Investigation on factors affecting drug delivery using polymers and phospholipids 2

Table 1.1 An overview of lipid vesicle research in transdermal drug delivery.1998 Niosome, proniosome Keshary-Chien type diffusion cell mouse skin In vivo rat - Skin permeation increase

cells proliferate After replication, cells leave the basal layer and start to differentiateand migrate upwards through the epidermis towards the skin surface where they aretransformed into dead keratin filled cells (corneocytes) (Bouwstra and Honeywell-Nguyen 2002) Image of the epidermis is shown in Fig 1.1.

(a)

(b)

Fig 1.1 (a) Binary image of the human epidermis and localization of green fluorescence,

staining of cell nuclei with DAPI is shown as blue signal Slice view of stratum granulosum is shown in red fluorescence (b) Cross-section of human epidermis The nucleated cells of the epidermis have been stained blue, unsaturated lipids, including fatty acids and esters have been stained red Details on the method of sample preparation are mentioned in section 2.2.9 and 5.2.6.

The SC, also known as the horny layer, consists of 10-15 cell layers of keratin-richcorneocytes embedded in a lipid matrix (Silva et al., 2006) The SC has beenrepresented as a two-compartment mortar brick model proposed by Peter Elias (Elias1981) In this model the keratinized cells represent the “bricks” which are imbedded

in the hydrophobic crystalline lamellar lipid-rich matrix (mortar) (Menon 2002;Glombitza and Müller-Goymann 2002; Bouwstra and Honeywell-Nguyen 2002) Theintercellular SC lipids (mortar) comprise mainly ceramides (~40% w/w), free fattyacids (~10% w/w) and cholesterol (~25% w/w) The distinct lipid composition of theskin is the major rate-limiting barrier for topical and transdermal drug delivery(Wiedersberg et al., 2008; Elias, 1983; Downing 1992; Fatouros et al., 2006; Kim etal., 2008; Glombitza and Müller-Goymann 2002)

For any molecule applied to the skin, three pathways of skin permeation have beenidentified: (1) the intercellular lipid domains in SC; (2) transcellular pathway throughthe keratinocytes and (3) transappendageal permeation through the sweat glands andacross the hair follicles (Godin and Touitou 2007; El Maghraby et al., 2008)

1.2 Topical and Transdermal Drug Delivery

Topical drug delivery is widely used for the treatment of localized skin disease such

as acne vulgaris as well as musculoskeletal disorders However, over the past fewdecades there is an increasing emphasis on the transdermal delivery of drugs to treatsystemic diseases Both topical and transdermal delivery systems require the activeingredient to overcome the stratum corneum barrier Topical drug delivery helps to

the site of application while maintaining low serum concentrations However,transdermal delivery is defined as delivery of the drug through intact skin so that itreaches the systemic circulation in sufficient quantity to achieve therapeutic action(Stanos 2007).

Compared to conventional oral delivery methods, transdermal drug delivery (TDD)offers better patient compliance, improved bioavailability, reduced side-effects,elimination of first-pass effect, and easy termination of drug input Additionally,sustained drug delivery via the skin would reduce the dosing frequency and eliminatepeak plasma levels of the drug (Barry 2001; Schreier and Bouwstra 1994; Cappel andKreuter 1991; Kim et al., 2008; Park et al., 2008; Kiptoo et al., 2008)

Despite these advantages, the barrier nature of the skin presents a significant obstaclefor molecules to be delivered through it; most drugs do not cross skin at therapeuticrates and less than 20 drugs have been approved by FDA for transdermal delivery.Drugs that cross the stratum corneum barrier can generally diffuse to deepercapillaries for systemic distribution Therefore, many techniques have been used todisrupt the highly organized crystalline lipid matrix of stratum corneum Penetrationenhancers help to facilitate the absorption of active compounds through the skin.These include chemical penetration enhancers, supersaturated drug delivery systems,iontophoresis, electroporation, sonophoresis and vesicle delivery systems (ElMaghraby 2008)

Most permeation enhancers act on the SC to increase drug solubility in theformulation, enhance drug partitioning within the SC layer, disrupt the crystalline

lipid lamella and increase its fluidity, increase transepidermal water loss (TEWL) orcause skin lipid extraction (Barry 2001; Valenta et al., 2004; Vávrová et al., 2008;Bommannan et al., 1991) Some of the chemical enhancers that can temporarilydisrupt the barrier properties of the skin include; water, Azone derivatives, fatty acids,fatty esters, sulphoxides, alcohols, pyrrolidones, glycols, surfactants, terpenes andphospholipids (Williams and Barry 2004; Kim et al., 2008; Barry 1987; Foldvari2000).

