1. Introduction

2. Development of PCL

microcapsules

3. Development of PCL

nanocapsules and PCL

lipid-core nanocapsules

4. Conclusion

5. Expert opinion

Review

Poly(e-caprolactone)microcapsules and nanocapsulesin drug deliveryAdriana Raffin Pohlmann†, Francisco Noe Fonseca, Karina Paese,Cassia Britto Detoni, Karine Coradini, Ruy CR Beck & Silvia S Guterres†Departamento de Quımica Organica, Instituto de Quımica, Universidade Federal do Rio Grande

do Sul, Porto Alegre, Brazil

Introduction: Poly(e-caprolactone) (PCL), a biodegradable and biocompatible

polymer, is useful to encapsulate a wide range of drugs making it an interes-

ting material for the preparation of carriers with potential applications

in therapeutics.

Areas covered: The design and development of those carriers to modulate

drug release, to improve the drug stability or apparent solubility in aqueous

media, as well as to target tissues and organs are discussed.

Expert opinion: Microencapsulation is a well-established process in pharma-

ceutical industry to protect drugs from chemical degradation and to control

drug release. In this context, PCL is a useful polymer to prepare microcapsules.

Nanoencapsulation, a more recent approach, offers new possibilities in drug

delivery. PCL can be used as polymer to prepare different types of nanocap-

sules presenting diverse flexibility according to the chemical nature of the

core. Those nanocapsules are capable of controlling drug release and impro-

ving photochemical stability. In addition, they can modulate cutaneous drug

penetration/permeation and act as physical sunscreen due to their capability

of light scattering. Considering the pharmaceutical point of view, PCL nano-

capsules are versatile formulations, once they can be used in the liquid

form, as well as incorporated into semi-solid or solid dosage forms.

Keywords: drug delivery systems, lipid-core nanocapsules, microcapsules, nanocapsules,

poly(e-caprolactone), polymer

Expert Opin. Drug Deliv. [Early Online]

1. Introduction

Poly(e-caprolactone) (PCL), a semicrystalline aliphatic polyester, is obtained by ringopening polymerization using e-caprolactone as monomer. The PCL glass andmelting temperatures are about -60�C and 60�C, respectively. At room tempera-ture, PCL is soluble in aromatic solvents and in chlorine solvents (dichloromethaneand chloroform), partially soluble in polar solvents, such as acetone, acetonitrile anddimethylformamide, but insoluble in alcohols and water [1]. Moreover, PCL formsblends with a wide variety of polymers conferring interesting and versatilephysicochemical and mechanical properties to the new devices, such as swelling [2],porosity [3] and stability in different media [4,5].

The use of PCL in implants and surgical absorbable sutures has been approved bythe Food and Drug Administration. Considering its biodegradability and biocom-patibility, PCL has been studied for the development of different medical devices,tissue engineering and drug carriers as described in different review articles. TheThomson Reuters database (Web of Knowledge) has a universe of 13,707 docu-ments concerning the terms ‘polycaprolactone or PCL’ (access in 20 November2012). Limiting this search by using the term ‘drug’, the number of documents

10.1517/17425247.2013.769956 © 2013 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 1All rights reserved: reproduction in whole or in part not permitted

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reduces to 1,662. In two parallel searches by using each timethe terms ‘micro*’ or ‘nano*’ we found 732 and 759 docu-ments, respectively. Regarding exclusively the Web of Science,we found 10,557 documents by searching the term‘polycaprolactone or PCL’. Limiting this universe by usingthe term ‘drug’, we identified 1,519 documents. Once againlimiting the search by using the terms ‘micro*’ or ‘nano*’,we found 688 and 738 documents, respectively. The searchusing ‘PCL, drug, review and micro* or PCL, drug, reviewand nano*’ (Web of Science) showed 19 review articles men-tioning PCL, of which only 7 are focused on this polymer ascentral theme (Table 1) [6-12].PCL microcapsules or nanocapsules for drug delivery have

been intensively investigated in the past decade. Using theterms ‘PCL, drug and microc* or nanoc*’, 209 documents(Web of Science) have been published since 1998 (Figure 1).Considering all abovementioned aspects, our review is focusedon the development of microcapsules and nanocapsules, pre-senting at least two compartments in their structures. In thisway, PCL microcapsules, PCL nanocapsules and PCL lipid-core nanocapsules were chosen as subject of our review. Thosecarriers have been designed to improve the pharmaceuticalproperties of drugs and vaccines, to control the drug release,to enhance the drug physicochemical stability, to provideenhanced photochemical stability for the drugs, to modulatethe drug skin penetration/permeation and to increase the bio-logical (or pharmacological) responses of drugs. Additionally,

the use of nanocapsule suspensions to develop intermediateproducts or semisolid or solid dosage forms is also discussed.

2. Development of PCL microcapsules

Polymeric microcapsules are vesicles with one or morecompartments surrounded by polymer, with granulometricprofiles ranging from 1 to 1000 µm [13]. PCL microcapsulesfor drug delivery are mostly prepared by the emulsion/solvent evaporation method [3,4,14-16]. In this method, PCLor a PCL polymer blend and drug are dissolved in an organicsolvent forming the organic phase, which is emulsified understirring with an aqueous phase containing polyvinyl alcohol(PVA) to form an oil-in-water (O/W) emulsion. The emul-sion is maintained under stirring to evaporate the organicsolvent. Alternatively, the solvent can be eliminated underreduced pressure using a rotary evaporator [15,17]. The micro-capsules are then filtered and dried [6]. Modifications to thismethod have been proposed, such as the use of an oil1/oil2/water (O1/O2/W) primary emulsion [4].

Microcapsules are particles presenting at least twoidentified domains having a structure with two or multiplecompartments (Figure 2). The domains have differentchemical nature, and the microcapsule compartments can beexemplified as a hollow polymeric matrix [5,15,16], a solidheterogeneous mixture [14] or an oily centered structure [18].The multiple compartment structures are similar to thosedescribed above as hollow polymeric matrix [17] and solid orliquid heterogeneous mixtures [19,20].

The drug release behavior and, consequently, the biologicalactivity are dependent on the physicochemical characteristicsof the formulation. The most important parameters to bedetermined are the granulometric profiles, the specificsurface area, the drug--polymer interactions and thepolymer--polymer interactions (in the case of blends). Instru-mental methods such as thermal analysis, X-ray and infraredspectroscopy are often used for this purpose [16,18], as well aslaser diffractometry and microscopy techniques [17].

The drug release mechanisms can be driven by the diffusionof the drug from the particles, the erosion/degradation of theparticle or both mechanisms combined. The Fick’s second lawis applied, in general, to determine those mechanisms [21].Considering that the swelling of the polymer can influencethe release mechanism of the drug, particle hydration/swelling or dissolution/erosion are also important aspects tobe studied. In this way, those phenomena can be evaluatedby gravimetry [2] or particle size variations [4]. Moreover, theaddition of a positively charged polymer, such as Eudragit�

RS100 (Evonik Degussa), or the protein content mayaccelerate the hydration process of the particles [2,4].

