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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 11  |  Issue : 1  |  Page : 83-95  

Optimization and Designing of Amikacin-loaded Poly d, l-Lactide-co-glycolide Nanoparticles for Effective and Sustained Drug Delivery


1 Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, India
2 Product Development Cell-II, National Institute of Immunology, New Delhi, India

Date of Web Publication12-Feb-2019

Correspondence Address:
Dr. Farhan J Ahmad
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JPBS.JPBS_60_18

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   Abstract 

Purpose: Amikacin, a water-soluble aminoglycoside antibiotic used to treat gram-negative bacillary infections, is a Biopharmaceutics Classification System class III drug having poor permeability and short half-life. It is given parenterally, which limits its use in patients warranting “at-home care.” An oral drug delivery of amikacin is, therefore, imminent. Aim: This work focused on establishing poly d, l-lactide-co-glycolide (PLGA)-based nanoparticles of amikacin with consolidated pharmaceutical attributes capable of circumventing gastrointestinal tract membrane barriers and promoting oral administration of the drug. The partied attributes are suggestive of enhanced uptake of the drug via Peyer’s patches overlaying small intestine and support successful oral delivery. Materials and Methods: To have a robust delivery system, a statistical Box–Behnken experimental design was used and formulation parameters such as homogenization time, probe sonication time, and drug/polymer ratio of amikacin-loaded PLGA nanoparticles (A-NPs) for obtaining monodispersed nanoparticles of adequate size and high drug loading were optimized. Results: The model suggested to use the optimum homogenization time, probe sonication time, and drug/polymer ratio as 30s, 120s, and 1:10, respectively. Under these formulation conditions, the particle size was found to be 260.3nm and the drug loading was 3.645%. Conclusion: Biodegradable PLGA nanoparticulate systems with high payload, optimum size, and low polydispersity index will ensure successful uptake and ultimately leading to better bioavailability. Hence, under the aforementioned optimized conditions, the A-NPs prepared had particle size of 260.3nm, which is appreciable for its permeability across small intestine, and drug loading of 3.645%.

Keywords: Amikacin-loaded poly d, l-lactide-co-glycolide nanoparticles, aminoglycoside antibiotic, drug loading, preformulation studies


How to cite this article:
Fatima S, Panda AK, Talegaonkar S, Iqbal Z, Ahmad FJ. Optimization and Designing of Amikacin-loaded Poly d, l-Lactide-co-glycolide Nanoparticles for Effective and Sustained Drug Delivery. J Pharm Bioall Sci 2019;11:83-95

How to cite this URL:
Fatima S, Panda AK, Talegaonkar S, Iqbal Z, Ahmad FJ. Optimization and Designing of Amikacin-loaded Poly d, l-Lactide-co-glycolide Nanoparticles for Effective and Sustained Drug Delivery. J Pharm Bioall Sci [serial online] 2019 [cited 2019 May 25];11:83-95. Available from: http://www.jpbsonline.org/text.asp?2019/11/1/83/252093




   Introduction Top


Amikacin, a semisynthetic derivative of kanamycin-A,[1] is endowed with inactivating bacterial aminoglycoside enzymes, thus leading to widest spectrum of antibacterial activity against aerobic gram-negative bacilli and many organisms that are resistant to other aminoglycosides.[2],[3] Its bactericidal nature is due to “binding irreversibly” to the specific 30S-ribosomal subunit proteins, thereby, inhibiting an initiation complex formation with messenger ribonucleic acid, thus preventing protein synthesis that results in cell death.[4]

Clinically available formulations of amikacin are meant for intravenous and intramuscular administration only, as it belongs to class III drugs of Biopharmaceutics Classification System, which are highly soluble in water and have low permeability and consequently poor oral bioavailability. The oral delivery of amikacin is, hence, highly challenging and much desired. Also, the drug has short mean half-life of 114±16.7min.[5] Consequently, it has to be administered frequently at higher doses to maintain the therapeutic level that results in adverse effects such as dose-dependent nephrotoxicity and ototoxicity.[2] As oral administration of any drug has always remained fascinating owing to its several advantages, it is preferred most for the treatment of chronic diseases, which require prolonged treatment. Moreover, better quality of life, noninvasive nature, painless administration, ease of dosage form development, reduced dosing frequency, and low health-care cost are the other merits of this route. In addition, it could also prevent hospitalization, eventually leading to better patient compliance. Recently, nanoformulations such as nanoemulsion,[6] self-emulsifying drug delivery system,[7] solid lipid nanoparticles (NPs),[8] dendrimers,[9] polymeric NPs,[10] and polymeric micelle,[11] have gained considerable attention for the successful oral delivery and enhanced bioavailability of various drugs.

