图解制备胶束、纳米囊必备基础知识

International Journal of Pharmaceutics 385 (2010) 113–142 Contents lists available at ScienceDirect International Journal of Pharmaceutics journa l homepage: www.e lsev ier .com/ locate / i jpharm Pharmaceutical Nanotechnology Polymer-based nanocapsules for drug delivery C.E. Mora a Université de b Université Lyo a r t i c l Article history: Received 22 Ju Received in re Accepted 3 Oc Available onlin Keywords: Nanocapsules Nanoencapsul Active substan Therapeutic ap Characterizati Polymers Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 2. Nanocapsule definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 3. Methods for the preparation of nanocapsules and their fundamental mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 3.1. Nanoprecipitation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 3.2. 3.3. 3.4. 3.5. 3.6. 3.7. 4. Behav 4.1. 4.2. 4.3. 4.4. 4.5. 4.6. 4.7. 4.8. 5. Discu Ackno Refer ∗ Correspon d’Automatique F-69622, Ville E-mail add elaissari@lage 0378-5173/$ – doi:10.1016/j. Emulsion–diffusion method. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 Double emulsification method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 Emulsion-coacervation method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 Polymer-coating method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Layer-by-layer method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Strategies for the concentration, purification and stabilization of nanoencapsulated systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 iour of nanocapsules as drug delivery systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Mean nanocapsule size . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Nanocapsule zeta-potential . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Nanocapsule dispersion pH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Nanocapsule shell thickness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 Nanocapsule encapsulation efficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Nanocapsule active substance release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 Nanocapsule stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 Nanocapsule performance evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 ssion and concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 wledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 ding authors at: Université Lyon 1, CNRS, UMR 5007, Laboratoire et de Génie des Procédés, LAGEP-CPE-308G, 43 bd. du 11 Nov.1918, urbanne, France. Tel.: +33 472431841; fax: +33 472431682. resses: fessi@lagep.univ-lyon1.fr (H. Fessi), p.univ-lyon1.fr (A. Elaissari). see front matter © 2009 Elsevier B.V. All rights reserved. ijpharm.2009.10.018 -Huertasa,b, H. Fessi a,b,∗, A. Elaissari a,b,∗ Lyon, F-69622, Lyon, France n 1, CNRS, UMR 5007, Laboratoire d’Automatique et de Génie des Procédés, LAGEP-CPE-308G, 43 bd. du 11 Nov.1918, F-69622, Villeurbanne, France e i n f o ly 2009 vised form 1 October 2009 tober 2009 e 13 October 2009 ation methods ce plication on a b s t r a c t A review of the state of knowledge on nanocapsules prepared from preformed polymers as active substances carriers is presented. This entails a general review of the different preparation methods: nanoprecipitation, emulsion–diffusion, double emulsification, emulsion-coacervation, polymer-coating and layer-by-layer, from the point of view of the methodological and mechanistic aspects involved, encapsulation of the active substance and the raw materials used. Similarly, a comparative analysis is given of the size, zeta-potential, dispersion pH, shell thickness, encapsulation efficiency, active substance release, stability and in vivo and in vitro pharmacological performances, using as basis the data reported in the different research works published. Consequently, the information obtained allows establishing criteria for selecting a method for preparation of nanocapsules