(T1430-06-32) Reverse Engineering of Invega Sustenna^® (paliperidome palmitate suspension)

Purpose: Paliperidone palmitate (PP) is a second-generation dopamine-2 receptor antagonist used for the treatment of schizophrenia. Several long-acting injectable suspension formulation for PP have been approved by Food and Drug Administration (FDA). The aqueous suspension formulations generally have less excipients, and could avoid gastrointestinal absorption and first-pass effect through intramuscular injection. Moreover, due to the low solubility of PP, the aqueous suspension can achieve long-term therapeutic effects at a controlled drug release rate, allowing for low dose frequency, low recurrence rate and higher patient adherence. However, there is no generic products of PP long-acting injectable suspension on the market. The physical and chemical properties and other critical quality attributes will determine the effectiveness and safety of the products. In this study, we analyzed several quality characteristics of Invega Sustenna^® (one-month paliperidone palmitate injectable suspension), including particle size distribution, particle morphology ,thermal characteristics ,and in vitro dissolution kinetics. This work may help generic pharmaceutical companies and regulatory agencies in the the development and regulatory assessment of generic products of long-acting PP injectable suspension.

Methods: The size distribution of aqueous PP suspension was measured by Mastersizer 2000 system with Hydro 2000s accessory. The morphology of aqueous PP suspension were determined using scanning electron microscope (SEM). The thermal characteristics of PP suspension were characterized by differential scanning calorimetry (DSC). Dissolution methods were also developed to determine the in vitro dissolution kinetics. The PP suspension was loaded into the dialysis bag and dialyzed against simulated muscle fluid (SMF) supplemented with 1% or 2% SDS. The dissolution test was performed in shake incubator at 37 °C at 80 rpm. The PP content in release buffer was quantified by LC/MS.

Results: The particle size distribution is shown in Figure 1A. The average volume weighted size is 0.992 μm and the span is 2.555. D10, D50 and D90 are 0.150 μm, 0.774 μm and 2.219 μm, respectively. The morphology of PP suspension showed irregular granular shape under SEM (Figure 1B). The DSC thermograms of PP suspension are portrayed in Figure 2. The API powder showed a melting point of 116.7 °C, while the melting points of LCB2D01 and LHB4600 suspension were recorded at 112.8 °C and 113.4 °C, respectively. The decrease of the melting point of suspension compared to that of API powder was due to the reduction of particle size. The API and suspensions have very similar endothermal parameters, demonstrating the crystalline state of PP was reserved in the suspension and no transformation. The dissolution behaviors of the PP suspension were displayed in Figure 3. The Invege Sustenna^® suspension can achieve gradual and complete release from dialysis bag within 72h (3 days) in the SMF medium supplemented with 2% SDS. When the SDS concentration was lowered to 1%, the Invege Sustenna^® suspension can achieve gradual and complete release within 168h (7 days).

Conclusion: Analytical methods were established for reverse engineering Invega Sustenna^®. Several critical quality attributes of Invega Sustenna, including particle size distribution, particle morphology, thermal behaviors and in vitro dissolution kinetics, were evaluated using the methods established above.

Figure 1. (A) Particle size distribution of Invega Sustenna® (Lot: LCB2D01). (B) SEM images of Invega Sustenna® (Lot: LCB2D01).



Figure 2. DSC diagrams of Invega Sustenna® (Lot: LCB2D01and LHB4600)



Figure 3. In vitro dissolution profiles of Invega Sustenna® (Lot: LHB4600)