Skip to main content

Development of nanoemulsion of antiviral drug for brain targeting in the treatment of neuro-AIDS

Abstract

Background

Delivery of drugs via the nasal route directly to the brain utilizing the olfactory pathway is purportedly known to be a more efficient method to deliver neuro-therapeutics to the brain by circumventing the BBB, thereby increasing the bioavailability of these drugs in the brain. The main objective of the project work is to improve the bioavailability of the antiretroviral drug and to minimize the side effects of this therapy which are observed at the higher side in the chronic HIV treatment. The advantage of nasal drug delivery is its noninvasiveness and self-administration. Nanoformulation provides fast onset of action and helps to achieve site-specific delivery. In the current work, nanoemulsion formulation was developed with a ternary phase system. In vitro characterization of nanoemulsion was performed.

Result

Optimized batch B2 had a zeta potential of − 18.7 mV showing a stable emulsion system and a particle size of 156.2 nmin desirable size range. Batch B2 has the least variation in globule size with PDI 0.463. Results from ex vivo studies revealed that developed nanoemulsion (B2) possessed a higher rate of drug release compared to other formulations.

Conclusion

Phase diagrams indicated more width of the nanoemulsion region with an increase in surfactant ratio. Stable nanoemulsion was prepared with a combination of surfactant and co-surfactants. Nanoemulsions could prove one of the best alternatives for brain delivery of potent medications.

Graphical Abstract

1 Background

The delivery of drugs to the brain has been fraught with the low bioavailability of drugs in the brain. This is caused by the “Blood–Brain Barrier” (BBB) and the “Blood–Cerebrospinal Fluid Barrier” (BCSFB) which block therapeutics from gaining access to the (CNS) [1, 2]. Drugs that are administered via oral and intravenous are faced with this challenge of BBB, thereby making the treatment of neurodegenerative diseases difficult to manage [3]. Delivery of drugs via the nasal route directly to the brain utilizing the olfactory pathway is more significant, delivering successively to the brain by passing the BBB, thereby increasing the bioavailability of drugs in the brain [4, 5].

Nervous system alterations occur due to direct or indirect effects of HIV infection, collectively known as neuro-AIDS [6, 7]. The estimated overall prevalence of nervous system disorders among patients receiving highly active antiretroviral therapy but also requiring neurological care is over 25% [8]. According to WHO (Global HIV & AIDS statistics—2020), there are ~ 34 million people in the world infected with HIV [8]. Out of 95 percent of these cases as well as deaths from AIDS that occur in the developing world [9], dementia (HIV-associated dementia) is becoming common in HIV-infected adults having a prevalence of up to 40% in western countries [10, 11].

The evaluation of the nanoemulsions includes (1) appearance testing by visual as well as under radiation observation; (2) stability testing by centrifugation; (3) stability under differential atmospheric conditions includes temperature, humidity, and change in forms such as cracking (flocculation) and creaming; (4) viscosity with respect to (i) change in time and (ii) change in RPM; and (5) pH of the formulation of such parameters indicates whether the formulation remains stable under certain circumstances. Characterization of the formulation includes (i) droplet size analysis, (ii) zeta potential, (iii) percent transmittance, (iv) morphology studies by transmission electron microscopy, (v) pH of the formulation, (vi) refractive index studies, and (vii) drug content and some other tests like polydispersity test, dye test, fluorescence test, dilution test, conductance test, and filter paper test. Furthermore, ex vivo diffusion study with the help of sheep nasal mucosa and cytotoxicity studies using cultured cell beds so that any damaging effects to tissues can be determined [12, 13].

Tenofovir disoproxil fumarate, the oral pro-drug of tenofovir, is a nucleotide reverse transcriptase inhibitor [14]. It inhibits viral polymerases by directly competing with the natural deoxyribonucleotide substrate and, after incorporation into deoxyribonucleic acid (DNA), by DNA chain termination [15, 16]. Tenofovir disoproxil fumarate is used to treat HIV and chronic hepatitis. Tenofovir has poor water solubility and low bioavailability (25%), thus a suitable candidate to formulate nanoemulsion for nasal drug delivery [12, 16].