It is also possible that some chemicals will stabilize the skin lipids and retard thedelivery of drugs across human skin (Hadgraft et al., 1996) Such compounds havepotential uses in dermatological formulations containing sunscreens, insect repellants,

or acne vulgaris-protecting agents They can increase the accumulation of the activecompound on the skin surface and minimize the adverse side effects which may becaused by systemic absorption (Asbill and Michnaik 2000)

An ideal drug for the transdermal delivery should have a low molecular weight (< 500Da) and sufficient lipophilicity to partition into the SC, but also be hydrophilic enough

to penetrate deeper into the skin and reach the systemic circulation Due to the barrierlimiting properties of the SC layer, this delivery method is limited for theadministration of potent drugs (Davidson et al., 2008; Kalia and Guy 2001; Guy andHadgraft 1987)

A number of physical techniques are used to gain information on the barrier function

of the SC and to study the interaction of penetration enhancers with the skin Some of

transform infrared spectroscopy (FTIR) and confocal laser scanning microscopy(Boncheva et al., 2008; Alvarez-Román et al., 2004; ABüyüktimkin et al., 1996;Beastall et al., 1988).

1.3 Skin Permeation Models

Bioavailability of topically or transdermally applied drugs may be determined usingvarious techniques The ideal method for assessment would be to study the systemicuptake in vivo by blood or urine sampling and measure the drug deposition on the skinlayers by tape stripping However due to compliance and ethic issues, these methodsare not feasible during the initial development of a novel pharmaceutical dosage form,and in vivo testings are mainly carried out in animal models (Puglia et al., 2004;Godin and Touitous 2007)

Numerous in vitro models, including diffusion cells are employed to assess the skinpermeation profiles and kinetic parameters (Bender et al., 2008) The most relevantmembrane for in vitro permeation studies is the human skin which is usuallyobtained from cosmetic surgery However, human skin is often difficult to obtaintherefore a wide range of animal models have been used as replacement for humanskin These include porcine, rabbit, mouse, rat, guinea pig and snake models (Godinand Touitous 2007; Bartek et al., 1972; Nicoli et al., 2006; Shin and Choi 2005).Other alternative substitutes include reconstructed skin models and artificialmembranes (Pappinen et al., 2008; Iervolino et al., 2000; Nolan et al., 2003)

1.4 Recent Formulation Developments

In the last two decades, colloidal drug delivery systems such as microemulsion,nanoemulsion, and lipid nanoparticles, have been employed to improve delivery ofdrug to the skin (Padamwar et al., 2006; Touitou et al., 1997; Verma et al., 2003;Puglia et al., 2004; Chen et al., 2007; Honeywell-Nguyen and Bouwstra 2005) Thesesystems provide controlled release of the active ingredients, they can be used for bothhydrophilic and hydrophobic drugs as well as have low production cost The smallparticulate vehicles can ensure close contact with the SC which significantly promotesdrug delivery into the skin (Fang et al., 2008) Ultra deformable vesicles have alsobeen developed which can pass the stratum corneum as intact vesicular form beforepermeating deeper in to the skin layers thus improve drug diffusion into the skin(Cevc et al., 1998 and 2002)

Another strategy for enhancing the percutaneous absorption of topically applied drugs

is to use a vehicle or a carrier such as polymers which facilitate transport of drugs intoand across the skin without affecting the physiochemical properties of stratumcorneum (Tadicherla and Berman 2006; Asbill and Michniak 2000) Polymericdelivery systems can protect the active ingredient from degradation and prolong ormodify the drug release pattern Polymers such as chitosan, polyacrylic acid (Silva etal., 2008), cellulose (Bodhibukkana et al., 2006; taepaiboon et al., 2007), poloxymer

(Nair and Panchagnula 2003), poly N-isopropylacrylamide (PNIPAM) (Lopez et al.,

2004) poly (ε-caprolactone) (Jiménez et al., 2004; Shim et al., 2004), polylactide (Ga

de Jalón et al., 2001a and b; Rolland et al., 1993; Tsujimoto et al., 2007), poly

vinylalcohol (Kenawy et al., 2007; Tao and Shivkumar 2007) in forms of hydrogels,membranes, micro or nanoparticles, have been explored as promising carriers forcontrolled delivery of drugs to the skin Recent research advances for the topicaldelivery of peptides, proteins, DNA and RNA to the skin include incorporation oflipid or polymer particles into devices such as microneedles (Prausnitz 2004; Tao andDesai 2003; Gill and Prausnitz 2007) and gene guns (Lee et al., 2008; Babiuk et al.,2000) to help target large protein molecules to Langerhans cells for vaccinationpurposes.

