US20080139522A1 - Re-epithelializing pharmaceutical compositions comprising xanthan gum - Google Patents
Re-epithelializing pharmaceutical compositions comprising xanthan gum Download PDFInfo
- Publication number
- US20080139522A1 US20080139522A1 US12/031,495 US3149508A US2008139522A1 US 20080139522 A1 US20080139522 A1 US 20080139522A1 US 3149508 A US3149508 A US 3149508A US 2008139522 A1 US2008139522 A1 US 2008139522A1
- Authority
- US
- United States
- Prior art keywords
- xanthan gum
- epithelializing
- active principle
- buffer
- sodium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229920001285 xanthan gum Polymers 0.000 title claims abstract description 56
- 239000000230 xanthan gum Substances 0.000 title claims abstract description 46
- 229940082509 xanthan gum Drugs 0.000 title claims abstract description 46
- 235000010493 xanthan gum Nutrition 0.000 title claims abstract description 46
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- 239000000872 buffer Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 13
- 239000008213 purified water Substances 0.000 claims description 12
- 239000003963 antioxidant agent Substances 0.000 claims description 10
- 230000003078 antioxidant effect Effects 0.000 claims description 8
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 8
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 7
- 239000001509 sodium citrate Substances 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 3
- 229960003957 dexamethasone Drugs 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 3
- 235000019800 disodium phosphate Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 45
- 210000000981 epithelium Anatomy 0.000 abstract description 18
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 abstract description 16
- 229920002674 hyaluronan Polymers 0.000 abstract description 16
- 229960003160 hyaluronic acid Drugs 0.000 abstract description 16
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 208000027418 Wounds and injury Diseases 0.000 description 27
- 206010052428 Wound Diseases 0.000 description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 238000009472 formulation Methods 0.000 description 22
- 239000007951 isotonicity adjuster Substances 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- 210000004087 cornea Anatomy 0.000 description 18
- 230000006870 function Effects 0.000 description 13
- 239000000499 gel Substances 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 210000000110 microvilli Anatomy 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- GJCOSYZMQJWQCA-UHFFFAOYSA-N 9H-xanthene Chemical compound C1=CC=C2CC3=CC=CC=C3OC2=C1 GJCOSYZMQJWQCA-UHFFFAOYSA-N 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 235000006708 antioxidants Nutrition 0.000 description 9
- 239000001488 sodium phosphate Substances 0.000 description 9
- 229910000162 sodium phosphate Inorganic materials 0.000 description 9
- 235000011008 sodium phosphates Nutrition 0.000 description 9
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 7
- 229920002385 Sodium hyaluronate Polymers 0.000 description 6
- 230000001413 cellular effect Effects 0.000 description 6
- 229940010747 sodium hyaluronate Drugs 0.000 description 6
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- CZPLANDPABRVHX-UHFFFAOYSA-N cascade blue Chemical compound C=1C2=CC=CC=C2C(NCC)=CC=1C(C=1C=CC(=CC=1)N(CC)CC)=C1C=CC(=[N+](CC)CC)C=C1 CZPLANDPABRVHX-UHFFFAOYSA-N 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 229960000808 netilmicin Drugs 0.000 description 5
- 229960004832 netilmicin sulfate Drugs 0.000 description 5
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 230000008520 organization Effects 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- KIUKXJAPPMFGSW-YXBJCWEESA-N (2s,4s,5r,6s)-6-[(2s,3r,5s,6r)-3-acetamido-2-[(3s,4r,5r,6r)-6-[(3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H](C(O[C@@H]3[C@@H]([C@@H](O)C(O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)C(C(O)=O)O1 KIUKXJAPPMFGSW-YXBJCWEESA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 230000024245 cell differentiation Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 230000001788 irregular Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002831 pharmacologic agent Substances 0.000 description 3
- 230000035807 sensation Effects 0.000 description 3
- 238000007669 thermal treatment Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 238000004626 scanning electron microscopy Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- -1 viscous Substances 0.000 description 2
- 230000029663 wound healing Effects 0.000 description 2
- XDNBGBASBLCTIN-UHFFFAOYSA-L 2-(dimethylamino)ethyl 4-(butylamino)benzoate;n,n-dimethylformamide;n-[2-ethyl-2-(3-methoxyphenyl)butyl]-4-hydroxybutanamide;trimethyl-[4-[[4-(trimethylazaniumyl)cyclohexyl]methyl]cyclohexyl]azanium;diiodide;hydrochloride Chemical compound Cl.[I-].[I-].CN(C)C=O.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1.OCCCC(=O)NCC(CC)(CC)C1=CC=CC(OC)=C1.C1CC([N+](C)(C)C)CCC1CC1CCC([N+](C)(C)C)CC1 XDNBGBASBLCTIN-UHFFFAOYSA-L 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 101100225553 Caenorhabditis elegans epg-4 gene Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000016359 Fibronectins Human genes 0.000 description 1
- 108010067306 Fibronectins Proteins 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000005411 Van der Waals force Methods 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 241000589636 Xanthomonas campestris Species 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 1
- 150000008043 acidic salts Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- AEMOLEFTQBMNLQ-WAXACMCWSA-N alpha-D-glucuronic acid Chemical compound O[C@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-WAXACMCWSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000000739 chaotic effect Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000009878 intermolecular interaction Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 239000002637 mydriatic agent Substances 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- CMHHMUWAYWTMGS-UHFFFAOYSA-N oxybuprocaine Chemical compound CCCCOC1=CC(C(=O)OCCN(CC)CC)=CC=C1N CMHHMUWAYWTMGS-UHFFFAOYSA-N 0.000 description 1
- 229960003502 oxybuprocaine Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 229920000867 polyelectrolyte Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000004043 trisaccharides Chemical group 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- POZPMIFKBAEGSS-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;trihydrate Chemical compound O.O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O POZPMIFKBAEGSS-UHFFFAOYSA-K 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000010246 ultrastructural analysis Methods 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/723—Xanthans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to re-epithelializing pharmaceutical compositions especially for ophthalmic use.
- epithelial cells for example in the cornea, may suffer injuries caused by foreign bodies, such as abrasions, cuts and wounds (accidental, surgical, immunological etc), and postinfective ulcers. Injuries of this sort generally require long wound healing periods; cause much discomfort and often an imperfect wound closure.
- the object of the present invention is a pharmaceutical composition that can accelerate re-epithelialization, especially of the corneal tissue, and is also well tolerated.
- xanthan gum for the preparation of a medication for the treatment of epithelial wounds, as well as of pharmaceutical compositions containing xanthan gum, as detailed in the claims herewith annexed.
- xanthan gum shows a high re-epithelializing function, that is to say, it is able to accelerate the formation of new epithelial cells at the level of the damaged epithelial zone, as shown also in an in vivo experiment reported later in the present description.
- Xanthan gum is a heteropolysaccharide with a molecular weight between 3-7, 5 ⁇ 10 6 Da, produced through a process of fermentation by the bacterium Xanthomonas campestris.
- the primary structure of xanthan is a branched chain, with a main chain of ⁇ (1 ⁇ 4)-D-glucose identical to cellulose wherein, a trisaccharide chain with a glucosidic link ⁇ (1 ⁇ 3), composed of acetylated mannose, glucuronic acid, and mannose is linked to every other second residue; finally, to each carbon C4 and C6 of the terminal unit of mannose a molecule of pyruvic acid is linked in a variable proportion of 25-50%, that completes the structure of the lateral chain of the polymer.