2 Materials and methods

Tenofovir disoproxil fumarate was gifted by Mylan Pharmaceutical Private Limited, Nashik, India. Oleic acid (oil) was gifted by S.D. Fine-Chem Limited, Mumbai, India. Tween 60 and tween 80 were purchased from Merck Specialties Pvt. Ltd. Mumbai, India. Ethanol and methanol were purchased from Changshu Yangyuan Chemicals, China. The water used was semi-quartz distilled. All other chemicals and reagents used were of analytical grade, procured commercially, and used as received.

2.1 Determination of partition coefficient

The partition coefficient of the drug in oil and water was determined with the shake flask method. The drug was partitioned into the oil and water phase. After shaking for 1.5 h, the mixture was kept aside after appropriate dilution. The concentration in oil was determined on the UV spectrophotometer (UV 1800 Shimadzu) at 260 nm [17].

2.2 Screening of oil for nanoemulsion

The solubility of tenofovir disoproxil fumarate (TDF) in various oils like oleic acid, olive oil, and castor oil was determined by dissolving the excess amount of TDF in 5 ml of each selected oil in stoppered vials separately for the determination of solubility. The mixture vials were then kept in a shaker for 48 h to get equilibrium. The equilibrated samples were then centrifuged at 9000 RPM for 10 min. The supernatant was collected and filtered through a 0.45-µm membrane filter. The concentration of drug was determined in each oil by a UV spectrophotometer (UV 1800 Shimadzu) with suitable dilution with 0.1 N HCl at a wavelength of 260 nm [6].

2.3 Screening of surfactant and co-surfactant

Surfactants and co-surfactants were selected based on their capability to form stable nanoemulsion with relevant surfactants at minimum concentration. Of the several surfactants, tween 80 provided better outputs. Based on trials, ethanol was chosen as a co-surfactant [6].

2.4 Construction of phase diagram

On the basis of drug solubility in various nanoemulsion components, different combinations of oil, water, and surfactant/co-surfactant were selected. The pseudo-ternary phase diagrams of oil, surfactant/co-surfactant, and water were developed using the surfactant titration method [18]. The mixtures of oil and water at different weight ratios varying from 1:9 to 9:1 were titrated with surfactant/co-surfactant mix in a dropwise manner. Pseudo-ternary phase diagram was achieved by titrating with four different ratios of surfactant and co-surfactant (1:1, 1:2, 2:1, and 4:1) until it turns from hazy to transparent. After the identification of nanoemulsion region in the phase diagrams, formulation component ratios were selected in order to form the nanoemulsion [19, 20].

On the basis of the solubility study, oleic acid was selected as the oil phase. Tween 80 and ethanol were selected as surfactant and co-surfactant, respectively. Distilled water is used as an aqueous phase. The drug was dissolved in the required quantity of oil, surfactant, and co-surfactant with varying ratios. Distilled water was added to the above mixture as a fixed ratio. Surfactant and co-surfactant were added gradually with continuous stirring, which resulted in the formulation of a transparent and homogenous nanoemulsion [20, 21].

2.5 Characterization of nanoemulsion

2.5.1 Thermodynamic stability studies

The formulation consists of a couple of immiscible phases, so as to overcome the problems such as instability these thermodynamic stability studies were performed. Prepared formulations were centrifuged at 3000 rpm for 30 min and then examined for phase separation. Those formulations that did not show any phase separation were taken for the heating and cooling cycles at a temperature of 4 °C and 45 °C for 48 h. The formulations were then observed for phase separation. The formulations which were stable at these temperatures passed the thermodynamic stability test and were selected for further evaluation studies [21, 22].

