TOPICAL DRUG DELIVERY SYETEM & EMULGEL FORMULATION

SOUVIK GUIN
ROLL NO-19301916024
B.PHARM , 4th YEAR

INTRODUCTION
Topical drug delivery having several years of history, still new technology and methods are investigated; as skin is most accessible organ and are potential to facilitate the delivery of several drugs with better efficacy than rest of any other route of administration. With the recent advancement in technology and knowledge it can deliver drug to the skin and also for systemic purpose. This route is one of the best options for the cutaneous purpose.1 Topical drug delivery is defined as the application of a drug containing formulation to the skin to treat cutaneous disorder directly. The topical drug delivery system is generally used where others routes (like oral, sublingual, rectal, parental) of drug administration fails or in local skin infection like a fungal infection.2 This delivery is preferred when other system fails or has some limitation and generally used for the skin fungal infection. Basically there is two type of topical products one is external topical that is spread to the tissue to cover the diseased area and other is internal topical that are applied for topical effect to mucous membrane in oral cavity, vagina, or rectal tissues.3 These formulations range in physicochemical nature from solid through semisolid to liquid. Drug substances are seldom administered alone, but rather as part of a formulation, in combination agents that serve varied and specialized pharmaceutical function. Drugs are administered topically for their action at the site of application or for systemic effects.4 The main advantage of the topical delivery system is to bypass first pass metabolism. Avoidance of the risks and inconveniences of intravenous therapy and of the varied conditions of absorption, like pH changes, the presence of enzymes, gastric emptying time are another advantage of the topical drug delivery system is generally used where the others system of drug administration fails. The study is also carried out for the avoidance of the risks and inconvenience of intravenous therapy and of the varied conditions of absorption, like pH changes, the presence of enzymes and gastric emptying time 5 Dermatological products are diverse in formulation and range in consistency from liquid to powder, but the most popular products are semisolid preparation.6,7 In spite of many advantages of gels, a major limitation is there in ability to the delivery of hydrophobic drugs. To overcome this problem, an emulsion-based approach is being used so that a hydrophobic therapeutic moiety can be fruitfully incorporated and delivered through gels. When gels and emulsions are used in united form, the dosage forms are referred as emulgels.8
Emulgel is emerging field for the topical drug delivery, and till date it has less marketed product, so it
is interesting and challenging to focus on emulgel. Before going to emulgel we need to know the advantages of emulsion and gel that is being used for the topical drug delivery. Emulsions are controlled release systems containing two immiscible phases in which one is dispersed (internal or discontinuous phase) into other (external or discontinuous phase), with the use of emulsifying agent to stabilize the system. Emulsion are of oil-in-water or water-in-oil type, where the drug particle entrapped in internal phase passes through the external phase and then slowly gets absorbed into the skin to provide controlled effect. USP defines gel as a semisolid system consisting of dispersions made up of either small inorganic particles or large organic molecules enclosing and interpenetrated by liquid. The gel contains the larger amount of aqueous or hydro alcoholic liquid in a cross-linked network of colloidal solid particles where it captures small drug particles and maintain the controlled release of drug. The liquid phase builds a three-dimensional polymeric matrix which results a physical or chemical cross-linking. The continuous structure results solid like behavior that are homogenous and clear.The emulsion &gel both are responsible for the controlled drug release from the systems.9-11

EMULGEL, IT’S ADVANTAGES & DISADVANTAGES

Advantages of emulgel:
1. It has increased patient acceptability.
2. It Provide targeted drug delivery.
3. It has an easy termination of the therapy.
4. Avoidance of first pass metabolism.
5. Avoidance of gastrointestinal incompatibility.
6. It is more selective to a specific site.
7. It provides controlled release.
8. It has better loading capacity.
9. There is production feasibility and low preparation cost.
10. No intensive sonication.
11. Stable formulation by decreasing surface interfacial tension resulting in increase in viscosity of aqueous phase. It is more stable than Transdermal preparations that are comparatively less stable, powders are hygroscopic, creams show phase inversion or breaking and ointment shows rancidity due to oily base.
12. Improve bioavailability and even the low doses can be effective in comparison with other conventional semi solid preparation.12-16

