TheriForm Technology Mrs. Maria Saifee Associate Professor Pharmaceutics

INTRODUCTION TheriForm manufacturing of drug delivery devices is a novel method of fabrication based on Three Dimensional Printing (3DP), a solid freeform fabrication technology. Dosage forms are fabricated in a layer-by-layer fashion using inkjet printing technology to allow fine spatial placement of specific substances within the body of the dosage form, thus providing control over the release of active drug from the assembled structure.

DESCRIPTION OF THE TECHNOLOGY

Previous publications have shown that TheriForm is capable of : High accuracy placement of liquid droplets. High accuracy metering of active dosage. And the ability to construct oral dosage forms with complex release profiles. These complex release profiles are generally achieved by placing the active substance within various matrices to control the release of the active. These matrices are often compartments within the dosage form, surrounded by walls of the release- controlling material. The compartments can be made quite small, on the order of 500 m to several millimeters.

RESEARCH AND DEVELOPMENT Oral dosage forms were fabricated with a binder solution containing Eudragit RL PO and a standard pharmaceutical grade microcrystalline cellulose powder (Avicel PH 301, FMC). A 20% (w/w) Eudragit RL PO/acetone solution was printed through a 45-mm nozzle with a flow rate of 0.85 g/min. A total of 20 layers of 200 mm each was used in oral dosage form construction. The printhead velocity was 140 cm/s. Three rows of devices were printed with line spacings of 70, 100, and 130mm to produce devices with polymer volume fractions of 16.7%, 11.7%, and 9%,respectively.

Six placebo layers were printed using the polymeric binder to form the floor of the oral dosage form. Next, eight active- containing layers were printed followed by another six placebo layers to form the top cap of the dosage form. The drug was incorporated in the active-containing region using the following two-step procedure. The first step was to print a binder identical to the placebo layers. Next, a total of 4.23 μL of 30% (w/w) chlorpheniramine maleate solution was deposited in three passes of the printhead. The powder bed was dried between each pass to minimize bleeding due to oversaturation with the binder liquid. The piston was lowered, and the process was repeated for eight layers to deliver a total dosage of 5.45 mg into the region. It was assumed that migration and capillary effects were small and that the drug distribution was uniform.

In this study, a suspension containing 2 In this study, a suspension containing 2.5% (w/w) microfine 9-nitrocamptothecin, an anticancer compound, was formulated to deliver the active to the core of cylindrical constructs with a size designedfor insertion into #3 capsule shells. The shell region functioned as a release barrier to retard the initial burst of active, which has been observed with the traditionally formulated capsules, in an attempt to minimize gastrointestinal side effects. The powder mixture was composed of 49% (w/w) hydroxypropylmethyl cellulose (Pharmcoat 603, Shin- Etsu Chemical Co.), 49% spray dried lactose (Pharmatose DCL 11), and 2% Avicel PH 301. The shell binder was 11% (w/w) aqueous PVP K25 solution.

An example of a more complex release profile is a dual pulsatory device. These dosage forms were designed to release the initial burst first in the stomach at low pH and pulse the second payload in the intestine at high pH. This was accomplished by printing drug compartments inside different polymer environments. One drug compartment was printed into a polymeric section of cationic nature (Eudragit E-100) and another drug compartment was printed into a polymeric section of anionic nature (Eudragit L-100). These dosage forms were manufactured with a 25-gm dose of diclofenac sodium.

The powder used for these devices was 30 wt% Avicel PH301, 30 wt% spray-dried lactose (Pharmatose DCL 11), and 40 wt% Eudragit L100. The L- 100 binder was 5% (w/w) Eudragit L100 in ethanol. The printing parameters were 200-μm layer thickness, 100-mm line spacing, 105-cm/s printhead velocity, and a 1.1-g/min flow rate. The E-100 sections of the device were printed with a solution of 13.5% (w/w) Eudragit E-100 in acetone. The printing parameters were 200-mm layer thickness, 100-μm line spacing, 105-cm/s print head velocity, and a 1.28-g/min flow rate.

Two E-100 placebo layers were printed, followed by three drug-containing layers and two additional E- 100 placebo layers to complete the first compartment. The second compartment was six placebo L-100 layers, six active-containing layers, and six placebo L-100 layers. The top compartment was built identically to the first compartment. The dissolution profiles of the dual pulsatory delivery systems are demonstrated in Figure 6. The dissolution testing was performed using simulated gastric fluid at pH 2 for 1 h, then changing the solution to simulated intestinal fluid at pH 7.4.

Applications 1. Microdose, for potent compounds with narrow therapeutic windows, which require small-dose delivery with precise drug loading. By delivering the active to the dosage forms in the liquid state, the variation in drug content uniformity normally encountered with conventionaldry powder mixing or wet granulation can be effectively minimized. A placebo outer shell can be fabricated to avoid unnecessary physical or human contact as well.

2.Pulsatile release, for actives that need to be given to patients at inconvenientadministration schedules for the desired therapeutic effect. For example, a dosage form can be designed to release an anti- Parkinson’scompound at midnight to achieve the therapeutic blood level to controlthe patient’s morning symptoms. The core-shell design can be appliedto generate a lag phase and an immediate drug release phase for sucha therapeutic/chronobiological purpose.

3.Zero-order release or release kinetics following specific pharmacokinetic/ pharmacodynamic models. Several technologies have been used to fabricate dosage forms with zero-order release; however, most of them require multi processes during their manufacture. With TheriForm technology, fabrication can be achieved within one single process. Furthermore, with the flexibility of the TheriForm process,the release pattern can be adjusted to match specific pharmacokinetic/ pharmacodynamic needs