novel carriers for transdermal, review-india_2010

7/31/2019 Novel Carriers for Transdermal, Review-India_2010

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I J PA S International Journal of Pharmaceutical and Applied Sciences/1 (2)/2010ISSN 0976-6936

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Novel Carriers For Transdermal Drug Delivery: A Review

J. Jain 1*, A. Bhandari 1, D. Shah 1

1. APMC College of Pharmaceutical Education and Research, Motipura, Himatnagar, Gujarat, India,

383001

*Corresponding Author: Tel.:+919426025790, E-mail: [email protected]

Abstract:Various new technologies have been

developed for the transdermal delivery of someimportant drugs. Physical and chemical meansof crossing the lipophilic stratum corneum, the

outermost layer of the skin, are being explored.A thorough understanding of skin physiologyand the basics behind the new technologieswould be useful for understanding these excitingnew drug delivery systems. To facilitate drugthrough the transdermal barrier somenanocarriers like nanospheres, nanoparticlaes,nanocapsules, lipid nanocarriers, polymers etc.,are utilized. This review deals with the skinstructure, problems associated with transdermaldelivery, nanocarriers, interaction andtransportation of nanocarriers through skin andtoxicology of nanocarriers.Keywords: Transdermal Delivery, SkinPhysiology, Nanocarriers, Toxicology.

1. Introduction:Transdarmal delivery can provide a number ofadvantages over conventional methods of drugadministration, including enhanced efficacy,increased safety, greater convenience andimproved patient compliance. By delivering asteady flow of drugs into the bloodstream over anextended period of time, transedarmal systemscan avoid the peak and valley effect of oralinjectable therapy and can enabal morecontrolled, effective treatment. By avoiding firstpass metabolism through the gastrointestinal tractand the liver, the therapeutically equivalent for thetransdermal delivery of certain compounds canbe significantly less than the corresponding oraldosage, potentially reducing dosage related sideeffects.[1]

1.1 The Dermal BarrierThe skin, in Latin called cutis , is considered

the largest organ of the body, accounting morethan 10% of the body mass and having anaverage surface of approximately 2 m. This organenables the body to interact most intimately and

dynamically with the environment. The functionsof the skin are considered essential for thesurvival of the human beings in a relativelyaggressive environment, providing amultifunctional interface between the body and

the surrounding media. These functions havebeen classified as protective, homeostatic, orsensorial. The first two mentioned are mainlyfunction of its barrier properties, allowing thesurvival of humans among changes inenvironmental temperature, relative humidity,dangerous substances such as chemicals,bacteria, allergens, radiation, etc. To maintain itscharacteristics, this organ is in a continualrenewing process [2]. Due to its barrierproperties, the skin membrane is equally capableat limiting the molecular transport from and intothe body. Overcoming this barrier function will bethe purpose of transdermal drug delivery.In orderto understand the biopharmaceutical effects ofdermatological formulations, it is necessary toknow the anatomy, physiology and chemicalcomposition of the skin. Anatomically, the skinconsists on 4 basic layers: the stratum corneum(nonviable epidermis), viable epidermis, dermisand subcutaneous tissues (Figure 1). In additionto these structures, there are also severalassociated appendages: hair follicles, sweatglands, apocrine glands, and nails. Thesubcutaneous tissues , the inner most layer, ischaracterized by a fibrous connective structure,which is composed mainly by elastic fibres andfat. This layer acts as insulator, shock absorber,and reserve depot of calories and supplier ofnutrients for the more superficial skin layers. Onits domain are found the base of the hair follicles,the secretory portion of the sweat glands, thecutaneous nerves as well as networks of lymphand blood vessels. The dermis is a fibrous layerthat supports and strengthens the epidermis. Itsthickness varies from 2-3 mm. It consists of amatrix of loose connective tissue composed bycollagen, a fibrous protein, embedded in asemigel matrix, which contains water, ions andmucopolysaccharides. This matrix helps to hold


