are currently used in cosmetics and pharmaceutical formulations (Sheskey et al., 2020).

## 4.1. Cellulose derivatives

Cellulose is a linear glucose homopolymer consisting of glucopyranose units linked by b-1,4-glycosidic linkages ($C_6H_{10}O_5$m), with a degree of polymerization depending on its origin. Cellulose derivatives are widely used in food, cosmetic and pharmaceutical formulations.

Available studies on the toxicity of cellulose derivatives have mainly been conducted on the dietary exposure of humans to cellulose derivatives as food additives. For example, studies on the safety of cellulose derivatives in animals and humans show their stability in the gastrointestinal tract, as they are detected in the feces after consumption (European Commission, 2011). Moreover, the EFSA re-evaluated cellulose derivatives: methylcellulose (E461), ethyl cellulose (E462), hydroxypropyl cellulose (E463), hydroxypropyl methylcellulose (E464), ethyl methylcellulose (E465), sodium carboxymethyl cellulose (E466), enzymatically hydrolysed carboxymethyl cellulose (E469) and cross-linked carboxymethyl cellulose (E468) as food additives. The EFSA estimated the mean intake of cellulose derivatives from food additives (and natural sources) in different population categories. In patients aged 12 months to 9 years, the mean intake is estimated at 35 mg/kg bw. The estimated oral dose of cellulose and cellulose derivatives as food additives does not raise safety concern. The panel concluded that it was not necessary to establish a numerical ADI. Although, as there is no official limit set, the EFSA value (35 mg/kg bw) will be considered as the threshold oral exposure dose for the pediatric population (EFSA, 2018).

### 4.1.1. Microcrystalline cellulose

Microcrystalline cellulose is a purified, partially depolymerized cellulose widely used as food additive (E460), and in pharmaceutical industry. Different grades are manufactured depending on their molecular weight or particle size, for instance Avicel PH® (Dupont), Tabulose® (Roquette) or Vivapur® (JRS) (Sheskey et al., 2020).

**Safety information on MCC.** MCC is not in the list of substances Generally Recognized As Safe (GRAS), but the committee on GRAS substances considers its use as non-hazardous. In addition, MCC is accepted as a food additive in Europe (Sheskey et al., 2020), with a maximum oral daily dose of 132 mg approved by the FDA for all patients, without any indication for the pediatric population (FDA, 2023). Considering the body weight, the EFSA panel suggested 660–990 mg/kg/day bw as an indicative total exposure for all patients (Sheskey et al., 2020). Given MCC bioavailability, it has little toxic potential when administrated orally. However, consumption of large quantities of MCC may have a laxative effect when used as excipient in pharmaceutical formulations.

**MCC in 3D printing.** While in the production of conventional oral forms MCC can be used as a binder, diluent and disintegrant. In SSE, MCC has been only reported as a binder agent (14% (w/w) i.e. 10.5 mg per form) (Callede et al., 2022). This oral dose reported is lower than the threshold fixed by the FDA and the EFSA. Thus, the use of MCC, as binder in SSE, could be considered suitable for children, (EFSA, 2018; FDA, 2023).

### 4.1.2. Methylcellulose

Methylcellulose (MC) is a long-chain substituted cellulose with approximately 27–32% of the hydroxyl groups under methyl ether form, manufactured under different grades depending on the degree of polymerization and degree of substitution. It is widely used in the food industry as food additive E461 and in pharmaceutical formulations as it

is GRAS-listed, accepted as a food additive in Europe and included in the FDA Inactive Ingredients Database (IID) (Sheskey et al., 2020).

**Safety information on MC.** Orally administered MC is neither digested nor absorbed (non-caloric material). However, oral ingestion of large amounts of MC may temporarily increase flatulence, gastrointestinal distention and laxative effect; consequently, medium- and high-viscosity MC grades are used as bulk laxatives. Adverse effects have been reported when MC is used as a bulk laxative.

Toxicity studies, first realized on mice, estimated a LD50 at 275 g/kg (Sheskey et al., 2020); in a second study, dogs (with an age of 6 and 10.5 months) were fed with 5 ml/kg/day of a MC solution (0.5%, 400cps) in their diet for 39 weeks day, resulting in soft, mucoid feces. In another study, non-human primates received 28 doses at 5 ml/kg/dose of a MC solution (0.5%) and no adverse reactions were reported (Gad et al., 2016). To date, the World Health Organization (WHO) has not set an ADI for MC, as the level of use in food has not been considered a health risk.

**MC in 3D printing.** The rheological properties of emulsion gels are critical, as demonstrated in a study on solid lipid tablets printed from emulsion gels using SSE (Johannesson et al., 2021). In this work, MC (Methocel A4M) was used at 12% (w/w) (11–15 mg) as a viscosity modifier to achieve high viscosity, non-Newtonian, shear-thinning emulsion gels for SSE 3D printing. The EFSA Panel established an appropriate exposure dose of 35 mg/kg bw for patients aged 12 months to 9 years for the oral dose of MC, therefore the use of this excipient at the considered amount could be suitable for all children in this range of age (EFSA, 2018).

### 4.1.3. Hydroxypropyl cellulose

The Ph. Eur. (Eu. Ph. 11.3, 2023) describes HPC as a partially substituted poly(hydroxypropyl) cellulose ether (Sheskey et al., 2020). HPC is a water-soluble synthetic cellulose ether manufactured under different grades, such as Klucel™ HPC EF (80 K g/mol) and LF (95 K g/mol) from Ashland. The HPC (E463) is a food additive and an excipient widely used in pharmaceutical formulations.

**Safety information on HPC.** HPC is generally considered a non-toxic, non-irritating excipient, as it is GRAS listed. It is accepted for food additive usage in Europe and FDA approved for use in oral capsules or tablets, among other forms. The WHO has specified an ADI for HPC up to 1500 mg/kg bw, however, excessive consumption of HPC may have a laxative effect (Sheskey et al., 2020). Animal toxicity studies realized with low-substituted HPC showed no adverse effects in rats fed orally with 6 g/kg/day over 6 months, and no teratogenic in rabbits and rats fed with 5 g/kg/day. The EFSA estimated exposure to low-substituted HPC at a maximum use level of 20 000 mg/kg and a typical use level of 10 000 mg/kg. Based on available human (age unspecified) and animal data, it was determined that oral ingestion of HPC presents no safety concerns (EFSA, 2018b). As these thresholds were fixed without considering the age, the threshold for orally administered HPC on children considered in this review will be that fixed by the EFSA report on cellulose derivatives, set as 35 mg/kg/day bw, regardless of the substitution level (EFSA, 2018; Sheskey et al., 2020).

**HPC in 3D printing.** HPC is manufactured under different grades with various molecular weight. As polymer Tg depend, among others things, on the Mw, this variability in chain length enhances HPC potential use in FDM, with different process temperatures. In fact, HPC filaments were extruded with a non-negligible difference of 20 °C just by using two different grades, Klucel™ HPC EF (80 K g/mol) extruded at 130 °C and LF (95 K g/mol) extruded at 150 °C (Samaro et al., 2020). Interestingly, although HPC filaments were obtained with both grades, tablet printing was only possible using Klucel™ HPC EF filaments; the higher molecular
weight of Klucel™ HPC LF resulted in poor flowing behavior, unsuitable for FDM printing. These observations were supported by the Melt Flow Index (MFI) analysis which provides indications of a material's flowability as inversely proportional to the viscosity. At 160 °C, the MFI for Klucel™ HPC LF was 8.9 g/10 min compared to 23.3 g/10 min for Klucel™ HPC EF (Samaro et al., 2020). This example highlights the significance of selecting the appropriate polymer for extrusion and printing. The hydrophilic or hydrophobic characteristics of the polymer are also noteworthy concerning the targeted release kinetics. HPC stands out due to its hydrophilic nature, making it particularly interesting. However, the release kinetics are influenced not only by the polymer but also by other factors such as the formulation (including the addition of others excipients) and the nature of the Active Pharmaceutical Ingredient (API). For instance, a loratadine loaded printed form with Klucel™ HPC EF as polymer carrier reached 85 % of API release after 30 min due to the good wettability of the printed tablets; while longer release times were observed for theophylline-loaded forms 30 % after 30 min (Omari et al., 2022; Samaro et al., 2020).

The hydrophilic nature of HPC could enhance API dissolution rate, but it can be restrictive regarding the mechanical properties of the printed form. For instance, while SSE printed buccal films of HPC presented good flexibility properties at moisture contents around 5 %, with water acting as plasticizer, higher moisture levels made films sticky and difficult to manipulate (Sjöholm and Sandler, 2019). Overall, HPC is used most extensively used in FDM printing, between 21 and 90 % (w/w) of the formulation (42–400 mg), while in SSE proportion are lower, between 10 and 20 % (w/w) (0.1–20 mg) (Gorkem Buyukgoz et al., 2020; Omari et al., 2022; Samaro et al., 2020; Sjöholm and Sandler, 2019; Tabriz et al., 2021). Based on the exposure dose of HPC (EFSA, 35 mg/kg/bw), the use of this excipient at the reported amounts can be considered suitable for children over two years of age or weighing at least 11 kg (EFSA, 2018).

### 4.1.4. Hypromellose acetate succinate

Hypromellose acetate succinate is a mixture of acetic acid and monosuccinic acid ester of hydroxypropyl methylcellulose. HPMCAS is considered as an enteric polymer due to the carboxyl groups on its side chains, insoluble at low gastric pH but soluble at neutral intestinal pH (Yoshida et al., 2013). It is available under various grades classified based on the substitution degree of acetyl and succinyl groups and the particle size. The molecular weight of HPMCAS is around 55 K to 93 K g/mol (Sheskey et al., 2020). It is marketed in different grades depending on the degree of chemical substitution of the acetyl and succinyl groups –L, M and H with pH thresholds of 5.5, 6.0 and 6.5, respectively (“Shin-Etsu AQOAT® for amorphous solid dispersion – SE Tylose,” n.d.).

