Solving parenteral solubility challenges in the development of oncology therapeutics

It’s no secret that solubility and bioavailability issues continue to challenge formulators and drug developers. Approximately 60-90% of potential new active pharmaceutical ingredients (APIs) in development pipelines, and more than 40% of those in reformulation, are poorly water-soluble. ⁽¹⁾ Due to the increasing number of poorly water-soluble drug candidates, it is clear that effective solubility-enhancing solutions are needed. However, the statistics clearly demonstrate that there are still not enough effective technologies or excipients on the market – nor those which are saleable enough – to provide sufficient solubility enhancement.

The lack of appropriate solutions for scalable and efficient solubility enhancement is impacting development across many dosage forms. Of these, it’s important to highlight parenteral dosages due to the wide-ranging application of parenteral systems in various therapeutic areas. In 2019, the FDA estimated that around 42% of new molecular entities (NMEs) approved were parenteral formulations.⁽²⁾The wide-ranging applications of parenteral dosage forms mean that solubility challenges can impact a variety of therapeutic areas, including anti-cancer drugs.

Parenteral dosage forms are a key delivery system for the oncology sector. In 2017, 27.5% of parenteral NMEs were for oncology drugs. ⁽³⁾ For the industry to meet the continuous need for new and effective anticancer drugs, scalable solutions for enhancing parenteral solubility will be vital. Let’s take a closer look at oncology development to understand the specific needs of anti-cancer formulations and the tools and techniques available to improve solubility.

Understanding the current challenges for oncology drug formulation

In addition to the rising number of hydrophobic APIs in development, drug developers seeking viable oncology therapies must also mitigate the challenges of potent APIs and potential adverse effects. Compounds and delivery vehicles used to treat cancer are much more toxic than most other drug moieties used to treat other diseases.

Safety, quality, and efficacy are the core values driving the modern drug pipeline. To meet these pillars, early-stage discovery and development teams estimate and work towards the maximum tolerated dose (MTD), which is the highest dose that does not cause unacceptable side effects. However, increasingly toxic and insoluble drug candidates are adding to the complexities of striking the right balance.

If carefully considered, drug delivery methods can provide a tool to overcome these challenges. Ideally, oncology therapeutics would be delivered orally, as this negates the need for specialized equipment – such as a syringe and intravenous (IV) infusion apparatus – and it is also more appealing for patients. However, most APIs used in oncology treatments have poor oral bioavailability and have an increased potential for gastrointestinal (GI) tract irritation. Additionally, the overall toxicity of the oncology drug can be exacerbated by the toxicity of the drug vehicle or excipient used in the formulation. Therefore, it is more common that anti-cancer drugs are delivered parenterally – either by IV infusion or injection. On top of reducing GI tract irritation, IV is the most effective way to deliver medication directly to the bloodstream, thereby increasing drug bioavailability. Nevertheless, achieving an acceptable bioavailability threshold is still hindered by poorly water-soluble APIs in the development pipeline.

Potential of next-generation parenteral excipients in oncology therapeutics

With current solubility-enhancing solutions not fully meeting the demands of the pharmaceutical industry, novel polymeric excipients are becoming an attractive option for the development of oncology therapeutics, as well as drugs for a variety of other diseases. Although the incorporation of novel excipients is rising in new drug formulations – especially in the search for effective anti-cancer agents – there is still hesitation from some developers and formulators.

With drug regulators tolerating a much higher risk-to-benefit ratio in the oncology space, suboptimal drug formulations have found it easier to make their way to market. However, it is this higher risk-to-benefit ratio and acceptance that has meant many more oncology formulators are open to the idea of leveraging novel excipients in their drug development projects. This will allow for a safer approach to drug formulation and the creation of therapeutics that are better tolerated by patients.

Apisolex™ polymer, developed by Lubrizol Life Science Health (LLS Health), is a versatile, efficient, and safe technology to help overcome the shortcomings of existing solubility enhancement techniques. [1][2][3][CFR4][CFR5][GJ6] Apisolex excipient is a biodegradable, biocompatible, amphiphilic block copolymer that utilizes micellar technology. Although polymeric micelles are not directly involved in API solubilization, their encapsulation mechanism is a commercially proven way to create stable nanoparticles that can help increase API solubility.

Improving solubility

API particle size reduction is an effective way to combat solubility issues by creating nanoparticles of crystalline API that can be used for virtually any route of administration. Polymeric micelles are another proven method to create stable nanoparticles. Apisolex polymer utilizes micellar technology to encapsulate molecules of hydrophobic API, enhancing API solubility by up to 50,000-fold with minimal API loss and more than 90% API recovery.

Table 6_Examples of polymeric micelle-based drug products in clinical trials or approved

Enabling higher drug loading

Traditional inclusion complexing agents used in formulations only achieve API to solubilizer ratios of 1:100. However, Apisolex excipient can achieve an API to solubilizer ratio as high as 40:100. This greatly reduces the amount of polymeric excipient used in the final dosage form, allowing for an increased MTD or reduction in the overall volume of drug administered.

Improving safety

Compared to other water-soluble polymers like PEG, Apisolex polymer has a better safety and toxicity profile. Generated from safe amino acid-based building blocks, this amphiphilic copolymer incorporates a hydrophilic poly(sarcosine) block and a second drug-encapsulating block comprised of a mixture of hydrophobic D- and L- poly (amino acids). As such, Apisolex polymer exhibits inherently low toxicity.