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associated with the skin barrier properties.Nevertheless, the transdermal delivery offersseveral advantages: the skin represents arelatively large and readily accessible surfacearea for absorption, the application is a non-invasive procedure that allows a continuousintervention, and it is possible to cease theabsorption preventing overdose or undesirableeffects. Compared with the traditional oraladministration route, transdermal delivery showsadditional advantages: it minimizes the first-passmetabolism, it avoids drug degradation under theextreme acidity of the stomach, it prevents erraticdelivery due to food interactions, and it providesmore controlled delivery. Among its majordisadvantages are: not all compounds aresuitable for transport across the skin, there aredifferent permeation rates depending on age,race, site of application and individuals, and alsoskin diseases can influence it [6, 7]. The goal ofthe transdermal administration of drugs is not toachieve a bolus-type drug input; rather, it isusually designed to offer a slow, sustainedrelease of drug over long periods of time. Currenttransdermal delivery systems, as transdermalocclusive patches, are capable to deliver drugs incases that oral administration is limited by poorbioavailability, side effects associated with highpeak plasma concentrations or poor compliancedue to the need of frequent administration [4, 8].

The criteria that merit consideration intransdermal delivery of drugs are: the nature ofthe barrier (discussed in the previous section),the balance between physicochemical propertiesof the membrane and the drug, and thetechnologies available to facilitate thetransdermal transport. Under normal conditions,there are three pathways postulated for theabsorption of substances through the SC:transcellular, intercellular (paracellular) (Figure 2)and transappendageal [6]. The predominant routeof transdermal penetration of the majority of theapplied drugs is through intercellular spaces;

therefore, the transdermal pathway is muchlonger than the normal stratum corneumthickness (~20 m) which was estimated as longas 500 m. If the transce llular pathway ispredominant, the diffusion involves severalpartitioning steps into the lipo- and hydrophilicdomains of the corneocytes and the lipid layersbefore reaching the viable epidermis [9]. Thetransdermal absorption process requires drugcharacteristics or an appropriate carrier whichshould be able to deliver the drug to the desiredskin deepness to reach topical or systemiceffects. In general the barrier limitations imposesthat the drug chosen for transdermal delivery

should be pharmacologically potent and hasphysicochemical characteristics which allow it tocross the main barrier, the stratum corneum.Among these requirements are: the drug mustpossess both lipoidal and aqueous solubility,which promote its permeation through thedomains of the stratum corneum, i.e. andappropriate partition coefficient (K~ 1-3) to havean optimum absorption ; the drug mobility mustbe high, i.e. molecular weight and volume mustbe appropriate to facilitate its diffusion through thelipid bilayer. The permeation through the skin willalso depend on the ionization degree of the drugat physiological and formulation pH, influencingas well its solubility and partition behaviour [4, 5,9, 10]. A good transdermal delivery system mustnot only provide an adequate drug release fromthe formulation, but also allow considerableamounts of drug to overcome the skin barrier,ensure a non-irritancy of the skin, and alsoensure that the drug will not be inactivated on theskins surface or during the permeation process[11].

2. Strategies to overcome the epidermalbarrier:

Since several years, researchers have beenworking on the development of new strategies toimprove the delivery of drugs through the skin.These could be separated in physical and

chemical methods.

2.1 Physical enhancement methods:Iontophoresis , which involves the use of

low current via an electrode in contact with theskin, inducing the drug delivery promotionthrough ion repulsion, decrease on the resistanceof the skin and electroosmosis in case of largemolecules.

Electroporation that uses the applicationof high voltage impulses during a very short timeto create temporary pores on the skin, the drivingforce of the drug permeation is the ion repulsion

or the electroosmosis.Sonophoresis uses low frequencyultrasonic energy to disrupt the lipid packing inthe SC creating aqueous pores which improvethe drug delivery.

Micro-needles array inducing thetemporary loose of the barrier properties until thelayer is recovered by the normal turnover cycle,as well as local thermal treatments have beenused to deliver drugs [13].

2.2 Drug delivery systems: Lipidic flexible particles as liposomes,

niosomes, ethosomes and transferosomes ,Solid


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lipid nanoparticles and nanostructured lipid carriers, Solid lipid nanoparticles and nanostructured lipid carriers.

