Comprehensive review on additives of topical dosage forms for drug delivery

Abstract

Skin is the largest organ of the human body and plays the most important role in protecting against pathogen and foreign matter. Three important modes such as topical, regional and transdermal are widely used for delivery of various dosage forms. Among these modes, the topical dosage forms are preferred because it provides local therapeutic activity when applied to the skin or mucous membranes. Additives or pharmaceutical excipients (non-drug component of dosage form) are used as inactive ingredients in dosage form or tools for structuring dosage forms. The main use of topical dosage form additives are controling the extent of absorption, maintaining the viscosity, improving the stability as well as organoleptic property and increasing the bulk of the formulation. The overall goal of this article is to provide the clinician with information related to the topical dosage form additives and their current major applications against various diseases.

• Additives
• cream
• liniments
• lotions
• topical dosage forms

Introduction

Skin is often known as largest organ of the human body. Skin is composed of three primary layers – epidermis, dermis and hypodermis. The skin is an ever-changing organ that contains many specialized cells and structures. It plays the most important role in protecting against pathogens. It gathers sensory information from the environment and plays an active role in the immune system protecting us from disease. It is also involved in maintaining the proper temperature for the body to function well. Natural and synthetic cosmetics are frequently used to treat the appearance of the face and condition of the skin (Dominguez-Huttinger et al., 2013). Three important modes such as topical, regional and transdermal are widely used for delivery of various dosage forms. Among these modes, the topical dosage forms are preferred because are protective, emollient and deliver therapeutic agents to exert local activity when applied to the skin or mucous membranes. Topical dosage forms are classified into three major categories such as solid (dusting powder), liquid (lotion, liniment) and semi-liquid (ointment, paste, cream and gel) (Chuo & Kaminska, 2009). Additives or pharmaceutical excipients (nondrug component of dosage form) are used as inactive ingredients in dosage form or tools for structuring dosage forms. The main use of topical dosage form additives are to control the extent of absorption, maintain the viscosity, improve the stability as well as organoleptic property and increase the bulk of the formulation. Topical dosage forms are widely used for delivery of various bio-active molecules to the target site as well as improve the bioavailability of encapsulated dug substance (Andersson et al., 2013).

Modes of delivery to the skin

Three important modes such as topical, regional and transdermal are widely used for delivery of various dosage forms (Figure 1).

Figure 1. Various modes of drug delivery to the skin (A) topical (B) regional and (C) transdermal delivery.

Topical delivery

Topical delivery can be defined as the application of a drug containing formulation to the skin. It is used mainly to directly treat cutaneous disorders such as acne or the cutaneous manifestations of a universal disease such as psoriasis. The main goal of this delivery is confining the pharmacological or other effect of the drug to the surface of the skin or within the skin. Various formulations such as foams, sprays, medicated powders, solution or others forms are widely used by topical route (Pando et al., 2013).

Regional delivery

Regional delivery is defined as the application of a drug containing formulation to the skin for treating or alleviating disease symptoms in deep tissues. The main aim of this delivery is to effect the pharmacological actions of the drug within musculature, vasculature joints, and other, beneath and around the site of application. Regional activity requires percutaneous absorption and deposition as well as regional concenttrations are considered to be higher than systemic administration at the same total body exposure to the drug. Various formulations such as ointments, creams, large adhesive patches, plasters, poultices and cataplasms are widely used by topical route (Crommelin et al., 2003).

Transdermal delivery

Transdermal delivery can be defined as the application of a drug to the skin for treat systemic disease. The main aim of this delivery is achieving systemically active levels of the drug. The main important requisite for this delivery is percutaneous absorption with appreciable systemic drug accumulation. Although such traditional dosage forms as ointments can be employed in this kind of therapy (e.g. nitro-glycerin ointments) due to no local accumulation of drug (Mazzitelli et al., 2013).

Topical dosage form

Among of these modes, the topical dosage forms are preferred because they are protective, emollient and delivered therapeutic agents to exert local activity when applied to the skin or mucous membranes. Topical dosage forms are classified into three major categories (Figure 2).

Figure 2. Classification of topical dosage forms.

Solid topical dosage form

Dusting powder

It is a finely divided insoluble powder containing ingredients such as talc, zinc oxide or starch used on the skin or on wounds especially for allaying irritation or absorbing moisture, which discourage bacterial growth and some used for their lubricant properties.

Semisolid topical dosage form

Cream

It is a semisolid emulsion formulation for application to the skin or mucous membranes. Water in oil (w/o) emulsion type creams are less greasy and good spreadability as comparison to ointments whereas oil in water (o/w) emulsion creams readily rub into the skin is termed as vanishing cream and is readily removed by water.

Ointment

It is a greasy semisolid preparation of dissolved or dispersed drug. Ointment bases influence topical drug bioavailability due to their occlusive properties of the stratum corneum, which enhances the flux of drug across the skin and they affect drug dissolution and drug partitioning within or from the ointment to the skin, respectively.

Gel

Gels are transparent or translucent semisolid preparations of one or more active ingredients in suitable hydrophilic or hydrophobic bases. Gels may be clear or opaque, and polar hydroalcoholic or nonpolar. Gels are prepared by either a fusion process or a special procedure necessitated by the gelling agents, humectants and preservatives (Garg et al., 2013).

Paste

It is a stiff preparation containing a high proportion of finely powdered solid such as starch, zinc oxide, calcium carbonate and talc. Pastes are less greasy than ointment.

Liquid topical dosage form

Lotion

A lotion is a low- to medium- viscosity topical preparation intended for application to unbroken skin. Lotions are applied to external skin with bare hands, a clean cloth, cotton wool or gauze and provide cooling effects to the skin by evaporation of solvents.

Liniments

The liniments are liquid or semiliquid preparations meant for application to the skin. Applied to skin with friction and rubbing of the skin. They act as rubefacient, soothing or stimulant. The vehicle may be alcohol, oil or soap based.

Additives of topical dosage forms

Additives or pharmaceutical excipients (nondrug component of dosage form) are used as inactive ingredients in dosage form or tools for structuring dosage forms. Generally, they have little or no therapeutic value but are useful in the manufacturing and compounding of various pharmaceutical dosage forms. Some ideal properties or characteristics of additives are: (1) they must be non-toxic, (2) commercially available in acceptable grade, (3) acceptably cheap, (4) physically and chemically stable and (5) not be contraindicated and must be color compatible (Park et al., 2013). The main use of topical additives are control the extent of absorption, maintain the viscosity as well as stability of dosage form, improve the organoleptic property and increase the bulk of the formulation. Additives are classified according to nature of solvent, base, diluents, vehicles and patient acceptability (Luo et al., 2012). Table 1 shows classification of additives according to requirements or applications.

Table 1. Classification of additives according to requirements or applications.

Classification of additives	Purpose or applications of additives
Physical form providers	• Provide them a certain physical form to the formulations such as surfactants and hydrocolloids.
Solvents/diluents/bases	• They form the bulk of a formulation. • Solvents used for dissolution of drugs. • Bases are semisolid material used for formulation of ointments.
Organoleptic additives	• They make the formulation acceptable to the human.
Formulation stabilizers/preservatives	• Provide stability of the formulation against various environmental or atmospheric conditions such as temperature, pressure, microorganisms etc.
	• These are antimicrobial compounds  maintain chemical stability of the formulation.

Additives in dusting powder

Dusting powder is designed for application to the unbroken or broken skin. Easy powder flow ability and spread ability are two important parameters that are always considered at the time of manufacturing and evaluation of topical powder. The dusting powders should adhere to the skin providing good covering and adsorptive property, absolutely free from irritant effect, and should protect the skin from drying and irritation (Kircik & Del Rosso, 2010). Dusting powders are generally prepared by mixing two or more ingredients. one of which must be starch, talc or kaolin as one of the ingredients of the formulation. Due to the chemically inert nature of talc and kaolin, they are the most commonly used ingredients in the formulation of dusting powder. Sometimes, crust formation may take place in the presence of significant quantities of fluids (Mariappan et al., 2013). Table 2 shows the important properties and their use of various additives used in the formulation of topical powder. Topical dusting powders are widely used for drug delivery to the target site. Some of the important applications associated with topical drug delivery through dusting powder shown in Table 3.