Encapsulation efficiency is another relevant aspect to bedetermined for the drug-loaded microcapsules. This para-meter should be especially considered for the therapeuticapplications of those formulations, since the pharmacologicalresponse is a consequence of the administered dose, which in

Article highlights.

. PCL has been studied for the development of differentmedical devices and drug delivery systems, due to itsbiocompatibility and biodegradability.

. PCL microcapsules, nanocapsules and lipid-corenanocapsules are vesicular structures capable ofimproving the pharmaceutical, pharmacological andcosmetic properties of anti-inflammatory, antitumoral,antimalarial drugs and antioxidants, as well as sunscreens.

. The main advantages of the microencapsulation usingPCL or its blends consist in prolonging the drug releaseand enhancing the drug stability.

. Some potential advantages of drug nanoencapsulationusing PCL are the modulation of the drug releaseprofile, the improvement of the photochemical stability,the control of the drug penetration/permeation into theskin and the increase of the pharmacological response.

. PCL nanocapsules provide both temporal and spatialcontrol of the drug release and distribution, that is,prolonged drug release and enhancement of drugconcentration in specific cells and tissues, respectively.

. Pharmaceutical scientists have proposed different PCLnanocapsule or lipid-core nanocapsule dosage forms:aqueous suspension, tablets or semisolid formulations.Different intermediate products, such as suspensions,spray-dried powders, granules and pellets have beenused to produce those final products.

This box summarizes key points contained in the article.

A. R. Pohlmann et al.

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turn is dependent of the drug loading capacity of themicrocapsules. The encapsulation efficiency can be affectedby variations in the concentrations of PCL [2,19], of thesurfactants [19] or of the drug [4].

The variation of the size distribution and the mean particlediameter impacts on the control of the specific surface areacontributing, among other factors, to the modulation of thedrug release. By blending different polymers with PCL,changes in the size distribution and mean particle diameterscan be observed. For example, a size reduction was observedin PCL/poly(oxyethylene) (PEO) microcapsules by increasingPEO proportion in the blend [16]. Furthermore, theelectrostatic interactions between PCL and Eudragit RS100produced narrower size distributions and smaller mean sizesby reducing the PCL proportion [2].

The increase of the PCL proportion in poly(hydroxybuty-rate-co-hydroxyvalerate) blended microcapsules reduced themean particle size [15]. The loading of diclofenac or indo-methacin in those blended microcapsules did not affect theinfluence of PCL on the mean diameters. Previously,

Table 1. Authors, titles and references of the seven review articles concerning the topic ‘polycaprolactone and

drug or PCL and drug’, while restraining the use of the term ‘review’, followed by ‘micro* or nano*’, as central

theme.

Authors Title Refs.

Sinha et al. Poly-epsilon-caprolactone microspheres and nanospheres: an overview [6]

Wei et al. Biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol) copolymers as drug delivery system [7]

Kumari et al. Biodegradable polymeric nanoparticles based drug delivery systems [8]

Woodruff andHutmacher

The return of a forgotten polymer -- polycaprolactone in the 21st century [9]

Gou et al. PCL/PEG copolymeric nanoparticles: potential nanoplatforms for anticancer agent delivery [10]

Dash et al. Poly-epsilon-caprolactone based formulations for drug delivery and tissue engineering: a review [11]

Wang et al. Pharmacokinetics and disposition of nanomedicine using biodegradable PEG/PCL polymers as drug carriers [12]

Year

0

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1994 1996 1998 2000 2002 2004 2006 2008 2010 2012

Microc*

Nanoc*

20

40

60

80

100

120

140

160

Figure 1. Cumulative number of documents between 1994 and 2012 recorded in the Web of Science database with regard to

the search for terms such as ‘microc* and PCL and drug’ or ‘nanoc* and PCL and drug’.

A.

D. E. F.

B. C.

Figure 2. Illustrative models of microcapsules containing two

domains air-polymer (A and D), solid-polymer (B and E) and

liquid-polymer (C and F).

PCL microcapsules and nanocapsules in drug delivery

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protein-loaded biodegradable microcapsules containing anoily core have been investigated showing particle size variationas a function of the polymer molecular weight (Mw). Themean diameter based on the equivalent sphere (volume-weighted average diameter, d4,3) increases with the increasein the molar mass of the polymer. This difference was attrib-uted to the increase of the viscosity of the oily phase, whichdecreases the emulsification efficiency. In addition, microcap-sules prepared with PCL having average Mw of 14 g mol-1

were irregular and aggregated, while microcapsules preparedwith PCL having Mw of 40 or 80 g mol-1 were sphericaland isolated [4].Poly(butylene succinate)/PCL microcapsules prepared with

increasing concentrations of gelatin (0.5 -- 2%) producedmicrocapsules with decreasing mean diameters [3]. The typeof surfactant used in the aqueous phase for the emulsificationstep of the emulsion/solvent evaporation method had influ-ence on the microcapsule morphology. Sorbitan monooleateand polysorbate 80 rendered aggregated particles with a roughand fractured surface morphology. On the other hand, thePCL microcapsules prepared with gelatin or PVA resulted insmooth surfaces [18].

2.1 Pharmaceutical propertiesMicrocapsules are designed to modulate the pharmaceuticalproperties of different drug and vaccines depending on theircompositions (Table 2). The main reason for microencapsula-tion is to control the drug release, but enhancement of thechemical stability of the drug may also be intended. Thosefeatures are detailed in the next sections.

2.1.1 Controlling the drug releasePolymer blends may enhance the drug release rate from PCLmicrocapsules. Eudragit RS100, PEO and poly(ethyleneglycol) (PEG) have been used to accelerate the drug releasefrommicrocapsules [2,16,18]. Following the same line of thought,the addition of PCL to other kind of microcapsules showedslower drug release as observed for poly(butylene succinate)/PCL microcapsules [3]. PCL was added to poly(butylene succi-nate) microcapsules leading to a slower drug release. Whenthe PCL amount was gradually increased, the porous aspect ofpoly(butylene succinate) microcapsule decreased. This resultwas attributed to a crystal coating effect promoted by PCL.Considering these findings, the retardant release effectpromoted by PCL is explained by the reduction of pores as aconsequence of a PCL coating on the particle surface.The increase in the drug release rate as a function of the

increase in the PCL concentration in the poly(hydroxybuti-rate-co-hydroxyvalerate) microparticles can be explainedby the increase in the surface area due to the formationof hollows in the particles [15,17]. The studies showed thatthose polymeric structures did not swell or dissolve in therelease media, and dexamethasone acetate, indomethacinand diclofenac showed as faster release when the porosity ofthe microcapsules was high.

