INTRODUCTION:

Oral drug delivery is viewed as the most advantageous and safe route for the delivery of the drug having higher patient compliance and lower cost in comparison to the parenteral route for the drug delivery. Despite of these elucidating traits, therapeutic adequacy of oral route is obstentatious. Poor solubility or potentially poor permeability of the drugs add to the fundamental causes for their poor oral bioavailability (BA). So as to conquer the difficulties related with oral administration, nanoparticles (NPs) are seen as an option in contrast to different traditional drug deliveries as they fundamentally tend to improve the oral BA of the drugs¹. Primer proof proposes that certain nano-pharmaceutical details may improve the intensity, safety and efficacy of zidovudine for controlled drug delivery system.

The biodegradable idea of SLNs makes them less lethal in contrast with polymeric nanoparticles. SLN improves the capacity of the drug to enter through a barrier and is viewed as a promising drug delivery system. In this way, strong lipid nanoparticles of zidovudine were set up so as to assess their potential for controlled discharge. Constrained viability, poor biodistribution, and absence of selectivity are some of the delivery applications^1,2. In controlled drug delivery system (CDDS) the drug is targeted to the objective site hence any toxicity to the other tissues is minimized¹. NPs are also found to enhance the stability of drugs in the gastrointestinal tract while attuning their physicochemical and biological properties. Nano pellets³, lipospheres⁴ and SLNs^5-7 are the similar systems made of solid lipids introduced by different co-workers. The primary purposes behind improvement of SLNs are combinational points of interest from various carrier systems, for example, liposomes and polymeric NPs. Indistinguishable from polymeric NPs, the solid system of the SLNs can adequately ensure that the incorporated drug against any physiochemical degeneration under biological environment and give the most astounding adaptabilities in the control of drug release profiles^8-10. All these useful properties make SLNs magnificent carriers for oral route of drug administration. Oral/intra duodenal directed SLNs are accepted to upgrade BA of the drugs by improving passage through intestinal epithelial layer and by securing them against the acidic and basic conditions of GIT. Poorly water-soluble drugs can be incorporated using the intravenous SLNs administration^11-12.Biocompatibility and non-toxicity of excipients, when contrasted with toxicologically less adequate solubilizing excipients, for example, Cremophor EL, achievability of incorporation of both lipophilic and hydrophilic drugs and other bioactives¹³, high drug payload, possibility of controlled drug discharge and drug targeting, high drug stability¹⁴ shirking of organic solvents during preparations¹³, decreased toxicity with defensive impact against genuine danger, for instance, triptolide-induced hepatotoxicity are some of the advantages of the SLNs¹⁵. Zidovudine (ZD) is a nucleoside reverse transcriptase inhibitor (NRTI) that is responsible for the inhibition of human immunodeficiency virus type-1 (HIV) replication. The phosphorylated form of zidovudine which is 5-triphosphate interferes with the viral reverse transcriptase and interferes with chain elongation of the viral DNA, leading to inhibition of viral replication. Zidovudine therapy is safe and efficacious with limited adverse reactions¹⁶.Zidovudine is classified under Biopharmaceutical Classification System (BCS) as a class III drug with a short half life and undergoes extensive first pass metabolism. Average bioavailability of the drug due to first pass metabolism is about 63%. More than 75% of administered dose of Zidovudine is metabolised by liver through glucuronidation in liver helps in metabolism of more than 75% of the drug remaining drug is excreted in urine in an unchanged form¹⁷. In the present investigation, Zidovudine Solid Lipid Nanoparticle are prepared for oral administration to increase the bioavailability of zidovudine. The objective of the present study is to formulate and evaluate solid lipid nanoparticles for controlled drug delivery of zidovudine.

MATERIALS AND METHODS:

Materials:

Zidovudine is obtained as gift sample from AstraZeneca Bangalore (India). Poloxamer 188 (triblock copolymer of polyoxyethylene and polyoxypropylene), Mannitol, Sodium chelate were obtained from Sigma-Aldrich Ltd., New Delhi; Compritol® ATO888 (US/NF: glyceryl behenate, is a mixture of monoglycerides, diglycerides, and triglycerides of behenic acid) and Imwitor® 900K (glyceryl monostearate) was kindly gifted from Sigma-Aldrich Pvt. Ltd., (India). Tween 80 (PEG Sorbitan monooleate) was purchased from Adwic.

