Issue:June 2023
EXCIPIENT TECHNOLOGY - A Juggling Act: Factors at Play in Your Choice of Solubilizing Parenteral Excipients
INTRODUCTION
It is a well-known fact the oral drug delivery route is preferred to any injectable route by the majority of patients. However, parenteral delivery, which includes intramuscular, subcutaneous, and intravenous administration, is invaluable for a variety of compelling reasons. Chief among these is the ability of injectable drugs to bypass gastrointestinal first-pass metabolism, which greatly reduces the concentration of an administered drug and its bioavailability.
Not all injectable formulations have equal requirements, however, and particle size is a key consideration that must be taken into account. For intramuscular and subcutaneous administration, API particle size can be larger, but for intravenous delivery, particles must be on the nanoscale. In addition, some APIs can also be cytotoxic and irritating to tissue, ruling out the oral or subcutaneous routes and necessitating intravenous administration.
Adding to the complexity, as in other routes of administration, poor water solubility can be a challenge for injectable drugs that must be addressed. A trend for new drug candidates with poor aqueous solubility exacerbates the issue. At present, 60% to 90% of potential new APIs in development pipelines, and more than 40% of those on the market, are poorly water soluble.1
Insolubility issues can effectively prevent life-changing parenteral drugs from achieving the necessary bioavailability for the desired therapeutic effect, causing them to fail in clinical trials. With the price tag on bringing a new drug to market amounting to approximately $1 billion, candidate failure during clinical trials due to poor solubility can have harsh financial consequences.2 Most importantly, patients can ill afford otherwise viable drugs being discounted due to low solubility, especially in light of the fight to develop cures for cancers and orphan diseases.
Taken together, these factors have led to a strong drive for effective, non-toxic solutions to poor drug solubility. Finding options that can provide adequate drug loading can be a challenge.
EXCIPIENT-BASED METHODS TO COMBAT POOR SOLUBILITY
There are a number of methods for enhancing the solubility of parenteral drugs, and each comes with its own advantages and disadvantages.
Tweens are ubiquitous in the pharmaceutical industry as solubilizing excipients. Referring to polysorbates, most commonly polysorbate 20 and polysorbate 80, these long chain molecules have both hydrophilic and hydrophobic segments that allow them to emulsify poorly water-soluble chemicals. While effective in many situations, they can suffer from instability and are known to give rise to hypotensive effects in dogs – a drop in blood pressure that can induce fainting.3
Cyclodextrins have been effectively associated with neutral, anionic, and cationic APIs to enhance their solubility. They can be utilized for both lyophilized or solution formulations. However, as the molecules work by complexing APIs in a hydrophobic pocket, it is not applicable across the board and is limited to APIs with the ideal shape, size, and charge. With an inclusion ratio of 1:100 (API:solubilizer), cyclodextrins give rise to low drug loading compared to other options, making it potentially difficult to achieve the maximum tolerated dose of the API.
Polyethylene glycols (PEGs) are another traditional excipient used to enhance the solubility of drugs. Containing both polar and non-polar groups, PEGs are soluble in a wide variety of solvents, including water, and when included in a drug formulation, can effectively enhance aqueous solubility. However, potential toxicity concerns and adverse side effects related to the use of PEG are driving the industry to seek out alternative means of enhancing solubility.4
Apisolex™ polymer, composed of building blocks occurring or produced through natural processes in the body, has emerged as a non-toxic, non-immunogenic, and biocompatible alternative to PEG that can rise to the challenge of poor solubility. The technology leverages an amphiphilic multi-block copolymer. This incorporates a hydrophilic poly(sarcosine) block and a second drug-encapsulating block composed of a mixture of hydrophobic D- and L- poly (amino acids). Unlike organic cosolvents and surfactants, Apisolex polymer is a benign ingredient that doesn’t add toxicity to the drug vehicle. It works through a highly flexible nanoencapsulation method, which allows it to be universally applicable to APIs as a solubilizer and to outperform alternatives.
THE MECHANISM OF NANOENCAPSULATION
Apisolex technology works by forming nanomicelles around API molecules. The insoluble API, either crystalline or amorphous, and Apisolex polymer are solubilized and then mixed in an aqueous media. Operating on the principle that “like attracts like,” the hydrophobic ends of the Apisolex polymer cluster around the hydrophobic API. Meanwhile, the hydrophilic ends point outward, creating soluble nanomicelles. The solution can be sterile filtered or autoclaved depending on the physical and chemical stability of the API.
These micellular structures that encapsulate the API form as the solvent is removed from the solution or emulsion during diafiltration and/or lyophilization. If lyophilized, the drug product reconstitutes in saline in less than 30 seconds, ready for administration.
This mechanism of action allows Apisolex excipient to be more universally applicable to APIs, offering the flexibility to accommodate molecules of wide-ranging shapes and sizes. As nanomicelles form on the nanoscale with Apisolex technology, it can produce soluble drug particles in the appropriate size range for intravenous administration, while offering the flexibility to create larger particles for the subcutaneous and intramuscular routes. It also enables rapid evaluation, facilitating a shorter development cycle for clinical formulations. Apisolex polymer’s highly effective performance has been shown to enhance solubility by up to 50,000-fold.