The addition of Eudragit RS100 is a feasible strategy toenhance the permeability of the particles in acidic environ-ments and to modulate tulobuterol release [2]. Blends ofPCL and Eudragit RS100 instead of pure PCL have beenused to obtain porous particles. The pore formation increasedwith the reduction of the PCL proportion in the blend.Besides the pore formation, quaternary ammonium groupsare solvated in the acid environments leading to a higherhydration of the particle, which favors the drug release.

The increase of PEG in PCL microcapsules facilitated thefragrant oil release as a consequence of the hydrophilic poly-mer swelling in the presence of water [14]. A similar behaviorwas observed when PEO was added to PCL microcapsules [16].PEO not only favored the particle swelling but also led to aselective dissolution of the particle shell, which was confirmedby scanning electron microscopy of the particles during therelease assay.

Surface modifications may also be used as a strategy tomodulate the physicochemical behaviors of the particles. Oneof the possible surface modification techniques is Ar/O2

plasma treatment, which use increased the hydrophilic groupsat the PCL microcapsule surface [18]. This surface treatmentenhanced the tocopherol release rate from the microcapsules.

Squalene was used as an oily core to encapsulate bovineserum albumin (BSA) in microcapsules using PCL in differentproportions [4]. The protein release behavior was irregular andpulsatile for all concentrations of PCL, but differences wereobserved in the release rate. A high concentration of PCLled to a very slow release of the protein.

Different proportions of PCL/drug/oil may also be used asan approach to modulate the drug release, being slower whenthe polymer content is increased in relation to the core con-tent (oil) [4,18]. The result can be explained by the formationof microcapsules with a denser and less porous polymericwall as a function of the decrease in the oil proportion [4].

PCL microcapsules containing fragrant oil adsorbed toSiO2, as a core, were developed as an alternative strategy tocontrol the oil release [14]. The SiO2 particles presentedsmaller pore diameter but higher total pore volume than theoriginal silica when treated with acid, while the SiO2 had mes-opores but a lower total pore volume than the original silicawhen treated with alkali. The oil release was the slowestwhen the SiO2 treated with alkali was used, and it was thehighest when the SiO2 was treated with acid.

2.1.2 Enhancing the chemical stabilityPCL microcapsules with an oily core are advantageous for drugstabilization due to the physical separation of the active mole-cule (drug or cosmetic) and the acid terminal group of PCL pro-viding a minimum contact with water in the microenvironmentof the particle [4]. BSA loaded in those microcapsules remainedintact during its release. This is an interesting result consideringthat similar particles made with poly(D,L-lactide-co-glycolide)showed fragmented protein in the release medium [4]. Similarly,Eudragit S100/PCL blended microcapsules is valuable in

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protecting an acid labile drug, pantoprazol, while pure EudragitS100 microcapsules (insoluble in acid medium) are incapable ofprotecting it [5].

3. Development of PCL nanocapsules and PCLlipid-core nanocapsules

Polymeric nanocapsules are submicrometric vesicular systemspresenting Brownian movement. Their composition corre-sponds to a core surrounded by a polymeric wall stabilizedby a surfactant system [22].

Interfacial deposition of preformed polymers [23] followedby emulsification-diffusion [24] are the most reported methodsused in producing PCL nanocapsules. Briefly, the interfacialdeposition of preformed polymer method consists in the injec-tion of an organic phase containing the particle constituentsinto an aqueous one containing a surfactant or a stabilizer [23].Afterward, the organic solvent is removed and the suspensionconcentrated by evaporation under reduced pressure.

The emulsification-diffusion method starts with a presatu-ration of the organic solvent and water in a separatoryfunnel [24]. Then, in separate flasks the organic phase andthe aqueous phase are prepared by dissolving the correspon-dent materials in each one. The phases are mixed and emulsi-fied under high-speed homogenization (rotor stator stirrer).The diffusion step is obtained by adding an excess of waterto the emulsion. Then, the organic solvent is removed andthe suspension concentrated under reduced pressure.

The differences between those methods result in distinctphysicochemical characteristics of the nanocapsules, suchas size, stability, drug release profiles and others [25].The selection of the components (oil, surfactants andpolymer) must consider the physicochemical basis of theprocess to succeed and to have a vesicular supramolecularstructure, as well as a stable colloidal suspension. Nanocap-sules are obtained with PCL using different Mws(Table 3) [25-63]. Triglycerides are in general the oils mostlyused as core. The main oil component is the caprylic/caprictriglyceride [25,30,40-47,51,55,57,59-61,64-68], followed by vegetable

fixed oils [25,65,69], octyl methoxycinnamate [26,27,45,38,70],mineral oil [39] and vitamin K1 [59]. Alternatively, essential oilscan be used considering their pharmacological properties [62].

It is fundamental to assure that the selected oil is a nonsol-vent for the polymer as previously demonstrated for PCLformulations containing caprylic/capric triglyceride insteadof benzyl benzoate [71]. This is a simple evaluation based ona swelling experiment carried out with PCL films immersedin the candidate oil for the formulation.

The surfactant system used in formulating PCL nanocap-sules are mixtures of nonionic surfactant with differenthydrophilic-lipophilic balance or mixtures of ionic and non-ionic surfactants (Table 3). Moreover, stabilizers such aspoloxamers are also used in combination or not with ionicor nonionic surfactants. Regarding the polymer Mw, no com-parative study has been specifically performed by varying thisparameter, impairing a comparative analysis of the influenceof PCL Mw on the nanocapsule physicochemical properties.

The supramolecular architecture of the PCL nanocapsulescan be impacted by the selection of the surfactant and stabi-lizer systems. The flexibility and rigidity of the nanocapsule,or even of the polymer wall, is influenced by the presence ofsorbitan monostearate in the formulation [67], which is dis-persed in the oil core [44,60]. Previously, small angle X-rayanalysis and differential scanning calorimetry showed that sor-bitan monostearate is dispersed in the oily core of the PCLnanocapsules stabilized at the particle--water interface withpolysorbate 80 [43,60]. Furthermore, the release of indometha-cin ethyl ester from those nanocapsules has been modulatedby varying the concentration of sorbitan monostearate in theformulation [51]. The different behavior of this kind ofnanocapsules led it to be named as lipid-core nanocapsules.

A preformulation study showed that the optimal propor-tion of sorbitan monostearate, caprylic/capric triglycerideand PCL, for exclusively obtaining this vesicular complexstructure, is 1:4.6:2.6 (w/w/w) [68]. More recently, the self-assembling was determined as the mechanism whereby thelipid-core nanocapsules are formed [57]. The controls of themean size and the narrow size dispersity are achieved by using

Table 2. Structural components of microcapsules and drugs.

