REVIEW ON UPDATED TREATMENT OF ACNE VULGARIS USING …

www.wjpps.com │ Vol 9, Issue 12, 2020. │ ISO 9001:2015 Certified Journal │

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Nagamia et al. World Journal of Pharmacy and Pharmaceutical Sciences

REVIEW ON UPDATED TREATMENT OF ACNE VULGARIS USING

EMULGEL AS NOVEL FORMULATION APPROACH

*Mehvish Nagamia and Dr. Jigar Vyas, M.pharm, Phd.

Ajwa Nimeta Road, Bakrol, Vadodara, Gujarat.

ABSTRACT

Propionibacterium acnes is an important target in acne management.

Acne can persist for years and result in disfigurement and permanent

scarring, and it can have serious adverse effects. Acne lesions are

typically classified as non-inflammatory (open and closed comedones)

or inflammatory (papules and pustules). Both topical and systemic

agents may be employed for treatment of acne i.e. topical retinoid, oral

antibiotics, hormonal therapy, Isoretenin and some other medications.

Topical clindamycin reduces free fatty acid concentrations on the skin

and suppresses the growth of propionibacterium acnes

(corynebacterium acnes). Antibiotic resistance has increased, reducing its clinical efficiency.

To overcome these problems and for better efficacy against the macrolide or clindamycin

resistant P.acnes many combinational therapies and new formulation approach was studied

treatment and underlined the benefit of a combination therapy with a topical retinoid such as

adapalene and a topical antibiotic, Clindamycin and benzoyl peroxide, Zinc ascorbate and

clindamycin shows the additive effect against the P.acnesin the treatment of inflammatory

acne also had given an improved results. The topical applications of the drug offers the

potential advantages of delivering the drug directly to the site of action and delivering the

drug for extended period of time at the effected site that mainly acts at the related regions.

The Emulgel had enhancing the topical delivery of drug, have several favourable properties

for dermatological use such as being thixotropic, greaseless, easily spredable, easily

removable, emollient, nonstaining, long shelf life, transparent and pleasing appearance. This

review gives knowledge about the acne pathogenesis, causes, treatmentand formulation,

preparation and characterization of emulgeland combinational drug therapy to provide

effective at least dose amend drug release.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 12, 603-629 Review Article ISSN 2278 – 4357

*Corresponding Author

Mehvish Nagamia

Ajwa Nimeta Road, Bakrol,

Vadodara, Gujarat.

Article Received on

29 September 2020,

Revised on 19 October 2020,

Accepted on 09 Nov. 2020

DOI: 10.20959/wjpps202012-17818


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KEYWORDS: Emulgel, Propionibacterium acne, Benzoyl peroxide, Clindamycin and Zinc

ascorbate.

1. Objective

The prime focus of the literature review is to review the best individualized treatment of acne;

Combinational drug therapy and novel approach drug delivery system for the increased

efficacy of the medication against the P.acne was reviewed.

2. INTRODUCTION

2.1 History and Background of Study

The involvement of microorganisms in the development of acne has a long and checker

history. Just over 100 years ago, propionibacteriumacnes(then known as Bacillus acne) was

isolated from acne lesions and it was suggested that p.acnes was involved in the pathology of

the disease. Acne vulgaris is a common skin disorder affecting the pilosebaceous unit.,

affecting nearly 80 percent of persons at some time between the ages of 11 and 30 years.

Acne can persist for years and result in disfigurement and permanent scarring, and it can have

serious adverse effects on psychosocial development, resulting in emotional problems,

withdrawal from society, and depression. Acne lesions are typically classified as

noninflammatory (open and closed comedones) or inflammatory (papules and pustules).

Seborrhoea, or grease production, is also a feature.[11]

Scarring is often present following

inflammation[12]

as illustrated in figure1.1

The pathophysiological events occurring in acne are also relatively well studied. Lesions start

when keratinocytes lining the hair follicle desquamate creating a microcomedone.

Figure 2.1

At puberty increased sebum production creates an environment that can sustain the

colonization of Propionibacterium acnes. As P. acnes proliferates, inflammatory and


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chemotactic mediators are produced, which in turn drive inflammatory processes.[13]

2.2 Epidemiology

Despite advances in understanding the pathophysiology of acne, much appears to have been

written about its epidemiology, which is strange considering that acne is almost universal in

teenage years. Epidemiology not only describes the burden of disease in terms of incidence,

prevalence and variations according to age, sex, social class, ethnic group and geography, but

also has the potential to identify specific risk factors for disease occurrence or progression,

which may be amenable to manipulation. Discovery of risk factors or factors that exacerbate

existing disease could lead to appropriate primary or secondary preventative measures and

treatments, which in turn could lead to population benefits in terms of health and reduced

expenditure on relatively ineffective treatments. Epidemiology is also concerned with natural

history and progression.

2.3 Classification of Acne

(i) Indian authors gave a simple grading system for acne vulgaris as follows:[16] Grade

1:Comedones,occasional papules.

Grade 2: Papules, comedones, few pustules.

Grade 3: Predominant pustules, nodules, abscesses. Grade 4: Mainly cysts, abscesses,

widespread scarring.

(ii) According to American Academy of Dermatology a consensus Conference classified acne

severity.[17]

According to this consensus, thegrading system of acne vulgaris includes.

1. Mild acne, the presence of comedones as well as feew to several papules-pustules.

2. Moderate acne, differentiated by several papules, pustules and few to several nodules.

3. Severe acne, characterized by numerous or extensive papules-pustules,or both, along with

many nodules.

