IJPCBS 2013, 3(3), 495-503 Kamal Saroha et al. ISSN: 2249-9504

INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES

Available online at www.ijpcbs.com Review Article

TRANSDERMAL GELS - AN ALTERNATIVE VEHICLE FOR DRUG DELIVERY

Kamal Saroha1*, Sarabjeet Singh1, Ajay Aggarwal1 and Sanju Nanda2 1Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, India. 2Department of Pharmaceutical Sciences, Maharishi Dayanand University, Rohtak, India.

ABSTRACT Delivery of drugs through the skin has been an attractive as well as a challenging area for research. Compared to other conventional routes of drug delivery such as oral, injection and inhaler, transdermal delivery has a variety of advantages. Transdermal systems are non-invasive, convenient, and inexpensive and can be self-administered. They can provide sustained plasma concentration profile for long periods of time. There are many transdermal formulations like lotions, creams, ointments, patches, etc. out of these gel is preferred. Transdermal gels are becoming more popular due to ease of application and better precutaneous absorption. The term gel are semi-solid, three dimensional, polymeric matrices comprising small amounts of solid dispersed in relatively large amount of liquid, yet possessing more solid like character. These system form a three dimensional, polymeric matrix in which a high degree of physical reticulation has been compromised. Gel formulations provide better application property and stability in comparison to cream and ointments. In these study methods, advantages, gel forming substances, structure of gel, their properties, their absorption mechanism, evaluation and future perspective are discussed to improve the permeability and bioavailability of gels.

Keywords: Transdermal gel, precutaneous absorption, bioavailability, plasma concentration.

INTRODUCTION vehicle ranging from solids to semisolids and Topical drug administration is localized drug liquid preparation is available to clinician and delivery system anywhere in the body through patients. Within the major group of semisolid ophthalmic, rectal, vaginal and skin as topical preparations, the use of transdermal gels has routes1. Skin is one of the most readily accessible expanded both in cosmetics and in pharmaceutical organs on human body for topical administration preparations. Transdermal application of gels at and is the main route of topical drug delivery pathological sites offer great advantage in a faster system release of drug directly to the site of action, For the topical treatment of dermatological independent of water solubility of drug as diseases as well as skin care, a wide variety of compared to creams and ointments30,31

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CLASSIFICATION OF MEDICATED FORMULATION FOR THE SKIN8

LIQUID SEMI SOLID SOLID MISCELLANEOUS PREPARATIONS PREPARATIONS PREPARATIONS PREPARATIONS

 Liniment  Topical  Lotions  Ointments powder  Tapes and  Paints  Creams  Poultices gauzes  Topical  Pastes  Rubbing solution  Gels alcohol  Topical  Poultices  Liquid tinctures cleanser  Colloids  Topical aerosol

Out of these, gel are becoming more popular due restore a fundamental function of a skin or to ease of application and better precutaneous pharmacologically alter an action in the absorption underlined tissues. Such products are referred to The term ‘gel’ was introduced in the later 1800 to as topical or dermatological products4. Hydroxy name some semisolid material according to propyl methyl cellulose (HPMC), Carbopol 934P, pharmacological, rather than molecular criteria. sodium alginate has been used as hydrophilic The U.S.P. defines Gels29 as a semisolid system polymers topically in gel drug delivery system5,6. A consisting of dispersion made up of either small series of grades based on molecular fractions of inorganic particles or large organic molecules these polymers are used at a concentration enclosing and interpenetrated by liquid. The between 1 to 5% in topical gel formulation. Due to inorganic particle forms a three –dimensional their non greasy properties, they can easily “house of card” structure. Gels consists of two provide a washable film on the skin5,7. HPMC, phase system in which inorganic particles are not Carbopol 934P, sodium alginate polymers of high dissolved but merely dispersed throughout the molecular weight do not penetrate the skin and continuous phase and large organic particles are are non toxic in nature. dissolved in the continuous phase, randomly coiled in the flexible chains. Drug Permeation through Skin9 Within the major group of semisolid preparations, Skin acts as a major barrier for permeation of any the use of transdermal gels has expanded both in substance into the body and this is mainly due to cosmetics and in pharmaceutical preparations2. A the stratum corneum, which is its outer layer. In gel is colloid that is typically 99% weight liquid, most of its areas, there are 10-30 layers of stacked which is immobilized by surface tension between corneocytes with palms and soles having the most. it and a macromolecular network of fibers built Each corneocyte is surrounded by a protein from small amount of a gelating substances envelope and is filled with water-retaining keratin present3. Topical drug administration a localised proteins. The cellular shape and orientation of the drug delivery system anywhere in the body keratin proteins add strength to the stratum through ophthalmic, rectal, vaginal and skin as corneum (Figure 1). topical routes. Skin is one of the most accessible When a formulation is applied onto the skin, organs of human body for topical administration several gradients are established across it, and and main route for topical drug delivery system. drugs, to a certain extent, are able to pass through Numbers of medicated products are applied to the stratum corneum. It is also reported that one skin or mucous membrane that either enhance or important factor for drugs to permeate stratum