Disadvantages:
1.Poor absorption of macromolecules.
2.Poor permeability of some drugs through the skin.
3.Entrapment of bubble during formulation.
4.Hydrophobic drugs are best choice for such delivery system.3,11Emulgel are being used for the treatment of various anti-inflammatory activity and other skin related
viral, bacterial and fungal infections.17,18  

Diclofenac potassium is used to relieve pain and swelling or inflammation from various mild-tomoderate painful conditions. It is responsible for the anti-inflammatory, analgesic, and antipyretic
activity is through restricting prostaglandin synthesis by inhibiting cyclooxygenase. Diclofenac potassium is well absorbed following oral administration. It undergoes first-pass metabolism only 50–60% dose reaches systemic circulation as unchanged drug. It is absorbed into systemic circulation
following topical administration as gel or transdermal system, plasma concentration generally very low compared with oral administration.19


RATIONAL OF EMULGEL AS A TOPICAL DRUG DELIVERY SYSTEM

Many widely used topical agents such as ointment, cream, and lotion have many disadvantages.
They have very sticky causing uneasiness to the patient when applied. Moreover, they also have lesser spreading coefficient and need to apply with rubbing. Moreover, they exhibit the problem of stability also. Due to all these factors within the major group of semisolid preparation, the use of transparent gels has expanded both in cosmetics and a pharmaceutical preparation.20

A gel is a colloid that is typically 99% wt. liquid, which is immobilized by surface tension between gel and a macromolecular network of fibres built from a small amount of a gelatin substance present. Gels have many advantages, but a major limitation is in the delivery of hydrophobic drugs. So, to overcome this limitation an emulsion-based approach is being used so that even a hydrophobic therapeutic moiety can be successfully incorporated and deliver through gels.21

Numbers of medicated products are applied to the skin or mucous membrane that either enhances or
restores a fundamental function of skin or pharmacologically alters an action in the underlined tissues. These products are referred as topical or dermatological products. Many widely used topical agents such as ointments, creams, and lotions have many disadvantages. They are sticky in nature causing uneasiness to the patient when applied, have lesser spreading coefficient so applied by rubbing, and they also exhibit the problem of stability. Due to all these factors within the major group of semisolid preparations, the use of transparent gels has expanded both in cosmetics and pharmaceutical preparations.20


FACTORS AFFECTING TOPICAL ABSORPTION OF DRUGS


Physiological factors: -
1.Skin thickness.
2.Lipid content.
3.The density of hair follicles.
4.The density of sweat glands.
5.Skin pH
4.Blood flow.
5.Hydration of skin.
6.Inflammation of skin.

Physicochemical factors: -
1.Partition coefficient
2.The molecular weight (<400 Dalton)
3.The molecular weight (<400 Dalton)
4.The degree of ionisation (only unionised drugs gets absorbed well).
5.Effect of vehicles.22,23

PHYSOLOGY OF SKIN

Most of the topical preparations are meant to be applied to the skin. Hence, a basic knowledge of the skin and its physiology function are very important for designing topical dosage form. The skin of an average adult body covers a surface area approximately 2 m2 and receives about one-third of the blood circulating through the body. An average human skin surface is known to contain, on the average 40 70 hair follicles, and 200–300 sweat ducts on every square centimeter of the skin. The Ph of the skin varies from 4 to 5.6. Sweat and fatty acid secreted from sebum influence the Ph of the skin surface. The skin can be considered to have four distinct layers of tissue.


Non-viable epidermis:
Stratum corneum is the outermost layer of skin. It is the actual physical barrier to the most substance that comes in contact with the skin. The stratum corneum is 10 to 20 cell layers thick over most of the body. Each cell is a flat, plate-like structure-34-44 µm long, 25- 36 µm wide, 0.5 to 0.20 µm thick with a surface area of 750 to 1200 µm stocked up to each other in brick-like fashion. Stratum corneum consists of lipid (5-15%) including phospholipids, glycosphingolipid, cholesterol sulphate and a neutral lipid, protein (75-85%) which is mainly keratin.