Table 2. Properties and use of additives in topical powder formulation.

Property of additives	Use/applications of additives
(1) Talc (Seka et al., 2002): It is also known as Talcum powder, Purified Talc, French Chalk, Soapstone, and Steatite. It is a mineral composed of hydrous magnesium silicate and sometimes contains a small proportion of aluminum silicate.
• Fine in nature    • Occurs as foliated to fibrous masses    • Grayish white color    • Crystalline powder    • Adhering readily to the skin    • Free from grittiness    • Insoluble soluble in water	• Extensively used for toilet purposes. • Used as a lubricant in the manufacture of tablets. • Used as a dusting powder in the manufacture of suppositories. • Used as a lubricant for putting on and removing rubber gloves.
(2) Starch (Zhu et al., 2013): It is also known as Corn Starch, Wheat Starch and Potato Starch. It is a carbohydrate; consisting of a large number of glucose units. It consists of two types of molecules: the linear and helical amylose and the branched amylopectin.
• White masses or fine powder    • Odorless, slight, characteristic taste.    • Size range: 35–100 µm    • Insoluble in cold water or alcohol    • Have absorbent and demulcent properties	• Used as a thickening, stiffening or gluing agent. • Used as a dustiing powder in various dermatological preparations. • Used as a pharmaceutical aid (filler, binder and disintegrant).
(3) Kaolin (Naganathan et al., 2010): It is also known as Light Kaolin, White Bole, China Clay and Kaolin-Pectin suspension. It is produced by the chemical weathering of native hydrated aluminium silicate mineral and freed from gritty particles by elutriation.
• Soft, white or yellowish white powder    • Characteristic earthy or clay-like taste    • Becomes darker in presence of moisture	• Used medicinally as an adsorbent. • Used as a poultice, dusting powder, and an ingredient of toilet powders. • Used in tooth paste and cosmetic products
(4) Zinc stearate (Koseki et al., 2008): It is also known as octadecanoic acid and zinc salt. It is a “zinc soap” of Stearic acid that is widely used industrially.
• Fine, white, bulky powder    • Free from grittiness    • a faint characteristic color    • Insoluble in water, alcohol, and ether    • Soluble in benzene	• Used as a dusting powder in dermatological practice for its desiccating, astringent and protective effects. • It makes the product soothing. • Used as a lubricant in the production and processing of polyolefin.
(5) Zinc oxide (Mouzakis et al., 2010): It is also known as flowers of zinc and zinc white. It is an inorganic compound, and occurs naturally as the mineral zincite but mostly zinc oxide is produced synthetically.
• Fine amorphous form    • Free from gritty particles    • Absorbs carbon dioxide from air    • Insoluble in water or alcohol    • Soluble in dilute acids	• Used as a mild astringent • Exhibit antiseptic properties • Helps in relieving prickling caused by prickly heat during summer and rainy seasons.
(6) Aluminium chlorohydrate (Saukkoriipi & Laasonen, 2008): It is a group of specific aluminium salts, commercially manufactured by reacting aluminium with hydrochloric acid. The FDA considers that up to 25% concentration is safe in antiperspirants.
• A clear amber liquid with little or no odor    • Will be soluble in water with release of heat	• Used in deodorant and antiperspirants. • Used as a coagulant in water purification.
• Undesirable odor and yellowish in color	• Used as an antiperspirant in many deodorant products.
(7) Aluminium zirconium chlorhydrex (Belov et al., 2013): It is also called AZG, which contains a mixture of monomeric and polymeric Zr4+ and Al3+ complexes with hydroxide, chloride and glycine.
• Undesirable odour and yellowish in color	• Used as an antiperspirant in many deodorant products.
(8) Micronized wax: It is commonly used as a partitioning agent in ethylene-vinyl acetate (EVA), EVA co-polymer, polyolefin (PO) and amorphous polyolefin (APO) hot melt adhesives. The powder is carefully deposited (dusted) onto the surface of the thermoplastic adhesive where it de-tacks the surface.
• High saponification value    • Insoluble in water    • Soluble in organic, nonpolar solvent	• Provide high performance micronized polyethylene and Fischer–Tropsch wax to maximize block resistance without affecting viscosity and bond strength.
(9) Chlorhexidine: Chlorhexidine is usually encountered as the acetate, gluconate or hydrochloride salt. It is widely used in pharmaceutical formulations in Europe and Japan for their antimicrobial properties.
• Odorless and bitter tasting    • White crystalline powder    • Stable at normal storage temperature    • Maximum stability occurs at pH 5.6.	• Exhibit antimicrobial activity against gram positive and gram negative micro-organisms. • Used as constituents of medicated dressing, dusting powders, sprays and creams.

Table 3. Applications of topical dusting powder dosage form in drug delivery.

Drug	Results/applications
Ibuprofen	Improved percutaneous absorption to avoid the use of permeation enhancers or synthetically modifying chemical structure (Yuan & Capomacchia, 2013).
Triamcinolone acetonide (TA)	Improved the efficacy of entrapped drug for the treatment of endotoxin-induced uveitis (EIU) (Sabzevari et al., 2013).
Rapamycin	Showed a high scleral retention and successful permeation of rapamycin (Elsaid et al., 2012).
Gentamicin sulphate (GS)	Antibiotic activity was preserved at 6 days against Staphylococcus aureus (Aquino et al., 2013).
Tretinoin	Showed a significant improvement in tretinoin photo stability (Marchiori et al., 2013).
Clarithromycin (CLR)	CLR nanoparticles are more potent against S. aureus with improved minimum inhibitory concentration (MICs) (Mohammadi et al., 2011).
Lutein	Showed the ability to protect the skin from photo damage (Mitri et al., 2011).
Acitretin	Significant improvement in therapeutic response and reduction in local side effects as well as effectiveness in the topical treatment of psoriasis (Agrawal et al., 2010).
Econazole nitrate	Showed improved anti-fungal activity against fungal infections, such as Candida intertrigo and Tinea pedis (Ambrogi et al., 2010).

Additives in cream and paste

It is a semisolid emulsion formulation for application to the skin or mucus membranes (Parnami et al., 2013) Emulsifying agent used in cream formulation as additive (a) w/o emulsifying agent and (b) o/w emulsifying agent. Tables 4 and 5 shows the important properties and their use of various additives used in the formulation of w/o and o/w topical cream, respectively. Topical creams as well as paste are widely used for drug delivery to the target site. Some of the important applications associated with topical creams and paste are shown in Tables 6 and 7, respectively.

Table 4. Properties and use of additive in topical cream (w/o emulsifying agent – cleansing cream) formulation.

