Topical Gel: A Novel approach for drug delivery - Journal of ...

Feb-Apr.2012, Vol.2.No.2, 856-867. e- ISSN: 2249 –1929Journal of Chemical, Biological and Physical SciencesAn International Peer Review E-3 Journal of SciencesAvailable online at www.jcbsc.orgSection B: Biological SciencesCODEN (USA): JCBPATResearch ArticleTopical Gel: A Novel approach for drug delivery1* Sudhir Bharadwaj , 2 G.D.Gupta and 3 V.K.Sharma1Department of Pharmaceutics, Shriram College of Pharmacy,Banmore, Near Gwalior, M.P. India.2ASBASJS college of pharmacy, Bela, District-Roper, Punjab, India.3 Department of Chemistry, M.L.S.Uniuersity, Udaipur, Rajasthan, IndiaReceived: 31 January 2011; Revised: 30 February 2012; Accepted: 30 March 2012ABSTRACTTopical drug administration is a localized drug delivery system anywhere in the body throughophthalmic, rectal, vaginal and skin as topical routes. Skin is one of the most readily accessible organson human body for topical administration and is main route of topical drug delivery system. Thisreview is concern with all detail information regarding rational approach to topical formulations,principles of topical permeation and basic components of topical drug delivery systems. Overall, theclinical evidence indicates that topical gel is a safe and effective treatment option for use in themanagement of skin related diseases.Keywords: Gels, Topical drug delivery, Permeation enhancersINTRODUCTIONThe field of pharmaceutical science has been developing steadily over the years, and has today becomeinvaluable in helping to keep us healthy and prevent disease. An avenue of research that has progressed agreat deal in the past few decades is the treatment of diseases via biomolecules such as drugs, proteins etc.Initially these could only be administered in limited manner, due to limitations of drug delivery throughharmful environments in the body. Thus limited mobility reduced the effectiveness of administereddrugs 1 .Topical drug administration is a localized drug delivery system anywhere in the body through ophthalmic,rectal, vaginal and skin as topical routes. Skin is one of the most readily accessible organs on human bodyfor topical administration and is main route of topical drug delivery system. The skin of an average adultbody covers a surface area approximately 2 m 2 and receives about one third of the blood circulating856 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.through the body. An average human skin surface is known to contain, on the average 40-70 hair folliclesand 200-300 sweat ducts on every square centimeter of the skin 1 . Although skin has been dividedhistologically into the stratum corneum, the living epidermis and the dermis, collectively it can beconsidered a laminate of barrier, permeation of this laminate can occur by diffusion via:a. Transcellular penetration (across the cells)b. Intracellular penetration (between the cells)c. Transappendageal penetration (via hair follicles, sweat and sebum glands) 2, 3A myriad of medicated product are applied to the skin or readily accessible mucous membrane that insome way either augment or restore a fundamental function of a skin or pharmacologically modulate anaction in the underlined tissues. Such products are referred as topical or dermatological product 4 .1.RATIONAL APPROACH TO TOPICAL FORMULATIONS 5Topical formulation can be used to:• Manipulate the barrier function of the skin, e.g., topical antibiotics and antibacterial help a damagedbarrier to ward off infection, sun screening agents and the horny layer protect the viable tissues fromU.V. radiation.• Direct drugs to the viable skin tissues without using oral, systemic or other routes of therapy, e.g.,anaesthetic, anti-inflammatory, antipruritic and antihistaminics drugs are to be delivered to viableepidermis and dermis.• For skin appendage treatment, e.g., antiperspirants, exfolients and depilatories are to be delivered tothe skin appendages.