- xanthan gum in preformed gel form, makes it possible to carry out adequately the important function of mechanical protection.
- wound-healing studies carried out under a scanning electron microscope revealed a surprising degree of epithelial organization following a treatment with the pharmaceutical re-epithelializing composition according to the invention, as will be explained in detail.
- hyaluronic acid not only favors cellular proliferation but also stabilizes the basal layer of the epithelium stimulating the production of lamina and fibronectin.
- Hyaluronic acid is an high molecular weight polysaccharide with polyanionic features, high capacity to retain water, viscous, bioadhesive and pseudoplastic properties with no evidence of tixotropy. Its primary structure consists of ⁇ (1 ⁇ 4) disaccharide blocks each constituted of D-glucuronic acid and N-acetyl-D-glucosamine linked together through a ⁇ (1 ⁇ 3) bond.
- a further embodiment of the present invention is to provide topical re-epithelializing pharmaceutical compositions in preformed gel consisting essentially of xanthan gum as active principle, eventually mixed with hyaluronic acid, and pharmacologically accepted additives.
- the percentage of xanthan gum relative to the total volume of the preformed gel is preferably between 0.7% to 5%, more preferably between 0.8% and 3%, and more highly preferably between 0.9% and 1.5%.
- excipients are chosen among isotonic agents, buffers, solvents or vehicles, antioxidants, pH adjusting and similar.
- the possible isotonic agents of the composition of the invention may be ionic, such as NaCl, KCl or non-ionic, for example glycerol, mannitol or a mix thereof.
- Possible buffers may be those commonly used for instance in ophthalmic formulations such as phosphate or borate, acetate, a mix of these buffers such as citrate/phosphate, or even buffers not frequently used in the ophthalmic field, such as Tris.HCl, or based on histidine or arginine.
- the composition of a preformed gel with xanthan may be a balanced saline solution, or otherwise, o saline composition not necessarily balanced because of the presence of ions of Ca +2 e Mg +2 .
- Possible antioxidants include sodium citrate, ascorbate or sulfate.
- Possible pH adjusting are organic or inorganic acids or bases with their respective acid and basic salts.
- Possible solvents or vehicles are water or a mixture of water/oil.
- xanthan behaves differently toward the variations of ionic force than other polyelectrolytes, toward which the presence of salts (that decreases the degree of hydration and repulsion between chains) promotes intermolecular interaction and a molecular collapse from a random coil (with a higher viscosity) to a compact coil structure (with a lower viscosity).
- the single helixes tend to associate forming a complex ordered meshwork of rigid molecules held together mainly by weak Van der Waals forces.
- the effect of the distinctive and unique structure of xanthan in solution is, already for moderate concentrations (1-2.5%), a gel-like consistency with significant yield stress values (hence, excellent ability to favor the formation of suspensions and emulsions) and good viscosity.
- an additional embodiment of the present invention may include hyaluronic acid.
- the quantity of hyaluronic acid present in said composition ranges from 0.01% to 1% of the total volume of the preformed gel, preferably from 0.05% to 0.5%, better still from 0.1% to 0.4%.
- Hyaluronic acid is present as a salt.
- Possible counter ions may be, for example, sodium, potassium, calcium or magnesium.
- the re-epithelializing pharmaceutical composition may include, aside from the admixture of xanthan gum and hyaluronic acid as re-epithelializing agents, one or several pharmacological agents chosen among antiinfective, antiinflammatory, anesthetizing and mydriatic agents.
- FORMULATION 7 Components Quantity Function Netilmicin sulfate 0.4550 g Active principle equivalent to Netilmicin base 0.3000 g Sodium hyaluronate 0.1500 g Active principle, re-epithelializing Xanthan gum 1.0000 g Active principle, re-epithelializing Tris base 0.2425 g Buffer HCl 1M q.s. to pH 7.4-7.6 Buffer Sodium citrate dihydrate 2.1000 Buffer/antioxidant Purified water q.s. to 100.0 ml Solvent
- FORMULATION 8 Components Quantity Function Netilmicin sulfate 0.4550 g Active principle equivalent to Netilmicin base 0.3000 g Sodium hyaluronate 0.1500 g Active principle, re-epithelializing Xanthan gum 1.0000 g Active principle, re-epithelializing Tris base 0.2423 g Buffer HCl 1M q.s. to pH 7.4-7.6 Buffer Sodium chloride 0.7000 g Isotonic agent Purified water q.s. to 100.0 ml Solvent
- glycerol displays a dispersing action towards xanthan gum, preventing the formation of clumps and lumps during the dispersal phase of the polymer in H 2 O.
- composition requires it, a predetermined quantity of one or more of the pharmacological agents listed above is added to the solution until said pharmacological agent(s) is/are completely dissolved or mixed.
- one gram of xanthan gum is added to 50 ml of water and is dispersed on the surface of the liquid, without stirring, to avoid the formation of lumps.
- the dispersion may be homogenized with a paddle stirrer or a homogenizer so as to accelerate the process while avoiding the formation of lumps. If the composition requires it, hyaluronic acid is also dispersed in this phase.
- the gel may be aseptically distributed in the appropriate containers.
- the difference between the two experiments lies in the fact that the first is designed to assess the dynamic and quantitative aspects of re-epithelialization and the second to assess the morphological and qualitative aspects of re-epithelialization following treatment with the various formulations.
- CSLO confocal opthalmoscope
- SEM scanning electron microscope
- the animals were allocated in animal rooms maintained in standard conditions of humidity (50% ⁇ 10% RH) and temperature (19 ⁇ 2° C.) with alternating cycles of artificial light (12 hours darkness/light). The animals were fed and allowed water ad libitum.
- the animals were anesthetized by an i.m. injection of ketamine (37.5 mg/kg b.w.) and xylazine (10 mg/kg b.w.), and with oxybuprocaine (1 drop/eye).
- the corneal wound was executed using an Algerbrush with a 1 mm tip. With the aid of a sterile parafilm mask, with a 6 mm hole at the center, a circular area was de-epithelialized. The eye was immediately washed with sterile BBS to remove cell debris and the treatment was performed.
- the rabbits were evaluated at 0, 24, 48, 72 and 96 hours with a CLSO coupled to an image-processing system, or they were sacrificed for SEM analysis (0, 24, 48, and 72 hours).
- the eyes of the rabbits of each treatment group were treated with a 25 ⁇ l solution of 0.5% sodium fluorescein. After 2 minutes the excess of fluorescein was washed away with a physiological solution. The sedated rabbits were then examined through CLSO. This system detects the fluorescent signal that originates from the epithelium lacking damaged zone and measures quantitatively the damaged area through an image-processing system.
- the group treated with the formulation containing only xanthan gum as active principle (XNT) showed an accelerated re-epithelialization process already 24 hours after the treatment.
- the wound's closure was at least 30% more advanced than in the groups “Untreated wound”, EYP and SOL.
- a higher re-epithelialization rate (50% higher than the other groups) was observed 48 hours after the treatment in both the group treated with xanthan gum only (XNT) and the group treated with xanthan gum mixed with hyaluronic acid (EPG).