Property of additives	Use/applications of additives
(1) Wool fat (Qiao et al., 2007): It is also known as an anhydrous lanolin or refined wool fat. It is the purified fats which obtained from the wool of sheep. It contains the sterols, cholesterol, oxycholesterol, triterpene and aliphatic alcohol.
• Soluble in hot alcohol    • Insoluble in water    • Yellow in color    • Melting point (36–42 °C)    • Absorb about 50% of its weight of water	• Used in protective baby skin treatment • Used in lip balm products • Used as a lubricant • Used as a raw material for producing vitamin D3
(2) Waxes (Jin et al., 2006): It is an organic compounds, both naturally (esters of fatty acids and free alcohols) and synthetic occurring (long-chain hydrocarbons lacking functional groups).
• High saponification value    • Insoluble in water    • Soluble in organic, non-polar solvent    • Melt above 45 °C	• Used as colorants for plastic • Used as releasing agents • Used as slip agents • Used as writing surfaces
(3) Bivalent soaps (Rhoades et al., 2013): They are esters of higher fatty acids (carbon chain of 12–18 atoms) or rosin acids. They are prepared by reacting the naturally occurring triglycerides of higher fatty acids (vegetable or animal oil) with alkalis.
• Hydrophobic in nature    • Soluble in organic, non-polar solvent	• Used as a lubricant • Used as slip agents
(4) Sorbitan esters (Span) (Marchal et al., 2013):It is also known as arlacels. It is a mixture of isomeric organic compound and they are lipophillic nonionic surfactants. They are produced by esterification of fatty acid with sorbitol derivatives.
• Melting point <25 °C (liquid)    • Viscous liquid, light yellow    • Boiling point >300 °C    • Vapor pressure <1.0 × 10    • Water solubility: dispersible	• Used as emulsifying agents in the preparation of emulsions, creams, and ointments for pharmaceutical and cosmetic. • Used as emulsifiers and stabilizers in food
(5) Borax: It is also known as sodium borate and investigated in the prevention of crystal formation in freeze dried solutions.
• White, hard crystals, granules, or crystalline powder    • Odorless and efflorescent    • At about 880 °C, the substances melt into a glassy state: borax beads.	• Act as alkalizing agents, antimicrobial, preservatives, buffering agents, disinfectants, emulsifying agents, and stabilizing agents.
(6) Oleic Acid: It is also known as ethyl oleate, which is mainly prepared by the reaction of ethanol in the presence of a suitable hydrogen chloride acceptor.
• Pale yellow to almost colorless    • React with oxidizing agents    • Flammable in nature	• Used as a oleaginous vehicle and solvent
(7) Chlorocresol: It is also known as Chlorocresolum and mainly used as an antimicrobial preservative in cosmetics and pharmaceutical formulations.
• Colorless dimorphs crystals powder    • Characteristic phenolic odor    • Most active in acidic media	• Used as antimicrobial preservatives and disinfectant • Has bactericidal activity against bacteria, molds, spores, and yeasts.

Table 5. Properties and use of additive in topical cream (with emulsifying agent – vanishing cream) formulation.

Property of additives	Use/applications of additives
(1) Polysorbates (Garg et al., 2012): It is also known as Tween. These are non-ionic surfactant. It is a Polyoxyethylene derivative such as Sorbitan monooleate (Tween 80), Sorbitan monolaurate (Tween 21) and Sorbitan monopalmitate (Tween 40).
• Viscous in nature    • Water soluble yellow liquid	• Used to stabilize parenteral formulation • Used in some eye-drops
(2) Methylcellulose (Shimoyama et al., 2013): It is cellulose derived chemical compounds, produced by heating cellulose with caustic solution and treating it with methyl chloride.
• White powder (pure form)    • Hydrophilic (in cold water)    • Not digestible, Nontoxic    • LCST: 40–50 °C	• Used in emulsion of mineral oils • Used as a thickener in various food and cosmetic products • Treatment of constipation
(3) Acacia (Min et al., 2012): It is also known as thorn tree or wattle. It is a Ca, Mg and K Salts of polysaccharide Arabic acids.
• Insoluble in alcohol    • Completely soluble in water    • Stable at pH 2–10	• Prepare attractive emulsion • Cure for rabies • Uses in folk medicine
(4) Tragacanth (Keshtkaran et al., 2013): It is a natural gum. It is the mixture of 70% bassorin and 30% soluble gum.
• Insoluble in alcohol    • viscous, odorless, tasteless	• Used as emulsifying agent to increase consistency
(5) Triethanolamine oleate (Masoumi et al., 2011): It is a combination of triethanolamine and oleic acid, which prepared from mono and diaethanolamine.
• Viscous in nature    • Weakly basic in nature	• Used as detergent, emulsifier and surfactant
(6) Arachis oil: It is also known as Peanut oil. The composition of the acids present as glycerides to be arachidic acid, behenic acid, palmitic acid, stearic acid, lignoceric acid, linoleic acid and oleic acid.
• Colorless or pale yellow liquid    • Faint nutty odor and taste    • Saponified by alkali hydroxides    • At 3 °C it becomes cloudy, and at lower temperature it partially solidifies	• Used as a vehicle for topical preparations and as a solvent for vitamins and hormones. • It is a part of sustained release formulations. • Used in nutrient regimens.
(7) Cetostearyl alcohol: It is a mixture of solid aliphatic alcohols consisting mainly of stearyl and cetyl alcohols. A small quantity of other alcohols mainly myristyl alcohol make up the remainder of the material.
• White or cream colored unctuous masses    • Faint characteristic sweet odor    • Incompatible with strong oxidizing agents and metal salts	• Emollient • Emulsifying agents • Viscosity increasing agent • Mainly used in cosmetic and topical pharmaceutical formulations

Table 6. Applications of topical cream dosage form in drug delivery.

Drug	Results/applications
Cetirizine dihydrochloride	Recommended for treatment of pruritus associated with atopic dermatitis. (Goindi et al., 2013)
Silver sulfadiazine (SSD)	Showed increase bactericidal activity in burn therapy. (Venkataraman & Nagarsenker, 2013)
Papaverine	Blood flow in expanding tissue improved by these carrier systems. (Tang et al., 2012)
5-Fluorouracil (5-FU)	Increased the local bioavailability of 5-FU in comparison to the marketed formulation. (Puri & Jain, 2012)
Olive oil	Significantly reduce the incidence and the severity of Striae gravidarum (SG). (Soltanipoor et al., 2012)
18β-glycyrrhetic acid (GA)	Safe and effective in the treatment of chronic allergic dermatitis. (Li et al., 2012b)
Paromomycin sulfate (PM)	Useful as a candidate for the topical treatment of cutaneous leishmaniasis (CL). (Bavarsad et al., 2012)
Silver sulfadiazine (SSD)	Showed in the effective treatment of babies with a giant omphalocele. (Ein & Langer, 2012)
Nalmefene (SRD174)	Showed long acting opioid antagonist for the management of pruritus associated with atopic dermatitis (AD). (Herzog et al., 2011)
Retinoic acid (RA)	Reduce RA-induced skin irritation without reducing efficacy, and constitutes an innovative approach for the topical treatment of acne with RA. (Castro et al., 2011)
Betamethasone-17-valerate (BMV)	A promising alternative system for the topical application of BMV. (Senyigit et al., 2011)
Fluorouracil	Well-tolerated and effective in treating and preventing recurrence of actinic keratoses lesions up to 18 months after initial treatment. (Stough et al., 2008)
Hesperetin	Showed that a significantly topical photo protective effect with acceptable skin irritation. (Huang et al., 2010)
Perillyl alcohol (POH)	Inhibits both UVB-induced murine skin carcinogenesis (squamous cell tumor models) and 7,12-dimethylbenz(a)anthracene-induced murine melanoma (transgenic models involving tyrosinase-driven Ras). (Stratton et al., 2010)
Lidocaine-prilocaine (EMLA)	Showed local anesthetic infiltration in the reduction of pain during perineal suturing after childbirth. (Sanchez-Lozada et al., 2010)
Pimecrolimus	Showed treatment of patients with atopic dermatitis especially in the head/neck area. (Leung et al., 2009)
Lidocaine/tetra Caine	Provided effective anesthesia with an application time as short as 10 min. (Sawyer et al., 2009)
Alprostadil	Showed safety and efficacy of topical alprostadil cream in male patients with erectile dysfunction. (Rooney et al., 2009)
Imiquimod	In vitro release rates of Imiquimod were significantly faster than other products. (Harrison et al., 2009)
Fluorouracil	Extending treatment for up to 4 weeks will further improve actinic keratoses (AKs) lesion clearance rates. (Menter et al., 2008)

Table 7. Applications of topical paste dosage form in drug delivery.