**Safety information on HPMCAS.** HPMCAS is FDA approved, furthermore, the safety and pharmacological profile of HPMCAS is reported to be similar to those of ether and ester derivatives of cellulose. No toxicity has been observed with HPMCAS in available nonclinical studies (Sheskey et al., 2020). Several studies on animals are available in the STEP Database. For example, the effect on gestation was studied on juvenile rats (70 to 84 days); daily doses of 50, 150, 625 and 2500 mg/kg/day bw were administered orally during the gestational period (12 days). No abnormalities nor toxicity during the development were observed. An acute toxicity study in rats at a single dose of 2.5 g/kg resulted in no deaths and no behavioral abnormalities. Also, chronic toxicity was studied in juvenile rats for 90 days (1.25 or 2.5 g/kg/day, 5 days a week, for 26 weeks) and no significant adverse effects were reported (Hoshi et al., 1985). Based on these results, a type V-DMF file was submitted to the FDA, with pre-clinical safety and Absorption Distribution Metabolism Elimination (ADME) information to support chronic use HPMCAS at high doses (Sheskey et al., 2020).

It is important to note that these studies can be used as indicators of oral exposure to HPMCAS, but conclusions about potential risks to

children cannot be drawn from them.

**HPMCAS in 3D printing.** HPMCAS is regularly used as a polymer carrier (Goyanes et al., 2017; Kozakiewicz-Latala et al., 2022a; Malebari et al., 2022). Enteric polymers such as HPMCAS are interesting to used develop site-specific release forms, as reported by Goyanes et al., 2017. In this work, the drug release of printed forms prepared with L, M and H HPMCAS with pH thresholds of 5.5, 6.0 and 6.5 respectively, were compared. The dissolution study was carried out first in 0.1 M HCl to simulate gastric media, then at pH 7 to 7.4 and finally at pH 6.5 for the intestinal media. The gastro-resistance of the printed forms was demonstrated since all the drug release occurred in the small intestine and colon as a function of HPMCAS pH thresholds; release was faster at lower pH-threshold (HPMCAS LG > AS MG > AS HG) (Goyanes et al., 2017). In the reviewed articles, HPMCAS represented 40–95 % (w/w) of the FDM printed form (12–78 mg) (Goyanes et al., 2017; Kozakiewicz-Latala et al., 2022a; Malebari et al., 2022). Toxicity studies on rats showed no adverse effects for the tested doses (2.5 g/kg) (Hoshi et al., 1985). However, due to the lack of data on children, it is not possible to conclude on the potential risks to HPMCAS exposure.

### 4.1.5. HPMC

Hydroxypropyl methyl cellulose (E464) is a food additive, widely used as an excipient in pharmaceutical formulations. HPMC (or hydro-mellose) is described by the Ph. Eur. as a partly O-methylated and O-(2-hydroxypropylated) cellulose (Sheskey et al., 2020).

**Safety information on HPMC.** HPMC is GRAS listed and included in the FDA IID. HPMC is regarded as a nontoxic and nonirritant material, although excessive oral consumption may have a laxative effect. Although the WHO has not specified an acceptable daily intake for HPMC since the levels consumed were not considered to represent a hazard to health, the FDA-approved a maximum daily intake of 480 mg for an average person (C. Brown, 2009; Sheskey et al., 2020). As presented previously, EFSA estimated the dose of cellulose derivatives for patients aged 12 months to 9 years, with a mean intake estimated at 35 mg/kg bw (EFSA, 2018).

**HPMC in 3D printing.** Specific HPMC grades developed for HME are marketed with low and high molecular weight, 15cP HPMC (90 K g/mol) and 4 M HPMC (550 K g/mol) (Affinisol™). HPMC is a water-soluble amorphous polymer with a glass transition temperature around 115 °C, and thermally stable up to 250 °C. HPMC is commonly used in FDM as a polymer carrier (Chow et al., 2023; Linares et al., 2019; Malebari et al., 2022; Saydam and Takka, 2020) and due to its hydrophilic property, the wetting can be improved to enhance API's dissolution. For instance, the dissolution rate of theophylline-loaded forms obtained by FDM was increased from 10 to 4 h (80 % of the drug released) by using a lower molecular weight HPMC (Affinisol™ 15cP) instead than Affinisol™ 4 M. Drug release was first controlled by the swelling of HPMC in contact with water, then by its erosion. Thus, a higher molecular weight HPMC requires longer water uptake to swell and leads to lower erosion (Samaro et al., 2020).

HPMC also raises interest for its mechanical properties. For instance, a FDM printed form composed of Kollidon® VA64, HPMC and Soluplus® was developed. Pure HPMC was successfully extruded while it was not possible with the two others polymers. Thus, it was used as a polymer carrier in filament, providing good mechanical properties, with a breaking force at 52 N for neat HPMC compared to 17 N when mixed with Kollidon® VA64 and Soluplus® (Saydam and Takka, 2020). Similarly, the mechanical properties of a pullulan film produced by SSE printing were improved by addition of HPMC. The incorporation of 50 % of HPMC resulted in an increase of the average elastic modulus of the printed composited film, from 1.17 for pure Pullulan to 1.56 GPa (Elbadawi et al., 2021).
Moreover, HPMC can also be used in SSE as a binder agent as demonstrated by Tagami et al. in presence of gelatin affecting the printability of the ink. Furthermore, an increased proportion of HPMC in the mixture led to a delayed drug release (Tagami et al., 2021, 2019). As previously mentioned, the molecular weight of the excipients affects the dissolution time, therefore, the grade of HPMC can be chosen based on the targeted drug release profile.

In another study, Roche et al. developed a SSE printed form by combining HPMC and sodium alginate as carriers. HPMC was selected to increase viscosity and enhance shape retention of the printed forms. At high concentrations, 15 to 20% (w/w, HPMC was reported to display a better printability than sodium alginate, however, lower quantities were used due to risks of nozzle clogging (Roche et al., 2023).

All these examples show that HPMC is a versatile polymer, used in FDM between 151–266 mg per tablet (20 and 80% (w/w)) and between 0.92 and 8.5 mg (1.4–4.8% (w/w)) in SSE (Conceição et al., 2019; Roche et al., 2023; Tagami et al., 2021). Based on the dose estimated by the EFSA, oral administration of 0.92 mg of HPMC per tablet could be suitable for a 12-months child, while for 266 mg per tablet, the patient should be weighing at least 9 kg (EFSA, 2018).

### 4.1.6. Carboxymethylcellulose sodium

Carboxymethylcellulose Sodium (CMC-Na) also known as E466, is commonly used as a super disintegrant in commercial oral medicines.

**Safety information on CMC.** CMC is included in the FDA IID with a maximum daily exposure at 50 mg for adult patients (FDA, 2023). Medium and high viscosity grades of CMC-Na were used in 4–10 g divided doses as a bulk laxative. Even if, consumption of large amount of CMC-Na may induce laxative effects, the levels currently used do not raise concerns. No information is available on the effects of oral administration of CMC on children (Sheskey et al., 2020).

**CMC in 3D printing.** As in the current manufactured tablet, CMC is used in 3D printed forms as a release modifier, to improve the disintegration time of the printed form. In SSE, CMC represents 2 to 3% (w/w) of the final form, leading to a final administered mass ranging from 6.5 to 11 mg (Cui et al., 2019; Rouaz et al., 2023). Without specific information on the potential toxicity of CMC in the pediatric population, the threshold is fixed based on the EFSA report. As the calculated amount of CMC per printed form is below the estimated dose of 35 mg/kg bw, it might be considered that exposure to CMC through these printed forms does not represent a risk to the pediatric population (EFSA, 2018).

### 4.1.7. Croscarmellose sodium

Croscarmellose sodium is a crosslinked polymer of carboxymethylcellulose sodium. It is used in oral pharmaceutical formulations as a disintegrant. It can be used in direct-compression as well as wet-granulation, up to 5% (w/w) (Sheskey et al., 2020).

**Safety information on croscarmellose sodium.** Croscarmellose is included in the FDA's IID for oral capsules, granules and tablets. Large consumption of croscarmellose have a laxative effect. The oral toxicity of croscarmellose sodium was tested on rats for 90-days at 3 concentrations (0, 10,000 and 50 000 ppm). As no adverse effect were reported, the NOAEL was set at 50,000 pm, representing 3922 mg/kg/day bw in males and 4712 mg/kg/day bw in females (C. Brown, 2009).

**Croscarmellose sodium in 3D printing.** In FDM, croscarmellose sodium represents 5–10% (w/w) of the printed form (5–10 mg) (Omari et al., 2022). In SSE croscarmellose sodium have been used to improve retention of the printed form's shape and 30% (w/w) of disintegrant were reported to result in less friable forms (Roche et al., 2023). From the reviewed articles, croscarmellose sodium represents between 2.5–52% (w/w) of the final form (4.5–24.3 mg) (Callede et al., 2022; Conceição et al., 2019; Johannesson et al., 2021; Roche et al., 2023; Suárez-González et al., 2021).

As there is no information on the potential toxicity of croscarmellose sodium in the pediatric population, it is not possible to draw a conclusion on its use in the reviewed articles.

### 4.2. Polyethylene glycol and polethylene oxide

Polyethylene glycol (PEG) is a neutral, odorless substance of low volatility hydrophilic homopolymer. A myriad of PEG is commercially available with different molecular weight from 100 (liquid solution) up to 35 K g/mol (crystal) for the low molecular weight (LMW) PEGs. High molecular weight (HMW) PEGs, from 100 K to 10,000 K g/mol are known as poly(ethylene oxide) (PEO) which are thermoplastic homopolymer (Isreb et al., 2019).

**Safety information on PEGs**

LMW and HMW PEGs are both non-toxic and soluble. PEGs are among the few polymers FDA approved for clinical application and thus, the most commonly used polymers in the pharmaceutical industry. When LMW PEGs are used to adjust the viscosity, only a small amount is required. However, in solid forms (tablet, suppositories) LMW PEGs are used in higher proportions. Among pediatric medicines currently on the market, PEG 3350 (or 4 K) is used to treat constipation (MOVICOL, MACROGOL and Transipeg). For instance PEG 4 K and 6 K are used as laxative agent up to 20 g/day for children aged 8–18 years (VIDAL, 2024). While PEO has been extensively used for oral formulations such as extended release tablets produced by powder compression (Isreb et al., 2019). LMW PEGs have been widely studied on children. Studies found in the STEP database concluded that an administered dose of 0.8 g/kg bw per day, in children under 2 years of age is effective, well tolerated and appears safe for the treatment of functional constipation in children (Loening-Baucke et al., 2004). For other medications, LMW PEG have a maximum ADI of 10 mg/kg bw when used as an excipient for children, due to its laxative properties (Sheskey et al., 2020; van Kampen et al., 2023).

