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At Afera’s most recent Annual Conference, Dr. Thomas Hille, Director of R&D at LTS Lohmann Therapie-Systeme AG, shed light on the niche market of transdermal delivery systems (TDSs) and the role that adhesive tapes play in creating these specialised medical products. Dr. Hille described the various types of TDSs available on the market and the essentials for pharmaceutical ingredients. He then discussed both the requirements of adhesive tapes for adhesion to foils and human skin, and for purity of polymers and tackifiers of adhesive tapes in TDSs.
The bottom line: Adhesive tapes are one of the most important components of TDSs. In every kind of TDS, the polymer matrix must adhere to a foil regardless of whether it is a rate controlling membrane or backing layer, and it must stick to the skin over the entire application area while delivering the drug to the human body without causing an allergic reaction. Adhesion to foils must be permanent, while adhesion to skin must be reversible. Adhesive tapes should be manufactured according to strict standards of purity. Tackifiers are an option for improving skin adhesion, but the process of hydrogenating abietic acid using Raney nickel should be avoided by resin suppliers, as the derivatives can cause ‘plaster allergy’.
Tapes are one of the most important components of TDSs
Similar to traditional plasters used as wound tapes, TDSs are flat and consist of active pharmaceutical ingredients (APIs) and adhesive tapes which deliver medicinal drugs via to the skin to the human body.
What transdermal systems are available on the market?
Different drugs require different types of TDSs:
A matrix system consists of an API (solvent) in a polymer, the backing layer and a removable release liner.
Monolithic matrix systems are considered very simple and easy and are recommended if the API is inexpensive. Note that the API in the system is not deliverable in total to the human body as residuals remain attached during the application period, and each utilisation of the drug, especially hormones such as estradiol, is relatively low. In the case of estradiol, more than 90 % of the incorporated drug cannot be absorbed transdermally.
More sophisticated is a micro-reservoir system, which consists of a drug suspended or emulsified in a polymer, backing layer and a removable release liner.
If utilisation of the API is important, a polymer with a very low concentration of saturation for the API must be chosen so that much of the drug is delivered into the body. Because of its relative complexity, manufacturing the reservoir matrix system is more difficult. You should therefore consider the purpose of the system required, the expense of the API and whether utilisation of the API is important.
The oldest system, the reservoir system, consists of a drug-loaded liquid, a rate-controlling membrane, skin contact layer, backing layer and a removable release liner.
A membrane system consists of a drug in a polymer, a rate controlling membrane, backing and a removable release liner. Membrane systems are optimal if you have an API with a very narrow therapeutic window. In this case, the adhesive supply must be controlled very carefully.
What do the various TDSs need in adhesion?
All TDSs have the same requirements for adhesion concerning the skin contact layer:
1.The polymer matrix, or skin contact layer, must adhere to a foil whether it is a rate controlling membrane or a backing layer.
2.The polymer matrix, or skin contact layer, must also stick to the skin over the entire application area while delivering the drug to the skin. The greatest challenge to TDSs is that they have to stick to the skin for 24 or more hours. This is not a simple feat.
3.The polymer matrix must not cause skin irritation or other allergic reactions. An application dosage form worn for the treatment of chronic conditions must not be associated with these symptoms during or after the patch application.
4.Lastly, polymers should not interfere with the drug.
Adhesion in transdermal applications
In the transdermal field, adhesion means connection of two surfaces by either a liquid or a polymer in a rubber-like state. In the case of transdermals, one surface is a foil (the rate-controlling membrane or the backing layer) and the other human skin. Adhesion to foils must be permanent, while adhesion to the skin must be reversible. Thus both the surfaces and purposes of adhesion bear different challenges.
Adhesion of the polymers to foils is not technically problematic as pretreatment of foils, with e.g. a primer or corona treatment, is possible. The backing layer or the rate-controlling membrane that best complements the adhesive tape can be chosen.
Adhesion to the skin must be achieved by wetting and intermolecular interactions, while pretreatment of the surface, human skin, is not possible. Hydrogen bond bridges are key if the adhesive tape must stick to the skin. Polar groups can be strong but can increase the glass transition temperature, causing a lack of adhesion. Therefore, the adhesive tape must have a glass transition temperature below 0°C and must be in a rubber state.
Reversible bonding can be achieved by intermolecular interactions such as Van der Waal forces, and, perhaps even better, hydrogen bond bridges might be possible. While Van der Waal forces are weak but always present, the advantage of hydrogen bond bridges is their strength, although they can increase the glass transient temperature of adhesive tapes. Interference of the API with the polymer itself should also be avoided or utilisation of the drug will be very poor.
