AIM: FORMULATION AND EVALUATION OF CREAM CONTAINING

ANTIFUNGAL AGENTS, ANTIBACTERIAL AGENTS

INTRODUCTION
Topical drug delivery can be defined as application of drug via skin to directly treat or cure the skin disorders. These
systems are generally used for local skin infection like fungal infection or in place where other routes of the drug
administration fails1. Topical dosage forms are generally confined to a small area anywhere in the body through
ophthalmic, rectal, vaginal and skin as route. Skin is one of the most easily accessible organ of human body. Skin of an
average adult body covers a surface of about 2m2 and receives around one-third of the blood circulating through the
body. Over the pass three decades, controlled drug delivery has become increasingly important in the pharmaceutical
industry. The surface of human skin is known to contain, on an average, 10-70 hair follicles and 200 to 250 sweat ducts
on every cm2 of the skin area. Skin is a very difficult barrier to the ingress materials allowing only small quantities of
drug molecules to penetrate over a period of time. Transport of hydrophilic or charged molecules is especially difficult
attributable to the lipid-rich nature of the stratum corneum and its low water content; this layer is composed of about
40% lipids, 40% protein, and only 20% water. Transport of lipophilic drug molecules is facilitated by their dissolution into
intercellular lipids around the cells of the stratum corneum. Absorption of hydrophilic molecules into skin can occur
through ‘pores’ or openings of the hair follicles and sebaceous glands, but the relative surface area of these openings is
barely 1% of the total skin surface. This small surface area limits the amount of drug absorption. Percutaneous
absorption of drug molecules is a key factor of particular importance in the case of topical drug delivery systems
because the drug has to be absorbed to an adequate extent and rate to achieve and maintain uniform, systemic,
therapeutic levels throughout the duration of use. In general, once drug molecules cross the stratum corneal barrier,
passage into deeper dermal layers and systemic uptake occurs relatively quickly and easily. Drugs with the lipophillic
character, are better suited for topical delivery. These systems ensure that the drug get into the body and reach the
area where it is needed.

The development of topical drug delivery systems designed to have systemic effects appears to be beneficial for a large
number of drugs on account of the several advantages over conventional routes of drug administration in order to
optimize both the release of the drug from the topical vehicle and skin permeation1 . The topical antifungal agents have
varying mechanisms of action and different spectrums of activity and have few adverse reactions or drug interactions.

Different dermatological preparations have been indicated for topical application for the prevention and treatment of
various skin disorders and infections. Notable among these are Benzoic acid Ointment, Compound, containing benzoic
acid and salicylic acid in emulsifying ointment and indicated for skin infection due to Tinea Spp., e.g. Ringworm.
Another one is Salicylic acid and Sulphur Ointment, containing salicylic acid and precipitated sulphur in hydrous
ointment (oily cream) and indicated for acne, eczema, psoriasis, and dandruff [1]. The raw materials and the products
are imported into Nigeria.

So far, no single topical preparation has been reported for all the above-named skin disorders and infections [2]. This
work, therefore, aims at compounding with sizeable proportion of local raw materials a topical water-free oily cream
that prevents and treats most skin disorders and infections. This will reduce dependence on foreign products and raw
materials as well as save foreign exchange.
Topical route of drug administration:-
Even though the intact skin is less permeable than other tissues, many of the drug molecules do penetrate
the skin to some degree at relatively slow rates. The penetration of the drug and other substances depends
mainly on the physiochemical properties of the penetrating agent, the condition of the skin and the nature of
the vehicle. Commercially available drugs that are applied topically provide local action includes anti-fungal,
anti-septic, anti-inflammatory agents as well as skin emollients for the protective effects. Topically applied
drug can diffuse through the skin through hair follicles, sweat glands or sebaceous glands but permeation
through multiple lipid bilayers of stratum corneum is a dominant pathway though the rate is very slow. 2 This
route can also be used for systemic drug delivery.

Advantages of topical drug delivery systems:_

 Avoidance of the first pass metabolism.

 Convenient and easy to apply.

 Avoidance of risks and inconveniences of the intravenous therapy and of diverse conditions of absorption
like pH changes, presence of enzymes, gastric emptying time.

 Easily terminate the medications, when needed.

 Deliver drug more selectively to a specific site.

 Avoidance of the gastro-intestinal incompatibility.

 Providing utilization of drugs with short biological half life, narrow therapeutic window.

 Improved patient compliance.

 Provide suitability for self-medication.

 Achievement of effectiveness with lower total daily dose of drug by continuous drug input.

 Avoids fluctuation in drug levels, inter- and intra patient variations.

