| PHARMACOLOGY AND TERMINOLOGY OF TOPICAL PREPARATIONS
1. BASIC PHARMACOLOGY
Knowledge of different forms and physicochemical properties of drugs, and nature of the skin is important as all these can affect percutaneous drug absorption. The interplay of these factors ultimately affects the therapeutic efficacy. Moreover, correct drug mixing and drug storage not only improves efficacy but saves money too.
Some practical points on percutaneous drug absorption are discussed below :
1.1 Routes of Percutaneous Drug Absorption
All topical preparations must make their way into the skin before they can exert effects.
Percutaneous absorption involves :
(i) Dissolution of the drug in its vehicle,
(ii) Diffusion of the drug from the vehicle to the surface of the skin, and
(iii) The actual penetration of the drug through the different layers of the skin.
Percutaneous absorption may be effected by the following routes :
(i) Transcellular diffusion
(ii) Diffusion through channels between the epidermal cells
(iii) Diffusion through sebaceous ducts
(iv) Diffusion through the hair follicles
(v) Diffusion through the sweat ducts
Passage of the drug through the stratum corneum is often the slowest step in the process and hence the rate-limiting step in percutaneous absorption.
1.2 Factors Affecting the Absorption of Topical Drugs
1.2.1 Nature of the Skin
The stratum corneum that consists of 40% protein, 40% water and 20% lipids is the rate-limiting barrier. Skin with a disrupted epidermal layer allows up to 80% of hydrocortisone to pass into the dermis but only 1% is absorbed if the skin is intact.
Hydration of the skin also increases drug penetration as hydration causes swelling of the stratum corneum rendering it more permeable to drug molecules. The use of occlusive dressings can increase the hydration by preventing water loss by perspiration.
Increased absorption also occurs in flexural surfaces, face and scrotum because of the thin stratum corneum.
Drug penetration is generally greater in infant and in elderly because they have thinner stratum corneum.
1.2.2 Nature of the Pharmaceutical Product
This refers to the active drug concentration in the preparation, the composition and physicochemical properties of the active component and the base vehicle.
Lipid soluble compounds are more easily absorbed than water soluble ones because the former can diffuse through lipids within the stratum corneum.
Take triamcinolone as an example; triamcinolone acetonide has a topical activity 1,000 times that of the parent steroid because of its high lipid solubility. Similarly, 0.1% hydrocortisone butyrate (Locoid) cream is more potent than 1% hydrocortisone acetate cream.
Topical medicaments can be available in a variety of physical forms; e.g., ointment, cream, lotion, paste and gel etc. Different forms of the same drug have different activities; e.g., betamethasone valerate is more active as an ointment than as a cream.
1.3 Drug Mixing & Drug Storage
1.3.1 Efficient drug mixing is important because it ensures uniformity of dosage.
(i) Mixing of Liquids :
Simple stirring and shaking is sufficient to produce a completely homogeneous mixture provided that the ingredients are miscible.
(ii) Mixing of Solids with Liquids :
The solubility of the solid has an important effect on successful mixing.
(iii) Mixing of Solids :
A good mixing device is required to ensure ample space for thorough mixing. This is achieved by allowing movements of particles to take place in all directions.
If small quantities of powders are mixed in equal proportions, mixing can be effected by simple rotation or shaking in a jar.
Where a small quantity of medicament is incorporated in a large bulk of powder, mixing is best achieved by geometric dilution1.
For incorporation of a medicament in a semi-solid basis, the most convenient method is by fusion of the semi-solid ingredients on a water-bath to produce a liquid mass. Any insoluble medicaments to be incorporated must be in fine power. The mixture is then stirred continuously until cold in order to avoid segregation of the components as setting occurs.
1.3.2 Most of the commercial preparations is labelled with expiry dates.
The 'normality' of a medicament can be assessed by our vision, but it is not accurate.
The longevity of a medicament is governed by its Shelf-life . Shelf-life of a drug is the duration from the time the product is manufactured till the potency of the drug has been reduced by 10%. This limit is usually considered acceptable in practice; more stringent standard is required if the degradation products are more toxic or irritative than the parent drugs.
Products with a shelf-life of more than 3 years are considered to be 'stable' as these are expected to sold and used within his period. Products with a shorter half-life should be labelled with expiration date2.
As a guide to good pharmaceutical practice it is suggested that mixtures recommended to be 'freshly prepared' should be prepared not more than 24 hours before issue to the patient. Mixtures recommended to be 'recently prepared' should be stored in unopened bottles in the dispensary for not more than 3 months. Should there be any doubt, the pharmacist should be consulted.