2.3 Chemical enhancement methods : Increasing the hydration state of the SC by

a high water content in the formulation or byocclusion (which prevents the trans-epidermalwater loss from the tissue), some examples ofthis effect are given by patches and ointments,but tissue over-hydration is not a general rule forpenetration enhancement; enhancers whichdisrupt the lipid organization in the SC such asazone, terpenes, fatty acids, dimethylsulphoxide(DMSO) and alcohols; compounds able to alterthe protein organization in the SC, such asDMSO or urea ; compounds which increase thesolubility of the drug within the SC, e.g.Transcutol. The enhancement effect can also actindirectly, for example: modifying thethermodynamic activity of the drug in theformulation at the moment of the application, e.g.ethanol; solubilizing the drug in the donor, incase of poor soluble substances, e.g.surfactants.The main disadvantage of thechemical penetration enhancers is that most ofthem induce irritation or sensitation, causedamage and reduce the barrier function for alonger time. These conditions are not desirable inthe process of transdermal drug administration

[12, 14]

3. Drug Carrier Systems For DermalDelivery:

3.1 Solid nanocarriers in transdermaldrug delivery:

During the last decades, the study ofinorganic and colloidal particles such asnanocapsules, nanospheres, nanostructured lipidcarrier, etc. has been focused asdermal/transdermal drug delivery carriers. Some

of them will be addressed in detail in the followingsection. In general, solid colloidal nano-carrierssystems have been extensively studied as drugdelivery systems (DDS), mostly for oral andparenteral applications, and have shown to beone of the most promising strategies to achievesite-specific drug delivery [15]. To be consideredas potential human drug delivery systemsrequires that the material has to bebiocompatible, preferentially biodegradable, or atleast should be able to be excreted [16]. This maybe the reason why only a limited number ofbiodegradable polymeric nanoparticles [10, 17-21], solid lipid nanoparticles (SLN) and

nanostructured lipid carriers (NLC) [22-31] havebeen studied with respect to their potential fordrug systemic and topical administration.Nanoparticles can be used to deliver a widevariety of substances as hydrophilic orhydrophobic drugs, proteins, vaccines, biologicalmacromolecules, etc., and they can beformulated for targeted delivery, e.g. to the brain,lungs, lymphatic system, or made for long termsystemic circulation [17].

3.2 Lipid nanocarriers:Both, SLN and NLC, are composed of

physiological and biodegradable lipids, whichpossess a low cytotoxicity and also low systemictoxicity [32]. SLN consist of pure solid lipid whileNLC are made of a solid matrix entrapping liquidlipid compartment [26]. These carriers have beenthe most extensively studied for drug andcosmetic dermal applications.There are two mainpreparation methods described for SLN, the highpressure homogenization methods, which can beperformed under hot or cold conditions dependingon the drug stability, and the microemulsiontechnique. SLN posses some advantages whencompared with liposomes (also lipid carriers butwithout a solid structure) and emulsions, e.g. theprotection against chemical degradation of thedrug and the modulating capacity of the activecompound release. The main disadvantage of

SLN is that during storage the drug entrapped isexpulsed due to a change in the lipidconformation to a lower energy crystal state, atransformation from polymorphic to perfectcrystals, which allow no guest molecules in thestructure. To overcome this problem NLC weredeveloped. In these nano-carriers, solid and liquidlipid are mixed in such a combination that theparticle solidifies upon cooling but does not re-crystallize, remaining in amorphous state. Thisallows the drug to be accommodated in theparticle for a longer time and will increase thedrug loading capacity of the systems [25].Several

authors have studied the potential of SLN andNLC as topical delivery systems. Examples of theuse of lipid solid nanocarriers are: Santos Maia etal (2000) have shown that the incorporation ofprednicarbate into SLN increase the amount ofdrug which penetrated the human skin layerscompared with a commercially available cream[28]; on the other hand, Wissing and Mller(2002) incorporating the sunscreen oxybenzoneinto SLN, reported a decrease of the SCpenetration, characteristic desired whensunscreens are used [33]. The potential of thesecarriers are variable and must be studiedspecifically for the drug and delivery system.