Drug	Results/applications
Gentamycin	Showed controlled release patterns and drug stability of in situ gels as well as their in vivo performances and local safety following nasal administration (Wang et al., 2013b).
Gentamycin, Vancomycin	Showed high antimicrobial potency against Staphylococcus aureus in an agar diffusion test (Vorndran et al., 2013).
Vancomycin	Prepared phosphate based orthopedic cements, which do not generate any exothermicity during setting (Zhou et al., 2013).
Simvastatin	Showed ability of slowly releasing the drug, leading to a prolonged stimulation of osteogenesis (Montazerolghaem et al., 2013).
Capsaicin	Showed high therapeutic efficacy in chronic neuropathic pain in adults (Derry et al., 2013).
P-monochlorophenol-propylene glycol	Showed the largest zones of inhibition against all the tested microorganisms (Pacios et al., 2012).
Vancomycin	Adsorption of vancomycin from an aqueous solution and showed an almost complete release within 2 h. (Moseke et al., 2012).
Prilocaine	Showed the most prolonged local analgesic effects and enhanced local anesthetic action (Kang & Shin, 2012).
Acyclovir	Showed enhanced iontophoretic transdermal delivery of acyclovir (ACV), a model hydrophilic small-drug molecule, across hairless rat skin on Franz diffusion cells (Siddoju et al., 2012).
Beta lactone	Confers applicability and potency for topical treatment, and will translate into a new formulation of this highly potent drug candidate for the treatment of skin and soft tissue infections (Lorenz-Baath et al., 2012).
Betamethasone	Holds a high potential for a selective therapy to the inflamed skin by increasing the local intradermal availability with simultaneous reduction in systemic adverse effects (Abdel-Mottaleb et al., 2012).
Tacrolimus	Improved penetration to the target site without any toxic-effects and would represent an efficient and commercially viable alternative for atopic-dermatitis treatment (Pople & Singh, 2012).
Triantibiotics	Induced moderate reactions for endodontic tissue self-regeneration of nonvital immature permanent teeth at 7 days (Gomes-Filho et al., 2012).
Clobetasol propionate	Provided prolonged release of clobetasol propionate and to reduce systemic absorption and side effects of the drug (Badilli et al., 2011).
5-fluorouracil (5-FU)	Showed effectiveness colon specific delivery of 5-FU so as to treat colon carcinoma (Dev et al., 2011).
Tacrolimus	Increased the encapsulation efficiency of drug with improved performance in terms of stability and skin localization (Pople & Singh, 2013).
Fragmin/protamine	Helps to improve graft volume retention and survival in soft-tissue reconstruction through accelerating adipocyte-survival rates and angiogenesis (Nakamura et al., 2011).
Mefenamic acid	Improved bioavailability of mefenamic acid eliminates the gastrointestinal disorders associated with its oral administration (Ahmed et al., 2011).
Corticosteroids	Enhancing the topical delivery of anti-vitiligo agents, whilst reducing the side effects of drugs commonly used in its topical treatment (Garg et al., 2010).
Hydrocortisone	Topical application of hydrocortisone in the form of proniosomes leads to prolonged action (Sankar et al., 2009).

Additives in ointment

An ointment is a semisolid, homogenous, viscous preparation, which is intended for external application to the skin or mucus membranes. Ointments are used topically on a variety of body surfaces. They usually have moisturizing property, and are good for dry skin, as well as have a low risk of sensitization due to their having few ingredients beyond the base oil or fat, and low irritation risk (El-On et al., 2007). They are often disliked by patients due to greasiness. The vehicle of an ointment is known as the ointment base.

Ointment base

An ideal ointment base should possess the following properties such as should be pharmaceutically well-designed, should have a low manifestation of irritation, should be companionable with other ingredients, easily washable with water, secure on storage, have a low sensitization catalog and should release the medicament efficiently at the site of application (Fellinger et al., 2013). The USP recognizes four general classes of ointment bases to be used therapeutically or as vehicles for active ingredients.

Oleaginous bases

These bases are composed entirely of lipophilic materials. They are anhydrous, hydrophobic, insoluble in water or not removable by water. The major advantages of these bases are that they are inexpensive, nonreacting, nonirritating, good emollient, have protective and occlusive properties and are not water washable. However, they suffer from major drawbacks such as greasy nature, not removed easily with washing, and cannot absorb water, and therefore most liquid ingredients are difficult to incorporate into hydrocarbon bases (Hidaka et al., 2006). Table 8 shows a list of materials used as oleaginous bases.

Table 8. List of materials used as oleaginous bases.

Oleaginous bases	Examples of oleaginous bases
Hydrocarbons	Petrolatum, paraffin wax, liquid paraffin, microcrystalline wax, plastibase (Jelene), Ceresi
Vegetable oils and animal fat	Coconut oil, bees wax, olive oil, lanolin, peanut oil, spermaceti wax, sesame oil, almond oil
Hydrogenated and sulphated oils	Hydrogenated castor, cotton seed, soya been corn oils, hydrogenated sulphated castor oils
Alcohols, acids and esters	Cetyl alcohol, stearic acid, stearyl alcohol, oleic acid, oleyl alcohol, palmitic acid, lauryl alcohol, lauraic acid, myristyl alcohol, ethyl oleate, isopropyl myristicate, ethylene glycol
Silicones	Dimethylpropylsiloxanes, methyl phenyl polysiloxanes, steryl esters of dimethyl polysiloxanes

Absorption bases

Absorption bases are known to take up several times their own weights of water but not the absorption of medicament from the bases. Theycan be classified into two subgroups: anhydrous absorption bases and water-in-oil emulsions. The advantages of absorption bases are that they are good protective, occlusive and emollient properties, can absorb liquids and do not wash off easily so they hold incorporated medications in contact with the skin. Chemical stability problems, microbial growth and poor patient acceptance are the major drawbacks associated with these bases. Hydrophilic petrolatum and anhydrous lanolin of USP are examples of monograph on absorption bases (Das & Kumar, 2013).

Emulsion bases

W/O emulsion bases

Lanolin and cold cream are examples of ointments without emulsion bases. They are used as emollients. The aqueous phase hydrates the skin. The oily phase forms an occlusive covering which prevents loss of water by evaporation. The main drawback of ointments without emulsion base is their greasy and sticky nature. Example w/o emulsion base is cold cream (Ozsoy et al., 2004).

O/W emulsion base

Hydrophilic ointment and vanishing cream are type of o/w emulsion base. They are easily removed with water. They are non-greasy and non-sticky. Example of o/w emulsion is vanishing cream, which is often used as a cosmetic (Noda et al., 2011).

Water soluble bases

Water soluble bases are also known as greaseless ointment bases. They consist of water soluble ingredients such as polyethylene glycol polymer. Polyethylene glycol is known as carbowax. Carbowax is water soluble, nonvolatile and inert. Some water washable bases are also prepared by glyceryl monostearae (GMS), cellulose derivative, sodium alginate, bentonite and carbopol 934. The main advantages of water soluble bases are leaving no oil residue, easily removed by washing and absorbs some water or alcohol, but these bases can be irritating, especially on denuded or abraded skin or mucus membranes. Compatibility problems have been found with incorporated drugs that are subject to oxidation (Jain et al., 2010).

Preservatives in ointment

The antimicrobial compounds and their quantities is a crucial parameter to prevent contamination and spoilage of ointment bases by microorganisms such as bacteria, virus and fungi. Various antimicrobial compounds show irritation or toxicity to the tissue. For instance, methyl and propyl parabens are irritant to nasal passages. Boric acid and quaternary ammonium compounds or phenyl mercuric nitrates are toxic as well as irritant to nasal tissues. On some occassions, the preservatives reducing the antimicrobial compounds availability for antimicrobial action by making the complex. In the presence of Tween 80, methylparaben, benzalkonium chloride, benzoic acid etc. are inactivated to a significant extent. The partition coefficient of the antimicrobial compound between aqueous and oily phases plays an important role in bactericidal activity (Kempf et al., 2011).

Antioxidants in ointment

Antioxidants should be included to prevent the oxidative degradation of the base from the oxidation. It may be more desirable to select two antioxidants instead of one. The concentration of antioxidants would depend upon their partition coefficients between the aqueous and oily phases if both the phases are present in a base. Generally, compounds like butylated hydroxy anisole, propyl gallate, nor-dihydroguaiaretic acid etc. are used in ointment bases (Gupta, 2012).

Chelating agents

The traces of metallic ions are likely to catalyze oxidative degradations, so small amounts of substances such as citric acid, maleic acid; phosphoric acid etc. may be added to chelate the metallic ions (Sugawara et al., 2007).