Drug PCL Mw (g mol-1) Blend polymer Phase II or core Hollow Refs

BSA 14, 40 and 80 - Squalene - [4]

Fragrant oil 80 PEG SiO2 - [14]

Tocopherol 80 - Tocopherol - [18]

Indomethacin 80 PBS - yes [3]

Dexamethasone 65 P(HBHV) - yes [17]

Diclofenac and Indomethacin 65 P(HBHV) - yes [15]

Pantoprazol Eudragit S100 - yes [5]

BSA 65 - - yes [19]

Tulobuterol 80 Eudragit RS100 - yes [2]

Endothelial growthfactor

40 Chitosan - yes [20]

PBS: Poly(butylene succinate); PCL: Poly(e-caprolactone); PEG: Poly(ethylene glycol); P(HBHV): Poly(hydroxybutyrate-co-hydroxyvalerate).

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the organic solution under the critical aggregation concentra-tion of the materials (Figure 3). This finding opens the possi-bility to produce drug-loaded formulations having higherdrug contents by the augmentation of the particle numberdensity without losing the controls of the mean size and thepolydispersity [57].Another aspect of the selection of surfactants to produce

nanocapsules and lipid-core nanocapsules is the impact on theirsurface chemistry. When lecithin is used combined withsorbitan monostearate in the organic phase, the lipid-corenanocapsules have anionic surface presenting negative zetapotential due to the presence of phosphatidic acid in the rawlecithin [30]. Using a layer-by-layer strategy based on electro-static interaction, those anionic lipid-core nanocapsules canbe coated with chitosan leading to cationic lipid-core nanocap-sules. Stable formulations are achieved by maintaining thepolysorbate 80 in the formulation.

3.1 Pharmaceutical properties3.1.1 Controlling the drug releaseThe mechanism of the drug encapsulation influences thein vivo behavior of the formulations. Recently, an algorithmwas proposed to class drug-loaded lipid-core nanocapsuleaqueous suspensions in six different drug distributionsfrom the drug mainly concentrated in the outer pseudo-phase

(type I) to the drug mainly concentrated in the core of thenanocapsules (type VI) [72]. The logarithm of the drug distri-bution is the only parameter which correlates (r = 0.9084)to the types of the drug distributions, as experimentallydemonstrated for eight drug models.

Alternatively, the comparison of the in vitro drug release pro-files can give information about the mechanism of the drugencapsulation. Among other methods, the dialysis bag [26,73,74]

and the ultrafiltration-centrifugation technique [25] are com-monly applied to separate the released drug from the colloids.The mechanisms of release are: i) drug desorption from thepolymeric wall, ii) the drug diffusion from the core throughthe polymer wall and iii) the erosion of the polymer, whichcan occur solely or in combination of two or more pro-cesses [73,75]. Usually, lipophilic drugs encapsulated withinnanocapsules show biexponential release profiles consisting ofa burst phase and a sustained phase [44,73,74].

The lipid-core nanocapsules have two diffusional barriersdue to the tortuosity of both the polymer wall and the lipiddispersion in the core, in contrast to the nanocapsules, whichhave only one barrier, the polymer wall. When the drug isinteracting with the colloid at the particle--water interface,whatever the colloidal system, the drug release profiles aresimilar, while if the drug is encapsulated within the core ofthe particles, diverse release rates are observed in comparativestudies [42,44,51,73,74].

The drug release rate can be modulated by varying thepolymer concentration [46]. However, this is not a satisfactorystrategy to control the release rate because of the presence ofnanospheres or nanoemulsion in the nanocapsule formula-tion. Nanospheres are simultaneously formed with nanocap-sules when there is an amount left of polymer, whilenanoemulsion is also formed when there is an amount leftof oil. Furthermore, for lipid-core nanocapsules, the drugrelease rate can be modulated by varying the concentrationsof oil or sorbitan monostearate. The variation of sorbitanmonostearate concentration is better than the variation ofthe oil concentration, because of the impact of the formeron the viscosity of the core that also controls the drug release,and the latter on the production of mixtures of lipid-corenanocapsules and nanoemulsion [51].

Clobetasol propionate released from lipid-core nanocapsules,which are prepared by using poly(lactide), poly(lactide-co-gly-colide) or PCL, showed slower release rate for the latter [76].The higher crystallinity of PCL led to a higher tortuosity forthe diffusion of the drug compared to the amorphous polymers.

Formulations prepared by interfacial deposition of polymerwere more effective in controlling the drug release rate thanthe nanocapsules obtained by emulsification-diffusionmethod (60% within 48 h and 100% within 15 min, respec-tively) [25]. The authors suggest that the colloids obtained byemulsification-diffusion method possibly had the simultaneousformation of nanocapsules and nanoemulsions.

The drug release rate is affected by the viscosity of the outerpseudo-phase of the formulations, as demonstrated by

Table 3. Components commonly used for preparation

of PCL nanocapsules.

Material Refs.

PCL 10 g mol-1 [26,27]

14 g mol-1 [25,28-30]

40 g mol-1 [31-34]

42,5 g mol-1 [35-37]

60 g mol-1 [38-44]

65 g mol-1 [45-59]

80 g mol-1 [60-63]

Oil Caprilic/caprictriglyceride

[25,30,40-47,51,55,57,59-61,64-68]

Sunflowerseed oil

[65]

Grape seed oil [69]

Corn oil [25]

Almond oil [25,69]

Tee tree oil [62]

Vitamin K1 [59]

Mineral oil [39]

Octylmethoxycinnamate

[26,27,45,38,70]

Surfactant Poloxamer 188 [25,31-34]

Polysorbate 80 [25,30,40-47,51,55,57,59-61,64-68]

Phospholipids [25,30-34,45,53,56]

Sorbitanmonostearate

[25,30,40-47,51,55,57,59-61,64-66,68]

Sorbitanmonooleate

[62,65,66]

PCL: Poly(e-caprolactone).

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drug-loaded nanocapsule suspensions and semisolid formu-lations containing those nanocapsules. In general, the drugdiffusion rate is inversely proportional to the viscosity of theouter pseudo-phase [26]. The thickening of the external phaseby using hydrophilic polymers directly in the drug-loadednanocapsule aqueous suspensions did not affect the viscosityof the hydrogels as compared to the drug-loadedhydrogels [77,78]. The comparative study carried out with thosesemisolid formulations showed that the limiting step ofthe drug release was the diffusion of the drug through thepolymer wall of the nanocapsules.

3.1.2 Enhancing the chemical stabilitySome substances, when exposed to light, undergo photodegra-dation leading to inactive compounds [58]. PCL nanocapsulesare useful in protecting photosensitive substances due to theircapacity to reflect/scatter ultraviolet (UV) light [45,52,58,65].Tretinoin, a retinoid used in the treatment of dermatologicaldiseases, was better photoprotected using nanocapsules thanthe respective nanoemulsion [65]. In addition, the lipid-core

nanocapsules show protective effect when tretinoin wasexposed to UVA or UVC light [79]. The photoprotection waseven higher for tretinoin exposed to UVA after incorporatingthe tretinoin-loaded lipid-core nanocapsules in a hydrogel [80].