Polymeric NPs, investigated as carriers for oral drug-delivery systems, have shown myriad benefits ranging from physicochemical attributes such as stability, entrapment efficiency, release behavior, surface characteristics, and biological capabilities such as bioadhesion, targeting, and enhanced cellular uptake.[12] It allows the easy permeability of drugs through intestinal membrane by endocytosis because of submicron size of polymeric NPs,[13] thereby, paving the way for improved bioavailability with a concomitant reduction in their dose-related toxicity and increased resident time in body because of sustained release from polymeric NPs than that from intravenous route.

Studies published elsewhere have supported the use of nanoparticulate system, which could contribute to the safe and effective delivery of therapeutic molecules with pharmaceutical limitations including amikacin.[14],[15] Moreover, the poly d, l-lactide-co-glycolide (PLGA)-based NPs of amikacin developed so far have larger size, higher burst effect (40%) in 1h, and slow release of up to 10h only.[14],[16] These characteristics of the formulation will limit the permeability of amikacin across the gut barrier and will increase the drug burden with reduced therapeutic affordability because of narrow therapeutic window under the clinical setting. We, therefore, intended in this study to overcome the aforementioned limitations through developing and optimizing the PLGA-based NPs of amikacin that would improve the permeability of amikacin across biological barriers and its biodisposition. At the same time, sustained-release profile of the drug would maintain the therapeutic concentration for extended period at lower dose that would eventually reduce systemic toxic effects, leading to improved safety and efficacy. Keeping these facts in view, we carried out preformulation studies and optimization of amikacin-loaded PLGA nanoparticles (A-NPs) for the enhanced drug loading and improved bioavailability. However, the entrapment of hydrophilic amikacin in hydrophobic PLGA is quite challenging; hence, a novel tool, Box–Behnken design of experiment (DOE) was used to optimize the formulation for incorporating the best attributes in this study.


   Materials and Methods Top


Materials

Amikacin sulfate (AS) and polyvinyl alcohol (PVA, molecular weight [MW], 25,000 Da) were procured from Sigma-Aldrich, Spruce Street, St. Louis, Missouri. PLGA 50:50 (Resomer 503H; MW, 7,000–17,000 Da) was purchased from Sigma-Aldrich, Steinheim, Germany. Rest of the chemicals used were of analytical grade.

Pre-optimization studies

Qualitative characterization of amikacin sulfate

AS was inspected visually to check its organoleptic properties. Its melting point and partition coefficient were determined by the capillary and shake flask method, respectively. Also, the drug was authenticated using Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and mass analysis techniques.

Fluorescence spectrophotometric method for the quantitative estimation of amikacin sulfate

The method was adopted from a study by Gubernator et al.[17] with modification. A stock solution of 1000 µg/mL of AS in distilled water was prepared. From this stock solution, 50 µg/mL concentration was made. A total of 1mL from 50 µg/mL solution was then derivatized with 1mL of the 0.0625% O-phthaldialdehyde (OPA) reagent in 2-mL Eppendorf tube and immediately scanned for the fluorescence (within 10min) in CARY Eclipse fluorescence spectrophotometer (Varian, CA, USA). The fluorescence spectrum was obtained and λex/λem was determined.