1.5 Hypothesis and Objective

Over the past decades, there has been a general realization that the bioavailability oftopically applied drugs is very low Drugs in topical or transdermal delivery systemsmay not penetrate the skin in sufficient amounts to exert a therapeutic effect Inattempts to overcome the poor penetration of drugs and to optimize drug releasecharacteristics, various strategies have been explored Tables 1, 2 and 3 depict some

of the recent developments in the field of topical and transdermal drug delivery Thepotential of polymers and phospholipids for improving the topical and transdermaldelivery of therapeutic agents and cosmetic ingredients is worth exploring

Factors that influence transdermal and topical drug delivery may be divided into threecategories: 1) drug related, 2) vehicle related and 3) skin related factors Drug relatedfactors include; particle size, molecular weight, stability, partition coefficient (Kp),diffusion coefficient and solubility of the drug in the chosen vehicle Factors related tothe vehicle include; amount of drug release from the vehicle, physicochemical

properties of the vehicle and the use of penetration enhancer Skin related factors are;metabolism, barrier structure of the skin and biological variation pertaining to race,sex and age This thesis attempts to explore some of these factors that influencetransdermal drug delivery Chapter 2 and 3 look into drug related factors, chapters 4-7explore some vehicle related factors while Chapter 8 looks at skin related factor.

Lipid vesicles are being widely used as vehicles in transdermal delivery systems A lot

of work has been done regarding the effect of lipid concentration, vesicle content,polarity and size as well as method of production of these vesicles on the skinpermeation of drug molecules However the effect of mixture of surfactants and theirhydrophilic-hydrophobic balance (HLB value) on the structure of the vesicles, theirstability, drug solubility as well as their effect on the skin permeation is still in theinitial stages Therefore the objective of Chapter 2 was to:

1) Explore the effect of two groups of non-ionic surfactants (Spans andTweens) on drug solubility

2) Study the effect of surfactant mixtures on skin permeability ofhaloperidol

3) Investigate the HLB value and surface tension on the structuralcharacteristics and stability of the vesicle as well as skin permeation ofdrug molecule

Properties of the drug molecule are the most important factor that influencestransdermal delivery As most drugs are solid in nature, therefore they are poorly

drug and optimize its delivery through the skin One approach to increase thesolubility of low water soluble drugs is the use of cyclodextrins Theseoligosaccharides can also help to decrease local irritation and reduce photosensitivity

of the drug The effect of cyclodextrin as a penetration enhancer is subject tocontroversies While most authors agree that cyclodextrins may help increase the skinpermeation of drugs, however the parabolic effect of cyclodextrin concentration onskin permeation of drug molecules is yet not clear This chapter was the first attempt

to explore the surface active effect of cyclodextrin derivatives and to relate the criticalmicelle concentration (CMC) of these surface active molecules to their penetrationenhancing effect This finding will help to explain the parabolic relationship betweenthe cyclodextrin concentration and skin permeation of drug molecules Objective ofthis chapter was to:

1) Explore the effect of cyclodextrin derivatives on the aqueous solubility

of haloperidol and study the molecular complexation mode2) Investigate the effect of ionization on the solubility and skinpermeability of haloperidol

3) Study the surface active effect of cyclodextrin derivatives and to helpexplain the parabolic relationship regarding the cyclodextrinconcentration and skin permeation of haloperidol

Recently much attention has been given to the role of polymers as potential carriers intransdermal delivery Polymers in the forms of nanoparticles, microparticles,hydrogels, and conjugated forms with lipid vesicles have been widely explored A

new form of polymeric carriers called nanofibers has been recently developed Thesesystems are being used in tissue engineering, however their potentials in drug deliverysystem has not been widely explored Nanofibers are easy to produce, do not requiremany excipients or complicated methods of production therefore may provide goodalternatives to conventional delivery systems Therefore in this thesis variouspolymers have been used to produce nanofiber mats for either topical or transdermaldrug delivery In Chapter 4 we intended to:

1) Develop a novel multilayered fiber mat from hydrophobic andhydrophilic polymers intended for transdermal delivery