4. Very severe of acne, including the most destructive conditions of the disease, such as acne

conglobata, acne fulminans and follicular occlusion triad.[18]

2.4 Pathophysiology

The Origin of acne Vulgaris is complex and incompletely understood. At least 4

pathophysiologic events take place within acne-infected hair follicles(1)androgen-mediated

stimulation of sebaceous gland activity.(2)abnormal Kertinization leading to follicular

plugging(comedo formation)(3)Proliferation of the bacteriumpropionibacterium acnes within


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the follicle.(4)Inflammation.[15]

In addition to these four Basicmechanisms, genetic factors,

stress and possibly diet may influence the development and severity of acne.

Figure 2.4.1 Pathophysiology of acne.

Recently, reactive oxygen species (ROS) have been identified as inflammatory mediators in

acne vulgaris. P. acnes infection causes the release of chemotactic factors leading to

neutrophil accumulation, and ROS generated by the attracted neutrophils contribute to an

inflammatory reaction, correlating with acne development and skin aggravation in acne

vulgaris.[6]

propionibacterium acnes is an anaerobic, Gram-positive skin microbe that

colonizes sebaceous glands and pilosebaceous follicles. This organism is considered to play a

principle role in the development of acne vulgaris. Acne vulgaris is a chronic inflammatory

disease characterized by typical inflammatory events, including the overproduction of sebum,

abnormal desquamation of the sebaceous follicle epithelium, and p.acnes proliferation.

Regarding the pathogenic factors for acne development and aggravation, ultraviolet

irradiation and peroxidation of sebum lipids have been reported to activate inflammatory

mediators.[8]

The events of pathogenesis is carried in followingsteps;

Step 1. The excess production of sebum from sebaceous glands.

Step2.Hyperkeratinisation leading to microcomedo that becomeenlarges into comedo.

Step 3. Growth of anaerobic bacteria leading to Colonizationof thefollicle.

Step 4. Inflammatory responses.


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Figure2.4.2[22]

2.5 Treatment

Untreated inflammatory acne or nodulocystic acne can cause dyspigmentation or permanent

scarring.[24]

Treatment regimens should be designed based upon an understanding of the

multifactorial basis of pathogenesis. Both topical and systemic agents may be employed to

normalize keratinization, decrease sebaceous gland activity, decrease the follicular P. acnes

population, and minimize inflammation. Historically, dietary advice was common place as

part of acne therapy. Because early studies hinted that patients with acne had impaired glucose

tolerance and altered carbohydrate metabolism, patients were advised to avoid excessive

carbohydrate and sugary foods.[25][26]

A. Skin Care: Do proper washing with mild soap and avoiding excessive scrubbing. Look for

oil-free or noncomedogenic cosmetics and lubricants. Oil-free or water-based

moisturizers may help the skin dryness and irritation that can result from acne treatment.

Diet usually does not affect acne.

B. Topical Retinoids:- Retinoids, first shown in 1970s to be value for treating acne, are

derivatives of Vitamin A that prevent comedone formation by follicular epithelium. The 3

main retinoids are tretinoin, adapalene and tazarotene. Retinoids prevent

hyperkeratinization and blockage of the pore. They are the most effective keratolytic

agents. They have also been shown in several studies to have anti-inflammatory and

antibacterial properties. The first retinoid brought to market was tretinoin (Retin-A),

available in gel (0.01% and 0.025%), cream (0.025%, 0.05%, and 0.1%), and microgel

(0.04% and 0.1%). Adapalene, available as a cream (0.1%) or gel (0.1% and 0.3%), is a

https://www.sciencedirect.com/topics/medicine-and-dentistry/lubricating-agent

https://www.sciencedirect.com/topics/medicine-and-dentistry/retinoid

https://www.sciencedirect.com/topics/medicine-and-dentistry/tretinoin

https://www.sciencedirect.com/topics/medicine-and-dentistry/adapalene


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synthetic retinoid that has been shown to be less irritating that tretinoin in several studies.

Another topical retinoid product tazarotene (Tazorac), available in a cream (0.1%) and gel

(0.1%), is one of the most effective retinoids, but often the most irritating. In general, all

retinoids can be drying and irritating to the skin. These products should be applied to the

face in the evening. A useful analogy for the patient is to use a “pea-sized” amount of

product for a full face application, avoiding areas around the eyes, nose, and mouth. It is

important to use a sunscreen (SPF 15 or higher) while outdoors. Use of retinoids can

seem to worsen acne initially because of irritation, redness, and peeling. Differin, Retin-A,

Tazorac, are some example of marketed product of topical retinoids.

C. Topical Antimicrobials:-Currently available topical antimicrobials include clindamycin,

erythromycin, tetracylines and benzoyl peroxide. Azelaic acid may also be considered

within this group because it has demonstrated antibacterial activity against intrafollicular

P.acnes. Topical antibiotics like erythromycin 2% gel and clindamycin 1% gel, solution,

lotion, and pledgets should only be used on inflammatory acne in combination with a

product with comedolytic activity. Many over-the-counter “acne” products contain some

BPO, salicylic acid, and α-hydroxy acid (AHA). These ingredients may contribute to the

dryness and peeling if combined with prescription therapy. Azelaic acid 15% and 20%

cream has mild antibacterial and comedolytic activity. It is effective for mild acne in

darker skinned patients because it can lighten postinflammatory hyperpigmentation.

Benzyl peroxide has antibacterial action, reduces free fatty acid concentrations, and has

comedolytic activity. Use a 5% gel; it is as effective as 10% gel but less irritating.

Although the liquid and cream forms are less irritating, they are much less effective.