Viable epidermis:
Viable epidermis of the skin resides between the stratum corneum and the dermis and has a thickness ranging from 50-100 µm. The structures of the cells in the viable epidermis are physiochemically similar to other living tissues. Cells are held together by tonofibrils. The density of this region is not much different than water. The water content is about 90%.



Dermis:
Just beneath the viable epidermis is the dermis. It is a structural fibrin and very few cells are like it can be found histological in normal tissue. Dermis thickness ranges from 2000 to 3000 µm and consists of a matrix of loose connective tissue composed of fibrous protein embedded in an amphorphose ground substance.


Subcutaneous connective tissue:
The subcutaneous tissue or hypodermis is not actually considered a true part of the structured connective tissue which is composed of loose textured, white, fibrous connective tissue containing blood and lymph vessels, secretary pores of the sweat gland and cutaneous nerves. Most investigators consider drug is permeating through the skin enter the circulatory system before reaching the hypodermis, although the fatty tissue could serve as a depot of the drug.20,24,25

DRUG DELIVERY ACROSS THE SKIN

There are two important layers in the skin: the epidermis and dermis. Blood vessels aredistributed profusely beneath the skin in the subcutaneous layer. There are three primary mechanisms for drug absorption through the skin: intercellular, trans cellular and follicular. The next most common route of delivery is through the pilosebaceous route permeation tends to occur through the intercellular matrix, but through the transcellular pathway, it has been shown to provide a faster alternative route of highly polar molecules. A unique aspect of dermatological pharmacology is the direct accessibility of the skin as a target organ for diagnosis and treatment. The skin acts as a two-way barrier to prevent
absorption or loss of water and electrolytes. Most drugs pass through the torturous path around corneocytes and the lipid bilayer to viable layers of the skin. The next most common (and potentially under-recognized in the clinical setting) route of delivery is through the pilosebaceous route. The barrier resides in the outermost layer of the epidermis, the stratum corneum, as evidenced by approximately equal rates of penetration of chemicals through isolated stratum corneum or whole skin. The drug penetration for skin can be enhanced by using organic solvents such as propylene glycol, surfactants and DMSO. The permeation enhancers are altered the barrier properties of the stratum corneum by types of a mechanism including enhancing solubility, partitioning the stratum corneum, fluidising the crystalline structure of the stratum corneum. Creams and gels that are rubbed into the skin have been used for years to deliver pain medication and infection-fighting drugs to an affected site of the body. These include, among others, gels and creams for vaginal yeast infections, topical creams for skin infections, and creams to soothe arthritis pain. New technologies now allow other drugs to be absorbed through the skin (transdermal). These can be used to treat not just the affected areas (the skin) but the whole body (systemic).20,24

CLASSIFICATION OF TOPICAL PREPARATION 14

Solid Preparation	Liquid Preparation	Semisolid preparation	Miscellaneous Preparation
1.Topical powder 2. Poultices 3.Plaster	1.Lotion 2. liniment 3.paints 4.solution 5.emulsion 6.suspension	1.ointments 2.cream 3.pastes 4.gel 5.suoppositories	1.TDDS 2.tapes and gauge 3.rubbing alcohols 4.liquid cleaner 5.Topical aerosol

Factors to be Considered When choosing a Topical Preparation

1. Effect of the vehicle e.g. An occlusive vehicle enhances penetration of the active ingredient
and improves efficacy. The vehicle itself may have a cooling, drying, emollient or protective action.
2. Match the type of preparation with the type of lesions. For example, avoid greasy ointments
for acute weepy dermatitis.
3. Match the type of preparation with the site. (e.g., gel or lotion for hairy areas)
4. Irritation or sensitization potential. Generally, ointments and w/o creams are less irritating,
while gels are irritating. Ointments do not contain preservatives or emulsifiers if allergy to
these agents is a concern.26,27