To assess the suitability of the drug for oral administration, the calibration curves of AS (5–50 μg/mL) were prepared in distilled water, phosphate buffer saline (PBS) (pH, 6.8), PBS (pH, 7.4), and 0.1-N HCl (pH 1.2) using the aforementioned method.

pH-based solubility profile and short-term solution stability studies of amikacin sulfate

The solubility of AS was determined in distilled water, 0.1-N HCl (pH, 1.2), and PBS (pH, 6, 6.8, and 7.4). The stability of the drug solution in distilled water, 0.1-N HCl (pH, 1.2), and PBS (pH, 6, 6.8, and 7.4) was tested by freeze-thaw method. From a stock solution of 1000 μg/mL, 50 μg/mL concentration of AS in each of the above solution was prepared. All solutions were incubated at 37°C in incubator shaker and removed at 0, 6, 12, 24, 48, 72, 90, and 120h, and placed at −70°C. Later, all solutions were removed from −70°C and thawed. The drug, thereafter, was analyzed by the method described in the earlier section using fluorescence spectrophotometer.

Drug–excipient compatibility studies

Drug–excipient compatibility study was performed by placing 5mg each of excipient (PVA and PLGA), drug, and both drug and excipient combination in separate vials in three batches and sealing them. Thereafter, the contents in the first batch of vials were examined at 0 time. The contents in the second batch of vials were incubated at 37°C in shaker incubator and examined after 14th day. In the third batch, 5% moisture was added in each vial and then, the contents in the vials were incubated at 37°C and examined after 14th day. The examination was carried out by infrared (IR) spectroscopy.[18]

Formulation development and optimization of amikacin-loaded poly D, L-lactide-co-glycolide nanoparticles

Formulation development

A method developed by Tariq et al.[15] was modified by us and applied for the preparation of A-NPs.[19] In this modified method, internal aqueous phase (IAP) was prepared by adding AS in 200 μL of Milli Q water containing 0.5% w/v PVA. For the preparation of organic phase (OP), 100mg of PLGA was dissolved in 4mL of dichloromethane. Under sonication on an ice bath for 60s at 25 W, 40% duty cycles, 30% amplitude (Sonoplus, Bandelin, Germany), IAP was emulsified in OP and the primary emulsion (w/o) formed was added dropwise into 16mL of external aqueous phase (EAP) (1% w/v PVA) with continuous homogenization (Silent Crusher M, Heidolph, Germany) at 10,000rpm for 0.5–3min over an ice bath. The resulting secondary emulsion (w/o/w) was then sonicated on an ice bath for 1–3min at 25 W, 40% duty cycles, and 30% amplitude. From the obtained dispersion, the solvent was evaporated at room temperature under gentle stirring at 400rpm. The nanoemulsion thus obtained was centrifuged at 4°C for 15min at 15,000rpm in Sorvall Centrifuge RC6+ (Thermo Scientific, Wisconsin, USA), followed by washing of the pellet with ice cold Milli Q water (three times) and subsequent lyophilization for 24h in freeze dryer (Labconco, Kansas, USA) to achieve A-NPs.

Formulation optimization

The formulation was optimized by using Box–Behnken DOE. As directed by the DOE Design-Expert software (Stat-Ease, Minneapolis, USA), 17 formulations were developed and optimized for drug loading and particle size (dependent variants). The homogenization time, probe sonication time, and drug/polymer ratio were chosen as independent variants for optimization. The three-factor Box–Behnken design is shown in [Table 1].
Table 1: Three factor Box–Behnken design for formulation optimization

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The final polynomial equation generated for size (Y1) is as follows:



The final polynomial equation generated for polydispersity index (PDI) (Y2) is as follows:



where, X1, X2, and X3 are the independent variants: homogenization time, probe sonication time, and drug/polymer ratio.

Particle size determination

A-NPs were analyzed for the particle size and PDI using (Malvern Instruments Ltd., Worcestershire, UK), employing dynamic light scattering method, and deduced by “DTS nano” software (Malvern Instruments Ltd., Worcestershire, UK). The sample for the analysis was prepared by dispersing 1mg of A-NPs in 2mL of Milli Q water.[19]

Drug load

To determine the amount of AS encapsulated in 1mg of A-NPs, the amount equal to 10mg of A-NPs was dispersed in 200 μL dimethyl sulfoxide, and the total volume was made up to 10mL with Milli Q water. The resulting suspension was centrifuged at 10,000rpm for 10–15min. A total of 100 μL of OPA reagent was added to 100 μL of the aforementioned sample. Using fluorescence spectrophotometer, fluorescence was measured immediately (within 10min) at λex/λem of 340/450nm. The formula used to calculate drug loading (% w/w) is as follows[19]:




   Results and Discussion Top


Pre-optimization studies

Qualitative characterization of amikacin sulfate

On visual inspection, AS was found to be white, odorless, and crystalline powder. As determined by the capillary method using a melting point apparatus, the melting point of AS was found to be 240°C, which is comparable to the reported value in literature.[20] Log P value of AS determined by shake flask method in octanol–water, octanol–HCl (0.1N; pH, 1.2), octanol–PBS (pH, 6), octanol–PBS (pH, 6.8), and octanol–PBS (pH, 7.4) system was found to be −0.62, −0.52, −0.62, −0.64, and −0.62, respectively. This clearly indicates that AS is hydrophilic in nature. The IR spectrum [Figure 1]A showed characteristic bands of the stretching vibration of N-H2, N-H, O-H at 3346.50cm−1 and the C-H2 and C-H aliphatic stretch vibrations at 2918.30cm−1. The CONH and C-O stretch bands were at 1637.56, 1566.20, and 1114.86cm−1, respectively. These results clearly indicated the authenticity of AS, which was further supported by NMR analysis. The NMR spectra [Figure 1B] showed overlapping multiplets with an integral value of 4 at 1.547–2.028ppm because of C2H2 and CβH2, overlapping multiplets with an integral value of 21.34 at 2.946–4.107ppm because of methylenes and methines, and two doublets with an integral value of one each at 4.986–5.41ppm because of C1’H and C1’’H. Mass analysis was also used to authenticate the drug. The base peak of AS (ESI-MS, negative mode) was found to be 778.6429g/mol (M+−4). Thus, the mass obtained was comparable to the reported mass of AS, that is, 781.8g/mol [Figure 1C].[21]
Figure 1: (A) Fourier transform infrared spectroscopy. (B) Nuclear magnetic resonance. (C) Mass spectrum of amikacin

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Fluorescence spectrophotometric method for the quantitative estimation of amikacin sulfate

As amikacin lacks a chromophore necessary for its determination,[22] its estimation was, therefore, carried out using a fluorescence spectrophotometric method involving the derivatization reaction between OPA and primary amino groups present in the antibiotic molecule.[17] Therefore, λex/λem obtained from fluorescence spectra was found to be 340/450nm [Figure 2].
Figure 2: Fluorescence spectrum of amikacin in distilled water

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Calibration curves of AS in different solvents, that is, distilled water, PBS (pH, 6.8), PBS (pH, 7.4), and 0.1-N HCl (pH, 1.2) were prepared for its oral delivery, wherein the pH of the stomach is highly acidic and it gradually increases from pH 6 in duodenum to pH 7.4 in the terminal ileum. A good correlation coefficient, R2, was obtained in all the solvents [Table 2].
Table 2: Regression coefficients (R2) of the calibration curves of amikacin in different solvents

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pH-based solubility profile and short-term solution stability study of amikacin sulfate

The solubility studies confirmed that AS was highly hydrophilic in nature and freely soluble in water, PBS (pH, 6, 6.8, and 7.4), and 0.1-N HCl (pH, 1.2). The drug solution stability data represented as fluorescence unit [Table 3] revealed the stability of AS in all of the aforementioned solvents even with the increased time of shaking during incubation. These data suggested that the stock solution of AS in the aforementioned solvents can be stored for 5 days as per the studies performed, which is in agreement with the stability studies reported in literature.[20]
Table 3: Values of drug solution stability in phosphate buffer saline (pH, 6, 6.8, and 7.4), distilled water, and 0.1-N HCl (pH 1.2) given as fluorescence unit

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Drug–excipient compatibility studies

Drug–excipient compatibility was evaluated by FTIR spectroscopy. The characteristic peaks of drug, polymer (PLGA), and stabilizer (PVA) were retained in all the samples [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]. Hence, the drug was found to be compatible with both PLGA and PVA.[21],[23],[24]
Figure 3: Fourier transform infrared spectroscopy spectra of drug incubated and examined (A) at time 0, (B) at 37°C after 14 days, and (C) with 5% moisture at 37°C after 14 days[19]

