INTRODUCTION:

Human skin has been considered as the largest organ as well as one of the most important physiological barriers of the body for different types of causative agents responsible for various skin inflammatory diseases. It is made up of epidermis, known as stratum corneum which is the outermost layer (major barrier of the skin); dermis, just lower the epidermis; hypodermis, next to the dermis and skin appendages, mainly contain hair follicles with associated sebaceous glands, eccrine and apocrine sweat gland and nails. Each layer in the skin has its own function for protecting the body against infectious diseases and maintaining the texture of the skin, temperature and pH of the body (13, 6). From the various skin inflammatory diseases, acne vulgaris is most common. Initially, the pathological condition of acne vulgaris can be observed in the form of microscopic micro come do; which can later, develops in the form of come dones, papules, pustules and cyst on the pilosebaceous units of the skin. Although, acne vulgar is multifactoral, interplay activity of four well known factors have been observed as a major cause of this skin disorder. A surplus of sebum production secondary to sebaceous gland hyperplasia; faulty keratinization of epidermal hair follicles, causes hyper proliferation of follicles and formation of an in apparent micro come do and accumulation of lipids and cellular debris inside the blocked follicles encourages the enhancement in concentration and action of a bacterium, Propionibacterium acnes. The action of this bacterium triggers both adaptive and innate immunity with the activation of inflammatory cascade including cytokines and chemokines, along with neutrophils inflammatory factors. The result of inflammation is observed by enhancement in follicular rupture and subsequent leakage of lipids, bacteria, and fatty acids into the dermis. Besides it, it has been noticed that the action of keratinocytes and sebocytes in the developing acne vulgaris. Both the cells express Toll-like receptors (pattern recognition receptors) which recognize pathogen associated molecular pattern to induce innate immunity, necessary for pathogenesis of acne. Sebocytes are also able to induce innate immune response by activating lipid metabolism. Lesions of acne vulgaris can be observed on the areas of the neck, face, chest, upper arms and back because there is the highest concentration of sebaceous glands. A long with the internal factors, some external factors like mechanical obstruction (i.e., helmets, shirt collars), occupational exposures, or medications can induce the formation of acne. Hormonal imbalances are also capable in developing acne flares in women, during premenstrual times, and with an increased level in androgens, either from an adrenal or ovarian source. Excessive use of anabolic steroids can also trigger acne flares in men (4, 10, 13). Effect of various medications can also develop the condition of acne which has listed below in the table:

Table 1: Medications Responsible to Trigger Acne Development in Men

More Commonly	Less Commonly
Anabolic Steroids · Testosterone · Danazol (Danocrine)	Azathioprin (Imuran)
Bromides	Cyclosporin · Sandimmune · Neoral
Corticosteroids · Prednisone (Deltasone)	Disulfram (Antabuse)
Corticotropin	Phenobarbitol
Isoniazid (Nydrazid)	Quinidine
Lithium	Tetracycline
Phenytoin (Dilantin)	Vitamin B₁, B₆, B₁₂ and D₂

Referenced by Steven Feldman, Rachel E. Careccia, Kelly L. Barham, and John Hancox (2004). Diagnosis and Treatment of Acne. American Academy of Family Physicians (69: 2123-30, 2135-6)

For the treatment of acne vulgaris topical therapy has been applied on the affected areas. Various retinoids like adapalene (differin), tazarotene (tazorac), tretinoin (retin-A), tertinoin microsphere (micro) have been used in the treatment. Clindamycin (generic), arithromycin like antibiotics are also involved in the treatment of acne vulgaris (4, 7, 10, 13). The following table which has showed below is able to describe the formulation and side effects of the applied medications:

Table 2: Medications used for the Treatment of Acne vulgaris and their side effects

Medications

Side effects

Retinoids

· Adapalene (Differin)

· Tazarotene (Tazorac)

· Tretinoin (Retin-A)

· Tretinoin microsphere (Retin-A Micro)

Dryness, scaling, erythema, burning, irritation, and photosensitivity

Antibiotics

· Clindamycin (generic)

· Erythromycin

Local irritation; stains clothes

Referenced by Steven Feldman, Rachel E. Careccia, Kelly L. Barham, and John Hancox (2004). Diagnosis and Treatment of Acne. American Academy of Family Physicians (69: 2123-30, 2135-6)

