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Oral Administration System Based on Meloxicam Nanocrystals: Decreased Dose Due to High Bioavailability Attenuates

Noriaki Nagai¹, Fumihiko Ogata¹, Hiroko Otake¹

¹Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan.

|April 5, 2020

Abstract:

Meloxicam (MLX) is widely applied as a therapy for rheumatoid arthritis (RA); however, it takes far too long to reach its peak plasma concentration for a quick onset effect, and gastrointestinal toxicity has been observed in RA patients taking it. To solve these problems, we designed MLX solid nanoparticles (MLX-NPs) by the bead mill method and used them to prepare new oral formulations. The particle size of the MLX-NPs was approximately 20-180 nm, and they remained in the nano-size range for 1 month. The tmax of MLX-NPs was shorter than that of traditional MLX dispersions (MLX-TDs), and the intestinal penetration of MLX-NPs was significantly higher in comparison with MLX-TDs (P < 0.05). Caveolae-dependent endocytosis (CavME), clathrin-dependent endocytosis (CME), and micropinocytosis (MP) were found to be related to the high intestinal penetration of MLX-NPs. The area under the plasma MLX concentration-time curve (AUC) for MLX-NPs was 5-fold higher than that for MLX-TDs (P < 0.05), and the AUC in rats administered 0.05 mg/kg MLX-NPs were similar to rats administered the therapeutic dose of 0.2 mg/kg MLX-TDs. In addition, the anti-inflammatory effect of the MLX-NPs was also significantly higher than that of MLX-TDs at the corresponding dose (P < 0.05), and the therapeutic effect of 0.2 mg/kg MLX-TDs and 0.05 mg/kg MLX-NPs in adjuvant-induced arthritis (AA) rats showed no difference. Furthermore, the gastrointestinal lesions in AA rats treated repetitively with 0.05 mg/kg MLX-NPs were fewer than in rats receiving 0.2 mg/kg MLX-TDs (P < 0.05). In conclusion, we demonstrate that MLX solid nanoparticles allow a quick onset of therapeutic effect and that three endocytosis pathways, CavME, CME, and MP, are related to the high absorption of solid nanoparticles. In addition, we found that MLX solid nanoparticles make it possible to reduce the amount of orally administered drugs, and treatment with low doses of MLX-NPs allows RA therapy without intestinal ulcerogenic responses to MLX. These findings are useful for designing therapies for RA patients.

Insights

New meloxicam nanoparticles (MLX-NPs) offer faster rheumatoid arthritis (RA) relief with reduced gastrointestinal toxicity. These MLX-NPs enhance drug absorption and efficacy, allowing for lower therapeutic doses.

Area of Science:

Nanotechnology in Pharmaceutical Sciences
Drug Delivery Systems
Rheumatoid Arthritis Therapeutics

Background:

Meloxicam (MLX) is a common rheumatoid arthritis (RA) therapy.
Traditional MLX formulations have slow onset and cause gastrointestinal toxicity.
Need for improved MLX delivery for faster, safer RA treatment.

Purpose of the Study:

To develop and characterize MLX solid nanoparticles (MLX-NPs) for oral administration.
To evaluate the pharmacokinetic and anti-inflammatory effects of MLX-NPs compared to traditional MLX dispersions (MLX-TDs).
To investigate the intestinal absorption mechanisms of MLX-NPs.

Main Methods:

MLX-NPs were prepared using the bead mill method.
Particle size, stability, and in vivo pharmacokinetics were assessed.
Intestinal penetration mechanisms (Caveolae-dependent endocytosis, clathrin-dependent endocytosis, micropinocytosis) were investigated.

Main Results:

MLX-NPs exhibited particle sizes of 20-180 nm and remained stable for 1 month.
MLX-NPs showed a shorter Tmax, significantly higher intestinal penetration, and a 5-fold increase in AUC compared to MLX-TDs.
MLX-NPs demonstrated superior anti-inflammatory effects and reduced gastrointestinal lesions at lower doses compared to MLX-TDs.

Conclusions:

MLX solid nanoparticles provide a rapid onset of therapeutic effect for RA.
High intestinal absorption of MLX-NPs is mediated by endocytosis pathways (CavME, CME, MP).
MLX-NPs enable reduced drug dosage, offering effective RA therapy with diminished gastrointestinal side effects.

Read full analysis

Keywords:

drug delivery system gastrointestinal lesion meloxicam nanocrystals oral absorption

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