New delivery forms create new challenges
By Mike Bly, Ph.D.
A qualitative description of generic preformulation of drug in adhesive patches is given. The goal is to make a stable product with good tack that delivers the same amount of active pharmaceutical ingredient (API) as the innovator product (the patch already on the market) without infringing upon patents that are in effect. The generic product is not required to contain the same inactive ingredients as the innovator product. However, the generic product must have the same drug delivery rate as the innovator product. In addition, the generic product must be stable (constant structure visually and microscopically as well as a constant drug delivery rate) over its shelf life (at least two years). What must you do to reach these targets?
The package insert of the innovator product will contain a list of active ingredients and inactive ingredients. The amount of active ingredient — but not necessarily the amount of inactive ingredients — will be given. Also, the patch size, drug delivery rate, and wear time will be indicated.
The patent status of the innovator product must be known. The Electronic Orange Book will list pertinent patents. These patents must be obtained and understood. Pay particular attention to the patent examples and claims. In addition, a patent search at the U.S. Patent and Trademark Office web site on the active and inactive ingredients should be made. Discuss the findings with a patent attorney. Patents may influence the design of the generic product. For example, innovator patents may require that the generic patch be either a solution or suspension of the active ingredient. In addition, innovator patents may limit the enhancers or other ingredients that can be used.
FDA List of Inactive Ingredients
A helpful tool in the design of generic products is the FDA List of Inactive Ingredients It provides a list of ingredients, an amount, and the mode of application. If ingredients other than this (or a larger amount than this) are used, additional studies such as toxicology, irritation, etc., will have to be conducted. This list may not be current. A drug in adhesive patch is listed as “transdermal; film, controlled release.” Amounts will generally be listed in mg. To convert to a total amount in the patch, we use the industry standard of 100 grams/square meter (G.S.M.) and approximate the maximum patch size as 50 cm2. A partial list of enhancers given in the FDA List of Inactive Ingredients is given in Table 1.
|Table 1: A partial list of enhancers from the FDA List of Inactive Ingredients is given. 100 G.S.M. and 50 cm2 were used for the calculations of the dry weight %. |
Enhancer: Dry Weight %
Butylene glycol: 1.6%
Propylene glycol: 11.6%
Methyl laurate: 3.5%
Light Mineral Oil: 32.4%
Dipropylene glycol: 2.4%
Oleic Acid: 4.4%
Many APIs can be detected using a high performance liquid chromatography (HPLC) method with ultraviolet/visible detection. An alternative method might employ mass spectrometry. Detection using an HPLC is illustrated here. Since it is a generic product, many detection methods will be given in the literature. The following will need to be completed:
- Construct a calibration curve for the concentration of API versus absorbance for example.
- Determine the solubility of the API in the mobile phase.
- Determine the stability of the API in the mobile phase over a time period and temperature for which the samples will be run.
- Establish a limit of detection and linear range for the API.
Free samples of adhesives and enhancers can generally be obtained from the manufacturers. A hundred grams of API will likely be necessary for preformulation studies.
The major types of pressure-sensitive adhesives are silicone, polyisobutylene (PIB), acrylate, and styrenic rubber-based. Dow Corning is the major supplier of silicone pressure sensitive adhesives. The tack, solvent, and solids content will vary among the adhesives. Examples of the standard silicone adhesives are BIO-PSA 7-4401 and 7-4402. The amine-compatible adhesives include BIO-PSA 7-4301 and BIO-PSA 7-4302. Refer to the manufacturer for adhesive specifics.
Henkel is a major supplier of PIB, acrylate, and styrenic rubber adhesives. They have more than 20 adhesives that are made from acrylic copolymers which display unique solids, shear, and tack characteristics.
An initial screen of adhesives should include the following:
- Two of the standard silicone adhesives.
- An amine compatible silicone adhesive.
- A PIB adhesive.
- A styrenic rubber adhesive.
- An array of acrylate adhesives.