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,
Figure 4: Fourier transform infrared spectroscopy spectra of poly d, l-lactide-co-glycolide incubated and examined (A) at time 0, (B) at 37°C after 14 days, and (C) with 5% moisture at 37°C after 14 days[21]

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,
Figure 5: Fourier transform infrared spectroscopy spectra of polyvinyl alcohol incubated and examined (A) at time 0, (B) at 37°C after 14 days, (c) with 5% moisture at 37°C after 14 days[22]

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,
Figure 6: Fourier transform infrared spectroscopy spectra of drug and poly d, l-lactide-co-glycolide mixtures incubated and examined (A) at time 0, (B) at 37°C after 14 days, and (C) with 5% moisture at 37°C after 14 days

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,
Figure 7: Fourier transform infrared spectroscopy spectra of drug and polyvinyl alcohol mixtures incubated and examined (A) at time 0, (B) at 37°C after 14 days, and (C) with 5% moisture at 37°C after 14 days

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Formulation development and optimization of amikacin-loaded poly D, L-lactide-co-glycolide nanoparticles

Formulation development

PLGA shows an inclination toward better entrapment of hydrophobic drugs, possessing a challenge for the encapsulation of hydrophilic drugs. Being a water-soluble drug, amikacin too faces a similar challenge. Thus, a modified double emulsion solvent evaporation (DESE) method was attuned for its encapsulation.[25] This trait of amikacin is credited to its susceptibility to leach out from the IAP into the EAP. To obviate the leaching of amikacin from the center of the particle, 0.5% w/v PVA was incorporated in IAP that enhanced its viscosity, thereby, improving its retention. Also, high drug loading was achieved in developed A-NPs using polymer with acid end groups, which is attributed to the fact that ionic interaction or hydrogen bonding prevails between carboxylic groups of polymer and amine groups of drug, which resulted in better entrapment.[26]

Formulation optimization

Polymeric NPs are being majorly used as carriers for smart and effective delivery of therapeutic molecules. The development of NPs is, however, an intricate process as it involves several materials and process variants that may result into non-reproducible outcome because of the lack of understanding and control over process variants.[27] Fortunately, it can be resolved by mathematical models, the time-saving tools. Moreover, these models reduce the number of trials for optimization. The number of recommended trials varies with the number of variants, for example, Box–Behnken design recommends 17, 29, and 45 trials, respectively, for 3, 4, and 5 variants at three levels.

The PLGA-based A-NPs were, thus, optimized using Box–Behnken design, comprising a set of points located at the midpoint of each edge and the replicated center point of a multidimensional cube. Independent and dependent variants are given in [Table 4].
Table 4: Independent variants chosen with their levels and dependent variants for the design

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Following is the polynomial equation obtained by this experimental design:



where, Yi is the dependent variant, b0 is the intercept, b1b33 are the regression coefficients, and X1, X2, and X3 are the independent variants screened from preliminary experiments. The DOE software (Design-Expert, version 9) suggested 17 formulations (runs). The formulations were prepared and the dependent variants were then measured [Table 5].
Table 5: Three-factor Box–Behnken design

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Effects of different factors are discussed in detail as follows:

  1. Effect of homogenization time, probe sonication time, and drug/polymer ratio on particle sizeIt is clearly shown that on increasing the homogenization time from level (−1) to level (0), size of particle was reduced, whereas increasing it further from level (0) to level (+1), particle size was increased. Variation in particle size of NPs could be due to the net shear stress applied to the system. At time (t = 0), system was not exposed to any shear stress than at 30s, resulting into the formation of large-sized particles. However, at 180s, increased NP size can be attributed to the generation of smaller nanodroplets because of higher shear stress, resulting into aggregation of smaller droplets to stabilize the system, thus, increasing particle size.[27] Similarly, on increasing the secondary sonication time from level (−1) to level (+1), size of particle was reduced and the smallest size was recorded at 180s because sonication leads to the development of forces or shear stress, which breaks down the droplets into smaller ones, thereby decreasing particle size. On the contrary, no significant difference was observed in the size of particle by increasing drug/polymer ratio, which could be due to the distribution of drug into a large number of particles.[26] Thus, for obtaining particles with low particle size, optimum homogenization time, probe sonication time, and drug/polymer ratio were identified in the three-dimensional (3D) surface diagrams [Figure 8].


