In this section, the range of materials being considered may be seen described as retinoids, retinoid types, or retinoid prodrugs. The appropriate description to use will depend on the individual compound being considered, but all the materials are used in topical treatments for acne, and are described in more detail elsewhere.
Retinoids are highly active, and from a formulator ’s viewpoint, often unstable compounds being affected variously by light, heat, and oxygen. There are a number of compounds that fall within this classification, including:
B Tretinoin, [Retin Aw (Johnson & Johnson Corporation, New Jersey, U.S.A.)]
B Isotretinoin, [Accutanew (Hoffman-La Roche Inc., New Jersey, U.S.A.)]
B Adapalene, [Differinw (Galderma S.A., Lausanne, Switzerland)]
B Tazarotene, [Tazoracw (Allergan Inc., California, U.S.A.)]
For many, use in actinic lighting conditions should be avoided, and the raw material and finished product storage vessels should be flushed with nitrogen after use. In emulsion products, care should be taken during manufacture, both to avoid excess heat and to minimize incorporation of air that may lead to longer-term stability problems.
Retinoids are generally insoluble in water, but have varying solubility in alcohol, other solvents, and oils.
Products should be packed for storage and consumers in protective materials such as amber glass, metal, or plastic laminated tubes.
The clinical effectiveness of benzoyl peroxide is well-established and is discussed elsewhere. Benzoyl peroxide is a highly effective oxidizing agent, and contact should be avoided with reducing agents, metals (particularly transition metals), and organic materials to prevent the risk of fire and explosion. Peroxides break
down when heated and are capable of rapidly continuing their decomposition even if the heat source is removed.
Insoluble in water and barely soluble in other solvents, it can most commonly be found in emulsion and gel formats. Ensuring adequate and equal dispersion throughout the formulation is critical. Milling with a colloid mill or high-shear mixers should be undertaken carefully to avoid high levels of heat generation. Mixing equipment should be of stainless steel manufacture and no transition metals, for example, copper collars, should be in contact with the product. Alterna- tively, benzoyl peroxide is dispersed well in a small amount of cooled bulk, under more controllable conditions before adding to the remainder of the product.
Products should be packed in airtight containers to maximize product life. Examples of products in use with this material include:
B Clearasilw Maximum Strength
B Benzac ACw Wash (Galderma Laboratories L.P., Texas, U.S.A.)
B Panoxylw (Stiefel Laboratories Inc., Florida, U.S.A.)
Table 6 shows an example of a cream containing benzoyl peroxide.
The clinical effectiveness of salicylic acid is well-established and is discussed else- where. Salicylic acid is a white crystalline powder showing slight solubility in water but being freely soluble in alcohol. Salicylic acid is most active in its acid form, and formulators should use suitable buffer solutions in formulations to maintain the pH between 2 and 4.
Salicylic acid can be found in most of the formats described earlier under a number of brands, for example, Clearasilw, Clean & Clearw, and Neutrogenaw.
There are a variety of antibiotics used for topical applications and these include Tetracyclines and Macrolides such as Erythromycin. Although they each have unique physical properties and solubility, a common feature is their stability in aqueous solutions. It has been suggested that antibiotics such as erythromycin show increased loss of anti-microbial activity, over time, although this varies with product base (4). Varying pH can change this loss of activity, but, for products requir- ing extended shelf life of greater than a few weeks, alternative solvents or systems should be considered. Antibiotics are also adversely affected by heat and light.
For topical application gels, alcoholic solutions or ointments are the most commonly produced formats. Examples include:
B Akne-Mycinw [Erythromycin (Hermal Kurt Hermann GmbH, Reinbek, Germany)]
B Cleocin Tw [Clindamycin (Pharmacia & Upjohn Company LLC, New Jersey, U.S.A.)]
B Topicyclinew [Tetracycline (Shire LLC, Pennsylvania, U.S.A.)].
Resorcinol is colorless to slightly pink – grey and is very reactive to light and air, turning red when oxidized.
The effectiveness of resorcinol has been recognized and claims that can be made through the use of this material are available (5).
Due to its good solubility in water and alcohol, resorcinol can be incorporated into a wide range of products, including emulsions, being stable to heat at normal emulsification temperatures and times. Manufacturing under vacuum reduces the risk of loss of activity, and products containing this material should be packed in materials with good oxygen barriers.
Examples of products containing resorcinol include Clearasilw Adult Carew
Acne Treatment Cream.
Sulfacetamide has been widely utilized for its antibacterial properties for a con- siderable period of time. In the sodium form, it is a white to off-white crystalline substance showing good solubility in water but reduced solubility in alcohol.
This material can be found in a 10% form in Klaronw (Aventis Pharmaceutical Inc., New Jersey, U.S.A.). Sulfacetamide has also been shown to be effective in com- bination with sulfur (6).
Azelaic acid was first licensed for use in the United States in the late 1990s for mild- to-moderate inflammatory acne. While its exact mode of action remains unclear, it
has antimicrobial properties and is active in reducing hyper keratinization. It has been reported to be active in a number of areas, including against hyper pigmenta- tion, so there may exist a risk of skin lightening (7). Studies have suggested that it has similar activity to other active agents (8).
Azelaic acid is soluble in boiling water and alcohol and is, therefore, able to be formulated into a range of different product types.
Products containing this material include Azelexw (Allergan Inc., California, U.S.A.) and Finevinw (Schering Aktiengesellschaft, Berlin, Germany).
Sulfur is a yellow powder with a characteristic odor and should be stored away from light. It is practically insoluble in water, but shows some solubility in vegetable oils.
Due to its lack of solubility, sulfur must be well-dispersed. High-shear mixing appropriate for dispersing powders or making pastes prior to incorporation in the remainder of the formulation should be considered.
