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Back to Journal »International Journal of Nanomedicine» Volume 14

Preparation of sustained-release apremilast loaded PLGA nanoparticles: in vitro characterization and in vivo pharmacokinetics study in rats

Author Answer MK, Mohammad M, Ezzeldin E, Fatima F, Alalaiwe A, Iqbal M

Published on March 1, 2019, Volume 2019: 14 pages, 1587-1595 pages

DOI https://doi.org/10.2147/IJN.S195048

Single anonymous peer review

Editor approved for publication: Prof. Dr. Anderson Oliveira Lobo

Md Khalid Anwer,1 Muqtader Mohammad,1 Essam Ezzeldin,2,3 Farhat Fatima,1 Ahmed Alalaiwe,1 Muzaffar Iqbal2,3 1Sattam Bin Abdulaziz Department of Pharmacy, Prince University School of Pharmacy, Al-Kharj 11942, Saudi Arabia; 2 King Saud University Department of Medicinal Chemistry, School of Pharmacy, Riyadh 11451, Saudi Arabia; 3 Bioavailability Laboratory, School of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia Background: Aprinast (APM) is a new type of oral small molecule drug that has been approved Used to treat psoriasis or psoriatic arthritis. Due to its low solubility and permeability, it is classified as a Class IV drug according to the BCS classification. Due to its tolerability and the twice-daily dosing regimen, it is recommended to perform dose titration during APM treatment. Materials and methods: In this study, three different APM-loaded PLGA nanoparticles (F1-F3) were prepared by single emulsion and evaporation methods. Based on particle size, PDI, zeta potential (ZP), encapsulation efficiency (%EE), drug loading (%DL) and spectral characterization, the nanoparticles (F3) were optimized. The in vitro release of F3 nanoparticles and the in vivo pharmacokinetic studies in rats were further evaluated. Results: The optimized nanoparticles (F3) have a particle size of 307.3±8.5 nm, a PDI value of 0.317, a ZP of -43.4±2.6 mV, an EE of 61.1±1.9%, and a DL of 1.9±0.1%. The in vitro release curve shows the sustained release pattern of APM's F3 nanoparticles. The pharmacokinetic results showed that the bioavailability of F3 nanoparticles was increased by 2.25 times compared with normal APM suspension. In addition, the significant increase in half-life and average residence time confirms the long-term retention of F3 nanoparticles. Conclusion: The enhanced bioavailability and long-term retention of APM-loaded PLGA nanoparticles may be helpful for a once-daily regimen. Keywords: apramilast, poly(D,L-lactide-coglycolide), nanoparticles, bioavailability, sustained release

Psoriasis or psoriatic arthritis is a chronic immune-mediated inflammatory disease that affects 2%–3% of the global population. 1–4 Aprinast (APM) is a new type 4 phosphodiesterase inhibitor that is administered orally and has been approved for the treatment of psoriasis or psoriatic arthritis. 3 Although the maintenance dose of APM is 30 mg twice a day, it is recommended that the initial dose be titrated to 10 to 30 mg to reduce the risk of gastrointestinal adverse reactions. APM has low solubility and low permeability, so it is classified as a class IV drug according to the biopharmaceutical classification system. 5 Due to its low solubility and permeability, its oral bioavailability varies greatly among different species (73% for humans, 20%–33% for mice, 12%–63% for rats, 78% for monkeys, and rabbits). ≤0.1%) 6.

Due to the chronic nature of the disease, APM is usually recommended for long-term treatment. Traditional APM immediate-release preparations have problems with tolerance and dosage regimens, which may impair patient compliance and affect the therapeutic effect. 7,8 Therefore, there is an urgent need for an alternative drug delivery system to overcome tolerance and dosing schedules. Frequent daily administration and increase the bioavailability of APM. Recently, Tang et al. (2016) developed a sustained-release formulation of APM to solve the problem of dosage and tolerability. 9

Poly(D,L-lactide-co-glycolide) (PLGA) is considered to be a smart polymer used to maintain the release of drugs and improve the oral bioavailability and therapeutic effects of several poorly water-soluble drugs in vivo . 10-12 PLGA polymer can also protect the drug from premature degradation and liver metabolism. In order to extend the drug release time, reduce the frequency of dosing, improve drug efficiency and patient compliance, various drugs are encapsulated in biodegradable PLGA nanoparticles (PLGA NPs). 13-15 The sustained release time of PLGA NPs can be programmed by optimizing the particles, size, morphology and molecular weight of PLGA.16

Some drug delivery systems, such as topical formulations, 17,18 sustained-release tablets, 9 and nail polish containing APM19, have been studied to improve their in vitro dissolution, efficacy, PK profile and in vivo bioavailability. To the best of the authors' knowledge, APM's PLGA polymer nanoparticles have not been studied in the literature, although the latter has several favorable characteristics for nanoparticle preparation, including poor water solubility, low bioavailability, and significant side effects.

