Topical Drug Delivery Systems

Topical preparations are used for the localized effects at the site of their application by virtue of drug penetration into the underlying layers of skin or mucous membranes.

 The main advantage of topical delivery system is to bypass first pass metabolism. Avoidance  of  the risks and inconveniences of intravenous therapy and of the varied conditions of absorption, like pH changes, presence of enzymes, gastric emptying time are other advantage of topical preparations. Semi-solid formulation in all their diversity dominate the system for topical delivery, but foams, spray, medicated powders, solution, and even medicated adhesive systems are in use. The topical drug delivery system is generally used where the others system of drug administration fails or it is mainly used in pain management, contraception, and urinary incontinence. This review describes the various formulation aspects, various excipients, evaluation tests, challenges and drugs explored in the field of topical drug delivery. 

 Introduction 

 Over the last decades the treatment of illness has been accomplished by administrating drugs to human body via various routes namely oral, sublingual, rectal, parental, topical, inhalation etc. Topical delivery can be defined as the application of a drug containing formulation to the skin to directly treat cutaneous disorders (e.g. acne) or the cutaneous manifestations of a general disease (e.g. psoriasis) with the intent of containing the pharmacological or other effect of the drug to the surface of the skin or within the skin. Semi-solid formulation in all their diversity dominate the system for topical delivery, but foams, spray, medicated powders, solution, and even medicated adhesive systems are in use.

 

Topical delivery includes two basic types of product:

• External topicals that are spread, sprayed, or otherwise dispersed on to cutaneous tissues to cover the affected area.
• Internal topicals that are applied to the mucous membrane orally, vaginally  or on  anorectal tissues for local activity.  

For the most part topical preparations are used for the localized effects at the site of their application by virtue of drug penetration into the underlying layers of skin or mucous membranes. Although some unintended drug absorption may occur, it is sub therapeutics quantities and generally of minor concern.

Advantages of Topical Drug Delivery Systems:

• Avoidance of first pass metabolism.
• Convenient and easy to apply.
• Avoidance of  the risks and inconveniences of intravenous therapy and of the varied conditions of absorption, like pH changes, presence of enzymes, gastric emptying time etc.
• Achievement of efficacy with lower total daily dosage of drug by continuous drug input.
• Avoids fluctuation in drug levels, inter- and intrapatient variations.
• Ability to easily terminate the medications, when needed.
• A  relatively large area of application in comparison with buccal or nasal cavity
• Ability to deliver drug more selectively to a specific site.
• Avoidance of gastro-intestinal incompatibility.
• Providing utilization of drugs with short biological half-life, narrow therapeutic window.
• Improving physiological and pharmacological response.
• Improve patient compliance.
• Provide suitability for self-medication.

Disadvantages of Topical Drug Delivery Systems:

• Skin irritation of contact dermatitis  may  occur  due to the drug and/or excipients.
• Poor permeability of some drugs  through  the  skin.
• Possibility of allergenic reactions.
• Can be used only for drugs which require very small plasma concentration for action
• Enzyme in epidermis may denature the drugs
• Drugs of larger particle size not easy to absorb through the skin

Classification of Topical Drug Delivery Systems:

Classification of Topical Drug Delivery Systems based on physical state

(A) Solid:

• Powder
• Aeroso
• Plaster

(B)Liquid :

• Lotion
• Liniment
• Solution
• Emulsion
• Suspension
• Aerosol

(c)  Semi-solid :

• Ointment
• Cream
• Paste
• Gel
• Jelly
• Suppository

Permeation through skin

Most of topical preparations are meant to be applied to the skin. So basic knowledge of skin and its physiology, function and biochemistry is very important for designing topicals. The skin is the heaviest single organ of the body, combines with the mucosal lining of the respiratory, digestive and urogenital tracts to from a capsule, which separates the internal body structures from the external environment. The  pH of the skin varies from 4 to 5.6. Sweat and fatty acids secreted from sebum influence the pH of the skin surface. It is suggested that acidity of the skin helps in limiting or preventing the growth of pathogens and other organisms¹¹.