Figure 1: Chemical structure of Zidovudine

Methods:

Preparation of Zidovudine SLNs by the Ultrasonication technique:

Zidovudine loaded SLNs were successfully prepared by a homogenization followed by ultrasonication technique at a temperature range of 75-80°C. A hot aqueous phase containing drug and Tween 80 was added to the lipid phase containing glycerylbehenate, poloxamer and sodium cholate to obtain water in oil microemulsion. At the beginning cycles of homogenization, the temperature of the sample would decrease because the homogenizer could not provide the heat preservation. Homogenization time was optimized to 3 min. to reduce the particle size below 1μm probe sonicator was used. The prepared microemulsion was subjected to sonication for 25 min to obtain solid lipid nanoparticles in the range of 30-100nm with narrow size distribution. The SLN formulations were stored at a room temperature¹⁸. During lyophilisation mannitol (2%) was added which act as a cryoprotectant. The composition of prepared SLN batches is cited in Table 1.

Table 1: ZD-loaded solid lipid nanoparticles

Serial No.	Batch Code	Zidovudine (mg)	Glycerylbehenate (%w/w)	Poloxamer 188 (%w/w)	Sodium cholate (%w/w)	Tween 80 (%w/w)
1.	ZDSLN-1	300	5	1.5	1.5	1.5
2.	ZDSLN-2	300	6	1.5	1.5	1.5
3.	ZDSLN-3	300	7	1.5	1.5	1.5
4.	ZDSLN-4	300	5	0.5	1.5	1.5
5.	ZDSLN-5	300	5	1.0	1.5	1.5
6.	ZDSLN-6	300	5	2.0	1.5	1.5
7.	ZDSLN-7	300	5	2.5	1.5	1.5
8.	ZDSLN-8	300	5	1.5	0.5	1.5
9.	ZDSLN-9	300	5	1.5	1.0	1.5
10.	ZDSLN-10	300	5	1.5	2.0	1.5
11.	ZDSLN-11	300	5	1.5	2.5	1.5

Figure 2: Fabrication method for solid lipid nanoparticles.

Physicochemical Characterization:

Fourier transform infrared spectroscopy (FTIR) study:

The FTIR spectroscopy study (Alpha, Bruker) was done so as to determine the various functional groups present in the sample as for the reported pure drug. Percentage transmittance (%T) was found in the spectral region of 400-4000 cmˉ¹.

Particle size, polydispersity index and zeta potential measurements:

Photon correlation spectroscopy (PCS) was used to determine the particle size and poly dispersity index (PDI) of the SLN with the help of a Zeta sizer Nano ZS-90 (Malvern Instruments Ltd., Worcestershire, UK). Double distilled water was used for the dilution of SLN formulation samples before the analysis. Laser-doppler-anemometer coupled with Zeta sizer Nano ZS-90 (Malvern Instruments Ltd. Worcestershire, UK) were used to measure zeta potential of the formulations electrophoretic mobility of particles was also validated. All the analysis was repeated in triplicate. Measurements were obtained at an angle of 90˚ and pH of sample ranged from 6.0 to 6.2.

Encapsulation efficiency:

The encapsulation efficiency (EE) is the percentage of the drug encapsulated within and adsorbed on to the SLN. It was calculated by measuring the concentration of free drug in the dispersion medium^19-20. SLN dispersion was centrifuged at 14, 000 rpm (24 BL Model, Remi, Mumbai, India) at 10°C for about 30 minutes. The concentration of zidovudine entrapped into the SLN was the amount that was found in the supernatant and the difference between the total amounts used to prepare the SLN. The amount of free drug in the filtrate was determined spectrophotometrically at 265 nm using a UV-visible spectrophotometer (Systronics, 2701, Mumbai, India). The EE% is given as:

(W_t – W_f)

% EE = -----------------

W_t

Where, W_t. = total concentration of drug used in the formulation, W_f = Concentration of free drug remaining in the supernatant.

Transmission electron microscopy:

Transmission electron microscopy (TEM) was used to perform the morphological observations of the ZD-loaded SLNs. Phosphotungstic acid (2% w/v) was applied to stain the sample nanoparticles. Small amount of nanoparticle suspension (about 5–10μL) was planted on the copper grids with films for viewing by TEM (Hitachi H-7500 Tokyo, Japan). Capturing of the images were done by digital monographs and image viewing software.