The purpose of this research is to develop APM-loaded PLGA NPs, which may sustain the release of the drug, and may reduce the frequency of administration and improve the efficacy of the drug.

APM was purchased from Mesochem Technology (Beijing, China). PLGA lactide: glycolide (50:50), mol wt 4,000-15,000,000 and polyvinyl alcohol (PVA) were purchased from Sigma-Aldrich, St. Louis, Missouri, USA. All chemicals and solvents used in this study are analytical/HPLC grade. The ultrapure water is collected from the Milli-Q water purifier unit and used to prepare the aqueous solution.

Preparation of PLGA NP with APM

A single emulsion and evaporation method was used to prepare APM-loaded PLGA NPs (Table 1). In short, APM (10 mg) was dissolved in 5 mL of prepared PLGA (50-150 mg) dichloromethane solvent, and the organic phase was further emulsified into an aqueous phase (PVA, 0.5% w/v). Ultrasonic treatment in the probe ultrasonic instrument (ultrasonic processor, gx-130, Berlin, Germany) for 3 minutes, the voltage efficiency is 25°C, and the voltage efficiency is 60%. The volatile organic solvent dichloromethane was evaporated under reduced pressure at 40°C. A high-speed centrifugation (16,000 rpm) was used for 20 minutes to separate the APM-loaded PLGA NPs from a large amount of water, and then washed with cold distilled water three times and freeze-dried.

Table 1 Abbreviations of the composition of PLGA NPs carrying APM: APM, apremilast; PLGA NPs, poly(D, L-lactide-co-glycolide) nanoparticles; PVA, polyvinyl alcohol.

Particle size, polydispersity index (PDI) and zeta potential (ZP)

The developed PLGA NP loaded with APM was freeze-dried and then dispersed in Milli-Q water (20 μg/mL). Then use dynamic light scattering technology to characterize the particle size, polydispersity index (PDI) and zeta potential (ZP) of the suspension. The Malvern particle size analyzer (Malvern Instruments Ltd, Holtsville, NY, USA) is used to measure the average particle size and PDI of different developed NPs (F1-F3). The NP sample was diluted 200 times with deionized water and sonicated for 10 minutes to obtain a transparent water dispersion. Transfer each sample (3 mL) to a transparent disposable plastic cuvette, and measure the average particle size and PDI. The same analyzer is used to measure the ZP of NPs (F1-F3), but the measurement is done with glass electrodes.

Determination of drug encapsulation efficiency (%EE) and drug loading (%DL)

The indirect method was used to determine the drug encapsulation efficiency (%EE) and drug loading (%DL) of APM in PLGA NPs (F1–F3). Centrifuge the newly prepared emulsion at 12,000 rpm for 10 minutes to obtain a transparent supernatant. The unencapsulated drug in the supernatant was measured by an ultraviolet spectrometer at 229 nm. 20 %EE and %DL are calculated using the following formula:

ALPHA-FTIR spectrometer (OPTIK, Billerica, MA, USA) was used to record the FTIR spectra of pure APM and APM-loaded PLGA NP (F1-F3). Use transparent potassium bromide (KBr) particles and apply appropriate pressure to prepare a disc for each sample. The spectra were recorded in the 4,000-400 cm-1 wavelength range and interpreted with the help of IR software.

Use a DSC thermal analyzer (DSC N-650; SINCO; Taipei, Taiwan) to obtain differential scanning calorimetry (DSC) curves of pure APM and its PLGA NPs (F1–F3) in the temperature range of 50°C–200° At a temperature rise rate of 10°C/min. The flow rate of nitrogen was set to 20 mL/min. Take an accurately weighed sample (~5 mg) and place it in a sealed aluminum pan.

