Fabrication of complex oral drug delivery forms by Three Dimensional Printing (tm)

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering, 2001.Includes bibliographical references (p. 237-241).Three Dimensional Printing 3DPTM is a novel solid freeform fabrication technology that has been applied to the fabrication of complex pharmaceutical drug devices. Limitations of the technology as relating to pharmaceuticals have been addressed and prototype dosage forms have been fabricated. The resolution of the 3DP tablets was found to depend on particle size and liquid migration during printing and drying. The surface finish of 3DP tablets was enhanced by uniaxial pressing. Migration inhibiting additives were effective in limiting transport. Both aqueous and ethanol-based solutions showed a decrease in migration on the order of 20% when appropriate powder bed additives were introduced. Migration was also decreased by pre-printing barriers to confine secondary printed drug solutions. Low dosage forms were fabricated with as little as 2.3 nanograms. Lower dosages are expected upon dilution of the initial drug solution. Printing forms with high dosage is limited by powder void volume, filling efficiency, and drug solubility limits. Multiple print passes increased the dosage per tablet volume, 6, at the expense of process time. The use of drug suspensions to overcome solubility limits and uniaxial compression to reduce tablet volume was shown to significantly increase 6. The highest 8 achieved was 427 mg/cc for pressed suspension-printed tablets, representing 74% of the theoretical limit. Complex oral dosage forms were fabricated with 3DP to show lagged-release, extended-release, double-release, and zero-order-release. Release properties, such as lag time and release rate, were manipulated by varying the printing parameters.(cont.) Dual-release and zero-order-release forms were fabricated using a surface degradation/erosion system based on HPMC, lactose, and Eudragitʾ L100. Erosion rate constants were used to model release from tablets with non-uniform drug distributions. Diclofenac and chlorpheniramine dual-release tablets were designed with 3 drug regions, and dissolution of the tablets followed the model closely, exhibiting 2 onsets. Two types of zero-order tablets were invented and fabricated by 3DP. These contained drug concentration gradients designed to complement the volumetric nonuniformity of eroding shells. Three formulations showed constant release of diclofenac sodium over 1-7 hours (9.6mg/hr), 1-15 hours (6.8mg/hr), and 1-36 hours (2.5mg/hr).by Wendy E. Katstra.Ph.D

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

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

Emergence of 3D Printed Dosage Forms: Opportunities and Challenges

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such as extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, including design flexibility and control and manufacture which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry

Nondestructive and on-line monitoring of tablets using light-induced fluorescence technology

A system using light-induced fluorescence (LIF) technology was developed for rapid and nondestructive analysis of active pharmaceutical ingredients on tablet surfaces. Nonhomogenous tablets with defined layer of active ingredients were made by 3-Dimensional Printing technology to determine penetration depths of the light source and the resultant fluorescence responses. The LIF method of analysis showed penetration to depths of up to 3 mm into tablets. A correlation between LIF signals from analysis of tablet surfaces and the total drug content of the respective tablets was established. This method of surface analysis was verified with UV spectrometric methods for the total drug content of each respective tablet. The results from a small sample population of tablets made from both homogeneous and nonhomogeneous powder mixtures established good correlation between LIF surface monitoring and total tablet content. The use of on-line monitoring of the individual tablet for surface content demonstrated consistent LIF profiles from simulated production rates up to 3000 tablets a minute. The instrument was also field tested successfully on a tablet analyzer