METHOD TO ENHANCE DRUG PENETRATIONAND ABSORPTION

1. Chemical enhancement.
2. Physical enhancement.
3. Biochemical enhancement.
4. Supersaturation enhancement.28


IMPORTANT CONSTITUENTS OF EMULGEL PREPARATION

1..Vehicle:The vehicle has following properties.
• Efficiently deposit the drug on the skin with even distribution.
• Release the drug so it can migrate freely to the site of action.• Deliver the drug to the target site.• Sustain a therapeutic drug level in the target tissue for a sufficient duration to provide a
pharmacologic effect.• Appropriately formulated for the anatomic site to be treated.• Cosmetically acceptable to the patent.24


2.Aqueous Material:This forms the aqueous phase of the emulsion Commonly used agents are water, alcohols.29


3. Oils:These agents form the oily phase of the emulsion. For externally applied emulsions, mineral oils, either alone or combined with soft or hard paraffins, are widely used both as the vehicle for the drug and for their occlusive and sensory characteristics. Widely used oils in oral preparations are nonbiodegradable mineral and castor oils that provide a local laxative effect, and fish liver oils or various fixed oils of vegetable origin (e.g., arachis, cottonseed, and maize oils) as nutritional supplements.30,31


Use of oils 2

Chemical	Quantity (%)	Dosage form
Light liquid paraffin	7.5	Emulsion and Emulgel
Isopropyl myristate	7-7.5	Emulsion
Isopropyl stearate	7-7.5	Emulsion
Isopropyl palmitate	7-7.5	Emulsion
Propylene glycol	3-5	Gel

4.Emulsifiers:Emulsifying agents are used both to promote emulsification at the time of manufacture and to control stability during a shelf life that can vary from days for extemporaneously prepared emulsions to months or years for commercial preparations.
Eg -Polyethylene glycol3240 stearate, Sorbitan monooleate 33(Span 80) etc.


5.Gelling Agent:These are the agents used to increase the consistency of any dosage form can also be used as thickening agent.34,35

Use of Gelling agents 20

Gelling agents	Quantity (%)	Dosage form
Carbopol-934	1	Emulgel
Carbopol-940	1	Emulgel
HPMC-2910	2.5	Emulgel
Sodium CMC	1	Gel
HPMC	3.5	Gel
Poloxamer	1	Gel

6.Penetration Enhancers:To promote absorption of drugs, vehicles often include penetration enhancing ingredients that temporarily disrupt the skin barrier, fluidize the lipid channels between corneocytes, alter the partitioning of the drug into skin structures, or otherwise enhance delivery into the skin.2


Properties of penetration enhancer:• They should be non-toxic, non-irritating, and non- allergenic.
• They would ideally work rapidly, and the activity and duration of effect should be both predictable
and reproducible.
• They should have no pharmacological activity within the body, i.e., should not bind to receptor sites.
• The penetration enhancers should work unidirectional, i.e., should allow therapeutic agents into the
body while preventing the loss of endogenous material from the body.
• The penetration enhancers should be appropriate for formulation into diverse topical preparations,
thus should be compatible with both excipients and drugs.
• They should be cosmetically acceptable with an appropriate skin “feel.2


Mechanism of penetration enhancers:Penetration enhancers may act by one or more of three main mechanisms:
1. Disruption of the highly ordered structure of stratum corneum lipid.
2. Interaction with intercellular protein.
3. Improved partition of the drug, enhancer, or solvent into the stratum corneum.
The enhancers act by altering one of three pathways. The key to altering the polar pathway is to cause
protein conformational change or solvent swelling. The fatty acid enhancers increased the fluidity of the lipid-protein portion of the stratum corneum. Some enhancers act on both polar and non-polar pathway by altering the multi-laminate pathway for penetration. Enhancers can increase the drug diffusivity through skin proteins. The type of enhancer employed has a significant impact on the design and development of the product.20,36

Use of Penetration Enhancers5

Penetration enhancer	Quantity	Dosage form
Oleic acid	1%	Gel
Lecithine	5%	Gel
Urea	10%	Gel
Isopropyl myristate	5%	Gel
Linoleic acid	5%	Gel
Clove oil	8%	Emulgel
Menthol	5%	Emulgel
Cinnamon	8%	Emulgel