Use an X-ray diffractometer (Ultima-IV, Rigaku, Tokyo, Japan) to record the powder X-ray diffraction (XRD) pattern (2θ) of pure APM and APM-loaded PLGA NP (F1-F3) in the range of 3°-90° At a scan rate of 4°C/min. The XRD curve of each sample was recorded at a voltage and current of 30 kV and 25 mA, and the target/filter (monochromator) was copper.

The electron beam from the scanning electron microscope is used to obtain the morphological characteristics of the optimized APM-loaded PLGA NPs (F3). Freeze-dried PLGA NP is coated with a thin layer (2-20 nm) of metal such as gold, palladium or platinum under vacuum using a sputter coater. The pretreated sample is then bombarded with an electron beam, and the interaction results in the formation of secondary electrons, called Auger electrons. From this interaction between the electron beam and the sample atoms, only electrons scattered by ≥ 90° are selected and further processed according to Rutherford and Kramer's laws to obtain an image of the surface topography.

An in vitro drug release study was conducted to determine the drug release pattern from APM-loaded PLGA NPs (F3). In short, the pure APM and lyophilized NP are dispersed in a dialysis bag (cut-off value of 12 kDa) containing phosphate buffer (pH 6.8), and then placed in a bio-shaker (LBS-030S-Lab Tech, South Korea), horizontal shaking at 37°C at 100 rpm. At different time intervals (1, 2, 3, 4, 5, 6, 12, 24, and 48 hours), draw the supernatant of the sample. The collected samples were centrifuged at 12,000 rpm for 5 minutes, and 229 nm UV spectroscopy was used to analyze the drug content. 20 Draw and fit the data obtained from the release study to various kinetic models to obtain the release pattern of the drug. Polymer matrix.

Ultra performance liquid chromatography coupled with tandem mass spectrometry (MS/MS) is used to quantify APM in rat plasma samples. The assay we previously reported was modified for this purpose. 21 In order to improve the sensitivity of the determination, electrospray ionization is run in positive mode, the calibration range is between 1 and 1,000 ng/mL, and the lower limit of quantification is 1 ng/mL plasma sample. Due to the change in ionization mode, Losartan was used as an internal standard (IS). In the multiple reaction monitoring (MRM) mode, the precursor ion transitions of 461.16 >178.08 and 423.13 >207.12 are used to detect and quantify the analyte (APM) and IS (Losartan), respectively. The optimized MS/MS parameters of capillary voltage 4.00 kV, ion source temperature of 150°C, desolvation temperature of 350°C, and collision gas flow rate of 0.17 mL/min were used for sample ionization. The analyte and IS use cone voltages of 26 V (analyte and internal standard) and collision energies of 28 and 20 eV as compound-specific parameters, respectively. Due to changes in ionization mode and IS, according to the US Food and Drug Administration's 2013 Bioanalytical Method Validation Guidelines, the precision and accuracy of the assay have been partially validated. The intra-day and inter-day variation of precision and accuracy are within an acceptable range of ±15%.

Twelve male Wistar albino rats weighing 180-220 grams were used for the comparative pharmacokinetic study of rat APM. The animals were obtained from the Department of Animal Care, School of Pharmacy, Prince Satam Bin Abdulaziz University. Before the test, the rats were placed in a plastic enclosure with a temperature of 25°C±2°C and %RH 55%±5% under standard research center conditions. The light/dimming cycle was 12 hours. The pellet feed was given free drinking water. The study was conducted in accordance with the international standard guidelines for animal care and use, and the agreement was approved by the Animal Ethics Committee of the School of Pharmacy, Prince Al Hajisatam bin Abdulaziz University, Saudi Arabia. In a single-dose parallel study, the animals were randomly divided into two groups (n=6), which were treated as APM suspension (0.5% hydroxypropyl methylcellulose) and APM-loaded PLGA NPs (F3) treatment groups. Give each group APM (equivalent to 2mg/kg, oral) after overnight fasting, and at different time intervals (pre-dose, 0.5, 1, 1.5, 2, 3, 5, 8, 12, 24, 36 and 48 hours ). The blood samples were centrifuged at 4,500×g for 8 minutes to collect plasma and stored frozen at 80°C±10°C until further analysis.

Pharmacokinetic calculation and data analysis

The pharmacokinetic parameters were calculated using WinNonlin software (Pharsight Co., Mountain View, CA, USA), and all values ​​were expressed as mean ± SD. The non-compartmental pharmacokinetic model is used to calculate Cmax and time to maximum concentration (Tmax), area under the curve from 0 to t (AUC0-48) and 0-inf (AUC0-inf), elimination rate constant (kz ), half-life (T½) and mean residence time (MRT).