Physiology of the skin: ^11-14

The skin has several layers. The overlaying outer layer is called epidermis, the layer below epidermis is called dermis. They dermis contain a network of blood vessels, hair follicle, sweat gland & sebaceous gland. Beneath the dermis are subcutaneous fatty tissues. Bulbs of hair project in to these fatty tissues.

Figure 2 -Cross section of human skin

The layers of epidermis are:

• Stratum Germinativum (Growing Layer)
• Malpighion Layer (pigment Layer)
• Stratum Spinosum (Prickly cell Layer)
• Stratum Granulosum (Granular Layer)
• Stratum Lucidum
• Stratum Corneum (Horny Layer)

Epidermis

It is the outermost layer of the skin, which is approximately 150 micrometers thick. Cell from lowers layers of the skin travel upward during their life cycle and become flat dead cell of the corneum. The source of energy for lower portions of epidermis is also glucose, and the end product of metabolism, lactic acid accumulates in skin.
Stratum Germinativum: Basal cells are nucleated, columnar. Cells of this layer have high mitotic index and constantly renew the epidermis and this proliferation in healthy skin balances the loss of dead horny cells from the skin surface.
Malpighion Layer: The basal cell also include melanocytes which produce the distribute melanin granules to the keratinocytes required for pigmentation a protective measure against radiation.
Stratum Spinosum: The cell of this layer is produced by morphological and histochemical alteration of the cells basal layers as they moved upward. The cells flatten and their nuclei shrink. They are interconnected by fine prickles and form intercellular bridge the desmosomes. These links maintain the integrity of the epidermis.
Stratum Granulosum: This layer is above the keratinocytes. They manufacturing   basic staining particle, the keratinohylline granules. This keratogenous or transitional zone is a region of intense biochemical activity and morphological change.
Stratum Lucidum: In the palm of the hand and sole of the foot, and zone forms a thin, translucent layer immediately above the granule layer. The cells are non-nuclear.
Stratum corneum: At the final stage of differentiation, epidermal cell construct the most superficial layer of epidermis, stratum corneum.  At friction surface of the body like palms and soles adapt for weight bearing and membranous stratum corneum over the remainder of the body is flexible but impermeable. The horny pads (sole and palm) are at least 40 times thicker than the membranous horny layer

Dermis

Non-descriptive region lying in between the epidermis and the subcutaneous fatty region. It consist mainly of the dense network of structural protein fibre i.e. collagen, reticulum and elastin, embedded in the semigel matrix of mucopolysaccaridic 'ground substance'. The elasticity of skin is due to the network or gel structure of the cells. Beneath the dermis the fibrous tissue open outs and merges with the fat containing subcutaneous tissue. Protein synthesis is a key factor in dermal metabolism.

Subcutaneous tissue

This layer consist of sheet of fat rich areolar tissue, know as superficial fascia, attaching the  dermis to the underlying structure. Large arteries and vein are present only in the superficial region.

 Skin Appendages

The skin is interspersed with hair follicle and associated sebaceous gland like regions two types of sweat glands eccrine and apocrine. Collectively these are referred to as skin appendages.

Functions of skin:¹⁵

• Containment of body fluids and tissues.
• Protection from external stimuli like chemicals, light, heat, cold and radiation.
• Reception of stimuli like pressure, heat, pain etc.
• Biochemical synthesis.
• Metabolism and disposal of biochemical wastes.
• Regulation of body temperature.
• Controlling of blood pressure.
• Prevent penetration of noxious foreign material & radiation.
• Cushions against mechanical shock.
• Interspecies identification and/ or sexual attraction.