• Deliver drugs for systemic treatment, e.g., transdermal therapeutic systems provide systemic therapyfor motion sickness, angina and hypertension.1.1. TOPICAL GELSThe term ‘Gel’ was introduced in the late 1800 to name some semisolid material according to theirphysiological characteristics rather than molecular composition.Gels are semisolid systems in which a liquid phase is constrained within a three dimensional polymericmatrix of natural or synthetic gums in which a high degree of physical or chemical cross linking has beenestablished 6 .The U.S.P. defines gels 7 as a semisolid system consisting of dispersion made up of either small inorganicparticle or large organic molecule enclosing and interpenetrated by liquid. The inorganic particles form athree-dimensional ‘house of cards’ structure. Gels consist of two-phase system in which inorganicparticles are not dissolved but merely dispersed throughout the continuous phase and large organicparticles are dissolved in the continuous phase, randomly coiled in the flexible chains. These chains areentangled with each other and shown as a single phase. The interaction between the colloidal phase,(inorganic or organic) set up the ‘structural viscosity’.Most topical gels are prepared with organic polymers, such as carbomers, that impart an aestheticallypleasing, clear, sparkling appearance to the products and are easily washed off from the skin with water.The type of base used in formulating a topical dermatological product greatly influences its effectiveness.Bases containing large amounts of oleaginous substances provide an emollient effect to dry irritated skin.More importantly, bases made up of non-volatile oleaginous substances (e.g. hydrocarbon bases) can form857 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.an occlusive barrier on the skin that prevents escape of moisture from the skin into the environment. As aresult, moisture accumulates between the skin and the ointment layer that cause hydration of the stratumcorneum. Hydration of stratum corneum all ‘opening up’ of intra and inter-cellular channels and pathwayfor easier passage of drug molecules. Additionally, the moisture layer provides a medium for dissolutionof the drug that is otherwise dispersed as fine particles in the ointment base. Since only the dissolved drugpresented to the skin, as an individual molecular entity is able to enter the stratum corneum, skinocclusion generally results in enhanced percutaneous drug absorption 8 .1.1.1. ClassificationGels are classified mainly by two methods based on 9 :a. Nature of colloid phasei. Inorganic gelsii.Organic gelsb. Based on nature of solventi. Aqueous gelsii.Non aqueous gels1.1.2. Gel forming substances 10Polymers are used to give the structural network, which is essential for the preparation of gels. Gelforming polymers are classified as follows:1. Natural polymera. Proteinsi. Collagenii. Gelatinb. Polysaccharidesi. Agarii. Alginic acidiii. Sodium or Potassium carrageenaniv. Tragacanthv. Pectinvi. Guar Gumvii. Cassia toraviii. Xanthinix. Gellum Gum2. Semisynthetic polymersa. Cellulose derivativesi. Carboxymethyl cellulose858 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.ii. Methylcelluloseiii. Hydroxypropyl celluloseiv. Hydroxypropyl methyl cellulosev. Hydroxyethyl cellulose3. Synthetic polymersa. Carbomeri. Carbopol -940ii. Carbopol -934iii. Carbopol -941b. Poloxamerc. Polyacrylamided. Polyvinyl alcohole. Polyethylene and its co-polymers4. Inorganic substancesa. Aluminium hydroxideb. Bentonite5. Surfactantsa. Cetostearyl alcoholb. Brij – 961.1.3. AdvantagesThe topical administration of drug in order to achieve optimal cutaneous and percutaneous drug deliveryhas recently gained an importance because of various advantages :• To avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH and enzymaticactivity and drug interaction with food and drinks.• To avoid the first pass effect, that is, the initial pass of drug substance through the systemic and portalcirculation following gastrointestinal absorption, possibly avoiding the deactivation by digestive andliver enzymes.• Non-invasive and have patient compliance.• Less greasy and can be easily removed from the skin.• Economic.• Reduction of doses as compare to oral dosage forms.