CARBOMER CHEMISTRY - Breaking Ground in Controlled Release

INTRODUCTION

Controlled-release medicines are increasingly in demand, with market share forecasted to more than double by 2032.¹ This growth is driving a need for techniques that can optimize the properties of controlled-release medicines. Active pharmaceutical ingredients (APIs) that are challenging to formulate often require multiple doses, leading to a high pill burden for patients. Improv­ing patient comfort, convenience, and compliance are therefore key motivators for developing controlled-release drugs. As they maintain release of the API over a defined period from a single dosage form, these products can often be administered less fre­quently – a significant benefit for patients.

The need for controlled-release drugs is further fueled by the increased prevalence of chronic diseases and the global aging population. It is estimated the number of people in the US alone aged 50 years and older will increase by 61.11% from 2020 to 2050.² Of the population 50 years and older, the number with at least one chronic disease is estimated to increase by 99.5% in that same period.²

Chronic diseases, such as diabetes, can be a daily inconven­ience for a patient’s foreseeable future, so innovations in con­trolled-release dosages that can reduce administration frequency promise to improve patients’ quality of life and increase compli­ance with prescribed medication. Meanwhile, elderly patients often have complex medication regimens and a lower tolerance to high dosages, and can also suffer from dysphagia, or difficulty swallowing.¹ As such, the geriatric population in particular stands to benefit from reduced administration frequency and dosage form improvements through advancements in sustained release.

In addition to the important patient-centric drivers, controlled release is also commercially valuable to pharmaceutical compa­nies as a lifecycle management tool. For some novel immediate-release products nearing the end of patent protection, leveraging the 505(b)(2) pathway with an extended-release version can ex­tend the lifetime of a drug, differentiating from generic competi­tion, and protecting the developer’s investment.

Innovative excipient technologies are key to accommodating the growing demand and enabling more patients to benefit from controlled-release dosage forms.

FACTORS TO CONSIDER WHEN SELECTING AN ORAL EXCIPIENT FOR CONTROLLED RELEASE

A variety of factors influence excipient choice for controlled-release drugs. The first step when selecting an excipient is often to look at precedence of use, with the aim of repeating previously successful methods for achieving controlled release. As a result, it is common for existing products to make use of grades of hy­droxypropyl methylcellulose (also known as HPMC or hypromel­lose). This ubiquitous cellulosic polymer forms a gel layer around the API, which subsequently erodes to achieve extended release.

However, the success of previously implemented approaches is not guaranteed. For example, in some cases, formulators are unable to achieve a high enough drug loading or are unable to exercise the desired control over release within a given therapeu­tic window. There could even be compatibility issues between the specific API and the chosen excipient – particularly with formula­tions containing multiple APIs.

In addition, it is necessary to consider compliance with GMP standards and scalability at the formulation stage and choose an excipient that will be compatible with mainstream manufacturing techniques at scale later down the line.

When challenges arise with excipients that are already widely used commercially, it is necessary to look beyond precedence of use to new solutions.

METHODS TO ACHIEVE CONTROLLED RELEASE & ASSOCIATED CHALLENGES

The most straightforward method to produce controlled release is through a matrix tablet. This typically involves gran­ulating the API with the chosen controlled-release excipient and forming the material into a tablet, following which controlled re­lease is achieved out of the matrix.

Recently, direct compression has also gained interest as a manufacturing tech­nique for matrix tablets. Utilizing free-flow­ing ingredients and bypassing several manufacturing steps associated with gran­ulation, direct compression can reduce manufacturing time and costs. While gran­ulation is still the dominant technology in the controlled-release space, direct com­pression is expected to grow in popularity in the future.

In addition to matrix forming, there are also companies that utilize coating technologies to provide a layer for sus­tained release. More complex approaches are typically used when there’s a challenge with the API that makes it difficult to for­mulate a simpler matrix or coated tablet, such as strong hydrophilicity. This leads to the API being highly soluble and dissolving quickly in solution, making it difficult to control release through traditional sys­tems. Additionally, if it is necessary to achieve a high dose of API, it can be diffi­cult to then control release.

Alternative systems for APIs that are challenging to formulate often rely on technologies, such as multi-particulate sys­tems and osmotic pumps, to control re­lease. This lengthens processing time and would only be used when more simple ap­proaches, such as coating and matrix tableting, have failed.

When it comes to excipients for sus­tained release, one of the biggest chal­lenges formulators experience is usage levels. It is common for a large amount of excipient to be needed to control release of an API – for example, using HPMC by itself – especially for hydrophilic or high-dose APIs.

The excipient polymer could comprise as much as 30% of the tablet, leaving less flexibility for adding different excipients to provide other much-needed properties. It also leaves less space to incorporate a high-dose API and may lead to large pill sizes that are challenging for some pa­tients to swallow.

SEEKING OUT PROVEN INNOVATIONS

In response to controlled-release for­mulation challenges and the associated need for simpler, effective solutions, tried and tested excipients like carbomer poly­mers can come into play.

When carbomer tablets are placed in contact with dissolution media, the exter­nal surface of the tablet becomes hy­drated. It then swells and forms a gel layer that efficiently controls the release of the drug from the tablets.

Due to the crosslinked nature of the polymer, the hydrogel is not composed of single entangled chains of polymer (as in the case of the water-soluble polymeric matrix), but discrete microgels made up of many polymer particles, in which the drug is dispersed (Figure 1). Because the car­bomer is not water soluble, it does not dis­solve, and erosion in the manner of linear polymers such a HPMC does not occur. Rather, when the hydrogel is fully hy­drated, osmotic pressure from within may break up the structure, essentially by sloughing off discrete pieces of the hydro­gel.

