Cutaneous preparations

A main challenge of processing an active substance if it is not dissolved is the dispersion of the particles. This affects many dosage forms such as oral suspensions, cutaneous preparations and suspension-type suppositories. It appeared that this process could be performed in different ways on a small scale, making a difference in the result. It was felt justified to use different words for these different ways. Table 1.1 (also as Table 29.4) shows the result. 

In the case of medicines for cutaneous use (e.g. dermatology medicines), the concentration of the active substance is usually written as a percentage. The prescriber writes the amount and the frequency with which the dermatologic medicine has to be applied. The doctor usually writes the part of the body on which the patient should apply the preparation. In this way the pharmacist can check whether the prescribed amount is sufficient. Furthermore it is also important to know whether the cutaneous medicine has to be applied thickly (liberally) or thinly. A practical device for dosing a cutaneous preparation is the fingertip unit (FTU), see Table 12.3. In Germany, the Neues Rezeptur-Formularium for doctors [7] contains a useful outline figure for the prescriber to mark the area of application (Fig. 2.7). 

The preparation of semisolid oromucosal preparations is the same as that of cutaneous preparations (see Sect. 12.6). The same is true for the in process controls. 

Release controls for nasal ointments and gels are similar to those on the corresponding cutaneous preparations, i.e. gels and creams (see Sect. 12.6.5). 

Finally, semisolid preparations for rectal and vaginal administration are focused on. Little difference exists from the corresponding cutaneous preparations and they are only discussed as far as there are specific requirements. 

Preparations for cutaneous (or dermal) application may be used for local treatment as well as for transdermal administration with a systemic effect. The chapter focuses on preparations with a local effect and on design of formulation and method of preparation of those prepared in pharmacies. The interaction between skin, active substance and base, the anatomy of the skin and biopharmaceutical aspects of cutaneous preparations are discussed as well as the therapeutic effect of the base. Because of the important role of the pharmacist in prescription assessment some recommendations for the communication with the physician are given. One aspect is how to proceed with a request for the mixing of two licensed medicines or for the addition of an active substance or an excipient to a licensed product. The formulation design is generally following the several phases of the multicomponent preparations. Based on the... 

The following general recommendations may be helpful for handling prescriptions of cutaneous preparations ... 

Is combination or adaptation of licensed products aimed at a better adherence, it is to be preferred that physician and pharmacist give clear advice about the administration of the original products or start from a standard pharmacy formulation. For the instruction of patients where, how, how often and how long to apply cutaneous preparations, a special form with an outline figure may be helpful, see Fig. 2.5. 

Prescribing extemporaneous cutaneous preparations is a privilege that many physicians appreciate as weU as some... 

In the eighth edition of the European Pharmacopoeia cutaneous preparations are classified as liquid preparations for cutaneous application, semisolid preparations for cutaneous application and powders for cutaneous application [4]. 

Ointments are cutaneous preparations consisting of one phase, hydrophilic or hydrophobic, in which a solid phase may be dispersed. They are subdivided in hydrophobic ointments, water-emulsifying ointments and hydrophilic ointments. 

Official definitions for the different types of cutaneous preparations are given in the European Pharmacopoeia (Ph. Eur.). But in the physicians practice, in licensed... 

In cutaneous preparations the base as such has an influence on the therapeutic effectiveness. It also very much influences the therapeutic effect of the active substance... 

The base of a cutaneous preparation also influences the rate and extent of absorption. The base can be simple, such as an aqueous solution, but can also be very complex such as an emulsion. The base can alter the skin conditions, for example by hydration. As a result, the penetration of the active substance into the skin may be modified. 

Ultimately, the release and penetration of active substances from cutaneous preparations is difficult to predict. 

Cutaneous preparations for the skin should contain the base as such or the base has to be formed from lidocaine hydrochloride. Three concepts may be followed ... 

The base of cutaneous preparations does not only influence the release of the active substance, it can contribute to the therapeutic effectiveness of the preparation itself. In some cases the base alone may sufficiently influence healing, by which the addition of an active substance is unnecessary. In such cases the physical properties of the base are utilised, such as cooling dehydration or protection by indifferent solids prevention of dehydration by hydrophobic components. The correct choice of the base is very important for wet and dry skin disorders. If the... 

Usually the base of a cutaneous preparation is prescribed by the physician. But sometimes the pharmacist is free to choose it on his own authority. Both, physician and pharmacist, have to take the following factors into consideration ... 

In modem wound management aqueous solutions (irrigatiOTis) and hydrogels are mentioned to be applied on deep and chronic wounds. Other preparations such as creams ointments and powders are described as well but have some disadvantages. Components of these preparations may not be removed from the wound easily and HpophUic compounds can hinder secretion. Cutaneous preparations with zinc oxide should not be used on open wounds because... 

If the cutaneous preparation is going to be applied because of its physical properties, such as the prevention of dehydration, ample application is desirable. If the preparation is mainly acting by its active substance, the amount to be applied is expressed in fingertip units to prevent underdosing when the patient is told to apply thin , as well as overdosing [9],... 

How long a cutaneous preparation has to be used depends on the disorder and the typical period in which an active substance reaches its therapeutic effect. Usually corticosteroids or antibiotics should be applied for only a few days if applied every day. The treatment with an antimycotic may take a longer time. In general the physician should see the patient regularly to assess the effectiveness of the therapy. The preparation should therefore be prescribed in a limited amoimt appropriate to the treatment scheme. 

