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

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2. 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
3. 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.
4. 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.