  2. Effect of homogenization time, probe sonication time, and drug/polymer ratio on drug loadingIt is clearly shown that the drug loading was found to be continuously decreased on increasing the homogenization time from level (0) to level (+1). High entrapment at 30s than at 180s could be attributed to minimal breakdown of nanodroplets, preventing drug leakage by homogenization-induced net shear stress. However, during the optimization of sonication time, unmarked difference in the drug loading of NPs was observed. Drug/polymer ratio too does impart a significant effect on the drug entrapment. In this investigation, polymer amount was kept constant (100mg), whereas the quantity of drug varied from –5 to 10 and 20mg. Drug loading was found to be increase on increasing the drug amount from level (−1) to level (0) then plateau. Plateau could be associated to the saturation of free carboxylic groups of polymer, which imparted a significant role in the entrapment of amikacin into PLGA-NPs. Thus, for obtaining particles with highest drug loading, optimum homogenization time, probe sonication time, and drug/polymer ratio were observed in the 3D surface diagrams [Figure 9].
Figure 8: Three-dimensional surface plot showing the effect of (A) probe sonication time and drug/polymer ratio, (B) homogenization time and drug/polymer ratio, and (C) probe sonication and homogenization time on the size of the nanoparticles

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,
Figure 9: Three-dimensional surface plot showing the effect of (A) probe sonication time and drug/polymer ratio, (B) homogenization time and drug/polymer ratio, and (C) probe sonication and homogenization time on drug loading of the nanoparticles

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Validation and optimization of amikacin-loaded poly D, L-lactide-co-glycolide nanoparticles

Particle size and drug loading are the two most important aspects of nanoparticulate systems for the efficient drug delivery. It is generally hypothesized that nano-metric carriers should have reduced particle sizes and enhanced drug loading to ensure their utmost benefits. Hence, Design-Expert software was used to optimize the A-NPs by keeping the criteria, particle size (minimum) and drug loading (maximum). Once the design was completed, numerical optimization was carried out and emulsions were generated/predicted. Synthesis was carried out according to the predicted emulsions. Particles with sizes and drug loading close to the predicted values were obtained [Table 6] and [Figure 10].
Table 6: Data showing solutions suggested by the design and successfully reproduced

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,
Figure 10: Average size of amikacin-loaded poly d, l-lactide-co-glycolide nanoparticles

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In this work, the optimized formulation yielded lower sized NPs of 260.3±2.05nm. Also, in the study, the method applied supported a reduced burst effect of 33.94±0.98% within 1h, which was sufficient enough to cater to the minimum inhibitory concentration/minimum bactericidal concentration requirements of the target organisms. This also conserved the drug pool, while allowing a sustained effect for over 24h. This, when extended to clinical settings later, might reduce the drug burden and offer therapeutic affordability. This would also add value as the drug is reported to have minimal clinical benefit and high toxicity.[16] Moreover, the drug loading reported by our group was also found to be higher (40.10±1.87 µg/mg of NPs). The aforementioned data generated by our group have been published elsewhere.[19]


   Conclusion Top


Chronic infections because of gram-negative bacilli warrant special pharmaceutical interventions to yield better pharmacotherapeutic outcomes. Biodegradable PLGA nanoparticulate systems with high payload, optimum size, and low PDI will ensure successful uptake, ultimately leading to better bioavailability. Keeping these facts in view, the process parameters to prepare PLGA NPs using DESE method were optimized using Box–Behnken design. The model suggested to use the optimum homogenization time, probe sonication time, and drug/polymer ratio as 30s, 120s, and 1:10, respectively. Under these optimized conditions, the A-NPs prepared had particle size of 260.3nm, which is appreciable for its permeability across small intestine, and drug loading of 3.645%. This optimized formulation can further be evaluated for pharmacokinetic and pharmacodynamic parameters.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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