Cutaneous preparatimis are inefficient formulations since only small amounts of the applied active substance penetrate the skin and reach the site of action. The first attempts to understand the mechanism of skin permeation and formulation effects of cutaneous preparations were described in 1960 [10]. Since then more research has been performed on rational design of dermal formulations. Much research is focused on improved skin penetration [11, 12]. Skin... 

Skin permeation of the active substance after application of cutaneous patches is enhanced compared to conventional cutaneous preparations because of the occlusive effect of the patch. In this way relatively high concentrations in the skin are obtained. In contrast to transdermal patches plasma concentrations will be low and no systemic side effects are observed. 

Adverse effects of cutaneous preparations may be undesirable systemic effects, (photo) toxicity, irritation or (photo) allergic responses after sensitisation. Substance monographs [15], package leaflets or SmPCs of licensed products and medicine databases give information about these adverse effects. 

Toxic systemic effects have been reported for salicylic acid, resorcinol, lindane or mercury substances. These effects are related to the substance, the amount of preparation and the body surface area to which it is applied, the skin conditions and duration of treatment. Symptoms for systemic intoxications are for example headache, nausea and vomiting, convulsions, fall in blood pressure, kidney damage or metabolic acidosis. Apart from salicylic acid the mentioned substances are no longer used because of these systemic adverse effects and the limited therapeutic significance in cutaneous preparations. Especially infants and toddlers are susceptible for systemic adverse effects because their skin is thinner. Additionally, the relative body surface area in relation to body contents in children is larger than in adults. For salicylic acid in infants and toddlers the only indication is psoriasis. It should be used in low concentrations and on a limited body surface area. 

Cutaneous preparations may consist of a simple or a more complex formulated base in which one or more active substances can be dissolved, dispersed or mixed. Bases often contain several phases a solid phase, an aqueous, a lipophilic phase and an interphase. In this section the properties, function and excipients of each phase are discussed. Active substances or excipients may make up the solid phase. The aqueous phase may contain the active substance, excipients that improve the microbiological stability or sometimes excipients that improve physical stability of the preparation. The lipophilic phase influences and improves the consistency of the cutaneous preparation. If there is an aqueous and a lipophilic phase in the preparation. 

In practice the more stable ponderosum quality can be dispersed in cutaneous preparations anyway by firstly triturating with water in a mortar with a pestle. It is likely that due to the water the outer layer of the tetracycline hydrochloride particles dissolves causing the particles to disperse. 

The particle size of solid substances of both excipients and active substances is important not just for biopharmaceutical properties (see Sect. 12.3.2) but also for the physical and chemical properties of cutaneous preparations. If the solid is dispersed in a liquid base, the particles must be sufficiently fine to obtain a physically stable suspension (see Sect. 18.4.2). However decrease of particle size may increase the rate of degradation. Additionally processing small particles may lead to agglomerates. 

Many solid raw materials are meant to be used in cutaneous preparations are processed in their micronised state (see Sect. 23.1.8 for definitions) mainly for improving the release of the active substance (see Sect. 12.3.2). 

Apart from the general descriptions in Chap. 23, some details, also on function, are given on the most important solid excipients for cutaneous preparations ... 

Zinc oxide is an astringent. It dries, cools and protects the skin and is weakly antibacterial. It may be used in nearly all types of cutaneous preparations. However, it is unsuitable for the hairy skin because it cannot be washed out. 

Hydrocarbons such as liquid paraffin and white soft paraffin are also called mineral oils. They hardly penetrate the skin and in cutaneous preparations they are mainly used for protection of the surface of the skin or occlusion. They absorb little or no water. Because they cover the skin they prevent evaporation of water and hydrate the skin. Hydrocarbcais are used in lipophilic creams, hydrophobic ointments and pastes. 

In chemical terms fatty oils and fats are esters of glycerol and fatty acids. Arachidis oil and Miglyol 812 (medium chain triglycerides) are examples of often used fatty oUs. In contrast to hydrocarbons they are biodegradable. They hardly absorb water but cover the skin less extensive than the hydrocarbons. Fatty oils and fats reduce the viscosity of semisolid cutaneous preparations and improve their spread-ability. They are used in soft pastes for example. 

Water easily evaporates from warm skin. Due to evaporation a cutaneous preparation looses its characteristics. To prevent water loss humectants are added. Humectants are non-volatile solvents that prevent water loss during storage as well as after application to the skin. Examples are propylene glycol, glycerol 85 % and sorbitol 70 %. Humectants are often used in cutaneous suspensions, hydrophilic creams and hydrogels. 

To ensure the microbiological quality of cutaneous preparations the following measures should be taken ... 

Table 23.21 gives an overview of preservatives. For cutaneous preparations as said sorbic add and methyl... 

Chemical degradation in cutaneous preparations usually concerns oxidation (see Sect. 22.2.2) and hydrolysis (see... 

Oxidising agents in cutaneous preparations may be active substances (benzoyl peroxide), peroxides from the base, oxygen from the air, light and ions of heavy metals. Oxidation is promoted by an increase in pH and temperature. 

An example of a cutaneous preparation in which an antioxidant - butylhydroxytoluene - is added to prevent oxidation of the active substance is a tretinoin cutaneous solution (Table 12.11). During preparation tretinoin has to be protected from light and no metal utensils should be used. 

The complexity of many cutaneous preparations may cause incompatibilities. This may lead to an excipient not functioning and an active substance being not effective anymore, hi literature [28, 29] many excipients and their incompatibilities are described. 

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