 A quite large area of application in comparison with buccal or nasal cavity.

 Ability to deliver drugs more selectively to a specific site.

Disadvantages of topical drug delivery systems:-

 Skin irritation or dermatitis may occur due to the drug or excipients.

 Poor permeability of some drugs through skin.

 Drugs with larger particle size can’t be easily absorbed through the skin.

 Risk of allergenic reactions.

 Can be used only for the drugs which need very small plasma concentration for action.

Physiology of human skin:-

The skin is the largest organ of human body, accounting for about 15% of the whole adult body weight. Skin is one of
the most readily accessible parts of the human body for topical administration. Penetration of molecules in the skin
mainly occurs through three routes i.e through intact stratum corneum, through the sebaceous follicle and through
sweat ducts. Topical drug delivery approach is used for localized action on the body through skin, ophthalmic, rectal and
vaginal as topical routes.7 Skin performs various important functions:
  Protection against the physical, biological and chemical assailants.

 Prevention of excess loss of water from the body.

 Vital role in the thermoregulation.

 Enzyme in epidermis can denature the drug

Epidermis:
It is a stratified squamous epithelium layer which is composed primarily of two types of cells: dendritic and
keratimocytes cells. The epidermis layer harbour a number of other cells such as melanocytes, Merkel cells
and Langerhans cells. But the keratinocytes cells type comprises the majority of the cells by far. The layers of
epithelium are -

Stratum germinativum (basal layer or rowing layer): It contains column-shaped keratinocytes that attach to the
zone of basement membrane with their long-axis perpendicular to the dermis

Stratum spinosum (prickly cell layer or squamous cell layer): Its thickness vary from 5-10 cells. Intercellular
spaces between spinous cells are bridged by abundant desmosomes (adhering spot) to promote coupling
between cells of the epidermis and provide resistance to the physical stresses

Stratum granulosum (granular layer): It consists of living cells, these are responsible for further synthesis and
modification of the proteins involved in keratinization. It is 1-3 cells layer in thickness

Stratum corneum (horny layer): the corneocytes are rich in protein and low in lipid content (hydrophilic nature)
are surrounded by a continuous extra cellular lipid matrix

Malpighian layer ( pigment layer): the layer whose protoplasm has not yet change into horny material

Stratum lucidium7
The skin consists of three layers that are the epidermis, the dermis and the
subcutaneous tissue. An average human skin surface contain, on an average 40-70
hair follicles and 200-300 sweat ducts on every cm² of the skin. The pH of the skin
vary from 4-5.
the skin of an average adult body covers a surface area of about 2m² and receives
about one third part of the blood circulating through the body.

Salicylic acid is used on the skin to treat psoriasis and other dry, scaly
skin conditions. This medication is also used to help remove dead skin
from warts, the palms of the hands, and the soles of the feet. It
belongs to the same class of drugs as aspirin (salicylates). This
medication should not be used in children younger than 2 years.

Salicylic acid causes the skin to shed dead cells from its top layer by
increasing the amount of moisture in the skin and dissolving the
"cement" between the cells. This makes it easier to shed the skin cells,
softens the top layer of skin, and decreases scaling and dryness.

Sulfur has antifungal, antibacterial, and keratolytic activity. In the past,

its use was widespread in dermatological disorders such
asacne vulgaris, rosacea, seborrheic dermatitis, dandruff, pityriasis
versicolor, scabies, and warts.

Benzoic acid helps prevent infection caused by bacteria. Salicylic

acid helps the body shed rough or dead skin cells. Benzoic
acid and salicylic acid topical (for the skin) is a combination medicine used
to treat skin irritation and inflammation caused by burns, insect bites, fungal
infections, or eczema.

Table I: Physical and Chemical Tests for Benzoic Acid, Salicylic Acid and
Precipitated Sulphur Powder
S/NO MATERIAL PHYSICAL INSPECTIONS CHEMICAL REACTIONS
.

1. Benzoic acid, C 1. White crystalline solid 1. Dissolves in hot water, but

2. Melting point: 1210C separates as shining whites
6356

3. Sparingly soluble in cold flakes on cooling

water, but fairly soluble 2. Its natural solution gives a
in hot water, alcohol and white precipitate with silver
ether nitrate, AgNO3
Page

