DRUG DISCOVERY/DEVELOPMENT/DELIVERY

Topical drug development:
Formulation through preclinic

Betsy Hughes-Formella, PhD and Daniel Bucks, PhD, Directors, Business Development and Consultings, bioskin GmbH

Bronaugh Flow -Through Diffusion Cell

Topical drug development is a multidisciplinary process requiring assimilation of input from multiple areas of expertise: research and development, non-clinical / toxicology, clinical, marketing and regulatory affairs. To be successful, the therapeutic needs and expectations of both clinicians and patients must be met in a safe and efficacious final product, which also meets the stringent requirements of the licensing authorities.

The following overview briefly details some of the key processes associated with topical development programmes up to entry into clinical trials.

Formulation development

The days are long past when topical drugs were developed by incorporating drug compounds into off-the-shelf vehicles such as Hydrophilic Petrolatum, USP. Modern dermatological formulations are high-performance, “designer vehicles”, developed to optimise drug delivery, and drug product shelf stability, in addition to demonstrating cosmetic elegance and, most importantly, therapeutic efficacy.

Typical product performance criteria include:

• Topical dosage form (composition) is compatible with the target disease indication;
• Drug delivery to target skin layer is optimised;
• Excipients are not sensitisers, have low irritation potential, and are appropriate for disease indication;
• Formulation is user-friendly and aesthetically pleasing; Formulation is physically stable;
• Active ingredients are chemically stable in the vehicle;
• Formulation can be scaled-up and produced commercially.

Multiple initial prototype formulations may well be developed and evaluated based on the above objectives. The optimised vehicle for the drug is then developed from the evaluation of these potential prototypes. In addition, a back-up formulation is usually identified as a safeguard and, sometimes, an alternate dosage form for subsequent product launch.

Choice of formulation type

Topical formulations can be classified into two broad categories: dispersions and solutions. Dispersions include creams, lotions, suspensions and foams. Solutions include gels, washes/cleansers, shampoos, solvent solutions, pledgets/pads, nail lacquers and ointments. Gels and ointments can be defined as solutions that contain an additive that forms a structural network, transforming a liquid into a semi-solid.

Franz Static Diffusion Cell

The selection of formulation type is dependent on many factors including indication and patient acceptability, physiochemical properties of the active pharmaceutical ingredient (API), drug release, and stability issues, among others. For skin conditions such as atopic dermatitis or psoriasis, which are characterised by extremely dry skin or scaling, a vehicle with good moisturising properties such as a fatty cream or ointment is usually desirable. In contrast, formulations to be applied to the skin of acne patients should be non-greasy; alcoholic and non-alcoholic gels are often vehicles of choice. A good formulator will take all aspects of a project into account and make recommendations for acceptable formulation types.

Skin penetration and drug release

In vitro skin penetration studies are conducted during topical drug formulation development to identify prototypes with optimal drug release and drug deposition into the target skin layer (stratum corneum, epidermis, or dermis). The optimal drug delivery profile depends on the intended use of a topical product. Enhanced retention in the outermost layer of the skin, the stratum corneum, is desirable for sunscreens, antifungals and keratolytic products. Deposition in the viable epidermis and dermis is needed for products intended to modify the physiology of the skin. Greater than 20- fold differences in drug deposition-penetration have been observed among rationally designed formulations tested with the same drug and concentration, depending on factors such as dosage form, excipients and penetration enhancers. Formulation optimisation for skin penetration and deposition can reduce potential irritation (if the drug is irritating), lower drug cost (by using a lower concentration) and maximize potential for clinical efficacy.

Franz and Bronaugh Diffusion Cell Manifolds, Water Baths, and Fraction Collectors

The most commonly used systems for in vitro skin penetration studies are the Franz static diffusion cell system and the Bronaugh flow-through diffusion system. The flow-through system offers the advantage of continuous perfusion of the underside of the skin (the dermis) with fresh receptor fluid to maintain sink conditions for drug diffusion. For a typical drug release or skin penetration study, test formulations are applied to excised skin mounted on a cell diffusion system. The best source of skin is dermatomed human skin from patients who underwent elective surgery. Receptor fluid samples are collected at regular intervals over the exposure period for each cell. Residual formulation is removed at the end of the exposure period by washing, wiping or tape-stripping. Diffusion cell washes, skin surface material removal samples, epidermis, dermis and receptor-fluid samples are then analysed for drug content.