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corneum is the water gradient, which can be which each polymer chain grows during the altered by application of several formulations onto reaction is random, resulting in final the skin. Hence for effective drug delivery through microstructure of this gel being completely the skin, an external water gradient could be disordered. The gel point for co- established. polymerization between equimolar Drugs, when applied onto the skin, can penetrate concentrations of two monomer species can it via three major routes viz., through sweat be predicted, using modified Carothers glands, stratum corneum or hair follicles (Fig 1) equation: There has been a continuous effort for understanding the structural barrier and Xn = 2/2-Pfav properties of stratum corneum. The permeation of Where, drugs through hair follicles compared to the Xn = the number average degree of stratum corneum is also widely being discussed20. polymerization Further, it is reported that the follicular route is P = the fractional conversion and more favorable for permeation of polar molecules, fav = the average functionality of monomers as their influx through the stratum corneum is involved difficult25. There are specific factors which The gel point reaches when Xn → ∞ determine efficiency of drug permeation through {indicating that critical conversion for the skin. The physicochemical nature of drug, site gelation (PG) is equal to 2/fav} and condition of skin, the formulations, and their influence on the properties of stratum corneum 2) Physically bonded structure are also important26. Physically bonded gel networks are reversible systems. Factors such as temperature and ion Classification of Gels additions can induce a transition between the Gels are classified mainly by two methods based sol and gel phases. These gels are formed on8,33: primarily by natural organic polymers a) Nature of colloid phase (proteins and polysaccharides) and semi i) Inorganic gels synthetic derivatives. The particular ii) Organic gels organization of polymer chains in a junction b) Based on nature of solvent zone depends on a chemical structure of the i) Aqueous gels repeating unit. For example, sulfated ii) Non aqueous gels polysaccharides (e.g. agar and carrageenans) that contain assortment sulfated galacatose Pharmaceutical gels may be loosely categorized residues from double helicles, two or more of based upon their network microstructure which aggregate into multi-helicles functional according to the following scheme suggested by zone. However, presence of few concomitant Faucci21 residues produces links that effectively block A. Covalently bonded polymer network with helix formation in large section of chains completely disordered structure. indicating that steric fit is critical to get B. Physically bounded polymer network formation. predominantly discovered but containing Other zone junction requires the presence of ordered loci. multivalent ions to form a bridge between C. Well ordered lamellar, including gel polymer chains. An egg box model was mesophases formed by inorganic clays. proposed by Pawel et al. for the formation of calcium alginate gels, in which calcium cations 1) Covalently Bonded Structure are cooperatively bound between ionized Covalently cross-lined gel networks are carboxy groups located on the polyguluronate irreversible systems. They are typically sequence of alginic acid. Locations are prepared from synthetic hydrophilic polymer coordinated in the interstices of ordered in one of two ways. segments of the polysaccharides chains. In first method of preparation, infinite gel network arises from the non-linear co- 3) Well Ordered Gel Structure polymerization of two or more monomer Under suitable conditions, certain silica, species with the one being at least alumina and clay soils form rigid gels or trifunctional. Both direction and position by lyogels. When clay belongs to smectite class,

