Novel in situ self-assembly nanoparticles for formulating a poorly water-soluble drug in oral solid granules, improving stability, palatability, and bioavailability.
OBJECTIVE
The purpose of this study was to develop a novel lipid-based nanotechnology to formulate poorly water-soluble drugs in oral solid granules to improve stability, palatability, and bioavailability.


METHODS
In one method, we prepared ritonavir (RTV) nanoparticles (NPs) by a microemulsion-precursor method and then converted the RTV NPs to solid granules by wet granulation to produce RTV NP-containing granules. In the other innovative method, we did not use water in the formulation preparation, and discovered novel in situ self-assembly nanoparticles (ISNPs). We prepared RTV ISNP granules that did not initially contain NPs, but spontaneously produced RTV ISNPs when the granules were introduced to water with gentle agitation. We fully characterized these RTV nanoformulations. We also used rats to test the bioavailability of RTV ISNP granules. Finally, an Astree electronic tongue was used to assess the taste of the RTV ISNP granules.


RESULTS
RTV NP-containing granules only had about 1% drug loading of RTV in the solid granules. In contrast, RTV ISNP granules achieved over 16% drug loading and were stable at room temperature over 24 weeks. RTV ISNPs had particle size between 160 nm and 300 nm with narrow size distribution. RTV ISNPs were stable in simulated gastric fluid for 2 hours and in simulated intestinal fluid for another 6 hours. The data from the electronic tongue showed that the RTV ISNP granules were similar in taste to blank ISNP granules, but were much different from RTV solution. RTV ISNP granules increased RTV bioavailability over 2.5-fold compared to RTV solution.


CONCLUSIONS
We successfully discovered and developed novel ISNPs to manufacture RTV ISNP granules that were reconstitutable, stable, and palatable, and improved RTV bioavailability. The novel ISNP nanotechnology is a platform to manufacture oral solid dosage forms for poorly water-soluble drugs, especially for pediatric formulation development.
State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
Shujie
S
Guo
Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA.
Kevin
K
Pham
Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA.
Diana
D
Li
Department of Pharmacotherapy, University of North Texas Health Science Center, Fort Worth, TX, USA.
Scott R
SR
Penzak
Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX, USA.
Xiaowei
X
Dong
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001826:Body Fluids; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D025341:Principal Component Analysis; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D013649:Taste; D013997:Time Factors; D014867:Water / Q000737:chemistry*
D014867:Water; D019438:Ritonavir
drug loading; lipid formulation; pediatric formulation; pharmacokinetics; ritonavir; taste