3D printed "Starmix" drug loaded dosage forms for paediatric applications

Purpose: Three- dimensional (3D) printing has received significant attention as a manufacturing process for pharmaceutical dosage forms. In this study, we used Fusion Deposition Modelling (FDM) in order to print "candy - like" formulations by imitating Starmix sweets to prepare paediatric medicines with enhanced palatability. Methods Hot melt extrusion processing (HME) was coupled with FDM to prepare extruded filaments of indomethacin (IND), hypromellose acetate succinate (HPMCAS) and polyethylene glycol (PEG) formulations and subsequently feed them in the 3D printer. The shapes of the Starmix objects were printed in the form of a heart, ring, bottle, ring, bear and lion. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Fourier Transform Infra-red Spectroscopy (FT-IR) and confocal Raman analysis were used to assess the drug - excipient interactions and the content uniformity. Results: Physicochemical analysis showed the presence of molecularly dispersed IND in the printed tablets. In vivo taste masking evaluation demonstrated excellent masking of the drug bitterness. The printed forms were evaluated for drug dissolution and showed immediate IND release independently of the printed shape, within 60min. Conclusions: 3D printing was used successfully to process drug loaded filaments for the development of paediatric printed tablets in the form of Starmix designs

Home based formulation of personalised medicines by means of inkjet printing technique

The potential application of inkjet printing technology to produce precisely dosage care is demonstrated in this thesis. Inkjet printing technology as it offers the opportunity to deliver quantities with high accuracy can produce medicines tailored for each patient. The viability of this method was first demonstrated by using Felodipine as an active pharmaceutical ingredient polyvinyl pirrolidone (PVP) as an excipient. Felodipine is an antihypertensive drug which is poorly soluble in water and PVP is a highly soluble polymer commonly used to improve drugs' bioavailability. These were dissolved at various ratios in a mixture of ethanol and DMSO (95/5). Using a piezoelectric driven dispenser, picolitre size droplets of the solutions were dispensed onto suitable hydrophobic substrates. The dried products were characterized using AFM, localized nano-thermal analysis and high resolution vibrational spectroscopy (ATR-IR and Raman). Results indicate intimate mixing of the micro-dot API and excipient mixtures. Specifically, ATR-IR confirmed the interaction of felodipine and PVP by means of hydrogen bonding. Nanothermal analysis indicates a single glass transition point which is lowered as the API concentration increases. Finally, confocal Raman microscopy mapping on single droplets allows the visualization of the homogeneous distribution of the drug. Also, capozide has been used as a model therapeutic system which could be produced rapidly as a viable formulation using the inkjet printing technology. Capozide consists of captopril, an angiotensin converting enzyme (ACE) inhibitor and hydrochlorothiazide, a thiazide diuretic drug, in varying ratios. These active pharmaceutical ingredients (APIs) and poly(lactic-co-glycolic acid) (PLGA) were dissolved in appropriate solvents and using a piezoelectric driven dispenser and pipetting, picolitre and microlitre size droplets respectively were deposited onto hydrophobic coated glass slides. Captopril and PLGA were dissolved in chloroform, ethanol and DMSO (75/18/7). Hydrochlorothiazide (HCT) and PLGA were dissolved in acetone and DMSO (93/7). The dried products where characterised using AFM and high resolution Raman microscopy. The results showed that both capropril and HCT are phase separated with the PLGA. Also, the dissolution profiles of the final products were measured using HPLC where it has been shown that PLGA can control the release of the drug from the formulation. These results are a promising first step to produce pharmaceutical by means of inkjet printing

3D printed chitosan dressing crosslinked with genipin for potential healing of chronic wounds

