Industrial PharmacyLec. 10 Husam Tizgam

Semisolid Dosage Forms

Ointments, creams, and gels are semisolid dosage forms intended for topical

application. They may be applied to the skin, placed on the surface of the eye, or used

nasally, vaginally, or rectally. Most of these preparations are used for the effects of the

therapeutic agents they contain. The unmedicated ones are used for their physical effects

as protectants, emollients or lubricants.

Topical preparations are used for both local and systemic effects. To distinct between

them, one should follow the following important role: A topical dermatological product

is designed to deliver drug into the skin in treating dermal disorders, with the skin as the

target organ. A transdermal product is designed to deliver drugs through the skin

(percutaneous absorption) to the general circulation for systemic effects, with the skin

not being the target organ.

Ointments

Ointments are one of the most commonly used semisolids. They compose of active

ingredient and ointment base. Ointment bases are used as vehicles for medicated

ointments.

Ointment Bases

Ointment bases are generally classified into four groups:

(a) Oleaginous bases.

(b) Absorption bases.

(c) Water-removable bases.

(d) Water-soluble bases.

1

Oleaginous Bases

Oleaginous bases are also termed hydrocarbon bases. On application to the skin, they

have an emollient effect and protect against the escape of moisture. They can remain on

the skin for relatively long periods without drying, and because of their immiscibility

with water are difficult to wash off. Water and aqueous preparations may be

incorporated, but only in small amounts and with some difficulty. Petrolatum (Vaseline)

is an example of hydrocarbon bases. When powdered substances are to be incorporated

into hydrocarbon bases, liquid petrolatum (mineral oil) may be used as the levigating

agent.

Absorption Bases

Absorption bases (or emulsion bases) are those that permit the incorporation of

aqueous solutions resulting in the formation of W/O emulsions. They have the capacity to

absorb water up to three times their weight. Absorption bases are not easily removed

from the skin by washing, because the external phase of the emulsion is oleaginous.

Absorption bases are useful to incorporate small volumes of aqueous solutions and are

used mostly in the preparation of ophthalmic ointments.

Water-Removable Bases

Water-removable bases are O/W emulsions resembling creams. Because the external

phase of the emulsion is aqueous, they are easily washed from skin. They may be diluted

with water or aqueous solutions.

Water-Soluble Bases

Water-soluble bases do not contain oleaginous part (greaseless). They are completely

water washable. Because they soften greatly with the addition of water, large amounts of

aqueous solutions cannot be incorporated into these bases (only small amounts of

aqueous solutions). They mostly are used for incorporation of solid substances.

Polyethylene glycol ointment is the prototype example of a water-soluble base.

2

PEGs having molecular weight below 600 are clear, colorless liquids; those with

molecular weight above 1,000 are waxy solid materials; and those with molecular weight

in between are semisolids and used in ointments.

Selection of the Appropriate Base

It depends on careful assessment of a number of factors such as:

• Desired release rate of the drug substance from the ointment base.

• Desirability of topical or percutaneous drug absorption.

• Desirability of occlusion of moisture from the skin.

• Stability of the drug in the ointment base.

• Effect of the drug on the consistency or other features of the ointment base.

• Desire for a base easily removed by washing with water

• Characteristics of the surface to which it is applied

For example, an ointment is generally applied to dry skin; a cream is applied to weeping

surfaces.

Preparation of Ointments

Ointments are prepared by two methods, depending on the nature of the ingredients:

1. Incorporation method: the active ingredient and the ointment base are mixed together

until a uniform preparation is obtained. On a small scale, the pharmacist may mix the

components using a mortar and pestle, or a slab and spatula. On large scale (up to 1500

kg), ointments are manufactured in stainless steel tank which has a built-in mixer.

Before the incorporation of the active ingredient, it is often desirable to reduce the

particle size of any powder (if any) so the final product will not be gritty. Alternatively,

solids may first be dissolved in small amount of a solvent (e.g., water or alcohol) and the

solution is then mixed with the ointment base. Alcoholic solutions of small volume may

be added easily to both oleaginous or emulsion bases.

Liquid drugs are added to an ointment only after consideration of an ointment base’s

capacity to accept the volume required. For example, only very small amounts of an

3

aqueous solution may be incorporated into an oleaginous ointment, whereas absorption

bases readily accept more amounts of aqueous solutions. When it is necessary to add an

aqueous preparation to a hydrophobic base (such as oleaginous base), the solution first

may be incorporated into a minimum amount of a hydrophilic base (such as absorption

base) and then this mixture is added to the hydrophobic base. However, all bases, even if

hydrophilic, have their limits to retain liquids, beyond which they become too soft or

semiliquid.

2. Fusion method: by the fusion method, all or some of the components of an

ointment are melted together and cooled with constant stirring until congealed.

Components that not melted at the beginning (e.g. heat sensitive and volatile substances)

are added last to the congealing mixture as it is being cooled and stirred. Ointments

containing components such as beeswax, paraffin, stearyl alcohol and high molecular

weight PEGs, which cannot be mixed well by incorporation method, are prepared by

fusion.

Preservation

With the exception of ophthalmic preparations, topical preparations usually are not

required to be sterile. However, preparations that contain water tend to support microbial

growth to a greater extent than water-free preparations and may therefore, require

preservation.

Creams

Creams are semisolid preparations containing a medicinal agent dissolved or

dispersed in emulsion. After application of the cream, the water evaporates, leaving

behind a thin film of the oleaginous component.