Physicochemical parameters and in vitro drug release data were evaluated by one-way analysis of variance using Dunnett's test. However, unpaired t-tests are used for statistical evaluation of pharmacokinetic parameters. GraphPad InStat software was used for statistical analysis, and P<0.05 was considered significant.

Particle size, PDI and ZP

It was found that the size of the developed APM-loaded PLGA NP (F1-F3) was in the range of 281.9-307.3 nm, and in the nanometer range of ≤1,000 nm. This increase in particle size may be due to an increase in the PLGA polymer concentration leading to an increase in viscosity, which prevents the organic phase from diffusing into the water phase, thereby increasing the size of the NPs. 22 PDI value NPs is in the range of 0.317-0.451, <0.7 which makes the dispersion suitable for differential light scanning analysis. The PDI value ≤ 1 indicates the relative distribution of single-sized nanoparticles23, which may lead to the prolonged stability of the prepared APM-loaded PLGA NP (Table 2). However, both size and PDI are within acceptable expectations for further research.

Table 2 Abbreviations of particle characterization: %DL, drug loading; %EE, encapsulation efficiency; PDI, polydispersity index; ZP, zeta potential.

The ZP of the three batches (F1-F3) are significantly different; the highest ZP is related to the maximum concentration of PLGA polymer used in the formulation. The ZP values ​​of F1, F2, and F3 were measured to be -32.8, -39.1, and -43.4 mV, respectively (Table 2). The negative ZP value of APM-loaded PLGA NPS can be attributed to ion adsorption, modification of particle surface functional groups, or ionizing active carboxyl functional groups of PLGA polymer. 24 According to DLVO electrostatic theory, nanoparticles may be stable because of Brownian motion and repulsive force. The (-) anion or (+) cation on the NP has a higher ZP, which makes them repel each other and stabilize the system. 25 Absolute PLGA showed ~±50 mV ZP, while APM loaded PLGA NP (F3) graded approximately -43.4 mV ZP, indicating a drop in particle potential; this negativeness may be due to the surface adsorption of NPs and PVA.

Determination of drug encapsulation efficiency (%EE) and drug loading (%DL)

The amount of drug incorporated in the polymer matrix was evaluated as drug encapsulation efficiency and %DL efficiency, as shown in Table 2. The measurement of %EE provides an estimate of the percentage of drugs successfully embedded. However, %DL treats the nanoparticles after separating them from the medium to understand their content. The %EE and %DL of APM in PLGA NPs (F1–F3) were measured in the range of 39.5%–61.1% and 1.3%–1.9%, respectively. The results show that the increase in the concentration of PLGA polymer leads to the retention of APM and the increase in particle size; this may be due to the increase in the viscosity of the polymer solution, which prevents the diffusion of the drug into the water phase. 23,26

Fourier transform infrared spectroscopy (FTIR) research

The FTIR spectra of APM and its developed PLGA polymer nanoparticles (F1-F3) were recorded to evaluate the interaction between the drug and the polymer. The spectral absorption bands of APM and PLGA NP loaded with APM were observed in the region of 400–4,000 cm-1 (Figure 1). The main peak assigned to pure APM confirms the presence of different functional ketone carbonyl and amide groups (-C=O, -NH-COCH3) in the fingerprint region. Due to the stretching vibrations of the amide-C=O, ketone (-C=O) and amide (-NH) groups of APM, peaks at 1,682, 1,764, and 3,363 cm-1 can be seen in the spectrum, respectively. The peak does not move significantly, but the peak intensity of the drug fingerprint area can be seen in the spectrum of the developed NPs. This reveals that APM is encapsulated in a PLGA polymer matrix in an amorphous state.

Figure 1 FTIR spectra of APM and APM-loaded PLGA NPs (F1–F3). Abbreviations: APM, apremilast; PLGA NPs, poly(D,L-lactide-co-glycolide) nanoparticles.

Thermal behavior studies are useful tools for evaluating whether drug particles have been encapsulated in a polymer matrix. 13 Compare the DSC curve of pure APM with the DSC curve of different developed PLGA NPs (F1-F3) loaded with APM, as shown in Figure 2. In the case of free APM, a sharp endothermic peak corresponding to 159.4°C was obtained, and it was found to be closer to the value reported in the literature. 27 In PLGA NP (F1 and F2) at 159.4°C, it can be seen that the endothermic peak has a reduced intensity compared to pure APM. This comparison shows that APM exists in a partially crystalline form and does not completely encapsulate the drug; this may be due to the smaller amount of PLGA polymer used in F1 and F2 PLGA NP. However, in the case of APM-loaded PLGA NPs (F3), the endothermic peak of the drug completely disappeared, confirming that it was completely encapsulated in the polymer matrix.