A monomer reactivity study can reduce the number of acrylate adhesives that need to be screened. Residual monomers in the adhesive may react with the API The API is monitored as a function of time and temperature in a solution containing a monomer and HPLC mobile phase.
Weigh each ingredient into a clear or amber jar (if the API is light sensitive) with a Teflon covered lid liner. Mix the ingredients with an impeller mixer for two minutes or until the solution appears homogeneous. Roll the blends on a bottle roller for at least 24 hours to remove dissolved air.
A simple but effective device for making laminates is shown in Figure 1.
|Figure 1: Laminate making device. |
Feeler gauges are used to adjust the thickness of the laminates. The release liner is placed underneath the dam. The blend is poured onto the release liner, which is then pulled at a constant speed under the dam until the blend is gone. Let the laminate sit at room temperature for five minutes, and then dry it at 50°C for 40 minutes. These conditions should be sufficient to dry a 100 G.S.M. laminate. Remove the laminate from the oven and place it onto backing material with the aid of a roller. Place the laminate at room temperature for at least two weeks before use. Determine the G.S.M. of the laminate. If it is not close to 100, repeat making the laminate while varying the feeler gauge thickness. Evaluate the tack of the laminate as well as its visual and microscopic appearance over the course of the project.
The stratum corneum generally represents the rate-limiting diffusion barrier for the API through the skin. Cadaver skin can be obtained through a tissue bank and should be stored at -80°C until use. The same donor skin and preferably the same donor site should be used for a given flux study. Immediately prior to use, the skin is thawed at room temperature and placed into room temperature 30 mM phosphate buffer, pH 7.4. A solution of 30 mM phosphate buffer, pH 7.4 is heated to 60°C. This solution is removed from heat and up to 100 square inches of skin is placed into it. The skin is carefully stirred for two minutes and then placed into a solution of room temperature 30 mM phosphate buffer, pH 7.4. The stratum corneum is carefully pealed from the skin and placed with the surface side up onto no-lint wipes. After drying (about one to two hours) at room temperature, the skin can be used immediately or placed at -80°C for a few days. Prior to use, the skin/wipe is thawed, and the skin is removed from the wipe by hydration with water.
The simplest tool for flux studies is the batch operated Franz diffusion cell.1 The cells should be maintained at a constant temperature and a constant stir speed. The reservoir volume should be large enough to approximate sink conditions at all times. To approximate sink conditions, the concentration of API in the reservoir should never exceed 10% of its solubility.
Before beginning the flux studies, the solubility and stability of the API in the reservoir phase must be determined. Common reservoir phases are:
- 30 mM Phosphate buffered saline (0.15 M NaCl), pH 7.4 (PBS) with and without azide (0.1% by weight).
- 30 mM Phosphate buffer, pH 7.4 with and without azide (0.1% by weight).
- The above buffers with polyethylene glycol 500 molecular weight to increase API solubility in the reservoir.
The flux study should be planned to include at least three sampling points. The first sampling point should be at about the lag phase of the system (typically four to eight hours after the study has begun).
At least four replicates per sample should be run. Use the innovator product as the positive control, and separated skin as the negative control.
One of the first flux studies should be an experiment containing saturated solutions of drug and enhancer for a number of enhancers. While not a real world condition, maximum flux values will be obtained. If the enhancer isn’t a liquid at room temperature, dissolve it in mineral oil or propylene glycol. Pick three or four of the best performing enhancers for future study.
Prepare a set of laminates for a given adhesive with API using enhancer concentrations as given in Table 1. A good starting API amount is 50% more than is required to be delivered.
Flux values for a given laminate may vary by as much as 50% between donors. As a result, use only one donor skin for direct comparison of laminates.
Once a stable laminate has been obtained which matches the drug delivery rate of the innovator product, additional studies on different donor skins should be conducted. In addition, studies such as API adsorption to the release liner and backing should be conducted. Also, the effects of varying ingredients by +/- 10% should be performed to approximate variations in the production phase.
1. Franz, T.J. (1975). Percutaneous Absorption – Relevance of In vitro Data. 64, 190-195.