Lipid-core nanocapsules showed a better photoprotectionfor clobetasol propionate when compared to similar nano-spheres and nanoemulsions [73]. On the contrary, the photo-stability of rutin [74] or isotretinoin [81] was similar wheneach drug was encapsulated in lipid-core nanocapsules or ina nanoemulsion. However, it is important to notice that atleast 50% of rutin or isotretinoin was adsorbed on the parti-cle--water interface, whereas more than 90% of the clobetasolpropionate was entrapped within the colloids.

Recently, the photoprotective capacities of liposomes,nanostructured lipid carriers, lipid-core nanocapsules andnanospheres were compared for (E)-resveratrol after UVAlight exposure [58]. The photoisomerization of (E)-resveratrolwas lower for the liposomes than the other nanocarriers, butthe small amount of isomerization was enough to affect thephospholipid bilayer leading to a bimodal size distribution

Moderate stirring

Water

Organic phase

Polymer

Triglyceride

Sorbitan monostearate

Evaporation underreduced pressure

Lipid-corenanocapsules

Polysorbate 80

Aqueous phase

w+x+y+z = 20

HO OH

OH

OO

OO

OOH

O

O

O

O n

OHO

O

O

O

O OO

OH

OHx

yz

w

Drugacetone

Figure 3. Illustrative model of the mechanism of self-assembling to produce the lipid-core nanocapsules.

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for the liposomes. The photoisomerization of (E)-resveratrolwas similar for the lipid-core nanocapsules and the nanostruc-tured lipid carriers, while the nanospheres showed the higheramounts of (Z)-resveratrol.The use of radical oxygen scavengers (such as the antioxi-

dants) in association with sunscreens or with photosensitivesubstances in a co-encapsulation in nanocapsules or lipid-core nanocapsules showed satisfactory photostability for quer-cetin and octyl methoxycinnamate [45], as well as for butylatedhydroxytoluene and isotretinoin [81]. Indeed, PCL nanocap-sules or lipid-core nanocapsules act as physical sunscreensand, when used together with chemical sunscreens, such asbenzophenone-3, can improve the photoprotective effect ofthe formulations [52]. Semisolid formulations containingbenzophenone-3-loaded lipid-core nanocapsules remainedstable within 13 h of UVA light irradiation, showing asustained photoprotection.

3.1.3 Modifying skin penetration/permeationPolymeric nanocapsules have been used as vehicles for thetopical administration of lipophilic substances aiming a con-trolled skin penetration/permeation [82]. Depending of theactive compound, the nanocapsules can improve the perme-ation [83,84] or enhance the penetration into the differentskin layers limiting the permeation and avoiding the systemicabsorption of drugs [27,59,61,70,80]. For the in vitro penetration/permeation experiments, the nanocapsule suspensions can bedirectly applied on the skin [27,56,58,59,83,84] or incorporatedin a semisolid vehicle (see Section 3.3.2) [35,38,61,70,80].This kind of nanocarrier (nanocapsule, nanosphere or

nanoemuslion) influences the control of the drug penetrationthrough the skin [61]. A comparative study showed thatthe PCL lipid-core nanocapsules improved the nimesulidepenetration in the stratum corneum, as well as into the viableepidermis, demonstrating the reservoir capacity of that kindof colloid compared to nanospheres or nanoemulsion.The use of nanocapsules or lipid-core nanocapsules to

encapsulate chemical sunscreens showed an increase of thesunscreens levels in the outermost layers of the skin, restrictingits permeation when compared to similar conventionalsemisolid formulations [27,38,56,70]. Moreover, cationic PCLnanocapsules (coated with chitosan) showed higher amountsof benzophenone-3 in the outermost layers of the skin [56].The skin penetration of octyl methoxycinnamate was not

influenced by the semisolid vehicles (O/W and W/O emul-sions) when the sunscreen was encapsulated in nanocapsules [70].In another study, comparing suspension and semisolid formula-tions, the tretinoin nanoencapsulation was the limiting factor toa decrease in the drug permeability coefficient and an increase inits retention in the outermost layers of the skin [80].

3.2 Improvement of the biological or

pharmacological responsesThe main advantages of the colloidal drug delivery systems,considering their potential application in therapeutics, include

i) the increase of the therapeutic index by increasing the phar-macological response and reducing the side effects, ii) theincrease in the apparent solubility of water insoluble drugs,affecting the drug bioavailability and iii) the increase in thedrug chemical stability in physiological environments [6,8].

Common side effects related to nonsteroidal anti-inflammatory drugs (NSAID) are lesions in the gastrointesti-nal tract (stomach and gut). In this context, nanocapsulesand lipid-core nanocapsules have been studied for protectionof the gastrointestinal tract from the lesions caused bydiclofenac and indomethacin (Table 4).

A comparative study of the gastrointestinal tolerancecarried out with diclofenac-loaded lipid-core nanocapsulesand diclofenac-loaded nanospheres administered to ratsshowed significant reductions (about 90%) of the lesionalindices compared to the sodium diclofenac solution [60]. Thefreeze-dried powder of the diclofenac-loaded lipid-core nano-capsules showed similar protection after oral administration ofthe reconstituted product, indicating the stability of thosenanocapsules within the drying step [41].

The spray dried powders of the diclofenac-loaded lipid-corenanocapsules and the diclofenac-loaded nanospheres showed80 and 40% of protection, respectively, after the administrationof the reconstituted products to rats [60]. In addition, a compar-ative study carried out with lipid-core nanocapsules, nano-spheres and nanoemulsion loaded with indomethacin showedthat only the reconstituted nanocapsule formulation showedprotection of the gastrointestinal tract [40]. The resultsindicated the great advantage of the dried product of lipid-corenanocapsules over those of nanospheres and nanoemulsion [60].

The effect of lipid-core nanocapsules containing NSAID wasassessed in different classical inflammation models, such as ratpaw edema and neuroinflammation (Table 4). The treatmentof rats (8 days) with indomethacin-loaded lipid-core nanocap-sules was effective in reducing the paw edema induced bycomplete Freund’s adjuvant (CFA), a classical model for arthri-tis [85]. Similarly, the topical application of a hydrogel contain-ing nimesulide-loaded lipid-core nanocapsules reduced bothpaws edema induced by CFA and the granuloma formationon a cotton pellet (intradermic) [63]. In another study, simula-ting in vitro cerebral ischemia, organotypic hippocampal culturewas deprived of oxygen and glucose and cell death was reducedup to 20% with the administration of indomethacin-loadedlipid-core nanocapsules [86]. Additionally, the microglia acti-vation and the levels of inflammatory interleukins (IL-1b,IL-6 and TNF-a) were reduced, while the level of IL-10increased (anti-inflammatory interleukin).

