Kamla Pathak.
Pharmacy College Saifai, Uttar Pradesh University of Medical Sciences, Etawah 206130, Uttar Pradesh, India.
Keywords: Hydrogels, biologics, sustained release.

In the past decade, depot systems for tissue engineering, cell therapy, biomedical research, and therapeutic proteins, have been extensively investigated. Hydrogels offer an interesting platform for sustained delivery of biologicals as these can be readily formulated with limited impact on their integrity and stability. Their high-water content and porous structures make them especially suitable for loading with therapeutic proteins However, relatively rapid release of the hydrophilic compounds (period of hours to days) and limited drug loading capacity (<10%) present major challenges. Cleavable cross-linker or hydrogels that respond to an external trigger such as ultrasound have been suggested as suitable alternatives. However, scale-up and cost-effective manufacturing using safe and established excipients remains a challenge and hydrogels for biologicals are at present scarcely developed beyond the clinical evaluation phases. While some commercial products are available the future of hydrogels for biologicals depends on the medical needs, the general benefit/risk balance, and overall costs.

Article Information

Identifiers and Pagination:
First Page:01
Last Page:05
Publisher Id:JAppPharm (2018 ). 10. 01-05
Article History:
Received:May 3, 2018
Accepted:May 17, 2018
Collection year:2018
First Published:May 22, 2018

Hydrogels as depot systems for sustained release of low molecular weight therapeutic proteins are attractive options for pharmaceutical industry. These are of particular industrial interest because many hydrogels can be produced solely by mixing aqueous solutions. Thus, the relatively “delicate” proteins (e.g. immunoglobulins) can be formulated without compromising their integrity and stability1. Besides full-sized immunoglobulins, the amenable architecture of antibodies has made it possible to develop more than 60 alternative antibody formats2. More than thirteen have proceeded into clinical development3.  The antibody formats with molecular weights less than 50 kDa are of interest to the formulators for development as depot systems because of their relative short circulation half-life that requires frequent subcutaneous or intravenous dosing. The most commonly used depot systems are inserts, coatings, microparticles, based on natural products or synthetic polymers; and hydrogels4. Currently an increasing number of antibody formulations are developed as high concentrated liquid formulations (50 to 150 mg/ml) that can be self administered5. However, the advantage is contrasted by the manufacturing complexities that require special equipment and novel excipients. 

From a manufacturer’s point of view, hydrogels appear to be an attractive format as compared to other depot systems since hydrogels are typically produced by a simple mixing procedure of biocompatible materials in aqueous solutions at ambient temperature. Hydrogels are elastic, hydrophilic, cross-linked, 3-dimensional networks, composed of natural or synthetic polymeric, water insoluble materials that can bind a high amount of water6. Their high-water content and their mechanical properties of soft matter and porous structures make them especially suitable for loading with therapeutic proteins7. However, hydrogels suffer from limited loading capacity; short time period (hours to days) in which hydrogels release their hydrophilic cargo and the relative high plasma concentrations needed to achieve a therapeutic effect. This may limit the use of hydrogels for antibodies but the same is not true for several alternative antibody formats namely Fab, Fab2, Fab3, scFv, triabodies, diabodies, minibodies, nanobodies, Bi-specific T-cell engagers (BiTE), dual-affinity re-targeting antibodies (DARTs) and single-domain antibodies which often possess plasma half-lives of less than one day and can be highly potent8.

In order to develop advanced and cost-effective depot formulations, the properties of hydrogels need to be optimized. Apart from pharmaceutical criteria (formulator/ manufacturer point of view) safety issues are equally important. From the drug developer’s point of view, hydrogel building blocks should be FDA approved and the cargo molecule should be stable and not interact with the hydrogel during the manufacturing process and during the entire release period at body temperature9. The manufacturing process should be simple without the use of heat or organic solvents leading to a formulation that can be sterile-filtered and injected within seconds through a 27G or 30G needle. The hydrogel depot formulations should represent a platform technology, which could serve for a variety of drugs or drug categories. Loading capacities should be ideally at least 10% and drug product shelf-life at 2-8°C should be at minimum two years10. The reality is, however, quite different. Many delivery systems currently developed by research groups in academic institutions aim at increasing complexity rather than simplicity. Academic researchers tend to work on innovative and rather complicated delivery systems, whereas industrial research is focused on ease of production, cost of goods and manufacturing, process scalability, process robustness, and on reducing the number of excipients to the bare minimum. Collaborations between academia and industry need to be fostered to keep exchanging ideas, acknowledging all aspects needed for the development of a depot formulation, such as drug metabolism and pharmacokinetics, pharmacology, and toxicology.