On the other hand, PEO is not included in the STEP database, thus, for the moment, so there currently no dose limit for humans. However, PEO is included in the FDA IID for use in sustained release tablets (Sheskey et al., 2020). Subacute toxicity experiments were carried out on 4,000 K molecular weight on rats and dogs. For the highest dosage tested 2.76 g/kg/day and 0.56 g/kg/day respectively, no side effects were reported. Overall, animal studies suggest that PEO is poorly absorbed from the gastrointestinal tract and is largely excreted unchanged (Sheskey et al., 2020; Smyth et al., 1970). In general, high molecular weight polymer are not absorbed by biological tissues or in the gastrointestinal track, and are therefore not considered toxic (Sheskey et al., 2020). Despite these data, no studies have been carried out on the pediatric population, so it is not possible to draw any conclusion regarding PEO.

**PEGs in 3D printing**

PEGs and PEOs are suitable for HME coupled with FDM due to their low glass transition (~55 °C) and melting temperature (~50 °C). In 3D printing, and more precisely in FDM, PEGs can be used as both polymer carrier and plasticizer (Hoffmann et al., 2022). HMW PEGs provide good mechanical flexibility to the filament and can be extruded at temperatures lower than 100 °C (Roulon, 2021).

The PEOs used as polymeric carriers typically exhibit a molar mass exceeding 200 K g/mol (Isreb et al., 2019; Roulon, 2021). The extrusion and printing parameters for PEO are influenced by its molecular weight, affecting both mechanical properties and release kinetics. Comparative analysis of PEO with different molecular weights revealed that PEOs with molar masses of 100 K g/mol and 200 K g/mol were unsuitable for producing printable filaments due to their frequent breakage when subjected to gear pressure, whereas PEO with molar masses of 300 K g/mol, 600 K g/mol, and 900 K g/mol exhibited greater resistance to
tension (Isreb et al., 2019). These tests demonstrate that peak load breaking increases with longer polymer chains.

Additionally, molecular weight has an impact on the viscosity and behavior of the melted polymer. During the printing process, the polymer must pass through the nozzle, which requires good flowing properties. PEO with molar masses of 300 K g/mol and 600 K g/mol exhibited adequate flow characteristics, resulting in successful printing. In contrast, PEO with a molar mass of 900 K g/mol (η* = 22,610 Pa.s) exhibited restricted flow, leading to nozzle obstructions and hindered printing. Consequently, it was determined that a complex viscosity < 8K Pa.s was required to achieve optimal polymer flow (Isreb et al., 2019).

In another study, Elkanayati et al. developed a mucoadhesive buccal film loaded with adipic acid to treat xerostomia. PolyoxTM N80, a PEO 200 K, was chosen as the film-forming polymer to allow an immediate release of the API. The fast release profiles, achieving 100% of the API in 15 min, can be attributed to the hydrophilic nature of PEO, enhancing wettability and dissolution of the films (Elkanayati et al., 2022). Thus, the presented research highlights the main role of PEO as a support matrix in the 3D printing of oral solid forms.

On the other hand, LMW PEGs are often used as plasticizers. For instance, PEG 4 K was added at 14 wt% in a formulation for FDM printing to improve processability by reducing the torque from 38 % to 20 % and the pressure from 11 to 0 bar (Fanous et al., 2021). PEG can also interact with the API by lowering the glass transition (Tg), as observed in the case of amorphous ritonavir, with a decrease from 51 to 42 °C in the 3D-printed mini tablets (Malebari et al., 2022). Hess et al. compared the effect of various grades of PEG (300, 600 and 1000 g/mol) on two grades of PVA 3–82 and 4–88. In presence of PEG 300, PVA 3–82 or 4–88 DSC thermograms displayed one Tm and a single Tg with a strong shift of 18 °C, indicating a homogeneous blend and a strong plasticizing effect. The rheological studies display a lower viscosity when PVA are blended with PEG 300. Moreover, PEG 300 was reported to improve filament's flexibility, lowering the flexural modulus from 59 to 11.9 Pa. Thus, PEG 300 plasticizing effect was confirmed. However, formulation with PEG 600 displays a single Tm with PVA 3–82 while two Tm were detected with PVA 4–88, characteristics of a binary system and with PEG 1000 g /mol, two melting peaks were reported for both PVAs. The preferential miscibility of PEG 600 with PVA 3–82 was attributed to the lower degree of hydrolysis of this PVA, as the acetate groups seems to stabilize longer PEGs chains. Thus, this study demonstrate the potential of PEG as plasticizer and the influence of its molecular weight on its miscibility with the polymer carrier (Hess et al., 2024).

Due to its hydrophilic nature, PEG can also enhance the dissolution of the printed forms. When combined with Kollidon® VA64, PEG 4 K resulted in a rapid release, with 80 % of the drug dissolved within 15 min (Fanous et al., 2020).

In summary, low quantities of LMW PEGs are often used to prepare printed forms, ranging from 28 to 86 mg per form (10 to 22.5 % (w/w)), making them suitable for children weighing more than 3–5 kg (Fanous et al., 2020; Hoffmann et al., 2022; Isreb et al., 2019; Malebari et al., 2022; Omari et al., 2022). In contrast, in PEO-based formulations, the administered amount ranges from 26 to 121 mg per form (35–80 % (w/w)) (Elkanayati et al., 2022; Isreb et al., 2019; Omari et al., 2022; Roulon, 2021). However, the specific limitations of PEO necessitate further consideration, making it challenging to draw a definitive conclusion regarding the administered dose for the pediatric population.

## 4.3. Polyols

### 4.3.1. Mannitol

Mannitol is a naturally occurring sugar alcohol found in animals and plants; it is present in small quantities in almost all vegetables. It can be used as a pore former, dissolution aid or as a sweetener (Omari et al., 2022; Wang et al., 2021).

**Safety information on mannitol.** Mannitol is GRAS listed, accepted for use as a food additive (E421) in Europe and included in the FDA's IID (Sheskey et al., 2020). The amount of mannitol consumed as a sweetener is not considered a health risk and yet, the WHO has not set an ADI. In the absence of an established limit, a hypothetical baseline for our study was settled by cross-referencing several sources. Studies in animals (mice, rats and non-human primates) and adult humans were selected.

The toxicity of mannitol was evaluated in a long-term study (103 weeks) in mice and rats fed 0, 2.5, or 5 % mannitol per day. No significant differences were observed between treated and control animals. Following studies in mice, the oral lethal dose was determined to be 22 g/kg (Sheskey et al., 2020). In addition, no signs of adverse effects were reported after oral administration of 10 ml/kg/day for 2 weeks, in a toxicity study in non-human primates (Gad et al., 2016).

In an adult human study, 10 patients (age not specified) received an oral dose of 28 to 100 g of mannitol as a 5% aqueous solution. In this dose range, approximately 20% of the ingested mannitol was excreted unchanged in the urine. However, laxative effects were reported when mannitol is consumed orally in large amounts. If it is used in foods as a bulking agent with a foreseeable daily consumption of more than 20 g, the product label should bear the statement “excessive consumption may have laxative effects” (Internationally Peer Reviewed Chemical Safety Information (IPCS), n.d.). Moreover, the EMA fixed a threshold at 10 g for orally administered mannitol with the following statement for the package leaflet information: “May have a mild laxative effect”. (EMA, 2018a; Internationally Peer Reviewed Chemical Safety Information (IPCS), n.d.).

**Mannitol in 3D printing.** In FDM, mannitol is used as a pore-forming agent to improve drug release (Omari et al., 2022) or combined with superdisintegrant (Duranović et al., 2021). FDM printed form developed with PVPP and mannitol to increase drug release, however, both formulations with 10 % (w/w) of PVPP and with 10 % (w/w) of PVPP and mannitol, reached a complete drug release after 4 h. Interestingly, the faster drug release was achieved with printed form combining 10 % (w/w) of PVPP and only 5 % (w/w) of mannitol, in 2 h. Mannitol is an osmotic agent, promoting water intake which leads to the disintegration of the printed form. It enhances drug release but with increasing concentration, it lengthen disintegration time as observed with PVPP and others disintegrants. Thus, this study shows the interest of combining agent enhancing drug release, and display the importance of their concentration limits (Duranović et al., 2021). In these studies, mannitol ranges between 5–15 %, 10 to 26 mg in the printed form, however, as there is no specific data on children exposure to mannitol, so, it is not possible to conclude on the potential risk for the pediatric population.

### 4.3.2. Xylitol

Xylitol, also known as E967, is a polyol found in fruits and vegetables such as strawberries and cauliflower and is also produced in small amounts by the human metabolism. Because xylitol has an extremely low glycemic index and is metabolized independently of insulin, it is widely used as a bulking agent in foods and in medications such as dental care products, chewing gum and candy (Sheskey et al., 2020).

**Safety information on xylitol.** The WHO has not established an ADI for xylitol, as the levels used in foods do not present a health risk. Xylitol is GRAS-listed and its use as a food additive is accepted in Europe. It is also included in the FDA IID for oral solutions and chewing gums. Finally, it is included in non-parenteral medicines approved in the United Kingdom and in the Canadian List of Acceptable Non Medical Ingredients (Sheskey et al., 2020). Moreover, the EMA fixed the threshold of orally administered xylitol at 10 g, for adult patients and reported mild laxative effects (European Medicine Agency (EMA), n.d.).

When administered orally, 25–50 % of xylitol is absorbed, while 50–75 % passes to the lower intestine where it is metabolized by
fermentative degradation by the intestinal flora. However, as with other polyols, there is a laxative threshold that depends on several factors, including the age of the patient (Chukwuma and Islam, 2016). In most patients, a divided oral dose of xylitol up to 100 g daily and a daily dose of 0.5–1.0 g/kg bw are generally well tolerated, but this is not well understood in the pediatric population (Sheskey et al., 2020). The tolerability of an oral dosage of xylitol was evaluated in a 3-month study in 120 children aged 6 and 36 months. Patients were given 5 g three times a day or 7.5 g once a day, which were well tolerated by young children. (Vernacchio et al., 2007).