Carbopol® polymers are an example of carbomer chemistry that has been suc­cessfully leveraged in controlled-release formulations. These are efficient matrix-forming excipients that are highly effective at low concentrations – indeed, more ef­fective than linear (cellulosic) materials such as HPMC in sustaining drug release. Chemically, Carbopol polymers are high  molecular weight polymers of acrylic acid, with a 3D structure that enables efficiency in controlled/extended release.

Drug-release rates are affected by dif­ferences in the rates of hydration and swelling of the polymer hydrogel, which are dependent on the molecular structure of the polymers, including crosslink den­sity, chain entanglement, and crystallinity of the polymer matrix.

Generally, increasing the level of Car­bopol polymer in a formulation leads to slower and more linear drug release, with a stronger gel layer, fewer regions of low micro viscosity, and fewer interstitial spaces between microgels.

Powder grades of Carbopol polymers, such as Carbopol 971P NF polymer and Carbopol 974P NF polymer, are amenable to traditional wet and dry gran­ulation processes. These grades can achieve robust control over drug release at usage levels as low as 5%. There is also a granular form of carbomer called Car­bopol 71G polymer, which is free-flowing and directly compressible, leading to sim­plified processing.

In addition, all these grades of Car­bopol polymers are IID-listed ingredients used in FDA-approved oral drug products. Their strong precedence of use in the oral space facilitates their use in novel ex­tended-release tablets and 505(b)(2) products.

One of the most important features of Carbopol polymers is they can help reduce tablet size and control release of a high-dose API. As a result, Carbopol polymers can enable formulators to bypass complex processing techniques, such as an osmotic pump or multi-particulate system. It is pos­sible to continue working with more simple matrix tablets using Carbopol polymers and still achieve control over release.

As a result of their useful characteris­tics, carbomer polymers have been used as controlled-release excipients for several decades now. Commercial examples in­clude Lyrica CR, the extended-release ver­sion of Lyrica for the management of chronic pain, which utilizes carbomer poly­mers. Mucinex, an expectorant that re­lieves symptoms of the common cold, delivers controlled release in a bilayer for­mat, utilizing Carbopol polymer in the ex­tended-release layer to enable the drug to be delivered for up to 12 hours.

The applications of Carbopol poly­mers even extend to metformin, the front-line treatment for type-2 diabetes. Case studies show Carbopol polymers can be of great benefit for conferring sustained re­lease to metformin formulations, as well as reducing tablet size by 20%-30%, po­tentially improving the quality of life for millions of patients worldwide.³

COMBINING EXCIPIENTS TO FACILITATE IMPROVED PROPERTIES

Carbopol polymers are a strong first-choice alternative to HPMC, one of the most widespread excipients for controlled release on the market. It is possible to apply Carbopol polymer as a stand-alone excipient or supplement an HPMC formu­lation with Carbopol polymer as a co-ex­cipient.

Carbopol polymer combined with other controlled-release excipients results in more efficient extended-release tablets with improved performance, as illustrated in Figures 2 and 3. As the data shows, whether HPMC or carbomer performs best as a stand-alone matrix former, the com­bination of both excipients provides the best control over drug release. This “syn­ergistic” effect can be a valuable tool for formulating challenging APIs into ex­tended-release formats.

With carbomer chemistry, a full refor­mulation may not be necessary to formu­lators struggling to achieve release targets using HPMC alone. Simply adding Car­bopol polymers to cellulosic-based formu­lations may solve the problem.

UNLOCKING CONTROLLED-RELEASE MEDICINES FOR PATIENTS

Patients stand to benefit greatly from controlled-release treatment options that reduce administration frequency, espe­cially those with chronic diseases or complex drug regimens. Innovative, com­mercially proven excipients such as car­bomers are key to both unlocking patient-friendly formulations and helping pharma companies extend the lifetime of their portfolios.

By working alone or alongside other well-established excipients for controlled release such as HPMC, the power of car­bomer chemistry can help drug developers to overcome common challenges associ­ated with controlled-release formulations without resorting to more complex tech­niques. Patient-centric, formulator-friendly carbomer polymers offer a long runway for innovation for small molecule formu­lations, enabling a new wave of con­trolled-release medicines that can be streamlined to the market and improve patients’ lives.

REFERENCES

1. Precedence Research: Controlled Release Drug Delivery Market – Global Industry Analysis, Size, Share, Growth, Trends, Regional Outlook, and Forecast 2023-2032. Janu­ary 2023 https://www.precedenceresearch.com/con­trolled-release-drug-delivery-market
2. Ansah JP, Chiu CT. Projecting the chronic disease burden among the adult population in the United States using a multi-state population model. Front Public Health. 2023 Jan 13;10:1082183. doi: 10.3389/fpubh.2022.1082183.
3. Carbopol® Polymers for Nitrosamines (NDMA) Compliant Metformin Extended Release Tablets https://www.lubrizol.com/-/media/Lubrizol/Health/Litera­ture/Carbopol-Polymers-for-Nitrosamines-NDMA-Compli­ant-Metformin-Eextended-Release-Tablets.pdf.

Nick DiFranco is the Global Market Segment Manager for Oral Treatments at Lubrizol Life Science Health (LLS Health). In his role, he coordinates a multi-disciplinary team offering excipients and services for controlled release and solubility enhancement in oral solids and liquids, including Carbopol® and Apinovex™ polymers. Prior to this role, held positions as an Applications Scientist and Market Manager at Lubrizol supporting long-acting drug delivery and CDMO services. He earned his BS in Biomedical Engineering (Biomaterials focus) and a Master of Engineering and Management degree from Case Western Reserve University.