WO2005092929A1 - Hyaluronic acid butyric esters with a low degree of substitution, procedure for their preparation and use - Google Patents
Hyaluronic acid butyric esters with a low degree of substitution, procedure for their preparation and use Download PDFInfo
- Publication number
- WO2005092929A1 WO2005092929A1 PCT/IB2005/000780 IB2005000780W WO2005092929A1 WO 2005092929 A1 WO2005092929 A1 WO 2005092929A1 IB 2005000780 W IB2005000780 W IB 2005000780W WO 2005092929 A1 WO2005092929 A1 WO 2005092929A1
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- WO
- WIPO (PCT)
- Prior art keywords
- butyric
- hyaluronic acid
- esters
- ester
- salt
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
Definitions
- the sodium salt of butyric acid has the disadvantage of a very short half-life which strongly limits its clinical use due to the difficulties in achieving plasma concentrations which are sufficient to provide a therapeutic effect.
- sodium butyrate when administered intravenously, sodium butyrate has a half-life of only 5 -6 minutes before being metabolised.
- the chemical approach aimed at stabilizing the molecule by esterification in order to slow down its degradation and prolong its biological activity.
- certain simple esters of butyric acid such as phenyl butyrate are known to exhibit antineoplastic activity in various forms of tumour such as prostate cancer (Proceedings of the American Association for Cancer Research, vol.
- esterification simply has the purpose of increasing plasma half-life of the active principle, transforming the compound into a prodrug which on hydrolysis induces the slow release of butyric acid into the target organ.
- the activity of these esters is always lower than that of the free acid due to the reduced bioavailability of the active principle.
- esters of hyaluronic acid (HA) with butyric acid obtained by a procedure in which hyaluronic acid is dissolved in H 2 O, acidified and precipitated by adding collidine salts. Even though the HA is dissolved in dimethylformamide (DMF), the procedure is not completely anhydrous and the esters obtained have a degree of substitution (ratio of average mole value of butyric acid residues to number of moles of disaccharide units GlcNAc-GlcUA) never lower than 0.1.
- DMF dimethylformamide
- esters of the invention of cell proliferation was evaluated by MTT colorimetry and expressed as percentage inhibition compared to the control consisting of cells maintained in culture medium alone.
- Panel B Shows the growth inhibition effect induced by three butyric esters (HB4,
- HB10 and HB 11 compared with sodium butyrate in cell line HepB3.
- liver sections of animals injected intrasplenically with tumour cells and treated with the esters of the invention Microscopic images depicting liver histology of animals injected intrasplenically with Lewis carcinoma LL3 cells and either treated or not treated with HA-But.
- the 4 ⁇ m thick histological sections were taken from liver samples of treated or control animals, fixed in 10% formalin and enclosed in paraffin. After staining with Cajal- Gallego the sections were examined by optical microscope.
- mice intrasplenically inoculated with B16/F10 melanoma cells and treated daily s.c. with HB10 at a dose of 4.8 ⁇ moles/mouse/day with weekly i.p boosters of 12 ⁇ moles/mouse on days 4, 11 , 18, 25, 31 was evaluated using the Kaplan-Meier method. After 90 days' observation, 8 out of 10 of the treated animals were still alive, as opposed to only 3 out of 11 of the control animals.
- the present invention relates to hyaluronic acid butyric esters with a degree of substitution (ratio of average mole value of butyric residues to number of moles of disaccharide units GlcNAc-GlcUA of hyaluronic acid) being less than or equal to 0.1 and preferably less than or equal to 0.01.
- esters characterised by a degree of substitution comprised from 0.001 to 0.08, preferably from 0.002 to 0.03 or even more preferably from 0.003 to 0.01.
- the esters of the present invention have a hyaluronic acid molecular weight of between 10,000 and 100,000 D, even more preferably between 50,000 and 85,000 D.
- esters of the present invention have demonstrated an antiproliferative, antitumour and antimetastatic activity, surprisingly greater than that of butyric esters characterised by a higher degree of substitution. Said effect is observed both in in vitro experiments on tumour cell lines and in in vivo experiments on animal models of metastatic dissemination.
- esters of the invention are particularly active on primary and metastatic liver tumours and this activity seems to correlate with the levels of expression of CD44 on the tumor. Therefore, one of the main aspects of the invention relates to the use of the aforedefined esters for preparing drugs targeted for the treatment of pathologies characterised by cell hyperproliferation as in the case of tumours, particularly indicated for primary or metastatic liver tumours.