**Xylitol in 3D printing.** In FDM, xylitol can be used as a hydrophilic plasticizer (Fanous et al., 2021, 2020), as sweetener and also to as a salivary stimulant (Elkanayati et al., 2022), representing between 16 and 48 mg (12–15% (w/w)) for each printed form. According to the Vernacchio et al. study, the dose of 15 mg/day is exceeded for children between 6 and 36 months (Vernacchio et al., 2007). Thus, the 3D printing forms developed in Fanous et al. work cannot be administered to the youngest children (Fanous et al., 2021, 2020). However, as there is not enough information for the rest of the pediatric population it is not possible to conclude on the potential oral toxicity of xylitol.

### 4.3.3. Sorbitol

Sorbitol occurs naturally in the ripe berries of many trees and plants. It is produced industrially by catalytic hydrogenation of glucose. It is used as a diluent in tablet formulations and, also used in chewable tablets due to its pleasant sweet taste and cooling sensation (Sheskey et al., 2020).

**Safety information on sorbitol.** Sorbitol is on the GRAS list, is accepted as a food additive (E420) in Europe and is included in the FDA IID. Due to its low caloric value of 16.7 J/g (4 cal/g), it is better tolerated by diabetics than sucrose and is used in many sugar-free products. Compared to glucose, it is absorbed more slowly by the gastrointestinal tract and is metabolized into the liver to fructose and glucose. As a result, large amounts of sorbitol should be avoided (>20 g/day in adults). It is also contraindicated in pediatric patients with hereditary fructose intolerance and hypoglycemia (Sheskey et al., 2020).

The adverse effects reported for sorbitol are generally due to its high osmotic nature, so it can cause abdominal pain, flatulence and diarrhea. Other adverse reactions have also been reported in pediatric forms; the absorption of the API may be reduced when sorbitol is used concurrently as an excipient. This phenomenon may be related to the high osmotic nature of sorbitol, leading to a shortened transit time in the small intestine. This was demonstrated in a lamivudine absorption study, showing a dose-dependent effect of sorbitol on drug absorption. The study reported that at higher doses of oral sorbitol (3.2 g, 10.2 g, and 13.4 g), the maximum lamivudine concentration was reduced by 28%, 52%, and 55%, respectively (Belayneh et al., 2020).

Finally, the threshold for orally administered sorbitol found in the literature was set by the EMA at 5 mg/kg/day for human patients, without age indication (EMA, 2018).

**Sorbitol in 3D printing.** In the articles reviewed, sorbitol was used to produce fast disintegrating formulations due to its high solubility (Roulon, 2021). This polyol can also be added to SSE and FDM formulations for a filler role or as a plasticizer (Ganatra et al., 2024; Kozakiewicz-Latala et al., 2022a; Palekar et al., 2019; Roulon, 2021). The processing torque and temperature to extrude pure PVA, 47–51% at temperature above 180 °C, were much higher than PVA with sorbitol. Addition of sorbitol up to 20% (w/w) reduced the processing torque to 11–14% and extrusion at a lower temperature was facilitated. Tian et al. (2019) suggested that the reduction in temperature and torque could be due to the interaction between the –OH groups of sorbitol and PVA to form stronger hydrogen bonds, weakening the interactions between the

PVA chains (Palekar et al., 2019). Similarly, Kozakiewicz et al. used PVA with sorbitol to print a hydrochlorothiazide loaded form using a FDM 3D printer. The effect of sorbitol on the material was analyzed with Differential Scanning Calorimetry (DSC). The thermograms displayed a decrease of the PVA Tg with increasing sorbitol content in the material, demonstrating a plasticizing effect. This effect was experimentally observed with a decrease in processing temperature when sorbitol was added to PVA (Kozakiewicz-Latala et al., 2022a).

The plasticizing effect of polyols was also compared in several studies. Ikeda et al. worked on the development of a fast dissolving FDM printed form. PVA was selected as polymer carrier and 35% (w/w) of polyols (mannitol, sorbitol, xylitol) were added to improve the drug release. The rheological measurements display a lower viscosity for the PVA-sorbitol formulation. This can be attributed to the hygroscopic property of sorbitol, resulting in a combined plasticizing effect of sorbitol and water (Ikeda et al., 2023). Others studies, compared the plasticizing effect of mannitol and sorbitol in FDM printed forms developed with pregelatinized hydroxypropyl pea starch carrier (Chow et al., 2023). Although both polyols have a similar structure, sorbitol showed a higher plasticizer effect than mannitol as reported by Hess et al. on the effect of plasticizer on PVA's properties (Hess et al., 2024). The DSC thermograms displayed a shift in Tg from 62.6 °C to 52.1 °C with mannitol and to 49.9 °C with sorbitol. The same variation was reported for the filament's mechanical properties, with a slight increase of the flexural modulus with mannitol, from 59 to 52.7 Pa and a similar brittleness compare to pure PVA, while sorbitol improved the filament's flexibility from 59 to 37.9 Pa but 30% of the filaments broke. The same differences were observed in another study, when both polyols are combined with starch. As observed with PVA, mannitol also increased starch's the brittleness. The molecular structure and the conformation of the hydroxyl group of sorbitol are more similar to the glucose unit than mannitol. This induce a higher capacity to form hydrogen bonds with starch than mannitol. Even if the interactions between polyols and starch are not transposable to PVA, this study provides information on the differences between mannitol and sorbitol. Additionally, in aqueous solution, mannitol adopts a planar zig-zag conformation while sorbitol has a bend-chain conformation leasing to a stronger structure breaker property (Grigera, 1988). Hence, sorbitol's conformation may disrupt more hydrogen bond between the PVA chains compared to mannitol (Hess et al., 2024).

As presented, sorbitol is mainly used as a plasticizer to lower the processing temperature and thus, improve processability. In the reviewed articles, sorbitol is used in amount ranging from 10 to 37% (w/w) of the printed form, corresponding to an administered sorbitol mass between 6 and 112 mg per take. However, there are no toxicity studies of oral exposure to sorbitol in the pediatric population, so no conclusions can be drawn.

## 4.4. Polyvinylpyrrolidone and derivatives

### 4.4.1. Polyvinylpyrrolidone and crospovidon

Polyvinylpyrrolidone (PVP) also known as povidone is widely used as an excipient in oral tablets and solutions. It is a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups, whose variable degrees of polymerization gives polymers of different molecular weights, ranging from 12 K to 300 K g/mol. It is marketed by BASF as a pharmaceutical-grade product under the names Kollidon® 12PF, Kollidon® 17 PF, and Kollidon® 30, each corresponding to a specific K-value indicative of its molecular weight. These Kollidon® grades are produced through free-radical polymerization of vinylpyrrolidone (Kolter, 2012).

PVP is linear while polyvinylpolypyrrolidone (PVPP) also known as crospovidone is cross-linked. PVP and PVPP are homopolymers of the N-vinyl-2-pyrrolidone. In direct compression, PVPP is used as a water-insoluble tablet disintegrant and dissolution agent. It is commercially available as Kollidon® CL and Kollidon® CL-M (BASF) with various particle size or Polyplasdone™ XL, Polyplasdone™ XL-10, depending
on the level of impurities (Ashland) (Sheskey et al., 2020).

**Safety information on PVP and PVPP.** PVP finds applications in the food industry as a food additive, designated as E1201. It is used in pharmaceutical preparations, mainly as a binder in oral dosage forms. The WHO has set a temporary ADI 25 mg/kg bw (EFSA, 2020). Moreover, PVP is included in the FDA IID and for PVP K 30 there is a maximum daily exposure between 15 and 60 mg for oral forms (tablets or capsules) (FDA, 2023). Robinson's team examined the impact of PVP's molar mass on its absorption and concluded that PVP with a molar mass below 2000 g/mol would be readily absorbed in both humans and rats, while less than 0.04 % of PVP with a molar mass of 42 K g/mol is absorbed. Further investigations, conducted over two years in dogs, cats, and rats with a dose of 10 % PVP, affirmed the overall safety of PVP (Robinson, 1990). However, there is no studies on pediatric population.

Crospovidone is generally also regarded as a non-toxic and non-irritating material in pharmaceutical formulations. Short-term toxicity studies in animals have revealed no adverse effects associated with crospovidone. However, due to the lack of available data, the WHO has not established an acceptable daily intake for humans. From a regulatory perspective, crospovidone is approved for use as a food additive in Europe and is included in the FDA IID for oral capsules and tablets (Sheskey et al., 2020).

In 2020, the EFSA evaluated the level of use of PVP and PVPP as food additives. PVP used as a food additive does not raise safety concerns, so no ADI has been established. Absorption of PVP and PVPP is very low and the genotoxicity of PVP and PVPP is not a concern. Although there are no data available on the chronic toxicity and carcinogenicity of PVPP, no ADIs were fixed, due to the lack of adverse effects in PVP toxicity studies and the chemical similarity between PVP and PVPP (European Commission, 2011).

**PVP in 3D printing.** In the articles consulted, PVP was used in SSE between 1.6 to 2.2 mg per form (0.5–8.1 % (w/w)). It was used as a binding agent due to its ability to produce harder printed forms. It is interesting to note that no data comparing the hardness of the printed forms with and without PVP has been reported. With the available data, these doses may be suitable for all patients, but no conclusion can be drawn for the pediatric population. However, as mentioned above, excipient toxicity studies performed in adult patients may not be applicable to the pediatric population (Cui et al., 2019; Suárez-González et al., 2021).