Figure 2 DSC thermograms of APM and APM-loaded PLGA NPs (F1-F3). Abbreviations: APM, apremilast; DSC, differential scanning calorimetry; PLGA NPs, poly(D,L-lactide-coglycolide) nanoparticles.

Perform powder X-ray (XRD) studies to study the crystalline and amorphous structures of APM and PLGA-NP. The diffraction pattern of the drug and its PLGA NPs is shown in Figure 3. Compared with APM-loaded PLGA NPs (F1-F3), the diffraction pattern of pure APM shows different peak intensities. The XRD pattern of pure APM has several characteristic strong peaks at 10.08° 2θ, 12.38° 2θ, 13.48° 2θ, 20.82° 2θ, 22.50° 2θ, 24.10° 2θ, 24.66° 29θ, 26° and 26°. 27 However, these peaks are absent or have low peak intensity in PLGA-NP loaded with APM. The decrease in crystallinity of the precipitated PLGA NP clearly confirms that the APM is encapsulated in the PLGA polymer.

Figure 3 Powder X-ray diffraction patterns of APM and APM-loaded PLGA NPs (F1–F3). Abbreviations: APM, apremilast; PLGA NPs, poly(D,L-lactide-co-glycolide) nanoparticles.

Figure 4 provides the morphology of the prepared APM loaded PLGA-NPs (F3). Most particles are placed discretely, and bridges between particles are rare. The surface of the particles looks smooth and delicate. The presence of aggregation may be due to PVA residues, even after washing with deionized water for 2 to 3 times. Another cause of agglomeration may be freeze-drying or sample processing for SEM characterization using metal-coated particles. Another hypothesis for interparticle bonds may be the high-energy centrifugal force used to separate the particles from the dispersion; it may force the particles to bond, leading to the formation of clumps. It is found that the manufactured PLGA NPs loaded with APM are uniform, clear, spherical, and have a smooth surface.

Figure 4 SEM image of optimized PLGA NPs (F3) loaded with APM. Abbreviations: APM, apremilast; PLGA NPs, poly(D,L-lactide-co-glycolide) nanoparticles.

Conduct in vitro release studies to gain insights into the release behavior of drugs from nanoparticles, as well as detailed information on release mechanisms and kinetics, so as to provide a reasonable and scientific method for drug product development. Figure 5 provides the drug release curves of pure APM and APM-loaded PLGA NPs (F3). The initial burst is followed by a sustained release. After the first 6 hours of the study, the burst rate of drug release of F3 nanoparticles was found to be 67.8%, which may be due to the adsorption of the drug on the surface, 28 and the large surface area of ​​the nanoparticles, which are prone to surface diffusion in the medium. Thereafter, a second phase of slow/sustained release was observed; this may be due to the diffusion release of the encapsulated drug in the PLGA polymer matrix. The sustained release of the drug may help reduce the frequency of oral administration of the drug. 26 48 hours after the start of the study, APM-loaded PLGA NP showed a cumulative drug release rate of 74.2%, while pure APM was 43.2%. In order to understand the mechanism of drug release from PLGA polymers, the release data of F3 nanoparticles were fitted to different kinetic models. The drug release mechanism of F3 is consistent with the Higuchi model, and the R2 value is ≥0.993 (Figure 6).

Figure 5 Release curves of pure APM and APM-loaded PLGA NPs (F3). Abbreviations: APM, apremilast; PLGA NPs, poly(D,L-lactide-co-glycolide) nanoparticles.

Figure 6 Higuchi releases kinetics of APM-loaded PLGA NPs (F3). Abbreviations: APM, apremilast; PLGA NPs, poly(D,L-lactide-co-glycolide) nanoparticles.