1.3.3 Environmental factors that may affect the chemical stability of a drug :
(i) pH - affect rate of chemical reaction and hence longevity of a drug.
(ii) Temperature - An increase in temperature usually increases the rate of chemical reaction. Storage of a medicine in a cool place (below 15 C) will prolong the shelf-life. Refrigeration may prolong shelf-life of a medicament that is unstable in room temperature but solid particles may grow and precipitate in a suspension. The temperatures suitable for storage of topical drugs lies in the range of 15-25 C.
(iii) Oxygen - Many drugs show slow oxidation in the presence of atmospheric oxygen. If the rate of degradation is significant, the addition of an anti oxidant may be needed.
(iv) Light - Can induce photochemical degradation. This can be reduced by the use of light-resistant containers, or more effectively, by storage in the dark.
(v) Humidity - Low humidity may be responsible for the powdering of granular solids containing effervescent salts and for the 'drying out' of creams. High humidity brings about the deterioration of effervescent tablets and solid preparations that contain hygroscopic materials. The adverse effects of humidity can be avoided by the use of moisture-proof containers.
(vi) Pharmaceutical containers :
(a) The basic requirement for a container is that it should not interact with the formulation. Glass, plastics are commonly used components of containers.
Glass containers have some disadvantages, e.g., leaching of alkali and insoluble flakes into the formulation; these can be offset by the choice of an appropriate glass material.
Plastic containers are convenient to handle but the major disadvantage is the two-way permeation or 'breathing' through the container walls. Volatile oils, perfumes and flavouring agents can permeate through plastics to some extent. Components of emulsions and creams have been reported to migrate through the walls of some plastics causing either a deleterious change in the formulation or collapse of the container. Loss of moisture from a formulation is also common.
(b) Closure must form an effective seal for the container. It must not react chemically nor physically with the formulation. Rubber is a common component of stoppers, cap liners, and parts of dropper assemblies. Absorption of the active ingredients, preservatives into the rubber and the extraction of one or more components of rubber into the formulation is a common problem.
The application of an epoxy lining to the rubber closure reduces the amount of leached extractives but has no effect on the absorption of the preservative from the solution. Teflon-coated rubber stoppers may prevent most of the leaching and absorption.
Notes :
1. Geometric dilution :
The medicament is first mixed with an equal weight of diluent; a further quantity of diluent equal in weight to the mixture is then incorporated. The process is repeated until all the diluent has been added.
2. Expiration date is defined as the time in months and years after which a drug product is expected to be subpotent or to be degraded under designated storage condition.
2. COMMON TERMINOLOGY IN TOPICAL THERAPEUTICS
A correct choice of a medicament for a dermatologic condition means a correct choice of an active ingredient with an appropriate companion vehicle base. It is well recognised that the properties of a base can influence the activities of the active ingredient and hence the therapeutic efficacy.
Explanation for some common terms for different forms of topical preparations is given below (arranged in alphabetical order) in an effort to make them more familiar and understandable to doctors and health personnel.
2.1 Astringents
Are substances that check oozing, discharge or bleeding when applied to the skin or mucous membranes and work by coagulating protein. The protein precipitate which forms serve as a protective coat, allowing new tissue to regenerate underneath. They are commonly used to reduce the extent of weeping in dermatitis. Zinc oxide, calamine lotion and Burrow's solution (aluminium acetate) are common astringents.
2.2 Collodions
Are liquid preparations consisting of a solution of proxylin in a mixture of ether and alcohol. When collodions are painted on the skin and allowed to dry they leave a flexible film over the site of application. Collodions may be used to seal minor cuts and wounds or as a mean of holding a dissolved drug in contact with the skin for a long time.
2.3 Creams
These are either water-miscible and readily washed-off, or oily and not so easily washed off. Creams are less messy and less occlusive than ointments, and are suitable for use in the flexural or napkin areas. They are the preferred form of treatment for exudative dermatoses and for use under wet dressings. Since creams contain water, they are liable to fungal and bacterial contaminations and therefore preservatives are usually added. Commonly used preservatives are chlorocresol and hydroxybenzoates, both of which may cause skin allergy.
Barrier creams often contain water-repellent substances such as dimethicone or other silicones. They give protection against irritation or repeated hydration and is useful in the treatment of napkin rash and bedsores, etc.
Creams can only be diluted with suitable diluents specified in the appropriate entries and diluted creams must be freshly prepared without the application of heat. Creams should be stored in cool place and supplied in well-closed containers that prevent evaporation and contamination of the contents.