The topical therapy has not been considered as a successful procedure to cure skin inflammatory diseases including acne vulgaris because of various side effects of the medications used in the treatment of acne vulgaris. Besides it, the major problem for the topical medication is the upper desquamating horny layer of skin, stratum corneum (epidermis) acts as a physiological barrier for the passage of foreign particles through the skin, inside the body. Stratum corneum has thickness of 10-20 µm having approximately 15-25 layers of dead, flattened, keratinized, stacked, cornified cells embedded in an intercellular matrix of lipids. The complex structure made of lipid intercellular matrix makes the epidermis a barrier to prevent transepidermal water loss. Among other skin layers, this layer possesses a rate-limiting barrier property for percutaneous drug transport. Lipid richness and low water content inside the epidermis makes it difficult for the passage of hydrophilic and charged molecules inside the skin. To overcome these difficulties, intense studies of researchers have introduced transdermal drug therapy which is a new way for the treatment and overall management of almost all kinds of skin inflammatory disorders including acne vulgaris. This work is a reviewed research applied on all the researches which have been done in the treatment of acne vulgaris through transdermal therapy (2, 3, 4, 7).

Mechanism of Introducing Transdermal Drugs:

Drug delivery from transdermal systems have become more convenient, attractive and less painful way for both researchers (to study) and patients. It has almost eliminated the concept of oral administration of drugs and hypodermic injections; hence, made an important contribution in the medical sciences. This therapy has been categorized into three generations which described the advanced procedure of delivering drugs as different kinds of the transdermal drug therapy. First generations of transdermal system have used transdermal patches which are able to deliver small, lipophillic and low-dose drugs. Second generations transdermal systems have introduced the technique of chemical enhancers, non-cavitational ultrasound and iontophoresis for drug delivery. Third generations of transdermal systems have targeted the uppermost layer of skin, the stratum corneum (physiological skin barrier), to deliver drugs inside the human skin. These systems include micro needles, thermal ablation, microdermabrasion, electro oration and cavitational ultrasound. With these advanced generations strategies, transdermal therapy have gained more positive impact among various other disease management methods (1, 5, 6, 9, 12).

First Generation Transdermal System (Transdermal Patches):

These products require a low molecular weight, lipophillic and efficient drug molecules in low doses. In transdermal patch designs, there is a reservoir for the storage of drug which is enclosed with an impermeable backing and has an adhesive which is able to make a contact with the skin. Water and sweat prevents the patch from permanent adhesion. Some designs employ drug dissolved in a liquid or gel-based reservoir, which can simplify formulations and permit the use of liquid chemical enhancers, such as ethanol. Transport of drug through stratum corneum follows passive diffusion pathway through intercellular lipids via twisted winding around corneocytes. This includes movement of hydrophilic molecules through lipid head group regions and lipophillic molecules through lipid tails. Therefore, this overall pathway is compelled by the requirements of structure and solubility of the drug molecule to diffuse across lipid bilayer of stratum corneum. There are some products available which diffuse transdermally like the transdermal patches. These include metered liquid spray, topical gels or other topical formulations that deliver small lipophillic drug into the stratum corneum after evaporation and absorption of the drug, which in turn, serve as a drug reservoir for over 10 hours. A transdermal spray to deliver estradiol is has been recently approved (5, 9, 11, 12). In a recenty study, it has been observed that tretinoin in proniosome colloidal vesicle have been used to treat acne vulgaris to reduce the problem of skin irritation (3).

Second Generation Transdermal Systems:

To increase skin permeability and reducing skin irritation, these transdermal systems have been developed. Conventional chemical enhancers have been designed in such a way that can easily disrupt the bilayer structured intracellular lipids found in stratum corneum with the help of integrating amphiphilic molecules into it, which then extract out lipids from the matrix of uppermost layer or disorganize the packing of the entire cellular matrix. Other molecules like liposomes, micro emulsions, prodrugs and dendrimers have also been developed as a chemical enhancer, which are capable in enhancing drug solubilization in the formulation, increasing drug lipophilicity and portioning of drug into the skin (9, 12).

