INTRODUCTION:

Pilosebaceous unit plays an important role in permeation and penetration processes of topically applied compounds. Hair follicle is not only an important reservoir but also an entry point for topically applied substances and significantly contributes to transport of drugs into the skin.¹ The concept of targeted drug delivery to pilosebaceous unit is a worthwhile consideration in regard to the potential applications for treating conditions like acne, androgenetic alopecia, alopecia areata and some skin cancers. In addition to localized drug delivery to the pilosebaceous compartment, systemic delivery via the hair follicle could be appreciated.

Drug delivery and targeting using trans-epidermal pathway has been a major area of research for last few decades. However, pilosebaceous targeting is an emerging area in the field of drug delivery. Till date limited reports are available involving pilosebaceous targeting.

Therefore, this review discusses feasibility of pilosebaceous targeting along with experiment strategies, models and formulations. Particles having smaller size can penetrate to deeper layer of hair follicle. Thus, nanoformulations like liposomes, niosomes, microparticles represent a promising drug delivery module for pilosebaceous targeting.

Pilosebaceous unit:

Pilosebaceous unit comprise of hair follicle and associated sebaceous gland. Human pilosebaceous unit shows an extreme diversity with regard to its variation according to localization along the human body.² Figure 1 illustrates the hair follicle and associated structures.

Skin is traditionally divided into three major regions: stratum corneum, viable epidermis and dermis. The outermost of these layers, the stratum corneum serves as a barrier against external invaders. Viable epidermis lies below the stratum corneum and consist of stratified keratinized epithelial cells, whose ultimate function is to produce stratum corneum. Deepest layer of skin is dermis, which consists of dense, irregularly arranged connective tissue and it is nourished directly by blood vessels. Hair shaft consists of an outer cuticle, a cortex of melanin producing keratinocytes and an inner medulla. Root sheath, which surrounds the hair shaft, is composed of an outer and inner layer. Sebaceous glands are collaborated to hair follicles by ducts. Sebaceous gland produces sebum. Marked differences are seen in sebum composition among mammals. Triglycerides constitute the principle class of lipids present in sebum. Squalene, sterols, sterol esters, wax esters and various types of wax diesters are frequently present in sebum.³

Fig. 1: ‘A’ represents structure of hair follicle and ‘B’ represents keratinocytes in the hair matrix and their differentiation into the hair follicle shaft and root sheath lineages.

Hair growth cycle:

All hair follicles undergo a species specific growth cycle of alternating active growth and rest stages, as illustrated in Figure 2. There are three main phases of the hair growth cycle; anagen, catagen and telogen. Anagen represents the period of active cell division and upward migration of hair matrix cells to form hair shaft. Anagen phase is followed by relatively short catagen phase, which results into cessation of mitosis and resorption of the lower portion of hair follicle by apoptosis (programmed cell death). Upon completion of catagen, follicle withdraws from the dermal papilla and then follicle passes into the resting stage known as telogen phase. The cycle then returns to anagen after completion of telogen stage and the lower follicle is reformed.⁴

Fig.2: Development and cycling of hair follicles. Selected stages of the morphogenesis of hair follicles and the three stages of follicular cycling (anagen, catagen, and telogen) are shown. The roman numerals indicate morphologic substages of anagen and catagen. The pie chart shows the proportion of time the hair follicle spends in each stage.

Control of hair growth cycle:

Seasonal changes in hair growth are controlled by endocrine system under the coordinating influence of pineal gland, which transduces the environmental signals. It has been known for many years that plucking of resting hairs from telogen follicles advances the onset of anagen. This led to the idea that hair cycle is controlled by a locally active inhibitors that accumulates during anagen causing entry into catagen, when present in sufficient concentration (Chalone hypothesis).^5,6The Chalone hypothesis is based on the current concepts of paracrine and autocrine regulation of cell growth and differentiation. Studies revealed that levels of tissue growth factor (TGF), i.e., TGFb-1, TGFb-2, and TGFa remained constant during the cycle, whereas signals for TGF b-3 and bFGF (basic fibroblast growth factor) were present in anagen.⁷ More variable epidermal growth factor (EGF) levels were observed. EGF induces a catagen like changes in cultured human hair follicle.⁸ Modulators of hair follicle cycling in human are summarized in table 1.

