3D Printing of Orodispersible Film for Poorly Soluble Drug

INTRODUCTION

Orodispersible film (ODF) is well known as a patient-centric dosage form. Its ease of administration with minimal need of water facilitates high patience compliance especially for pediatrics, geriatrics, and patients with difficulty swallowing.

3D printing is an attractive tool for ODF fabrication due to its ability to deliver personalized medicine, a very much needed element in the treatment of pediatric and geriatric populations.

In this study, we aim to 3D print ODF containing a poorly soluble model API using hydroxypropyl b-cyclodextrin as a solubilizing and filler excipient. The specific objective of this study is to optimize an ODF formulation of a poorly soluble drug, loratadine, for 3D printing using the pressure-assisted microsyringe technology, also known as bioprinting.

OBJECTIVES

To optimize the ODF formulation of poorly soluble drug, loratadine for 3D printing using the pressure-assisted microsyringe technology, also known as bioprinting.

MATERIALS AND METHODS

Materials

Loratadine (USP40, Chemigran Pte. Ltd., Singapore) was used as model API. KLEPTOSE® HPB, oral grade hydroxypropyl ß-cyclodextrin (HPBCD, Roquette) was used as solubilizing agent. NEOSORB® P 100 T sorbitol (Roquette) was used as film plasticizer. HPMC E50 (Shandong Head Co. Ltd., China) was used as film-forming polymer.

Methods

The ODF formulation used in this study was adapted from an earlier optimized ODF formulation based on solvent-casting into unit-dose plate developed by Foo et al.¹

Preparation of HPBCD-Loratadine solution

HPBCD solution was prepared by dissolving 15 g of HPBCD in 50 ml of purified water followed by the addition of 2.5 g of loratadine. The mixture was subjected to heat-cool-heat cycling in an autoclave (121 °C, 1 atm) over 3 cycles to enhance complexation efficiency. Water was added up to the original weight of the final cooled mixture to compensate for water loss during the autoclave cycles. The mixture was filtered through 0.45 mm regenerated cellulose filter to obtain a clear solution. Solubilized loratadine concentration in the HPBCD solution was assayed using UV spectroscopy. Chemical stability of loratadine undergoing the autoclave cycle has been established in the earlier study by Foo et al.¹

Fabrication of ODF films

Sorbitol was dissolved in 5 ml of HPBCD-only solution or HPBCD-loratadine solution pre-heated to 90 °C, followed by addition of HPMC E50 with gentle stirring. Stirring of the mixture was continued at room temperature until a clear hydrogel was obtained.

ODF films were fabricated using an extrusion-based, pressure-assisted microsyringe device, also called a bioprinter (Bio X^TM, Cellink, MA, USA). Hydrogel was loaded into the printing cartridge consisting of a 3ml syringe. The cartridge was centrifuged at 3000 rpm for approximately 3 mins to remove bubbles. Printing was performed using a 27-gauge print tip on a piece of Parafilm lined on a petri dish. Formulation and printing parameters optimization were carried out on API-free hydrogel samples. The ranges of printing parameters used during optimization were as follows: Pressure 40 - 102 kPa, speed 1 - 4 mm/s, infill density 50 - 85%, compensation 75 - 80%, Layer height 0.1 - 0.2 mm.

Cylindrical CAD model (20 mm diameter, 0.4 mm height) designed using the Rhino 6 design software (McNeel, WA, USA) was used. Slicing of the design was performed by the printer before printing.

Characterization of ODF

Differential scanning calorimetry (DSC)

Differential scanning calorimeter (TA Instruments, Q2000, DE, USA) was used to determine the presence of any crystalline loratadine in the film. DSC thermogram was obtained on samples in Tzero pans at a heating rate of 5 °C/min from 40 to 200 °C and analyzed using Universal Analysis 2000 (TA, Instruments, DE, USA).