In vitro drug release studies are simplified skin penetration studies. The skin is substituted by use of an appropriate membrane. After application of the test formulations to the membrane mounted on the Franz diffusion cell, receptor fluid samples are collected at defined intervals of drug exposure and subsequently analysed for drug content. In order to optimise clinical efficacy and safety, it is essential to achieve the correct balance between drug deposition on and in the skin and skin penetration. Comparative skin penetration and drug release studies provide important data essential to final selection of the formulation destined for non-clinical and clinical evaluation and are a key step in formulation development that should not be omitted.

Stability

Stability assessments begin when a prototype formulation is first developed and proceeds until the formulation is discontinued. Physical stability is assessed by monitoring the product for such changes as colour, odour, viscosity, pH and consistency. An analytical method must be developed to specifically evaluate the drug substance stability in the formulation. Accelerated stability testing is used to predict longterm room temperature shelf-life of the potential product by assaying formulation samples stored at elevated temperature, eg 40°C and 30°C. The ultimate expiration date of a product is established using stability data.

Microbiology

For multiple use formulations containing water, a preservative system must be selected to protect the product from microbial growth. Selection of an effective preservative system while avoiding sensitisers, keeping preservative levels below the irritation threshold, preventing inactivation of excipients and maintaining a stable formulation can be a challenge. The ability of the preservative system in the formulation to reduce viable counts of added bacteria, yeasts and moulds is tested using the Antimicrobial Preservatives Effectiveness Test.

Preclinical requirements

Preclinical pharmacological and toxicological studies generally required for topical products include pharmacokinetic studies investigating percutaneous absorption, single-dose toxicity studies, genotoxicity studies, local tolerability studies and investigation of phototoxic and sensitizing potential. Local tolerability studies must include single dose ocular and dermal irritation as well as repeat-dose tolerability studies. Investigation of phototoxicity is typically required if the formulation absorbs light between the wavelengths 290 and 700nm.

The API for new dermatological formulations is often a candidate for systemic administration or is already marketed in a preparation given via another route. In these cases the preclinical package must simply be expanded to include the studies specific for topical application. However, in the event that the API is a NCE without a development history by other routes of administration, the preclinical pharmacology and toxicology package may be very extensive, including studies relating to distribution, metabolism and excretion, reproductive and developmental toxicity, and carcinogenicity, among others.

There may be country-specific differences in the design of the preclinical studies not only needed for entry into the clinic but also as part of the licensing package. For example, the FDA advises repeat-dose tolerance to be performed in mini-pigs; in Europe other species may also be acceptable. In order to avoid costly delays due to faulty planning, it is highly advisable to seek guidance from a toxicological expert for the regions of interest or the competent authorities before beginning the preclinical package.

Development strategy

The shortest overall development time to marketing is always achieved by spending more time developing a topical formulation prior to preclinical and clinical studies. Formulation development should include making multiple lab batches from different lots of raw materials and different lots of API. Choice of primary packaging and suppliers should be made early in development. Ideally all preclinical and clinical studies are completed using the tobe- marketed formulation. To-be-marketed implies no changes in the components, composition, packaging, API/excipient suppliers, or process of manufacture. However, stability, compatibility, manufacturability and efficacy issues often require changes in the formulation during development. These changes in the formulation may cause repeat of certain preclinical and clinical studies.

Alternatively, a concept formulation may first be developed to speed time and save costs to proof-of-concept (POC). For drugs with adequate previous human experience this approach can save six to nine months between beginning concept formulation development and finishing POC. This is easy for new formulations of already marketed drugs in which a low exposure POC model exists or for new chemical entities (NCEs) that have already been developed through Phase II for systemic indications. Low exposure POC models include the microplaque assay in psoriasis or bilateral studies of small lesional areas in atopic dermatitis. This approach offers less time and costs saving for NCEs with no previous use in man. When using this approach it should be kept in mind that unless traditional formulation development is continued throughout the POC study, once the POC is successful at least four months of formulation development will be required prior to beginning with missing preclinical toxicology studies or returning to the clinic.

Acknowledgements

The authors would like to thank Dr Gordon Dow and DR David Osborne of Dow Pharmaceutical Sciences, Inc., for their contributions to this article.

 

Authors:
Betsy Hughes-Formella, PhD (1) and Daniel Bucks, PhD (2)

1) Director Business Development and Consulting
bioskin GmbH
Burchardstrasse 17
20095 Hamburg
Germany
betsy.hughes@bioskin.de
Tel: +49 40 606 897 0
Tel: +49 40 606 897 30

2) Director Skin Biology and Drug Delivery
Dow Pharmaceutical Sciences, Inc.
1330A Redwood Way
Petaluma, CA 94954-1169 USA
dbucks@dowpharmsci.com
Tel: +1 707 793 2600
Fax: +1 707 793 0145

 

back