according to its advantages, limitations and behaviours as a drug carrier. © 2009 Elsevier B.V. All rights reserved. Administrator 线条 Administrator 线条 114 C.E. Mora-Huertas et al. / International Journal of Pharmaceutics 385 (2010) 113–142 1. Introduction Generally, nanoparticles are defined as solid colloidal parti- cles that include both nanospheres and nanocapsules. They can be prepared preformed Bouchemal size, which size limit o 100–500nm As asser show prom drugs (Cruz allows relat systems (Fu of active su ble with tis either bioco Other ad stance carr optimized d pared to oth polymeric s light and th (Pinto et al. Polymer carriers in t 2000; Chau 2007) and d the nanopa Moinard-Ch lated system preparation et al., 2006a updating th nanocapsul cases, amo ied are mea release, nan logical perf 2. Nanocap First of a in which a uid core su 1998a). How nano-vesicu in which th rounded by 2007; Anto stance in li et al., 1989 Likewise, th to the prep into accoun nanocapsul or imbibed 2008) (Fig. 3. Method fundament Generall of nanocap iffere bstan ficat er (Fi lsion poly ardin sed f er, t inter s ph e pr s the polymers, can restrict solvent diffusion, which, when ed rapidly during the evaporation step, makes nanocapsule ion difficult. ough Pisani et al. obtained preparation of nanocapsules timising the parameters of emulsion–evaporation pro- ccording to Moinard-Chécot et al. (2008) this method n performed using microencapsulation technology and is commended for nanoencapsulation. They suggest that the psules do not resist direct evaporation of the solvent, possi- e to the mechanical stress caused by the gas bubbles formed the aqueous suspension. s, in agreement with the previous arguments, the on–evaporation method is not currently recognized as fea- hereby opening the path for other research works to provide s for nanocapsule synthesis. the other hand, regarding block copolymer-based vesi- so called polymer-based liposomes or polymersomes, they to be promising for drug encapsulation because their dou- er recalls the structure of lipids in membrane cells which acilitate their biological performance and the design of tar- nanoparticles (Meng et al., 2005; Rodríguez-Hernández et 05). They can be obtained from amphiphilic di-block, tri- graft or charged copolymers by means of self-assembled alently-assembled strategies. Among the copolymers used or PEO biodegradable derivatives, although researches has eveloped using new materials as polypeptides and choles- by both polymerization methods and synthesis with polymers (Fattal and Vauthier, 2002; Vauthier and , 2008). One of their fundamental characteristics is their is generally taken to be around 5–10nm with an upper f ∼1000nm, although the range generally obtained is (Quintanar et al., 1998a). ted by different authors, nanoparticulated systems ise as active vectors due to their capacity to release et al., 2006; Amaral et al., 2007); their subcellular size ively higher intracellular uptake than other particulate rtado et al., 2001a,b); they can improve the stability bstances (Ourique et al., 2008) and can be biocompati- sue and cells when synthesized from materials that are mpatible or biodegradable (Guinebretière et al., 2002). vantages of nanoencapsulated systems as active sub- iers include high drug encapsulation efficiency due to rug solubility in the core, low polymer content com- er nanoparticulated systems such as nanospheres, drug hell protection against degradation factors like pH and e reductionof tissue irritationdue to thepolymeric shell , 2006a; Anton et al., 2008). ic nanoparticles have been extensively studied as drug he pharmaceutical field (Legrand et al., 1999; Barratt, bal, 2004; Sinha et al., 2004; Letchford and Burt, ifferent research teams have published reviews about rticle formation mechanisms (Quintanar et al., 1998a; ecot et al., 2006), the classification of nanoparticu- s (Letchford and Burt, 2007) and the techniques for of nanocapsules (Moinard-Checot