2.5.2 Evaluation of the nanoemulsion

The nanoemulsion prepared with optimized composition was evaluated for the parameters like zeta potential, viscosity, pH, conductivity, and refractive index [23]. The results are given in Tables 3 and 4.

2.5.3 Transmittance test

To assess the transparency and clarity of the nanoemulsion, this test was performed. The transparency of nanoemulsion was checked by measuring transmittance at 650 nm with 0.1 N HCl as blank by using a UV spectrophotometer (UV 1800 Shimadzu). It was determined with the formula in Eq. 1. The results are given in Table 5.

$${\text{Absorbance}} = - \log \left( {\% T{/}100} \right).$$
(1)

2.5.4 Drug content estimation

Nanoemulsion containing 100 mg drug was dissolved in 100 ml 0.1 N HCl taken in a volumetric flask. Then, the solvent was filtered; 1 ml was taken in 50 ml volumetric solution and diluted up to the mark with 0.1 N HCl and analyzed spectrometrically at 260 nm (UV 1800 Shimadzu). The concentration of tenofovir in mg/ml was obtained by using a standard calibration curve of the drug. Drug content studies were carried out in triplicate for each formulation batch [2, 24].

2.5.5 Particle size and zeta potential measurement

The particle size and zeta potential of the optimized nanoemulsion were determined by dynamic light scattering with Zetasizer ver.7.12 (Malvern Instruments Ltd.) [22, 24]. The results are shown in Tables 3 and 4.

2.5.6 Ex vivo diffusion studies

Egg membrane and sheep nasal mucosa were used for preliminary preclinical evaluation of nasal dosage forms. Sheep nasal mucosa is used for an experiment as it mimics human nasal vasculature. A diffusion study was carried out using an isolated egg membrane for the trial batches (B1–B4) in phosphate buffer pH 6.4 (PBS 6.4) for a period of 3 h using a Franz diffusion cell [25, 26]. Diffusion of drug from egg membrane was observed. Later, best batch B2 was forwarded to diffusion study from sheep nasal mucosa. The sheep nose piece was obtained from a local slaughterhouse; the nasal mucosa layer was excised and used for diffusion study. Nasal mucosa was placed in Franz diffusion cells having a diffusion area of 0.785 cm2. PBS pH 6.4 was added to the receiver chamber maintained at 37 °C temperature. Franz cell was pre-incubated for 20 min, and formulation equivalent to10 ml of B2 sample was placed in the donor chamber. Withdrawn 1 mL samples from the receiver chamber at predetermined time intervals, added 1 mL of PBS 6.4 after each sampling to maintain sink condition. All the samples were filtered and analyzed using a UV spectrophotometer at 224 nm, and cumulative drug release was determined [27, 28].

Observations after diffusion from goat nasal mucosa are mentioned in Table 6.

3 Results

3.1 Formulation and optimization of nanoemulsion

The solubility of tenofovir in various oils was investigated and found to be highest in oleic acid, i.e., 26.69 ± 0.3 mg/ml (Fig. 1). Among surfactants, in tween 80 the drug showed the highest solubility of 30.31 ± 1.5 mg/ml. In ethanol, the drug showed the highest solubility among the co-surfactants of 41.57 ± 0.6 mg/ml, followed by PEG 400. The nanoemulsion existence region was determined by constructing phase diagrams. From the pseudo-ternary phase diagrams, it was concluded that the highest nanoemulsion zone was obtained for the nanoemulsion having tween 80 and ethanol in the ratio of 4:1 as shown in Fig. 2 and (Table 1) [29, 30].