**PVPP in 3D printing.** PVPP is often used to promote printed form's disintegration into small segments enhancing drug release. Its super-disintegrant property derives from its ability to swell rapidly in water without gelling, due to its high cross-linking density and high porosity. This enhance water penetration into the tablet to achieve rapid disintegration. A study of a loratadine-loaded FDM printed tablets, with and without PVPP, resulted in a disintegration time twice as fast with PVPP (8.5 min) compare to formulation without PVPP (15 min). In another study, printed form with an infill density of 70 % were prepared with a blend of PVA and HPMC and paracetamol as model drug. Formulations with and without 10 % wt of various disintegrant were printed and compared though dissolution studies. The results show an increasing drug release as follow: without disintegrant (55 %), sodium starch (67 %), croscarmellose (75 %), mannitol (90 %), Kollidon® CL (100 %), after 5 h. This work demonstrates the efficiency of disintegrants on this formulation with better effect of Kollidon. The same experiment was carried out with lower infill density (20 %) to improve the dissolution. Interestingly, for all the formulations, there were no significant effect of the infill density on the dissolution profiles, suggesting that the release kinetic is mainly governed by the disintegrant rather than the printed form's porosity. In the same study, Kollidon® CL as disintegrant (10 % wt) was combined with mannitol as pore-forming agent (5 % wt), resulting in a faster drug release, completed in 2 h instead of 4 h

(Duranović et al., 2021).

In these articles, PVPP represented between 5 and 15 % of the formulations, implying an oral absorption of 5 to 33 mg of PVPP per printed form. However, due to the lack of data, it is not possible to conclude on the potential risks of PVPP (Duranović et al., 2021; Omari et al., 2022).

#### 4.4.2. Kollidon® VA64

Copovidone is an acetic acid vinyl ester polymer with 1-vinyl-2-pyrrolidinone; copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 3:2 mass ratio. Among the commercial products available on the market there is Kollidon® VA64 from BASF. It is manufactured by free-radical polymerization of 6 parts of N-vinylpyrrolidone and 4 parts of vinyl acetate. Vinylpyrrolidone is a hydrophilic, water-soluble monomer while vinyl acetate is lipophilic and water-insoluble. The ratio between the monomers is balanced, 60 % vinylpyrrolidone and 40 % vinyl acetate, in such a way that the resultant polymer is still water soluble (Kolter, 2012).

**Safety information on Kollidon® VA64.** Although Kollidon® VA64 is broadly used in tablet formulation as a film-forming agent or a tablet's binder, there is little information on the administrable oral dose limit. Copovidone is included in the FDA IID list and in general, it is considered non-toxic in the pharmaceutical formulations. However, gastric disturbances have been reported after its ingestion (Sheskey et al., 2020).

As presented for PVP and PVPP, the EFSA has evaluated the safety and toxicity of PVP-VA based on its molar mass. The 2010 report concluded that PVP-VA with a molar mass of 24 K-30 K g/mol is only minimally absorbed after oral administration, with approximately 2 % of the administered dose being largely excreted intact in the feces. Moreover, long-term oral toxicity studies in rats (24 months) and dogs (52 months) resulted in Non-Observed Adverse Effect Level (NOAEL) of 2800 and 2500 mg/kg/day bw, respectively, which were the highest dose levels tested (Eisele et al., 2011; Mellert et al., 2004). Finally, the oral LD50 of PVP-VA in rats was found to exceed 10 g/kg (Sheskey et al., 2020).

**Kollidon® VA64 in 3D printing.** Kollidon® VA 64 is currently used in FDM (Fanous et al., 2020; Nyavanandi et al., 2022; Saydam and Takka, 2020) at 15–60 % (w/w) of the formulation. It has been reported that it is not to be printable in FDM as a single matrix, but it can be used in a blend up to 50–60 % (w/w) (Boniatti et al., 2021). It is also added to formulations to increase the drug's dissolution, from 90 % to 95 % of drug release after 30 min (Fanous et al., 2021).

In another study, Kollicoat® IR formulations, with and without Kollidon® VA64, were extruded and printed. The addition of Kollidon® VA64 resulted in an increase of the process torque, rising from 35-40 % to 45-50 %, attributed to its high molecular weight. The filament's mechanical properties were also modified, reducing the breaking force from 430 ± 10.67 g to 320 ± 13.89 g. These results are consistent with previous studies reporting that Kollidon® VA64 is more brittle than PEO and polycaprolactone. Despite this changes in the mechanical properties, filaments made from the polymer blend were still possible (Nyavanandi et al., 2022).

Overall, Kollidon® VA64 is widely used in FDM with amounts varying from 7.5 up to 266 mg per printed form (15 to 60 % (w/w)) of the tablet mass (Boniatti et al., 2021; Fanous et al., 2020; Nyavanandi et al., 2022; Saydam et al., 2022; Saydam and Takka, 2020). As it is not expected to be absorbed over 1000 g/mol (Eisele et al., 2011) it can be considered safe for adults. However, as this excipient is not included in the STEP database and as there are no data available for the pediatric population it is not possible to conclude on its safety or toxicity.

### 4.5. Polyvinyl alcohol

Polyvinyl alcohol (PVA) is a synthetic polymer that has found diverse
application in industries, medicine and food, since the early 1930s. The physical characteristics of PVA depend on production method, resulting in PVA with molecular weights ranging from 20 K to 400 K g/mol (DeMerlis and Schoneker, 2003).

## Safety information on PVA

In the food industry, PVA is known as E1203 (European Commission, 2011). It is generally considered a nontoxic material. It is included in the FDA IID for ophthalmic preparations and oral tablets (Sheskey et al., 2020).

There are no relevant data from human studies to assess the oral toxicity of PVA. Controlled clinical studies are limited to the potential dermal toxicity, irritation, and sensitization effects of PVA associated with its use in a variety of cosmetic products. Although controlled human studies are limited, some studies have reported inflammatory reactions to injected or implanted PVA. Partially hydrolyzed PVA is used in film coating formulations for tablets and capsules containing pharmaceutical products. There is no evidence that this use has led to any adverse effects in humans (EFSA, 2006; Sheskey et al., 2020).

PVA is generally considered safe and biocompatible. The oral acute toxicity of PVA in rats and mice are LD50 = 23.854 g/kg and 14.27 g/kg, respectively (Sheskey et al., 2020). Orally administered PVA is poorly absorbed from the gastrointestinal tract, and does not accumulate in the body. A single dose of 0.01 mg/kg of PVA administered orally to Fischer 344 rats was almost completely eliminated unchanged in the feces within 48 h. Sub-chronic toxicity and genotoxicity studies were conducted on rats at doses of 2000, 3500 and 5000 mg/kg body weight/day for at least three months. In rats, receiving 3500 and 5000 mg/kg/day bw, unformed stools with anogenital staining were reported. Despite this, no treatment-related adverse effects were reported. The NOAEL obtained for this study is 5000 mg/kg/day bw (DeMerlis and Schoneker, 2003).

## PVA and 3D printing

In FDM and SSE, PVA is mainly used as a polymer carrier (Palekar et al., 2019; Saviano et al., 2019; Sjöholm and Sandler, 2019). PVA is extruded at temperature above 180 °C, leading to a lower processing torque (47–51 %). Extrusion at lower temperature (160–170 °C) increased torque considerably (>77 %). As presented in section 4.3.3, torque (to 11–14 %) and extrusion temperature can be reduced by adding sorbitol. Among the different studies on PVA and plasticizers such as sorbitol, it can be assumed that the processing parameters of PVA for extrusion are quite high due to the strong intermolecular and intramolecular hydrogen bonding interactions of the PVA. The addition of small molecules enable to increase the space between polymer chains, could weaken these interactions and thus, may reduce the processing temperature and torque (Hess et al., 2024; Palekar et al., 2019).

In summary, 65 to 90 % of the printed forms are typically composed of PVA, representing an exposure to 43 to 376 mg. However, due to the lack of information it is not possible to raise any conclusion on the potential risks on the pediatric population.

## 4.6. Kollicoat® IR

Kollicoat® IR is a synthetic copolymer of polyethylene glycol and polyvinyl alcohol. It is a hydrophilic semi-crystalline polymer with a melting temperature of 208 °C, a glass transition temperature of 45 °C and a degradation temperature of 200 °C (Samaro et al., 2020).

### Safety information on Kollicoat® IR

Currently, PVA-PEG graft-copolymer (E1209) is an authorized food additive and pharmaceutical in the EU. However, there is no recommended threshold of use and available data on Kollicoat® IR as an excipient in pediatrics is limited (EFSA, 2013).

The developmental toxicity of polyethylene glycol-g-polyvinyl alcohol grafted copolymer was evaluated in rats and rabbits. Pregnant

rats and rabbits were fed with 100, 300, or 1000 mg PEG-PVA grafted copolymer per kg bw per day. The animals were sacrificed after the administration of the treatment. No adverse effects on fetal development or any teratogenic potential were observed after clinical examination. Based on these results, the NOAEL for maternal and developmental toxicity in rats and rabbits was set at 1000 mg/kg/day bw (Heuschmid et al., 2013).

In 2013, the EFSA Panel prepared a report on the safety of PVA-PEG graft copolymer as a food additive. Short-term repeated-dose oral toxicity studies in animals did not show any adverse effects. In addition, the copolymer is practically not absorbed from the gastrointestinal tract after oral administration. A subchronic feeding study was conducted in the dog and a NOAEL of approximately 800 mg/kg/day bw was identified. The dietary intake of PVA-PEG graft copolymer was also estimated to be 4.3 mg/kg/day bw for children and 5 mg/kg/day bw for adults, which provides an adequate safety margin with respect to the NOAEL (EFSA, 2013). Although it is a threshold for exposure to PVA-PEG graft copolymer as a food additive, it will be considered as a reference in this review.

### Kollicoat® IR and 3D printing

Filaments of pure Kollicoat® IR and mixed with Kollidon® VA64 were extruded and FDM printed, while Kollidon VA®64 is not printable alone, as mentioned in part 3.4.2. Filament obtained from pure Kollicoat® IR exhibits a lower torque (35–40 %) and higher breaking force (430 g), compared with filaments made from a blend of both polymers (45–50 % and 320 g). Therefore Kollicoat® IR is an interesting polymer carrier suitable to extrude and print others polymers and providing filament's good mechanical properties (Nyavanandi et al., 2022).

