Polymeric Therapeutic Nanoparticles

Polymeric Therapeutic Nanoparticles: Design, Development and Evaluation for Ophthalmic Drug Delivery System

Ophthalmic diseases are generally treated by topical application of the drugs, especially eye drops.

The major drawback of eye drops is that more than 90% of the applied drug is lost to the defensive mechanisms of the eye.

To achieve therapeutic drug levels, frequent drug administration is required which leads to patient non-compliance.

Sustained Release Formulations for Ocular Delivery

Different sustained release formulations such as nanoparticles and nanoparticles laden in-situ gels are getting attention for ophthalmic drug delivery due to their smaller particle size, good stability, sustained drug release, and lack of irritation effect to the iris, cornea, and conjunctiva.

Study Objective

The objective of this study was to develop sustained release nanoformulations for Moxifloxacin hydrochloride (MX) and Dexamethasone sodium phosphate (DS) with the aim to improve their ophthalmic bioavailability and reduce their dosing frequency.

Phase 1: Preformulation and Analytical Method Development

This study was carried out in different phases.

The first phase of the study consisted of preformulation studies and development and validation of methods of analysis.

The compatibility studies were performed using a 1:1 binary mixture approach via FTIR.

The results confirmed the absence of any interaction/incompatibility between the drugs and excipients.

Two analytical methods (UV-visible spectrophotometric and RP-HPLC-UV methods) were developed and validated.

• The UV-visible spectrophotometric method was specific, accurate and linear with R² values of 0.997 for MX and 0.998 for DS.
• The RP-HPLC-UV method was novel, sensitive, and validated for determination of MX in physiological fluids.
• The method is linear in concentration range of 0.018–100 mg/mL for MX with 97.52% and 94.48% recovery in human plasma and bovine aqueous humor respectively.
• The LOD was 10.0 ng/mL in plasma and 16.0 ng/mL in aqueous humor while LOQ was 18.0 ng/mL in plasma and 16 ng/mL in aqueous humour.

Phase 2: Polymeric Nanoparticle Formulation and Evaluation

In the second phase of the study, polymeric nanoparticles were developed for the above-mentioned drugs using PLGA RG 752H as a polymer.

The nanoparticles were formulated using modified double emulsion solvent evaporation technique.

Various formulation parameters were optimized such as:

• Polymer grade
• pH of the outer aqueous phase
• Adding surfactant to the inner phase
• Changing drug to polymer ratios
• Different PVA concentrations

This was done in order to achieve optimum particle size and higher entrapment efficiency.

Nanoparticle Characterization and Drug Release

These nanoformulations were then subjected to characterization including:

• Particle size
• PDI and zeta potential measurement
• Drug encapsulation
• XRD
• Scanning electron microscopy (to determine the shape and morphology of the NPs)
• In-vitro drug release
• Stability studies at 4°C and at room temperature
• In-vivo evaluation

Moxifloxacin (MX) Nanoparticles

• Particle size: 167.4 ± 16.6 nm to 622.4 ± 18.3 nm
• PDI: 0.09 to 0.48
• Zeta potential: -1.3 to -14.54 mV
• Entrapment Efficiency (%EE): 9.0 ± 0.5% to 81.69 ± 8.1%

Dexamethasone (DS) Nanoparticles

• Particle size: 198.2 ± 12.4 nm to 369.8 ± 12.9 nm
• PDI: 0.10 to 0.82
• Zeta potential: -1.96 to -21.6 mV
• %EE: 6.45 ± 0.9% to 84.94 ± 6.5%

SEM studies revealed that the nanoparticles of both MX and DS were spherical with smooth surfaces.

Among various cryoprotectants used, mannitol (5%) showed better results.

No significant changes were observed in the particle size when formulations were stored at 4°C, while formulations stored at room temperature showed significant changes.

In-vitro drug release demonstrated initial burst release followed by sustained release of the drug.

• In case of MX formulations, only Higuchi model equation best fitted the release data.
• For DS formulations, both Peppas and Sahlin model and Higuchi model best fitted the release data.

Ocular Tolerance and In-Vivo Studies

Ocular tolerance studies showed that these polymeric nanoparticles were safe and lacked any injurious effects to the ocular tissues.

In-vivo studies showed that the polymeric nanoparticles can sustain the drug aqueous humour level for longer time as compared with the marketed eye drops.

The Cmax, MRT, AUC₀₋ₜ and T½ increased significantly for both MX and DS while the clearance decreased.

Phase 3: Thermoreversible In-Situ Gel Development

In the third phase of the study, one nanoparticle formulation was selected for each drug and incorporated into thermoreversible in-situ gel.

These in-situ gels were characterized for:

• Clarity
• Viscosity
• Gelation temperature
• pH before and after autoclaving

Results showed that the in-situ gels were:

• Clear
• Possessed viscosity of 135.3 ± 0.7 cps at 25°C and 436 ± 6.3 cps at 37°C
• Gelation temperature: 32.9 ± 0.3°C
• pH: 7.34 ± 0.4

Autoclaving did not significantly affect the clarity, viscosity, gelation temperature, or pH of the in-situ gels.

Safety and Pharmacokinetics of In-Situ Gel

Ocular tolerance studies showed that these in-situ gels did not produce any inflammation in the rabbit’s eyes.

These formulations were tolerable, safe, and free from any harmful effects to the eyes.

Pharmacokinetic studies showed that:

• Nanoparticles laden in-situ gels sustained the drugs for 12 hours in the aqueous humour, higher compared with drug-loaded nanoparticles and commercial eye drops.
• Cmax, MRT, AUC₀₋ₜ and T½ increased significantly while the clearance decreased for nanoparticles laden in-situ gel compared with the polymeric nanoparticles and conventional eye drops.

Conclusion

This project suggests that the developed polymeric nanoparticles and nanoparticles laden in-situ gels can sustain the drug for longer time on the ocular surface compared with conventional eye drops, leading to a decline in dosing frequency.

The developed formulations are safe, tolerable, and free of any injurious effects to the ocular surface and can be utilized as potential drug delivery systems for the eye.

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Ophthalmic Nanoparticle Gel Formulations Full PDF Copy of the Thesis

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Disclaimer

“This abstract is re-organized for readability. For 100% original text, read the full thesis PDF linked above.”

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Sources & Thesis Details

Thesis Title: Polymeric Therapeutic Nanoparticles: Design, Development and Evaluation for Ophthalmic Drug Delivery System
Researcher: Fahim Ullah Khan
Supervisor/Guide: Not listed in abstract
Institution: University of Peshawar, Peshawar
Department: Biological & Medical Sciences, Pharmacy
Degree Year: 2018
Gov’t Doc No.: 17507
Publisher: University of Peshawar

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