IDEAL PROPERTIES OF EXCIPIENTS CANDIDATE 37

Properties	Criteria
Skin reaction	Nonirritant and non-allergic
Effects of final preparation	Little or no deleterious effect on activity and stability
Regulatory status	IIG listed, GRAS listed, or biologically safe
Compatibility	Compatible with API and the other excipients, etc.
Concentration	Under regulatory limit

PRIMARY REQUIREMENTS OF CHEMICAL MOIETY 37

Properties	Criteria
Effective concentration	< 10 mg
Half life	10 hr. or less than that
Molecular mass	800 Dalton or less desirability 500 Dalton or less, limit could indeed more than this by a change in permeability of skin
Log P value	0.8-5
Skin permeability coefficient	1.5 – 3 cm /hr. or more than that
Irritation of skin	Nonirritating
Polarity	Less
Molecular size	Small
PKa	Higher

EMULGEL PREPARATIOM


There are three basic steps in the preparation of emulgel.
Step 1: Formulation of emulsion either O/W or W/O.
Step 2: Formulation of gel base.
Step 3: Incorporation of emulsion into gel base with continuous stirring.

Emulgel was prepared by the method reported by Mohammad et al. al. (2004) with minor modification.
The gel in formulations was prepared by dispersing Carbopol 934 in purified water with constantstirring at a moderate speed and Carbopol 940 in purified water with constant stirring at a moderate speed then the pH is adjusted to 6 to 6.5 using triethanolamine. The oil phase of the emulsion was prepared by dissolving Span 20 in light liquid paraffin while the aqueous phase was prepared by dissolving Tween 20 in purified water. Methyl and propylparaben were dissolved in propylene glycol whereas drug was dissolved in ethanol and both solutions were mixed with the aqueous phase. Both the oily and aqueous phases were separately heated to 70°–80°C; then the oily phase was added to the aqueous phase with continuous stirring until cooled to room temperature and add glutaraldehyde in during of mixing of gel and emulsion in ratio 1:1 to obtain the Emulgel.37,38

MARKETED PREPARATION OF EMULGEL39

The various preparations of Emulgels available in market are shown in Table-

Product name	Drug	Manufacturer
Voltaren emulgel	Diclofenac-diethyl-ammon ium	Novartis pharma
Miconaz-H-Emulgel	Miconazole nitrate, hydrocortisone	Medical union pharmaceuticals
Excex gel	Clindamycin, adapalene	Zee laboratories
Pernox gel	Benzoyl peroxide	Cosme remedies Ltd.
Lupigyl gel	Metronidazole, clindamycin	Lupin pharma
Clinagel	Clindamycin phosphate, allantoin	Stiefel pharma
Topinate gel	Clobetasol propionate	Systopic pharma
Kojivit gel	Kojic acid, dipalmitate arbuti	Micro gratia pharma
Accent gel	Aceclofenac	Intra Labs India Pvt. Ltd.
Avindo gel	Azithromycin	Cosme pharma lab
Cloben gel	Clotrimazole, betamethasone	Indoco remedies
Nadicin cream	Nadifloxacin	Psycho remedies
Zorotene gel	Tazarotene	Elder pharmaceutical

EVALUATION OF EMULGEL

1.Fourier transforms infrared spectroscopy (FTIR):
The primary objective of this investigation was to identify a stable storage condition for the drug in
solid state and identification of compatible excipients for formulation.


2.Physical examination:
The Prepared emulgel formulations were inspected visually for their colour, homogeneity, consistency and phase separation.


3.Determination of PH:
pH of the formulation was determined by using digital pH meter. pH meter electrode was washed by
distilled water and then dipped into the formulation to measure pH and this process was repeated 3 times.

4.Measurement of viscosity:
The viscosity of the formulated batches was determined using a Brookfield Viscometer (RVDV-I Prime, Brookfield Engineering Laboratories, USA) with spindle 63. The formulation whose viscosity was to be determined was added to the beaker and was allowed to settle down for 30 min at the assay temperature (25±1 °C) before the measurement was taken. Spindle was lowered perpendicularly into the center of emulgel taking care that spindle does not touch the bottom of the jar and rotated at a speed of 50 rpm for 10 min. The viscosity reading was noted.