Furthermore, carboxylic groups, which are the most prominent functional groups associated with hydrogen bond bridges, can form salts with basic APIs, and the presence of too many of these groups can cause skin irritation. This is important as many APIs are bases. Dr. Hille stated that he favoured polyacrylates as carboxylic groups. If these exceed 5% however, skin irritation will result. An R&D balance of requirements for skin adhesion and functional groups must therefore be achieved.
Lastly, the impact of the drug and especially its concentration towards the glass transition temperature of a polymer matrix must be investigated. The API must be used at least during the application period (the glass transition period), meaning that the concentration is lowered during this period. This naturally has an impact on the adhesion of the adhesive tape that must be studied.
Pharmaceutical requirements of tapes in TDSs
Safety issues of PSAs
TDSs and the adhesive tapes they incorporate are considered quality products which must fulfil specifications of identity, strength and purity. In the regulatory arena, purity of adhesive tapes is the most important parameter. In terms of adhesive tapes, purity signifies the absence of impurities such as degradation products or residuals of process solvents, monomers, initiators and cross linkers, but also of microbiologicals and metals, e.g. nickel, which is an allergenic component.
Achieving a total absence of impurities is impossible if not averted in synthesising adhesive tapes. Impurities can be specified according to their toxicological potentials, however, and tested either in the adhesive tapes or later in the final TDSs. For example, if you have watertight components which are impurities in the adhesive tape solution, you can determine their concentrations after the coating process when you have manufactured the TDS.
The higher the toxicity, the lower the specification limit and the more difficult the analytical method and its validation. In general, the specification limits of solvents are wider than those of monomers with the exception of the solvent benzene. Benzene is so toxic that it must be either avoided or used in manufacturing in quantities at or below 2 parts per million (ppm). It is a great challenge to find and validate an analytical test method that can measure the presence of a solvent at 2 ppm.
How can purity in adhesive tapes be achieved?
The phrase ‘garbage in, garbage out’ should be kept in mind. This suggests that pure process solvents should be used rather than blends in the manufacturing process, e.g. pure n-heptane rather than fractions in ‘technical quality’. If you use a blend of different hydrocarbons, later you must determine in the TDS the presence and amount of each individual solvent, making the ultimate use of the technical quality assessment relatively expensive. Not only do you have to test for the single solvent but later all those components that are described in the technical quality assessment. If it contains benzene, it may not be used in pharmaceutical products.
Also, in terms of micrological purity, polymers dissolved in organic solvents rather than aqueous dispersions should be used to avoid the growing of germs during storage and distribution of adhesive tapes. The impurities caused by germs must be specified in the manufacture of TDSs. Testing must be performed either batch by batch of the final drug product, or if one batch of testing is performed per year, this must be justified. In the case of organic solvents, however, you can show that no growth of germs is possible.
As not all ingredients of polymers are listed in European pharmacopoeias, reference is made to solvents, monomers and catalysts listed for polymers which come into direct contact with food. As the manufacturer and/or supplier of an adhesive tape for pharmaceuticals, if you are uncertain of what types of monomers or catalysts you can utilise, access this guidance from the food industry.
Safety issues of tackifiers
Adhesive tapes used in TDSs must adhere sufficiently to the skin because of the risks associated with using tackifiers. A potential risk of the widely used tackifier abietic acid and its derivatives can be seen in the chemical structures enabling oxidation during storage. The conjugated double bond might be the root cause for forming 15 perhydroxy abietic acid derivatives through the resin’s exposure to oxygen during storage. This degradation product can oxidise the API in the TDS during the shelf life of the TDS. If you use a resin, you must be aware that you have to specify the dioxide value, which, if too high, can create stability problems for the API.
Furthermore, purified abietic is non-allergenic, but its oxidative product is 15 perhydroxy abietic acid. In the past, suppliers of resins used hydrogenation catalysed by Raney nickel to stabilise abietic acid derivatives. The so-called ‘plaster allergy’ might therefore be a reaction to 15 perhydroxy abietic acid derivatives or traces of nickel—and not caused by the patch itself.
About Thomas Hille
Thomas Hill studied pharmacy in Bonn and got his PhD in 1985. He gained his first industry experience in 1980 at Henkel in Dusseldorf as a student and started his career in Knoll, Ludwigshafen in 1986 as head of an R&D lab. Since October 1986, Thomas has been head of an R&D lab in Andernach, developing transdermal therapeutic systems (TTS) registered and launched worldwide. Dr. Hille is listed as inventor in more than 50 patents.
Questions and comments?
Dr. Thomas Hille
Director of Research & Development
LTS Lohmann Therapie-Systeme AG
D- 56626 Andernach
Tel.: +49 (0) 2632 99 - 2239
Fax: +49 (0) 2632 99 - 1239
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