- the esters of the invention compared to those of the prior art US 6,140,313 are obtained under anhydrous reaction conditions. Under these conditions the esterification reaction proceeds in a more controlled manner than under not fully anhydrous conditions, hence esters with low degrees of substitution can be obtained by suitably varying concentrations of the reagents.
- the acylating agent is partially hydrolysed and, because of the poor solubility of hyaluronic acid in organic solvents, acylation takes place in a heterogeneous phase: the ester groups are thus distributed in a non-uniform manner on the polymer matrix.
- the tetrabutylammonium salt (HA-TBA) is preferred, obtained according to known methods, for example by passing the sodium salt of hyaluronic acid over an ion exchanger conditioned with TBA.
- a preferred ion exchanger is an amberlite resin IR 120 column in acid form, in which a 40% aqueous solution of TBA is recycled for at least 4 days at 40°C and subsequently washed with distilled H 2 O until the pH is ⁇ 10.
- the hyaluronic acid quaternary salt is preferably dissolved in N,N- dimethylformamide (DMF) even if other solvents such as dimethyl sulfoxide (DMSO) or N-methylpyrrolidone can be used.
- the process for preparing hyaluronic acid butyric esters with a degree of substitution less than or equal to 0.1 comprises the following passages: a) dissolving a hyaluronic acid quaternary nitrogen salt at a concentration between 1 and 100 g/litre in a polar aprotic solvent, optionally heating to temperatures above 50°C, b) preparing the acylating reagent by mixing, in a polar aprotic solvent, butyric anhydride and a 4-dialkylaminopyridine, c) adding the acylating reagent to the hyaluronic acid salt solution under anhydrous conditions, d) purifying the reaction product or alternatively converting the ester obtained into the corresponding sodium salt by means of acidification.
- the acylating reaction is carried out under anhydrous conditions, for example under nitrogen atmosphere.
- Preferred catalysts of the acylation reaction are 4- dialkylaminopyridines, among which 4-dimethylaminopyridine (DMAP) and 4- pyrrolidinopyridine (PPY).
- DMAP 4-dimethylaminopyridine
- PY 4- pyrrolidinopyridine
- the hyaluronc acid is preferably prepared as HA-TBA in anhydrous DMF, at concentrations between 1 and 100 g/litre, more preferably between 10 and 50 g/litre, preferably heated to 80°C until dissolved then left to cool to ambient temperature.
- a quantity of butyric anhydride at a concentration comprised from 0.01 to 5 moles/litre (preferably from 0.1 to 2 moles/litre) and of dimethylaminopyridine (DMAP) in a molar ratio with the butyric anhydride between 0.1 and 10 (preferably between 0.5 and 2 or actually in an equimolar ratio with the butyric anhydride quantity), in a suitable volume of anhydrous DMF, are added drop-wise to the HA- TBA solution, under mechanical agitation, leaving it to react for at least an hour. The reaction is then stopped with distilled H 2 O.
- DMAP dimethylaminopyridine
- the acylating reagent is added in a quantity such that the molar ratio between butyric anhydride and the repeating disaccharide unit of hyaluronic acid is between 0.004 and 0.3, preferably between 0.008 and 0.1 , or even more preferably between 0.01 and 0.03.
- a further aspect of the invention relates to the possibility of obtaining pharmaceutical compositions containing, as active principle, a therapeutically efficient quantity of a butyric ester of the invention in association with suitable pharmaceutically acceptable diluents and excipients.
- said compositions can also contain other active principles and can be employed for oral use, in the form of granular powders, tablets, pills or gels.
- the administration of the butyric esters of the invention can be systemic, oral, parenteral, topical or transdermal, they also being suitable for administration via the following routes: oral, intravenous, intraperitoneal, intraarticular, intramuscular, subcutaneous, rectal, intracavital (intravesicular or intravaginal).
- the effective therapeutic dose varies preferably from 0.2 to 2 g/day for 1-15 days or, more preferably, from 0.3 and 1.5 g/day.
- the butyric esters of the invention are non- toxic and can therefore be used at the proposed doses or at even higher doses.
- the butyric ester is administered preferably at the dose of 0.2-50 mg/kg/day for 8-12 days. If injected intraperitoneally, the butyric ester is preferably administered as a solution, preferably in physiological solution, at a dose of 1-100 mg/kg/day (preferably 10-50 mg/kg/day) for 8-12 days.
- the butyric ester is preferably administered at a dose of 300-500 mg/kg/day for 8-12 days.