Kollicoat® IR is often used as a hydrophilic polymer carrier and can also be used to enhance API release kinetics (Fanous et al., 2020; Nyavanandi et al., 2022; Samaro et al., 2020). In a study on FDM printing, theophylline-loaded tablets were prepared with different thermoplastics polymers: Kollicoat® IR and two grades HPMC, selected to improve the dissolution rate of the API. Theophylline loaded filaments at 20 and 40 % (w/w) were successfully extruded and printed with both polymers. Dissolution studies showed that Kollicoat® IR enabled faster drug release, which was completed in 150 min versus 210 min and 12 h, depending on the HPMC's grade. This can be explained by the different drug release mechanisms. For Kollicoat® IR matrix, release was controlled by the polymer dissolution while for HPMC, it was driven by polymer swelling and subsequent erosion. This is consistent with the increase in theophylline release when the amount of Kollicoat® IR decreases from 40 min to 150 min, for a 20 % (w/w) to a 40 % (w/w) loaded form (Samaro et al., 2020).

Similarly, Kollicoat® IR was used as hydrophilic matrix to developed levetiracetam immediate release loaded form using pressure-assisted micro-syringes (PAM). The printed forms met the expected specifications with rapid drug release within 15 min (El Aita et al., 2019).

Based on these data and on the quantity of Kollicoat® IR in all the formulations presented, the quantity of this polymer ranges between 28 to 141 mg in the printed form (42 and 80 % (w/w)). Considering the exposure threshold of children to Kollicoat® IR is 4.3 mg/kg/day bw, the developed printed forms are suitable for patient weighing from 7 kg (1 year old) to 33 kg (10 years old) (EFSA, 2013).

## 4.7. Soluplus®

Soluplus® is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer commercially marketed by BASF. It has an amphiphilic structure and is soluble in water. This amorphous polymer has a glass transition temperature of 70 °C and a degradation temperature of 250 °C (Kolter, 2012).

### Safety information on Soluplus®

Soluplus® is not in the FDA IID, nor is it GRAS listed. Long-term
studies have been conducted in Wistar rats and beagle dogs with chronic dosing and there was no evidence of target organ toxicity. A lethal dose was determined in an acute oral toxicity study in rats, LD50 over 5000 mg/kg, and a 13-weeks study in rats was conducted to determine a NOAEL of 2000 mg/kg. Finally, a NOAEL of 1000 mg/kg/day bw was established following a 26-week study in dogs. Based on these levels of Soluplus® in animals, a safe initial human dose of 30 mg/kg can be estimated (Schmitt, 2022).

Soluplus® has been tested in adults in several clinical trials; where a single dose of up to 312.5 mg was administered as an excipient in tablets. No adverse events were reported. In another study, the dose tested was increased to 2000 mg, representing 80% of the tablet's content, equivalent to 28.6 mg/kg for a patient with a body weight of 70 kg. Thus, the adult dose is therefore 30 mg/kg. As there are no specific age-related concerns, the use of Soluplus® in pediatric populations at these levels is presented by the authors as potentially safe and acceptable (Schmitt, 2022). However, in the absence of clinical studies in the pediatric population, this threshold cannot be extrapolated.

### Soluplus® and 3D printing

As presented previously, Samaro et al. compared a wide range of thermoplastic polymers to prepare filaments for subsequent FDM printing. Soluplus® was successfully extruded, but resulting filament was too brittle. Indeed, the traction measurement showed that Soluplus® had the lowest Young's modulus (67.6 MPa) and a comparatively low tensile strength (7.4 MPa) when compared to the other polymer filaments, ranging from 69 MPa to 158.7 MPa (Young's Modulus) or 15.2 MPa to 62.2 MPa (tensile strength). Consequently, experiments were not pursued with Soluplus® (Samaro et al., 2020). However, filaments with Soluplus® can be extruded and printed when mixed with others polymers. For instance, a mixture of HPMC, Soluplus® and Kollidon® VA64 (20:34:20% (w/w)) was successfully extruded at 120°C and printed at 215°C (Saydam et al, Takka 2020). In another study, Soluplus® and Eudragit® EPO, as matrix carriers, were successfully extruded (150°C) and printed (180°C) in a blend with PEO with a thermos-sensitive API (Hoffmann et al., 2022; Jennotte et al., 2023).

Based on clinical studies conducted in adults exposed to Soluplus®, the recommended dose is established at 30 mg/kg (Schmitt, 2022). In the formulations outlined, Soluplus® represents 20% to 45% of the tablet's total weight, resulting in a range of 45 to 450 mg per printed form (Hoffmann et al., 2022; Samaro et al., 2020; Saydam et al., 2022; Saydam and Takka, 2020). Thus, in the reviewed article, the use of Soluplus® at the indicated levels does not increase risks for adults, but no conclusion can be drawn for children.

## 4.8. Glycerol

Glycerol or glycerin is used in food (E422), cosmetics and pharmaceuticals. Glycerol occurs naturally in animal and vegetable fats and oils that are consumed as part of a normal diet. Glycerol is readily absorbed from the intestine and is either metabolized to carbon dioxide and glycogen or used in the synthesis of body fats (Sheskey et al., 2020).

### Safety information on glycerol

Glycerol is GRAS listed and accepted for use as a food additive in Europe. It is included in the FDA IID for many products such as dental pastes, buccal preparations, oral capsules, solutions, suspensions and tablets (Sheskey et al., 2020).

Glycerin is currently used as a solvent for the preparation of suspensions due to its good suspending properties and taste. When used as an excipient or food additive, glycerin is not usually associated with adverse effects and is generally considered a non-toxic and non-irritating material. Oral doses of glycerin have a mild laxative effect, and larger doses may lead to symptoms such as headache, thirst, nausea, and hyperglycemia. Glycerol can be used orally in doses of 1–1.5 g/kg

body weight to lower intraocular pressure. It can act as an anti-crystallization agent in drug solutions and as a plasticizer. It is a sweetener that can cause oral digestive disorders and mild laxative effect (diarrhea) at amounts ≥ 1 g, headache and digestive disorders (diarrhea) at amounts ≥ 10 g per dose (Potier, 2017; Sheskey et al., 2020). Based on the studies carried out on animals, lethal dose for oral administration is estimated at 12.6 g/kg for rats (Sheskey et al., 2020).

For adult patient, the TDLo (Toxic Dose Low), i.e. the lowest dose causing a toxic effect for an oral exposure, is set at 1428 mg/kg (« Glycerin »). In 1981, it was concluded that it was not necessary to establish an ADI for humans, due to the low toxicity of glycerol. Based on the available studies, the EFSA estimated that the lowest oral dose of glycerol required to achieve a therapeutic effect was 125 mg/kg bw per hour. It was also highlighted that infants and young children can be exposed to this dose by drinking less than the volume of one can (330 ml) of a flavored beverage (EFSA, 2017).

### Glycerol and 3D printing

Glycerol was selected for its plasticizing properties to prepare homogeneous ink for SSE printing and to reduce extrusion temperature to obtain a flexible filament suitable for FDM 3D-printing (Mathiyalagan et al., 2023; Roulon, 2021). For instance, formulations of PVA with 10% (w/w) of various amount of glycerol were compared through thermal and mechanical analysis. Glycerol strongly decreased the Tg (about 25 °C), the Tm (10 to 20 °C) and also improved filament's flexibility, reducing the flexural modulus from 59 to 11.1 Pa. Filament's flexibility could be increased with higher amount of glycerol but it can also lead to a lower Tg and physical instability of the solid dispersion. Glycerol was also used as a moisturizing agent (gelatin paste in SSE) at a dose of 5.5 to 120 mg (2–15% (w/w)) per printed form (Rouaz et al., 2023; Yang et al., 2020). These results underline the various effects of plasticizer such as glycerol and the need to determine the optimal amount to achieve the targeted properties (Hess et al., 2024). The concentration of glycerol usually used is lower than the dose used to achieve therapeutic effect and lower than the dose a child might ingest in flavored beverage (EFSA et al., 2017). Glycerol dose in printed form does not therefore appear to be dangerous, but studies focused on children are needed before a conclusion can be drawn.

## 4.9. Polysorbate

Polysorbates are polyoxyethylenated sorbitan esters widely used as surfactants in formulations administered to adults and children.

### Safety information on polysorbates

Safety data are available for adults, but less documented for the pediatric population. In the EU, polysorbates 20, 40, 60, 65 and 80 have been approved under the Food Additives Directive. Polysorbate 80 is GRAS and polysorbates 20 and 80 are listed in the FDA IID. According to the WHO, the acceptable oral daily intake of polysorbates for adults is 25 mg/kg, while the Scientific Committee on Food suggests 10 mg/kg (Kriegel et al., 2019).

Animal toxicity studies have shown that polysorbates have a very low acute toxicity in rats and mice by the oral, IP and IV routes with a LD50 > 2 g/kg bw. In chronic toxicity studies, in rhesus monkeys, no adverse effects were reported after a 10 months of exposure to 0.1 g/kg/day to polysorbate 80 (EMA, 2018b).

Based on an oral carcinogenicity study with polysorbate 80 in rats, the NOAEL determined was 2500 mg/kg/day bw. Using this value and applying a factor of 100, a group ADI of 25 mg/kg/day bw was established for polysorbates 20, 80, 40, 60 and 65 (E 432, E 433, 209 E 434, E 435 and E 436, respectively). It was then estimated that toddlers exposure at the highest level was very close to the ADI (24.5 mg/kg/day bw) (EMA, 2018b).

Pharmacokinetics in children have also been studied. Ester hydrolysis is reported to be low in neonates and appears to be significantly
related to developmental stage. In fact, esterase activity increases with age and with plasma proteins, reaching adult's values at 1 year of age. Consequently, polysorbate hydrolysis in neonates and infants is not clear. Finally, several neonatal deaths have been reported after parenteral administration of vitamin E preparations containing 9% polysorbate 80 and 1% polysorbate 20. High levels of polysorbate (100 µg/ml) were found in the peritoneal fluid, suggesting that the neonate was unable to metabolize the compound (EMA, 2018b).

