Commercial Low Molecular Weight Heparins — Patent Ecosystem and Technology Paradigm for Quality Characterization

Abstract

Heparin is a subject of ever-growing interest for laboratory researchers and pharmaceutical industry. One of the driving factors is its critical life-saving drug status, which during the COVID-19 pandemic has assumed a central role in disease treatment and/or prevention. Apart, heparin is one amongst few drugs enjoying a “demand constant” status. In 2020, heparin market size was valued to US$6.5 bn., and given the ongoing stability in the COVID-19 health crisis, it is expected to reach US$11.43 bn. by 2027 with yearly growth rate momentum (CAGR) of 3.9% during the forecast period (Pepi et al., Mol Cell Proteomics 20:100,025, 2021). As patent is a limited monopoly, every year, many patents on low molecular weight heparin (LMWH; a chemically or enzymatically degraded product of unfractionated heparin) are losing market exclusivity worldwide, inviting the generic/biosimilar drug manufacturers to capture market share with cheaper drug products. By tracking patent expiration, drugs in patent litigation, regulatory setbacks for innovator companies (such as those seeking data exclusivity or patent term extension), or other unexpected events affecting market demand and competition, generics can make investment decisions in manufacturing off-patent LMWH drug products of commercial significance. However, given the US Food and Drug Administration (FDA), European Medicine Agency (EMA), Drug Regulatory Authority of Pakistan (DRAP), and other regulatory authorities scientifically rigorous standards for generic/biosimilar LMWH drug products marketing approval, the market is secured and momentous for drug makers that could demonstrate through scientific and clinical dataset that the generic/biosimilar LMWH drug product is of the same quality and purity as the innovator drug product. This study presents an overview of the patent landscape of commercially available LMWHs and advanced analytical techniques for their structural and biochemical characterization for quality control and quality assurance during manufacturing and post-marketing. The study also covers FDA, EMA, Health Canada, and DRAP’s current approaches to evaluating the generic/biosimilar LMWH drug products for quality, safety including immunogenicity, and efficacy.

A Screening Approach to Assess the Impact of Various Commercial Sources of Crude Marine λ-Carrageenan on the Production of Oligosaccharides with Anti-heparanase and Anti-migratory Activities

“…This suggests that with a real-time adjustment of the reaction (looking “live” at M n and DS parameters), it is possible to obtain similar formulations with identified characteristics. Such “live” controls are quite common for the preparation of LMW PS, e.g., a biological control based on anti-Xa activities is performed for the industrial production of standard batches of LMW heparins [ 59 ].…”

Heparinized Acellular Hydrogels for Magnetically Induced Wound Healing Applications

“…25,26 The two main forms of heparin that are currently employed in clinical settings are unfractionated heparin, which includes the heparin sodium salt (HSS) used in this study, and lowmolecular-weight heparins (such as enoxaparin, tinzaparin, and dalteparin). 27 HSS is known to control cell adhesion, spreading, migration, proliferation, and differentiation by interacting with particular cell surface receptors, like integrins and selectins, and by modulating the secretion of growth factors like fibroblast growth factors (FGFs), platelet-derived growth factors (PDGFs), VEGF, and transforming growth factor-beta (TGF-β) . 28 Nonetheless, the biological activity of HSS is known to be significantly impacted by subtle variations in its sulfation pattern.…”

“…The two main forms of heparin that are currently employed in clinical settings are unfractionated heparin, which includes the heparin sodium salt (HSS) used in this study, and low-molecular-weight heparins (such as enoxaparin, tinzaparin, and dalteparin) …”

A Unique Enoxaparin Derived from Bovine Intestinal Heparin: A Single Purification Step of the Starting Material Assures a Bovine Enoxaparin Like the Standard from Porcine Origin

“…Enoxaparin, among various LMWHs, stands out as the most widely used worldwide. 4 LMWHs are traditionally derived from porcine intestinal heparin (HPI) through a meticulously controlled chemical such as a ß-elimination reaction. This process involves two key steps: (i) cleavage of the polysaccharide backbone and (ii) hydrolysis of residual esters under alkaline conditions, contributing to the high production costs and limited availability.…”

“…Here, subcutaneous UFH administration persists, driven by economic constraints and raising questions about its effectiveness. Enoxaparin, among various LMWHs, stands out as the most widely used worldwide …”