- the new esters of the invention in which butyric acid is esterified with HA are characterised by a high affinity for a specific membrane receptor (CD44). This specificity is therefore exploitable for preferentially delivering the drug to target cells which express high levels of said receptor. Due to their specificity, the esters of the invention are an effective solution to the treatment of neoplastic lesions surrounded by normal tissue, such as intrahepatic lesions, with greatly reduced cell damage to normal cells as normally occurs with classical treatments with cytotoxic drugs.
- Da Dalton (unit of atomic mass) [equivalent to g/mole]
- HA-Na sodium salt of hyaluronic acid sodium hyaluronate
- the ion exchange resin Amberlite IR-120 (plus) in the form of tetrabutylammonium salt (TBA) was obtained from that in acid form (Sigma-Aldrich) by treatment with an aqueous 40 weight.% solution of tetrabutylammonium hydroxide, recycled for 4 days through a jacketed column at 40°C.
- HA-Na 500 g - 1.25 eq ⁇ moles of repeating dimer units
- the solution was loaded and recycled in cocurrent (descending flow with velocity of ⁇ 100 ml/minute) for ⁇ 24 hours through a column containing Amberlite IR-120 (plus) ion exchange resin in the form of TBA salt (7 kg - 30.8 eq).
- the column was unloaded and the resin washed with bidistilled water ( ⁇ 13 litres) to recover all the residual product.
- the conversion from the tetrabutylammonium salt (TBA) to the sodium salt (Na) of the HA-But product was undertaken by acidification with 0.1 M hydrochloric acid (HCI) and neutralization with a saturated sodium hydrogen carbonate (NaHCO 3 ) solution.
- HCI hydrochloric acid
- NaHCO 3 saturated sodium hydrogen carbonate
- the solution was then concentrated to about one fifth of the original volume with a rotary evaporator under reduced pressure; the polymer was then precipitated by pouring the concentrated solution into at least three volumes of acetone, then the precipitate was separated by filtration and dried under vacuum.
- the product obtained was then purified by dialysis of the aqueous solution of the crude solid against distilled water, using cellulose membrane dialysis tubes with a molecular weight cut-off equal to 12-14 kDa (Visking).
- the butyric esters of hyaluronic acid in the form of sodium salt were then obtained, by lyophilising, as white or whitish solids.
- the structure of the compounds was determined by proton magnetic resonance spectroscopy ( 1 H-NMR), undertaken on deuterated dimethylsulfoxide solutions (DMSO-d6) at 200 or 500 MHz using Bruker 200 AC or Varian Inova 500 spectrometers, respectively.
- the compound with the lowest degree of substitution (0.004 - HB10) was found to induce, in the HT29 cells, a 50% inhibition at a concentration (in terms of butyrate) about 60 times lower than that required to obtain the same effect with the active principle (figure 3A). All the butyric monoesters tested also showed a dose-dependent inhibitory effect on Hep3B cells which was clearly greater than that exerted by the active principle alone (figure 3B). In these cells in particular, the compound with the lowest degree of substitution was found to be capable of inhibiting cell growth by 50° ⁇ at a concentration (in terms of butyrate) about 120 times lower than that necessary to obtain the same effect with the active principle.
- the cells were incubated with propidium iodide (5 g/ml), RNase (10 kU/ml), (Sigma), and Nonidet P40 (0.005%) and fluorescence was measured with a FAC Scan flow cytometer (Becton Dickinson, San Jose, CA) equipped with argon laser. The fluoresce nt signal was acquired in both linear mode and logarithmic mode. The cytometr ⁇ c examination demonstrated that only 18% of the HepG2 cells express CD44 receptors on their cell surfaces, in contrast to 78% of HepB3 cells (figure 5A).
- HA-But was found to be much more effective than sodium butyrate with an approximately 10 fo ld reduction in IC 50 value compared to that observable with the active principle alone (2.1 vs 0.12 mM in HepG2 cells and 3 vs 0.31 mM in HepB3 cells) suggesting that the use of a suitable carrier can significantly increase biological activity of the sodium butyrate without negatively influencing its biological activity due to the presence of a bulky molecule such as that of HA.
- Example 6 Evaluation of binding kinetics with labelled butyric esters. In vitro and in vivo studies.