Considering the therapeutic of cancer, specifically malig-nant gliomas, indomethacin-loaded lipid-core nanocapsuleswere selectively cytotoxic having an antiproliferative effectfor two glioma cell cultures [48]. Comparing the drug solutionwith the indomethacin-loaded lipid-core nanocapsules, thelatter had a more pronounced effect within the range of 5 to100 µmol L-1. On the contrary, the indomethacin ethyl estersolution had a more pronounced effect than the indomethacin

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ethyl ester-loaded lipid-core nanocapsules. Those differencesare related to the types of drug distributions in the formula-tions. The indomethacin is mainly concentrated at the poly-mer (mechanism type IV) and the indomethacin ethyl esteris mainly concentrated in the core of the lipid-corenanocapsules (mechanism type VI) [72]. The co-encapsulationof indomethacin and its ethyl ester in the lipid-core nanocap-sules showed the best antiproliferative effect for the glioma cellcultures [48]. After the in vivo administration of indomethacin-loaded lipid-core nanocapsules to rats, half of the animals pre-sented only residual glioblastoma cells, while the rest of thisgroup developed smaller-sized tumor (68% smaller comparedto the negative control) [50]. The result of the reduction was

comparable to that of the positive control group treated withtemozolomide. The lipid-core nanocapsules enable the drug tocross the blood--brain barrier.

Recently, a study showed that the indomethacin-loadedlipid-core nanocapsules were able to reduce cell death andneuroinflammation induced by ab-amyloid protein in orga-notypic hippocampal cell, increasing the levels of IL-10 andreducing glial activation [87]. Moreover, the treatment(14 days) conferred cognitive improvement to rats previouslydamaged with the protein, suggesting the potentiality of thisformulation for the treatment of Alzheimer’s disease.

PCL nanocapsules have been also proposed as drug carriersfor ophthalmic administration [31-34]. These devices are capable

Table 4. Biological evaluation of PCL nanocapsules and lipid-core nanocapsules.

Drug Evaluation Results Refs.

Diclofenac Gastrointestinal tolerance in rats Protective effect on gastrointestinal tissue [41,60]

Indomethacin Gastrointestinal tolerance in rats Prevention of gastrointestinal lesions [40]

Indomethacinand its ethyl ester

Cytotoxicity against glioma celllines in vitro

Decrease of cell viability in human and rat glioma cells;inhibition of glioma cells growth;synergic effect of both drug in inhibiting glioma cells growth;no cytotoxic effects on organotypic hippocampal culture

[48]

Indomethacin Glioblastoma growth in rats Reduction in tumor size;decrease of mitotic index and other histological characteristics;increase of intracerebral drug concentration in the hemispherewith glioma;improvement of survival rate

[50]

Indomethacin Ischemia in organotypichippocampal cells in vitro

Protection of the cells from damage induced by oxygen-glucosedeprivation;prevention of the increase in inflammatory cytokines levels(IL-1b, IL-6 and TNF-a);suppression of glial activation

[86]

Indomethacin Alzheimer’s disease in vitro andin vivo

Inhibition of cell death induced by ab-amyloid peptide inorganotypic hippocampal culture;elevation in anti-inflammatory cytokine level (IL-10) in organotypichippocampal culture;attenuation of memory impairment in rats;decrease in synaptic dysfunction triggered by ab-amyloid peptidein rats;suppression of glial and microglial activation in vitro and in vivo;increase of drug concentration in brain tissue;no alteration in organs and biochemical and hematological parameters

[87]

Indomethacinethyl ester

Anti-inflammatory activity inacute model

Reduction of paw edema after oral treatment [43]

Indomethacin CFA-induced arthritis in rats Reduction of paw edema;decrease of serum inflammatory cytokines (IL-6 and TNF-a);increase of serum anti-inflammatory cytokine (IL-10)

[85]

Nimesulide Anti-inflammatory activity inchronic models

Decrease of paw edema;reduction of granuloma formation

[63]

Clobetasolpropionate

Contact dermatitis andNTPDase activity

High NTPDase activity in the treatment of contact dermatitis;immunosuppressive effect

[78]

Quinine Antimalarial efficacy Reduce the effective dose by almost 30%, from 105 to 75 mg/kg/day;increase the partition coefficient of quinine into erythrocytes

[53]

Halofantrine Cardiovascular parameters, ECGand arterial blood pressure

Reduction of QT intervals; prolongation of ECG in rats [88]

Trans-Resveratrol Tissue distribution Increase of drug concentration in brain after intraperitoneal and oraladministration

[55]

Benzophenone-3 Immune response No immune response and cutaneous sensitization in mice after topicalapplication

[52]

CFA: Complete Freund’s adjuvant; ECG: Electrocardiogram; IL: Interleukin; NTPDase: Nucleoside triphosphate diphosphohydrolase; TNF: Tumor necrosis factor.

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of interacting [32] and even penetrating [31,34] the corneal epithe-lium. The cornea cells were viable after the instillation ofPCL nanocapsules [31]. Moreover, by using rhodamine-loadednanocapsules, it was demonstrated that PEG-coated nano-capsules had higher penetration, while chitosan-coated PCLnanocapsules presented higher corneal permeation [34]. PCLnanocapsules may also alter the quantitative elimination ofcyclosporin A, a model drug, from the eye [32].A possible drawback to the ophthalmic application of PCL

nanocapsules is the enzymatic degradation of the particles.After incubation with lysozymes, the nanocapsules aggregatedand the analysis of the polymer showed a decrease in theaverage Mw confirming the polymer degradation. In orderto stabilize the nanocapsules in the presence of lysozyme,poly(L-lysine) was adsorbed onto the nanocapsule surface [33].The pharmacokinetic parameters of indomethacin ethyl

ester [49] or diclofenac [60] in lipid-core nanocapsules, as wellas of quinine in nanocapsules [53], were similar to those deter-mined for the drugs in solutions. Interestingly, some influen-ces in the pharmacological response have been observed, forinstance when chitosan-coated quinine-loaded nanocapsulesreduced the effective dose in about 30% compared to thedrug solution. This pharmacodynamic improvement is aresult of the nanocapsule uptake by erythrocytes, in a waythat the drug concentration was twofold higher in erythro-cytes infected with Plasmodium berghei as compared to theadministration of the drug solution [53]. Another studyshowed that the cardiotoxicity of an antimalarial drug, halo-fantrine, was reduced after nanoencapsulation [88]. Addition-ally, the lipid-core nanocapsules might also be a valuabletool to treat parasitic diseases affecting blood cells consideringtheir uptake by macrophages [89].The pharmacokinetic study conducted with indomethacin

ethyl ester-loaded lipid-core nanocapsules [49] explained thereduction of the pharmacological effect by 30% when thisformulation was compared to the oral administration of theindomethacin solution [43]. The difference was a consequenceof the in vivo conversion of the ester to indomethacin [49], dif-ferently from the results observed when the in vitro invertedgut sac model was used showing no ester conversion [54].Tissue distribution of nanoencapsulated drugs can also be

modulated. The oral administration of (E)-resveratrol-loadedlipid-core nanocapsules to rats showed increases of the druglevels in liver, kidney and brain [55]. High levels of (E)-resvera-trol in the brain are strong evidences that this tissue is targetedusing the lipid-core nanocapsules by the oral route. In addition,after intraperitoneal administration, the drug in vivo distribu-tion and the gastrointestinal safety were analyzed showinghigh levels of the drug in liver, kidney and brain with lowlesional index when compared to the drug solution.The cutaneous application of lipid-core nanocapsules neither

caused sensitization nor induced immune and inflammatoryresponse [52,78]. Anionic or cationic lipid-core nanocapsules,prepared using lecithin and chitosan, are hemocompatible [30].Moreover, nonionic lipid-core nanocapsules did not show any

significant systemic toxic effect in acute and subchronic toxicitystudies, indicating that those nanocapsules are safe candidates toact as a drug delivery system [90].