Biochemistry of skin:^15-16

Epidermis

The source of energy for the lower portion of epidermis is also glucose and the end product of metabolism; lactic acid accumulates in the skin, which result in a drop in tissue pH from the usual 7 to less then 6. During differentiation from basal cells to stratum corneum by degradation of the existing cellular components, the entire cellular make-up changes. Specialized cellular organelles called lysosomes contain a host lytic enzyme, which they release for intracellular lysis. The epidermis is reservoir of such lytic enzymes. Many of these enzymes are inactivated (probably by auto catalytic processes) in upper granular layer; however, many also survive into the stratum corneum. The stratum corneum also has proteolytic enzymes involved in this desquamation.

Dermis

Despite its greater volume, the dermis contains far fewer cells than the epidermis and instead much of its bulk consists of fibrous and amorphous extra cellular matrix interspersed between the skin's appendages, nerves, vessels, receptors and the dermal cells. The main cell type of the dermis is the fibroblast, a heterogeneous migratory cell that makes and degrades extracellular matrix extracellular matrix components. There is significant current interest in the factors that control the differentiation of the dermal fibroblast, particularly in the context of their increased synthetic and proliferative activity during wounding healing. The dermis is home to several cell types including multi-functional cells of the immune system like macrophages and mast cells, the latter which can trigger allergic reactions by secreting bioactive mediators such as histamine.

Skin surface

The skin surface has a population of microorganisms.  They can contribute to the skin enzymology. Their diversity and abundance can vary considerabely among individuals and body sites. They can also effect skin surface lipid composition via hydrolysis of secreted sebum.

Absorption through skin:^16-18

Two principal absorption route are identified:

Transepidermal absorption

It is now generally believed that the transepidermal pathway is principally responsible for diffusion across the skin. The resistance encountered along this pathway arises in the stratum corneum. Permeation by the transepidermal route first involves partitioning into the stratum corneum. Diffusion then takes place across this tissue. The current popular belief is that most substances diffuse across the stratum corneum via the intercellular lipoidal route. This is a tortuous pathway of limited fractional volume and even more limited productive fractional area in the plane of diffusion. However, there appears to be another microscopic path through the stratum corneum for extremely polar compounds and ions. Otherwise, these would not permeate at rates that are measurable considering their o/w distributing tendencies. When a permeating drug exits at the stratum corneum, it enters the wet cell mass of the epidermis and since the epidermis has no direct blood supply, the drug is forced to diffuse across it to reach the vasculature immediately beneath. The viable epidermis is considered as a single field of diffusion in models. The epidermal cell membranes are tightly joined and there is little to no intercellular space for ions and polar nonelectrolyte molecules to diffusionally squeeze through. Thus, permeation requires frequent crossings of cell membranes, each crossing being a thermodynamically prohibitive event for such water-soluble species. Extremely lipophilic molecules on the other hand, are thermodynamically constrained from dissolving in the watery regime of the cell (cytoplasm). Thus the viable tissue is rate determining when nonpolar compounds are involved.
Passage through the dermal region represents a final hurdle to systemic entry. This is so regardless of whether permeation is transepidermal or by a shunt route. Permeation through the dermis is through the interlocking channels of the ground substance. Diffusion through the dermis is facile and without molecular selectivity since gaps between the collagen fibers are far too wide to filter large molecules. Since the viable epidermis and dermis lack measure physiochemical distinction, they are generally considered as a single field of diffusion, except when penetrants of extreme polarity are involved, as the epidermis offers measurable resistance to such species.

Transfollicular (shunt pathway) absorption

The skin’s appendages offer only secondary avenues for permeation. Sebaceous and eccrine glands are the only appendages, which are seriously considered as shunts bypassing the stratum corneam since these are distributed over the entire body. Though eccrine glands are numerous, their orifices are tiny and add up to a miniscule fraction of the body’s surface. Moreover, they are either evacuated or so profusely active that molecules cannot diffuse inwardly against the glands output. For these reasons, they are not considered as a serious route for percutaneous absorption. However, the follicular route remains an important avenue for percutaneous absorption since the opening of the follicular pore, where the hair shaft exits the skin, is relatively large and sebum aids in diffusion of penetrants. Partitioning into sebum, followed by diffusion through the sebum to the depths of the epidermis is the envisioned mechanism of permeation by this route. Vasculature sub serving the hair follicle located in the dermis is the likely point of systemic entry. Absorption across a membrane, the current or flux is and terms of matter or molecules rather then electrons, and the driving force is a concentration gradient (technically, a chemical potential gradient) rather then a voltage drop. A membranes act as a “diffusional resistor.” Resistance is proportional to thickness (h), inversely proportional to the diffusive mobility of matter within the membrane or to the diffusion coefficient (D), inversely proportional to the fractional area of a route where there is more than one (F), and inversely proportional to the carrying capacity of a phase.
R = h/FDK
R =Resistance of diffusion resistor
F = Fractional area
H = Thickness
D = diffusivity
K = Relative capacity