Determine the concentration of APM in actual rat samples according to the plasma calibration curve (1–1,000 ng/mL) prepared in blank plasma. Table 3 shows the results of pharmacokinetic parameters obtained after oral administration of 2 mg/kg APM. It can be seen from the results that the APM-loaded PLGA NPs (F3) are significantly (P<0.05) higher than the pure APM suspension, while the absorption rate (Cmax) does not change significantly. This result confirmed that the bioavailability of APM-loaded PLGA NPs was increased (2.25 times) compared with normal APM suspensions, and there was no significant effect on peak exposure. In addition, the elimination rate (Kel) of PLGA NP loaded with APM was significantly reduced (P<0.01), followed by a significant increase in T1/2 (P<0.001) and MRT (P<0.01) values. This result indicates that nanoparticles (F3) not only increase the bioavailability of APM, but also promote long-term retention, which may be helpful for a once-daily regimen. In this study, compared with our previous research report, the absorption rate and degree of APM is higher. This may be due to the gender-specific absorption of APM. It was found that the bioavailability of APM in female rats was 5 times that of male rats. 6 The average plasma concentration curve of APM after oral administration of 2 mg/kg (APM suspension and F3) in male rats is shown in Figure 7. A representative MRM chromatogram of APM and IS 1 hour after oral administration of APM (2 mg/kg) is shown in Figure 8.

Table 3 Pharmacokinetic characteristics of the developed PLGA NP loaded with APM Note: Compared with the standard suspension, aP<0.05 is significant. bP<0.01 is very significant compared with normal suspension. Compared with normal suspension, cP<0.001 is extremely significant. Abbreviations: APM, apremilast; MRT, average residence time; PLGA NPs, poly(D,L-lactide-co-glycolide) nanoparticles.

Figure 7 Pharmacokinetic characteristics of pure APM suspension and APM-loaded PLGA NPs (F3). Abbreviations: APM, apremilast; PLGA NPs, poly(D,L-lactide-co-glycolide) nanoparticles.

Figure 8 Representative MRM chromatograms of APM and IS in actual plasma samples 1 hour after oral administration of APM (2 mg/kg). Abbreviations: APM, apremilast; IS, internal standard; MRM, multiple reaction monitoring.

This research aims to develop APM-loaded PLGA NPs to improve bioavailability and maintain APM release. Three formulations (F1-F3) were prepared with different PLGA concentrations. The optimized NPs (F3) have the appropriate size and %EE to delay the release of the drug, which is confirmed by in vitro release studies and in vivo pharmacokinetic evaluation. Therefore, it is concluded that the developed NPs benefit from the nano size and are expected to achieve better therapeutic effects. Therefore, PLGA NPs loaded with APM can well replace traditional formulations, and have the advantages of reducing the frequency of dosing, improving bioavailability, and better patient compliance.

The author is grateful to the Dean of the Institute of Science at King Saud University for funding this work through Research Group Project No. 1. RGP-203.

The authors report no conflicts of interest in this work.

Menter A, Gottlieb A, Feldman SR, etc. Guidelines for Care of Psoriasis and Psoriatic Arthritis Treatment: Part 1. Overview of Psoriasis and Nursing Guidelines for the Use of Biological Agents to Treat Psoriasis. J Am Acad Dermatol. 2008;58(5):826–850.

Gottlieb A, Korman NJ, Gordon KB, etc. Guidelines for the care of psoriasis and psoriatic arthritis: Section 2. Psoriatic Arthritis: Overview and treatment and care guidelines, with an emphasis on biological agents. J Am Acad Dermatol. 2008;58(5):851–864.

Dix ed. Aprinast: A review of psoriasis and psoriatic arthritis. drug. 2015;75(12):1393–1403.

Hoffman MB, Hill D, Feldman SR. Current challenges in the treatment of psoriasis and emerging drug delivery strategies. Expert opinion on drug delivery. 2016;13(10):1461–1473.

The evaluation report of Apremilast (Otezla). European Medicines Agency Committee on Medicinal Products for Human Use. Year 2014.

US Food and Drug Administration. Center for Drug Evaluation and Research. Overview of the pharmacology of OTEZLA (aprinast) tablets. Available from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205437Orig1s000PharmR.pdf. Visited on October 1, 2018.

Papp K, Cather JC, Rosoph L, etc. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomized controlled trial. Lancet. 2012;380(9843):738-746.

OTEZLA® (aprinast) tablets [prescription information] 2017. New Foundation Corporation Summit, New Jersey. Available from https://media.celgene.com/content/uploads/otezla-pi.pdf. Visited on October 1, 2018.