Combining benzoyl peroxide continues with topical or systemic antibiotics may decrease

the development of resistance to the co- adminitered antibiotic.

D. Oralantibiotics:-Systemic antibiotics used in acne vulgaris have both antimicrobial and

anti-inflammatory production of bacterial-induced in-inflammatory cytokines.

Tetracycline has fallen from favour in the face of increasing P.acnes antibiotic resistance.

Tetracycline and erythromycin suppress leukocyte chemotaxis and bacterial lipase activity

while Doxycline and minocycline inhibit cytokines and matrix metalloproteinases thought

to contribute to inflammation and tissue breakdown. These doses of doxycycline do no

alter the microbial colony counts in acne patients and yet acne improves. Low-dose

antibiotics maintain their anti-inflammatory properties and though they do not decrease

microbial colony counts, likely render P.acnes less biologically active and less capable of

inciting further inflammation. Long- term use of antibiotics in the acne population has

https://www.sciencedirect.com/topics/medicine-and-dentistry/tazarotene

https://www.sciencedirect.com/topics/medicine-and-dentistry/sunscreen

https://www.webmd.com/drugs/2/drug-6445/differin%2Btopical/details

https://www.webmd.com/drugs/2/drug-6445/differin%2Btopical/details

https://www.webmd.com/drugs/2/drug-3329/tazorac%2Btopical/details


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raised concerns regarding the development of colonization with potential pathogens and

bacterial resistance. P.acnesresistanc to tetracycline is well known to dermatologists.

E. Hormonal Therapy:- Hormonal treatments for acne are tolerated in women, these

treatments decrease androgen expression, are based on the requirement for androgens in

the pathophysiologic development of acne. A direct relationship between levels of

circulating androgens and severity has not been established although prior studies suggest

some degree of hyperandrogenemia in women with acne. Androgenic compounds include

oral contraceptives (OCs) and androgen-receptor blockers such as flutamide,

spironolactone, and cyproter and one acetate. Several OCs are now approved for use in

acne. anti- androgen medications such as aldactone (Spironolactone) - oral or clascoterone

(Winlevi) - topical. Winlevi can be used in both males and females as it is a local skin

androgen blocker.

F. Isotretinoin:- Systemic retinoid, was approved for use in acne Vulgaris on 1982. It is arguably

the most effective acne lesions in 85% of its users. It is naturally occurring metabolite of

Vitmin A, inhibits sebaceous gland differentiation and proliferation, reduces sebaceous

gland size, suppresses sebum production and normalizes follicular epithelial desquamation.

A long list of potential side effects limits its use to those individuals with severe, scarring

acne or to individuals who do not respond to first-line topical and systemic acne treatments.

The potential side effects, teratogenic effects and potential psychiatric disturbances have

received the most attention in the lay press. The alleged risk of depression and other

psychiatric disturbances.[23][15]

Current Medical treatment of Acne[50]

The 1960s saw the use of antibiotics to treat acne, and the consequent clinical success

combined with reductions in p.acnes gave new impetus to the debate. Over the past two

decades, the inevitable emergence of antibiotic-resistant strains of p.acnes as a consequence

https://www.webmd.com/drugs/index-drugs.aspx

https://www.webmd.com/drugs/2/drug-6671/aldactone-oral/details

https://www.webmd.com/drugs/2/drug-6288/spironolactone%2Boral/details


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of acne therapy not only has reopened the debate as to the role of p.acnes in acne, but also

created some serious health care implementation.[1]

Many topical and systemic treatments have been proposed for acne vulgaris. Clindamycin

and erythromycin are the most frequently used against p.acnes. Topical clindamycin

reduces free fatty acid concentrations on the skin and suppresses the growth of

propionibacterium acnes (corynebacterium acnes), an anaerobe found in sebaceous glands and

follicles.[1]

On the other hand, many studies have reported the emergence of p.acnes with high

level resistance to macrolides including clindamycin because long-term antibiotic therapy is

commonly used to treat acne vulgaris. In Japan, a study conducted between 1994 and 1995

revealed that macrolide-resistant strains were found in only 4% of P.acnes isolates from

patients with acne vulgaris. However, they were found in 10% of P.acnes isolate between 2006

and 2007, showing P.acnes resistance to macrolides has been increasing in Japan. Macrolides

resistance in P.acne is considered to be caused by mutation of the peptidyl transferase region

in the domain V of 23s rRNA dimethylase that is encoded by erm(X).[9]

In addition, these

mutations is associated with cross resistance to clindamycin. Therefore, the increasing

prevalence of macrolide-resistant P.acnes, including clindamycin-resistant P.acnes, is

serious problem, because acne treatment by clindamycin is extremely difficult. To

overcome these problems and for better efficacy against the macrolide or clindamycin

resistant P.acnesmany combinational therapies was studied; treatment and underlined the

benefit of a combination therapy with a topical retinoid such as adapalene and a topical

antibiotic in the treatment of inflammatory acne also had given an improved results.[28]

In the

treatment of acne, topical clindamycin/benzoyl peroxide combination gel is well tolerated and

superior to either individual ingredient, benzoylperoxide and clindamycinis(Z-Clinz)

combination is available in market, but it may have some side effects likedryness, redness,

mild irritation/itching of the skin.[27]

Propionobacterium acnes induces monocytes cytokine (interleukins 12 and 8) production

through a toll-like receptor 2-dependent pathway that contributes to inflammation. Zinc salts

have been found to be either as good or better thancyclines, but this is probably dependent on

the base used as results to the contrary have also been noted. Invitro data suggested that

sensitivity to zinc salts is the same in erythromycin –resistant and erythromycin-sensitive

strains of p.acnes and addition of zinc in the culture medium could restore p.acnes sensitivity

to erythromycin. Furthermore, bacteriologic in vitro studies of erythromycin minimal

https://www.medicinenet.com/itch/article.htm


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KatsuhiroIinuma,1 NorihisaNoguchi,

2HidemasaNakaminami,

2 MasanoriSasatsu, Setsuko

Nishijima,3 and Isami Tsuboi

1Clinical,Cosmetical and Investigational Dermatogy.