2) Control drug release pattern from these fibers by manipulating thestructure of the fiber mat

3) Study the skin permeation profile of haloperidol from the fiber mat

In Chapter 5 we intended to develop a novel nanofiber mat for topical delivery of skinnutrients which can disintegrate within 15 min upon contact with water The specificobjectives of this chapter was to:

1) Develop a polymeric nanofiber mat that can be used to accommodateseveral skin nutrients such as ascorbic acid, retinoic acid, collagen andgold

2) Explore the effect of gold as a penetration enhancer

3) Compare these facial masks to commercial cotton masks in the market

In Chapter 6 we looked at the possibility of producing thermosensitive nanofiber matwhich can provide temperature response drug release and contain the skin permeation

of levothyroxine in the outer layer of the skin and prevent systemic toxicity Here wewanted to:

1) Develop a nanofiber mat from blends of polymers

2) Observe the physical structure and stability of the resulting fibers bymeans of electron microscopy and fourier transform infraredspectroscopy

3) Study the temperature-dependent drug release pattern

4) Investigate the skin permeation of levothyroxine from these fibersusing confocal microscopy

In Chapter 7 a different type of carrier using the polymers used in Chapter 6 wasformulated The influence of the size of the vehicle in the skin permeation of the drugwas investigated Therefore polymeric microparticles were developed and were tested

in terms of:

1) Drug encapsulation and long term stability

2) Drug release pattern and degradation rate

3) Polymer transition temperature and its effect on the skin permeation oflevothyroxine

Finally Chapter 8 looks at the skin related factors that influence the transdermaldelivery of molecules Here we intended to explore the barrier properties of the skin

structure and the changes induced during the course of skin permeation Morespecifically we intended to study the skin lipid fluidization and protein conformationchanges induced after skin treatment and to explore its effect on the skin permeation

of a hydrophilic drug

Details on the objective of this thesis are shown in Table 1.4 Further details on theobjective of each part of the work can be found in the respective chapters.

Table 1.1 An overview of lipid vesicle research in transdermal drug delivery.

1998

Niosome, proniosome

Keshary-Chien type diffusion cell (mouse skin)

In vivo ( rat)

- Skin permeation increased as the chain lengths of the alcohol increased

- Formulations with Span 80 resulted in higher skin permeation

- A single patch of proniosomal formulations produced same in vivo effect in the uterine mucosa as compared to daily application of ointment formulation.

Rhodes

1999

Niosome, proniosome

release

- Proniosome formulations were optimized in terms of their morphology, particle size, size distribution, and drug release profiles.

2001

Niosome, proniosome

Franz diffusion cell

diffusion cell (rabbit skin)

- Formulations with Span 60 yielded higher ketorolac flux across the skin than those with Tween 20.

- Change in lecithin content did not decrease the flux rate.

al., 2008

Proniosome, niosome

Chien diffusion cell (rat and human skin)

In vivo ( rat)

- Drug permeation from proniosomes was significantly higher due to the synergistic enhancing effect of surfactant and soya lecithin which increased the partitioning of the drug.

- In vivo studies showed that proniosome sustained the delivery of drug into the plasma.

etal., 2008

Proniosome, niosome

Remarks/ scope for future work:

The effects of a few non-ionic surfactants on the skin permeation have been studied; however there was no detailed investigation on theeffect of structural characteristics including the hydrophilic-liphophilic balance (HLB) and interfacial tension of non-ionic surfactants

on the rate of drug permeation across the skin

Table 1.1 An overview of lipid vesicle research in transdermal drug delivery.

In vivo (human subjects)

- Percutaneous permeation was significantly higher for Bola-niosomes than that observed for the free drug.

- Bola-niosomes were non toxic to human keratinocyte cells

- Ethosomal formulations increased skin permeation in vitro and in vivo, however due to the formation of a reservoir of the drug on the skin surface a more sustained release was observed as compared to water-ethanol solutions.

et al., 2008

Niosome, elastic niosome

Diclofenac diethylammonium

In vitro, Franz diffusion cell (rat skin)

Azidothymidine (AZT)

In vitro, Franz diffusion cell (rat skin)

- The aspasomal AZT showed much higher permeation than AZT solution With a lipophilic structure it partitioned into lipids of the skin and altered its structure thus enhancing the drug permeation into skin.

oedema; however cyclodextrin solutions were more effective than niosomes.

