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 poly¬mers 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 formula¬tions and solve the challenges
associated with many drugs.

Company profile

Penwest Pharmaceuticals has a family of well established drug delivery technologies with a proven track record, including TIMERx, Geminex, SyncroDose and GastroDose, all of which are available for product development.

Oral controlled release technologies

In an era where formulation challenges are increasingly common, established, flexible, oral controlled release technologies are important tools for creating approvable, innovative products.

A number of established oral controlled release companies have shifted their investment focus towards product development. Today, few companies exist that offer established, flexible, oral controlled release technologies that resolve product development problems and result in clinically meaningful products.

Penwest Pharmaceuticals has a suite of established, approved technologies that enable the development of oral-controlled release products. These technologies can be customised to deliver drugs via a wide range of desired release profiles.

TIMERx

TIMERx consists of a proprietary blend of materials combined to achieve the desired drug release profile. The technology is not dependent on the acidic environment in the intestinal tract or other factors that can vary greatly between individuals and their diet

TIMERx is inexpensive, and can be used to create tablets using standard tablet manufacturing equipment and processes. It has been used in approved products worldwide. Its most recent product success was Opana® ER, a sustained release formulation of oxymorphone for the treatment of pain.

When some controlled-release formulations are consumed with alcoholic beverages, the formulations can rapidly fall apart, resulting in the drug to be released and absorbed quickly, causing major side effects, such as respiratory depression observed with potent pain medications. TIMERx is not susceptible to this alcohol-induced ‘dose-dumping’ effect observed with other oral controlled-release technologies.

Geminex

Geminex is a bilayer tablet system that allows the creation of a single tablet with two different release profiles. It is suited for the development of products in which two-drug combinations can improve patient compliance, or where they can result in unique indications and patents.

SyncroDose

SyncroDose is designed to release drug after a preprogrammed period of time. It can be used for the treatment of diseases of the large intestine, such as ulcerative colitis and Crohn’s Disease. In one application, Penwest developed a SyncroDose formulation of a medication for the treatment of morning stiffness caused by arthritis. This product is dosed at bedtime, and the drug is released during the overnight hours. By the time the patient wakes up, morning stiffness has been substantially reduced.

GastroDose

Gastrodose is retained in the stomach for extended periods of time. This approach is used for the treatment of disorders of the stomach or upper gastrointestinal tract. It is also suited for drugs that are readily absorbed into the circulation from the stomach or upper small intestine.

Why Penwest?

Oral controlled-release technologies such as TIMERx can help solve problems that emerge during formulation development. For example, small molecules are becoming increasingly difficult to formulate because of low solubility, low permeability, or both. Flexible systems such as TIMERx can incorporate other ingredients to address these challenges.

These technologies can also be used to convert injectable drugs into oral medications, as is being done with a pain medication currently in clinical development. Penwest Pharmaceuticals has the technologies and experience to craft novel oral controlled-release products.

Company profile

Penwest Pharmaceuticals is a speciality pharmaceutical company focused on the development and commercialisation of therapies for the treatment of neurological disorders. Its oral controlled release technologies are also available for the development and commercialisation of products in multiple therapeutic areas.

CRITICAL POINTS TO CONSIDER WHEN CHOOSIING A DRUG DELIIVERY PARTNER

  • Is the technology currently in use in an approved product in the US or in Europe?
  • Does the technology require special manufacturing or other incremental equipment?
  • Are the components of the technology generally regarded as safe?
  • Is the technology sufficiently flexible enough to allow the inclusion of other drugs or ingredients?
  • Does the drug delivery partner have a proven track record of product development, from product concept to finished formulation?