5.Spreadability:
To determine spreadability of the gel formulations, two glass slides of standard dimensions were selected. Formulation whose spreadability was to be determined was placed over one slide and the other slide was placed over its top such that the gel is sandwiched between the two slides. The slides were pressed upon each other so as to displace any air present and the adhering gel was wiped off. The two slides were placed onto a stand such that only the lower slide is held firm by the opposite fangs of the clamp allowing the upper slide to slip off freely by the force of weight tied to it. 20 g weight was tied to the upper slide carefully. The time taken by the upper slide to completely detach from the lower slide was noted.


6.Globule size and its distribution in emulgel:
Globule size and distribution is determined by Malvern zeta sizer. A 1.0 g sample is dissolved in purified water and agitated to get homogeneous dispersion. The sample was injected to photocell of zeta sizer. Mean globule diameter and distribution is obtained.


7.Swelling index:
To determine the swelling index of prepared topical emulgel, 1 g of gel is taken on porous aluminium
foil and then placed separately in a 50 ml beaker containing 10 ml 0.1 N NaoH. Then samples were removed from beakers at different time intervals and put it on a dry place for some time after it reweighed.


8.In vitro drug release study:
The in vitro drug release studies of the Emulgel were carried out on Diffusion cell using egg membrane. This was clamped carefully to one end of the hollow glass tube of dialysis cell. Emulgel (1g) was applied onto the surface of egg membrane dialysis membrane. The receptor chamber was filled with freshly prepared PBS (pH 7.4) solution to solubilize the drug. The receptor chamber was stirred by a magnetic stirrer. The samples (1 ml aliquots) were collected at suitable time interval sample were analyzed for drug content by UV-visible spectrophotometer after appropriate dilutions. Cumulative corrections were made to obtain the total amount of drug released at each time interval. The cumulative amount of drug release across the egg membrane was determined as a function of time. The cumulative % drug release was calculated using standard calibration curve.


9.Microbiological assay:
Ditch plate technique was used. It is a technique used for evaluation of bacteriostatic or fungim static
activity of a compound. It is mainly applied for semisolid formulations. Previously prepared Sabouraud’s agar dried plates were used. Three grammes of the Gellified emulsion are placed in a ditch cut in the plate. Freshly prepared culture loops are streaked across the agar at a right angle from the ditch to the edge of the plate.


11.Skin irritation test:
A 0.5 g sample of the test article was then applied to each site (two sites per rabbit) by introduction
under a double gauze layer to an area of skin approximately 1” x 1” (2.54 x 2.54 cm2 ) .The gellified
emulsion was applied on the skin of a rabbit. Animals were returned to their cages. After a 24 h exposure, the Gellified emulsion is removed. The test sites were wiped with tap water to remove any remaining test article residue.20,40


12.Stability studies:
The prepared emulgels were packed in aluminium collapsible tubes (5 g) and subjected to stability studies at 5 °C, 25 °C/60% RH, 30 °C/65% RH, and 40 °C/75% RH for a period of 3 mo. Samples were withdrawn at 15-day time intervals and evaluated for physical appearance, pH, rheological properties, drug content, and drug release profiles 41






CONCLUSION
In the coming years, topical drug delivery will be used extensively to impart better patient compliance. Recently most of the new drug molecules are hydrophobic in nature, and difficulty has been raised to researcher for the delivery of such drug in any form of dosage, because of their limited solubility. There has been always a challenging task for the formulation of such drugs; here the focus is given for the hydrophobic drug that needs to deliver topically. When we consider delivering these drugs in conventional dosage form as cream, ointment, lotions, emulsion the problem of stability and bioavailability rises due to their hydrophobic nature. In gel also it is almost negative result to deliver hydrophobic drugs. so the new concept of formulation emulsion in gel has shown better delivery as here the drug are incorporated in oil phase of emulsion and emulsion is better stabilize in the gel and the combination of both of the phase provide the controlled release effect, that improves the bioavailability of that drugs. Since emulgel possesses an edge in terms of spreadability, adhesion, viscosity and extrusion, they will become a popular drug delivery system. Moreover, they will become a solution for loading hydrophobic drugs in a water-soluble gel bases.



