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"Ph-Sensitive Hyaluronic Acid Derivative and Uses Thereof" in Patent Application Approval Process

August 8, 2014



By a News Reporter-Staff News Editor at Drug Week -- A patent application by the inventors Yang, Jean-Dean (Dayuan Township, TW); Chou, Ayi-Man (Taichung City, TW); Chen, Jui-Hsiang (Hsinchu City, TW); Liu, Hsia-Wei (Taipei City, TW); Wang, Shian-Jy (Jhudong Township, TW); Teng, Tse-Min (Ji'an Township, TW); Liang, Hsiang-Fa (Hsinchu City, TW); Wei, Ming-Cheng (Yangmei City, TW); Lu, Maggie J.M. (Jhudong Township, TW), filed on December 29, 2011, was made available online on July 24, 2014, according to news reporting originating from Washington, D.C., by NewsRx correspondents (see also Industrial Technology Research Institute).

This patent application is assigned to Industrial Technology Research Institute.

The following quote was obtained by the news editors from the background information supplied by the inventors: "Hyaluronic acid is a linear mucopolysaccharide consisting of repeated units of N-acetyl-D-glucosamine and D-glucuronic acid. Hyaluronic acid was first discovered in the vitreous body of bovine eyes. Afterward, hyaluronic acid has also been found in other tissues, such as the extracellular matrix (ECM) or synovial fluid. The biological function of hyaluronic acid is primarily for cell protection and lubrication, modulation of cell movement on the viscoelastic matrix, stabilization of the collagen network structures and protection of the collagen network structure from mechanical damage.

"The cell receptor on the cell surface against hyaluronic acid is CD44. The binding of hyaluronic acid and CD44 enhances cell aggregation, movement, proliferation, activation and activities among cells and the adhesion therebetween. The bonding of hyaluronic acid and CD44 enhances epithelial-mesenchymal transition (EMT) of cancerous cells, causing cancerous cells invading circulatory systems and lymphoid systems and binding to originally normal cells, and, finally, resulting in cancer metastasis.

"The formation of micelles by using hyaluronic acid has been studied. When the concentration is higher than the critical micelle concentration (CMC), according to thermodynamics, hyaluronic acid is going to self-assemble in an aqueous matrix to form nano-scaled micelles. Several articles have disclosed the formation of micelles and encapsulated drugs with hyaluronic acid, for example, U.S. Pat. No. 6,350,458B1 or No. 7,780,982B1.

"U.S. Pat. No. 6,350,458B1 has disclosed a composition comprising at least one micelle-forming material, macromolecular pharmaceutical agent-like hormones or antibodies, alkali metal alkyl sulfate, alkali metal salicylate and pharmaceutically acceptable edetate, for delivering the macromolecular pharmaceutical agent that hardly passes through gastrointestinal tracts to tissues or cells.

"U.S. Pat. No. 7,780,982B1 has disclosed a hyaluronic acid derivative for improving the biodegradability thereof and the biodegradability of the micelle formed therewith, which has C.sub.2.about.C.sub.16 hydrocarbons binding to the carboxyl group (--OH) of the hyaluronic acid and forms a urethane group.

"However, studies have shown that, although drug-encapsulated micelles enter into cancer cells though endocytosis, they might be expelled by the cancer cell through exocytosis before the drug is released to kill the cancer cells. Thus, there is a demand for an improvement of the hyaluronic acid derivative and the micelle formed therewith."

In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent application: "The disclosure provides a hyaluronic acid derivative which comprises at least one repeating unit as shown in the following formula (I):

"##STR00002##

"In the formula,

"HA represents a unit comprising N-acetyl-D-glucosamine and D-glucuronic acid, q represents an integer of 2 to 10,000;

"A represents a biocleavable linkage comprising at least one group of hydrazone, acetal, ketal and imine;

"M represents at least one of a hydrophobic fragment, a hydrophilic fragment, and an amphiphilic fragment, and

"p represents the number of [A-M] directly grafted onto each HA unit, p represents an integer of 0 to 4, and the p of each HA unit is not 0 at the same time;

"wherein the hyaluronic acid derivative is biodegradable and pH-sensitive, and linkages of the hyaluronic acid derivative are broken in acidic conditions.

"The disclosure also provides a micelle formed by the hyaluronic acid derivative described above in a hydrophilic medium.

"The disclosure furthermore provides a drug delivery system which comprises a carrier and a bioactive ingredient encapsulated with the carrier, wherein the carrier consists of the hyaluronic acid derivative described above.

"In addition, the disclosure provides a flavor enhancer for encapsulating a bioactive material to mask the flavor thereof, in which the flavor enhancer consists of the hyaluronic acid derivative described above.

BRIEF DESCRIPTION OF THE DRAWINGS

"FIG. 1 shows a chemical formula of HA-g-.sub.HzPCL in one example of the disclosure, in which HA represents a unit of hyaluronic acid, g represents grafting of chemical bonds, HZ represents a group of hydrazine and PCL represents a chain fragment of polycaprolactone;

"FIG. 2 shows a chemical formula of HA-g-(.sub.HZPCL-PEG) in one example of the disclosure, in which HA represents a unit of hyaluronic acid, g represents grafting of chemical bonds, HZ represents a group of hydrazone, PCL represents a chain fragment of polycaprolactone and PEG represents a chain fragment of polyethylene glycol;

"FIG. 3 shows .sup.1H-NMR spectra of HA-COONa and HA-TBA in one example of the disclosure;

"FIG. 4 shows a .sup.1H-NMR spectrum of HA-TBA-CHO in one example of the disclosure;

"FIG. 5 shows a FT-IR spectrum of PCL-hydrazide in one example of the disclosure;

"FIG. 6 shows a .sup.1H-NMR spectrum of HA-g-(.sub.HzPCL) in one example of the disclosure, in which HA represents a unit of hyaluronic acid, g represents a chemical grafting, HZ represents a hydrazone linkage and PCL represents a chain fragment of polycaprolactone;

"FIG. 7 shows a .sup.1H-NMR spectrum of HA-g-(.sub.HZPCL-PEG) in one example of the disclosure, in which HA represents a unit of hyaluronic acid, g represents a chemical grafting, HZ represents a hydrazone linkage, PCL represents a chain fragment of polycaprolactone and PEG represents a chain fragment of polyethylene glycol;

"FIG. 8 shows the drug release curve of the micelle in one example of the disclosure; and

"FIG. 9 shows the drug release curve of the micelle in one example of the disclosure."

URL and more information on this patent application, see: Yang, Jean-Dean; Chou, Ayi-Man; Chen, Jui-Hsiang; Liu, Hsia-Wei; Wang, Shian-Jy; Teng, Tse-Min; Liang, Hsiang-Fa; Wei, Ming-Cheng; Lu, Maggie J.M. Ph-Sensitive Hyaluronic Acid Derivative and Uses Thereof. Filed December 29, 2011 and posted July 24, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=2529&p=51&f=G&l=50&d=PG01&S1=20140717.PD.&OS=PD/20140717&RS=PD/20140717

Keywords for this news article include: Cancer, Oncology, Hydrazines, Hydrazones, Industrial Technology Research Institute.

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Source: Drug Week


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