Creams have applications in topical skin products and in products used rectally and

vaginally. Many patients and physicians prefer creams to ointments because they are

easier to spread and remove. Pharmaceutical manufacturers frequently manufacture

4

topical preparations of a drug in both cream and ointment bases to satisfy the preference

of the patient and physician.

Gels

Gels (sometimes called jellies) are semisolid preparations consisting of medicinal

agent dispersed in aqueous liquid rendered jelly-like by the addition of a gelling agent.

Among the gelling agents used are carbomer, CMC or HPMC. Gels may thicken on

standing and must be shaken before use to liquefy the gel and enable pouring.

Medicated gels may be prepared for administration by various routes, including the

skin, the eye, the nose, the vagina, and the rectum.

Transdermal Drug Delivery Systems

Transdermal drug delivery systems (TDDS) are designed for the passage of drugs

through the skin into the general circulation for their systemic effects. TDDS may be

ointment, cream, gel or patch. However, transdermal patches are the most commonly

used type, e.g., nitroglycerin patches, nicotine patches and estradiol patches.

Percutaneous absorption of a drug generally results from penetration (passive

diffusion) of the drug through the stratum corneum. After the stratum corneum, drug

molecules may pass through the deeper epidermal tissues and into the dermis. When the

drug reaches the vascularized dermal layer, it becomes available for absorption into the

general circulation.

Normal unbroken skin acts as a natural barrier, limiting both the rate and degree of

drug penetration. The skin is divided into three layers: the stratum corneum (the outer

layer), the living epidermis, and the dermis. These layers form barriers against the

permeation of external agents and loss of water from the body. Sebaceous glands, sweat

glands, and hair follicles originating in the dermis and subcutaneous layers rise to the

skin’s surface.

5

The stratum corneum is the horny layer which is dead epidermal cells. It is composed

of 40% protein (mainly keratin) and 40% water, with the remaining 20% being lipid. The

stratum corneum, being keratinized tissue, behaves as a semipermeable membrane. Hair

follicles and gland ducts can provide rapid entry for drugs, but because their relative

surface area is so small compared to the total epidermis, they have little effect on drug

absorption.

Drug blood levels achieved by transdermal delivery systems may be measured (by

calculating the AUC) and evaluated against desired standard formula; but the same is not

true for topical nonsystemic products. For topical preparations, the therapeutically

effective drug concentration in the skin is not known, so treatment is based on qualitative

measures.

Factors Affecting Percutaneous Absorption

Not all drug substances are suitable for transdermal delivery. Among the factors

playing a part in percutaneous absorption are the physical and chemical properties of the

drug, including its molecular weight, solubility, partitioning coefficient and dissociation

constant (pKa), the nature of the vehicle, and the condition of the skin. Generally, the

most important factors affecting percutaneous absorption are:

1. Drug concentration is an important factor. Generally, the amount of drug absorbed

increases with an increase in the concentration of the drug in the TDDS.

6

2. The drug should have a greater attraction to the skin than to the vehicle so that the drug

will leave the vehicle in favor of the skin. Some solubility of the drug in both lipid and

water is essential for effective percutaneous absorption. The aqueous solubility

determines the drug concentration that is ready for absorption while the lipid solubility

influences the rate of transport across the skin. Accordingly, drugs penetrate better in

their unionized form.

3. Drugs with molecular weights of 100 to 800 can penetrate skin. The ideal molecular

weight of a drug for transdermal drug delivery is believed to be 400 or less.

4. Hydration of the skin generally increases percutaneous absorption. Therefore, TDDS

that utilizes an occlusive base may have more absorption than non occlusive types.

5. Percutaneous absorption is greater when the TDDS is applied to a site with a thin

horny layer than with a thick one.

Absorption Enhancers

These are chemical permeation enhancers and physical methods that can increase

percutaneous absorption of therapeutic agents.

Chemical Enhancers

A chemical penetration enhancer increases skin permeability by reversibly altering the

physicochemical nature of the stratum corneum to reduce its diffusional resistance.

Among the alterations are increasing hydration of the stratum corneum, a change in the

structure of the lipids and proteins denaturation.

More than 275 chemical compounds have been listed in the literatures as skin

penetration enhancers; e.g., acetone, dimethyl sulfoxide, ethanol, polyethylene glycol,

and sodium lauryl sulfate. The selection of a permeation enhancer should be based not

only on its efficacy in enhancing skin permeation but also on its dermal toxicity and its

compatibility with the other components in the dosage form.

7

Physical Methods

In addition to chemical means, some physical methods are being used to enhance

transdermal drug delivery and penetration, namely, iontophoresis. Iontophoresis is

delivery of a charged compound across the skin membrane by using an electrical field. A

number of drugs have been the subject of iontophoretic studies; e.g., dexamethasone,

propranolol, peptides, and insulin. It shows some success in peptide and protein

administration.

Release Study

To study the release of drugs from TDDs, the following methods are used:

1. In vivo method: by taking blood samples and finding the amount of drug absorbed.

2. In vitro method: skin permeation may be tested using various skin tissues (human skin,

animal skin, or artificial skin) in a diffusion cell. In these systems, skin membrane or

synthetic membranes may be employed as barriers to simulate the biologic system. The

diffusion cell has two chambers, one on each side of the membrane.

A temperature-controlled solution of the drug is placed in one chamber and a receptor

solution in the other chamber. When skin is used as the test membrane, it separates the

two solutions. Drug diffusion through the skin may be determined by periodic sampling

and assay of the drug content in the receptor solution. The skin may also be analyzed for

drug content to show permeation rates and/or retention in the skin.

FIGURE: Franz diffusion cell.

8