- EPG hyaluronic acid
- the animals of the different treatment groups were sacrificed (Tanax i.v.). Rapidly following the sacrifice the bulb was enucleated and the corneas excised and immediately fixed with 2% glutaraldehyde during 24 hours. Following fixation the corneas were processed for SEM analysis.
- corneas processed for observation immediately after corneal de-epithelialization exhibit wounds with sharp raised margins and naked stroma.
- the controls intact corneas
- the corneas of the group “Untreated wound” exhibit a de-epithelialized area with an entirely naked stroma, with the margin of the epithelium lacking zone sharp but hardly raised. All the newly formed cells present at the margins of the “wound” or slightly outside show few microvilli, and are not clearly differentiated into dark, medium and light.
- the margins of the wounds of the corneas of the SOL group are similar to those of the preceding group, but the newly formed cells are more differentiated, with the presence of the three differentiation stages, and more profuse microvilli. Moreover, the cells are centripetally elongated, in contrast to the samples taken from the “Untreated wound” group, where the oblong shape is less evident.
- the margin of the epithelium-deprived zone is flattened and circumscribed by a ring of differentiated newly formed cells with a centripetally elongated aspect.
- the corneas of the XNT group have an aspect to a large extent similar to those of the EYP group.
- the corneas in the EPG group exhibit a flattened wound margin with cells with microvilli more numerous than in the other treatment groups.
- the newly formed cells exhibit a fair number of “holes”.
- the samples of the SOL group also exhibit a de-epithelialized zone with quite irregular contours with marked margins, although the newly formed cells appear more differentiated, and the microvilli more numerous with virtually normal shape.
- the edges of the cells bordering the margins of the re-epithelialized zone are enlarged and in some cases raised.
- the corneas of the EYP group re-epithelialized similarly to the corneas of the other groups.
- the contours of the de-epithelialized zone remain irregular, even if the degree of differentiation, the distribution and the quality of the microvilli of the newly formed cells is good.
- the samples from the XNT treatment group exhibit irregular wound contours, but the state of the newly formed epithelium is notably better than that of the other groups.
- the new epithelium zone at the proximities of the wound margins presents a ring of centripetally elongated cells.
- the degree of cellular differentiation, as well as the cellular contours are good, although zones where the cells appear raised in part persist.
- the microvilli are normal and numerous.
- the differences between the groups treated with the products containing biopolymers persist even at 72 hours, although the corneas treated with EPG are better that those treated with XNT, and the latter are better than those of the EYP group.
- the aspect of the corneas treated with EPG is similar to that of the controls (intact corneas), with numerous and long microvilli, a fair number of holes uniformly distributed in the cellular layer, and a good representation of cells at the diverse differentiation stages.
- the re-epithelializing pharmaceutical composition in preformed gel form accelerates the reconstruction of the damaged epithelium.
- said composition advantageously favors the reorganization of the epithelium and consequently increases the adhesion and stability of the new epithelium in the underlying connective tissue.
- a further advantage of the composition, according to the present invention is its formulation as a preformed gel as a consequence of which the re-epithelializing pharmaceutical composition also performs a mechanically protective function.
- composition of the invention includes the sodium salt of hyaluronic acid
- its formulation exhibits extremely favorable characteristics for a product of topical use.
- the consistency is that of an almost transparent, light cream colored, pleasant to the touch, non-sticky, easily spreadable and absorbed soft gel.
- the sensations upon instillation are similar: the preparation does not burn, the “blurry vision” sensation is very limited o non-existent while that of freshness and lubrication of the eye persists.
- the product is easily administered both in terms of release from the container (ease of drop formation and delivery) and distribution of the drops on the ocular surface.
- hyaluronic acid although present in water at concentrations almost seven times lower than that of xanthan gum, has notable stabilization ability with respect to the conformation of the latter.
- viscosity/shear rate ( ⁇ / ⁇ ) diagram of a composition consisting of 1% xanthan gum+hyaluronic acid was studied and compared to a composition of 1% xanthan+saline solution (BSS) and 1% xanthan+H 2 O.
- the rheological profile of the complete product presents very high ⁇ (viscosity) and well-defined shear stress at low ⁇ , and therefore, good strength, reticule consistency, and retention at the site of application.
- Viscosity ( ⁇ ) decreases rapidly as shear rate increases with a high degree of pseudoplasticity that confers good spreadability and distribution to the system at the application site, and gives the user a comfortable sensation.
- the ⁇ / ⁇ curve obtained by gradually increasing the shear rate coincides with that of the reverse path, obtained by gradually diminishing it; therefore, the system presents no tissuetropy and reacquires its structure instantaneously upon cessation of the shear stress.
- a re-epithelializing pharmaceutical composition according to the present invention answers to the needs mentioned in the introductory section and overcomes the shortcomings of the current state of the arts.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Ophthalmology & Optometry (AREA)
- Inorganic Chemistry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Saccharide Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Steroid Compounds (AREA)
Abstract
The present invention relates to the use of xanthan gum as re-epithelializing agent and, in particular, to a pharmaceutical formulation comprising xanthan gum as a re-epithelializing active principle eventually mixed with hyaluronic acid. Said use and composition speed up and improve advantageously the formation of newly grown epithelium.
Description
- This application is a divisional of application Ser. No. 10/512,521 filed Oct. 25, 2004, which is a National Stage Under 35 U.S.C. §371 of PCT/IT03/00257, filed Apr. 24, 2003 claiming priority under Section 119(e) to application number EPO 02425274.4 filed Apr. 30, 2002, the contents of which are hereby incorporated by reference
- The present invention relates to re-epithelializing pharmaceutical compositions especially for ophthalmic use.
- It is well known that epithelial cells, for example in the cornea, may suffer injuries caused by foreign bodies, such as abrasions, cuts and wounds (accidental, surgical, immunological etc), and postinfective ulcers. Injuries of this sort generally require long wound healing periods; cause much discomfort and often an imperfect wound closure.
- The object of the present invention is a pharmaceutical composition that can accelerate re-epithelialization, especially of the corneal tissue, and is also well tolerated.
- This goal is achieved using xanthan gum for the preparation of a medication for the treatment of epithelial wounds, as well as of pharmaceutical compositions containing xanthan gum, as detailed in the claims herewith annexed.
- Other characteristics, and the advantages of the pharmaceutical topical composition, as described in the present invention, will become apparent from the following description of some preferred embodiments of formulations of the pharmaceutical composition, which are presented for purposes of illustration and are not intended to be construed as limiting.
- A surprising experimental finding was the observation that xanthan gum shows a high re-epithelializing function, that is to say, it is able to accelerate the formation of new epithelial cells at the level of the damaged epithelial zone, as shown also in an in vivo experiment reported later in the present description.
- Xanthan gum is a heteropolysaccharide with a molecular weight between 3-7, 5×106 Da, produced through a process of fermentation by the bacterium Xanthomonas campestris.
- The primary structure of xanthan is a branched chain, with a main chain of β(1→4)-D-glucose identical to cellulose wherein, a trisaccharide chain with a glucosidic link β(1→3), composed of acetylated mannose, glucuronic acid, and mannose is linked to every other second residue; finally, to each carbon C4 and C6 of the terminal unit of mannose a molecule of pyruvic acid is linked in a variable proportion of 25-50%, that completes the structure of the lateral chain of the polymer.