Tang M, Hu P, Huang S, Zheng Q, Yu H, He Y. The development of aprestige sustained-release preparations and the A-level in vitro-in vivo correlation study of beagle dogs. Chemical pharmaceutical bull. 2016;64(11):1607-1615.

Zhang Y, Wischke C, Mittal S, Mitra A, Schwendeman SP. Design of hydrophobic fenretinide controlled release PLGA microspheres. Moore Pharmaceuticals. 2016;13(8):2622–2630.

Cossé A, König C, Lamprecht A, Wagner KG. Hot melt extrusion for sustained protein release: matrix erosion and in vitro release of PLGA-based implants. AAPS Pharmaceutical Technology. 2017;18(1):15-26.

Li L, Li C, Zhou J. Effective sustained release of 5-FU-loaded PLGA implants improves the therapeutic index of 5-FU in colon tumors. Int J Pharm. 2018;550(1–2):380–387.

Anwer MK, Al-Mansoor MA, Jamil S, Al-Shdefat R, Ansari MN, Shakeel F. Development and evaluation of quercetin nanoparticles based on PLGA polymers. Int J Biol Macromol. 2016; 92: 213-219.

Anwer MK, Jamil S, Ansari MJ, Iqbal M, Imam F, Shakeel F. Development and evaluation of PLGA nanoparticles loaded with Olmesartan medoxomil. Material innovation. 2016;20(3):193-197.

Padhi S, Kapoor R, Verma D, Panda AK, Iqbal Z. Formulation and optimization of topotecan nanoparticles: in vitro characterization, cytotoxicity, cellular uptake and pharmacokinetic results. J Photochem Photobiol B. 2018;183:222-232.

Preparation, evaluation and bioavailability study of Anwer MK, Al-Shdefat R, Ezzeldin E, Alshahrani SM, Alshetaili AS, Iqbal M. eudragit coated PLGA nanoparticles, used for sustained release eluxadoline to treat irritable bowel syndrome. Former pharmacist. 2017; 8:844.

Abraham J, Mishra V, Chaudhari K, Mittal V. Apremilast for external use. Patent number WO2017216738A1; 2017.

Ganarajan G, Sharma DC, Tangri P, Kothyal P. Design and characterization of apremilast-loaded emulsions for topical treatment. IJPBS. 2018; 8(3): 552–562.

Kushwaha AS, Repka MA, Narasimha Murthy S. A new Apremilast nail polish formulation for the treatment of nail psoriasis. AAPS Pharmaceutical Technology. 2017;18(8):2949–2956.

Lonkar NA, Dole MN, Sawant SD. Development and verification of UV spectrophotometry for estimating Apster in bulk form by absorbance maximum method. World J Pharm Pharm Sci. 2017; 6(7): 758–766.

Iqbal M, Ezzeldin E, Al-Rashood KA, Al-Shdefat R, Answer MK. Determination of eluxadoline in plasma samples based on high-throughput μ-SPE elution combined with UPLC-MS/MS: Application in the pharmacokinetic characterization of rat PLGA nanoparticle preparations. J Pharm Biomedical Anal. 2018; 149: 172-178.

PLGA nanoparticles designed by Jain AK, Das M, Swarnakar NK, and Jain S.: An emerging delivery tool in cancer treatment. Crit Rev Ther Drug Carrier Syst. 2011;28(1):1–45.

Obadalova I, Dammer O, Krejcik L, etc. A solid form of Apster and its preparation method. Patent number WO2016169533A1; 2016.

Budhian A, Siegel SJ, Winey KI. PLGA nanoparticles loaded with haloperidol: a systematic study of particle size and drug content. Int J Pharm. 2007;336(2):367–375.

Soni A, Dandagi P, Gadad A, Mastiholimath V. Simvastatin-loaded PLGA nanoparticles are used to improve oral bioavailability and sustained release: the influence of formulation variables. J Pharm Asia. 2011;5(2):57–64.

Yeo Y, Park K. Encapsulation efficiency and initial burst control in polymer particle systems. Arch Pharm Res. 2004;27(1):1-12.

Anzar N, Mirza MA, Anwer K, etc. Preparation, evaluation and pharmacokinetic study of simvastatin spray-dried PLGA polymer submicron particles for effective treatment of breast cancer. J Mol Liq. 2018; 249: 609-616.

Honary S, Zahir F. The effect of Zeta potential on the properties of nano-drug delivery systems-a review (part 1). Trop J Pharm Res. 2013; 12: 255-264.

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