## Polysorbates and 3D printing

Overall, polysorbates are suitable with SSE (Johannesson et al., 2021; Lafeber et al., 2022; Mathiyalagan et al., 2023) and with FDM (Saydam and Takka, 2020). In a study on improving rufinamide disintegration in a FDM printed form, Tween® 80 was compared with other solubility enhancers. This resulted in a 76% API dissolution in 120 min for the formulation with 4% (w/w) of Tween® 80 per dose (52 mg) compared to 61% (w/w) with Gelucire® 44/14 and 90% (w/w) with Gelucire® 48/16 (Saydam and Takka, 2020).

In SSE, polysorbate has been also used to develop lipid-based formulation, such as for the improvement of the bioavailability of lipophilic drugs. In order to avoid the potential degradation of the drug, for this study SSE of emulsion gels, stabilized by Tween 85 And Kolliphor® EL, was chosen. The 3D printed tablets were then characterized by in vitro disintegration, dispersion and digestion studies. Droplet size was also measured before 3D printing and after tablet disintegration. In both cases, the Tween 85 based emulsion produced larger droplets than the Kolliphor EL emulsion, resulting in lower lipid digestion for the Tween 85 based emulsion, 48% after 60 min compared to 98 and 78% for Kolliphor EL (Johannesson et al., 2021).

The exposure to polysorbate in the printed forms analyzed can be estimated to be between 1% (w/w) and 35% (w/w). The average mass per unit dose is 3 to 8.5 mg (Johannesson et al., 2021; Kozakiewicz-Latala et al., 2022b). Based on the available information on polysorbate, it is not recommended for newborns and children under 1 year of age, and above this age the WHO has defined an ADI of 25 mg/kg, so it may be appropriate for older patients. However, further information is needed to reach a conclusion in this case (Kriegel et al., 2019).

## 4.10. Silicon dioxide

Silicon dioxide (SD) is commercially available under several grades, produced by different manufacturing processes that modify particle size, surface area, and density: Aerosil® (Evonik) or Cab-O-Sil® (Thermo Scientific). SD is used to improve powder flow properties, as stabilizing agent in emulsions and as a thixotropic thickening and suspending agent in gels and semi-solid preparations. It can also be used as a tablet disintegrant and as an adsorbent dispersant for liquids in powders (Sheskey et al., 2020).

### Safety information on Silicon dioxide

SD is widely used in oral and topical pharmaceutical products and is generally regarded as nontoxic and nonirritant excipient. SD is GRAS listed and included in the FDA IID for the preparation of oral capsules, suspensions, and tablets. Oral toxicity studies on rat resulted in a LD50 = 3.16 g/kg (Sheskey et al., 2020).

In 1991, the scientific committee on food established a ADI 'not specified' meaning that there was no need to set a numerical limit for the ADI for E551 considering the doses used in food. The EFSA Panel conducted a safety evaluation of SD as a food additive (E5551) and determined it does not raise concerns regarding genotoxicity. Based on the available data, there is no evidence of toxicity associated with the reported uses and used levels of E551. However, due to limited data, the EFSA panel could not confirm the ADI fixed in 1991. The specifications outlined by the European Union for SD (E551) are considered insufficient for adequately characterizing its use as a food additive. It is recommended to incorporate the characterization of particle size

distribution with statistical descriptors (range, median, and quartile). Along with the percentage (in number and by mass) of particles in the nanoscale, with at least one dimension measuring less than 100 nm in silicon dioxide (E551) used as a food additive (EFSA, 2018a).

With regard to size, the effects of SD particles of two different sizes, 20 nm and 100 nm, were analyzed in rats in a 90-day study. Based on the results, the NOAEL was set to 2000 mg/kg for both particle sizes and no target organ was identified. With the oral toxicity studies of SD presented, no conclusion can be drawn regarding its use as an excipient in pediatric formulations (EFSA, 2018a).

### Silicon dioxide in 3D printing

As presented on the work of Roulon et al. and Hoffman et al., SD is used to improve powder flowability in HME coupled with FDM. However, no data is available to compare the flow of the powder with and without silicon dioxide. Quantity of SD commonly used falls within the range of 0.5 to 2% (w/w) of the printed form, which corresponds to 0.5 to 3 mg of SD in each form (Roulon, 2021; Hoffmann et al., 2022).

## 4.11. Methacrylate polymer

Basic Methacrylate Copolymer (BMC) is a fully polymerized cationic copolymer based on dimethylaminoethyl methacrylate and the neutral methacrylic esters butyl methacrylate and methyl methacrylate. The copolymer is described in the IUPAC nomenclature as poly(butyl methacrylate-co-(2-dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1. The molecular weight is about 47,000 g/mol (Eisele et al., 2011).

Basic Methacrylate Copolymer (BMC) has been employed as an excipient for oral pharmaceutical formulations since 1959. It is used as a film coating material to mask taste and allow rapid disintegration in the gastrointestinal tract. BMC is marketed as EUDRAGIT® (Evonik Röhm GmbH.) in granular form (EUDRAGIT® E 100) and powder form (EUDRAGIT® E PO). The product is also supplied as a 12.5% organic solution in a mixture of 60% (w/w) 2-propanol and 40% (w/w) acetone (EUDRAGIT® E 12.5) for specific pharmaceutical purposes (Eisele et al., 2011).

### Safety information on Methacrylate Copolymer

The STEP database does contain no information on BMC. However, in February 2010, the EFSA published a positive scientific opinion on the use of BMC as a food additive. Based on studies in rat, the NOAELS values of 1000 mg/kg/day bw (the only dose level tested) and 2000 mg/kg/day bw from a 26-week dietary study (the highest dose tested) were determined. In contrast, due to the lack of studies on the reproductive toxicity, no ADI was calculated.

The panel also determined the estimated exposure dose (EED) for heavy users exposed to food supplements and pharmaceuticals to 23.4 mg/kg/day bw for a 60 kg adult and 16 mg/kg/day bw for children aged 4 to 18 years old. As, the BMC manufacturing process uses monomers (methyl methacrylate (MMA), butyl methacrylate (BMA) and dimethylaminoethyl methacrylate (DMAEMA)) which may remain partially in the final product, the quantity of monomers was also estimated using the Tolerable Daily Intake (TDI). The TDI is an estimation of the quantity of a substance in food or drinking water that is not added intentionally (e.g. contaminants) and can be ingested throughout a person's lifetime without posing a significant health risk. The exposure to MMA, BMA and DMAEMA was estimated to be significantly below the TDI of 0.1 mg/kg/day bw (as methacrylic acid) established by the scientific committee on food (EFSA, 2010a).

The ratio of the NOAELS to EED corresponds to the Margin of Safety (MOS). The MOS is the difference between the actual consumption of a substance by a specific population and the daily dose over a lifetime that experts deem as safe. A MOS ≥ 100 is generally regarded as protective. When considering exposure to both food and pharmaceuticals, a MOS of at least 43 to 85 for adults and 63 to 125 for children (in the case of
heavy users) was estimated. If only dietary exposure is considered, the MOS ranges from 85 to 171 for adults and from 125 to 250 for children. Due to the high molecular weight of the substance, limited absorption and low toxicity profile, the EFSA panel considers these safety margins to be adequate (EFSA, 2010a).

In addition, Eisele's team reviewed the EFSA report and noted in its "Note for Guidance for Petitioners Presenting an Application for the Safety Assessment of a Substance to be Used in Food Contact Materials Prior to its Authorisation" "that components with a molecular mass above 1000 Dalton (D) are very unlikely to be absorbed by the gastrointestinal tract and thus are not considered to present a toxicological risk. Thus, based on the FDA's approach, ADI for BMC is estimated to 20 mg/kg bw (Eisele et al., 2011).

Similarly, to BMC, the EFSA has addressed the oral toxicity of synthetic polymeric substances used in food in a limited number of publications. Two of these substances, Neutral Methacrylate Copolymer (NMC) with a molecular weight of 600 K g/mol and Anionic Methacrylate Copolymer (AMC) with a molecular weight of 280 K g/mol, were evaluated in publications from 2010 (EFSA, 2010b, 2010c). From studies on toxicokinetics, acute and subchronic oral toxicity, genotoxicity, and developmental toxicity, the EFSA panel concluded that both NMC and AMC are essentially not absorbed. Even in cases where small amounts of the material were absorbed, they were not retained in the tissues. Therefore, it was determined that the use of these polymers in solid food supplements at the proposed levels of use does not raise safety concerns. (Eisele et al., 2011).

### Methacrylate Copolymer and 3D printing

In the reviewed articles, EUDRAGIT® was used as polymer carrier with various release properties depending on the grade (Hoffmann et al., 2022; Linares et al., 2019; Tabriz et al., 2022). EUDRAGIT® EPO stands out as a robust drug delivery carrier offering benefits such as taste masking, moisture protection, and favorable mechanical properties. Furthermore, it proved to be a valuable asset in enhancing the release of APIs, as demonstrated in FDM printed tablets loaded with lumefantrine. The printed form with a 65% infill density achieved a 90% release within 30 min, whereas a compressed tablet achieves 83% release (Fanous et al., 2021). EUDRAGIT® EPO is pH sensitive, insoluble at pH above 5 (in saliva), but highly soluble in acidic media, (stomach) making it very interesting for taste masking (Tabriz et al., 2022).

Another study combined FDM and Injection Volume Filling (IVF) to develop a theophylline loaded film. Eudragit® FS30D was selected as a delaying release polymer carrier. Film with Eudragit® FS30 displayed approximately 80% of drug release after 8 h while, more than 60% of drug was dissolved in the first 5 min without 5 min (Linares et al., 2019).

Eudragit® represents between 44 and 75% (w/w) of the printed forms (Fanous et al., 2021; Hoffmann et al., 2022; Linares et al., 2019; Tabriz et al., 2022, 2021). These amounts comply with the EFSA, which estimates an average exposure of 16 mg/kg/day bw BMC polymer as food additive. For example, 44 mg were used to prepare a 100 mg tablet, suitable for children over 4 months (Hoffmann et al., 2022), 69–104 mg is used in the formulation which is suitable for children over 4 months, i. e. 5 kg bw (Fanous et al., 2021) and tablet with 150 mg is suitable for a 9.4 kg child (Tabriz et al., 2022). At the concentration considered in the different formulations studied, it could be considered as safe. However, these results are indicative and a study should be performed to evaluate its toxicity.