- The available data suggests a single helix conformation (but a double or triple helical structure cannot be ruled out) where the lateral chains of the polymer tend to align with the main chain (with non covalent type of interactions) protecting the glucosidic links present there. The result is a stiff rod-like structure that confers great stability to the molecule with an excellent protection from strong acids and bases, high temperatures, freezing and thawing cycles, enzymatic attack, prolonged mixing, shear degradation, variations of ionic force and pH.
- Consequently, on account of the structural properties just described, xanthan gum, in preformed gel form, makes it possible to carry out adequately the important function of mechanical protection.
- Furthermore, following lot of experiments, it has been surprisingly observed that the admixture of xanthan gum with hyaluronic acid, as an active principle of a re-epithelializing composition in a preparation as a preformed gel, causes an increase in the rate of re-epithelializing of the damaged epithelium and, in addition, promotes the reorganization of the newly formed epithelium that results in the formation of cellular layer of superior quality.
- In particular, wound-healing studies carried out under a scanning electron microscope, revealed a surprising degree of epithelial organization following a treatment with the pharmaceutical re-epithelializing composition according to the invention, as will be explained in detail.
- It is well known that hyaluronic acid not only favors cellular proliferation but also stabilizes the basal layer of the epithelium stimulating the production of lamina and fibronectin.
- In any event, when xanthan gum and hyaluronic acid are used as a mix in their capacity as re-epithelializing agents, they have a surprising synergic effect.
- Hyaluronic acid is an high molecular weight polysaccharide with polyanionic features, high capacity to retain water, viscous, bioadhesive and pseudoplastic properties with no evidence of tixotropy. Its primary structure consists of β(1→4) disaccharide blocks each constituted of D-glucuronic acid and N-acetyl-D-glucosamine linked together through a β(1→3) bond.
- In view of the observations previously described, a further embodiment of the present invention is to provide topical re-epithelializing pharmaceutical compositions in preformed gel consisting essentially of xanthan gum as active principle, eventually mixed with hyaluronic acid, and pharmacologically accepted additives.
- The percentage of xanthan gum relative to the total volume of the preformed gel is preferably between 0.7% to 5%, more preferably between 0.8% and 3%, and more highly preferably between 0.9% and 1.5%.
- The excipients are chosen among isotonic agents, buffers, solvents or vehicles, antioxidants, pH adjusting and similar.
- In particular, the possible isotonic agents of the composition of the invention may be ionic, such as NaCl, KCl or non-ionic, for example glycerol, mannitol or a mix thereof.
- Possible buffers may be those commonly used for instance in ophthalmic formulations such as phosphate or borate, acetate, a mix of these buffers such as citrate/phosphate, or even buffers not frequently used in the ophthalmic field, such as Tris.HCl, or based on histidine or arginine.
- Therefore, the composition of a preformed gel with xanthan may be a balanced saline solution, or otherwise, o saline composition not necessarily balanced because of the presence of ions of Ca+2e Mg+2.
- Possible antioxidants include sodium citrate, ascorbate or sulfate.
- Possible pH adjusting are organic or inorganic acids or bases with their respective acid and basic salts.
- Possible solvents or vehicles are water or a mixture of water/oil.
- It has been observed that when salts are added to a composition containing >0.25% xanthan, there is an increase of viscosity proportional to the concentration of xanthan and of the added salts, although a viscosity plateau is reached, for example, with as little as 0.1% of NaCl. Therefore, xanthan behaves differently toward the variations of ionic force than other polyelectrolytes, toward which the presence of salts (that decreases the degree of hydration and repulsion between chains) promotes intermolecular interaction and a molecular collapse from a random coil (with a higher viscosity) to a compact coil structure (with a lower viscosity). In xanthan solutions the addition of salts decreases the degree of hydration and the charge repulsion between the carboxylate anions of the lateral chains of the molecule, which consequently stabilizes the stiff rod-like conformation and promotes a stronger and more rigid three-dimensional network that increases viscosity (about twofold at 0.1% of NaCl for 1% xanthan) and significant yield-value, that in general render the solutions of the polymer more protected against factors such as thermal treatment, attacks from acids and bases, prolonged mixing, etc.
- In solution, the single helixes tend to associate forming a complex ordered meshwork of rigid molecules held together mainly by weak Van der Waals forces. The effect of the distinctive and unique structure of xanthan in solution is, already for moderate concentrations (1-2.5%), a gel-like consistency with significant yield stress values (hence, excellent ability to favor the formation of suspensions and emulsions) and good viscosity.
- Taken together, the properties thus far examined, along with the low toxicity, bioadhesiveness, and compatibility with the most common excipients and available commercial packaging render xanthan gum advantageously suitable also as delivery system as well as a protective agent on purely mechanical grounds.
- As mentioned before, an additional embodiment of the present invention may include hyaluronic acid.
- Specifically, the quantity of hyaluronic acid present in said composition ranges from 0.01% to 1% of the total volume of the preformed gel, preferably from 0.05% to 0.5%, better still from 0.1% to 0.4%. Hyaluronic acid is present as a salt. Possible counter ions may be, for example, sodium, potassium, calcium or magnesium.
- In yet another embodiment of the present invention the re-epithelializing pharmaceutical composition may include, aside from the admixture of xanthan gum and hyaluronic acid as re-epithelializing agents, one or several pharmacological agents chosen among antiinfective, antiinflammatory, anesthetizing and mydriatic agents.
- The invention is further disclosed by means of the following non limiting examples of same formulations.