2.4 Emollients
Are fats or oils in a two-phase system (one liquid is dispersed in the form of small droplets throughout another liquid). Emollients soften the skin by forming an occlusive oil film on the stratum corneum, thus preventing drying from evaporation from the deeper layers of skin. Thus, emollients are employed as protectives and as agents for softening the skin and rendering it more pliable in conditions like dry eczema, ichthyosis and psoriasis. They also serve as vehicles for more active drugs.
2.5 Gargles
Are aqueous solutions, usually in concentrated forms intended for use, after dilution, for treatment of affections of oral cavity and throat. Gargle is commonly used to alleviate painful and inflammatory conditions of the oral cavity including tonsillitis, oral candidiasis, herpes gingivostomatitis, radiation mucositis, blistering diseases affecting the oral cavity, aphthous ulcers, post orosurgical and periodontal procedures etc. A gargle does not, however, act as a protective covering to mucous membranes.
Examples of gargles are Thymol gargle, Chlorhexidine gargle and Difflam gargle. In the treatment of mucositis, try to avoid a gargle that contains a high concentration of alcohol as it may produce irritation.
2.6 Gels
Are semisolids or solids prepared from high molecular weight polymers in an aqueous or alcoholic base. They are easy to apply and wash off. Gels are useful for promoting wound granulation (e.g., Actovegin Jelly), in treatment of acne (e.g., Panoxyl gel) and scalp psoriasis (e.g., Synalar gel mix). Due to their drying effect and especially the alcoholic ones, they may cause irritation to the skin.
2.7 Humectants
Are substances that promote water retention due to their hygroscopicity. They act by being absorbed into the skin and attract water from atmosphere and serve as a reservoir for the stratum corneum. Commonly used humectants are propylene glycol and glycerin.
2.8 Liniments
Is viscous liquid containing substances possessing analgesic, soothing or stimulating properties when applied on the skin. They are usually made with a base of oil, alcohol, or soap solutions, e.g., methyl salicylate liniment. Liniments should not be applied to broken skin.
2.9 Lotions
Are aqueous solutions or suspensions that cool diffusely inflamed unbroken skin. They cool by evaporation and should be applied frequently. Lotions are also used to apply drugs to the skin when only a thin layer of the preparation is intended to apply over a large surface area. Shake lotions (e.g., calamine lotion) that contain insoluble powders are applied to less acute, scabbed, dry lesions. In addition to cooling, they leave a deposit of inert powder on the skin surface.
2.10 Ointments
Are semisolid substances that are greasy, normally anhydrous and insoluble in water. The most commonly used ointment bases consist of soft paraffin or a combination of soft paraffin with liquid paraffin and hard paraffin. Due to their anhydrous nature ointments do not require any preservatives. They have the advantages of being moisturizing, more occlusive than creams and forming a protective film over the skin. The occlusive effect tends to prolong and enhance drug penetration. They are, however rather messy to use.
Today, there are ointments that possess both hydrophilic and lipophilic properties so that they become water soluble and readily washed off. Ointments are very useful particularly for chronic, dry skin lesions. Ointments should be diluted to the required strength with the suitable diluent in the relevant entry. They should be kept in well-closed container that prevents evaporation and contamination in a temperature not exceeding 25C.* The material making up the container should be resistant to absorption or diffusion of the contents.
2.11 Pastes
Are stiff preparations containing a high proportion of finely powdered solids such as zinc oxide and starch. They are less occlusive than ointments and can be used in subacute, lichenified, or excoriated skin conditions. Due to the stiff nature, they can be applied accurately to a particular lesion such as chronic eczema and psoriasis, and are therefore useful for the local application of irritating drugs.
2.12 Spirits
Are alcoholic or hydroalcoholic solutions of volatile substances prepared usually by simple solutions or by admixture of the ingredients. Spirits require storage in tight, light-resistant containers to prevent loss by evaporation and to limit oxidative changes.
2.13 Suspensions
Are preparations of finely divided, undissolved drugs dispersed in liquid vehicles. The particulate matter of a suspension may settle slowly from the liquid vehicle in which it is dispersed and therefore suspensions should be shaken well before use to ensure uniform distribution of solid in the vehicle and thereby uniform and proper dosage. Suspensions require storage in tight containers.
2.14 Tinctures
Are alcoholic or hydroalcoholic solutions prepared from vegetable materials or from chemical substances. Tinctures require storage in tight, light-resistant containers, away from direct sunlight and excessive heat. Podophyllin tincture and iodine tincture are examples.
* This may explain the difference in shelf life for the same ointment in areas of different latitude if stored in ambient temperature.
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