• Localized effect with minimum side effects..1.1.4. Desirable Properties of Gelsa. It should be inert, compatible with other additives and non-toxic.859 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.b. It should be stable at storage condition.c. It should be free from microbial contamination.d. It should maintain all rheological properties of gel.e. Economical.f. It should be washable with water and free from staining nature.g. It should not affect biological nature of drug.h. It should be convenient in handling and its application.i. It should possess properties such as thixotropic, greaseless, emollient, non-staining etc.1.1.5. Desirable Properties of Gellants 11a. It should be inert, compatible with addition and non-toxic.b. It should produce gels at low concentration.c. It should help gel formation.d. It should be economical.e. It should be free from microbial contamination.1.2 ANATOMY OF THE HUMAN SKIN 12The skin of an average adult body covers a surface area of approximately 2 sq.m. and receives about onethird of the blood circulating through the body and serves as a permeability barrier against the topicalabsorption of various chemical and biological agents to achieve a localized pharmacological action in theskin tissues in the various forms i.e., ointment, paste, creams, gels etc. When topical gels are applied tothe skin, the drug molecules are considered to diffuse to a target tissue and produce therapeutic effectprior to its systemic distribution for elimination. It is one of the most readily available organs of the bodywith a thickness of only a few millimeters (2.97 0.28 mm). The skin• Separates the underlying blood circulation network from the outside environment.• Serves as a barrier against physical, chemical & microbiological attacks.• Acts as a thermostat in maintaining body temperature.• Plays role in the regulation of blood pressure.• Protects against the penetration of UV rays.As skin is major factor in determining the various drug delivery aspects like permeation and absorptionof drug across the dermis. The diffusional resistance of the skin is greatly dependent on its anatomy andultra structure. The skin is capable of metabolizing many substances and through its microvasculature,limits the transport of most substances into regions below the dermis. Although the flux of solutesthrough the skin should be identical for different vehicles when the solute exists as a saturated solution,the fluxes vary in accordance with the skin penetration enhancement properties of the vehicle. It istherefore desirable that the regulatory standards required for the bio-equivalence of topical products860 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.include skin studies. Deep tissue penetration can be related to solute protein binding, solute molecularsize and dermal blood flow 12 .Fig. 1 Schematic of Skin Absorption1.2.1. Principles of Topical PermeationBefore a topically applied drug can act either locally or systemically, it must penetrate the stratumcorneum - the skin permeation barrier. Percutaneous absorption involves passive diffusion of substancesthrough the skin. The mechanism of permeation can involve passage through the epidermis itself(transepidermal absorption) or diffusion through shunts, particularly those offered by the relativelywidely distributed hair follicles and eccrine glands (transfollicular or shunt pathway). In the initialtransient diffusion stage, drug molecules may penetrate the skin along the hair follicles or sweat ductsand then absorbed through the follicular epithelium and the sebaceous glands. When a steady state hasbeen reached the diffusion through the intact stratum corneum becomes the primary pathway for topicalpermeation 13 .The release of a therapeutic agent from a formulation applied to the skin surface and its transport to thesystemic circulation is a multistep process, which involves• Dissolution within and release from the formulation• Partitioning into the skin’s outermost layer, the stratum corneum (SC)• Diffusion through the stratum corneum, principally via a lipidic intercellular pathway, (i.e., the ratelimitingstep for most compounds)• Partitioning from the stratum corneum into the aqueous viable epidermis, diffusion through theviable epidermis and into the