[5]

by studied was This

Zinc ascorbate 160–640 (640)80–320 (160)

Abbreviations: MIC, minimum inhibitory concentration (μg/mL); FIC, fractional

inhibitory concentration; MIC90, concentration of drugs which inhibited growth in 90%

of the strains tested.[5]

Additive 0.84 0.63–1 0.06–1 (1) Clindamycin 0.13–2 (2)

Average Range Combined Alone

Interaction MIC ranges FIC Drug

inhibitory concentration have proved that addition of increasing doses of zinc salts decreased

resistance to the p.acne strain. A recentstudy had found that zinc ascorbate alone effectively

inhibited the growth of all p.acnes, including clindamycin resistant strains. Those added

facet that zinc should be explore and it would be successful if correct base is used.[2]

Ascorbic

acid derivatives are one of the most widely used antioxidants for protecting the skin. The

antioxidative effect of 5% sodium ascorbyl phosphate has demonstrated efficacy in acne

vulgaris.

Recently it had been reported that antibiotic combination enhances the therapeutic effect. In

that study, efficacy of clindamycin alone in vitro and in combination with zinc ascorbate was

studied.[7]

Clindamycin is approved and commonly used in Japan for the treatment of acne vulgaris.[8]

In

the study, it was found that zinc ascorbate inhibited growth of the clindamycin-resistant

P.acnes strains(MIC 640µg/mL). In addition, the FIC(fractional inhibitory concentration)

index of strain with clindamycin-resistant P.acnes was 0.75, exhibit an additive effect. These

result strongly suggest that the combination of zinc ascorbate and clindamycin useful for

preventing the emergence of clindamycin resistant P.acnes and for treating acne vulgaris.

Table 2.5.1 Combined effect of Zinc ascorbate and clindamycin against

Propionibacterium acnes isolated from patients with acne an its activity was studied.[5]

Moreover emergence of resistance also correlates with low and variable concentrations of the

drug achieved in the pilosebaceous ducts. Therefore, reliable drug delivery systems providing

better drug penetration can result in better efficacy and also help in the prevention of

https://www.ncbi.nlm.nih.gov/pubmed/?term=Iinuma%20K%5BAuthor%5D&cauthor=true&cauthor_uid=22087070

https://www.ncbi.nlm.nih.gov/pubmed/?term=Noguchi%20N%5BAuthor%5D&cauthor=true&cauthor_uid=22087070

https://www.ncbi.nlm.nih.gov/pubmed/?term=Nakaminami%20H%5BAuthor%5D&cauthor=true&cauthor_uid=22087070

https://www.ncbi.nlm.nih.gov/pubmed/?term=Sasatsu%20M%5BAuthor%5D&cauthor=true&cauthor_uid=22087070

https://www.ncbi.nlm.nih.gov/pubmed/?term=Nishijima%20S%5BAuthor%5D&cauthor=true&cauthor_uid=22087070


https://www.ncbi.nlm.nih.gov/pubmed/?term=Tsuboi%20I%5BAuthor%5D&cauthor=true&cauthor_uid=22087070


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Dermis Epidermis Stratum

corneum

Adhesive Topical

formulation

development of resistance.

2.6 Topical formulation

Topical therapy has been used for centuries for the treatment of dermatological disorders. The

spectrum of drugs/agents applied directly to the skin ranges from anti-inflammatory,

antiseptic, antibacterial, antifungal, antiviral, anti-acne, antipigmentary, anesthetic

compounds to skin emollients and protectants. Topical route has main advantage of direct

delivery of drug to the target tissue i.e. skin and mucous membranes, bypassing the first-pass

effect. However, skin permeation of drug moiety from topical formulation is a multi-step

process. It starts as release from the dosage form, diffusion through adhesive layer if it is

present between the skin and drug loaded matrix, sorption or adhesion through stratum

corneium, diffusion through stratum corneum entry into the layer of the dermis. Stratum

corneum is barrier which prevents drug penetration.[49]

Figure 1.6 Pathway of Drug Penetration of topical dosage.

2.6.1 PHYSIOLOGY OF SKIN

The topical preparations are meant to be appliedto 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 2m2 and receives about

one-third of the bloodcirculating 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

centimetre 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.[34]


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Figure 1.6.1 Physiology of skin.

Non-viable epidermis Stratum corneum is the outermost layer of skin, which is the actual

physical barrier to the most substance that comes in contact with the skin. The stratum

corneum is 10–20 cell layer thick over most of the body. Each cell is a flat, platelike structure -

34–44 μm long, 25–36 μm wide, and 0.5–0.20 μm thick with a surface area of 750–1200 μm

stocked up to each other in brick-like fashion. Stratum corneum consists of lipid (5–15%)

including phospholipids, glycosphingolipid, cholesterol sulfate, and a neutral lipid, protein

(75–85%) which is mainly keratanin.[32]

Viable epidermis: This layer of the skin resides between the stratum corneum and dermis

and has a thickness ranging from 50 to 100 μm. The structures of the cells in the viable

epidermis are physicochemically 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 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.[33]

2.6.2 Factors Affecting Topical Absorption of Drug

(i) Physiological Factors

1. Skin thickness.

2. Lipid content.

3. Density of hair follicles.


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4. Density of sweat glands.