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3.3 Polymeric nanocarriers:Not as extensively as SLN the potential of

polymeric nanocarriers have been studied for skindrug delivery.Polymeric nanoparticles areparticles of less than 1000 nm in diameter thatcan be prepared from natural or syntheticpolymers. Natural polymers, such as protein andpolysaccharides, have been not widely usedsince they vary in purity, and often requirepreparation processes which can lead to drugdegradation. The most widely used polymers aresynthetic polymers as polyalkylcyanoacrylates,poly(lactic acid), poly(glycolic acid) or theircopolymers, poly(lactide-co-glycolide), etc. Thelast mentioned polymers have a very well knownbiocompatibility and resorbability through naturalpathways, and their degradation and drug releaserate can be regulated according to the polymercomposition (monomers proportions andlinkages) [17, 34]. Poly(D,L-lactide-co-glycolide)(PLGA) have been extensively studied fordifferent therapeutic applications such assustained drug, vaccine, and gene delivery [35-37]. PLGA microparticles were described asvehicles for topical drug delivery, providing areservoir system for release into the skin [20, 37].Other polymeric nanoparticles examples havebeen: poly(-caprolactone) NP, used by Alvarez-Romn (2004) et al to increase the availability of

octyl methoxycinnamate within the SC [10]; andchitosan NP, used by Cui and Mumper (2001) forvaccine delivery to the viable epidermis [18].Despite of the apparent advantages comparedwith other DDS, polymeric nanoparticles appearrather unexplored for drug delivery to the skin.

4. Nanocarrier skin interactionmechanism:

Following the topical application of adermatological formulation the absorption of theactive compound could follow the transcellular,

intercellular (paracellular) and transappendagealpathway through the epidermal barrier.Themechanism of interaction of the nanoparticulatedcarrier systems and the skin and also thetransport pathways within the membrane of thedrug and/or the carrier, are required to establishthe possibility of using such systems to optimizethe drug transport process [10]. It has beendescribed that SLN, due to its particle size, areable to ensure a high adhesion to the SCenhancing the amount of drug which penetratesinto the viable skin. Furthermore, for SLNparticles between 200 and 400 nm an occlusiveeffect has been described on artificial membranes

[31], and reducing the trans-epidermal water lossand increasing the penetration of a occlusionsensitive drug into the skin layers [30, 38]. Inanother hand, in vivo studies indicated that NLChave been able to increase the anti-inflamatoryeffect of indomethacin on the time, correlated wellwith an increased permanence of the drug in theSC layers studied using tape stripping method[24]. The role of the hair follicles in thepenetration process is often neglected based onthe fact that the orifices of the hair follicles occupyonly approximately 0.1% of the total skin surfacearea. However it is not considered that the hairfollicles is an invagination of the epidermisextended deep into the dermis, increasing theabsorption area below the skin surface [39, 40].In the case of polymeric carriers, Rolland et alhave demonstrated hair follicle targeting using 5m PLGA -adapalen-loaded microparticles [39],as well as de Jalon et al have shown PLGA-microparticles penetration into porcine skin [37].In other studies, copolymer nanoparticles havebeen shown by Shim et al to deliver monoxidilthrough the skin in a size dependent form whenhairy rats where used [21]. Using polystyrenenanoparticles of 20 and 200 nm in diameter andporcine ear skin, Alvarez-Romn et al havedemonstrated that particles accumulate in thefollicular opening and that smaller particles favourthis localization [41]. Bigger particles of the same

polymer (0.75 6 m) were tested byLademanns group showing in vitro and in vivo size dependent particle penetration that wasindependent of the hair type (terminal vs. vellushairs). A massage increased the penetration intothe hair follicle [42]. Finally, the same group haveextensively studied the follicle penetration ofparticles using human skin and titanium dioxidemicroparticles which were found to reach only theouter layers of the SC as well as deep into thehair follicles. They stated out that particlepenetration was dependent on the activity of thehair follicle, i.e. hair growth and sebum production

will influence the particle penetration process [43-46]. As described before, follicular penetration ofnanoparticles (see figure 3) appear to be apromising mechanism The hair follicle deliveryhas several pharmacokinetic advantages as areduction or bypass of the tortuous pathway ofthe transepidermal absorption, decrease of thedrug systemic toxicity when the follicle act as longterm delivery reservoir and increasing additionallythe therapeutic index of some drugs as well asreducing the applied dose or frequency ofadministration for drug delivery.