et al., 2006; Pinto ; Vauthier and Bouchemal, 2008). As a contribution to e state of knowledge, the present review focuses on es obtained from preformed polymers, using prototype ng others, to provide illustrations. The aspects stud- n size, zeta-potential, encapsulating efficiency, active odispersion stability and in vivo and in vitro pharmaco- ormance behaviours. sule definition ll the nanocapsules can be likened to vesicular systems drug is confined in a cavity consisting of an inner liq- rrounded by a polymeric membrane (Quintanar et al., ever, seen from a general level, they can be defined as lar systems that exhibit a typical core-shell structure e drug is confined to a reservoir or within a cavity sur- a polymer membrane or coating (Letchford and Burt, n et al., 2008). The cavity can contain the active sub- quid or solid form or as a molecular dispersion (Fessi ; Devissaguet et al., 1991; Radtchenko et al., 2002b). is reservoir can be lipophilic or hydrophobic according aration method and raw materials used. Also, taking t the operative limitations of preparation methods, es can also carry the active substance on their surfaces in the polymeric membrane (Khoee and Yaghoobian, 1). s for the preparation of nanocapsules and their al mechanisms y, there are six classical methods for the preparation sules: nanoprecipitation, emulsion–diffusion, double Fig. 1. D active su emulsi by-lay as emu tion of Reg been u Howev ferent aqueou fore th such a remov format Alth by op cess, a is ofte not re nanoca bly du inside Thu emulsi sible, t option On cles, al appear ble lay could f geted al., 20 block, or cov are PEG been d nt nanocapsular structures: (a) liquid core, (b) polymer matrix and (c) ce in molecular dispersion. ion, emulsion-coacervation, polymer-coating and layer- g. 2). Nevertheless, other methods have been used such –evaporation and the methodologies for the prepara- mer liposomes. g to the solvent emulsion–evaporation method, it has or the preparation of nanocapsules (Pisani et al., 2008). he latter research showed that several apparently dif- facial organizations coexist between the organic and ases at the same time within a single emulsion. There- esence of compounds with high molecular weights, Administrator 线条 Administrator 线条 Administrator 线条 C.E. Mora-Huertas et al. / International Journal of Pharmaceutics 385 (2010) 113–142 115 terol deriva 2005; Zhou Typically be classified In the first contact wit vesicles. In organic solv solvent is e butions of treated by s a combinati cross-linkin Table 1 Suggeste precipita Mater Active Polym Oil w/o su Solven Stabili Non-s Fig. 2. General procedure of the different methods for the pr tes (Chécot et al., 2003; Photos et al., 2003; Xu et al., et al., 2006). , the procedures for the polymersome preparation can as solvent free and solvent displacement techniques. method, the dried amphiphile polymer is brought in h the aqueous medium and then is hydrated to form the second method, the block copolymer is dissolved in ents, thenwater is added and subsequently the organic liminated. In order to reach monodisperse size distri- the polymer vesicles, the obtained suspension can be onication, vortexing, extrusion or freeze-thaw cycles or onof these techniques (Kita-Tokarczyk et al., 2005). The g process of the block polymers allows optimizing the d composition for preparation of nanocapsules by the nano- tion method. ial Suggested composition substance 10–25mg er 0.2–0.5% of solvent 1.0–5.0% of solvent rfactant 0.2–0.5% of solvent t 25ml zer agent 0.2–0.5% of non-solvent olvent 50ml vesicular m protection The enca cles is obta or lipophili of the polym ing to the b Some exam cancer drug al., 2006) a al., 2009), t therapy (Ch Fig. 3. Set-up method. eparation of nanocapsules. embrane properties associated with active substance and release effect (Chécot et al., 2003). psulation of active substances inside the polymer vesi- ined by incubation based techniques. The hydrophilic