Disintegration test

Film disintegration was conducted using a modified setup as shown in Figure 1. Two 10-ml pipette tips were cut into half. The film was sandwiched in between the base of the pipette tips, and the connection was secured tightly with a Parafilm. The setup was placed vertically on a 50 ml beaker with a piece of paper towel at the bottom. The timer was started upon the dispensing of 1 ml water onto the film and stopped as soon as the towel became wet. The time taken was recorded as the disintegration time of the film.

Figure 1. Setup used film for disintegration test

RESULTS

The criteria observed for formulation and printing parameters optimization were extrudability of the hydrogel, appearance of sol, shape fidelity of the freshly printed wet film, and appearance and flexibility of the dried films.

The ODF formulation composition optimized for printing is shown in Table 1. The amount of loratadine was calculated based on the assayed concentration of 30 mg/ml in the HPBCD-loratadine solution.

Table 1. Optimized ODF formulation composition.

The absence of loratadine melting peak at 134-136 °C in the DSC thermogram (Figure 2) of the ODF indicates the amorphous state of the drug.

The amorphous state of loratadine in the ODF was brought about by inclusion complexation with HPBCD. Inclusion complexation is the key mechanism behind the solubilizing function of HPbCD which enables incorporation of poorly soluble drugs in relatively high concentrations in ODFs. The usefulness of HPBCD as solubilizing excipient in ODFs has also been reported for furosemide and indomethacin.² 

Figure 2. DSC thermogram of loratadine (green curve) and ODF containing loratadine (blue).

Selected examples of printing parameters optimization are provided in Table 2 below.

Table 2. Selected examples of printing parameters optimization using API-free HPBCD-HPMC hydrogel

	Non-optimized printing parameters			Optimized printing parameters
Pressure	90 kPa	100 kPa	102 kPa	100 kPa
Speed	2 mm/s	2 mm/s	2 mm/s	1 mm/s
Infill density	70 %	70 %	70 %	55 %
Compensation	80 %	80 %	80 %	80 %
Layer height	0.2 mm	0.2 mm	0.2 mm	0.2 mm
Shape fidelity	Good	Good	Good	Good
Appearance of sol	Clear, transparent	Clear, transparent	Clear, transparent	Clear, transparent
Extrudability	Poor flow	Poor flow	Poor flow	Good flow
Film (appearance and flexibility)	Many gaps in film	Line of holes due to printer limitation	Line of holes due to printer limitation	Perfect film without any holes
Wet films
Dry films

The HPBCD-HPMC-loratadine hydrogel demonstrated shear thinning property with slight thixotropy (see figure 3). This behavior has enabled extrusion from the syringe tip during printing and shape recovery immediately after printing.

Figure 3. Rheograms of HPBCD-HPMC-loratadine hydrogel presenting shear thinning and slight thixotropic behavior.

The ODFs physical properties presented on table 3 demonstrate a good reproducibility of the films in size as well as satisfactory disintegration time with an average value of 146 s.

Table 3. Physical properties of ODFs containing loratadine. 

CONCLUSION

• A hydrogel formulation suitable for fabrication of ODF via 3D printing using the pressure-assisted microsyringe technology has been optimized.
• A set of printing parameters has been optimized for 3D printing of ODF.
• HPBCD has been shown to be an effective solubilizing and filler excipient for ODF hydrogel formulation for 3D printing.

REFERENCES

1. Foo W.C., Zhang C., Zhang H., Chow K.-T., Gokhale R. A multifunctional orodispersible film system with hydroxypropyl-β-cyclodextrin. AAPS PharmSci360 2020, New Orleans, USA

2. Alopaeus, J.F.; Göbelb, A.; Breitkreutz, J.; Sande S.A. and Tho, I. Investigation of hydroxypropyl-β-cyclodextrin inclusion complexation of two poorly soluble model drugs and their taste-sensation - Effect of electrolytes, freeze-drying and incorporation into oral film formulations. J. Drug Deliv. Sci. Technol., 61, 102245, 1-9 (2021). 
https://doi.org/10.1016/j.jddst.2020.102245