5. Skin pH.

6. Blood flow.

7. Hydration of skin.

8. Inflammation of skin

(ii) Physiochemical Factors

1. Partition coefficient.

2. Molecular weight (less than 400 Dalton)

3. Degree of ionization (only unionized drugs gets absorbed well).

4. Effect of vehicles

3. Emulgels

Topical formulation can vary in consistency from solid, semisolid to liquid depending on their

physiocochemical properties, Besides the acccctive substance (drug), each formulation has

many non-medicinal ingredients(excipients) with diverse pharmacological functions.

Sometimes more than one formulations can be combined to enhance the drug delivery. When

gels and emulsion are used in combined form dosage forms are referred as EMULGELS.[10]

Emulsion: Emulsions are phases of two or more immiscible liquids. The one phase is

dispersed medium. Several types as oil in water(O/W), water in oil (W/O), oil in oil (O/O),

micro-emulsions, double and multiple emulsions etc. For preparation and stability of emulsion

the emulsifier is necessary. Various factors could affect the process of emulsification, such as

the nature of oil, emulsifier, the emulsifier concentration used, rpm, as well as the temperature.

GEL: Gels are constituted by entrapment of large amounts of aqueous or hydroalcoholic liquid

in a network of colloidal solid particles, which may be inorganic or organic polymers of

natural or systhetic origin. The higher aqueous component permits easy migration of the drug

as compared to the ointment or cream base. However, this makes gels poor vehicle for

hydrophobic drugs. The limitation of gels can be overcome by making emulgel.

Emulgel:-The topical drug delivery system such as emulgel (gellified emulsion) generally

used where the other systems of drug administration fail to directly treat cutaneous disorders

such as fungal infections, acne, psoriasis etc.[51]

Since the mid-1980’s, emulsion gels have

been of growing importance in the field of pharmaceutical semisolid dosage forms. Emulsion


615


and gels could be mixed in preparation called Emulgel, O/W emulsion for lipophilic materials

while W/O for hydrophilic materials. They also have a high ability to penetrate the skin. The

presence of the gelling agent in water phase converts a classical emulsion into an emulgel.

The emulsion and gel preparations have their own properties. But the gels show some

limitations as hydrophobic drug delivery. This limitation is overcoming by emulgel.

Molecule can basically penetrate into the skin by three routes: through intact stratum

corneum, sweat ducts or sebaceous follicle. The surface of the stratum corneum presents

more than 99% of the total skin surface available for percutaneous drug absorption. Passage

through this outermost layer is the rate limiting step for percutaneous adsorption.

Figure 3: Structure of emulgel.[52]

The major steps involved in percutaneous absorption include the establishment of a

concentration gradient, which provides the driving force for drug movement across the skin,

release of drug from the vehicle (partition coefficient), and drug diffusion across the layers of

the skin (diffusion coefficient). Emulgels are thixotropic, greaseless, easily spreadable, easily

removable, emollient, nonstaining, bio friendly, transparent and cosmetically acceptable.[29]

Incorporation of emulsion into gel makes it a dual control release system to further solve the

problems such as phase separation, creaming associated with emulsion, and improvement of

stability. They also have good cutaneous penetration[30]

and long shelf- life.[31]

This all make

emulgels an advantageous topical drug delivery system.

3.1 Rationale of Emulgels as a new formulation

Number of medicated products are applied to the skin or mucous membrane that either

enhance or restore a fundamental function of skin or pharmacologically alter an action in the

underlined tissues. Such products are referred as topical products. Many widely used topical


616


agents like ointments, creams lotions 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. And they exhibit the problem of stability also.

Due to all these factors within the major group of semisolid preparations. A gel is colloid that

is typically 99% wt liquid, which is immobilized by surface tension between it and a

macromolecular network of fibers built from a small amount of gelating substance present. In

spite of many advantages of gels 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 delivered through gels.

Emulgel could be prepared from selected oil on the term of solubility of drug can be made

available in solubilised form in made emulgel, which can penetrate stratum corneum for drug

action at viable soft tissue of skin. As globules of drug could penetrate stratum corneum

comparatively larger surface area could be available for drug action, so less dose of drug may

provide more pharmacological action. Moreover, selected other excipients may assist

pharmacological action by one or other way. EMULGEL could provide benefits of both

emulsion and gel. Emulgel increases drug deposition over to the skin.

3.2 Important Constituents of Emulgel Preparation

3.2.1 Aqueous Material: This forms the aqueous phase of the emulsion. Commonly used

agents are water, alcohols.

3.2.2 Oils: These agents form the oily phase if 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.[39,40]

Table 3.2.2 Uses of Oils.

Chemical Quantity Dosage REFERENCE

Isopropyl myristate According to

phase diagram Emulsion Subramanian, N. Drug Dev. Ind. Pharm.

Capmul According to

phase diagram Emulsion Subramanian, N. Drug Dev. Ind. Pharm.

Isopropyl Stearate 7-7.5% Emulsion Montenegro, L., Drug Dev. Ind. Pharm

Light liquid paraffin 7.5% Emulgel Jain, Ankur. IJPRD

Prpylene glycol 3-5% Gel Arellano, A., European J. Pharm. Sci


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3.2.3 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 glycol 40 stearate, Sorbitan mono-oleate (Span 80),

Polyoxyethylenesorbitan monooleate (Tween 80), Stearic acid, Sodium stearate23.[36]

3.2.4 Gelling Agent: These are the agents used to increase the consistency of any dosage

form can also be used as thickening agent 24.[41]

The examples are given in table.