-
FORMULATION 1 Components Quantity Function Xanthan gum 1.0000 g Active principle, re-epithelializing Sodium chloride 0.3500 g Isotonic agent Sodium phosphate, 0.3638 g Buffer dibasic•12H2O Sodium phosphate 0.0354 g Buffer monobasic•H2O Glycerol 1.0000 g Isotonic agent Purified water q.s. to 100.0 ml Solvent -
FORMULATION 2 Components Quantity Function Xanthan gum 1.0000 g Active principle, re-epithelializing Sodium chloride 0.3500 g Isotonic agent Potassium chloride 0.1500 g Isotonic agent Magnesium•chloride 6H2O 0.0120 g Isotonic agent Calcium chloride•2H2O 0.0084 g Isotonic agent Sodium phosphate 0.0890 g Buffer dibasic•12H2O Sodium phosphate 0.0069 g Buffer monobasic•H2O Sodium citrate•2H2O 0.0590 g Buffer/antioxidant Glycerol 1.0000 g Isotonic agent Purified water q.s. to 100.0 ml Solvent -
FORMULATION 3 Components Quantity Function Hyaluronic acid sodium salt 0.1500 g Active principle, re-epithelializing Xanthan gum 1.0000 g Active principle, re-epithelializing Sodium chloride 0.3500 g Isotonic agent Potassium chloride 0.1500 g Isotonic agent Magnesium chloride•6H2O 0.0120 g Isotonic agent Calcium chloride•2H2O 0.0084 g Isotonic agent Sodium phosphate dibasic•12H2O 0.0890 g Buffer Sodium phosphate 0.0069 g Buffer monobasic•H2O Sodium citrate•2H2O 0.0590 g Buffer/antioxidant Glycerol 1.0000 g Isotonic agent Purified water q.s. to 100.0 ml Solvent -
FORMULATION 4 Components Quantity Function Hyaluronic acid sodium salt 0.1500 g Active principle, re-epithelializing Xanthan gum 1.0000 g Active principle, re-epithelializing Sodium chloride 0.3500 g Isotonic agent Potassium chloride 0.1500 g Isotonic agent Magnesium chloride•6H2O 0.0120 g Isotonic agent Calcium chloride•2H2O 0.0084 g Isotonic agent Tris base 0.2425 g Buffer HCl 1N q.s. to pH 7.4-7.6 Buffer Sodium citrate•2H2O 0.0590 g Buffer/antioxidant Glycerol 0.5000 g Isotonic agent Purified water q.s. to 100.0 ml Solvent -
FORMULATION 5 Components Quantity Function Netilmicin sulfate 0.4550 g Active principle equivalent to Netilmicin base 0.3000 g Sodium hyaluronate 0.1500 g Active principle, re-epithelializing Xanthan gum 1.0000 g Active principle, re-epithelializing Sodium chloride 0.8700 g Isotonic agent Sodium hydroxide 1M q.s. to pH = 7.00-7.6 pH adjusting Purified water q.s. to 100.0 ml Solvent -
FORMULATION 6 Components Quantity Function Netilmicin sulfate 0.4550 g Active principle equivalent to Netilmicin base 0.3000 g Sodium hyaluronate 0.1500 g Active principle, re-epithelializing Xanthan gum 1.0000 g Active principle, re-epithelializing Sodium phosphate dibasic 0.5000 g Buffer dodecahydrate. Sodium phosphate monobasic 0.1465 g Buffer monohydrate Sodium citrate dihydrate 2.1000 g Buffer/antioxidant Purified water q.s. to 100.0 ml Solvent -
FORMULATION 7 Components Quantity Function Netilmicin sulfate 0.4550 g Active principle equivalent to Netilmicin base 0.3000 g Sodium hyaluronate 0.1500 g Active principle, re-epithelializing Xanthan gum 1.0000 g Active principle, re-epithelializing Tris base 0.2425 g Buffer HCl 1M q.s. to pH 7.4-7.6 Buffer Sodium citrate dihydrate 2.1000 Buffer/antioxidant Purified water q.s. to 100.0 ml Solvent -
FORMULATION 8 Components Quantity Function Netilmicin sulfate 0.4550 g Active principle equivalent to Netilmicin base 0.3000 g Sodium hyaluronate 0.1500 g Active principle, re-epithelializing Xanthan gum 1.0000 g Active principle, re-epithelializing Tris base 0.2423 g Buffer HCl 1M q.s. to pH 7.4-7.6 Buffer Sodium chloride 0.7000 g Isotonic agent Purified water q.s. to 100.0 ml Solvent -
FORMULATION 9 Components Quantity Function Dexamethasone disodium 0.1500 g Active principle phosphate Xanthan gum 1.0000 g Active principle, re-epithelializing Sodium phosphate 0.5000 g Buffer dibasic•12H2O Sodium phosphate 0.1465 g Buffer monobasic•H2O Sodium citrate•2H2O 2.1000 g Antioxidant Purified water q.s. to 100.0 ml Solvent -
FORMULATION 10 Components Quantity Function Dexamethasone disodium 0.1500 g Active principle phosphate Netilmicin sulfate 0.4550 g Active principle equivalent to Netilmicin base 0.3000 g Xanthan gum 1.0000 g Active principle, re-epithelializing Sodium phosphate 0.5000 g Buffer dibasic•12H2O Sodium phosphate 0.1465 g Buffer monobasic•H2O Sodium citrate•2 H2O 2.1000 g Antioxidant Purified water q.s. to 100.0 ml Solvent - In general, in the compositions of the invention, glycerol displays a dispersing action towards xanthan gum, preventing the formation of clumps and lumps during the dispersal phase of the polymer in H2O.
- A general description of a procedure for the preparation of a pharmaceutical composition in accordance with the present invention will now follow. By way of illustration, the formulation prepared is for 100 ml/g of product.
- Procedure for the Preparation of a Preformed Re-Epithelializing Gel
- In a volume of purified water of about 50 ml all the additives of the formulation are added and dissolved, adding each component after the preceding one has been completely dissolved.
- If the composition requires it, a predetermined quantity of one or more of the pharmacological agents listed above is added to the solution until said pharmacological agent(s) is/are completely dissolved or mixed.
- Separately, one gram of xanthan gum is added to 50 ml of water and is dispersed on the surface of the liquid, without stirring, to avoid the formation of lumps. Alternatively, the dispersion may be homogenized with a paddle stirrer or a homogenizer so as to accelerate the process while avoiding the formation of lumps. If the composition requires it, hyaluronic acid is also dispersed in this phase.
- The homogeneous dispersion is then autoclaved until a minimum F0=15 valid for the sterility is obtained (lethality, expressed in terms of equivalent of time in minutes at a 121° C. temperature with reference to the killing of microorganisms during the process of steam sterilization).
- A this point, the solution of the additives sterilized through filtration (if a suspension sterilize in suitable manner) is aseptically added to the xanthan gum dispersion and stirred for about 1 hr. at a speed that will allow for smooth mixing without excessive turbulence, until a homogeneous gel is obtained.
- Finally, the gel may be aseptically distributed in the appropriate containers.
- To illustrate the efficacy of the main compositions of the invention, two experiments will be describe that were carried out to verify, in an in vivo re-epithelializing model, the effect of 2 preformed gels according to the aforesaid formulations—one (Formulation 2) containing only xanthan gum (XNT) and another (Formulation 3) containing both xanthan gum and hyaluronic acid (EPG)—in comparison to a solution containing only 0.15% sodium hyaluronate and salts (EYP) and a saline solution with no polymers (SOL).
- Re-Epithelialization Efficacy
- The difference between the two experiments lies in the fact that the first is designed to assess the dynamic and quantitative aspects of re-epithelialization and the second to assess the morphological and qualitative aspects of re-epithelialization following treatment with the various formulations. In the first experiment a confocal opthalmoscope (CSLO) was used to follow the re-epithelialization rate and in the latter a scanning electron microscope (SEM) was used for the ultrastructural analysis.
- For each experiment New Zealand albino rabbits, subdivided in 6 treatment groups according to what is described in the next two paragraphs, were used
- Animals
- Male New Zealand albino rabbits (Charles River Italia), medium weight 2.400 Kg, were used.
- The animals were allocated in animal rooms maintained in standard conditions of humidity (50%±10% RH) and temperature (19±2° C.) with alternating cycles of artificial light (12 hours darkness/light). The animals were fed and allowed water ad libitum.
- Treatment Scheme and Regimen
- After checking the eyes of the animals to exclude eventual opthalmological pathologies, the animals were assigned to six different treatment groups according to the following scheme:
- Animals used during the different observation and treatment times
-
T0 T24 h T48 h T72 h T96 h Control 4 — — — Untreated wound 4 4 4 4 4 EPG 4 4 4 4 4 XNT 4 4 4 4 4 EYP 4 4 4 4 4 SOL 4 4 4 4 4 Legend Control: animals with intact cornea not pharmacologically treated. Untreated wound: animals with corneal wound not pharmacologically treated EPG, XNT, EYP, SOL: animals with corneal wound treated with the different formulations - All the tested substances were administered 5 times a day until the end of the experiment.
