Ｒｅｓｅａｒｃｈ?。幔洌觯幔睿悖澹恚澹睿簟。铮睢。螅铮欤椋洹。欤椋穑椋洹。睿幔睿铮穑幔颍簦椋悖欤澹蟆。幔蟆。睿澹鳌。悖幔颍颍椋澹颉。铮妗。洌颍酰纭。洌澹欤椋觯澹颍。螅螅簦澹?/h1>
2009-10-16 09:21ＣＨＥＮＴｏｎｇｋａｉＬＩＹｕａｎＬＩＮＨｕａｑｉｎｇ
中國醫(yī)藥導(dǎo)報 2009年24期 關(guān)鍵詞：載體
ＣＨＥＮ?。裕铮睿纾耄幔椤。蹋伞。伲酰幔睢。蹋桑巍。龋酰幔瘢椋睿?/p>
[Abstract] In recent years, the SLNs have been reported as potential drug carrier systems. They offer the possibility of controlled drug release and drug targeting and produce protection of incorporated active compounds against degradation, which combine the advantages of other traditional collodial systems(i.e. microemulsions, liposomes and polymeric nanoparticles). SLNs formulations for various application routes(oral, parenteral, dermal, pulmonary, ocular) have been developed and thoroughly characterized in vitro and in vivo. This paper is focused on general ingredients, the preparation, application routes and development prospect.
[Key words] Solid lipid nanoparticles; Carrier; Oral administration; Transdermal administration
[CLC number] R966 [Document code]A [Article ID]1673-7210(2009)08(c)-010-03
固體脂質(zhì)納米粒給藥系統(tǒng)新載體的研究進展
陳桐楷,李 園,林華慶
(廣東藥學(xué)院,廣東省藥物新劑型重點實驗室,廣州 510006)
[摘要] 固體脂質(zhì)納米粒是近年來很受重視的一種新型藥物傳遞載體,它綜合了傳統(tǒng)膠體給藥系統(tǒng)如乳劑、脂質(zhì)體及聚合物納米粒等的優(yōu)點,具有靶向、控釋、提高藥物穩(wěn)定性、毒性小、可大批量生產(chǎn)等特性,可供多途徑給藥。本文就近年來固體脂質(zhì)納米粒的組成、制備方法、在給藥途徑中的應(yīng)用以及發(fā)展前景作一綜述。
[關(guān)鍵詞] 固體脂質(zhì)納米粒;載體;口服給藥;經(jīng)皮給藥
Recently, solid lipid nanoparticles (SLNs) have gained increasing attention as a promising colloidal carrier system, particularly for lipophilic drugs. SLNs are high melting point lipid as a solid core coated by surfactants such as lecithin, Tween-80. Thus, lipophilic drugs can be highly efficiently incorporated in the lipid core of SLNs. The solid core of SLNs, instead of fluid core of liposomes and emulsions, allows the prolonged and controlled release of drugs and may protect the incorporated drugs against chemical degradation[1].
It has been claimed that SLNs combine the advantages and avoid the disadvantages of other colloidal carriers, such as controlling drug release and drug targeting to decrease the drug toxicity, high temporal and physical stability, high loading capacities, incorporation of lipophilic and hydrophilic drugs, no biotoxicity of the carrier, avoidance of organic solvents, no problems with respect to large scale production and sterilization[2].
1 Production of SLNs
1.1 High pressure homogenization
1.1.1 Hot homogenization Hot homogenization is carried out at temperatures above the melting point of the lipid and can therefore be regarded as the homogenization of an emulsion[3]. A pre-emulsion of the drug loaded lipid melt and the aqueous emulsifier phase is obtained by high-shear mixing device. The hot pre-emulsion is then processed in a temperature controlled high pressure homogeniser, generally a maximum of three cycles at 500 bar are sufficient[4].
1.1.2 Cold homogenization The Cold homogenization is a suitable technique for processing temperature labile drugs or hydrophilic drugs. Here, lipid and drugs are melted together and then rapidly ground under liquid nitrogen forming solid lipid microparticles. A pre-suspension is then homogenized at or below room temperature forming SLNs, the homogenizing conditions are always five cycles at 500 bar[5].