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Figure 3 Size dependence of hair follicleparticle penetration.

Micro- as well as nanoparticles have been

demonstrated to reach deep into the hair follicles,where the barrier posses only a few layers ofdifferentiated corneocytes and can be consideredhighly permeable, and additionally the hairfollicles can act as long-term reservoir, beneficialcondition when transdermal delivery isintended.Techniques as confocal laser scanningmicroscopy (CLSM) offer the possibility ofvisualizing the distribution of fluorescent probes ina skin sample by optical sectioning withoutprevious cryofixation or embedding of the tissue,and it is considered as a valuable method forreporting the extent of penetration of moleculesinto the skin and for identifying the transportpathways [10]. Multi-photon fluorescence imagingcan also be applied as technique fordeterminations in vivo tissueabsorption/accumulation of dermatological andcosmetical preparations, such as interaction ofnanoparticulated systems with the skin [47, 48].

5. Nanocarrier toxicology:Nanocarriers are present in different

dermatological and cosmetic formulations. Themost commonly used carriers are liposomes;solid poorly soluble materials as titanium dioxideand zinc oxide; polymer particles and SLN. Thesmall size of the carriers give them an increasedratio surface to total atoms or molecules exposedto the interaction with cellular systems, increasingits biological activity. This large activity can eitherpositive (e.g. antioxidant, carrier capacity fortherapeutics, penetration of cellular barriers fordrug delivery) or negative (e.g. toxicity, inductionof oxidative stress or of cellular disfunction), or amixture of both. However, in strong contrast tothe efforts to increasing its positive properties forimproving the human health are the limitedattempts to evaluate the potentially undesirableeffects of nanoparticles when administered for

medical or cosmetical purposes [49]. Some of thestudies undertaken to evaluate the toxicologicalpotential of dermatologically appliednanoparticles have reported the following results:

Titanium dioxide nano- andmicroparticles have been studied byLademann et al who report that micro-sized particles get through the human SCand into the hair follicles [45];On other study, carried by Menzel et al,

using commercially available sunscreencreams and pig skin has reported thepenetration of nanoparticles(approximately 15 nm in diameter) in theSC and into the underlying stratumgranulosum through the intercellularspace [50].

Gamer et al studied the penetration of zinc oxideby tape-stripping method on porcine skin andfound that approximately 100% of the appliedamount remain in the uppermost layers of the SC,only a few samples showing the presence ofparticles in the deeper layers [51]. PLGAmicroparticles (1- 10 m in diameter) have beenstudied by de Jaln et al using pig skin and werefound to penetrate into the viable epidermis [37].Solid lipid nanoparticles have shown lowertoxicity than poly(lactide-co- glycolide) orpolyalkylcyanoacrylate nanoparticles whenadministered intravenously [32], but there are nostudies performed when topically applied.

6. Conclusion:Successful transdermal drug delivery requiresnumerous considerations owing to the natureand function of the site of application. It shouldalways be kept in mind, that the basic functionsof the skin are protection and containment. Asper these rulings, it would seem exceptionallydifficult to cross the skin for systemic absorption.However, with continuous exploration of thestructure, function and physicochemicalpropertties of the skin, more and more new drug

products are being developed for transdermaldelivery. The safe and effective drug delivery isthe ultimate target for each and every newtechnology ever explored.