THE IMPORTANCE OF SCALE
While innovative technologies are key to solving the challenge presented by poor solubility, in order to be practicable, they must also be scalable. Complex manufacturing techniques can cause complications during scale up. As such, allowing developers to stick with simpler techniques they are familiar with gives more confidence when it comes to scaling up production. For example, injectable-grade Apisolex polymer is compatible with standard, scalable formulation techniques, such as solution mixing or oil-in-water emulsion formulation, with more than 90% API recovery. This can help to streamline development and reduce API waste, helping life-changing drugs reach patients in need faster.
TAKING A LONG-TERM VIEW: IP PROTECTION
Intellectual property (IP) protection is an invaluable resource to protect future success when developing a new drug formulation or adapting an existing one. Incorporating a novel excipient with robust patent protection can assist with securing IP protection. For instance, with a long patent life remaining, Apisolex technology enables both the formulation of new chemical entities and the reformulation of existing APIs to enhance their therapeutic effect and deliver improved patient outcomes via the FDA’s 505(b)(2) regulatory pathway. By breathing new life into APIs that failed to progress due to solubility issues – while also ensuring patent protection – novel technologies such as Apisolex excipient open up new avenues for pharma companies to deliver important drugs to the market.
PUTTING APISOLEX TECHNOLOGY TO THE TEST
Scalability, safety, and IP protection are all important concerns. But ultimately, if performance is lacking, it will be necessary to seek out a different approach to improve solubility. This is a crucial factor in your choice of excipient. The solubilization properties of Apisolex polymer were examined in comparison with other excipients for a series of poorly water-soluble APIs. The experiments were conducted by non-optimized, standard dispersion techniques (mixing or homogenization), followed by dilution or lyophilization and reconstitution with a goal of simply evaluating the comparative performance of the various excipients. Toward that end, relatively low success metrics were selected:
- A target API concentration of 500 μg/ml after dilution or reconstitution
- Turbidity (NMT 100 NTU)
- Particle diameter (NMT 150 nm)
- Drug recovery after filtration (NLT 80%)
These metrics, if met, would result in end-product solutions that would be clear, homogeneous, or at worst, slightly turbid.
Series A compared Apisolex technology to the tweens, polysorbate 20, polysorbate 80, and Cermophor® for a variety of poorly water-soluble APIs. Only Apisolex polymer worked across the board, successfully solubilizing every API, and it did so at an API to solubilizer ratio much higher than that of traditional excipients.
Similar results were found when Apisolex excipient was tested against PEG-PLGA, TPGS and Captisol®. The universal applicability of Apisolex technology relative to other techniques with this series of APIs was again demonstrated in comparison with other solubilizers processed using the same lyophilization and reconstitution technique.
In additional experiments conducted for the experimental APIs, Apisolex excipient increased drug solubility by up to 50,000-fold.
The safety and toxicity of the Apisolex excipient was also evaluated. The polymer was used to solubilize paclitaxel, a chemotherapy medication. The Apisolex/paclitaxel formulation was well tolerated in test animals, demonstrating equivalent activity to paclitaxel on its own in terms of in vitro cytotoxicity, and in vivo tolerability. The lyophilized drug product was reconstituted in less than 30 seconds. Moreover, the process was shown to be more than 90% efficient, with a small particle size and narrow size distribution obtained. The Apisolex/paclitaxel formulation has further demonstrated more than 24 months’ stability under ambient conditions to date, with no change in physicochemical properties.
In light of the technology’s remarkable capabilities, an approved oncology API reformulated with Apisolex excipient is currently under development by a pharmaceutical client. This project has progressed to the GMP manufacturing stage with clinical trials scheduled for 2023.
DRIVING CHANGE FOR PATIENTS
With the continued trend for poorly soluble new drug candidates – and the need to bring new cures to market for cancer and other diseases – novel solubilization approaches have never been more important. Excipients are a vital tool in this effort and in the industry-wide movement to make drugs more patient-centric. The power of novel excipients such as Apisolex polymer could revolutionize the parenteral drug development landscape, effectively solubilizing a wide range of APIs without compromising on safety or stability. Ultimately, this will be felt by patients as life-changing medicines that would otherwise fail in clinical development are now able to reach the market. u
REFERENCES
- Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B. 2015 Sep;5(5):442-53. doi: 10.1016/j.apsb.2015.07.003.
- Wouters OJ, McKee M, Luyten J. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018. JAMA. 2020;323(9):844–853. doi:10.1001/jama.2020.1166
- Torres-Arraut E, Singh S, Pickoff AS. Electrophysiologic effects of Tween 80 in the myocardium and specialized conduction system of the canine heart. J Electrocardiol. 1984 Apr;17(2):145-51. doi: 10.1016/s0022-0736(84)81088-2. PMID: 6736837.
- Shiraishi K, Yokoyama M. Toxicity and immunogenicity concerns related to PEGylated-micelle carrier systems: a review. Sci Technol Adv Mater. 2019 Apr 15;20(1):324-336. doi: 10.1080/14686996.2019.1590126.
Joey Glassco is the Senior Global Market Manager for Injectable Drug Delivery at Lubrizol Life Science Health (LLS Health). She leads a cross-functional team to provide pharmaceutical excipient and contract development and manufacturing solutions to the pharmaceutical industry. She serves as the Director of Marketing for the CDMO division and was responsible for two new product launches. Prior to joining LLS Health, she spent nearly 15 years in marketing roles in various Lubrizol business units. She also has more than 10 years of experience in finance at Lubrizol, Ford Motor Company, and The Franklin Mint. She earned her Bachelor of Science degrees in Finance and Accounting from Juniata College and her MBA from the Smeal College of Business at Pennsylvania State University.
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