As it is a powder, the overall stability of the product will depend on the effec- tive maintenance of the dispersion. This may be achieved through the appropriate choice of formulation and a good understanding of the rheology of the system to prevent migration and agglomeration of the powder. Although it may be accep- table to allow the consumer to remix the formulation through the process of shaking, the formulator should ensure that adequate dispersion is maintained throughout the shelf life of the product. Although not commonly used, products uti- lizing sulfur include Stiefelw Sulfur Soap (Stiefel Laboratories Inc., Florida, U.S.A.).
Sulfur is often used in combination with other ingredients, for example:
B With resorcinol in products such as Clearasilw Adult Carew Acne Treatment
B With sulfacetamide in Sulfacet – Rw (Aventis Pharmaceuticals Inc., New Jersey, U.S.A.).
Table 7 shows an example formulation utilizing sulfur and resorcinol.
Stability trials are used to identify problems that may affect the long-term quality and safety of the product. Due to the nature of the products under test, a number of testing regimes are possible. In this context, a distinction will be drawn between licensed (whether via prescribing requirements, monograph status, or OTC) and nonlicensed, where the product claims and/or ingredients are such that the product is more cosmetic in nature.
During the normal course of product development, informal testing will be under- taken. This will normally be carried out at a limited number of locations not necess- arily used for formal stability testing, for example, freeze-thaw testing. Testing may be undertaken in glass to allow easy visual assessment of formulation instability, for example, separation, discoloration. Active analysis may be performed, but is not the main focus of this testing.
Formal Stability Testing
Prescribed, Monographed, and Over-the-Counter Drugs
For the purposes of this section, drug products are considered to be those that contain either drugs that must be prescribed by a physician or, in certain countries, by virtue of a monograph or OTC.
Where products are drugs, there are clear reasons for stability testing in a way that conforms to the ICH guidelines in place for drug products (9). These define:
B Number of batches to be tested
B Site of batch manufacture
B Testing protocols
B Degree of testing
B Shelf life allocation
ICH guidelines are updated on a regular basis, and formulators should use a stability-testing regime that conforms to the latest requirements.
Active ingredients are quantified by analysis using validated analytical methods and organoleptic assessment of the product for each temperature location at each time interval. Samples are removed from test and not replaced.
Due to the nature of the product, sign-off for sale and allocation of shelf life should be by an appropriately qualified person, as defined by the relevant legis- lation applicable in the country of intended sale.
There are no clear rules for stability testing of nonlicensed (Cosmetic) products at present. These products will be considered in the same way as mentioned earlier, that is:
B Number of batches to be tested
B Site of batch manufacture
B Testing protocols
B Degree of testing
The products to be formally tested will be determined by the degree of novelty. Where products have been developed from existing products, it is concei- vable that only one laboratory-produced batch would be tested, but it is always good practice to carry out production trials and test samples generated.
An assessment should be carried out to determine the areas that would present most risk to the product stability. A typical testing regime is illustrated in Table 8.
Microbiological testing should also be carried out at regular intervals. Organoleptic testing would be the main test that is carried out, although it is prudent to carry out analysis for the presence of raw materials, where significant claims have been made. Sign-off for sale and allocation of shelf life should be done by someone who has sufficient experience and knowledge to make an objec- tive assessment of the risk of this product failing to conform to its specification, or causing harm for its likely shelf life, and to conform to local regulation.
Safety of the finished product is a primary objective of the formulator. Consider- ation of the safety of the product should be an iterative process with consideration and review at all stages of the product’s development.
Safety assessment takes place at three levels:
B Assessment of formulation raw materials and existing formulation adverse event/sales ratio
B Initial evaluation of the formulation to assess need for safety testing
B Assessment of formulation for suitability for in vivo trial or sale
New raw materials or materials being used in a novel way should be screened for potential safety issues. This will include detailed scrutiny of the Material Safety Data Sheet (MSDS), and the formulator should always discuss the implications with an expert in the field such as a toxicologist or medical practitioner. For licensed pro- ducts, new raw materials (drugs and excipients) will require a full toxicological package to be provided to the appropriate regulatory body.
A record of adverse events that may have an impact on the safety should be maintained on all products sold. In some countries, this is a mandatory requirement and forms good practice if it is not. This serves two purposes:
B It allows ongoing assessment of the safety of the product to be made
B It provides a means by which existing formulations can be assessed for safety before further development
The figures stored within the database should be used with the number of products sold to determine the degree of the potential problem and whether the base could be used. Monitoring of existing formulations allows reformulation to be rapidly undertaken, should adverse events rise to an unacceptable level. All reports related to safety issues should be investigated further, as it is important that only true adverse reactions are considered.
If a formulation is judged to be different from known base formulations, safety testing should be carried out. These may take the following forms:
B In vitro tests for example:
. 3-D human skin model to measure the effects on cell viability.
. 3T3 NRU photo toxicity test to measure the number of cells that survive after exposure to the test chemical and UV light, compared with the number that survive after exposure to the chemical in the absence of UV light.
B Transcutaneous electrical resistance (TER) procedure to measure skin corrosiv- ity through electrical properties.
B Repeat Insult Patch testing on human volunteers to assess the irritancy potential of the formulation. Such studies should always be undertaken under the super- vision of medical practitioner and with appropriate ethical approval.
B A user trial (controlled or uncontrolled) on a group of people.
Once the testing is complete, the product should be assessed to decide whether it is safe for sale. This may involve submission to a regulatory authority.
For products where this is not the case, assessment should be made by a suit- ably qualified and experienced assessor. There are published guidelines and requirements in certain countries as to the qualifications needed by these individ- uals (10,11). Formulators should always ensure that local regulations regarding this important aspect of developing a new product are met.