Delivering new products from existing drugs

It has become very attractive to develop new pharmaceutical products based on existing active ingredients to reduce development costs and the risks of failure are much lower while achieving substantial therapeutic benefits. Microtablets for automatic dispensing have particular requirements in terms of size and shape, and choosing the right development partner for the project is crucial

Excellent powder flow a prerequisite for high speed tablet production

A recent project involving Sensidose and Recipharm has produced a novel microtablet dosage form that will benefit specific patients suffering from Parkinson’s disease. The two companies reveal how such collaborations can create new products from existing active ingredients.

The diminished number of new chemical entities being introduced onto the market in recent years is a significant challenge for the pharmaceutical industry and may jeopardise the steady stream of new valuable medicines that the healthcare sector and consumers have got used to. There are multiple factors that, it might be argued, have contributed to this shortfall, including the fact that the easy, low-hanging fruit have already been picked and supplied; the expense and inefficiencies of r&d organisations in pharmaceutical companies; and the increasing regulatory hurdles.

As a consequence, it has become very attractive to develop new pharmaceutical products based on existing active ingredients. This approach means that development costs and the risks of failure are much lower, and substantial therapeutic benefits can be achieved.

Presently, there are many small companies working with innovative ideas in this area. But to turn these ideas into actual developed products requires effective collaboration between these small innovative companies and Contract Development and Manufacturing Organisations (CDMOs).

Sensidose is a drug delivery company based in Sweden that has developed an innovative delivery concept for individualised patient dosing. The concept is based on the use of microtablets, each containing an exact and sub- therapeutic amount of the active substance in combination with a dose automate for counting out individual numbers of microtablets.

The first product using this concept is comprising the active ingredients levodopa and carbidopa for the treatment of Parkinson’s disease. A registration application for this product was submitted in Sweden in late 2011.

outsourcing strategy

When a small company faces the challenge of developing a new product for the market, several important decisions have to be taken. First, there is the decision of whether the development will be carried out in-house or outsourced. In many cases, time and money constraints make contract development unavoidable, for some activities at least.

For development of innovative products it is difficult to compare the level of experience of different contractors

If choosing contract development, another important decision will be how to choose the right service provider. This is by no means an easy call; different contractors will often propose different approaches with varying cost and risk levels, making it difficult to compare offers. Additionally, for development of innovative products it is difficult to compare the level of experience of different contractors.

When purchasing contract development for a conventional dosage form it is common to look at the service provider’s track record for similar products, but for an innovative dosage form that may not be possible. Other ways of evaluating different service providers need to be found. Then a strategy for communicating and collaborating with the chosen service provider must be selected.

On the other hand, a CDMO asked to develop an innovative product may also have some problems to face. What is the optimal development programme for this novel product? What experiences from other projects are applicable? What are the most serious risks and how can they be mitigated?

In putting its novel ideas into practice, Sensidose chose to outsource contract development for the clinical programme, for the development of the dosing device and for the development of the microtablets.

For the pharmaceutical development and manufacture of the microtablets Sensidose chose Recipharm, a leading European CDMO with nine commercial manufacturing facilities for production of most dosage forms from tablets and capsules to semi-solids and parenterals. The basis for this decision was both that Recipharm was geographically close but also the largest contract manufacturer in Scandinavia. Sensidose was aware that the Recipharm staff included personnel with high academic training, which provided confidence.

It was important that the microtablets disintegrated rapidly and that the resulting dispersion had attractive organoleptic properties

At first it may appear that the development of microtablets for a dose automate is a trivial task and no more complex than the development of any standard tablet. However, there were several complicating factors. First, it was considered important for the patient to be able to disperse a number of tablets in a glass of water prior to ingesting the medication. This made it important that the microtablets disintegrated rapidly and that the resulting dispersion had attractive organoleptic properties.

Second, the diameter of the microtablets was only about 3mm, making excellent powder flow a prerequisite for high speed tablet production. Another complicating factor was that all dimensions of the tablet were critical to ensure proper operation of the dose automate.

Figure 1: The microtablets have a spheroidal shape and a diameter of approximately 3mm

For conventional tablets, the diameter is carefully controlled by the diameter of the die during manufacture while the tablet height is less critical (even though it has to be controlled within some relatively wide limits to ensure a smooth packaging process). Furthermore, the dose automate works best with spheroid microtablets. Hence, cupped tablet punches with an almost hemispherical shape had to be used, but this accentuated any tendencies to adhesion or capping of the formulation.

Another challenge of the project was that the microtablets had to be developed with minimal resources as the possibility to finance a large development project was limited until clinical data was obtained.

To deal with the development challenges, a project group was formed consisting of two or three key people from each company. This project group worked closely together during the critical phases of the project, making the best use of key competences from both companies. The strengths of Sensidose that were most important for the success of this collaboration were a clear vision of the final product, rapid decision-making and a high level of involvement in the development process. The high level of involvement was facilitated and accentuated by an excellent understanding of the pharmaceutical development process within Sensidose.

A broad experience of various dosage forms is important as it makes it easier to approach novel formulation without being confined mentally to one standard solution

Important for Recipharm’s contribution to a successful outcome was its experience of development as well as commercial manufacture of a wide variety of different dosage forms. A broad experience of various dosage forms is important as it makes it easier to approach novel formulation without being confined mentally to one standard solution. An understanding of commercial manufacture is, of course, necessary to develop a product that can be scaled up and manufactured efficiently.

By working closely together with frequent quick meetings during the critical phases, as well as working together in the lab on some occasions, the project group developed a prototype formulation in just a few weeks. This prototype was subjected to optimisation and evaluation, including an accelerated stability study. It was then decided that the improved prototype was suitable to be used for the clinical programme.

Figure 2: The microtablets are filled into cassettes that are designed to be easily inserted into the dose automate

microtablet concept

Two clinical Phase I studies have now been carried out, demonstrating that the concept of dividing up a standard tablet into several microtablets works well clinically. In addition to the fact that the microtablets offer personalised dosing in tablet form, the studies also show that the system enables a more steady clinical effect compared with today’s standard tablet formats. Members of the project group are convinced that a close collaboration characterised by flexibility, openness and trust was critical for the collaborative development of this novel dosage form. In a project like this it is difficult to foresee all aspects of the development programme from the start. Consequently, there may be a need for numerous amendments to the original development agreement. This will take time and effort and makes rapid progress impossible.

The alternative is a collaboration in which both parties realise that everything cannot be included in a written agreement. Instead the work is guided by general clauses, a common understanding of the objective of the development and that confirmation of changes from the original plan may be made by telephone or e-mail. However, this alternative approach is possible only if there is a high level of flexibility and mutual trust between the parties.

After launch, this new product is expected to improve the quality of life and reduce side-effects for thousands of patients suffering from Parkinson’s disease. Furthermore, the concept may be applicable to many other drugs where a carefully individualised dose is important. Hence, this innovation will be a powerful tool to provide a product with significant therapeutic benefits without the high development cost and risk associated with new chemical entities. The project also illustrates how, if managed in the right way, contract development can be used not only for the development of conventional dosage forms but may also be a way to realise truly innovative concepts in drug delivery.

Written by:

Jonas Berggren, head of pharmaceutics, Torkel Gren, sales director, and Fredrik Strandberg, project manager, Recipharm Pharmaceutical Development

Christer Nyström, former professor and head of Department of Pharmaceutics at Uppsala University

Jack Spira, ceo, Sensidose