The lipid-core nanocapsules did not present toxic effect fororganotypic hippocampal cultures [86]. Furthermore, in vivostudies performed with indomethacin-loaded or (E)-resvera-trol-loaded lipid-core nanocapsules (10 and 14 days) did notcause mortality or raise body weight in comparison with thecontrol group. Additionally, the necropsy showed modifica-tions neither on liver, stomach, kidney, heart and lung noron the weight of these organs [50,55].

3.3 Development of intermediate and dosage formsThe nanocapsule aqueous suspension can be used either as aliquid dosage form or as an intermediate product to preparesolid and semisolid products. The technological aspects ofthose preparations are discussed below.

3.3.1 Solid dosage formsNanocapsule suspensions generally do not separate phaseswithin a period of months. Nevertheless, powders containingnanocapsules can be prepared with the view of improving thephysicochemical stability and reducing the microbial growth,polymer hydrolysis, drug leakage or chemical degrada-tion [28,39,91]. In this way, drying techniques, such as spray-drying and freeze-drying, represent promising strategies [91,92].The freeze-drying technique (lyophilization) is a process ofdrying commonly used in the pharmaceutical industry. Inthe case of nanocapsules, cryoprotectants should be used toavoid the stress of the polymer wall [28], whereas for lipid-core nanocapsules those adjuvants prevent agglomeration [41].

PCL nanocapsules produced using PVA, as a stabilizer, didnot need the addition of cryoprotectants during the freeze-dried step, since PVA protected the particles from thestress [28]. However, after removing PVA, cryoprotectantssuch as sucrose, trehalose, maltose, glucose, mannitol, polyvi-nylpyrrolidone (PVP) and hydroxypropyl-b-cyclodextrinwere needed to maintain the nanocapsule diameters afterlyophilization [28]. After 6 months of storage, the lyophilizedPVP-coated nanocapsules did not collapse. On the otherhand, the nanocapsules that were dried using sucrose and glu-cose had significant decreases in the mean particle sizes withinthe first month of storage. The lyophilized product should bestored at temperatures below the glass transition temperatureof the formulations [29].

Another technique widely used in the pharmaceutical sec-tor viewing the production of powders from liquid prepara-tions is spray drying. This technique was first used toconvert nanocapsule aqueous suspensions to powders in2000 [93]. Spray drying of lipid-core nanocapsules using col-loidal silica as drying adjuvant showed powders presentingnanostructures at the particle surfaces [93]. When the silicaconcentration is insufficient, the particles become agglomer-ated, irregular and highly adhesive on the powder particle sur-face [36]. Another approach has also been proposed to obtain

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nanocapsules-coated drug-loaded silicon dioxide micropar-ticles as a new system to control either the release of hydro-philic or lipophilic drugs [94]. In this case, the model drug(diclofenac or sodium diclofenac) was incubated with colloi-dal silicon dioxide, which respective powders were added inblank-nanocapsule suspensions followed by a subsequentspray-drying step.

Lipid-core nanocapsules before and after spray dryingshowed similar mean diameters (photon correlation spectros-copy) [60,64,93]. However, when nanospheres were submittedto this process, a size reduction was observed due to their diffe-rent supramolecular structure compared to the lipid-corenanocapsules [39]. The stability of spray-dried powders consti-tuted either of indomethacin-loaded or diclofenac-loadedlipid-core nanocapsules showed constant drug contents andstable morphologies after 5 and 14 months of storage,respectively [39,95]. The use of colloidal silicon dioxide as dryingadjuvant was efficient, presenting different advantages mainlyfor oral administration [64]. In order to expand the range ofapplications, other adjuvants such as lactose, mannitol andPVP have also been proposed. When nanocapsules are spraydried using lactose, the powders are easily redispersible havingsimilar mean diameter to the original suspensions [37,96,97].

Recently, dexamethasone-loaded lipid-core nanocapsuleshave been used to prepare granules [66]. By wet granulationprocess, granulated microcrystalline cellulose, pregelatinizedstarch and stearic acid have been manually milled and mixedwith the nanocapsule suspension containing PVP. This inter-mediate product had stable drug content for 6 months [66]. Ina subsequent study, these granules were compressed to pro-duce tablets [98]. The average weight, hardness, friability anddrug content were in agreement with the requirements ofthe official guidelines. Scanning electronic microscopy analy-sis indicated that the nanocapsules are on the surface as well asin the inner compartment of the tablets, which solid dosageform controlled the dexamethasone release [98].

3.3.2 Semisolid dosage formsNanocapsules and lipid-core nanocapsules can be directly incor-porated in semisolid pharmaceutical dosage forms allowingtheir easy topical application. Several studies have evaluatedthe cutaneous performance of nanoencapsulated active substan-ces in semisolids, most of them hydrogels. Hydrogels ofCarbomer 940 [63,96], Carbomer Interpolymer Type A [78,80]

or hydroxyethyl cellulose [38,56] were prepared using partial ortotal nanocapsule suspension in the place of water.

In general, the nanocapsule structure is not modifiedafter incorporating the aqueous suspension in a gel. Particlediameter before and after gel incorporation was main-tained [56,77,78,96]. The nanocapsule morphology in thegel was similar to that in the aqueous solution [52,56]. In addi-tion, gels containing either PCL nanocapsules or chitosan-coated PCL nanocapsules were stable, the latter being morestable probably due to the more effective electrostaticrepulsion [56].

In general, hydrogels present a non-Newtonian behaviorwith pseudoplastic characteristics. The rheological behavior ofhydrogels (Table 5) is usually not altered by the incorporationof the nanocapsule suspensions [56,77,78,80].

3.3.3 Process scale up and commercial productsThe few scale-up studies of industrial production of nanocap-sules involve the interfacial deposition of preformed polymermethod [99], and the emulsification-diffusion method [100].The use of laboratory equipment geometrically close to theones used in laboratory scale and a right selection of operationalparameters guarantee the reproducibility of the mean size andsize distribution of particles during the scale up.

Another important step to industrialize a product is aprofitability analysis. Trierweiler and Trierweiler [99] com-pared different plants for the PCL lipid-core nanocapsuleproduction using the interfacial polymer deposition method.Regarding the selling price, the authors conclude that it isbetter to divide the daily production in two batches of10 kg instead of one batch of 20 kg.