Table 1: Modulators of hair follicle cycling in human

Modulator	Action
Androgen	Promote miniaturization of follicles and shorten duration of anagen stage in androgen-sensitive areas of scalp; enlarge follicles in androgen–dependent areas (e.g. male beard) during adolescence.
Estrogen	Prolong the anagen stage; postpartum reduction in estrogen secretion causes telogem effluvium.
Growth hormone	Acts synergistically with androgen during virilization in adolescence.
Prolactin	Can induce hirtutism.
Thyroxine	Low levels cause telogen effluvium; higher levels may cause telogen effluvium

Types of hair follicle:

Human hair can be divided into two major types: terminal hairs and vellus hairs (Fig. 3). Terminal hairs are macroscopically long, thick, pigmented, and mostly contain a medullary cavity. In contrast, the non-pigmented vellus hairs are thinner than terminal hair, silky, and do not grow longer than 2 cm. In the scalp region, hair follicles are arranged in so-called follicular unit, containing the pilosebaceous unit as well as 1–4 terminal hairs and 1–2 vellus hairs and encircled by branches from the same arrector pili muscle.

Fig. 3: Types of hair follicle

Disorders or diseases associated with hair follicle:

Disorders associated with hair follicle have been seen very widely in world. Many people are suffering from hair loss and affects about 35 million men and 21 million women in the United States alone. Acne is being the most common disorder affecting almost 80 % of world population. According to recent statistics, 2 in 8 women suffer from hirsutism sometimes during their life. Other disorders or diseases associated with hair follicle include hypertrichosis, cancer, etc. They are enlisted in table 2 along with their characteristics. Pilosebaceous targeting provides a new strategy in treatment of these disorders.

Potential target sites for drug delivery within the hair follicle:

Several target sites within the hair follicle may be accessible for topical delivery of compounds. Outer root sheath has been the major target site, which is in continuation with epidermis. The sebaceous glands are desirable target site in treatment of some skin disorders, such as acne and androgenetic alopecia, since their etiology is believed to be associated with sebaceous gland activity.⁹ Regulatory receptors for retinoic acid, epidermal growth factor and transforming growth factor have also been identified within the hair follicle, and identifies as feasible target sites for drug delivery.¹⁰

Table 2: List of disorders or diseases associated with pilosebaceous unit

Sr. No.	Diseases/ Disorders	Characteristics of disorders
1.	Alopecia	Abnormal hair loss, resulting in decreased density of hair
	a) Androgenetic alopecia	Baldness caused by miniaturization of genetically predisposed follicles in the male pattern (frontal recession and thinning at the vertex) or the female pattern (loss of hair primarily over the crown, with sparing of frontal hair)
	b) Alopecia areata	Hair loss in patches, thought to be caused by an autoimmune response to hair follicles in the anagen stage; extensive forms of the disorder are called alopecia areata totalis (hair loss over the entire scalp) and alopecia areata universalis (hair loss over the entire body)
	c) Permanent alopecia	Caused by destruction of hair follicles as a result of inflammation, trauma, fibrosis, or unknown causes; examples include lichen planopilaris and discoid lupus erythematosus
2.	Hirsutism	Excessive growth of coarse terminal hair in female
3.	Hypertrichosis	Excessive growth of long, often non-pigmented hair
4.	Acne	Characterized by seborrhoea and comedone formation, and inflammatory lesions such as papules, pustules, nodules and cysts may develop
5.	Cancer	Involved in uncontrolled growth (cancer) in pilosebaceous unit like trichofolliculoma

The mid-follicle bulge area may also be considered as a potentially significant site for targeted drug delivery. This population of cells, found just below the sebaceous gland, possesses one of the fastest rates of cell division in mammals.¹¹ Some kinds of skin cancer have been thought to be linked to this highly proliferative area of hair follicle, particularly during telogen phase. Studies have proved involvement of immunocompetent cell in hair growth, which encourage new therapeutic approaches to target these cells within the hair follicle. Etiologically alopecia areata is an autoimmune disease, which may lead to immunotherapeutic targeting of immune cells.¹² Gene therapy may also have great potential as many genes which control hair growth are identified. Hair follicle could also be exploited for systemic drug delivery in addition to localized targets. A bunch of capillaries surrounding hair follicles and sebaceous glands may facilitate systemic absorption through hair follicle.³

Formulation design for pilosebaceous targeting:

Studies have suggested that follicular delivery may be dependent on physiochemical properties of the drug and/ or vehicle.^13-19 Lipoidal environment of follicular canal may favour certain drugs and vehicle. Solvents (e.g. ethanol) may be used to delipidize or reorganize the sebum, thereby opening passageway for drug deposition within follicle. Wetting agents (e.g. sodium lauryl sulphate) may be useful in decreasing interfacial tension between hydrophilic drugs and sebum, thereby promoting drug partitioning and absorption.