Powder x-ray diffraction (PXRD) analysis:

Crystallinity of the prepared SLNs was examined by PXRD. The X-ray powder diffraction patterns of the samples were recorded with the XPERT-PRO A multipurpose X-Ray diffractometer XPERT-PRO (PAN alytical, Netherland) was applied to examine X-ray powder diffraction patterns of the prepared SLNs. It was done by using the PRS measurement program in which CuKα radiation which was generated at 45 kV and a current intensity of 40 mA and filtered using Ni. 2θ angles from 5° to 40° were operated using the diffraction angle range of the instrument.

Differential scanning calorimetry (DSC) analysis:

DSC was done of the different prepared samples and thermograms were generated using DSC TA-60 (Shimadzu, Tokyo, Japan) 208 calorimeter. 3-5 mg of samples were placed in crimped aluminium pans and were heated in a temperature range of 40°C to 200 °C at a scanning rate of 10°C/min. Empty alumina pan was used as a reference and inert nitrogen purge (35mL/min) was used for the analysis.

In vitro drug release study:

Modified USP dissolution apparatus 1 with two-sided open glass cylinder was used to check the in vitro drug release which was set at a temp of 37±0.5ºC and study was done for 12 hours. Dialysis membrane, molecular weight of around 12000-14000 A° (Himedia, Mumbai) was used as a diffusion barrier. The glass cylinder was fixed on the stirrer and 5ml solid lipid nano-suspension was introduced from the open side. Phosphate buffer of pH 7.4 maintained at a temp of 37ºC ± 0.5ºC was used at as the dissolution medium and the stirrer was suspended in it which was allowed to rotate at a speed of 100 rpm. A small part from samples was withdrawn at a predetermined interval and volume was made up by the phosphate buffer. Drug content was then analysed by measuring the samples for absorbance at 265nm by the UV-visible spectrophotometer (Systronics, Mumbai, India). During the whole process sink conditions were maintained. After the data was obtained, it was graphically represented (percent drug release vs time).

RESULTS AND DISCUSSION:

The influence of the ultrasonication on the physiochemical character of the prepared ZD-SLNs was checked. Ultrasonication method utilized for the preparation of SLNs depends upon the dispersion method which requires high-energy for the breakdown of the droplets into the nanometre range. Easy handling of the SLNs, fast production process are some of the advantages offered when the aggregates are broken down and there is decrease in polydispersity index and reduction in particle size of the nanoparticles^21-22.

Physicochemical characterization of Zidovudine loaded SLNs

FTIR spectroscopy studies:

FT-IR is the analytical technique for the stability of crystallinity of SLNs. In FTIR spectrum of pure ZD the characteristic peak was at the wave number 1109.37 cmˉ¹ indicating the presence of C-N (amine) stretching, NH bond stretching was found at 3463.53 cmˉ¹, a peak at wave number 1685.48 cmˉ¹ indicated the presence of C=O bond, 2086.78 cmˉ¹ wave number had the presence of azide group stretching, C-H aromatic at the wave number 2879.48 cmˉ¹, 1469.78 cmˉ¹ for C-H deformation (CH₃) and at 1276 cmˉ¹ for C-O stretch²³. Absorption peaks of glyceryl behenate, mannitol and lyophilized nanoparticles ZDSLN-1 and ZDSLN-2 are shown in the Table 2. The IR spectra of lyophilized nanoparticles (ZDSLN-1) showed the characteristic peaks of glyceryl behenate at 1700 cmˉ¹, 2312.4 cmˉ¹. Poloxamer 188 had a peak at wave number 2900 cmˉ¹ which corresponded to OH stretching. The IR spectra of lyophilized nanoparticles (ZDSLN-2) showed the characteristic peaks of glyceryl behenate at 1750 cmˉ¹, poloxamer 188 at 2100 cmˉ¹ due to stretching of O–H. This determined that the characteristic peak of drug in both the formulations were not able to be detected due to the dilution effect of the lipid¹⁹.