Basic principle of permeation:⁹

In the initial transient diffusion stage, drugs molecules may penetrate the skin along the hair follicles or sweat ducts and then be absorbed through the follicular epithelium and sebaceous glands. When a steady state has been reached diffusion through stratum corneam becomes the dominant pathway.
The membrane-limited flux (J) under steady condition is described by expression.
             DAK_O/W r C
J =        ---------------------
                        h                                                                   
Where:
J = Amount of drug passing through the membrane system per unit area, per unit area per unit time.
D= Diffusion coefficient
A= Area of the membrane
C= Concentration gradient
K_o/w= Membranes / vehicle partition coefficient
h= Thickness of the membrane.

Kinetics of permeation:^16-18
Knowledge of skin permeation is vital to the successful development of topical formulation. Permeation of a drug involves the following steps,

• Sorption by stratum corneum,
• Penetration of drug though viable epidermis,
• Uptake of the drug by the capillary network in the dermal papillary layer.

This permeation can be possible only if the drug possesses certain physicochemical properties. The rate of permeation across the skin (dQ/dt) is given by:
    dQ
  -----    =      P_s(c_d-c_r)
dt
Where C_d and C_r are, the concentrations of skin penetrant in the donor compartment (e. g., on the surface of stratum corneum) and in the receptor compartment (e.g., body) respectively. P_s is the overall permeability coefficient of the skin tissues to the penetrant. This permeability coefficient is given by the relationship:
K_s  D_ss 
P_s =    --------------
                   H_s
Where K_s is the partition coefficient for the interfacial Partitioning of the penetrant molecule form a solution medium on to the stratum corneum, D_{ss is the} apparent diffusivity for the steady state diffusion of the penetrant molecule through a thickness of skin tissues and h_s is the overall   thickness of skin tissues. As K_s, D_ss and hs are constant under given conditions, the permeability coefficient (P_s) for a skin penetrant can be considered to be constant.
From equation (1) it is clear that a constant rate of drug permeation can be obtain when C_d >> C_r i.e., the drug concentration at the surface of the stratum corneam  (C_d) is consistently and substantially greater than the drug concentration in the body (C_r). The equation  (1) becomes:
And the rate of skin permeation (dQ/dt) is constant provide the magnitude of C_d remains fairly constant throughout the course of skin permeation. For keeping C_d constant, the drug should be released from the device at a rate (R_r) that is either constant or greater than the rate of skin uptake (R_a) i.e., R_r >> R_a.

Factor affecting topical permeation:

Physicochemical properties of drug substances^19-20

• Partition coefficient
• pH-condition
• Drug solubility
• Concentration
•  Particle size
• Polymorphism
• Molecular weight

Penetration enhancer ^21-26

Percutaneous absorption can be enhancing in two ways either by chemical enhancer or by physical method.
Chemical penetration enhancer: By definition, a chemical skin penetration enhancer increase skin permeability by reversibly damaging or by altering the physicochemical nature of the stratum corneam to reduce its diffusional resistance. Among the alterations are increased hydration of stratum corneam and / or a change in the structure of the lipids and lipoproteins in the intercellular channels through solvent action or denaturation. These may conveniently be classified under the following main heading:

• Solvents: These compounds increase penetration possibly by swelling the  polar pathway and/or by fluidizing lipids. Examples include water, alcohols, methanol and ethanol; alkyl methyl sulfoxide, dimethyl sulfoxide, alkyl homologs of methyl sulfoxide, dimethyl acetamide and dimethylformamide; pyrrolidones- 2 -pyrrolidone, N-methyl, 2- pyrrolidone; laurocapram (Azone), miseellancous solvents- propnylene glycol, glyeerol, silicone fluids, isopropyl palmitate.
• Surfactant: These compounds are proposed to enhance polar pathway  transport, especially of hydrophilic drugs. The ability of the surfactant to alter penetration is a function of polar head group and the hydrocarbon chain length. Commonly used surfactant are as follow

Anionic surfactant: can penetrant and interact strongly with skin. Examples include are Dioctyl sulphosuccinate, Sodium lauryl sulphate, Decodecylmethyl sulphoxide etc.
Cationic surfactant: Cationic surfactants are reportedly more irritating than anionic surfactants and they have not been widely studied as skin permeation enhancer.
Nonionic surfactant: Nonionic surfactants have least potential for irritation. Example includes are Pluronic F127, Pluronic F68 etc.

• Bile salts: Sodium taurocholate, Sodium deoxycholate, and Sodium tauroglycocholate.
• Binary system: These systems apparently open the heterogeneous    multilaminated pathway as well as the continuous pathways.  Examples include  are Prolylene glycol -oleic acid and 1,4-butane diol- linoleic acid.
• Miscellaneous chemicals: These includes urea, N,N-dimethyl-m-toluamide, calcium thioglycolate etc

Physical method of topical drug delivery

• Intophorosis: Intophorosis is a process or a technique involving the transport of ionic or charged molecules into a tissue by the passage of direct or periodic electric current through an electrolyte solution containing the ionic molecules to be delivered using an appropriate electrode polarity.
• Electroporation: The process involves the application of transient high voltage electrical pulse to cause rapid dissociation of the stratum corneam through which large and small peptides, oligonucleotides and other drugs can pass in significant amounts. Electroporation or elecro-permeabilization involves changes in membrane cells due to application of large transmembrane voltage. The change in the membrane involves structural arrangement and conductance leading to temporary loss of semi-permeability of cell membranes suggesting formation of pores.
• Sonophoresis: Sonophoresis involves the usage of the frequency ultrasound waves. The ultrasound application has resulted in permeation of low frequency ultrasound was shown to increase the permeability of human skin to many drugs including high molecular weight protein by several orders of magnitude.
• Phonophoresis: The movement of drugs through living intact skin and into soft tissues under the ultrasound perturbation is called phonophoresis. The technique involves placing an ultrasound-coupling agent on the skin over the area to be treated and massaging the area with an ultrasound source.
• Vesicular concept: Drug enclosed vesicle made from phospholipids and nonionic surfactants are used for transport of drug into and across the skin. The various vesicles used for this purpose are liposomes, niosomes and transferosome. The lipid vesicle serve as a rate limiting membrane barrier for system absorption of drug, non-toxic penetration enhancers for drug, organic solvents for solubilization of poorly soluble drugs and can incorporate both hydrophillc and lipophillic drugs.
• Microfabricated microneedles technology: This technology employed micron-sized needales made silicon. These microneedles after insertion into the skin create conduits for transfer of drug through the stratum corneum. The drug after crossing stratum corneum diffuses rapidly through deeper tissues and taken up by capillaries for systemic adminitration.

Physicochemical properties of topicals ¹⁵

• Release characteristics: The mechanism of drug release depends on Whether the drug molecules are dissolved or suspended in the delivery system. The interfacial partition coefficient of drug from delivery systems to the skin pH of the vehicle

• Composition of drug delivery system: Example polyethylene glycols of low molecular weight decrease permeation.
• Nature of vehicle : Liphophilic vehicle increase permeation where as lipophobic vehicle decrease permeation.