7. References:[1] Vyas, S. P and Khar.K.R, transdermal drugdelivery, controlled drug delivery concepts andadvances, 1 st edition, Vallabh Prakashan,NewDelhi, 2002, pp. 412[2] Walters, K. A. and Roberts, M. S. Thestructure and function of skin, in K. A. Walters,ed., Dermatological and Transdermal

Formulations: Drugs and the Pharmaceutical


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Sciences, v. 119: New York, Marcel Dekker,2002, pp. 1-39.[3] Washington, N. , et al. Transdermal DrugDelivery, in N. Washington, ed., PhysiologicalPharmaceutics, Taylor and Francis,pp181-198(2001)[4] Naik, A. , et al. Transdermal drug delivery:overcoming the skin's barrier function,Pharmaceutical Science & Technology Today, 3(9) 2000, pp 318-326.[5] Cevc, G. Lipid vesicles and other colloids asdrug carriers on the skin, Advanced Drug DeliveryReviews, 56 (5):675-711 (2004)[6] Roberts, M. S. and Cross, S. E. Skin transport,in K. A. Walters, ed., Dermatological andtransdermal formulations: Drugs and thePharmaceutical Sciences, v. 119: New York,Marcel Dekker, 2002, pp. 89 - 195.[7] Cleary, G. W. Transdermal and transdermal-like delivery system opportunities: today and thefuture, Drug Delivery Technology, 3 (5):35-40.(2003)[8] Thomas, B. J. and Finnin, B. C. Thetransdermal revolution, Drug Discovery Today,9(16):697-703.(2004).[9] Hadgraft, J. Skin deep, European Journal ofPharmaceutics and Biopharmaceutics, 58(2):291-299.(2004).[10] Alvarez-Romn, R. , et al. Enhancement oftopical delivery from biodegradable nanoparticles,

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targeting, Current Opinion in Solid State &Materials Science, 6 (4), 2002, pp 319-327[18] Cui, Z. Chitosan-based nanoparticles fortopical genetic immunization, Journal ofControlled Release, 75 (3):409-419.(2001).[19] Mu, L. and Feng, S. S. A novel controlled

release formulation for the anticancer drugpaclitaxel (Taxol(R)): PLGA nanoparticlescontaining vitamin E TPGS, Journal of ControlledRelease, 86 (1):33-48.(2003).[20] de Jalon, E. G. , et al. Topical application ofacyclovir-loaded microparticles: quantification ofthe drug in porcine skin layers, Journal ofControlled Release, 75 (1-2):191-197(2001).[21] Shim, J. , et al Transdermal delivery ofminoxidil with block copolymer nanoparticles,Journal of Controlled Release, 97 (3):477-484.(2004).[22] Lombardi Borgia, S. , et al. (2005) Lipidnanoparticles for skin penetration enhancement -correlation to drug localization within the particlematrix as determined by fluorescence andparaelectric spectroscopy, Journal of ControlledRelease, 110 (1),151-163.(2005).[23] Mei, Z. , et al. Solid lipid nanoparticle andmicroemulsion for topical delivery of triptolide,European Journal of Pharmaceutics andBiopharmaceutics, 56 (2):189-196.(2003).[24] Ricci, M. , et al. Evaluation of indomethacinpercutaneous absorption from nanostructured

lipid carriers (NLC): in vitro and in vivo studies,Journal of Pharmaceutical Sciences, 94 (5):1149-1159.(2005).[25] Souto, E. B. , et al. Development of acontrolled release formulation based on SLN andNLC for topical clotrimazole delivery, InternationalJournal of Pharmaceutics, 278 (1):71-77(2004).[26] Mller, R. H. , et al. Solid lipid nanoparticles(SLN) and nanostructured lipid carriers (NLC) incosmetic and dermatological preparations,Advanced Drug Delivery Reviews, 54 (Suppl 1):131-S155.(2002).[27] Mller, R. H. , et al. Solid lipid nanoparticles

(SLN) for controlled drug delivery - a review of thestate of the art, European Journal ofPharmaceutics and Biopharmaceutics, 50(1):161-177(2002).[28] Santos Maia, C. , et al. Solid lipidnanoparticles as drug carriers for topicalglucocorticoids, International Journal ofPharmaceutics, 196 (2): 165-167.(2000).[29] Wissing, S. A. and Mller, R. H. A novelsunscreen system based on tocopherol acetateincorporated into solid lipid nanoparticles,International Journal of Cosmetic Science, 23 (4),2001, pp 233-243.[30] Jenning, V. , et al. Vitamin A loaded solid lipid