Table 2: Peaks obtained in the FTIR spectra of zidovudine

Functional group	Observed peaks (cmˉ¹ )
ZIDOVUDINE
C=O(stretch)	1685.48
C-N (stretch)	1109,37
C-H (stretch)	2879.48
Poloxamer	3447, 2886, 1112
Glyceryl Behenate	2914, 2849, 1730
Mannitol	3400,1420,1081,701
ZDSLN-1	1700, 2900, 2312.4
ZDSLN-2	1750, 1200, 2100

Figure 3: FTIR spectrum of: (A) Zidovudine (B) Glyceryl behenate (C) ZDSLN-3 (D) ZDSLN-1( (E) ZDSLN-2 (F) Poloxamer.

Table 3: Physiochemical characterization of ZD-SLNs

S. No	Batches	Particle size (nm) ± PDI	Zeta potential (mv) ± S.D	% E.E ± S.D
1	ZDSLN-1	100 ± 0.1	-32.56 ± 2.6	80 ± 4.2
2	ZDSLN-2	350 ± 0.3	-30.3 ± 2.8	52.1 ± 3.7
3	ZDSLN-3	600 ± 0.6	-29.6 ± 2.1	35.4 ± 4.8
4	ZDSLN-4	250 ± 0.4	-22.70 ± 1.1	25.2 ± 2.1
5	ZDSLN-5	200 ± 0.3	-27.21 ± 1.6	35 ± 3.5
6	ZDSLN-6	350 ± 0.5	-24.73 ± 1.4	38 ± 4.3
7	ZDSLN-7	450 ± 0.7	-28.83 ± 1.8	40 ± 5.1
8	ZDSLN-8	380 ± 0.6	-26.46 ± 2.4	25 ± 3.2
9	ZDSLN-9	250 ± 0.4	-27.94 ± 1.6	36 ± 1.5
10	ZDSLN-10	450 ± 0.5	-23.5 ± 1.2	38 ± 4.3
11	ZDSLN-11	500 ± 0.8	-28.55 ± 1.8	40 ± 4.5

Determination of particle size, PDI, zeta potential response, drug content and entrapment efficiency Particle size:

Table 3 and Figure 4 depicts the mean particle size of the lyophilized ZD-SLNs which are formulated with ultrasonication technique. All the SLN formulations depicted a mean particle size below 600nm which is considered to be an optimal size for controlled drug delivery. The particle size of formulations i.e. ZDSLN-1 and ZDSLN-2 are 100±0.1nm and 350±0.3nm respectively. This was made clear by the fact that particles breakdown into smaller droplets due to the ultrasonication method during the preparation process^24-25. Reduction in the particle size is seen with an increase in the concentration of surfactant used. Due to the loss of integrity of the nanoparticles during freeze-drying process many problems may come forth, for example, destabilization of nanoparticles due to mechanical stress exerted on them during crystallization of ice which may further result in changes in the particle size. The large number of nanoparticles in the final dried product may lead to irreversible coalescence in some of the cases. So, resistance to freezing and drying stresses is incorporated with the addition of cryoprotectants and also there is increase in the stability for long term storage. Sugars like mannose, lactose, mannitol, sucrose, maltose and glucose are used for stabilization but it depends on their concentration. Addition of mannitol in the concentration range of 2%, acts as a cryoprotectant, preserving the stability of nanoparticles during the process of freeze drying and averts the recrystallization process which further leads to increase in the particle size.

Poly dispersity index (PDI):

An indication of particle size distribution is known as polydispersity index (PDI). PDI lying in the range 0.15-0.3 specifies size homogeneity, whereas PDI value above 0.3 demonstrates heterogeneity in the particle size. If the value is 0.3 it indicates excellent particle size and value 0 indicate all particles are of same size. Polydispersity index data of various formulations of Zidovudine loaded SLN with varying concentrations of glycerylbehenate (GB), Poloxamer188, sodium cholate are depicted in Table 3 and Figure 5 which indicated narrow size distribution which further reveals the higher stability of the solid lipid nanoparticles. It is evident that the particle size and polydispersity index of SLN increase with increase in the GB content in final dispersion.

Figure 5: Polydispersity index of ZD loaded SLNs.