REFERENCES

1.Rathbone MJ, Hadgraft J, Roberts MS, Lane ME. Dermal and transdermal drug delivery. Modified
–release drug delivery technology, 2nd ed. U.K: Informa healthcare; 2002. p. 263-71
2. Pant S, Badola A, Baluni S, Pant W. A review on emulgel novel approach for topical drug delivery
system. World J Pharm Pharm Sci 2015; 4:1728-43
3. Ashara KC, Paun JS, Soniwala MM, Chavada JR, Mori NM. Micro-emulsion based emulgel: a novel topical drug delivery system. Asian Pac J Trop Dis journal 2014; 4:27- 32.
4. Rashmi M. Topical gel: A review august vol. 2008; available from http:// www.pharmainfo.com
5. Single V, Saini S, Joshi B, Rana AC. Emulgel: a new platform for topical drug delivery. Int J Pharm Biol Sci 2012; 3:485-98.

6. Mohammad KP, Mohanta PG, Nayar C. Emulgel: An Advanced Review. J Pharm Sci Res 2013;
5:254-8
7. Sonam V, Charu S, Easwari TS, Shukla VK. Emulgel based gel technique: Novel approach for
enhancing topical drug delivery of hydrophobic drugs. Int J Pharm Res Sch 2014; 3:1-2.
8. Kapoor D, Vyas RB, Lad C, Patel M, Lal B, Parmar R. Formulation characterization of emulgel of
NSAID. Pharm Chem J 2014; 1:9-16. 

9. Mulye SP, Wadkar KA, Kondawar MS. Formulation development and evaluation of Indomethacin
emulgel. Der pharmacia sinica 2013; 4:31-45.
10. Sabu KR, Basarkar GD. Formulation, Development and In-vitro Evaluation of Terbinafine
Hydrochloride Emulgel for Topical Fungal Infection. Int. J. Pharm. Sci. Rev. Res. 2013; 21:168-73.

11. Bhoyar N, Giri TK, Tripathi DK, Alexender A, Ajazuddin. Recent advances in novel drug delivery system through gels: review. J. Pharm. allied health sci 2012; 2:21-39.
12. Mishra AN. Controlled and novel drug delivery. 4th ed CBS Publisher and Distributers, Delhi;
1997. p. 107-9.
13. Swarbrick J. Encyclopedia of pharmaceutical technology. 3rd ed. Vol. 1. Informa Healthcare; 2007. p. 1311-23
14. Vats S, Saxena C, Easwari TS, Shukla VK. Emulsion Based Gel Technique: Novel Approach for
Enhancing Topical Drug Delivery of Hydrophobic Drugs. IJPRS 2014;3: 649-60
15. Singh RP, Parpani S, Narke R, Chavan R. Emulgel: A Recent Approach For Topical Drug Delivery System. AJPRD 2014; 2:112-23.
16. Baibhav J, Singh Gurpreet S, Rana AC, Seema S and Singla V. Emulgel: A comprehensive review on recent advancement on topical drug delivery. IRJP 2011; 2:66- 70.
17. Caddeo C, Sales OD, Valenti D, Sauri AR, Fadda AM, Manconi M. Inhibition of skin inflammation in mice by diclofenac in vesicular carriers: liposomes, ethosomes and PEVs. Int J Pharm 2013; 443:128–36
18. Raut S, Uplanchiwar V, Bhadoria S, Gahane A, Jain SK, Patil S. Comparative evaluation of
zidovudine loaded hydrogels and emulgels. Res. J Pharm Technol 2012;5: 41–45
19. Available from: https://en.wikipedia.org/wiki/Diclofenac.