Recently, various additive manufacturing (3D printing) approaches have been employed to fabricate dressings such as film scaffolds that possess well defined architecture and orientation at the micro level. In this study, crosslinked chitosan (CH) based film matrices were prepared using 3D printing with genipin (GE) as a crosslinker, with glycerol (GLY) and poly ethylene glycol (PEG) as plasticizer. The 3D printed films were functionally characterized using (tensile, fluid handling, mucoadhesion, drug dissolution, morphological properties and cell viability as well physico-chemical characterization using scanning electron microscopy, Fourier transform infrared spectroscopy and X-ray diffraction. CH-GE-PEG600 3D printed films having the ratio of 1:1 polymer: plasticizer was selected due to their appropriate flexibility. Fourier transform infrared results showed intermolecular interaction between CH, GE and PEG which was confirmed by X-ray diffraction showing amorphous matrix structure. In vitro mucoadhesion studies of CH-GE-PEG600 films showed the capability of the 3D printed film to adhere to the epithelial surface. Scanning electron microscopy images showed that the surface of the plasticised films were smooth indicating content uniformity of CH, GE and PEG whilst micro cracks in unplasticised films confirmed their brittle nature. Plasticised films also showed high swelling capacity which enhanced water absorption. Cytotoxicity (MTT) assay using human skin fibroblast cell lines demonstrated that more than 90% of cells were viable after 48 h confirming non-toxic nature of the 3D printed CH-GE-PEG600 films and therefore promising dressing for chronic wound healing applications

Home based formulation of personalised medicines by means of inkjet printing technique

The potential application of inkjet printing technology to produce precisely dosage care is demonstrated in this thesis. Inkjet printing technology as it offers the opportunity to deliver quantities with high accuracy can produce medicines tailored for each patient. The viability of this method was first demonstrated by using Felodipine as an active pharmaceutical ingredient polyvinyl pirrolidone (PVP) as an excipient. Felodipine is an antihypertensive drug which is poorly soluble in water and PVP is a highly soluble polymer commonly used to improve drugs' bioavailability. These were dissolved at various ratios in a mixture of ethanol and DMSO (95/5). Using a piezoelectric driven dispenser, picolitre size droplets of the solutions were dispensed onto suitable hydrophobic substrates. The dried products were characterized using AFM, localized nano-thermal analysis and high resolution vibrational spectroscopy (ATR-IR and Raman). Results indicate intimate mixing of the micro-dot API and excipient mixtures. Specifically, ATR-IR confirmed the interaction of felodipine and PVP by means of hydrogen bonding. Nanothermal analysis indicates a single glass transition point which is lowered as the API concentration increases. Finally, confocal Raman microscopy mapping on single droplets allows the visualization of the homogeneous distribution of the drug. Also, capozide has been used as a model therapeutic system which could be produced rapidly as a viable formulation using the inkjet printing technology. Capozide consists of captopril, an angiotensin converting enzyme (ACE) inhibitor and hydrochlorothiazide, a thiazide diuretic drug, in varying ratios. These active pharmaceutical ingredients (APIs) and poly(lactic-co-glycolic acid) (PLGA) were dissolved in appropriate solvents and using a piezoelectric driven dispenser and pipetting, picolitre and microlitre size droplets respectively were deposited onto hydrophobic coated glass slides. Captopril and PLGA were dissolved in chloroform, ethanol and DMSO (75/18/7). Hydrochlorothiazide (HCT) and PLGA were dissolved in acetone and DMSO (93/7). The dried products where characterised using AFM and high resolution Raman microscopy. The results showed that both capropril and HCT are phase separated with the PLGA. Also, the dissolution profiles of the final products were measured using HPLC where it has been shown that PLGA can control the release of the drug from the formulation. These results are a promising first step to produce pharmaceutical by means of inkjet printing

Inkjet printing of insulin microneedles for transdermal delivery

Inkjet printing technology was used to apply insulin polymeric layers on metal microneedles for transdermal delivery. A range of various polymers such as gelatin (GLN), polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol (SOL), poly(2-ethyl-2-oxazoline) (POX) and trehalose (THL) were assessed for their capacity to form thin uniform and homogeneous layers that preserve insulin intact. Atomic force microscopy (AFM) showed homogeneous insulin–polymer layers without any phase separation while SOL demonstrated the best performance. Circular discroism (CD) analysis of rehydrated films showed that insulin’s alpha helices and β–sheet were well preserved for THL and SOL. In contrast, GLN and POX insulin layers revealed small band shifts indicating possible conformational changes. Insulin release in Franz diffusion cells from MNs inserted into porcine skin showed rapid release rates for POX and GLN within the first 20 min. Inkjet printing was proved an effective approach for transdermal delivery of insulin in solid state