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such as bentonite, hectorite and loponite, delivery has recently gain an importance because come into contact with water, they undergo of various advantages: interlayer swelling spontaneously followed by  They can avoid gastrointestinal drug osmotic swelling to produce a gel. The plate absorption difficulties caused by like clay particles associates into a “cubic gastrointestinal pH and enzymatic activity cardhouse” ordered structure, which is and drug interaction with food and stabilized by repulsive forces, caused by drinks. interacting electrical double layer. Highly  They can substitute for oral ordered lamellar gel microstructures are administration of medication when that formed by certain mixture of surfactant and route is unsuitable. long chain fatty alcohols in water using small  To avoid the first pass effect, that is, the angle X-ray scattering (SAXS), an ordered initial pass of drug substance through the lamellar stack lattice model was proposed for systemic and portal circulation following the gel formed by 10% w/w cetosteryl alcohol gastrointestinal absorption, possibly containing 0.5% cetrimide surfactant. In avoiding the deactivation by digestive and contrast, the microstructure of Brij 96 gel liver enzyme. depends on the surfactants concentrations. A  They are non-invasive and have patient hexagonal liquide-crystalline gel structure compliance. was detected by SAXS at concentration of 40-  They are less greasy and can be easily 60% w/w in water, whereas extended removed from the skin. lamellar structure was detected at higher  Cost effective. concentration (70-80% w/w).  Reduction of doses as compare to oral dosage forms. GEL FORMING SUBSTANCES8  Localized effect with minimum side Polymers are used to give the structural network, effects. which is essential for the preparation of gels. Gel  Improving drug bioavailability, reducing forming polymers are classified as follows: dose frequency. 1. NATURAL POLYMERS  Stabilizing drug delivery profiles.  Proteins – Collagen, Gelatin  Polysaccharides – Agar, Alginate acid, Limitations10 Sodium or Potassium carageenan,  The drug must have some desirable Tragacanth, Pectin, Guar Gum, Cassia physicochemical properties for tora, Xanthan, Gellum Gum penetration through stratum corneum 2. SEMISYNTHETIC POLYMERS CELLULOSE and if the drug dose required for DERIVATIVES therapeutic value is more than 10 Carboxymethyl cellulose, Methylcellulose, mg/day, the transdermal delivery will be Hydroxypropyl cellulose, Hydroxy propyl very difficult. (methyl cellulose), Hydroxyethyl cellulose  Only relatively potent drugs are suitable 3. SYNTHETIC POLYMERS candidates for TDDS because of the  Carbomer – Carbopol 940, Carbopol natural limits of drug entry imposed by 934 the skin‟s impermeability.  Poloxamer  Some patients develop contact dermatitis  Polyacrylamide at the site of application for one or more  Polyvinyl alcohol of the system components, necessitating  Polyethylene and its co-polymers discontinuation. 4. INORGANIC SUBSTANCES  The barrier function of the skin changes  Aluminium hydroxide from one site to another on the same  Bentonite person, from person to person and with 5. SURFACTANTS age.  Cebrostearyl alcohol  Brij – 96 MECHANISM OF DRUG ABSORPTION22 The rate of permeation across various layers of Advantages10,23,24 skin tissues in the course of topical application can The topical administration of drug in order to be expressed mathematically as achieve optimal cutaneous and percutaneous drug

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dQ / dt = Ps (Cd – Cr) surfactants and terpenes. These compounds where increase skin permeability by increasing the dQ / dt = rate of permeation across various layers. partition coefficient of the drug into the skin and Cd = concentration of drug in the donar phase. by increasing the thermodynamic activity of the Cr = concentration of drug in the receptor phase. drug in the vehicle. Ps = permeability coefficient of the skin tissues. Classification of penetration enhancers The concentration in the systemic circulation  Terpenes (essential oils) which is penetrating in the form of E.g. Nerodilol, menthol, 1 8 cineol, limonene, pharmacological active form such as: carvone etc.  Pyrrolidones Ps = KcDs / hs E.g. N‐methyl‐2‐pyrrolidone(NMP), azone etc. where  Fatty acids and esters Kc = partition coefficient of the penetrant E.g. Oleic acid, linoleic acid, lauric acid, capric acid molecules. etc. hs = overall thickness of the skin tissues.  Sulfoxides and similar compounds Ds = apparent diffusivity for the steady state E.g. Dimethyl sulfoxide(DMSO), N,Ndimethyl diffusion of penetrate moles. formamide If Cd >>> Cr than the equation is written  Alcohols, Glycols, and Glycerides dq / dt = PsCd E.g. Ethanol, Propylene glycol, Octyl alcohol etc.  Micellaneous enhancers PHYSIOLOGICAL FACTORS IN PERCUTANEOUS E.g. Phospholipids, Cyclodextrins, Amino acid ABSORPTION8 derivatives, Enzymes etc. 1. Skin integrity 2. Hydration Methods of Preparation21, 33 3. Temperature  DISPERSION METHOD: In this method 4. Anatomic location polymer is dispersed over water for 2 hours 5. Age till all the polymer is soaked with water after 6. Disease that other chemical ingredients are mixed and stirred well until a homogenous mass is FORMULATION FACTORS IN PERCUTANEOUS obtained ABSORPTION8 1. Occlusivity  COLD METHOD: In this method all the 2. Drug concentration ingredients are mixed together to form a 3. pH homogenous mass, under low temperature at 5. Surfactant about 50C. In this polymer is mixed with 4. Solubility permeation enhancer to form solution A, 6. Penetration enhancer drug is mixed with solvent to form solution Permeation Enhancer11 B. After that solution B is poured into The skin is a barrier to topically administered solution A slowly with complete stirring. drugs. Although the outer layer also provides resistance to the global permeation process, in-  CHEMICAL REACTION: In the preparation of vitro experiments have shown that the stratum sols by precipitation from solution, e.g., corneum, with 10 – 15 micrometer thickness is Aluminum hydroxide sol precipitated by the principal barrier. Penetration enhancement interaction in aqueous solution of an technology is a challenging development that aluminum salt and sodium carbonate, would increase significantly the number of drugs increased concentration off reactants wil available for topical administration. The produce a gel structure .Silica gel is another permeation of drugs through skin can be example and is produced by interaction of enhanced by physical methods such as mechanical sodium silicate and acids in aqueous disruption, electrical disruption, chemical solution. modification and by chemical penetration enhancers e.g. sulphoxides (dimethyl  TEMPERATURE EFFECT: As lower the sulphoxides), pyrrolidone, alcohols, glycols, temperature the solubility of most lyophilic

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colloids, e.g., gelatin, agar, sodium-oleate, is equation, which is obtained by linear regression reduced, so that, if cooling a concentrated analysis of calibration curve. hot sol will often produce a gel. Similarly to hydrogen bonding with water. Increasing the 3. Viscosity study temperature of these sols will break the The measurement of viscosity of the prepared gel hydrogen bonding and the reduced solubility is done with a Brookfield Viscometer. The gels are will produce gelatin. rotated at 0.3, 0.6 and 1.5 rotations per minute. At each speed, the corresponding dial reading is  FLOCCULATION WITH SALTS AND NON- noted. The viscosity of the gel is obtained by SOLVENTS: Gelatin is a popular collagen multiplication of the dial reading with factor given derivative primarily used in food, in the Brookefield Viscometer catalogues. pharmaceutical, photographic and technical products. In foods, gelatin provides a melts- 4. Spreadability in-the-mouth function and to achieve a One of the criteria for a gel to meet the ideal thermo-reversible gel property. Gelatin is quantities is that it should possess good produce by adding just sufficient precipitant spreadability. It is the term expressed to denote to produce the gel structure state but in the extent of area to which gel readily spreads on sufficient to bring about complete application to skin or affected part. The precipitation .It is necessary to ensure rapid therapeutic efficacy of a formulation also depends mixing to avoid local high concentration of upon its spreading value. precipitants. Solutions of ethyl cellulose, Spreadability is expressed in terms of time in polystyrene, etc, in benzene can be gelled by seconds taken by two slides to slip off from gel rapid mixing with suitable amount of a and placed in between the slides under the nonsolvent such as petroleum ether. The direction of certain load. Lesser the time taken for addition of salts to moderately sols such as separation of two slides, better the spreadability. aluminum hydroxide, ferric hydroxide and It is calculated by using the formula: bentonite, produces gels. S = M. L / T 1.14 Evaluation12-17 Where M = wt. tied to upper slide  pH L = length of glass slides  Drug content T = time taken to separate the slides  Viscosity  Spreadability 5. Extrudability study  Extrudability study The formulations are filled in the collapsible tubes  Skin irritation studies after the gels are set in the container. The  In vitro release extrudability of the formulation is determined in  In vivo study terms of weight in grams required to extrude a 0.5  Stability cm. ribbon of gel in 10 second.  Consistency 6. Skin irritation study 1. Measurement of pH Guinea pigs (400-500 g) of either sex are used for The pH of various gel formulations is determined testing of skin irritation. The animals are by using digital pH meter. One gram of gel is maintained on standard animal feed and had free dissolved in 100 ml distilled water and stored for access to water. The animals are kept under two hours. The measurement of pH of each standard conditions. Hair is shaved from back of formulation is done in triplicate and average guinea pigs and area of 4 cm2 is marked on both values are calculated. the sides, one side served as control while the other side is test. Gel is applied (500 mg / guinea 2. Drug content pig) twice a day for 7 days and the site is observed 1 g of the prepared gel is mixed with 100ml of for any sensitivity and the reaction if any, is suitable solvent. Aliquots of different graded as 0, 1, 2, 3 for no reaction, slight patchy concentration are prepared by suitable dilutions erythema, slight but cofluent or moderate but after filtering the stock solution and absorbance is patchy erythema and severe erythema with or measured. Drug content is calculated using the without edema, respectively.

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7. In vitro Diffusion studies 8. Stability The diffusion studies of the prepared gels can be The stability studies are carried out for all the gel carry out in Franz diffusion cell for studying the formulation by freeze - thaw cycling. In this dissolution release of gels through a cellophane syneresis is observed by subjecting the product to membrane. Gel sample (0.5g) is taken in a temperature of 4° C for 1 month, then at 25°C for cellophane membrane and the diffusion studies 1 month, then at 40°C for 1 month. After this gel is are carried out at 37 ± 1° using 250 ml of exposed to ambient room temperature and liquid phosphate buffer (pH 7.4) as the dissolution exudates separating is noted. medium. Five milliliters of each sample is withdrawn periodically at 1, 2, 3, 4, 5, 6, 7 and 8 h 9. Consistency 32 and each sample is replaced with equal volume of The measurement of consistency of the prepared fresh dissolution medium. Then the samples are gels is done by dropping a cone attached to a analyzed for the drug content by using phosphate holding rod from a fix distance of 10cm in such buffer as blank. way that it should fall on the centre of the glass cup filled with the gel. The penetration by the cone is measured from the surface of the gel to the tip of the cone inside the gel. The distance traveled by cone is noted down after 10sec.

Table 1: Required properties of pharmaceutical gels18 Pharmaceutical Favorable properties gel application Highly thixotropic, optimal viscosity for filling fissure, adherent DENTAL to enamel surface, optically clear, water soluble, oral digestible. Thixotropic, good spreadability, greasless, easily removable, DERMATOLOGICAL emollient, demulcent, non-staining, compatible with number of excipients (water soluble or miscible). NASAL Adherent, odourless, non-irritant, water-soluble. OPHTHALMIC Optically clear, sterile, mucomimetic, lubricating or non-sensitizing,water soluble or miscible. SURGICAL AND MEDICAL Lubricating, adherent to instrument surfaces, maximal contact with mucus. PROCEDURES Acid stable, adherent, does not liquefy at body temperature; slow VAGINAL dissolving, lubricating, greaseless and non-tacky, non-irritating.

Table 2: General classification and description of gels18

Class Description Examples Aluminium hydroxide gel, bentonite magma Inorganic Usually two-phase systems

Carbopol®, tragacanth Organic Usually single-phase systems

Silica, bentonite, pectin, sodium alginate, Hydrogels Contains water methylcellulose, alumina Hydrocarbon type Petrolatum, mineral oil/polyethylene gel, Plastibase

Lard, cocoa butter Animal/vegetable fats Aluminium stearate with heavy mineral-oil gel Organogels Soap-base greases Carbowax bases (PEG ointment) Hydrophilic organogels Organic hydrogels Pectin paste, tragacanth jelly Natural and synthetic gums Methylcellulose, sodium carboxymethylcellulose, Pluronic® F-127

Hydrogels Bentonite gel (10% to 25%), Veegum® Inorganic hydrogels

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Figure 1: Structure of skin(19)

CONCLUSION availability of physical permeation enhancement Transdermal drug delivery system is useful for methods and new breakthroughs in topical drug topical and local action of the drug. The drugs which formulations, such as liposomes, microemulsions, shows hepatic first pass effect and unstable in GI nanoparticles and evaporating gels. conditions are the suitable candidate for TDDS Breakthroughs in chemical permeation enhancer through gel. analogs showing significant improvements in limiting cutaneous irritation show promise for the FUTURE PROSPECTIVE development of safe chemical enhancers and Expanding the use of novel permeation should be further examined in the future enhancement techniques with macromolecules and other conventional molecules for a wider REFERENCES range of indications is highly desirable for the 1. Debjit Bhowmik, Chiranjib, R.Margret transdermal industry. Physical enhancement Chandira, K.K.Tripathi, K.P.Sampath methods afford substantial improvement in the Kumar Nanomedicine : An Overview. Int.J. rate of delivery of therapeutic agents across skin. PharmTech Res.2010; 2(1): 2143-2151. Currently, a variety of them are undergoing 2. Provost C. Transparent oil-water gels: A extensive investigation and new device-based TDS Review. Int J Cosmet Sci. 1986; 8: 233- can be expected in the near future. One can also 247. expect the first transdermal prodrug product to 3. Ferry John D. Viscoelastic Properties of emerge on the market in the near future. Novel Polymers, New York: Wiley, 1980. prodrugs would not only help to reach the 4. Shivhare UD, Jain KB, Mathur VB, Bhusari therapeutic levels for some drugs, but may also KP and Roy AA. Formulation development help alleviate skin irritation. and evaluation of Diclofenac sodium gel The incidence and significance of skin irritation using water soluble polyacrylamide reactions will decrease with the increasing

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