Increasing demand for controlled release

Despite the investment focus on internal product development, established flexible oral controlled-release technologies by specialist companies retain key advantages and benefits, particularly as many drugs remain difficult to formulate and differentiate.

In recent years, many established oral controlled-release (OCR) companies have shifted their investment focus away from the traditional partner-dependent drug delivery business model to internal product development. This is because the traditional model depends heavily on the partner’s ability to rapidly advance a programme, which then triggers milestones and sales-based royalties.

Yet the demand for OCR product development remains strong. This is because solubility, bioavailability and other formulation-related issues remain for approved drugs and drugs in development.

Dynamics and challenges
Three key trends continue to drive the increasing demand for oral controlled-release technologies:

• Several major branded controlled-release products will lose patent protection over the next five years. Some of these drugs are known to have solubility or other issues that can complicate the formulation
  
• Speciality and emerging pharma require products that can be inexpensively developed, patented and commercially differentiated. Similarly, companies remain interested in lifecycle management approaches through novel formulations
  
• Many high-throughput synthesis and screening methods generate lead compounds that have solubility or other characteristics that present formulation and pharmacokinetic issues

Under these scenarios, formulation challenges continue to emerge that may require proprietary technologies and the corresponding expertise necessary to resolve them quickly. Interestingly, few companies can offer this blend of technology and expertise. In Penwest’s experience, the key competitor is the in-house formulator, which uses
off-the-shelf excipients to resolve these issues.

For many formulations, this approach is sufficient. However, for other formulations, standard excipients may be insufficient. This is especially the case for drugs that have low solubility/high permeability or low solubility/low permeability (BCS Classes II and IV, respectively).

New molecular entities developed through high-throughput screening methods frequently have large molecular weights, are lipophilic and have poor water solubility. This implies that the core controlled-release technology must be sufficiently robust to accept solubilisers and maintain tablet integrity during manufacturing, storage
and handling.

Similarly, site-specific delivery to the upper or lower intestinal tract can enhance the bioavailability and efficacy of many agents, such as antibiotics and steroids. These agents may require complex combinations of functional excipients and tablet coatings to achieve the desired release characteristics.

CASE STUDY: nifedipine Nifedipine is a calcium channel blocker indicated for essential hypertension. This molecule is highly insoluble, making it difficult to create a sustained release formulation without the addition of solubilisers. Penwest satisfied the need for an oral controlled-release formulation of nifedipine by including a solubiliser in the TIMERx® formulation. The corresponding tablets were shown to be bioequivalent to the branded product, resulting in the successful launch of a valuable generic product. There are many types of functional excipients available, ranging from simple buffer salts to complex poly­mers and coatings. Few controlled-release technologies are robust enough to accept these solubilisers without creating other problems, such as a loss of tablet integrity under standard manufacturing conditions. TIMERx technologies do not have this issue, and can be used with many solubilisers and other excipients to create formula­tions and solve the challenges associated with many drugs.