## 4.12. Lactose

Lactose is a dissacharide of glucose and galactose it can be found in more than 20% of the marketed solid dosage forms. It is commonly used as a filler and diluent in tablets, capsules and infants formulas. Different grades are manufactured depending on their particles size distribution and flowing properties for instance Tablettose® (Meggle Pharma), Pharmatose® or SuperTab® 30GR (DFE Pharma). There are also many

co-processed excipients with lactose, such as with starch (Starlac, Meggle/Roquette Frères), microcrystalline cellulose (Microcelac, Meggle), povidone and crospovidone Ludipress LCE (BASF) (Sheskey et al., 2020).

### Safety information on Lactose

In pediatric lactose can lead to hypersensitivity reactions due to the immaturity of intestine with low levels of lactase enzyme to hydrolyze it. Flatulence, diarrhea and cramps are reported for patient with lactose intolerance. These symptoms are due to the osmotic effect of unabsorbed lactose leading a raising level of water and sodium in the lumen. Some patient can present prolonged reaction to lactose which can cause metabolic acidosis, jaundice or bacterial proliferation. The WHO recommend a maximum daily dose of 3 g for children (Belayneh et al., 2020; Sheskey et al., 2020).

### Lactose and 3D printing

In SSE lactose is used as a filler (Callede et al., 2022; Suárez-González et al., 2021). It was considered as a filler to replace sucrose and to improve consolidation and spreadability. The orodispersible forms were successfully printed with a uniform average mass and drug content. In these studies, the printed form was composed of 18 to 35% (w/w) of lactose, resulting in 5 to 63 mg. Based on the WHO recommendation, these doses are suitable for children (Belayneh et al., 2020).

## 4.13. Poloxamer

Poloxamers are nonionic copolymers composed a hydrophilic segment of polyoxyethylene and polyoxypropylene which is hydrophilic, resulting in an amphiphilic system. They are used in pharmaceutical formulations as emulsifying and solubilizing agent in syrup and as binder and coatings in tablets. Various types of poloxamers are commercially available, with different ratios of propylene and ethylene oxide. For instance, the average molecular weight of poloxamer 188 is around 8400 g/mol while it is around 12600 g/mol for poloxamer 407. There are also known as Kolliphor® P 188 or P 407 (BASF).

### Safety information on Poloxamer

Poloxamer 407 and 188 are included in the FDA IID for oral powders, solutions suspension and syrups. Poloxamer 407 is also GRAS listed, in the STEP database and included as excipients for pediatric formulations by the WHO. However, there no available ADI (van Kampen et al., 2023). In a study on mice, chronic administration of Poloxamer 407 in their diet resulted in a higher plasma cholesterol level and development of atherogenic arterial lesion. A 2-years toxicity study on rats receiving 3% w/w or 5% w/w of poloxamer 188 in their diet did not exhibit any adverse effects. However, in a long-term study, rats receiving 7.5% w/w of poloxamer 188 showed some decrease in growth rate. The oral LD50 value for poloxamer 188 was determined as > 34.6 g/kg. However, with the information on both poloxamer 188 and 407 is not possible to estimate a threshold for children. (Sheskey et al., 2020; Singh-Joy and McLain, 2008).

### Poloxamer and 3D printing

In a proof of concept, Poloxamer 188 was used as a co-surfactant to develop a solid based lipid formulation using SSE. 3D printed form were successfully printed without solid carrier at 65 °C (Vithani et al., 2019). Kampen et al. screened excipients for the development of SSE printed pediatric forms and formulation of poloxamer 407 and lactose 78% (w/w) was successfully printed. In FDM, poloxamer 407 is often used as a plasticizer but Kempin et al. selected as a polymeric carrier. The dissolution tests displayed a slow drug release, completed after 2 h, which was explained by the formation of a gel layer around the tablet, slowing drug's diffusion (Kempin et al., 2018). From the reviewed articles, poloxamer 407 was used between 23.3 to 90% (w/w) resulting in 50 to 90 mg per printed forms (Kempin et al., 2018) but due to the lack of
information, it is not possible to conclude on its potential toxicity in pediatrics.

The excipients mainly used in the development of personalized medicine with extrusion based 3D printing were reviewed. Overall, the formulations the polymer(s) carrier(s) and excipients are selected based on the 3D printing method selected and then the printed form properties required:

* Decrease the process temperature: plasticizer (Hess et al., 2024; Hoffmann et al., 2022; Palekar et al., 2019)

* Improve mechanical properties: plasticizer (Elbadawi et al., 2021; Hess et al., 2024)

* Adjust viscosity: viscosity modifier, plasticizer, increase/decrease the molecular weight of the polymer carrier (Isreb et al., 2019; Johannesson et al., 2021; Popescu et al., 2014)

* Form of the printed form: film, gum, printed tablet (Sjöholm and Sandler, 2019; Tagami et al., 2021)

* Acceptability: taste-masking agent, sweetener (Elkanayati et al., 2022)

* Increase the API's dissolution rate: nature of the support carrier, molecular weight of the support carrier, pore-forming agent, disintegrant, (Duranović et al., 2021; Omari et al., 2022; Samaro et al., 2020)

As presented in this review excipients have several applications, which need to be considered during the formulation's development. This was illustrated with plasticizers (PEG, glycerol, sorbitol) reducing the extrusion and printing temperatures while increasing the filament's flexibility. However, further increase in plasticizer is reported to induce thermal instability of the solid dispersion and result in filaments with poor mechanical properties (Hess et al., 2024). Thus, setting the amount of excipient in the formulation requires an overview of the effect on the printed form and so often needs experimental screening. In response, studies focusing on the use of machine learning, to help formulators, are raising interest (Elbadawi et al., 2021). However, as highlighted in this review, there is a concerning lack of data, resulting in uncertainty about the potential toxicity of excipient in pediatrics.

Throughout the development of pharmaceutical forms, API's and excipients and are selected, the formulation is developed followed by toxicity and pre-clinical trials. Despite extensive research on 3D printed medicines, there still are few pre-clinical or toxicity trials. A rufinamide-loaded tablet was FDM printed and cell culture, in-vitro and in-vivo studies were performed to compare it to a marketed medicine (Inov Lon®). Upon evaluating the pharmacokinetic data, the resulting maximal concentration values were higher in the 3D printed form compared to the reference product. Moreover, pharmacokinetics parameters such as the API's half-life, its mean residence time or the apparent first order disposition suggested that the 3D printed form dissolves faster under physiological conditions and is excreted faster form the body. This study displays the feasibility of implementing a "dose reduction" strategy with 3D printed forms achieving the same effect with a lower dose (Saydam and Takka, 2020). In pediatrics, conducting clinical trials is particularly difficult due to the constraints imposed. Yet, Goyanes et al. evaluated the first use of 3D printing in the hospital to treat patients with urinary maple syrup disease. The study involved four patients aged 3 to 16 years to compare conventional and 3D printed forms. 3D printed forms were well accepted and the patient's blood API levels were close to the targeted value. This work demonstrates, for the first time, the possibility of using 3D printing to prepare customized oral therapies in hospitals (Goyanes et al. 2019). Even though there are few clinical studies and toxicity trials at the moment, this example show that 3D printing can help address issues and enhance the development of treatments.

## 5. Conclusion and perspectives

This literature review has highlighted the regulation of the excipients used in 3D printing for pediatric oral forms. In general, the available information on the oral administration threshold of these excipients, their ADI and the absence of clinical studies in many of the cases highlight the lack of information on the pediatric population. Overall, polymeric excipients are the main components used in I3D (from 20 to 90% (w/w) per tablet). Therefore, toxicity studies of polymers widely used in FDM and SSE: PEO, cellulose derivative, PVP and its derivatives, PVA, Soluplus®, Eudragit® or Kollicoat®IR in the pediatric population, are necessary.

The available threshold for excipient oral administration given in mg/kg/day, underlines the importance of considering patient's weight. As pediatric population is divided in subcategories, each requires an adapted medicine. Depending on the patient's weight, the API's concentration, as well as the amount of excipients as to be tailored. Overall, based on the available information, the quantities of excipients used in the formulations presented in the articles are suitable for the pediatric population, if the patient's weight is considered. This general overview shows that for many excipients (cellulose derivatives, PVA or Kollicoat®IR) the information come mainly from food regulations and EFSA reports. Thus, the conclusions drawn, when it was possible, are given as indications, they are not intended to serve as regulations. Considering the rising researches on development of 3D printed medicines, this review helps to understand how much regulation need to be established.

Even if many points have to be addressed, 3D printed pediatric medicines remain promising for the future of pharmaceutical research. In the case of pediatric orphan drugs, researchers with a 3D printing approach could accelerate the path from drug discovery to actual medicine and provide precise, personalized treatment for pediatric patients. With the expansion of 3D printing research as a new manufacturing technology, new excipients may be needed to manufacture a tailored pediatric dosage form. Beyond the regulatory considerations regarding excipients, the increasing prominence of 3D printing in research and its potential democratization in the future have the potential to revolutionize drug manufacturing. This evolution leads to numerous questions for all stakeholders in the pharmaceutical sector and may give rise to new challenges. In fact, the growing role of 3D printing in the pharmaceutical industry is reshaping discussions around product quality and necessitating a reevaluation of standards by including this innovative manufacturing process. Thus, questions about the equipment used for the production of these drugs are also raised. Ensuring the quality and safety of 3D-printed drugs induce the integration of new equipment such as hardware (such as printers and print heads) and software (digital design). Consequently, research focused on the development of 3D-printed medications, both for pediatric and non-pediatric use will change the current processes and regulations. As for other medical applications, such as dental, podiatric prosthesis, drug 3D printing might become a first line solution within the next few years.

## 6. Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used ChatGPT in order to diversify vocabulary and avoid repetition in sentence structure. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.

### CRediT authorship contribution statement

**M. Monteil:** Investigation, Writing – original draft, Writing – review & editing. **N. M.Sanchez-Ballester:** Supervision, Writing – review & editing. **J.M. Devoisselle:** Writing – review & editing. **S. Begu:** Supervision, Writing – review & editing. **I. Soulairol:** Supervision, Writing –
review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

Data will be made available on request.

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