Perfumes

Essential oils from plant materials are used as perfumes in ointment bases. The floral group blends such as jasmine, rose, lily and gardenia are widely used in bases.

Topical ointments are widely used for drug delivery to the target site. Some of the important applications associated with topical ointments are shown in Table 9.

Table 9. Applications of topical ointment dosage form in drug delivery.

Drug	Results/applications
Tacrolimus (TAC)	Success of topical tacrolimus (TAC) therapy with custom trays in the treatment of oral chronic graft-versus-host disease (cGVHD) (Brown et al., 2013)
Tacrolimus (TAC)	The ethosomal tacrolimus delivery systems may be a promising candidate for topical delivery of tacrolimus in treatment of atopic dermatitis (AD). (Li et al., 2012a)
Nystatin	Permeation studies demonstrated that nystatin was not absorbed into systemic circulation and the retained amount in the skin was sufficient to ensure an antifungal effect. (Fernandez-Campos et al., 2013)
Silver sulfadiazine (SSD)	Initial topical coverage with SSD is associated with excellent outcomes for infants with giant omphalocele who cannot undergo immediate closure. (Ein & Langer, 2012)
Evodiamine and Rutaecarpine	Higher cutaneous fluxes of evodiamine and rutaecarpine were achieved. (Zhang et al., 2011)
Ketoconazole	Improved formulation characteristics, which increased the solubility and subsequent release of a poorly soluble drug. (Shalviri et al., 2011)
Sulfadiazine	The blended ointment can properly regulate amount of exudates in wounds and may be useful for treatment of pressure ulcers. (Noda et al., 2011)
Essential oils (EO)	EO-containing ointment down-modulates the severity of adjuvant arthritis in Lewis rats by inhibiting defined mediators of inflammation. (Komeh-Nkrumah et al., 2012)
Hyaluronic acid	Showed the therapeutic effectiveness for treatment of acute and chronic joint disease in rabbit. (Birkenfeld et al., 2011)
Ketoconazole	Considered in the treatment of denture stomatitis and has comparable efficacy with the ketoconazole tablet. (Khozeimeh et al., 2010)
Betamethasone dipropionate, fish oil	Fish oil enhanced the delivery and the anti-inflammatory activity of drug across skin. (Zulfakar et al., 2010)
Corticosteroids	Showed therapeutic effectiveness against psoriasis. (Zivkovich & Feldman, 2009)
Acyclovir	Complete suppression of development of herpetic skin lesions. (Shishu et al., 2009)
Diclofenac	Controlled delivery of the active drug in various acute and chronic painful inflammatory conditions. (Rainsford et al., 2008)
Nonsteroidal anti-inflammatory drugs	Enhanced NSAID efficacy in eye preparations. (Ahuja et al., 2008)
Anesthetic drug	Enhanced percutaneous absorption of drug for local pain control. (Stocker & Houghton, 2001)
Methyl aminolevulinate (MAL)	Showed enhance penetration of drug into nodular basal cell carcinomas (BCCs) using an oxygen pressure injection device. (Campbell et al., 2007)
5-aminolevulinic acid (5-ALA)	Appropriate for the diagnosis and treatment of actinic keratosis in photodynamic therapy. (Gruning & Muller-Goymann, 2008)
Methyl nicotinate (MN)	Improved drug solubility in the skin which was confirmed by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). (Remane et al., 2006)
Miconazole nitrate in a zinc oxide/petrolatum	Successful treatment of Diaper dermatitis (DD) complicated by candidiasis. (Spraker et al., 2006)

Additives in gels

Gels are semisolid preparations of solution or dispersion of one or more active ingredients as well as hydrocolloidal substances (gelling agent). Gelling agents (also known as solidifiers or stabilizers and thickening agents) exhibit pseudoplastic property and gives a thixotrophic consistency to the gel. Gelling agents are more soluble in cold water (e.g. methylcellulose and poloxamers) than hot water (e.g. bentonite, gelatin and sodium carboxymethylcellulose). Gelling agents are used in concentrations of 0.5–10% for easy addition to the active drug before the gel is formed and maintain the viscosity of the gelling agents in the gelling layer within a range of about 1000 cps to about 100 000 cps (Chiang et al., 2013). Table 10 shows the important properties and their use of various additives used in the formulation of topical gel. Topical gels are widely used for drug delivery to the target site. Some of the important applications associated with topical gel shown in Table 11.

Table 10. Properties and use of additives in topical gel formulation.