upper dermis, and uptake into the papillary dermis and into themicrocirculation.1.2.2. Kinetics of Topical Permeation 14-16Knowledge of skin permeation kinetics is vital to the successful development of topical systems. Topicalpermeation of a drug involves the following steps :a. Sorption by stratum corneumb. Penetration of drug through viable epidermis861 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.c. Uptake of the drug by the capillary network in the dermal papillary layerThis permeation can be possible if the drug possesses certain physico-chemical properties. The rate ofpermeation across the skin (dQ/ dt) is given by:dQ / dt = P s (C d – C r ) Eq. 1Where,C d = Concentration of skin penetrant in the donar compartment (e.g., on thesurface of stratum corneum)C r = Concentration in the receptor compartment (e.g., body) respectivelyP s = Overall permeability constant of the skin tissue to the penetrantWhere,P s = ( K s D ss ) / h s Eq. 2K s is the partition coefficient for the interfacial partitioning of the penetrant molecule from a solutionmediumD ss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through a thicknessof skin tissuesh s is the overall thickness of skin tissues.As K s , D ss and h s are constant under given conditions, the permeability coefficient (P s ) for a skinpenetrant can be considered to be constant.From Eq.1 it is clear that a constant rate of drug permeation can be obtained only when C d >>C r i.e., thedrug concentration at the surface of the stratum corneum (C d ) is consistently and substantially greaterthan the drug concentration in the body (C r ), then Eq. 1 becomes:dQ / dt = P s C s Eq. 3Permeability coefficient = (KsDss) / hs = 1 / resistance1.2.3. Physiological Factors in Percutaneous AbsorptionPhysiological factors are those that involve the properties of the barrier itself. Some important factorsare:1. Skin integrity2. Hydration3. Temperature4. Anatomic location5. Age6. Disease862 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.1.2.4. Drug Factors in Percutaneous AbsorptionThe drug factors affecting percutaneous absorption are given as follows :1. Molecular size2. Chemical nature of drug3. Partition coefficient4. Binding to the skin5. Metabolism6. Thermodynamic activity of drug in donar1.3.5. Formulation Factors in Percutaneous AbsorptionThe nature of the dosage form is an extremely important factor in determination of skinpenetration characteristics and various formulation factors such as :1. Occlusivity2. Drug concentration3. pH4. Solubility5. Surfactant6. Penetration enhancer1.3 BASIC COMPONENTS OF TOPICAL DRUG DELIVERY SYSTEMS 17-18Topical gel may include the following components:(A).Polymer: Polymer is an integral and foremost important component of Topical Gel. Different classesof polymeric materials have been used to achieve rate controlled drug delivery. The mechanism of drugrelease depends upon the physicochemical properties of the drug and polymer used in the manufacture ofthe device.The following criteria should be satisfied for a polymer to be used in a topical system:1. Molecular weight, glass transition temperature, chemical functionality of polymer must allowdiffusion and release of the specific drug.2. The polymer should permit the incorporation of a large amount of drug.3. The polymer should not react, physically or chemically with the drug.4. The polymer should be easily manufactured and fabricated into the desired product andinexpensive.5. The polymer must be stable and must not decompose in the presence of drug and other excipientsused in the formulation, at high humidity conditions, or at body temperature.6. Polymers and its degradation products must be non-toxic 17 .No single material may have all these attributes, certain excipients may be incorporated to alter someproperties, e.g., Cosolvents such as ethanol, propylene glycol, PEG 400 could be added to increase drugsolubility.863 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.Table -1: Useful Polymers for Topical GelNatural polymers Semisynthetic polymers Synthetic polymersa. Proteinsi. Collagenii. Gelatinb. Polysaccharidesi. Agarii. Alginic acidiii. Sodium or