Increased dissolution rates of tranilast solid dispersions extruded with inorganic excipients

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT) based solid dispersions using continuous melt extrusion (HME) processing. Twin – screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterisation showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, the in line NIR studies revealed a possible intermolecular H–bonding formation between the drug and carrier resulting in the increase of dissolution of TLT. The capsules containing TLT extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben® product

Desktop 3D printing of controlled release pharmaceutical bilayer tablets

Three dimensional (3D) printing was used as a novel medicine formulation technique for production of viable tablets capable of satisfying regulatory tests and matching the release of standard commercial tablets. Hydroxypropyl methylcellulose (HPMC 2208) (Methocel™ K100M Premium) and poly(acrylic acid) (PAA) (Carbopol® 974P NF) were used as a hydrophilic matrix for a sustained release (SR) layer. Hypromellose® (HPMC 2910) was used as a binder while microcrystalline cellulose (MCC) (Pharmacel® 102) and sodium starch glycolate (SSG) (Primojel®) were used as disintegrants for an immediate release (IR) layer. Commercial guaifenesin bi-layer tablets (GBT) were used as a model drug (Mucinex®) for this study. There was a favourable comparison of release of the active guaifenesin from the printed hydrophilic matrix compared with the commercially available GBT. The printed formulations were also evaluated for physical and mechanical properties such as weight variation, friability, hardness and thickness as a comparison to the commercial tablet and were within acceptable range as defined by the international standards stated in the United States Pharmacopoeia (USP). All formulations (standard tablets and 3D printed tablets) showed Korsmeyer-Peppas n values between 0.27 and 0.44 which indicates Fickian diffusion drug release through a hydrated HPMC gel layer

Taste masked thin films printed by jet dispensing

Taste masking of bitter active substances is an emerging area in the pharmaceutical industry especially for paediatric/geriatric medications. In this study we introduce the use of jet – dispensing as a taste masking technology by printing mucosal thin films of three model bitter substances, Cetirizine HCl, Diphenylhydramine HCl and Ibuprofen. The process was used to dispense aqueous drugs/polymer solutions at very high speed where eventually the drugs were embedded in the polymer matrix. The in vivo evaluation of jet – dispensed mucosal films showed excellent taste masking for drug loadings from 20 - 40%. Jet dispensing was proved to make uniform, accurate and reproducible thin films with excellent content uniformity

3D printing of five-in-one dose combination polypill with defined immediate and sustained release profiles

We have used three dimensional (3D) extrusion printing to manufacture a multi-active solid dosage form or so called polypill. This contains five compartmentalised drugs with two independently controlled and well-defined release profiles. This polypill demonstrates that complex medication regimes can be combined in a single personalised tablet. This could potentially improve adherence for those patients currently taking many separate tablets and also allow ready tailoring of a particular drug combination/drug release for the needs of an individual. The polypill here represents a cardiovascular treatment regime with the incorporation of an immediate release compartment with aspirin and hydrochlorothiazide and three sustained release compartments containing pravastatin, atenolol, and ramipril. X-ray powder diffraction (XRPD) and Attenuated Total Reflectance Fourier Transform Infrared Spectroscopy (ATR-FTIR) were used to assess drug-excipient interaction. The printed polypills were evaluated for drug release using USP dissolution testing. We found that the polypill showed the intended immediate and sustained release profiles based upon the active/excipient ratio used

Continuous manufacturing of high quality pharmaceutical cocrystals integrated with process analytical tools for in-line process control

A continuous manufacturing process for pharmaceutical indomethacin–saccharine cocrystals was achieved by extrusion processing with high throughput. Down-stream milling and blending of the extrudates was followed by feeding the formulated cocrystals in a capsule-filling machine. By applying a quality by design approach, the process was optimized and scaled up to produce 3000 capsules/h of pharmaceutical cocrystals. Process analytical tools such as near infrared reflectance and spatial filter velocimetry probes were coupled at various process stages for in-line monitoring and quality control. Further physicochemical characterization of extruded batches confirmed the manufacturing of high quality cocrystals. A fully integrated continuous process starting from raw materials to produce a finished product was assembled with only six unit operations and a small footprint. The study is a paradigm of continuous manufacturing of pharmaceutical cocrystals