Recent advances in crystalline and amorphous particulate protein formulations for controlled delivery

Puhl, Sebastian; Meinel, Lorenz; Germershaus, Oliver

doi:10.1016/j.ajps.2016.06.003

Cited by 26 publications

(24 citation statements)

References 59 publications

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“…Meanwhile, as (semi)synthetic derivatives, genetically modified molecules with an adapted amino acid sequence are being extensively developed towards amelioration of enzymatic stability and prolonged time of action (Vlieghe et al, 2010), and crystalline precipitates of such molecules have a lot to offer. Crystalline formulations of small organic molecules have been successfully used in pharmaceutical compounds for decades while a steadily increasing number of products consisting of macromolecular crystals are available today in the market (Govardhan et al, 2005;Jiang et al, 2010;Puhl et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Revisiting the structure of a synthetic somatostatin analogue for peptide drug design

Fili

Valmas

Spiliopoulou

et al. 2019

Acta Crystallogr B Struct Sci Cryst Eng Mater

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Natural or artificially manufactured peptides attract scientific interest worldwide owing to their wide array of pharmaceutical and biological activities. X-ray structural studies are used to provide a precise extraction of information, which can be used to enable a better understanding of the function and physicochemical characteristics of peptides. Although it is vulnerable to disassociation, one of the most vital human peptide hormones, somatostatin, plays a regulatory role in the endocrine system as well as in the release of numerous secondary hormones. This study reports the successful crystallization and complete structural model of octreotide, a stable octapeptide analogue of somatostatin. Common obstacles in crystallographic studies arising from the intrinsic difficulties of obtaining a suitable single-crystal specimen were efficiently overcome as polycrystalline material was employed for synchrotron and laboratory X-ray powder diffraction (XPD) measurements. Data collection and preliminary analysis led to the identification of unit-cell symmetry [orthorhombic, P2 1 2 1 2 1 , a = 18.5453 (15), b = 30.1766 (25), c = 39.798 (4) Å ], a process which was later followed by complete structure characterization and refinement, underlying the efficacy of the suggested (XPD) approach.

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Section: Discussionmentioning

confidence: 99%

Revisiting the structure of a synthetic somatostatin analogue for peptide drug design

Fili

Valmas

Spiliopoulou

et al. 2019

Acta Crystallogr B Struct Sci Cryst Eng Mater

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“…Crystallization has largely been utilized to image essential protein folding and observe target-agent interactions 36 , or, in more industrial fields, for purification purposes 37 . Crystallized drug formulations for controlled drug release have been described in the literature, however they have typically been used as nano to few micron surface coatings 38,39 or in carrier-based formulations with low encapsulation efficiencies and limited release duration from hours to weeks 40,41 . Crystalline materials have also exhibited advantages of enhanced chemical stability 42 .…”

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confidence: 99%

Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations

et al. 2019

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Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled release formulations for local antiinflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sitessubcutaneous, intraperitoneal and intramuscular. In particular incorporation of GW2580, a Colony Stimulating Factor 1 Receptor (CSF1R) inhibitor, into a range of devices including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and musclestimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials. Implanted biomedical devices are an integral part of modern therapeutics, playing key roles in many clinical applications including neural interfacing 1 , monitoring vital signs 2 , pacemakers 3 , controlled drug release 4 , scaffolds for tissue reconstruction 5 , vascular stenting, cell encapsulation and transplantation 6. While the immunological response to materials can be therapeutic, for example with particulate vaccines 7 , some device materials, including polysaccharides, polymers, ceramics, and metals 8 , can induce host immune-mediated foreign body and rejection responses This response can lead to fibrotic encapsulation, and in some cases, reduced efficacy or failure 8-12. Current approaches for long-term maintenance of biomedical device implant biocompatibility often involve broad-spectrum antiinflammatories 13. Short-term steroid or anti-fibrotic drug delivery can transiently inhibit inflammatory cell recruitment as well as improve protein secretion of immuno-isolated cellular grafts 14,15. However, many anti-inflammatory drugs have multiple targets and differential effects in vivo, and associated toxicity 13,16. In particular, macrophages are known to be key mediators of the immune response to implanted biomaterials 8-10. Recently it was shown that the implant-induced foreign body response can be inhibited through selective targeting of the monocyte/macrophage-expressed colony stimulating factor-1 (CSF1R) receptor 10. Importantly, while macrophage numbers in the IP space as well as Farah et al.

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“…Each of these polymorphs exhibits a unique packing of HI hexamers in the unit cell which, along with the distinct binding affinities of the different ligands, gives rise to unique dissolution properties for each crystal polymorph. Pharmaceutical products containing such crystal polymorphs with high protein concentration could lead to fewer injections, since the crystals could constitute an intrinsically controlled release system (Puhl et al, 2016), improving the quality of life of millions of patients. Evidently there are still many opportunities for exploration of the human insulin chemical space even though this protein has been meticulously studied for almost half a century.…”

Section: Discussionmentioning

confidence: 99%

Insulin polymorphism induced by two polyphenols: new crystal forms and advances in macromolecular powder diffraction

Triandafillidis

Parthenios

Spiliopoulou

et al. 2020

Acta Crystallogr D Struct Biol

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This study focuses on the polymorphism of human insulin (HI) upon the binding of the phenolic derivatives p-coumaric acid or trans-resveratrol over a wide pH range. The determination of the structural behaviour of HI via X-ray powder diffraction (XRPD) and single-crystal X-ray diffraction (SCXRD) is reported. Four distinct polymorphs were identified, two of which have not been reported previously. The intermediate phase transitions are discussed. One of the novel monoclinic polymorphs displays the highest molecular packing among insulin polymorphs of the same space group to date; its structure was elucidated by SCXRD. XRPD data collection was performed using a variety of instrumental setups and a systematic comparison of the acquired data is presented. A laboratory diffractometer was used for screening prior to high-resolution XRPD data collection on the ID22 beamline at the European Synchrotron Radiation Facility. Additional measurements for the most representative samples were performed on the X04SA beamline at the Swiss Light Source (SLS) using the MYTHEN II detector, which allowed the detection of minor previously untraceable impurities and dramatically improved the d-spacing resolution even for poorly diffracting samples.

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Recent advances in crystalline and amorphous particulate protein formulations for controlled delivery

Cited by 26 publications

References 59 publications

Revisiting the structure of a synthetic somatostatin analogue for peptide drug design

Revisiting the structure of a synthetic somatostatin analogue for peptide drug design

Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations

Insulin polymorphism induced by two polyphenols: new crystal forms and advances in macromolecular powder diffraction

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