Potassiumcarrageenaniv. Tragacanthv. Pectinvi. Guar Gumvii. Cassia toraviii. Xanthinix. Gellum Guma. Cellulose derivativesi. Carboxymethylcelluloseii. Methylcelluloseiii. Hydroxypropylcelluloseiv. Hydroxypropyl methylcellulosev. Hydroxyethylcellulosea. Carbomeri. Carbopol-940ii. Carbopol-934iii. Carbopol-941b. Poloxamerc. Polyacrylamided. Polyvinyl alcohole. Polyethylene and its copolymersVarious techniques have been employed to modify the polymer properties and thus drug release rates.a. Cross-linked polymers: The higher the degree of cross-linking, the more dense the polymer andslower the diffusion of drug molecules.b. Polymer blends: Polymers have been blended on varying ratios to combine the advantages of theindividual polymers. Advantages of polymer blends include easy fabrication of devices, manipulation ofdrug incorporating and other devices properties such as hydration, degradation rate and mechanicalstrength.(B).Drug Substance:Judicious choice of the drug plays an important role in the successful developmentof a topical product. The important drug properties that effect its diffusion through the device as well asthrough skin are as follows 18 :a. Physicochemical properties: Drug should have a molecular weight of less than 500 Daltons. Drug must have adequate lipophilicity. A saturated aqueous solution of the drug should have a pH value between 5 and 9. Drugs highly acidic or alkaline in solution are not suitable for topical delivery.864 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.b. Biological properties:• The drug should not be directly irritated to the skin.• The drug should not stimulate an immune reaction in the skin.• Drugs, which degrade in gastrointestinal tract or are inactivated by hepatic first pass effect, aresuitable for topical delivery.• Tolerance to the drug must not develop under the near zero order release profile of topicaldelivery.• Drugs which have to be administered for a long time or which cause adverse effects to non-targettissue can also be formulated for topical delivery.(C)Penetration Enhancers: These are the compounds, which promote skin permeability by altering theskin as a barrier to the flux of a desired penetrant and are considered as an integral part of most topicalformulations. To achieve and maintain therapeutic concentration of drug in the blood, the resistance ofskin (stratum corneum) to diffusion of drugs has to be reduced in order to allow drug molecules to crossskin and to maintain therapeutic levels in blood. They can modify the skin’s barrier to penetration eitherby interacting with the formulation that applied or with the skin itself.Various criteria that ideal penetration enhancers must meet are:• Ability to act specifically, reversibly and for predictable duration.• Pharmacological inertness.• Non-toxic, non-allergenic, non-irritating.• Controlled and reverse enhancing action.• Should not cause loss of body fluids, electrolytes or other endogeneous materials.• Chemical and physical compatibility with drugs and other pharmaceutical excipients with which itis used.• Following removal of the enhancer, the stratum corneum should immediately and fully recover itsnormal barrier property.• Odourless, colorless and economical and cosmetically acceptable.Enhancers increase the penetration of permeants by disrupting the structure of skin’s outer layer‘stratum corneum’ and increasing penetrant solubility. Disruption either by chemical means, may affectboth intracellular and extracellular structure. Disruption may be due to protein denaturation, fluidizationand randomization of intercellular lipids or intercellular delamination and expansion. The accelerantscause keratin to swell and leach out essential structural material from the stratum corneum, thusreducing the diffusional resistance and increasing the permeation of drugs through skin.In hydrophilic topical penetration enhancer, the miscibility and solution properties of solvent are usedfor the enhanced topical permeation of a water-soluble drug.Lipophilic enhancers assist the percutaneous absorption of both water soluble and oil soluble drugs. Theenhancement in the absorption of oil soluble drugs is