A REVIEW ON SOLID LIPID NANOPARTICLES; FOCUS ON EXCIPIENTS AND FORMULATION TECHNIQUESHTML Full Text
A REVIEW ON SOLID LIPID NANOPARTICLES; FOCUS ON EXCIPIENTS AND FORMULATION TECHNIQUES
Ruhi Anjum and P. K. Lakshmi *
G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad- 500028, Telangana, India.
ABSTRACT: Nanotechnology has brought about a significant change in the drug delivery system. A plethora of BCS class II drugs are formulated as solid lipid nanoparticles (SLN) due to its poor solubility and bioavailability and has potential applications in drug delivery system. The formulation of SLN involves use of a different type of surfactants and lipids in different concentrations which has shown a greater impact on various physicochemical parameters such as entrapment efficiency, drug release, particle size, zeta potential, storage and stability of the drug. Apart from its unique size-dependent property, merits and demerits, different excipients characterization technique, scale up, storage and stability are reviewed.
Solid lipid nanoparticles, Surfactant, Lipid
INTRODUCTION: Nanotechnology has shown a wide range of applications in drug delivery, diagnostics, prognostics and in treatment of diseases. It is an emerging branch with an enormous scope which makes the drug targeting more specific in the form of different type of nanoparticles 1, 2. Nanoparticles may be defined as solid particles with a size range of 10-1000 nm in which the drug can be dissolved, encapsulated, entrapped or attached 3, 4. Solid lipid nanoparticles are prepared from lipids which are solid at room temperature and body temperature 5. These comprise of lipid which is biocompatible such as compritol 888, Cetyl alcohol, stearic acid, glyceryl monooleate (GMO), tripalmitin/dynasan, tristearin/ dynasan, etc. and surfactant for emulsification. These are the nanoparticles which have a small size, large surface area, high drug loading capacity and have a great potential application (intravenous, oral, dermal) 6. There are different formulation techniques for the preparation of solid lipid nanoparticles (SLNs) which include high-pressure homogenization, solvent injection, ultra-sonification, microemulsion spray drying 5. This is a potential delivery system for targeted action of cytotoxic drug 7. As solid lipid nanoparticles are biocompatible and biodegradable, hence these are used as the carrier for formulating the wide variety of poorly water-soluble drugs 8. Both hydrophilic and lipophilic drugs are feasible to formulate SLN, and it improves the efficacy of the drug and protects the sensitive drugs from external environmental conditions (water, light) 5. These nanoparticles have good physical stability and low toxicity 9.
Lipids: Lipids are the main ingredient of solid lipid nanoparticles. Usually, the lipids used in the preparation are physiological lipids with low toxicity 5. Before use, the selection of lipid type and the amount is more desirable criteria anyhow there is no specific criteria but based on the solubility of the drug in the lipid. The drug can accommodate in the structural defects of the lipid due to different crystal lattice as lipid polymorphism influences lipid nanoparticle system. More thermo-dynamically stable form is perfect crystalline lattice however less stable form or metastable forms tend to transform into more stable form. Since the drug molecules are accommodated in the structural defects of the crystal thus this transformation from one form to another pose a problem in the development of the solid lipid nanoparticles this will create an issue of drug loading. Burst release on administration and drug expulsion on storage may result due to drug loading and other factor that influences the selection of lipid is the rate at which transition from metastable to stable from takes place and the tendency to form perfect crystalline lattice 10.
Surfactant: The other critical component of solid lipid nanoparticles is surfactant which is amphipathic with lipophilic moiety and hydrophilic moiety which form head and tail of surfactant. These are used to reduce the interfacial tension between the two phases. Most commonly used surfactants are from the family of Pluronic® and Tween® 8.
Surfactants for the preparation of solid lipid nanoparticles are chosen based on several factors: hydrophilic-lipophilic balance (HLB) scale, intended route of administration, role in in-vivo degradation of the lipid, the effect of particle size and lipid modification 10.
FIG. 1: TYPES OF NANOCARRIER
TABLE 1: DIFFERENT TYPES OF LIPIDS USED IN SOLID LIPID NANOPARTICLES
|Fatty acid||Dodecanoic acid, Myristic acid, Palmitic acid, Stearic acid||11|
|Monoglyceride||Glyceryl monostearate (GMS), Glyceryl hydroxy stearate, glyceryl behenate||11|
|Diglycerides||Glyceryl palmitostearate, Glyceryl dibehenate||11,12|
|Caprylate triglyceride, Caprate triglyceride, Glyceryl tristearate/tristearate, Glyceryl trilaurate/trilaurate Glyceryl trimyristate/trimyristin, Glyceryl tripalmitate/tripalmitin, Glyceryl tribehenate/tribehenin||11,12|
|Waxes||Cetyl palmitate, Bees wax||11|
|Soya bean oil, Oleic acid, Medium chain triglycerides (MCT) / caprylic and capric triglycerides, Alpha-tocopherol/vitamin E, Squalene Hydroxy octa-cosanyl, hydroxy stearate Isopropyl myristate||11,12,13|
|Stearyl amine (SA), Benzalkonium chloride, Cetrimide, Cetyl pyridinium chloride, Dimethyl dioctadecyl ammonium bromide (DDAB)||13|
TABLE 2: DIFFERENT TYPES OF SURFACTANTS USED IN SOLID LIPID NANOPARTICLES
|Sodium cholate, sodium taurocholate, sodium taurodeoxycholate, sodium glucocholate, sodium oleate, sodium dodecyl sulphate||13|
|Tween 20, Tween 80, Span 20, Span 85, Tyloxapol, Poloxamer 188, Poloxamer 407, Poloxamer 908, Brij 78, Tego care 450, Solutol HS15||13, 14|
|Egg phosphatidylcholine, soy phosphatidylcholine, Hydrogenated egg Phosphatidylcholine, Hydrogenated soy phosphatidylcholine, Phospholipon 80 H, Phospholipon 90 H||13, 14|
TABLE 3: MERITS AND DEMERITS OF SOLID LIPID NANOPARTICLES
|Biocompatible and biodegradable colloidal carrier||Poor drug loading capacity||11, 12, 16|
|Prevention of degradation of the drug in body fluid due to encapsulation||Drug expulsion after polymeric transition during storage||11, 12, 16|
|Relatively high-water content of the dispersions (70-99%)||12, 16|
|The longer half-life of a drug||Particle growth||14, 15, 16|
|Possibility of sustained release and controlled release of the drug||Unpredictable gelation
|Unexpected dynamics of polymeric transitions||15, 16|
|Drug targeting||Burst release may occur||12, 16|
|Increased drug dissolution, absorption, and drug bioavailability||Difficulty in
|11, 15, 16|
|Feasibility of sterilization and large-scale manufacturing||Appropriate selection of
|15, 12, 16|
TABLE 4: COMMONLY USED FORMULATION TECHNIQUES IN THE PREPARATION OF SOLID LIPID NANOPARTICLES
|High-pressure homogenization||Economical and
established at lab scale
|Energy exhaustive method, biomolecule damage, polydisperse distributions, unconfirmed scalability.||Triamcinolone acetonide acetate, Hydrocortisone, Diazepam, Clotrimazole,
Vitamin-E, Retinol, Stavudine, Cyclosporine, Oxybenzone, γ-Oryzanol,
(Precirol®), Glycerol distearate, Glycerol dibehenate, Cetylpalmitate,
Glyceryl tripalmitate & (Dynasan® 114), Cetyl palmitate, Glyceryl tripalmitate, Glyceryl tripalmitate, Cetyl palmitate and GMS, Glyceryl palmitostearate,
Stearic acid, Tripalmitin,
Cetyl palmitate, Tricaprin,
Glyceryl behenate and Tribehenate (compritol),
Trimyristin (Dynasan 11),
Stearic acid, GMS, Cetyl palmitate, Glyceryl behenate, GMS 17-30
|Ultrasonication-high speed homogenization
solvent evaporation method
|Decrease shear stress, scalable, continuous process, commercially established||Potential metal contamination, extremely energy intensive process, polydisperse distributions||Indomethacin, Vinpocetine,
|Glyceryl behenate and Tribehenaten (compritol),
GMS, Tristearin glyceride,
GMS, Stearic acid,
|The solvent emulsification-diffusion method||Void heat during the production procedure||Biomolecules may get damage||Clobetasol propionate,
Gonadorelin Rifampicin, Isoniazid, Pyrazinamide,
|Supercritical fluid method||Avoid the use of solvents, instead of suspension powder product formed,
mild pressure and temperature conditions
|Very expensive method||Indomethacin and ketoprofen
Bovine serum albumin
|Tristearin, tripalmitin and glyceryl behenate (gelucire-50/13), Trimyristin and glyceryl behenate (Gelucire®-50/02) 40-41|
|Microemulsion method||Little input of mechanical energy, hypothetical stability||Particularly sensitive to change, labor demanding formulation work, low nanoparticles conc.||Curcuminoids, Podophyllotoxin, Verapamil
Tea polyphenol, Cyclosporine A, Insulin, Ketoprofen
|Stearic acid and GMS,
Stearic acid, Cacao butter,
Stearic acid, Stearic acid,
Beeswax and carnauba wax42-48
TABLE 5: SOLID LIPID NANOPARTICLES AS A CARRIER FOR DIFFERENT DRUGS
|Drug||BCS class of drug||Therapeutic
|Darunavir||II||Anti-HIV||GMS/Glyceryl Caprylate||High-pressure homogenization||Ex-vivo studies using everted rat intestine model 50|
|Corneal permeation studies (freshly excised from goat) 51|
|Gemcitabine||III||Anticancer||Stearic acid||Double emulsification||In-vivo drug targeting studies in Wistar rats 7|
|Mometasone furoate||II||Treat skin allergies||GMS||Solvent injection||Ex-vivo skin permeation studies52|
|Ramipril||II||Antihypertensive||GMO||Hot homogenization||In-vitro drug release studies 8|
|Vinpocetine||-||Treat Senile dementia||GMS||Ultrasonic solvent emulsification||Oral pharmacokinetic studies in male rats 53|
|IV||Anti-cancer||Stearic acid, Tripalmitate||Solvent injection||Pharmacokinetic studies in KM mice 54|
|Buspirone||I||Anti-anxiety||Cetyl alcohol||Emulsion evaporation||Pharmacokinetic studies in male Wistar rats 55|
|Clozapine||II||Antipsychotic||Triglycerides||Hot homogenization||Bioavailability studies in male Wistar rats, tissue distribution studies in Swiss albino rats 56|
|Cyclosporine A||II||Immunosuppressant||GMS||Hot homogenization, Microemulsion||Pharmacokinetic studies in young pig 57|
|Hot melt emulsification method||In-situ intestinal absorption studies, in-vivo studies in rats 58|
|Carbamazepine||II||Anticonvulsant||Tristearin||Solvent injection||Maximal electroshock method in male albino Wister rats 59|
|Diazepam||II||Antianxiety agent||Cetyl palmitate||Hot homogenization||61|
|Clotrimazole||II||Antifungal agent||Glyceryl tripalmitate||Hot homogenization||62|
|Isotretinoin||II||Treat acne||Precirol||Hot homogenization||In-vitro skin permeation studies 63|
|Doxorubicin||III||Anticancer agent||Glyceryl Caprate
|Solvent emulsification-diffusion technique||Cell viability assay 36|
|Oridonin||IV||Anticancer agent||Oleic acid, glyceryl monostearate||High-pressure homogenization||Cell culture, cell viability assay 64|
|Indomethacin||II||NSAID||Glyceryl behenate and Tribehenate
|Homogenization method||In-vitro corneal permeation studies 28|
|Piroxicam||II||NSAID||compritol||Pre-emulsion probe sonication method||Ex-vivo skin permeation studies in rat 65|
|Rosuvastatin calcium||II||Treat Primary hyperlipidemia, mixed dyslipidemia, and hypertriglyceridemia.||Stearic acid||Solvent emulsification-diffusion technique||Pharmacokinetics studies in male albino Wistar rat 66|
|Candesartan cilexetil||IV||Antihypertensive||Stearic acid||Modified emulsification-ultrasonication method.”||Pharmacokinetics studies in male albino Wistar rat 67|
Characterization and Evaluation of SLN:
Particle Size: As per the reported studies, usually a combination of surfactant produces smaller particle size compared to one surfactant alone. For example, tween 80 alone might give higher size nanoparticles when compared to tween 80 and poloxamer 188 in combination. This combination gave smaller size particles because tween 80 and poloxamer 188 rapidly covered the new lipid surfaces generated through the shearing process; thus, reducing aggregation and increasing surface area. Also, surface absorption can be altered by a different combination of emulsifier and their HLB value 68. Another report had shown that when poloxamer concentration was varied from 0.5% to 1.5% to obtain stable nano-size particles and their effect on particle size was measured, but it was reported that the poloxamer concentration below 1.5% and above 0.5% was effective in producing smaller size SLN.
Larger size SLNs were obtained by increasing the concentration of poloxamer to 1.5%. This report recommends that an optimum concentration of 1% poloxamer was sufficient to give nano-size particles as it covers the surface of nanoparticles effectively and prevent agglomeration during the process. The high concentration of surfactant should be avoided to prevent the reduction in the entrapment efficiency and also toxic effects associated with a high concentration of surfactants 69, 70.
Increasing the lipid content resulted in a subsequent increase in particle size. The viscosity of the samples is one factor to increase the particle size. The use of a low viscosity lipid phase improves size reduction and enhances stability in SLN production. At higher lipid concentrations, the efficiency of homogenization drops due to the higher viscosity of the sample, resulting in larger size particles. Also, high lipid contents increase the chance of particle contact and subsequent aggregation 71, 72.
In addition to lipid concentration, the number of the fatty acid side chain on lipids plays an important role in particle size distribution 73. In another study of ramipril loaded SLN prepared by using GMS and GMO as a lipid matrix with a different type of surfactant. SLN prepared using GMS has shown large particle size when compared to SLN prepared using GMO. This may be due to the melting point of the lipid; GMS has shown a higher melting point than GMO, which shows slower lipid crystallization from the hot homogenized condition increasing in particle size 8. In addition to lipid concentration, the number of the fatty acid side chain on lipids play an essential role in particle size distribution 73.
Zeta Potential: Zeta potential is one of the important surface characterization techniques as it indicates a repulsive force between particles, to prevent the aggregation of nanoparticles, helps in determining the possible stability and surface charge of the nanoparticulate system 74. Usually, large negative or positive zeta potential value is required for formulation stability, as electrostatic repulsion between particles with same charges avoid aggregation of particles. It was noticed in the previous studies that as the amount of surfactant is increased in the formulation, the zeta potential became more negative. A similar result was reported earlier upon increasing tween 80 concentrations from 0.5 to 1%, which was attributed to the formation of a denser surfactant film. Poloxamer 188 being non-ionic surfactant was able to produce the stable SLN formulation.
Although, non-ionic surfactant might not ionize into a charging group like ionic ones, still demonstrated its zeta potential. The reason behind it might be due to molecular polarization and the adsorption of emulsifier molecule on the charge in the water; it gets absorbed to the emulsion layer of the particle/water interface and electric double layer similar to ionic was formed. Poloxamer 188 was one of the most effective non-ionic surfactants to avoid aggregation in the formulation. In addition to electrostatic stabilization poloxamer, 188 can also provide additional steric stabilization to particles. So, the combined effect of both electrostatic and steric stabilization is expected in the SLN formulations 72. In previous studies, it was found that due to the carboxyl group of stearic acid the formulation which contains stearic acid as the lipid phase has shown negative values of zeta potential67.
Entrapment Efficiency (EE): Entrapment efficiency is a significant factor for characterizing SLN. In earlier studies by Ekambaram P, Sathali AA reported that all SLN formulations showed high entrapment efficiency using a higher concentration of surfactant irrespective of the type of surfactant. Thus, by increasing surfactant concentration may show a positive effect on EE. This might be due to the enhanced solubility of the drug in the lipid by increasing the concentration of the surfactant. The result was in agreement with the results obtained in previous studies, as the formulation in the studies contain span 20 as a surfactant which has lower HLB value this might be the reason why the formulations containing span 20 showed lower entrapment efficiency. Hence, the entrapment efficiency of various SLNs stabilized by different non-ionic surfactants and increased in the order of span 20 > tween 80 > poloxamer 188. 8
The data provided by Rawia M. Khalil et al., suggested that all formulations possessed high EE. The results might be related to the structure of the lipid as drug incorporation capacity is dependent on structure of lipid. Drug expulsion might occur in formulation with lipids, which form highly crystalline particles with a perfect lattice (e.g., non-acid triglycerides); a large number of drugs is incorporated by complex lipid forms which have less perfect crystals with several imperfections provide space too. It was found that compritol and precirol SLNs exhibited the highest entrapment of drug compared to geleol SLNs. This can be due to the difference in composition and chain length of these three lipids used.
Due to the long chain, fatty acids attached to the triglycerides, resulting in increased accommodation of lipophilic drug, thus higher drug EE noticed with compritol and precirol. It was also evident that increasing the amount of surfactant at a constant amount of lipid resulted in a significant gradual decrease in the EE of the produced SLNs. This observed decrease in EE could be explained by partition phenomenon. An increase in the partition of the drug from internal to an external phase of the medium may be due to the high surfactant level in the external phase. The increased solubilization of the drug in the external aqueous phase increased the partition so that more drug can disperse and dissolve in it. In case of the formulation containing geleol as lipid, there was no further decrease in EE upon increasing the poloxamer 188 concentrations signifying that an optimum concentration of surfactant was reached enough to cover up the surface of nanoparticles effectively 72. The higher drug content and entrapment efficiency might be due to the high hydrophobicity due to the long chain fatty acids attached to the triglyceride resulting in high loading of lipophilic drug 75.
Apart from the influence of different lipids and surfactants effect of pH was also found on the EE. The formulations prepared with different fractions of tween 80 and adjusted to different pH values. Indeed, both the fractions of tween 80 in the formulation and the formulation pH had a significant effect on the percentage of drug incorporated within the SLNs. weakly acidic drugs having (pKa of 4.5) demonstrated a pH-dependent EE, consistent with the pH-dependent solubility, which exists predominately in the ionized form above pH 4.5, which will help localize in the aqueous medium. The reported data showed that at all pH values SLNs were stabilized, but with only tween 80, it has shown higher EE. As the fraction of tween 80 in the formulation decreased, a significant decrease in the entrapment of drug in the SLNs was observed at all pH values 76.
In-vitro Drug Release Studies: In recent studies by Ekambaram P, Sathali AA et al., reported that the melting point of lipid, the crystal structure of lipid and HLB value of surfactant affects drug release. Formulations prepared by using GMS as a lipid matrix, with tween 80, poloxamer 188 and span 20 as stabilizers showed a higher drug release. There was an increase in the drug release with the increase in the concentration of the surfactant from the SLN.
But this variation could not be attributed to the formulations prepared by using GMO as a lipid matrix with tween 80, poloxamer 188, and span 20. With an increase in the concentration of surfactant, there was a decrease in the drug release, which could be due to the higher melting point of the GMS than the GMO. The results indicated that formulation with GMS+ poloxamer 188 exhibited a higher drug release and formulation with GMO + span 20 showed a higher decline in the drug release among the three surfactants studied. The reason might be due to the lower HLB value of span 20 (8.6) than the other surfactants used as stabilizers. Thus, the order of the percentage of drug release was span 20 < tween 80 < poloxamer 188 based on the stabilizer. The higher drug release was found for the formulations containing GMS than GMO as a lipid matrix, which showed a more sustained release.
The drug expulsion might occur in GMS when compared to GMO because it has less ordered crystals than GMS and there is less or no drug expulsion from the formulation with GMO because of the imperfect lattice of GMO, leading to the prolonged release of the lipophilic drug. Moreover, GMO has a lower melting point when compared to GMS. The order of the percentage of drug release was GMO < GMS based on the lipid matrix. The drug released was much controlled and slower from the formulation prepared by using GMO with Span 20. 8
In the recent studies, it was reported that among all the glycerides used, the formulation with different lipid melting points might show impact release profile, this was in attribution with recent studies with ibuprofen and acylglycerols differing in melting points. The mean diameter of geleol nanoparticles tested was small which suggested the higher amount released from geleol particles. Increase in the lipid concentration resulted in a subsequent decrease in the percentage drug release. However, for geleol and precirol SLNs further increase of the lipid resulted in a significant decrease in the release. This decrease in release profile observed can be attributed to the higher lipid content, the drug encapsulation thus reducing drug partition in the external phase and consequently its release in the receiver media 72.
SLN has the property of initial burst release but later sustained release of drug from SLNs which suggests that drug might have dispersed in the lipid matrix and the adsorption of drug onto the surface of SLNs need not be considered. It generally depends on the preparation procedure. After the organic solvent had been evaporated, the drug gets dissolved in the lipidic Nanoemulsion. The rapid quenching of the nanoemulsion might not have allowed the drug to crystallize, and the drug gets trapped in the solid lipid 77.
Storage and Stability: SLNs have been used in different dosage forms such as oral, topical, etc using various drugs. Some drugs are temperature and light sensitive, and several studies have shown that light and temperature have an impact on the stability of SLN, it may induce particle growth. To keep SLN and dosage form stable it should be stored at 4°C and in dark environment 16, 78. The way to increase its stability is to convert it into spray dried form another way to increase the stability is by lyophilization. In the case of lyophilization done without cryoprotectants may cause the formation of aggregates in the final product. The commonly used cryoprotectants are trehalose, glucose, maltose, sucrose, and sorbitol. Trehalose was found to be the most effective cryoprotectant for preventing the drug expulsion upon reconstitution 79, 80, 81.
Scale Up of Solid Lipid Nanoparticles: Nanomedicine products are superior to conventional drug delivery system in their therapeutic performance. Hence, they are highly in demand. All the methods described for the production of SLN are either bottom-up methods or top-down methods. Top-down methods are adopted at the industrial level as bottom-up methods require removal of the residual solvents. There are some of the components associated with the scale-up of SLNs from the bench to the market. They are:
- Nature of material.
- Generally regarded as safe (GRAS) status.
- Toxicological features associated with the shape and size of SLN.
For balancing the multi-component system at large scale, one has to be careful before selecting the material, solvent, procedure, cost and the acceptability of finished product by clinician and patients. After the product is optimized, the product has to go through different steps 82.
FIG. 2: SCALE-UP OF SOLID LIPID NANOPARTICLES
CONCLUSION: SLN formulations are widely used to deliver lipophilic drugs. This system has shown potential to improve gastrointestinal absorption and oral bioavailability of many oral drug delivery systems apart from its applications in topical drug delivery. This delivery system is used for sustained, controlled and targeted drug delivery systems.
Wide ranges of excipients are available in the market for the formulation of SLN, but these excipients used should be approved by the regulatory authority. The attractive feature of this formulation system is that it can be easily scaled up. Toxicity studies are required for the excipients with doubtful, unapproved and if used in higher quantities.
CONFLICT OF INTEREST: Nil
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How to cite this article:
Anjum R and Lakshmi PK: A review on solid lipid nanoparticles; focus on excipients and formulation techniques. Int J Pharm Sci & Res 2019; 10(9): 4090-99. doi: 10.13040/IJPSR.0975-8232.10(9).4090-99.
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