Property of additives	Use/applications of additives
(1) Tragacanth (Farzi et al., 2013): It is also known as Shiraz gum and Gum dragon. It is a natural gum obtained from the dried sap of several species of genus Astralagus plant. Preservative used: Methyl hydroxybenzoate (0.2% w/v) with propyl hydroxybenzoate (0.05% w/v).
• Viscous, odorless, and tasteless    • Acidic in nature    • High molecular weight 8 400 000    • Yields glucuronic acid and arabinose when hydrolyzed	• 5% concentration is used in medicated gels • Used as topical treatment for burns • Acts as demulcent and suspending agent • Stimulate the production of T-cells and antibody producing plasma cells
(2) Fenugreek mucilage (Nayak et al., 2013): Polysaccharide mucilage derived from the seeds of Trigonella foenum graceum. It contains polysaccharide galactomannan. Preservative used: Benzoic acid (0.2% w/v), or Chlorocresol (0.1–0.2% w/v).
• Swelling Index is 9    • Slowly soluble in cold water    • Quick soluble in hot water    • Viscosity is 1.4849 cps    • Gelling concentration lies between 2.5 and 3.5% w/v	• Used as anti-inflammatory agent • Used as an antioxidant • Exhibits better disintegrating property • Exhibits anti-diabetic activity • Useful to treat stomach ulcer • Heals burn injuries
(3) Methyl cellulose (Shahzad et al., 2013): It is a chemical compound, mainly derived from cellulose. It is synthetically produced by heating cellulose with caustic solution and treating with methyl chloride. Marketed methyl cellulose is Methocel HG and Methocel MC. Preservative used: Phenyl mercuric nitrate (0.001% w/v) or Benzalkonium Chloride Solution B.P.C. (0.02% v/v).
• Soluble in cold water but insoluble in hot water    • Non-ionic and stable over a wide spectrum of pH    • Nontoxic behavior    • Maximum clarity, hydration and viscosity obtain it the gel is cooled to 0–10 °C for about an hour	• Used as a thickener and emulsifier in various food and cosmetic products such as shampoo, toothpaste • Used for the treatment of constipation • Used as a lubricant • Used in the manufacture of capsules in nutritional supplements • Used as a binder in medications
(4) Hydroxy ethyl cellulose (Kulhari et al., 2011): It is a hydroxyl ethyl ether of cellulose. It is produced by treating cellulose with sodium hydroxide and reacting with ethylene oxide and hydroxy ethyl. Preservative used: Methyl hydroxybenzoate (0.2% w/v) with Propyl hydroxybenzoate (0.02% w/v).
• Water soluble behavior    • Exhibit pseudo plastic solution behavior    • Smooth and uniform nature    • Hygroscopic in nature    • White in color    • High clarity and viscosity	• Forms an occlusive dressing when lightly applied to the skin and allow drying • Widely used in cosmetics and cleaning solutions • Used with hydrophobic drugs in capsule formulations
(5) Hydroxy Propyl cellulose (Sabale & Vora, 2012): It is ether of cellulose where some of the hydroxyl groups of the cellulose have been hydroxypropylated. Preservative used: Chlorocresol (0.1–0.2% w/v).
• Makes thinner gels with high tolerance for added drugs and salts    • Hydrates and swells in water or hydro alcoholic solution	• Used as a topical ophthalmic protectant and lubricant for artificial eyes • Used as an emulsion stabilizer • Used as a binder and disintegrant in tablet
(6) Hydroxy propyl methyl cellulose (Vijay et al., 2012): It is also known as hypromellose. It is a semi synthetic, inert, visco elastic polymer and found in a variety of commercial products. Preservative used: Benzalkonium Chloride Solution B.P.C. (0.02% v/v).
• Slightly off white solid nature    • Makes thicker gels but lower tolerance for positively charge ions    • Disperse in cool water    • Exhibit thermal gelation property	• Used as an ophthalmic lubricant • Used as controlled-delivery component in oral medicaments • Good gelling agent for time released formulation
(7) Carboxy methylcellulose (Asha et al., 2012): Generally used as the sodium salt known as carmellose sodium. It contains carboxy methyl group (-CH2 COOH). It is synthesized by the alkali catalyzed reaction of cellulose with chloroacetic acid. Preservative used: Methyl hydroxybenzoate (0.2% w/v) with Propyl hydroxybenzoate (0.02% w/v).
• Makes thicker gels but less tolerance than hydroxyl propyl methylcellulose • Maximum stability at pH 7–9 • High viscous in nature • Odorless, tasteless, non-toxic white powder or micro-yellow fibrous	• Used in pharmaceuticals as a thickening agent • Acts as a viscosity modifier and water retention agent • Used as constituents of tooth paste, laxative, diet pills
(8) Carbopol (Geraud et al., 2013): Also known as carbomer. It is acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol. Preservative used: Methyl hydroxybenzoate (0.15% w/v) with propyl hydroxybenzoate (0.05% w/v).
• Fluffy, white, and dry powders    • High bulk densities    • Form acidic aqueous solution of 3.0 pH.    • Glass transition temperature 100–105 °C	• Provide Controlled release in tablets • Provide bioadhesion in buccal, ophthalmic, intestinal, nasal, vaginal and rectal application
(9) Pectin (Wikiera & Mika, 2013): It is also known as pectic polysaccharides. It is obtained from plant tissue and act as an intracellular cementing material. It consists of linear D- galacturonan. “Sure gel” and “Certa” is pectin product widely used as gel formulation. Preservative used: Benzoic acid (0.2% w/v) or methyl hydroxybenzoate (0.12% w/v) or chlorocresol (0.1–0.2% w/v).
• White to light brown powder    • Water soluble nature    • Practically odorless    • Mucilaginous in nature    • Stable at ordinary temperature	• Used as a gelling agent, thickening agent and stabilizer • Used against constipation and diarrhoea • Used in throat lozenges as a demulcent • Used in wound healing preparations
(10) Poloxamers (Pluronics) (Jansen et al., 2013): Pluronic F-127 is a grade of poloxamer. Poloxamers are copolymer of polyoxy ethylene and polyoxy propylene. They form thermoreversible gels in concentration ranging from 15 to 50%. Preservative used: Methyl hydroxybenzoate (0.1–0.2% w/v).
• White, waxy granules    • Amphiphilic in nature    • Have surfactant properties    • Form clear liquid when dispersed in cold water	• Preferentially target cancer cells • Used for delivery of active ingedients in various parts of the organs • Used for cell culture • Used in ointment and suppository bases and as a tablet binder
(11) Alginate (Cohen et al., 2010): It is also known as algin. It is an anionic polysaccharides consisting of linear chains of uronic acid unit. Marketed in form of sodium, potassium, ammonium alginates. Preservative used: Methyl hydroxybenzoate (0.1–0.2% w/v), chlorocresol (0.1% w/v) or benzoic acid (0.2% w/v).
• Solid, granular or powdered form    • White to yellowish-brown color    • Adsorbs water quickly    • Water soluble gum    • Calcium salt increase viscosity of sodium alginate	• In 5–10% concentration act as dermatological vehicle • Used as gelling agents in cosmetic products • Used in the food industry, for thickening soups and jellies
(12) Gelatin (Cohen et al., 2013): It is Produced by the hydrolysis of collagen form the skin, white connective tissue and bones of animal. It is in two form “pharmagel A” and “pharmagel B”. Preservative used: Benzoic acid (0.2% w/v) or methyl hydroxybenzoate.
• Translucent, colorless, brittle (when dry), and flavorless solid    powder    • Soluble in hot water    • Have adhesive property but easily remove from skin	• Widely used for gel formulation • Act as a raw material to form cross linked gelatin gel • Cause sustained releasing action
(13) Starch (Moussa et al., 2012): Starch or amylum is a carbohydrate consisting of a large number of glucose units and is contained in large amounts in staple foods. Preservative used: Methyl hydroxybenzoate (0.1–0.2% w/v) or benzoic acid (0.2% w/v).
• White, tasteless and odorless powder    • A translucent gel formed by starch solution    • Has short shelf life    • Insoluble in cold water or alcohol	• Starch in combination with gelatin and glycerin used for gel formulation • Used as thickeners and stabilizers in foods • Used as tablet disintegrant or as binder
(14) Poly vinyl alcohol (Cho et al., 2009): It is manufactured from vinyl acetate monomer (VAM) via a multistep process. VAM is polymerized into polyvinyl acetate and then converted to polyvinyl alcohol. Preservative used: Chlorhexidine acetate (0.02% w/v).
• Water soluble synthetic polymer    bullet; Odorless and nontoxic    • Adhesive nature    • High tensile strength and flexibility	• It used at 2.5% concentration to prepare gel • Used as an embolisation agent in medical procedures
(15) Povidone (Kiyoyama et al., 2009): It is also known as polyvidone or polyvinyl pyrrolidone. It is used as suspending and dispersing agents. Preservative used: Chlorocresol (0.1% w/v) or benzoic acid (0.2% w/v).
• Water soluble nature    • High molecular weight substance    • Compatible in solution with a wide range of inorganic salts, natural    and synthetic resin.    • Readily absorb water	• Used to prepare gels in concentration up to 10% • Used as a blood plasma substitute • Wide variety of applications in medicine, pharmacy, cosmetics and industrial production
(16) Propylene glycol (Farber et al., 2010): It is an organic compound, also called 1,2-propanediol or propane-1,2-diol. It contains Propylene glycol an asymmetrical carbon atom, so it exists in two stereoisomers. Preservative used: Chlorhexidine acetate (0.02% w/v).
• Clear, colorless and hygroscopic liquid    • Faintly sweet taste    • Hygroscopic in nature    • Miscible in water, acetone, chloroform	• Used as a humectants, solvent and preservative in pharmaceutical products • Used as solvent in many pharmaceuticals including oral, injectable and topical formulations
(17) Ethylene diamine tetra acetic acid (EDTA) (Song et al., 2012): It is a polyamino carboxylic acid. Mainly synthesized from ethylenediamine, formaldehyde and sodium cyanide. Preservative used: Chlorocresol (0.1% w/v) or Benzoic acid (0.2% w/v).
• Colorless solid    • Powerful chelating property    • Preserve and stabilize solution    • Easily soluble in cold water	• Used as a stabilizers in pharmaceutical products • Prevent metal ion impurity • Used in shampoos, cleaners and other personal care products

Table 11. Applications of topical gel dosage form in drug delivery.