4. Faint aromatic odour 3. Gives effervescence with

PLAN OF WORK:-

5. Readily sublimes sodium bicarbonate, NaHCO3 The

6. Volatile in steam 4. Gives a buff-colour precipitate
with ferric chloride, FeCl3

2. Salicylic acid, E 1. White crystalline solid 1. Dissolves in hot water, but

2. Melting point: 1550C separates as shining whites
3. Sparingly soluble in cold flakes on cooling
water, but fairly soluble 2. Gives effervescence with
in hot water, alcohol and sodium carbonate, Na2CO3, or
ether sodium bicarbonate, NaHCO3,
4. Poisonous in nature releasing carbon dioxide, CO2,
5. Readily sublimes to form sodium salt, sodium
6. Volatile in steam salicylate
3. Gives a violet colour with ferric
chloride, FeCl3, in aqueous
solution
4. Gives 2,4,6-tribromophenol
with bromine water, this
reaction forming the basis of
quantitative estimation of the
acid in medicinal
preparations
3. Sulphur 1. Yellow powder solid 1. Gives characteristic sulphide
2. Melting point: 113-119 0C odour

with Mg as MgS is formed.

2. Vapour from melted sample

gives

pale yellow solid on contact with

a

cold surface.

main aim of our research was to develop a novel cream formulation consisting of
combination of sulfur and salicylic acid and benzoic acid for the treatment of
secondary skin infections.

salicylic acid
 Benzoic acid

Preparation of cream formulation

Preparation of oil phase: -

Cetomacrogol 1000, Cetostearyl alcohol, white soft paraffin and Glyceryl monostearate were melted in a
stainless steel vessel. To this mixture Isopropyl myristate, Liquid paraffin, Butylated hydroxyl anisole were
added and allowed to melt. The temperature of oil phase maintained between 65 – 70°C and salicylic
acid is introduced into the oil phase just prior to addition into the aqueous phase (Table 1).

Preparation of Aqueous Phase

Water was heated to 65 – 70°C. In this weighed benzoic acid were added the temperature of the phase
was maintained at 65 – 70°C. 2.2.3.

Dispersion part: -
sulfur were sieved through appropriate mesh and dispersed in propylene glycol

Development of Cream formulation

Oil portion was then slowly incorporated into the aqueous phase at 65-70°C and mixed for 10 to 15
minutes. Then dispersion part was added into the above part slowly when temperature reaches to 40°C.
pH of cream kept between 3.5 – 4.5.

FORMULATION TABLE:-

Drugs in Percentage (%)/gm/mg

Ingredients
Sulfur
Salicylic acid
Cetostearyl alcohol
Glyceryl monostearate
Liquid paraffin
Propylene glycol
 Isopropyl myristate
Benzoic acid
White soft paraffin
Purified water

Evaluation parameters

Take about 1 gram of cream in a clean petri dish and observe visually.

PHYSICAL EXAMINATION:-
The prepared topical creams were inspected visually for their color, homogeneity,
consistency, spreadability and phase separation. The pH was measured in each
cream, using a pH meter, which was calibrated before each use with standard
buffer solutions at pH 4, 7, 9. The electrode was inserted in to the sample 10 min
priors to taking the reading at room temperature.

VISCOSITY :-
The viscosity of formulated creams was measured by Brook field Viscometer LVD
using spindle S 94 at varying speed and shear rates 6. The measurements were
done over the range of speed setting from 0.10, 0.20, 0.30, 0.40 and 0.50 rpm in
60 s between two successive speeds as equilibration with shear rate ranging from
0.20 s-1 to 1.0 s-1. Viscosity determinations were performed at room temperature.

TUBE EXTRUDABILITY :-

In the present study, the method adopted for evaluating cream formulation for
extrudability was based upon the quantity in percentage cream extruded from
tube on application of finger pressure 7. More quantity extruded better was
extrudability. The formulation under study was filled in a clean, lacquered
aluminium collapsible 5 gm tube with a nasal tip of 5 mm opening and applied the
pressure on the tube by the help of finger. Tube extrudability was then
determined by measuring the amount of cream extruded through the tip when a
pressure was applied on a tube.
DETERMINATION OF DRUG CONTENT :-

To ensure uniform formulation of the cream, it was sampled from the

different locations in the mixer and assayed for the drug content 6, 7. Drug
content of the cream was determined by following method using liquid
chromatography.

MICROBIOLOGICAL STUDIES

Topical formulation with broad, non-resistance promoting activity against

staphylococci, streptococci, dermatophytes or yeast or molds can be of great
use in dermatology preparation were infections are often mixed. Since
formulation containing antimicrobial agents as active moiety, it is likely to
protect from microbial growth 8, 9. To determine the activity of formulation is
subject to study the prepared formulation with standard method called
standard cup plate method and the inhibition zone diameters were measured
with the help of zone reader. Soya bean agar media was used for aerobic
culture and incubated at temperature of 37° C for 48 hours.