Table 3.2.4 Use of different Gelling Agent.

Gelling Agent Quantity Dosage Reference

Carbopol-934 1% Emulgel Mohamed, M.I., AAPS

HPMC 2910 2.5% Emulgel Mohamed, M.I., AAPS

Carbopol-940 1% Emulgel Jain, Ankur. IRJD

Sodium CMC 1% Gel Singh. S, Pak J. Pharm. Sci

3.2.5 Permeation Enhancers

These are agents that partition into, and interact with skin constituents to induce a temporary

and reversible increase in skin permeability. Some of these materials included in Table.

Properties of penetration enhancers are as follows:[41,42,43]

• 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.”

Mechanism of penetration enhancers[33,35]

: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, coenhancer, or solvent into the stratum corneu


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Table 3.2.5 Use of penetration enhancers.

Penetration Enhancer Quantity Dosage Reference

Oleic Acid 1% Gel Mortazavi S.A, Iranian Journal of Pharmaceutical

Science.

Lecithine 5% Gel Mortazavi S.A, Iranian Journal of Pharmaceutical

Science

Isopropyl myristate 5% Gel Mortazavi S.A, Iranian Journal of Pharmaceutical

Science

Urea 10% Gel Mortazavi S.A, Iranian Journal of Pharmaceutical

Science

Lineolic Acid 5% Gel Kasliwal, N., AJIPS

In recent years, there has been great interestin the use of novel polymers with complex

functions as emulsifierand thickeners because the gelling capacity of these compounds allows

the formulation of stable emulsions by decreasing surface and interfacial tension and at the

same time increasing the viscosity of the aqueous phase. Emulgels use have several

favourable long shelf life, bio-friendly, transparent and pleasing appearance.

3.3 EMULGEL PREPARATION

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. (2004) with minor

modification. The gel in formulations was prepared by dispersing Carbopol 934 in purified

water with constant stirring 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 propyl lene 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.[36,37]

Oil Phase Aqueous Phase Emulsification

O/W or W/O emulsion


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3.4 Characterization of emulgel

The emulgel can be evaluated using several parameters like physical appearance,

spreadability, extrudability study, globule size distribution, rheological study, swelling index,

ex–vivo bioadhesive strength measurement, drug content determination, in-vitro release

study, microbiological assay, skin irritation test, accelerated stability studies and drug release

kinetic study.

A. Physical appearance

The emulgel were inspected visually for colour, homogeneity, consistency and pH. The pH

value of aqueous solution of emulgel was measured by a pH meter.

B. Spreadability

Spreadability is determined by an apparatus that consists of a wooden block, provided by a

pulley at one end. A ground glass slide is fixed on this block. An excess of emulgel is

sandwiched between this slide and another glass slide provided with the hook. A 1 Kg weight

is placed on the top of the two slides for 5 minutes to expel air and to provide a uniform film

of the emulgel between the slides. Excess of the emulgel was scrapped off from the edges.

The top plate was then subjected to pull off 80 gm. With the help of string attached to the

hook, the time (in seconds) required by the top slide to cover a distance of 7.5 cm is noted. A

shorter interval indicates better spreadability. Spreadability is calculated by using the

formula,

S= M.L/T

Where, S = spreadability,

M = Weight tied to upper slide L = Length of glass slides

T = Time taken to separate the slides apart

C. Extrudability study

It is a test to determine the force required to extrude the material from a lacquered aluminum

collapsible tube. The test is based upon the quantity of emulgelextruded from the tube on

application of weight in grams required to extrude at least 0.5cm ribbon of emulgel in 10

seconds. More quantity extruded better is extrudability.

Extrudability = Applied weight to extrude emulgel from tube (in gm) / Area (in cm2)


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D. Globule size distribution

A 1.0 gm sample to be dissolved in purified water and agitated to get homogeneous

dispersion. Inject sampleto photocell of zeta sizer. Mean globule diameter and distribution

can be obtained.

E. Rheological study

The viscosity of the different emulgelformulations can be determined at 25°C using a cone

and plate viscometer with spindle; connected to a thermostatically controlled circulating

water bath.

F. Swelling index

To determine the swelling index of emulgel, 1 gm 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

are removed from beakers at different time intervals and reweighed. Swelling index is

calculated as follows:

Swelling Index (SW) % = [(Wt –W0) / W0] × 100

Where,

(SW) % = Equilibrium percent swelling.

W0= Original weight of emulgel, Wt = Weight of emulgel after time t

G. Ex–vivo study

Bioadhesive strength measurement. The fresh skin of shaven mice is cut into pieces and

washed with 0.1N NaOH. Two pieces of skin are tied to the two glass slide separately. One of

the glass slides is fixed on the wooden piece and other piece is tied with the balance on right

hand side.1 gm of topical emulgel is placed between the two slides containing skin pieces,

and extra weight from the left pan is removed to sandwich the two pieces of skin and some

pressure is applied to remove the presence of air. The balance is kept in this position for

5minutes. Weight is added slowly at 200 mg/ min to the left hand pan until the patch gets

detached from the skin surface. The weight required to detach the emulgel from the skin

surface indicates the bioadhesive strength. The bioadhesive strength can be calculated by

using formula: Bioadhesive Strength = Weight required (gm) /Area (cm2)

H. Drug content determination

Drug concentration in emulgel is measured by spectrophotometer. A known quantity of

emulgel is dissolved in solvent (methanol); sonication is done if required. Absorbance is


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measured after suitable dilution in UV spectrophotometer.

