LTS Lohmann Therapie-Systeme - Absorption rate boost for transdermal applications

LTS Lohmann Therapie-Systeme has developed a product that has an increased absorption when released to the skin compared to natural isotope methods.


Although the transdermal application of drugs has great advantages, its downside is that the amount of the drug absorbed via the skin is limited. Thus, when the therapy of dermal application began, attempts were made to find a way of increasing the capacity of drugs to penetrate the skin.

The development of penetration enhancers, which are added to the dosage for dermal application, was regarded as the solution for this problem. However, these substances change subjacent skin structures, at least for a short time, and can result in undesired side effects. Furthermore, the toxicity of components, such as Azone®, is not yet fully understood and no transdermal delivery system containing Azone has been approved by authorities worldwide. Therefore, the substitution of very polar active pharmaceutical ingredients (API) by their derivatives has been investigated. These approaches are known under the technical term 'prodrugs'.

The dermal application of prodrugs seems an interesting alternative. In this case, structural elements of a drug considered unfavourable for dermal absorption are derivatised or esterified.

The characteristic feature of a chemical modification of prodrugs is that the derivatised element is extremely unstable so that the drug underlaying the prodrug is quickly and completely formed in vitro. However, it is recognised that this concept can only rarely be realised in practice, since the intended quick and complete metabolic degradation does not take place in vivo. Thus, some toxicological questions arise with respect to the prodrugs which still require extensive pharmacological studies.


Toxicological qualification

In general, a prodrug has to be identified as a new chemical entity, and include all necessary work for its toxicological qualification.

Consequently, chemical procedures must be found for derivatives of APIs containing one or more O-H and/or N/H groups that can be easily converted to its prodrug and vice versa. The hydrogen atom in those functional groups can be easily substituted by deuterium and vice versa. Because intermolecular forces created by D-O/N are weaker than H bridge bonds, it was suggested that the exchange of hydrogen against its isotope deuterium might create products feasible for transdermal absorption. The exchange under in vivo conditions takes place quickly.

Hydrogen always represents an isotopic mixture of 1H, 2D and 3T. For this reason, all chemical compounds compared with hydrogen are always present as a mixture of deuterated and non-deuterated compounds, with the proportion of 2D amounting to about 0.015%. Due to its high level of exchangeable hydrogen items, Salbutamol was chosen as a model API.


Experimental qualification

For the production of deuterated Salbutamol, 0.5g of Salbutamol was dissolved with heat in 20g of deuterium oxide. Because the substance does not crystallise, evaporation under vacuum at room temperature is carried out. This resulted in the following:

  • a yield of 0.5g
  • a melting point of 149.8°C (the melting point of Salbutamol is 153.4°C)
  • infrared spectra of educts and product (Figure 1).

During skin permeation studies experiments were conducted with exercised guinea pig skin fixed in a Franz-Diffusion cell. Physiological saline solution was used as the acceptor medium and the determinations of contents were carried out by HPLC. Here, 200g each of Salbutamol and deuterated Salbutamol were dissolved in a blend of 800mg deuterated or undeuterated oleic acid and 2g of 2-Butanone. After completion of the solution the 2-Butanone was removed under vacuum.

The denaturated Salbutamol penetrated the guinea pig skin by a factor of more than two. Therefore, the exchange of active hydrogen against deuterium might be a good approach in enhancing the permeability of APIs.

Oral drug delivery for the 21st century

In this age of scientific and technological advance, one company is ready to take the delivery of oral drugs to the next level. LTS Lohmann's Dr Keith Jensen has a vision of the future.

When I was a growing up, the 21st century was advertised as being a cool, futuristic place with such things as hotels in space and flying cars.

I'm pretty happy with my cell phone, which has more computing power than NASA used to land a man on the moon, but where is my flying car? OK, if I can't have a flying car, how about a flying tablet?

LTS Lohmann's pioneering work with oral thin films led to the introduction of Listerine PocketPaks. I like to think of these films as tiny translucent rectangles that look like mini flying carpets for APIs. These strips are ready to take oral drug delivery to the next stage, both for the pharmaceuticals developer and for the consumer/patient.

Oral thin films provide numerous advantages for the developer. Perhaps the most exciting is the ability of oral thin films to overcome solubility problems. Such issues prevent many potent drugs from reaching the market or hinder the performance of products which could prove to be much more effective and safer for patients. A well-formulated oral strip is able to increase bioavailability from often non-measurable levels in tablets to over 80%. The second major advantage of properly formulated oral thin films is the capability to deliver compounds with good permeation via the oral or buccal mucosa. This avoids the GI tract, the first-pass through the liver and degradation of sensitive compounds before they have a chance to circulate and reach their target.


Lower doses

These two advantages often result in large increases in oral bioavailability of a drug. This allows lower doses to be administered with the same or better therapeutic effects. Lower doses often mean fewer or significantly reduced side effects. This can remove barriers to product approval and result in increased patient compliance. Lower doses translate into less API use and a significant decrease in costs.

Better bioavailability can also result in higher blood concentrations than can be achieved via more traditional formulations, opening up new therapeutic categories. The delivery of drugs by oral strips can be modified from instant release to controlled release of the drug over 12 hours, allowing custom delivery and personalised medicine. Oral thin films are also one of the best ways for local delivery of the drug in the oral cavity. They have less food effects, faster onset and often result in new IP.

The last major advantage to the pharmaceutical producer is the robustness of the manufacturing process and product. This robust process ensures a reliable product supply, and a robust product means less loss due to damage from manufacturing through to consumer/ patient use. Oral thin films also provide unique advantages to the consumer/patient. They offer a new, attractive design for safer, pain-free oral delivery of drugs. Patients prefer to take drugs orally and these films provide additional advantages not even dreamed of by other dosage forms. They are very discreet, allowing easy administration of medications and do not require liquids. They are ideal for patients who have difficulty swallowing, such as children or older people. They cannot be spat out, making them ideal for veterinary applications.

This type of film can be designed with unique low-volume packaging, making it an innovative and highly mobile product. Oral thin films bring together so many of the aspects preferred by consumers and patients, which result in better, safer products and increased patient compliance; they are bringing oral drug delivery into the 21st century... Someone else has to work on my flying car.

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Figure 1. Infrared spectra of Salbutamol
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