apparently due to the partial leaching of theepidermal lipids by the enhancer, resulting in the improvement of the skin condition for wetting and fortopical and transfollicular penetration.The effect of surfactant action upon the skin may change the physical stage of water in the skin in such865 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.a way as to permit greater freedom to the passage of charged hydrophilic substances. Their permeationpromoting activity is due to the action to decrease the surface tension, to improve the wetting of the skinand to enhance the distribution of drugs. Furthermore it was observed that the more hydrophilicsurfactants interact more strongly with keratin and alter permeation as compared to less hydrophilicsurfactants (long chain alcohols).Classification of permeation enhancers• Water• Sulphoxides (especially dimethylsulphoxide) and their analogues• Pyrrolidines• Fatty acid and alcohols• Azone and its derivatives• Surfactants – anionic, cationic and nonionic• Urea and its derivatives• Alcohols and glycols• Essential oils• Terpenes and derivatives• Synergistic mixtures(D). ExcipientsClass Examples Mechanism Transport PathwaySurfactants Sodium lauryl sulphate(SLS)Polyoxyethylene-9-Phospholipid acyl chainperturbationReduction mucusTranscellularParacellularlauryletherBile salts : Sodium -deoxycholate,Sodium - glycocholateSodium -taurocholateviscosityPeptidase inhibitionFatty acids Oleic acid Phospholipid acyl chain TranscellularperturbationCyclodextrins -, - and cyclodextrins Inclusion of membranecompoundsTranscellularParacellularChelatorsMethylated -cyclodextrinsEDTAComplexation of Ca 2+ openingof tight junctionsTranscellularParacellularREFERENCES1. J.R.Robinson and Lee, H.L.Vincent; Controlled Drug Delivery, 2nd Edn., Vol. 29, Marcel Dekker, Inc.,Madison Avenue, New York, 524-526.2. L.Lachman. and H.A. Lieberman; The Theory and Practice of Industrial Pharmacy, 3rd Edn., VarghesePublishing house, 1991, 536-537.3. N.K.Jain and Misra, Controlled and Novel Drug Delivery, CBS Publishers and Distributors, NewDelhi, 2005,866 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867

Formulation...Sudhir Bharadwaj et al.4. G.S. Banker and C.T.Rhodes; Modern Pharmaceutics, 2nd Edn., Vol. 40, Marcel Dekker, Inc., MadisonAvenue, New York, 1990,5. K.P.R.Chowdary and M.E. Gupta;Topical Dosage Forms, The Eastern Pharmacist, 1996,6. G.S. Banker and C.T.Rhodes; Modern Pharmaceutics, 2nd Edn., Vol. 40, Marcel Dekker, Inc., MadisonAvenue, New York, 1990,7. H.C.Ansel, N.G. Popovich and Allen, V.Loyd Pharmaceutical Dosage Forms and Drug DeliverySystems, 8th Edn., B. I. Publications Pvt. Ltd., 2005, .8. R.M.Mehta; Pharmaceutics II, Vallabh Prakashan, 2000,9. H.C.Ansel, N.G. Popovich. and Allen, V.Loyd ; Pharmaceutical Dosage Forms and Drug DeliverySystems, 8th Edn., B. I. Publications Pvt. Ltd., 2005, 418.10. Ansel, H. C., Popovich, N. G. and Allen, Loyd V., Pharmaceutical Dosage Forms and Drug DeliverySystems, 8th Edn., B. I. Publications Pvt. Ltd., 2005, 419-423.11. M.F.Saettons, B.Giannacint and F. Marca; Solubilization of tropicamide by poloxamers:physicochemical data and avtivity data in rabbits and humans, Int. J. Pharm., 1988, 43, 67.12. Y.W.Chien; Transdermal therapeutic system, 2nd Edn., Vol. 29, Marcel Dekker, Inc., MadisonAvenue, New York, 524-526.13. N.K.Jain, and A.N.Misra A. N., Controlled and Novel Drug Delivery, CBS Publishers andDistributors, New Delhi, 2005, 101-106.14. Y.W.Chien,; Transdermal therapeutic system, 2nd Edn., Vol. 29, Marcel Dekker, Inc., MadisonAvenue, New York, 528-531.15. S.P.Vyas and Khar,K. Roop ;Controlled Drug Delivery, 1st Edn., Vallabh Prakashan, 2002,16. N.K.Jain, and A.N.Misra; Controlled and Novel Drug Delivery, CBS Publishers and Distributors,New Delhi, 2005,17. N.K.Jain, and A.N.Misra, Controlled and Novel Drug Delivery, CBS Publishers and Distributors, NewDelhi, 2005,18. S.P.Vyas and Khar,K. Roop ; Controlled Drug Delivery, 1st Edn., Vallabh Prakashan, 2002,*Correspondence Author: Sudhir Bharadwaj; Department of Pharmaceutics, Shriram College ofPharmacy, Banmore, Near Gwalior,M.P.India.867 J. Chem. Bio. Phy. Sci. Sec.B, 2012, Vol.2, No.2,856-867