I. In-vitro release study

Franz diffusion cell is used for the drug release studies. A fixed quantity of emulgel was

applied onto the surface of egg membrane evenly. The egg membrane clamped between the

donor and the receptor chamber of diffusion cell. The receptor chamber is filled with freshly

prepared phosphate buffer (pH 5.5) solution. The receptor chamber, stirred by a magnetic

stirrer. The samples (1.0 ml aliquots) are collected at suitable time interval and analyzed for

drug content by UV visible spectrophotometer after appropriate dilutions. The cumulative

amount of drug released across the egg membrane is determined as a function of time.

J. Microbiological assay

Ditch plate technique is used, which is meant for evaluation of bacteriostatic or fungistatic

activity of a compound. It is mainly applied for semisolid formulations.

Sabouraud’s agar dried plates are used. Three grams of the emulgel placedin 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. After incubation for 18 to 24 hours at 25°C, the fungal growth

is observed and the percentage inhibition is measured as follows.

% inhibition = L2 / L1 × 100

Where, L1 = total length of the streaked culture, L2 =length of inhibition

K. Skin irritation test

0.5 gm sample of the emulgel applied to each site (two sites per rabbit) by introduction under

a double gauze layer to an area of skin approximately 1”x1” (2.54 x 2.54 cm2). Animals are

returned to their cages and remained as such for 24 hours. After a 24 hour exposure, the

emulgelis removed. The test sites are wiped with tap water to remove any remaining residue

and the animals are observed for any sign of irritation or rashes.

L. Accelerated stability studies

Stability studies are performed according to ICH guidelines. The emulgel formulations stored

in hot air oven at 37 ± 2, 45 ± 2 and 60 ± 2C for a period of 3 months. The samples are

analyzed for drug content every two weeks by UV-Visible spectrophotometer. Stability study

is carried out by measuring the change in drug concentration and pH of emulgel at regular

intervals of time.


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M. Drug release kinetic study

To analyze the mechanism of drug release from the emulgel, the release data are fitted to

following equations: Zero order equation: Q = k0 t Where, Q is the amount of drug released

at time t, and k0 is the zero order release rate.

First order equation: In (100 –Q) = In 100 –k1 t

Where, Q is the percent of drug release at time t, and k1 is the first order release rate constant.

Higuchi’s equation: Q = k2√t

Where, Q is the percent of drug release at time t, and K2 is the diffusion rate constant.

3.5 Advantages and Disadvantages

3.5.1 Advantages

1. Avoidance of first pass metabolism.

2. Avoidance of gastrointestinal incompatibility.

3. More selective to a specific site.

4. Improve patient compliance.

5. Suitability for self-medication.

6. Providing utilization of drug with short biological halflife and narrow therapeutic

window.[45]

7. Ability to easily terminate medication when needed.

8. Convenient and easy to apply.

9. Incorporation of hydrophobic drugs: The hydrophobic moieties cannot be added directly to

the gel bases because of the improper release shown by the drug as of lack of solubility.

The emulgel allows the addition of such hydrophobic drugs in the oil phase which leads

to the dispersion of oil globules in an aqueous phase resulting in the formation of o/w

emulsion. Further, this emulsion can be simply added to the gel base, thereby providing

good stability, and better release of drugs.

10. Better loading capacity: Other novel approaches such as niosomes and liposomes are of

nano size and due to vesicular structures may result in leakage and result in lesser

entrapment efficiency. However, gels due to the vast network have comparatively better

loading capacity.

11. Better stability:[46,47]

Other transdermal preparations are comparatively less stable than

emulgels. Like powders are hygroscopic, creams show phase inversion, or breaking and

ointment show rancidity due to the oily base.

12. Production feasibility and low preparation cost:Preparation of emulgels comprises simpler


623


and short steps which increase the feasibility of the production. There are no specialized

instruments needed for the production of emulgels. Moreover, materials used are easily

available and cheaper. Hence, decreases the production cost of emulgels.

13. Controlled release:Emulgels can be used to prolong the effect of drugs having shorterT1/2.

14. No intensive sonication:[46,47]

Production of vesicular molecules needs intensive

sonication which may result in drug degradation and leakage. However, this problem is

not seen during the production of emulgels as no sonication is needed.

3.5.2 Disadvantages[33,36]

1. Skin irritation on contact dermatitis.

2. The possibility of allergenic reactions

3. The poor permeability of some drug through the skin.

4. Drug of large particle size not easy to absorb through the skin.

5. The occurrence of the bubble during formation of emulgel.

3.6 Marketed products

Table 3.6 Marketed products of Emulgel.

Product Name Drug Manufactures

Voltaren emulgel Diclofenac-diethyl-ammonium Novartis Pharma

Miconaz-H-Emulgel Miconazole nitrate, hydrocortisone Medical Union pharmaceutical

Excess gel clindamycin, adapalene Zee Laboratories

Permox benzoyl peroxide Cosme remedies Ltd

Lupigyl gel Metronidazole, clindamycin Lupin Pharma

Clinagel Clindamycin phosphate, allantoin Stiefel Pharma

Zoratene gel Tazoretene Elder Pharmaceutical

4. Future prospects and Conclusion

4.1 Future Prospects

Many antibiotics were formulated and marketed but the inevitable emergence of antibiotic-

resistant strains of p.acnes as a consequence of acne therapy can be overcome by using the

combinational drug therapy formulated in Emulgel dosage form will provide the increased

efficacy towards the antibiotic/other Drug P.acne resistant strain and better patient

compliance. Emulgels provides a suitable medium for delivery of hydrophobic drugs where

such drugs can be incorporated into oily phase and delivered to the skin. All advantages of

emulgel over other topical delivery systems make them more efficient and productive. In

future these all such type of development of formulation will show better results.