Table 1.1 An overview of lipid vesicle research in transdermal drug delivery.

al., 2004;

2005

Transferosome, niosome, liposome

Franz diffusion cell (nude mouse skin)

In vivo ( rat skin)

- Transferosomes could elicit immune response relative to intramuscular immunization where as niosomes and liposome produced weaker effects.

2008

Ethosome, liposome

Franz diffusion cells (human skin)

higher from ethosome when compared with conventional liposomes and ethanolic solutions of the drug.

al., 2006

Ethosome, transferosome

Franz diffusion cell (human skin)

In vivo (rat skin)

- Ethanol and the lipids synergistically increased the skin permeation of the drug.

- Ethanol disturbed the lipid bilayer of the stratum corneum and enhanced skin lipid fluidity It also fluidized the lipid structure

of ethosomes and produced soft vesicles that penetrated the disturbed SC layer.

- Drug quantity, partitioning from vesicle to the SC, drug release from the vesicle and diffusion of the free drug to the skin layers are some of the factors that influence the skin permeation of drug molecules.

- Affinity of the drug to the vesicle and its solubility in the skin lipids determines the drug release from the vesicles.

- Electron microscopic studies did not find any vesicles in the deepest layers of the SC.

Table 1.1 An overview of lipid vesicle research in transdermal drug delivery.

al., 1994;

2000; 2001

Liposome, ethosome

Fluorescence dye, caffeine,

minoxidil, testosterone

In vitro, Valia-Chien or Franz diffusion

(rabbit and nude mouse skin)

In vivo (rabbit)

- Liposome increased the accumulation of caffeine on the skin surface and decreased its skin permeation but oleic acid and transcutol enhanced the skin penetration.

- Ethosomes, can efficiently entrap molecules of various lyophilicities and can significantly enhance skin

permeation.

- Minoxidil and testosterone skin penetration was significantly higher from ethosomes compared to liposomes and ethanolic solution or commercial products.

- Ethosomes are non toxic to human fibroblast cells.

Touitou

2000

Ethosome, liposome

diffusion cell (mouse skin)

- Ethosomes entrapped more fluorescent probe and resulted in higher drug permeation when compared to that from liposomes.

al., 2001

Liposome, niosome

diffusion cell (mouse skin)

- Skin permeation of dithranol from liposomes was higher than niosomes.

al., 2002;

2006

Franz diffusion cell (Silastic membrane, pig skin)

- Very hydrophilic surfactants improve diffusion of TRA through the pig skin Less hydrophilic surfactants enhance skin retention; therefore depending on the structure of the surfactant, either transdermal or cutaneous delivery of drug-loaded niosome can be achieved.

- Pretreatment with the rigid vesicles decreased the

formation of a lipid barrier on the skin surface.

Table 1.1 An overview of lipid vesicle research in transdermal drug delivery.

2004; 2000

Franz diffusin cell (human epidermis)

- Oleic acid or surfactants can lead to more flexible liposomes and increase the drug permeation across skin.

- At higher concentration of surfactants, micelles were formed and skin delivery of estradiol was decreased.

increases the drug permeation from transferosomes.

- The content of phospholipids and the chelating agent influenced the permeation of drug into the skin.

Insulin, fluorescence dye,

gap junction protein (GJP)

In vitro, Franz diffusion cell (artificial

membrane, human skin)

In vivo (mouse and human)

- Ultradeformable vesicles can penetrate the SC layer.

- Insulin can penetrate the intact skin cells with high efficiency compared to subcutaneous administration.

bio Nonbio invasive transepidermal immunization with GJP loaded transfersomes, can simulate same immune response as those achieved by the repeated subcutaneous immunizations.

- Pretreatment with surfactant and phospholipids, caused

an increase in the skin permeation.

liposome

Hepatitis B surface antigen (HBsAg)

gave higher skin permeation and improved immunological response.

Remark /scope for future work:

The penetration enhancer/ retarding effect of lipid vesicles, on the skin permeation of various drug molecules can further be explored

by studying drug characteristics and lipid contents of these carriers.

Table 1.2 An overview of the drug-cyclodextrin inclusion research in transdermal drug delivery.

et al., 2008

Cyclodextrin, liposomes

diffusion cell, (guinea pig skin)

In vivo (guinea pig)

- Ketorolac-CD solution significantly increased the skin permeation when compared to Ketorolac-CD liposomes.

