With the increasing prevalence of poorly soluble drugs in the pharmaceutical pipeline, Matt Finkelhor, commercial manager, Global Novel Polymers at Lubrizol, explores how to realise therapeutic potential with the right excipients.
Lubrizol
The effective delivery of poorly soluble drugs remains one of the pharmaceutical industry’s biggest challenges. Up to 90% of new chemical entities (NCEs) have poor aqueous solubility, requiring modification – whether through physical, chemical, microencapsulation or inclusion complex techniques – to achieve a therapeutic effect.
“Brick-dust” active pharmaceutical ingredients (APIs) are typically BCS Class II (highly permeable, poorly soluble) or Class IV (poorly permeable, poorly soluble). They exhibit high crystallinity, high molecular weight and a high melting point, dissolving slowly and poorly in formulation and in vivo, which limits their bioavailability.
Novel excipient technology can play a critical role in transforming promising, brick-dust APIs into effective, patient-centric therapeutics, while providing formulation benefits for lean manufacturing. This article explores key formulation, solubility and bioavailability considerations for oral, injectable and IV dosages.
1. Unlocking solubility in oral solid-dose forms
Oral solid-dose forms continue to dominate pharmaceutical markets, but their effectiveness is often compromised by poor solubility. The use of amorphous solid dispersion (ASDs) is a widely used physical modification technique for poorly soluble APIs. ASDs disrupt their crystalline structure, increasing the surface area to improve dissolution in the gastrointestinal (GI) tract.
ASDs can be formed using solvent evaporation processes such as spray-drying, where a liquid feed of API, polymer excipient and solvent is atomised, dried and collected as solid particles. Here, excipient selection depends on factors such as its solubility in common solvents, viscosity in solution and ability to stabilise a high API level in an amorphous form.
Traditional polymer excipients such as hydroxypropyl methylcellulose (HPMC) and povidone have been industry mainstays for decades, but typically only support drug loading of up to 40%. Modern alternatives have demonstrated the ability to stabilise higher drug loading in spray-dried ASDs – up to 80% in the case of Apinovex, Lubrizol’s high-molecular-weight polyacrylic acid polymer.
2. Enhancing parenteral solubility
Injectable and intravenous dosage forms are important for treating both acute and chronic conditions. Yet their formulation is hindered by the poor solubility and bioavailability of many promising APIs. Historically, excipients such as polyethylene glycol (PEG) have been used to solubilise IV-administered APIs, but they can be associated with adverse effects such as hypersensitivity and neuropathy. This underscores the need for safer and more effective alternatives.
Microencapsulation is an increasingly accepted solution. Polymer micelles – nano-sized colloidal carriers with a hydrophobic core and a hydrophilic shell – dissolve hydrophobic APIs and stabilise them in an aqueous environment. Lubrizol’s Apisolex, for example – a novel poly-amino acid-based amphiphilic polymer – is biologically inert, enhancing solubility up to 50,000-fold and offering high drug loading without side effects.
3. Improving extended-release oral-solid dosages
Extended-release oral solid dosage forms are indicated where API absorption in the GI tract needs to be sustained over a specific period to maintain constant drug concentration in the bloodstream. This can minimise the risk of side effects associated with high concentration peaks and enhance the treatment’s overall effectiveness by maximising absorption and extending the duration of action.
Solubility issues become more complex in extended-release applications, where consistent, prolonged dissolution is essential for optimising therapeutic efficacy. For APIs with particularly poor solubility, combining extended-release delivery with solubility-enhancing excipients such as Apinovex enables consistent release and higher bioavailability over time. This hybrid approach addresses two of the most pressing formulation challenges in a single design.
4. Enhancing patient-centricity
A crucial aspect of excipient choice for solubility enhancement is its impact on patient-centricity. This is of increasing importance in drug development as regulatory bodies become more focused on the patient experience. Large tablets, for example, can reduce compliance in children, who can struggle to swallow even normal-sized tablets, and in elderly patients, who are more likely to have age-related dysphagia. Likewise, injectables or IV forms with high excipient loads or large volumes can be painful and less tolerable to patients.
By improving solubility and reducing the required excipient concentration, novel excipients contribute directly to more manageable, patient-friendly drug delivery. For example, a higher drug load that allows for smaller tablets may encourage adherence to a medication regimen. Similarly, extended-release drugs can enable a reduction in dosing frequency, which can be crucial in chronic conditions requiring ongoing drug treatment, such as cardiovascular disease. This is a key issue, as up to 75% of patients fail to take their medication as prescribed, with an increasing number of daily doses correlated with declining patient compliance.
In oncology, some traditional excipients can exert severe adverse biological effects, adding to the overall toxicity of therapeutic delivery and reducing the maximum tolerated dose. Novel excipients with more attractive safety profiles that enable lower-volume IV dose forms can improve the patient experience by minimising side effects, administration time and dosage frequency.
5. Supporting a lean manufacturing ethos
Beyond technical efficacy, excipients also offer tangible benefits in terms of simplified production and greater scalability. Choosing the right excipient can maximise a novel API’s therapeutic efficacy, accelerating time to market during drug development while minimising processing complexity and waste. For example, for injectable dosages, Lubrizol’s Apisolex facilitates a simple formulation process, forming micellar structures which encapsulate the API during lyophilisation and reconstitute in saline in less than 30 seconds.
6. Driving innovation
Novel excipients that enable higher drug loading, better bioavailability and enhanced patient-centricity are both functional components and drivers of innovation. Their use can also allow a level of IP protection not offered by traditional products and unlock the benefits of the FDA 505(b)(2) accelerated regulatory pathway for drug approval.
Indicative new IP protection from novel excipients means there is a long patent life ahead for drug developers to capitalise on. While NCEs can generally rely on their own IP, novel excipients may be useful for older clinical candidates that had been sidelined due to their solubility issues. Despite this, there has been hesitancy within the industry to use novel excipients due to perceived regulatory and scale-up challenges. Choosing an established and reliable excipient supplier can mitigate these risks by establishing robust processes under GMP guidelines, providing safety and toxicity data, and creating drug master files.
Optimising therapeutic potential with next-generation excipients
As the pharmaceutical industry grapples with an expanding pipeline of poorly soluble APIs, the strategic use of novel excipients has become increasingly critical. Whether stabilising ASDs for oral delivery, achieving consistent extended-release profiles or solubilising hydrophobic APIs for parenteral use, these innovative technologies offer attractive solutions to the solubility dilemma.
With solubility now a key determinant of new drug candidates’ success, integrating novel excipients early in the development process will be crucial for optimising therapeutic potential, formulation efficiency and patient-centricity.