Encyclopedia
A number of studies have used the solvent injection method to produce solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), and various drugs have been loaded into these carriers for different applications. Here, we present major SLNs and NLCs systems and details of applications that use this method in 2006-2020. Furthermore, we discuss the effects of various parameters of solvent injection method on SLNs and NLCs production and propose some suggestions regarding future developments and applications.
- Lipid Nanoparticles
- Nanostructured Lipid Carriers
- Drug Delivery
- Aqueous phase
- Organic phase
- Emulsifier
1. Introduction
SLNs and NLCs have been produced using numerous methods, such as high-pressure homogenization, emulsion/solvent evaporation, phase inversion, and microemulsion [1][2][3][4][5]. The solvent injection is an alternative method for preparing SLNs and NLCs. It was first used in 1973 and has been one of the effective approaches to prepare liposomes [6]. Many studies have been performed on liposome preparation using this method. In 2003, Schubert et al. first used solvent injection to prepare SLNs and NLCs [7]. The advantages of this method include a fast production process and easiness of handling [8]. In addition, it can be easily performed in laboratories as no complicated instruments, such as high-pressure homogenizers or high-speed stirrers are required [9]. Some studies have investigated the solvent injection method for the production of SLNs and NLCs for different applications [10]. Others have investigated the effects of solvent injection process parameters on the physicochemical properties of SLNs and NLCs [11][12]. In this entry, we summarize important developments made up until now using this method, discuss the effects of various parameters of solvent injection method on SLNs and NLCs production, and propose some suggestions regarding future developments and applications.
2. Preparation of SLNs and NLCs Using SSolvent Injection Method (2006-2020)
Table 1 summarizes the major features of studies that utilized the solvent injection method, including the lipids used, drugs incorporated, and primary outcomes. References can be found in the original article [13].
Table 1. Overview of lipids, emulsifiers, drugs, and solvents used to prepare SLNs and NLCs by solvent injection method and their significant outcomes.
| Lipid(s)/Emulsifier(s) | Drug or Active Ingredient | Solvent | Outcomes | Year |
|---|---|---|---|---|
| Lipoid®S 100/sucrose fatty acid ester | Paclitaxel | Acetone | PS: 188 nm, PDI: 0.396, and EE: 92.2%SLNs showed sustained-release for 14 days (in vitro) | 2006 |
| Palmitic or stearic acid/phosphatidylcholine | Idebenone | Ethanol | PS: 170–183 nm, PDI: 0.113–0.134, and EE: 83–86% SLNs showed sustained-release for 7 days (in vitro) SLNs increased drug protecting activity against free radical-induced oxidative damage of astrocyte cells |
2006 |
| Stearic acid, soya lecithin/poloxamer 188 | Paclitaxel | Diethyl ether | Drug amount and emulsifier concentration were varied to get the optimized SLNs (PS: 113 nm, PDI: 0.156, and EE: 89.0%) SLNs had lower toxicity on HepG2 cell than free drug SLNs was stable for 90 days |
2009 |
| Tristearin, soya lecithin/polysorbate 80 | Miconazole nitrate | Ethanol | Parameters were varied to obtain optimized NLCs (PS: 206 nm, PDI: 0.21, and EE: 90.9%) NLCs-based hydrogels increased skin retention 10-fold as compared with miconazole suspension and miconazole hydrogel |
2010 |
| Tristearin/polysorbate 80 | Hepatitis B surface antigen (HBsAg) | Acetone | HBsAg was loaded onto SLNs surface Mannosylated SLNs (PS: 96.6 nm, PDI: 0.05, and EE: 64.5%) SLNs showed better cellular uptake, lesser toxicity, and greater immune response Subcutaneous administration of SLNs was potential for vaccine delivery against hepatitis B |
2010 |
| Monostearin/poloxamer 407 | Simvastatin | Isopropanol | A 23 factorial design was performed to optimize SLNs (PS: 259 nm, EE: 75.8%) SLNs showed sustained-release for 55 h (in vitro) |
2010 |