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4.2 CONCLUSION

Combinational drug therapy like Zinc ascorbate and clindamycin gave the additive effect,

Benzoylperoxide and clindamycin, topicalretenoids such as Adapalene and topical antibiotic

combinations, Ascorbic acid derivatives had shown the effective result against P.acnes

according to the study reports. These findings provide us novel evidence to acne therapy. Such

drugs can be delivered in the form of emulgel where they can be incorporated in the emulsion

and than combined with gel for better efficacy of drug.

5. Literature Review

Author Titles Description

1. Richard A. Bojar PhD,

Keith T. Holland PhD.

Clinics in Dermatology

Volume 22, Issues 5,

September-october2004,pg

375-379.

Acne and

propionibacterium acnes.

In this review, detailed description of

involvement of microorganism in the

development of acne was studied. It was

suggested that P.acnes was involved pathology

of the disease, the use of antibiotics to treat

acne and consequent clinical success combined

with reductions in P.acnes gave new impetus

to the debate and also created some serious

health care implications.

2. Katsuhiro linuma Norihisa

Noguchi Hidemasa

Nakaminami Masanori

Sasatsu Setsuko Nishijima

Isami Tsuboi.

Clinical, Cosmetical and

Investigational Dermatogy

Susceptibility

of propionibacterium

acnes isolated from

patients with acnevulgaris

to zinc ascorbate and

antibiotics

The Invitro antimicrobial activity of ascorbic

acid derivatives against

Propioonibacteriumacnes was tested either

alone or in combination with a variety of

antimicrobial agents, and their fractional

inhibitory concentration index was determined

using checkerboard tests. The antimicrobial

effectiveness of zinc ascorbate in the treatment

of acne vulgaris, either alone or in

combination with antibiotics such as

clindamycin that are commonly used in Japan

for the treatment of acne vulgaris, was

therefore examined. The antimicrobial

susceptibility of 41 strains of clindamycin-

sensitive and/orclindamycin-resistant P. acnes

isolated from acne vulgaris patients was tested,

in comparison with a type strain of P. Acnes

and the result

was studied that Zinc ascorbate showed

antimicrobial activity against a type strain of

P. acnes and its concentration (0.064%) was

sufficiently lower than the normal dose (5%)

of other ascorbic acid derivatives.

Combinations of zinc ascorbate with

clindamycin, erythromycin, and

chloramphenicol showed an additive effect,

and zinc ascorbate alone effectively inhibited


625


the growth of all P. acnes including

clindamycin-resistant strains.

3. Rachit Khullar Saini s

Seth N Rana AC

International Journal of

Pharmacy and Biological

Sciences/ Volume 1/Issue

3/July-Sep/2011/117-128

Emulgels: A Surrogate

Approach For Used

Hydrophobic Drugs.

This Review article gives detail information

regarding the emulgels preparation, drug

delivery across the skin, Factors affecting the

absorption of the drug, method to enhance

penetration and absorption, classification to

topical drug delivery system, Advantages of

Emulgel as a drug delivery system,

Importantconstitutents of emulgel preparation

and its evaluation tests.

4. Priya Ranjan, Vivek Jain,

Shradha Shende, Prabhat

Kumar Jain.

Journal of Drug Delivery and

therapeutics, 2019; 9(4):

202- 207

Formulation Development

and Evaluation of

Clindamycin phosphate

for effective Treatment of

Acne.

The clindamycin phosphate was formulated in

Emulgel dosage form prepared with Carbopol-

941, Light liquid paraffin, tween-20, Span-20

and propylene glycol and its Evaluation was

done, It showed acceptable physicalproperties,

drug release and anti acne activity, which

remained unchanged upon storage for 3

months. The Carbopol-941 based emulgel in

its low concentration showed the highest drug

release and anti-acne activity as compare to

marketed clindamycin gel.

5. Aamir Haider, James C.

Shaw.

JAMA, August 11, 2004-

Vol292, No.6

Treatment of Acne

Vulgaris

The article does the double blind trials for the

evaluation of the inflammatory, non

inflammatory and total counts of acne using

different agents for effective treatment of acne.

topical retinoids, topical anti-microbials, oral

antibiotic, hormonal therapy and Isotretinoin

were studied. All gave high response rate.

6. Manoj A. Suva, Ankita

M. Patel, Neeraj Sharma,

Chandrayee Bhattacharya,

Ravi K. Maangi.

Research and Reviews:

Journal of Pharmacology.

A Brief Review on Acne

Vulgaris: Pathologenesis,

Diagnosis and Treatment.

This review had given brief on the Acne

vulgaris its causes, epidemalogy, etiologytypes

of Acne, Pathogenesis, Diagnosis and different

methods used for the treatment of the acne

with the pharmaceutical dosage forms of oral

and topical administrations. Various

medications for acne treatment like benzoyl-

peroxide, anti-seborrheic medications were

discussed.

7. Anil R. Phad, Nandgude

Tanaji Dilip, R. Sundara

Ganapathy.

Asian Journal of

Pharmaceutics. Apr-

Jun2018(suppl).12(2)|S382

Emulgel; A

Comprehensive Review

for Topical Delivery of

Hydrophobic Drug.

This review gives knowledge about emulgel,

its rationale and the physiological and

physicochemical factors affecting the topical

dosage form, Drug delivery across the skin,

formulation, preparation of emulgel and its

physical examination, Ph determination,

spreadability and other evaluation parameters

are discuss.


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