- mice strains C57BL/6, C57BL/6xDBA/2F1 (BD2F1) and CBA/Lac were used acquired from Harlan & Nossan, San Rafael al Natisone, Udine, Italy, aged from 3 to 6 months and weighing 18-20 g. All the experiments were conducted in accordance with the regulations currently in force in Italy (DDL 116, 21/12/92) and The Guide for the Care and Use of Laboratory Animals. (DHHS Publ. No [NIH], 86-23, Bethesda, MD: NIH, 1985). Cells.
- tumour cells thus obtained were then inoculated intrasplenically in a sterile environment, into female strain BD2F1 mice previously anaesthetised by i.p injection with Zoletil (70 mg/kg) (Virbac srl, Milan, Italy).
- Zoletil 70 mg/kg
- About 2x10 5 Lewis LL3 carcinoma cells or 1x10 5 B16/F10 melanoma cells were inoculated after suitably dissolving in a Matrigel solution (150 ⁇ g/ml, Beckton Dickinson) to enable a better implantation in the organ. 4 days after the inoculation, (required to allow the tumour cells to implant), groups of 8 animals were each treated i.p. or s.c.
- HA-But whose carrier molecule (HA) is characterised by a high affinity for a specific membrane receptor known to be overexpressed by the tumour cells, could constitute a turning point in the treatment of primary and metastatic intrahepatic lesions of other origins.
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EP05718276A EP1781707A1 (en) | 2004-03-29 | 2005-03-25 | Hyaluronic acid butyric esters with a low degree of substitution, procedure for their preparation and use |
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ITMI2004A000605 | 2004-03-29 | ||
ITMI20040605 ITMI20040605A1 (en) | 2004-03-29 | 2004-03-29 | BUTYRICAL ESTERS OF HYALURONIC ACID WITH LOW DEGREE OF SUBSTITUTION PROCEDURE FOR THEIR PREPARATION AND USE |
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WO2005092929A1 true WO2005092929A1 (en) | 2005-10-06 |
WO2005092929A8 WO2005092929A8 (en) | 2006-03-02 |
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PCT/IB2005/000780 WO2005092929A1 (en) | 2004-03-29 | 2005-03-25 | Hyaluronic acid butyric esters with a low degree of substitution, procedure for their preparation and use |
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Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
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US20100305061A1 (en) * | 2007-11-27 | 2010-12-02 | Sigea S.R.L. | Mixed butyric-formic esters of acid polysaccharides, and their preparation and use as skin cosmetics |
EP2319503A2 (en) * | 2008-05-29 | 2011-05-11 | Soon-Chang Kwon | Drug delivery carrier |
US8247546B2 (en) * | 2006-12-29 | 2012-08-21 | Siega S.R.L. | Derivatives of acid polysaccharides |
EP2522337A2 (en) | 2011-05-13 | 2012-11-14 | Rottapharm S.P.A. | Hyaluronic acid esters, their preparation and use in dermatology |
CN103724455A (en) * | 2013-12-11 | 2014-04-16 | 四川大学 | Hyaluronic acid derivative and preparation method for hyaluronic acid hydrogel |
WO2014082609A1 (en) | 2012-11-27 | 2014-06-05 | Contipro Biotech S.R.O. | C6-c18-acylated derivative of hyaluronic acid, method of preparation thereof, nanomicellar composition on its basis, method of preparation thereof and method of preparation stabilized nanomicellar composition, and use thereof |
WO2015074632A1 (en) | 2013-11-21 | 2015-05-28 | Contipro Biotech S R.O. | Nanofibers containing photocurable ester derivative of hyaluronic acid or its salt, photocured nanofibers, method of synthesis thereof, preparation containing photocured nanofibers and use thereof |
WO2016113192A1 (en) * | 2015-01-13 | 2016-07-21 | Sigea S.R.L. | Process in water for the preparation of butyric esters of hyaluronic acid sodium salt |
US10023658B2 (en) | 2014-03-11 | 2018-07-17 | Contipro A.S. | Conjugates of oligomer of hyaluronic acid or of a salt thereof, method of preparation thereof and use thereof |
US10414832B2 (en) | 2015-06-26 | 2019-09-17 | Contipro A.S | Derivatives of sulfated polysaccharides, method of preparation, modification and use thereof |
US10617711B2 (en) | 2014-06-30 | 2020-04-14 | Contipro A.S. | Antitumor composition based on hyaluronic acid and inorganic nanoparticles, method of preparation thereof and use thereof |