- The anti-inflammatory activity of the topically applied

ketorolac-CD gel was equal to the oral dosage and higher than the drug-ketorolac-CD inclusion in liposomes.

al., 2008

Chitosan film

cell (rat skin)

In vivo (rat)

- Skin permeation was significantly increased from chitosan films containing β-CD, but in vivo studies were not successful when compared to oral dosage forms.

2008

Transferosome β-CD

Franz diffusion cell

(rat skin)

- Addition of β-CD to the transferosomes increased the skin permeation.

- The enhanced water solubility of the drug-β-cyclodextrin complex

is responsible for the improved skin permeability.

- A parabolic relationship was found between the concentration of

CD and the penetration of the drug.

- Cyclodextrin increased MPZ solubility and its bioavailability on the skin surface.

Table 1.2 An overview of the drug-cyclodextrin inclusion research in transdermal drug delivery.

In vitro, Franz diffusion cell

increased the pharmacodynamic profile of bupranolol.

- No apparent erythema or skin reactions were found during the study in rabbits.

diffusion cell (rat skin)

- Addition of 20% CD did not change the drug permeation through skin significantly.

(cellulose nitrate membrane)

- 6-armPEG- α -CD enhanced the release of ascorbic acid from the acrylic-type pressure sensitive adhesives.

Table 1.2 An overview of the drug-cyclodextrin inclusion research in transdermal drug delivery.

al., 2006

DM--CD,

-CD, HP--CD, HP--CD

Franz diffusion cell

(rat skin)

In vivo (rat)

- In vitro drug permeation was significantly increased from the

permeation through the skin.

- Incorporating CD in propylene glycol increased the skin permeation

(rat skin)

- Ionization and HP- β-CD increase the skin permeation significantly

as compared to unionized drug.

- HP- β-CD may alter the barrier properties of the SC by extracting the lipids and enhancing the penetration of the drug.

al., 2002

Franz diffusion cell

(mouse skin)

- Increase in HP- β-CD concentration increased the skin permeation

of oxybenzone, however a parabolic relationship was observed between the CD concentration and drug permeation which was found

to be due to the formation of a drug reservoir on the skin surface.

Piribedil, S-9977 (a novel cognition enhancing drug)

In vitro, Franz diffusion cell

(rat skin)

- Drug-CD inclusion decreased the skin permeation.

- Skin permeation observed from S-9977-CD solution is due to the lack of complex formation.

- Combination of oleic acid and RM- β-CD synergistically increased the permeation of S-9977 through the skin.

- CDs extracted cholesterol from the SC layer in a dependent manner.

concentration Skin pretreated with CD did not increase the permeation of the drug.

Table 1.2 An overview of the drug-cyclodextrin inclusion research in transdermal drug delivery.

al., 1995

HP- β-CD, RM- β-CD

and Loftsson

1995

Methyl β-CD, CM-β-CD, maltosyl- β-CD

- PVP increased the drug-CD complexation, and had

a co-enhancing effect on drug permeation.

- The penetration enhancing effect depends on the type of the CD used.

Pandit 2004

HP- β-CD, PM- β-CD

- Both HP- β-CD and PM- β-CD interacted with the skin lipids.

- The flux of the drug was highest when the drug was

in the ionized state.

2005

by side diffusion cell (mouse skin)

- HP- β-CD did not act as a penetration enhancer and did not alter the lipid structure of the skin.

cells (cellulose nitrate membranes and rat skin)

- Skin permeation from solutions of drug-CD complex was enhanced.

- Incorporation of these complexes in liposomes decreased the skin permeation.

Table 1.2 An overview of the drug-cyclodextrin inclusion research in transdermal drug delivery.

al., 2004

HP- β-CD, β-CD

Piroxicam, carboxyfluorescein

In vitro, vertical diffusion apparatus (pig epidermis),

- HP- β-CD retarded the diffusion rate of hydrophilic drugs.

al., 1986

β-CD, DM- β-CD

Butylparaben, indomethacin, sulfanilic acid

In vitro, Flow through diffusion cell

(guinea pig skin)

- Drug-CD complex did not penetrate the skin

- Skin penetration of sulfanilic acid increased due to the lack of complex formation with CD and the induction of lipid extraction by DM- β-CD

- CDs decreased the skin penetration of butylparaben and indomethacin due to complex formation.

2003

HP- β-CD, β-CD

Franz diffusion cell (silicone membrane)

- Skin permeation from solutions containing different

CD concentrations was similar

- Addition of HPMC (antinucleant polymer) stabilized these supersaturated systems and prevented drug crystallization, and thus increased the permeation rate.