Recent studies have indicated that particle size of the drug carrier systems may also be an important consideration in designing follicular delivery systems.²⁰ Delivery systems with optimally sized particles may allow preferential targeting to hair follicle rather than through stratum corneum lipid-keratinocyte matrix.

Models and techniques used for studying follicular delivery:

Specific role of hair follicle in percutaneous transport remains difficult to elucidate due to the lack of an appropriate animal model to distinguish transfollicular from transepidermal percutaneous absorption. Stump-tailed macaque monkeys have been extensively used for in vivo study of hair growth.²¹ Hormonal and genetic factors that cause alopecia in macaque have been proved to be identical to those in human androgenetic alopecia. Thus, macaque alopecia became a pertinent animal model for studies of human androgenetic alopecia. Besides this, Syrian hamster ear and Rodent models like fussy rat, follicle free rat (scar) skin are also used.²² Ventral side of the syrian hamster ear is rich in sebaceous glands and resemble human sebaceous glands which are large and androgen-sensitive.²³

In addition to difficulties in establishing appropriate models, problems associated with follicular skin sectioning and stripping techniques have also made the follicular route difficult to elucidate. Skin must be carefully sectioned to minimize cross-contamination of sections. Incomplete tape stripping may result in detection of artificially high marker levels in the residual skin. Harsh histological fixation techniques and varying visual interpretation have also hindered definition of transfollicular route. Besides this, follicular casting method, laser scan microscopy, fluorescence microscopy, autoradiography, etc. are also used for a careful observation and logical interpretation.²⁴

Pilosebaceous targeting using delivery systems

Drug delivery and targeting using transepidermal pathway has been a major area of research for last few decades. However, pilosebaceous targeting is an emerging area in the field of drug delivery. Till date limited reports are available involving pilosebaceous targeting and few delivery systems have been exploited.³

(A) Pilosebaceous targeting by liposomes:

Recent research efforts emphasize that micro- and nanoparticles, including solid lipid nanoparticles and liposomes,²⁵ represent effective carrier systems for topically applied drugs and cosmetics. Liposomal formulations provide several advantages over non-liposomal formulations, due to incorporation of hydrophilic as well as hydrophobic drugs. Hydrophilic molecules possess greater affinity for the hydrophilic head groups and aqueous core, whereas hydrophobic molecules tend to be intercalated into the lipid bilayer of liposomes. Recent studies have shown that liposomes serve as efficient carrier for topical delivery of small hydrophilic compounds to pilosebaceous unit.²⁶

Quantitative deposition of carboxyfluorescein (CF), into pilosebaceous unit has been studied.²⁷ Deposition of carboxyfluorescein from phospholipid liposomes was enhanced almost 8-fold than that of aqueous solution. Li et al. prepared hair follicle delivery system of liposomes entrapping fluorescent dye calcein and pigment melanin and applied topically to mice.²⁸ They observed negligible amounts of delivered molecules enter dermis, epidermis and blood stream, thereby demonstrating the enrichment of follicle delivery.

Antiandrogen RU 58841, used for hair loss treatment, was encapsulated in liposomes and compared with an alcoholic solution containing antiandrogen RU 58841.²⁹ In-vivo cutaneous distribution of alcoholic solution encouraged localization of drug into stratum corneum, whereas antiandrogen RU 58841 entrapped liposomes showed targeting to hair follicle. The topical application of monoclonal antibody entrapped liposomes to doxorubicin completely prevented doxorubicin-induced alopecia in rats.³⁰ Multilamellar phospholipid based liposomes labeled with a fluorescent, lipophilic dye have been utilized for delivery of 16000 Da DNA repair enzyme, T4 endonuclease V.³¹ An appreciable amount of enzyme was detected in pilosebaceous unit.