Although the technologies for the industrial production ofnanocapsules and lipid-core nanocapsules are recent, thereare already examples of trademarks and commercial productsin the market. For instance, Nanochlorex� is a registerednamed of a patented product consisting of chlorexidine-loaded PCL nanocapsule-based gel. This product providesimmediate and sustained antibacterial activity against skinflora without causing discomfort to the volunteers. As anexample of commercial use of PCL nanocapsules, thePhotoprot� is a sunblock product, which novelty is basedon a dual technology of absorbing and scattering UVA andUVB light providing high sun protection.

4. Conclusion

PCL, a semicrystalline polymer, is biocompatible, biodegradableand is easy commercially available. For these reasons, this poly-mer has been widely studied in drug delivery especially for thepast 15 years. PCL microcapsules for drug encapsulation areproduced mainly to control the drug release, playing an impor-tant role on drug protection and stability. PCL polymer blendscan improve and modulate the properties of microcapsules.

PCL nanocapsules and PCL lipid-core nanocapsules havebeen proposed in pharmaceutical and cosmetic fields tomodulate the substance release, to control skin penetration/permeation and to enhance drug stability. Considering drug tar-geting, those carriers have been demonstrating promising resultsto deliver drugs reaching especially liver, kidney and brain.

5. Expert opinion

Microencapsulation is a well-established process in pharma-ceutical industry to protect drugs from chemical degradation,as well as a way to promote prolonged and controlled drugrelease. In this context, PCL is a useful polymer to prepare

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microcapsules. In general, the physicochemical properties ofthe formulations are affected by the concentration of PCLin the polymer blend. The higher the PCL concentration,the longer is the release. In other cases, the interaction ofPCL with other polymers in the blends leads to different mor-phologies, which influence the drug release. For example, theformation of pores in the microcapsules by blending PCLwith other polymers increases the rate of drug release. Fur-thermore, the chemical stability provided by PCL microen-capsulation is observed for both storage and enzymaticdegradation simulating biological environments.Nanoencapsulation, a more recent approach, offers new

possibilities in drug delivery. Interfacial deposition of polymerand emulsification-diffusion are the mostly used methods toproduce nanocapsules. Few studies compared formulationsobtained by those techniques using similar compositions. Inthis way, at the moment the similarities and differencesbetween the nanocapsule formulations prepared either byinterfacial polymer deposition or by emulsification-diffusion are not clear. Furthermore, in the near future thesupramolecular structure models for the nanocapsules pre-pared by one another method might be slightly differentfrom a simple core-shell model representing two compart-ments. The investigations tend toward the description of thesupramolecular structure on a lower hierarchical level of mat-ter organization considering the molecular arrangement of thematerials in the particle.PCL can be used as polymer to prepare different types of

nanocapsules presenting diverse flexibility according to thechemical nature of the core. Those nanocapsules are capableof controlling drug release and improving photochemicalstability. The physicochemical properties of the polymerwall affect the drug release rate mainly when the drug is moreconcentrated within the nanocapsules. In addition, they canmodulate cutaneous drug penetration and permeation andcan act as physical sunscreen due to their capability of lightscattering. Considering the pharmaceutical point of view,

PCL nanocapsules are versatile formulations; they can be usedin the liquid form, as well as incorporated into semisolid dosageforms, as hydrogels, not affecting their rheological profiles. Inaddition, powders, granules and tablets containing lipid-corenanocapsules are feasible and their structure remains intactindependent of the technique used (spray drying andfreeze-drying, wet granulation and compression, respectively).

The in vivo efficacy and safety of these systems are a funda-mental aspect to be addressed. Among the main advantages ofusing PCL nanocapsules or PCL lipid-core nanocapsules, it isworthy to highlight the reduction of side effects, a selectivedrug tissue distribution and better pharmacological responses,when compared either to a drug solution or to other kind ofcolloids, such as nanospheres or nanoemulsion. Furthermore,the lipid-core nanocapsules can deliver drugs across the bio-logical barriers, such as the blood--brain barrier, providingpassive targeting to brain even though the oral route is elected.Passive targeting is also achieved for inflamed tissues, demon-strating a great advantage for the treatment of chronic inflam-mation diseases. Moreover, the lipid-core nanocapsules can beconsidered as a good platform for delivering drugs in brain tis-sue to treat diseases, such as Alzheimer or others in whichinflammation is involved. Recently, acute and subchronic tox-icity studies demonstrated that lipid-core nanocapsules aresafe nanoparticles. The first reports concerning the safety ofPCL-based nanocapsules are published, showing promisingresults. The safety and the easy scale-up production openthe possibility of moving toward clinical trials.

Acknowledgement

The authors thank the Brazilian Agencies: CNPq/MCTI,CAPES and FAPERGS.

Declaration of interest

The authors declare that they have no conflict of interest.

Table 5. Semisolid formulations (hydrogels) containing PCL nanocapsules.

Polymer network former (concentration) Active ingredient Flow model/

rheological behavior

Refs

Carbomer 940 (0.25% w/w) Benzophenone-3 ND [52]

Carbomer 940 (0.2% w/v) Coenzyme Q10 Ostwald model/pseudoplastic behavior

[96]

Carbomer interpolymer type A (1.0% w/w) Dexamethasone ND [77]

Hydroxyethyl cellulose (2.0% w/v) Octyl methoxycinnamate ND [38]

Hydroxyethyl cellulose (1.0% w/v) Benzophenone-3 Ostwald model/pseudoplastic behavior

[56]

Carbomer interpolymer type A (0.5% w/w) Clobetasol propionate Herschel--Bulkley model/pseudoplastic behavior

[78]

Carbomer interpolymer type A (0.5% w/w) Tretinoin Herschel--Bulkley model/pseudoplastic behavior

[80]

Carbomer 940 (0.2% w/v) Nimesulide ND [63]

ND: Not determined.

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AffiliationAdriana Raffin Pohlmann†1,2,3,

Francisco Noe Fonseca2, Karina Paese2,

Cassia Britto Detoni2, Karine Coradini2,

Ruy CR Beck2 & Silvia S Guterres2

†Author for correspondence1Departamento de Quımica Organica,

Instituto de Quımica,

Universidade Federal do Rio Grande do Sul,

Av Bento Goncalves, 9500, PBox 15003,

Porto Alegre, CEP 91501-970, RS, Brazil2Programa de Pos-Graduacao em Ciencias

Farmaceuticas, Faculdade de Farmacia, UFRGS,

Av. Ipiranga, 2752, Porto Alegre,

CEP 90610-000, RS, Brazil3Professor,

Departamento de Quımica Organica,

Instituto de Quımica,

Universidade Federal do Rio Grande do Sul,

Av Bento Goncalves, 9500, PBox 15003,

Porto Alegre, CEP 91501-970, RS, Brazil

Tel: +55 51 33087237;

Fax: +55 51 33087304;

E-mail: adriana.pohlmann@ufrgs.br

A. R. Pohlmann et al.

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