Drug	Results/applications
Halobetasol propionate (HP)	Represent a promising carrier for topical delivery of HP, having controlled drug release, and potential of skin targeting with no skin irritation. (Bikkad et al., 2013)
Tranexamic acid	Improved external hemostatic dressing and useful on a range of internal surgical wounds. (Bartley, 2013)
Ciclopirox	The topical availability of Ciclopirox was found to be relatively low and endured rapid clearance with minimal systemic uptake. (Nair et al., 2013)
Croconazole	Showed an excellent activity against different species of fungi as compared with miconazole cream. (El-Badry et al., 2014)
Vancomycin	Showed the complete inhibition (106-fold reduction in growth compared to control) of methicillin-sensitive S. aureus and methicillin-resistant S. aureus. (Bhattacharyya et al., 2013)
Tenofovir disoproxil fumarate	Showed effective tools in preventing the sexual transmission of HIV in humans. (Smith et al., 2013)
Tenofovir	Showed effectiveness against HIV infection due to increase bioavailability of encapsulated drugs. (Gao & Katz, 2013)
Aceclofenac (ACF)	The results of the study indicate that ACF could be administered topically by using iontophoresis from a suitably formulated gel for effective control of pain and inflammation. (Bhatt et al., 2013)
Mometasone furoate (MF)	Developed hydrogel formulation containing MF can be of actual value for improving the clinical effectiveness in the treatment of scalp dermatitis. (Salgado et al., 2013)
Diclofenac epolamine (DE)	Enhanced transport of drug into the skin forming in-skin drug depot for sustained transdermal delivery of drug. (Fouad et al., 2013)
Ketorolac	Enables local enhanced topical delivery to subjacent muscle and have clinical application in the treatment of localized inflammation and pain. (Gratieri et al., 2013)
Griseofulvin	Provide a good skin permeation effect and may be a promising carrier for topical delivery of griseofulvin. (Aggarwal & Goindi, 2013)
Isoflavone genistein (GEN)	Potential applications for skin cancer treatment and chemoprevention and a promising nanocarrier system for skin delivery of GEN. (Zampieri et al., 2013)
Doxorubicin	Showed an effectiveness of antitumor drug carrier for topical cancer therapy. (Wang et al., 2013a)
Ketoconazole	Showed prolonged action than formulations containing ketoconazole in non-niosomal form and it can be developed successfully to improve the antifungal activity. (Shirsand et al., 2012)
Terbinafine hydrochloride (TH)	Showed skin targeting ability and may serve as a promising carrier in treatment of fungal skin infections. (Vaghasiya et al., 2013)
Ketoprofen, Celecoxib	Both formulations were superior to oral placebo and non-inferior to celecoxib in reducing knee pain. (Conaghan et al., 2013)
Diflucortolone valerate (DFV)	Promising carrier for dermal delivery of DFV in various skin disorders. (Ozcan et al., 2013)
Tamoxifen	Widely employed in the treatment of breast malignancies and is also found to be effective in psoriasis treatment. (Bhatia et al., 2013)
Terbinafine hydrochloride	Promising system for ungual drug delivery due to the better accumulation and easier application of the formulation for treatment of onychomycosis. (Tanriverdi & Ozer, 2013)

Additives in lotions

Lotions are usually suspensions of solids in an aqueous medium. It is a low to medium viscosity topical preparation intended for application to unbroken skin. They are thicker and emollient in nature in comparison to solution. They are usually oil mixed with water, and more often than not have less alcohol than solutions. The main advantages of this delivery system are avoidance of first pass metabolism, easy to apply, improved patient compliance, improved physiological and pharmacological response, avoidance of gastro-intestinal incompatibility and ability to easily terminate medications when needed (Meyer et al., 2008). However, various disadvantages are associated with these systems such as skin irritation or contact dermatitis, which may occur due to the drug and/or additives, poor permeability of some drugs, chances of allergic reactions and sometime drugs are not absorbed through the skin due to larger particle size. Table 12 shows the important properties and their use of various additive used in the formulation of topical lotion (Hussain Shah et al., 2013). Topical lotions are widely used for drug delivery to the target site. Some of the important applications associated with topical lotions shown in Table 13.

Table 12. Properties and use of additives in topical lotion formulation.

Property of additives	Use/applications of additives
(1) Bentonite (Chen et al., 2013): It consists of montmorillonite: a clay mineral belonging to a class of phyllosilicates called smectites. It may include lesser amounts of other clay minerals such as kaolin, mica, illite, as well as non-clay minerals like quartz, feldspar, calcite and gypsum.
• Absorb water and expand    • High viscosity and thixotropy    • High vitrification temperature    • High specific surface	• Used as a bulk laxative • Used as a base for many dermatologic formulas • Used in battlefield wound dressings
(2) Sodium carboxymethylcellulose (Huang et al., 2013): It is also known as cellulose gum. It is a cellulose derivative with carboxy methyl groups bound to some of the hydroxyl groups of the glucopyranose monomers.
• Lower freezing point    • Micro-yellow fibrous in pure state    • Odorless and tasteless    • Easy to absorb moisture	• Used as food additive • Used as lubricant in eye drops • Used in pharmaceuticals as a thickening agent
(3) Alcohol (Delany et al., 2013): An alcohol is an organic compound, are the simple acyclic alcohols.
• Higher boiling point (78.29 °C)    • Slightly weaker acid    • pKa of around 16–19	• Provide drying and cooling effect of a lotion • Used as an antiseptic
(4) Glycerin (Patel et al., 2010): It is a simple sugar alcohol compound. It is a neutral, sweet-tasting, colorless, thick liquid which freezes to a gummy paste and which has a high boiling point.
• Colorless, odorless    • Viscous liquid    • Water soluble and hygroscopic nature	• Improving smoothness, providing lubrication • Used as humectants
(5) Preservative (Amaral et al., 2011): It is a naturally occurring or synthetically produced substance that is added to products to prevent decomposition by microbial growth or by undesirable chemical changes.
Organic acid	Good antifungal and antibacterial preservative
Ester of parahydroxy benzoic acid	Active against moulds, yeasts, bacteria at pH 7–9
Chlorocresol	Powerful bactericide of low toxicity
Phenoxyethanol	Excellent activity against Pseudomonas aeruginosa
Quaternary ammonium compound	Bactericidal to vegetative forms of gram-positive organisms
Phenyl mercuric nitrate	Preserve emulsified preparations containing non- ionic emulgents

Table 13. Applications of topical lotion dosage form in drug delivery.

Drug	Results/applications
Desonide	Showed a better drug delivery with increased epidermal retention as well as partially prevented the steroid-induced side effects, such as skin barrier impairment. (Sul et al., 2013)
Estradiol	Safe and effective for treatment of vasomotor symptoms and represents the commercial validation of estrogen therapy for postmenopausal women. (Valenzuela & Simon, 2012)
Testosterone	Feasibility of using transdermal systems for pulsatile T delivery in a variety of clinical applications, including hormone supplementation and male contraception. (Malik et al., 2012)
Curcumin	Showed high entrapment efficiency and can be used to transport curcumin effectively into the skin. (Suwannateep et al., 2013)
22-oxacalcitriol-1α, 25-dihydroxy vitamin D(3)	Enhance the skin permeability of the drug into the hairless mouse skin. (Harada et al., 2011)
Betamethasone valerate (BMV)	BMV 0.1% plaster is more efficacious than BMV 0.1% cream in the treatment of patients with mild-to-moderate chronic plaque psoriasis in a clinical setting. (Naldi et al., 2011)
Niacinamide and N-acetyl glucos amine (NAG)	Reduced the appearance of irregular pigmentation including hypermelaninization. (Kimball et al., 2010)
Clobetasol propionate	Achieving success after 2–4 weeks of treatment of psoriasis in well controlled clinical trials. (Feldman & Yentzer, 2009)
Metronidazole	Showed enhance absorption of drug in the human cadaver skin model. (Elewski, 2007)
Clobetasol propionate (CP)	Showed safe and effective treatments for psoriasis affecting scalp and nonscalp regions of the body. (Stein, 2005)
Fluocinolone acetonide	0.1% of drug leads to a significantly better improvement for scale psoriasis. (Pauporte et al., 2004)
Dexamethasone & Hydrocortisone	Showed high biological potency, prolonged effects and reduce therapeutic dosage. (Cevc & Blume, 2004)
Fluocinolone acetonide	Showed therapeutic effects against scalp psoriasis as well as atopic dermatitis. (Paller et al., 2003)
Betamethasone valerate (BVM)	BVM lotion is more effective and used in the treatment of scalp psoriasis, and has higher patient acceptability. (Andreassi et al., 2003)
Tacrolimus (TAC)	Topical lotion was effective in this model of immune-mediated skin disease and an effective delivery system for TAC in the treatment of psoriasis. (Erdogan et al., 2002)
Tacrolimus	The tacrolimus lotion had a significant effect on the recalcitrant facial erythema in adult patients with atopic dermatitis who were resistant to tacrolimus ointment. (Sugiura et al., 2001)
Diclofenac	Enhance the drug transport through intact skin and into the target tissues. (Cevc & Blume, 2001)
5-Fluorouracil	Showed therapeutic effectiveness against dystrophic psoriatic fingernails. (de Jong et al., 1999)
Betamethasone valerate (BMV)	Showed enhanced BMV bioavailability and increased efficacy in the treatment of scalp psoriasis without an associated increase in toxicity. (Franz et al., 1999)
Diclofenac	A continuous delivery of diclofenac sodium from the lotion into and through the skin. (Hui et al., 1998)
Insulin	The experimental evidence indicates a substantial increase in the penetration of insulin in conjunction with iontophoretic enhancement in chronic diabetic rats. (Zakzewski et al., 1998)