Fig. 1
figure 1

Solubility of TNF in different oils, surfactants, and co-surfactants

Fig. 2
figure 2

Ternary phase diagram studies for ratio 4:1

3.2 Dispersion stability studies

The objective of thermodynamic stability is to evaluate the phase separation and effect of temperature on formulation stability. In the thermodynamic stability studies, the formulation selected was subjected to stress tests like heating–cooling cycle and centrifugation. It was observed that all formulations were stable, clear liquid, and no phase separation occur under stress condition. This confirms the liquid formulations were stable for the storage [31, 32]. Nanoemulsions are thermodynamically stable formulation composed of a fixed proportion of oil, surfactant, co-surfactant, and water which does not tend to show any phase separation after multiple changes in the temperature and centrifugation. After centrifugation at 3000 RPM for 20 min, all the formulations were still stable, clear liquid, and no phase separation occurred under stress conditions. The conditions are mentioned in Table 2. It proves that the formulations are thermodynamically stable [33, 34].

Table 1 Trial batches preparation
Table 2 Thermal and centrifugation stability of tenofovir nanoemulsion

3.3 Evaluation of the nanoemulsion composition

The nanoemulsion prepared by the selected composition was evaluated for the parameters like droplet size, PDI, zeta potential, viscosity, pH, conductivity, and refractive index. The result is given in Tables 3 and 4.

It was observed that there was no any significant difference between placebo formulation and formulation with drug. It indicates the formulation has isotropic nature. This confirms the drug was in a dissolved state and uniformly distributed in liquid formulation.

Table 3 Evaluation of nanoemulsion
Table 4 Physicochemical parameters of developed tenofovir nanoemulsion

3.4 Transmittance test

From the results of the transmittance test in Table 5, it was observed that the transparency of the formulation goes on decreasing as the concentration of S-mixture. So it shows high transparency of the first formulation, and later it gets decreased [18].

The viscosity of four formulations was observed in the range of 400–500 cps, and after the variations in the RPM it is concluded that the system of all the nanoemulsion formulations was observed as a shear thinning system. That is viscosity gets decreased by a sudden increase in the resistance. But with respect to time the viscosity of the formulations remained stable and no major fluctuations were observed in it.

Nasal pH has a range which is between 5.6 and 6.5, and the observed values of the pH of all the formulations were in the range so it proves that the developed nanoemulsion formulations are applicable to the nasal drug delivery system.

3.5 Drug content estimation

The concentration of tenofovir in mg/ml was obtained by using a standard calibration curve of the drug. Drug content studies were carried out in triplicate for each formulation batch. The results are given in Table 5. Drug content determination helps to find out the amount of drug entrapped in the formulation. From results, more drug content was observed in batch B2 than in other batches [23, 35].

Table 5 Drug content and percent transmittance

3.6 Particle size, polydispersity index, and zeta potential measurement

The particle size and zeta potential of the optimized nanoemulsion were determined by dynamic light scattering with Zetasizer ver.7.12 (Malvern Instruments Ltd.). The results are shown in Figs. 3 and 4. The zeta potential is − 18.7 and the size (z average) is 156.2 nm with PDI 0.463. The ideal size of globules in nanoemulsion is in between the range of 100 and 500 nm, the polydispersity index should be narrow, and the zeta potential should be within the range of  − 15 to + 20 mV for prediction of stability of nanodroplets in emulsion [35, 36]. The obtained results are appropriate with these values. Batch B2 has a large globule size, but it has the minimum polydispersity index that means the variation in the globule size throughout the formulation is very less in the batch B2 [37, 38].

Fig. 3
figure 3

Particle size and polydispersity index graph of optimized nanoemulsion batch

Fig. 4
figure 4

Zeta potential graph of optimized nanoemulsion batch

3.7 Ex vivo diffusion studies

Ex vivo study was performed using egg membrane in nanoemulsion batches B1, B2, B3, and B4. Here, batch B2 shows greater drug diffusion that is 74.98 ± 1.06% after 3 h. For the sheep nasal mucosal membrane, B2 batch showed 75.9841 ± 0.14% of diffusion in the system, which is determined by taking triplicate readings with standard deviation (n = 3) [35]. From the above studies, it is concluded that B2 is the optimized batch and has a greater diffusion ratio compared to all other batches. The diffusion of the drug from the formulations is comparable through egg membrane and sheep nasal mucosa (Fig. 5; Table 6) [39, 40].