Iontophoresis, another technique in second generation transdermal drug delivery, transport drugs by an electrical driving force across stratum corneum. In this technique, charged drug are moved with the help of electrophoresis while weakly charged or uncharged compounds prefer their movement by the electrosomotic flow of water produced due to the movement of mobile cations like Na⁺ instead of fixed anions like keratins in the stratum corneum. These small charged molecules and some macromolecules are able to change the skin barrier effect. The major advantage of this technique is high rate of drug delivery with the electric current which can be turned off or turned on and even modulated according the drug delivery profiles (9, 12).

Non-cavitational ultrasound, one of the advanced techniques in second generation transdermal systems that are able to deliver drugs more efficiently with the effect of pressure gradient and oscillations associated with ultrasound, which acts as a driving force to drug delivery by disrupting stratum corneum lipid structure and thereby enhancing skin permeability to that drug (9, 12).

Third Generation Transdermal Systems:

These transdermal systems have been created to deliver drugs more effectively across the stratum corneum without damaging the deeper tissues. Various techniques have been designed in it. Eletroporation, a technique in third generation transdermal systems, disrupts lipid bilayer structure of the skin by electrophoretic force (applied for milliseconds). The diffusion of drugs by the effect of this technique can persist for up to hours, resulting in an increased magnitude of transdermal products (9).

Cavitational ultrasound, another transdermal technique, a coupling medium (hydrogel) is used to allow oscillating the bubbles within densely packed tissue, between the ultrasound transducer and skin. These bubbles collapse at the skin surface and generate localized shock waves and liquid microjets towards stratum corneum. Due to the disruption of stratum corneum, the permeability for the drug is increased up to several hours (9, 12).

Micro needles therapy, also known as collagen induction therapy or percutaneous collagen induction (PCI), has been proved very useful in the treatment of acne scars. With this technique, high molecular weight drugs can be easily introduced through the skin, by creating micropores from micro needles, without disturbing the dermal nerves. This method increases the skin permeability for many compounds, ranging from small chemicals to nano-sized molecules. Depending upon the length of micro needle, the opening and the reversible nature of micro channels vary (close within few hours). Reversible nature of micro channels is very useful for the therapeutic compounds or cosmetic agent delivery in a controlled manner (8, 9, 12).

Thermal ablation, provide selective heating to the surface of the skin for generating micron-scale perforations into the stratum corneum. Heating for microseconds to milliseconds at hundreds of degrees is responsible for transfer of heat to skin surface without affecting the viable tissues below. Rapid vaporizing of water into the stratum corneum occurs in such a manner which results in volumetric expansion in the skin’s surface (9, 12).

Microdermabrasion, a final way in which tissues has been removed and altered for cosmetic purposes. This method is related to sand blasting at microscopic level, to increase the skin permeability for drugs (9, 12).

Adverse Effects of Transdermal Drug Therapy

A long with various benefits, there are certain weaknesses of transdermal therapy. As there are various advanced techniques introduced in the transdermal therapy to overcome the problem of skin irritation, but sometimes, local irritation can be caused at the target site (especially in case of transdermal patches). Micro needles can cause pain during applying the procedure, visibility of post-inflammatory hyper pigmentation, transient erythema and oedema. Besides it, composition of transdermal patches, might cause erythema, oedema or itching on the applied surface. Transdermal patches always require low molecular weight drug compounds, less than 500 Da. These patches might result in allergic reaction at the local site (5, 8).

CONCLUSION:

Transdermal therapy has various benefits over its adverse effects. Diseases like Acne vulgaris can be easily cured with the help of this method. Techniques like transdermal patches can be easily applied in case of mild to moderate acne conditions whereas micro needles can be used for the treatment of moderate to severe acne cases. Recently, researchers are continuously trying for successful application of transdermal techniques to cure various skin inflammatory diseases including acne vulgaris, which shows the bright scope for the use of transdermal drug delivery methods in future.

REFERENCES:

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11. Gregor Cevc, Gabriele Blume, Andreas Schätzlein, Dieter Gebauer, Amla Paul (1996). The Skin: A Pathway for Systemic Treatment with Patches and Lipid Based Agent Carriers. Science Direct, Advanced Drug Delivery Reviews. 349-378: 18(3).

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Received on 07.10.2015 Accepted on 22.10.2015

Research J. Topical and Cosmetic Sci. 7(1): Jan.-June 2016 page 23-26

DOI: 10.5958/2321-5844.2016.00005.4