| Tristearin, soya lecithin/polysorbate 80 | Doxorubicin hydrochloride | Acetone + ethanol | Mannosylated SLNs (PS: 360 nm, PDI: 0.135, and EE: 70.3%) Mannosylated SLNs showed sustained-release in mice. They delivered a higher dug concentration to the tumor mass. |
2010 |
| Glycerol monostearate, oleic acid/poloxamer 407 | Simvastatin | Isopropanol | A 23 factorial design was performed to optimize NLCs (PS: 212 nm, PDI: 0.344, and EE: 84%) NLCs showed a higher bioavailability than drug suspension and drug-loaded SLNs |
2011 |
| Monostearin, soya lecithin/poloxamer 188 | Puerarin | Methanol + ethanol | SLNs enhanced oral bioavailability of the drug 3 times Tissue concentration of the drug increased, particularly the hearts and brain after oral administration of SLNs |
2011 |
| Stearylamine, soya lecithin, α-tocopherol/poloxamer 188 |
Paclitaxel | Diethyl ether | Drug amount and emulsifier concentration were varied to obtain optimized SLNs (PS: 96 nm, PDI: 0.162, EE: 75.4%, and DL: 31.5%) SLNs increased oral bioavailability of the drug 10 times in mice |
2011 |
| Monostearin/Lecithin + poloxamer 188 | Ondansetron hydrochloride | Ethanol | A 23 factorial design was performed to get the optimized SLNs (PS: 320 nm, PDI: 0.296, and EE: 49.7%) The SLNs effectively delivered the drug to the brain by intranasal administration on rabbits |
2012 |
| Stearic acid/polysorbate 80 | Cytarabine | Isopropanol | Drug and lipid was conjugated prior to SLNs preparation - PS: 137 nm, PDI: 0.151, and EE: 58.4% SLNs showed drug sustained-release (3 days in vitro) and increased toxicity on leukemic EL-4 cells as compared with drug solution |
2012 |
| Glyceryl behenate (Compritol® 888 ATO)/poloxamer 407 | Terbinafine hydrochloride | Isopropanol | A 33 factorial design was performed to get the optimized SLNs (PS: 274 nm, PDI: 0.32, and EE: 74.6%) SLN-based gel was more effective than a commercial product when applying in rats (pharmacodynamics studies) - SLNs were stable for 90 days |
2013 |
| Monostearin/polysorbate 80 + poloxamer 188 | Thymoquinon | Ethanol | Box-Behnken design was used to optimize the SLNs (PS: 166 nm, EE: 71.6%) Oral bioavailability increased 5-fold in rats as compared with drug suspension |
2013 |
| Dynasan 114, soya phosphatidylcholine/poloxamer 407 |
Adefovir dipivoxil | Isopropanol | Different process and formulation parameters were evaluated to optimize SLNs (PS: 267 nm, EE: 73.5%, and DL: 2%) SLNs increased oral bioavailability 2- and 1.5-fold as compared with micro-suspension and nanosuspension, respectively SLNs increased drug accumulation in liver, kidneys, intestine, and stomach. |
2013 |
| Cetyl alcohol/polysorbate 80 | Andrographolide | Ethanol | PS: 154 nm, PDI: 0.172, EE: 91.4%, and DL: 18.6% SLNs increased oral bioavailability (3.41-fold) and antitumor activity as compared with the drug suspension |
2014 |
| Tristearin, soya lecithin/polysorbate 80 | Adapalene | Acetone + ethanol | PS: 148 nm, PDI: 0.169, and EE: 89.9% SLNs-based gel showed sustained-release in vitro |
2014 |
| Tristearin, hydrogenated soya phosphatidylcholine/polysorbate 80 | Aceclofenac | Ethanol | SLNs was conjugated with chondroitin sulfate (CS-SLNs) with PS: 154 nm, PDI: 0.403, and EE: 65.4% SLNs and CS-SLNs increased drug amount in the inflammatory knee joint (2- and 10-fold as compared with the drug solution, respectively) after IV administration in rats |
2014 |
| Monostearin/polysorbate 80 | Halobetasol propionate | Isopropanol | A 32 full factorial design was applied to optimize the SLNs (PS: 200 nm and EE: 93%) SLNs-based carbopol gels prolonged drug release up to 12 h on human cadaver skin, reduced systemic uptake, increased drug accumulation in skin, and were nonirritant to rabbit skin |
2014 |
| Monostearin or stearic acid/polysorbate 80 or poloxamer 188 | Tamoxifen | Methanol | Lipid and emulsifier were varied to obtain optimized SLNs (PS: 130 nm, PDI, 0.231, and EE: 86.1%) SLNs increased oral bioavailability (1.6-fold) following oral administration in rats |
2014 |
| Monostearin, Tefose-63/polysorbate 80 | Mometasone furoate | Ethanol | SLNs was optimized (PS: 124 nm, and EE: 55.6%) SLNs-based carbopol gel increased skin deposition 2.67- and 20-fold as compared with a marketed cream and drug-loaded gel SLNs-based gel increased skin permeability 15.2-fold as compared with a marketed cream |
2014 |
| Tristearin, distearoyl-phosphatidyl ethanolamine/polysorbate 80 | Paclitaxel | Acetone + ethanol | Mannosylated SLNs (PS: 254 nm, PDI: 0.312) Mannosylated SLNs improved antiproliferative efficacy in lung cancer cells. They delivered a higher drug concentration to alveolar cells after IV injection in rats |
2015 |
| Tristearin, soya lecithin, stearylamine/polysorbate 80 | Rifampicin | Ethanol | Drug-loaded SLNs was coupled with lactoferrin to enhance SLNS delivery to lung (PS: 271 nm, PDI: 0.124, and EE: 68.4%) In vivo biodistribution study: lactoferrin-coupled SLNs had 47.7% drug uptakes by the lungs (3.05 times higher than uncoupled SLNs) following IV injection in rats |
2015 |
| Tripalmitin/polysorbate 80 | Sumatriptan | Ethanol | A 23 randomized full factorial design was performed to optimize the SLNs (PS: 236 nm, and EE 91.3%) SLNs showed a 4.54-fold increase in brain/blood ratio of drug (2 h after oral administration in rats) SLNs improved anti-migraine potential in behavioral studies |
2015 |
| Tristearin, hydrogenated soya phosphatidylcholine/polysorbate 80 | Nifedipine | Ethanol | SLNs was further coated with polysorbate 80 (PS: 121 nm, PDI: 0.261, and EE: 71.5%) Coated-SLNs increased bioavailability about 5- and 2-fold as compared with free drug and uncoated SLNs, respectively (IV administration in rats) Coated-SLNs increased drug accumulation in brain |
2015 |
| Compritol® 888 ATO, Gelucire® 50/13/polysorbate 80 | Resveratrol | Ethanol | Box–Behnken design was applied to optimize SLNs (PS: 191 nm, PDI: 0.156, and EE: 73.7%) SLNs increased oral bioavailability nearly 5-fold in rats as compared with resveratrol suspension Pharmacodynamic data showed a decrease in the serum biomarker enzymes as compared with control and marketed formulation (against paracetamol-induced liver cirrhosis) |
2016 |
| Monostearin/poloxamer 188 | Asiatic acid | Ethanol | A Box–Behnken design was used to optimize the formulations (PS: 237 nm, EE: 64.4%, and DL: 31.9%) SLN increased oral bioavailability 2.5-fold following oral administration in rats |
2016 |
| Vitamin B6-stearic acid conjugation/polysorbate 80 | Doxorubicin | Ethanol | Vitamin B6 was conjugated with lipid to modify charge of SLNs (PS: 114 nm, PDI: 0.101, and DL: 7.1%) Vitamin B6-modified SLNs had an increased therapeutic efficacy and lower toxicity in tumor-bearing rats as compared with free drug Vitamin B6-modified SLNs prolonged drug circulation in blood and increased drug accumulation to tumor site in rats |
2016 |
| Sophorolipid/poloxamer 407 and 188 | Rifampicin + dapsone | Ethanol | Five different polymers were used to stabilize SLNs, and poloxamer 407 and 188 were the best options - There was no in vivo study |
2018 |
| Tripalmitin, Phosal® 53MCT/polysorbate 80 | Ondansetron hydrochloride | Ethanol | Various parameters were investigated to get the optimized NLCs (PS: 185 nm, PDI: 0.214, EE: 93.2%, and DL: 10.43%) NLCs showed sustained-release in vitro and in vivo for up to 4 days following subcutaneous administration in rats |
2019 |
| YSK05, cholesterol, DMG-PEG2K | siRNA | Ethanol | NLCs were subjected to post-treatment using an integrated baffle device (PS: 33 nm and EE: 90%) The siFVII knocked down the plasma coagulation factor VII at mice liver tissue more than 80% (IV injection, mice) |
2020 |
| Compritol® 888 ATO, oleic acid/poloxamer 407 | Temazepam | Acetone + ethanol | A 42 full factorial design was applied to optimize NLCs (PS: 307 nm, PDIL 0.09, and EE: 75.2%) NLCs increase oral bioavailability nearly 3-fold in rats as compared with temazepam suspension NLCs improved brain uptake of 99mTc-temazepam |
2020 |
| Stearic acid, phosphatidylcholine | Alpha-tocopherol | Ethanol | Various parameters were evaluated to optimize SLNs (PS: 175 nm, EE: 90.9%, and DL: 59.4%)No in vivo study was conducted | 2020 |
Particle sizes (PSs), polydispersity indices (PDIs), entrapment efficiencies (EEs), and drug loadings (DLs) are for optimized SLNs and NLCs.
3. Effect of Process Parameters on SLNs and NLCs Produced by Solvent Injection Method
3.1. Aqueous Phase
The pH, temperature, and viscosity of an aqueous phase may critically influence SLNs and NLCs, particularly when drugs exhibit pH-dependent solubility. Details can be found in Figure 2 of the original article [13].
3.2. Organic Phase
The organic phase consists of drug and lipid mixtures dissolved in a water-miscible solvent or solvent mixture. Here, we summarize the influences of solvent type on SLNs and NLCs. For the solvent injection method, diffusion of organic solvent is a critical factor, and thus, the appropriate solvent selection is important. Details can be found in Figure 2 of the original article [13].
3.3. Ratio of Aqueous Phase to Organic Phase
Overall, the relative ratio of aqueous phase to organic phase (Va/Vo) does not considerably affect PSs or PDIs unless it exceeds a critical value. Details can be found in Figure 3 of the original article [13].
3.4. Dispersion Energy
Sonication is frequently used to supply dispersion energy to produce SLNs and NLCs. Overall, the use of short sonication times (2–4 min) is favored for reducing PS and PDI slightly. Longer sonication times should be carefully evaluated because they may have undesirable effects, such as increased PS and PDI or decreased EE and DL.
4. Effect of Formulation Parameters on SLNs and NLCs Produced by Solvent Injection Method
4.1. Total Lipid Concentration
It is important to use an appropriate concentration of lipid in the organic phase. As long as PS and PDI remain within accepted ranges, this concentration can be maximized. Details can be found in Table 3 of the original article [13].
4.2. Liquid Lipid Level
The incorporation of liquid lipids at appropriate levels is beneficial to NLCs with respect to PS, PDI, EE, and DL. Details can be found in Table 4 of the original article [13].
4.3. Drug Hydrophilicity and Drug Amount
Initial drug amounts critically affect the properties of SLNs and NLCs, particularly EE and DL. There is a range in which increasing the initial drug amount improves EE and DL and does not significantly change PS or PDI. One may select the highest initial drug amounts in this range to incorporate drugs into SLNs and NLCs. Details can be found in Table 5 of the original article [13].
4.4. Emulsifier
Although there are differences in the literature, emulsifiers are considered crucial for the preparation of SLNs and NLCs using the solvent injection method. The use of emulsifiers at high concentrations does not favor SLNs or NLCs formation due to increases in PS and PDI, and in some cases, increases in EE and DL. Thus, emulsifiers should be used in their appropriate ranges, usually 0.1–0.5%, and if possible, at low concentrations. Details can be found in Figure 4 of the original article [13].
5. Summary
This entry presents most of the critical issues concerning the preparation of SLNs and NLCs using the solvent injection method. Studies on SLNs and NLCs are certain to be performed due to their potential applications for drug delivery. The solvent injection method requires further investigation as a means of preparing SLNs and NLCs at commercial levels.
The entry is from 10.3390/molecules25204781.
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