Fig. 5
figure 5

Comparison of diffusion study profiles of batches B1–B4

4 Discussion

HIV treatment is a combination of antiretroviral drugs. Most people who treat their HIV will take two or more drugs each day for the rest of their lives. Sticking to the treatment plan isn’t always easy. The main purpose of this study was to improve the bioavailability of the antiretroviral drug and to minimize the dose of the antiretroviral drug and ultimately reduce the side effects of this therapy which is observed at the higher side in the other formulations/administration process [41]. Nasal route delivery to the brain utilizing the olfactory pathway is purportedly known to be more efficient and deliver neuro-therapeutics to the brain by passing the BBB, thereby increasing the bioavailability of drugs in the brain. The advantage of this method is that nasal drug delivery administration is noninvasiveness in nature, essentially painless, and particularly suited for children [42].

Tenofovir disoproxil fumarate is selected for the study. On the basis of drug solubility in various nanoemulsions components, different combinations of oil, water, and surfactant/co-surfactant were selected. The pseudo-ternary phase diagrams of oil, surfactant/co-surfactant, and water were developed using the surfactant titration method. Phase diagrams indicated more width of the nanoemulsion region with an increase in surfactant ratio. Diffusion study was carried out using egg membrane for the trial batches (B1–B4) and sheep nasal mucosa for the optimized batch (B2) in phosphate buffer (PB) pH 6.4 for a period of 3 h using diffusion cell apparatus. Firstly, in the study using egg membrane in batches B1, B2, B3, and B4 of nanoemulsions, batch B2 shows greater diffusion that is 74.98 ± 1.06, and for the sheep nasal mucosal membrane B2 batch showed 75.9841 ± 0.14 of drug release.

The drug amount was kept fixed in all batches (25 mg). Oil (%) and surfactant mix (%) are variable in all batches. B2 batch has the highest surfactant mix (%), showing comparatively better diffusion. With respect to the dependent variable zeta potential, batch B2 was showing the highest magnitude (− 18.7 mV), showing good stability of emulsion. The polydispersity index of 0.463 is within the acceptable range. Other batches (B1, B3, and B4) have a very small magnitude of zeta potential which may lead to droplet coalescence and aggregation during storage. Surfactant mix concentration of 45% was found to give good stability to internal phase globules. Considering the results of four batches, B2 is found to be the optimum combination of drug, oil, and surfactant mix.

Table 6 % CDR values after diffusion profile studies

5 Conclusion

Nanoemulsion was found to be one of the potential drug delivery strategies for nose-to-brain delivery. For poorly soluble and poorly permeable drugs, nanoemulsion approach increases the surface area and gives lipophilic nature to disperse the drug. The development of nanoemulsion formulation was done with ternary phase studies. Surfactant selection is the heart of preparing stable dispersions. TNF could be given via the nasal route after performing clinical studies on such preparations. For CNS HIV infection, nose-to-brain delivery options are emerging strategies. The advantage of this method is that nasal drug delivery administration is noninvasiveness in nature, essentially painless, and particularly acceptable for all age-groups. Nanoformulation provides fast onset of action and helps to achieve site-specific delivery.

Availability of data and materials

All the data are available in the manuscript.

Abbreviations

TDF:

Tenofovir disoproxil fumarate

BBB:

Blood–brain barrier

RPM:

Revolutions per minute

BCSFB:

Blood–cerebrospinal fluid barrier

HIV:

Human immunodeficiency virus

PB:

Phosphate buffer

AIDS:

Acquired immune deficiency syndrome

CNS:

Central nervous system

References

  1. Erdő F, Bors LA, Farkas D, Bajza Á, Gizurarson S (2018) Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Res Bull 143:155–70

