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3D Printing: Pharmacy Applications
Part 1
Introduction and Applications
Introduction
Individualized medications, based on a patient's medical, biological, and pharmaceutical profile, may be produced in the future utilizing three-dimensional (3D) printing. These new medications, based on a patient's weight, race, kidney, and liver functions, may be possible utilizing 3D printing to increase medication effectiveness and reduce side effects. When realized, one should be able to input the patient's information for a specific drug, and the software will calculate the dosage required and then generate the 3D-printed medication. Tablets with wide dosage ranges, high reproducibility, and tight standard deviations have been prepared. These tablets can be varied each time the patient refills their medication, and this adds a new dimension to pharmaceutical compounding.
3D printing is a layer-by-layer production of three-dimensional objects from digital designs. The technology has developed as a combination of chemistry, optics, and robotics over about 30 years. 3D printing quickly became a standard tool in the automotive, aerospace, and consumer goods in industry and, recently, 3D printing is gaining traction in pharmaceutical manufacturing. 3D printing has been steadily growing and has received a boost with U.S. Food and Drug Administration (FDA) approval of Spritam (levetiracetam), a 3D-printed orodispersible tablet. This new product supports the application of 3D printing to manufacturing complex and customized dosage forms. 3D printing supports a move from the "Centralization" of manufacturing to "Decentralization" and closer to the patient.
3D printing is synonymous with:
- Rapid prototyping (RP)
- Solid freeform fabrication, and
- Additive manufacturing
Whether it's called additive manufacturing or 3D printing, the critical distinction is that the final structure develops from the serial addition of raw materials largely independent of the equipment or raw material geometries.
Briefly, underlying all current RP techniques is the construction of a CAD model, which is in the stereolithography .stl file format. While the CAD file describes the geometry and size of the parts to be built, the .stl format file lists the coordinates of triangles that together make up the surface of the 3D structure design. The RP machine then processes the .stl file by creating sliced layers of the model. Three dimensions are built by subsequent over-printing, and, when the first layer is deposited, the model is reduced by the thickness of the next layer. The process is repeated until completion of the desired structure; for this to work every layer must solidify.
In one technique, there is a process for making a component by depositing a first layer of a fluent porous material, such as powder, in a confined region and then depositing a binder material to selected regions of the lower layer of powder material at the selected region. These steps are repeated the desired number of times to produce successive layers of selected regions of a bound powder material that forms the desired component; the unbound powder material is then removed.
Background
Three attributes distinguish 3D printing from traditional manufacturing processes:
1. Product complexity
2. Personalization
3. On-demand manufacturing/compounding
Increased Product Complexity
Pharmaceutical dosage forms have evolved in complexity from harvested botanicals to ointments, powders, lotions, etc. to complex tablets, transdermal systems, implants, and others. Recently dosage form design has been fueled largely by polymer science resulting in extended- and delayed-release tablets, transdermal systems, and long-acting implants.
3D printing introduces a new element into dosage form development (i.e., digital control over the arrangement of matter). This is a step function that may produce striking changes in immediate-release, modified-release, and combination-drug products.
Personalization
Personalized dosing allows for individualizing the amount of drug delivered based on a patient's mass and metabolism. Also, another personalized dosing concept is preparing multidrug poly pills to combine all of the patient's medications into a single daily dose. Personalized implants allows for printing implants that match patients' anatomical features; this technique is gaining traction for medical devices such as tracheal splints and bone grafts.
On-demand Manufacturing/Compounding
Similar to a home inkjet printer, a 3D printer can make a variety of quality products within minutes. Three situations where this on-demand capability may be applicable include:
- Printing directly on the patients
- Printing "in-time" or in other resource-constrained settings
- Printing low-stability drugs for immediate consumption
Extrusion and ink-jet techniques have been used to create wound-healing gels on demand.
3D printing also can be used to:
- Avoid incompatibilities between drugs
- Design multiple-release dosage forms
- Increase the solubility of poorly soluble drugs by producing an amorphous form
- Produce very porous material with the rapid onset of action
- Limit degradation of biological molecules
Additional novel characteristics that can be developed include:
- Creating radial gradients of diffusion controlling excipients, such as ethylcellulose, to achieve near-zero order release
- Joining osmotic pumps (composed of cellulose acetate, D-mannitol and PEG) and hypromellose-based structures to create a single product with multiple-release modalities
- Altering the in-fill of polyvinyl alcohol products as a means of accelerating or decelerating drug release
- Implementing structured breakaway components to deposit different parts of a solid, oral dosage form in different parts of the lumen
- Printing solid, oral dosage forms with all but one side covered by an impermeable membrane so that the dissolvable portion maintains a constant surface area during drug release
- Stacking six or more distinct layers in a single product for multiphasic release
- Printing toroidal solid, oral dosage forms that achieve near-zero order release.
U.S. Food and Drug Administration-approved Product
Spritam is the first drug using 3D technology that has been approved by the FDA. Spritam uses ZipDose Technology, which combines formulation science with the unique manufacturing capabilities of 3D printing. Using 3D printing technology, Aprecia is developing formulations of medicines that rapidly disintegrate with a sip of liquid, even at high-dose loads.
The technology involves the following steps:
- A powder blend is deposited as a single layer
- The binding fluid is applied to bind the particles
- This process is repeated several times to manufacture orodispersible dosage forms
This produces a porous formulation that rapidly disintegrates with a sip of liquid.
Spritam is for oral use as a prescription, adjunctive therapy in the treatment of partial onset seizures, myoclonic seizures, and primary generalized tonic-clonic seizures in adults and children with epilepsy and marks the first time a drug product manufactured with this technology has been approved by the FDA. Spritam is an antiepileptic drug available as 250-mg, 500-mg, 750-mg, and 1000-mg round, white to off-white, spearmint-flavored tablets for oral suspension. Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste and is very soluble in water.
Spritam tablets for oral suspension contain 250 mg, 500 mg, 750 mg, or 1000 mg of levetiracetam, and the following inactive ingredients:
- Colloidal silicon dioxide
- Glycerin
- Mannitol
- Microcrystalline cellulose
- Polysorbate 20
- Povidone
- Sucralose
- Butylated hydroxyanisole
- Natural and artificial spearmint flavor
The tablets for oral suspension are unitary porous structures produced by a 3D-printing process that binds the powders without compression; they disintegrate in the mouth, in a mean time of 11 seconds (ranging from 2 seconds to 27 seconds), when taken with a sip of liquid, to produce small particles that may be swallowed.
ZipDose Technology is the first and only drug-formulation platform that uses 3D printing. This proprietary process does not rely on compression forces, punches, or dies. Instead, 3D printing binds layers of powdered medication together with an aqueous fluid to manufacture pharmaceutical products that are solid, yet highly porous. The porous design helps medication disintegrate rapidly in the mouth when taken with a sip of liquid.
ZipDose Technology enables the delivery of a high-drug load; up to 1,000 mg in a single dose. As a result, large doses of Spritam can be administered with just a sip of liquid. Also, there is no measuring required as each dose is individually packaged, making it easy to carry this treatment on the go.
Next Issue: Technologies involved in 3D printing.
Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy, Twenty-second edition
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