Additives in liniments

Liniments are alcoholic or oil-based solutions or emulsions formulations, containing therapeutic active agents mainly used for external application. These formulations are also known as embrocations because they are rubbed onto the affected area with friction. Liniments should not be applied to skin that is bruised or broken. Presence of the oil base or soap base providing ease of application and massage on affected areas. Alcoholic liniments are generally used due to their various characteristics property such as excellent rubefacient, counterirritant, mildly astringent and penetrating effects. At the time of massage, oily liniments are more useful and exhibit milder action. Fixed oils are thick, viscous liquids and contain unsaturated fatty acids which cause good penetration into the skin. Table 14 shows the important properties and their use of various additives used in the formulation of topical liniments (Oplander et al., 2012). Topical liniments are widely used for drug delivery to the target site. Some of the important applications associated with topical liniments shown in Table 15.

Table 14. Properties and use of additives in topical liniment formulation.

Property of additives	Use/applications of additives
(1) Castor oil (Goswami et al., 2013): It is known as Emuls oil, Neoloid and Purge oil. This fixed oil obtained from the seed of Ricinus communis Linne (Fam. Euphorbiaceae).
• Pale yellowish or almost colorless    • Transparent, visccid liquid with a faint and mild odur    • Slightly acrid and nauseating taste    • Soluble in alcohol, chloroform and ether	• Used externally as an emollient • Provide soothing to the skin • Stimulates water secretion in the intestine • Stimulates colonic motility • Used in constipation
(2) Cotton seed oil (Panagiotopoulos et al., 2013): It is known as seed oil and cotton oil. It is extracted from the seeds of cotton plant of various species, mainly Gossypium hirsutum and Gossypium herbaceum.
• Pale yellow, oily liquid with a bland taste    • Solidifies at about 0 to −5 °C    • Specific gravity 0.915 to 0.921    • Slightly soluble in alcohol	• Used in the manufacture of soaps, oleomargarine, lard substitutes, glycerin, lubricants and cosmetics • Used in food
(3) Peanut oil (Hilten et al., 2011): It is also known as arachis oil, Groundnut oil, Nut oil, and Earth-Nut oil. Its major component of fatty acids such as oleic acid, linoleic acid, palmitic acid, stearic acid and other fatty acids.
• Colorless or pale yellow oily liquid    • Charactteristic nutty odor with bland taste    • Specific gravity 0.912 to 0.920    • Very slightly soluble in alcohol	• It also is used for ointments, plasters, and soaps, as a subsstitute for olive oil • Used as a massage oil • Used as a tasting agents in the formulations
(4) Sesame oil (Johnson et al., 2011): It is known as veel oil, benne oil, and gingelly oil. It is an edible vegetable oil, obtained from sesame seeds. Its major component of fatty acids such as palmitic acid, stearic acid, oleic, eicosenoic and other fatty acid.
• Pale yellow and almost odorless    • Oily liquid with a bland taste    • Specific gravity 0.916 to 0.921    • Slightly soluble in alcohol    • Contains triunsaturated and diunsaturated glycerides	• Used as solvent and vehicle in official injections • Used medicinally and for food. • Used in the manufacture of cosmetics, iodized oil, liniments and ointments • Show good permeation effects
(5) Oleic acid: It is a fatty acid that occurs naturally in various animals and vegetable fats as well as oils.
• Odorless and colorless    • Commercial samples may be yellowish    • Contain saponification value	• Major component of soap as an emulsifying agent • Used as an emulsifying or solubilizing agent in aerosol products
(6) Ammonia solution: Ammonia solution, also known as ammonium hydroxide, ammonia water, ammonical liquor, ammonia liquor, aqua ammonia, aqueous ammonia, or simply ammonia, is a solution of ammonia in water
• Strong ionizing power    • Colorless liquid    • “Fishy”, highly pungent odor	• Provide alkaline medium • Used for “flavor” enhancement and as a “processing aid".

Table 15. Applications of topical liniment dosage form in drug delivery.

Drug	Results/applications
Cycloferon	Showed therapeutic effectiveness against herpetic infection in patients with latent form of HIV infection. (Shul'diakov et al., 2012b)
Cycloferon	Showed shortened duration of eruption and local inflammation, accelerated epithelization of herpetic erosion, and decreased the frequency of relapses during the follow-up. (Shul'diakov et al., 2012a)
Cycloferon	Showed reduced the level of the endogenous intoxication that provided acceleration of the recuperation processes and decreased the frequency of stomatitis backsets. (Khlamova et al., 2011)
Nitric oxide	Showed therapeutic potential for systemic hemodynamic disorders that might arise from local or systemic insufficient. (Oplander et al., 2012)
Cycloferon	Treatment of herpetic stomatitis and periodontitis by decreases the infectious load in periodontal recess, reduces the manifestations of local inflammation, and normalizes the immunity indices. (Soboleva et al., 2011)
Geniposide	Blood analysis showed that the geniposide could be absorbed and accumulated by subcutaneous tissue within 1 h after drug administration, and it would be eliminated by blood circulation 1 h after drug treatment. (Wang et al., 2010)
Antibacterial drug	Showed anti-inflammatory and antihistaminic activity against ocular inflammation in rabbits. (Abdul et al., 2010)
Cycloferon	The drug efficacy in herpetic lesions of the mouth and lips mucosa was observed. The treatment of the buccal mucosa affections in HIV-infected subjects was substantiated. (Romantsov et al., 2009)
Levamisole	Liniment levamisole may reinforce cellular immune functions of patients with chronic hepatitis B. (Wang et al., 2005)
Capsaicin	Showed strong inhibitory effect in histamine-induced itch in healthy persons as well as in patients with atopic eczema. (Weisshaar et al., 2003)
Pectins	The best results were demonstrated when the pectins application was performed since the first day after the burned injury. (Lazareva et al., 2002)
Ophthacare	Showed significant antibacterial activity against Escherichia coli and Staphylococcus aureus and antifungal activity against Candida albicans. (Mitra et al., 2000)
Capsaicin (CAP)	Showed therapeutic effectiveness against serotonin induced itch in healthy volunteers. (Weisshaar et al., 2000)
Oleocalcareo, Zinc oxide	Showed evidence slowness and decrease in the intensity of the skin damage caused by the radiation treatment. (Faure et al., 1998)
Methyl salicylate	Provide an excellent relief of musculoskeletal aches and pains. (Chan, 1996)
Erythromycin, Zinc acetate	Zinc acetate thus provided to prolong the residence time of erythromycin on the skin and show effectiveness against Acne vulgaris. (van Hoogdalem et al., 1996)
Aloe	Useful in domestic conditions for increasing the defensive forces of the body during radiation lesions. (Iena Ia, 1993)
Dibunol	Permitted to reduce the period of preparation for auto dermoplasty. The anti-inflammatory effect of Ddbunol was also established. (Shalonov et al., 1989)
Peplomycin (PEP)	Showed strong affinity to mucosa of the organ and in the management of patients with bladder tumors. (Asakawa et al., 1989)
Dibunol	Ability to produce pronounced epithelialization of ulceroerosive and ulceronecrotic lesions of the mucosa without rough scarring in rats. (Shatalov et al., 1988)

Conclusion

Topical dosages form such as ointment, cream, paste, gel, lotion, powder and liniments place a very important role in pharmaceutical as well as cosmetics fields. Additives of topical dosage forms show their excellent role in dosage form design, dosage form stability, controlled drug release pattern and deliver the drug to the target place for the longer duration of period. Now-a-days, topical dosage forms are the first choice as delivery systems in pharmaceutical and other fields.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.