    Article  PubMed  Google Scholar 

  2. Kakad S, Kshirsagar S (2021) Nose to brain delivery of Efavirenz nano suspension for effective neuro AIDS therapy: in-vitro, in-vivo and pharmacokinetic assessment. Heliyon. https://doi.org/10.53879/id.58.04.11888

  3. Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994

    Article  CAS  PubMed  Google Scholar 

  4. Illum L (2003) Nasal drug delivery—possibilities, problems and solutions. J Control Rel 87:187–98

    Article  CAS  Google Scholar 

  5. Varatharajan L, Thomas SA (2009) The transport of anti-HIV drugs across blood-CNS interfaces: summary of current knowledge and recommendations for further research. Antiviral Res 82:A99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Nowacek A, Gendelman HE (2009) Nano-ART, neuro-AIDS and CNS drug delivery. Nanomedicine 4:557–574

    Article  CAS  PubMed  Google Scholar 

  7. Jayant RD, Atluri VSR, Agudelo M, Sagar V, Kaushik A, Nair M (2015) Sustained-release nanoART formulation for the treatment of neuroAIDS. Int J Nanomed 4(10):1077–1093

    Article  Google Scholar 

  8. Global HIV & AIDS statistics—2020 fact sheet. Accessed online https://www.unaids.org/en/resources/fact-sheet Accesed on 25 Apr 2021

  9. Saravanan M, Asmalash T, Gebrekidan A, Gebreegziabiher D, Araya T, Hilekiros H et al (2018) Nano-medicine as a newly emerging approach to combat Human Immunodeficiency Virus (HIV). Pharm Nanotechnol 9:06

    Google Scholar 

  10. McArthur JC (2004) HIV dementia: an evolving disease. J Neuroimmunol 157:3–10

    Article  CAS  PubMed  Google Scholar 

  11. Shapshak P, Kangueane P, Fujimura RK, Commins D, Chiappelli F, Singer E et al (2011) Editorial NeuroAIDS review. AIDS 25:123–141

    Article  PubMed  Google Scholar 

  12. Djupesland PG (2013) Nasal drug delivery devices: characteristics and performance in a clinical perspective—a review, drug delivery and translational research, vol. 3, Springer, pp 42–62

  13. Delshadi R, Bahrami A, McClements DJ, Moore MD, Williams L (2021) Development of nanoparticle-delivery systems for antiviral agents: a review. J Control Release 331:30–44

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kearney BP, Flaherty JF, Shah J (2004) Tenofovir Disoproxil Fumarate clinical pharmacology and pharmacokinetics, vol 43, ClinPharmacokinet

  15. Gallant JE, Deresinski S. Tenofovir Disoproxil Fumarate (2003) Reviews of anti-infective agents. In: Clinical infectious diseases, vol 37. https://academic.oup.com/cid/article/37/7/944/422616

  16. Liner KJ, Ro MJ, Robertson KR (2010) HIV, antiretroviral therapies, and the brain. Curr HIV/AIDS Rep 7:85–91

    Article  PubMed  Google Scholar 

  17. Vyas TK, Shah L, Amiji MM (2006) Nanoparticulate drug carriers for delivery of HIV/AIDS therapy to viral reservoir sites. Expert Opin Drug Deliv 3:613–628

    Article  CAS  PubMed  Google Scholar 

  18. Chhabra G, Chuttani K, Mishra AK, Pathak K (2011) Design and development of nanoemulsion drug delivery system of amlodipine besilate for improvement of oral bioavailability. Drug Dev Ind Pharm 37(8):907–916

    Article  CAS  PubMed  Google Scholar 

  19. Wong HL, Chattopadhyay N, Wu XY, Bendayan R (2010) Nanotechnology applications for improved delivery of antiretroviral drugs to the brain. Adv Drug Deliv Rev 62:503–517