Pilosebaceous targeting of liposomally entrapped high molecular weight DNA has been reported,³² using mouse skin histocultures with hair follicles. DNA was labelled with 35S-dATP and entrapped in phosphatidylcholine-based liposomes. Autoradiograms indicated specific high radioactive labelling in cell membranes and cytoplasm of hair follicle cells in samples applied with liposomes as compared with application of DNA. Li et al. has shown that liposomes can selectively target hair follicles for delivery of small and large molecules.³³ They selectively targeted lac-Z reporter gene to hair follicles in mice after topical application of this gene entrapped in liposomes. They demonstrated that highly selective, safe gene therapy for hair process is feasible. Liposome entrapped melanin, proteins, genes and small molecules have been selectively targeted to hair follicle.³⁴ A novel method for isolation and maintenance of human pilosebaceous unit has been documented.³⁵ This method makes it possible to obtain viable human pilosebaceous units by microdissection, and to maintain them in vitro for up to 7 days with apparently full retention of hair follicle function, but only partial retention of sebaceous gland. This method provides a means for successful in vitro studies related with human pilosebaceous units. Besides liposome, hair follicles and sebaceous glands can be privileged pathways for some formulations, which enter faster into these shunts than the stratum corneum.³⁶ Lieb et al. studied elements that govern intrafollicular delivery of large molecules to follicles of human scalp skin in vitro.³⁷ Effect of size, charge and formulation on intra-follicular disposition of large molecular weight molecules were observed. Topical administration of liposome-DNA mixtures (lipoplex) to mouse skin and to human skin xenografts resulted in efficient in vivo transfection of hair follicle cells.³⁸ Transfection depended on liposome composition, and occurred only at the onset of a new growing stage (anagen phase) of the hair cycle.

(B) Pilosebaceous targeting by niosomes:

Niosomes are non-ionic surfactant based vesicles with closed bilayer structures, formed from self-assembly of non-ionic amphiphiles in aqueous media. Non-ionic surfactants overwhelm the problem of natural variability of phospholipids which is seen in case of liposomes and are reported to follow pilosebaceous route for entry into systemic circulation when vesicles based on these surfactants are applied topically. Niosomes formation involves a particular class of amphiphiles and aqueous solvent.³⁹In some cases, cholesterol is required for vesicle formation. Vesicle aggregation may be overcome by inclusion of molecules that stabilizes the system against formation of aggregates by repulsive steric or electrostatic effects.

In vivo hamster ear model has been used to quantitate pilosebaceous deposition of a predominantly hydrophilic peptide, a-interferon, and a predominantly hydrophobic peptide, cyclosporine.⁴⁰ Deposition from niosome, egg phosphatidylcholine based liposome, aqueous interferon, and hydro alcoholic cyclosporin solution was assessed. It was shown that greatest drug level resulted after application of a niosome formulation denoted as Novasome I. It consists of glyceryl dilaurate, cholesterol and polyoxyethylene 10-stearyl ether at a weight percent ratio of 57:15:28, respectively.

A correlation has been established between in vivo deposition of cimetidine and its anti-androgenic effect.⁴¹ Appreciable deposition of 3H-cimetidine was attained into pilosebaceous unit of hamster ear after topical application of 50% ethanol solution (pH 7.4), glyceryl dilaurate-based niosomes (pH 5.5) and egg phosphatidylcholine based liposomes (pH 5.5). It has been shown that hydro-alcoholic and niosome solutions appeared equipotent in suppressing sebaceous gland growth and pharmacological efficacy showed by niosomes were found to be more superior to liposomes.

(C) Pilosebaceous targeting by microspheres:

Microspheres display better stability and may allow a controlled release of active compound. Rolland et al reported that microspheres of 3–10 µm topically applied to human skin aggregated in the follicular orifices whereas particles larger than 10 µm remained on the skin surface.⁴² Particles <1 µm spread widely on intact skin and also penetrate into upper layers of stratum corneum of interfollicular epidermis, but no penetration into viable epidermis was observed. Specific delivery and controlled release of adapalene into hair follicles for 5 µm microspheres were demonstrated in vitro and in vivo on hairless rats and on human skin respectively.⁴³ Similarly, rhodamine-6G loaded 5 µm microspheres dispersed into silicone entered into follicular duct without penetration within the stratum corneum.⁴³ Methylene blue-loaded 5 µm microspheres penetrated into the follicular duct and in sebaceous glands structures of hairless rat skin without penetration into the stratum corneum.⁴⁴ Building on these findings, Toll et al recently performed a large series of investigations, to create a penetration profile regarding penetration using microparticles from 6.0 µm down to 0.75 µm on freshly excised human scalp skin. 6.0 µm particles aggregated in infundibular region of terminal hair follicles and penetrated down to approx. 500 µm, which corresponds approximately to entry level of sebaceous duct.⁴⁵ Smaller particles with a diameter of 1.5 or 0.75 µm penetrated deeper with 40% of terminal hair follicles targeted down to depth of the bulge region at approx. 800 µm.