1.2 Solvent diffusion method
An important advantage of this method is the avoidance of heating during the preparation, which makes it suitable for the incorporation of highly thermolabile drugs[6]. The present study demonstrated that the solvent diffusion method in a W/O miniemulsion system favors the formation of SLN with smaller particle size and higher drug loading capacity. Such properties can substantially enhance the target capability and oral bioavailability of the SLN. This method presented a potential prospect in the preparation of lipid nanoparticles[7].
1.3 Microemulsion
Microemulsions as two-phase systems are composed of an inner and outer phase. SLNs are made by stirring an optically transparent mixture at 65–70℃ which is typically composed of a low melting fatty acid, an emulsifier, coemulsifiers and water. The hot microemulsion is dispersed in cold water (2–3℃) under stirring. Typical volume ratios of the hot microemulsion to cold water are in the range of 1∶25 to 1∶50. The dilution process is critically determined by the composition of the microemulsion[8].
1.4 Membrane contactors
Membrane contactors have known recently an increasing interest[9]. Catherine et al[10] used this method to prepare vitamin E-loaded SLNs and the influence of process parameters on the particle size and on the lipid phase flux was investigated. The advantages of this new process for the preparation of SLN are shown to be its facility of use, the control of the SLNs size by an appropriate choice of process parameters and its scaling-up abilities.
2 Administration routs
2.1 Oral administration
The SLNs in improving bioavailability of orally administered drug compounds has been demonstrated in the clinic[11]. R. Pandey et al[12] evaluated the chemotherapeutic potential of oral solid lipid nanoparticles (SLNs) incorporating rifampicin, isoniazid and pyrazinamide against experimental tuberculosis. Their findings suggest that SLNs offer an economical and patient friendly approach for the administration of anti-TB drugs, bearing a high chemotherapeutic potential.
2.2 Parenteral administration
The main features of SLNs with regard to parenteral administration are the excellent physical stability, protection of incorporated labile drugs from degradation, controlled drug release depending on the incorporation model, good tolerability and site-specific targeting[13]. Because of their small size, SLN may be injected intravenously and used to target drugs to particular organs. The particles, as with all intravenously injected and colloidal particulates, are cleared from the circulation by the liver and spleen[14].
2.3 Transdermal administration
SLNs have shown great potential as novel drug carrier for dermal and transdermal system[15]. It has been found in vitro that SLNs have UV reflecting properties. The use of physiological components in SLNs is a clear advantage over existing UV protective systems with respect to skin penetration and potential of skin toxicity. Wissing et al[16] studied on the comparison of two different formalations (SLNs and conventional O/W emulsion) as carrier systems for the molecular sunscreen oxybenzone. Their studies showed clearly that incorporation of the molecular sunscreen oxybenzone in SLNs decreased the rate of release compared to equally sized emulsion by up to 50%. Therefore, SLNs as novel UV sunscreen system offer two main advantages[17]. Firstly, SLNs act as physical sunscreens on their own, the incorporation of potentially hazardous molecular sunscreen can be decreased while maintaining the sun protection factor. For another thing, SLNs are able to provide a sustained release carrier system, therefore the sunscreen remains longer on the surface of the skin where it is intended to act.
2.4 Pulmonary administration
For both topical and systemic administration of drug through the pulmonary route, nanoparticulate formulations offer several important advantages when compared to more traditional microparticlessuspensions. If a water-insoluble drug is intended for immediate action, nanoparticles will result in a bioavailability enhancement, attributable to either better drug delivery, more rapid dissolution or increased residence time in the lung [18]. Chattopadhyay et al[19] showed that lipid nanosuspensions were successfully aerosolized at efficiencies and aerosol particle size distributions sufficient to enable delivery to the lung for either topical applications or systemic delivery. The particle size distribution of the aerosol was consistent with minimal oropharyngeal deposition and delivery to the peripheral lung for uptake by the systemic circulation.