    Article  CAS  PubMed  Google Scholar 

  20. Shafiq-un-Nabi S, Shakeel F, Talegaonkar S, Ali J, Baboota S, Ahuja A, Khar RK, Ali M (2007) Formulation development and optimization using nanoemulsion technique: a technical note. AAPS PharmSciTech 8(2):E12-28. https://doi.org/10.1208/pt0802028

    Article  PubMed Central  Google Scholar 

  21. Prabhakar K, Afzal SM, Surender G, Kishan V (2013) Tween 80 containing lipid nanoemulsions for delivery of indinavir to brain. ActaPharmaceuticaSinica B 3(5):345–53. https://doi.org/10.1016/j.apsb.2013.08.001

    Article  Google Scholar 

  22. Pokharkar VB, Jolly MR, Kumbhar DD (2015) Engineering of a hybrid polymer-lipid nanocarrier for the nasal delivery of tenofovirdisoproxil fumarate: physicochemical, molecular, microstructural, and stability evaluation. Eur J Pharm Sci 25(71):99–111

    Article  Google Scholar 

  23. Laxmi M, Bhardwaj A, Mehta S, Mehta A (2015) Development and characterization of nanoemulsion as carrier for the enhancement of bioavailability of artemether. Artif Cells Nanomed Biotechnol 43(5):334–344. https://doi.org/10.3109/21691401.2014.887018

    Article  CAS  PubMed  Google Scholar 

  24. Shakeel F, Baboota S, Ahuja A, Ali J, Aqil M, Shafiq S (2007) Nanoemulsions as vehicles for transdermal delivery of aceclofenac. AAPS PharmSciTech 8(4):191. https://doi.org/10.1208/pt0804104

    Article  PubMed Central  Google Scholar 

  25. Cojocaru FD, Botezat D, Gardikiotis I, Uritu CM, Dodi G, Trandafir L, Rezus C, Rezus E, Tamba BI, Mihai CT (2020) Nanomaterials designed for antiviral drug delivery transport across biological barriers. Pharmaceutics 12(2):171. https://doi.org/10.3390/pharmaceutics12020171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mahajan HS, Mahajan MS, Nerkar PP, Agrawal A (2014) Nanoemulsion-based intranasal drug delivery system of saquinavirmesylate for brain targeting. Drug Deliv 21(2):148–154

    Article  CAS  PubMed  Google Scholar 

  27. Chin LY, Tan JY, Choudhury H, Pandey M, Sisinthy SP, Gorain B (2021) Development and optimization of chitosan coated nanoemulgel of telmisartan for intranasal delivery: a comparative study. J Drug Deliv Sci Technol 62:102341

    Article  CAS  Google Scholar 

  28. Kumar M, Misra A, Babbar AK, Mishra AK, Mishra P, Pathak K (2008) Intranasal nanoemulsion based brain targeting drug delivery system of risperidone. Int J Pharm 358(1–2):285–291. https://doi.org/10.1016/j.ijpharm.2008.03.029

    Article  CAS  PubMed  Google Scholar 

  29. Ogunwuyi O, Kumari N, Smith KA, Bolshakov O, Adesina S, Gugssa A, Anderson WA, Nekhai S, Akala EO (2016) Antiretroviral drugs-loaded nanoparticles fabricated by dispersion polymerization with potential for HIV/AIDS treatment. Infect Dis 9:21–32. https://doi.org/10.4137/IDRT.S38108

    Article  Google Scholar 

  30. Belgamwar A, Khan S, Yeole P (2018) Intranasal chitosan-g-HPβCD nanoparticles of efavirenz for the CNS targeting. Artif Cells Nanomed Biotechnol 46(2):374–386

    Article  CAS  PubMed  Google Scholar 

  31. Kakad SP, Kshirsagar SJ (2021) Development of reverse phase high-performance liquid chromatographic method for the estimation of HIV non-nucleoside reverse transcriptase inhibitor drug efavirenz in the rat brain. Futur J Pharm Sci 7:11. https://doi.org/10.1186/s43094-020-00158-3