(D) Pilosebaceous targeting by nanoparticles:

In large series of investigations in animal models (e.g. pig skin) as well as on human skin explants, Lademann and colleagues demonstrated that particles of different sizes and structures aggregated in the hair follicle openings and penetrated along the follicular duct, when applied onto the skin surface.⁴⁶ Penetration depths strongly depended on the size of particles and on hair follicle type. For example, Toll and colleagues demonstrated that microparticles with diameters of 750 and 1,500 nm penetrate deeper into scalp terminal hair follicles than microparticles with diameters of 3,000–6,000 nm.

Consistent with this observation, Vogt et al. found that, in small vellus hair follicles, particles in the size range of 750 nm remained in superficial parts of the infundibulum, while particles sized 40 nm penetrated deeply into follicular duct of vellus hair-bearing skin.⁴⁷ In a recent study, Lademann et al compared penetration depths of two fluorescein-containing hydrogels.⁴⁸ In one formulation, fluorescein was covalently bound to nanoparticles sized 320 nm, while other hydrogel contained free fluorescein. These experiments were performed in vitro on pig ear skin, because a high quantity of biopsies was required to receive statistically significant results. Furthermore, pig skin is known to be a suitable model for human skin.^49-51 Penetration depths were found to be approximately 300 µm in the case of both formulations. In order to confirm in vitro results, Lademann et al performed additional in vivo experiments.⁴⁸Under in vivo conditions, particulate formulation penetrated significantly deeper into hair follicles (approx. 1,500 µm) than nonparticulate formulation (approx. 500 µm).⁴⁸Same hydrogels (containing free fluorescein and fluorescein covalently labeled to 320-nm particles, respectively) were applied on calf region of male volunteers, which is characterized by a high follicular reservoir.⁵²

In case of nanoparticle containing formulation, fluorescein was detectable for a significantly longer period of time in the hair follicles (10 days) than when using the non-particulate formulation (4 days). Furthermore, it was calculated that storage time of nanoparticle containing formulation in hair follicles was significantly longer (10 days) in comparison to stratum corneum, where the particles were completely removed after 24 hrs.⁴⁶ This may be due to the particles being located only in superficial layers of the stratum corneum, which can be easily removed by washing, textile contact and the physiological process of desquamation.

Thus, above discussion confirms the targeting potential of various types of micro- and nano-carriers to pilosebaceous unit.

Marketed formulations:

Liposome hair energizer was launched by Lazartigue of Paris in 1990 for hair loss. It was claimed to be the first hair product with liposome technology. Then multiple cosmetic hair products have been introduced in market with nanoformulation technology. Some of them are enlisted in table 3 with their characteristics.

FUTURE PROSPECTS:

Topically applied liposomes, niosomes, microspheres, nanoparticles are capable of targeting wide range of drugs, including macromolecules into hair follicle. Targeted drug delivery to the pilosebaceous compartment may have profound therapeutic applications for treating several hair follicle associated disease states. Besides localized delivery, systemic delivery via hair follicle may be achieved. Thus, the pilosebaceous targeting could serve as the major paradigm in targeted delivery of bioactives in forthcoming future.

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53. http://www.regaine.co.uk Accessed on 25/06/2011

54. http://www.sinere.com/nanominox_en.html Accessed on 2/04/2011

55. http://www.sinere.com/nanominox-ms_en.html Accessed on 2/04/2011

56. http://www.sinere.com/nanominox-fms_en0.html Accessed on 2/04/2011

57. http://www.lipoxidil.com Accessed on 4/04/2011

Received on 21.07.2011 Accepted on 11.08.2011

Res. J. Topical and Cosmetic Sci. 2(2): July – Dec. 2011 page 45-51

Brand name	Formulation ingredients	Characteristics	References
Regaine	Liposomes contain 5% minoxidil	Liposomes improve the flux of content into skin and prevent or slow down hair loss	53
Nanominox©	Ethosomes contain 4% minoxidil	Ethosomes combine the penetration enhancing effects of liposomes and ethanol and achieve a better skin penetration than bare liposomes or ethanol water mixtures.	54
Nanominox-MS	Minoxidil sulfate in PG (propylene glycol)-liposomes.	Used as hair growth promoter	55
Nanominox-FMS	Minoxidil sulfate in PG-liposomes and Finasterid	Used as hair growth promoter	56
NanoSal™Minoxidil	Minoxidil in Solid hydrophobic nanosphere	A controlled release delivery system with bioadhesive properties, Completely free from alcohol and PG.	57
Lipoxidil Pro-6 MLL	Minoxidil (6 %) entrapped in multi-layer liposomes (MLL)	Accumulates in deeper skin layers, targets sebaceous glands and provides a constant flow to hair roots.	57