Physiological and Pathological Condition of Skin^27-30

• Reservoir effect of horny layer: The horny layer, depot and modify the transdermal permeation characteristics of some drugs. The reservoir effect is due to irreversible binding of a part of the applied drug with the skin. This binding can be reduced by pretreatment of skin surface with anionic surfactants.
• Lipid film: The lipid film on the skin surface acts a protective layer to prevent the removal of moisture from the skin and helps in maintaining the barrier function of the stratum corneum.       
• Skin hydration: Hydration of stratum corneum can enhance transdermal permeability. Covering or occluding the skin with plastic sheet leading to sweet and condensed water vapor can achieve skin hydration.
• Skin temperature: Raising skin temperature results in an increase in rate of skin permeation. This may be due to.
  Thermal energy required diffusivity.
  Solubility of drug in skin tissues.
  Increased vasodilatation of skin vessels.
• Regional Variation: Differences in the nature and thickness of barrier layer of skin causes variation in permeability. Rate of permeation increase in an atomic order: Plantar anterior fore arm, scalp, ventral thigh, scrotum and posterior auricular area.
• Pathologic injuries to the skin: Injuries that disrupt the continuity of stratum corneum increase permeability
• Cutaneous Drug Metabolism: Catabolic Enzymes present in the viable epidermis may render a drug inactive by metabolism and thus affect topical bioavailability of the drug. Example. Testosteron is 95% metabolized.

References:

1.Surver, C. and Davis, F.A., Bioaviability and Bioequivalence, In Walter, K.A..(Ed. ) , Dermatological and Transdermal Formulation, Marcal  Dekker, INC. NewYork , 119,2002,pp. 403,323,326,327,403.
2.Stan-posthumd J.J., Vink J., Lecessies, Bruijn J.A., Et.al., “Topical Tretinoin Under Oocclusion on a Typical Navei”, 1998, 548.
3.Ansel H.C., Allen L.V., “Pharmaceutical Dosage Forms and Drug Delivery System”, 7^th edition, Lippincott Willams and Wilkens, Baltimore, 2000, 244-246,249-251, 253-255,264-265.
4.Nayank S.H., Nkhat P.D., and Yeole P.G., “The Indian Pharmacist”, Vol. III, No. 27, Sept. 2004, 7-14.
5.Jain N.K., Et. al., “Pharma Times”, May 2000, 21.
6.Misra A.N.,“Controlled and Novel Drug Delivery”, CBS Publishers and Distributors, New Delhi,1997, 107-109.
7.Nandu S., Et.al.., “Ind. J.Pharm. Sci.”, Vol. 60. No.4., 1998, 185-188.
8.Mishr B., Et.al., “Ind. J. Exp. Biol”, 1990, 28,1001.
9.Kumari P., Shankar C. and Mishra B., “The Indian Pharmacist”, Vol III., No. 24, June 2004, 7-16. 

Mr.J.P.Goswami  is a M.Pharm. final year (Pharmaceutics) student of ASBASJSM College of Pharmacy, Bela, Ropar, India. He had completed his graduation from B.N.College of Pharmacy, Udaipur, Raj. He has great intrest in tablet technology and its reproducibility.

Shailesh Sharma is working a lecturer cum research scholar in department of pharmaceutics in ASBASJSM College of Pharmacy, Bela, Ropar, India. He had completed his graduation from B . R. Nahata Collegeof pharmacy, Mandsaur, (MP) and  post graduation from B.N.College of pharmacy, Udaipur, Raj. He has very good academic and extra circular record. He has more than 20 articles in reputed peer reviewed journals. He has great intrest in tablet technology and its reproducibility.

Dr.G.D.Gupta is working as a professor and principal in ASBASJSM College of Pharmacy, Bela, Ropar, India. Dr. Gupta has author of number of books and published more than 100 Research Paper / Abstract in National and International conferences.

Mr.Anis Mustafa is a M.Pharm. final year student of ASBASJSM College of Pharmacy, Bela, Ropar , India.

Mr.Deepak Chaudhary is a M.Pharm. final year student of ASBASJSM College of Pharmacy, Bela, Ropar, India
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