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nanoparticles for topical use: occlusive propertiesand drug targeting to the upper skin, EuropeanJournal of Pharmaceutics and Biopharmaceutics,49 (3), 2000, pp 211-218.[31] Jenning, V. , et al. Vitamin A-loaded solid lipidnanoparticles for topical use: drug releaseproperties, Journal of Controlled Release, 66 (2-3), 2000, pp115-126.[32] ] Mller, R. H. , et al. Cytotoxicity of solid lipidnanoparticles as a function of the lipid matrix andthe surfactant, Pharmaceutical Research, 14 (4),1997, pp 458-462.[33] Wissing, S. A. and Muller, R. H. Solid lipidnanoparticles as carrier for sunscreens: in vitrorelease and in vivo skin penetration, Journal ofControlled Release, 81 (3), 2002, pp 225-233.[34] Brannon-Peppas, L. Recent advances on theuse of biodegradable microparticles andnanoparticles in controlled drug delivery,International Journal of Pharmaceutics, 116 (1),1995, pp 1-9.[35] Panyam, J. and Labhasetwar, V.Biodegradable nanoparticles for drug and genedelivery to cells and tissue, Advanced DrugDelivery Reviews, 55 (3), 2003, pp 329- 347.[36] Yoo, H. S. , et al. Biodegradable NanoparticlesContaining Doxorubicin- PLGA Conjugate forSustained Release, Pharmaceutical Research,16 (7), 1999, pp 1114- 1118[37] de Jalon, E. G. , et al. PLGA microparticles:

possible vehicles for topical drug delivery,International Journal of Pharmaceutics, 226 (1-2),2001, pp 181-184.[38] Wissing, S. A. , et al. Investigations on theocclusive properties of solid lipid nanoparticles(SLN), Journal of Cosmetic Science, 52 (5):313-324.(2001).[39] Rolland, A. , et al. Site-specific drug deliveryto pilosebaceous structures using polymericmicrospheres Pharmaceutical Research, 10 (12),1993, pp 1738-1744.(1993).[40] Lauer, A. C. , et al. (1995) Transfollicular drugdelivery, Pharmaceutical Research, 12 (2):179-

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[42] Toll, R. , et al. Penetration profile ofmicrospheres in follicular targeting of terminal hairfollicles, Journal of Investigative Dermatology,123 (1):168-176(2004).[43] Lademann, J. , et al. Investigation of follicularpenetration of topically applied substances, SkinPharmacology and Applied Skin Physiology, 14(Suppl 1):17-22(2001).[44] Lademann, J. , et al. Hair Follicles - A long-term reservoir for drug delivery, SkinPharmacology and Physiology, 19 (4);232-236(2006).[45] Lademann, J. , et al. Penetration of TitaniumDioxide Microparticles in a SunscreenFormulation into the Horny Layer and theFollicular Orifice, Skin Pharmacology and AppliedSkin Physiology, 12 (5);247-256.(1990).[46] Schaefer, H. and Lademann, J. The Role ofFollicular Penetration, Skin Pharmacology andApplied Skin Physiology, 14 (Suppl 1), 2001, pp23 27.[47] Schenke-Layland, K. , et al. Two-photonmicroscopes and in vivo multiphoton tomographs-- Powerful diagnostic tools for tissue engineeringand drug delivery, Advanced Drug DeliveryReviews, 58 (7):878-896(2006).[48] Stracke, F. , et al. (2006) Multiphotonmicroscopy for the investigation of dermalpenetration of nanoparticle-borne drugs, Journalof Investigative Dermatology, 126 (10):2224-

2233(2006).[49] Oberdrster, G. , et al. Nanotoxicology: Anemerging discipline evolving from studies ofultrafine particles, Environmental HealthPerspectives, 113 (7):823 839(2005).[50] Menzel, F. , et al. Investigation ofpercutaneous uptake of ultrafine TIO 2 particles atthe high energy ion nanoprobe LIPISION, NuclearInstruments and Methods in Physics ResearchSection B: Beam Interactions with Materials andAtoms,219-220(2004).[51] Gamer, A. O. , et al. The in vitro absorption ofmicrofine zinc oxide and titanium dioxide through

porcine skin, Toxicology in Vitro, 20 (3):301-307(2006).

novel carriers for transdermal, review-india_2010

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