As many as nine in ten new chemical entities (NCEs) are poorly soluble and poorly bioavailable.1 Commonly classed as “brick-dust” active pharmaceutical ingredients (APIs), they are typically characterised by a high molecular weight, a high melting point and high crystallinity. Dissolving slowly and poorly both during formulation and in vivo, their bioavailability is compromised, which can prevent them from coming to market and deprive patients of urgently needed new therapeutics for chronic and life-threatening diseases.
One key sticking point is that excipient use is lagging behind these market needs. Many established excipients are incapable of unlocking the benefits of these promising APIs. Yet, formulators are hesitant to use novel technologies because of regulatory ambiguity. Excipients are typically assessed as part of a drug product submission package, placing the regulatory risk on the drug developer. Because of this, many formulators will opt to use an excipient with precedence of use in an approved drug … despite more appropriate novel ones being available. This article examines the benefits of novel excipients to realise the potential of promising Class II and Class IV APIs when developing effective, patient-centric drugs.
Overcoming the challenge of parenteral solubility
Injectable and intravenous dosage forms play a key role when treating acute and chronic conditions. This is especially the case in oncology, with a recent review highlighting that 27.5% of parenteral NCEs were for oncological therapeutics.2 Yet, many APIs being considered for parenteral delivery exhibit poor solubility and bioavailability. Although excipients such as polyethylene glycol (PEG) have been used to solubilise IV-administered APIs, they can cause adverse effects such as hypersensitivity; as such, safer and more effective alternatives are required.
One solution is microencapsulation. Here, polymer micelles — nanosized colloidal carriers with a hydrophobic core and a hydrophilic shell — dissolve hydrophobic APIs and stabilise them in an aqueous environment. Lubrizol’s injectable-grade Apisolex, a novel polyamino acid-based amphiphilic polymer, offers the advantages of being biocompatible, non-toxic and biodegradable, with up to 50,000 times greater solubility enhancement than commonly used alternatives. It also allows for drug loading up to 40% (compared with 1% with traditional solubilisers such as PEG), which enables more API delivery in a smaller dose. This offers the advantages of lower dosage frequency or reduced treatment times.
Enhancing solubility in oral solid-dose drug delivery
In oral solid dosage forms, amorphous solid dispersion (ASD) is a common physical modification technique for poorly soluble APIs. ASDs disrupt the drug’s crystalline structure and increase the surface area to improve gastrointestinal dissolution. Solvent evaporation processes such as spray drying can be used to create ASDs, in which a liquid feed of API, polymer excipient and solvent is atomised, dried and collected as solid particles.
However, polymer excipients such as hydroxypropyl methylcellulose (HPMC) typically only support drug loading up to 40%. Apinovex, Lubrizol’s high-molecular-weight polyacrylic acid polymer, can stabilise spray-dried ASDs even after 6 months under accelerated conditions. It also offers higher drug loading up to 80% — double that of Soluplus and AFFINISOL HPMC excipients. In studies with BCS Class II ritonavir and itraconazole, it offers a ten-fold improvement in crystalline API dissolution. With chemistry similar to Lubrizol’s existing and widely used Carbopol polymers, it is non-mutagenic, compatible with a wide range of APIs and forms low-viscosity solutions for ease of processing.
Extended-release solid dosage formulations are preferred when consistent, sustained dissolution in the gastrointestinal tract is necessary to optimise therapeutic efficacy and minimise the risk of side-effects from high-concentration peaks. However, this can create even greater formulation complexity for APIs with poor solubility. Using solubility enhancing excipients, such as Lubrizol’s Apinovex, enables consistent release and greater bioavailability during a specific time period.
Addressing patient needs
As regulatory bodies increasingly focus on the patient experience, a crucial aspect of excipient choice for solubility enhancement is its impact on patient-centricity. Parenteral dosage formats with high excipient loads or large volumes can be painful. Similarly, for elderly patients with age-related dysphagia, large tablets may present a choking risk. Research has also shown that up to 40% of children struggle to swallow even normal-sized tablets. For chronic conditions requiring ongoing drug treatment, such as cardiovascular disease, this is a particularly salient issue. As many as three in four patients fail to take their medication as prescribed; the greater the number of daily doses required, the more patient compliance declines. To improve patient compliance with their treatment, more tolerable dosage forms are imperative.
Novel excipients that enhance solubility and reduce the excipient concentration can play a key role when it comes to more manageable patient-friendly drug delivery. A higher drug load that enables smaller tablet sizes may encourage compliance, whereas extended-release drugs might facilitate a reduction in dosing frequency. Some of the traditional excipients used in oncology can cause severe side-effects, amplify the overall toxicity of therapeutic delivery and reduce the maximum tolerated dose. Novel excipients with more attractive safety profiles that enable lower-volume IV dose forms can reduce side-effects, administration time and dosage frequency.
The outlook for novel solubility enhancing excipients
Poorly soluble APIs are not going away. If anything, with ongoing scientific and computational advancements, drug candidates are only going to become more complex. The adoption of novel excipients is therefore increasingly important to enhance solubility. In addition, new ingredients that enable higher drug loading, improved bioavailability and enhanced patient-centricity can drive innovation. They can also afford a level of IP protection that traditional products cannot.
Engaging with an established supplier early in the development process can help to derisk the adoption of novel excipients. Including the excipient in animal toxicity studies, for example, can accelerate development by identifying safety concerns and data gaps at an early stage. For instance, if a novel excipient shared similar chemistry with an approved one, existing safety data may support the new drug application. Lubrizol actively encourages collaboration by working with formulators to develop data and regulatory submissions, with data-sharing agreements in Europe and Drug Master Files in the US, Canada and China. Novel excipients are the key to unlocking innovation in drug development, enabling highly promising APIs to reach the market and provide patients with therapeutics that can change their lives.
References
1. M. Rodriguez-Aller, et al., “Strategies for Formulating and Delivering Poorly Water-Soluble Drugs,” Journal of Drug Delivery Science and Technology 30(Part B), 342–351 (2015).
2. P. Dupont, “Snapshot of the Parenteral Delivery Market,” Pharmaceutics International (17 June 2022): retrieved from Outsourced Pharma website (www.outsourcedpharma.com/doc/snapshot-of-the-parenteral-drug-delivery-market-0001).
For more information
Meera Raghuram
Director of Regulatory and Sustainability Strategy
Lubrizol
www.lubrizol.com