US10618984B2 (en) | 2016-06-27 | 2020-04-14 | Contipro A.S. | Unsaturated derivatives of polysaccharides, method of preparation thereof and use thereof |
US10689464B2 (en) | 2015-03-09 | 2020-06-23 | Contipro A.S. | Self-supporting, biodegradable film based on hydrophobized hyaluronic acid, method of preparation and use thereof |
US10759878B2 (en) | 2015-06-15 | 2020-09-01 | Contipro A.S. | Method of crosslinking of polysaccharides using photoremovable protecting groups |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998023648A1 (en) * | 1996-11-29 | 1998-06-04 | Societa' Cooperativa Centro Ricerche Poly-Tech A Responsabilita' Limitata | New butyric esters with antiproliferative activity and the pharmaceutical compositions containing them |
-
2004
- 2004-03-29 IT ITMI20040605 patent/ITMI20040605A1/en unknown
-
2005
- 2005-03-25 WO PCT/IB2005/000780 patent/WO2005092929A1/en not_active Application Discontinuation
- 2005-03-25 EP EP05718276A patent/EP1781707A1/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998023648A1 (en) * | 1996-11-29 | 1998-06-04 | Societa' Cooperativa Centro Ricerche Poly-Tech A Responsabilita' Limitata | New butyric esters with antiproliferative activity and the pharmaceutical compositions containing them |
Non-Patent Citations (2)
Title |
---|
CORADINI D ET AL: "Hyaluronic acid as drug delivery for sodium butyrate: improvement of the anti-proliferative activity on a breast-cancer cell line", INTERNATIONAL JOURNAL OF CANCER, NEW YORK, NY, US, vol. 81, no. 3, 5 May 1999 (1999-05-05), pages 411 - 416, XP002245583, ISSN: 0020-7136 * |
KAWAGUCHI Y ET AL: "The relation between the adsorption behavior at the interface and the conformational changes in hyaluronates partially modified with various acyl chains", CARBOHYDRATE POLYMERS, APPLIED SCIENCE PUBLISHERS, LTD. BARKING, GB, vol. 26, no. 2, 1995, pages 149 - 154, XP004034490, ISSN: 0144-8617 * |
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US8247546B2 (en) * | 2006-12-29 | 2012-08-21 | Siega S.R.L. | Derivatives of acid polysaccharides |
AU2007341078B2 (en) * | 2006-12-29 | 2013-03-07 | Sigea S.R.L. | Derivatives of acid polysaccharides |
US8530450B2 (en) * | 2007-11-27 | 2013-09-10 | Sigea S.R.L. | Mixed butyric-formic esters of acid polysaccharides, and their preparation and use as skin cosmetics |
US20100305061A1 (en) * | 2007-11-27 | 2010-12-02 | Sigea S.R.L. | Mixed butyric-formic esters of acid polysaccharides, and their preparation and use as skin cosmetics |
EP2319503A2 (en) * | 2008-05-29 | 2011-05-11 | Soon-Chang Kwon | Drug delivery carrier |
EP2319503A4 (en) * | 2008-05-29 | 2012-12-05 | Kwon Soon Chang | Drug delivery carrier |
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US9062129B2 (en) | 2011-05-13 | 2015-06-23 | Rottapharm S.P.A. | Hyaluronic acid esters, their preparation and use in dermatology |
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JP2018501385A (en) * | 2015-01-13 | 2018-01-18 | シジェア ソシエタ ア レスポンサビリタ リミタータ | In-water method for the preparation of butyric acid ester of sodium hyaluronate |
RU2708994C2 (en) * | 2015-01-13 | 2019-12-12 | Сиджеа С.Р.Л. | Water-based method of producing esters of butyric acid and hyaluronic acid sodium salt |
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US10618982B2 (en) | 2015-01-13 | 2020-04-14 | Bmg Pharma S.P.A. | Process in water for the preparation of butyric esters of hyaluronic acid sodium salt |
KR102636528B1 (en) | 2015-01-13 | 2024-02-15 | 시제아 에스.알.엘 | Process in water for the preparation of butyric esters of hyaluronic acid sodium salt |
US10689464B2 (en) | 2015-03-09 | 2020-06-23 | Contipro A.S. | Self-supporting, biodegradable film based on hydrophobized hyaluronic acid, method of preparation and use thereof |
US10759878B2 (en) | 2015-06-15 | 2020-09-01 | Contipro A.S. | Method of crosslinking of polysaccharides using photoremovable protecting groups |
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Also Published As
Publication number | Publication date |
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EP1781707A1 (en) | 2007-05-09 |
ITMI20040605A1 (en) | 2004-06-29 |
WO2005092929A8 (en) | 2006-03-02 |
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