Zeta potential:

Zeta potential determines the surface charge of the nanoparticle and its potential stability. It is the surface characterization technique for the nano- particulate system. Usually, for the stability of a prepared colloidal dispersion absolute large negative or positive zeta potential values are required, this is due to the fact that there is no formation of aggregates of same charge due to electrostatic repulsion between the particles²⁶. Formulations shows negative zeta potential values as depicted in Table 3 and Figure 6, 7(A), (B), (C), which were significantly p˂0.01 varies from -22.70 ±1.1mV to -32.56 ± 2.6 mV which ensures physical stability.

Figure 6: Zeta potential of ZD-SLNs.

Entrapment efficiency (EE %):

The comparative correlation between the theoretical drug loading and the actual drug loading is known as the entrapment efficiency²⁷. The formulations studied demonstrated moderate to high Zidovudine entrapment efficiency in the range of 25-80% (w/w). The effect of the amount of lipid on the entrapment efficacy was studied by maintaining the amount of surfactant while varying the amount of lipid. The results showed that entrapment efficacy decreased as the amount of lipid increased. It was found experimentally that the entrapment efficiency was optimal at 5% lipid, 1.5% (w/w) poloxamer 188 and 1.5% (w/w) sodium cholate respectively. The zidovudine entrapment efficiency was significantly decreased with increasing the amounts of Poloxamer 188 and sodium cholate in the formulations respectively as depicted in Figure 8(A), (B) and (C). In the batches of SLN formulations the increased concentration of surfactant lead to increased surface coverage on the nanoparticles, which in turn resulted in increased entrapment efficiency, hence prevents leaching of drug from the matrix²⁷.

Transmission electron microscopy

Transmission electron microscopy (TEM) was used to perform the morphological examination of optimized formulation (ZD-SLN-1). The images of ZD-SLNs formulated by ultrasonication method are shown in Figure 9. This unveiled that the prepared formulations had a smooth surface with spherical shape and this suggested stability of nanoparticles. Thus these isometric nanoparticles having obtuse angles and edges are likely to cause less irritability as compared to the particles containing sharp angles and edges. It may be assured by the fact that the solubility and film forming capability of the lipid tends to determine the structure of the solid lipid nanoparticle.

Figure 9: TEM image of ZD-SLN.

Powder x-ray diffraction (PXRD):

To test the crystalline character of ZD-SLNs prepared by ultrasonication method and their lipid matrices X-Ray diffraction was conducted. Figure 10 indicates the X-ray diffractograms of lipids matrices, zidovudine, surfactant and lyophilized formulations of both ZDSLN1, ZDSLN2 and ZDSLN-3. Pure ZD showed crystalline peaks at 2Ɵ, 8.9°C, 15.6⁰C, 21.4⁰C, 22.3⁰C and 27.9⁰C. The β polymorphic form of mannitol depicted it’s crystallinity at several distinct peaks at 10.55°, 15.35°, 18.78°, 19.89°, 23.39°, 24.22°, 29.43°, 33.29°, 34.98° and 39.53° 2θ (mannitol exists in α, β and δ polymorphic forms). Glyceryl behenate solely displayed two distinct sharp peaks at 21.2 and 21.3° (2θ) indicating the crystallinity. XRD for pure poloxamer 188, the characteristic peaks were observed at 19.17° and 23.33°. Crystalline peaks of ZD were shown at 4.9⁰C, 8.7⁰C, and 15.5⁰C in different diffractograms of lyophilized ZD-SLN1 and ZD-SLN2, which indicates fragmentary recrystallization of drug. The reason for this could be the use of sonication process for the preparation of SLN which started nucleation of the drug and further led to crystal growth²⁸. Surfactants could be added to reduce the crystallization of the drug²⁹. Considering this, poloxamer could be used along with sodium cholate for efficiently controlling the process of recrystallization. The crystalline peaks of lipid material were observed at almost similar positions, whereas the formulation ZDSLN-1, ZDSLN-2 and ZDSLN-3 indicated peaks that showed reduced crystallinity. Therefore, it can be concluded that, the use of combination of poloxamer and sodium chelate was proved to be commanding in order to decrease the crystallinity of both lipid and drug. Thus, it was strongly ensured that there was a less drug expulsion from the carrier matrix due to the reduced lipid crystallinity in both the drug and the lipid, and in succession indicates a potential to hold the incorporated ZD. Peaks at 10.6^0, 15.98°, 19.70°, 20.42°, 20.54°, 21.44°, 28.60° 2θ showed freeze dried SLNs containing zidovudine, mannitol, glycerylmonostearate, glycerylbehenate, sodium cholate and poloxamer³⁰.