- Experimental Model
- The animals were anesthetized by an i.m. injection of ketamine (37.5 mg/kg b.w.) and xylazine (10 mg/kg b.w.), and with oxybuprocaine (1 drop/eye).
- The corneal wound was executed using an Algerbrush with a 1 mm tip. With the aid of a sterile parafilm mask, with a 6 mm hole at the center, a circular area was de-epithelialized. The eye was immediately washed with sterile BBS to remove cell debris and the treatment was performed.
- In time course the rabbits were evaluated at 0, 24, 48, 72 and 96 hours with a CLSO coupled to an image-processing system, or they were sacrificed for SEM analysis (0, 24, 48, and 72 hours).
- The research method and results of each experiment are described hereafter.
- CLSO Experiment
- The eyes of the rabbits of each treatment group were treated with a 25 μl solution of 0.5% sodium fluorescein. After 2 minutes the excess of fluorescein was washed away with a physiological solution. The sedated rabbits were then examined through CLSO. This system detects the fluorescent signal that originates from the epithelium lacking damaged zone and measures quantitatively the damaged area through an image-processing system.
- Results
- The CLSO analysis revealed that the wound heals spontaneously after 72 hours in all the treated groups.
- The group treated with the formulation containing only xanthan gum as active principle (XNT) showed an accelerated re-epithelialization process already 24 hours after the treatment. The wound's closure was at least 30% more advanced than in the groups “Untreated wound”, EYP and SOL. A higher re-epithelialization rate (50% higher than the other groups) was observed 48 hours after the treatment in both the group treated with xanthan gum only (XNT) and the group treated with xanthan gum mixed with hyaluronic acid (EPG). There were no observed differences between the group treated with only sodium hyaluronate (EYP) and the groups SOL and “untreated wound”.
- SEM Experiment
- At predetermined times (0, 24, 48, 72 hours from the beginning of treatment) the animals of the different treatment groups were sacrificed (Tanax i.v.). Rapidly following the sacrifice the bulb was enucleated and the corneas excised and immediately fixed with 2% glutaraldehyde during 24 hours. Following fixation the corneas were processed for SEM analysis.
- Results
- All the corneas processed for observation immediately after corneal de-epithelialization (T0) exhibit wounds with sharp raised margins and naked stroma. The controls (intact corneas) exhibit an homogeneous epithelium with a good degree of cellular differentiation, and a normal presence of “holes” (circumscribed areas lacking microvilli that are present on the surface of the epithelial cells with probable communication functions), serrated cellular contacts and numerous microvilli, presence of superficial epithelium with the typical mosaic aspect that reflects the different maturation stages (dark, medium light and light cells).
- T24 Ore
- Twenty four hours after the beginning of the experiment, the corneas of the group “Untreated wound” exhibit a de-epithelialized area with an entirely naked stroma, with the margin of the epithelium lacking zone sharp but hardly raised. All the newly formed cells present at the margins of the “wound” or slightly outside show few microvilli, and are not clearly differentiated into dark, medium and light.
- The margins of the wounds of the corneas of the SOL group are similar to those of the preceding group, but the newly formed cells are more differentiated, with the presence of the three differentiation stages, and more profuse microvilli. Moreover, the cells are centripetally elongated, in contrast to the samples taken from the “Untreated wound” group, where the oblong shape is less evident.
- In the corneas of the EYP group the margin of the epithelium-deprived zone is flattened and circumscribed by a ring of differentiated newly formed cells with a centripetally elongated aspect.
- The corneas of the XNT group have an aspect to a large extent similar to those of the EYP group.
- The corneas in the EPG group exhibit a flattened wound margin with cells with microvilli more numerous than in the other treatment groups. The newly formed cells exhibit a fair number of “holes”.
- T 48 Ore
- The corneas of the “Untreated wound” group observed after 48 hours at the lowest magnification, exhibit a quite disorganized de-epithelialized zone, with marked and indented margins, and newly formed cells with partially enlarged junctions. A small number of cells are elongated and the small number of microvilli is short and distributed uniformly with no differentiation between light, medium and dark cells.
- The samples of the SOL group also exhibit a de-epithelialized zone with quite irregular contours with marked margins, although the newly formed cells appear more differentiated, and the microvilli more numerous with virtually normal shape. The edges of the cells bordering the margins of the re-epithelialized zone are enlarged and in some cases raised.
- The corneas of the EYP group re-epithelialized similarly to the corneas of the other groups. However, the contours of the de-epithelialized zone remain irregular, even if the degree of differentiation, the distribution and the quality of the microvilli of the newly formed cells is good.
- The samples from the XNT treatment group exhibit irregular wound contours, but the state of the newly formed epithelium is notably better than that of the other groups. The new epithelium zone at the proximities of the wound margins presents a ring of centripetally elongated cells. Moreover, the degree of cellular differentiation, as well as the cellular contours are good, although zones where the cells appear raised in part persist. The microvilli are normal and numerous.
- The organization of the samples of the EPG treatment group is similar to that of groups EYP and XNT. However, the edge of the wound, as in the previous observation time, is still flat. Consequently, the newly formed zone with centripetally oriented cells is larger, and in general, even at the lowest magnification, the aspect of the de-epithelialized zone is more uniform.
- T 72 Ore
- After 72 hours of treatment all the groups exhibit a healed wound, although small, spottily-distributed areas barren of cells and with enlarged junctions persist. This phenomenon is part of the normal re-epithelialization process and is caused by the continuous rearrangement of the newly formed epithelium.
- The differences between the groups lie in the organization of the newly formed epithelium. In fact, in the “Untreated wound” group the epithelium appears uniform because of the presence of short and scant microvilli that give the epithelium a “pasty” appearance. Thus, the typical dark, medium and light cell differentiation is not present, except in the zones of newly formed epithelium more distant from the center, probably because in those zones the cellular turnover has returned to normal, while at the center cellular multiplication is still chaotic.
- A certain degree of epithelial organization is exhibited by the SOL samples. In fact, even at the central zone, re-epithelialized later, a hint of differentiation is present, and in comparison to the corneas of the “Untreated wound” group, the microvilli are more numerous and “not-pasty”.
- The differences between the groups treated with the products containing biopolymers persist even at 72 hours, although the corneas treated with EPG are better that those treated with XNT, and the latter are better than those of the EYP group. In general the aspect of the corneas treated with EPG is similar to that of the controls (intact corneas), with numerous and long microvilli, a fair number of holes uniformly distributed in the cellular layer, and a good representation of cells at the diverse differentiation stages.
- According to what has been described so far, the re-epithelializing pharmaceutical composition in preformed gel form accelerates the reconstruction of the damaged epithelium.
- Moreover, said composition advantageously favors the reorganization of the epithelium and consequently increases the adhesion and stability of the new epithelium in the underlying connective tissue.
- A further advantage of the composition, according to the present invention, is its formulation as a preformed gel as a consequence of which the re-epithelializing pharmaceutical composition also performs a mechanically protective function.
- Preferably, when the composition of the invention includes the sodium salt of hyaluronic acid, its formulation exhibits extremely favorable characteristics for a product of topical use.
- In particular, the consistency is that of an almost transparent, light cream colored, pleasant to the touch, non-sticky, easily spreadable and absorbed soft gel. The sensations upon instillation are similar: the preparation does not burn, the “blurry vision” sensation is very limited o non-existent while that of freshness and lubrication of the eye persists. Additionally, the product is easily administered both in terms of release from the container (ease of drop formation and delivery) and distribution of the drops on the ocular surface.