    Article  Google Scholar 

  32. dasNeves J et al (2010) Nanotechnology-based systems for the treatment and prevention of HIV/AIDS. Adv Drug Deliv Rev 62(4–5):458–477. https://doi.org/10.1016/j.addr.2009.11.017

    Article  CAS  Google Scholar 

  33. Kotta S, Khan AW, Ansari SH, Sharma RK, Ali J (2014) Anti HIV nanoemulsion formulation: optimization and in vitro-in vivo evaluation. Int J Pharm 462(1–2):129–134. https://doi.org/10.1016/j.ijpharm.2013.12.038

    Article  CAS  PubMed  Google Scholar 

  34. Singh Y, Meher JG, Raval K, Khan FA, Chaurasia M, Jain NK, Chourasia MK (2017) Nanoemulsion: concepts, development and applications in drug delivery. J Control Release Off J Control Rel Soc 252:28–49. https://doi.org/10.1016/j.jconrel.2017.03.008

    Article  CAS  Google Scholar 

  35. Mulam TR, Kshirsagar SJ, Kakad SP (2021) Formulation and optimization of ritonavir nasal nanosuspension for brain targeting. https://doi.org/10.53879/id.58.04.11888

  36. Alukda D, Sturgis T, Youan BC (2011) Formulation of tenofovir-loaded functionalized solid lipid nanoparticles intended for HIV prevention. J Pharm Sci 100(8):3345–3356. https://doi.org/10.1002/jps.22529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ibrahim MA, Shazly GA, Aleanizy FS, Alqahtani FY, Elosaily GM (2019) Formulation and evaluation of docetaxel nanosuspensions: in-vitro evaluation and cytotoxicity. Saudi Pharm J 27(1):49–55

    Article  PubMed  Google Scholar 

  38. Kuo YC, Chen HH (2009) Entrapment and release of saquinavir using novel cationic solid lipid nanoparticles. Int J Pharm 365(1–2):206–13

    CAS  PubMed  Google Scholar 

  39. Shah BM, Misra M, Shishoo CJ, Padh H (2015) Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization. Drug Deliv 22(7):918–30

    Article  CAS  PubMed  Google Scholar 

  40. Sharma D, Maheshwari D, Philip G, Rana R, Bhatia S, Singh M, Gabrani R, Sharma SK, Ali J, Sharma RK, Dang S (2014) Formulation and optimization of polymeric nanoparticles for intranasal delivery of lorazepam using Box-Behnken design: in vitro and in vivo evaluation. Biomed Res Int 2014:156010. https://doi.org/10.1155/2014/156010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kakad SP, Kshirsagar SJ (2020) Neuro-AIDS: current status and challenges to antiretroviral drug therapy (ART) for its treatment. Curr Drug Ther 15(5):469–81. https://doi.org/10.2174/1574885515666200604123046

    Article  CAS  Google Scholar 

  42. Khalil NM, Carraro E, Cótica LF, Mainardes RM (2011) Potential of polymeric nanoparticles in AIDS treatment and prevention. Expert Opin Drug Deliv 8:95–112

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We sincerely thank AISSMS College of Pharmacy, Pune, for providing us the facilities for carrying out research work. We also thank Mylan Pharmaceuticals Limited, Sinnar, for providing tenofovir disoproxil fumarate as a gift sample.

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

SMN, SPK, SJK, and TRP read and approved the final manuscript.

Corresponding author

Correspondence to S. P. Kakad.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nemade, S.M., Kakad, S.P., Kshirsagar, S.J. et al. Development of nanoemulsion of antiviral drug for brain targeting in the treatment of neuro-AIDS. Beni-Suef Univ J Basic Appl Sci 11, 138 (2022). https://doi.org/10.1186/s43088-022-00319-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43088-022-00319-8

Keywords

  • Antiretroviral therapy
  • Nanoemulsion
  • Nose-to-brain delivery
  • Ex vivo diffusion study
  • Cytotoxicity study