Differential scanning colorimetry:

Recrystallization behaviour of the substance is investigated by Differential Scanning Colorimetry. Figure 12 represents the thermograms of zidovudine formulations. The thermogram of zidovudine has a sharp and characteristic melting endotherm peak at 125.86ºC, heat of fusion of 118.03 J/g and the purity 99.83%. Broad endothermic peaks were observed for glyceryl behenate at 70.4°C in DSC thermogram and sharp endothermic peak for glyceryl monostearate was observed at 60.0⁰C, indicating their crystalline nature. The DSC of poloxamer 188 has shown endothermic peaks at 85°C. The DSC thermogram of ZDSLN-2 had two endothermic peaks within 85ºC and 142ºC and ZDSLN-1 had peaks at 90ºC and 164ºC and ZDSLN-3 had at 64ºC and 161ºC. This depicted that the drug was molecularly dispersed within the matrix of the lipid carrier³¹.

Figure 11: DSC of the durg

Figure 12: DSC of: (a) Zidovudine (b) ZDSLN-3 (c) Potoxmer (d) Glyeerylbehenate (e) ZDSLN-2 (f) ZDSLN-1

In vitro drug release:

In vitro release of drug from solid lipid nanoparticles is represented in Fig:13. Dialysis membrane was used to evaluate the drug release from SLN preparations, using phosphate buffer (pH 7.4) acting as the release medium. The solid nanoparticles made with ultrasonication method (ZDSLN-1) showed drug release 17.19% in 1 hr and 92.76 % drug release in 12 hr while (ZDSLN-2) demonstrated 29.9 %, 99.96 % drug release in 1 hr and 8 hr respectively and ZDSLN-3 shows 28.47% and 99.65 % in 1 hr and 8 hr respectively. According to the results a sustained drug release of upto 12 hours was demonstrated using the ultrasonication method as indicated by the percentage drug release versus time profile (Fig 13).

Figure 13: In vitro drug release profile of zidovudine SLN formulations through dialysis membrane.

Zidovudine being a hydrophilic drug has maximum solubility of 25 mg/ml at 25° C. Zidovudine has a melting point 122°C. The major hindrance to its use is low bioavailability. Hence, in this present study the Zidovudine Solid Lipid Nanoparticle were prepared in order to remove this limitation. The purity of the obtained drug sample was confirmed by FTIR spectroscopy studies, melting point and solubility studies. A suitable analytical method was developed for zidovudine by UV/V is spectrophotometry. According to the above information, preparation of zidovudine loaded solid lipid nanoparticles successfully by technique i.e. ultrasonication method was carried out. In this present investigation, glyceryl behenate with different concentrations (5%, 6% and 7%) was used as lipid in the preparation of SLN because it is known to form strong matrices. A combination of surfactant (poloxamer: sodium cholate) was also used in different concentration. The characterization of prepared SLNs revealed ZDSLN-1 formulation has particle size of 100 nm, good PDI of 0.1 and a zeta potential of -32.566. Physicochemical parameters were found in the range that favours the prepared SLNs (ZDSLN-1) suitability for controlled release. The PXRD and DSC studies indicated decrease in drug crystallinity in the prepared nanoparticles. Hence the prepared ZDSLN-1 formulation can be further explored as a means of drug delivery as it is seen it enhances the oral absorption of various water soluble drugs like zidovudine.

CONCLUSION:

In conclusion, SLN of Zidovudine having enhanced bioavailability and physical stability are prepared successfully using ultrasonication technique. It was also found that glyceryl behenate helps in increased the solubility of Zidovudine which may be one of the reasons for attaining the highest entrapment efficiency reported so far for this drug.

FINANCIAL SUPPORT AND SPONSORSHIP:

Nil.

CONFLICTS OF INTEREST:

There are no conflicts of interest.

ACKNOWLEDGEMENTS:

The authors are grateful to Chitkara University, Punjab, India for support and institutional facilities.

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Received on 24.02.2020 Modified on 11.06.2020

Research J. Pharm. and Tech. 2021; 14(5):2548-2556.

DOI: 10.52711/0974-360X.2021.00449