c nature of the active molecule determines the choice ersome core nature which in turn is obtained accord- lock polymer chosen and to the assembly technique. ples of active substances encapsulated are mainly anti- s as adriamycin (Xu et al., 2005), paclitaxel (Ahmed et nd doxorubicin (Ahmed and Discher, 2004; Zheng et herapeutic proteins and antisense molecules for gene ristian et al., 2009; Kim et al., 2009). used for preparation of nanocapsules by the nanoprecipitation 116 C.E.M ora-H uertas et al./InternationalJournalofPharm aceutics 385 (2010) 113–142 Table 2 Examples of raw materials used for preparation of nanocapsules by the nanoprecipitation method. Active ingredient Therapeutic activity Polymer Oil core Solvent Stabilizer agent Non- solvent Reference Gemcitabine Antineoplastic PACA or Poly[H2NPEGCA-co-HDCA] Caprylic/capric triglyceride Acetone ethanol Water Stella et al. (2007) 4-(N)-stearoylgemcitabine 4-(N)-valeroylgemcitabine 4-(N)-lauroylgemcitabine PLAa PLA Mw 60kDa PCL Mw 65kDa PCL Mn 60kDa Benzyl benzoate Phospholipids Capric/caprylic triglycerides Sorbitan monoestearate Acetone Acetone Poloxamer 188 Polysorbate 80 Water Water Fessi et al. (1989) Fawaz et al. (1996) Pohlmann et al. (2008) Cattani et al. (2008) Indomethacin Anti-inflammatory, analgesic Selective cytotoxicity PCL Mw 60kDa or PLAa Mineral oil Sorbitan monostearate Acetone Polysorbate 80 Water Pohlmann et al. (2002) PCL Mw 40kDa Propylene glycol dicaprylate/dicaprate Lecithin Acetone Poloxamer 188 Chitosan Water Calvo et al. (1997) PCL Mw 40kDa Propylene glycol dicaprylate/dicaprate Lecithin Acetone Poloxamer 188 Water Calvo et al. (1997) Indomethacin ethyl ester Anti-inflammatory, analgesic PCL Mw 65kDa Capric/caprylic triglycerides Sorbitan monostearate Acetone Polysorbate 80 Water Cruz et al. (2006) Cattani et al. (2008) Poletto et al. (2008a,b) PLA Mw 200kDa, PCL Mw 65 or 100kDa, PLGA Mw 40kDa Benzyl benzoate Soybean lecithine Acetone Poloxamer 188 Water Cauchetier et al. (2003) Atovaquone Antipneumocystic Capric/caprylic triglycerides Benzyl benzoate PLA Mw 88kDa Caprylic/capric triglycerides PEG-4 complex Acetone Poloxamer 188 Water Dalenc¸on et al. (1997) Oleic acid Phospholipids Capric/caprylic triglycerides Benzyl benzoate Rifabutine Antibacterial (tuberculostatic) PLA Mw 88kDa Caprylic/capric triglycerides PEG-4 complex Acetone Poloxamer 188 Water Dalenc¸on et al. (1997) Phospholipids Tretinoin Topical treatment of different skin diseases (acne vulgaris, ichtiosys, psoriasis), antineoplastic (hormonal) PCLa Capric/caprylic triglycerides Sunflower seed oil. Sorbitan monooleate Acetone Polysorbate 80 Water Ourique et al. (2008) Fluconazole labeled with 99mTechnetium Antifungal PLA Mw 75kDa or PLA–PEG (90% PLA Mw 49kDa–10% PEG Mw 5kDa) Capryc/caprylic triglycerides Soybean lecithin Methanol Acetone Poloxamer 188 Water Nogueira de Assis et al. (2008) Primidone Anticonvulsant PCL Mw 64kDa Benzyl alcohol Acetone Poloxamer 188 Water Ferranti et al. (1999) Vitamin E Vitamin antioxidant PCL Mn 10kDa Acetone Polysorbate 20 Water Charcosset and Fessi (2005) Spironolactone Diuretic PCL Mw 10 and 80kDa Caprylic/capric triglycerides PEG-4 complex Acetone Poloxamer 188 Water Limayem et al. (2006) Sorbitan monooleate Polysorbate 80 Sorbitan monolaurate Polysorbate 20 Griseofulvine Antifungal PCL Mw 80kDa Benzyl benzoate Sorbitan monooleate Acetone Polysorbate 80 Water Zili et al. (2005) 99mTc-HMPAO complex Radiotracer PLA MW/5kDa or PLA–PLG (90% PLA Mw 49kDa–10% PEG Mw 5kDa) Capric/caprylic triglycerides Soybean lecithin Acetone Poloxamer 188 Water Pereira et al. (2008) Melatonin Antioxidant Eudragit S100 Capric/caprylic triglyceride Sorbitan monooleate Acetone Polysorbate 80 Water Schaffazick et al. (2008) C.E.M ora-H uertas et al./InternationalJournalofPharm aceutics 385 (2010) 113–142 117 Diclofenac Anti-inflammatory PCL Mw 80 or Eudragit S90 Capric/caprylic triglyceride Benzyl benzoate Sorbitan monostearate Acetone Polysorbate 80 Water S