A significant challenge of hydrogel formulations is their hydrophilicity and high-water content, which typically results in relatively rapid drug release of hydrophilic molecules (hours or days).  The concepts to prolong the release duration to weeks/months include accentuating the interactions between the drug and the hydrogel matrix, or incorporation of a diffusion barrier to retard the drug release. These strategies have been successfully implemented for hydrophobic drugs in InGell gamma by InGell Labs (Groningen, The Netherlands) wherein the depot system based on the gamma technology releases its hydrophobic cargo over a period of days to weeks11. For hydrophilic drugs, such as antibodies and other immunoglobulins, the challenges are far greater. In addition to short release period, challenges concerning use of hyaluronidase to widen the injection space and their loading capacities (1-5% by weight) are significantly important. Typical antibody dose ranges between 2 to 6 mg/kg, which translates into a plasma concentration of 50-150 µg/ml12. Depending on the plasma half-life, this concentration will, however, only be a fraction of that when released over the course of a week or even a month. A depot formulation for therapeutic proteins is therefore especially useful for highly potent drugs. An alternative solution to increase the loading capacity by use of highly concentrated crystalline/ solid amorphous protein solutions and to pre-administer an IV bolus dose followed by subcutaneous depot maintenance dose to achieve clinically relevant steady state concentrations.

Despite enormous academic research on hydrogel-based drug delivery systems, the number of hydrogels approved by the FDA or those in clinical development is limited. One of the few marketed hydrogels used for subcutaneous drug delivery is “Supprelina LA” by Endo Pharmaceuticals Solutions Inc., Dublin, Ireland, for sustained delivery formulation for histrelin acetate13. Another is Eligard™ 7.5 mg, (Novelon therapeutics, US) a polymeric matrix formulation for controlled delivery of leuprolide acetate, for over a month14. A platform technology from Foresee Pharmaceuticals Co., Ltd., Taipei, Taiwan, is a stabilized injectable formulation, for controlled-release formulations of small molecules, peptides, and proteins. Amongst the various successful research products, Foresee's FP-001(LHRH agonist), is in clinical phase III study for advanced prostate carcinoma therapeutics and FP02C-14-001 (MMP-12 inhibitor) is in phase I study15. Another platform sustained release technology BEPO® developed by MedinCell (Jacou, France) claimed as a game changer by the company is a simple yet flexible technology. BEPO®  on subcutaneous injection forms a fully bioresorbable depot  that can provide controlled release of therapeutic molecules for days, weeks or months and therefore can be used for treatment of chronic and short term illnesses16.

For proteins that require intravitreal injections, a hydrogel formulation is particularly attractive to improve patient convenience and compliance. For example, the anti-VEGF Fab-fragment ranibizumab (LucentisR) and the anti-VEGF monoclonal antibody bevacizumab (AvastinR) are clinically used to for age-related macular degeneration and proliferative diabetic retinopathy. Both treatments need to be administered via intravitreal injection every four to six weeks17. Many academic groups have developed intravitreal depot formulations for ranibizumab and bevacizumab so as to extend the duration to months instead of weeks.  Considering the extreme uncomforting injection procedure, any reduction in the injection frequency would be an instant marketing advantage. Besides ophthalmological applications, hydrogels have been researched for anti-cancer mAbs such as a trastuzumab (HerceptinR) hydrogel for breast cancer therapy18.

Though the progress in hydrogel technologies is evident, the commercialization of hydrogel formulations remains challenging. Scale up and cost-effective manufacturing using safe and established excipients need special mention. Hydrogels for biologicals are at present scarcely developed beyond the clinical evaluation phases. The future of “next generation” hydrogels for biologicals will thus depend on the success of suitable molecule formats especially those that are highly potent or exhibit short plasma half-lives in addition to the medical needs, the general benefit/risk balance, and overall costs.



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Prof. Dr. Cornelia M. Keck (Philipps-Universität Marburg)
Marburg, Germany


Welcome to the research group of Prof. Dr. Cornelia M. Keck in Marburg. Cornelia M. Keck is a pharmacist and obtained her PhD in 2006 from the Freie Universität (FU) in Berlin. In 2009 she was appointed as Adjunct Professor for Pharmaceutical and Nutritional Nanotechnology at the University Putra Malaysia (UPM) and in 2011 she obtained her Venia legendi (Habilitation) at the Freie Universität Berlin and was appointed as a Professor for Pharmacology and Pharmaceutics at the University of Applied Sciences Kaiserslautern. Since 2016 she is Professor of Pharmaceutics and Biopharmaceutics at the Philipps-Universität Marburg. Her field of research is the development and characterization of innovative nanocarriers for improved delivery of poorly soluble actives for healthcare and cosmetics. Prof. Keck is executive board member of the German Association of Nanotechnology (Deutscher Verband Nanotechnologie), Vize-chairman of the unit „Dermocosmetics“ at the German Society of Dermopharmacy, active member in many pharmaceutical societies and member of the BfR Committee for Cosmetics at the Federal Institute for Risk Assessment (BfR).

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