- Furthermore, it was surprisingly observed that hyaluronic acid, although present in water at concentrations almost seven times lower than that of xanthan gum, has notable stabilization ability with respect to the conformation of the latter.
- In fact, the viscosity of xanthan gum solutions without salts decrease in about 30% following thermal treatment.
- On the contrary, the viscosity of xanthan gum solutions and hyaluronic acid sodium salt decreases only in 10-15% after thermal treatment.
- In particular, the study of the rheological characteristics of the product has given the following results.
- As an illustration, the viscosity/shear rate (η/γ) diagram of a composition consisting of 1% xanthan gum+hyaluronic acid was studied and compared to a composition of 1% xanthan+saline solution (BSS) and 1% xanthan+H2O.
- The rheological profile of the complete product presents very high η (viscosity) and well-defined shear stress at low γ, and therefore, good strength, reticule consistency, and retention at the site of application. Viscosity (η) decreases rapidly as shear rate increases with a high degree of pseudoplasticity that confers good spreadability and distribution to the system at the application site, and gives the user a comfortable sensation. The η/γ curve obtained by gradually increasing the shear rate coincides with that of the reverse path, obtained by gradually diminishing it; therefore, the system presents no tissuetropy and reacquires its structure instantaneously upon cessation of the shear stress.
- In particular for ocular applications, this translates itself advantageously in the recovery of the structure and viscosity of the product between blinks consequently increasing the time of corneal contact.
- As may be assessed from what has been described herewith, a re-epithelializing pharmaceutical composition according to the present invention answers to the needs mentioned in the introductory section and overcomes the shortcomings of the current state of the arts.
- Obviously an expert in the field, in order to satisfy contingent and specific requirements may introduce numerous modifications and variations to the above-described composition, without departing from the scope of the invention as defined by the following claims.
Claims (3)
1-18. (canceled)
19. Pharmaceutical composition consisting of:
20-23. (canceled)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/031,495 US20080139522A1 (en) | 2002-04-30 | 2008-02-14 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02425274.4 | 2002-04-30 | ||
EP02425274A EP1358883B8 (en) | 2002-04-30 | 2002-04-30 | Re-epithelializing pharmaceutical compositions containing xanthan gum |
PCT/IT2003/000257 WO2003092706A1 (en) | 2002-04-30 | 2003-04-24 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
US51252105A | 2005-06-06 | 2005-06-06 | |
US12/031,495 US20080139522A1 (en) | 2002-04-30 | 2008-02-14 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IT2003/000257 Division WO2003092706A1 (en) | 2002-04-30 | 2003-04-24 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
US51252105A Division | 2002-04-30 | 2005-06-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
US20080139522A1 true US20080139522A1 (en) | 2008-06-12 |
Family
ID=28799773
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/512,521 Active 2027-01-19 US8912164B2 (en) | 2002-04-30 | 2003-04-24 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
US12/031,495 Abandoned US20080139522A1 (en) | 2002-04-30 | 2008-02-14 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
US12/031,518 Abandoned US20080146530A1 (en) | 2002-04-30 | 2008-02-14 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
US12/031,483 Abandoned US20080139502A1 (en) | 2002-04-30 | 2008-02-14 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
US15/054,090 Abandoned US20160166601A1 (en) | 2002-04-30 | 2016-02-25 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/512,521 Active 2027-01-19 US8912164B2 (en) | 2002-04-30 | 2003-04-24 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
Family Applications After (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/031,518 Abandoned US20080146530A1 (en) | 2002-04-30 | 2008-02-14 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
US12/031,483 Abandoned US20080139502A1 (en) | 2002-04-30 | 2008-02-14 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
US15/054,090 Abandoned US20160166601A1 (en) | 2002-04-30 | 2016-02-25 | Re-epithelializing pharmaceutical compositions comprising xanthan gum |
Country Status (15)
Country | Link |
---|---|
US (5) | US8912164B2 (en) |
EP (2) | EP1913948B1 (en) |
JP (2) | JP4837912B2 (en) |
CN (1) | CN100502884C (en) |
AT (2) | ATE367165T1 (en) |
AU (1) | AU2003230224B2 (en) |
BR (1) | BR0304655A (en) |
CA (2) | CA2484020C (en) |
DE (2) | DE60221227T2 (en) |
DK (1) | DK1358883T3 (en) |
ES (2) | ES2290264T3 (en) |
MX (1) | MXPA04010668A (en) |
PT (1) | PT1358883E (en) |
RU (1) | RU2297230C2 (en) |
WO (1) | WO2003092706A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20102404A1 (en) * | 2010-12-27 | 2012-06-28 | Altergon S A 50 | COMPOSITIONS OF HYALURONIC ACID STABILIZED TOWARDS THE DEGRADATION OF HEAT OR ENZYMES |
Families Citing this family (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1913948B1 (en) * | 2002-04-30 | 2011-10-12 | Sifi S.p.A. | Re-epithelializing pharmaceutical compositions containing xanthan gum |
US20050142208A1 (en) | 2002-05-09 | 2005-06-30 | Won Min Yoo | Pharmceutical composition for treatment of wounds conntaining blood plasma or serum |
US7939511B2 (en) * | 2004-09-28 | 2011-05-10 | Senju Pharmaceutical Co., Ltd. | Ophthalmic composition containing xanthan gum and amino acid |
ITRM20050443A1 (en) * | 2005-08-12 | 2007-02-13 | Opocrin Spa | OPHTHALMIC PREPARATIONS BASED ON MUCO-ADHESIVE POLYSACCHARIDES WITH A RECYCLABLE CAPACITY OF CORNEA. |
US7875271B2 (en) | 2006-03-23 | 2011-01-25 | Senju Pharmaceutical Co., Ltd. | Ophthalmic composition comprising xanthan gum and glucose |
WO2010004594A1 (en) * | 2008-07-08 | 2010-01-14 | S.I.F.I. Societa' Industria Farmaceutica Italiana S.P.A. | Ophthalmic compositions for treating pathologies of the posterior segment of the eye |
JP5620168B2 (en) * | 2010-06-30 | 2014-11-05 | Dsp五協フード&ケミカル株式会社 | Xyloglucan-cation complex and stabilized composition containing the same |
ES2751248T3 (en) * | 2011-11-24 | 2020-03-30 | Toyo Sugar Refining Co Ltd | Keratoconjunctival protective agent or inhibitory agent for keratoconjunctival disorders |
WO2016185935A1 (en) * | 2015-05-18 | 2016-11-24 | 柿原秀己 | Antibacterial substance and liquid antibacterial agent, and method for manufacturing liquid antibacterial agent |