3 Summary and outlook
The SLNs are attractive carriers for topical cosmetic and pharmaceutical products. They possess the potential to develop as the new generation of carrier systems after the liposomes. However, despite the fact that the use of lipid particles for topical administration is very promising and a highly attractive application area, further basic research needs to be done. For example, it is highly desirable to have a much better understanding of the reasons for formation of certain lipid modifications, the effect of surfactants used on these modifications, and their transition during storage. Interesting work on these effects has recently been published[20]. Also, a better understanding is needed of how lipid nanoparticles modify drug penetration into the skin, how lipid particles interact with the lipids of the stratum corneum, and how they then affect drug penetration. Apart from application of lipid nanoparticles to the skin, future research should also consider mucosal applications. To achieve these goals, more research groups need to focus on this area, as has happened for oral and parenteral administration of lipid nanoparticles.
[References]
[1]E Merisko-Liversidge, GG Liversidge, ER Cooper, Nanosizing: a formulation approach for poorly-water-soluble compounds[J].Eur J Pharm Sci,2003,18(2):113-120.
[2]Worle G,Siekmann B,Bunjes H. Effect of drug loading on the transformation of vesicular into cubic nanoparticles during heat treatment of aqueous monoolein/poloxame dispersions[J].Eur J Pharm Biopharm, 2006,63:128-133.
[3]Xia Q, Lu Y, Gu N.Controlable preparation of 10 nm solid lipid nanoparticles based on phase behaviors of drug-loading hot microemulsions[J].Nanoteeh,2005,1:176-178.
[4]Lim S, Kim C. Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid[J].International Journal of Pharmaceutics,2002,243:135-146.
[5]CM Keck, RH Muller.Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation[J].Eur J Pharm Biopharm,2006, 62(1):3-16.
[6]M Trotta, F Debemardi, O Caputo. Preparation of solid lipid nanoparticles by a solvent emulsification-diffusion technique[J]. International Journal of Pharmaceutics, 2002, 233:121-128.
[7]Hong Y, Huang L, Du Y, et al. Solid lipid nanoparticles prepared by solvent diffusion method in a nanoreactor system[J].Colloids and Surfaces B:Biointerfaces, 2008, 61:132-137.
[8]Chiara Dianzani, Roberta Cavalli, Gian Paolo Zara, etal.Cholesteryl butyrate solid lipid nanoparticles inhibit adhesion of human neutrophils to endothelial cells[J].British Journal of Pharmacology,2006,148:648-656.
[9]E Drioli, A Criscuoli, E Curcio. Membrane contactors and catalytic membrane reactors in process intensification[J].Chem Eng Technol, 2003, 26:975-981.
[10]Catherine Charcosset, Assma El-Harati, Hatem Fessi. Preparation of solid lipid nanoparticles using a membrane contactor[J].Journal of Controlled Release, 2005,108:112-120.
[11]O Kayser, C Olbrich, V Yardley, et al. Formulation of amphotericin B as nanosuspension for oral administration[J].Int J Pharm,2003,254(1):73-75.
[12]Rajesh Pandey, Sadhna Sharma, GK Khuller. Oral solid lipid nanoparticle-based antitubercular chemotherapy[J].Tuberculosis,2005, 85:415-420.
[13]SA Wissing, O Kayser, RH Muller. Solid lipid nanoparticles for parenteral drug delivery[J].Advanced Drug Delivery Review,2004,56(9):1257-1272.
[14]Freitas C, Muller R. Spray-drying of solid lipid nanoparticles(SLN)[J].Eur J Pharm Biopharm, 2008, 46:145-151.
[15]Wang JX, Zhang ZR. Research and development of solid lipid nanoparticles [J].Chin Pharm J, 2001,36(2):73-76.
[16]SA Wissing, RH Muller Solid lipid nanoparticles as carrier for sunscreens: in vitro release and in vivo skin penetration[J]. Journal of Controlled Release, 2002, 81:225-233.
[17]RH Muller, M Radtke, SA Wissing. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers(NLC) in cosmetic and dermatological preparations[J]. Advanced Drug Delivery Reviews,2002,54 (1):131-155.
[18]B.E. Rabinow. Nanosuspensions in drug delivery[J].Nat Rev Drug Discov,2004,3:785-796.
[19]P Chattopadhyay, BY Shekunov, D Yimb. Production of solid lipid nanoparticle suspensions using supercritical fluid extraction of emulsions (SFEE)for pulmonary delivery using the AERx system[J].Advanced Drug Delivery Reviews,2007,59:444-453.
[20]H Bunjes, K Westesen.Stabilizers may decrease the amount of supercooling in Lipid Nanoparticle dispersions, in: Proceedings of the 4th World Meeting, ADRITELF/APGI/ APV,2002:671-672.
(Received date:2009-02-24)
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[Abstract] In recent years, the SLNs have been reported as potential drug carrier systems. They offer the possibility of controlled drug release and drug targeting and produce protection of incorporated active compounds against degradation, which combine the advantages of other traditional collodial systems(i.e. microemulsions, liposomes and polymeric nanoparticles). SLNs formulations for various application routes(oral, parenteral, dermal, pulmonary, ocular) have been developed and thoroughly characterized in vitro and in vivo. This paper is focused on general ingredients, the preparation, application routes and development prospect.
[Key words] Solid lipid nanoparticles; Carrier; Oral administration; Transdermal administration
[CLC number] R966 [Document code]A [Article ID]1673-7210(2009)08(c)-010-03
固體脂質(zhì)納米粒給藥系統(tǒng)新載體的研究進展
陳桐楷,李 園,林華慶
(廣東藥學(xué)院,廣東省藥物新劑型重點實驗室,廣州 510006)
[摘要] 固體脂質(zhì)納米粒是近年來很受重視的一種新型藥物傳遞載體,它綜合了傳統(tǒng)膠體給藥系統(tǒng)如乳劑、脂質(zhì)體及聚合物納米粒等的優(yōu)點,具有靶向、控釋、提高藥物穩(wěn)定性、毒性小、可大批量生產(chǎn)等特性,可供多途徑給藥。本文就近年來固體脂質(zhì)納米粒的組成、制備方法、在給藥途徑中的應(yīng)用以及發(fā)展前景作一綜述。
[關(guān)鍵詞] 固體脂質(zhì)納米粒;載體;口服給藥;經(jīng)皮給藥
Recently, solid lipid nanoparticles (SLNs) have gained increasing attention as a promising colloidal carrier system, particularly for lipophilic drugs. SLNs are high melting point lipid as a solid core coated by surfactants such as lecithin, Tween-80. Thus, lipophilic drugs can be highly efficiently incorporated in the lipid core of SLNs. The solid core of SLNs, instead of fluid core of liposomes and emulsions, allows the prolonged and controlled release of drugs and may protect the incorporated drugs against chemical degradation[1].
It has been claimed that SLNs combine the advantages and avoid the disadvantages of other colloidal carriers, such as controlling drug release and drug targeting to decrease the drug toxicity, high temporal and physical stability, high loading capacities, incorporation of lipophilic and hydrophilic drugs, no biotoxicity of the carrier, avoidance of organic solvents, no problems with respect to large scale production and sterilization[2].
1 Production of SLNs
1.1 High pressure homogenization
1.1.1 Hot homogenization Hot homogenization is carried out at temperatures above the melting point of the lipid and can therefore be regarded as the homogenization of an emulsion[3]. A pre-emulsion of the drug loaded lipid melt and the aqueous emulsifier phase is obtained by high-shear mixing device. The hot pre-emulsion is then processed in a temperature controlled high pressure homogeniser, generally a maximum of three cycles at 500 bar are sufficient[4].
1.1.2 Cold homogenization The Cold homogenization is a suitable technique for processing temperature labile drugs or hydrophilic drugs. Here, lipid and drugs are melted together and then rapidly ground under liquid nitrogen forming solid lipid microparticles. A pre-suspension is then homogenized at or below room temperature forming SLNs, the homogenizing conditions are always five cycles at 500 bar[5].
1.2 Solvent diffusion method
An important advantage of this method is the avoidance of heating during the preparation, which makes it suitable for the incorporation of highly thermolabile drugs[6]. The present study demonstrated that the solvent diffusion method in a W/O miniemulsion system favors the formation of SLN with smaller particle size and higher drug loading capacity. Such properties can substantially enhance the target capability and oral bioavailability of the SLN. This method presented a potential prospect in the preparation of lipid nanoparticles[7].
1.3 Microemulsion
Microemulsions as two-phase systems are composed of an inner and outer phase. SLNs are made by stirring an optically transparent mixture at 65–70℃ which is typically composed of a low melting fatty acid, an emulsifier, coemulsifiers and water. The hot microemulsion is dispersed in cold water (2–3℃) under stirring. Typical volume ratios of the hot microemulsion to cold water are in the range of 1∶25 to 1∶50. The dilution process is critically determined by the composition of the microemulsion[8].
1.4 Membrane contactors
Membrane contactors have known recently an increasing interest[9]. Catherine et al[10] used this method to prepare vitamin E-loaded SLNs and the influence of process parameters on the particle size and on the lipid phase flux was investigated. The advantages of this new process for the preparation of SLN are shown to be its facility of use, the control of the SLNs size by an appropriate choice of process parameters and its scaling-up abilities.
2 Administration routs
2.1 Oral administration
The SLNs in improving bioavailability of orally administered drug compounds has been demonstrated in the clinic[11]. R. Pandey et al[12] evaluated the chemotherapeutic potential of oral solid lipid nanoparticles (SLNs) incorporating rifampicin, isoniazid and pyrazinamide against experimental tuberculosis. Their findings suggest that SLNs offer an economical and patient friendly approach for the administration of anti-TB drugs, bearing a high chemotherapeutic potential.
2.2 Parenteral administration
The main features of SLNs with regard to parenteral administration are the excellent physical stability, protection of incorporated labile drugs from degradation, controlled drug release depending on the incorporation model, good tolerability and site-specific targeting[13]. Because of their small size, SLN may be injected intravenously and used to target drugs to particular organs. The particles, as with all intravenously injected and colloidal particulates, are cleared from the circulation by the liver and spleen[14].
2.3 Transdermal administration
SLNs have shown great potential as novel drug carrier for dermal and transdermal system[15]. It has been found in vitro that SLNs have UV reflecting properties. The use of physiological components in SLNs is a clear advantage over existing UV protective systems with respect to skin penetration and potential of skin toxicity. Wissing et al[16] studied on the comparison of two different formalations (SLNs and conventional O/W emulsion) as carrier systems for the molecular sunscreen oxybenzone. Their studies showed clearly that incorporation of the molecular sunscreen oxybenzone in SLNs decreased the rate of release compared to equally sized emulsion by up to 50%. Therefore, SLNs as novel UV sunscreen system offer two main advantages[17]. Firstly, SLNs act as physical sunscreens on their own, the incorporation of potentially hazardous molecular sunscreen can be decreased while maintaining the sun protection factor. For another thing, SLNs are able to provide a sustained release carrier system, therefore the sunscreen remains longer on the surface of the skin where it is intended to act.
2.4 Pulmonary administration
For both topical and systemic administration of drug through the pulmonary route, nanoparticulate formulations offer several important advantages when compared to more traditional microparticlessuspensions. If a water-insoluble drug is intended for immediate action, nanoparticles will result in a bioavailability enhancement, attributable to either better drug delivery, more rapid dissolution or increased residence time in the lung [18]. Chattopadhyay et al[19] showed that lipid nanosuspensions were successfully aerosolized at efficiencies and aerosol particle size distributions sufficient to enable delivery to the lung for either topical applications or systemic delivery. The particle size distribution of the aerosol was consistent with minimal oropharyngeal deposition and delivery to the peripheral lung for uptake by the systemic circulation.
3 Summary and outlook
The SLNs are attractive carriers for topical cosmetic and pharmaceutical products. They possess the potential to develop as the new generation of carrier systems after the liposomes. However, despite the fact that the use of lipid particles for topical administration is very promising and a highly attractive application area, further basic research needs to be done. For example, it is highly desirable to have a much better understanding of the reasons for formation of certain lipid modifications, the effect of surfactants used on these modifications, and their transition during storage. Interesting work on these effects has recently been published[20]. Also, a better understanding is needed of how lipid nanoparticles modify drug penetration into the skin, how lipid particles interact with the lipids of the stratum corneum, and how they then affect drug penetration. Apart from application of lipid nanoparticles to the skin, future research should also consider mucosal applications. To achieve these goals, more research groups need to focus on this area, as has happened for oral and parenteral administration of lipid nanoparticles.
[References]
[1]E Merisko-Liversidge, GG Liversidge, ER Cooper, Nanosizing: a formulation approach for poorly-water-soluble compounds[J].Eur J Pharm Sci,2003,18(2):113-120.
[2]Worle G,Siekmann B,Bunjes H. Effect of drug loading on the transformation of vesicular into cubic nanoparticles during heat treatment of aqueous monoolein/poloxame dispersions[J].Eur J Pharm Biopharm, 2006,63:128-133.
[3]Xia Q, Lu Y, Gu N.Controlable preparation of 10 nm solid lipid nanoparticles based on phase behaviors of drug-loading hot microemulsions[J].Nanoteeh,2005,1:176-178.
[4]Lim S, Kim C. Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid[J].International Journal of Pharmaceutics,2002,243:135-146.
[5]CM Keck, RH Muller.Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation[J].Eur J Pharm Biopharm,2006, 62(1):3-16.
[6]M Trotta, F Debemardi, O Caputo. Preparation of solid lipid nanoparticles by a solvent emulsification-diffusion technique[J]. International Journal of Pharmaceutics, 2002, 233:121-128.
[7]Hong Y, Huang L, Du Y, et al. Solid lipid nanoparticles prepared by solvent diffusion method in a nanoreactor system[J].Colloids and Surfaces B:Biointerfaces, 2008, 61:132-137.
[8]Chiara Dianzani, Roberta Cavalli, Gian Paolo Zara, etal.Cholesteryl butyrate solid lipid nanoparticles inhibit adhesion of human neutrophils to endothelial cells[J].British Journal of Pharmacology,2006,148:648-656.
[9]E Drioli, A Criscuoli, E Curcio. Membrane contactors and catalytic membrane reactors in process intensification[J].Chem Eng Technol, 2003, 26:975-981.
[10]Catherine Charcosset, Assma El-Harati, Hatem Fessi. Preparation of solid lipid nanoparticles using a membrane contactor[J].Journal of Controlled Release, 2005,108:112-120.
[11]O Kayser, C Olbrich, V Yardley, et al. Formulation of amphotericin B as nanosuspension for oral administration[J].Int J Pharm,2003,254(1):73-75.
[12]Rajesh Pandey, Sadhna Sharma, GK Khuller. Oral solid lipid nanoparticle-based antitubercular chemotherapy[J].Tuberculosis,2005, 85:415-420.
[13]SA Wissing, O Kayser, RH Muller. Solid lipid nanoparticles for parenteral drug delivery[J].Advanced Drug Delivery Review,2004,56(9):1257-1272.
[14]Freitas C, Muller R. Spray-drying of solid lipid nanoparticles(SLN)[J].Eur J Pharm Biopharm, 2008, 46:145-151.
[15]Wang JX, Zhang ZR. Research and development of solid lipid nanoparticles [J].Chin Pharm J, 2001,36(2):73-76.
[16]SA Wissing, RH Muller Solid lipid nanoparticles as carrier for sunscreens: in vitro release and in vivo skin penetration[J]. Journal of Controlled Release, 2002, 81:225-233.
[17]RH Muller, M Radtke, SA Wissing. Solid lipid nanoparticles (SLN) and nanostructured lipid carriers(NLC) in cosmetic and dermatological preparations[J]. Advanced Drug Delivery Reviews,2002,54 (1):131-155.
[18]B.E. Rabinow. Nanosuspensions in drug delivery[J].Nat Rev Drug Discov,2004,3:785-796.
[19]P Chattopadhyay, BY Shekunov, D Yimb. Production of solid lipid nanoparticle suspensions using supercritical fluid extraction of emulsions (SFEE)for pulmonary delivery using the AERx system[J].Advanced Drug Delivery Reviews,2007,59:444-453.
[20]H Bunjes, K Westesen.Stabilizers may decrease the amount of supercooling in Lipid Nanoparticle dispersions, in: Proceedings of the 4th World Meeting, ADRITELF/APGI/ APV,2002:671-672.
(Received date:2009-02-24)
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