20. Yadav S, Mishra M, Tiwari A, Shukla A. Emulgel: A novel approach for enhanced topical drug
delivery. Int J Curr Pharm Res 2017; 9:15-9.
21. Cecv G, Mazgareanu S, Rother M. Preclinical characterization of NSAIDs in ultra deformable
carriers or conventional topical gels. Int J Pharm 2008; 360:29-39.

22. Kalia YN, Guy RH. Modeling transdermal drug release. Adv Drug Delivery Rev 2001; 48:15972.
23. Ayub AC, Gomes AD, Lima MV, Vianna-Soares CD, Ferreira LA. Topical delivery of fluconazole: in vitro skin penetration and permeation using emulsions as dosage forms. Drug Dev Ind
Pharm 2007; 33:273-80
24. Sonaje S, Gondkar S, Saudagar R. Gellified emulsion: A new born formulation for topical delivery of hydrophobic drugs. World J Pharm Pharm Sci 2013:3:233-51
25. More S, Nandgude T, Poddar S. Vesicles as a tool for enhanced topical drug delivery. Asian J
Pharm 2016;10: S196-209.

26. Gaur PK, Mishra S, Purohit S, Dave K. Transdermal Drug Delivery System: A Review. AJPCR 2009; 2: 14-20.
27. Subranayam N, Ghosal SK, Moulik SP. Enhanced In Vitro Percutaneous Absorption and In Vivo
Anti-Inflammatory Effect of a Selective Cyclooxygenase Inhibitor Using Microemulsion. Drug Dev.
and Industrial Pharm., 2005
28. Pathan, I.B.; Setty, C.M. Chemical penetration enhancers for transdermal drug delivery systems.
Trop J Pharm Res. April 2009; 8:173-179.
29. Lachman, L.; Lieberman, H.A. The Theory and Practice of Industrial Pharmacy. 3rd Ed.Varghese
Publishing house; 1990. pp. 534.
30. Vyas, S.P.; Khar, R.K. Controlled Drug Delivery. 1st Ed. Vallabh Prakashan; 2002. pp. 416-417.
31.Bonacucina G, Cespi M, Palmieri GF. Characterization and Stability of Emulsion Gels Based on Acrylamide/Sodium Acryloyl dimethyl Taurate Copolymer AAPS PharmSciTech. June 2009; 10 (2). 

32.Curr AEB. Transdermal Drug Delivery: Penetration Enhancement Techniques Heather. Drug
Deliv. 2005; 2:23-33.
33. Rutrer N. Drug absorption through the skin: a mixed blessing. Arch Dis Child 1987; 62:220-221.
34. Aher SD, Banerjee SK, Gadhave MV, Gaikawad DD. Emulgel: A new dosage form for topical
drug delivery. Int J Inst Pharm Life Sci 2013; 3:1-10
35. Ajazuddin A, Alexander A, Khichariya A, Gupta S, Patel RJ. Recent expansion in an emergent
novel drug delivery technology: Emulgel. J Controlled Release 2013; 171:122-32.
36. Mortazavi SA, Aboofazeli R. An investigation into the effect of various penetration enhancers on
percutaneous absorption of piroxicam. Int J Pharm Res 2003;135-40.
37. Ashara K, Shah K. Emulgel: A novel drug delivery system. J Prev Alzheimer’ Dis 2016;26:243-9
38. Rieger MM, Lachman L, Lieberman HA, Kanig JL. The Theory and Practice of Industrial
Pharmacy. 3rd ed. Philadelphia, PA: Lea and Febiger; 1986. p. 502-33

39. Anil R. Phad, Nandgude Tanaji Dilip, R. Sundara Ganapathy, Emulgel: A Comprehensive Review
forTopical Delivery of Hydrophobic Drugs. Asian Journal of Pharmaceutics; Apr-Jun 2018 (Suppl),
12 (2) | S382
40. Narendran H, Koorapati S, Mamidibathula L. Formulation and evaluation of aceclofenac-lycopene transemulgel. World J Pharm Res 2013; 2:1036-45.
41.Jones DS, Woolfson AD, Brown AF. Textural, viscoelastic and mucoadhesive properties of
pharmaceutical gels composed of cellulose polymers. Int J Pharm 1997; 151:223-33