WO2017114775A1 (en) | 2015-12-29 | 2017-07-06 | Intervet International B.V. | Coccidiosis vaccine |
CN106236704A (en) * | 2016-08-30 | 2016-12-21 | 上海昊海生物科技股份有限公司 | A kind of Moxifloxacin eye drop having bionical and target function concurrently and preparation method thereof |
WO2020250252A1 (en) | 2019-06-11 | 2020-12-17 | Sifi S.P.A. | Microemulsion compositions |
IT202000002296A1 (en) * | 2020-02-06 | 2021-08-06 | Sifi Spa | Topical ophthalmic formulations based on xanthan with reduced dosage |
MX2021003369A (en) * | 2021-03-22 | 2022-09-23 | Laboratorios Grin S A De C V | Triple ocular tear. |
IT202200000821A1 (en) * | 2022-01-19 | 2023-07-19 | Sifi Spa | TOPICAL OPHTHALMIC FORMULATIONS BASED ON XANTHANE WITH REDUCED DOSAGE |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4136177A (en) * | 1977-01-31 | 1979-01-23 | American Home Products Corp. | Xanthan gum therapeutic compositions |
US4370324A (en) * | 1980-09-17 | 1983-01-25 | Bernstein Joel E | Method and composition for treating and preventing irritation of the eyes |
US4525346A (en) * | 1981-09-28 | 1985-06-25 | Alcon Laboratories, Inc. | Aqueous antimicrobial ophthalmic solutions |
US4826872A (en) * | 1986-12-03 | 1989-05-02 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition for treatment of cataract |
US6919321B2 (en) * | 2000-12-20 | 2005-07-19 | Alcon, Inc. | Ophthalmic lubricating solution adapted for use in lasik surgery |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4711780A (en) * | 1984-06-11 | 1987-12-08 | Fahim Mostafa S | Composition and process for promoting epithelial regeneration |
JPH0723317B2 (en) * | 1988-03-17 | 1995-03-15 | 生化学工業株式会社 | Corneal epithelial disorder treatment |
JPH0651638B2 (en) * | 1989-02-13 | 1994-07-06 | 新技術事業団 | Eye drops for corneal epithelial wound treatment |
US5271943A (en) * | 1989-10-27 | 1993-12-21 | Scott Health Care | Wound gel compositions containing sodium chloride and method of using them |
IT1243435B (en) * | 1990-10-05 | 1994-06-10 | Altergon Sa | PHARMACEUTICAL COMPOSITIONS FOR TOPICAL USE INCLUDING HYALURONIC ACID SODIUM SALT AND DISINFECTANT SUBSTANCES |
US5804213A (en) * | 1991-10-09 | 1998-09-08 | Lectec Corporation | Biologically active aqueous gel wound dressing |
US6277365B1 (en) * | 1997-09-18 | 2001-08-21 | Bausch & Lomb Incorporated | Ophthalmic composition including a cationic glycoside and an anionic therapeutic agent |
AU2797400A (en) * | 1999-01-19 | 2000-08-07 | Dr. Gerhard Mann Chemisch-Pharmazeutische Fabrik Gmbh | Artificial lacrimal fluid in gel form |
JP2004506688A (en) * | 2000-08-23 | 2004-03-04 | フェアーソン・メディカル・インコーポレーテッド | Treatment of injuries and other indications |
EP1913948B1 (en) * | 2002-04-30 | 2011-10-12 | Sifi S.p.A. | Re-epithelializing pharmaceutical compositions containing xanthan gum |
-
2002
- 2002-04-30 EP EP07108593A patent/EP1913948B1/en not_active Expired - Lifetime
- 2002-04-30 AT AT02425274T patent/ATE367165T1/en active
- 2002-04-30 ES ES02425274T patent/ES2290264T3/en not_active Expired - Lifetime
- 2002-04-30 ES ES07108593T patent/ES2304913T3/en not_active Expired - Lifetime
- 2002-04-30 DE DE60221227T patent/DE60221227T2/en not_active Expired - Lifetime
- 2002-04-30 AT AT07108593T patent/ATE528009T1/en not_active IP Right Cessation
- 2002-04-30 EP EP02425274A patent/EP1358883B8/en not_active Expired - Lifetime
- 2002-04-30 DE DE07108593T patent/DE07108593T1/en active Pending
- 2002-04-30 PT PT02425274T patent/PT1358883E/en unknown
- 2002-04-30 DK DK02425274T patent/DK1358883T3/en active
-
2003
- 2003-04-24 RU RU2004131550/15A patent/RU2297230C2/en active
- 2003-04-24 WO PCT/IT2003/000257 patent/WO2003092706A1/en active Application Filing
- 2003-04-24 AU AU2003230224A patent/AU2003230224B2/en not_active Expired
- 2003-04-24 CA CA2484020A patent/CA2484020C/en not_active Expired - Lifetime
- 2003-04-24 JP JP2004500890A patent/JP4837912B2/en not_active Expired - Lifetime
- 2003-04-24 US US10/512,521 patent/US8912164B2/en active Active
- 2003-04-24 BR BR0304655-9A patent/BR0304655A/en not_active Application Discontinuation
- 2003-04-24 CN CNB038095068A patent/CN100502884C/en not_active Expired - Lifetime
- 2003-04-24 MX MXPA04010668A patent/MXPA04010668A/en active IP Right Grant
- 2003-04-24 CA CA2749172A patent/CA2749172C/en not_active Expired - Lifetime
-
2008
- 2008-02-14 US US12/031,495 patent/US20080139522A1/en not_active Abandoned
- 2008-02-14 US US12/031,518 patent/US20080146530A1/en not_active Abandoned
- 2008-02-14 US US12/031,483 patent/US20080139502A1/en not_active Abandoned
-
2011
- 2011-01-14 JP JP2011005761A patent/JP5203472B2/en not_active Expired - Lifetime
-
2016
- 2016-02-25 US US15/054,090 patent/US20160166601A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4136177A (en) * | 1977-01-31 | 1979-01-23 | American Home Products Corp. | Xanthan gum therapeutic compositions |
US4370324A (en) * | 1980-09-17 | 1983-01-25 | Bernstein Joel E | Method and composition for treating and preventing irritation of the eyes |
US4525346A (en) * | 1981-09-28 | 1985-06-25 | Alcon Laboratories, Inc. | Aqueous antimicrobial ophthalmic solutions |
US4826872A (en) * | 1986-12-03 | 1989-05-02 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition for treatment of cataract |
US6919321B2 (en) * | 2000-12-20 | 2005-07-19 | Alcon, Inc. | Ophthalmic lubricating solution adapted for use in lasik surgery |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20102404A1 (en) * | 2010-12-27 | 2012-06-28 | Altergon S A 50 | COMPOSITIONS OF HYALURONIC ACID STABILIZED TOWARDS THE DEGRADATION OF HEAT OR ENZYMES |
WO2012089537A1 (en) * | 2010-12-27 | 2012-07-05 | Altergon S.A. | Hyaluronic acid compositions stabilised against the degrading effect of heat or enzymes |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080139522A1 (en) | Re-epithelializing pharmaceutical compositions comprising xanthan gum | |
CA2839898C (en) | Ophthalmic compositions containing a synergistic combination of two polymers | |
US11878030B2 (en) | Ophthalmic formulations comprising cooperative complexes of low- and high-molecular-weight hyaluronic acid | |
US20050043271A1 (en) | Heparin-containing ophthalmic agent | |
US20040019010A1 (en) | Carrageenan viscoelastics for ocular surgery | |
RU2764117C2 (en) | Ophthalmic composition | |
Kao et al. | Treating allergic conjunctivitis using in situ polyelectrolyte gelling systems | |
EP1749541A1 (en) | Thickener for ophthalmic use | |
CN115803014A (en) | Ophthalmic compositions and their use in the treatment of ocular diseases |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |